WO2023287310A1 - A pharmaceutical composition based on a vegetable oil and a triblock copolymer, a multiphase emulgel composition and a method of preparation of the composition - Google Patents

A pharmaceutical composition based on a vegetable oil and a triblock copolymer, a multiphase emulgel composition and a method of preparation of the composition Download PDF

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Publication number
WO2023287310A1
WO2023287310A1 PCT/PL2022/000040 PL2022000040W WO2023287310A1 WO 2023287310 A1 WO2023287310 A1 WO 2023287310A1 PL 2022000040 W PL2022000040 W PL 2022000040W WO 2023287310 A1 WO2023287310 A1 WO 2023287310A1
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mass
parts
composition
phase
gel phase
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PCT/PL2022/000040
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French (fr)
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Katarzyna MALOLEPSZA-JARMOŁOWSKA
Michał Smoleński
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Uniwersytet Medyczny Im. Piastów Śląskich We Wrocławiu
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Publication of WO2023287310A1 publication Critical patent/WO2023287310A1/en

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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
    • A61K9/10—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
    • A61K9/0012—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
    • 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
    • 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
    • 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
    • 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
    • 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

  • the object of the invention is a pharmaceutical composition based on rapeseed oil, a copolymer which is poloxamer 407 or poloxamer 188.
  • the second object of the invention is a multiphase composition based on a vegetable oil in the form of an emulgel.
  • the invention also includes a method of preparation of the composition.
  • the compositions are intended for use in gynecology and obstetrics as an antibacterial, antifungal and antiprotozoal agent.
  • 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
  • the Polish patent PAT.210178B1 describes a method of producing oil-in-water (o/w) and water-inoil (w/o) microemulsion systems, based on paraffin oil and rapeseed oil, stabilized with selected surfactants, intended for use in the 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, the surfactant is mixed with the co-surfactant in a 1:4, 4:1 or 8:1 weight ratio, at room temperature, until a clear, homogeneous emulsifier mixture is obtained.
  • the publication KR 20040028336 discloses a thermal antibacterial gel administered vaginally, comprising 30-35% by weight of poloxamer, 0.2-1% by weight of polycarbophil and 0.9- 1.1% 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 an emulsion oil base comprising only an oil of natural origin, which could be used in the preparation of vaginal pharmaceutical formulations, wherein this base could be used alone as a drug carrier.
  • Another problem faced by the invention is to provide a gel formulation for vaginal use with increased affinity to the vaginal walls, which would have a neutral pH towards the vaginal environment, enable the incorporation of lipophilic and/or hydrophilic active substances into the formulation and maintain a high concentration of active substance in formulation.
  • Another problem is to provide a method for the preparation of an oil base and a gel formulation for vaginal use with increased adhesion to the vaginal walls, wherein the process of preparation of gel formulation should be carried out at room temperature.
  • the first object of the invention is an emulsion composition based on a vegetable oil and a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide, characterized in that the composition comprises from 20 to 60 parts by mass of vegetable oil, which is rapeseed oil, from 1 to 20 parts by mass of a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide, from 50 to 65 parts by mass of purified water, from 1 to 20 parts by mass of a surfactant which is a sorbitan ester.
  • the composition comprises from 30 to 50 parts by mass of vegetable oil, more preferably from 30 to 50 parts by mass of rapeseed oil.
  • the sorbitan ester surfactant is selected from the group comprising: polyoxymethylene sorbitan monooleate in an amount from 1-20 parts by mass of the composition, preferably 10 parts by mass of the composition, or sorbitan monooleate in an amount of 1-12 parts by mass of the composition, preferably 5 parts by mass of the composition.
  • the composition comprises 50 parts by mass of purified water.
  • the composition comprises a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide in an amount of 5 to 10 parts by mass of the composition.
