Pharmaceutical composition for preventing or treating viral perivaginal diseases

Abstract

The purpose of the present invention is to provide a pharmaceutical composition for preventing and / or treating a viral disease in the vaginal or perivaginal area. The present invention provides a pharmaceutical composition for preventing or treating a disease caused by a pathogenic virus in the vaginal or perivaginal area, said pharmaceutical composition comprising, as an active ingredient, a compound selected from the group consisting of an aniline derivative represented by general formula (I) [wherein W represents S or O], a pharmaceutically acceptable salt thereof and a solvate of the same. This pharmaceutical composition, which is in the form of a vaginal insert (e.g., a vaginal tablet, a vaginal capsule or a vaginal suppository) containing a granular formulation comprising core particles, said core particles containing the aforesaid compound, needle- and / or nearly column-shaped crystalline cellulose, a pharmaceutically acceptable additive in a nearly spherical form and a nonionic surfactant, and a coating layer coating the core particles, is characterized in that, in the core particles, voids are present between the crystalline cellulose and the additive.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for the prevention and / or treatment of viral peri-vaginal diseases. [Background technology]

[0002] Cervical cancer is one of the most common malignant lesions in women, and its treatment and early detection are desired worldwide. Cervical cancer accounts for approximately 70% of uterine cancers and approximately 20% of all gynecological cancers, making it an important disease target. Cervical cancer affects 500,000 people worldwide and approximately 10,000 people in Japan every year, and the number of patients is increasing.

[0003] It is known that most cervical cancers are caused by infection with the human papillomavirus (HPV). Of the 100 types of HPV, 14 main types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are called high-risk types, and HPV16 and 18 in particular are known to be most closely related to the induction of cervical cancer.

[0004] HPV is a common virus that infects both men and women, and is often transmitted through sexual intercourse. However, even in cases of infection with high-risk HPV, in many cases (approximately 90%) the infection disappears naturally due to the host's immune system. However, in approximately 10% of people, HPV infection persists, and some of these people who do not heal naturally will develop precancerous lesions called dysplasia and progress to cervical cancer over a period of several to 10 years.

[0005] Cervical dysplasia is a precursor to cervical cancer (precancerous lesion) and is also called cervical intraepithelial neoplasia (CIN). In recent years, in Japan, the incidence of cervical cancer and cervical dysplasia has rapidly increased among women in their 20s and 30s. Cervical dysplasia is classified into three types according to the severity of the lesion: mild dysplasia (CIN1), moderate dysplasia (CIN2), and severe dysplasia / carcinoma in situ (CIN3). In addition, cervical dysplasia is classified into LSIL (mild abnormality) and HSIL (moderate to severe abnormality) according to the Bethesda classification based on vaginal cytology. It is known that squamous cell lesions of the cervix progress in stages from mild dysplasia, moderate dysplasia, severe dysplasia / carcinoma in situ, microinvasive squamous cell carcinoma, to invasive carcinoma. Cervical dysplasia often shows no symptoms and is often discovered through cervical cancer screening (cytology), so early treatment is important. It has been reported that the detection rate of high-risk HPV is about 60% for mild squamous dysplasia, about 85% for moderate dysplasia, about 90% for severe dysplasia / intraepithelial carcinoma, and almost 100% for squamous cell carcinoma.

[0006] Cervical dysplasia is primarily diagnosed by methods known as cytology, colposcopy, and histology. Cytology is the primary test in cervical cancer screening, and if abnormalities are found in the cytology test, colposcopy and histology are performed as secondary (more detailed) tests. With current diagnoses, mild dysplasia (CIN1) and moderate dysplasia (CIN2) are often followed up rather than immediately treated. This is because in about half of patients, the condition will heal naturally (regress) without treatment, while the current surgical treatments are very invasive and burdensome to the patient.

[0007] Surgical treatment is chosen for cases of severe dysplasia / carcinoma in situ (CIN3) or cases where the CIN2 condition persists for a long period of time. A typical surgical treatment is conization, in which the cervix (entrance) is excised in a cone shape. This surgery is sometimes performed not only for CIN3, but also for microinvasive squamous cell carcinoma (stage Ia1). In particular, this surgery is the first choice for patients who wish to become pregnant (preserve the uterus), but for patients who do not need to preserve the uterus, a total hysterectomy may be chosen.

[0008] In addition, although cytology suggests moderate / severe dysplasia or intraepithelial carcinoma or higher, there are cases where a definitive diagnosis is difficult to make with colposcopy or tissue biopsy, and particularly in elderly patients, there are many cases where cytology suggests invasive cancer, but colposcopy and endocervical curettage reveal no lesions. In such cases, cervical conization is necessary for diagnostic purposes.

[0009] Currently, there is no effective drug therapy for cervical dysplasia and intraepithelial neoplasia. On the other hand, although the HPV vaccine is effective in preventing HPV infection, it is not effective in treating dysplasia or cancer. For this reason, there is a strong demand for therapeutic drugs for cervical dysplasia and intraepithelial neoplasia.

[0010] Genital warts are a sexually transmitted disease caused by the human papillomavirus. Both men and women can be infected, and in Japan, it is reported that several dozen people per 100,000 are infected. In women, they develop in the vagina, vaginal vestibule, labia majora and minora, cervix, anus, and surrounding areas. Even if they do develop, they often heal naturally. The human papillomaviruses that cause genital warts are mainly HPV6 and 11, which are types of viruses with a low risk of causing cancer. However, malignant types of viruses such as HPV16 and 18, which have a high risk of causing cervical cancer, can also be infected at the same time. In women, when genital warts develop on the vulva, they may also be infected with malignant types of HPV that can cause uterine cancer.

[0011] Genital herpes is caused by infection with the herpes simplex virus, which develops on the genitals or around them. In women, lesions are seen on the vulva, vagina, and cervix. Genital herpes can occur as a result of initial infection caused by an external virus, or as a result of reactivation of a virus that is latent in the sacral ganglion.

[0012] It is known that aniline derivatives, such as the CDK9 inhibitor N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinthioamide, can be used as antiviral agents that suppress virus production (e.g., Non-Patent Documents 1 to 4).

