WO2014026707A1 - Compositions anti-vaginite à libération et adhérence améliorées - Google Patents

Compositions anti-vaginite à libération et adhérence améliorées Download PDF

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Publication number
WO2014026707A1
WO2014026707A1 PCT/EP2012/065825 EP2012065825W WO2014026707A1 WO 2014026707 A1 WO2014026707 A1 WO 2014026707A1 EP 2012065825 W EP2012065825 W EP 2012065825W WO 2014026707 A1 WO2014026707 A1 WO 2014026707A1
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Prior art keywords
pharmaceutical composition
active agent
composition
poloxamer
vaginal
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PCT/EP2012/065825
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English (en)
Inventor
Koral Embil
Ray Figueroa
Juan Reynold DOMINGUEZ
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Edko Pazarlama Tanitim Ticaret Limited Sirketi
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Priority to PCT/EP2012/065825 priority Critical patent/WO2014026707A1/fr
Publication of WO2014026707A1 publication Critical patent/WO2014026707A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K31/41—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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina

Definitions

  • the present invention relates to novel compositions for treatment of vaginal infections.
  • the invention is particularly pertaining to anti-vaginitis compositions with improved release profile and superior adherence to mucosal surface of the vaginal cavity.
  • One of the problems associated with topically applied anti-vaginitis formulations is their short duration of action which, at least in part, is due to their limited retention at the mucosal surface of the vaginal cavity.
  • the mucous coating is particularly susceptible to this problem due to its non-adherent nature and the fact this is rapidly replaced.
  • a major problem in the delivery of drugs to a vaginal cavity is thus maintaining the active drug at the intended site of action for a sufficient period to achieve desired delivery of drug and effective treatment of the infectious condition.
  • Thermoreversible gels have been proposed for use in improving drug delivery to mucosal surfaces. These are liquid at room temperature but form a semi-solid when warmed to body temperature.
  • US 4,188,373 describes the use of Pluronic® poloxamers as thermally gelling polymers.
  • Figure 1 demonstrates a tensile testing to compare the bioadhesion of the formulation of Example 2 (RFA41 1 -15) with Universal Placebo base (RFA41 1 -46).
  • Figure 2a shows drug release (whole) in ⁇ g from the formulation of Example 2 (RFA41 1 -15) through PVDF membrane.
  • Figure 2b shows drug release (diluted 10% with VFS) in ⁇ g from the formulation of Example 2 (RFA41 1 -15) through PVDF membrane.
  • Figure 3a shows drug release (whole) in % release from the formulation of Example 2 (RFA41 1 -15) through PVDF membrane.
  • Figure 3b shows drug release (diluted 10% with VFS) in % release from the formulation of Example 2 (RFA41 1 -15) through PVDF membrane.
  • Figure 4a shows comparative drug release (whole) in ⁇ g from the formulation of Example 2 (RFA41 1 -15) through porcine vaginal tissue.
  • Figure 4b shows comparative drug release (diluted 10% with VFS) in ⁇ g from the formulation of Example 2 (RFA41 1 -15) through porcine vaginal tissue.
  • Figure 5a shows comparative drug release (whole) in % release from the formulation of Example 2 (RFA41 1 -15) through porcine vaginal tissue.
  • Figure 5b shows comparative drug release (diluted 10% with VFS) in % release from the formulation of Example 2 (RFA41 1 -15) through porcine vaginal tissue.
  • Vaginal infections are conditions which are typically caused by mixed infection with Candida albicans, Trichomonas vaginalis and/or Gardnerella sp.
  • the conventional compositions to treat these kind of conditions may be in the form of a pessary, gel, cream, tampon or foam containing the active medicaments, which however suffer of the drawbacks as per mentioned above.
  • one of the objectives of the present invention is to provide anti-vaginitis compositions with thermoreversible gelling properties in order to control the release profile of the active materials.
  • Thermoreversible vehicles as provided within novel compositions according to the present invention following application to an internal or external body surface, undergo a thermoreversible transformation (sol-gel transition) on warming to body temperature thereby improving their retention at the target site.
  • these also have the benefit that they continue to release the active (or actives) for an extended period of time, e.g. up to several days.
  • the number and frequency of applications can be reduced and, in certain cases, a single dose (i.e. once only) treatment will suffice.
  • a further advantage of the pharmaceutical vehicles which have been developed is their ability to tailor or 'tune' the release profile of one or more active agents which may be dispersed or otherwise dissolved therein. This is particularly beneficial where more than one active agent is to be delivered, the different actives having different degrees of solubility in the delivery vehicle. For example, a first active which is only slightly soluble or insoluble in the vehicle may exhibit a rapid or 'burst' release following delivery to the target site, whereas a second active which is more soluble may be released more slowly from the vehicle thereby providing an 'extended' release profile.
  • the vehicles are thus able to function not only as highly effective carriers for active agents, but also as a "depot" from which these can be delivered over extended periods of time.
  • the invention provides a pharmaceutical composition suitable for treating a vaginal condition, said composition comprising:
  • At least one active agent effective against Candida spp. (more preferably Candida albicans), Trichomonas vaginalis and/or Gardnerella vaginalis in an extended release form,
  • compositions in accordance with the invention are generally liquid or semi-solid at ambient temperature (i.e. below about 30 ⁇ , preferably below about 25 ' ⁇ ) which means that these can be applied to the vaginal cavity by conventional means.
