Vaginal contraceptive composition for reinforcement of mucus barrier properties

Abstract

To provide a mucoadhesive polymer capable of cross-linking the cervical-vaginal mucus layer without aggregation of the mucus, or with a lesser degree of aggregation compared to a prior composition.SOLUTION: The disclosure relates to a vaginal contraceptive composition comprising one or more active ingredients and a physiological acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, wherein the mucoadhesive polymer has a molecular weight between 20,000 Da and 100,000 Da, wherein the mucoadhesive polymer consists of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations hereof, wherein the monomer units are selected from C6 sugars, amino-functionalised C6 sugars, amino acids, or combinations hereof, and wherein at least 50% of the monomer units comprise at least one amino group.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] Technical Field The present invention relates to a vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients being a mucoadhesive polymer. The present invention also relates to the use of such a vaginal contraceptive composition in therapy or contraception. The mucoadhesive polymer is capable of cross-linking the mucus layer without causing the mucus to aggregate. [Background technology]

[0002] Background technology Citations and incorporation of patent documents herein are done for convenience only and do not reflect any review of the validity, patentability, and / or enforceability of such patent documents.

[0003] A rapidly increasing number of women are dissatisfied with hormonal contraceptives, but are unable to find an alternative that is convenient (no implants, easy to use, flexible to use) and effective (more than 90% effective with typical use). In fact, 125 million couples in Europe and the United States use birth control, and hormonal contraceptives (pills, patches, implants, rings, etc.) are by far the most used birth control method. However, the growing awareness of side effects caused by hormones has a strong impact on the contraceptive market. There is now solid evidence of side effects of hormonal contraceptives.Three studies involving 500,000 to 1.8 million women found that hormonal contraception use increased the proportion of women taking antidepressants by 23%, nearly doubled among teenagers (Charlotte Wessel Skovlund, Lina Steinrud Morch, Lars Vedel Kessing, and Ojvind Lidegaard. 2016. "Association of Hormonal Contraception With Depression." JAMA Psychiatry 73(11):1154-62), increased the proportion of women attempting suicide by 197%, and increased the suicide rate by 308% (Charlotte Wessel Skovlund, Lina Steinrud Morch, Lars Vedel Kessing, Theis Lange, and Ojvind Lidegaard. 2017. "Association of Hormonal Contraception With Suicide Attempts and Suicides." The American Journal of Psychiatry,November) and increases the risk of developing breast cancer by 9% if used for less than a year and up to 38% if used for 10 years (Lina S. Morch, Charlotte W. Skovlund, Philip C. Hannaford, Lisa Iversen, Shona Fielding, and Ojvind Lidegaard. 2017. "Contemporary Hormonal Contraception and the Risk of Breast Cancer." The New England Journal of Medicine 377(23):2228-39). Many women want to stop using hormonal contraception but are unable to find a suitable alternative. Current alternatives are either inconvenient (condoms, diaphragms) or invasive (copper and hormone-eluting implants) and may be less effective when actually used (e.g., condoms are only 85% effective on average).

[0004] There are over 400 square meters of epithelial surface hidden within the human body, including the lungs, digestive tract, and female reproductive tract. Moist epithelial surfaces rely on mucus gel for protection from dehydration, shear stress, and infection. Besides water, mucus contains mainly mucin biopolymers mixed with proteins, lipids, and salts. Mucins are large glycoproteins consisting of an elongated central protein core tightly conjugated with oligosaccharides that may account for up to 50% of the molecular weight of the molecule. Mucins play a central role in protective functions, creating a barrier that acts as a size-exclusion and affinity-based selective filter, preventing many harmful molecules from reaching the epithelial surface.

[0005] Mucoadhesive polymers have been used in drug delivery due to their adhesive properties, for example, they have been used to deliver drugs to sites of inflammation.

[0006] Mucoadhesive polymers are typically assembled together with drugs into a material or gel, which is intended to concentrate the drug at the surface of the mucus layer and improve drug delivery.

[0007] WO2004069230 relates to pharmaceutical compositions containing a physiologically active agent, i.e. a drug, and a sustained release or mucoadhesive agent, such as chitosan, which serves to prolong the release of the active agent from the composition.

[0008] Another use of chitosan is in female contraception. One example of this can be found in CN102895256, which relates to a chitosan gel foam suitable for female contraception and fungicidal effects and its preparation method, belonging to the technical field of foam manufacturing. According to this disclosure, chitosan molecules are trapped in a solid foam matrix together with polyacrylic acid, which physically prevents the passage of sperm. Moreover, chitosan has a molecular weight distribution of 2000-5000 Da, a degree of deacetylation of more than 95%, and a concentration of 5-10% by weight, while polyacrylic acid is at a concentration of 1-3% by weight.

[0009] Another example of chitosan for female contraception can be found in WO2018185321, which relates to a mucoadhesive polymer, more specifically chitosan, capable of cross-linking the mucus layer without causing the mucus to aggregate. Chitosan consists of 4-20 monomer units and a degree of deacetylation of more than 50%.

[0010] A third example is found in US Pat. No. 4,474,769, which relates to a method for killing or inactivating mammalian sperm by injecting a chitosan formulation directly into the uterine cavity of a woman over an extended period of time.

[0011] Although mucoadhesive molecules are known to promote the tightness and thickening of mucosal tissue or enhance the barrier function, use has shown that mucoadhesive polymers and mucus-penetrating nanoparticles crosslink and aggregate mucus, resulting in the formation of highly expanded interpenetrating polymer networks. Thus, aggregation of mucus leads to the opening of pores in the mucus, weakening the barrier properties of mucus. Thus, there remains a need in the art for compositions that show improvements in crosslinking mucus without aggregation. Summary of the Invention [Problem to be solved by the invention]

[0012] It is therefore an object of the present invention to provide a mucoadhesive polymer capable of cross-linking the mucus layer at the female cervical introitus, i.e. the cervicovaginal region, without causing mucus clumping or with a lesser degree of clumping compared to prior compositions in the art. The cervicovaginal region is the outer protective mucous membrane of the cervix. Preferably, the mucoadhesive polymer is also capable of cross-linking the mucus layer at the female cervical introitus in the endocervix, the mucous membrane of the cervical canal. The cross-linking should be sufficient to prevent motile spermatozoa from migrating through the mucus layer.

[0013] Another object of the present invention is to provide a mucoadhesive polymer that provides a more reliable barrier effect to prevent cells and microorganisms, such as bacteria, viruses, and / or sperm, from penetrating the crosslinked mucus and spreading into the mucosa.

[0014] It is yet another object of the present invention to provide a mucoadhesive polymer that provides a sufficient barrier effect to prevent pregnancy and / or sexually transmitted infections (STIs). [Means for solving the problem]

[0015] overview Now, a newly developed technology has been discovered that offers a non-invasive, easy to use, and effective alternative to hormonal contraception. The approach relies on temporarily rendering the cervical mucus, the body's natural barrier between the vagina and uterus, impermeable to sperm cells. Cervical mucus protects women from infections and is primarily impermeable to foreign cells throughout the month. However, around the day of ovulation, hormonal changes loosen the mucus, which then becomes highly permeable to sperm cells. It has been found that delivery of mucoadhesive (bio)polymers to the cervical mucus can alter the microstructure of the mucus gel, thereby reinforcing the body's own natural barrier and preventing fertilization.

[0016] It was previously stated that low molecular weight mucoadhesive polymers containing 4-20 monomers (see for example WO 2018185321 or Biomacromolecules, 2018, 19, 3, 872-882) are ideal mucoadhesive polymers that enhance mucus barrier properties by crosslinking said mucus. The view was that the small size of the polymers allows the molecules to diffuse favorably inside the mucus. This should improve the diffusion of the mucoadhesive polymer into the mucus and allow crosslinking the mucus layer over a large thickness without clumping the mucus. Small mucoadhesive polymer complexes will thereby block the pores of the network and enhance the barrier properties. However, while such enhancement of barrier properties, for example by chitosan, was shown to work for small chitosan sizes in porcine gastric mucin and colonic mucin cell lines, for applications as contraceptive compositions, the mucus that needs to be targeted is very different from the mucin in the digestive tract. At ovulation, cervical mucus loosens to allow the passage of sperm through the gel. Compared to gastric or colonic mucus, the mucin content is reduced and the overall mucus structure and composition is very different. It is therefore very important that the mucus layer is sufficiently cross-linked to prevent the migration of motile sperm through the mucus layer without clumping the mucus.

[0017] Mucus aggregation occurs when mucin polymers condense around mucoadhesive polymers. This results in the production of regions of very dense mucin polymer aggregates and regions of very loose and very loose mucin meshwork. These loose regions can allow sperm to pass through.

[0018] Accordingly, the present invention relates to a vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0019] It is disclosed herein that treatment with mucoadhesive polymers of 4 to 20 monomers as described above for gastric and colonic mucus is in fact shown to be not suitable for effective reinforcement of the mucus barrier in ovulatory mucus. Mucoadhesive polymers of at least 20,000 Da are shown to be much more effective in forming a barrier against, for example, sperm cells attempting to penetrate the mucus barrier. Furthermore, it is shown herein that mucoadhesive polymers of more than 100,000 Da are too large to interact well with the mucus.

[0020] The compositions disclosed herein can be efficiently delivered to the cervix when formulated in a vaginal gel. The gel components can prevent the diffusion of the mucoadhesive polymer from the gel into the mucus by steric hindrance effects or by intermolecular interactions that form aggregates with the mucoadhesive polymer and the gel; for example, when the mucoadhesive polymer is provided as a carboxymethylcellulose (CMC)-based excipient soft gel, which is typically used as a gelling agent, this component strongly interacts with, for example, chitosan when used as a mucoadhesive polymer. At least two different types of gelling agents are suitable for vaginal formulations, natural and positively charged, without preventing the penetration of the mucoadhesive polymer into the ovulatory cervical mucus of women and without interfering with the barrier-strengthening effect provided by the mucoadhesive polymer. The gelling agent must be either natural or positively charged to avoid strong interactions with the mucoadhesive polymer. In another example, when the mucoadhesive polymer interacts with the mucus through a thiol group, the excipient must not contain a thiol group.

[0021] The present invention further relates to the use of a vaginal contraceptive composition as a contraceptive agent, said vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients being a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids or combinations thereof, and at least 50% of the monomer units comprising at least one amino group.