[0013] However, since the above compounds have low solubility in water, it is difficult for the inhibitor contained in the formulation to dissolve in an effective amount and exhibit sufficient efficacy. In general, as a formulation that can contain a therapeutically effective amount of a poorly water-soluble drug, a capsule containing a liquid containing an organic solvent has been proposed as a drug with improved oral absorbability (e.g., Patent Document 1). However, due to its nature, capsules containing a liquid have the problem that they are prone to leak depending on the manufacturing method. In addition, as a vaginal insert, it is not preferable to use a form that causes irritating substances such as organic solvents to diffuse in the vagina. Furthermore, as a vaginal insert, it is preferable to use a solid preparation rather than a liquid.

[0014] In addition, poorly water-soluble drugs tend to have poor absorption and low bioavailability due to their low solubility in water. The above compounds are also highly soluble in organic solvents such as methanol, ethanol, ethyl acetate, and acetone, but are almost insoluble in water. Drug preparations containing granules in which a drug and a solubilizing substance are combined and formulated have been proposed, and it has been reported that a surfactant can be used as the solubilizing substance and that the granules can be coated (e.g., Patent Document 2). However, since surfactants have adhesive and cohesive properties and reduce the fluidity of powders and granules, there is a problem that the amount of surfactant used in the preparation of pharmaceutical preparations such as tablets is limited. Thus, it is difficult to prepare a vaginal insert that contains the above compounds, which are poorly water-soluble drugs, in a therapeutically effective amount and can provide sufficient absorption to the living body. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] Special Publication No. 2003-508386 [Patent Document 2] Special Publication No. 2007-517062 [Non-patent literature]

[0016] [Non-Patent Document 1] Ajiro et. al., Clin Cancer Res. 2018 Sep 15;24(18):4518-4528. doi: 10.1158 / 1078-0432.CCR-17-3119. Epub 2018 Apr 30 [Non-Patent Document 2] Tanaka et. al., Antiviral Res. 2016 Sep;133:156-64. doi: 10.1016 / j.antiviral.2016.08.008. Epub 2016 Aug 8 [Non-Patent Document 3] Okamoto et. al., Antiviral Res. 2015 Nov;123:1-4. doi: 10.1016 / j.antiviral.2015.08.012. Epub 2015 Aug 21 [Non-Patent Document 4] Yamamoto et. al., J Clin Invest. 2014 Aug;124(8):3479-88. doi: 10.1172 / JCI73805. Epub 2014 Jul 8 Summary of the Invention [Problem to be solved by the invention]

[0017] The object of the present invention is to provide a pharmaceutical composition for preventing and / or treating viral intravaginal or peri-vaginal diseases, particularly cervical cancer, cervical intraepithelial neoplasia, or genital warts, which are diseases caused by human papillomavirus and occur in the peri-vaginal area. [Means for solving the problem]

[0018] The present inventors have succeeded in producing a vaginal tablet containing the following compound having antiviral activity against human papillomavirus and herpes simplex, which exhibits good stability, dissolution, and bioabsorbability of the compound, and have completed the present invention.

[0019] [ka] The present invention includes the following: [1] The following general formula (I)

[0020] [ka] [Wherein, W represents S or O] or a hydrate thereof, wherein the compound is selected from the group consisting of an aniline derivative represented by the formula (I): The pharmaceutical composition is a pharmaceutical composition in the form of a vaginal insert (e.g., vaginal tablet, vaginal capsule, or vaginal suppository) containing a granular preparation comprising a core particle containing the compound, needle-shaped and / or roughly columnar crystalline cellulose, a pharma- ceutically acceptable roughly spherical additive, and a nonionic surfactant, and a coating layer coating the core particle, A pharmaceutical composition, wherein the core particle has a void between the crystalline cellulose and the additive. [2] The compound is represented by the following formula (Ia)

[0021] [ka] or a hydrate thereof. [3] The pharmaceutical composition according to [1] or [2] above, wherein at least a portion of the compound and at least a portion of the nonionic surfactant are retained in the voids of the core particle. [4] The pharmaceutical composition according to any one of the above [1] to [3], wherein the nonionic surfactant is contained in an amount not more than twice that of the compound. [5] The pharmaceutical composition according to any one of the above [1] to [3], wherein the nonionic surfactant is contained in an amount 1.5-fold or less relative to the compound. [6] The pharmaceutical composition according to any one of the above [1] to [5], wherein the nonionic surfactant is contained in an amount of 1.5% by weight or more and less than 10% by weight, based on the total amount of the pharmaceutical composition. [7] The pharmaceutical composition according to any one of the above [1] to [5], wherein the nonionic surfactant is contained in an amount of 7 to 8% by weight based on the total amount of the pharmaceutical composition. [8] The pharmaceutical composition according to any one of the above [1] to [3], wherein the nonionic surfactant is contained in an amount of 1.5% by weight or more and less than 10% by weight based on the total amount of the pharmaceutical composition, and in an amount of 1.5 times or less than the amount of the compound. [9] The pharmaceutical composition according to any one of the above [1] to [8], wherein the nonionic surfactant is a polysorbate.

[10] The pharmaceutical composition according to any one of the above [1] to [9], wherein the pathogenic virus is human papillomavirus or herpes simplex virus.

[11] The pharmaceutical composition according to any one of the above [1] to [9], wherein the disease is cervical cancer or cervical intraepithelial neoplasia.

[12] The pharmaceutical composition according to

[11] above, wherein the disease is at least one disease selected from the group consisting of diseases diagnosed as LSIL, ASC-US, ASC-H, or HSIL according to the Bethesda classification, and diseases diagnosed as mild dysplastic cervical intraepithelial neoplasia (CIN1), moderate dysplastic cervical intraepithelial neoplasia (CIN2), or severe dysplastic cervical intraepithelial neoplasia (CIN3).

[13] The pharmaceutical composition according to any one of the above [1] to [9], wherein the disease is genital warts.

[14] The pharmaceutical composition according to any one of the above-mentioned [1] to

[13] , wherein the vaginal insert is in the form of a vaginal tablet.

[15] The pharmaceutical composition according to the above

[14] , which is a vaginal tablet containing the compound in a dose of 10 mg to 50 mg.