  • ambient temperature i.e. below about 30 ⁇ , preferably below about 25 ' ⁇
  • these undergo a sol-gel transition to become viscous (or, in certain cases, more viscous) and to form a non-flowing gel which is capable of delivering the active agent (or active agents) as required for prolonged periods of time.
  • They typically have a sol- gel transition temperature in the range of from about 25 to about 40 °C, preferably from about 25 to about 37 ⁇ €, e.g. around 35°C.
  • the compositions will be viscous liquids, gels or creams at ambient temperature.
  • the degree of viscosity of the compositions forms another important aspect of the present invention because of the objectives of obtaining better retention and bioadherence in the vaginal cavity. While advantageous viscosity values can majorly be attained by virtue of the poloxamers, these can vary widely and will depend on a number of factors such as temperature, pH, bioadhesive component(s), drug loading, etc.
  • the formulations may range from thin liquids to gels; these will typically have viscosities in the range of from 1 ,000 to 500,000 cps at ambient temperature.
  • the viscosity of the formulations will preferably lie in the range of from 80,000 to 200,000 cps, more preferably from 120,000 to 180,000 cps at ambient temperature (e.g. about 25 ' ⁇ ), and in the range 250,000 to 350,000 cps, more preferably from 270,000 to 300,000 cps in vaginal conditions (when measured using a Brookfield Viscometer with a Spindle RV-TF @ 10 rpm for 1 minute).
  • thermoreversible gelling properties of the vehicles and compositions arise from the use of a mixture of poloxamers.
  • Poloxamers are a family of ethylene oxide-propylene oxide block copolymers. They may also be referred to as copolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO) and may be represented by the formula:
  • a and b denote the number of polyethylene oxide or polypropylene oxide units, respectively (i.e. the PEO and PPO segments).
  • the values of a and b will vary depending on the particular grade of poloxamer. In general, each a is about 10 to about 150, preferably from 12 to 101 , and b is about 20 to about 60, preferably from 20 to 56.
  • Ethylene oxide-propylene oxide block copolymers in which the number of polyethylene oxide units is at least about 50% of the number of units in the molecule are preferred for use in the invention, in particular those in which at least about 60%, more preferably at least about 70% of the units are polyethylene oxide. Those having approximately 70% or approximately 80% polyethylene oxide units are especially preferred. Copolymers having an average molecular weight of from about 5,000 to about 15,500, preferably from about 7,000 to about 15,500, yet more preferably from about 7,500 to about 15,000 may be used.
  • Suitable poloxamers for use in the invention are those sold under the tradenames Pluronic® and Lutrol® by BASF. Preferred grades of poloxamers include Poloxamer 407, Poloxamer 188, Poloxamer 124, Poloxamer 237, Poloxamer 338 and mixtures thereof, the specifications of which are detailed below:
  • the poloxamer mixture contains at least two poloxamer polymers, preferably first and second poloxamers.
  • the first poloxamer is selected from Poloxamers 407, 124, 237 and 338. More preferably, the first poloxamer is Poloxamer 407.
  • the second poloxamer is selected from Poloxamers 188, 124, 237 and 338. More preferably, the second poloxamer is Poloxamer 188.
  • Particularly preferred for use in the invention are Poloxamer 407 (available from BASF as Pluronic® F127) and Poloxamer 188 (available from BASF as Pluronic® F68). It is noted that this particular selection of the poloxamers enables to adjust gelling temperature of the composition to around body temperature, and more specifically to around 25-37°C, and most preferably 33-36°C that is ideal in vaginal conditions.
  • first and second poloxamer polymers may be present in a weight ratio of about 6:1 to about 1 :6, more preferably about 2:1 to about 1 :2, e.g. about 1 .5:1 to 1 :1 .5.
  • the total amount of the poloxamer polymers in the vehicles and compositions herein described will generally be in the range of from 1 to 30 wt.%, preferably 20 to 30 wt.%, yet more preferably from 25 to 30 wt.%. It is generally preferred that the total amount will not exceed 30 wt.%.
  • thermoreversible character of the formulation imparts a low viscosity at ambient temperature. Generally, this will thus be in liquid or semi-solid form at ambient temperature and viscous at body temperature. Administration of the formulation in liquid or semi-solid form permits ready and uniform application and distribution on the desired body surface (whether external or internal). On warming to body temperature, the more viscous form permits improved adhesion by limiting the flow of the product.
  • the superior bioadhesion effect of the compositions herein described is achieved using a combination of a fatty acid ester derived from a C 8 to C 22 saturated or unsaturated fatty acid, a glycol ether and a poloxamer mixture.
  • saturated fatty acids which may be used to form the fatty acid esters according to the invention include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid and behenic acid.
  • Unsaturated fatty acids which may be used include palmitoleic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid.
  • Preferred for use in the invention are unsaturated fatty acids, in particular oleic acid.
  • fatty acid esters of polyhydric alcohols are particularly suitable for use in the invention.
  • the hydroxy-containing component may be partially or fully esterified with one or more fatty acid components.
  • Suitable polyhydric alcohols include glycerol, 1 ,2- propanediol and 1 ,3-propanediol.
  • Fatty acid esters formed from polyhydric alcohols may be mono-, di- or tri-valent. Those which comprise a single ester group (i.e. monoesters) are preferred for use according to the invention.
  • the fatty acid components may be the same or different.
  • the polyhydric alcohol is glycerol.
