Compositions and methods for entrapping and inactivation of pathogenic microorganisms and spermatozoids

FIELD: medicine, contraception.

SUBSTANCE: invention proposes antibacterial and contraceptive compositions that comprise the following components: (1) matrix-forming substance; (2) bioadhesive substance; (3) buffer substance; (4) moistening substance, optionally; (5) preserving agent, optionally, and (6) water. Proposed compositions are suitable for their placement into vagina wherein compositions form semisolid matrix in contact with testicular fluid, cause thickening cervical mucus, form a bioadhesive layer on vagina surfaces, maintain the natural acid pH value in vagina about less 5 in the presence of testicular fluid ejected by a male and don't disturb essentially the natural microbiological balance in vagina. Compositions and methods decrease and/or prevent transfer of diseases transferring by sexual way and act as vaginal contraceptives with less adverse effect as compared with conventional vaginal contraceptives and can be used therefore for a long time. Compositions and methods are simple for using and don't require a physical device for their retention into vagina during using.

EFFECT: improved and valuable properties of compositions and methods.

36 cl, 17 tbl, 11 ex

 

The technical field to which the invention relates.

This invention relates to the field of medicine and, in particular, to compositions and methods of preventing transmission of sexually transmitted diseases (STDs), and/or reduce the rate of transmission of such diseases among sexually active individuals. This invention also relates, mainly, to compositions and methods of preventing fertilization and/or reduce the risk of fertilization in sexually active women. Without going into theory, it should be noted that, as expected, the composition of the present invention when used in the vagina during sexual intercourse tend to physical capture and inactivation of pathogenic microorganisms associated with STIs and the sperm contained in the semen, which can be deposited in the vagina. Compositions and methods of the present invention is particularly effective to prevent or reduce the likelihood of fertilization in sexually active women and reduce the risk of Contracting or transmitting sexually transmitted diseases during sexual intercourse men and women. However, you can use them heterosexual, homosexual and bisexual individuals to reduce the risk of Contracting or transmitting diseases transmitted sexes is m by, during sexual contact. The method of the present invention is particularly effective when used in combination with the methods of the so-called "safe sex".

The method of this invention generally comprises applying an effective amount of the trapping gel (linking gel) into the vagina. Although to make the trapping gel into the vagina, you can use the applicator, which should be removed before sexual contact. Preferably, the trapping gel applied prior to sexual contact. Though probably not as effective, it can also be used after sexual intercourse; this delayed application after sexual contact should be implemented as soon as possible. Greater protection can be obtained by using the trapping gel both before and after sexual contact. Although the trapping gel of the present invention designed to provide anti-STD activity during heterosexual contact, it can also provide protection against STDs during other sexual contact (e.g., heterosexual or homosexual anal sex); in this description when referring to heterosexual intercourse means and other forms of sexual contact.

Trapping-gels of the present invention possess both antimicrobial and contraceptive activity. Antimicrobial and contrace the effective composition of the present invention, as a rule, have less side effects than regular vaginal contraceptives (such as nonoxynol-9). For example, the trapping-gels useful in this invention in their effective amounts, generally non-toxic (or low toxicity) in relation to natural and healthy vaginal microflora and, thus, does not significantly disrupt the microbial balance of the vagina. Of course, inclusion in the trapping-gels of the present invention contraceptives, such as nonoxynol-9, will increase the risk of side contact. However, typically, these contraceptives can be added to the compositions of the present invention in smaller quantities than are available in the normal vaginal contraceptives, while maintaining their effectiveness. In addition, the compositions of the present invention, generally non-toxic (or not toxic and do not cause irritation or damage to the vagina or cervix. In addition, the trapping-gels of the present invention contribute to the preservation of the natural acidic pH of the vagina (usually about pH 3.5 to 4.5) and therefore provide even more protection. Maintaining an acidic pH reduces the risk of fertilization, as well as contamination with microorganisms that cause STDs, and at the same time saved the microbiological balance of the vagina. Moreover, when reducing the risk and damage of the vaginal lining also reduces the risk of STDs, including HIV. In addition, the trapping-gels of the present invention can be used for the prevention and/or treatment of vaginitis and/or bacterial vaginosis.

When semen erupts into the vagina, the trapping gel of the present invention causes the solidification of the mixture of gel and seminal fluid, forming a semi-solid structure from which igneous pathogenic microorganisms (e.g., microorganisms that cause STDs, including HIV) and the sperm can not be allocated or allocated only in a small amount, and by this means prevented or significantly reduced migration through the lower sexual way. The trapping gel also has a tendency to be cured of cervical mucus, and through this prevents or reduces the penetration of sperm from vaginal mucus and difficult passage through the cervical canal. Additional prevention of STDs through the trapping gel occurs because of the formation of bioadhesive protective barrier over the vaginal lining (for example, a multilayered squamous epithelium) or above the rectal lining in the case of anal sex. To further improve the activity against STDs and/or contraceptive activity of the trapping gels of the present invention in the composition of the present invention can include bactericides and/or Spa shall miticide (for example, nonoxynol-9 and others). It is expected that the compositions and methods of the present invention bactericides and/or spermicides can be used in low concentrations while maintaining a high contraceptive activity, and through this reduces side effects such bactericides and/or spermicides.

The level of technology

In recent years, sexually transmitted diseases, are becoming more serious health problem, and the entire world. The increase in the number of cases of HIV/AIDS in the last decade significantly and clearly shows the population of the importance of STD treatment. It seems that the best and probably the only realistic approach to the growing problem of STDs (especially HIV/AIDS) is to reduce the risk of transmission of STD pathogens and, thus, reducing the number of newly infected individuals. Even when treatment is available, prevention of infection at the initial stage will remain the first line of defense. Medical, physiological, and economic reasons it is preferable prevention individuals STDs, not treatment.

Currently, an extensive education in the field of STDs, ways of transmission and methods of the so-called "safe sex" promises, at least in some of the more developed the country is, reducing the risks of transmission of STDs during sexual contacts. Screening of donated blood helps to reduce the risk of transmission causing STDs microorganisms in blood transfusions and other medical procedures. However, the spread of STDs cannot be reduced to an acceptable level even in developed countries with active progressive educational programs. Despite the wide popularity of information about the effectiveness of existing methods of safe sex to prevent STDs, such methods are not always used or are not always used correctly for many reasons (e.g., carelessness, lack of knowledge, wrong methods, cultural barriers, unplanned or spontaneous sexual contacts and the like). Moreover, even when the methods of safe sex are used, they are not always effective (except, probably, abstinence). For example, when using only condoms, as a rule, the prevention of fertilization is usually about 80-90%, so the microorganisms that cause STDs, if they are present, can move from one sexual partner to another.

Now available various means of birth control, including barrier methods and vaginal contraceptives. Some of them may additionally possess, at least to some extent, activity against STDs. For example, condoms can help prevent transmission of STDs as long as their correct use, and/or they are made properly. It is reported that one of the most widely used contraceptive nonoxynol-9, at least in some cases, reduces the risk of transmission of some STDs. Nonoxynol-9, which is a non-ionic detergent with a strong surface-active properties, acts like most other contraceptives on the basis of chemical compounds, killing the sperm or immobilize them in other ways (for example, destroying the sperm). Nonoxynol-9 is a powerful cytotoxic agent, which tends to nonspecific destruction of cellular membranes. These properties lead to some very significant disadvantages. Nonoxynol-9 can damage the epithelial and other cells of the vagina or cervix even at such low concentrations, approximately 0,0005% (in vitro). Clinical studies confirm damage to the vagina and cervix at concentrations that are generally available in the vaginal contraceptive compositions (typically more than about 3% nonoxynol-9). Nonoxynol-9 also disrupts the normal vaginal microflora, creating a protective mechanism, ver is pleasant, by maintaining an acidic pH, for protection against invasion of pathogenic microorganisms. Nonoxynol-9 can also partially dissolve or remove the protective glycoprotein layer of the vagina. Cytotoxic destroying the microflora of the action and the effect of removing glycoprotein nonoxynol-9 may cause disruption or damage to the vagina, including injury. Some women are particularly sensitive to nonoxynol-9 and find it, even when casual use. The destruction of these protective mechanisms nonoxynol-9 may actually increase the risk of STDs, since the destruction of the protective mechanisms and especially the emergence of injury creates organisms that cause STDs, lighter pathways in cells. In addition, the destruction of these protective mechanisms nonoxynol may increase the risk of disease vaginitis and/or bacterial vaginosis.

Of course, currently available commercial creams and ointments that are commercially available or recipes, or they are in various stages of development. Nonoxynol-9, octoxynol-9 and benzalkonium chloride, usually available in the form of suppositories, pads, creams, films, foams and gels. Examples of such commercial products are, for example, K-Y Plus™ (2.2% nonoxynol-9; Advanced Care Products, Raritan, new is gersi); Encare™ (3% nonoxynol-9; Thompson Medical Co., West Palm beach, Florida); Gynol II (Advanced Care Products, Raritan, NJ); ortho-option-conceptrol (Advanced Care Products, Raritan, NJ); Semitic (Whitehall Robbins Healthcare, Madison, NJ) and Advantage-S (Columbia Laboratories, Aventura, Florida). As mentioned above, the amount of nonoxynol-9 or other cytotoxic agents contained in such products, as a rule, is destructive to the vagina and cervix and disrupts the normal vaginal environment. Moreover, such compositions have only a limited ability to prevent STDs if they do have this ability. Indeed, many women using these tools will report a burning sensation and pain, sufficient for termination of the use of these products. Also available gels created to regulate vaginal pH. For example, Aci-Jel™ (Ortho-McNeil Pharmaceutical Corp., Raritan, new Jersey) is dispersible in water buffered gel with a pH of 3.9 to 4.1, which is used to restore and maintain normal pH of the vagina. Such gels are created to regulate vaginal pH and are not intended to prevent STDs and/or fertilization; these gels are not intended to bind and/or inactivate cause of STD pathogens and/or sperm.

In U.S. patent 5439685 (8 August 1995) describes f is rmaceuticals composition for prevention or sexually transmitted. It is reported that such compositions form a film or barrier layer on the mucous membrane of the vagina, which prevents the contacting of the microorganisms that cause STDs, with the surface of the vagina. However, these compositions do not form a semi-solid matrix with ejaculate for efficient binding of causing STDs microorganisms and/or sperm; and they do not cause seals the cervical mucus to prevent sperm penetration. Such gels may also contain cytotoxic agents such as nonoxynol-9, benzalkonium chloride and sodium chlorate, which, despite the film or the barrier can still cause damage to the vagina and cervix. Finally, these gels are designed for use in combination with vaginal tool, such as a tampon, unlike the present invention.

Later he conducted clinical trials buffer-gel™ (BufferGel™, ReProtect LLC, Baltimore, Maryland), developed at Johns Hopkins University. It is reported that BufferGel™ is negatively charged neabsorbiruemye high molecular gel, created to maintain vaginal pH below 5 in the presence of seminal fluid. As specified in U.S. patent 5617877 (8 April 1997), the basis of BufferGel™ to regulate vaginal pH is a polymer, SOS is Oasi of carboxylating monomers (preferably, crosslinked polyacrylic acids, such as, for example, polymers of the type of carbopol® (high molecular weight Homo - and copolymers of acrylic acid, crosslinked simple polyalkyleneglycol, available from BF Goodrich)). The buffer-gel™ captures not cause STDs microorganisms and/or vomit of the sperm and does not cause seals the cervical mucus, which allows the calling STD microorganisms and/or vomit of the sperm to easily migrate through the lower sexual way. In addition, the composition is designed for use with the device inserted into the vagina and is closing the cervix. In order to be effective, such a device should remain in position, closing the cervix. The device is removed or shifted from its position relative to the cervix can destroy or at least significantly reduce its effectiveness. As specified in the patent, the device is positioned lowest number of relevant buffers in a domed configuration that ensures a stable position of the device around the neck. The large surface of the device and its elastic round shape are the reason for its placement in the posterior vaginal fornix, and vaginal mucosa gently spread against the surface of the device, which prevents the accumulation of semen in relation to the sustained fashion unavailable blind bag. The device is highly absorbent and fast sequestered and acidify as semen and menstrual fluid. Of course, the use of such devices in combination with the buffer-gel™ requires user has the appropriate skills and motivation to obtain and maintain the correct placement of the device. In addition, the weakening of pleasant sensations and sensitivity to sexual intercourse with the use of such devices. Consequently, the use of such devices on a regular basis is unlikely because of the difficulty of application, especially in cases of "spontaneous" sexual contact.

Such crosslinked polyacrylic acid (i.e. polycarbophil) is also used for delivery of a drug (such as nonoxynol-9 or progesterone) in the vagina. Robinson et al., J.Controled Release, 28, 8 (1994).

It would therefore be desirable to create an improved compositions and methods that reduce the risk of transmission and/or infection of STDs during sexual activities. It would also be desirable if such improved compositions and methods also had the contraceptive activity. It would also be desirable if such improved compositions and methods did not prevent the natural and protective vaginal mechanisms. It would also be desirable if such improved compositions and methods it was possible to use the substance for the prevention and/or treatment of vaginitis and/or bacterial vaginosis. It would also be desirable if such improved compositions and methods would be relatively simple to use and had significantly fewer side effects than the methods currently available (i.e. nonoxynol-9 with a relatively high content), so that they could be applied on a permanent basis. It would also be desirable if such improved compositions and methods did not require a physical device to save the vagina during use. The present invention, as described in detail hereinafter, relates to such methods.

The invention

This invention relates to compositions and methods to prevent and/or reduce the risk of transmission of sexual diseases, sexually transmitted diseases, and also a contraceptive. This method is particularly suitable for use by heterosexual couples to prevent pregnancy and significantly reduce the risk of Contracting or transmitting STDs during sexual contacts. Although you can only use the method according to the invention, generally, it is preferable that it be used in combination with other methods, the so-called "safe sex" in order to further reduce the risk of pregnancy and/or transmitting or Contracting an STD.