[16] The pharmaceutical composition according to any one of the above [1] to

[15] , wherein the compound is administered to a patient at a dose of 10 mg to 50 mg per day.

[17] The pharmaceutical composition according to any one of the above [1] to

[16] , wherein the compound is administered to a patient at a dose of 10 mg to 50 mg per day for 1 to 5 weeks.

[18] The following general formula (I)

[0022] [ka] [Wherein, W represents S or O] or a hydrate thereof, the pharmaceutical composition for treating or preventing a disease caused in the vagina or around the vagina by a pathogenic virus, comprising as an active ingredient an aniline derivative represented by the following formula (I): (a) a step of mixing a core particle raw material containing crystalline cellulose having a needle-like and / or substantially cylindrical shape and a pharma- ceutically acceptable substantially spherical additive to obtain a core particle mixture; (b) dissolving or suspending the compound in a mixture of a nonionic surfactant and a solvent to obtain a mixture; (c) contacting the core particle mixture obtained in step (a) with the mixed liquid obtained in step (b) to obtain core particles containing the compound, the acicular and / or roughly cylindrical crystalline cellulose, the roughly spherical additive, and the nonionic surfactant; (d) coating the core particles obtained in step (c) to obtain a granular preparation comprising the core particles having voids formed between the microcrystalline cellulose and the substantially spherical additive and a coating layer coating the core particles; and (e) processing the obtained granular preparation to obtain a vaginal insert in the form of any one of vaginal tablets, vaginal suppositories, or vaginal capsules; A manufacturing method comprising:

[19] The compound is represented by the following formula (Ia)

[0023] [ka] or a hydrate thereof.

[20] The manufacturing method described in

[18] or

[19] above, wherein at least a portion of the compound and at least a portion of the nonionic surfactant are retained in voids formed in the core particles.

[21] The method according to any one of the above

[18] to

[20] , wherein the step (e) is a step of compressing a granular preparation to obtain a vaginal tablet.

[22] The method according to any one of the above

[18] to

[21] , wherein in the step (b), the nonionic surfactant is mixed in an amount that is not more than twice that of the compound.

[23] The method according to any one of the above

[18] to

[21] , wherein in the step (b), the nonionic surfactant is mixed in an amount 1.5 times or less relative to the compound.

[24] The method for producing a pharmaceutical composition according to any one of

[18] to

[23] above, wherein the nonionic surfactant is contained in an amount of 1.5% by weight or more and less than 10% by weight based on the total weight of the pharmaceutical composition.

[25] The method for producing a pharmaceutical composition according to any one of the above

[18] to

[23] , wherein the nonionic surfactant is contained in an amount of 7 to 8% by weight based on the total amount of the pharmaceutical composition.

[26] The method according to any one of the above

[18] to

[25] , wherein the nonionic surfactant is a polysorbate.

[27] The method according to any one of

[18] to

[26] above, wherein the pathogenic virus is human papillomavirus or herpes simplex virus.

[28] The method according to any one of

[18] to

[26] above, wherein the disease is cervical cancer or cervical intraepithelial neoplasia.

[29] The method for producing a pharmaceutical composition according to any one of

[18] to

[26] above, wherein the disease is genital warts. Effect of the Invention

[0024] The pharmaceutical composition of the present invention, which is a vaginal insert, can contain a sufficient amount of the active ingredient of the present invention, and even in this case, the active ingredient, the compound, is stably retained, and when inserted into the vagina, the active ingredient is dissolved out well. Due to such characteristics, the pharmaceutical composition of the present invention shows good bioabsorbability. [Brief description of the drawings]

[0025] [Figure 1] Fig. 1 is a schematic diagram of the internal structure of a granular preparation contained in the pharmaceutical composition of the present invention. The active ingredient, as well as a core particle component 1 having a needle-like and / or roughly cylindrical shape and a core particle component 2 having a roughly spherical shape are contained in the core particle. [Diagram 2] This shows the results of confirming the dissolution of an active ingredient from a vaginal tablet, which is a pharmaceutical composition of the present invention. [Diagram 3] This shows the results of confirming the dissolution of an active ingredient from a vaginal tablet, which is a pharmaceutical composition of the present invention. [Figure 4] This shows the results of confirming the stability of the active ingredient in a vaginal tablet, which is a pharmaceutical composition of the present invention. [Diagram 5] This shows the results of confirming the stability of the active ingredient of the pharmaceutical composition of the present invention against a surfactant. [Figure 6] The results show that a vaginal tablet, which is the pharmaceutical composition of the present invention, was administered once to rats, and its transfer to plasma and each tissue was confirmed. [Figure 7] The results show that a vaginal tablet, which is the pharmaceutical composition of the present invention, was repeatedly administered to rats, and its transfer to plasma and each tissue was confirmed. [Figure 8] The results are obtained by administering a vaginal tablet, which is the pharmaceutical composition of the present invention, to humans and confirming its transfer into the blood. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention will be described below with exemplary embodiments as examples, together with preferred methods and materials that can be used in the practice of the present invention, but the present invention is not limited to the embodiments described below. Unless otherwise specified in the text, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In addition, any materials and methods equivalent or similar to those described in this specification can be used in the practice of the present invention. In addition, all publications and patents cited in this specification in relation to the present invention are cited in this specification and constitute a part of this specification, for example, as showing methods, materials, etc. that can be used in the present invention.

[0027] In this specification, the description of "A to B" indicating a numerical range means a numerical range including the endpoints A and B. The same applies to "A to B." In addition, in this specification, "about" is used to mean an allowance of ±10%.

[0028] The pharmaceutical composition of the present invention can be used for treating or preventing diseases caused by pathogenic viruses in the vagina or surrounding area. Pathogenic viruses are viruses that cause diseases in the vagina or surrounding area, such as human papillomavirus and herpes simplex virus.

[0029] As used herein, the term inside or around the vagina is used to mean the vagina, vaginal cavity and opening, uterus, uterine body, endometrium and cervix, and vulva (labia majora, labia minora, perineal lips, and urethral opening).

