• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    Water-based vaginal lubricant formulation, containing at least one moisturizing agent, a lubricating agent and a viscosifying agent, for the relief of symptoms associated with vaginal dryness. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2685002A1
    申请号:ES201700388
    申请日:2017-03-31
    公开日:2018-10-05
    发明作者:Jaime Moscoso Del Prado；Pedro Enrique ESQUINAS GONZÁLEZ
    申请人:ITF Res Pharma S L U；ITF RESEARCH PHARMA SLU；
    IPC主号:
    专利说明:

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    DESCRIPTION
    Lubricating formulations
    Field of the Invention
    The present invention relates to vaginal lubricant formulations and their use in the treatment of vaginal dryness.
    State of the art
    Although it is particularly common during and after menopause, vaginal dryness is prevalent among women of all ages. The reported values vary but it is estimated that approximately 15% of premenopausal women and up to 60% of postmenopausal women experience this condition.
    In many women the symptoms associated with vaginal dryness have a negative impact on their quality of life, affecting daily activities, mood and sexual intercourse. Insufficient lubrication is a common complaint in women of all ages, who as a result suffer episodes of burning, stinging and vulvovaginal discomfort that can lead to pain during sexual activity (dyspareunia).
    Vaginal dryness, also called urogenital atrogia or atrophic vaginitis, is caused by a decrease in estrogenic levels.
    When the vagina is well supplied with estrogen, the epithelial tissue that lines the genitourinary tract is thicker and presents more folds, which allows its stretching during sexual intercourse and childbirth. When estrogen levels drop, the vaginal mucosa becomes thinner and has fewer folds, which makes it more fragile and less flexible. In addition, vaginal discharge and, therefore, lubrication are reduced. When this occurs, the vulvovaginal epithelium is more susceptible to injury and bleeding, and many women experience local symptoms (dryness, irritation, burning, itching and / or dyspareunia).
    Estrogen levels naturally decrease after menopause or may decrease as a result of the use of antiestrogenic drugs (for treatment of breast cancer, endometriosis, uterine fibroids or infertility), ovarian removal, pelvic radiotherapy, chemotherapy, lactation, Stress or excessive physical exercise.
    The vulvovaginal epithelium can also be damaged by the use of personal hygiene products (soaps, lotions, perfumes or douching), tobacco use and the use of tampons or condoms.
    First-line treatments for vaginal atrophy include non-hormonal vaginal lubricants and moisturizers. Lubricants have proven effective for quick and short-term relief of vaginal dryness and dyspareunia. They should be applied frequently, in order to provide more permanent relief, and require a new application before sexual intercourse, to minimize friction and consequent irritation.
    Although vaginal lubricants have proven effective in relieving vaginal dryness, their components and / or their properties may be of concern to the doctor or patient in specific situations.
    Lactobacilli constitute the dominant microbial flora in the vagina under normal conditions and have a critical role in maintaining the vaginal ecosystem by preventing
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    excessive proliferation of other usual microorganisms, such as Gardnerella vaginalis, and preventing colonization by pathogenic microorganisms, such as Escherichia coli.
    Therefore, it is highly recommended that vaginal lubricants do not affect the local microbiota, since dysbiosis of the vaginal cavity leads to the appearance of vaginal infections (vaginosis).
    On the other hand, the pH and osmolarity of lubricants should be similar to those of the vagina under normal conditions, so as not to cause changes in the vaginal epithelium or be irritating.
    The World Health Organization (WHO) recommends that the osmolarity of lubricant formulations not exceed 380 mOsm / kg. Greater osmolarity has been linked to a greater potential to cause mucosal irritation and damage to the vaginal epithelium. Despite this, the osmolarity of vaginal lubricants available on the market varies widely, many of them exceeding 1200 mOsm / kg.
    In women of childbearing age, the vaginal pH ranges between 3.8 and 5, depending on the phase of the menstrual cycle in which it is found, while it happens to be around 7 in postmenopausal women. The pH of the various commercial lubricants varies within a wide range. Animal studies suggest that values less than or equal to 3 would not be acceptable for human use.
