Vaginal contraceptive composition for enhancing mucus barrier properties

Abstract

The present disclosure 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, the mucoadhesive polymer having a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consisting of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units being selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, and at least 50% of the monomer units containing at least one amino group. The present disclosure further relates to uses of the vaginal contraceptive composition, vaginal contraceptive compositions for therapeutic use, vaginal contraceptive compositions for use as contraceptives or contraceptive agents, and vaginal contraceptive compositions for use in birth control or birth control therapy.

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, wherein at least one of the one or more active ingredients is a mucoadhesive polymer. The present invention also relates to the use of such a vaginal contraceptive composition in therapy or contraception. The mucoadhesive polymer can crosslink the mucus layer without aggregating the mucus.

Background Art

[0002] Background Art The citation and incorporation of patent documents in this specification are for convenience only and do not reflect any overview of the validity, patentability, and / or enforceability of such patent documents.

[0003] The number of women dissatisfied with hormonal contraceptives is increasing rapidly, but no alternative methods that are convenient (implant-free, easy to use, and flexible in use) and effective (more than 90% effective in typical use) can be found. In fact, 125 million couples in Europe and the United States are using birth control, and hormonal contraceptives (pills, patches, implants, rings, etc.) are the most widely used birth control method by far. However, the growing awareness of side effects caused by hormones is having a strong impact on the contraceptive market. Currently, there is conclusive evidence about the side effects of hormonal contraceptives.Three studies, including women numbering from 500,000 to 1.8 million, have shown that the use of hormonal contraceptives increases the proportion of women taking antidepressants by 23%, almost doubling the rate 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), increases the proportion of women attempting suicide by 197%, and increases 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% when used for less than one year and up to 38% when 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 wish to stop using hormonal contraception but are unable to find a suitable alternative. Current alternatives are either inconvenient (condoms, pessaries) or invasive (copper and hormonal - releasing implants) and may be less effective in actual use (for example, condoms are only on average 85% effective).

[0004] There is an epithelial surface of over 400 square meters hidden in the human body, including the lungs, digestive tract, and female reproductive tract. The moist epithelial surface relies on the mucus gel for protection against dehydration, shear stress, and infection. In addition to water, mucus mainly contains mucin biopolymers mixed with proteins, lipids, and salts. Mucin is a large glycoprotein consisting of an extended central protein core densely conjugated with oligosaccharides that can account for up to 50% of the molecular weight of the molecule. Mucin plays a central role in the protective function, generating a barrier that acts as a selective filter based on size exclusion and affinity, preventing many harmful molecules from reaching the epithelial surface.

[0005] Mucoadhesive polymers are used in drug delivery due to their adhesive properties. For example, they are used to deliver drugs to the site of inflammation.

[0006] Mucoadhesive polymers are typically assembled with drugs into materials or gels, which are intended to collect the drugs on the surface of the mucus layer and improve drug delivery.

[0007] WO 2004 / 069230 relates to a pharmaceutical composition containing a physiologically active agent, i.e., a drug, and a sustained release or mucoadhesive agent, such as chitosan, that acts to prolong the release of the active agent from the composition.

[0008] Another use of chitosan is in female contraception. An example of this can be found in CN 102895256, which relates to a chitosan gel foam suitable for female contraception and antifungal effects and its preparation method, belonging to the technical field of foam agent production. According to the present disclosure, chitosan molecules are trapped in a solid foam matrix together with polyacrylic acid, which physically prevents the passage of sperm. Furthermore, chitosan has a molecular weight distribution of 2000 - 5000 Da, a degree of deacetylation of over 95%, and a concentration of 5 - 10 wt%, while polyacrylic acid has a concentration of 1 - 3 wt%.

[0009] Another example of chitosan for female contraception can be found in WO 2018 / 185321, which relates to a mucoadhesive polymer, more specifically chitosan, that can crosslink the mucus layer without aggregating the mucus. The chitosan consists of 4 to 20 monomer units and a degree of deacetylation of more than 50%.

[0010] A third example can be found in US Patent No. 4,474,769, which relates to a method for killing or inactivating mammalian sperm by directly injecting a chitosan formulation into the uterine cavity of a female over a long period of time.

[0011] Mucoadhesive molecules are known to promote the tightness and thickening of mucosal tissue or enhance the barrier function, but it has been shown that the use of mucoadhesive polymers and mucus-permeable nanoparticles crosslinks and aggregates the mucus, resulting in the formation of a highly swollen interpenetrating polymer network structure. Thus, mucus aggregation leads to the opening of pores within the mucus and weakens the barrier properties of the mucus. Accordingly, there remains a need in the art for compositions that show an improvement in crosslinking the mucus without aggregation. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0012] Accordingly, it is an object of the present invention to provide a mucoadhesive polymer that can crosslink the mucus layer at the entrance of the female cervix, i.e., the mucus layer of the endocervicovaginal region, without aggregating the mucus or with a lesser degree of aggregation compared to prior compositions in the art. The endocervicovaginal region is the protective mucosa outside the cervix. Preferably, the mucoadhesive polymer can also crosslink the mucus layer at the entrance of the female cervix in the endocervical mucosa, which is the mucosa of the cervical canal. The crosslinking should be sufficient to prevent motile sperm from moving 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 invading the cross-linked mucus and diffusing into the mucosa.

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

Means for Solving the Problems

[0015] Overview Here, a newly developed technique has been discovered that provides a non-invasive, easy-to-use, and effective alternative to hormonal contraception. This approach relies on temporarily making the cervical mucus, a natural barrier in the body between the vagina and the uterus, impermeable to sperm cells. Cervical mucus protects women from infections and is mainly impermeable to foreign cells throughout the month. However, around the time of ovulation, hormonal changes loosen the mucus and then make it highly permeable to sperm cells. It has been found that the delivery of a mucoadhesive (bio)polymer to the cervical mucus changes the microstructure of the mucus gel, thereby strengthening the body's own natural barrier and preventing fertilization.