[0030] Diseases occurring in the vagina or around the vagina include, but are not limited to, cervical cancer, diseases diagnosed as LSIL, ASC-US, ASC-H, or HSIL according to the Bethesda classification, mild dysplasia cervical intraepithelial neoplasia (CIN1), moderate dysplasia cervical intraepithelial neoplasia (CIN2), severe dysplasia cervical intraepithelial neoplasia (CIN3), genital warts, and genital herpes. In general, LSIL, ASC-US, ASC-H, or HSIL according to the Bethesda classification is diagnosed by vaginal cytology, and CIN1 to CIN3 is diagnosed by vaginal tissue biopsy.

[0031] (Active ingredient of the present invention) The active ingredient of the pharmaceutical composition of the present invention is represented by the following general formula (I):

[0032] [ka] [Wherein, W represents S or O] or a pharma- ceutical acceptable salt thereof, or a hydrate thereof (in this specification, it may be referred to as "an active ingredient of the pharmaceutical composition of the present invention", "an active ingredient of the present invention", "a compound of the pharmaceutical composition of the present invention" or "a compound used in the present invention", and when it is clear from the context, it may be referred to simply as "an active ingredient").

[0033] A specific example of the drug represented by the general formula (I) is N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinthioamide represented by the following formula (Ia).

[0034] [ka]

[0035] The active ingredient of the present invention exhibits antiviral activity against pathogenic viruses. Examples of viruses against which the active ingredient of the present invention exhibits antiviral activity include, but are not limited to, human papillomavirus and herpes simplex virus. Human papillomaviruses include HPV16 and 18, etc., which are known to cause cervical cancer, and HPV6 and 11, etc., which are known to cause genital warts, and the active ingredient of the present invention exhibits effective antiviral activity against these viruses (e.g., Non-Patent Citations 1 to 4).

[0036] The pharmaceutical composition of the present invention may contain other drugs in addition to the above-mentioned active ingredients. Examples of other drugs include antiviral agents, anti-inflammatory agents, antibacterial agents, and antifungal agents. Examples of antiviral agents include acyclovir. Examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of antibacterial agents include metronidazole and clindamycin. Examples of antifungal agents include fluconazole and itraconazole.

[0037] The amount of the above-mentioned active ingredient in the pharmaceutical composition of the present invention is not particularly limited as long as the pharmaceutical composition of the present invention exerts the desired effect; however, in the treatment and / or prevention of diseases caused by human papillomavirus, for example, the lower limit may be 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg, and the upper limit may be 1000 mg, 800 mg, 600 mg, 500 mg, 400 mg, 300 mg, 200 mg, or 100 mg, per tablet; and in the treatment and / or prevention of diseases caused by herpes simplex, for example, the lower limit may be 2 mg, 5 mg, or 10 mg, and the upper limit may be 200 mg, 100 mg, or 80 mg, per tablet.

[0038] (Nonionic surfactant) The pharmaceutical composition of the present invention contains a nonionic surfactant. The nonionic surfactant is not particularly limited as long as it is pharma- ceutically acceptable and does not have a significant effect on the stability and dissolution of the active ingredient contained in the pharmaceutical composition of the present invention. Examples of the nonionic surfactant include alkyl polyoxyethylene ether, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, etc., more preferably polysorbate, and even more preferably polysorbate 80. These surfactants may be used alone or in combination of two or more. In addition, these surfactants may be dissolved in, for example, water, alcohol, etc., in the manufacturing process of the pharmaceutical composition of the present invention so as to be contained in the pharmaceutical composition of the present invention.

[0039] The amount of nonionic surfactant in the pharmaceutical composition of the present invention is not particularly limited as long as it does not interfere with the use of the pharmaceutical composition as a vaginal insert that exhibits antiviral activity, which is the object of the present invention, but is contained in an amount of 1.5% by weight or more and less than 10% by weight based on the total amount of the pharmaceutical composition. If the content of surfactant is more than 10% by weight, the moldability and granulation property are deteriorated, making it difficult to manufacture it as a vaginal insert (in the form of vaginal tablet, vaginal capsule, or vaginal suppository). In addition, if the content of surfactant is less than 1.5% by weight, the active ingredient may not be sufficiently dissolved from the pharmaceutical composition containing the therapeutically effective amount of the active ingredient. The content of the surfactant is determined taking into consideration the amount of the active ingredient of the present invention contained in the pharmaceutical composition, and the lower limit of the total amount of the pharmaceutical composition can be 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, 5.0% by weight, 5.5% by weight, 6.0% by weight, 6.5% by weight, or 7.0% by weight, and the upper limit of the total amount of the pharmaceutical composition can be 10.0% by weight, 9.5% by weight, 9.0% by weight, 8.5% by weight, or 8.0% by weight. The content of the surfactant is preferably 6 to 9% by weight, more preferably 7 to 9% by weight, and even more preferably 7 to 8% by weight, based on the total amount of the pharmaceutical composition.

[0040] In the pharmaceutical composition of the present invention, the amount of the nonionic surfactant relative to the active ingredient of the present invention is not particularly limited as long as the object of the present invention is achieved, but it is preferable that the amount is 2 times or less relative to the active ingredient. If the amount of the surfactant is 2 times or less relative to the active ingredient, the active ingredient can be stably stored, and the decomposition products derived therefrom can be ignored. In addition, the lower limit of the amount of the surfactant relative to the active ingredient is not particularly limited as long as the active ingredient is sufficiently eluted, but for example, it can be at least 0.4 times relative to the active ingredient. In the pharmaceutical composition of the present invention, the surfactant is contained in an amount of 0.4 times, 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, or 1.0 times as the lower limit, and 2.0 times, 1.9 times, 1.8 times, 1.7 times, 1.6 times, 1.5 times, 1.4 times, or 1.3 times as the upper limit relative to the active ingredient. The content of the surfactant is preferably 1.0 to 1.7 times, more preferably 1.0 to 1.6 times, even more preferably 1.0 to 1.5 times, still more preferably 1.0 to 1.4 times, and most preferably about 1.2 times, the amount of the active ingredient.

