EP4370096A1 - Pharmaceutical composition in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions - Google Patents

Pharmaceutical composition in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions

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Publication number
EP4370096A1
EP4370096A1 EP22783381.1A EP22783381A EP4370096A1 EP 4370096 A1 EP4370096 A1 EP 4370096A1 EP 22783381 A EP22783381 A EP 22783381A EP 4370096 A1 EP4370096 A1 EP 4370096A1
Authority
EP
European Patent Office
Prior art keywords
mass
parts
polysaccharide
phase
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22783381.1A
Other languages
German (de)
French (fr)
Inventor
Katarzyna Malolepsza-Jarmolowska
Michal SMOLENSKI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Uniwersytet Medyczny Im Piastow Slaskich We Wroclawiu
Original Assignee
Uniwersytet Medyczny Im Piastow Slaskich We Wroclawiu
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Publication of EP4370096A1 publication Critical patent/EP4370096A1/en
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • compositions in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions
  • the object of the invention is a pharmaceutical composition based on rapeseed oil and poloxamer 188, a multiphase composition, and methods of preparation of these compositions.
  • the compositions are intended for topical use in gynecology and obstetrics as an antibacterial, antifungal and antiprotozoal agent. Additionally, it can be a vehicle for the vaginal administration of systemic drugs (omitting the effect of passage through the hepatic circulation).
  • the natural defense mechanism of the reproductive system is the flora that inhabits the inner environment of the vagina.
  • the most numerous group are bacteria of the genus Lactobacillus spp. and fungi of the genus Candida albicans.
  • the balance between the bacterial and fungal flora ensures homeostasis.
  • vaginal biocenosis against the overgrowth of other elements present in physiological conditions in the vagina, such as: Staphylococcus aureus, Streptococcus agalactiae (group B), Enterococcus species, Gardnerella vaginalis, Escherichia coli, Bacteroidesfragilis and Mobiluncus.
  • group B Streptococcus agalactiae
  • Enterococcus species Enterococcus species
  • Gardnerella vaginalis Enterococcus species
  • Gardnerella vaginalis Escherichia coli
  • Bacteroidesfragilis and Mobiluncus.
  • An additional difficulty in the conducted therapies is the anatomical and physiological conditions of the female vagina. The drug is kept in the vagina only in the supine position of the patient.
  • the adherence of the drug is hindered by the presence of vaginal secretions in this organ in a different volume depending on the period of the woman's menstrual cycle, as well as
  • vaginal medicine available on the market are tablets, globules and capsules in sizes adapted to patients who have reached puberty. These forms are not adapted to be applied to little girls.
  • vaginal tablets (often with sharp edges) are not easy to divide into the correct dose portion. Globules, like tablets, are a problem when dividing, crumbling and preventing application.
  • the Polish patent application P.383267 discloses a composition containing lactic acid and a selected alkaline polymer or a mixture of such polymers in a stoichiometric ratio ranging from 1:1 to 8:1, and the vehicle for these substances is micronized Poloxamer 407 in an amount of 90 to 95 parts by mass, calculated in relation to the sum of ingredients, or an aqueous solution of Poloxamer407 with a concentration of 15 to 35 parts by mass, calculated in relation to the sum of ingredients. Both in powdered and semi-liquid form, it is preferred that the composition additionally comprises known anti-inflammatory, antibacterial, antifungal and antiprotozoal agents.
  • PAT.210178B1 describes a method of producing oil-in-water (o/w) and water-in-oil (w/o) microemulsion systems, based on paraffin oil and rapeseed oil, stabilized with selected surfactants, intended for use in agrochemical, pharmaceutical and cosmetic industries. It consists in mixing four ingredients: surfactant, co-surfactant, oil and water, resulting in new transparent oil-in-water (o/w) or water-in-oil (w/o) microemulsion systems.
  • a surfactant selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene (30) 2,4,7,9-tetramethyl-5-decin-4,7-diol, polyoxyethylene castor oil or ethoxylated 17-carbon fatty alcohol is mixed with a co-surfactant in form of n-butyl or isopropyl alcohol in a weight ratio of 1:4 or 4:1 or 8:1 until a clear, homogeneous mixture is obtained, and then to the thus obtained emulsifier, used in a proportion of 1 to 98% by weight, from 1 to 65% by weight of rapeseed or paraffin oil constituting the oily phase and from 1 to 98% by weight of demineralized water are added and all ingredients are mixed until a homogeneous mixture is obtained.
  • the publication KR20040028336 discloses a thermal antibacterial gel administered vaginally, containing 30-35% by weight of poloxamer, 0.2-1% by weight of polycarbophil and 0.9-l.l% by weight of clotrimazole, where the poloxamer is a mixture of Poloxamer 188 and Poloxamer 407 in a 1, 1-1,5 weight ratio.
  • the technical problem faced by the invention is to provide a nanosized liquid vehicle for clotrimazole, which could be a stand-alone pharmaceutical formulation for use in gynecology and could also be used to obtain other drug forms, a gel.
  • the vehicle should also enable other active substances, i.e. lipophilic or hydrophilic, with different affinities to be incorporated into the vehicle.
  • the gel obtained on the basis of the said emulsion should be characterized by increased adhesion to the vaginal walls.
  • the vehicle, whether used alone or as a gel should also not lead to inflammation and have a neutral pH for the vaginal environment, and be suitable for use in pediatric patients.
  • Another problem faced by the invention is the method of obtaining the vehicle or its gel form.
  • the first object of the invention is a pharmaceutical composition in the form of a vegetable oil based nanoemulsion, characterized in that it comprises a vegetable oil, which is rapeseed oil, in an amount of 10 to 60 parts by mass of rapeseed oil, 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, from 40 to 60 parts by mass of purified water, from 1 to 12 parts by mass of sorbitan monooleate, from 5 to 20 parts by mass of polyol, from 0.10 to 0.50 parts by mass of lactic acid, from 0.5 to 5.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 50 nm to 70 nm.
  • rapeseed oil in an amount of 10 to 60 parts by mass of rapeseed oil, 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, from 40 to 60 parts by mass of purified water, from 1 to 12 parts by
  • the nanoemulsion is a vehicle for the active ingredient - clotrimazole.
  • Formulations with a vehicle size of less than 500 nm enable more efficient transport of the active substance through the layers of vaginal secretions and vaginal mucosa and increase the effectiveness of the therapy. This allows to obtain a higher effectiveness of the therapy while using smaller doses of active substances compared to conventional forms with a vehicle size of more than 1 pm.
  • they allow for the administration of drugs that exert not only local (like conventional emulsions) but also systemic effects.
  • nanoemulsions exhibit the kinetics of the sustained release of active substances, which allows to reduce the frequency of drug administration.
  • the composition comprises rapeseed oil in an amount of 20 parts by mass, 15 to 20 parts by mass of ethylene oxide/propylene oxide block copolymer P188, 45 to 55 parts by mass of purified water, 1 to 5 parts by mass of sorbitan monooleate, 5 to 10 parts by mass of polyol, from 0.40 to 0.50 parts by mass of lactic acid, from 0.5 to 2.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 55 nm to 65 nm.
  • the composition comprises rapeseed oil in an amount of 20 parts by mass, from 18 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, 51.83 parts by mass of purified water, 4 parts by mass of sorbitan monooleate, from 5 to 7 parts by mass of polyol, 0.50 part by mass of lactic acid, from 0.5 part by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 58 nm to 64 nm.
  • the composition comprises a polyol in an amount of 6.67 parts by mass of the composition, wherein the polyol is selected from the group comprising 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
  • the oil phase droplet polydispersity index is from 0.148 to 0.175.
  • the second object of the invention is a multiphase composition based on a nanoemulsion of vegetable oil according to the first object of the invention, characterized in that it contains a polysaccharide phase, preferably a polysaccharide, in an amount of 10 to 50 parts by mass and a nanoemulsion according to the first object of the invention in an amount of 50 to 90 parts by mass, wherein the multiphase composition is in the form of a nanoemulgel, wherein the multiphase composition has a dynamic viscosity from 220 mPa ⁇ s to 580 mPa ⁇ s.