  • the second object of the invention is a multiphase composition
  • a vegetable oil-based composition according to the first object of the invention characterized in that it comprises a gel phase and an emulsion phase according to the first object of the invention in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances, wherein the emulgel composition has a dynamic viscosity from 250 mPa » s to 750 mPa*s, preferably from 300 mPa*s to 700 mPa»s, wherein the gel phase comprises 0.1 to 10 parts by mass of Gellan gum and from 90 to 99.9 parts by mass of water, preferably 0.2 parts by mass of Gellan gum and 99.8 parts by mass of water.
  • hydrophilizing substances e.g. polyols
  • hydrophilizing substances make it possible to obtain the maximum concentration of the polysaccharide in the gel.
  • Increasing the polysaccharide content leads to an improvement in the adhesive properties, i.e. affinity, of the finished formulation form, i.e. the emulgel.
  • the absence of hydrophilizing substances therefore adversely affects the desired viscosity of the final emulgel and it is necessary to mix the thinner gel in greater proportion with the emulsion.
  • the gel phase and the emulsion phase are mixed in a 1:1 weight ratio.
  • the gel phase and the emulsion phase are mixed in a 1:4 weight ratio.
  • hydrophilizing substances polyols
  • the gel phase comprises from 0.1 to 10 parts by mass of the polysaccharide, which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
  • the gel phase comprises 10 parts by mass of the Gellan gum polysaccharide, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
  • the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
  • PEG-200 polyoxyethylene glycol 200
  • the emulgel composition has a dynamic viscosity from 320 mPa » s to 670 mPa*s.
  • Another object of the invention is a method for preparing a vegetable oil-based emulsion composition as defined in the first object of the invention, comprising: a) preparation of the hydrophilic phase, b) combining the lipophilic (oil) phase with the hydrophilic phase, characterized in that the hydrophilic phase is prepared by com bining 50 to 65 parts by mass of water with a triblock copolymer in an amount of 1 to 20 parts by mass and a surfactant in an amount of 1 to 20 parts by mass of the surfactant, which is the sorbitan ester, then a lipophilic phase is added and the phases are prehomogenized for 15 min to 20 min, and the mixture is subjected to high pressure homogenization for 60 s to 80 s at a pressure of 400 bar to 1300 bar, wherein the high pressure homogenization cycle is carried out from two to ten times.
  • high pressure homogenization is carried out at a temperature of 37 °C to 69 °C, preferably 45 °C to 58 °C, most preferably 48 °C to 57 °C.
  • the process is carried out at a pressure of 600 bar to 800 bar.
  • the high pressure homogenization cycle is performed six to eight times.
  • Another object of the invention is a method for preparing a multiphase composition based on vegetable oil according to the second object of the invention, comprising: a) preparation of the gel phase, b) combining the emulsion phase with the hydrophilic phase, characterized in that a gel phase is prepared and the gel phase is combined with the emulsion phase, as defined in the second object of the invention, in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances.
  • the gel phase is prepared by mixing 0.1 to 10 parts by mass of Gellan gum and 90 to 99.9 parts by mass of water, preferably 0.2 parts by mass of Gellan gum and 99.8 parts by mass of water.
  • the gel phase and the emulsion phase are mixed in a 1:1 weight ratio.
  • the gel phase and the emulsion phase are mixed in a 1:4 weight ratio.
  • the gel phase is prepared by mixing 0.1 to 10 parts by mass of the polysaccharide, which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances, and from 60 to 100 parts by mass of water.
  • the polysaccharide which is Gellan gum
  • the gel phase is prepared by mixing 10 parts by mass of the polysaccharide, which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
  • the polysaccharide which is Gellan gum
  • the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
  • the invention relates to a pharmaceutical composition for the treatment of inflammation with a multiphase dosage form.
  • 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 multiphase form is constructed on the basis of a polysaccharide, which has adhesive properties with respect to the vaginal mucosa. The adhesiveness of this drug form allows it to remain on the vaginal mucosa longer than is provided by prior art therapeutic methods.
  • 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 addition of hydrophilizing substances allows to obtain the form of a formulation with a higher polysaccharide content, which has a positive effect on the adhesive properties to the vaginal walls.