  • fatty acid esters for use in the invention in which the hydroxy-containing component is a polyhydric alcohol are glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate, glyceryl monostearate, glyceryl palmitostearate, and combinations thereof. Particularly preferred is glyceryl monooleate (monoolein).
  • the fatty acid esters for use according the invention are either commercially available or may readily be synthesized using esterification methods well known in the art. Many of the commercially available fatty acid esters are not 100% pure, but tend to contain more than about 80%, typically more than about 90% by weight of the desired fatty acid ester. Other components of the mixtures may include other fatty acid esters and other fatty acids.
  • Glyceryl monooleate is available commercially from various sources, e.g. as Myverol from Kerry Bio-Science. Typically, GMO is supplied as a mixture of glycerides of oleic acid (primarily) and other fatty acids. GMO products having a monoester content of not less than 90% are preferred for use in the invention. Typically, the melting point of the mixture will lie in the range 35 to 37 ⁇ ⁇ and the water content will be less than 1 .0%.
  • the amount of fatty acid ester present in the compositions herein described will generally be in the range of from about 0.1 to about 1 wt.%. More preferably, this will be present in an amount of less than 0.5 wt.%, e.g. in an amount in the range 0.1 to 0.3 wt.%.
  • Suitable glycol ethers for use in the invention include ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, propylene glycol monoethyl ether and dipropylene glycol monoethyl ether. Although a mixture of glycol ethers may be used, a single glycol ether is preferred. Particularly preferred is diethylene glycol monoethyl ether or DGME (also known as ethoxydiglycol). DGME is a pharmaceutical grade transparent liquid (MW 134.2) with unique solubilizing properties. It has the ability not only to solubilize both hydrophilic and hydrophobic materials, but also has penetration enhancing properties. It is marketed as a highly purified liquid under the tradename Transcutol® (Gattefosse s.a., Saint Pres Cedex, France).
  • the amount of glycol ether present in the compositions herein described will generally be in the range of from about 0.05 to about 1 wt.%, preferably from 0.1 to 0.6 wt.%, e.g. about 0.5 wt.%.
  • bioadhesive character of the formulation improves the contact between the active or combination of actives and the body surface. This results in improved retention and increased therapeutic efficacy, thereby reducing the number of applications and the duration of treatment required.
  • the bioadhesive nature of the formulation further limits the flow of the product once in situ.
  • Other natural or synthetic bioadhesive enhancing agents may also be present in the vehicles and compositions herein described in addition to the fatty acid ester and glycol ether components. Examples of such agents are disclosed in WO 2005/087270, the entire content of which is hereby incorporated by reference.
  • poly(carboxylic acid-containing) based polymers such as poly(acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic, methoxyethyl methacrylic, methoxyethoxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters.
  • bioadhesives having this form are available commercially (e.g. from Goodrich) as Polycarbophil, e.g. Noveon AA-1 , Carbomer (Carbopol), e.g. Carbopol EX165, EX214, 434, 910, 934, 934P, 940, 941 , 951 , 971 , 974P, 980, 981 , 1342 and 1382.
  • bioadhesives which may be present include cellulose derivatives such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof, e.g. hydroxypropyl methyl cellulose-E15 (HPMC E-15) or sodium carboxymethyl cellulose-H (Sodium CMC-H). Combinations of two or more cellulose derivatives may also be employed, for example HPMC E-15 and Sodium CMC-H.
  • acacia gums e.g. acacia gums, xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psillium seed gum and gum arabic; clays such as manomorillonite clays, e.g.
  • Veegum attapulgite clay
  • polysaccharides such as dextran, pectin, amylopectin, agar, carrageenan, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch
  • lipophilic formulations containing polysaccharides e.g. Orabase (Bristol Myers Squibb); carbohydrates such as polysubstituted with groups such as sulphate, phosphate, sulphonate or phosphonate, e.g.
  • sucrose octasulphate polypeptides such as casein, gluten, gelatin, fibrin glue
  • polypeptides such as casein, gluten, gelatin, fibrin glue
  • chitosans which are a natural polycationic copolymer consisting of glycosamine and N- actylglucosamine units (e.g.
  • glycosaminoglycans such as hyaluronic acid and its derivatives
  • metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate
  • schleroglucan adhesives containing bismuth oxide or aluminium oxide
  • atherocollagen polyvinyl polymers such as polyvinyl alcohols, polyvinylmethyl ethers, polyvinylpyrrolidone, polycarboxylated vinyl polymers (such as polyacrylic acid); polysiloxanes; polyethers; polyalkylene oxides and glycols, e.g.
  • polyethylene oxides and glycols polyalkoxys and polyacrylamides and derivatives and salts thereof; polyglycolic and polylactic acid homopolymers and copolymers; glycolide and lactide copolymers, e.g. poly-L-(lactide co-glycolide); and polymeric emulsifiers, e.g. PemulenTM polymeric emulsifiers which are high molecular weight, cross-linked copolymers of acrylic acid and a hydrophobic comonomer.
  • polymeric emulsifiers e.g. PemulenTM polymeric emulsifiers which are high molecular weight, cross-linked copolymers of acrylic acid and a hydrophobic comonomer.
  • bioadhesive components these will preferably be selected from: poly(carboxylic acid-containing) based polymers; tragacanth gums; pectin; carrageenan; chitosan; starches; gelatin; hyaluronic acid and derivatives thereof; cellulose derivatives; polyethylene glycols; and polymeric emulsifiers.