The method of the present invention including the em making effective amount of the compositions of this invention into the vagina before sexual contact or after him as quickly as far as possible. Compositions of the present invention, in addition to activity against STDs, act as vaginal contraceptives and generally have fewer side effects than traditional vaginal contraceptives (such as nonoxynol-9). The compositions of this invention form a semi-solid matrix upon contact with seminal fluid, traveled by ejaculated into the vagina. Semi-solid matrix effective to bind microorganisms that cause STDs, including HIV, and sperm, and by this means prevented or significantly reduced their migration through and beyond the lower genital tract. Contraceptive activity is also enhanced by obtaining hypertensive composition, which leads to compaction of the cervical mucus, and by this means prevented or impeded the penetration of sperm into the cervix. As it is clear to experts in the field of technology, hypertonic solution or gel, as a rule, contain more salt than the reference solution. For the purposes of the present invention, the reference solution is a conventional fluid genital tract or vaginal mucus. Fluid genital tract, usually have the osmolarity is about the same as blood plasma or higher, and typically from about 300 to 350 mosmol/kg Osmolarity cervical mucus can the t to change during the cycle, as the layer of mucus becomes thinner in the middle of the cycle (phase ovulation occurs when a Mature egg) and thickens in the phase of anovulation. If necessary, the osmolarity of the gel can be measured using osmometry.

Warning transmission and STDs is also enhanced by the inclusion of bioadhesive funds that can form bioadhesive film on the surfaces of the vagina and cervix (as well as the surfaces of the rectum during anal sex), preventing contact of the microorganisms that cause STDs, with the walls of the lower genital tract. Finally, the compositions of the present invention contribute to the preservation of the natural pH balance in the vagina even in the presence of seminal fluid (normal pH of semen is about 7,2-7,8 - neutral to slightly alkaline). It is reported that during unprotected sex vaginal pH increases from about 4 to about 6-7 a short time after ejaculation and is maintained at such a high level within two to eight hours. It turns out that the restoration or preservation of acidic pH promotes the destruction, inactivation and/or immobilization causing some STDs microorganisms (including HIV) and sperm in the vagina, and through this prevents or reduces the risk of transmitting or Contracting STDs. In Stanovlenie or maintaining an acidic pH in the vagina also contributes to the preservation of natural and healthy vaginal microflora. Moreover, the protective glycoprotein floor of the vagina does not substantially destroyed or damaged. The destruction of the natural vaginal microflora and/or the removal or destruction of protective glycoprotein coating of the vagina when using normal vaginal contraceptives can lead to inflammation of the vaginal wall and/or damage to the vaginal walls, which can facilitate and/or make more likely the transmission of STDs.

Trapping-gels of the present invention have a number of other features that make them particularly useful as tools against STDs and/or contraceptives. For example, it is possible to obtain compositions of gels with the formation of a thick, viscous, smooth, soft and pleasantly sour taste gels. Gels also are dispersed in water, but retain their viscosity upon dilution. Trapping-gels of the present invention can also be obtained in a rapidly dispersible solid forms (for example, powders, tablets, etc. see example 11), which, when inserted into the vagina, forming the desired trapping gel due to the rapid disintegration or dispersion under the action of the vaginal or other liquids present in the vagina. Such solid forms are especially comfortable to wear, for example, in the handbag. Of course, if desired, you can use other dosage forms the trapping gels. P is chodashim dosage forms are, for example, gels, creams, lotions, viscous liquids, tablets, powders, films, suppositories, foams, etc. Although solid form (for example, tablets, and powders), as a rule, will contain only a small amount of water, vaginal and other fluids in the vagina can provide the necessary water for the formation of a composition of the trapping gel. The main components are generally considered safe (list U.S.P or GRAS). Such gels can be easily shared through a syringe or similar applicator or applied by hand, or they can be in the form of tablets or other solid forms in the vagina. Gels are created to provide controlled release of any active ingredients (such as nonoxynol-9), and, therefore, are expected to provide long-term effectiveness. Due to their moisturizing activity, gels also increase the amount of moisture in the vagina, through which suppresses the occurrence of vaginal damage and increase pleasant aspects of sexual contacts. Gels can also contain lubricants that also contribute to the pleasant aspects of sexual contacts. Gels should also reduce proactivenet and achieve messiness. Many of the just mentioned aspects and advantages of the compositions of the gels of the present invention will instill hope for consistent application,and due to this protection will even increase. Gels are also useful as delivery systems for active ingredients with antimicrobial and/or contraceptive properties.

One of the purposes of the present invention is antimicrobial and contraceptive composition that reduces the risk of transmitting or Contracting diseases, sexually transmitted by sexual contact involving the vagina and penis. This composition comprises (1) a substance forming a matrix, (2) bioadhesive substance, (3) a buffering agent, and (4) water; and such a composition is suitable for introduction into the vagina; where the composition forms a semi-solid matrix upon contact with seminal fluid; causing the seal cervical mucus; forms bioadhesive layer on the surface of the vagina; supports acidic vaginal pH of about 5 in the presence of seminal fluid, ejected by man (e.g., before, during or after sexual contact); does not substantially disturb the natural microbiological balance in the vagina and is hypertensive. If it is desirable antimicrobial and contraceptive composition may also include additional antimicrobial and/or contraception (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, the phosphorylated hesperidin, sulfonated hesperidin, polystyrenesulfonate, substituted copolymers of benzols Lanovoy acid and formaldehyde and modified H 2SO4almond acid, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin, ciclopiroxolamine etc). Preferably, antimicrobial and contraceptive composition also contains a wetting agent, a preservative and/or grease.

Another objective of the present invention is a method of reducing the risk of transmission and infection with sexually transmitted diseases during sexual contacts involving the vagina and the penis, and this method includes the introduction of an effective amount of antimicrobial and contraceptive composition into the vagina before or a short time after sexual contact; moreover, this composition comprises (1) a substance forming a matrix, (2) bioadhesive substance, (3) a buffering agent, and (4) water; and the composition is suitable for introduction into the vagina; where the composition forms a semi-solid matrix upon contact with seminal fluid; causing the seal cervical mucus; forms bioadhesive layer on the surface of the vagina; supports acidic vaginal pH of about 5 in the presence of seminal fluid, ejected the man; not substantially disturb the natural microbiological balance in the vagina and is hypertensive. If you want the part, the composition may also include additional antimicrobial and/or contraception (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, the phosphorylated hesperidin, sulfonated hesperidin, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acid, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin, ciclopiroxolamine etc). Preferably, antimicrobial and contraceptive composition also contains a wetting agent, a preservative and/or grease.

Another objective of the present invention is antimicrobial and contraceptive composition to reduce the risk of transmission and infection with sexually transmitted diseases, sexual contact, including (1) from about 1 to 10% of one or more substances forming the matrix, (2) about 1 to 10% of one or more bioadhesive substances, (3) about 1 to 10% of one or more buffer substances, and (4) water; and the composition is suitable for introduction into the vagina, where it forms a semi-solid matrix upon contact with seminal fluid, causes the seal cervical mucus forms bioadhesive layer on the surface is rnost vagina, supports acidic vaginal pH of about 5 in the presence of seminal fluid, ejected the man; not substantially disturb the natural microbiological balance in the vagina (e.g., before, during or after sexual contact) and is hypertonic. Optionally, antimicrobial and contraceptive composition may also include additional antimicrobial and/or contraception (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, the phosphorylated hesperidin, sulfonated hesperidin, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acid, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin, ciclopiroxolamine etc). Preferably, antimicrobial and contraceptive composition also contains a wetting agent, a preservative and/or grease.

These and other advantages of the present invention will become apparent from the above description.

Detailed description of the invention

The present invention relates to a trapping-gel, which when placed in the hole of the body (e.g., vagina) binds and inactivates sperm cells and/or microorganisms, calling the e disease, sexually transmitted diseases (STDs). Without going into theory, it should be noted that the compositions of this invention form a semi made more compact or semi-solid matrix when exposed to ejaculate, and through this sequestered sperm cells and the microorganisms that cause STDs. In addition, the compositions of this invention form bioadhesive and essentially impermeable layer on the surface of the holes (e.g., tissue of the vagina and cervix), preventing contact and/or penetration of sperm cells and/or microorganisms that cause STDs. The compositions of this invention are hypertensive; thus, when placed in the vagina such composition will sequestrati water from the mucus in the cervix and thereby to cause the seal of mucus and to provide even more protection by preventing or significantly reduce the penetration of sperm cells and/or microorganisms that cause STDs in the cervix. These properties provide the opportunity for efficient binding of sperm cells and/or microorganisms that cause STDs, vagina, and effectively prevent the penetration of such sperm cells and/or microorganisms that cause STDs, in the body or through the vaginal lining or through the cervix. The composition is an acidic buffer that supports normally the Yu vaginal environment and the environment what also contributes to the inactivation of some cause STDs microorganisms and sperm; the preservation of the normal vaginal environment also contributes to the preservation of the natural protective mechanisms of the body against some microorganisms that cause STDs. The composition may contain ingredients that inactivate sperm and/or STDs-organisms, such as spermicides and/or bactericides. Binding or immobilization of spermatozoa and/or microorganisms that cause STDs, vagina compositions of the present invention provides such ingredients, inactivate sperm and/or STD microorganisms, enough time for a more complete inactivation of sperm cells and/or microorganisms that cause STDs that may be present. The compositions of this invention can also be used for prevention and/or treatment of vaginitis and/or bacterial vaginosis.

Compositions and methods are intended to (1) prevent and/or reduce the degree or probability of transmission of sexually transmitted diseases, between sexual partners, when one or more of the partners is infected, and (2) prevent and/or reduce the risk of pregnancy. Although such compositions is addressed mainly to heterosexual behavior (i.e. vaginal intercourse men and women), com is osili of the present invention can also be used by people belonging to other types of sexual behavior. For example, the compositions of this invention can be used for anal sex (male/female or male/male); the composition of the present invention, intended for use in anal sex, it is preferable to modify the regulation buffering capacity for pH found in the rectum, and with more lubricants. Of course, the method of the present invention is not limited to the use of sexual partners, when it is known that one of the partners is infected with an STD or has the danger of STDs. Rather, this method can be applied to sexual partners, when it is known that none of them have STDs, when one partner has an STD or there is a risk of STDs, or when both partners have an STD or is there such a danger. Because STDs can be passed from an infected partner even before the symptoms are usually sexually active individuals, it is recommended to consistently apply this method. Of course, since the compositions are contraceptives, they can apply to heterosexual couples, where it is also desirable to avoid pregnancy. Furthermore, since none of the methods of preventing the transmission of STDs and/or fertilization - except, perhaps, lead the abstinence from sexual activity - is not fully effective, the method of the present invention, it is preferable to use in combination with other methods of reducing the likelihood of transmission of STDs and/or fertilization. For example, the method of the present invention can be combined with the use of condoms (male or female) and other safer sex methods, to improve the overall efficiency compared to the efficiency in the use of any one method; such combined methods can provide long-term elimination or at least substantial reduction of transmission of STDs from one sexual partner to another.

Prevention of primary infection (or decreased risk of infection), as opposed to treatment of sexually transmitted diseases, critical medical, physiological, and economic points of view. In particular, in the case of STDs, such as HIV/AIDS, for which method of treatment is unknown, the importance of prevention it is difficult to overestimate. In addition, as is clear to experts in the field of technology, prevention of disease, as a rule, is very different from, and much preferable to treat the disease (even if such treatment is available). For example, AZT and other drugs against HIV/AIDS can reduce disease progression (and in some cases with the use of al the other strategies to prevent transmission from HIV-positive women illness of her unborn child), but they cannot cure the disease itself. Except in the particular example, an infected mother and her unborn child the use of drugs such as AZT, to initial infection could not be medically or economically benign practice and could not reduce the risk of infection without having to expose infected individuals undesirable side effects normally associated with the use of such relatively toxic drugs. Similarly, first and foremost the prevention of unwanted pregnancy, and not later referring to medical procedures for abortion, could have significant benefits with medical, psychological and economic point of view.

The method of the present invention is carried out, introducing an effective amount of the trapping gel into the vagina. For the purposes of the present invention an "effective amount" is an amount of composition sufficient to (1) to link cause STDs microorganisms and sperm from the ejaculate, (2) education bioadhesive film on the surfaces of the vagina and (3) low or acidic pH in the vagina before or after normal ejaculation in men during sexual intercourse. Single dose, generally will fluctuate, primerno 1 to 8 ml trapping-gel; preferably, a single dose is approximately 3 to 5 ml. of Course, if desired, can be used doses above or below specified amounts. For the purposes of this invention it is believed that low or acidic pH in the vagina, as a rule, is within the normal pH in healthy women. Preferably, such an acidic pH of approximately less than 5; more preferably, such an acidic pH ranging from about 3.5 to 4.5. In other words, in addition to the quantity, ensure the effective binding causing STDs microorganisms and sperm and the formation of a protective film on the surface of the vagina, the effective amount of the composition of the present invention is an amount that provides sufficient buffering capacity to maintain the acidic pH of the vagina in the presence of a typical amount (usually about 1 to about 5.0 ml) of semen from one "normal" ejaculation, which has an alkaline pH in the range of from about 7.2 to about 7.6. The compositions of this invention are also hypertensive (i.e., greater water activity or osmotic pressure relative to the mucus in the cervix of the uterus in normal healthy women). Generally, it is expected that fluid genital tract, including the cervical mucus, have an osmolarity similar to the osmolarity of blood plasma (typically from about 290 to 320 mosmol/the d). Thus, the osmolarity of the trapping gels of the present invention when measuring normal osmometer should be higher than the normal osmolarity of blood plasma. Although compositions of this invention are intended primarily for use in situations where the vagina's normal pH, they can also be used in cases where vaginal microbiological balance are disrupted (for example, acute infection with yeast); the buffer capacity can help bring the pH level in the vagina at the right interval and recovery. In other words, the compositions of this invention can, if necessary, be used for the prevention and/or treatment, for example, vaginal infections, including, for example, vaginitis or bacterial vaginosis.

Trapping-gels of the present invention can also be applied with conventional means of birth control or safe sex. For example, the trapping-gels can be used in combination with condoms (i.e. with lubricating substances applied to the inner and/or outer surfaces), diaphragms, cervical caps or similar devices. Trapping-gels of the present invention can, for example, be inserted into the vagina by hand, using suppositories or using a conventional swab or syringe. Route of administration or delivery of the trapping gel in the vagina is not critical circumstance, while delivers the vagina effective amount. Trapping-gels of the present invention can also be used for protection during anal intercourse and can be applied using similar methods.