[0022] The present invention also relates to a vaginal contraceptive composition for therapeutic use, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0023] The present invention further relates to a vaginal contraceptive composition for use as a contraceptive or birth control agent, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0024] The present invention further relates to a vaginal contraceptive composition for use in birth control or birth control treatment, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight of from 20,000 Da to 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0025] Finally, the present invention relates to a method of treatment, a method of avoiding pregnancy, a method of contraception, and / or a method of birth control or birth control therapy, comprising the step of using a vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomeric units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomeric units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomeric units comprise at least one amino group. [Brief description of the drawings]

[0026] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1A] Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 A, B, C - The graph on the left is the diffusion profile of chitosan in CVM for various molecular weights of crustacean shell derived chitosan at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile in CVM expressed as relative fluorescence intensity (RFI) of labeled chitosan from crustacean shell at various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. All samples were dissolved in 32.5 mM LAC. [Figure 1B]Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 A, B, C - The graph on the left is the diffusion profile of chitosan in CVM for various molecular weights of crustacean shell derived chitosan at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile in CVM expressed as relative fluorescence intensity (RFI) of labeled chitosan from crustacean shell at various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. All samples were dissolved in 32.5 mM LAC. [Figure 1C] Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 A, B, C - The graph on the left is the diffusion profile of chitosan in CVM for various molecular weights of crustacean shell derived chitosan at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile in CVM expressed as relative fluorescence intensity (RFI) of labeled chitosan from crustacean shell at various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. All samples were dissolved in 32.5 mM LAC. [Figure 1D] Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 D, E, F, G, H - The graph on the left is the diffusion profile of chitosan in CVM for non-animal derived chitosans of various molecular weights at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile of chitosan in CVM expressed as relative fluorescence intensity (RFI) for non-animal derived labeled chitosans of various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. Samples were dissolved in 32.5 mM LAC. [Figure 1E]Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 D, E, F, G, H - The graph on the left is the diffusion profile of chitosan in CVM for non-animal derived chitosans of various molecular weights at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile of chitosan in CVM expressed as relative fluorescence intensity (RFI) for non-animal derived labeled chitosans of various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. Samples were dissolved in 32.5 mM LAC. [Figure 1F] Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 D, E, F, G, H - The graph on the left is the diffusion profile of chitosan in CVM for non-animal derived chitosans of various molecular weights at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile of chitosan in CVM expressed as relative fluorescence intensity (RFI) for non-animal derived labeled chitosans of various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. Samples were dissolved in 32.5 mM LAC. [Figure 1G] Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 D, E, F, G, H - The graph on the left is the diffusion profile of chitosan in CVM for non-animal derived chitosans of various molecular weights at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile of chitosan in CVM expressed as relative fluorescence intensity (RFI) for non-animal derived labeled chitosans of various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. Samples were dissolved in 32.5 mM LAC. [Figure 1H]Diffusion of chitosan in cervical, ovulatory mucus: 0.5% CS / / pH 5.5 D, E, F, G, H - The graph on the left is the diffusion profile of chitosan in CVM for non-animal derived chitosans of various molecular weights at 20 ms exposure time expressed as chitosan concentration (% w / v). The graph on the right is the diffusion profile of chitosan in CVM expressed as relative fluorescence intensity (RFI) for non-animal derived labeled chitosans of various molecular weights measured by microscopy at 800 ms exposure time. The decrease in fluorescence indicates the maximum diffusion distance after 30 min of exposure to mucus. Samples were dissolved in 32.5 mM LAC. [Figure 1I] Diffusion of chitosan into cervical and ovulatory mucus: Representative images of chitosan penetration studies performed with 0.5% CS / pH 5.5 I-chitosan of various sizes. Intensity profiles were measured on these images to generate the graphs in Figure 1A-C. [Diagram 2] Quantification of chitosan accumulation in human cervical ovulation mucus after 30 min exposure as a function of chitosan molar mass. [Figure 3A] Sperm penetration through the cervix and ovulation mucus: 0.5% (w / v) CO chitosan in water (HO) only (A), phosphate-buffered saline (PBS) (B), or a pH 5.5 solution containing 100 mM lactic acid (LAC) (C). [Figure 3B] Sperm penetration through the cervix and ovulation mucus: 0.5% (w / v) CO chitosan in water (HO) only (A), phosphate-buffered saline (PBS) (B), or a pH 5.5 solution containing 100 mM lactic acid (LAC) (C). [Figure 3C] Sperm penetration through the cervix and ovulation mucus: 0.5% (w / v) CO chitosan in water (HO) only (A), phosphate-buffered saline (PBS) (B), or a pH 5.5 solution containing 100 mM lactic acid (LAC) (C). [Figure 4A]Sperm penetration through human cervical ovulation mucus (A-7.1 kDa, B-18.9 kDa, C-27.9 kDa, D-36.2 kDa, and E-251.8 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC) (100 mM lactic acid solution for A-7.1 kDa), or treated with fungal-based chitosan dissolved in 32.5 mM lactic acid solution (100 mM lactic acid solution for A-7.1 kDa). The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 4B] Sperm penetration through human cervical ovulation mucus (A-7.1 kDa, B-18.9 kDa, C-27.9 kDa, D-36.2 kDa, and E-251.8 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC) (100 mM lactic acid solution for A-7.1 kDa), or treated with fungal-based chitosan dissolved in 32.5 mM lactic acid solution (100 mM lactic acid solution for A-7.1 kDa). The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 4C] Sperm penetration through human cervical ovulation mucus (A-7.1 kDa, B-18.9 kDa, C-27.9 kDa, D-36.2 kDa, and E-251.8 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC) (100 mM lactic acid solution for A-7.1 kDa), or treated with fungal-based chitosan dissolved in 32.5 mM lactic acid solution (100 mM lactic acid solution for A-7.1 kDa). The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 4D] Sperm penetration through human cervical ovulation mucus (A-7.1 kDa, B-18.9 kDa, C-27.9 kDa, D-36.2 kDa, and E-251.8 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC) (100 mM lactic acid solution for A-7.1 kDa), or treated with fungal-based chitosan dissolved in 32.5 mM lactic acid solution (100 mM lactic acid solution for A-7.1 kDa). The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 4E] Sperm penetration through human cervical ovulation mucus (A-7.1 kDa, B-18.9 kDa, C-27.9 kDa, D-36.2 kDa, and E-251.8 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC) (100 mM lactic acid solution for A-7.1 kDa), or treated with fungal-based chitosan dissolved in 32.5 mM lactic acid solution (100 mM lactic acid solution for A-7.1 kDa). The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 5A] Sperm penetration through human cervical ovulation mucus (A-1.4 kDa, B-35.0 kDa, C-1.4 kDa+35.0 kDa, and D-150.0 kDa). Mucus was either untreated (w / o), treated with 100 mM lactic acid solution (LAC), or treated with crustacean shell-based chitosan dissolved in 100 mM lactic acid solution. The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 5B] Sperm penetration through human cervical ovulation mucus (A-1.4 kDa, B-35.0 kDa, C-1.4 kDa+35.0 kDa, and D-150.0 kDa). Mucus was either untreated (w / o), treated with 100 mM lactic acid solution (LAC), or treated with crustacean shell-based chitosan dissolved in 100 mM lactic acid solution. The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 5C] Sperm penetration through human cervical ovulation mucus (A-1.4 kDa, B-35.0 kDa, C-1.4 kDa+35.0 kDa, and D-150.0 kDa). Mucus was either untreated (w / o), treated with 100 mM lactic acid solution (LAC), or treated with crustacean shell-based chitosan dissolved in 100 mM lactic acid solution. The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 5D]Sperm penetration through human cervical ovulation mucus (A-1.4 kDa, B-35.0 kDa, C-1.4 kDa+35.0 kDa, and D-150.0 kDa). Mucus was either untreated (w / o), treated with 100 mM lactic acid solution (LAC), or treated with crustacean shell-based chitosan dissolved in 100 mM lactic acid solution. The molar mass of the chitosan used is indicated on the left side of the graph. [Figure 6] Solubility test of chitosan in formulations containing viscosity enhancers as excipients. The light transmittance (%T), or turbidity (at 600 nm), was measured for solutions of lactic acid (32.5 mM, LAC) and hydroxyethylcellulose in LAC (HEC). The molar masses of the chitosans used correspond to the following: Z10-36.2 kDa, 95 / 5-35 kDa, and CO-1.4 kDa. [Figure 7A] Diffusion of chitosan in ovulatory cervical mucus: 0.5% CS / / pH 5.5 (A-35.0 kDa w / o, B-35.0 kDa+2.7% HEC, and C-35.0 kDa+1.6% HEC+2.5% glycerol). Chitosan concentration (%, w / v) in ovulatory cervical mucus for chitosan alone and chitosan mixed with excipients at 20 ms after 30 min exposure. Samples were dissolved in 32.5 mM LAC. Relative fluorescence intensity (RFI) measured by microscopy at an exposure time of 800 ms. Samples were dissolved in 32.5 mM LAC. The molar mass of chitosan used is indicated above each graph. [Figure 7B] Diffusion of chitosan in ovulatory cervical mucus: 0.5% CS / / pH 5.5 (A-35.0 kDa w / o, B-35.0 kDa+2.7% HEC, and C-35.0 kDa+1.6% HEC+2.5% glycerol). Chitosan concentration (%, w / v) in ovulatory cervical mucus for chitosan alone and chitosan mixed with excipients at 20 ms after 30 min exposure. Samples were dissolved in 32.5 mM LAC. Relative fluorescence intensity (RFI) measured by microscopy at an exposure time of 800 ms. Samples were dissolved in 32.5 mM LAC. The molar mass of chitosan used is indicated above each graph. [Figure 7C]Diffusion of chitosan in ovulatory cervical mucus: 0.5% CS / / pH 5.5 (A-35.0 kDa w / o, B-35.0 kDa+2.7% HEC, and C-35.0 kDa+1.6% HEC+2.5% glycerol). Chitosan concentration (%, w / v) in ovulatory cervical mucus for chitosan alone and chitosan mixed with excipients at 20 ms after 30 min exposure. Samples were dissolved in 32.5 mM LAC. Relative fluorescence intensity (RFI) measured by microscopy at an exposure time of 800 ms. Samples were dissolved in 32.5 mM LAC. The molar mass of chitosan used is indicated above each graph. [Figure 8A] Sperm penetration through human cervical ovulation mucus. Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC), or treated with 35 kDa crustacean shell-based chitosan (95 / 5) dissolved in 32.5 mM lactic acid solution (A), 32.5 mM lactic acid and 2.7% hydroxyethylcellulose (HEC) (B), or 32.5 mM lactic acid, 2.7% hydroxyethylcellulose and 2.5% glycerol (Gro) (C). [Figure 8B] Sperm penetration through human cervical ovulation mucus. Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC), or treated with 35 kDa crustacean shell-based chitosan (95 / 5) dissolved in 32.5 mM lactic acid solution (A), 32.5 mM lactic acid and 2.7% hydroxyethylcellulose (HEC) (B), or 32.5 mM lactic acid, 2.7% hydroxyethylcellulose and 2.5% glycerol (Gro) (C). [Figure 8C] Sperm penetration through human cervical ovulation mucus. Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC), or treated with 35 kDa crustacean shell-based chitosan (95 / 5) dissolved in 32.5 mM lactic acid solution (A), 32.5 mM lactic acid and 2.7% hydroxyethylcellulose (HEC) (B), or 32.5 mM lactic acid, 2.7% hydroxyethylcellulose and 2.5% glycerol (Gro) (C). [Figure 9A]Sperm penetration through human cervical ovulation mucus of poly-L-lysine (PLL) (A-1.6 kDa, B-66 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC), or treated with low molar mass poly-L-lysine (A) dissolved at a concentration of 5 mg / mL in 32.5 mM lactic acid solution or high molar mass poly-L-lysine (B) dissolved at a concentration of 5 mg / mL in 32.5 mM lactic acid solution. [Figure 9B] Sperm penetration through human cervical ovulation mucus of poly-L-lysine (PLL) (A-1.6 kDa, B-66 kDa). Mucus was either untreated (w / o), treated with 32.5 mM lactic acid solution (LAC), or treated with low molar mass poly-L-lysine (A) dissolved at a concentration of 5 mg / mL in 32.5 mM lactic acid solution or high molar mass poly-L-lysine (B) dissolved at a concentration of 5 mg / mL in 32.5 mM lactic acid solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Detailed Description A description herein of any aspect or embodiment of the invention using terms such as "comprising," "having," "including," or "containing" in connection with one or more elements is intended to provide support for similar aspects or embodiments of the invention that "consists of," "consists essentially of," or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context; for example, a composition described herein that includes a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by context. It will be further understood that the terms "comprises," "comprising," "includes," and / or "including," as used herein, specify the presence of the stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0028] Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. It will be further understood that terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant art, and are not interpreted in an idealized or overly formal sense unless expressed as defined herein.