[0016] Low molecular weight mucoadhesive polymers containing 4 to 20 monomers (see, for example, WO 2018 / 185321 or Biomacromolecules, 2018, 19, 3, 872-882) have previously been noted to be ideal mucoadhesive polymers that enhance mucus barrier properties by cross-linking said mucus. The small size of the polymer was the view that would allow the molecule to diffuse favorably within the mucus. This should enable the mucoadhesive polymer to improve its diffusion into the mucosa and cross-link the mucus layer over a thick thickness without aggregating the mucus. Thereby, small mucoadhesive polymer complexes would occlude the pores of the network structure and enhance the barrier properties. However, such enhancement of barrier properties by, for example, chitosan has been shown to function for small chitosan sizes in porcine gastric mucin and colonic mucin cell lines, but in the use as a contraceptive composition, the mucus to be targeted is very different from the mucin in the digestive tract. At ovulation, the cervical mucus loosens to allow sperm to pass through the gel. Compared to gastric mucus or colonic mucus, the mucin content is reduced and the overall mucus structure and composition are very different. Therefore, it is very important that the mucus layer is cross-linked sufficiently to fully prevent motile sperm from moving through the mucus layer without aggregating the mucus.

[0017] Aggregation of mucus occurs when mucin polymers condense around the mucoadhesive polymer. The result is the formation of regions of very dense mucin polymer aggregates and regions of very coarse and very loose mucin network structures. These coarse 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0019] It is disclosed herein that treatment with a mucoadhesive polymer of 4 to 20 monomers as described above for gastric mucus and colonic mucus is not actually suitable for effectively strengthening the mucus barrier in ovulatory mucus. It is shown that a mucoadhesive polymer of at least 20,000 Da is much more effective, for example, in forming a barrier against sperm cells attempting to penetrate the mucus barrier. Further, it is shown herein that a mucoadhesive polymer having a molecular weight exceeding 100,000 Da is too large and difficult to interact with mucus.

[0020] The compositions disclosed herein, when formulated in a vaginal gel, can be efficiently delivered to the cervix. The components of the gel can prevent the diffusion of the mucoadhesive polymer from the gel into the mucus by means of a steric hindrance effect or 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 typically used as a gelling agent, this component strongly interacts with chitosan, for example, when used as a mucoadhesive polymer. At least two different types of gelling agents are natural and positively charged and suitable for vaginal formulations, without preventing the penetration of the mucoadhesive polymer into the cervical mucus of women and without interfering with the barrier-enhancing effect obtained by the mucoadhesive polymer. The gelling agent needs to be either natural or positively charged in order to avoid strong interactions with the mucoadhesive polymer. In another example, when the mucoadhesive polymer interacts with the mucus via a thiol group, the excipient should not contain a thiol group.

[0021] The present invention further relates to the use of a vaginal contraceptive composition as a contraceptive, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0022] The present invention also relates to a vaginal contraceptive composition for use in treatment, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0023] Furthermore, the present invention relates to a vaginal contraceptive composition for use as a contraceptive drug or agent, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0024] The present invention further relates to a vaginal contraceptive composition for use in fertility restriction or fertility restriction treatment, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0025] Finally, the present invention is a method of treatment, a method of avoiding pregnancy, a method of contraception, and / or a method of birth control or birth control treatment, 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0027] Detailed Description The description in this specification of any aspect or embodiment of the present invention using terms such as "comprising", "having", "including", or "containing" related to one or more elements is, unless otherwise specified or clearly inconsistent in context, intended to provide support for similar aspects or embodiments of the present invention that "consist of", "consist essentially of", or "substantially comprise" that particular one or more elements. For example, a composition described in this specification that includes a particular element should be understood to also describe a composition consisting of that element, unless otherwise specified or clearly inconsistent in context. The terms "comprises", "comprising", "includes", and / or "including", when used in this specification, define the presence of the recited features, integers, steps, operations, elements, and / or components, but it will further be understood that they 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 (including technical and scientific terms) used in this specification have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning that conforms to their meaning in the context of the relevant art, and it will further be understood that they are not to be interpreted in an idealized or overly formal sense unless expressly so represented in this specification.

[0029] As used in this specification, the singular forms "a", "an", and "the" are intended to include the plural form as well, including "at least one", unless the context clearly dictates otherwise. "At least one" should not be construed as limiting "a" or "an".

[0030] Any examples provided in this specification, or the use of exemplary terms (such as "etc.") are merely intended to better illustrate the present invention and do not impose limitations on the scope of the present invention, unless otherwise specifically claimed. No term in this specification should be construed as indicating that an element not claimed is essential for the practice of the present invention.

[0031] When explaining the following embodiments, aspects, and definitions, the present invention assumes all disclosed embodiments and definitions combined with the disclosed aspects. Furthermore, combinations and modifications of all possible embodiments are not clearly described. Nevertheless, the fact that certain means are described in different dependent claims or in different embodiments alone does not indicate that combinations of these means cannot be used to achieve benefits. The present invention assumes all possible combinations and modifications 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0033] Disclosed in a second aspect of the present invention is the use of a vaginal contraceptive composition as a contraceptive, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer is composed of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0034] Disclosed in the third, fourth, and fifth aspects of the present invention is a vaginal contraceptive composition for use in therapy, for use as a contraceptive drug or agent, and for use in fertility limitation or fertility limitation therapy, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer is composed of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[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 treatment, 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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.

[0036] As disclosed herein, a contraceptive composition is a composition that prevents a woman from becoming pregnant by separating egg cells and sperm cells by a barrier method that can further help prevent sperm from reaching an egg or ovum and protect against sexually transmitted infections. By creating a barrier at the cervicovaginal portion and the endocervical mucosa, sperm cells are retained within the vagina (or vaginal canal), thereby preventing sperm from reaching an egg or ovum. Thus, sperm cells will not have the opportunity to enter the uterus through the cervix and thereby enter the fallopian tubes (or oviducts) and reach the ovum. Instead, sperm cells will be killed by the acidic fluid in the vagina or lost during "backflow".

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

[0038] A mucoadhesive polymer is a polymer that exhibits mucoadhesion. Mucoadhesion is described herein as an interfacial tension that binds two biological materials, such as the attractive force between a biomaterial and mucus or mucosa. Thus, a mucoadhesive polymer means a polymer having an attractive force for mucus or mucosa.

[0039] Mucus is the protective cover of all epithelial surfaces, which maintains the lubrication of the epithelial layer and prevents microorganisms from invading the epithelium. Mucus captures microorganisms and promotes their distal transport, thus achieving a natural protective effect. When referring to the barrier effect achieved by mucoadhesive polymers, it is the reinforcement of mucus by cross-linking of the polymer. The effect of the enhanced barrier is based on the tightness of the cross-linked mucus that stops diffusion and how long the mucus complexed with the mucoadhesive polymer is strengthened. The latter is determined by the natural turnover of mucus secreted by cells from the mucosa that removes the mucus containing the cross-linked polymer.

