FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
“CLINDAMYCIN AND CLOTRIMAZOLE COMBINATION FOR
VAGINAL INFECTIONS"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
FIELD OF THE INVENTION:
This invention relates to pharmaceutical compositions comprising a combination of Clindamycin and Clotrimazole for vaginal use for the treatment of bacterial infections, fungal infections or mixed infections of the vagina.
BACKGROUND OF THE INVENTION;
Bacterial infections of the vagina such as, for example, bacterial vaginosis (BV) and mixed vaginitis are the most common vaginal infection in women of childbearing age. BV is associated with an imbalance in the bacteria that are normally found in a woman's vagina. The vagina normally contains mostly "good" bacteria, and fewer "harmful" bacteria. BV develops when there is an increase in harmful bacteria. Not much is known about how women get BV. There are many unanswered questions about the role that harmful bacteria play in causing BV. However, some activities or behaviors can upset the normal balance of bacteria in the vagina and put women at increased risk including: 1) having a new sex partner or multiple sex partners, 2) douching, and 3) using an intrauterine device (IUD) for contraception.
It is not clear what role sexual activity plays in the development of BV. Women do not get BV from toilet seats, bedding, swimming pools, or from touching objects around them. Women that have never had sexual intercourse are rarely affected. Women with BV may have an abnormal vaginal discharge with an unpleasant odor. Some women report a strong fish-like odor, especially after intercourse. Discharge, if present, is usually white or gray; it can be thin. Women with BV may also have burning during urination or itching around the outside of the vagina, or both. Some women with BV report no signs or symptoms at all.
Conventional therapies for the treatment of bacterial vaginosis, which are caused by the interaction of Gardnerella vaginalis and anaerobic bacteria are treated with chemotherapeutics acting on anaerobes and protozoa, such as, for example,
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metronidazole or tinidazole, or the treatment with an antibiotic, such as amoxicillin or Clindamycin. Treatment is carried out either by topical vaginal application or orally.
Antifungal or antibacterial oral dosage forms such as tablets and capsules, in the prior art, are available with treatment regimens has considerable disadvantages as the occurrence of considerable adverse effects or else undesirable interactions with other medicaments. More over, Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. There fore topical delivery systems are preferred to systemic administration to avoid above discrepancies.
Topical therapies with metronidazole had dosages of from 500 to 1000 mg of metronidazole as a single dose or, in the case of a 5-day-therapy, 200-500 mg of metronidazole per day. Even in a topical therapy, the same or similar side effects have been described as in the oral use of the active compounds. In the case of oral and topical therapy a secondary infection, such as vaginal candidosis frequently occurs, or a mixed infection, within the month following the treatment, thus requiring another treatment with a further medicament. Currently, there is a dearth of medications available for the effective treatment of vaginal candidosis. Hence the combination of drugs for effective treatment must be selected in the treatment of vaginal candidosis. However, successful delivery of drugs through the vagina remains a challenge, primarily due to the poor absorption across the vaginal epithelium. The rate and extent of drug absorption after intravaginal administration may vary depending on dose of active ingredients, formulation factors, vaginal physiology, age of the patient and menstrual cycle.
An antimycotic drug such as Clotrimazole is commonly used in the treatment of fungal infections of both humans and animals such as vaginal yeast infections and ringworm e.t.c. It is used topically on the skin, inserted vaginally or allowed to dissolve in the mouth for local fungal infections. In topical therapy with Clotrimazole, dosages of 500 mg are used in the case of a single application. Dosages of about 100-200 mg of Clotrimazole are employed in treatment therapies lasting for several days.
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Topical Clotrimazole has been used to treat vulvovaginal candidiasis in several dosage forms and formulations. Studies suggest that Clotrimazole 100 mg vaginal tablets administered twice daily for 3 days are as effective as one 100 mg vaginal tablet once daily for 6 to 7 days in the treatment of vaginal candidiasis, with cure rates greater than 70% at 4 weeks after treatment.
Clindamycin vaginal cream is an effective alternative for treating bacterial vaginosis: 1) Clindamycin cream applicatorful (5 grams containing 100 mg Clindamycin phosphate) administered once intravaginally at anytime of the day; 2) Clindamycin cream applicatorful (5 grams containing 100 mg of Clindamycin phosphate) intravaginally at bedtime for 3 or 7 days in non-pregnant women and 7 days in pregnant women; 3) Clindamycin ovule intravaginally (2.5 grams containing 100 mg of Clindamycin phosphate) at bedtime for 3 days in non-pregnant women.