    As previously mentioned, vaginal dryness is a very preferred pathology and affects women of all ages.
    For women with a desire to conceive, it is important that lubricant formulations do not affect the integrity and function of sperm, as this would decrease their fertilization potential. Despite this, several studies have reported a detrimental effect of commercially available lubricants on sperm motility and function.
    Finally, for women who only seek to improve their sexual relations, it is important that the components of the lubricant formulation do not affect the integrity of condoms.
    Lubricants can be formulated based on water, silicone or oily derivatives. However, the use of oil-based formulations is often discouraged since, in addition to being more difficult to wash and favor vaginal infections, they can damage latex condoms.
    Summary of the Invention
    There is therefore a need for a vaginal lubricant formulation that meets, at the same time, the following characteristics:
    - do not alter the normal vaginal flora,
    - do not irritate the vaginal mucosa,
    - be compatible with condoms,
    - maintain sperm viability.
    The inventors of the present have found that a careful selection of their components allows to obtain a lubricant formulation that meets all these
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    requirements and, in addition, it has organoleptic / physicochemical characteristics similar to those of normal vaginal secretions.
    In particular, they have developed an aqueous formulation that combines the following properties:
    - pH: between 5.5 and 7.5, preferably between 6 and 7;
    - viscosity: between 2000 and 4800 mPas, preferably between 2500 and 4500 mPas;
    - osmolarity: less than or equal to 380 mOsm / kg, preferably between 300 and 380 mOsm / kg.
    Accordingly, a first aspect of the present invention relates to a water-based vaginal lubricant formulation, which comprises:
    - a wetting agent;
    - a lubricating agent;
    - a viscosifying agent.
    A second aspect of the present invention relates to the use of the vaginal lubricant formulation for the relief of symptoms associated with vaginal dryness.
    A third aspect of the present invention relates to the process for the preparation of the vaginal lubricant formulation.
    Figures
    Fig. 1: Preparation scheme of the lubricant formulation on an industrial scale.
    Detailed description
    In a preferred embodiment the lubricant formulation is an aqueous gel comprising:
    - a wetting agent selected from glycerin (or glycerol) and propanediol,
    - a lubricating agent selected from glyceryl acrylate / acrylic acid copolymer and methyl vinyl ether / maleic anhydride copolymer (PVM / MA copolymer) and mixtures thereof.
    - a viscosifying agent selected from hydroxyethyl cellulose (of varying degrees of viscosity), xanthan gum, acacia gum and mixtures thereof.
    Preferably, the wetting agent is glycerin in an amount between 1 and 2% w / w, more preferably in an amount of (1.2 ± 0.1)% w / w. Alternatively, it may contain propanediol in an amount between 1 and 3% w / w or a mixture of 1% w / w glycerin and 0.25% w / w propanediol as a wetting system.
    Preferably, the lubricating agent is a mixture containing at least one glyceryl acrylate / acrylic acid copolymer, in an amount between 0.005 and 0.007% w / w, and a methyl vinyl ether / maleic anhydride copolymer, in an amount between 0.0025 and 0.0035% w / w
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    More preferably, the lubricant is a mixture of glyceryl acrylate / acrylic acid copolymer in an amount of (0.006 ± 0.0005)% w / w and MVA / MA copolymers in an amount of (0.003 ± 0.0002)% w / p.
    Particularly preferably, the lubricating agent is incorporated into the formulation as part of a lubricating system that further includes a wetting agent and a preservative. For example, an amount of (0.5 ± 0.1)% by weight can be used of the formulation of the lubricating system marketed under the Lubrajel Oil-Free® brand, which contains glycerin (36.5 - 44.6% w / w), glyceryl acrylate / acrylic acid copolymer (1.07 - 1.31% p / p), PVM / MA copolymer (0.56-0.68% w / w) and phenoxyethanol (0.99-1.2% w / w) and water (50.8-60% w / w) .
