WO2022091016A1 - Pharmaceutical composition suitable for vaginal administration in the form of ovules and use thereof - Google Patents
Pharmaceutical composition suitable for vaginal administration in the form of ovules and use thereof Download PDFInfo
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- WO2022091016A1 WO2022091016A1 PCT/IB2021/060020 IB2021060020W WO2022091016A1 WO 2022091016 A1 WO2022091016 A1 WO 2022091016A1 IB 2021060020 W IB2021060020 W IB 2021060020W WO 2022091016 A1 WO2022091016 A1 WO 2022091016A1
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- Prior art keywords
- pharmaceutical composition
- composition according
- pharmaceutically acceptable
- acceptable salt
- weight
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
Definitions
- composition suitable for vaginal administration in the form of ovules and use thereof Field of the invention
- the present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules, the method for manufacturing the composition and the ovules, and the use of said composition in the prevention and/or treatment of infectious diseases of the female reproductive system.
- Background art 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 tricomonal vaginitis (TV), which account for about 90% of cases in women of reproductive age in first level clinics.
- BV bacterial vaginosis
- VVC vulvovaginal candidiasis
- TV tricomonal vaginitis
- Infectious vaginitis occurs in a significant percentage of 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 women of reproductive age is colonized by a normal microbiota formed by lactobacilli, which protects against pathogenic bacterial species when present in sufficient quantities.
- Internal factors such as altered vaginal microenvironment and pH, and external factors such as unprotected sexual activity, smoking, vaginal showers, immune system deficiencies, diabetes, and radiotherapy, among others, are the most common causes of infectious vaginitis.
- Bacterial vaginosis is the second most common female genital infection in Mexico, although it is reported in medical literature of North America in 35 to 50% of cases and ranges from 32 to 64% in sexually transmitted infection clinics. Bacterial vaginosis is a common condition in women of reproductive age. It is a vaginal infection that is usually associated with a greyish-white, abundant and malodorous transvaginal flow, without itching or burning; in addition, it is known that within the reproductive and perinatal sphere it is considered a risk factor in pregnant woman and for inflammatory pelvic disease for the non-pregnant woman.
- Bacterial vaginosis is due to an imbalance of the vaginal biota, wherein as the lactobacillary flora decreases there is an increase in the rest of the bacteria of the vaginal flora: Gardnerella vaginalis, Atopobium vaginae, Mobiluncus spp, Mycoplasma hominis, Ureaplasma urealyticum, Peptococcus, Peptostreptococcus and other anaerobes (Casanova-Román G., Madrid H., Ram ⁇ rez –Palacios C.D. Sánchez –Contreras J., (2010).
- Vulvovaginal candidiasis is caused by the excessive growth of yeasts, mainly Candida albicans, which are essentially part of the vaginal flora. Symptoms of vulvovaginal candidiasis include vaginal discharge, itching, pain, and swelling.
- Candida albicans is the most common cause of vulvovaginal candidiasis
- Candida non-albicans species such as Candida glabrata, Candida parapsilosis, Candida krusei, Candida cerevisiae, Candida tropicalis, Candida lusitaniae and Trichosporon sp. have increasingly been identified as a cause of vulvovaginal candidiasis.
- Vulvovaginitis is one of the gnoseological entities with the greatest demand for medical care. It has even been reported that it is currently one of the infectious diseases that causes more emotional problems and economic losses.
- An antifungal or antibacterial agent is commonly used in monotherapy (because the causative agent is unique); however, since 14.6 to 33% of the cases are mixed infections, the indicated treatment is a combined one.
- the most frequently reported associations are bacterial vaginosis with vaginitis due to candida, so combination therapy is the most frequently used option; thus, mainly antifungals and antibacterials have been mixed.
- This type of therapy has involved the simultaneous administration of combined drugs administered orally (tablets or capsules); and/or topically (vaginal cream or ovule); or, both.
- Treatment regimens vary in duration: long regimens range from seven to 14 days, while short regimens may last three days or a single day.
- vaginal infections include fungicidal and/or antibiotic treatments with azole derivatives.
- Reference and consolidated therapies (whether local or systemic) for the treatment of the above conditions are well established.
- the increasing incidence of mixed vaginal infections poses a therapeutic challenge because such infections require treatment with multiple drugs.
- the present inventors have developed a new composition in the form of concentrated vaginal ovules comprising as active ingredients ketoconazole, clindamycin, and lidocaine, the main advantages of which are: - all the active ingredients are uniformly mixed in the composition, - the composition obtained can be manufactured on a commercial scale in a consistent manner and maintaining the quality attributes; - no phase separations or migration of the drugs are observed during the manufacture of the composition or within the dose unit. Additionally, the inventors have found that the ovules of the invention are very easy to apply. Description of the Invention In a first aspect, the present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules.
- the present invention relates to a pharmaceutical composition, according to the first aspect of the invention, for use in the prevention and/or treatment of infectious diseases of the female reproductive system, in particular, for use in the prevention and/or treatment of a disease or condition selected from bacterial vaginosis, mixed vaginitis and vaginal candidiasis.
- the present invention relates to a method for manufacturing a pharmaceutical composition, according to the first aspect of the invention.
- the present invention relates to a method for manufacturing an ovule for vaginal administration containing a pharmaceutical composition, according to the first aspect of the invention.
- Figure 1 shows an exemplary schematic of the manufacturing process steps of the composition of the invention (active ingredients: ketoconazole, lidocaine, and clindamycin). See also Example 1.
- Figure 2 shows an exemplary schematic of the manufacturing process steps of the composition of the invention further containing tinidazole (active ingredients: ketoconazole, lidocaine, clindamycin and tinidazole). See also Example 2.
- Figure 3 shows the results of the comparative study on ease of application (see example 3) for the products: (A) Comparator drug (leftmost bar), (B) Ovule of the invention containing ketoconazole, lidocaine, clindamycin, and tinidazole from Example 2 (centre bar), and (C) Ovule of the invention containing ketoconazole, lidocaine, and clindamycin from Example 1 (rightmost bar).
- the present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules, comprising or consisting of: a) ketoconazole or a pharmaceutically acceptable salt thereof; b) clindamycin or a pharmaceutically acceptable salt thereof; c) lidocaine or a pharmaceutically acceptable salt thereof; d) a bioadhesive agent; e) a hard fat together with an emulsifier and an emulsion stabilizer.
- Ketoconazole whose systematic name is 1-[4- [4 - [[(2S, 4R) - 2- (2,4 - dichlorophenyl) - 2- (imidazole - 1 - ilmethyl) - 1,3 - dioxolan - 4 - yl] methoxy] phenyl]
- Piperazin - 1 - yl] ethanone is a synthetic derivative of imidazole whose essential pharmacological action is antifungal, although it also has in vitro activity against some gram-positive bacteria including Staphylococcus aureus and S. epidermidis.
- Ketoconazole has been shown to be effective in the treatment of vaginal candidiasis, either with topical vaginal therapy or orally, and the development of fungal resistance has so far not been demonstrated in vitro and in vivo (IPP AMPLIA FEMISAN® 3D, 2005).
- ketoconazole applied vaginally, practically does not reach the bloodstream, it does not undergo biotransformation and is eliminated by the self-cleansing mechanisms of the vagina (IPP AMPLIA FEMISAN® 3D, 2005).
- Clindamycin whose systematic name is (2S, 4R) - N- [2 - chloro - 1 - [(2R, 3R, 4S, 5R, 6R) - 3, 4, 5 - trihydroxy - 6 - methylsulfanyloxan - 2 - yl] propyl] -4-propylpyrrolidine-2- carboxamide, is active against most gram-negative and gram-positive anaerobic and microaerophilic microorganisms including Bacteroides fragilis, Bacteroides melaninogenicus, Mobiluncus spp., Actinomyces, Eubacterium, Fusobacterium Propionibacterium, Peptococcus, Peptostreptococcus Veillonella, Clos
- clindamycin Some strains of Haemophilus influenzae and Neisseria gonorrohoeae may be inhibited by clindamycin (IPP AMPLIA FEMISAN® 3D, 2005). Topically applied clindamycin has a very poor systemic absorption rate. No blood concentration data are available when administered vaginally. Skin concentrations with topical application are very small (0 to 3 ng/mL). In the absence of vaginally administered systemic absorption, clindamycin is not metabolized and is eliminated by the self-cleansing mechanisms of the vagina (FEMISAN ® 3D WIDE IPP, 2005).