  • the multiphase composition comprises a nanoemulsion in an amount of 85 and 15 parts polysaccharide.
  • the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide, preferably the ratio of nanoemulsion to gel phase containing polysaccharide is 50 parts by mass of nanoemulsion to 50 parts by mass of a gel phase containing the polysaccharide.
  • the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 0.1 to 10 parts by mass, preferably 2 to 10 parts by mass.
  • the polysaccharide-containing gel phase comprises a polysaccharide in an amount of 2 parts by mass and water in an amount of 98 parts by mass.
  • the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide and optionally containing hydrophilizing substances, preferably the ratio of the nanoemulsion to the gel phase containing the polysaccharide is 80 parts by mass of a nanoemulsion to 20 parts by mass of a gel phase containing the polysaccharide and optionally hydrophilizing substances.
  • the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 10 parts by mass and water up to 100 parts by mass, wherein optionally gel phase containing the polysaccharide comprises hydrophilizing substances in an amount of 5-30 parts by mass, preferably 30 parts by mass.
  • the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200.
  • the polysaccharide phase is selected from the group comprising a gel phase with a polysaccharide or a polysaccharide.
  • Another object of the invention is a method for the preparation of a pharmaceutical composition in the form of a nanoemulsion based on vegetable oil, comprising the steps of: a) preparation of the lipophilic phase, b) introduction of the active substance, c) preparation of the hydrophilic phase, d) preparation of macroemulsions, e) high-speed homogenization, f) high pressure homogenization, characterized in that in step a) 10 to 60 parts by mass of rapeseed oil are mixed with 5 to 20 parts by mass of polyol and from 1 to 12 parts by mass of sorbitan monooleate in 60 minutes, and in step b) into the lipophilic phase from step a) the active ingredient is introduced in an amount of 0.5 to 5.0 parts by mass, preferably clotrimazole, and the mixture is cooled for 20 hours, and in step c) the hydrophilic phase is prepared by dissolving 0.10 to 0.50 parts by mass of lactic acid in purified water in an amount of 45 to 55 parts by mass and
  • step a) mixing is carried out at 20% of the stirrer power.
  • step b mixing is carried out at 15% of the stirrer power.
  • step b) the mixture is heated for 30 minutes until the active substance is completely dissolved.
  • step d) the hydrophilic phase is introduced into the lipophilic phase mixed at a rotational speed of 400 rpm to 1000 rpm.
  • step f) is carried out twice.
  • Another object of the invention is a method for the preparation of a multiphase composition based on nanoemulsion of vegetable oil according to the first subject of the invention, characterized in that the nanoemulsion according to the first object of the invention in an amount of 50 to 90 parts by mass is combined with a polysaccharide phase, preferably with a polysaccharide, in an amount of 10 up to 50 parts by mass.
  • the nanoemulsion in an amount of 90 parts by mass is combined with the polysaccharide phase in an amount of 10 parts by mass of the polysaccharide.
  • the nanoemulsion in an amount of 50 to 80 parts by mass is combined with the polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide, preferably the ratio of the nanoemulsion to the gel phase comprising the polysaccharide is 50 parts by mass of the emulsion to 50 parts by mass of the gel phase comprising the polysaccharide.
  • the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 0.1 to 10 parts by mass, preferably 2 to 10 parts by mass.
  • the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 2 parts by mass and an amount of water in an amount of 98 parts by mass.
  • the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of from 20 to 50 parts by mass, if the polysaccharide phase is a gel phase comprising the polysaccharide and optionally comprising hydrophilizing substances, preferably the ratio of the nanoemulsion to the gel phase comprising the polysaccharide is 80 parts by mass of a nanoemulsion to 20 parts by mass of a gel phase comprising the polysaccharide and optionally hydrophilizing substances.
  • the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 10 parts by mass and water up to 100 parts by mass, wherein optionally the polysaccharide-containing gel phase comprises hydrophilizing substances in an amount of 5-30 parts by mass, preferably 30 parts by mass.
  • the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200.
  • the polysaccharide phase is selected from the group comprising: a gel phase with a polysaccharide or a polysaccharide.
  • the polysaccharide phase is understood to mean the emulsion component of the gel, making it possible to obtain a multi-phase composition in the form of a gel.
  • a component may be a pure polysaccharide (gelling agent) added directly to a nanoemulsion, e.g. Gellan gum, or a mixture containing it (gel), the mixture being prepared in advance (gel phase) and combined with a vehicle.
  • the gel phase may be a simple mixture, e.g. a gelling agent and a solvent, as well as a multi-component mixture, i.e. containing more than two components.
  • the polysaccharide phase within the meaning of the present invention is a polysaccharide or a gel phase containing the polysaccharide.
  • the invention relates to a pharmaceutical composition for the treatment of inflammation with a multiphase drug form (based on nanotechnology).
  • the purpose of multiphase is to create the possibility of introducing medicinal substances with different physicochemical properties.
  • a multiphase composition with a hydrophilic-lipophilic character makes it possible to incorporate drugs with hydrophilic and lipophilic properties in one drug form.
  • the nanoemulsion allows the introduction of substances that pass through the vaginal mucosa in order to achieve a general effect.
  • the multiphase form is constructed on the basis of a polysaccharide, which has adhesive properties with respect to the vaginal mucosa. The adhesiveness of this form of the drug allows it to remain on the vaginal mucosa longer than is possible by traditional treatments.
  • the presented form of the drug is characterized by a pH in the physiological range for the vaginal environment (3.5-4.5), conditioning the development of the physiological bacterial flora, preventing vaginal inflammation.
  • An additional advantage of this form of the drug is the possibility of using it in pediatric patients.
  • the nanoemulgels according to the invention ensure easy application without irritating the mucous membranes.
  • the nanomulgel can be in the form of suppositories or globules. This makes it possible to prepare further single-dose forms.
  • the form of suppositories and globules have a gel consistency and are easy to apply and can be divided into smaller portions, e.g. by cutting. The soft consistency of gel suppositories and globules does not irritate the mucous membranes during application.
  • nanoemulgel has the following properties (in parentheses there is information on which form the properties are based on):
  • Poloxamer 188 (P188 block copolymer of ethylene oxide and propylene oxide) 18.0 parts by mass, Lactic acid 0.5 parts by mass,
  • Span 80 (sorbitan monooleate) 2.0 parts by mass Clotrimazole 1.0 parts by mass.
  • Span 80 and PEG-200 are added to rapeseed oil. Then, the previously obtained oil phase was stirred with a magnetic stirrer at 20% power for 60 minutes. The active ingredient is introduced into the heated mixture of the lipophilic phase with constant stirring. Heating is maintained for 30 minutes until the active substance is completely dissolved. The solution was allowed to cool and continued to be stirred at 15% power for 20 hours. Lactic acid was added to the weighed amount of distilled water according to FP XII. The resulting lactic acid aqueous solution was stirred with a magnetic stirrer at 18% power. Poloxamer 188 flakes were then added with continued mixing.
  • the obtained form is a nanoemulsion.
  • Span 80 and 1,2-propylene glycol are added to rapeseed oil.
  • the previously obtained oil phase was then stirred by means of a magnetic stirrer at 20% power for 60 minutes.
  • the active substance is introduced into the heated mixture of the lipophilic phase with constant stirring. Heating is maintained for 30 minutes until the active substance was completely dissolved.
  • the solution was allowed to cool and continued to be stirred at 15% power for 20 hours.
  • Lactic acid was added to a weighed amount of water distilled according to Pharmacopoeia XII.
  • the resulting lactic acid aqueous solution was stirred with a magnetic stirrer at 18% power. Poloxamer 188 flakes were then added with continued stirring.
  • the solution was allowed to stabilize under continuous stirring at 12% power for 30 minutes.
  • the hydrophilic phase was then introduced into the lipophilic phase and allowed to stabilize with continuous stirring at 1000 rpm for 20 hours.
  • High shear homogenization and high pressure homogenization were applied sequentially, each time cooling the mixture to room temperature.