    Preferably, the viscosifying agent is selected from hydroxyethylcellulose of varying degrees of viscosity, hydration and biological and degradative resistance. In a more preferred embodiment, the viscosifying agent is high viscosity hydroxyethylcellulose (for example, commercially available under the Natrosol 250HHX® brand), in an amount between 0.6 and 1% w / w, preferably in an amount of (0 , 8 ± 0.1)% w / w.
    The lubricant formulation of the present invention may also contain other excipients. Preferably, it also contains at least one preservative agent and a pH regulating system (buffer).
    The preservative agent is selected from phenoxyethanol, methyl sodium paraben, sodium propyl paraben and mixtures thereof.
    Additionally, it may contain a preservative enhancing agent selected from ethylhexylglycerol (or ethylhexylglycerin), phenethylalcohol, phenylpropanol and caprylglycol.
    In a preferred embodiment, the formulation contains phenoxyethanol in an amount between 0.45 and
    1% w / w, preferably in an amount of (0.9 ± 0.1)%
    p / p.
    In another preferred embodiment, the formulation contains phenoxyethanol in an amount of (0.9 ± 0.1)% w / w and ethylhexyl glycerol in an amount of (0.09 ± 0.01)% w / w.
    Optionally, the preservative agent can be incorporated premixed with the enhancer. For example, an amount between 0.5 and 1% by weight of the preservative system formulation marketed under the brand Euxyl PE-9010®, containing phenoxyethanol (90% w / w) and ethylhexylglycerol (10% wt. / p).
    The buffer is any pharmaceutically acceptable pH regulator system that allows maintaining the pH of the formulation between 6 and 7, preferably at a value of 6.5 ± 0.2.
    Preferably it is selected from potassium phosphate buffer (monobasic potassium phosphate), citrate buffer (trisodium citrate) and lactic buffer (lactic acid) and is prepared according to European Pharmacopoeia.
    In a preferred embodiment, the pH regulating system is formed by monobasic potassium phosphate in an amount between 0.65 and 0.70% w / w, more preferably in an amount of (0.68 ± 0.02)% w / p, and 10% w / v sodium hydroxide in an amount between 0.2 and 1.2%, w / w, more preferably in an amount of (0.7 ± 0.1)% w / w.
    The lubricant formulation of the present invention may also contain other pharmaceutically acceptable excipients. Thus, some ingredient with soothing and / or regenerative properties could be incorporated, such as Biosaccharide Gum-1, an acid polysaccharide
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    galacturonic, L-Fucose and D-Galactose, with moisturizing and soothing properties of the skin (commercially available, for example, with the Fucocert® brand) or Biosaccharide Gum-2, a galacturonic acid, galactose and rhamnosa polysaccharide, which acts by decreasing inflammatory reactions and promoting skin regeneration (marketed, for example, under the brand name Rhamnasoft®).
    In an especially preferred embodiment, the formulation of the present invention is an aqueous gel comprising:
    - glycerin between 1 and 2% w / w,
    - a mixture of glyceryl acrylate / acrylic acid copolymer between 0.005 and 0.007% w / w and PVM / MA copolymer between 0.0025 and 0.0035% W / W,
    - high viscosity hydroxyethylcellulose between 0.6 and 1% w / w,
    - a mixture of phenoxyethanol between 1 and 0.8% w / w and ethylhexyl glycerol between 0.1 and 0.08% w / w,
    - monobasic potassium phosphate between 0.65 and 0.70% w / w,
    - 10% w / v sodium hydroxide between 0.2 and 1.2% w / w.
    The viscosity is measured with a rotary viscometer (Brookfield RVT or equivalent), with spin 4, at a speed of 20 rpm. The formulation must be at a temperature of 20 ± 1 ° C at the time of analysis.
    Osmolarity is determined according to European Pharmacopoeia and pH using a pH meter.
    The lubricant formulations of the present invention are useful for treating vulvovaginal symptoms associated with vaginal dryness, in particular dyspareunia, and improving lubrication during sexual intercourse.
    The lubricant formulations of the present invention can be prepared according to any procedure known to a person skilled in the art.
    In a particular embodiment, the lubricant formulation of the present invention is prepared according to the procedure described below.
    The invention is illustrated by the following non-limiting examples.