- Lidocaine whose systematic name is 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, is an anaesthetic agent indicated for the production of local or regional anaesthesia and for the treatment of ventricular tachycardia that occurs during cardiac manipulation, such as surgery or catheterization, or that may occur during acute myocardial infarction, digital toxicity or other heart diseases. (PubChem, lidocaine CID 3676). Lidocaine is a synthetic aminoethylamide with local anaesthetic and antiarrhythmic properties.
- Lidocaine stabilizes the neuronal membrane by binding and inhibiting the sodium channels with voltage, thus inhibiting the ionic flows necessary for the initiation and conduction of impulses, carrying out local anaesthesia (PubChem, lidocaine CID 3676).
- pharmaceutically acceptable salts of the active ingredients used in the present invention are the phosphate, dihydrogen phosphate and hydrochloride salts for clindamycin and the hydrochloride salt for lidocaine. If such salts are used, at the time of preparation of the formulations it should be taken into account that the amount to be used of the salt corresponds to the desired amount of active ingredient.
- a "hard fat” is understood as a mixture of esters of triglycerides, diglycerides, and monoglycerides derived from saturated fatty acids C10-C18, the part of triglycerides being greater than that of diglycerides and monoglycerides.
- ingredient e) of the formulation of the present invention such hard fats are present together with at least one emulsifier and at least one emulsion stabilizer.
- emulsifier and emulsion stabilizer there are commercial products that already incorporate emulsifier and emulsion stabilizer in the hard fat.
- Witepsol® for example, Witepsol S55®, Witepsol W15®.
- Witepsol S55® containing hard fat, polyoxyethylene (25) cetyl stearyl ether, as emulsifier, and beeswax as emulsion stabilizer is used as ingredient e) of the composition of the invention.
- fatty acid and glycerol esters such as gly
- polyoxyethylene (25) cetyl stearyl ether is used.
- emulsion stabilizers that may be used in component e) of the composition include, but are not limited to, lecithin, cassava extract, quillay bark extract, lanolin, candelilla, carnauba, jojoba, rice bran, beeswax, xanthan gum, quince seed, glyceryl oleate, glyceryl stearate, citrate, and mixtures thereof.
- beeswax is used.
- the pharmaceutical composition also comprises the active ingredient tinidazole or a pharmaceutically acceptable salt thereof.
- Tinidazole whose systematic name is 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole, is a synthetic antiprotozoal agent. Tinidazole shows activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis, Giardia duodenalis (also called Giardia lamblia) and Entamoeba histolytica.
- Tinidazole is active against Gardnerella vaginalis and many anaerobic bacteria, including: Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides spp., Clostridium spp., Eubacterium spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp. and Veillonella spp. (Fasigyn® - Tinidazole). At this point, the known insolubility of tinidazole should be noted.
- the pharmaceutical composition of the present invention is capable of incorporating tinidazole with the other components resulting in a homogeneous dispersion useful for the purposes of the present invention.
- - the ketoconazole or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 23 and 27 %, preferably about 25%
- - the clindamycin or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 3 and 4.5 %, preferably about 3.7 %
- - the lidocaine or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 3 and 4.5 %, preferably about 3.6 %.
- the term “about” as applied to the values used above and hereon includes a margin of error of ⁇ 5%, such as, for example, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%.
- the pharmaceutical composition further comprises tinidazole or a pharmaceutically acceptable salt thereof, it is preferably in a percentage by weight with respect to the weight of the ovule between 8.5 and 10.25%, more preferably about 9.4%.
- the bioadhesive agent or mucoadhesive is present in the composition to increase the residence time of the ovule-shaped pharmaceutical composition in the vaginal cavity.
- the bioadhesive agent (or mucoadhesive) included in the pharmaceutical composition of the present invention is selected from polycarbophile, polyacrylates, polyacrylamides, cellulose derivatives selected from hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylpropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carbopol, polyvinyl alcohol and derivatives thereof, hyaluronic acid derivatives, chitosan, dextran, pectin, alginate, or mixtures thereof. More preferably, said bioadhesive is polycarbophil.
- the bioadhesive or mucoadhesive agent included in the pharmaceutical composition of the present invention is in a percentage by weight with respect to the weight of the ovule between 0.5 and 4 %, preferably about 2.5 %.
- the bioadhesive or mucoadhesive agent is selected from polycarbophilic and is in a percentage by weight with respect to the weight of the ovule between 0.5 and 4 %, preferably is in about 2.5 %.
- “hard fat” or mixture of esters of triglycerides, diglycerides and monoglycerides derived from C10-C18 saturated fatty acids included in the pharmaceutical composition of the present invention it is in a percentage by weight with respect to the weight of the ovule between 40 and 60 %.
- - ketoconazole or a pharmaceutically acceptable salt thereof is in an amount between 720 and 880 mg in the composition, preferably about 800 mg;
- - clindamycin is in an amount between 90 and 110 mg in the composition, preferably of about 100 mg, or a pharmaceutically acceptable salt thereof is in an amount between 106 and 130 mg in the composition, preferably of about 118 mg, preferably the pharmaceutically acceptable salt is clindamycin phosphate;
- - lidocaine is in an amount between 90 and 110 mg in the composition, preferably about 100 mg, or a pharmaceutically acceptable salt thereof is in an amount between 103 and 127 mg in the composition, preferably about 115 mg, preferably the pharmaceutically acceptable salt is lidocaine HCl;
- - if present, the tinidazole or a pharmaceutically acceptable salt thereof is in an amount between 270 and 330 mg in the composition, preferably about 300 mg;
- the bioadhesive agent preferably polycarbophil
- the pharmaceutical composition of the present invention further comprises an antioxidant.
- the antioxidant agent included in the pharmaceutical composition of the present invention is selected from alkylated hydroxyaromatic compounds, preferably butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA), propyl gallate, sodium bisulfite and sodium metabisulfite.
- BHT butylhydroxytoluene
- BHA butylhydroxyanisole
- propyl gallate sodium bisulfite and sodium metabisulfite.
- the antioxidant is preferably at a percentage by weight with respect to the weight of the ovule of about 1%.
- said antioxidant is BHT (butyl hydroxytoluene).
- the antioxidant is BHT and is in a percentage by weight with respect to the weight of the ovule of about 1%.
- the pharmaceutical composition of the present invention further comprises an agent for reducing the viscosity of the final product in the form of a non-ionic surfactant.
- the non-ionic surfactant is selected from polysorbates, preferably polysorbate 80 or polysorbate 81, polyoxyglycerides, polyoxyethylene stearate, and glycerol monooleate.
- the non-ionic surfactant is preferably in a percentage by weight with respect to the weight of the ovule of about 7% and 18%.
- the non-ionic surfactant is polysorbate 80.
- the non-ionic surfactant is polysorbate 80 and is at a percentage by weight with respect to the weight of the ovule of about 9%-12%, and more preferably at a percentage by weight with respect to the weight of the ovule of about 10%.
- the pharmaceutical composition of the present invention further comprises BHT and polysorbate 80. More preferably, BHT is in a percentage by weight with respect to the weight of the ovule of about 1 wt % and polysorbate 80 is in a percentage by weight with respect to the weight of the ovule of about 10 %.
- the present invention relates to the pharmaceutical composition, according to the first aspect of the invention in each of its embodiments alone or in combination, for use in the prevention and/or treatment of infectious diseases of the female reproductive system.
- the present invention relates to the use of the pharmaceutical composition, according to the first aspect of the invention in each of its embodiments alone or in combination, in the manufacture of a medicinal product for the prevention and/or treatment of infectious diseases of the female reproductive system.
- the present invention relates to a method of preventing and/or treating infectious diseases of the female reproductive system comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, according to the first aspect of the invention in each of its embodiments, alone or in combination.
- therapeutically effective amount means an effective amount, at the doses and for the periods of time necessary, to achieve the desired prophylactic/therapeutic result.
- desired prophylactic/therapeutic outcome refers to a prophylactic action or a decrease/elimination of symptoms related to the diseases or conditions mentioned herein.
- said disease or condition is selected from bacterial vaginosis, mixed vaginitis, and vaginal candidiasis.
- said disease or condition is caused by Gardnerella vaginalis, Mobiluncus spp, or Bacteroides fragilis.