  • the obtained form is a nanoemulsion.
  • Example III Composition ingredients:
  • the multiphase composition is prepared as in Example I or II. Then a gel is prepared (gel phase): Gellan rubber 2.0 parts by mass,
  • Purified water 98.0 parts by mass. Gellan gum is combined with purified water at 90 degrees C. Then the mixture is stirred with a magnetic stirrer at 40% power for 80 minutes until a homogeneous gel is obtained. The resulting gel is cooled to room temperature.
  • composition according to Examples 1 or 2 is combined with the obtained gel using a high shear homogenizer at room temperature, obtaining a composition consisting of 20 to 50 parts by mass of a gel and 50 to 80 parts by mass of a nanoemulsion. It is preferable to combine the nanoemulsion in an amount of 50 parts by mass with 50 parts by mass of the resulting gel, to obtain a formulation with a dynamic viscosity from 220 mPa.s to 260 mPa.s.
  • Clotrimazole - a substance with antifungal activity - was used as a model substance in the research. The results of laboratory tests have produced very favorable results. Both the particle size of the nanoemulsion containing the drug substance and the other parameters characterizing this form of the drug turned out to meet the high requirements for application and therapy.
  • nanoemulgel emulgel
  • suppositories globules.
  • the emulsion can be a vehicle for medicinal substances with various effects, e.g. anti-inflammatory, analgesic, etc. it can be applied to other body cavities covered with mucosa. Enteral use - inflammation of the large intestine. They can be used rectally: enemas or rectal enemas, in the form of suppositories, similar to vaginal use.
  • the presented nanoemulsions can be used in laryngology as nasal, sinus irrigation and ear preparations. They can also be used as nanoemulsion eye drops.
  • Example IV A method of making a pharmaceutical multiphase (nano) composition for vaginal use.
  • composition is made of rapeseed oil, water, poloxamer 188, PEG-200 or propylene glycol, lactic acid, clotrimazole with the addition of Span 80.
  • a) Preparation of the lipophilic phase Weighed rapeseed oil is mixed with Span 80 and PEG-200 or 1,2-propylene glycol. The oil phase is then subjected to magnetic stirring at 20% power for 60 minutes. Odwazony olej rzepakowy miesza si ⁇ ze Spanem 80 i PEG-200 tub glikolem 1,2-propylenowym.
  • Introduction of active substance if prescribed)
  • the active ingredient is weighed to the nearest 0.001 g (clotrimazole).
  • the previously prepared lipophilic phase was preheated (if necessary) to 50 degrees C.
  • the active substance was added to the heated mixture under constant stirring. Heating was maintained for 30 minutes until the active ingredient was completely dissolved.
  • the solution was allowed to cool and continued to be stirred at 15% power for 20 hours.
  • the lactic acid solution was added to the weighed amount of water distilled according to Pharmacopoeia XII with an accuracy of 5.0 mg (resulting from the dropwise introduction of the acid solution).
  • the resulting lactic acid aqueous solution was stirred with a magnetic stirrer at 18% power. Then, weighed down to 0.01 g of Poloxamer 188 flakes were added with continuous mixing. After the polymer was completely dissolved, the solution was allowed to stabilize under continuous stirring at 12% power for 30 minutes in order to prevent foaming of the hydrophilic phase. d) Preparation of macroemulsions
  • the previously obtained lipophilic phase was stirred by means of a magnetic stirrer at 1000 r pm.
  • the previously prepared hydrophilic phase was introduced into the lipophilic phase dropwise, keepingthe maximum possible mixing speed in the range of 400-1000 rpm (the change of the mixing speed resulted from the change of the viscosity of the obtained system).
  • the macroemulsion was allowed to stabilize the system under continuous stirring at 1000 rpm for 20 hours.
  • the formulations obtained in the process of high-speed homogenization were subjected to the high- pressure homogenization process in the GEA Niro Soavi Panda Plus homogenizer.
  • the emulsion was homogenized at 1200-1300 bar for 60 seconds. Homogenization was carried out twice. The sample was then cooled to room temperature. Two cycles of homogenization were performed for each emulsion. After the completion of the two-stage high-pressure homogenization process, the obtained composition has the character of a nanoemulsion.
  • composition may be a standalone pharmaceutical nanoemulsion for vaginal use.
  • Example V A method of making a polysaccharide-based multiphase pharmaceutical nanocomposition for vaginal use.
  • the essence of the invention consists in the possibility of additional enrichment of the nanoemulsion composition with a polysaccharide forming a hydrophilic nanogel.
  • a pharmaceutical nanoemulsion with a gel (gel phase containing polysaccharide) based on a polysaccharide (Gellan gum) creates a new form - nanoemulgel.
  • the new form has the property of high adhesiveness to the mucosa, affecting the longer duration of this form of the drug in the vagina.
  • the multiphase composition was prepared as set out in Example 4. Then a gel form is prepared.
  • the polysaccharide Gellan gum
  • water purified according to Pharmacopeia XII at room temperature with the addition of hydrophilizing substances such as: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200, obtaining the following proportions: from 0.1 to 10 parts of polysaccharide, preferably 10 parts, 5-30 parts of hydrophilizing substances, preferably 30 parts by mass, made up with water, Water is a complementary component of up to 100 parts by mass and its content depends on the polyol content. Then the mixture is subjected to magnetic stirring at 30- 40% power for a period of 60-80 minutes until a homogeneous gel is obtained.
  • hydrophilizing substances such as: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200
  • the nanoemulsion obtained according to examples 1, 2 or the method of example 4 in an amount of 50 to 80 parts by mass is combined with the gel obtained according to this example in an amount of 20 to 50 parts of the obtained gel using a high-speed homogenizer until a homogeneous nanoemulgel is obtained.
  • the most advantageous properties are obtained when this ratio is 80:20, obtaining a formulation with a dynamic viscosity from 480 mPa » s to 510 mPa*s.
  • the form of the emulgel increases the stability of the emulsion and does not significantly affect the optical properties of the formulation, therefore it should not have a significant effect on the size of the oil droplets.
  • Example VI A method of making a pharmaceutical polysaccharide-based multiphase (nano) composition for vaginal use.
  • the multiphase composition was prepared as described in Example IV.
  • the nanoemulsion is then transformed into a nanoemulgel by adding a polysaccharide (polysaccharide phase) directly, preferably Gellan gum, thereto.
  • a polysaccharide polysaccharide phase
  • the polysaccharide - Gellan gum is added directly to the nanoemulsion obtained according to example I, II or IV in a weight ratio of 85-90 parts of nanoemulsions to 10-15 parts of Gellan gum.
  • the mixture is stirred by means of a magnetic stirrer/mechanical stirrer for a period of 60-120 minutes.
  • the obtained nanoemulgel is cooled to room temperature, to obtain a formulation with a dynamic viscosity from 550 mPa»sto 580 mPa.s.
  • Haemophilus influenzae An underrated cause of vulvovaginitis in young girls. J. Clin. Pathol. 1997, 50, 765-768, doi:10.1136/jcp.50.9.765. Bumbuliene, Z.; Venclaviciute, K.; Ramasauskaite, D.; Arlauskiene, A.; Bumbul, E.; Drasutiene, G. Microbiological findings of vulvovaginitis in prepubertal girls. Postgrad. Med. J. 2014, 90, 8-12, doi:10.1136/postgradmedj-2013-131959. Yilmaz, A.E.; Celik, N.; Soylu, G.; Donmez, A.; Yuksel, C.
  • BMC Pregnancy Childbirth 2019, 19, 1-10, doi:10.1186/sl2884-019-2488-z. Bachhav, Y.G.; Patravale, V.B.
  • Microemulsion-based vaginal gel of clotrimazole Formulation, in vitro evaluation, and stability studies.
  • Biopharmaceutical profile of a clotrimazole nanoemulsion Evaluation on skin and mucosae as anticandidal agent. Int. J. Pharm.