[0029] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms, including "at least one," unless the context clearly indicates otherwise. "At least one" is not to be construed as limiting "a" or "an."

[0030] Any examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to better illustrate the invention and do not impose limitations on the scope of the invention unless specifically claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0031] In describing the following embodiments, aspects, and definitions, the present invention contemplates all disclosed embodiments and definitions in combination with the disclosed aspects. Moreover, all possible combinations and permutations of the embodiments have not been explicitly described. Nevertheless, the mere fact that certain measures are recited in mutually different dependent claims or in different embodiments does not indicate that a combination of these measures cannot be used to advantage. The present invention contemplates all possible combinations and permutations of the described embodiments.

[0032] Disclosed in a first aspect of the present invention is a vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer being composed of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0033] In a second aspect of the present invention, there is disclosed a use of a vaginal contraceptive composition as a contraceptive agent, said vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients being a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer being composed of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids or combinations thereof, and at least 50% of the monomer units comprising at least one amino group.

[0034] In a third, fourth, and fifth aspect of the present invention, there is disclosed a vaginal contraceptive composition for use in therapy, for use as a contraceptive or contraceptive agent, and for use in birth control or birth control therapy, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight of from 20,000 Da to 100,000 Da, said mucoadhesive polymer being comprised of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0035] Disclosed in the sixth, seventh, eighth, and ninth aspects of the present invention are methods of treatment, methods of avoiding pregnancy, methods of contraception, and methods of birth control or birth control therapy, comprising the step of using a vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units comprise at least one amino group.

[0036] As disclosed herein, a contraceptive composition is a composition that prevents a woman from becoming pregnant by keeping egg and sperm cells apart by a barrier method that may further help prevent sperm from reaching the egg or egg and protect against sexually transmitted diseases. Sperm are prevented from reaching the egg or egg by creating a barrier in the cervix and endocervix, thereby retaining the sperm cells within the vagina (or vaginal canal). Thus, sperm cells would not have a chance to enter the uterus through the cervix and thereby into the fallopian tubes (or fallopian tubes) to reach the egg. Sperm cells are instead killed by the acidic fluids in the vagina or lost during "reflux".

[0037] As disclosed herein, an active ingredient is one or more compounds in a contraceptive composition that provide contraceptive capabilities, i.e., prevent a woman from becoming pregnant by preventing sperm from reaching the ovum or egg.

[0038] Mucoadhesive polymers are polymers that exhibit mucoadhesion. Mucoadhesion is described herein as the interfacial tension that holds two biomaterials together, such as the attractive force between a biomaterial and mucus or mucus. Thus, mucoadhesive polymers refer to polymers that have an attractive force for mucus or mucus.

[0039] Mucus is a protective covering for all epithelial surfaces, which keeps the epithelial layer moist and prevents microorganisms from penetrating the epithelium. A natural protective effect is achieved because the mucus traps microorganisms and facilitates their distal transport. When referring to the barrier effect achieved by mucoadhesive polymers, it is the strengthening of the mucus by cross-linking the polymer. The strengthened barrier effect is based on the tightness of the cross-linked mucus, which stops diffusion, and how long the mucus is strengthened by the complexed mucoadhesive polymer. The latter is determined by the natural turnover of mucus secreted by cells from the mucosa, which removes the mucus containing the cross-linked polymer.

[0040] The mucus layer in the mucous membrane of the cervix has different rheological properties according to the four stages of the menstrual cycle. At ovulation, the cervical mucus is loose enough to allow the passage of sperm through the gel, and therefore the pore size of the mucus will also be increased. The thickness of the barrier layer can be adjusted to be impermeable to relatively large cells such as sperm, but it can also be adjusted to a tighter barrier layer that may be required to be impermeable to bacteria, viruses, or other microorganisms or pathogens.

[0041] It is widely accepted that cervical mucus barrier properties can be utilized as a contraceptive method, given the effective barrier that thickening of cervical mucus can produce. Indeed, the primary mechanism of contraception for the levonorgestrel intrauterine system (LNG-IUS) and the progestin-only minipill is by thickening of cervical mucus. The approach disclosed herein differs from these approaches not by the nature of the barrier, but by the means of creating the barrier: a non-hormonal, non-invasive, on-demand contraceptive without side effects.

[0042] Thus, the mucoadhesive polymer provides a more reliable barrier effect that prevents cells and microorganisms, such as bacteria, viruses, and sperm, from penetrating the crosslinked mucus and spreading throughout the mucosa. Vaginal contraceptive compositions create a crosslinked mucus that is so tight that it can prevent even the smallest microorganisms from penetrating, thereby preventing not only pregnancy, but also sexually transmitted infections (STIs).

[0043] Thus, in one or more embodiments of any aspect, the composition is a contraceptive composition. Moreover, the present invention provides a contraceptive composition that does not contain hormones or chemicals that have undesirable side effects. Undesirable effects may include mild side effects such as embolism, migraines, or affecting the menstrual cycle. The effective time of the mucoadhesive polymer of the present invention is determined by the turnover of mucus, which means that the contraceptive effect is temporary. After the effective time and the effect of conception is gone, the contraception is resolved. The sufficient time of contraception is influenced by several factors, such as the biological turnover of mucus, the concentration of the mucoadhesive polymer, etc. The contraceptive effect lasts for a certain time, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, 1, 2, 3 days, or up to 10 days, which is a sufficient time to prevent sperm cells from entering the cervix. By preventing sperm from entering the cervix, the acidic environment of the vagina reduces the motility of the sperm and weakens them so that they cannot fertilize the egg. Under natural conditions, sperm cells need to enter the cervix within minutes to survive. Full contraceptive efficacy is obtained from a single application, which means that non-coherent use of the contraceptive composition provides the same protection as coherent use. Full contraceptive efficacy from a single application may also mean that momentary contact of cervical mucus with the contraceptive composition may provide the same complete protection as sustained contact with cervical mucus.

[0044] The size of the mucoadhesive polymer allows the molecules to diffuse inside the mucus. This diffusion of the mucoadhesive polymer into the mucosa allows it to bridge the mucus layer over a thickness that is thick enough to prevent motile sperm from migrating through the mucus without clumping the mucus. The mucoadhesive polymer forms a complex with the mucus, thereby blocking the pores of the network and enhancing its barrier properties. At ovulation, the cervical mucus is loose to allow the passage of sperm through the gel, and therefore the pore size of the mucus will also be increased compared to non-ovulatory mucus. The size of the mucoadhesive polymer should be adjusted to this increased pore size of the ovulatory cervical mucus. The size of the mucoadhesive polymer that serves for the increased pore size of the ovulatory cervical mucus also works effectively when the pore size of the cervical mucus does not increase due to ovulation.

[0045] Furthermore, the size of the mucoadhesive polymer is generally more soluble and has less steric hindrance at lower molecular weights. If the mucoadhesive polymer is large, it cannot pass through or pass through the pores of the mucus, and therefore it will end up interacting with an increased number of mucin molecules, and therefore will not diffuse through the gel, but if it is too small, it may pass right through without interacting with the mucin molecules. Therefore, a compromise is needed between a larger, but not too large, size to avoid the mucoadhesive polymer from penetrating all the way through the pores of the mucus, and a smaller size to obtain high enough solubility for proper delivery to the mucosa of the subject. This allows the mucoadhesive polymer to be delivered more efficiently to the mucosa, which in turn allows stronger and therefore more effective cross-linking than that obtained with smaller or larger mucoadhesive polymer molecules (less than 20,000 Da or more than 100,000 Da).

[0046] Mucoadhesive polymers are generally cationic, with at least 50% of the monomers being charged. The monomer units may, for example, contain amino groups that are physically pH positively charged. They may also be hydrophobic, for example, with up to 50% of the monomers having hydrophobic side chains. These two characteristics of mucoadhesive polymers may play a role when selecting suitable excipients.

[0047] In chemistry, an amino group is a functional group consisting of a nitrogen atom attached by a single bond to a hydrogen atom, an alkyl group, an aryl group, or a combination of the three. Organic compounds containing amino groups are called amines. Amines are derivatives of the inorganic compound ammonia, NH3. When one, two, or all three of the hydrogens in ammonia are replaced with alkyl or aryl groups, the resulting compounds are known as primary, secondary, or tertiary amines, respectively. Like ammonia, amines are weak bases because the unshared electron pair of the nitrogen atom can form a coordinate bond with a proton. Water-insoluble amines can be rendered soluble by adding an acid to form its water-soluble amine salt. The amino group makes the mucoadhesive polymer basic, which favors their attachment to the mucosa due to the large amount of negatively charged molecules it contains. The basic amino group, in particular, provides more efficient cross-linking. Furthermore, when a portion of the monomers of the mucoadhesive polymer, up to 50%, contain hydrophobic groups, the mucoadhesive polymer can also adhere to and diffuse into the mucosa, cross-linking the mucus without clumping it. In the context of the present invention, an amino group is -NH2, where one or both hydrogen atoms may be replaced by a group R, or the amino group is a quaternary amino group having three R groups, i.e. -N +R may be R3. R may be selected from C1-C4 alkyl optionally substituted with one or more -OH, -SH, or -NH2. When two or more R are present on the same nitrogen atom, they may be the same or different R groups. As long as R has four or fewer carbon atoms, especially when the hydrogen atoms of the R group are substituted with one or more -OH, -SH, or -NH2, the amino groups disclosed herein are generally considered to be basic. Although longer alkyl chains, e.g., having five or more carbon atoms, may mask the basicity of the amino group, amino groups having alkyls of five or more carbon atoms are also considered amino groups in the context of the present invention. Similarly, sugars may also contain amide groups, e.g., -CONHCH3, or -NHCHO, although such groups are not considered amino groups in the context of the present invention.

[0048] In one or more embodiments according to any aspect, the amino group does not include an alkyl of 10 or more carbon atoms.

[0049] In one or more embodiments according to any aspect, the amino group does not include an alkyl of 9 or more carbon atoms.

[0050] In one or more embodiments according to any aspect, the amino group does not include an alkyl of 8 or more carbon atoms.

[0051] In one or more embodiments according to any aspect, the amino group does not include an alkyl of 6 or more carbon atoms.

[0052] In one or more embodiments according to any aspect, the amino group does not include an alkyl of 5 or more carbon atoms.

[0053] In one or more embodiments according to any aspect, at least 55% of the monomeric units, such as at least 60% of the monomeric units, such as at least 65% of the monomeric units, such as at least 70% of the monomeric units, comprise at least one amino group.

[0054] In one or more embodiments of any aspect, one or more of the at least one amino group is a primary amine. In the context of this invention, a primary amine is an amino group in which none of the hydrogen atoms are replaced by a group R (i.e., -NH2).

[0055] In one or more embodiments of any aspect, at least one amino group is a primary amine.

[0056] A vaginal contraceptive composition comprises one or more active ingredients and a physiologically acceptable gelling agent. The one or more active ingredients may be administered in a physiologically acceptable gelling agent (or carrier) that ensures that the one or more active ingredients are soluble under the conditions in which it is used and ensures that the one or more active ingredients are uniformly distributed in the target area. As used herein, uniformly distributed means that the targeted mucus area is subjected to at least a minimal amount of the composition that contains enough active ingredient to diffuse into the mucus and strengthen the mucus barrier.

[0057] By physiologically acceptable gelling agents (or carriers) is meant non-toxic compounds that are not chemically or physically toxic to human and / or animal organisms in effective doses.

[0058] In one or more embodiments of any aspect, the physiologically acceptable gelling agent is selected from hydroxyethyl cellulose (HEC), glycerol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, guar gum, or combinations thereof. Any suitable pharmaceutical gelling agent may be used as long as the gelling agent does not interact with the one or more active ingredients, particularly the mucoadhesive polymer.