  • Poly(carboxylic acid- containing) based polymers such as polyacrylic acid are especially preferred.
  • bioadhesive enhancing agents these will typically be present in the compositions in an amount in the range of from about 0.1 to about 1 wt.%, preferably from 0.1 to 0.5 wt.%, e.g. 0.1 to 0.3 wt.%.
  • preservatives e.g. propylparaben, methylparaben, phenoxyethanol, etc.
  • antioxidants e.g. BHT or BHA
  • pH adjusters e.g. lactic acid, etc.
  • anti-foaming agents e.g. simethicone emulsion
  • Anti-foaming agents may be used to suppress foaming during manufacture of the vehicles and compositions.
  • Particularly suitable for use in this regard are simethicone-containing emulsions, e.g. Simethicone Emulsion, USP which is a non-ionic emulsion containing 30 wt.% simethicone.
  • Solubilizers which may be present include polyvinylpyrrolidones such as plasdone povidone which is a synthetic water-soluble homopolymer of N-vinyl-2-pyrrolidone. It has adhesive, film forming and surface active properties and may be used to enhance the solubility and bioavailability of poorly soluble drugs. In certain cases, it may also function to inhibit crystal growth of an active agent.
  • Inorganic bases such as sodium hydroxide, may be present to act as neutralizing agents. Other compounds suitable for this purpose include potassium hydroxide, triethanolaminine, aminomethyl propanol, trisamino- and tetrahydroxypropyl ethylenediamine. Amino acids such as ⁇ -alanine and lysine can also be used for neutralization and viscosity modification.
  • Sodium hydroxide may also function as a pH adjuster.
  • Dispersing agents which may be present include propylene glycol. This is also known for its emollient, humectant and viscosity modifier properties. Alternatives to propylene glycol include glycerine, sorbitol, butylene glycol, etc.
  • Agents may also be present to function as pH adjusters in the compositions according to the present invention. These aid in retaining the physical and chemical stability of the formulations. Suitable agents include lactic acid which is also particularly beneficial in the context of a product for application to the vaginal mucosa since it can help to mimic the natural vaginal microflora; normal microflora are primarily lactobacilli which produce sufficient lactic acid to acidify vaginal secretions to a pH in the range of 3.5 to 4.5. This value is maintained by the lactobacilli which convert glycogen from exfoliated epithelial cells into lactic acid.
  • the various components of the compositions will generally be admixed in an aqueous system comprising water and a solvent.
  • the solvent should be pharmaceutically acceptable and may be, for example, a Ci -6 alcohol, N-methylpyrrolidone, a glycol or a glycol ether (e.g. propylene glycol, 1 ,3-butylene glycol, dipropylene glycol, diethylene glycol or diethylene glycol monoethyl ether (DGME), or an ether (e.g. diethyl ether). Mixtures of any of these solvents may also be used.
  • a preferred solvent system is that containing water and DGME.
  • compositions herein described may take the form of a liquid, gel, paste, cream, pessary, viscous solution or dispersion.
  • a pharmaceutical composition in the form of a pessary refers to a solid or semi-solid composition having a similar shape as conventional pessaries, but having its own release profile without needing a capsule or plastic body for storing a medicament.
  • these take the form of a liquid, cream or gel which is easy to apply.
  • compositions which are in the form of a cream or viscous liquid e.g. gel).
  • compositions When brought into contact with vaginal area or cavity in vivo, the compositions undergo a phase transition whereby to form a highly effective drug delivery system from which the active agent (or active agents) may be delivered.
  • active agent or active agents
  • these form a depot from which the active or actives may be delivered over an extended period of time.
  • Methods for making the pharmaceutical vehicles and compositions herein described also form part of the invention. These may be made by methods which involve dissolving or dispersing the mixture of poloxamers in a solvent or solvent system at low temperature, e.g. at a temperature below about 25°C, preferably in the range 10-15°C, more preferably in the range 5-10°C.
  • the fatty acid ester may similarly be dissolved or dispersed in a solvent or solvent system prior to admixing with the poloxamer mixture.
  • the glycol ester may then be added to the resulting mixture.
  • the active agent or agents
  • these may be dispersed or dissolved in any of the components of the composition during its preparation.
  • the invention thus provides a method for the preparation of the pharmaceutical compositions herein described, said method comprising forming a mixture comprising: a) a poloxamer mixture containing at least two poloxamers; b) a fatty acid ester derived from a C 8 to C 2 2 saturated or unsaturated fatty acid; c) a glycol ether; and d) at least one biocompatible solvent or solvent system; and dissolving or dispersing at least one active agent effective against Candida spp., Trichomonas vaginalis and/or Gardnerella sp. in the resulting mixture or in at least one of components a) to d) prior to forming said mixture, wherein said active agent(s) is provided in an extended release form .
  • Drugs which are particularly suitable for administration in the compositions of the invention include those within the following classes: anti-infectives, anti-inflammatories, analgesics and anaesthetics. Most preferred are anti-infectives, such as anti-fungals, anti-bacterials, anti-protozoals, etc.
  • compositions herein described that are suitable for the treatment and/or prevention of primary and/or secondary vaginal infections, e.g. mixed vaginal infections such as those associated with acute and recurrent vulvovaginal candidiasis, bacterial vaginosis and trichomonal vaginitis and/or their causative agents.
  • vaginal infections due to group B and D streptococcus and the like, infections due to microorganisms causing vulvitis and vulvovaginitis, and other vaginal infections e.g.