- said pharmaceutical composition in the form of ovules is administered in a dosing regimen of three ovules for three consecutive days, one ovule each day.
- the present invention relates to a method for manufacturing a pharmaceutical composition, according to the first aspect of the invention in each of its single or combined embodiments, comprising or consisting of: i) preparing a preliminary mixture with the components of the ingredient e), according to the first aspect of the invention, that is, a hard fat together with an emulsifier and an emulsion stabilizer; ii) adding the bioadhesive to the mixture obtained in i); iii) adding to the mixture obtained in ii) of ketoconazole or a pharmaceutically acceptable salt thereof; clindamycin or a pharmaceutically acceptable salt thereof; and lidocaine or a pharmaceutically acceptable salt thereof, in any order and sequentially.
- polysorbate 80 is added to the mixture obtained in step i) prior to adding the bioadhesive.
- BHT is added to the mixture obtained in step i) prior to adding the bioadhesive.
- polysorbate 80 and BHT are added to the mixture obtained in step i) prior to adding the bioadhesive.
- the active ingredient of tinidazole or a pharmaceutically acceptable salt thereof is also added.
- the present invention relates to a method for manufacturing an ovule for vaginal administration containing a pharmaceutical composition, according to the first aspect of the invention in each of its embodiments, alone or in combination, comprising or consisting of the steps of: A) preparation of a pharmaceutical composition according to the third aspect of the invention in each of its embodiments alone or in combination; B) filling the preformed mould with the pharmaceutical composition obtained in step A); C) cooling of the composition.
- said method of manufacturing an ovule for vaginal administration containing a pharmaceutical composition according to the first aspect of the invention in each of its embodiments, alone or in combination, further comprises packaging said ovule in a suitable container.
- Example 1 Manufacturing Process of the Composition of the Invention
- the composition to be manufactured had the following components and quantities based on the dosage unit (one ovule): Laboratory scale First, the process was developed on a laboratory scale using the pour moulding method, using a glass container with a jacket heated by a water bath. In this vessel, the hard fat was melted and the active ingredients and other excipients were added and dispersed using a mixture with low shear and a homogenizer, and the melt was then poured into a PVC/PE preformed mould. The manufacturing process is described in figure 1.
- the proposed order and addition temperature were obtained using batches of 320 g to 1,000 g, equivalent to 100 to 312 ovules. This process is shown schematically in Figure 2.
- the process parameters established at this scale were used to establish a first approximation to develop the process at the pilot scale, which is described below. Pilot scale
- the next step was to expand and evaluate the manufacturing process at the pilot scale, with a planned batch size of 25 kg, equivalent to 7,812 ovules.
- two batches of different size were used to evaluate the critical parameters of the process.
- a first batch of 10 kg was used to explore the reproducibility of the manufacturing process developed at laboratory scale, before continuing with a batch size of 25 kg.
- the mixing/homogenization rates and the mixing time were the parameters to be evaluated.
- the coaxial mixer was maintained at a maximum speed of about 55 rpm
- the anchor type mixer was used at a maximum speed of about 30 rpm
- the homogenizer speed was used in the range of 3000 to 4500 rpm.
- the physical properties at each step of the process were characterized by evaluating that a homogeneous mixture has been obtained, since this is the most obvious criterion for evaluating the suitability of the manufacturing process.
- the filling process was performed by using the commercial equipment intended for the medicinal product, in which the mass is added to a heated container, mixed and then poured by a filling valve to the gravity preformed moulds: the critical parameters obtained in this step of the processes were the overall temperature and the mixing speed; the temperature in the filling valve, the filling speed and the weight of the ovule were established according to the usual practice and the properties of the product. After filling the moulds of the preformed ovules, four cooling temperatures (8 °C, 10 °C, 12 °C and 15 °C) were tested to evaluate the appearance of the product and the yield of the process after sealing.
- the Head of Pharmacy or delegated personnel was asked for the treatment for the patient. Such treatment could not be identified by the treating physician.
- the corresponding medicinal product was delivered to the patient by the Head of Pharmacy or delegated personnel and in the amount necessary to complete three days of treatment. Once the medicinal product was delivered to the patient, the treating physician gave the corresponding instructions to self-administer a tablet or ovule intravaginally, at night, for three days, as well as the necessary administration technique and hygienic measures. She then made an appointment with the patient for the final follow-up visit.
- a diary was given to the patient and indications were given for recording the time of application, tolerability and adverse events during treatment, which was given to the treating physician at the follow-up visit. The entire process was recorded in a medical note that was included in the patient's clinical file.
- Day 10 (+3 days) The patients attended their final follow-up visit, in which the gynaecologist or duly trained study delegate conducted an interrogation aimed at investigating the evolution of their condition, asked about the evolution of their symptoms as well as the presence of adverse events, and the patient’s opinion in relation to the treatment she received to evaluate tolerability, making the corresponding note, which was included in the clinical file.
- the patient was asked to deliver the containers of the medicinal product that was administered, either empty or with the remaining medicinal product, as evidence of its administration and to control the inventory. Re-dispensing a drug to another patient was not allowed if it was returned, even if the package was delivered intact. Patients were asked to return their diary completed for the period that the study treatment was self-administered. A new vaginal control culture was taken to assess changes relative to the first culture and the completion of their participation in the study was subsequently indicated. In case of therapeutic failure, the patient was provided with the specific treatment, according to the indications of the gynaecologist. Below is a time chart describing the procedure Table 3. Time chart of the comparative study procedure Population 81 women were included in the study, according to the criteria of the protocol.
- the inclusion criteria were: • Women aged 18 years or older. • Clinical picture compatible with vaginitis/vaginosis where one of the following symptoms is the reason for the consultation: o Pruritus o Vulvar Pain o Vaginal flow o Dyspareunias • Indications for treatment with the study medicinal products according to the criterion of the gynaecologist. • Negative (qualitative in urine) pregnancy test. In case of qualitative test with positive result, a confirmatory quantitative blood test was performed: if the result was negative, the patient was included. With a positive result, the patient was not included in the study. The exclusion criteria were: • Women with a history of hypersensitivity to any of the drugs being studied.
- Efficacy response in treatment groups Changes in vulvovaginal symptomatology were evaluated during the treatment period between visit day 1 and visit day 10 of the present study. Pruritus, vulvar pain and vaginal discharge were evaluated, dyspareunia was not evaluated in the absence of sexual activity during treatment. Table 5 shows the significant changes in symptoms between the Day 1 and Day 10 visit in the three treatment groups indicating an improvement in the presence and absence of initial and final vulvovaginal symptomatology. Table 5. Symptom assessment between visit day 1 and day 10 in the three treatment groups The ease of application of the three products under analysis was also analyzed, with the comparator drug being the most difficult for application.
- Table 6 below reflects that the exemplified combinations of the invention: combination B (comprising ketoconazole, lidocaine, clindamycin and tinidazole) and combination C (comprising ketoconazole, lidocaine, clindamycin) showed greater ease of application.
- Figure 3 also shows these same data in the form of bars, where the comparator drug corresponds to bar A; the combination called “combination B" of the invention containing ketoconazole, lidocaine, clindamycin and tinidazole corresponds to bar B (central bar) and the combination called "combination C" containing ketoconazole, lidocaine, clindamycin corresponds to bar C more to the right.
- Table 6 reflects that the exemplified combinations of the invention: combination B (comprising ketoconazole, lidocaine, clindamycin and tinidazole) and combination C (comprising ketoconazole, lidocaine,
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Abstract
The present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules and to its manufacture. The present invention also relates to such a pharmaceutical composition for use in the prevention and/or treatment of infectious diseases of the female reproductive system.