[0040] The mucus layer in the cervical mucosa has different rheological properties depending on the four stages of the menstrual cycle. At the time of ovulation, the cervical mucus is loose enough to allow sperm to pass through the gel, and thus the pore size of the mucus will also increase. The thickness of the barrier layer can be adjusted to be impermeable to relatively large cells such as sperm, but it may also be adjusted to a more tightly packed barrier layer that may be required to be impermeable to bacteria, viruses, or microorganisms or pathogens.

[0041] On the premise of an effective barrier that the thickening of cervical mucus can occur, it is widely recognized that the cervical mucus barrier properties can be utilized as a contraceptive method. In fact, the main mechanism of contraception of the levonorgestrel intrauterine contraceptive system (LNG-IUS) and the progestin-only minipill is the thickening of cervical mucus. The methods disclosed herein differ from these methods not by the nature of the barrier but by the means of generating the barrier: a contraceptive drug that is non-hormonal, non-invasive, and meets the requirement of having no 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 cross-linked mucus and diffusing into the mucosa. The vaginal contraceptive composition creates a tightly cross-linked mucus that prevents even the smallest microorganisms from penetrating, thereby preventing not only pregnancy but also sexually transmitted infections (STIs).

[0043] Thus, in one or more embodiments according to any aspect, the composition is a contraceptive composition. Further, the present invention provides a contraceptive composition that does not contain hormones or chemicals having undesirable side effects. The undesirable effects may include mild side effects such as plugs, headaches, or effects on the menstrual cycle. The effective time of the mucoadhesive polymer according to the present invention is determined by the turnover of the mucus, which means that the contraceptive effect is temporary. After the effective time and the effect on conception have passed, the contraception is resolved. The sufficient contraceptive time is affected by several factors such as the biological turnover of the mucus and the concentration of the mucoadhesive polymer. The contraceptive effect lasts for a predetermined 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 sufficient time to prevent sperm cells from entering the cervix. By preventing sperm from entering the cervix, the acidic environment of the vagina reduces sperm motility and weakens the sperm so that it cannot fertilize the egg. Under natural conditions, sperm cells need to enter the cervix within a few minutes to survive. A complete contraceptive effect is obtained from a single application, which means that non-coherent use of the contraceptive composition provides the same protection as coherent use. The fact that a complete contraceptive effect is obtained from a single application may also mean that a temporary contact of the endocervical mucus with the contraceptive composition can provide the same complete protection as a continuous contact with the endocervical mucus.

[0044] The size of the mucoadhesive polymer allows the molecule to diffuse within the mucus. This diffusion of the mucoadhesive polymer into the mucosa enables it to crosslink the mucus layer over a thickness sufficient to prevent motile sperm from moving through the mucus without aggregating the mucus. The mucoadhesive polymer forms a complex with the mucus, thereby plugging the pores of the network structure and enhancing its barrier properties. At the time of ovulation, the cervical mucus loosens to allow sperm passage through the gel, and thus 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 is useful due to 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 with a lower molecular weight and has less steric hindrance. If the mucoadhesive polymer is large, it cannot pass through or penetrate the pores of the mucus, and thus it will ultimately interact with an increased number of mucin molecules, thereby not diffusing through the gel. However, if it is too small, it can pass straight through without interacting with the mucin molecules. Therefore, adjustment is required between a size that is larger but not too large to avoid the mucoadhesive polymer from fully penetrating through the pores of the mucus and a smaller size to obtain a high enough solubility for proper delivery to the target mucosa. This allows the mucoadhesive polymer to be delivered more efficiently by the mucosa, which in turn enables a stronger and thus more effective crosslinking than can be obtained using smaller or larger mucoadhesive polymer molecules (less than 20,000 Da or more than 100,000 Da).

[0046] Mucoadhesive polymers are generally cationic and at least 50% of the monomers are charged. The monomer units can contain, for example, an amino group that is positively charged at the physical pH. It can also be hydrophobic, for example, up to 50% of the monomers have hydrophobic side chains. These two characteristics of mucoadhesive polymers can play a role when selecting compatible excipients.

[0047] An amino group is a functional group consisting of a nitrogen atom bonded by a single bond to a hydrogen atom, an alkyl group, an aryl group, or a combination of these three in chemistry. An organic compound containing an amino group is called an amine. An amine is a derivative of the inorganic compound ammonia, NH3. When one, two, or all three of the hydrogens in ammonia are replaced by an alkyl or aryl group, the resulting compounds are known as primary, secondary, or tertiary amines, respectively. Like ammonia, amines are weak bases because the non-bonding electron pair of the nitrogen atom can form a coordinate bond with a proton. Water-insoluble amines can be made soluble by adding an acid to form their water-soluble amine salts. The amino group makes the mucoadhesive polymer basic, which is advantageous for their binding to the mucosa because of the large number of negatively charged molecules it contains. The basic amino group, in particular, provides more efficient cross-linking. Furthermore, when up to 50% of the monomers of the mucoadhesive polymer contain a hydrophobic group, the mucoadhesive polymer can also adhere to the mucosa, diffuse therein, and cross-link the mucosa without aggregating the mucus. For the present invention, the amino group is -NH2, where one or both of the hydrogen atoms can be replaced by a group R, or the amino group is a quaternary amino group having three R groups, i.e., -N +It can be R3. R can be selected from C1-C4 alkyl optionally substituted with one or more -OH, -SH, or -NH2. When two or more Rs are present on the same nitrogen atom, they can be the same or different R groups. As long as R has 4 or fewer carbon atoms, especially when a hydrogen atom of the R group is substituted with one or more -OH, -SH, or -NH2, the amino groups disclosed herein are generally considered to be basic. For example, a longer alkyl chain having 5 or more carbon atoms can mask the basicity of the amino group, but an amino group having an alkyl of 5 or more carbon atoms is also considered an amino group with respect to the present invention. Similarly, a sugar can also contain an amide group, such as -CONHCH3, or -NHCHO, but such groups are not considered amino groups with respect to the present invention.