  • atrophic vaginitis may also be usefully treated using the compositions herein described. They also find use in treatment of any associated symptoms such as inflammation, irritation and itching.
  • Vaginitis is most often caused by infection with Candida albicans, Trichomonas vaginalis or Gardnerella sp, either singly or mixed.
  • Certain derivatives of imidazole and nitroimidazole are known to have anti-fungal, anti-bacterial and/or anti-protozoal activity and are often used to treat such conditions. Examples of such drugs include miconazole, clotrimazole and metronidazole.
  • Other types of drugs used in treating vaginal infections include nitrofurfuryl derivatives and various antibiotics.
  • Suitable triazole compounds for use in the invention include terconazole, itraconazole, fluconazole, voriconazole, ravuconazole, posaconazole, hexaconazole and fosfluconazole.
  • terconazole is preferred. It has a particularly broad spectrum of activity and has been shown to be effective against Candida spp., such as Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida pseudotropicalis, Candida stellatoidea and Candida lusitaniae.
  • Terconazole has the further advantage that this does not kill useful lactobacillus microorganisms which form part of a healthy vaginal flora.
  • Anti-fungal compounds suitable for use in the compositions according to the invention include griseofulvin, nystatin, polymixin B, terbinafin and atovaquone (Meprone).
  • Preferred anti-fungals are the imidazoles and pharmaceutically acceptable salts thereof.
  • Suitable fungicidally active imidazole compounds include those active against Candida albicans such as tioconazole, butoconazole, miconazole (e.g.
  • ketoconazole clotrimazole
  • isoconazole seperconazole, econazole, oxiconazole, sulconazole, azanidazole, neticonazole, clomidazole, croconazole, eberconazole, flutrimazole, bifonazole and spectazole.
  • anti-fungal agents which may be used include the echinocandins ( ⁇ -glucan synthase inhibitors) such as Anidulafungin, Caspofungin and Micafungin; allylamines (squalene monooxygenase inhibitors) such as Amorolfine; and benzimidazoles such as thiabendazole.
  • Anti-protozoal agents for use in the compositions of the invention include Paromomycin, Diclazuril (Clinacox) and Letrazuril. Preferred anti-protozoals are those which are known to be active against Trichomonas vaginalis.
  • anti-trichomonal drugs are those which also have anti-bacterial activity, in particular against Gardnerella sp and other pathogens capable of causing vaginitis, e.g. anaerobic bacteria, group B and D streptococcus and/or pathogens causing other primary or secondary vaginal/genital infections.
  • suitable anti-protozoal agents include tinidazole, metronidazole, ornidazole, secnidazole and nimorazole. Tinidazole is particularly preferred.
  • Anti-bacterial agents suitable for use in the invention include those which are active against Gardnerella sp and other pathogens capable of causing vaginitis, e.g.
  • antibiotics such as pivampicillin or clindamycin may usefully be included.
  • suitable anti-bacterial agents include chlorquinaldol, diiodohydroxyquinoline, chloramphenicole and spiramycin (rovamycin).
  • combinations of actives may usefully be used.
  • Particularly preferred for use in the invention is the combination of tinidazole and tioconazole.
  • anaesthetics include aptocaine, bupivacaine, butanilicaine, carticaine, cinchocaine, clibucaine, ethyl parapiperidinoacetyl-aminobenzoate, etidocaine, lidocaine (lignocaine), mepivacaine, oxethazaine, prilocaine, pyrrocaine, ropivacaine, tolycaine, vadocaine, benzocaine, pramoxine and mixtures thereof.
  • suitable anaesthetics include aptocaine, bupivacaine, butanilicaine, carticaine, cinchocaine, clibucaine, ethyl parapiperidinoacetyl-aminobenzoate, etidocaine, lidocaine (lignocaine), mepivacaine, oxethazaine, prilocaine, pyrrocaine, ropivacaine, tolycaine, vadoc
  • the anaesthetic may also be used in the form of a salt, optionally in combination with the base form whereby to achieve extended release of the anaesthetic.
  • the local anaesthetic may be used in an amount of 0.1 -10.0% by weight, preferably 1 .0- 7.0%.
  • the local anaesthetic is preferably lidocaine and may be used in the form of its free base (for example in an amount of 1 .0-3.0%, by weight, preferably about 1 .5%) or a salt such as its hydrochloride, for example 1 .5-4.0% by weight, preferably about 2%.
  • the use of the anaesthetic at these low concentrations results in the compositions being well tolerated.
  • One or more wound healing or skin protectant agents may also be present in the compositions. These may be selected from demulcents, absorbents and emollients and include dimethicone (demulcent), allantoin (absorbent), sucralfate and glycerin (absorbent, demulcent and emollient). Examples of other suitable emollients include cocoa butter, white petrolatum and shark liver oil. Dimethicone has been found to be particularly advantageous in facilitating healing of the vaginal mucosa and is therefore particularly preferred for use in the compositions herein described.
  • an anti-inflammatory and/or anti-pruritic agent such as hydrocortisone, hydrocortisone acetate, methylprednisolone acepronate, betamethasone valerate, or the like, or a weak topical steroid and/or plant-derived anti-inflammatory bioactive such as bisabolol or chamomille.
  • Boric acid and/or lactic acid may also advantageously be included as a further active ingredient.
  • the compositions may also include chlorophyll as a deodorant.