[0059] By combining with physiologically acceptable gelling agent, the contact area between the composition and mucus is maximized.The increased contact area can help ensure that the maximum amount of mucoadhesive polymer can diffuse into the mucus layer and change its properties.Also contributing to increased diffusion is the high density of the composition.For example, by having a high composition density similar to that of water, such as in a semi-solid gel, the applied composition can change shape and cover the entire surface of the cervical entrance.

[0060] Hydroxyethylcellulose (or ethylcellulose) is a gelling and thickening agent derived from cellulose. It is widely used in cosmetics, cleaning solutions, and other household products. Hydroxyethylcellulose and hydroxymethylcellulose (or methylcellulose) are often used with hydrophobic drugs in capsule formulations to improve the dissolution of the drug in gastrointestinal fluids. This process is known as hydrophilization.

[0061] In one or more embodiments of any aspect, the physiologically acceptable gelling agent is chosen from hydroxyethyl cellulose, hydroxymethyl cellulose, or a combination thereof.

[0062] Glycerol, also called glycerine or glycerin, is a simple polyol compound. It is a colorless, odorless, viscous liquid, sweet-tasting, and non-toxic. The glycerol backbone is found in many lipids known as glycerides. It is widely used as a sweetener in the food industry and as a humectant in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopicity.

[0063] In one or more embodiments of any aspect, the physiologically acceptable gelling agent is glycerol.

[0064] Hydroxypropyl methylcellulose (HPMC), also called hypromellose, is a semisynthetic, inert, viscoelastic polymer found in a variety of commercial products, eye drops, and used as an excipient and controlled delivery component in oral medications. As a food additive, hypromellose is an emulsifier, thickener, and suspending agent, and a substitute for animal gelatin. Its Codex Alimentarius code (E number) is E464.

[0065] In one or more embodiments of any aspect, the physiologically acceptable gelling agent is hydroxypropyl methylcellulose (HPMC).

[0066] Hydroxypropyl cellulose (HPC) is a derivative of cellulose that is both water-soluble and organic-soluble. It is used as an excipient, and as a topical eye protectant and lubricant. HPC is an ether of cellulose in which some of the hydroxyl groups in the repeating glucose units have been hydroxypropylated with propylene oxide to form -OCH2CH(OH)CH3 groups. The average number of substituted hydroxyl groups per glucose unit is called the degree of substitution (DS). Complete substitution would provide a DS of 3. Since the hydroxypropyl group added contains a hydroxyl group, it can also be etherified during the preparation of HPC. When this occurs, the molar substitution (MS), which is the number of moles of hydroxypropyl groups per glucose ring, can be greater than 3.

[0067] In one or more embodiments of any aspect, the physiologically acceptable gelling agent is hydroxypropyl cellulose.

[0068] Guar gum, also called guaran, is a galactomannan polysaccharide extracted from guar beans that has thickening and stabilizing properties useful in food, feed, and industrial applications. Guar seeds are mechanically dehulled, hydrated, ground, and screened for use. It is typically produced as a free-flowing, off-white powder. Chemically, guar gum is an exopolysaccharide composed of the sugars galactose and mannose. The backbone is a linear chain of β 1,4-linked mannose residues in which galactose residues are 1,6-linked to every two mannose residues to form short side chains. Guar gum has the ability to withstand temperatures of 80°C for 5 minutes.

[0069] In one or more embodiments of any aspect, the physiologically acceptable gelling agent is guar gum.

[0070] In one or more embodiments of any aspect, the pharma- ceutically acceptable gelling agent is a pharma- ceutically acceptable carrier, where the pharma- ceutically acceptable carrier can be water, dimethyl sulfoxide (DMSO), saline (saline solution), or a combination thereof.

[0071] In one or more embodiments of any aspect, the vaginal contraceptive composition is not a foam.

[0072] Foams are objects formed by trapping pockets of gas in a liquid or solid. In most foams, the volume of gas is large and thin films of liquid or solid separate the regions of gas.

[0073] The mucoadhesive polymer may be a polysaccharide in which C6 sugars are linked to each other via ether, ester, or amide bonds. The C6 sugar monomers may be linked, for example, via any ether bond, for example, C1 and C4 of two adjacent C6 sugars may be linked, or C1 and C6 of two adjacent C6 sugars may be linked. In particular, when the monomer is a C6 sugar, for example glucose, the monomer, for example glucose monomer, may be linked via β 1,4-bonds.

[0074] The at least one amino group can be attached to any carbon atom of the glucose monomer, for example, C2 or C3.

[0075] In one or more embodiments of any aspect, the mucoadhesive polymer is comprised of multiple monomer units linked together via ether bonds.

[0076] In one or more embodiments of any aspect, the monomer units are selected from C6 sugars, amino-functionalized C6 sugars, or combinations thereof.

[0077] C6 sugars are carbohydrates whose molecules have six carbons (i.e., hexoses). The best known example of this class is glucose, the main component of cellulose and starch molecules.

[0078] Amino-functionalized C6 sugars (or amino sugars) are sugar molecules in which a hydroxyl group has been replaced with an amine group. Over 60 amino sugars are known, one of the most abundant being N-acetyl-D-glucosamine, the main component of chitin. The amino-functionalization can be on C2, C3, C4, and / or C6 of the C6 sugar.

[0079] In one or more embodiments of any aspect, the monomer unit is an amino-functionalized C6 sugar.

[0080] In one or more embodiments of any aspect, the monomer units are a combination of D-glucosamine and N-acetyl-D-glucosamine.

[0081] D-Glucosamine (C6H 13NO5) is an amino sugar and a typical precursor in the biochemical synthesis of glycosylated proteins and lipids. D-Glucosamine is part of the structure of the polysaccharides, chitosan, and chitin. D-Glucosamine is one of the most abundant monosaccharides. It is commercially produced by hydrolysis of the exoskeletons of crustaceans or, less commonly, by fermentation of grains such as corn or wheat. [ka]

[0082] N-Acetyl-D-Glucosamine (GlcNAc, C8H 15 NO6) is a monosaccharide and derivative of glucose. It is important in several biological systems. It is part of the biopolymer in bacterial cell walls, which is built from alternating units of GlcNAc and N-acetylmuramic acid (MurNAc) cross-linked to oligopeptides at the lactic acid residues of MurNAc. This layered structure is called peptidoglycan (formerly called murein). GlcNAc is the monomer unit of the polymer chitin, which forms the cuticle of insects and crustaceans. [ka]

[0083] In one or more embodiments according to any aspect, at least 50% of the monomer units are D-glucosamine, while 50% or less of the monomer units are N-acetyl-D-glucosamine, e.g., 50% to 100% are D-glucosamine and 0% to 50% are N-acetyl-D-glucosamine.

[0084] At least 50% of the monomer units are D-glucosamine means that at least 50% of the total amount of monomers in the mucoadhesive polymer is derived from D-glucosamine. Similarly, 50% or less of the monomer units are N-acetyl-D-glucosamine means that 50% or less of the total amount of monomers in the mucoadhesive polymer is derived from N-acetyl-D-glucosamine. Furthermore, 50% to 100% or 0% to 50% means that 50% to 100% or 0% to 50% of the total amount of monomers in the mucoadhesive polymer is derived from said monomer units, including all end points (0%, 50%, and 100%).

[0085] In one or more embodiments according to any aspect, at least 65% of the monomer units are D-glucosamine while 35% or less of the monomer units are N-acetyl-D-glucosamine, e.g., 65%-100% are D-glucosamine and 0%-35% are N-acetyl-D-glucosamine, endpoints included.

[0086] In one or more embodiments according to any aspect, the mucoadhesive polymer is chitosan, in which at least 50% of the glucose monomers have an -NH2 group. Chitosan may also be referred to as being at least 50% deacetylated.

[0087] Chitosan is a linear polysaccharide composed of randomly distributed β 1,4-linked D-glucosamine (deacetylated units) and N-acetyl-D-glucosamine (acetylated units). It is produced by treating the chitin shells of shrimp and other crustaceans with alkaline substances such as sodium hydroxide, or it can be extracted from other sources such as fungal cell walls.

[0088] When the mucoadhesive polymer is chitosan, for example, it is important to avoid the presence of high molecular weight polyacrylic acid, since the carboxyl functional groups in the acrylic monomers form ionic complexes with the basic amino groups in the chitosan chains, which leads to the formation of highly expanded interpenetrating polymer networks, which can lead to aggregation of the mucus and thus opening of pores in the mucus, weakening the barrier properties of the mucus.

[0089] Chitosan is a strong mucoadhesive molecule, which means that it can entangle and bind to the mucin glycoproteins that make up the mucus gel. Therefore, they are used in mucosal drug delivery devices and are included in commercial hemostatic products. However, the chitosans used in the present disclosure are typically of high molar mass and therefore do not diffuse well in the mucus gel and tend to cause the mucus to aggregate and condense.

[0090] In one or more embodiments of any aspect, the mucoadhesive polymer is chitosan, wherein at least 50% of the glucose monomers have a -NH2 group and no more than 40% of the glucose monomers have a -CONHCH3 group.

[0091] In one or more embodiments of any aspect, the mucoadhesive polymer is chitosan, wherein at least 50% of the glucose monomers have a -NH2 group and no more than 20% of the glucose monomers have a -CONHCH3 group.

[0092] In one or more embodiments according to any aspect, the mucoadhesive polymer is chitosan, in which at least 70% of the glucose monomers have an -NH group. Chitosan may also be referred to as being at least 70% deacetylated.

[0093] In one or more embodiments of any aspect, the mucoadhesive polymer is chitosan, wherein at least 70% of the glucose monomers have a -NH2 group and no more than 20% of the glucose monomers have a -CONHCH3 group.

[0094] In one or more embodiments of any aspect, the mucoadhesive polymer is selected from chitosan, chitosan-trimethyl, chitosan-thioglycolic acid, chitosan-iminothiolane, chitosan-thioethylamidine, or combinations thereof.

[0095] Chitosan-trimethyl is a quaternized hydrophilic derivative of chitosan that is positively charged and soluble over a wide range of pH.

[0096] Chitosan-thioglycolic acid, chitosan-iminothiolane, and chitosan-thioethylamidine are chitosan derivatives modified by the introduction of different thiol groups. The thiol groups are introduced into chitosan by carbodiimide-mediated amide bond formation, whereby the properties of the resulting polymer are modified in terms of water solubility, mucoadhesion, biodegradability, and in situ gelation, compared to the original polymer.

[0097] In one or more embodiments according to any aspect, the mucoadhesive polymer is chitosan having a molecular weight of 20,000 Da to 100,000 Da, such as 30,000 Da to 90,000 Da, such as 30,000 Da to 80,000 Da, such as 30,000 Da to 70,000 Da, such as 40,000 Da to 60,000 Da, such as 45,000 Da to 55,000 Da, all endpoints within the above ranges.

[0098] In one or more embodiments according to any aspect, the mucoadhesive polymer is a peptide molecule of 180-900 amino acids in length linked via amide bonds. When the mucoadhesive polymer comprises amino acids, any amino acid may be included so long as at least 50% of the amino acids have a basic group, or at least 50% of the amino acids have an optional hydrophobic group, or at least 50% of the amino acids have a thiol group, or a combination of the three (basic, hydrophobic, and thiol). The mucoadhesive polymer is not limited to natural amino acids, and it is preferred that the amino acids are non-toxic and tolerated by the subject. It is preferred that the mucoadhesive polymer does not comprise D-amino acids, and that any amino acids included in the mucoadhesive polymer are L-amino acids.