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Abstract

The first object of the invention is a nanoemulsion composition based on vegetable oil, characterized in that it comprises vegetable oil, which is rapeseed oil, in an amount of 10 to 60 parts by mass of rapeseed oil, 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and oxide propylene, from 40 to 60 parts by mass of purified water, from 1 to 12 parts by mass of sorbitan monooleate, from 5 to 20 parts by mass of polyol, from 0.10 to 0.50 parts by mass of lactic acid, from 0.5 to 5.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 50 nm to 70 nm. The second object of the invention is a multiphase composition based on nanoemulsion of vegetable oil, characterized in that it contains a polysaccharide phase in an amount from 10 to 50 parts by mass and a nanoemulsion according to the first object of the invention in an amount from 50 to 90 parts by mass, wherein the multiphase composition is in the form of a nanoemulgel wherein the multiphase composition has a dynamic viscosity from 220 mPa • s to 580 mPa • s.

Description

Pharmaceutical composition in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions
The object of the invention is a pharmaceutical composition based on rapeseed oil and poloxamer 188, a multiphase composition, and methods of preparation of these compositions. The compositions are intended for topical use in gynecology and obstetrics as an antibacterial, antifungal and antiprotozoal agent. Additionally, it can be a vehicle for the vaginal administration of systemic drugs (omitting the effect of passage through the hepatic circulation).
Due to their physiological functions, female reproductive organs are exposed to bacterial, fungal and parasitic infections. The natural defense mechanism of the reproductive system is the flora that inhabits the inner environment of the vagina. The most numerous group are bacteria of the genus Lactobacillus spp. and fungi of the genus Candida albicans. The balance between the bacterial and fungal flora ensures homeostasis. The genus Lactobacillus spp. protects the vaginal biocenosis against the overgrowth of other elements present in physiological conditions in the vagina, such as: Staphylococcus aureus, Streptococcus agalactiae (group B), Enterococcus species, Gardnerella vaginalis, Escherichia coli, Bacteroidesfragilis and Mobiluncus. As a result of the imbalance between the bacterial and fungal flora, infections, bacterial or fungal inflammations occur. The wide range of drugs available on the market is not always effective in dealing with infections of complex etiology. An additional difficulty in the conducted therapies is the anatomical and physiological conditions of the female vagina. The drug is kept in the vagina only in the supine position of the patient. In addition, the adherence of the drug is hindered by the presence of vaginal secretions in this organ in a different volume depending on the period of the woman's menstrual cycle, as well as the phases of hormonal balance.
Consideration should also be given to another group of patients, namely pediatric patients. The traditional forms of vaginal medicine available on the market are tablets, globules and capsules in sizes adapted to patients who have reached puberty. These forms are not adapted to be applied to little girls. In addition, vaginal tablets (often with sharp edges) are not easy to divide into the correct dose portion. Globules, like tablets, are a problem when dividing, crumbling and preventing application.
The Polish patent application P.383267 discloses a composition containing lactic acid and a selected alkaline polymer or a mixture of such polymers in a stoichiometric ratio ranging from 1:1 to 8:1, and the vehicle for these substances is micronized Poloxamer 407 in an amount of 90 to 95 parts by mass, calculated in relation to the sum of ingredients, or an aqueous solution of Poloxamer407 with a concentration of 15 to 35 parts by mass, calculated in relation to the sum of ingredients. Both in powdered and semi-liquid form, it is preferred that the composition additionally comprises known anti-inflammatory, antibacterial, antifungal and antiprotozoal agents.
Another Polish patent, PAT.210178B1, describes a method of producing oil-in-water (o/w) and water-in-oil (w/o) microemulsion systems, based on paraffin oil and rapeseed oil, stabilized with selected surfactants, intended for use in agrochemical, pharmaceutical and cosmetic industries. It consists in mixing four ingredients: surfactant, co-surfactant, oil and water, resulting in new transparent oil-in-water (o/w) or water-in-oil (w/o) microemulsion systems. According to the invention, a surfactant selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene (30) 2,4,7,9-tetramethyl-5-decin-4,7-diol, polyoxyethylene castor oil or ethoxylated 17-carbon fatty alcohol is mixed with a co-surfactant in form of n-butyl or isopropyl alcohol in a weight ratio of 1:4 or 4:1 or 8:1 until a clear, homogeneous mixture is obtained, and then to the thus obtained emulsifier, used in a proportion of 1 to 98% by weight, from 1 to 65% by weight of rapeseed or paraffin oil constituting the oily phase and from 1 to 98% by weight of demineralized water are added and all ingredients are mixed until a homogeneous mixture is obtained.
The publication KR20040028336 discloses a thermal antibacterial gel administered vaginally, containing 30-35% by weight of poloxamer, 0.2-1% by weight of polycarbophil and 0.9-l.l% by weight of clotrimazole, where the poloxamer is a mixture of Poloxamer 188 and Poloxamer 407 in a 1, 1-1,5 weight ratio.
The technical problem faced by the invention is to provide a nanosized liquid vehicle for clotrimazole, which could be a stand-alone pharmaceutical formulation for use in gynecology and could also be used to obtain other drug forms, a gel. The vehicle should also enable other active substances, i.e. lipophilic or hydrophilic, with different affinities to be incorporated into the vehicle. On the other hand, the gel obtained on the basis of the said emulsion should be characterized by increased adhesion to the vaginal walls. The vehicle, whether used alone or as a gel, should also not lead to inflammation and have a neutral pH for the vaginal environment, and be suitable for use in pediatric patients. Another problem faced by the invention is the method of obtaining the vehicle or its gel form.
The first object of the invention is a pharmaceutical composition in the form of a vegetable oil based nanoemulsion, characterized in that it comprises a vegetable oil, which is rapeseed oil, in an amount of 10 to 60 parts by mass of rapeseed oil, 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, from 40 to 60 parts by mass of purified water, from 1 to 12 parts by mass of sorbitan monooleate, from 5 to 20 parts by mass of polyol, from 0.10 to 0.50 parts by mass of lactic acid, from 0.5 to 5.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 50 nm to 70 nm. The nanoemulsion is a vehicle for the active ingredient - clotrimazole. Formulations with a vehicle size of less than 500 nm enable more efficient transport of the active substance through the layers of vaginal secretions and vaginal mucosa and increase the effectiveness of the therapy. This allows to obtain a higher effectiveness of the therapy while using smaller doses of active substances compared to conventional forms with a vehicle size of more than 1 pm. In addition, they allow for the administration of drugs that exert not only local (like conventional emulsions) but also systemic effects. Moreover, nanoemulsions exhibit the kinetics of the sustained release of active substances, which allows to reduce the frequency of drug administration.
In a preferred embodiment of the invention, the composition comprises rapeseed oil in an amount of 20 parts by mass, 15 to 20 parts by mass of ethylene oxide/propylene oxide block copolymer P188, 45 to 55 parts by mass of purified water, 1 to 5 parts by mass of sorbitan monooleate, 5 to 10 parts by mass of polyol, from 0.40 to 0.50 parts by mass of lactic acid, from 0.5 to 2.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 55 nm to 65 nm.
In a further preferred embodiment of the invention, the composition comprises rapeseed oil in an amount of 20 parts by mass, from 18 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, 51.83 parts by mass of purified water, 4 parts by mass of sorbitan monooleate, from 5 to 7 parts by mass of polyol, 0.50 part by mass of lactic acid, from 0.5 part by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 58 nm to 64 nm.
In a further preferred embodiment of the invention, the composition comprises a polyol in an amount of 6.67 parts by mass of the composition, wherein the polyol is selected from the group comprising 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
In another preferred embodiment of the invention, the oil phase droplet polydispersity index is from 0.148 to 0.175.
The second object of the invention is a multiphase composition based on a nanoemulsion of vegetable oil according to the first object of the invention, characterized in that it contains a polysaccharide phase, preferably a polysaccharide, in an amount of 10 to 50 parts by mass and a nanoemulsion according to the first object of the invention in an amount of 50 to 90 parts by mass, wherein the multiphase composition is in the form of a nanoemulgel, wherein the multiphase composition has a dynamic viscosity from 220 mPa · s to 580 mPa · s.