  • Other active components which may be present in any composition intended for application to the vaginal mucosa include estrogens such as estriol, conjugated estrogens and promestrien.
  • Anti-viral agents such as acyclovir, penciclovir, trifluridine, afovirsen, arildone, brivudine, I- docosanol, edoxudine, ganciclovir, idoxuridine, moroxydine, tromantadine and valacyclovir may also be present.
  • microbicides capable of preventing HIV and/or other sexually transmitted infections may also be included in the compositions herein described when these are intended for application to the vaginal mucosa.
  • agents include those which disrupt or otherwise disable HIV, such as surfactants, e.g. menfegol, benzalkonium chloride, docosanol, C31 G (Savvy, nonoxynol-9, sodium cholate), polybiguanides, sodium dodecyl sulphate; antibiotics, e.g. gramicidin, magainins, defensins, protegrins; acidifying agents, e.g.
  • Buffer Gel Acidform, Lactobacillus crispatus
  • oxidising agents e.g. chlorhexidine, povidone iodine, hydrogen peroxide/peroxidase gel
  • antibodies e.g. anti-HIV antibodies
  • long-chain anionic polymers e.g. cellulose acetate phthalate
  • reverse transcriptase inhibitors e.g. UC-781 , loviride, tenofovir
  • agents which block HIV attachment/fusion such as long-chain anionic polymers, e.g.
  • compositions herein described include bromochlorosalicylanilide, methylrosaniline, tribromometacresol, polynoxylin, chlorophetanol, chlorophenesin, ticlatone, sulbentine, ethyl hydroxybenzoate, haloprogin, piroctone olamine, dimazole, tolciclate, sodium thiosulfate, potassium iodide, dapsone, tea tree oil, citronella oil, lemon grass, orange oil, patchouli and lemon myrtle.
  • the compositions will comprise at least first and second actives which are both anti-infectives.
  • the first active may be an antifungal agent, e.g. tioconazole
  • the second active may be an anti-protozoal agent, e.g. tinidazole.
  • the quantity of active may be readily determined by those skilled in the art and will depend on several factors, including the nature of the active(s) and of any other non- active components, the condition to be treated, and the duration of treatment, etc.
  • the actives may be used in amounts of from about 0.01 to 25% by weight, preferably from 1 to 20% by weight, more preferably from 5 to 15% by weight.
  • compositions herein described are adapted for the delivery of a combination of active drug substances which differ in their hydrophobic/hydrophilic properties.
  • Hydrophilic drug substances are those which have a tendency to interact with or be dissolved by water and other polar substances.
  • hydrophobic drug substances tend to be non-polar and prefer other neutral molecules and non-polar solvents; these are therefore poorly miscible or non-soluble in hydrophilic solvents such as water.
  • hydrophilic is generally used to refer to drug substances which have a solubility in water excess of 1 wt.% under ambient conditions. Those drug substances which have a solubility in water of less than 0.1 wt.% under the same conditions are generally considered to be "hydrophobic".
  • compositions may include a first active agent and a second active agent, preferably a first active agent which is provided in a form which is capable of rapid release and a second active agent which is provided in a form which is capable of extended release.
  • first active agent may be in a form adapted for release over a period of from 1 hour to 12 hours and the second active agent may be in a form adapted for release over a period of from 12 hours to 3 days.
  • the release of the second active will continue for a period of from 12 hours to 7 days after the end of the release period of the first active agent.
  • hydrophilic and hydrophobic actives which may be provided in the various formulations herein described are set out in Table 1 . In respect of the vaginal condition given, any of the actives listed may be used alone or, alternatively, in combination. Combinations of hydrophilic and hydrophobic actives are particularly preferred.
  • Sulfanilamide miconazole e.g.
  • butoconazole e.g., butoconazole
  • compositions When used to deliver drugs vaginally, the compositions may be administered using a suitable applicator which may be disposable.
  • a suitable applicator which may be disposable.
  • a syringe may be used to deliver this to the desired body cavity.
  • the syringe may be provided with an appropriate delivery tube or needle.
  • Kits comprising a composition as herein described and an applicator adapted for delivery of the composition to a body cavity and/or body surface form a further aspect of the invention.
  • a device e.g. a syringe pre-loaded with at least one dose of a composition as herein described also forms a further aspect of the invention. Any such device will generally be adapted to deliver one or more doses of the product in a highly uniform manner.
  • a single unit dose may comprise from about 1 to about 10 grams or mis of said composition, preferably from about 2 to about 7 grams or mis, e.g. from about 3 to about 5 grams or mis.
  • suitable delivery devices include those known in the delivery of vaginal creams, such as that used in the product Gynazole-1® (available from Ther-Rx Corporation).
  • compositions may be packaged in any conventional delivery means such as tubes, containers provided with an actuated plunger, etc.
  • these will ideally be packaged with instructions for storage below room temperature, e.g. in a refrigerator. Alternatively, or in addition, these may be housed in external packaging which provides insulation from any external temperature source.