Description
Pharmaceutical composition suitable for vaginal administration in the form of ovules and use thereof Field of the invention The present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules, the method for manufacturing the composition and the ovules, and the use of said composition in the prevention and/or treatment of infectious diseases of the female reproductive system. Background art 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 tricomonal vaginitis (TV), which account for about 90% of cases in women of reproductive age in first level clinics. Infectious vaginitis occurs in a significant percentage of 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 women of reproductive age is colonized by a normal microbiota formed by lactobacilli, which protects against pathogenic bacterial species when present in sufficient quantities. Internal factors such as altered vaginal microenvironment and pH, and external factors such as unprotected sexual activity, smoking, vaginal showers, immune system deficiencies, diabetes, and radiotherapy, among others, are the most common causes of infectious vaginitis. Bacterial vaginosis is the second most common female genital infection in Mexico, although it is reported in medical literature of North America in 35 to 50% of cases and ranges from 32 to 64% in sexually transmitted infection clinics. Bacterial vaginosis is a common condition in women of reproductive age. It is a vaginal infection that is usually associated with a greyish-white, abundant and malodorous transvaginal flow, without itching or burning; in addition, it is known that within the reproductive and perinatal sphere it is considered a risk factor in pregnant woman and for inflammatory pelvic disease for the non-pregnant woman. Bacterial vaginosis is due to an imbalance of the vaginal biota, wherein as the lactobacillary flora decreases there is an increase in the rest of the bacteria of the vaginal flora: Gardnerella vaginalis, Atopobium vaginae, Mobiluncus spp, Mycoplasma hominis, Ureaplasma urealyticum, Peptococcus, Peptostreptococcus and other anaerobes (Casanova-Román G., Madrid H., Ramírez –Palacios C.D. Sánchez –Contreras J., (2010).
Efectividad de dos óvulos de triple composición en el tratamiento de la vaginitis/vaginosis. Perinatol Reprod Hum 2010; 24 (1): 28-35). Vulvovaginal candidiasis is caused by the excessive growth 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, Candida non-albicans species, such as Candida glabrata, Candida parapsilosis, Candida krusei, Candida cerevisiae, Candida tropicalis, Candida lusitaniae and Trichosporon sp. have increasingly been identified as a cause of vulvovaginal candidiasis. Vulvovaginitis is one of the gnoseological entities with the greatest demand for medical care. It has even been reported that it is currently one of the infectious diseases that causes more emotional problems and economic losses. An antifungal or antibacterial agent is commonly used in monotherapy (because the causative agent is unique); however, since 14.6 to 33% of the cases are mixed infections, the indicated treatment is a combined one. The most frequently reported associations are bacterial vaginosis with vaginitis due to candida, so combination therapy is the most frequently used option; thus, mainly antifungals and antibacterials have been mixed. This type of therapy has involved the simultaneous administration of combined drugs administered orally (tablets or capsules); and/or topically (vaginal cream or ovule); or, both. Treatment regimens vary in duration: long regimens range from seven to 14 days, while short regimens may last three days or a single day. Currently, short schemes are sought, with a combination that favours clinical healing and bacteriological cure, as do long treatments. It is well known in the art that treatments of vaginal infections include fungicidal and/or antibiotic treatments with azole derivatives. Reference and consolidated therapies (whether local or systemic) for the treatment of the above conditions are well established. Additionally, the increasing incidence of mixed vaginal infections poses a therapeutic challenge because such infections require treatment with multiple drugs. The present inventors have developed a new composition in the form of concentrated vaginal ovules comprising as active ingredients ketoconazole, clindamycin, and lidocaine, the main advantages of which are: - all the active ingredients are uniformly mixed in the composition,
- the composition obtained can be manufactured on a commercial scale in a consistent manner and maintaining the quality attributes; - no phase separations or migration of the drugs are observed during the manufacture of the composition or within the dose unit. Additionally, the inventors have found that the ovules of the invention are very easy to apply. Description of the Invention In a first aspect, the present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules. In a second aspect, the present invention relates to a pharmaceutical composition, according to the first aspect of the invention, for use in the prevention and/or treatment of infectious diseases of the female reproductive system, in particular, for use in the prevention and/or treatment of a disease or condition selected from bacterial vaginosis, mixed vaginitis and vaginal candidiasis. In a third aspect, the present invention relates to a method for manufacturing a pharmaceutical composition, according to the first aspect of the invention. In a fourth aspect, the present invention relates to a method for manufacturing an ovule for vaginal administration containing a pharmaceutical composition, according to the first aspect of the invention. Brief Description of the Drawings Figure 1 shows an exemplary schematic of the manufacturing process steps of the composition of the invention (active ingredients: ketoconazole, lidocaine, and clindamycin). See also Example 1. Figure 2 shows an exemplary schematic of the manufacturing process steps of the composition of the invention further containing tinidazole (active ingredients: ketoconazole, lidocaine, clindamycin and tinidazole). See also Example 2. Figure 3 shows the results of the comparative study on ease of application (see example 3) for the products: (A) Comparator drug (leftmost bar), (B) Ovule of the invention containing ketoconazole, lidocaine, clindamycin, and tinidazole from Example 2 (centre bar), and (C) Ovule of the invention containing ketoconazole, lidocaine, and clindamycin from Example 1 (rightmost bar).
Detailed description of the invention In a first aspect, the present invention relates to a pharmaceutical composition suitable for vaginal administration in the form of ovules, comprising or consisting of: a) ketoconazole or a pharmaceutically acceptable salt thereof; b) clindamycin or a pharmaceutically acceptable salt thereof; c) lidocaine or a pharmaceutically acceptable salt thereof; d) a bioadhesive agent; e) a hard fat together with an emulsifier and an emulsion stabilizer. In the present description and in the claims, the terms "comprises", "comprising", "containing", and "having" are open-ended terms and may mean "includes", "including", and the like; while terms such as "consists of" or "consisting of" refer to the items mentioned after these terms and exclude others that are not mentioned. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention belongs. The singular terms "a", "an" and "the” include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Ketoconazole, whose systematic name is 1-[4- [4 - [[(2S, 4R) - 2- (2,4 - dichlorophenyl) - 2- (imidazole - 1 - ilmethyl) - 1,3 - dioxolan - 4 - yl] methoxy] phenyl] Piperazin - 1 - yl] ethanone, is a synthetic derivative of imidazole whose essential pharmacological action is antifungal, although it also has in vitro activity against some gram-positive bacteria including Staphylococcus aureus and S. epidermidis. Its action, mainly fungicidal, stands out against Candida albicans, with a minimum inhibitory concentration ranging from 1 to 16 µg/mL. Ketoconazole has been shown to be effective in the treatment of vaginal candidiasis, either with topical vaginal therapy or orally, and the development of fungal resistance has so far not been demonstrated in vitro and in vivo (IPP AMPLIA FEMISAN® 3D, 2005). Available pharmacokinetic information for ketoconazole, applied locally vaginally, indicates that systemic absorption is virtually nil. By this route of administration, a peak plasma concentration ranging from undetectable to 20.7 ng/mL is reached. Because ketoconazole, applied vaginally, practically does not reach the bloodstream, it does not undergo
biotransformation and is eliminated by the self-cleansing mechanisms of the vagina (IPP AMPLIA FEMISAN® 3D, 2005). Clindamycin, whose systematic name is (2S, 4R) - N- [2 - chloro - 1 - [(2R, 3R, 4S, 5R, 6R) - 3, 4, 5 - trihydroxy - 6 - methylsulfanyloxan - 2 - yl] propyl] -4-propylpyrrolidine-2- carboxamide, is active against most gram-negative and gram-positive anaerobic and microaerophilic microorganisms including Bacteroides fragilis, Bacteroides melaninogenicus, Mobiluncus spp., Actinomyces, Eubacterium, Fusobacterium Propionibacterium, Peptococcus, Peptostreptococcus Veillonella, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae and Mycoplasma. Some strains of Haemophilus influenzae and Neisseria gonorrohoeae may be inhibited by clindamycin (IPP AMPLIA FEMISAN® 3D, 2005). Topically applied clindamycin has a very poor systemic absorption rate. No blood concentration data are available when administered vaginally. Skin concentrations with topical application are very small (0 to 3 ng/mL). In the absence of vaginally administered systemic absorption, clindamycin is not metabolized and is eliminated by the self-cleansing mechanisms of the vagina (FEMISAN ® 3D WIDE IPP, 2005). Lidocaine, whose systematic name is 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, is an anaesthetic agent indicated for the production of local or regional anaesthesia and for the treatment of ventricular tachycardia that occurs during cardiac manipulation, such as surgery or catheterization, or that may occur during acute myocardial infarction, digital toxicity or other heart diseases. (PubChem, lidocaine CID 3676). Lidocaine is a synthetic aminoethylamide with local anaesthetic and antiarrhythmic properties. Lidocaine stabilizes the neuronal membrane by binding and inhibiting the sodium channels with voltage, thus inhibiting the ionic flows necessary for the initiation and conduction of impulses, carrying out local anaesthesia (PubChem, lidocaine CID 3676). Among the pharmaceutically acceptable salts of the active ingredients used in the present invention are the phosphate, dihydrogen phosphate and hydrochloride salts for clindamycin and the hydrochloride salt for lidocaine. If such salts are used, at the time of preparation of the formulations it should be taken into account that the amount to be used of the salt corresponds to the desired amount of active ingredient. For example, as seen in the examples, for 100 mg of clindamycin 118.8 mg of clindamycin phosphate is required.