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

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

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

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

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

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

[0054] In one or more embodiments according to any aspect, one or more of the at least one amino group is a primary amine. For the purposes of the present invention, a primary amine is an amino group (i.e., -NH2) in which none of the hydrogen atoms are substituted with a group R substitution.

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

[0056] The vaginal contraceptive composition comprises one or more active ingredients and a physiologically acceptable gelling agent. The one or more active ingredients can be administered in a physiologically acceptable gelling agent (or carrier), which 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 provided with at least a minimum amount of the composition containing an effective amount of the active ingredient sufficient to diffuse into the mucus and strengthen the mucus barrier.

[0057] A physiologically acceptable gelling agent (or carrier) means a non-toxic compound that is not chemically or physically toxic to human and / or animal organisms at an effective dose.

[0058] In one or more embodiments according to 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 can be used as long as the gelling agent does not interact with the one or more active ingredients, particularly the mucoadhesive polymer.

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

[0060] Hydroxyethyl cellulose (or ethyl cellulose) is a gelling agent and thickening agent derived from cellulose. It is widely used in cosmetics, cleaning liquids, and other household products. Hydroxyethyl cellulose and hydroxymethyl cellulose (or methyl cellulose) are often used together with hydrophobic drugs in capsule formulations to improve the dissolution of the drugs in gastrointestinal fluids. This process is known as hydrophilic modification.

[0061] In one or more embodiments according to any aspect, the physiologically acceptable gelling agent is selected 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 with a sweet taste and is 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 wetting agent in pharmaceutical formulations. Glycerol has three hydroxyl groups that contribute to its solubility in water and its hygroscopicity.

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

[0064] Hydroxypropyl methylcellulose (HPMC), also known as hypromellose, is a semi-synthetic, inert, viscoelastic polymer used as an excipient and controlled delivery component in eye drops and oral medications found in various commercial products. As a food additive, hypromellose is an emulsifier, thickener, and suspending agent and is an alternative to animal gelatin. Its Codex Alimentarius code (E number) is E464.

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

[0066] Hydroxypropyl cellulose (HPC) is a cellulose derivative having both water solubility and organic solubility. It is used as an excipient, and a topical eye protectant and lubricant. HPC is an ether of cellulose in which some of the hydroxyl groups in the repeating glucose units are 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 added hydroxypropyl groups contain hydroxyl groups, these can also be etherified during the preparation of HPC. When this occurs, the molar degree of 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 according to any aspect, the physiologically acceptable gelling agent is hydroxypropyl cellulose.

[0068] Guar gum, also known as guaran, is a galactomannan polysaccharide extracted from guar beans that has useful thickening and stabilizing properties in food, feed, and industrial applications. Guar seeds are mechanically dehulled, hydrated, milled, and sorted according to their intended use. It is typically produced as a free-flowing, off-white powder. Chemically, guar gum is an extracellular polysaccharide composed of the sugars galactose and mannose. The backbone is a linear chain of β 1,4-linked mannose residues with galactose residues 1,6-linked every 2 mannoses to form short side chains. Guar gum has the ability to withstand a temperature of 80 °C for 5 minutes.

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

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

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

[0072] A foam is an object 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 regions of gas.

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

[0074] At least one amino group can be attached to any carbon atom of the glucose monomer, such as C2 or C3.

[0075] In one or more embodiments according to any aspect, the mucoadhesive polymer consists of a plurality of monomer units linked to each other via ether bonds.

[0076] In one or more embodiments according to any aspect, the monomer unit is selected from C6 sugars, amino-functionalized C6 sugars, or combinations thereof.

[0077] A C6 sugar is a carbohydrate whose molecule has six carbons (i.e., a hexose). The best-known example of this class is glucose, which is the main component of cellulose and starch molecules.

[0078] An amino-functionalized C6 sugar (or amino sugar) is a sugar molecule in which a hydroxyl group is replaced by an amine group. More than 60 amino sugars are known, and one of the most abundant is N-acetyl-D-glucosamine, which is 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 according to any aspect, the monomer unit is an amino-functionalized C6 sugar.

[0080] In one or more embodiments according to any aspect, the monomer unit is 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 polysaccharides, chitosan, and chitin. D-glucosamine is one of the most abundant monosaccharides. It is commercially produced by the hydrolysis of the exoskeleton of crustaceans or, less commonly, by the fermentation of grains such as corn or wheat.

Chem.

[0082] N-acetyl-D-glucosamine (GlcNAc, C8H 15 NO6) is a derivative of monosaccharides and glucose. It is important in some biological systems. It is part of a biopolymer in the bacterial cell wall, which is constructed from alternating units of GlcNAc and N-acetylmuramic acid (MurNAc) cross-linked to an oligopeptide at the lactic acid residue of MurNAc. This layered structure is called peptidoglycan (formerly called murein). GlcNAc is a monomer unit of the polymer chitin that forms the exoskeletons of insects and crustaceans.

Chem.

[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. For example, 50% to 100% are D-glucosamine and 0% to 50% are N-acetyl-D-glucosamine.

[0084] At least 50% of the monomer units being 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 being 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. Further, 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 the said monomer units, and all endpoints (0%, 50%, and 100%) are included.

[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. For example, 65% to 100% are D-glucosamine and 0% to 35% are N-acetyl-D-glucosamine. The endpoints are included.

[0086] In one or more embodiments according to any aspect, the mucoadhesive polymer is chitosan, where at least 50% of the glucose monomers have an -NH2 group. Chitosan can also be shown to be 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 an alkaline substance such as sodium hydroxide, or it can be extracted from another source 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, because the carboxyl functional groups in the acrylic monomer form an ionic complex with the basic amino groups in the chitosan chain, which results in the formation of a highly swollen interpenetrating polymer network structure. This leads to the aggregation of mucus, and thus to the opening of pores within the mucus, weakening the barrier properties of the mucus.

[0089] Chitosan is a strongly 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 mucoadhesive drug delivery devices and are included in commercially available hemostatic products. However, the chitosan used when disclosed herein is typically of high molar mass and thus does not diffuse well in the mucus gel and tends to aggregate and condense the mucus.

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

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

[0092] In one or more embodiments according to any aspect, the mucoadhesive polymer is chitosan, where at least 70% of the glucose monomers have -NH2 groups. Chitosan can also be said to be at least 70% deacetylated.