Trapping-gels of the present invention contain (1) the substance constituting the matrix, (2) bioadhesive substance, (3) a buffering agent, and (4) water. More preferably, the trapping-gels of the present invention contain (1) the substance constituting the matrix, (2) bioactive substance, (3) a buffering agent, (4) wetting agent, (5) preservative and (6) water. If necessary, the composition may also contain antimicrobial and/or contraception (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, the phosphorylated hesperidin, sulfonated hesperidin, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acid, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin, ciclopiroxolamine etc).

Trapping-gels of the present invention typically contain (1) from about 1 to 10% of one or more substances forming the matrix, (2) about 1 to 10% of one or more bioadhesive substances, (3) from about 1 d is 10% of one or more buffer substances, (4) from about 0 to 2% of one or more moisturizing agents, (5) from about 0 to 2% of one or more preservatives, (6) from about 0 to 10% of one or more antimicrobial or contraceptive devices and (7) water. More preferably, the trapping-gels of the present invention contain (1) from about 3% to 5% of one or more substances forming the matrix, (2) from about 2.5 to 6% of one or more bioadhesive substances, (3) about 1 to 7% of one or more buffer substances, (4) from about 6% to 10% of one or more moisturizing agents preservatives, (5) from about 0.1 to 1% of one or more preservatives, (6) from about 0.2 to 5% of one or more antimicrobial or contraceptives and (7) is water.

Gelling or forming a matrix substance for use in the present invention must be stable in a wide range of pH, in particular at normal acidic pH found in the vagina. Suitable substances that make up the matrix are, for example, alginic acid, chitosan, gum Arabic on a gelatin basis, poloxamer and similar substances. Alginic acid is the preferred curing or forming the matrix substance of the gel and, as a rule, represents a linear glucuronosyl polymer containing a mixture of -(1,4)-D-holothruroidea acid and residue -(1,4)-D-gulesider the new acid. Typically, the molecular weight of alginic acid is from about 20 to 300000 g/mol, preferably from about 20,000 to 250000 g/mol and most preferably is approximately 240,000 g/mol. It is assumed that the alginic acid forms insoluble alginates through interaction with monovalent and divalent cations (in particular, Na+, K+and Ca++in plasma seminal fluid. Because vaginal fluid, usually contain very little CA++, semi-solid matrix is formed only when there is ejaculate. In such cases, semi-solid matrix will bind causing STDs microorganisms and sperm so that they cannot migrate through the lower sexual ways of the woman. Alginates also swell upon contact with water, which helps to preserve the vagina patterns of the gel or matrix. Of course, alginic acid or alginic acid salts can also contribute to the acid buffering capacity of the trapping gels of the present invention, since the pH in the aqueous solution is from about 1.5 to 3.5. Alginic acid may also contribute to bioadhesives the nature of the compositions of the present invention and, therefore, helps to ensure bioadhesives activity. Because of its large molecular weight alginic acid no absor the associated organism. Thus, the properties of the formation matrix, bioadhesive and acid buffer will be saved up until the gel remains in the vagina. In addition, due to the inherent bioadhesive property of the trapping gel will remain in the vagina in good condition for about 12-24 hours (or even longer), if a woman will not remove.

Bioadhesive agents suitable for use in the present invention are, for example, xanthan gum, hydroxypropylcellulose, hypromellose, sodium carboxymethyl cellulose, chitosan, polycarbophil, carbopol and similar substances. Preferred bioadhesive resin is xanthan gum, a high molecular weight polysaccharide resin containing D-glucosyl, D-mannosyl and the remains of the D-glucopyranose acid and O-acetyl and pyruvic acid acetal in different ratios. The main structure is the main cellulose chain with trisaccharide side chains; duplicate link is pentasaccharide. Typically, the molecular weight exceeds about 106g/mol. Hydroxyethyl cellulose is used, preferably, in the trapping-gels that do not contain nonoxynol-9.

Buffer substances are used in the trapping-gels of the present invention to maintain the natural acidic pH of the vagina (i.e., pH IU is it about 5,0, more preferably from about 3.5 to 4.5) even in the presence of normal amounts of ejaculate. Suitable buffer substances are, for example, lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid, acetic acid, malic acid and similar substances. Acid can be added in the form of free acids, hydrates or pharmaceutically acceptable salts. As a rule, preferable free acid. Of course, the free acid can be converted into the corresponding salts in situ (i.e. in the vagina). Generally, it is preferable that some of the buffer substances are involved in the trapping gel of the present invention to provide enhanced buffering capacity. Alginic acid in the trapping-gels of the present invention, of course, can also function as the substance constituting the matrix, and as a buffering agent. As alginic acid is not absorbed by the body, its acid bufonidae effect will last longer compared to other buffer substances which can be absorbed by the body.

Trapping-gels of this invention can also contain, and preferably contain SWL is greydie substances. Suitable wetting agents are, for example, glycerin, polyethylene glycols, propylene glycols, sorbitol, triacetin, and similar substances. Glycerin, which is the preferred moisturizing substance, when placed in the vagina prevents the formation of dry film. Glycerin can also act as a lubricating substance.

Trapping-gels of this invention can also contain, and preferably contain a preservative. Suitable preservatives are, for example, benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propylparaben, benzalkonium chloride, nitrate of finalstate, chlorhexidine and similar substances. The preferred preservative is benzoic acid. As described above, benzoic acid may also contribute to the buffering capacity of the gel.

Trapping-gels of the present invention, preferably, contain alginic acid as a substance that forms a matrix; xanthan resin and/or hydrocellulose as bioadhesive substances; a buffering agent selected from the group consisting of lactic acid, citric acid, benzoic acid, acid tartrate of potassium; glycerin as moisturizing agents; benzoic acid as preservative and water. Preferably, the trapping-gels of this invention contain xantinol the Yu resin, alginic acid, lactic acid, citric acid, benzoic acid, potassium bitartrate, glycerin and water. If also included other antimicrobial agent and/or contraceptives, trapping the gels of this invention contain, preferably, xanthan resin, alginic acid, lactic acid, citric acid, benzoic acid, potassium bitartrate, glycerin, water and antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acids, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin and ciclopiroxolamine.

Suitable antimicrobial and contraceptive means are, for example, nonoxynol-9, octoxynol-9, benzalkonium chloride, the phosphorylated hesperidin, sulfonated hesperidin, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acid, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, flucon is angry terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin, ciclopiroxolamine and similar substances. Typically, these antimicrobial and contraception, if used, are included in the amount of less than about 12%, preferably about 2 to about 6%. Nonoxynol-9 is a well known and commercially available contraceptive can cause some women to irritation of the vagina; in such cases, it may be preferable to reduce the concentration of nonoxynol-9, or even to exclude it. Suitable phosphorylated hesperidin and sulfonated hesperidin are described in U.S. patent 5925621 (20 July 1999). Suitable modified H2SO4almond acid are described in U.S. patent 5932619 (3 August 1999). Suitable substituted copolymers of benzosulfimide acid and formaldehyde described in U.S. patent 6028115 (22 February 2000); especially preferred copolymers are branched poly(methyl ether)gidrogensulfat and their derivatives. Suitable polystyrenesulfonate described in the patent application U.S. registration number 09/252417 (registered 18 February 1999). These patents and patent applications included in this description as a reference. Generally, the preferred acid-resistant non-toxic means, such as m definiowanie H 2SO4almond acids and branched poly(methyl ester)-gidrogensulfat and their derivatives.

Trapping-gels of the present invention is obtained using conventional methods to obtain gels. However, it is important to ensure that the final product of the buffer substance is completely dissolved and that the capture of air gel excluded or at least minimized. In order to reduce the capture of air gel, as a rule, it is preferable that the least hydrophilic agents (for example, alginic acid) was added in small portions. On the other hand, the trapping-gels of the present invention can also be obtained in an easily dispersible solid forms (for example, powders, tablets and the like), which can translate into the desired gel consistency, when required, by adding extraneous fluids water-based or present in the vagina. As it is clear to experts in the art, the methods of obtaining the trapping gels of this invention can be modified for periodic, properities or continuous operation up until the resulting trapping-gels have the right and favorable properties described in this specification.

In the case of heterosexual trapping-gel can be inserted into the vagina before intercourse. In the case and the sexual contact (heterosexual or homosexual) trapping-gel can be entered before intercourse rectum. In the case or vaginal, or anal intercourse trapping gel can also act as a lubricating substance. For additional protection, as a rule, it is preferable to apply the gel before intercourse or other sexual contact and, if appropriate, to use a condom. For even greater protection trapping-gel can be used again as soon as possible after sexual intercourse.

Optionally, the trapping gel, you can include flavorings, fragrances, flavorings and colorings as long as they do not interfere with the protection afforded by the trapping gel. Indeed, the inclusion in the composition of this invention such flavorings, fragrances, flavorings and colorings may even provide protection effect of increasing the likelihood that sexual contact is applied to the trapping gel.

One advantage of the method of the present invention is that it can be used for protection in a variety of sexual contacts (vaginal or anal) heterosexual, bisexual and homosexual. Another advantage of the method of the present invention reduce the transmission of STDs is that this way of understanding the person can make and/or use most easily. So, a woman can use this method to own for the ITA (and protect his partner) no matter, knows or does not know the partner about the used method. In addition, the partner will not need to rely on the statement of his partner about the lack of STDs or consent to the use of condoms or other protection. Any or both of the sexual side (especially party-woman) can take and implement the application of this method before or after intercourse. Preferably, the method is used before sexual contact, and, most preferably, both before and after sexual intercourse. Although the application of the method is only after sex can provide protection to a lesser extent, it is still desirable to carry out this method after, if the method according to any reasons you have not used before sexual contact (for example, in cases of rape). Of course, the sooner this method is used after sexual intercourse, the better. It is preferable to apply the method within one hour, more preferably within 15 minutes, and most preferably immediately after sexual intercourse. However, even as time passes, more specified, use this method as quickly as possible, can provide at least some protection (compared to the if processing is not to be taken).

Another advantage of the crust is asego of the invention is that, that, in contrast to other remedies, relying only on cytotoxic compound (e.g., nonoxynol-9), the trapping gel used in this invention, essentially no harmful effect or did not inhibit the development of normal vaginal microflora, or otherwise does not substantially irritate the tissue of the vagina, when used in inhibiting non-toxic or clinical concentrations. This advantage is, at least partially, a consequence of the absence of cytotoxic agents in the compositions of the present invention. In addition, even when the composition of the present invention include nonoxynol-9, the harmful properties of nonoxynol-9 less noticeable, because (1) the required amount of nonoxynol-9 can be reduced, since the trapping gel has its own contraceptive activity, and (2) bioadhesive the nature of the composition protects the vaginal mucosa by reducing contact of nonoxynol-9 vaginal lining. Thus, the useful components of the normal vaginal microflora generally not destroyed when the application of the present invention. Significant suppression or alteration of the vaginal microflora or other irritations (such, what happen when relatively large quantities of nonoxynol-9 in a traditional contraceptive is x) can lead to increased risk of infections (as a type of STD, and not STDs), unusual discharge, General discomfort, etc. that in turn may lead to reluctance to use or fully recognize the way of protection. In addition, the composition provides an additional advantage, as they can also be used for prevention and/or treatment of vaginitis and/or bacterial vaginosis.

By avoiding or reducing the intensity of these actions on vaginal microflora or tissue, the method of the present invention is more suitable for regular use. By reducing the number of sexual acts without protection (preferably to zero) and to promote the application of the methods of this invention, both before and after each sexual intercourse, the overall degree of protection should be increased substantially. Due to avoid or reduce the irritation of the vagina and especially damage to the walls of the vagina (or rectum in the case of anal intercourse) the possibility of transmission of STDs should be reduced because the transmission of microorganisms that cause STDs, is easier when there is damage to the walls of the cell. Thus, the improvement consisting in ease of use, reducing side effects, understanding person, if different and changing sexual behaviour and the possibility of maintaining normal vaginal the Noah microflora during the application give the compositions and methods of the present invention significant advantages as a contraceptive and/or method against STDs.

Information confirming the possibility of carrying out the invention

Variants of the embodiment of the present invention and the examples that are described and discussed below, are intended only to illustrate the present invention and do not limit the scope of the invention, which is defined in the attached claims. If no special instructions, all percentages are mass.

Example 1

With multiple ways to get gels having the compositions indicated below.

ComponentNumber (%)
Alginic acid4,25
Xanthan gum3,0
Glycerin8,0
Lactic acid2,0
Citric acid1,0
The potassium bitartrate0,4
Benzoic acid0,2
Nonoxynol-90-10,0
Distilled waterrest

Get gels containing different amounts of nonoxynol-9 (i.e. from approximately 0 to 10%). The pH value was adjusted to about 3.5 to 3.6 using sodium hydroxide. Get the trapping-gels good quality of the composition. In addition, unlike the components of the investments of example 2, these compositions show good stability over a long period of time even when nonoxynol-9 is present in an amount up to 5%.

As noted above, the trapping-gels of the present invention receives, as a rule, using conventional methods to obtain gels. However, it is important to ensure that the buffer substance in the final product is completely dissolved, and that managed to avoid trapping air gel, or, at least, it contains the minimum number. This example describes several ways in which you can get trapping-gels using laboratory equipment. Of course, you can use other ways (i.e. different order of addition of components as well as changes in other variables), if the trapping gel has properties similar to those described in this description. The following methods provide generally equivalent gels.

Method 1. Use the composition specified above; benzoic acid (4.0 g) is added with stirring to water (950 ml), and then add sodium hydroxide (150 ml of 1 N solution, or any other combination of volume and normality, providing an equivalent amount of sodium hydroxide). To the mixture of acid potassium tartrate (8.0 g), citric acid monohydrate (20,0 g) and lactic acid (40,0 ml); adjusted pH at which Erno to 3.3-to 3.6 with 1 N sodium hydroxide solution (stage 1 adjusting the pH). To the solution was added with stirring alginic acid (85 g) in small portions, to obtain a homogeneous dispersion and to avoid trapping air. Then to the solution was added sodium hydroxide (230 ml of 1 N solution, or any other combination of volume and normality, providing an equivalent amount of sodium hydroxide), and the solution is stirred for 10 minutes. Measure the pH and bring the pH to approximately 3,3-3,6 (using, if necessary, 1 N sodium hydroxide solution; stage 2 adjusting the pH). Stirring is continued until a homogeneous mixture.