  • thermo-reversible bioadhesive formulation having the following composition was prepared:
  • Plasdone K-1 7 PVP Polyvinylpyrrolidone (Povidone, USP, 3.00
  • Lactic Acid 88 % USP-FCC Lactic acid, 88 % USP-FCC 0.06
  • Phase D of the composition having the following composition was prepared as outlined below:
  • Phase A component was weighed into a suitable sized container and a moderate mechanical mixing was initiated. Heating of the Main Batch to 75-80 °C was initiated. In a separate vessel Phase B (Main Batch) was mixed and heated to 75-80 °C. Once both (A and B) phases were at 75-80 °C, a moderate to vigorous mechanical mixing was applied and very slowly Phase A was added into Phase B. The temperature and mixing conditions were maintained for an additional 20 to 30 minutes (during which time the container was covered in order to avoid loss of water through evaporation). Mixing was maintained at a temperature of 75-80 °C, and very slowly Phase C was added into the Main Batch.
  • Preparation of final composition 1 .
  • the water and propylene glycol components of Phase A were weighed into a suitable sized container and a slow to moderate mechanical mixing was initiated. Cooling of the mixture to 10-15°C, preferably between 5-10° was achieved by placing the container into a water bath (containing ice and water).
  • the Pluronic F 68 NF Prill was slowly sprinkled in with slow to moderate mechanical mixing (avoiding foam formation) until a clear solution was obtained.
  • the Pluronic F127 NF Prill was slowly added and mixed until the solids were in solution and/or a lump-free mixture was obtained.
  • the water component of Phase B was weighed out into a separate container and using a propeller or marine type impeller (to achieve moderate to vigorous mechanical motion) the Noveon AA1 Polycarbophil was sprinkled in. The resulting mixture was mixed until a homogeneous lump-free dispersion was obtained.
  • Phase B dispersion (no lumps nor "fish-eyes" are observed at this point)
  • the mixture was added into the Main Batch (Phase A mixture) with slow to moderate mixing and maintaining the temperature conditions ( " ⁇ ⁇ - ⁇ ⁇ ' ⁇ ). Further mixing was carried out to achieve uniformity.
  • Phase C sodium hydroxide, 20% solution
  • Phase D (0.50 % w/w) was then very slowly added into the Main Batch at 10-15°C and mixed to uniformity.
  • Simethicone emulsion USP.
  • a low mechanical mixing speed was maintained at low temperature conditions, preferably at 5-10°C, until a very uniform mixture was obtained.
  • Phase F The propylene glycol, USP component of Phase F was added to a stainless steel kettle equipped with a side-sweep mixer and Lightning mixer and the Plasdone K-17 component slowly sprinkled. Mixing was continued until a clear solution formed. The remainder of the Phase F ingredients (active components) were then added: Tinidazole Base, Micronized, EP and Tioconazole Base, Micronized, PH Eur. Mixing was maintained at ambient temperature conditions until a homogeneous-off white dispersion was obtained.
  • thermo-reversible bioadhesive composition having the following composition was prepared:
  • Tinidazole base micronized EP Tinidazole base micronized, EP (supplied 9.00
  • Lactic Acid 88% USP-FCC Lactic acid, 88% USP-FCC 0.06
  • the composition was prepared analogously to Example 1 .
  • the resulting product was a smooth, off-white cream having a pH of 6.4 and a viscosity of 160,000 cps (measured using Brookfield Viscosometer/Spindle RV-TF at 10 rpm for 1 min). Viscosity at 35-40°C will be 30 to 60% higher due to thermoreversible effect.
  • the Universal placebo gel had the following composition:
  • step 4 With continuous propeller mixing, the mix from step 4 was added to that from step 1 . Mixing was continued until a homogeneous gel was formed.
  • Tensile testing was performed on Instron 3342 equipped with a 0.1 -10 N load cell.
  • the assembly consisted of a movable measuring probe connected to the load cell and a fixed platform. 600 ⁇ _ of gel sample was loaded on the surface of the measuring probe (2.5 cm diameter). The tissue biopsy was attached to the fixed platform using cyanoacrylate adhesive. The movable probe was lowered in order to bring the gel in contact with the tissue. A preload of 0.5 N was applied for 60 sees following which the movable probe was raised at a constant speed of 0.1 mm/s and the force required to do so was recorded as a digital signal.
  • Figure 1 shows the results from tensile testing to compare the bioadhesion of the formulation of Example 2 to that of the Universal placebo base. Bioadhesion of both formulations was found to be comparable.
  • Example 4 Drug transport kinetics A study was carried out to evaluate the drug transport characteristics of the formulation of Example 2 as a whole and diluted with vaginal fluid stimulant (VFS) using the Static Franz cell system. Materials:
  • PVDF Polyvinylidene-fluoride
  • Tinidazole is a hydrophilic drug with LogP of -0.41 while tioconazole is hydrophobic with a LogP of 4.86.
  • tioconazole is hydrophobic with a LogP of 4.86.
  • Diluting gel with VFS The gel to be studied was diluted 10% with VFS in a 20 mL scintillation vial. The contents were mixed well with a spatula and left overnight for uniform mixing. The diluted gel was then used the next day for the release study.
  • Method for transport studies The transport studies were conducted using a Franz cell system (PermeGear, Riegelsville, PA). The Franz cells were water jacketed and temperature was maintained at 37 ⁇ ⁇ throughout the experiment via a circulating water bath. 1 % lecithin and 5% DMSO in phosphate buffered saline (pH 7.2) was used as the receptor medium. Permeability studies were conducted using both PVDF membrane (0.45 ⁇ ) and porcine vaginal tissue (approx.
  • the volume of the receiver chamber was 15 ml of the PVDF study and 5 ml for the tissue study and was continuously stirred by a magnetic stir bar.