[0093] In one or more embodiments according to any aspect, the mucoadhesive polymer is chitosan, where at least 70% of the glucose monomers have an -NH2 group and 20% or less of the glucose monomers have a -CONHCH3 group.

[0094] In one or more embodiments according to 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. This quaternized derivative of chitosan has a positive charge and is 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. Thereby, the properties of the resulting polymer are modified with respect to 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 are included within the above ranges.

[0098] In one or more embodiments according to any aspect, the mucoadhesive polymer is a peptide molecule having a length of 180 to 900 amino acids linked via an amide bond. If the mucoadhesive polymer contains amino acids, as long as at least 50% of the amino acids have a basic group, or as long as at least 50% of the amino acids have a hydrophobic group as required, or at least 50% of the amino acids have a thiol group, or are a combination of these three (basic, hydrophobic, and thiol), any amino acids can be included. 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 contain D-amino acids and that any amino acids contained in the mucoadhesive polymer are L-amino acids.

[0099] Generally, the following amino acids: arginine, lysine, histidine, ornithine, and β-alanine are considered to be basic. 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 can be selected from any amino acids, for example, any of the 20 amino acids defined by the genetic code, and in particular, glycine, serine, threonine, asparagine, and glutamine. Specific 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 according to any aspect, the mucoadhesive polymer is a peptide molecule having a length of 180 to 900 amino acids, wherein at least 50% of the amino acids have a hydrophobic group, and the amino acids are selected from the list consisting of alanine, methionine, cysteine, phenylalanine, leucine, valine, and isoleucine. 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 by the genetic code.

[0101] In one or more embodiments according to any aspect, the mucoadhesive polymer contains 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.

[0102] In one or more embodiments according to 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 according to 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 according to any aspect, the mucoadhesive polymer comprises an amino acid that is L-lysine. In one or more embodiments according to any aspect, the mucoadhesive polymer is poly-L-lysine (PLL).

[0105] Since the amino acid or hydrophobic amino acid is biodegradable, it is advantageous to use the amino acid or hydrophobic amino acid. Protein-peptide interactions between mucin and the polymer can promote mucoadhesion. Furthermore, amino acid polymers can be produced recombinantly or synthetically using bacteria.

[0106] In one or more embodiments according to any aspect, the mucoadhesive polymer comprises both a sugar monomer, such as a C6 sugar monomer, and an amino acid, where at least 50% of the monomers are basic, for example having an amino group, or at least 50% of the monomers are hydrophobic, for example having a hydrophobic group.

[0107] In one or more embodiments according to any aspect, the mucoadhesive polymer consists of 40 to 800 monomer units, for example 50 to 750 monomer units, for example 75 to 700 monomer units, for example 100 to 650 monomer units, for example 150 to 600 monomer units, that are linked to each other by ether bonds, ester bonds, amide bonds, or combinations thereof. The size of the mucoadhesive polymer is very important to ensure that it is small enough for the polymer to diffuse deeply into the mucus gel and large enough to form a tight cross-linked network structure. 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 20,000 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 are included within the above ranges.

[0110] The size or polymer ensures that the polymer is soluble under the conditions of use and that the polymer can diffuse through the pores of the mucus and form a thick, tight barrier.

[0111] The mucoadhesive polymer should be stable in the targeted mucosal environment, which has a low pH in the female abdomen. Thus, the pH range in which the mucoadhesive polymer is stable is in the range of 1 to 8. Different types and sizes of polymers can be used depending on the pH environment.

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

[0113] That the pH of the composition is 2.0 to 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, particularly the female vagina where the pH value is in the range of 3 to 5.

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

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

[0116] 0.05 wt% to 10.0 wt% means that 0.05% to 10.0% of the total weight of the vaginal contraceptive composition is derived from the mucoadhesive polymer. All endpoints are included within the above ranges.

[0117] Due to its adhesive properties and size, the mucoadhesive polymer penetrates into the mucus, diffuses into the surface of the mucus, and forms a thick layer. Next, the mucoadhesive polymer forms a complex with the mucus, thereby blocking the pores of the network structure and imparting enhanced barrier properties to the mucus. When the mucus is strengthened, it is impermeable to particles, for example preventing the passage of externally induced liquids, particles and cells, such as sperm. The complex 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 range of 0.3 μm, bacteria in the range of 0.5 - 5 μm, or sperm in the range of 3 μm.

[0118] Since the treated mucus is temporarily impermeable to sperm, the composition of the present invention comprising a mucoadhesive polymer and a pharmaceutically acceptable gelling agent as a contraceptive. The contraceptive effect associated with the present invention means the reversible and temporary prevention of pregnancy by a non-surgical and non-hormonal barrier effect achieved by a single use, which means that the contraceptive effect is achieved by a single application and does not require the concentration to be increased over a predetermined period of time as in the case of hormonal pills such as combined oral contraceptive pills (birth control pills or often called "the pill" colloquially).

[0119] The temporary effect implies that when applied to the mucus, the effect of the mucoadhesive polymer is reversible. The rate of reversal is determined by the amount of polymer diffused into the mucus and the biological turnover of the mucus itself.

[0120] In another aspect, the present 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 that uses a method in which the applicator is inserted into the vagina via a syringe or by introduction of a soft gel capsule that dissolves in the vagina to release the gel, the gel being in the form of a vaginal contraceptive composition. The gel is deployed from the applicator and applied to the cervical mucus; thereby, the mucus is 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 ejection mechanism.

[0121] A composition comprising a mucoadhesive polymer and a physiologically acceptable gelling agent can be a part of a kit that further includes an applicator. The applicator 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 includes a vaginal contraceptive composition, an applicator, and instructions for use.

[0124] The vaginal contraceptive composition according to any of the embodiments may be used at any time of the day before sexual intercourse. Preferably, it is from 24 hours to 30 seconds before sexual intercourse. The vaginal contraceptive composition can be intentionally used to prevent pregnancy, and it can be administered in an amount of 1 - 5 mL by intravaginal administration using either a syringe or a soft gel capsule. The vaginal contraceptive composition is inserted into the vagina using either a finger or 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 the following examples can be materials for realizing the present invention in its various forms, either separately or in any combination thereof.

[0126] Various embodiments are described hereinafter in this specification with reference to the figures. It should also be noted that the figures are only for the purpose of facilitating 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, exemplary embodiments need not have all the aspects or advantages shown. One aspect or advantage described 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 as such.