In a separate container xanthan resin (60 g) are mixed with glycerol (160 ml) and stirred until smooth, and then gradually mixed with just described a homogeneous mixture. Then add water to the mixture a quantity of 220 ml net volume used in stages 1 and 2 to bring the pH. Of course, the amount of added water will depend on the concentration of the sodium hydroxide solution used in stages 1 and 2 to bring the pH. The mixture is stirred for a short time (about 15 min) and then allowed to stand for a short period of time (about 10 min). Then the stirring is continued until obtaining a homogeneous gel consistency. Check the pH, which should be from about 3.25 to 3.80, and more preferably primerno,37-3,52. If necessary, the pH can be adjusted to the desired value by adding sodium hydroxide solution.

Method 2. Use the same composition; benzoic acid (4.0 g) dissolved in water (950 ml) under stirring (i.e. using a magnetic or mechanical stirrer, rotary mixer, rocking or ultrasonic mixer and the like). Without waiting for the complete dissolution of benzoic acid, add sodium hydroxide (150 ml of 1 N solution, or any other combination of volume and normality, providing an equivalent amount of sodium hydroxide) and continue mixing. Then added to the mixture of acid potassium tartrate (8.0 g). The mixing speed or efficiency can be improved to ensure dissolution of the components. Then with stirring, add citric acid monohydrate (20,0 g). Then the mixture is transferred lactic acid (40,0 ml): use a small amount of water for rinsing the portable vessel and bring the pH to about 3.3 to 3.6 with 1 N sodium hydroxide solution (stage 1 adjusting the pH). The buffer salt or acid can be dissolved or add in any order. To the solution was added with stirring alginic acid (85 g) in small portions (about poloski-spoonful to add when loading in laboratory equipment), to ensure that alginic acid RA is nomemo were distributed in the mixture without substantial trapping air. Then to the solution was added sodium hydroxide (230 ml of 1 N solution, or any other combination of volume and normality, providing an equivalent amount of sodium hydroxide), and the solution is stirred for 10 minutes. Measure the pH and bring the pH to approximately 3,3-3,6 (using, if necessary, 1 N sodium hydroxide solution; stage 2 bring pH). Stirring is continued for about 30 minutes or over a period sufficient to ensure uniform mixture.

In a separate container xanthan resin (60 g) are mixed with glycerol (160 ml) and stirred until homogeneous. Then just the resulting homogeneous solution slowly with continuous stirring is transferred into a vessel with xanthan resin and glycerin. The volume of 1 N sodium hydroxide solution used in stages 1 and 2 bring the pH stack and subtract from 220 ml Then add water to the mixture a quantity of 220 ml net volume of water used at stages 1 and 2 bring the pH. Of course, the amount of added water will depend on the concentration of the sodium hydroxide solution used in stages 1 and 2 bring the pH. The mixture is stirred so as to obtain a sufficiently homogeneous mixture without substantial trapping air of the gathering drug. The mixture is left to stand for about 10 min and C is the mix over time, sufficient to obtain a homogeneous gel consistency (usually about 15 minutes). Check the pH, which should be from about 3.25 to 3.80, and more preferably about 3,37-3,52. If necessary, the pH can be adjusted to the desired value by adding sodium hydroxide solution.

Trapping-gels obtained using methods 1 and 2 essentially have the same properties. For clinical application of the trapping-gels, of course, should be analyzed to determine, are achieved if the technical requirements for various physico-chemical parameters (e.g. color, texture, separation gel, the smell, the final pH (3,37-3,52), buffer capacity and concentration of any added active ingredient). The buffer capacity must be sufficient for the pH of a mixture of 400 μl of 1 N NaOH and 40 ml of 5% aqueous solution of the trapping gel was not more than 4,55. Of course, as is clear to experts in the art, some indicators technical specifications or product parameters (such as color or smell) alone cannot significantly affect the clinical efficacy, but may be important for recognition by the consumer and, thus, to the extent to which the product is used and protected.

Active ingredient (i.e. antimicrobial and/or contraceptives) which can be added at an appropriate stage, depending on the physico-chemical properties of substances. For example, surface-active substance, such as nonoxynol-9, which has a tendency to cause foaming, it is preferable to include in the mixture of xanthan resin and glycerin. Other antimicrobial and/or contraception can be enabled at any time obtain a gel, and most preferably before reaching the final consistency, in order to avoid air from entering the gel.

Example 2

Get other gels with hydroxyethyl cellulose as the second bioadhesive substances. Get the compositions indicated generally next.

ComponentNumber (%)
Alginic acid3,5
Xanthan gum2,0
Hydroxyethylcellulose1,75
Glycerin10,0
Lactic acid2,0
Citric acid1,0
The potassium bitartrate0,4
Benzoic acid0,2
Nonoxynol-90-10,0
Distilled waterrest

The gel obtained using the same General methods, the AK in example 1, except that with a mixture of xanthan resin and glycerin mix hydroxyethyl cellulose.

Get the trapping-gels containing different amounts of nonoxynol-9 (i.e. from approximately 0 to 10%). Bring the pH of the compositions to about a 3.5 to 3.6 using sodium hydroxide. Compositions obtained with the usual content of nonoxynol-9 (i.e., more than 5%), however, was not as stable as desired. The stability study shows that such compositions with nonoxynol-9 have a tendency to delaminate on liquid and semi-solid phase for about 60 days at a temperature of about 37°C. Other estimates show that the lack of stability is mostly due to the incompatibility of hydroxyethyl cellulose and nonoxynol-9. Thus, preferably, the trapping-gels with the use of hydroxyethyl cellulose as one of bioadhesive substances contained less than 5% (and preferably even less) of nonoxynol-9.

Example 3

This example illustrates the buffer capacity of the gels according to the invention. (Other and, in General, more detailed studies on the acid buffering capacity of the gels of the present invention, described below in example 10.) Using gel obtained as in example 1, determine the pH of the gel before and after mixing with different amounts of seed W is dcosta. Samples of semen collected from healthy volunteers and sceneroot on sperm count, motility, pH and volume; the initial pH of semen is about to 7.9. The gel was diluted with saline solution and mixed with seminal fluid in the desired proportions. Get the results below.

Dilution ratio 1:5 corresponds to a ratio of about 1 part gel and 1 part of semen; dilution in the ratio of 1:10 corresponds to a ratio of about 1 part gel and 2 parts of semen. As the average amount of ejaculate is from about 1 ml to 5 ml, and assumes a typical rate of application of the gel to about 5 ml, the ratio of gel and semen 1:1 should correspond to the average dilution, which can be expected in most cases. Thus, the gel of the present invention has sufficient buffer capacity to maintain a pH of about 5, even in the presence of quantities of ejaculate, greater than normal.

The gel also diluted with water to about 15% and titrate with 1 N NaOH solution. To bring the pH to 4 and 5 require approximately 0.5 and 1.5 milliequivalents NaOH, respectively. The magnitude of the PKanddrug 4,16 determine from the graph of the first derivative.

Along with its contraceptive action and action is Rotel STD gels of the present invention should restore and maintain the normal acidity of the vagina due to its BufferedReader actions. As shown above, the gel can neutralize the amount of semen up to two of his own volumes, and save about pH less than 4.5. In addition, as alginic acid, essentially not absorbed by the body (for the most part, due to the high molecular weight), it is expected that the buffer capacity of the composition will be maintained even after absorbed other buffer substances.

Example 4

This example illustrates the spermicidal activity of the gels of the present invention with addition and without addition of nonoxynol-9. (Other and, in General, more detailed studies on spermicidal activity gels of the present invention, described below in example 10.) Use the gel obtained as in example 1. Spermicidal activity determined by diluting the gel saline solution and mixing with seminal fluid in the ratio of 5:1 (diluted gel to semen) and specifying under a microscope, the percentage of motile sperm after 30 seconds (test sander Kramer). Samples of semen have an initial volume of about 4.5 ml, sperm concentration is approximately 56×106sperm/ml and total sperm motility approximately 55%. Get the results below.

In these conditions, the gel, diluted 1:5, when mixing the seminal fluid in a 5:1 ratio corresponds to the ratio of undiluted gel and seminal fluid of approximately 1:1; dilution 1:10 corresponds to the ratio of undiluted gel and seminal fluid of approximately 1:2; dilution 1:20 corresponds to the ratio of undiluted gel and seminal fluid of approximately 1:4. As the average amount of ejaculate is about 1 to 5 ml, and a typical rate of application of the gel is estimated to be approximately 5 ml, the ratio of gel and semen 1:1 should correspond to the average dilution, which can be expected in most cases of sexual intercourse. Thus, the gel of the present invention has sufficient spermicidal activity to inactivate essentially all of spermatozoa even in the presence of quantities of ejaculate, greater than normal.

As shown above, the gels of this invention without the addition of contraception are effective spermicide. All the sperm immediately immobilized by mixing the semen with gel, diluted 10 times (in the absence of nonoxynol-9).

Adding to the gel of varying amounts of nonoxynol-9 increases its spermicidal properties, as illustrated in the following table 1. Experiments carried out exactly as described above for gels without nonoxynol-9. The sample of semen used with gels containing 0.5% and 1.0% of nonoxynol-9, has a volume of 5.0 ml, the concentration of spermatos the Idov 70× 106sperm/ml and total sperm motility 69%. The sample of semen used with gel containing 2.5% nonoxynol-9, has a volume of 4.5 ml, sperm concentration 56×106sperm/ml and total sperm motility 55%.

Table I
Thinning gelSperm motility/inhibition (%)
The gel with 0.5% N-9Gel with 1.0% N-9Gel with 2.5% N-9
1:400/100%--
1:502/97%0/100%0/100%
1:10064/10%9/86%0/100%
1:200-55/20%12/78%
1:400--55/0%

Thus, it appears that the gels of this invention can use a reduced amount of nonoxynol-9 with preservation of spermicidal efficacy in vivo. Lowering the concentration of nonoxynol-9 can reduce the likelihood of irritation of the vagina because this detergent.

Example 5

Carry out the test for irritation of the vagina rabbit using a standard Protocol such tests with the tre is ping-gel from example 1, containing 0, 2.5 and 5% nonoxynol-9. Rabbits give vaginally test substance/composition (dose 1 ml) for ten consecutive days, followed by excision of the vaginal tissue, fixation in buffered formalin and histological verification of the three sections of the abdominal vagina. Fixed tissues straighten, block, poured into paraffin blocks, make slices and stained with hematoxylin and eosin. The slices obtained from the anterior abdominal, middle abdominal and posterior abdominal vagina. Histological assessment is based on changes of the epithelium, vascular congestion, leukocyte infiltration and edema. General estimate of the maximum rate of "four" for each criterion for a maximum of 16. A score of 4 or below complies with minimum irritation, 5-8 weak irritation, 9-11 moderate irritation and 12-16 noticeable irritation. Traditionally, the final classification as acceptable for clinical use is 0-8, at 9-11 and unacceptable in the case of a total of 12 or higher.

All animals are well tolerated, the dosage, and no farmacologiche signs in any group was not observed. Test item see in the fornix at necropsy, several animals treated with the drug trapping gel. Significant changes in the sheaths any doubt the treated animals do not see. Histopathologically the estimates are given next.

Table II
SampleAverage rating
Untreated (n=6)0,8
Only saline (n=6)3,7
The trapping gel (0% N-9) (n=10)5,3
The trapping gel (2.5% of the N-9) (n=10)6,8
The trapping gel (5% N-9) (n=10)8,6

Trapping-gels without the addition of nonoxynol-9, or with the addition of 2.5% nonoxynol-9 detect weak irritation, while gel with 5% nonoxynol-9 detects moderate irritation. All three songs trapping gels are considered to be acceptable from the point of view of the clinical evaluation.

Example 6

This example illustrates Antiherpes activity gels of the present invention (with and without the addition of nonoxynol-9). Use gels, obtained as in example 1. Carry out studies both in vitro and in vivo. On Antiherpes activity evaluation of the following composition:

(1) gel according to the invention without nonoxynol-9;

(2) the gel according to the invention with 5% nonoxynol-9;

(3) the gel according to the invention with 2.5% nonoxynol-9;

(4) K-Y-Jelly (Advanced Care Products) (control 1);

(5) K-Y-Jelly with 2.2% nonoxynol-9 (Advanced Care Products; K-Y-Plus™) (control is 2);

(6) phosphate buffered saline (PBS) (control 3).

In vitro studies. The gels according to the invention with the addition of nonoxynol-9, and without it, were evaluated for activity in vitro against herpes virus Dr. .Herold, Mount Sinai School of Medicine, New York, NY. Strain 186 HSV-2 is produced by cultivation of short-term passaged embryonic kidney rabbit (RK). Analyses to reduce belascoaran carried out as described in Herold et al., Antimicrobial Agents Chemother., 43, 745-751 (1999). The results are given in table III.

Table III
The gel according to the inventionThe gel according to the invention with 2.5% nonoxynol-9
mg/mlPFU/wellingibirovanie (%)mg/mlPFU/wellingibirovanie (%)
40cell death-masters-40cell death-masters-
412724cell death-masters-
0,424440,41760
0,044220,043226

The gel according to the invention is an effective inhibitor of herpes in vitro. It turns out that adding to the gel according to the invention of nonoxynol-9 increases Antiherpes action; however, it appears that the effect due to the addition of nonoxynol-9 is relatively weak. As expected, the addition of nonoxynol-9 increases the toxicity to host cells.

In vivo studies. The gels according to the invention with the addition of nonoxynol-9, and without it, the appreciate on the activity in vivo against herpes virus in mice. The results are presented V.Pilipenko, N.Boume, L.J.D.Zaneveld, S.Garg, D.P.Waller and L.R.Stanberry, Thirteenth Meeting of the International Society for Sexually Transmitted Diseases Research, Denver, CO, July 11-14, 1999. Strain 186 HSV-2 receive as described above.