[0041] Pharmaceutical Composition The pharmaceutical composition of the present invention is in the form of a vaginal insert to be inserted into the vagina. Examples of vaginal inserts include vaginal tablets, vaginal capsules, and vaginal suppositories, and vaginal tablets are preferred. The vaginal insert, which is the pharmaceutical composition of the present invention, includes a granular preparation comprising a core particle and a coating layer that covers the core particle. The core particle includes the active ingredient, crystalline cellulose having a needle-like and / or approximately columnar shape, a pharma-ceutically acceptable approximately spherical additive, and a nonionic surfactant. The granular preparation comprising a core particle and a coating layer that covers the core particle used in the present invention (herein, it may be referred to as "the granular preparation used in the present invention" or "the granular preparation of the present invention", or, if clear from the context, it may be simply referred to as "the granular preparation") has good fluidity. Therefore, the granular preparation can be made into a vaginal tablet by tableting or molding, encapsulated into a vaginal capsule, or made into a vaginal suppository by tableting or molding. In preparing the vaginal insert of the present invention, the molding is preferably compression molding, and the encapsulation is preferably compression encapsulation.

[0042] (Needle-shaped and / or roughly columnar shaped crystalline cellulose) The needle-shaped and / or roughly columnar crystalline cellulose contained in the pharmaceutical composition of the present invention (sometimes simply referred to as "needle-shaped crystalline cellulose" in this specification) has a needle-shaped or roughly columnar shape. Needle-shaped crystalline cellulose is a type of crystalline cellulose used as an additive in the preparation of pharmaceutical preparations, which has a needle-shaped or roughly columnar shape. By producing the pharmaceutical composition of the present invention using pharma- ceutically acceptable crystalline cellulose as a raw material, which mainly contains needle-shaped or roughly columnar crystals, the needle-shaped crystalline cellulose can be contained in the pharmaceutical composition of the present invention, more specifically, in the granular preparation of the present invention contained in the pharmaceutical composition. The crystalline cellulose used as a raw material may be any crystalline cellulose that can provide a sufficient proportion of needle-shaped and / or roughly columnar crystals to achieve the effects of the present invention when made into the pharmaceutical composition of the present invention. In the crystalline cellulose raw material that provides the needle-shaped crystalline cellulose contained in the pharmaceutical composition of the present invention, the proportion of crystals having a needle-like and / or roughly columnar shape is not particularly limited, but the lower limit is, for example, 60%, 65%, 70%, 75%, or 80%, and the upper limit is, for example, 100%, 98%, or 95%, based on the total number of crystals (particles). The number of crystals (particles) having a needle-like and / or roughly columnar shape is preferably 60 to 100%, more preferably 70 to 100%, and even more preferably 80 to 100% of the total. In the present specification, "needle-like or roughly columnar crystalline cellulose" refers to crystalline cellulose that has a significant difference in length and width in the cross section of the long axis direction of crystalline cellulose on an image (shape transferred to a flat surface) measured by an electron microscope. Here, the significant difference in length and width can be expressed, for example, by aspect ratio.

[0043] The aspect ratio of crystalline cellulose is not particularly limited as long as the effects of the present invention are achieved, but the lower limit is, for example, preferably 1.8, more preferably 2.2, and even more preferably 2.5, and the upper limit can be, for example, 10, 9, or 8. The average aspect ratio of needle-shaped crystalline cellulose is not particularly limited, but is preferably 1.8 to 10, more preferably 2.2 to 10, and even more preferably 2.5 to 10. In addition, in the case of the crystalline cellulose raw material that provides the needle-shaped crystalline cellulose contained in the pharmaceutical composition of the present invention, one having an average aspect ratio of crystals in the range of 1.7 to 10, particularly 2.0 to 10, is preferably used in the production of the pharmaceutical composition of the present invention.

[0044] The particle size of the crystalline cellulose raw material that provides the needle-shaped crystalline cellulose is not particularly limited as long as the effects of the present invention are achieved, but the average particle size (D50) is preferably 50 to 200 μm, more preferably 60 to 150 μm, and even more preferably 70 to 100 μm. The particle size and average particle size of the particles are measured, for example, by a laser diffraction method (measurement method: dry, scattering intensity: 1% or more, light scattering model: Mie scattering theory) using a commercially available particle size distribution meter (e.g., Mastersizer3000, manufactured by Spectris).

[0045] The content of the crystalline cellulose raw material that provides the needle-shaped crystalline cellulose in the entire pharmaceutical composition is not particularly limited as long as the effect of the present invention is achieved, but the lower limit is preferably 2% by weight, more preferably 3% by weight, and even more preferably 5% by weight, relative to the total mass of the pharmaceutical composition, while the upper limit is preferably 30% by weight, more preferably 20% by weight, but is appropriately selected according to the content of the needle-shaped crystalline cellulose in the crystalline cellulose raw material, the type and amount of other additives added to the pharmaceutical composition, and the desired properties of the pharmaceutical composition. The content of the crystalline cellulose raw material that provides the needle-shaped crystalline cellulose in the pharmaceutical composition is not particularly limited as long as the effect of the present invention is achieved, but the lower limit is preferably 5% by weight, more preferably 10% by weight, and the upper limit is preferably 50% by weight, more preferably 40% by weight, relative to the total mass of the granular formulation, while the content of the needle-shaped crystalline cellulose in the crystalline cellulose raw material, the type and amount of other additives added, and the desired properties of the pharmaceutical composition.

[0046] (Nearly spherical additive) The pharma- ceutically acceptable substantially spherical additive used in the pharmaceutical composition of the present invention (sometimes referred to as "substantially spherical additive" in this specification) is an additive that can be used in the field of pharmaceuticals and is substantially spherical. Here, substantially spherical (substantially spherical additive) means that the component is mainly composed of particles having a substantially spherical shape, and for example, the additive contains substantially spherical particles in an amount of 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and most preferably almost 100%. In this specification, "substantially spherical" refers to a shape in which there is no significant difference in length and width on an image (shape transferred to a flat surface) measured by an electron microscope. Therefore, in this specification, "substantially spherical" is used to mean a shape close to a sphere, as well as an ellipsoid, a polyhedron (including a cube), and a polyhedron with rounded corners. Therefore, "approximately spherical" does not necessarily mean that the image measured by an electron microscope is an exact sphere, but may be, for example, a distorted sphere, an ellipsoid, a polyhedron (including a cube), or a polyhedron with rounded corners.