Examples

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

[0128] All mucus gels share similar properties, but they also differ in some respects. This includes mucin contraction (e.g., pore size), mucin concentration, and the types of associated proteins and lipids, as well as salt concentration. Furthermore, they also differ in environmental factors such as pH, exposure to shear stress, exposure to bacteria, and different turnover rates. Therefore, based on these differences, it is not clear that a treatment designed for porcine mucin hydrogel would also function in enhancing the barrier properties of cervical mucus.

[0129] Example 1 The inventors conducted experiments mainly using various chitosan types with different molar masses and tissue origins (animal vs. fungal) from which they were extracted to test the ability of chitosan 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 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. Next, a solution of 10 mg / ml FITC in DMSO was added to achieve a ratio of 1:50 (1 fluorescein per 50 monomers), and then the mixture was shaken at room temperature in the dark for 2 hours. Chitosan was precipitated by the continuous addition of 2 mL of 2 M NaOH to increase the pH to 9 in 10 ml of ethanol. The supernatant was removed after centrifugation at 20,000×g for 25 minutes at 4°C. Next, the pellet was resuspended in ethanol and then centrifuged at 20,000×g for 10 minutes at 4°C, and the supernatant was removed to extract unconjugated FITC each time, and the pellet was rinsed 3 times. After removing ethanol by rotary evaporation for 2 hours, the pellet was frozen with liquid nitrogen, freeze-dried, and stored at 4°C.

[0131] [Table 1]

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

[0133] Semen evaluation Patient and volunteer semen samples collected at Andrology, Sexual Medicine, Transmedicine, clinic (ANOVA, Karolinska University Hospital, Sweden) were subjected to standard semen motility analysis and sperm penetration assay within 3 hours after collection. Data were obtained on collection time, abstinence time, and semen volume. After complete collection of semen by masturbation, the semen was gently liquefied in a rocker in an incubation chamber heated to 37 °C for 30 minutes. The viscosity of the semen was determined visually and by pipetting. The semen was analyzed microscopically by pipetting 6 μl of the sample into a pre-warmed Leja® (Netherland) counting chamber slide (20 μm). Subsequently, the sample was evaluated by a clinical ECLIPSE 50i microscope (Nikon Instruments, Japan) equipped with a stage heater MS 100 (37 °C, Linkam Scientific Instruments, UK), a 5-fold total magnification, a 10-fold objective lens (Ph1) and a 0.5-fold charge-coupled device camera UI-1540LE-M-HQ (IDS Imaging Development Systems GmbH, Germany). This system was connected to Computer Aided Semen Analysis software QualiSperm (v3.0.9.486, AKYmed, Switzerland). In addition to sperm concentration [106 / ml], progressive motility [%], motility [%], immotility [%], velocity [μm / sec], sperm size [μm2], and cell number were measured. Semen samples meeting the following criteria were included in this study: volume > 1.5 ml, concentration > 15 × 106 / ml and progressive motility > 40%.These criteria reflect the normal sperm values described in the World Health Organization (WHO) criteria limits (“WHO Laboratory Manual for the Examination and Processing of Human Semen” 2010) and 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 5 fields in 2 chambers.

[0134] Cervical mucus evaluation Ovulatory cervical mucus (CVM) (the CVM with the highest permeability) was collected from healthy donors at Karolinska University Hospital. The donors were not using hormonal contraceptives, were 18 - 30 years old, had a BMI of 19 - 25, were non-smokers, not on medication, and had no chronic diseases. Before the collection of CVM, the hormonal status of each healthy regularly cycling volunteer was examined by blood tests at the Karolinska University Laboratory. At the time of donation, analysis of the levels of FSH, LH, and estradiol in the women revealed ovulatory disorders. The mucus was collected at the external os of the cervix using the endometrial catheter Gynebiops standard CH9 (GYNEAS, France) and the 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 was performed 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). 0.5% (w / v) labeled chitosan (chitosan-FITC) was adjusted to pH 5.5 (pH ± 0.02) by the use of 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] Using a custom-made rectangular capillary tube (L 60 mm, ID 0.3×0.3 mm, OD 0.45×0.45 mm, borosilicate glass) together with a luer connector (Hilgenberg GmbH, Germany) and a 1 ml Soft-Ject® syringe (Henke-Sass Wolf GmbH, Germany), the CVM was aspirated into two capillaries. Next, the tube was broken at the luer connection and the broken ends were sealed with wax (Paul Marienfeld GmbH & Co. KG, Germany). This resulted in an airtight capillary completely filled with CVM. A hole was made in the septum of a short thread cap (55° Shore, Teknolab Sorbent AB, Sweden) with the sealed end of the capillary, and 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-warmed buffer or chitosan-FITC in buffer. The CVM in the capillary treated with buffer was used as a negative control. At the same time, by inserting the capillary into a glass vial containing 300 μl of 0.5% or 0.1% chitosan-FITC, which functions as a positive control and reference fluorescence intensity, the same rectangular capillary without a luer connector (L 50 mm, ID 0.3×0.3 mm, borosilicate glass, CM Scientific Ltd., UK) was filled with the chitosan-FITC solution. After incubation at 37 °C and 5% CO2 for 30 minutes, the capillaries were evaluated by fluorescence microscopy and images were recorded in the exposure time range of 0.01 s to 1 s. The images were acquired by a light source pE-300lite (10 milliseconds, CoolLED, UK) connected 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 2× objective lens were used.Images captured with an exposure time of 20 milliseconds showed non-saturated images that optimally identified the differences in fluorescence intensity between different CSs and were used to calculate chitosan in the CVM. At the time point of 800 milliseconds of exposure time, the fluorescence signal was saturated at the beginning of the capillary, but low chitosan-FITC concentrations were observed further inside the capillary, thereby obtaining the maximum diffusion distance.

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

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

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

[0140] Images were recorded at distances marked on a slide glass including the starting part (0.1 cm) of the capillary 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 produce a total magnification of 100x. The recorded microscopic field was 0.21×0.27 mm, corresponding to 0.0567 mm2. A resolution of 1280×1024 pixels was used to record images of three fields at each distance at 30 photos per second. The recording started from the upper outer surface of the capillary and then focused through the capillary to reach the lower surface to obtain a 3-D scan through the capillary. Sperm were counted in a volume (0.017 mm 3 ). The assay was performed in triplicate using semen from various volunteers.