A randomized, controlled clinical trial demonstrated that a single dose of Clindamycin phosphate vaginal cream 2% had similar cure rates as 7-day therapy with Clindamycin phosphate vaginal cream 2% for the treatment of bacterial vaginosis. In another study Women with a clinical diagnosis of BV were treated with a 3-day course of Clindamycin ovules or a 7-day course of Clindamycin cream administered intravaginally. A 3-day course of Clindamycin vaginal ovules is as effective and well-tolerated as a 7-day course of Clindamycin vaginal cream in the treatment of BV.
US 6537970 assigned to Hexal AG discloses the pharmaceutical compositions comprising 10 to 20 mg of Clindamycin and from 50 to 100 mg of Clotrimazole per application unit. The invention provides low dose of active ingredients for the treatment of vaginal infections. However such low dose combinations are not short duration of therapy with improved clinical outcomes.
There is currently a need to develop pharmaceutical compositions for improved and efficient treatment of vaginal infections. There fore it is an object of the present invention
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to provide the pharmaceutical compositions comprising the combination of active ingredients such as Clindamycin and Clotrimazole in high dosage amounts for short duration of therapy for treatment for mixed vaginitis as well as in bacterial vaginosis co existing with candidiasis. The pharmaceutical compositions of Clindamycin in the dose range of about 100-200mg and Clotrimazole in the dose range of about 200-400mg has to be given in the form of soft gelatin vaginal suppositories.
SUMMARY OF THE INVENTION:
Surprisingly, inventors of the present invention found that high doses of Clotrimazole and Clindamycin vaginal formulations provides the novel treatment for bacterial vaginosis co existing with candidiasis and mixed vaginitis. The present invention provides an improved, more efficient and effective treatment, prevention and control of the vaginal infections. Advantages of the present invention include a) higher mycological cure rates and early resolution of clinical symptoms and defervescence of disease, b) recommended once daily application of combination of Clotrimazole of about 200 mg and Clindamycin of about lOOmg for 3 days improves patient's compliance, c) shortens duration of treatment.
One aspect of the present invention is to provide the pharmaceutical compositions comprising a combination of active ingredients such as Clindamycin and Clotrimazole with a pharmaceutically acceptable carrier thereof.
Another aspect of the present invention is to provide the pharmaceutical composition of Clindamycin and Clotrimazole wherein Clindamycin is given in a dose range of about 100-200mg and Clotrimazole in the dose range of about 200 - 400mg per dose unit with a pharmaceutically acceptable carrier and more preferably Clindamycin is given in a dose range of about 100-150mg and Clotrimazole in the dose range of about 200 - 300mg and most preferably Clindamycin of about l00mg and Clotrimazole of about 200mg is present per dose unit.
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Another aspect of the present invention is to provide a process for the preparation of pharmaceutical compositions comprising a combination of Clindamycin and Clotrimazole wherein Clindamycin is given in a dose range of about 100-200mg and Clotrimazole in the dose range of about 200 - 400mg per dose unit with a pharmaceutically acceptable carrier.
Another aspect of the present invention provides pharmaceutical compositions comprising a Clindamycin is given in a dose range of about 100-200mg and Clotrimazole in the dose range of about 200 - 400mg with a pharmaceutically acceptable carrier thereof where in the formulation is conveniently administered by a route selected from the group consisting of vaginal route.
Another aspect of the present invention provides pharmaceutical compositions comprising Clindamycin given in a dose range of about 100-200mg and Clotrimazole in the dose range of about 200 - 400 mg with a pharmaceutically acceptable carrier thereof for the treatment, prevention and control of bacterial vaginosis co existing with candidiasis and mixed bacterial vaginitis and vaginal disorders such as colpitides, Candida colpitis (fungal infection). The pharmaceutical compositions of the present invention when administered intravaginally inhibits the microorganisms like Trichomonas (a flagellate protozoon), Gardnerella, Fusobacterium, Mobiuncus spp. and Mycoplasma hominis, Prevotella, Porphyromonas, Pseudomonas, or Bacteroides and other vaginitis/vaginosis-causing bacteria. The present invention also inhibits the fungal infections of vagina caused by most pathogenic fungi, including Candida species e.t.c.