In a preferred embodiment of the invention, the multiphase composition comprises a nanoemulsion in an amount of 85 and 15 parts polysaccharide.
In a further preferred embodiment of the invention, the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide, preferably the ratio of nanoemulsion to gel phase containing polysaccharide is 50 parts by mass of nanoemulsion to 50 parts by mass of a gel phase containing the polysaccharide.
In a further preferred embodiment of the invention, the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 0.1 to 10 parts by mass, preferably 2 to 10 parts by mass.
In yet another preferred embodiment of the invention, the polysaccharide-containing gel phase comprises a polysaccharide in an amount of 2 parts by mass and water in an amount of 98 parts by mass.
In a further preferred embodiment of the invention, the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide and optionally containing hydrophilizing substances, preferably the ratio of the nanoemulsion to the gel phase containing the polysaccharide is 80 parts by mass of a nanoemulsion to 20 parts by mass of a gel phase containing the polysaccharide and optionally hydrophilizing substances.
In yet another preferred embodiment of the invention, the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 10 parts by mass and water up to 100 parts by mass, wherein optionally gel phase containing the polysaccharide comprises hydrophilizing substances in an amount of 5-30 parts by mass, preferably 30 parts by mass.
In yet another preferred embodiment of the invention, the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200. In a preferred embodiment of the invention, the polysaccharide phase is selected from the group comprising a gel phase with a polysaccharide or a polysaccharide.
Another object of the invention is a method for the preparation of a pharmaceutical composition in the form of a nanoemulsion based on vegetable oil, comprising the steps of: a) preparation of the lipophilic phase, b) introduction of the active substance, c) preparation of the hydrophilic phase, d) preparation of macroemulsions, e) high-speed homogenization, f) high pressure homogenization, characterized in that in step a) 10 to 60 parts by mass of rapeseed oil are mixed with 5 to 20 parts by mass of polyol and from 1 to 12 parts by mass of sorbitan monooleate in 60 minutes, and in step b) into the lipophilic phase from step a) the active ingredient is introduced in an amount of 0.5 to 5.0 parts by mass, preferably clotrimazole, and the mixture is cooled for 20 hours, and in step c) the hydrophilic phase is prepared by dissolving 0.10 to 0.50 parts by mass of lactic acid in purified water in an amount of 45 to 55 parts by mass and then 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide are added and the mixture is allowed to stabilize for 30 min, then in step d) while stirring the lipophilic phase, the hydrophilic phase is introduced dropwise and the emulsion is allowed to stabilize with continuous stirring for 20 hours, then in step e) the emulsion is homogenized for 10 minutes at the 13,500 rpm rotation speed and cooled to room temperature, the mixture is successively high pressure homogenized in step f) for 60 seconds and at a pressure of 1200 bar to 1300 bar, wherein step f) is carried out twice.
In a preferred embodiment of the invention, in step a), mixing is carried out at 20% of the stirrer power.
In a preferred embodiment of the invention, in step b), mixing is carried out at 15% of the stirrer power.
In another preferred embodiment of the invention, in step b), the mixture is heated for 30 minutes until the active substance is completely dissolved.
In yet another preferred embodiment of the invention, in step d), the hydrophilic phase is introduced into the lipophilic phase mixed at a rotational speed of 400 rpm to 1000 rpm.
In a further preferred embodiment of the invention, step f) is carried out twice. Another object of the invention is a method for the preparation of a multiphase composition based on nanoemulsion of vegetable oil according to the first subject of the invention, characterized in that the nanoemulsion according to the first object of the invention in an amount of 50 to 90 parts by mass is combined with a polysaccharide phase, preferably with a polysaccharide, in an amount of 10 up to 50 parts by mass.
In a preferred embodiment of the invention, the nanoemulsion in an amount of 90 parts by mass is combined with the polysaccharide phase in an amount of 10 parts by mass of the polysaccharide.
In a further preferred embodiment of the invention, the nanoemulsion in an amount of 50 to 80 parts by mass is combined with the polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide, preferably the ratio of the nanoemulsion to the gel phase comprising the polysaccharide is 50 parts by mass of the emulsion to 50 parts by mass of the gel phase comprising the polysaccharide.
In a further preferred embodiment of the invention, the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 0.1 to 10 parts by mass, preferably 2 to 10 parts by mass.
In yet another preferred embodiment of the invention, the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 2 parts by mass and an amount of water in an amount of 98 parts by mass.
In a further preferred embodiment of the invention, the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of from 20 to 50 parts by mass, if the polysaccharide phase is a gel phase comprising the polysaccharide and optionally comprising hydrophilizing substances, preferably the ratio of the nanoemulsion to the gel phase comprising the polysaccharide is 80 parts by mass of a nanoemulsion to 20 parts by mass of a gel phase comprising the polysaccharide and optionally hydrophilizing substances.
In yet another preferred embodiment of the invention, the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 10 parts by mass and water up to 100 parts by mass, wherein optionally the polysaccharide-containing gel phase comprises hydrophilizing substances in an amount of 5-30 parts by mass, preferably 30 parts by mass.
In yet another preferred embodiment of the invention, the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200. In a preferred embodiment of the invention, the polysaccharide phase is selected from the group comprising: a gel phase with a polysaccharide or a polysaccharide.
In the context of the invention, the polysaccharide phase is understood to mean the emulsion component of the gel, making it possible to obtain a multi-phase composition in the form of a gel. Such a component may be a pure polysaccharide (gelling agent) added directly to a nanoemulsion, e.g. Gellan gum, or a mixture containing it (gel), the mixture being prepared in advance (gel phase) and combined with a vehicle. The gel phase may be a simple mixture, e.g. a gelling agent and a solvent, as well as a multi-component mixture, i.e. containing more than two components. Hence, the polysaccharide phase within the meaning of the present invention is a polysaccharide or a gel phase containing the polysaccharide.
The invention relates to a pharmaceutical composition for the treatment of inflammation with a multiphase drug form (based on nanotechnology). The purpose of multiphase is to create the possibility of introducing medicinal substances with different physicochemical properties. A multiphase composition with a hydrophilic-lipophilic character makes it possible to incorporate drugs with hydrophilic and lipophilic properties in one drug form. In addition, the nanoemulsion allows the introduction of substances that pass through the vaginal mucosa in order to achieve a general effect. The multiphase form is constructed on the basis of a polysaccharide, which has adhesive properties with respect to the vaginal mucosa. The adhesiveness of this form of the drug allows it to remain on the vaginal mucosa longer than is possible by traditional treatments. The presented form of the drug is characterized by a pH in the physiological range for the vaginal environment (3.5-4.5), conditioning the development of the physiological bacterial flora, preventing vaginal inflammation. An additional advantage of this form of the drug is the possibility of using it in pediatric patients. The nanoemulgels according to the invention ensure easy application without irritating the mucous membranes. The nanomulgel can be in the form of suppositories or globules. This makes it possible to prepare further single-dose forms. The form of suppositories and globules have a gel consistency and are easy to apply and can be divided into smaller portions, e.g. by cutting. The soft consistency of gel suppositories and globules does not irritate the mucous membranes during application.
The form of nanoemulgel (according to the invention) has the following properties (in parentheses there is information on which form the properties are based on):
- high adhesiveness to the mucosa (gel)
- prolonged release of the active substance (nanoemulsion, gel),
- better penetration through the vaginal secretions and mucosa (nanoemulsion), - greater resistance to washing out from the application site (gel),
- greater stability over time (nanoemulsion, gel).
There is a shortage of gynecological drugs in vaginal forms for girls on the pharmaceutical market. An important advantage of the proposed pharmaceutical compositions containing nanoemulsions and nanoemulgels are ingredients used in medicinal products and food products. The excipients used in the presented pharmaceutical compositions are approved for use in the pharmaceutical and food industries. Preparation of pharmaceutical compositions from the above-mentioned substances determines the safety of their use.
The object of the invention is illustrated in the following examples.