In the context of the present invention, a "hard fat" is understood as a mixture of esters of triglycerides, diglycerides, and monoglycerides derived from saturated fatty acids C10-C18, the part of triglycerides being greater than that of diglycerides and monoglycerides. As indicated in ingredient e) of the formulation of the present invention, such hard fats are present together with at least one emulsifier and at least one emulsion stabilizer. However, there are commercial products that already incorporate emulsifier and emulsion stabilizer in the hard fat. These products include Witepsol® (for example, Witepsol S55®, Witepsol W15®). In a preferred embodiment, Witepsol S55® containing hard fat, polyoxyethylene (25) cetyl stearyl ether, as emulsifier, and beeswax as emulsion stabilizer is used as ingredient e) of the composition of the invention. Examples of emulsifiers that may be used in component e) of the composition include, but are not limited to, fatty acid and glycerol esters such as glycerol monostearate, fatty acid and glycol esters such as propylene glycol monostearate, fatty acid and polyhydric alcohol esters such as polyethylene glycol (400) monooleate, fatty acid and polyoxyethylene esters such as polyoxyethylene (40) stearate, fatty alcohol and polyoxyethylene ethers such as polyoxyethylene (20) stearyl ether, polyoxyethylene (25) cetyl stearyl ether, fatty acid and polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan monostearate, sorbitan esters such as sorbitan monostearate, alkyl glycosides such as cearyl glycoside, fatty acid ethanolamides and their derivatives such as stearic acid diethanol and the like. Preferably, polyoxyethylene (25) cetyl stearyl ether is used. Examples of emulsion stabilizers that may be used in component e) of the composition include, but are not limited to, lecithin, cassava extract, quillay bark extract, lanolin, candelilla, carnauba, jojoba, rice bran, beeswax, xanthan gum, quince seed, glyceryl oleate, glyceryl stearate, citrate, and mixtures thereof. Preferably, beeswax is used. In a preferred embodiment, the pharmaceutical composition also comprises the active ingredient tinidazole or a pharmaceutically acceptable salt thereof. Tinidazole, whose systematic name is 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole, is a synthetic antiprotozoal agent. Tinidazole shows activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis, Giardia duodenalis (also called Giardia lamblia) and Entamoeba histolytica. Tinidazole is active against Gardnerella vaginalis and many anaerobic bacteria, including: Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides spp., Clostridium spp.,
Eubacterium spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp. and Veillonella spp. (Fasigyn® - Tinidazole). At this point, the known insolubility of tinidazole should be noted. The present inventors have found that, surprisingly, the pharmaceutical composition of the present invention is capable of incorporating tinidazole with the other components resulting in a homogeneous dispersion useful for the purposes of the present invention. In another preferred embodiment, in the pharmaceutical composition, independently: - the ketoconazole or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 23 and 27 %, preferably about 25%, - the clindamycin or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 3 and 4.5 %, preferably about 3.7 %, - the lidocaine or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 3 and 4.5 %, preferably about 3.6 %. It should be noted that the term “about” as applied to the values used above and hereon includes a margin of error of ± 5%, such as, for example, ± 4%, ± 3%, ± 2%, ± 1%. In the case that the pharmaceutical composition further comprises tinidazole or a pharmaceutically acceptable salt thereof, it is preferably in a percentage by weight with respect to the weight of the ovule between 8.5 and 10.25%, more preferably about 9.4%. The bioadhesive agent (or mucoadhesive) is present in the composition to increase the residence time of the ovule-shaped pharmaceutical composition in the vaginal cavity. In a preferred embodiment, the bioadhesive agent (or mucoadhesive) included in the pharmaceutical composition of the present invention is selected from polycarbophile, polyacrylates, polyacrylamides, cellulose derivatives selected from hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylpropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carbopol, polyvinyl alcohol and derivatives thereof, hyaluronic acid derivatives, chitosan, dextran, pectin, alginate, or mixtures thereof. More preferably, said bioadhesive is polycarbophil. In another preferred embodiment, the bioadhesive or mucoadhesive agent included in the pharmaceutical composition of the present invention is in a percentage by weight with respect to the weight of the ovule between 0.5 and 4 %, preferably about 2.5 %.
In a still more preferred embodiment the bioadhesive or mucoadhesive agent is selected from polycarbophilic and is in a percentage by weight with respect to the weight of the ovule between 0.5 and 4 %, preferably is in about 2.5 %. In another preferred embodiment of the “hard fat” or mixture of esters of triglycerides, diglycerides and monoglycerides derived from C10-C18 saturated fatty acids included in the pharmaceutical composition of the present invention, it is in a percentage by weight with respect to the weight of the ovule between 40 and 60 %. In another preferred embodiment, in the pharmaceutical composition, independently: - ketoconazole or a pharmaceutically acceptable salt thereof is in an amount between 720 and 880 mg in the composition, preferably about 800 mg; - clindamycin is in an amount between 90 and 110 mg in the composition, preferably of about 100 mg, or a pharmaceutically acceptable salt thereof is in an amount between 106 and 130 mg in the composition, preferably of about 118 mg, preferably the pharmaceutically acceptable salt is clindamycin phosphate; - lidocaine is in an amount between 90 and 110 mg in the composition, preferably about 100 mg, or a pharmaceutically acceptable salt thereof is in an amount between 103 and 127 mg in the composition, preferably about 115 mg, preferably the pharmaceutically acceptable salt is lidocaine HCl; - if present, the tinidazole or a pharmaceutically acceptable salt thereof is in an amount between 270 and 330 mg in the composition, preferably about 300 mg; - the bioadhesive agent, preferably polycarbophil, is in an amount between 72 and 88 mg in the composition, preferably about 80 mg. The inventors have observed that during the manufacture of the pharmaceutical composition of the invention a pinkish coloration may occur without evidence of decomposition of the active substances. Such staining can be avoided with the presence of an antioxidant. Therefore, in another preferred embodiment, the pharmaceutical composition of the present invention further comprises an antioxidant. In a preferred embodiment, the antioxidant agent included in the pharmaceutical composition of the present invention is selected from alkylated hydroxyaromatic compounds, preferably butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA), propyl gallate, sodium bisulfite and sodium metabisulfite. The antioxidant is preferably at a percentage by weight with respect to the weight of the ovule of about 1%. In a more preferred embodiment, said
antioxidant is BHT (butyl hydroxytoluene). Preferably, the antioxidant is BHT and is in a percentage by weight with respect to the weight of the ovule of about 1%. In another preferred embodiment, the pharmaceutical composition of the present invention further comprises an agent for reducing the viscosity of the final product in the form of a non-ionic surfactant. The non-ionic surfactant is selected from polysorbates, preferably polysorbate 80 or polysorbate 81, polyoxyglycerides, polyoxyethylene stearate, and glycerol monooleate. The non-ionic surfactant is preferably in a percentage by weight with respect to the weight of the ovule of about 7% and 18%. In a preferred embodiment the non-ionic surfactant is polysorbate 80. In another preferred embodiment the non-ionic surfactant is polysorbate 80 and is at a percentage by weight with respect to the weight of the ovule of about 9%-12%, and more preferably at a percentage by weight with respect to the weight of the ovule of about 10%. In another preferred embodiment, the pharmaceutical composition of the present invention further comprises BHT and polysorbate 80. More preferably, BHT is in a percentage by weight with respect to the weight of the ovule of about 1 wt % and polysorbate 80 is in a percentage by weight with respect to the weight of the ovule of about 10 %. In a second aspect, the present invention relates to the pharmaceutical composition, according to the first aspect of the invention in each of its embodiments alone or in combination, for use in the prevention and/or treatment of infectious diseases of the female reproductive system. Alternatively, the present invention relates to the use of the pharmaceutical composition, according to the first aspect of the invention in each of its embodiments alone or in combination, in the manufacture of a medicinal product for the prevention and/or treatment of infectious diseases of the female reproductive system. Alternatively, the present invention relates to a method of preventing and/or treating infectious diseases of the female reproductive system comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, according to the first aspect of the invention in each of its embodiments, alone or in combination. In the context of the present invention “therapeutically effective amount” means an effective amount, at the doses and for the periods of time necessary, to achieve the desired prophylactic/therapeutic result. In the present invention, said desired prophylactic/therapeutic outcome refers to a prophylactic action or a decrease/elimination of symptoms related to the diseases or conditions mentioned herein.