  • Another significant advantage is the possibility of carrying out the process of obtaining the formulation at room temperature.
  • the obtained gel is characterized by a higher viscosity, thanks to which it can be mixed with the emulsion in smaller proportions to obtain the desired emulsion consistency.
  • Example I Composition of the emulsion composition with Poloxamer 407:
  • Poloxamer 407 (P407 block copolymer of ethylene oxide and propylene oxide) 10.0 parts by mass, Purified water 50.0 parts by mass,
  • Tween 80 polyoxymethylene sorbitan monooleate 10.0 parts by mass.
  • the oil (lipophilic) phase of the composition is rapeseed oil.
  • Purified water is combined with Poloxamer 407 and Tween 80. Both lipophilic and hydrophilic phases are combined and then prehomogenized with a magnetic stirrer at 40% power for 15 minutes.
  • the mixture is homogenized in a high-pressure homogenizer. High-pressure homogenization is carried out in 6 cycles, the maximum temperature is 57 degrees C. The applied pressure is 600 bar. The duration of one cycle is 60 seconds. The resulting form is an emulsion.
  • Example II The composition of the emulsion composition with Poloxamer 188:
  • Poloxamer 188 (P188 block copolymer of ethylene oxide and propylene oxide) 5.0 parts by mass, Purified water 50.0 parts by mass,
  • Span 80 (sorbitan monooleate) 5.0 parts by mass.
  • the multiphase composition is prepared by mixing rapeseed oil with Span 80. Purified water is combined with poloxamer 188. Both lipophilic and hydrophilic phases are combined and then prehomogenized with a magnetic stirrer at 30% power for 20 minutes. In the next stage of preparing the composition, the mixture is homogenized in a high-pressure homogenizer. High-pressure homogenization is carried out in 8 cycles, the maximum temperature is 48 degrees C. The applied pressure is 800 bar. The duration of one cycle is 60 seconds. The resulting form is an emulsion.
  • Example III The composition of the multiphase composition in the form of an emulgel.
  • the pharmaceutical composition is prepared as in Example I or II. Then the gel is prepared:
  • 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 of 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 an emulsion. It is preferable to combine 50 parts by mass of the emulsion with 50 (1:1) parts by mass of the resulting gel.
  • the obtained composition has a dynamic viscosity of 326.68 mPa»s.
  • Example IV A method of making a pharmaceutical composition for vaginal use according to the first object of the invention.
  • composition is made of rapeseed oil, water, poloxamer 407 or poloxamer 188 with the addition of the surfactant: Tween 80 or Span 80 as in Example I or II.
  • Rapeseed oil is mixed with Span 80 (compositions containing Span 80).
  • Water purified according to Pharmacopeia XII 50 to 65 parts by mass
  • poloxamer 407 in the form of a white powder or poloxamer 188 in the form of white flakes and Tween 80 (compositions without Span 80).
  • the resulting mixture is prehomogenized with a magnetic stirrer at 30-40% power for 15-20 minutes.
  • the mixture is then homogenized in a GEA Niro Soavi Panda Plus high pressure homogenizer. High-pressure homogenization is carried out in 2 to 10 cycles at a temperature of 37- 69 degrees C.
  • the applied pressure is in the range of 400-1300 bar.
  • the duration of one cycle is 60 seconds.
  • the resulting form is an emulsion.
  • composition according to this example may be a self-contained pharmaceutical emulsion for vaginal use.
  • Example V A method for making a polysaccharide-based multiphase pharmaceutical composition for vaginal use according to the second object of the invention.
  • the multiphase composition is prepared as described in method I, II or IV. Then an emulsion is prepared in the form of an emulgel.
  • 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, from 60 to 100 parts of water, preferably 60 parts by mass.
  • 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 emulsion described in example I, II or IV 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. It is preferable to combine the emulsion in an amount of 80 parts by mass with 20 (4:1) parts by mass of the resulting gel.