[0047] Considering the nearly spherical shape in terms of the aspect ratio, for example, the upper limit can be 1.7, 1.6, 1.5, 1.4, 1.3, or 1.2, although this is not intended to be limiting. Therefore, the average aspect ratio of the nearly spherical additive in the core particle contained in the pharmaceutical composition of the present invention is preferably 1.0 to 1.6, more preferably 1.0 to 1.5, even more preferably 1.0 to 1.3, and even more preferably 1.0 to 1.2.

[0048] The particle size of the raw material that provides the roughly spherical additive in the core particle contained in the pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are achieved, but the average particle size (D50) is preferably 1 to 300 μm, more preferably 5 to 200 μm, and even more preferably 10 to 150 μm. The particle size and average particle size of the particles are measured, for example, by a laser diffraction method (measurement method: dry, scattering intensity: 1% or more, light scattering model: Mie scattering theory) using a commercially available particle size distribution meter (e.g., Mastersizer3000, manufactured by Spectris).

[0049] For example, by producing the pharmaceutical composition of the present invention using an approximately spherical additive having the above average aspect ratio as a raw material, the approximately spherical additive can be contained in the granular formulation contained in the pharmaceutical composition of the present invention. The content of the approximately spherical additive in the entire pharmaceutical composition is not particularly limited as long as the effect of the present invention is exhibited, but the lower limit is preferably 10% by weight, more preferably 15% by weight, and the upper limit is preferably 50% by weight, more preferably 40% by weight, relative to the total mass of the pharmaceutical composition, and is appropriately selected depending on the type and amount of other additives added to the pharmaceutical composition and the desired properties of the pharmaceutical composition. The content of the approximately spherical additive in the granular formulation contained in the pharmaceutical composition is preferably 30% by weight, more preferably 35% by weight, and the upper limit is preferably 90% by weight, more preferably 80% by weight, relative to the total mass of the granular formulation, and is appropriately selected depending on the type and amount of other additives added and the desired properties of the pharmaceutical composition.

[0050] The substantially spherical additive may be a single component, or a combination of two or more components, but preferably a combination of two or more components with different average particle sizes. When the substantially spherical additive is composed of two components, it is preferable that the average particle sizes of the components are different. The lower limit of the ratio of the average particle sizes of the two different components is not particularly limited, but can be, for example, 1.2, 1.3, 1.4, 1.5, or 2, and the upper limit is not particularly limited, but can be, for example, 20, 15, 10, 5, 4, or 3. The ratio of the average particle sizes of the two different components is not particularly limited, but can be, for example, 1.2 to 20, preferably 1.3 to 10, more preferably 1.5 to 5, and even more preferably 2 to 3.

[0051] The roughly spherical additive is not particularly limited as long as it is a pharma- ceutically acceptable additive, and examples thereof include excipients, binders, disintegrants, lubricants, etc., and these additives can be used without limitation as long as they achieve the effects of the present invention. Preferably, the roughly spherical additive in the present invention is an additive classified as an excipient. Specifically, examples thereof include, but are not limited to, sugars (including sugars, sugar hydrates, sugar alcohols, etc.), inorganic compounds, etc.

[0052] Examples of sugars include, but are not limited to, monosaccharides such as glucose, disaccharides such as lactose and sucrose, and polysaccharides such as starch and cellulose. Examples of starches include potato starch, wheat starch, corn starch, rice starch, and the like. As sugars, corn starch is preferably used. Examples of sugar hydrates include, but are not limited to, any hydrate of the above-mentioned sugars, and lactose hydrate is preferably used. Examples of sugar alcohols include, but are not limited to, sugar alcohols derived from any sugar, and mannitol or sorbitol is preferably used. Examples of inorganic compounds include, but are not limited to, phosphates such as anhydrous calcium phosphate, and the like.

[0053] As the roughly spherical additive, preferably, disaccharides such as lactose, lactose hydrate and sucrose, corn starch, and potato starch can be mentioned.

[0054] In this specification, "aspect ratio" refers to the ratio of the long axis to the short axis of a particle contained in a component (long axis / short axis) in particle image analysis using an electron microscope, and "average aspect ratio" refers to the average aspect ratio of the remaining particles obtained by measuring the aspect ratios of 10 or more arbitrarily selected particles and excluding the aspect ratio values ​​of the particles in the top 10% and bottom 10% of aspect ratio values.

[0055] The total mass of the crystalline cellulose raw material and the roughly spherical additive that provide the needle-shaped crystalline cellulose is not particularly limited as long as the effects of the present invention are achieved, but the lower limit is, for example, 10% by weight, 20% by weight, 25% by weight, or 30% by weight, while the upper limit is, for example, 90% by weight, 80% by weight, 70% by weight, or 60% by weight, preferably 20 to 80% by weight, more preferably 30 to 70% by weight. The ratio of the roughly spherical additive to the crystalline cellulose raw material that provides the needle-shaped crystalline cellulose (mass ratio: roughly spherical additive / crystalline cellulose raw material) is not particularly limited as long as the effects of the present invention are achieved, but is, for example, 1 to 10 times, preferably 2 to 5 times.

[0056] (covering layer) The coating layer covers the core particles and can suppress the surfactant and drug contained in the core particles from leaking to the surface of the granular preparation of the present invention. As a result of the coating layer suppressing the leakage of the surfactant, the aggregation of the granular preparation is suppressed and the decrease in flowability is suppressed, allowing the vaginal tablet to be successfully produced.

[0057] The component constituting the coating layer is not particularly limited, but may be, for example, a water-soluble coating agent. The water-soluble coating agent may be used alone or in combination of two or more. According to one embodiment, the water-soluble coating agent preferably contains at least one component selected from polyalkylene glycol and polysaccharides or derivatives thereof.

[0058] The polysaccharide or its derivative is preferably a cellulose derivative, such as methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, etc. The cellulose derivative may be used alone or in combination of two or more. The polyalkylene glycol may be, for example, polyethylene glycol, etc.