Example I. Composition ingredients:
Rapeseed oil 20.0 parts by mass,
Poloxamer 188 (P188 block copolymer of ethylene oxide and propylene oxide) 18.0 parts by mass, Lactic acid 0.5 parts by mass,
PEG-2006.67 parts by mass,
Purified water 51.83 parts by mass,
Span 80 (sorbitan monooleate) 2.0 parts by mass Clotrimazole 1.0 parts by mass.
In the first step of preparing the composition, Span 80 and PEG-200 are added to rapeseed oil. Then, the previously obtained oil phase was stirred with a magnetic stirrer at 20% power for 60 minutes. The active ingredient is introduced into the heated mixture of the lipophilic phase with constant stirring. Heating is maintained for 30 minutes until the active substance is completely dissolved. The solution was allowed to cool and continued to be stirred at 15% power for 20 hours. Lactic acid was added to the weighed amount of distilled water according to FP XII. The resulting lactic acid aqueous solution was stirred with a magnetic stirrer at 18% power. Poloxamer 188 flakes were then added with continued mixing. After the polymer was completely dissolved, the solution was allowed to stabilize under continuous stirring at 12% power for 30 minutes. The hydrophilic phase was then introduced into the lipophilic phase and allowed to stabilize with continuous stirring at 1000 rpm for 20 hours. High shear homogenization and high pressure homogenization were applied sequentially, each time cooling the mixture to room temperature. The obtained form is a nanoemulsion. The obtained parameters of the nanoemulsion presented in Example I are: mean hydrodynamic size of the oil phase droplets = 63.50 nm (measured by the Dynamic Light Scattering, DLS, Malvern Zetasizer method), PDI (PoliDispersity Index) = 0.175, Zeta potential = +17, 4 mV, pH = 4.18.
Example II. Composition ingredients:
Rapeseed oil 20.0 parts by mass,
Poloxamer 18816.0 parts by mass,
Lactic acid 0.5 parts by mass,
1,2-propylene glycol 6.67 parts by mass,
Purified water 51.83 parts by mass,
Span 804.0 parts by mass,
Clotrimazole 1.0 parts by mass.
In the first step of preparing the composition, Span 80 and 1,2-propylene glycol are added to rapeseed oil. The previously obtained oil phase was then stirred by means of a magnetic stirrer at 20% power for 60 minutes. The active substance is introduced into the heated mixture of the lipophilic phase with constant stirring. Heating is maintained for 30 minutes until the active substance was completely dissolved. The solution was allowed to cool and continued to be stirred at 15% power for 20 hours. Lactic acid was added to a weighed amount of water distilled according to Pharmacopoeia XII. The resulting lactic acid aqueous solution was stirred with a magnetic stirrer at 18% power. Poloxamer 188 flakes were then added with continued stirring. After the polymer was completely dissolved, the solution was allowed to stabilize under continuous stirring at 12% power for 30 minutes. The hydrophilic phase was then introduced into the lipophilic phase and allowed to stabilize with continuous stirring at 1000 rpm for 20 hours. High shear homogenization and high pressure homogenization were applied sequentially, each time cooling the mixture to room temperature. The obtained form is a nanoemulsion.
The obtained parameters of the nanoemulsion presented in Example 2 are: mean hydrodynamic size of the oil phase droplets = 58.14 nm (measured by the Dynamic Light Scattering, DLS method), PDI (polydispersity index) = 0.148, Zeta potential = +16.1 mV, pH = 4.06.
Example III. Composition ingredients:
The multiphase composition is prepared as in Example I or II. Then a gel is prepared (gel phase): Gellan rubber 2.0 parts by mass,
Purified water 98.0 parts by mass. Gellan gum is combined with purified water at 90 degrees C. Then the mixture is stirred with a magnetic stirrer at 40% power for 80 minutes until a homogeneous gel is obtained. The resulting gel is cooled to room temperature.
The composition according to Examples 1 or 2 is combined with the obtained gel using a high shear homogenizer at room temperature, obtaining a composition consisting of 20 to 50 parts by mass of a gel and 50 to 80 parts by mass of a nanoemulsion. It is preferable to combine the nanoemulsion in an amount of 50 parts by mass with 50 parts by mass of the resulting gel, to obtain a formulation with a dynamic viscosity from 220 mPa.s to 260 mPa.s.
In the further stages of the proposed development of the invention, it is planned to introduce various medicinal substances with antibacterial, antifungal and antiparasitic properties into the obtained drug forms. Additionally, a protein substance will be introduced, having a beneficial effect on the biocenosis of the vagina, acting synergistically in relation to antibiotics.
Clotrimazole - a substance with antifungal activity - was used as a model substance in the research. The results of laboratory tests have produced very favorable results. Both the particle size of the nanoemulsion containing the drug substance and the other parameters characterizing this form of the drug turned out to meet the high requirements for application and therapy.
The obtained nanoemulsion in combination with Gellan gum turns into an emulgel (nanoemulgel). In the further stages of adding the gelling agent, and then pouring the mass into molds, after solidifying, the dosage forms of the drug are obtained: suppositories, globules.
Due to the fact that the emulsion can be a vehicle for medicinal substances with various effects, e.g. anti-inflammatory, analgesic, etc. it can be applied to other body cavities covered with mucosa. Enteral use - inflammation of the large intestine. They can be used rectally: enemas or rectal enemas, in the form of suppositories, similar to vaginal use. The presented nanoemulsions can be used in laryngology as nasal, sinus irrigation and ear preparations. They can also be used as nanoemulsion eye drops.
Example IV. A method of making a pharmaceutical multiphase (nano) composition for vaginal use.
The composition is made of rapeseed oil, water, poloxamer 188, PEG-200 or propylene glycol, lactic acid, clotrimazole with the addition of Span 80. a) Preparation of the lipophilic phase Weighed rapeseed oil is mixed with Span 80 and PEG-200 or 1,2-propylene glycol. The oil phase is then subjected to magnetic stirring at 20% power for 60 minutes. Odwazony olej rzepakowy miesza się ze Spanem 80 i PEG-200 tub glikolem 1,2-propylenowym. b) Introduction of active substance (if prescribed)
The active ingredient is weighed to the nearest 0.001 g (clotrimazole). The previously prepared lipophilic phase was preheated (if necessary) to 50 degrees C. The active substance was added to the heated mixture under constant stirring. Heating was maintained for 30 minutes until the active ingredient was completely dissolved. The solution was allowed to cool and continued to be stirred at 15% power for 20 hours. c) Preparation of the hydrophilic phase
The lactic acid solution was added to the weighed amount of water distilled according to Pharmacopoeia XII with an accuracy of 5.0 mg (resulting from the dropwise introduction of the acid solution). The resulting lactic acid aqueous solution was stirred with a magnetic stirrer at 18% power. Then, weighed down to 0.01 g of Poloxamer 188 flakes were added with continuous mixing. After the polymer was completely dissolved, the solution was allowed to stabilize under continuous stirring at 12% power for 30 minutes in order to prevent foaming of the hydrophilic phase. d) Preparation of macroemulsions
The previously obtained lipophilic phase was stirred by means of a magnetic stirrer at 1000 r pm. The previously prepared hydrophilic phase was introduced into the lipophilic phase dropwise, keepingthe maximum possible mixing speed in the range of 400-1000 rpm (the change of the mixing speed resulted from the change of the viscosity of the obtained system). Upon completion of the process of introducing the hydrophilic phase into the lipophilic phase, the macroemulsion was allowed to stabilize the system under continuous stirring at 1000 rpm for 20 hours. e) High-speed homogenization
The resulting macroemulsion was mixed in a high-speed homogenizer for 10 minutes at 13,500 rpm. The emulsion was then cooled to room temperature. f) High pressure homogenization
The formulations obtained in the process of high-speed homogenization were subjected to the high- pressure homogenization process in the GEA Niro Soavi Panda Plus homogenizer. In a single cycle, the emulsion was homogenized at 1200-1300 bar for 60 seconds. Homogenization was carried out twice. The sample was then cooled to room temperature. Two cycles of homogenization were performed for each emulsion. After the completion of the two-stage high-pressure homogenization process, the obtained composition has the character of a nanoemulsion.