  • the resulting advantageous combination forms a formulation having a dynamic viscosity of 654,80 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.

Abstract

The first object of the invention is an emulsion composition based on a vegetable oil and a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide, characterized in that the composition comprises from 20 to 60 parts by mass of a vegetable oil, which is rapeseed oil, 1 to 20 parts by mass of P407 block copolymer of ethylene oxide and propylene oxide or P188 block copolymer of ethylene oxide and propylene oxide, from 50 to 65 parts by mass of purified water, from 1 to 20 parts by mass of a surfactant which is a sorbitan ester. The second object of the invention is a multiphase composition comprising a vegetable oil-based composition according to the first object of the invention, characterized in that it comprises a gel phase and an emulsion phase according to the first object of the invention, in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances, wherein the emulgel composition has a dynamic viscosity from 250 mPa•s to 750 mPa•s, preferably from 300 mPa•s to 700 mPa•s. The invention also includes methods of preparation of the above compositions.

Description

A pharmaceutical composition based on a vegetable oil and a triblock copolymer, a multiphase emulgel composition and a method of preparation of the composition
The object of the invention is a pharmaceutical composition based on rapeseed oil, a copolymer which is poloxamer 407 or poloxamer 188. The second object of the invention is a multiphase composition based on a vegetable oil in the form of an emulgel. The invention also includes a method of preparation of the composition. The compositions are intended for use in gynecology and obstetrics as an antibacterial, antifungal and antiprotozoal agent.
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.
The Polish patent PAT.210178B1 describes a method of producing oil-in-water (o/w) and water-inoil (w/o) microemulsion systems, based on paraffin oil and rapeseed oil, stabilized with selected surfactants, intended for use in the 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, the surfactant is mixed with the co-surfactant in a 1:4, 4:1 or 8:1 weight ratio, at room temperature, until a clear, homogeneous emulsifier mixture is obtained.
The publication KR 20040028336 (abstract) discloses a thermal antibacterial gel administered vaginally, comprising 30-35% by weight of poloxamer, 0.2-1% by weight of polycarbophil and 0.9- 1.1% 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 publication of Jung Yun Chang et al. "Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions" (International Journal of Pharmaceutics, v. 241, Issue 8 July 2002, Pages 155-163) describes a pharmaceutical composition intended for use in gynecology, comprising 20% of Poloxamer 407, 0,2% of polycarbophil and varying amounts of Poloxamer 188 (from 15 to 20%). The publication discloses that the use of Poloxamer 407 in vaginally administered gel preparations affects the effectiveness of active substances.
The technical problem faced by the invention is to provide an emulsion oil base comprising only an oil of natural origin, which could be used in the preparation of vaginal pharmaceutical formulations, wherein this base could be used alone as a drug carrier. Another problem faced by the invention is to provide a gel formulation for vaginal use with increased affinity to the vaginal walls, which would have a neutral pH towards the vaginal environment, enable the incorporation of lipophilic and/or hydrophilic active substances into the formulation and maintain a high concentration of active substance in formulation. Another problem is to provide a method for the preparation of an oil base and a gel formulation for vaginal use with increased adhesion to the vaginal walls, wherein the process of preparation of gel formulation should be carried out at room temperature.
The first object of the invention is an emulsion composition based on a vegetable oil and a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide, characterized in that the composition comprises from 20 to 60 parts by mass of vegetable oil, which is rapeseed oil, from 1 to 20 parts by mass of a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide, from 50 to 65 parts by mass of purified water, from 1 to 20 parts by mass of a surfactant which is a sorbitan ester.
In a preferred embodiment of the invention, the composition comprises from 30 to 50 parts by mass of vegetable oil, more preferably from 30 to 50 parts by mass of rapeseed oil.