    Example 1: Preparation Procedure
    A quantity of purified water between 85% and 90% of the total amount is added to a reactor.
    Next, all water-soluble excipients (humectant, lubricant, preservative and buffer) are added, one by one and under stirring, allowing sufficient time for complete dissolution in each case.
    Once the water-soluble components have been added, a pH check of the solution and an adjustment is made in the established pH range (6.3 - 6.7), to ensure that the subsequent wetting of the viscosizer is correct and to reach the values of desired viscosity.
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    When the pH of the solution has been adjusted to the preset value, the viscosifying agent is dispersed in the solution, adding it little by little and leaving enough time for proper distribution and wetting.
    Once the gel is formed, purified water is added until the final weight of the formulation is reached and the product is homogenized with a new stirring process.
    Figure 1 shows the industrial scale preparation procedure
    schematic
    Example 2. Formulation A
    Ingredient amount (g)
    Glycerin 1,203 g
    Acrylic acid / glyceryl acrylate copolymer 0.006 g
    Methylvinylene ether / maleic anhydride copolymer 0.003 g
    0.800 g hydroxyethyl cellulose
    Phenoxyethanol 0.900 g
    Ethylhexyl glycerol 0.099 g
    Potassium phosphate 0.680 g
    10% sodium hydroxide 0.700 g
    Purified water csp 100 g
    Example 3. Formulation B
    Ingredient amount (g)
    Glycerin 1,203 g
    Acrylic acid / glyceryl acrylate copolymer 0.006 g
    Methylvinylene ether / maleic anhydride copolymer 0.003 g
    Hydroxyethylcellulose 0.700 g
    Phenoxyethanol 0.800 g
    Ethylhexyl glycerol 0.089 g
    Potassium phosphate 0.680 g
    10% sodium hydroxide 0.700 g
    Purified water csp 100 g
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    Example 4. Essays
    1. NO ALTERATION OF THE VAGINAL FLORA
    A study was conducted to evaluate the compatibility of the vaginal lubricant formulation of the present invention with various strains of lactobacilli, typical of vaginal flora.
    To do this, 0.1 ml of a suspension of 3 strains in saline solution (0.9% NaCl):
    - Lactobacillus acidophilus CECT 362 4.3x107 CFU / ml,
    - Lactobacillus jensenii CECT 4306 5,7x107 CFU / ml, and
    - Lactobacillus crispatus CECT 4840 6.8x10 'CFU / ml,
    It was inoculated in 10 ml of different dilutions of Formulation B (Example 3) in saline solution (0.9% NaCl):
    - 100% Gel B: 1% bacteria suspension + 99% formulation B
    - 80% Gel B: 1% bacteria suspension + 80% formulation B + 19% saline solution 20
    - 60% Gel B: 1% bacteria suspension + 60% formulation B + 39% saline solution
    - Gel B 40%: 1% bacteria suspension + 40% formulation B + 59% saline solution
    - 20% Gel B: 1% bacteria suspension + 20% formulation B + 79% saline solution
    The suspension of 3 strains of Lactobacillus was also inoculated in 10 ml of saline solution (without Formulation B, as a negative control) and in 10 ml of a bactericidal solution (as a positive control).
    All samples were incubated for a preset contact time (30 minutes) at room temperature (20 ° -25 ° C).
    Once the contact time was over, the Lactobacillus count was made by plating.
    The samples were shaken and 1 ml of each was taken. The initial dilution was performed in neutralizer (peptone-lecithin-polysorbate broth) and the following dilutions in saline solution (0.9% NaCl).
    1 ml of each of the dilutions was seeded in TSA and incubated at 30-35 ° C. Once the incubation time was over, the count was performed.