[0099] Generally, the following amino acids are considered to be basic: arginine, lysine, histidine, ornithine, and β-alanine, and in one embodiment, the mucoadhesive polymer is a polypeptide of amino acids, where at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine. The remaining amino acids may be selected from any amino acid, for example, any of the 20 amino acids defined from the genetic code, but in particular glycine, serine, threonine, asparagine, and glutamine. Particular embodiments of the mucoadhesive polymer include poly-lysine, poly-ornithine, and / or poly-arginine. The advantage of using basic amino acids is that they have good solubility in aqueous solutions.

[0100] In one or more embodiments of any aspect, the mucoadhesive polymer is a peptide molecule of 180-900 amino acids in length, where at least 50% of the amino acids have a hydrophobic group and are selected from the list consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine, and the remaining amino acids may be selected from the list consisting of glycine, serine, threonine, asparagine, and glutamine, or the remaining amino acids may be selected from any amino acid, for example, any of the 20 amino acids defined from the genetic code.

[0101] In one or more embodiments of any aspect, the mucoadhesive polymer comprises amino acids, wherein at least 50% of the amino acids are selected from the group consisting of arginine, lysine, histidine, ornithine, and β-alanine, or wherein 50% of the amino acids have a hydrophobic group and are selected from the group consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine.

[0102] In one or more embodiments of any aspect, the mucoadhesive polymer is a peptide molecule linked via an amide bond, wherein at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine. In another embodiment, at least 60% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine. In yet another embodiment, at least 70% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0103] In one or more embodiments of any aspect, the mucoadhesive polymer is a peptide molecule linked via an amide bond, wherein at least 50% of the amino acids are lysine. In another embodiment, at least 60% of the amino acids are lysine. In yet another embodiment, at least 70% of the amino acids are lysine.

[0104] In one or more embodiments of any aspect, the mucoadhesive polymer comprises an amino acid that is L-lysine. In one or more embodiments of any aspect, the mucoadhesive polymer is poly-L-lysine (PLL).

[0105] It is advantageous to use amino acids or hydrophobic amino acids because they are biodegradable. Protein-peptide interactions between mucus proteins and the polymer can promote mucoadhesion. Furthermore, amino acid polymers can be produced recombinantly or synthetically using bacteria.

[0106] In one or more embodiments of any aspect, the mucoadhesive polymer comprises both sugar monomers, e.g., C6 sugar monomers, and amino acids, where at least 50% of the monomers are basic, e.g., have an amino group, or at least 50% of the monomers are hydrophobic, e.g., have a hydrophobic group.

[0107] In one or more embodiments according to any aspect, the mucoadhesive polymer comprises 40-800 monomer units linked together by ether bonds, ester bonds, amide bonds, or combinations thereof, such as 50-750 monomer units linked together by ether bonds, ester bonds, amide bonds, or combinations thereof, such as 75-700 monomer units, such as 100-650 monomer units, such as 150-600 monomer units. The size of the mucoadhesive polymer is very important to ensure that the polymer is small enough to diffuse deep into the mucus gel and large enough to form a tight crosslinked network. Tight means, for example, impermeable to microorganisms or sperm cells.

[0108] In one or more embodiments according to any aspect, the mucoadhesive polymer is selected from polymers having a low molecular weight, which should have a degree of polymerization (DP) that provides a molecular weight in the range of 20 to about 100 kDa, ensuring that the mucoadhesive polymer forms a stable complex with mucus.

[0109] In one or more embodiments according to any aspect, the mucoadhesive polymer has a molecular weight of from 20,000 Da to 90,000 Da, such as from 30,000 Da to 80,000 Da, such as from 30,000 Da to 70,000 Da, such as from 40,000 Da to 60,000 Da, such as from 45,000 Da to 55,000 Da, all endpoints within the above ranges.

[0110] The size or polymer ensures that the polymer is soluble in the conditions in which it is used and that it can diffuse through the pores of the mucus to form a thick, tight barrier.

[0111] Mucoadhesive polymers should be stable in the targeted mucosal environment, which is low pH in the female abdomen. Thus, the pH range in which mucoadhesive polymers are stable ranges from 1 to 8. Depending on the pH environment, different types and sizes of polymers can be used.

[0112] In one or more embodiments according to any aspect, the vaginal contraceptive composition has a pH of from 2.0 to 7.0, such as from 2.5 to 6.5, such as from 3.0 to 6.0, all endpoints of which are included within the above ranges.

[0113] A pH of the composition between 2.0 and 7.0 means that the pH, when measured, is between two values ​​and that the mucoadhesive polymer is stable within this range. A lower pH of the composition is preferred when the composition is to be applied to the female abdomen, especially the female vagina (where the pH value is in the range of 3 to 5).

[0114] Diffusion of the mucoadhesive polymer occurs when the mucoadhesive polymer and the physiologically acceptable gelling agent adhere to the mucus. The use of the mucoadhesive polymer in therapy is possible due to its degree of polymerization and acetylation, which results in good mucoadhesion. This allows the polymer to diffuse into the mucus and temporarily block the pores of the mucus. This occurs due to the temporary crosslinking effect of the mucus, which is controlled by the normal turnover of the mucus and the biodegradability of the mucoadhesive polymer. Thus, the effective crosslinking time can be adjusted by subjecting the mucus to various concentrations of the mucoadhesive polymer, such as, for example, a concentration of 1 mg / mL to 100 mg / mL, such as, for example, a concentration of 1 mg / mL to 75 mg / mL, such as, for example, a concentration of 1 mg / mL to 50 mg / mL, such as, for example, a concentration of 1 mg / mL to 25 mg / mL, such as, for example, a concentration in the range of 5 mg / mL. All endpoints are included in the above ranges.

[0115] In one or more embodiments according to any aspect, the mucoadhesive polymer is at a concentration of 0.05% to 10.0% by weight of the total weight of the vaginal contraceptive composition, such as 0.5% to 10.0% by weight of the total weight of the vaginal contraceptive composition, such as 1.0% to 10.0% by weight, such as 2.5% to 10.0% by weight. For example, 5.0% to 10.0% by weight, such as 0.05% to 10.0% by weight, for example, 0.05% to 8.0% by weight, such as 0.05% to 6.0% by weight, for example, 0.05% to 4.0% by weight.

[0116] 0.05% to 10.0% by weight means that 0.05% to 10.0% of the total weight of the vaginal contraceptive composition is derived from the mucoadhesive polymer, all endpoints being within the above ranges.

[0117] Due to their adhesive properties and size, the mucoadhesive polymer penetrates the mucus and diffuses into the surface of the mucus to form a thick layer. The mucoadhesive polymer then forms a complex with the mucus, thereby blocking the pores of the network and giving the mucus enhanced barrier properties. When the mucus is reinforced, it is impermeable to particles, for example preventing the passage of externally derived liquids, particles and cells, such as sperm. The complexes formed in the mucus can be targeted to cells of a specific size, thereby being impermeable to virions (or viruses) in the size range of 20-30 nm, mycoplasma in the 0.3 μm range, bacteria in the 0.5-5 μm range, or sperm in the 3 μm range.

[0118] The composition of the present invention, comprising a mucoadhesive polymer and a pharma- ceutically acceptable gelling agent, as a contraceptive agent, since the treated mucus is temporarily impermeable to spermatozoa. Contraceptive effect in the context of the present invention means reversible and temporary prevention of pregnancy by a non-surgical and non-hormonal barrier effect achieved by a single application, which means that the contraceptive effect is achieved by a single application and does not require increasing concentrations over a period of time, as is the case with hormonal pills, such as combined oral contraceptive pills (often referred to as birth control pills or colloquially as "the pill").

[0119] A temporary effect suggests that the effect of the mucoadhesive polymer when applied to mucus is reversible: the rate at which reversal occurs is determined by the amount of polymer that diffuses into the mucus and the biological turnover of the mucus itself.

[0120] In another aspect, the invention is a kit of parts comprising a vaginal contraceptive composition comprising a mucoadhesive polymer and a physiologically acceptable gelling agent, such as the contraceptive composition described above, and an applicator. In one embodiment, the applicator is a delivery device using the method, where the applicator comprises the vaginal contraceptive composition in the form of a gel, which is inserted into the vagina via a syringe or by introduction of a soft gel capsule that dissolves in the vagina and releases the gel. The gel is deployed from the applicator and applied to the cervical mucus; the mucus is thereby cross-linked by the mucoadhesive polymer. In one embodiment, the applicator is a container that contains the vaginal contraceptive composition and can be emptied by an expulsion mechanism.

[0121] The composition comprising a mucoadhesive polymer and a physiologically acceptable gelling agent can be part of a kit that further comprises an applicator that can be used to apply the composition, for example, to the surface of the cervix.

[0122] In one embodiment, the applicator is a syringe. In another embodiment, the applicator is a soft gel capsule.

[0123] In a further embodiment, the kit comprises a vaginal contraceptive composition, an applicator, and instructions for use.

[0124] The vaginal contraceptive composition of any embodiment may be used any time of day prior to sexual intercourse, preferably 24 hours to 30 seconds prior to sexual intercourse. The vaginal contraceptive composition may be used intentionally to prevent pregnancy, and may be administered in a volume of 1-5 mL by intravaginal administration, either with a syringe or a soft gel capsule. The vaginal contraceptive composition is inserted into the vagina, either with a finger or with an applicator.

[0125] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of protection. The features disclosed in the above description and in the following examples, separately or in any combination thereof, may be material for realizing the invention in diverse forms thereof.

[0126] Various embodiments are described herein below with reference to the figures. It should also be noted that the figures are merely intended to facilitate the description of the embodiments. They are not intended to be an exhaustive description of the claimed invention, nor are they intended to limit the scope of the claimed invention. Furthermore, an exemplary embodiment need not have all aspects or advantages shown. An aspect or advantage described in conjunction with a particular embodiment is not necessarily limited to that embodiment, and may be implemented in any other embodiment, even if not so illustrated or explicitly described. EXAMPLES

[0127] Working Example Here it is shown that mucus layer hydrogels produced by porcine gastric mucin and colon cell lines can be modified with low molar mass chitosan (less than 2,000 Da), which can enhance the barrier properties and slow down the diffusion of dextran polymers and cholera toxin subunits through the hydrogel.

[0128] Although all mucus gels share similar properties, they also differ in several ways. This includes mucin contraction (e.g., pore size), mucin concentration and the types of proteins and lipids associated, and salt concentration. In addition, they also differ in environmental factors such as pH, exposure to shear stress, exposure to bacteria, and different turnover rates. Thus, given these differences, it is not clear that a treatment designed for porcine mucin hydrogels would also function in enhancing the barrier properties of cervical mucus.

[0129] Example 1 The inventors performed experiments with various chitosan types, differing primarily in molar mass and the tissue origin from which they were extracted (animal vs. fungal), to test the ability of chitosans to interact and diffuse within human ovulatory cervical mucus and their ability to increase the barrier of human ovulatory cervical mucus against human sperm.