In a further preferred embodiment of the invention, the sorbitan ester surfactant is selected from the group comprising: polyoxymethylene sorbitan monooleate in an amount from 1-20 parts by mass of the composition, preferably 10 parts by mass of the composition, or sorbitan monooleate in an amount of 1-12 parts by mass of the composition, preferably 5 parts by mass of the composition. In a further preferred embodiment of the invention, the composition comprises 50 parts by mass of purified water.
In another embodiment of the invention, the composition comprises a P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide in an amount of 5 to 10 parts by mass of the composition.
The second object of the invention is a multiphase composition comprising a vegetable oil-based composition according to the first object of the invention, characterized in that it comprises a gel phase and an emulsion phase according to the first object of the invention in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances, wherein the emulgel composition has a dynamic viscosity from 250 mPa»s to 750 mPa*s, preferably from 300 mPa*s to 700 mPa»s, wherein the gel phase comprises 0.1 to 10 parts by mass of Gellan gum and from 90 to 99.9 parts by mass of water, preferably 0.2 parts by mass of Gellan gum and 99.8 parts by mass of water. The addition of hydrophilizing substances, e.g. polyols, makes it possible to obtain the maximum concentration of the polysaccharide in the gel. Increasing the polysaccharide content leads to an improvement in the adhesive properties, i.e. affinity, of the finished formulation form, i.e. the emulgel. The absence of hydrophilizing substances therefore adversely affects the desired viscosity of the final emulgel and it is necessary to mix the thinner gel in greater proportion with the emulsion.
In a further preferred embodiment of the invention, the gel phase and the emulsion phase are mixed in a 1:1 weight ratio.
In yet another embodiment of the invention, the gel phase and the emulsion phase are mixed in a 1:4 weight ratio. The addition of hydrophilizing substances (polyols) makes it possible to increase the polysaccharide content in the gel phase, making it possible to obtain a formulation in which the amount of the gel phase is reduced to 20 parts by mass, while increasing the viscosity at the same time.
In a further preferred embodiment of the invention, the gel phase comprises from 0.1 to 10 parts by mass of the polysaccharide, which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
In another preferred embodiment of the invention, the gel phase comprises 10 parts by mass of the Gellan gum polysaccharide, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass. In a preferred embodiment of the invention, the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200). Apart from the fact that the addition of polyols allows to obtain gels with a higher polysaccharide content, the use of polyols makes it possible to obtain gels at room temperature, i.e. the process of producing the emulgel is carried out at room temperature.
In yet another preferred embodiment of the invention, the emulgel composition has a dynamic viscosity from 320 mPa»s to 670 mPa*s.
Another object of the invention is a method for preparing a vegetable oil-based emulsion composition as defined in the first object of the invention, comprising: a) preparation of the hydrophilic phase, b) combining the lipophilic (oil) phase with the hydrophilic phase, characterized in that the hydrophilic phase is prepared by com bining 50 to 65 parts by mass of water with a triblock copolymer in an amount of 1 to 20 parts by mass and a surfactant in an amount of 1 to 20 parts by mass of the surfactant, which is the sorbitan ester, then a lipophilic phase is added and the phases are prehomogenized for 15 min to 20 min, and the mixture is subjected to high pressure homogenization for 60 s to 80 s at a pressure of 400 bar to 1300 bar, wherein the high pressure homogenization cycle is carried out from two to ten times.
In a preferred embodiment of the invention, high pressure homogenization is carried out at a temperature of 37 °C to 69 °C, preferably 45 °C to 58 °C, most preferably 48 °C to 57 °C.
In a further preferred embodiment of the invention, the process is carried out at a pressure of 600 bar to 800 bar.
In a further preferred embodiment of the invention, the high pressure homogenization cycle is performed six to eight times.
Another object of the invention is a method for preparing a multiphase composition based on vegetable oil according to the second object of the invention, comprising: a) preparation of the gel phase, b) combining the emulsion phase with the hydrophilic phase, characterized in that a gel phase is prepared and the gel phase is combined with the emulsion phase, as defined in the second object of the invention, in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances. In a preferred embodiment of the invention, the gel phase is prepared by mixing 0.1 to 10 parts by mass of Gellan gum and 90 to 99.9 parts by mass of water, preferably 0.2 parts by mass of Gellan gum and 99.8 parts by mass of water.