Female mice Swiss Webster weighing 18-21 g (Harlan, Indianapolis, Indiana) by subcutaneous injection into the upper arm injected 0.1 ml of a suspension containing 3 mg of medroxyprogesterone acetate (decision Upjohn Pharmacia, Kalamazoo, Michigan), 7 days before infection with the virus and then on the eve of the virus to increase the sensitivity to vaginal HSV infection. On the day of infection the animals give anesthesia by intraperitoneally injection of 0.25 ml of a solution containing 6.5 mg/ml pentobarbital sodium.

Take twice smears from vaginal fornix, first touching the swab type 1, hydrated calcium alginate (Fisher Scientific, Pittsburgh, PA), and then with a dry swab. the item twenty seconds infect animals intrawaginalno by instillation of 15 μl of the suspension, containing 4,0 (log10The BOUT of strain 186 HSV-2.

Two days after inoculation, all animals taken vaginal swabs and stored frozen (-80° (C) prior to analysis for the presence of virus by culturing on sensitive monolayers of RK cells. Daily up to 21 days after inoculation the mice are checked for signs of symptomatic infection, which include hair loss and erythema around the perineum, chronic incontinence, paralysis of hind limbs and mortality. For the purposes of this study the animals, which did not develop symptoms, defined as infected if excrete virus from vaginal smears taken on day 2 after inoculation. Incidence data are compared using Fisher's exact test. All comparisons performed twice.

The effectiveness of protection against infection with genital herpes nonoxynol-9 without entering into composition (i.e. normal saline) at various concentrations determined in the mouse model. As can be seen from the table. IV, animals treated for 20 seconds before infection with virus at a concentration of nonoxynol-9 at least 50%, protected from disease and infection significantly better compared to the control animals treated with only PBS (p<0.001 in each case); of course, such a large amount of nonoxynol-9 cannot be applied in practice because of the high irritation factor. In contrast, animals treated with 5% solution of nonoxynol-9 (i.e. at a concentration similar to the concentration in many commercial contraceptive compositions), become infected, although there is a decrease in the number of animals who develop symptomatic disease (p<0,05).

Table IV

The action of the control solutions of N-9 in PBS against the virus of genital herpes type 2 in mice
TimeThe number of inoculatedProtection from diseaseProtection from infectionb
(C)andanimalsNumber%Number%
PBS20150000
N-9 (100%)201515100c1493c
N-9 (50%)201515100c149c
N-9 (5%)2015640d213
a/Time relative to virus inoculation.

b/Animals that do not develop symptoms, defined as infected if excrete virus from vaginal smears taken on day 2 after inoculation.

with/p<0,001 relatively PBS, Fisher's exact test

d/p<0,05 relative to PBS, Fisher's exact test

Similar studies carried out using commercially available spermicidal products containing nonoxynol-9 in concentrations of from about 2.2 to 3.5 percent. Commercially available spermicidal preparations are K-Y-Plus™ (2.2% nonoxynol-9; Ortho-McNeil Pharmaceutical Corp., Raritan, new Jersey); Encare™ (3% nonoxynol-9; Thompson Medical Co., West Palm beach, Florida); Conceptrol™ (5% nonoxynol-9; Ortho-McNeil Pharmaceutical Corp.); Gynol II™ (2% nonoxynol-9; Ortho-McNeil Pharmaceutical Corp.) and Advantage™ (3.5% nonoxynol-9; Columbia Laboratories, currently available under the brand name Advantage-S™). As can be seen from .V, protection from disease and infection, only limited and comparable to the protection observed in previous studies with 5% nonoxynol-9, is not introduced into the composition.

They also carry a number of similar experiments using gels according to the invention. The results are given in tables VI and VII.

Tables VI and VII illustrate some features of the gel according to the invention, which make it particularly attractive as a song against STDs for vaginal use. For example, protection against disease and infection using a single gel according to the invention (i.e. without nonoxynol-9) is better than obtained with conventional contraceptives (i.e. with K-Y-Plus™ or Gynol II™). In addition, one trapping-gel according to the invention as active or more active than Conceptrol™ or Advantage™. Thus, one trapping gel as active as the currently marketed drugs, even if they are bioadhesive and contain from 2.2 to 3.5% of nonoxynol-9.

As can be seen from the table. VII, contents of nonoxynol-9 gel according to the invention is increased to about 5%. Such compositions provide good protection from disease and infection when the animal infected by a virus shortly after treatment. Compositions of the present invention provide sufficient protection from the disease, even when virus infection is delayed by thirty minutes. As will be clear to experts in the field of engineering, effective contraceptive composition or composition against STDs must provide long-term protection.

Example 7.

This example illustrates the activity of the gels of the present invention (with nonoxynol-9 and without it) is Rotel Chlamidia trachomatis. In all studies use biovars MoPn strain Nigg II .trachomatis (VR-123; American type culture collection, Manassas, Virginia). Uterine culture multiply in the cells of Msso using a modified procedure, Cooper et al. (Gen. Microbio., 1990; 136:1109-1115). Briefly, treated cycloheximide 175 cm2mattresses cells Msso after infection is separated by scraping and treated with ultrasound for lizirovania host cells. Chlamydial elementary bodies precipitated by centrifugation and again suspended in buffer with 0.2 M sucrose/0.02 M phosphate (Bird et al., Public Health Service, Center for Disease Control, 1981) and frozen (-80°). Define titles uterine cultures .trachomatis by insulinopenia cells MSO 48-hole culture tablets with 0.1 ml of 10-fold dilutions obtained from the frozen sample. After incubation for 48 hours culture fix and calculate the number of forming chlamydiales inclusion units using labeled with fluorescein antibodies to chlamydiales antigen (Barlets, Issaquah, WA).

Assess the activity against C. trachomatis as gels according to the invention, and some commercial products for vaginal use. Female mice Swiss Webster weighing 18-21 g (Harlan, Indianapolis, Indiana) by subcutaneous injection into the upper arm injected 0.1 ml of a suspension containing 3 mg of medroxyprogesterone acetate (decision Upjohn Pharmacia, Feces is mazoo, Michigan), 7 days before infection with the virus and then on the eve of the virus to increase the sensitivity to vaginal HSV infection. On the day of infection the animals give anesthesia by intraperitoneally injection of 0.25 ml of a solution containing 6.5 mg/ml pentobarbital sodium. Take twice smears from vaginal fornix, first touching the swab type 1, hydrated calcium alginate (Fisher Scientific, Pittsburgh, PA), and then with a dry swab. Then shot the animals before infection by a pathogen injected 15 µl of the test composition.

Animals inoculant by injection of 15 μl of the suspension containing 4,0 (log10) IFU of C. trachomatis MoPn. Vaginal swabs collected from all animals on days 3 and 6 after inoculation and stored frozen (-70° (C) prior to analysis for the presence of .trachomatis on monolayers of cells MoPn. Animals defined as having a sexual tract infection, if any sample emit .trachomatis. To determine the incidence of infection of the upper genital tract, animals killed at day 10 PI, and collect the fallopian tubes and ovaries. From the tissues get sliced into 2-3 mm2and stored frozen (-70°). Samples thawed, treated with ultrasound and purified by centrifugation before cultivation on monolayers of cells Msso. In some cases, animals omers is collected at 35 days after inoculation, and check the top sexual way, for signs of infection by a pathogen (i.e., hydrosalpinx). The results obtained with commercial products for vaginal use and gels according to the invention, are given in tables VIII and IX, respectively.

Table VIII
Lower sex wayTop sex way
Protected from infection/InocuLAN.aProtected from infection/InocuLAN.a
PBS2/29 (7%)4/29 (14%)
Gynol II™ (2% N-9)6/16 (38%)c6/16 (38%)
K-Y Plus™ (2,2% N-9)0/16 (0%)1/16 (6%)
Advantage-S™ (3,5% N-9)3/16 (19%)3/16 (19%)
Conceptrol™ (4% N-9)0/16 (0%)0/16 (0%)
andAnimals defined as infected if by culturing isolated C. trachomatis of strokes taken at days 3 and 6 after inoculation.

bSamples collected at day 10 after inoculation.

withp<0,05 relative to PBS

Table IX
Lower sex wayTop sex way
Protected from becoming infected/ inoculateddProtected from becoming infected/ inoculatedbProtected from hydrosalpinx/ inoculatedc
PBS1/16(6%)0/8 (0%)2/8 (25%)
The gel according to the invention (without N-9)13/16(81%)d8/8(100%)e7/8 (88%)f
The gel according to the invention: 5% N 910/16(62%)e4/8 (50%)f8/8(100%)e
andAnimals defined as infected if by cultivation allocate .trachomatis of strokes taken at days 3 and 6 after inoculation.

bSamples collected at day 10 after inoculation.

withConsider that mice developed hydrosalpinx, if 35 day seen any gidropushki.

dp<0,001 relatively PBS

ep<0,01 relative to PBS

fp<0,05 relative to PBS

The gel according to the invention with nonoxynol-9, or without it, to be highly effective in preventing infection of mice with chlamydia. In addition, the gel according to the invention is more effective than any of the commercial products, when assessing protection against infected with the chlamydia I in mice.

Example 8

The inventors have also conducted clinical trials gels according to the invention in cooperation with Dr. Eliana Amaral and Dr.Anibal Faundes, Kempinski University, Campinas, Brazil. These tests were conducted to determine the vaginal tolerance to the gel according to the invention with nonoxynol-9, or without it. Used the gel according to the invention is similar to the gel obtained in example 1. Used three gel composition according to the invention: (1) the gel according to the invention without the addition of nonoxynol-9; (2) the gel according to the invention with 2.5% nonoxynol-9 and (3) the gel according to the invention with 5% nonoxynol-9.

Randomised double blind phase I clinical trials conducted with 18 volunteers (six volunteers for each of the three test compositions). The study included women aged 20-49 years who are sexually active, with regular menstrual cycle, without the risk of pregnancy (i.e. using the tubal ligation, IUD, partner with vasectomy) and having good indicators of the health of the genital tract. Volunteers were asked to abstain from intercourse for 48 hours prior to testing and during testing. They also gave consent to the visit to the clinic for subsequent evaluations on the second and seventh days after the first visit and the beginning of the Protocol. Women with a history of STD in the last 12 months, using the Vaga is social tool within 7 days prior to testing or with a known Allergy to nonoxynol-9, was excluded.

From volunteers also required during the test period to refrain from the use of other intravaginal funds, including spermicides, sponges and blowing (without prescription researchers). They were also asked to abstain from intercourse for at least two days before the beginning of the research and during the time of applying the test of funds in order to avoid the influence of seminal fluid and possible injury during vaginal intercourse.

Volunteers were examined during four visits: screening, first visit (day 1), the second visit (day 2) and third visit (day 7). They were given a referral for screening and reception during the follicular phase of their menstrual cycle (days 6-9). When attending for screening provided them with a description of the research objectives, given the medical history, physical examination, tests for the presence of pregnancy and checklists with the criteria of inclusion and exclusion. Read and signed the proposed consent form. During this visit for screening checked the number of cells in the endocervical samples. Was ordered treatment endocervicitis, if in a strong field noted the presence of 30 or more cells, there was redness/friability of the cervix or were found positive for culture N.gonorrhea. For about Erki for vaginal infections has been Whiff test, tested vaginal pH, conducted staining gram and received fresh histological sections. Upon detection of ectropion or availability .vaginalis, hyphae, positive Whiff test, pH of 4.7 or the detection of the corresponding (clue) cells involved in the testing was postponed until negative results of the tests.

In the subsequent three visits was estimated irritation (i.e. irritation of the vulva, vagina and cervix) by checking the method of colposcopy according to the who Protocol for the assessment of new vaginal funds (world health organization, global programme against AIDS (who), "Manual for the Standartization of a colposcopy for the Evaluation of Vaginaly Administered Products, VMO/GPA/CRD/95, 10 Geneva 1995, 15 p.). Signs of irritation were considered ulceration, deepithelization, scratches and erythema. The results were registered and received pictures of the vulva, cervix and right lateral fornix. To clean the vault of the vagina and cervix before colposcopy standards who gently used tampon, moistened with saline.

The first visit (day 1) designate the next follicular phase (days cycle 6-9). After initial colposcopy researcher introduces five ml of randomly selected gel (0%, 2.5% or 5% nonoxynol-9). Volunteers give instructions to come back the next morning in order to assess the possible short-term the effect of the product on the bottom a sexual way. During the second visit (day 2) after treatment colposcopy volunteers are instructed on self-making five ml of gel every night just before going to sleep for five nights in the supine position. They also receive a form for comments on the symptoms and time independent use of the gel, which also describes how to contact the researchers if you have any questions or any significant discomfort. They plan to re-visit on the morning after the period of the five-day treatment period. During the third and last visit (day 7) carry out a final colposcopic evaluation. During this visit include the survey on observed during the application of the symptoms (for example, the feeling of "smazyvaete or expiration and other related effects). In this visit to collect the forms filled out by patients, containing a record of any unpleasant sensations in the specified six-day period.

In two cases (#2 and # 3) the Protocol was violated with respect to the first days of using the gel as a volunteer because of the difficulties in planning a visit. Therefore, these patients did not use the gel according to the invention in one day between the first application with the help of the researcher at the first visit and the beginning of independent five-time applications. In addition, the processing of the two other volunteers (cases # 5 and # 6) was begun on the 10th day of the cycle (instead of 6-9 days). Volunteers were given the right to withdraw from the experiment if they have any bleeding or they feel unacceptable pain, irritation or burning, or for any other reason. None of the volunteers did not come out of the experiment, and all volunteers completed the study.

None of the volunteers had no complaints at the second visit. In the first few days of application of registered complaints four patients (three reported burning and itching, and one reported "pain" of the vagina). All of these patients used the gel according to the invention containing nonoxynol-9. Only one of these four patients, the symptoms are considered serious, despite this, the patient completed the trial and at the last visit reported that the symptoms had disappeared. The same four patients in the last test method colposcopy detected erythema of the vulva and the cervix. The volunteer with the most severe symptoms were mild erythema of the cervix and weak erythema of the vulva, but the contents of the vagina was yellowish (pH 7.0). Eleven volunteers reported some leakage of the gel, only four described this phenomenon as "irritant" or "unpleasant". Two of the six consumers gel according to the invention (0% nonoxynol-9) indicated a slight leakage "in the time of visiting the toilet".