Another aspect of the present invention is to provide the pharmaceutical composition of Clindamycin and Clotrimazole wherein Clindamycin is given in a dose range of 100-200mg and Clotrimazole in the dose range of 200 - 400mg per dose unit with a pharmaceutically acceptable carrier, wherein the dosage form is vaginal suppository.
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Another aspect of the present invention is to provide the vaginal suppository comprising a dose range of 100 mg of Clindamycin along with a dose range of 200 mg of Clotrimazole per dose unit is administered intravaginally once daily for 3 days.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention has been described in detail, with reference to certain preferred embodiments, in order to enable the reader to practice the invention without undue experimentation. However, a person having ordinary skill in the art will readily recognizes that many of the components and parameters may be varied or modified to a certain extent without departing from the scope and spirit of the invention. Furthermore, titles, headings, definitions or the like are provided to enhance the reader's comprehension of this document.
Clotrimazole is a broad spectrum antifungal agent that inhibits the growth of most pathogenic fungi, including Candida spp. mainly Candida albicans, Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Dermatophytes, Histoplasma capsulatum, Malassezia furfur, Paracoccidioides brasiliensis, Sporotrichum schenckii. Apart from fungi Clotrimazole also has some activity against Haemophilus vaginalis trichomonas vaginalis.
Clindamycin is an antimicrobial agent active against most strains of the organisms that have been reported to be associated with bacterial vaginosis like Bacteroides spp. Gardnerella vaginalis Mobiluncus spp. Peptostreptococcus spp. and Mycoplasma hominis spp. In one of the comparative study the cure rate of metronidazole was 87.5% and that of Clindamycin 90.3% in the treatment of bacterial vaginosis.
The term "about" used with reference to a quantity includes variations in the recited quantity that are equivalent to the quantity recited, for instance an amount that is insubstantially different from a recited quantity for an intended purpose or function.
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The term "comprising" means various compositions, components, compounds, and steps can be conjointly employed in the present invention.
The term "unit dose" or "unit dosage" refers to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect.
The term "vagina" as used herein means the canal or cavity in a female mammal that leads from the uterus to the external orifice of the genital canal, including the vulva which is the external portion of the female genital organ.
The term "vaginal infection" means any vaginal infection of bacterial or fungal origin. Examples of some of the microorganisms which cause such infections include microorganisms Trichomonas (a flagellate protozoon), Gardnerella, Fusobacterium, Mobiuncus spp. and Mycoplasma hominis, Prevotella, Porphyromonas, Pseudomonas, or Bacteroides and other vaginitis/vaginosis-causing bacteria and Candida, particularly C. albicans and C. tropicalis e.t.c.
The term "dose range" means the selection of minimum and maximum amount of active ingredients which are effective in treating a particular infection and is determinable by a person of skill in the art. Preferred dosage range of the present invention is given in a dose range of about 100-200mg of Clindamycin and Clotrimazole in the dose range of about 200 - 400mg per dose and more preferably Clindamycin is given in a dose range of about 100-150mg and Clotrimazole in the dose range of about 200 - 300mg and most preferably Clindamycin of about lOOmg and Clotrimazole of about 200mg is present per dose unit.
The term "pharmaceutical composition" refers to a mixture of two or more of the active ingredients as described herein, or physiologically/pharmaceutically acceptable salts or solvates thereof, with other ingredients, such as physiologically/pharmaceutically
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acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
The term "vaginal suppository" is used herein mean a small globular mass which liquifies at body temperature or dissolves in the vaginal secretions.
In addition to the active components, the pharmaceutical composition optionally includes pharmaceutically acceptable carriers or auxiliaries. As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "pharmaceutically acceptable auxiliaries" includes any and all solvents, vehicles, shell formers, buffers, bulking agents, binding agent, disintegrants, lubricants, surfactants, fats, mucilaging agents, plasticizers, preservatives and the like. The compositions of the invention may also be used in combination with other medicines, such as antibiotics, antiinflammatories, thereby further broadening the compositions medical efficacy.