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     FORMULATION  lactobaciHus spp Suspension control Concentration 100% 80% 60% 40% 20%
     Dilution  102 103 102 103 102 103 102 103 102 103
     Gel B  L cr / maws 6.8x105 UFC / plate 159 17> 300 40> 300 44> 300 49> 300 56
     CFU / ml  1.6 x 104 4.0 x 104 4.4x104 4.9 x104 5.6x104
     L. $ c i0Qp hy! U $  4.3x105 CFU / plate 132 18> 300 77> 300 84> 300 96> 300 85
     CFU / ml  1.3 x104 7.7x104 8.4x104 9.6x104 8.5x104
     Ljensenii  6.7x105 CFU / plate> 300 48> 300 40> 300 43> 300 192> 300 | > 300
     CFU / ml  4.8x104 4.0x104 4.3x104 1.9 x105> 3.0x105
     FORMULATION  Lacmbacillus spp Suspension control Concentration 100% 80% 60% 40% 20%
     Dilution  102 103 102 103 102 103 102 103 102 103
     Bactericide  ■ C / 7SJJS.Í4 / S. 6.8x105 CFU / plate 0 0 4 0 24 6> 300 47> 300 110
     CFU / ml  <1.0 x 102 4.0x102 2.4x103 4.7x104 1.1 x 105
     L. dGi0Qphylu§  4.3x105 CFU / plate 0 0 0 0 6 0 19 2> 300 84
     CFU / ml  <1.0 x 102 <1.0 x102 6.0x102 1.9 x103 8.4 x 104
     LJmsmii  5.7x105 CFU / plate 0 0 16 0 ro or 4 * -> 300 52> 300 121
     CFU / ml  <1.0 x 102 1.6x103 2.0 x103 5.2x104 1.2x105
    The study allows us to conclude that there is a clear difference between the count obtained with the bactericidal product, which shows decreases in the number of colonies greater than 3 logarithms, and the rest of the samples, which show a decrease in the number of zero or no colonies. Almost nil.
    2. NO IRRITATION OF THE VAGINAL MUCOSA
    The osmolarity of Formulation B (Example 3) with 4 different concentrations of preservative was studied according to the European Pharmacopoeia:
    Gel B with phenoxyethanol 0.45%
    Gel B with phenoxyethanol 0.63%
    Gel B with phenoxyethanol 0.81%
    Gel B with phenoxyethanol 0.90%
    A value of less than 380 mOsm / kg was obtained in all cases, a limit recommended by the WHO to minimize the risk of epithelial damage that an intimate lubricant can cause. In particular, Formulation B with 0.81% phenoxyethanol and 0.90% phenoxyethanol had an osmolarity of 365 mOsm / kg and 368 mOsm / kg, respectively.
    According to the scientific literature regarding the effect of the osmolarity of 15 lubricating products on the vaginal mucosa, the osmolarity values obtained with the formulation of the present invention have no negative effects on the vaginal epithelium.
    3. COMPATIBILITY WITH PRESERVATIVES:
    The compatibility of the vaginal lubricant formulation of the present invention with preservatives, both latex and polyurethane, was studied.
    To do this, condoms were contacted with Formulation B (Example 3) and changes in tear and tear properties were evaluated according to the standard method (ASTM D7661-10).
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    Based on the results of the tests it can be concluded that the formulation of the present invention shows full compatibility with both types of condoms.
    4. MAINTENANCE OF Sperm Viability
    In vitro studies were conducted to evaluate the effect of the vaginal lubricant formulation of the present invention on the viability of human sperm. For this, the effect of the formulation on its motility and vitality was analyzed.
    First, semen samples from healthy donors were subjected to liquefaction at 37 ° C for 30 minutes and analyzed to ensure that their characteristics were within the reference limits established by WHO.
    Once liquefied, each of the samples was subjected to a count of the total number of sperm present and subsequently diluted in the different culture media: HTS + 10% HSA (human tubal fluid + 10% serum albumin, negative control), Octoxynol-9 spermicide solution in HTF + 10% HSA (positive control) and Gel B solution 10% in HTF + 10% HSA.
    Samples were incubated for 30 minutes at 37 ° C and 5% C02.
    Finally, with these samples the following studies were carried out:
    Motility study, which allows determining the percentage of sperm with progressive motility (PR), non-progressive (NP) and inmotility (IM) using a phase contrast microscope at x200 or x400.
    Vitality study by Eosina-Nigrosina, which allows counting the number of unstained (live) and stained (dead) spermatozoa.