Colposcopy at the first visit (i.e. before applying any gel), nine volunteers from 18 was observed individual petechiae in the cervix or vagina. Such petechiae associated with injuries caused by the introduction of a mirror or cleaning moistened swab. During the second visit (i.e. after one day of use of the gel) in seven patients had erythema of the vulva (2), cervix (3) and vagina (4). Six patients mentioned used the gel containing nonoxynol-9 (2.5 or 5%), and only one used the gel according to the invention without N-9.

At the third visit (i.e. after the independent application of the gel for five nights in a row) among consumers of the gel according to the invention without nonoxynol-9 was not observed neither eritem, no scratches. However, in all patients who applied the gel according to the invention containing nonoxynol-9 was observed erythema of the cervix. Of the twelve patients, who applied the gel according to the invention with nonoxynol-9, ten erythema was intense and generalized. The other two consumers gel with nonoxynol-9 gel which adheres to the cervix, and it was possible to observe localized erythema at the base of the specified area when the tape was removed. Scratches caused by cleaning the cervix or vagina moistened swab occurred in ten patients with generalized erythema. At Thu is, which of these ten volunteers also had intense erythema of the vagina, and the seven - erythema of the vulva. Ulcers, sores or deepithelization (i.e., more severe signs of irritation) were observed in any of the patients, regardless of the contained gel according to the invention nonoxynol-9, or did not contain.

Adhering a layer of gel according to the invention on the cervix in three patients observed by colposcopy during both the second and third visit. Adhering a layer of gel according to the invention on the neck of the uterus was observed in 83% of patients at the third visit (approximately 12 hours after the last gel application). Ten volunteers who had adhered layer on the cervix, a layer of gel according to the invention was also observed in the vagina. Washing the vaginal saline solution was sufficient to remove the film. In the other three cases, all of which used the gel without nonoxynol-9, was not observed adhesion of the gel to the cervix or vagina.

The total results of clinical trials are tblh

This clinical study shows the absence of any irritation of the vagina and cervix, when the gel according to the invention is used alone (i.e. without nonoxynol-9) and is applied in succession within six days. However, the gel according to the invention, containing 2.5 or 5.0% of nonoxynol-9, gives erythema, but no serious irritation is legalise. This erythema was insufficient to cause termination of the use of the drug by volunteers. Erythema was transient and disappeared within 1-2 days after cessation of treatment. Since the trapping gel has its own antimicrobial and contraceptive properties, it is expected that the content of nonoxynol-9 can be reduced even further, and by this means substantially attenuated or eliminated erythema caused by the gel containing nonoxynol-9, while maintaining at the same time, high activity against STDs and contraceptive activity. In addition, women are less sensitive to nonoxynol-9, can even benefit from the gel according to the invention with a higher content of nonoxynol-9 than in clinical trials.

Example 9

Assessment of the ability of various vaginal anaerobes and other vaginal microorganisms to survive in the mixture composition of the present invention and nourishing environment for Brucella at pH below about 4. One part of the composition of example 1 (without the addition of nonoxynol-9; pH approximately 3,55) is mixed with one part of a nutrient medium for Brucella; the mixture has a pH of about 3,48. The test specimens before the test leave under anaerobic conditions for at least two hours. In tested samples evaluate inoculum from about 5×107Organismo the per ml of various organisms. Samples will subcultured every hour for 24 hours using blood agar in an atmosphere with 5% CO2in order to determine how long the survival of every organism. The microbes listed in tablh survive for one hour or less.

Table XI
Sample numberThe microorganism
11423F.gonidiaformans
11653F.gonidiaformans
10481F.nucleatum
11518F.nucleatum
9052 projectPrev.melaninogen.
11142Prev.intermedia
11168Prev.intermedia
11697Prev.bivia
11683Prev.bivia
11579Prev.disiens
11698Prev.disiens
11690Porpb.asacch.
11656Porph.asacch.
11425Porph.levii
11601Porph.levii
11598Ps.magnus
11658Ps.magnus
11253Ps.tetradius
11287Ps.tetradius
11587Ps.asacch.
116079420Eubact.lentum
11700Eubact.lentum
R-53bPseudo.aeruginosa
R-68APseudo.aeruginosa
P-41bStrep.agalactiae
R-aStrep.agalactiae
11262Gardnerella vaginalis
P-51AGardnerella vaginalis

Thus, it appears that the gel according to the invention has a wide range of inhibitory effect on the microorganisms that cause vaginitis and/or bacterial vaginosis.

Example 10

This example provides additional data regarding the effectiveness of protection and other properties of the trapping gels of the present invention. Also a comparison with the various commercial compositions for vaginal use. The trapping gel of example 1 is Packed in 20-ounce plastic tubes with screw caps. Acid-bufferarray activity of the trapping gel according to the invention compared with the activity sold on the market vaginal acid-BufferedReader gel Aci-Jel™ (Ortho-McNeil Pharmaceutical, Raritan, NJ). Bioadhesive properties and properties maintain the viscosity of the trapping gel according to the invention compared with the properties of commercial gels, including Conceptrol™ (Advanced Care Products, Raritan, new Jersey; usually use the th available on the market vaginal contraceptive), Advantage-S™ (Columbia Laboratories, Aventura, Florida; vaginal contraceptive gel with the stated bioadhesive properties), Replens gel (Parke-Davis, Morris Plains, new Jersey; often used vaginal lubricant) and Aci-Jel™. Commercially available products are bought in local pharmacies.

Collect semen by cammasturbation five healthy volunteers after obtaining approval of the Commission on research (IRB) and the consent of the volunteers. The average volume of the samples of semen 2,3±0.45 ml, the average amount of sperm 74×106cells/ml (90% confidence limits: 46-120×106cells/ml), and the average initial percentage of motile sperm 62% (interval 56-67%).

The acid buffer capacity. The acid buffer capacity is determined by titration with NaOH solution. One gram of each gel was diluted to 10 ml with 0.9% NaCl (normal saline) solution (1:10, wt./vol.). With constant stirring, a solution of sodium hydroxide (1,0 N) 20-ml portions. Measure pH within 30 seconds after each addition using the standard composite electrodes. During pH measurement stirring ceased. This procedure continues up until the pH rises to approximately 7,0. For each gel, the titration is carried out at a threefold repetition. Titration curves for the best according to who tamper with the results obtained using the software TableCurve 2D (SPSS Software, Chicago, Illinois). The obtained curves are used to calculate the amount of NaOH required to bring the pH of the solution of each gel to a 5.0 as the buffer capacity of the gel and, in General, the value considered as the maximum desirable vaginal pH. For each curve, calculate the values of the first derivatives of X=0 (without adding NaOH; initial pH) to X = equivalentof NaOH required for the titration of a solution of the gel to a pH of 7.0. Values of the first derivatives are also evaluated directly from the data by interpolation using a spline function (StatMost software, DataMost Corporation, sandy, Utah). Lows, common to both estimates of the first derivative of the titration, is used to estimate the values of the apparent PKandat pH 7 or below.

Relevant buffer capacity of the gels is considered as the amount of NaOH required to bring the pH of the gel from its initial value to a 5.0. The gel according to the invention has a much higher acid buffer capacity than Aci-Jel™. To pH 1 g of the trapping gel according to the invention to increase from the initial pH 3,52 to 5.0, requires approximately 0.32 mEq NaOH; in contrast, to increase the pH of the Aci-Jel™ from its initial pH 4,07 to 5.0, takes about 0,076 mEq NaOH. These results are consistent with lower values of the apparent PKandfor the trapping gel (i.e. 3,7, of 4.0 and 4.7) compared to the PKandAci-Jel™ (i.e., a 4.4 and 5.0).

Physiologically relevant buffer activity gels evaluated by determining the pH after adding the whole of human semen (pH about 7.2 to 8.0) to undiluted gels in different ratios (typically from about 1:1 to 1:9). Measure the pH using a combination electrode for pH measurement with the pointed end at the Ross. Get the results below.

Table XII
The ratio of seminal fluid and gelThe average pH
The gel according to the inventionAci-Jel™
Only gel3,454,05
1:13,975,14
1:2of 4.455,79
1:45,18to 6.57
1:96,48not determined.
Only semenof 7.64

In confirmation of the results of the titration gel according to the invention acidify the ejaculate more effectively than Aci-Jel™. For example, when 1 part gel mixed with 2 parts of seminal fluid, the pH in the case of the gel according to the invention ostaa the camping below 4.5, but nearly 6.0 in the case of Aci-Jel™. Curves are consistent with the results obtained using the software TableCurve 2D (SPSS Software, Chicago, Illinois). The calculated ratio of the gel and the semen to obtain a pH of 5.0 is 1:3,4 (22,9% gel in a mixture of gel/semen) for gel according to the invention and 1:0,9 (52,5% gel in a mixture of gel/semen) for Aci-Jel™. The calculated pH of the resulting curves for 100% gel according to the invention and Aci-Jel™ amount of 3.53 and 4,08, respectively. These values are in good agreement with direct measurements of pH described above.

Bioadhesive. Biological adhesion strength of the gel according to the invention and other vaginal gels was measured using the facilities for testing bioadhesion in the horizontal and vertical position (Garg et al., "Rationalization of Selection of Polymers in the Development of Vaginal Formulations in Terms of Their Bioadhesion and Retention Properties", Conference Abstracts of Microbicides 2000, March 13-16, Washington, DC, p.41), based on the principle of measuring limit of the tensile strength (measured using test installation in a horizontal position) and shear stress (measured using test installation in a vertical position)required for breaking the adhesive bond between the model membrane and the test composition. As membranes use cellophane, by processing the config liquid, such vaginal fluid (SVF; Owen et al., "A Vaginal Fluid Simulant", Contraception, 1999; 59:91-5), and mucous membrane of the vagina sheep (obtained from a slaughterhouse). For measurement of biological adhesion 0.5 g of gel mixed with 0.25 ml of SFV and put between membranes in an area of approximately 12 cm2. The membrane is held in contact with the gel for 5 minutes. Horizontal installation contact gel membranes to be installed using a load on the upper substrate (10 g). Before measuring the weight removed. In a vertical installation to maintain contact with the gel using the screw that is removed before measurement. For biological adhesion strength taking the effort required to separate the two membranes.

Typically, the biological adhesive strength of a gel according to the invention is higher than that of any of the products available on the market. The results are given below in tables.

Table XIII

Biological adhesion vaginal compositions, measured using cellophane membrane
TrackBiological adhesion strength (Dyne/cm2; n=6)
Horizontal installationVertical installation
The gel posovremeni 1223774
Aci-Jel™904471
Advantage-S™441412
Conceptrol™944410
K-Y-Jelly™913375
Replens™717328
Table XIV

Biological adhesion vaginal compositions, measured using the membrane of the vaginal mucosa sheep
TrackBiological adhesion strength (Dyne/cm2; n=6)
Horizontal installationVertical installation
The gel according to the invention1191833
Aci-Jel™1143511
Advantage-S™363360
Conceptrol™641423
K-Y-Jelly™907390
Replens™1228676

On the horizontal mouth of the information using cellophane membrane biological adhesive strength of the gel according to the invention is about 1.3, the 2.8 and 1.3, 1.3 and 1.7 times, respectively, Aci-Jel™, Advantage-S™, Conceptrol™, K-Y-Jelly™ and Replens™. When using the membrane of the vaginal mucosa sheep on the same biological adhesive strength of the gel according to the invention is about 3.3, 1.9 and 1.3 times higher than, respectively, Advantage-S™, Conceptrol™ and K-Y-Jelly™but, essentially identical to the adhesion Aci-Jel™ and Replens™. For vertical installation using cellophane membrane gel according to the invention is about 1.6, and 1.9, and 1.9, 2.1 and 2.4 times more powerful bioadhesion than, respectively, Aci-Jel™, Advantage-S™, Conceptrol™, K-Y-Jelly™ and Replens™and with the membrane of the vaginal mucosa sheep stronger 1.6, and 2.3, and 2.0, 2.1 and 1.2 times, respectively. Generally, the membranes of both types get similar results with all compositions, except for the Aci-Jel™ and Replens™that show a greater propensity for biological adhesion to the membrane of the vaginal mucosa sheep than cellophane membrane.

The viscosity. It is expected that during use in the vagina will be diluted due to the amount of seminal fluid and partial leakage of the gel from the vagina over time. In order to assess the impact of dilution, determine the viscosity of the diluted gel according to the invention and commercially available is x vaginal gels. Samples of compositions for vaginal application weighed into 25-ml chemical cups. To samples of gels add deionized water (minimum resistance 16 IOM) to achieve 20% of the concentration of the solution/suspension (wt./about., 1 part gel to 4 parts water). Using the rod for magnetic stirrer samples stirred for 30 minutes. The viscosity is determined at a temperature of 30.0±0,5°using viscometer Brookfield DV-I+ (LVT spindle) with a transitional device for small samples (spindle No. 18). Pick up the speed of the spindle to provide a higher percentage of torque in the range of 10-100%, as recommended by the manufacturer.

Get the results for the gel according to the invention and various commercial vaginal gels, below.

Table XV
TrackViscosity (CP)
The gel according to the invention4332
Aci-Jel™206
Advantage-S™16
Conceptrol™42
K-Y-Jelly™41
Replens™24

The gel according to the invention when diluted retains its viscosity is significantly better than other gelinabaci diluted gel according to the invention in 21, 271, 103, 103 and 180 times higher than the Aci-Jel™, Advantage-S™, Conceptrol™, K-Y-Jelly™ and Replens™, respectively. As Replens™and Advantage-S™ do not dissolve in water; in fact, some of the components adhere to the surface of the vessel.