[0130] Materials and Methods Chitosan Labeling Chitosan (CS) and chitosan oligomers (CO) were labeled with fluorescein isothiocyanate (FITC) (Sigma-Aldrich) using a modified method previously reported in Kootala et al. 2018 (Kootala, Sujit, Luimar Filho, Vaibhav Srivastava, Victoria Linderberg, Amani Moussa, Laurent David, Stephane Trombotto, and Thomas Crouzier. 2018. "Reinforcing Mucus Barrier Properties with Low Molar Mass Chitosans." Biomacromolecules 19(3):872-82). Briefly, 40 mg / ml chitosan in 2 ml of lactic acid solution (pH 5) was prepared, 2 ml of methanol was added, and the mixture was treated with 2 M HCl or 2 M NaOH to adjust the pH to 5.5. A solution of 10 mg / ml FITC in DMSO was then added to achieve a 1:50 ratio (1 fluorescein for every 50 monomers) followed by shaking for 2 hours at room temperature in the dark. Chitosan was precipitated by successive addition of 10 ml ethanol plus 2 mL of 2 M NaOH to increase the pH to 9. The supernatant was removed after centrifugation at 20,000×g for 25 minutes at 4° C. The pellet was then rinsed three times to extract unconjugated FITC each time by resuspending it in ethanol and then centrifuging at 20,000×g for 10 minutes at 4° C. and removing the supernatant. After removing the ethanol by rotary evaporation for 2 hours, the pellet was frozen in liquid nitrogen, lyophilized and stored at 4° C.

[0131] [Table 1]

[0132] Turbidity Test The transmittance was measured by turbidity test using a Varian Cary 50 Bio UV-Visible spectrometer (Agilent Technologies, USA) at 600 nm. Samples containing 2.7% hydroxyethylcellulose were transferred to cuvettes and centrifuged at 600×g for 5 min in 50 ml plastic tubes to remove air pockets.

[0133] Semen evaluation Semen samples from patients and volunteers collected at the Andrology, Sexual Medicine, Transmedicine, clinic (ANOVA, Karolinska University Hospital, Sweden) were subjected to standard sperm motility analysis and sperm penetration assay within 3 hours after collection. Data were obtained for collection time, abstinence time, and semen volume. After complete collection of semen by masturbation, semen was gently liquefied for 30 minutes on a rocker in an incubation chamber heated to 37°C. Semen viscosity was determined visually and by pipetting. Semen was analyzed by microscopy by pipetting 6 μl of sample into pre-warmed Leja® (Netherland) counting chamber slides (20 μm). The samples were subsequently evaluated by a clinical ECLIPSE 50i microscope (Nikon Instruments, Japan) equipped with a stage heater MS 100 (37°C, Linkam Scientific Instruments, UK), a 10x objective (Ph1) and a 0.5x charge-coupled device camera UI-1540LE-M-HQ (IDS Imaging Development Systems GmbH, Germany) at a total magnification of 5x. The system was linked to the Computer Aided Semen Analysis software QualiSperm (v3.0.9.486, AKYmed, Switzerland). Sperm concentration [106 / ml] as well as progressive motility [%, motility [%, immobility [%, velocity [μm / sec], sperm size [μm2] and cell count were measured. Semen samples fulfilling the following criteria were included in the study: volume >1.5ml, concentration >15x106 / ml and progressive motility >40%.These standards reflect the World Health Organization (WHO) reference limits ("WHO Laboratory Manual for the Examination and Processing of Human Semen" 2010) and normal sperm values ​​described by Bjoerndahl (Lars Bjoerndahl. 2011. "What Is Normal Semen Quality? On the Use and Abuse of Reference Limits for the Interpretation of Semen Analysis Results." Human Fertility 14(3):179-86). In each test, 10 values ​​were generated by evaluating five fields in two chambers.

[0134] Cervical mucus assessment Ovulatory cervical mucus (CVM) (CVM with the highest penetrance) was collected from healthy donors at Karolinska University Hospital. Donors were not using hormonal contraception, were aged 18-30 years, had a BMI of 19-25, were non-smokers, were not on medication, and had no chronic diseases. Prior to collection of CVM, the hormonal status of each healthy, regularly cycling volunteer was examined by blood tests at Karolinska University Laboratory. At the time of donation, women's FSH, LH, and estradiol levels were analyzed, revealing ovulation disorders. Mucus was collected at the external cervical os using an endometrial catheter Gynebiops standard CH9 (GYNEAS, France) and a Pipelle de Cornier for endometrial biopsy (PRODiMED, France).

[0135] In vitro fluorescence profiling of chitosan diffusion into cervical mucus To determine the diffusion distance and amount of chitosan accumulated in the ovulatory CVM, a modified capillary diffusion assay according to Wu, et al. (Seyoum Ayehunie, Ying-Ying Wang, Timothy Landry, Stephanie Bogojevic, and Richard A. Cone. 2018. "Hyperosmolal Vaginal Lubricants Markedly Reduce Epithelial Barrier Properties in a Three-Dimensional Vaginal Epithelium Model." Toxicology Reports 5(January):134-40) was performed. 0.5% (w / v) labeled chitosan (chitosan-FITC) was adjusted to pH 5.5 (pH ± 0.02) by using 0.1 / 1 M hydrochloric acid (HCl, Merck KGaA, Germany), 0.1 / 1 M sodium hydroxide (NaOH, CPAchem Ltd., Bulgaria), or 50% NaOH (Sigma-Aldrich, USA).

[0136] CVM was aspirated into the two capillaries by using custom-made square capillary tubes (L 60 mm, ID 0.3×0.3 mm, OD 0.45×0.45 mm, borosilicate glass) with Luer connectors (Hilgenberg GmbH, Germany) and 1 ml Soft-Ject® syringes (Henke-Sass Wolf GmbH, Germany). The tubes were then broken at the Luer connections and the broken ends were sealed with wax (Paul Marienfeld GmbH & Co. KG, Germany). This resulted in airtight capillaries filled entirely with CVM. The septum of a short thread cap (55° Shore, Teknolab Sorbent AB, Sweden) was pierced with the sealed end of the capillary, the cap was placed into a short thread glass vial (ND9, 1.5 ml, VWR, USA) and the open end was gently inserted into 300 μl of pre-heated buffer or chitosan-FITC in buffer. CVM in the buffer-treated capillary was used as a negative control. At the same time, an identical square capillary without a Luer connector (L 50 mm, ID 0.3×0.3 mm, borosilicate glass, CM Scientific Ltd., UK) was filled with chitosan-FITC solution by inserting the capillary into a glass vial containing 300 μl of 0.5% or 0.1% chitosan-FITC, which served as a positive control and baseline fluorescence intensity. After 30 min of incubation at 37 °C and 5% CO2, the capillaries were evaluated by fluorescence microscopy and images were recorded in the exposure time range of 0.01 s to 1 s. Images were acquired with a light source pE-300lite (10 ms, CoolLED, UK) coupled to an Eclipse Ti inverted microscope (Nikon, Japan), a Zyla sCMOS camera (5.5 MP, Andor, Oxford Instruments, UK) and NIS-Elements BR 4.60.00 software (Nikon, Japan). Filter B for green fluorescence and a 2x objective were used.Images captured at an exposure time of 20 ms showed a non-saturated image that optimally identified the difference in fluorescence intensity between the different CSs and was used to calculate chitosan in the CVM. At an exposure time of 800 ms, the fluorescence signal was saturated at the beginning of the capillary, while a low chitosan-FITC concentration was observed further inside the capillary, thereby capturing the maximum diffusion distance.

[0137] The exported images were analyzed by ImageJ software (version 2.0.0-rc-43 / 1.52b, USA). A rectangle was drawn in the middle of each capillary (h=15, w=1314), starting 5 mm before the interface of air and CVM in the capillary, to obtain chitosan-FITC accumulation at the interface. Fluorescence intensity was plotted over distance in pixels. Each pixel corresponded to 3 μm. At the exposure time of 800 ms, the buffer-treated CVM showed background signal, and therefore the obtained value was subtracted from that obtained with the chitosan-FITC-treated CVM.

[0138] By using a control capillary with known chitosan-FITC concentration, the fluorescence intensity along the capillary with unknown chitosan-FITC concentration can be converted to chitosan-FITC concentration. The relative amount of accumulated chitosan at 20 ms and the relative fluorescence intensity along the capillary at 800 ms were plotted using Prism 8 (GraphPad, USA). Chitosan-FITC accumulation was obtained by calculating the area under the curve (AUC) for the sample analyzed at 0.02 s.

[0139] Phase contrast microscopy of sperm penetration After liquefaction and evaluation of semen and CVM, 100 μl of buffer only and chitosan in buffer were filled into glass vials (ND9, 1.5 ml, VWR, USA) closed by caps with septa (55° Shore, Teknolab Sorbent AB, Sweden) and preheated at 37° C. Aliquots of ovulated CVM were aspirated into two custom-made capillaries, which were sealed at the broken ends as described above. The septa of the cap were penetrated by the sealed ends of the capillaries filled with CVM. The capillaries embedded through the caps were first placed into a glass vial containing chitosan solution for 30 min at 37° C. (5 mm deep in solution). The capillaries were then transferred to a glass vial containing 100 μl of semen for sperm penetration for 30 min at 37° C. (5 mm deep in solution). In one control experiment, the same process was repeated except that the chitosan solution was replaced with buffer solution only. In another control experiment, the same process was repeated except that the capillary filled with ovulation CVM was immersed directly into the sperm. After incubation, the capillary was placed on a custom-made microscope slide marked at distances of 0.5, 1, 2, 3, 4, and 5 cm, placed on a pre-heated (37°C) stage heater DC 95 (Linkam Scientific Instruments, UK) and observed by microscopy.

[0140] Images were recorded at the distance marked on the glass slide including the beginning of the capillary (0.1 cm) by using an Eclipse Ci phase-contrast microscope (Nikon, Japan) equipped with a UI-3240LE-C-HQ camera (IDS Imaging Development Systems, Germany). A magnification of 10x was used for the objective lens (Ph1) and the camera to generate a total magnification of 100x. The recorded microscopic field was 0.21 x 0.27 mm, corresponding to 0.0567 mm2. A resolution of 1280 x 1024 pixels was used to record images of three fields at each distance at 30 pictures per second. Recordings started from the upper outer surface of the capillary and were subsequently focused through the capillary until the lower surface was reached, obtaining a 3-D scan through the capillary. Sperm were recorded in a volumetrically (0.017 mm2) and then in a 3-D-scan through the capillary. 3 ) were counted. Assays were performed in triplicate using semen from different volunteers.

[0141] Results of Example 1 The influence of chitosan molar mass was demonstrated by testing the diffusion of fluorescently labeled chitosans of different sizes through human ovulatory cervical mucus. For both chitosans of animal origin (CO, 95 / 5 and 95 / 100 extracted from crustacean shells) and fungal-based chitosans (Z49, Z56, Z13, Z10, Z43), the results (Figures 1, 2) clearly show that smaller chitosans penetrate deeper and accumulate more in the mucus. It was very noticeable that larger chitosans (>100 kDa) could not penetrate into the mucus gel network, probably due to steric hindrance, and therefore did not accumulate in the mucus. This would generate a very superficial barrier, which would be very vulnerable to destruction by, for example, shear stress. Chitosans above 100 kDa were therefore excluded for this reason.

[0142] The effect of chitosan molar mass on the barrier properties of human ovulatory cervical mucus was tested using chitosan-containing formulations of various molar masses. By using sperm penetration assays, human sperm, and ovulatory cervical mucus, it would be confirmed that the smaller chitosans, which were effective in strengthening the mucus expressed by porcine gastric mucin hydrogel and colon cell lines, were unable to stop the penetration of human sperm through the mucus. This was clearly demonstrated for CO chitosan in several different buffer systems at a pH of 5.5 and in lactate buffer (Figure 3). Even when CO was formulated in combination with the larger chitosan (95 / 5), the formulation failed to provide a barrier strengthening effect.

[0143] Similarly, fungal chitosans of 7.1 and 18.9 kDa, Z49 and Z56, respectively, were shown to be ineffective in halting sperm penetration (Figure 4). Conversely, the use of fungal chitosans of greater than 20 kDa (e.g., Z10) demonstrated a significant reduction in mean sperm penetration compared to the control group (untreated mucus) and compared to mucus treated with chitosan dissolution buffer alone (Figure 4).