The composition of the present invention is in any form suitable for treatment of the vaginal infections. Preferred administration dosage forms according to present invention include vaginal suppositories, vaginal ovula, vaginal rings or semi-solid vaginal preparations such as ointments, creams or gels, creme rinses, tablets and powders. Dosage forms like vaginal suppositories are most preferred according to the present invention. These include compositions appropriate for intravaginal, cervical, intrauterine, intrarectal, or intraurethral administration.
Where the composition is applied as a suppository, the active ingredients are combined with inert suppository bases depending on the nature of the suppository. The compositions of the present invention may include shell formers such as gelatin, plasticizers such as glycerin, sorbitol, opacifiers such as titanium dioxide, vehicles such as polyethylene glycol and propylene glycol, water, mucilaging agents such as crosslinked acrylic acid polymer-polycarbophil, buffers such as Sodium dihydrogen phosphate, monohydrate, and preservatives such as methylparaben and propylparaben and the like. Additionally, the formulation may comprise other biocompatible excipients
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such as cocoa butter, hydrogenated fats and oils, cetostearyl alcohol polyethylene glycol ether, sodium dodecyl sulfate, glycerol (mono-, di-, tri-)fatty acid ester (C12-C18) polyethylene glycol dodecyl ether mixture, paraffin, ethyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and petroleum jelly, and Sodium phosphate.
Customary auxiliaries for creams include: sorbitan monostearate, Polysorbate 60, cetyl palmitate, paraffin, cetylstearyl alcohol, benzyl alcohol, silica, triacetin, isopropyl monostearate, polyethylene glycol, glycerol monostearate, polyacrylic acid, sodium hydroxide, docusate sodium, dimethicone, triglycerides, octyldecanol and octyldodecanol. By way of example, where the composition is in the form of a cream, the cream is topically applied to the affected area.
Customary tablet auxiliaries include: starch, for example corn starch, rice starch, potato starch, wheat starch, milk sugar (lactose), glucose, sucrose, micro-crystalline cellulose, colloidal silica, magnesium stearate, stearic acid, talc, polyvinylpyrrolidone (linear and cross-linked), sodium chloride, polyethylene glycol, hydroxypropyl-methylcellulose, hydroxypropylcellulose, gelatin, calcium phosphate, cellulose, mannitol, sodium carboxymethylstarch, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium carboxymethylcellulose (linear and crosslinked), magnesium stearate and other pharmaceutically acceptable additives thereof and the like are also covered by the concept and scope of the present invention.
The suppositories according to the present invention in one embodiment solves the problem of how to provide medicaments to a local environment without generating, at essentially the same time, a systemic effect caused by solvation, melting or otherwise, of the vehicle acing as a carrier of the medicament. This technical effect is in sharp contrast to state of the art suppositories made of fat-like substances that are degraded during use, typically through a process of melting or dissolving the carrier matrix.
The degradation of suppositories has the effect that administration of the medicament is not targeted to a local environment over a prolonged period of time. As a local
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environment is not targeted exclusively with state of the art suppositories, the medicament is taken up by the organism and exerts a systemic effect in the entire body. Suppositories are usually globular or oviform e.t.c.
The present invention in one preferred embodiment aimed at ensuring a direct delivery of a medicament to a local environment while essentially preventing the medicament from being taken up by the body and thereby exerting a systemic effect. Furthermore, the biocompatible polymer does not melt or disintegrate, so that the medicament preferably is essentially retaining in a local environment. The present invention thus provides a means for sustained release administration of a medicament to a predetermined, local environment without essentially generating any systemic effects. However, in other embodiments of the present invention a systemic effect may be desirable.
Hence, the advantages of suppositories according to the present invention are: i) physiological compliance ii) fast adjustment to the shape of any body cavity iii) large contact surface between suppository and mucosal membrane iv) increased transport and mobility of the bioactive substance v) water solubility of the bioactive substance vi) local administration of the bioactive substance vii) promotes effective treatment of disease conditions.
As will be understood by those skilled in the art, the regimen for treating vaginal infection will depend on the severity of the infection and the form of the composition. By way of example, where the composition is in the form of a cream, the cream is topically applied to the affected area. Where the composition is in the form of a suppository, the suppository is inserted into the vagina, most preferably once daily for 3 days.
The below mentioned example do exemplify specific embodiments of the invention and should not be regarded as limiting for the invention.