Obtaining this form makes it possible to include hydrophilic medicinal substances in the hydrophilic phase, and lipophilic medicinal substances in the lipophilic phase.
This composition may be a standalone pharmaceutical nanoemulsion for vaginal use.
Example V. A method of making a polysaccharide-based multiphase pharmaceutical nanocomposition for vaginal use.
The essence of the invention consists in the possibility of additional enrichment of the nanoemulsion composition with a polysaccharide forming a hydrophilic nanogel.
The combination of a pharmaceutical nanoemulsion with a gel (gel phase containing polysaccharide) based on a polysaccharide (Gellan gum) creates a new form - nanoemulgel. The new form has the property of high adhesiveness to the mucosa, affecting the longer duration of this form of the drug in the vagina.
The multiphase composition was prepared as set out in Example 4. Then a gel form is prepared.
The polysaccharide, Gellan gum, is combined with water purified according to Pharmacopeia XII at room temperature with the addition of hydrophilizing substances such as: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200, obtaining the following proportions: from 0.1 to 10 parts of polysaccharide, preferably 10 parts, 5-30 parts of hydrophilizing substances, preferably 30 parts by mass, made up with water, Water is a complementary component of up to 100 parts by mass and its content depends on the polyol content. Then the mixture is subjected to magnetic stirring at 30- 40% power for a period of 60-80 minutes until a homogeneous gel is obtained.
The nanoemulsion obtained according to examples 1, 2 or the method of example 4 in an amount of 50 to 80 parts by mass is combined with the gel obtained according to this example in an amount of 20 to 50 parts of the obtained gel using a high-speed homogenizer until a homogeneous nanoemulgel is obtained. The most advantageous properties are obtained when this ratio is 80:20, obtaining a formulation with a dynamic viscosity from 480 mPa»s to 510 mPa*s. The form of the emulgel increases the stability of the emulsion and does not significantly affect the optical properties of the formulation, therefore it should not have a significant effect on the size of the oil droplets.
Example VI. A method of making a pharmaceutical polysaccharide-based multiphase (nano) composition for vaginal use. The multiphase composition was prepared as described in Example IV. The nanoemulsion is then transformed into a nanoemulgel by adding a polysaccharide (polysaccharide phase) directly, preferably Gellan gum, thereto.
The polysaccharide - Gellan gum is added directly to the nanoemulsion obtained according to example I, II or IV in a weight ratio of 85-90 parts of nanoemulsions to 10-15 parts of Gellan gum. The mixture is stirred by means of a magnetic stirrer/mechanical stirrer for a period of 60-120 minutes. The obtained nanoemulgel is cooled to room temperature, to obtain a formulation with a dynamic viscosity from 550 mPa»sto 580 mPa.s.
Literature:
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00752014000100012. Randelovic, G.; Mladenovic, V.; Ristic, L; Otasevic, S.; Brankovic, S.; Mladenovic-Antic, S.; Bogdanovic, M.; Bogdanovic, D. Microbiological aspects of vulvovaginitis in prepubertal girls. Eur. J. Pediatr. 2012, 171, 1203-1208, doi: 10.1007/s00431-012- 1705-9. Jones, R. Childhood vulvovaginitis and vaginal discharge in general practice. Fam. Pract. 1996, 13, 369-372, doi:10.1093/fampra/13.4.369. Cox, R.A. Haemophilus influenzae: An underrated cause of vulvovaginitis in young girls. J. Clin. Pathol. 1997, 50, 765-768, doi:10.1136/jcp.50.9.765. Bumbuliene, Z.; Venclaviciute, K.; Ramasauskaite, D.; Arlauskiene, A.; Bumbul, E.; Drasutiene, G. Microbiological findings of vulvovaginitis in prepubertal girls. Postgrad. Med. J. 2014, 90, 8-12, doi:10.1136/postgradmedj-2013-131959. Yilmaz, A.E.; Celik, N.; Soylu, G.; Donmez, A.; Yuksel, C. Comparison of clinical and microbiological features of vulvovaginitis in prepubertal and pubertal girls. J. Formos. Med. Assoc. 2012, 111, 392-396, doi:10.1016/j.jfma.2011.05.013. Aroutcheva, A.; Gariti, D.; Simon, M.; Shott, S.; Faro, J.; Simoes, J.A.; Gurguis, A.; Faro, S. Defense factors of vaginal lactobacilli. Am. J. Obstet. Gynecol. 2001, 185, 375-379, doi:10.1067/mob.2001.115867. Lirio, J.; Giraldo, P.C.; Amaral, R.L.; Sarmento, A.C.A.; Costa, A.P.F.; Goncalves, A.K. Antifungal (oral and vaginal) therapy for recurrent vulvovaginal candidiasis: A systematic review protocol. BMJ Open 2019, 9, doi:10.1136/bmjopen-2018-027489. Kendirci, M.; KoV, A.N.; Kurtoglu, S.; Keskin, M.; Kuyucu, T. Vulvovaginal candidiasis in children and adolescents with type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 2004, 17, 1545- 1549, doi:10.1515/jpem.2004.17.11.1545. Denning, D.W.; Kneale, M.; Sobel, J.D.; Rautemaa-Richardson, R. Global burden of recurrent vulvovaginal candidiasis: a systematic review. Lancet Infect. Dis. 2018, 18, e339-e347, doi:10.1016/S1473-3099(18)30103-8. Foxman, B.; Muraglia, R.; Dietz, J.P.; Sobel, J.D.; Wagner, J. Prevalence of recurrent vulvovaginal candidiasis in 5 European countries and the United States: Results from an internet panel survey. J. Low. Genit. Tract Dis. 2013, 17, 340-345, doi:10.1097/LGT.0b013e318273e8cf. Bhesania, A.H.; Narayankhedkar, A. Vulvovaginal Candidosis. Int. J. Curr. Microbiol. Appi. Sci. 2017, 6, 240-250, doi:10.20546/ijcmas.2017.601.029. Konadu, D.G.; Owusu-Ofori, A.; Yidana, Z.; Boadu, F.; Iddrisu, L.F.; Adu-Gyasi, D.; Dosoo, D.; Awuley, R.L.; Owusu-Agyei, S.; Asante, K.P. Prevalence of vulvovaginal candidiasis, bacterial vaginosis and trichomoniasis in pregnant women attending antenatal clinic in the middle belt of Ghana. BMC Pregnancy Childbirth 2019, 19, 1-10, doi:10.1186/sl2884-019-2488-z. Bachhav, Y.G.; Patravale, V.B. Microemulsion-based vaginal gel of clotrimazole: Formulation, in vitro evaluation, and stability studies. AAPS PharmSciTech 2009, 10, 476-481, doi:10.1208/sl2249-009-9233-2. Soriano-Ruiz, J.L.; Calpena-Capmany, A.C.; Canadas-Enrich, C.; Febrer, N.B. de; Suner-Carbo, J.; Souto, E.B.; Clares-Naveros, B. Biopharmaceutical profile of a clotrimazole nanoemulsion: Evaluation on skin and mucosae as anticandidal agent. Int. J. Pharm. 2019, 554, 105-115, doi:10.1016/j.ijpharm.2018.11.002. Soriano-Ruiz, J.L.; Suner-Carbo, J.; Calpena-Campmany, A.C.; Bozal-de Febrer, N.; Halbaut- Bellowa, L; Boix-Montanes, A.; Souto, E.B.; Clares-Naveros, B. Clotrimazole multiple W/O/W emulsion as anticandidal agent: Characterization and evaluation on skin and mucosae. Colloids Surfaces B Biointerfaces2019, 175, 166-174, doi:10.1016/j.colsurfb.2018.11.070.

Claims

Claims
1. Pharmaceutical composition in the form of a vegetable oil based nanoemulsion, characterized in that it contains vegetable oil, which is rapeseed oil, in an amount from 10 to 60 parts by mass of rapeseed oil, from 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, from 40 to 60 parts by mass of purified water, from 1 to 12 parts by mass of sorbitan monooleate, from 5 to 20 parts by mass of polyol, from 0.10 to 0.50 parts by mass of lactic acid, from 0.5 to 5.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 50 nm to 70 nm.