In a further preferred embodiment of the invention, the gel phase and the emulsion phase are mixed in a 1:1 weight ratio.
In yet another embodiment of the invention, the gel phase and the emulsion phase are mixed in a 1:4 weight ratio.
In a further preferred embodiment of the invention, the gel phase is prepared by mixing 0.1 to 10 parts by mass of the polysaccharide, which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances, and from 60 to 100 parts by mass of water.
In another preferred embodiment of the invention, the gel phase is prepared by mixing 10 parts by mass of the polysaccharide, which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
In a preferred embodiment of the invention, the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
The invention relates to a pharmaceutical composition for the treatment of inflammation with a multiphase dosage form. 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 multiphase form is constructed on the basis of a polysaccharide, which has adhesive properties with respect to the vaginal mucosa. The adhesiveness of this drug form allows it to remain on the vaginal mucosa longer than is provided by prior art therapeutic methods. 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 addition of hydrophilizing substances allows to obtain the form of a formulation with a higher polysaccharide content, which has a positive effect on the adhesive properties to the vaginal walls. Another significant advantage is the possibility of carrying out the process of obtaining the formulation at room temperature. The obtained gel is characterized by a higher viscosity, thanks to which it can be mixed with the emulsion in smaller proportions to obtain the desired emulsion consistency. This is not without significance for the final concentration of the active ingredient in the emulgel - the lower the gel-to-emulsion ratio, the smaller the decrease in API concentration in the final formulation. 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 emulsions and emulgels 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. The 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 of the emulsion composition with Poloxamer 407:
Rapeseed oil 30.0 parts by mass,
Poloxamer 407 (P407 block copolymer of ethylene oxide and propylene oxide) 10.0 parts by mass, Purified water 50.0 parts by mass,
Tween 80 (polyoxymethylene sorbitan monooleate) 10.0 parts by mass.
The oil (lipophilic) phase of the composition is rapeseed oil. Purified water is combined with Poloxamer 407 and Tween 80. Both lipophilic and hydrophilic phases are combined and then prehomogenized with a magnetic stirrer at 40% power for 15 minutes. In the next stage of preparing the composition, the mixture is homogenized in a high-pressure homogenizer. High-pressure homogenization is carried out in 6 cycles, the maximum temperature is 57 degrees C. The applied pressure is 600 bar. The duration of one cycle is 60 seconds. The resulting form is an emulsion.
Example II. The composition of the emulsion composition with Poloxamer 188:
Rapeseed oil 40.0 parts by mass,
Poloxamer 188 (P188 block copolymer of ethylene oxide and propylene oxide) 5.0 parts by mass, Purified water 50.0 parts by mass,
Span 80 (sorbitan monooleate) 5.0 parts by mass.
The multiphase composition is prepared by mixing rapeseed oil with Span 80. Purified water is combined with poloxamer 188. Both lipophilic and hydrophilic phases are combined and then prehomogenized with a magnetic stirrer at 30% power for 20 minutes. In the next stage of preparing the composition, the mixture is homogenized in a high-pressure homogenizer. High-pressure homogenization is carried out in 8 cycles, the maximum temperature is 48 degrees C. The applied pressure is 800 bar. The duration of one cycle is 60 seconds. The resulting form is an emulsion.
Example III. The composition of the multiphase composition in the form of an emulgel. The pharmaceutical composition is prepared as in Example I or II. Then the gel is prepared:
Gellan Rubber 0.2 parts by mass,
Purified water 99.8 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 of 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 an emulsion. It is preferable to combine 50 parts by mass of the emulsion with 50 (1:1) parts by mass of the resulting gel. The obtained composition has a dynamic viscosity of 326.68 mPa»s.
In the further stages of development of the invention, it is planned to introduce 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.