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EXAMPLE 1 - VAGINAL SUPPOSITORY
A suitable formulation for a composition in the form of a suppository for treating vaginal
infection is given as follows:
100 mg of Clindamycin and 200 mg of Clotrimazole vaginal soft gelatin capsules
(vaginal suppositories)
Batch Size: 1, 00, 000 capsules.
Tablel: GELATIN MASS MANUFACTURING

SR. NO. INGREDIENTS COMPOS ITION IN% VALUE PRACTICAL QTY. PER BATCH IN KG
1 Gelatin (Powder) 45.000 56.250
2 Glycerin 13.000 16.250
3 Sorbitol Solution 70 % 7.0000 8.750
4 Methylparaben 0.2000 0.250
5 Propylparaben 0.0500 0.0625
6 Purified Water 34.4520 43.065
7 Titanium Dioxide 0.3000 0.375
Table 2:

SR. NO. INGREDIENTS QTY.PERCAPSULE IN MG QTY. PERBATCH INKG O.A.% PRACTI CAL QTY. PERBATCH IN KG
I Carbopol Mucilage Preparation
1 Polyethylene Glycol 400 (Macrogol 400) — 2.250 — 2.250
2 Propylene Glycol ~ 2.250 — 2.250
3 Polycarbophil (Noveon AA1) ~ 0.050 — 0.050
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PROCEDURE
MANUFACTURING OF GELATIN MASS: Mixture of glycerin & purified water was heated to 70 to 80°C. Methylparaben & propylparaben was added and dissolved in it. Transferred to the gelatin manufacturing tank purified water through the liquid inlet. Hot water in the jacket by opening the inlet valve and outlet valve was started. The solution prepared in step 1 was transferred to the reactor. Sorbitol (70 % Solution) was transferred to the reactor; the agitator was started and mixed at speed 15 rpm. The temperature of reactor at 45 ± 5°C was maintained. Discharge valve of gelatin container was opened and allowed the gelatin granules / flakes to enter the reactor slowly. Purified water was transferred to the reactor. The vacuum was stopped and released slowly. The gelatin mass was allowed to melt slowly. Melting process would take approximately one hour and process temperature should be maintained at 70°C ± 5 °C. Once the gelatin mass had gone completely into the solution. The vacuum pump was started, and the vacuum valve was opened and with agitator 'ON' deaerates the gelatin mass for 30 minutes and further 10 minutes with agitator 'OFF'. Temperature of the gelatin mass has to be maintained at 55 C
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MEDICAMENT PREPARATION: The mixture of polyethylene glycol 400 & propylene glycol was heated to 60 to 65°C. Cetomacrogol 1000 was added & dissolved to it. Under mechnical stirring buffer prepared was added to the above material. Clindamycin Phosphate & Clotrimazole was added & dispersed to the above material under mechnical Stirring. Stirred untill complete dispersion takes place. Under mechnical stirring; Carbopol mucilage prepared was added & dispersed to the above material. The medicament was recirculated from the bottom valve of the vessel so that the uniform mixing can be assured, medicament was milled twice using triple roller mill followed by passing through 60 # sieve.
ENCAPSULATION: Encapsulated using encapsulation machine having die roll size 14.0 minim oval shape dies using cream colored gelatin ribbon having thickness in the limit of 0.85 + 0.10 mm. Fill weight 740.0 mg/capsule (Limit: +2%)
POLISHING: The encapsulated capsules are polished with absorbent cloth through 3 semi dryers in series.
DRYING: The capsules are dried using SS tray dryer maintaing the temperature condition of 25+ 50C & % Relative humidity of 25+ 5%.

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INSPECTION OF CAPSULES: The capsules are inspect and transferred the washed & dried capsules to quarantine area.
Table: 3: Final dosage form specifications

Sr.No. PARAMETERS DESCRIPTION
1 Appearance Cream colored oval shaped soft gelatin capsule containing white to off-white colored viscous paste.
2 Shape Oval
3 Fill weight per capsule Weight variation +2% 740.0 mgMin. 725.20 mg and Max. 754.80 mg
4 Fill weight for Individual Weight variation Limit ± 5% Min. 703.0 mg and Max. 777.0 mg
5 Disintegration Time Not more than 60 minutes
The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.
DATED THIS NINTH (9TH) DAY OF JULY, 2007

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