[0144] The size-dependence of the effective barrier-strengthening effect is also shown for chitosan from crustacean shells (Figure 5). Larger chitosans (150 kDa) may also stop sperm penetration in these assays. However, the results from the diffusion of chitosans (Figures 1 and 2) clearly show the low penetration of larger chitosans (150 kDa) in mucus. Thus, the barrier formed by larger chitosans (150 kDa) is due to a thin cross-linked layer at the mucus-gel interface. In the well-controlled conditions of the in vitro sperm penetration assay, such a thin cross-linked layer may indeed provide a barrier to sperm. However, such a thin layer is unlikely to sustain the shear and convective migration commonly seen in vivo. In contrast, the deeper penetration of 20 kDa to 100 kDa chitosans would constitute a more robust barrier in vivo. The inventors conclude that optimal chitosans for enhancing the barrier properties of human ovulatory cervical mucus are comprised within the range of 20 kDa to 100 kDa, as these chitosans combine deep penetration into the mucus with their ability to form an effective barrier against sperm.

[0145] For proper delivery of chitosan to the cervical canal, chitosan formulations should contain excipients that increase the viscosity of the solution to increase the residence time of the formulation and avoid leakage. It is important that the excipients do not interact with chitosan to allow complete interaction with the mucus components. The gelling excipients selected should at least be known for their good biocompatibility, have no negative charges that can interact with the positive charges of chitosan, and have no known interactions with chitosan. The compatibility of hydroxyethylcellulose and chitosan was tested by measuring the permeability of the mixture. The absence of permeability change suggests the absence of chitosan precipitates and good compatibility of chitosan with hydroxyethylcellulose as a thickening agent (Figure 6). The addition of 0.5% (w / v) fungal chitosan (Z10, 36.2 kDa) or animal-derived chitosan (CO, 1.4 kDa; 95 / 5, 35 kDa) did not change the permeability, indicating the absence of precipitates in these formulations and good compatibility of chitosan. Glycerol and hydroxyethylcellulose were also combined with chitosan to test for possible changes in chitosan penetration in human ovulatory cervical mucus. The results show that these excipients do not change the penetration of chitosan into ovulatory cervical mucus (Figure 7). The decrease in fluorescence in Figure 7 indicates the maximum diffusion distance of chitosan alone and chitosan mixed with excipients after 30 minutes of exposure to mucus. The barrier-enhancing effect on ovulatory cervical mucus was also not altered by the presence of the excipients tested (Figure 8).

[0146] Example 2 This example is to demonstrate mucus strengthening by "amino acid monomers". In this example, human sperm penetration into human ovulatory cervical mucus that was first exposed to a solution of poly-L-lysine (PLL) is examined. The results are shown in Figures 9A and 9B, which show a sperm penetration assay performed in human ovulatory mucus. Sperm counts were assessed 30 minutes after exposure to undiluted sperm.

[0147] The materials and methods used in Example 2 were similar to those used in Example 1, except that chitosan was replaced with PLL.

[0148] Figure 9A (left and right) shows human ovulatory cervical mucus exposed to 32.5 mM lactate buffer, low molar mass poly-L-lysine (wPLL, 1.6 kDa) in lactate buffer (32.5 mM), or unmodified (w / o). Figure 9B (left and right) shows human ovulatory cervical mucus exposed to high molar mass poly-L-lysine (wPLL, 66 kDa) in 32.5 mM lactate buffer, lactate buffer (32.5 mM), or unmodified (w / o).

[0149] Results of Example 2 From the results, it can be inferred that PLL compounds can strengthen the barrier properties of human ovulatory cervical mucus against sperm. Similar to chitosan, low molecular weight PLL had no effect. Only higher molecular weights could prevent sperm from entering. The point where sperm disappeared was further inside the mucus (about 3 cm for 66 KDa PLL), which was similar to some chitosans such as 7.1 kDa chitosan (about 2 cm, Figure 4A), but further inside than other chitosans such as 27.9 kDa and 36.2 kDa (about 0.5 cm, Figures 4C and 4D).

[0150] The invention is hereinafter illustrated by the following non-limiting items.

[0151] 1. A vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight between 20,000 Da and 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units contain at least one amino group.

[0152] 2. The vaginal contraceptive composition of any preceding item, wherein the vaginal contraceptive composition is not a foam.

[0153] 3. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer has a molecular weight of from 20,000 Da to 90,000 Da.

[0154] 4. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer has a molecular weight of from 20,000 Da to 75,000 Da.

[0155] 5. The vaginal contraceptive composition according to any preceding item, wherein the mucoadhesive polymer has a molecular weight between 20,000 Da and 60,000 Da.

[0156] 6. The vaginal contraceptive composition according to any preceding item, wherein the mucoadhesive polymer has a molecular weight of between 30,000 Da and 50,000 Da.

[0157] 7. The vaginal contraceptive composition according to any preceding item, wherein the mucoadhesive polymer has a molecular weight of between 30,000 Da and 40,000 Da.

[0158] 8. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer consists of a plurality of monomer units linked together via ether bonds.

[0159] 9. The vaginal contraceptive composition of any preceding item, wherein at least 55% of the monomer units contain at least one amino group.

[0160] 10. The vaginal contraceptive composition of any preceding item, wherein at least 60% of the monomer units contain at least one amino group.

[0161] 11. The vaginal contraceptive composition of any preceding item, wherein at least 65% of the monomer units contain at least one amino group.

[0162] 12. The vaginal contraceptive composition of any preceding item, wherein at least 70% of the monomer units contain at least one amino group.

[0163] 13. The vaginal contraceptive composition of any preceding item, wherein one or more of the at least one amino group is a primary amine.

[0164] 14. The vaginal contraceptive composition of any preceding item, wherein the monomer units are selected from C6 sugars, amino-functionalized C6 sugars, or combinations thereof.

[0165] 15. The vaginal contraceptive composition of any preceding item, wherein the monomer unit is an amino-functionalized C6 sugar.

[0166] 16. The vaginal contraceptive composition of any preceding item, wherein the monomer unit is a combination of D-glucosamine and N-acetyl-D-glucosamine.

[0167] 17. The vaginal contraceptive composition according to item 16, wherein at least 50% is D-glucosamine.

[0168] 18. The vaginal contraceptive composition according to any one of items 16 to 17, wherein 50% or less is N-acetyl-D-glucosamine.

[0169] 19. The vaginal contraceptive composition according to any one of items 16 to 18, wherein 50% to 100% is D-glucosamine.

[0170] 20.0% to 50% of the vaginal contraceptive composition is N-acetyl-D-glucosamine.

[0171] 21. The vaginal contraceptive composition according to any one of items 16 to 20, wherein at least 65% is D-glucosamine.

[0172] 22. The vaginal contraceptive composition according to any one of items 16 to 21, wherein 22.35% or less is N-acetyl-D-glucosamine.

[0173] 23. The vaginal contraceptive composition according to any one of items 16 to 22, wherein 65% to 100% is D-glucosamine.

[0174] 24. The vaginal contraceptive composition according to any one of items 16 to 23, wherein 24.0% to 35% is N-acetyl-D-glucosamine.

[0175] 25. The vaginal contraceptive composition according to any of items 1 to 7, wherein the mucoadhesive polymer is a peptide molecule of 180 to 900 amino acids in length linked via an amide bond.

[0176] 26. The vaginal contraceptive composition according to item 25, wherein the mucoadhesive polymer is a polypeptide of amino acids, wherein at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0177] 27. The vaginal contraceptive composition according to any of items 25 to 26, wherein the mucoadhesive polymer comprises poly-lysine, poly-ornithine, and / or poly-arginine.

[0178] 28. The vaginal contraceptive composition according to item 27, wherein the mucoadhesive polymer comprises poly-lysine.

[0179] 29. The vaginal contraceptive composition according to any of items 1 to 7, wherein the mucoadhesive polymer is a peptide molecule of 180 to 900 amino acids in length, in which at least 50% of the amino acids have a hydrophobic group, which may be selected from the list consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine, and the remaining amino acids may be selected from the list consisting of glycine, serine, threonine, asparagine, and glutamine.

[0180] 30. The vaginal contraceptive composition according to any of items 1 to 7, wherein the mucoadhesive polymer comprises amino acids, wherein at least 50% of the amino acids are selected from the group consisting of arginine, lysine, histidine, ornithine, and β-alanine, or 50% of the amino acids have a hydrophobic group and are selected from the group consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine.

[0181] 31. The vaginal contraceptive composition according to any of items 1 to 7, wherein the mucoadhesive polymer is a peptide molecule linked via an amide bond, in which at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0182] 32. The vaginal contraceptive composition according to item 31, wherein at least 60% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0183] 33. The vaginal contraceptive composition according to any of items 31 to 32, wherein at least 70% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0184] 34. The vaginal contraceptive composition according to any of items 1 to 7, wherein the mucoadhesive polymer is a peptide molecule linked via an amide bond, wherein at least 50% of the amino acids are lysine.

[0185] 35. The vaginal contraceptive composition according to item 34, wherein at least 60% of the amino acids are lysine, such as at least 70%.

[0186] 36. The vaginal contraceptive composition according to any of items 1 to 7, wherein the mucoadhesive polymer comprises an amino acid that is L-lysine.

[0187] 37. The vaginal contraceptive composition according to item 36, wherein the mucoadhesive polymer is poly-L-lysine (PLL).

[0188] 38. The vaginal contraceptive composition of any preceding item, wherein the physiologically acceptable gelling agent is selected from hydroxyethyl cellulose (HEC), glycerol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, guar gum, or combinations thereof.

[0189] 39. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer consists of 40 to 800 monomer units linked together by ether bonds, ester bonds, amide bonds, or combinations thereof.

[0190] 40. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer consists of 50 to 750 monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof.

[0191] 41. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer consists of 75 to 700 monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof.

[0192] 42. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer consists of 100 to 650 monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof.

[0193] 43. The vaginal contraceptive composition according to any preceding item, wherein the mucoadhesive polymer consists of 150 to 600 monomer units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof.

[0194] 44. The vaginal contraceptive composition of any preceding item, wherein the mucoadhesive polymer is at a concentration of 0.05% to 10.0% by weight of the total weight of the vaginal contraceptive composition.

[0195] 45. A vaginal contraceptive composition according to any preceding item, wherein the pH of the composition is from 2.0 to 7.0.

[0196] 46. ​​A vaginal contraceptive composition according to any preceding item, wherein the pH of the composition is from 2.5 to 6.5.

[0197] 47. A vaginal contraceptive composition according to any preceding item, wherein the pH of the composition is from 3.0 to 6.0.

[0198] 48. A vaginal contraceptive composition according to any preceding item, wherein the composition is a contraceptive composition.

[0199] 49. Use of a vaginal contraceptive composition according to any of items 1 to 48 as a contraceptive.

[0200] 50. A vaginal contraceptive composition for therapeutic use, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight of from 20,000 Da to 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units contain at least one amino group.

[0201] 51. A vaginal contraceptive composition for use as a contraceptive or birth control agent, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight of from 20,000 Da to 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units contain at least one amino group.

[0202] 52. A vaginal contraceptive composition for use in birth control or birth control treatment, the vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, at least one of the one or more active ingredients is a mucoadhesive polymer, said mucoadhesive polymer having a molecular weight of from 20,000 Da to 100,000 Da, said mucoadhesive polymer consisting of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, said monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units contain at least one amino group.