In a preferred embodiment, said disease or condition is selected from bacterial vaginosis, mixed vaginitis, and vaginal candidiasis. In another preferred embodiment, said disease or condition is caused by Gardnerella vaginalis, Mobiluncus spp, or Bacteroides fragilis. In another preferred embodiment, said pharmaceutical composition in the form of ovules is administered in a dosing regimen of three ovules for three consecutive days, one ovule each day. In a third aspect, the present invention relates to a method for manufacturing a pharmaceutical composition, according to the first aspect of the invention in each of its single or combined embodiments, comprising or consisting of: i) preparing a preliminary mixture with the components of the ingredient e), according to the first aspect of the invention, that is, a hard fat together with an emulsifier and an emulsion stabilizer; ii) adding the bioadhesive to the mixture obtained in i); iii) adding to the mixture obtained in ii) of ketoconazole or a pharmaceutically acceptable salt thereof; clindamycin or a pharmaceutically acceptable salt thereof; and lidocaine or a pharmaceutically acceptable salt thereof, in any order and sequentially. In a preferred embodiment, polysorbate 80 is added to the mixture obtained in step i) prior to adding the bioadhesive. In another preferred embodiment, BHT is added to the mixture obtained in step i) prior to adding the bioadhesive. In another preferred embodiment, polysorbate 80 and BHT are added to the mixture obtained in step i) prior to adding the bioadhesive. In another preferred embodiment, in step iii), the active ingredient of tinidazole or a pharmaceutically acceptable salt thereof is also added. In a fourth aspect, the present invention relates to a method for manufacturing an ovule for vaginal administration containing a pharmaceutical composition, according to the first aspect of the invention in each of its embodiments, alone or in combination, comprising or consisting of the steps of:
A) preparation of a pharmaceutical composition according to the third aspect of the invention in each of its embodiments alone or in combination; B) filling the preformed mould with the pharmaceutical composition obtained in step A); C) cooling of the composition. In a preferred embodiment, said method of manufacturing an ovule for vaginal administration containing a pharmaceutical composition, according to the first aspect of the invention in each of its embodiments, alone or in combination, further comprises packaging said ovule in a suitable container. Following are provided a number of examples which are intended to illustrate the present invention and in no way limit the scope thereof, which is set forth by the appended claims. EXAMPLES Example 1 Manufacturing Process of the Composition of the Invention The composition to be manufactured had the following components and quantities based on the dosage unit (one ovule):
Laboratory scale First, the process was developed on a laboratory scale using the pour moulding method, using a glass container with a jacket heated by a water bath. In this vessel, the hard fat was melted and the active ingredients and other excipients were added and dispersed using a mixture with low shear and a homogenizer, and the melt was then poured into a PVC/PE preformed mould. The manufacturing process is described in figure 1.
Pilot and commercial scale After optimization of the temperature, mixing and filling conditions with the laboratory-scale process (for approx.1 kg), the process was scaled to a pilot scale (25 kg) and proposed at a commercial scale (150 kg). Table 1 below shows the experimental parameters of the process: Table 1. Experimental Process Parameters
Example 2 Manufacturing process for the composition of the invention further comprising tinidazole The composition to be manufactured had the following components and quantities based on the dosage unit (one ovule):
Laboratory scale First, the laboratory-scale process was developed with equipment that differs in functionality to the pilot and commercial scales and that, therefore, only allowed defining the temperature range and the order of addition for the mixing process using prior experience. The proposed order and addition temperature were obtained using batches of 320 g to 1,000 g, equivalent to 100 to 312 ovules. This process is shown schematically in Figure 2. The process parameters established at this scale were used to establish a first approximation to develop the process at the pilot scale, which is described below. Pilot scale After defining the working ranges for the temperature and the order of addition at the laboratory scale, the next step was to expand and evaluate the manufacturing process at the pilot scale, with a planned batch size of 25 kg, equivalent to 7,812 ovules. To do this, and using the final formulation, two batches of different size were used to evaluate the critical parameters of the process. A first batch of 10 kg was used to explore the reproducibility of the manufacturing process developed at laboratory scale, before continuing with a batch size of 25 kg.
With the target batch size of 25 kg, critical process parameters for intensive physical properties, such as temperature, were confirmed and, in addition, critical process parameters for extensive properties, such as bulk uniformity, were studied to clearly define whether the laboratory-scale manufacturing process was scalable to pilot-scale batches, or whether changes were needed to meet Critical Quality Attributes (CQA) and to manufacture clinical and registration/stability batches. Pilot scale for 10 kg In the first batch of 10 kg, the main objective was to evaluate the scalability of the process defined in the laboratory and, as such, only the temperatures and order of addition in this process step were studied. The flowchart of the manufacturing process is presented in Figure 2. For this batch size, it was chosen to test the temperature used in successful laboratory- scale tests, since increasing the temperature would, in principle, increase the risk of generation of degradation products, so, according to this, the mixing/homogenization rates and the mixing time were the parameters to be evaluated. The coaxial mixer was maintained at a maximum speed of about 55 rpm, the anchor type mixer was used at a maximum speed of about 30 rpm, and the homogenizer speed was used in the range of 3000 to 4500 rpm. The physical properties at each step of the process were characterized by evaluating that a homogeneous mixture has been obtained, since this is the most obvious criterion for evaluating the suitability of the manufacturing process. The filling process was performed by using the commercial equipment intended for the medicinal product, in which the mass is added to a heated container, mixed and then poured by a filling valve to the gravity preformed moulds: the critical parameters obtained in this step of the processes were the overall temperature and the mixing speed; the temperature in the filling valve, the filling speed and the weight of the ovule were established according to the usual practice and the properties of the product. After filling the moulds of the preformed ovules, four cooling temperatures (8 °C, 10 °C, 12 °C and 15 °C) were tested to evaluate the appearance of the product and the yield of the process after sealing. The experimental parameters of the process are presented in the following Table. Table 2. Experimental Process Parameters for a 10 kg batch
ND: Unavailable No setbacks occurred during the manufacturing process and a homogeneous mixture was obtained at each stage of the process. For the purpose of checking the uniformity of the mixture, samples were taken once the components were added and after the final mixture. Appearance at all stages and in the final mixture was considered acceptable.
It was therefore concluded that the order of addition and process temperature used at the laboratory scale can be used for the pilot scale without the need to optimise the order of addition, since a homogeneous product was obtained. For the next step of the process, a global temperature of 55 °C, a mixing rate of 65 rpm, a filling valve temperature of 57 °C and an ovule weight of 3,200 mg ± 5% were used to evaluate the cooling temperature of the filled preformed ovule modules. The results obtained were that at 15ºC a deformation of the ovule was observed; this behavior was mainly attributed to the lack of solidification of the product in the preformed mould. 10°C was selected as the cooling parameter, because it complied with the specifications and was evaluated even with 2°C variations in this parameter and the product continued to comply with said specifications. When analyzing the uniformity of the ovule content at this cooling temperature, the same uniformity behavior observed previously was found. Pilot scale for 25 kg The same procedure was applied as with the 10 kg batch but adjusting the parameters that depended on the quantity of the batch. The uniformity of the mixture, the appearance, and the uniformity of the ovule were again evaluated without observing significant differences with respect to the 10 kg batch. Example 3. Comparison between the composition of the present invention and vaginal tablets comprising ketoconazole and clindamycin Experimental design A randomized, double-blind, comparative design was used to evaluate the therapeutic efficacy, clinical safety and tolerability of the following medicinal products: • Comparator drug (A): Femisan®3D (Ketoconazole 800 mg + Clindamycin 100 mg) in vaginal tablets from Laboratorios Grossman S.A. • Combination of the invention containing ketoconazole, lidocaine, clindamycin and tinidazole (B): Ketoconazole 800 mg + Tinidazole 300 mg + Clindamycin phosphate equivalent to 100 mg Clindamycin + Lidocaine hydrochloride equivalent to 100 mg Lidocaine in vaginal ovules according to example 2.