Spermicidal activity. In order to evaluate the spermicidal activity, the gel according to the invention is diluted with a physiological solution (0.9% NaCl) and get samples containing 100, 100, 50, 33 and 25 mg of gel per ml of saline. Five volumes of each diluted suspension of gel added to one volume of semen. Determine the percentage of motile sperm after 30 seconds after adding the semen in bright-field microscope method, which is a modification of the method of sander and Kramer (Anderson et al., "Evaluation of Poly (Styrene-4-Sulfonate) as a Preventive Agent for Conception and Sexually Transmitted Diseases", J. Androl., 2000 (in press); Sander et al., "A Practical Method for Testing the Spermicidal Action of Chemical Contraceptives", Hum. Fertil., 1941, 6:134-7). Checking about 200 sperm per sample. Get the results below.

Table XVI
The ratio of gel and semenpHMotile sperm (%)
Only semen8,0970
1:8 6,4662
1:66,0454
1:45,5433
1:24,560
1:13,970

Spermicidal activity of the gel according to the invention is increased depending on the amount, when the amount of gel in the mixture increases, and the pH of the mixture with seminal fluid is reduced. Research for the purpose of comparison (results not presented) showed that the gel according to the invention has a significantly higher spermicidal activity compared to Aci-Jel™. For example, a mixture of undiluted gel and seminal fluid in a ratio of 1:2 has a pH 4,56 and gives almost complete immobilization of spermatozoa; at the same dilution Aci-Jel™ has a pH 6,22 and does not affect sperm motility in identical conditions.

The sperm, as a rule, are inactivated at pH 5.0 (Garg and Zaneveld, unpublished results; see also Mann, The Biochemistry of Seme", New York: Wiley, 1964). Based on these results a mixture of undiluted gel according to the invention and seminal fluid in a ratio of 1 to 3,4 should have a pH of 5.0 and, thus, must be fully spermicidal. However, partial spermicidal activity can be observed at lower ratios of gel and seminal fluid; for example, a mixture of gel on from the retenu and seminal fluid in a ratio of 1:4 gives about 33% inhibition of sperm motility. Calculate the test conditions IC50and the specified indicator equivalentin value undiluted gel and semen 1 to 4,1.

The stability. Plastic tubes containing the gel according to the invention, stored at 4°, 27°s and 40°C. the Tubes extracted at intervals of 1, 2, 3 and 6 months, and material properties, which were kept at 27°s and 40°compare with the properties of the material stored at 4°S. Also conduct a comparison between the samples stored at 27°and 4°within 24 months. Samples for analysis receive, slitting the tube longitudinally like a butterfly (through the top, through the bottom, then the middle, connecting the sections at the top and bottom on the side opposite the seam), after which the walls of the tube gently open. Content consider on the subject of appearance and color, and the walls of the tubes at their condition and color change. Test samples for analysis is obtained from the upper, middle and lower parts of the tube. Using a pH meter (Orion, model 230V with electrode Orion Ross Sure-Flow) determine the pH of the three samples from the upper, middle and lower parts. The buffer capacity of the samples determined by mixing four 100-ml aliquots (400 ml), 1 N NaOH solution with 40 ml of 5% aqueous solution of the sample and determining the pH. Carry out tests to limit the content of microorganisms (in the case of contamination of microorganism and) and a test for infection with microorganisms (on the effectiveness of conservation; using Staphylococcus aureus, Aspergillus niger, Candida albicans, Escherichia coli and Pseudomonas aeruginosa) in the selected moments of time and environmental samples, tested the voltage from the storage.

't see any changes the General appearance, colour, smell, consistency, homogeneity, pH and buffer capacity of the samples stored at accelerated conditions impact stresses at 40°within 6 months or at ambient temperature within 24 months (the longest dimension), when such samples are compared to control samples stored at 4°C. in Addition, stored gels have been tested for microbial content in all the points selected for evaluation.

Example 11

This example illustrates the trapping gels of the present invention obtained in the form of tablets, designed to be inserted into the vagina. Receive the tablets of the composition specified below.

IngredientNumber (%)
Xanthan gum2,0
Alginic acid2,65
Sodium alginate2,65
Citric acid2,0
Lactic acid2,0
Tartaric acid0,5
Lactose63,0
L-Hydroxypropylcellulose10,0
D-Sorbitol5,0
Matrikamantraa5,0
Benzoic acid0,2
Croscarmeloseb3,0
Magnesium stearate1,0
Talc1,0
aAC-Di-Sol™ Mendell, United Kingdom

bExplotab™ from FMC, Belgium

All the solid ingredients are accurately weighed in the required quantities and pass through sieve number 85. Get a mixture of excipients, mixing the xanthan gum (about half of the total), alginic acid, sodium alginate, lactose, D-sorbitol, matrikamantra and L-hydroxypropylcellulose on oiled paper using a spatula; then the mixture of excipients is transferred into air-filled plastic bag and turned in for 10 minutes for thorough mixing. Get a binder solution by dissolving xanthan resin (remaining amount), citric acid, lactic acid, benzoic acid and tartaric acid in a small amount of distilled water. The amount of water in the binder solution, as a rule, SOS is to place approximately 7-8 ml on party composition 30,

A binder solution was added with stirring to the mixture of excipients. Stirring is continued until, until all of the salt will not be included in the composition, and the resulting wet mass can easily pass through sieve No. 16. After passing the wet mass through a sieve No. 16 it is dried at 45°C for 24 hours. Then the dry granules are passed through a sieve of No. 22. The obtained dried granules are mixed with croscarmellose, magnesium stearate and talc in a polyethylene bag. Then the resulting mixture was formed into tablets (about 1.2 g per tablet) using a single-cycle compression teletrauma machine (Cadmach; Ahmedabad, Gujarat, India) and using almond-shaped concave of poisonou.

As is well known in the technique, in tablets, if desired and/or necessary, you can include other ingredients. Such optional ingredients include, for example, excipients such as xanthan gum, alginic acid, sodium alginate, citric acid, lactic acid, tartaric acid, benzoic acid and the like; diluents, such as lactose, dehydrate disubstituted calcium phosphate, tizamidine calcium phosphate, starch, sorbitol, microcrystalline cellulose, calcium carbonate, dextrose, mannitol, kaolin and the like; substances that contribute to litter, such as 1-hydroxypropylcellulose, microcrystalline the cellulite, tighten the outside, sodium alginate, matrikamantra, colloidal silicon dioxide, sodium carboxymethyl cellulose, calcixerollic etc.; moisturizing agents such as D-sorbitol, triacetin, polyhydric alcohols such as glycerin and propylene glycol; and lubricating/facilitate slipping agents such as magnesium stearate, talc, calcium stearate, stearic acid, castor oil, sodium lauryl sulphate, zinc stearate, glycerylmonostearate, boric acid, etc.

Adding to the physiological solution (one tablet at approximately 10 ml) tablet swells and disintegrates within about 3 to about 5 minutes. After about the first 2 minutes diverges approximately half of the tablet; if you continue spilling increases the viscosity of the dispersion. The initial pH of the dispersion is approximately 3.1. The buffer capacity is determined by titration 0,97 N NaOH solution; the value of the PKandabout 2,96. The buffer capacity is sufficient for buffering and neutralization of from about 3 to about 7 ml of normal seminal fluid.

Biological adhesion strength tablets (one tablet is added to about 10 ml of physiological solution) is measured using a test installation on bioadhesion in a horizontal position, as described in example 10, using cellophane membrane, smoken the second liquids, such vaginal fluid. Also compare with commercially available vaginal tablets (1) Candid-V6® (clotrimazole IP (100 mg); Glenmark Pharmaceutical Ltd., Goa, India); (2) Betadine® (povidone-iodine IP 200 mg (available iodine (20 mg); Win-Medicare Ltd., New Delhi, India); (3) Infa-V® (metronidazole IP (500 mg), clotrimazole (100 mg) and lactic acid Bacillus (150 million spores); Lark Laboratories (India) Ltd., New Delhi, India); (4) Candizole-T® (tinidazole IP (500 mg), miconazole IP (200 mg) and neomycin sulphate IP equivalent to 20 mg of neomycin; Foreva Women's Healthcare, Unichem Laboratories Ltd, Mumbai, India). Get the results below.

Table XVII

Biological adhesion vaginal compositions in the form of tablets, measured using cellophane membrane
TrackBiological adhesion strength (Dyne/cm2; n=5)
The tablet according to the invention944±69
Candid-V6®713±70
Betadine®611±74
Infa-V®643±70
Candizole-T®529±65

Biological adhesion strength of the tablets according to the invention is about 1.3, and 1.5, 1.5 and 1.8 times higher, respectively, in the case of the Candid-V6®, Beadine® , Infa-V® and Candizole-T®.

Tablets of this invention can be inserted into the vagina and to obtain, in combination with vaginal and other liquids present in the vagina, trapping the gels of the present invention. If desirable, vaginal tablets, you can use other ingredients such as colorants and flavorings, to increase or improve the aesthetic appeal.

1. Antimicrobial and contraceptive composition for reducing the risk of infection with sexually transmitted diseases during sexual contacts involving the vagina and the penis, containing (1) a substance forming a matrix, (2) bioadhesive substance, (3) a buffering agent, and (4) water, and the composition is suitable for introduction into the vagina, while the agents (1)to(3) are sufficient to : (a) to form a semi-solid matrix upon contact with seminal fluid, (b) to cause the seal of mucus, (C) to form bioadhesive layer on the surface of the vagina, (d) to keep the vagina acidic pH values less than approximately 5 in the presence of seminal fluid, ejected by man, and (e) the composition was hypertensive.

2. The composition according to claim 1, additionally containing a wetting agent and a preservative.

3. The composition according to claim 1, additionally containing an antimicrobial and/or contraceptive is redtwo.

4. The composition according to claim 2, additionally containing antimicrobial and/or contraception.

5. The composition according to claim 1, containing from about 1 to 10% of the substance constituting the matrix, from about 1 to 10% bioadhesive substance and from about 1 to 10% of a buffering agent, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiological balance in the vagina.

6. The composition according to claim 2, containing from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents and from about 0.1 to 1% of a preservative, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiological balance in the vagina.

7. The composition according to claim 4, containing from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents, from about 0.1 to 1% of a preservative, and from about 0.2 to 5% of an antimicrobial and/or contraception, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiologists is a mini balance in the vagina.

8. The composition according to claim 2, in which the substance constituting the matrix are selected from the group consisting of alginic acid, chitosan, gum Arabic on a gelatin basis and poloxamer; bioadhesive substance selected from the group consisting of xanthan resin, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, chitosan, polycarbophil and carbopol; a buffering agent selected from the group consisting of lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid and malic acid; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; and a preservative selected from the group consisting of benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propyl paraben, benzalkonium chloride, nitrate of finalstate and chlorhexidine.

9. The composition according to claim 4, in which the substance constituting the matrix are selected from the group consisting of alginic acid, chitosan, gum Arabic on a gelatin basis and poloxamer; bioadhesive substance selected from the group consisting of xanthan resin, hydroxypropylcellulose, hydroxyprop is illiterate, of sodium carboxymethyl cellulose, chitosan, polycarbophil and carbopol; a buffering agent selected from the group consisting of lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid and malic acid; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; preservative selected from the group consisting of benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propyl paraben, benzalkonium chloride, nitrate of finalstate and chlorhexidine; antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde modified with N2SO4almond acids, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin and ciclopiroxolamine.

10. The composition according to claim 4, in which the substance constituting the matrix, predstavljaet an alginic acid; bioadhesive substance is a xanthan resin or hydroxypropylcellulose; a buffering agent selected from the group consisting of lactic acid, citric acid and acid tartrate of potassium; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; preservative selected from the group consisting of benzoic acid and sodium benzoate; antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acids.

11. The way to reduce the risk of infection with sexually transmitted diseases during sexual contacts involving the vagina and the penis, including the vagina effective amount of antimicrobial and contraceptive composition before or shortly after sexual contact, and this composition contains an effective amount of (1) the substance that forms the matrix, (2) bioadhesive substances, (3) a buffering agent, and (4) water, whereby the composition is suitable for introduction into the vagina, where the composition forms on overdue matrix upon contact with seminal fluid, composition causes the seal of the cervical mucus, the composition forms bioadhesive layer on the surfaces of the vagina, the composition maintains the natural acidic pH of less than approximately 5 in the presence of seminal fluid, those of the male, and the composition is hypertonic.

12. The method according to claim 11, in which the composition also contains a wetting agent and a preservative.

13. The method according to claim 11, in which the composition also contains antimicrobial and/or contraception.

14. The method according to item 12, in which the composition also contains antimicrobial and/or contraception.

15. The method according to claim 11, in which the composition contains from about 1 to 10% of the substance constituting the matrix, from about 1 to 10% bioadhesive substance and from about 1 to 10% of a buffering agent, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiological balance in the vagina.

16. The method according to item 12, in which the composition contains from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents and from about 0.1 to 1% of a preservative, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and significantly neareset natural microbiological balance in the vagina.

17. The method according to 14, in which the composition contains from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents, from about 0.1 to 1% of a preservative, and from about 0.2 to 5% of an antimicrobial and/or contraception, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiological balance in the vagina.

18. The method according to item 12, in which the substance constituting the matrix are selected from the group consisting of alginic acid, chitosan, gum Arabic on a gelatin basis and poloxamer; bioadhesive substance selected from the group consisting of xanthan resin, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, chitosan, polycarbophil and carbopol; a buffering agent selected from the group consisting of lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid and malic acid; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol, and is triacetin; and a preservative selected from the group consisting of benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propyl paraben, benzalkonium chloride, nitrate of finalstate and chlorhexidine.

19. The method according to 14, in which the substance constituting the matrix are selected from the group consisting of alginic acid, chitosan, gum Arabic on a gelatin basis and poloxamer; bioadhesive substance selected from the group consisting of xanthan resin, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, chitosan, polycarbophil and carbopol; a buffering agent selected from the group consisting of lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid and malic acid; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; preservative selected from the group consisting of benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propyl paraben, benzalkonium chloride, nitrate of finalstate and chlorhexidine; antimicrobial and/or contraceptive agent selected from the group consisting of nonox the Nola-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde modified with N2SO4almond acids, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin and ciclopiroxolamine.