Example IV. A method of making a pharmaceutical composition for vaginal use according to the first object of the invention.
The composition is made of rapeseed oil, water, poloxamer 407 or poloxamer 188 with the addition of the surfactant: Tween 80 or Span 80 as in Example I or II.
Rapeseed oil is mixed with Span 80 (compositions containing Span 80). Water purified according to Pharmacopeia XII (50 to 65 parts by mass) is combined with poloxamer 407 in the form of a white powder or poloxamer 188 in the form of white flakes and Tween 80 (compositions without Span 80). The resulting mixture is prehomogenized with a magnetic stirrer at 30-40% power for 15-20 minutes. The mixture is then homogenized in a GEA Niro Soavi Panda Plus high pressure homogenizer. High-pressure homogenization is carried out in 2 to 10 cycles at a temperature of 37- 69 degrees C. The applied pressure is in the range of 400-1300 bar. The duration of one cycle is 60 seconds. The resulting form is an emulsion.
Obtaining this form makes it possible to include hydrophilic medicinal substances in the hydrophilic phase, and lipophilic medicinal substances in the lipophilic phase. The composition according to this example may be a self-contained pharmaceutical emulsion for vaginal use. Example V. A method for making a polysaccharide-based multiphase pharmaceutical composition for vaginal use according to the second object of the invention.
The multiphase composition is prepared as described in method I, II or IV. Then an emulsion is prepared in the form of an emulgel.
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, from 60 to 100 parts of water, preferably 60 parts by mass. 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 emulsion described in example I, II or IV 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. It is preferable to combine the emulsion in an amount of 80 parts by mass with 20 (4:1) parts by mass of the resulting gel. The resulting advantageous combination forms a formulation having a dynamic viscosity of 654,80 mPa»s.
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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.; Girafdo, 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. Appl. 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.; Cahadas-Enrich, C.; Febrer, N.B. de; Suner-Carbo, J.; Souto, E.B.; Clares-IMaveros, 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.; Suher-Carbo, J.; Calpena-Campmany, A.C.; Bozal-de Febrer, N.; Halbaut- Bellowa, L; Boix-Montanes, A.; Souto, E.B.; Clares-IMaveros, B. Clotrimazole multiple W/O/W emulsion as anticandidal agent: Characterization and evaluation on skin and mucosae. Colloids Surfaces B Biointerfaces 2019, 175, 166-174, doi:10.1016/j.colsurfb.2018.11.070.

Claims

Claims
1. An emulsion composition based on a vegetable oil and a P407 block copolymer of ethylene oxide/propylene oxide or a P188 block copolymer of ethylene oxide/propylene oxide, characterized in that the composition comprises from 20 to 60 parts by mass of a vegetable oil which is rapeseed oil, from 1 to 20 parts by mass of P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide, from 50 to 65 parts by mass of purified water, from 1 to 20 parts by mass of surfactant which is a sorbitan ester.
2. The composition according to claim 1, characterized in that it contains from 30 to 50 parts by mass of vegetable oil, more preferably from 30 to 50 parts by mass of rapeseed oil.
3. The composition according to claim 1, characterized in that the sorbitan ester surfactant is selected from the group consisting of: polyoxymethylene sorbitan monooleate in an amount of 1-20 parts by mass of the composition, preferably 10 parts by mass of the composition, or sorbitan monooleate in an amount of 1-12 parts by mass of the composition, preferably 5 parts by mass of the composition.
4. The composition according to claim 1, characterized in that it comprises 50 parts by mass of purified water.
5. The composition according to claim 1, characterized in that it comprises P407 block copolymer of ethylene oxide and propylene oxide or a P188 block copolymer of ethylene oxide and propylene oxide in an amount of from 5 to 10 parts by mass of the composition.