• Combination of the invention containing ketoconazole, lidocaine and clindamycin (C): Ketoconazole 800 mg + Clindamycin phosphate equivalent to 100 mg Clindamycin + Lidocaine hydrochloride equivalent to 100 mg Lidocaine in vaginal ovules according to example 1. For the study design, balanced treatment groups were proposed, seeking to have the same number of patients in each arm. The patients were randomly assigned to the sequences of administration of the medicinal products under study. Patients were randomly assigned to any of the three treatment groups on Day 1 (prior to administration of the medicinal product studied), using a computer-generated randomization program, prepared prior to the start of the clinical phase of the study. Randomization maintained a 1:1:1 ratio (combination B: combination C: comparator drug) between treatments. A blinded design was contemplated for the physician evaluating the variables of therapeutic efficacy, clinical safety, and tolerability. To achieve the blinded condition, the medicinal products were handled by a third person, not an evaluator, instructing the patient not to discuss with the treating physician the type of medicinal product used. Study Procedure Day 1 Once the Informed Consent Form was signed, the eligibility of the patients was reviewed according to the inclusion and exclusion criteria. The clinical file was created with an identification sheet, clinical history, Informed Consent Form and official identification copy. To this dossier were added the results of the vaginal culture and the corresponding medical notes. Gynaecological examination was performed by the introduction of a vaginal speculum and visualization of the structures of the genital tract, by the doctor specializing in gynaecology. • A sample was obtained for vaginal culture. • Indication of treatment with the study drugs by a gynaecologist, recorded by means of a medical note.
Once the diagnosis of vaginitis/vaginosis was confirmed by the gynaecologist, the Head of Pharmacy or delegated personnel was asked for the treatment for the patient. Such treatment could not be identified by the treating physician. The corresponding medicinal product was delivered to the patient by the Head of Pharmacy or delegated personnel and in the amount necessary to complete three days of treatment. Once the medicinal product was delivered to the patient, the treating physician gave the corresponding instructions to self-administer a tablet or ovule intravaginally, at night, for three days, as well as the necessary administration technique and hygienic measures. She then made an appointment with the patient for the final follow-up visit. A diary was given to the patient and indications were given for recording the time of application, tolerability and adverse events during treatment, which was given to the treating physician at the follow-up visit. The entire process was recorded in a medical note that was included in the patient's clinical file. Day 10 (+3 days) The patients attended their final follow-up visit, in which the gynaecologist or duly trained study delegate conducted an interrogation aimed at investigating the evolution of their condition, asked about the evolution of their symptoms as well as the presence of adverse events, and the patient’s opinion in relation to the treatment she received to evaluate tolerability, making the corresponding note, which was included in the clinical file. The patient was asked to deliver the containers of the medicinal product that was administered, either empty or with the remaining medicinal product, as evidence of its administration and to control the inventory. Re-dispensing a drug to another patient was not allowed if it was returned, even if the package was delivered intact. Patients were asked to return their diary completed for the period that the study treatment was self-administered. A new vaginal control culture was taken to assess changes relative to the first culture and the completion of their participation in the study was subsequently indicated. In case of therapeutic failure, the patient was provided with the specific treatment, according to the indications of the gynaecologist.
Below is a time chart describing the procedure Table 3. Time chart of the comparative study procedure
Population 81 women were included in the study, according to the criteria of the protocol. The inclusion criteria were: • Women aged 18 years or older. • Clinical picture compatible with vaginitis/vaginosis where one of the following symptoms is the reason for the consultation: o Pruritus
o Vulvar Pain o Vaginal flow o Dyspareunias • Indications for treatment with the study medicinal products according to the criterion of the gynaecologist. • Negative (qualitative in urine) pregnancy test. In case of qualitative test with positive result, a confirmatory quantitative blood test was performed: if the result was negative, the patient was included. With a positive result, the patient was not included in the study. The exclusion criteria were: • Women with a history of hypersensitivity to any of the drugs being studied. • Women with a history of serious conditions such as cancer, HIV infection, or any other situation that, in the opinion of the gynaecologist, represents a risk for the patient or for the study. • Women with mental illness or level of understanding that limits adherence to study procedures and proposed treatment. • Women with a history of alcohol abuse, drug use, or any other condition that is associated with poor acceptance of and/or adherence to treatment and/or indications. • Women who received treatment for the current condition within 10 days prior to the date of inclusion, or who are receiving antibiotics, antifungals, antiparasitics, or systemic steroids. • Women who are in menstrual period. • Pregnant or breastfeeding women. • Women who have received an investigational medicinal product within 30 days prior to the start of the study. • Positive (qualitative in urine) pregnancy test. In case of qualitative test with positive result, confirmatory quantitative blood test was performed: if the result was positive, the patient was excluded. With a negative result, the patient was not excluded from the study. Three treatment groups were formed: - Comparator drug: 27 women - Combination B: 27 women - Combination C: 27 women
Finally, 86 female patients who met the inclusion criteria and none of the exclusion criteria were enrolled in the study. Of these 86 patients, 83 complied with the follow-up period according to the clinical protocol. The distribution of these 83 patients who completed the study was as follows: - Comparator drug: 27 women - Combination B: 28 women - Combination C: 28 women Results obtained As indicated in the time chart, all patients were vaginally cultured at baseline and at the end of the study. During the clinical stage, a total of 36 non-serious adverse events occurred, all recovered at the end of the study and with no sequelae. At the same time, the gynaecological history, the use of contraceptives and risk factors were evaluated to observe the possible incidence in the outcome. Table 4 below shows the efficacy response in the different treatment groups according to the criteria established in the clinical protocol, highlighting healing in the three treatment groups without statistically significant differences. Table 4. Efficacy response in treatment groups
Changes in vulvovaginal symptomatology were evaluated during the treatment period between visit day 1 and visit day 10 of the present study. Pruritus, vulvar pain and vaginal discharge were evaluated, dyspareunia was not evaluated in the absence of sexual activity during treatment. Table 5 shows the significant changes in symptoms between the Day 1 and Day 10 visit in the three treatment groups indicating an improvement in the presence and absence of initial and final vulvovaginal symptomatology. Table 5. Symptom assessment between visit day 1 and day 10 in the three treatment groups
The ease of application of the three products under analysis was also analyzed, with the comparator drug being the most difficult for application. Table 6 below reflects that the exemplified combinations of the invention: combination B (comprising ketoconazole, lidocaine, clindamycin and tinidazole) and combination C (comprising ketoconazole, lidocaine, clindamycin) showed greater ease of application. Figure 3 also shows these same data in the form of bars, where the comparator drug corresponds to bar A; the combination called "combination B" of the invention containing ketoconazole, lidocaine, clindamycin and
tinidazole corresponds to bar B (central bar) and the combination called "combination C" containing ketoconazole, lidocaine, clindamycin corresponds to bar C more to the right. Table 6. Assessment of the ease of application
Conclusions The patients evaluated represent a sample of the population with homogeneous demographic characteristics. The efficacy of the three treatments was shown to be comparable, the comparator and the combinations B and C showed clinical improvement, with the disappearance of the symptoms that determined the admission of the patients in the study. The evaluation through vaginal culture showed that most of the patients presented healing of the initial pathogenic microorganism, with no statistically significant difference between the three treatments. There was a low incidence of non-serious adverse events, with no serious adverse event. All reported events were resolved without sequelae. All treatments were well tolerated by the patients during the application period, with a high level of satisfaction. Based on the ease and tolerance in the application, the patients showed a clear trend for the use of combination B and C vs. the comparator drug.
Claims
CLAIMS 1. Pharmaceutical composition suitable for vaginal administration in ovule form, comprising: a) ketoconazole or a pharmaceutically acceptable salt thereof; b) clindamycin or a pharmaceutically acceptable salt thereof; c) lidocaine or a pharmaceutically acceptable salt thereof; d) a bioadhesive agent; e) a hard fat together with an emulsifier and an emulsion stabilizer.
2. A pharmaceutical composition according to claim 1, comprising the active ingredient tinidazole or a pharmaceutically acceptable salt thereof.
3. Pharmaceutical composition according to any one of the preceding claims, wherein the ketoconazole or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 23 and 27 %.
4. A pharmaceutical composition according to any one of the preceding claims, wherein the clindamycin or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 3 and 4.5 %. 5. A pharmaceutical composition according to any one of the preceding claims, wherein the lidocaine or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 3 and 4.
5 %.