[0059] According to one embodiment, the coating agent may be used in combination with a plasticizer. Examples of the plasticizer include acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, sorbitol, dextrin, diethyl phthalate, glycerin, polyalkylene glycol, polyethylene glycol monoethyl ether, propylene glycol, benzyl benzoate, purified water, sorbitol sorbitan solution, triacetin, tributyl citrate, triethyl citrate, and chlorobutanol. Among these plasticizers, polyalkylene glycol is preferably used, and polyethylene glycol (macrogol) is more preferably used. These plasticizers may be used alone or in combination of two or more.

[0060] The components constituting the coating layer may be used as they are, but may also be dissolved in water, alcohol, etc., as necessary.

[0061] The amount of the coating layer in the pharmaceutical composition of the present invention is not particularly limited as long as the granular preparation and pharmaceutical composition of the present invention exhibit the desired effects, but the lower limit, as a ratio to the total mass of the core particles to be coated (mass ratio: mass of coating layer / total mass of core particles), is, for example, 0.001, 0.002, 0.003 or 0.005, and the upper limit is, for example, 0.1, 0.05, 0.03 or 0.02, preferably 0.002 to 0.05, more preferably 0.005 to 0.05, and even more preferably 0.005 to 0.02. Furthermore, the ratio of the amount of components constituting the coating layer to the total mass of the pharmaceutical composition of the present invention (mass ratio: amount of coating layer components / total mass of pharmaceutical composition) has a lower limit of, for example, 0.0003, 0.001, or 0.002, and an upper limit of, for example, 0.05, 0.03, 0.02, or 0.01, and the ratio is preferably 0.001 to 0.03, more preferably 0.001 to 0.02, and even more preferably 0.002 to 0.01.

[0062] The particle size of the granular preparation of the present invention is not particularly limited, and the lower limit is, for example, 50 μm, 60 μm, 80 μm, or 100 μm, and the upper limit is, for example, 700 μm, 500 μm, 400 μm, or 300 μm. The average particle size (D50) is, for example, 100 to 400 μm, preferably 100 to 300 μm, and more preferably 120 to 250 μm. The average particle size of the granular preparation can be measured by the same method as the above-mentioned measurement method.

[0063] The pharmaceutical composition of the present invention has a coating layer that covers the core particles in the granular preparation, and therefore the surfactant and drug (active ingredient) contained in the core particles are prevented from leaking out of the granular preparation, and as a result, the aggregation of the granular preparation can be prevented, and the composition can be formulated as a vaginal insert. Although not limited thereto, since the aggregation of the granular preparation is prevented, molding, particularly compression molding, is possible when producing vaginal tablets and vaginal suppositories, and encapsulation, particularly compression encapsulation, is easy when producing vaginal capsules. Examples of vaginal capsules include hard capsules.

[0064] In the pharmaceutical composition of the present invention, many voids are formed between the acicular crystalline cellulose and the roughly spherical additive in the core particles in the granular preparation. FIG. 1 is a schematic diagram of this state. Therefore, the core particles have many voids, i.e., have a good porosity, and the nonionic surfactant and the active ingredient of the present invention can enter the voids. As a result, a pharmaceutical composition that holds a larger amount of the active ingredient of the present invention and the nonionic surfactant is provided. In addition, since the pharmaceutical composition of the present invention holds a larger amount of the active ingredient and the nonionic surfactant, when administered into the vagina, good migration to the tissues around the vagina can be achieved. This is also supported by the fact that migration into the blood is observed.

[0065] (Other Ingredients) The pharmaceutical composition of the present invention may contain pharma- ceutically acceptable additives other than the components contained in the core particles and the components constituting the coating layer that coats the core particles, as described above, as long as the effects of the present invention are not hindered. Examples of additives include excipients, disintegrants, release agents, separating agents, lubricants, binders, flow agents, stabilizers, adsorbents, glossing agents, wetting agents, wetting regulators, fillers, adhesion enhancers, thickeners, moisture-proofing agents, sweeteners, flavorings, and coloring agents. These additives may be ones that perform two or more functions. In addition, these additives may be used alone or in combination of two or more.

[0066] (Method of producing pharmaceutical composition) The pharmaceutical composition of the present invention can be prepared by the following steps. Step a: mixing a core particle raw material containing crystalline cellulose having a needle-like and / or substantially cylindrical shape and a pharma- ceutically acceptable substantially spherical additive to obtain a core particle mixture; Step b: dissolving or suspending the following compound in a mixture of a nonionic surfactant and a solvent to obtain a mixed solution; The following general formula (I)

[0067] [ka] [Wherein, W represents S or O] or a pharma- ceutically acceptable salt thereof, or a hydrate thereof; step c: contacting the core particle mixture obtained in step (a) with the mixed liquid obtained in step (b) to obtain core particles containing the compound, the acicular and / or roughly cylindrical crystalline cellulose, the roughly spherical additive, and the nonionic surfactant; Step d: coating the core particles obtained in step (c) to obtain a granular preparation having the core particles and a coating layer coating the core particles, in which voids are formed between the microcrystalline cellulose and the additive; and Step e: processing the obtained granular preparation to obtain a vaginal insert in the form of a vaginal tablet, a vaginal suppository, or a vaginal capsule;

[0068] The crystalline cellulose having a needle-like and / or roughly columnar shape that can be used in step (a) can be the same as that described for the pharmaceutical composition. Various crystalline celluloses have been reported or are commercially available as additives that can be added to pharmaceutical compositions, and among these, those that mainly contain crystals having a needle-like and / or roughly columnar shape can be used without limitation. For example, the ratio of the crystals having a needle-like and / or roughly columnar shape to the total number of crystals (particles) is, for example, 60%, 65%, 70%, 75%, or 80%, and the upper limit is, for example, 100%, 98%, or 95%. The number of crystals (particles) having a needle-like and / or roughly columnar shape is preferably 60 to 100%, more preferably 70 to 100%, and even more preferably 80 to 100% of the total. Examples of crystalline cellulose that contains a large amount of needle-like and / or roughly columnar crystals include, but are not limited to, products that contain a large amount of needle-like and / or roughly columnar crystals among crystalline cellulose that can be added to pharmaceuticals, such as Ceolus (registered trademark) (manufactured by Asahi Kasei Corporation).