[0203] 53. The vaginal contraceptive composition according to items 50 or 51 or 52, wherein the vaginal contraceptive composition is not a foam.

[0204] 54. The vaginal contraceptive composition according to any of items 50 to 53, wherein the mucoadhesive polymer has a molecular weight of 20,000 Da to 90,000 Da.

[0205] 55. The vaginal contraceptive composition according to any of items 50 to 54, wherein the mucoadhesive polymer has a molecular weight of 30,000 Da to 75,000 Da.

[0206] 56. The vaginal contraceptive composition according to any of items 50 to 55, wherein the mucoadhesive polymer has a molecular weight of 30,000 Da to 60,000 Da.

[0207] 57. The vaginal contraceptive composition according to any of items 50 to 56, wherein the mucoadhesive polymer has a molecular weight of 30,000 Da to 50,000 Da.

[0208] 58. The vaginal contraceptive composition according to any of items 50 to 57, wherein the mucoadhesive polymer has a molecular weight of 30,000 Da to 40,000 Da.

[0209] 59. The vaginal contraceptive composition according to any of items 50 to 58, wherein the mucoadhesive polymer consists of a plurality of monomer units linked together via ether bonds.

[0210] 60. The vaginal contraceptive composition according to any of items 50 to 59, wherein at least 55% of the monomer units contain at least one amino group.

[0211] 61. The vaginal contraceptive composition according to any of items 50 to 60, wherein at least 60% of the monomer units contain at least one amino group.

[0212] 62. The vaginal contraceptive composition according to any of items 50 to 61, wherein at least 65% of the monomer units contain at least one amino group.

[0213] 63. The vaginal contraceptive composition according to any of items 50 to 62, wherein at least 70% of the monomer units contain at least one amino group.

[0214] 64. The vaginal contraceptive composition according to any of items 50 to 63, wherein at least one amino group is a primary amine.

[0215] 65. The vaginal contraceptive composition according to any of items 50 to 64, wherein the monomer units are selected from C6 sugars, amino-functionalized C6 sugars, or combinations thereof.

[0216] 66. The vaginal contraceptive composition according to any of items 50 to 65, wherein the monomer unit is an amino-functionalized C6 sugar.

[0217] 67. The vaginal contraceptive composition according to any of items 50 to 66, wherein the monomer unit is a combination of D-glucosamine and N-acetyl-D-glucosamine.

[0218] 68. The vaginal contraceptive composition according to item 67, wherein at least 50% is D-glucosamine.

[0219] 69. The vaginal contraceptive composition according to any of items 67 to 68, wherein 50% or less is N-acetyl-D-glucosamine.

[0220] 70. The vaginal contraceptive composition according to any one of items 67 to 69, wherein 50% to 100% is D-glucosamine.

[0221] 71. The vaginal contraceptive composition according to any of items 67 to 70, wherein 0% to 50% is N-acetyl-D-glucosamine.

[0222] 72. The vaginal contraceptive composition according to any of items 67 to 71, wherein at least 65% is D-glucosamine.

[0223] 73. The vaginal contraceptive composition according to any of items 67 to 72, wherein 73.35% or less is N-acetyl-D-glucosamine.

[0224] 74. The vaginal contraceptive composition according to any of items 67 to 73, wherein 65% to 100% is D-glucosamine.

[0225] 75. The vaginal contraceptive composition according to any of items 67 to 74, wherein 75.0% to 35% is N-acetyl-D-glucosamine.

[0226] 76. The vaginal contraceptive composition according to any of items 50 to 59, wherein the mucoadhesive polymer is a peptide molecule of 180 to 900 amino acids in length linked via an amide bond.

[0227] 77. The vaginal contraceptive composition according to item 76, wherein the mucoadhesive polymer is a polypeptide of amino acids, wherein at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0228] 78. The vaginal contraceptive composition according to any of items 76 to 77, wherein the mucoadhesive polymer comprises poly-lysine, poly-ornithine, and / or poly-arginine.

[0229] 79. The vaginal contraceptive composition according to item 78, wherein the mucoadhesive polymer comprises poly-lysine.

[0230] 80. The vaginal contraceptive composition according to any of items 50 to 59, wherein the mucoadhesive polymer is a peptide molecule of 180 to 900 amino acids in length, in which at least 50% of the amino acids have a hydrophobic group, which may be selected from the list consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine, and the remaining amino acids may be selected from the list consisting of glycine, serine, threonine, asparagine, and glutamine.

[0231] 81. The vaginal contraceptive composition according to any of items 50 to 59, wherein the mucoadhesive polymer comprises amino acids, wherein at least 50% of the amino acids are selected from the group consisting of arginine, lysine, histidine, ornithine, and β-alanine, or 50% of the amino acids have a hydrophobic group and are selected from the group consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine.

[0232] 82. The vaginal contraceptive composition according to any of items 50 to 15, wherein the mucoadhesive polymer is a peptide molecule linked via an amide bond, in which at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0233] 83. The vaginal contraceptive composition according to item 82, wherein at least 60% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0234] 84. The vaginal contraceptive composition according to any of items 82 to 83, wherein at least 70% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

[0235] 85. The vaginal contraceptive composition according to any of items 50 to 59, wherein the mucoadhesive polymer is a peptide molecule linked via an amide bond, wherein at least 50% of the amino acids are lysine.

[0236] 86. The vaginal contraceptive composition according to item 85, wherein at least 60% of the amino acids are lysine, such as at least 70%.

[0237] 87. The vaginal contraceptive composition according to any of items 50 to 59, wherein the mucoadhesive polymer comprises an amino acid that is L-lysine.

[0238] 88. The vaginal contraceptive composition according to item 87, wherein the mucoadhesive polymer is poly-L-lysine (PLL).

[0239] 89. The vaginal contraceptive composition according to any of items 50 to 88, wherein the physiologically acceptable gelling agent is selected from hydroxyethyl cellulose (HEC), glycerol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, guar gum, or a combination thereof.

[0240] 90. The vaginal contraceptive composition according to any of items 50 to 89, wherein the mucoadhesive polymer consists of 40 to 800 monomer units linked together by ether bonds, ester bonds, amide bonds, or combinations thereof.

[0241] 91. The vaginal contraceptive composition according to any of items 50 to 90, wherein the mucoadhesive polymer consists of 50 to 750 monomer units linked together via ether bonds, ester bonds, amide bonds, or a combination thereof.

[0242] 92. The vaginal contraceptive composition according to any of items 50 to 91, wherein the mucoadhesive polymer consists of 75 to 700 monomer units linked together via ether bonds, ester bonds, amide bonds, or a combination thereof.

[0243] 93. The vaginal contraceptive composition according to any of items 50 to 92, wherein the mucoadhesive polymer consists of 100 to 650 monomer units linked together via ether bonds, ester bonds, amide bonds, or a combination thereof.

[0244] 94. The vaginal contraceptive composition according to any of items 50 to 93, wherein the mucoadhesive polymer consists of 150 to 600 monomer units linked together via ether bonds, ester bonds, amide bonds, or a combination thereof.

[0245] 95. The vaginal contraceptive composition according to any of items 50 to 94, wherein the mucoadhesive polymer is at a concentration of 0.05% by weight to 10.0% by weight of the total weight of the vaginal contraceptive composition.

[0246] 96. The vaginal contraceptive composition according to any of items 50 to 95, wherein the pH of the composition is from 2.0 to 7.0.

[0247] 97. The vaginal contraceptive composition according to any of items 50 to 96, wherein the pH of the composition is from 2.5 to 6.5.

[0248] 98. The vaginal contraceptive composition according to any of items 50 to 97, wherein the pH of the composition is from 3.0 to 6.0.

Claims

1. 1. A vaginal contraceptive composition comprising one or more active ingredients and a physiologically acceptable gelling agent, wherein at least one of the one or more active ingredients is a mucoadhesive polymer, the mucoadhesive polymer having a molecular weight of from 20,000 Da to 100,000 Da, the mucoadhesive polymer being composed of a plurality of monomeric units linked together via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomeric units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomeric units comprising at least one amino group.

2. The vaginal contraceptive composition of claim 1 , wherein the vaginal contraceptive composition is not a foam.

3. 3. A vaginal contraceptive composition according to claim 1 or 2, wherein the mucoadhesive polymer has a molecular weight of from 20,000 Da to 90,000 Da, such as from 30,000 Da to 75,000 Da, for example from 30,000 Da to 60,000 Da, such as from 30,000 Da to 50,000 Da, for example from 30,000 Da to 40,000 Da.

4. 4. The vaginal contraceptive composition according to any one of claims 1 to 3, wherein at least 55% of the monomer units comprise at least one amino group, such as at least 60% of the monomer units comprise at least one amino group, such as at least 65% of the monomer units comprise at least one amino group, such as at least 70% of the monomer units comprise at least one amino group.

5. The vaginal contraceptive composition according to any one of claims 1 to 4, wherein the at least one amino group is a primary amine.

6. 6. The vaginal contraceptive composition of claim 1, wherein the monomer units are selected from C6 sugars, amino-functionalized C6 sugars, or combinations thereof.

7. 7. The vaginal contraceptive composition of claim 1, wherein the monomer unit is an amino-functionalized C6 sugar.

8. A vaginal contraceptive composition according to any one of claims 1 to 7, wherein the monomer units are a combination of D-glucosamine and N-acetyl-D-glucosamine.

9. 9. The vaginal contraceptive composition of claim 8, wherein at least 50% is D-glucosamine and not more than 50% is N-acetyl-D-glucosamine, such as 50% to 100% is D-glucosamine, 0% to 50% is N-acetyl-D-glucosamine, such as at least 65% is D-glucosamine and not more than 35% is N-acetyl-D-glucosamine, such as 65% to 100% is D-glucosamine and 0% to 35% is N-acetyl-D-glucosamine.

10. 4. The vaginal contraceptive composition according to claim 1, wherein the mucoadhesive polymer is a peptide molecule linked via an amide bond.

11. 11. The vaginal contraceptive composition of claim 10, wherein the mucoadhesive polymer is a polypeptide of amino acids, wherein at least 50% of the amino acids are selected from the list consisting of arginine, lysine, histidine, ornithine, and β-alanine.

12. 12. The vaginal contraceptive composition of claim 10 or 11, wherein the mucoadhesive polymer comprises poly-lysine, poly-ornithine, and / or poly-arginine.

13. 13. The vaginal contraceptive composition of any one of claims 1 to 12, wherein the physiologically acceptable gelling agent is selected from hydroxyethyl cellulose (HEC), glycerol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, guar gum, or combinations thereof.

14. A vaginal contraceptive composition according to any one of claims 1 to 13, wherein the mucoadhesive polymer is at a concentration of 0.05% to 10.0% by weight of the total weight of the vaginal contraceptive composition.

15. A vaginal contraceptive composition according to any one of the preceding claims, wherein the pH of the composition is from 2.0 to 7.0, such as from 2.5 to 6.5, for example from 3.0 to 6.

0.

16. A vaginal contraceptive composition according to any one of claims 1 to 15, wherein the composition is a contraceptive composition.

17. Use of the vaginal contraceptive composition according to any one of claims 1 to 16 as a contraceptive agent.

18. A vaginal contraceptive composition for therapeutic use, the vaginal contraceptive composition being a vaginal contraceptive composition according to any one of claims 1 to 16.

19. A vaginal contraceptive composition for use as a contraceptive or contraceptive agent, the vaginal contraceptive composition being a vaginal contraceptive composition according to any one of claims 1 to 16.

20. A vaginal contraceptive composition for use in birth control or birth control treatment, the vaginal contraceptive composition being a vaginal contraceptive composition according to any one of claims 1 to 16.

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