6. The pharmaceutical composition according to any one of claims 2 to 5, wherein the tinidazole or a pharmaceutically acceptable salt thereof is in a percentage by weight with respect to the weight of the ovule between 8.5 and 10.25%.
7. Pharmaceutical composition according to any one of the preceding claims, wherein the bioadhesive agent is selected from polycarbophil, polyacrylates, polyacrylamides, cellulose derivatives selected from hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylpropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carbopol, polyvinyl alcohol and derivatives thereof, hyaluronic acid derivatives, chitosan, dextran, pectin, alginate, or mixtures thereof.
8. Pharmaceutical composition according to claim 7, wherein the bioadhesive agent is polycarbophil.
9. Pharmaceutical composition according to any one of the preceding claims, wherein the bioadhesive agent is in a percentage by weight with respect to the weight of the ovule between 0.5 and 4 %.
10. Pharmaceutical composition according to any one of Claims 1 to 9, wherein the mixture of esters of triglycerides, diglycerides and monoglycerides derived from C10-C18 saturated fatty acids is in a percentage by weight with respect to the weight of the ovule between 40% and 60%.
11. Pharmaceutical composition according to any one of the preceding claims, wherein the ketoconazole or a pharmaceutically acceptable salt thereof is in an amount between 720 and 880 mg in the composition.
12. A pharmaceutical composition according to any one of the preceding claims, wherein the clindamycin or a pharmaceutically acceptable salt thereof is in an amount between 106 and 130 mg in the composition.
13. A pharmaceutical composition according to any one of the preceding claims, wherein the lidocaine or a pharmaceutically acceptable salt thereof is in an amount between 103 and 127 mg in the composition.
14. Pharmaceutical composition according to any one of claims 2 to 13, wherein the tinidazole or a pharmaceutically acceptable salt thereof is in an amount between 270 and 330 mg in the composition.
15. Pharmaceutical composition according to any one of the preceding claims, wherein the bioadhesive agent is in an amount between 72 and 88 mg in the composition.
16. Pharmaceutical composition according to any one of the preceding claims, further comprising an antioxidant.
17. Pharmaceutical composition according to any one of the preceding claims, further comprising a non-ionic surfactant.
18. Pharmaceutical composition according to any one of the preceding claims, for use in the prevention and/or treatment of infectious diseases of the female reproductive system.
19. Pharmaceutical composition according to claim 18 for use in the prevention and/or treatment of a disease or condition selected from bacterial vaginosis, mixed vaginitis and vaginal candidiasis.
20. Pharmaceutical composition for use according to claim 18 or 19, wherein said disease or condition is caused by Gardnerella vaginalis, Mobiluncus spp or Bacteroides fragilis.
21. Pharmaceutical composition for use according to claim 18 to 20, wherein said pharmaceutical composition in the form of ovules is administered in a dosage regimen of three ovules for three consecutive days.
22. Method for manufacturing a pharmaceutical composition according to any one of claims 1 to 17, comprising: i) preparing a preliminary mixture with the components of ingredient e) according to claim 1; ii) adding the bioadhesive to the mixture obtained in i); iii) adding to the mixture obtained in ii) of ketoconazole or a pharmaceutically acceptable salt thereof; clindamycin or a pharmaceutically acceptable salt thereof; and lidocaine or a pharmaceutically acceptable salt thereof, in any order and sequentially.
23. Method for manufacturing of making a pharmaceutical composition according to claim 22, wherein polysorbate 80 is added to the mixture obtained in step i) before the bioadhesive is added.
24. Method for manufacturing a pharmaceutical composition according to claim 22 or 23, wherein BHT is added to the mixture obtained in step i) before the bioadhesive is added.
25.- Method for manufacturing a pharmaceutical composition according to any one of claims 22 to 24, wherein in step iii) also tinidazole or a pharmaceutically acceptable salt thereof is added.
26. Method for manufacturing a pharmaceutical composition according to any one of claims 22 to 25, wherein the bioadhesive is selected from polycarbophil, polyacrylates, polyacrylamides, cellulose derivatives selected from hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxyethylpropyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carbopol, polyvinyl alcohol and derivatives thereof, hyaluronic acid derivatives, chitosan, dextran, pectin, alginate, or mixtures thereof.
27.- Method for manufacturing a pharmaceutical composition according to claim 26, wherein the bioadhesive is polycarbophil.
28.- Method of manufacturing an ovule for vaginal administration containing a pharmaceutical composition, according to any one of claims 1 to 17, comprising the steps of: A) preparing a pharmaceutical composition according to any one of claims 22 to 27; B) filling the preformed mould with the pharmaceutical composition obtained in step A); C) cooling of the composition.
29. Method for manufacturing an ovule according to claim 28, further comprising packaging said ovule in a suitable container.
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MXMX/A/2020/011523 | 2020-10-29 | ||
MX2020011523A MX2020011523A (en) | 2020-10-29 | 2020-10-29 | Pharmaceutical composition suitable for vaginal administration in the form of ovules and use thereof. |
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WO2022091016A1 true WO2022091016A1 (en) | 2022-05-05 |
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PCT/IB2021/060020 WO2022091016A1 (en) | 2020-10-29 | 2021-10-29 | Pharmaceutical composition suitable for vaginal administration in the form of ovules and use thereof |
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CL (1) | CL2023001196A1 (en) |
EC (1) | ECSP23031196A (en) |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3800256A1 (en) * | 1987-01-08 | 1988-07-21 | Squibb & Sons Inc | BIOADHAESIVE SUPPOSITORIES |
DE69619052T2 (en) * | 1995-10-27 | 2002-11-14 | Monteres S R L | Solid, anhydrous, pharmaceutical preparations for vaginal use |
US6495157B1 (en) * | 1999-08-06 | 2002-12-17 | Pharmacia & Upjohn Company | Intravaginal clindamycin ovule composition |
US20030138503A1 (en) * | 2000-06-26 | 2003-07-24 | Staniforth John Nicholas | Topical pharmaceutical formulations and methods of treatment |
CN101584703A (en) * | 2008-05-21 | 2009-11-25 | 杨立新 | Pharmaceutical composition for treating colpitis and preparation method thereof |
KR20130130403A (en) * | 2012-05-22 | 2013-12-02 | 울산대학교 산학협력단 | Composition for treating or reducing poastoperative wound pain in laparoscopic assisted vaginal hysterectomy |
CN103520090B (en) * | 2013-10-11 | 2015-12-09 | 哈尔滨欧替药业有限公司 | Tinidazole vaginal expansible plug and preparation method thereof and detection method |
-
2020
- 2020-10-29 MX MX2020011523A patent/MX2020011523A/en unknown
-
2021
- 2021-10-29 WO PCT/IB2021/060020 patent/WO2022091016A1/en active Application Filing
-
2023
- 2023-04-26 CL CL2023001196A patent/CL2023001196A1/en unknown
- 2023-04-28 EC ECSENADI202331196A patent/ECSP23031196A/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3800256A1 (en) * | 1987-01-08 | 1988-07-21 | Squibb & Sons Inc | BIOADHAESIVE SUPPOSITORIES |
DE69619052T2 (en) * | 1995-10-27 | 2002-11-14 | Monteres S R L | Solid, anhydrous, pharmaceutical preparations for vaginal use |
US6495157B1 (en) * | 1999-08-06 | 2002-12-17 | Pharmacia & Upjohn Company | Intravaginal clindamycin ovule composition |
US20030138503A1 (en) * | 2000-06-26 | 2003-07-24 | Staniforth John Nicholas | Topical pharmaceutical formulations and methods of treatment |
CN101584703A (en) * | 2008-05-21 | 2009-11-25 | 杨立新 | Pharmaceutical composition for treating colpitis and preparation method thereof |
KR20130130403A (en) * | 2012-05-22 | 2013-12-02 | 울산대학교 산학협력단 | Composition for treating or reducing poastoperative wound pain in laparoscopic assisted vaginal hysterectomy |
CN103520090B (en) * | 2013-10-11 | 2015-12-09 | 哈尔滨欧替药业有限公司 | Tinidazole vaginal expansible plug and preparation method thereof and detection method |
Non-Patent Citations (1)
Title |
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PERINATOL REPROD HUM, vol. 24, no. 1, 2010, pages 28 - 35 |
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CL2023001196A1 (en) | 2023-10-20 |
MX2020011523A (en) | 2022-05-02 |
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