6. Multiphase vegetable oil-based composition, characterized in that it comprises a gel phase and an emulsion phase according to claim 1, in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances, wherein the emulgel composition has a dynamic viscosity from 250 mPa»s to 750 mPa*s, preferably from 300 mPa»s to 700 mPa»s, wherein the gel phase comprise 0.1 to 10 parts by mass of Gellan gum and 90 to 99.9 parts by mass of water, preferably 0.2 parts by mass of Gellan gum and 99.8 parts by mass of water.
7. The composition according to claim 6, characterized in that the gel phase and the emulsion phase are mixed in a 1:1 weight ratio.
8. The composition according to claim 6, characterized in that the gel phase and the emulsion phase are mixed in a 1:4 weight ratio.
9. The composition according to claims 6 to 8, characterized in that the gel phase comprises 0.1 to 10 parts by mass of the polysaccharide which is Gellan gum, 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
10. The composition according to claims 6 to 9, characterized in that the gel phase comprises 10 parts by mass of the polysaccharide which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
11. The composition according to claim 6, 10 or 10, characterized in that the gel phase comprises hydrophilizing substances selected from the group comprising: glycerol, 1,2- propylene glycol or polyoxyethylene glycol 200 (PEG-200).
12. The composition according to claim 6, characterized in that in the form of an emulgel, the composition has a dynamic viscosity from 320 mPa»s to 670 mPa»s.
13. A method of preparation of vegetable oil-based emulsion composition as defined in claim 1, comprising: a) preparation of the hydrophilic phase, b) combining the lipophilic (oil) phase with the hydrophilic phase, characterized in that the hydrophilic phase is prepared by combining 50 to 65 parts by mass of water with a triblock copolymer in an amount of 1 to 20 parts by mass and a surfactant which is a sorbitan ester in an amount of 1 to 20 parts by mass of surfactant, then a lipophilic phase is added and the phases are prehomogenized for 15 min to 20 min, and the mixture is subjected to high pressure homogenization for 60 s to 80 s at a pressure of 400 bar to 1300 bar, wherein the high pressure homogenization cycle is carried out two to ten times.
14. The method according to claim 13, characterized in that the high pressure homogenization is carried out at a temperature of 37 °C to 69 °C, preferably 45 °C to 58 °C, most preferably 48 °C to 57 °C.
15. The method according to claim 13, characterized in that the process is carried out at a pressure of 600 bar to 800 bar.
16. The method according to claim 13, characterized in that the high pressure homogenization cycle is carried out six to eight times.
17. A method of preparation of multiphase composition based on a vegetable oil, as defined in claim 6, comprising: a) preparation of the gel phase, b) combining the emulsion phase with the hydrophilic phase, characterized in that the gel phase is prepared and the gel phase is combined with the emulsion phase according to claim 1 in a 1:1 to 1:4 weight ratio, and the composition is in the form of an emulgel, wherein the gel phase optionally comprises hydrophilizing substances.
18. The method according to claim 17, characterized in that the gel phase is prepared by mixing 0.1 to 10 parts by mass of Gellan gum and 90 to 99.9 parts by mass of water, preferably 0.2 parts by mass of Gellan gum and 99.8 parts by mass of water.
19. The method according to claim 17 or 18, characterized in that the gel phase and the emulsion phase are mixed in a 1:1 weight ratio.
20. The method according to claim 17, characterized in that the gel phase and the emulsion phase are mixed in a 1:4 weight ratio.
21. The method according to claim 18 or 21, characterized in that the gel phase is prepared by mixing 0.1 to 10 parts by mass of the polysaccharide which is Gellan gum, 5 to 30 parts by mass of hydrophilizing substances, and 60 to 100 parts by mass of water.
22. The method according to claim 17, 20 or 21, characterized in that the gel phase is prepared by mixing 10 parts by mass of the polysaccharide which is Gellan gum, from 5 to 30 parts by mass of hydrophilizing substances and water to 100 parts by mass.
23. The method accordingto claim 17, 20, 21 or 22, characterized in that the hydrophilizing substances are selected from the group comprising: glycerol, 1,2-propylene glycol or polyoxyethylene glycol 200 (PEG-200).
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