20. The method according to item 12, in which the substance constituting the matrix, an alginic acid; bioadhesive substance is a xanthan resin or hydroxypropylcellulose; a buffering agent selected from the group consisting of lactic acid, citric acid and acid tartrate of potassium; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin, where the preservative is selected from the group consisting of benzoic acid and sodium benzoate; antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acids.

21. Antimicrobia and contraceptive composition for reducing the risk of infection with diseases, sexually transmitted during sexual contact, and this composition comprises (1) about 1 to 10% of the substance forming the matrix, (2) about 1 to 10% bioadhesive substances, (3) about 1 to 10% of a buffering agent, (4) from about 0 to 2% moisturizing agents, (5) from about 0 to 2% of a preservative, (6) from about 0 to 10% of one or more antimicrobial and/or contraceptives, and (7) water, and this composition is suitable to make the vagina, the composition forms a semi-solid matrix upon contact with seminal fluid, ejected the man in the vagina, the composition causes the seal of the cervical mucus of the vagina, the composition forms bioadhesive layer on the surfaces of the vagina, the composition retains acidic vaginal pH of less than about 5 in the presence of seminal fluid, those of the male, and the composition is hypertonic.

22. The composition according to item 21, containing from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents and from about 0.1 to 1% of a preservative, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiological balance in the vagina.

23. The composition is according to item 21, in which the substance constituting the matrix, an alginic acid; bioadhesive substance is a xanthan resin or hydroxypropylcellulose; a buffering agent selected from the group consisting of lactic acid, citric acid and acid tartrate of potassium; moisturizing agents, if present, are selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; preservative, if present, are selected from the group consisting of benzoic acid and sodium benzoate; antimicrobial and/or contraception, if present, are selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acids.

24. The composition according to item 22, in which the substance constituting the matrix, an alginic acid; bioadhesive substance is a xanthan resin or hydroxypropylcellulose; a buffering agent selected from the group consisting of lactic acid, citric acid and acid tartrate of potassium; wetting agent selected from the group consisting of glycerol, glycols, prop is langille, sorbitol and triacetin; preservative selected from the group consisting of benzoic acid and sodium benzoate; antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acids.

25. Solid composition for reducing the risk of infection with sexually transmitted diseases during sexual contact involving the vagina and the penis, and this composition contains an effective amount of (1) the substance that forms the matrix, (2) bioadhesive substances, and (3) a buffering agent, and a solid composition suitable for introduction into the vagina, where the solid composition is easily dispersible in aqueous medium or from the outside or vagina with the formation of the dispersed composition, where the dispersed composition forms a semi-solid matrix upon contact with seminal fluid, causes the seal cervical mucus forms bioadhesive layer on the surfaces of the vagina, maintains the natural acidic pH of the vagina approximately less than 5 in the presence of seminal fluid, ejected the man, and is hypertonic the Russian.

26. Solid composition according A.25, optionally containing wetting agent and preservative.

27. Solid composition according A.25, optionally containing antimicrobial and/or contraception.

28. Solid composition for p, optionally containing antimicrobial and/or contraception.

29. Solid composition according A.25 containing substance that forms the matrix, bioadhesive agent and a buffering agent in sufficient quantity to obtain the vagina dispersed composition containing from about 1 to 10% of the substance constituting the matrix, from about 1 to 10% bioadhesive substance and from about 1 to 10% of a buffering agent, and the specified composition maintains the natural acidic pH of the vagina approximately 3.5 to 4.5, and does not substantially disturb the natural microbiological balance in the vagina.

30. Solid composition for p containing substance that forms the matrix, bioadhesive agent and a buffering agent in sufficient quantity to obtain the vagina dispersed composition containing from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents and from about 0.1 to 1% of a preservative, and the specified composition maintains the natural acidic, rnwo vagina about 3.5 to 4.5, and substantially disrupts the natural microbiological balance in the vagina.

31. Solid composition for p containing substance that forms the matrix, bioadhesive agent and a buffering agent in sufficient quantity to obtain the vagina dispersed composition containing from about 3 to 5% of the substance constituting the matrix, from about 2.5 to 6% bioadhesive substance, from about 1 to 7% of a buffering agent, from about 6 to 10% moisturizing agents, from about 0.1 to 1% of a preservative, and from about 0.2 to 5% of an antimicrobial and/or contraception, and the specified composition maintains the natural acidic pH of the vagina from about 3.5 to 4,5, and does not substantially disturb the natural microbiological balance in the vagina.

32. Solid composition for p, in which the substance constituting the matrix are selected from the group consisting of alginic acid, chitosan, gum Arabic on a gelatin basis and poloxamer; bioadhesive substance selected from the group consisting of xanthan resin, hydroxypropylcellulose, hydroxypropylmethylcellulose, natrecor-maximalizalasi, chitosan, polycarbophil and carbopol; a buffering agent selected from the group consisting of lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric KIS is the notes, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid and malic acid; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; and a preservative selected from the group consisting of benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propyl paraben, benzalkonium chloride, nitrate of finalstate and chlorhexidine.

33. Solid composition for p, in which the substance constituting the matrix are selected from the group consisting of alginic acid, chitosan, gum Arabic on a gelatin basis and poloxamer; bioadhesive substance selected from the group consisting of xanthan resin, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, chitosan, polycarbophil and carbopol; a buffering agent selected from the group consisting of lactic acid, citric acid, acid tartrate of potassium, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid and malic acid; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; the preservative is ybiraut from the group consisting of benzoic acid, sodium benzoate, methylparaben, ethylparaben, butylparaben, propyl paraben, benzalkonium chloride, nitrate of finalstate and chlorhexidine; antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde, modified H2SO4almond acids, povidone-iodine, Itraconazole, ketoconazole, metronidazole, clotrimazole, fluconazole, terconazole, miconazole, tinidazole, econazole, chloramphenicol, nystatin and ciclopiroxolamine.

34. Solid composition for p, in which the substance constituting the matrix, an alginic acid; bioadhesive substance is a xanthan resin or hydroxypropylcellulose; a buffering agent selected from the group consisting of lactic acid, citric acid and acid tartrate of potassium; wetting agent selected from the group consisting of glycerol, polyethylene glycols, propylene glycols, sorbitol and triacetin; preservative selected from the group consisting of benzoic acid and sodium benzoate; and antimicrobial and/or contraceptive agent selected from the group consisting of nonoxynol the a-9, octoxynol-9, benzalkonium chloride, phosphorylated hesperidins, sulfated hesperidine, polystyrenesulfonate, substituted copolymers of benzosulfimide acid and formaldehyde and modified H2SO4almond acids.

35. Solid composition according A.25 made in the form of pills, which can be inserted into the vagina.

36. Solid composition for p made in the form of pills, which can be inserted into the vagina.



 

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10 cl, 2 dwg, 12 ex

FIELD: medicine, pharmaceutical industry, phytotherapy.

SUBSTANCE: invention proposes an agent used in treatment of infectious diseases. Agent used in treatment of infectious diseases comprises chitosan of polyfraction composition with amine groups of molecular mass from monomeric link - glucosamine to ˜350 kDa and deacetylation degree from ˜68 to ≤ 95% and vegetable raw aqueous extract chosen from the following group: Cetraria thallus, sage official herb, cocklebur leaves, black poplar buds, common wormwood herb, red roots, burdock roots, French honey-suckle herb, bur-marigold tripartite herb, sandy common immortelle flowers, dropwort elm-leaved flowers, river avens (Geum) roots, licorice glabrous roots, swampy sweet flag roots, burnet official roots,, nettle dioecious herb, swampy cudweed herb, common milfoil herb, sweet clover official herb, gum-free leaves, dropwort, willow bark, birch leaves, bilberry leaves, willow-herb narrow-leaves herb, peppermint herb, fenestrate Saint-John's-wort herb, knot-grass herb, shepherd's purse herb, violet pensy tricolor herb, speedwell herb, pot-marigold flowers, common tansy flowers, matricary official flowers, chicory roots, dandelion official roots, tormentil roots, cinnamon wild rose fruits, viburnum leaves, pinnate kalanchoe and maize stigmas. Aqueous extract is prepared by extraction of vegetable raw with demineralized water under definite conditions. Agent promotes to effective treatment of infectious diseases, such as chlamydiosis, herpes, erysipelas, viral hepatitis A and B, gastroenteric tract diseases, acute enteric infectious, and to declining period of clinical symptoms of diseases said.

EFFECT: valuable medicinal properties of agent.

10 cl, 2 dwg, 12 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: immunology, biotechnology.

SUBSTANCE: invention describes antibody and its fragments neutralizing rabies virus and a method for treatment of patient subjected for effect of rabies virus by using indicated antibody and its fragment. Invention discloses variants of isolated nucleic acids encoding polypeptides carrying light and heavy chain of antibody, respectively. Also, invention describes expressing vector carrying at least one of indicated nucleic acids. Using this invention enhances span-life of patients after effect with rabies virus on them and can be used in corresponding prophylactic therapy of such patients.

EFFECT: valuable medicinal properties of antibody and nucleic acid.

14 cl, 1 dwg, 1 tbl, 2 ex

FIELD: veterinary science, surgery.

SUBSTANCE: method involves applying the application of mixture comprising glue base with ligfol and Novocain on infected surface taken in the ratio, wt.-%: ligfol, 70; Novocain, 30. Method allows decreasing time for treatment of suppurative wounds by 1.5-2 times, economy of dressing material and time that improved labor conditions of veterinary expert. Invention can be used in treatment of suppurative wounds both aerobic and anaerobic etiology.

EFFECT: improved treatment method.

1 ex

FIELD: veterinary science.

SUBSTANCE: invention involves the combined use of antibacterial preparations and immunomodulator. Method involves complex of single and double RNA sodium salts from killer yeast Saccharomyces cerevisiae as an immunomodulator and synthetic polymer-carrier taken in the dose 0.3-0.4 mg/kg. Immunomodulator is administrated in animals in a single dose before onset of critical period, i. e. in 15-20 days of piglets growing. Method provides stimulation of factors of cellular and humoral immunity of animals without adverse reactions and complication due to selection of optimal dose of immunomodulator and its prolonged effect.

EFFECT: improved method for treatment and prophylaxis.

3 cl, 4 tbl, 3 ex

FIELD: medicine, virology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a synergetic composition comprising azidothymidine and glycyrrhizic acid penta-O-nicotinate - niglizine taken in physiologically blood concentrations: 0.0037-0.0254 mcM for azidothymidine and 0.0052-9.64 mcM for niglizine. Using the proposed composition provides effective inhibition of HIV-1 reproduction and significant reducing consumptions required for treatment. The composition shows high bioavailability and high effectiveness.

EFFECT: improved and valuable medicinal properties of composition.

6 tbl, 1 dwg

FIELD: veterinary science.

SUBSTANCE: invention proposes a preparation for treatment and prophylaxis of mastitis in cows at onset of the lactation period and in dry cows that comprises the following components, wt.-%: furacrylin, 0.4-0.6; dioxydin, 0.8-1.2; bee wax, 4-6, and sunflower oil, the balance. The preparation is heated to 38-40°C and administrated in cow mammary gland being in damaged and healthy lobules of udder through a nipple duct by using a syringe in the dose 5 ml. Using the preparation provides enhancing therapeutic and prophylactic effectiveness, decreasing labor intensity in treatment and prophylaxis of mastitis in cows at the lactation period and in dry cows.

EFFECT: enhanced and valuable properties of preparation.

3 tbl, 3 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising drospirenone as the first active agent in the amount corresponding to daily dose from 2 to 4 mg in administration of the composition, and ethynylestradiol as the second active agent in the amount corresponding to daily dose from 0.01 to 0.05 mg in combination with one or some pharmaceutically acceptable vehicles or additives. Drospirenone as a component of the pharmaceutical composition is in the finely divided form. The preparation comprises some separately packages and individually taken medicinal units placed in the unit package and designated for oral administration for at least 21 days at a time and indicated daily medicinal units comprise the combination of drospirenone and ethynylestradiol. The preparation can comprise 7 and less daily doses no containing any active agent or containing ethynylestradiol only. The combination of ethynylestradiol and drospirenone provides the safety contraceptive activity due to using the maximal dose of drospirenone being without adverse effects, in particular, excessive diuresis.

EFFECT: improved and valuable properties of combination.

34 cl, 5 dwg, 5 ex

FIELD: medicine, gynecology, contraceptives, pharmaceutical chemistry.

SUBSTANCE: invention proposes vaginal suppository comprising benzalconium chloride, benzoic acid, purified water and the preparation vitespol taken in the definite content of components. Invention provides the reliable inhibition of fungal microflora being especially against fungus Candida albicans and the absence of irritation and symptoms in vagina drying. Invention can be used as an individual agent for prophylaxis of undesirable pregnancy.

EFFECT: valuable properties of suppository.

5 tbl

The invention relates to medicine, in particular to hormonal tools, and comes with contraceptive activity gestagen-estrogenic composition

The invention relates to medicine, in particular to the gynecologist, and can be used to hold a contraceptive or hormone replacement therapy in women

The invention relates to a device for the delivery of therapeutically active agent from the controlled release, especially progestin or estrogen over an extended period of time, and above the device consists of a core containing a therapeutically active agent, and a membrane covering above the core, in which the above membrane made of elastomer

The invention relates to medicine, in particular to the gynecologist, and for hormonal contraception

The invention relates to medicine, namely to transdermal devices for the introduction of inhibiting ovulation 17-diacetylmorphine

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: method involves addition sugar-alcohol and/or saccharide showing melting point by 5°C lower or above as compared with the first mentioned sugar-alcohol and/or saccharide to sugar-alcohol and/or saccharide followed by combined treatment of prepared powder by pressing and heating. Invention allows preparing medicinal compositions decomposing in mouth cavity rapidly being without water and showing light using owing to the presence of sufficient strength in preparing, transport in usual using. Method involves mixing, pressing and heating components that represent two or more sugar-alcohol and/or saccharide and active component wherein difference between melting points of one among two or more indicated sugar-alcohol and/or saccharide that shows the higher content and any remaining indicated two or more sugar-alcohol and/or saccharide is 5°C or above. Invention provides preparing strength rapidly soluble tablets.

EFFECT: improved preparing method, improved pharmaceutical properties of composition.

30 cl, 12 tbl, 28 ex

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