    Vitality test due to hypo-osmotic swelling, which allows counting the number of sperm with membrane swelling (live) and without membrane swelling (dead).
    The conclusions of the study were that the presence of the formulation of the present invention:
    It does not affect sperm motility when compared to motility in the negative control.
    It does not significantly modify the sperm vitality measured using Eosin-Nigrosin when compared to the vitality observed in the negative control.
    Nor does it significantly modify the vitality of sperm 5 determined by hypo-osmotic swelling when compared to the vitality observed in the negative control.
    In addition, the osmolarity study serves to confirm the compatibility of the formulations of the present invention with sperm, since these 10 (osmolarity around 365 mOsm / kg) are practically isosmolar with seminal plasma, uterine and testicular fluid ( osmolarity between 300-400 mOsm / kg).
    权利要求:
    Claims (13)
    [1]
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    1. Vaginal lubricant composition, comprising:
    - A wetting agent selected from glycerin and propanediol.
    - A lubricating agent selected from glycol acrylate / acrylic acid copolymer and methyl vinyl ether / maleic anhydride co-meter and mixtures thereof.
    - A viscosifying agent selected from hydroxy ethylene cellulose of different viscosity grades, xanthan gum, acacia gum and mixtures thereof.
    [2]
    2. Composition according to claim 1 characterized in that the wetting agent is glycerin in an amount between 1% and 2% w / w.
    [3]
    3. Composition according to claim 1 characterized in that the lubricating agent is a mixture containing a glycol acrylate / acrylic acid copolymer, in an amount between 0.005% and 0.007% w / w, and a methyl vinyl ether / maleic anhydride copolymer, in an amount between 0.0025% and 0.0035% w / w.
    [4]
    4. Composition according to claim 1 characterized in that the viscosifying agent is high viscosity hydroxyethylcellulose, in an amount between 0.6% and 1% w / w.
    [5]
    5. Composition according to claim 1 characterized in that it further comprises a preservative selected from phenoxyethanol, sodium methylparaben, sodium propylparaben and mixtures thereof.
    [6]
    6. Composition according to claim 5 wherein the preservative is phenoxyethanol in an amount between 0.45% 1% w / w.
    [7]
    7. Composition according to claim 5 further comprising an enhancer of the preservative selected from ethylhexylglycerol, phenylalkyl alcohol, phenylpropanol and capryglycol.
    [8]
    8. Composition according to claims 6 and 7 wherein the preservative is a mixture of phenoxyethanol in an amount of (0.9 ± 0.1)% w / w and ethylhexyl glycerol in an amount of (0.9 ± 0 , 1)% p / p.
    [9]
    9. Composition according to claim 1, characterized in that it further comprises a pH agent selected from potassium phosphate buffer, clitrate buffer and lactic buffer.
    [10]
    10. Composition according to claim 9 wherein the pH regulating agent is the potassium phosphate buffer formed by monobasic potassium phosphate in an amount between 0.65% and 0.70% w / w, and sodium hydroxide. % w / v in an amount between 0.2% and 1.2% w / w.
    [11]
    11. Use of the composition of any of the preceding claims to prepare a formulation intended for the treatment of vaginal dryness.
    [12]
    12. Use according to claim 11 to prepare a formulation for the treatment of dyspareunia.
    [13]
    13. Use of the composition of any of claims 1 to 10 to prepare a formulation intended to improve lubrication during sexual intercourse.
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    ES201700388A|ES2685002B1|2017-03-31|2017-03-31|Lubricant formulations|ES201700388A| ES2685002B1|2017-03-31|2017-03-31|Lubricant formulations|
    PE2019001966A| PE20191536A1|2017-03-31|2018-03-28|LUBRICATING FORMULATIONS|
    CN201880023941.3A| CN110709070A|2017-03-31|2018-03-28|Lubricating oil formulation|
    EP18776381.8A| EP3603627A4|2017-03-31|2018-03-28|Lubricant formulations|
    PCT/ES2018/070266| WO2018178478A2|2017-03-31|2018-03-28|Lubricant formulations|
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