[0141] Results of Example 1 The effect of chitosan molar mass was demonstrated by testing the diffusion of fluorescently labeled chitosan of various sizes through human ovulatory cervical mucus. For both chitosan of animal origin (extracted from crustacean shells, CO, 95 / 5 and 95 / 100) and fungus-based chitosan (Z49, Z56, Z13, Z10, Z43), the results (Figure 1, Figure 2) clearly show that smaller chitosan penetrates deeper and accumulates more in the mucus. It was very remarkable that large chitosan (>100 kDa) could not penetrate into the mucus gel network structure, probably due to steric hindrance, and thus did not accumulate in the mucus. This generates a very superficial barrier, which would be very weak against, for example, disruption by shear stress. Therefore, chitosan with a molar mass exceeding 100 kDa was excluded for this reason.

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

[0143] Similarly, it was shown that the fungal chitosans of 7.1 and 18.9 kDa, Z49 and Z56 respectively, were also not effective in stopping sperm penetration (Figure 4). Conversely, the use of fungal chitosan over 20 kDa (e.g., Z10) was found to significantly reduce mean sperm penetration compared to the control group (untreated mucus) and mucus treated with chitosan lysis buffer alone (Figure 4).

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

[0145] For the proper delivery of chitosan to the cervical canal, the chitosan formulation 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 excipient does not interact with chitosan in such a way as to allow complete interaction with the mucus components. The selected gelling excipients should at least be known for their good biocompatibility, have no negative charge that can interact with the positive charge of chitosan, and have no known interaction with chitosan. The compatibility of hydroxyethylcellulose and chitosan was tested by measuring the permeability of the mixture. The absence of a change in permeability suggests the absence of chitosan precipitate and good compatibility of chitosan with hydroxyethylcellulose as a thickening agent (Figure 6). The addition of 0.5% (w / v) of 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 precipitate and good compatibility of chitosan in these formulations. Glycerol and hydroxyethylcellulose were also combined with chitosan to test for possible changes in the penetration of chitosan 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 shows the maximum diffusion distance of chitosan alone and chitosan mixed with excipients 30 minutes after exposure to mucus. The barrier-enhancing effect on ovulatory cervical mucus was also not changed by the presence of the excipients tested (Figure 8).

[0146] Example 2 This example is to demonstrate mucus enhancement by "amino acid monomers". In this example, the penetration of human sperm into human ovulatory cervical mucus first exposed to a solution of poly-L-lysine (PLL) is tested. The results are shown in Figures 9A and 9B, which show sperm penetration assays performed in human ovulatory mucus. The sperm count was evaluated 30 minutes after exposure to non-diluted sperm.

[0147] The materials and methods used in Example 2 were the same as 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 the PLL compound can enhance the barrier properties of human ovulatory cervical mucus against sperm. Similar to chitosan, low molecular weight PLL had no effect. Only the higher molecular weight was able to prevent sperm invasion. The point where sperm were no longer visible was deeper inside the mucus (about 3 cm for 66KDa PLL), which was similar to some chitosans such as 7.1 kDa chitosan (about 2 cm, Figure 4A), but deeper than other chitosans such as 27.9 kDa and 36.2 kDa (about 0.5 cm, Figures 4C and 4D).

[0150] The present invention is hereinafter described 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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 according to any of the preceding items, which is not in the form of a foam.

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

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

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

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

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

[0158] 8. The vaginal contraceptive composition according to any of the preceding items, wherein the mucoadhesive polymer is composed of a plurality of monomer units bonded to each other via ether bonds.

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

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

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

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

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

[0164] 14. The vaginal contraceptive composition according to any one of the preceding items, wherein the monomer unit is selected from C6 sugars, amino-functionalized C6 sugars, or combinations thereof.

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

[0166] 16. The vaginal contraceptive composition according to any one of the preceding items, 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. The vaginal contraceptive composition according to any one of items 16 to 19, wherein 0% to 50% 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 35% or less is N-acetyl-D-glucosamine.

[0173] The vaginal contraceptive composition according to any one of items 16 to 22, wherein 23.65% to 100% is D-glucosamine.

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

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

[0176] 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] The vaginal contraceptive composition according to any one of items 25 to 26, wherein the mucoadhesive polymer contains poly-lysine, poly-ornithine, and / or poly-arginine.

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

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

[0180] 30. The vaginal contraceptive composition according to any one of items 1 to 7, wherein the mucoadhesive polymer contains amino acids, and 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 one of items 1 to 7, wherein the mucoadhesive polymer is a peptide molecule bonded via an amide bond, and 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 one 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 one of items 1 to 7, wherein the mucoadhesive polymer is a peptide molecule bonded via an amide bond, and at least 50% of the amino acids are lysine.

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

[0186] 36. The vaginal contraceptive composition according to any one of items 1 to 7, wherein the mucoadhesive polymer contains 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. A vaginal contraceptive composition according to any of the preceding items, wherein the physiologically acceptable gelling agent is selected from hydroxyethyl cellulose (HEC), glycerol, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, guar gum, or a combination thereof.

[0189] 39. A vaginal contraceptive composition according to any of the preceding items, wherein the mucoadhesive polymer consists of 40 to 800 monomer units bonded to each other by ether bonds, ester bonds, amide bonds, or a combination thereof.

[0190] 40. A vaginal contraceptive composition according to any of the preceding items, wherein the mucoadhesive polymer consists of 50 to 750 monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or a combination thereof.

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

[0192] 42. A vaginal contraceptive composition according to any of the preceding items, wherein the mucoadhesive polymer consists of 100 to 650 monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or a combination thereof.

[0193] 43. A vaginal contraceptive composition according to any of the preceding items, wherein the mucoadhesive polymer consists of 150 to 600 monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or a combination thereof.

[0194] 44. A vaginal contraceptive composition according to any of the preceding items, 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. The vaginal contraceptive composition according to any one of the preceding items, wherein the pH of the composition is from 2.0 to 7.0.

[0196] 46. The vaginal contraceptive composition according to any one of the preceding items, wherein the pH of the composition is from 2.5 to 6.5.

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

[0198] 48. The vaginal contraceptive composition according to any one of the preceding items, wherein the composition is a contraceptive composition.