  • 12 mm biopsies were cut and mounted on Franz cells with their epithelial side facing the donor chamber and the connective tissue side facing the receiver chamber. 100 mg of the gel was loaded into each donor chamber. At regular time intervals 400 ⁇ of receptor media was removed from the receiver compartment and replaced with fresh media. Results were adjusted for the dilution of the receiver chamber and analyzed by HPLC. At the end of the study the remaining gel was extracted from the donor chamber and analyzed to obtain the mass balance.
  • Figures 2a, 2b, 3a and 3b show the comparative drug release (whole and diluted with 10% VFS) from the formulation through PVDF membrane.
  • Figures 4a, 4b, 5a and 5b show the comparative drug release (whole and diluted with 10% VFS) from the formulation through porcine vaginal tissue.
  • Release kinetics through PVDF membrane The formulation according to the invention shows a burst release for tinidazole and an extended release for tioconazole. The release kinetics profile did not change much with 10% dilution with VFS.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à traiter la vaginite et qui comprend : au moins un agent actif efficace contre Candida spp., Trichomonas vaginalis et/ou Gardnerella vaginalis sous une forme à libération prolongée ; un mélange de poloxamères contenant au moins deux poloxamères ; un ester d'acide gras dérivé d'un acide gras saturé ou insaturé en C8 à C22 ; et un éther glycolique. La nouvelle composition décrite est fortement bioadhésive et présente un temps de rétention amélioré, spécifiquement dans des conditions vaginales.
PCT/EP2012/065825 2012-08-13 2012-08-13 Compositions anti-vaginite à libération et adhérence améliorées WO2014026707A1 (fr)

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WO2017120492A1 (fr) * 2016-01-07 2017-07-13 Viramal Limited Compositions de gel pour administration transdermique permettant de maximiser la concentration de médicaments au niveau du stratum corneum et du sérum, et méthodes d'utilisation de ces dernières
CN111386129A (zh) * 2017-06-22 2020-07-07 维拉玛尔有限公司 用于药物递送的组合物及其使用方法
CN112957315A (zh) * 2021-02-18 2021-06-15 博凯药业有限公司 一种私护凝胶、制备方法及应用
US11166968B2 (en) 2015-09-29 2021-11-09 Kimberly-Clark Worldwide, Inc. Synergistic composition for maintenance of healthy balance of microflora
US11446236B2 (en) * 2015-08-05 2022-09-20 Cmpd Licensing, Llc Topical antimicrobial compositions and methods of formulating the same
US11596601B2 (en) 2018-10-26 2023-03-07 Viramal Limited Mucoadhesive gel composition
US11684567B2 (en) 2015-08-05 2023-06-27 Cmpd Licensing, Llc Compositions and methods for treating an infection
WO2023150345A1 (fr) * 2022-02-04 2023-08-10 Intact Therapeutics, Inc. Formulations pharmaceutiques de mésalamine et leurs méthodes d'utilisation
US11793783B2 (en) 2015-08-05 2023-10-24 Cmpd Licensing, Llc Compositions and methods for treating an infection
US12016953B2 (en) 2018-11-30 2024-06-25 Viramal Limited Method of preparing a gelling agent, the gelling agent obtained thereby, and the use of said gelling agent
US12029748B2 (en) 2017-02-28 2024-07-09 Kimberly-Clark Worldwide, Inc. Synergistic composition for maintenance of healthy balance of microflora

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US12029812B2 (en) 2015-08-05 2024-07-09 Cmpd Licensing, Llc Compositions and methods for treating an infection
US11446236B2 (en) * 2015-08-05 2022-09-20 Cmpd Licensing, Llc Topical antimicrobial compositions and methods of formulating the same
US11684567B2 (en) 2015-08-05 2023-06-27 Cmpd Licensing, Llc Compositions and methods for treating an infection
US11793783B2 (en) 2015-08-05 2023-10-24 Cmpd Licensing, Llc Compositions and methods for treating an infection
US11166968B2 (en) 2015-09-29 2021-11-09 Kimberly-Clark Worldwide, Inc. Synergistic composition for maintenance of healthy balance of microflora
CN108712901A (zh) * 2016-01-07 2018-10-26 维拉玛尔有限公司 用于经皮递送以使角质层和血清中的药物浓度最大化的凝胶组合物及其使用方法
WO2017120492A1 (fr) * 2016-01-07 2017-07-13 Viramal Limited Compositions de gel pour administration transdermique permettant de maximiser la concentration de médicaments au niveau du stratum corneum et du sérum, et méthodes d'utilisation de ces dernières
US12029748B2 (en) 2017-02-28 2024-07-09 Kimberly-Clark Worldwide, Inc. Synergistic composition for maintenance of healthy balance of microflora
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US11596601B2 (en) 2018-10-26 2023-03-07 Viramal Limited Mucoadhesive gel composition
US12016953B2 (en) 2018-11-30 2024-06-25 Viramal Limited Method of preparing a gelling agent, the gelling agent obtained thereby, and the use of said gelling agent
CN112957315B (zh) * 2021-02-18 2023-01-31 博凯药业有限公司 一种私护凝胶、制备方法及应用
CN112957315A (zh) * 2021-02-18 2021-06-15 博凯药业有限公司 一种私护凝胶、制备方法及应用
WO2023150345A1 (fr) * 2022-02-04 2023-08-10 Intact Therapeutics, Inc. Formulations pharmaceutiques de mésalamine et leurs méthodes d'utilisation

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