2. The composition according to claim 1, characterized in that it contains rapeseed oil in an amount of 20 parts by mass, from 15 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide, from 45 to 55 parts by mass of purified water, from 1 to 5 parts by mass of sorbitan monooleate, from 5 to 10 parts by mass of polyol, from 0.40 to 0.50 parts by mass of lactic acid, from 0.5 to 2.0 parts by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter of 55 nm to 65 nm.
3. The composition according to claim 1 or 2, characterized in that it contains rapeseed oil in an amount of 20 parts by mass, from 18 parts by mass of poloxamer 188, 51.83 parts by mass of purified water, 4 parts by mass of sorbitan monooleate, from 5 to 7 parts by mass of polyol, 0.50 parts by mass of lactic acid, from 0.5 part by mass of clotrimazole, wherein the oil phase droplets have a hydrodynamic diameter ranging from 58 nm to 64 nm.
4. The composition according to claim 1, 2 or 3, characterized in that the polyol is present in an amount of 6.67 parts by mass of the composition, the polyol is selected from the group compriding: 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
5. The composition according to claim 1, 2 or 3, characterized in that the oil phase droplet polydispersity index is from 0.148 to 0.175.
6. Multiphase composition based on nanoemulsion of vegetable oil, characterized in that it comprises a polysaccharide phase, preferably a polysaccharide, in an amount of 10 to 50 parts by mass and a nanoemulsion according to claim 1 in an amount from 50 to 90 parts by mass, wherein the multiphase composition is in the form of a nanoemulgel, wherein the multiphase composition has a dynamic viscosity from 220 mPa · s to 580 mPa.s.
7. The multiphase composition according to claim 6, characterized in that it comprises the nanoemulsion in an amount of 85 parts by mass and 15 parts by mass of the polysaccharide.
8. The multiphase composition according to claim 6, characterized in that it comprises the nanoemulsion in an amount from 50 to 80 parts by mass and the polysaccharide phase in an amount from 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide, preferably the ratio of the nanoemulsion to the gel phase containing the polysaccharide is 50 parts by mass of the nanoemulsion to 50 parts by mass of the gel phase containing the polysaccharide.
9. The multiphase composition according to claim 8, characterized in that the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 0.1 to 10 parts by mass, preferably 2 to 10 parts by mass.
10. The multiphase composition according to claim 8 to 9, characterized in that the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 2 parts by mass and water in an amount of 98 parts by mass.
11. The multiphase composition according to claim 6, characterized in that it comprises the nanoemulsion in an amount of 50 to 80 parts by mass and the polysaccharide phase in an amount of from 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide and optionally containing hydrophilizing substances, preferably the ratio of the nanoemulsion to the gel phase containing the polysaccharide is 80 parts by mass of a nanoemulsion to 20 parts by mass of a gel phase containing the polysaccharide and optionally hydrophilizing substances.
12. The multiphase composition according to claim 6 or 11, characterized in that the polysaccharide-containing gel phase comprises 10 parts by mass of the polysaccharide and up to 100 parts by mass of water, wherein optionally polysaccharide-containing gel phase comprises hydrophilizing substances in an amount of 5-30 parts by mass, preferably 30 parts by mass.
13. The multiphase composition according to claims 11 to 12, characterized in that the hydrophilizing substances are selected from the group comprising: glycerol, 1,2- propylene glycol or polyoxyethylene glycol 200.
14. The multiphase composition according to claim 6, characterized in that the polysaccharide phase is selected from the group comprising a gel phase with a polysaccharide or a polysaccharide.
15. A method for preparing a pharmaceutical composition in the form of a vegetable oil based nanoemulsion, comprising the steps of: a) preparation of the lipophilic phase, b) introduction of the active substance, c) preparation of the hydrophilic phase, d) preparation of macroemulsion, e) high-speed homogenization, f) high pressure homogenization, characterized in that in step a) 10 to 60 parts by mass of rapeseed oil are mixed with 5 to 20 parts by mass of polyol and from 1 to 12 parts by mass of sorbitan monooleate in 60 minutes, and in step b) into the lipophilic phase from step a) the active ingredient is introduced in an amount of 0.5 to 5.0 parts by mass, preferably clotrimazole, and the mixture is cooled for 20 hours, and in step c) the hydrophilic phase is prepared by dissolving 0.10 to 0.50 parts by mass of lactic acid in purified water in an amount of 45 to 55 parts by mass and then 12 to 20 parts by mass of P188 block copolymer of ethylene oxide and propylene oxide are added and the mixture is allowed to stabilize for 30 min, then in step d) while stirring the lipophilic phase, the hydrophilic phase is introduced dropwise and the emulsion is allowed to stabilize with continuous stirring for 20 hours, then in step e) the emulsion is homogenized for 10 minutes at the 13,500 rpm rotation speed and cooled to room temperature, the mixture is successively high pressure homogenized in step f) for 60 seconds and at a pressure of 1200 bar to 1300 bar, wherein step f) is carried out twice.
16. The method according to claim 15, characterized in that in step a) the mixing is carried out at 20% of stirrer power.
17. The method according to claim 15, characterized in that in step b) the mixing is carried out at 15% of stirrer power.
18. The method according to claim 15 or 17, characterized in that in step b) the mixture is heated for 30 minutes until the active substance is completely dissolved.
19. The method according to claim 15, characterized in that in step d) the hydrophilic phase is introduced into the lipophilic phase mixed at a rotational speed of 400 rpm to 1000 rpm.
20. The method according to claim 15, characterized in that step f) is carried out twice.
21. A method for the preparation of a multiphase composition based on a nanoemulsion of vegetable oil, characterized in that the nanoemulsion as defined in claim 1 in an amount of 50 to 90 parts by mass is combined with the polysaccharide phase, preferably with a polysaccharide, in an amount of 10 to 50 parts by mass.
22. The method according to claim 21, characterized in that 90 parts by mass of the nanoemulsion is combined with a polysaccharide phase in an amount of 10 parts by mass of the polysaccharide.
23. The method according to claim 21, characterized in that the nanoemulsion in an amount of 50 to 80 parts by mass is combined with the polysaccharide phase in an amount of 20 to 50 parts by mass, if the polysaccharide phase is a gel phase containing the polysaccharide, preferably the ratio of nanoemulsion to gel phase comprising the polysaccharide is 50 parts by mass an emulsion to 50 parts by mass of a gel phase comprising the polysaccharide.
24. The method according to claim 21 or 23, characterized in that the polysaccharide- containing gel phase comprises the polysaccharide in an amount from 0.1 to 10 parts by weight, preferably from 2 to 10 parts by weight.
25. The method according to claims 23 to 24, characterized in that the polysaccharide- containing gel phase comprises the polysaccharide in an amount of 2 parts by mass and water in an amount of 98 parts by mass.
26. The method according to claim 21, characterized in that the multiphase composition comprises a nanoemulsion in an amount of 50 to 80 parts by mass and a polysaccharide phase in an amount of from 20 to 50 parts by mass, if the polysaccharide phase is a gel phase comprising the polysaccharide and optionally comprising hydrophilizing substances, preferably the ratio of the nanoemulsion to the gel phase comprising the polysaccharide is 80 parts by mass of a nanoemulsion to 20 parts by mass of a gel phase comprising the polysaccharide and optionally hydrophilizing substances.
27. The method according to claim 26, characterized in that the polysaccharide-containing gel phase comprises the polysaccharide in an amount of 10 parts by mass and water up to 100 parts by mass, optionally the polysaccharide-containing gel phase comprises hydrophilizing substances in an amount of 5-30 parts by mass, preferably 30 parts by mass.
28. The method according to claims 26 to 27, characterized in that the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
29. The method according to claim 21, characterized in that the polysaccharide phase is selected from the group comprising: a gel phase with a polysaccharide or a polysaccharide.
EP22783381.1A 2021-07-16 2022-07-15 Pharmaceutical composition in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions Pending EP4370096A1 (en)

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