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

[0200] 50. A vaginal contraceptive composition for use in therapy, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of from 20,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units linked to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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] A vaginal contraceptive composition for use as a contraceptive or contraceptive agent, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer is composed of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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] A vaginal contraceptive composition for use in fetal restriction or fetal restriction treatment, wherein the vaginal contraceptive composition comprises 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, the mucoadhesive polymer has a molecular weight of 20,000 Da to 100,000 Da, the mucoadhesive polymer is composed of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are 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] The vaginal contraceptive composition according to item 50 or 51 or 52, wherein the vaginal contraceptive composition is not a foam.

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

[0205] The vaginal contraceptive composition according to any one 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 one 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 one 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 one 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 one of items 50 to 58, wherein the mucoadhesive polymer is composed of a plurality of monomer units bonded to each other via ether bonds.

[0210] 60. The vaginal contraceptive composition according to any one 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 one 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 one 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 one 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 one of items 50 to 63, wherein at least one amino group is a primary amine.

[0215] 65. The vaginal contraceptive composition according to any one 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 one of items 50 to 65, wherein the monomer unit is an amino-functionalized C6 sugar.

[0217] 67. The vaginal contraceptive composition according to any one 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 one 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 one of items 67 to 70, wherein 0% to 50% is N-acetyl-D-glucosamine.

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

[0223] 73. The vaginal contraceptive composition according to any one of items 67 to 72, wherein 35% or less is N-acetyl-D-glucosamine.

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

[0225] 75. The vaginal contraceptive composition according to any one of items 67 to 74, wherein 0% to 35% is N-acetyl-D-glucosamine.

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

[0227] 77. The vaginal contraceptive composition according to item 76, wherein the mucoadhesive polymer is a polypeptide of amino acids, and 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 one 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 one of items 50 to 59, wherein the mucoadhesive polymer is a peptide molecule having a length of 180 to 900 amino acids, and wherein at least 50% of the amino acids have a hydrophobic group, and the amino acids 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.

[0231] 81. The vaginal contraceptive composition according to any one of items 50 to 59, wherein the mucoadhesive polymer contains amino acids, and 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 one of items 50 to 15, wherein the mucoadhesive polymer is a peptide molecule bonded via an amide bond, and wherein 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 one 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 one of items 50 to 59, wherein the mucoadhesive polymer is a peptide molecule bonded via an amide bond, and wherein at least 50% of the amino acids are lysine.

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

[0237] 87. The vaginal contraceptive composition according to any one of items 50 to 59, wherein the mucoadhesive polymer contains 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 one 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 one of items 50 to 89, wherein the mucoadhesive polymer consists of 40 to 800 monomer units bonded to each other by an ether bond, an ester bond, an amide bond, or a combination thereof.

[0241] 91. The vaginal contraceptive composition according to any one of items 50 to 90, wherein the mucoadhesive polymer is composed of 50 to 750 monomer units bonded to each other via an ether bond, an ester bond, an amide bond, or a combination thereof.

[0242] 92. The vaginal contraceptive composition according to any one of items 50 to 91, wherein the mucoadhesive polymer is composed of 75 to 700 monomer units bonded to each other via an ether bond, an ester bond, an amide bond, or a combination thereof.

[0243] 93. The vaginal contraceptive composition according to any one of items 50 to 92, wherein the mucoadhesive polymer is composed of 100 to 650 monomer units bonded to each other via an ether bond, an ester bond, an amide bond, or a combination thereof.

[0244] 94. The vaginal contraceptive composition according to any one of items 50 to 93, wherein the mucoadhesive polymer is composed of 150 to 600 monomer units bonded to each other via an ether bond, an ester bond, an amide bond, or a combination thereof.

[0245] 95. The vaginal contraceptive composition according to any one of items 50 to 94, 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.

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

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

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

Claims

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 has a molecular weight of 30,000 Da to 100,000 Da, the mucoadhesive polymer consists of a plurality of monomer units bonded to each other via ether bonds, ester bonds, amide bonds, or combinations thereof, the monomer units are selected from C6 sugars, amino-functionalized C6 sugars, amino acids, or combinations thereof, at least 50% of the monomer units contain at least one amino group, and the mucoadhesive polymer is chitosan or poly-lysine.

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

3. The vaginal contraceptive composition according to claim 1 or 2, wherein the mucoadhesive polymer has a molecular weight of 30,000 Da to 75,000 Da, 30,000 Da to 60,000 Da, 30,000 Da to 50,000 Da, or 30,000 Da to 40,000 Da.

4. At least 55% of the monomer units contain at least one amino group, At least 60% of the monomer units contain at least one amino group, At least 65% of the monomer units contain at least one amino group, or At least 70% of the monomer units contain at least one amino group, The vaginal contraceptive composition according to any one of claims 1 to 3.

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. The vaginal contraceptive composition according to any one of claims 1 to 5, wherein the monomer unit is an amino-functionalized C6 sugar.

7. The vaginal contraceptive composition according to any one of claims 1 to 6, wherein the monomer unit is a combination of D-glucosamine and N-acetyl-D-glucosamine.

8. At least 50% of the monomer units are D-glucosamine and 50% or less are N-acetyl-D-glucosamine, or 50% to 100% of the monomer units are D-glucosamine and 0% to 50% are N-acetyl-D-glucosamine, The vaginal contraceptive composition according to claim 7.

9. The vaginal contraceptive composition according to any one of claims 1 to 5, wherein the mucoadhesive polymer is poly-lysine or poly-L-lysine.

10. The vaginal contraceptive composition according to any one of claims 1 to 9, wherein the physiologically acceptable gelling agent is selected from hydroxyethyl cellulose (HEC), glycerol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, guar gum, or a combination thereof.

11. The vaginal contraceptive composition according to any one of claims 1 to 10, 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.

12. The vaginal contraceptive composition according to any one of claims 1 to 11, wherein the pH of the composition is 2.0 to 7.0, 2.5 to 6.5, or 3.0 to 6.

0.

13. A vaginal contraceptive composition for use in treatment, which is the vaginal contraceptive composition according to any one of claims 1 to 12.

14. A vaginal contraceptive composition for use as a contraceptive drug or agent, which is the vaginal contraceptive composition according to any one of claims 1 to 12.

15. A vaginal contraceptive composition for use in birth control or birth control treatment, which is the vaginal contraceptive composition according to any one of claims 1 to 12.

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