[0069] The pharma- ceutically acceptable roughly spherical additives that can be used in step (a) can be those described for the pharmaceutical composition, including, but not limited to, disaccharides such as lactose, lactose hydrate, and sucrose, corn starch, and potato starch.

[0070] The nonionic surfactant that can be used in step (b) may be any of those described for the pharmaceutical composition, including, but not limited to, polysorbates, particularly polysorbate 80.

[0071] The solvent that can be used in step (b) is a solvent for dissolving or suspending poorly water-soluble substances that can be used in the production of pharmaceutical compositions, and can be exemplified by those that can fully dissolve or suspend the above-mentioned compounds. The solvent is preferably an organic solvent. In the pharmaceutical composition of the present invention, the solvent (particularly the organic solvent) added in the production process volatilizes in the drying process, so it can be used without any particular restrictions as long as the remaining substances do not cause problems. Examples of the solvent include, but are not limited to, methanol, ethanol, ethyl acetate, acetone, diethyl ether, etc., and preferably methanol, ethanol, or ethyl acetate, and particularly preferably methanol. These organic solvents volatilize in the drying process in the production method of the present invention, so they do not remain in the produced pharmaceutical composition, and the pharmaceutical composition of the present invention becomes a vaginal insert that does not contain them.

[0072] In this specification, dissolving or suspending the compound used in the present invention is used to mean a state in which the compound is partially dissolved and the other part is suspended, in addition to a state in which the compound is entirely dissolved or suspended.

[0073] In the above-mentioned manufacturing method, each step can be appropriately used with reference to a known method. The conditions for manufacturing the pharmaceutical composition can be appropriately adjusted with reference to a known method based on the type and amount of the components contained in the composition, the desired dosage form, and other factors. Specifically, but not limited to, the pharmaceutical composition of the present invention can be manufactured, for example, according to the following procedure. First, acicular and / or roughly columnar crystalline cellulose and at least one pharma-ceutically acceptable roughly spherical additive are mixed using a fluidized bed granulator (e.g., FD-MP-01D, manufactured by Powrex Corporation) to obtain a core particle mixture (primary particles). On the other hand, the active ingredient of the present invention is added to a nonionic surfactant and stirred using a stirrer (e.g., NZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) to obtain a mixture (drug liquid) in which the active ingredient is dissolved or suspended. Next, the obtained mixture and the mixture are brought into contact with each other using a fluidized bed granulator, and the mixture is attached to the core particles in the mixture to obtain core particles. Here, the mixture is contacted with the mixture by, for example, a method of spraying the mixture onto the mixture, a method of immersing the mixture in the mixture, or the like.

[0074] Next, the core particles are dried as necessary, and then coated with a component constituting the coating layer (coating layer component). Here, the core particles are coated, for example, by a method of spraying the coating layer component onto the core, or by a method of immersing the core particles in the coating layer component. Next, the particles having the core particles and the coating layer that coats the core particles are dried to obtain the granular preparation of the present invention. In the method for producing the pharmaceutical composition of the present invention, coating the core particles to obtain a granular preparation comprising a core particle having a void formed between the needle-shaped crystalline cellulose and the substantially spherical additive and a coating layer that coats it means, as described above, spraying the coating layer component onto the core particles, or immersing the core particles in the coating layer component, and then performing a drying step to obtain a granular preparation.

[0075] Next, the granular preparation is formulated into a dosage form of a vaginal insert (vaginal tablet, vaginal suppository, or vaginal capsule). Forming into a vaginal tablet can be performed, for example, by tableting. The method of tableting the granular preparation of the present invention is not particularly limited, and known methods can be used. The conditions for tableting are not particularly limited, and can be appropriately adjusted depending on the types of core particle components, surfactants, drugs, coating layer components, etc. Examples of methods for tableting the granular preparation include a method of tableting the preparation using a tableting machine such as a rotary tableting machine or a single-shot tableting machine. Of these, it is preferable to tablet the preparation using a rotary tableting machine. Examples of rotary tableting machines include VIRGO 0512SS2AY manufactured by Kikusui Seisakusho Co., Ltd. When the pharmaceutical composition in the form of a tablet contains a pharma- ceutical acceptable additive in addition to the granular preparation of the present invention, the granular preparation of the present invention and the pharma- ceutical acceptable additive are mixed in advance and then tableted. The method of mixing the granular preparation and the additive is not particularly limited, and can be performed using a known method. For example, the method of mixing the granular preparation and the additive can be a method of mixing using a mixer such as a V-type mixer. Specifically, it can be mixed using a V-type mixer (TCV-20) manufactured by Tokuju Co., Ltd.

[0076] The method of making the granular preparation of the present invention into a capsule is not particularly limited, and known methods can be used. Specifically, the granular preparation is produced by filling a capsule shell made of gelatin or a raw material derived from a plant. The filling into the capsule shell is not particularly limited, and can be carried out by known methods such as auger type powder filling, die compress type powder filling, and vibration type powder filling. For example, in the auger type powder filling, a granular pharmaceutical preparation is dropped from a hopper into a cap-shaped container, each of which is open at one end and is usually formed of a gelatin film, and then a predetermined amount of the granular pharmaceutical preparation is directly filled into the capsule body by the rotation pressure of the stirring blade and the auger, and then the containers are coaxially joined to produce a capsule.

[0077] The method of preparing the granular preparation of the present invention into a vaginal suppository is not particularly limited, and known methods can be used. Examples of bases for vaginal suppositories include, but are not limited to, cocoa butter, hard fat, macrogols such as PEG6000 (e.g., macrogol 6000), or a mixture of glycerin and gelatin. The suppository may further include a bioadhesive, such as a mucoadhesive, to promote adhesion and long-term contact of the composition to the mucosa, e.g., the vaginal epithelium. EXAMPLES

[0078] The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples.

[0079] Example 1: Antiviral activity of the active ingredient of the present invention The following compound, which is one of the active ingredients of the pharmaceutical composition of the present invention, has been reported to inhibit cyclin-dependent kinase (CDK) 9 and exhibit antiviral activity against viruses including human papillomavirus and herpes simplex virus (for example, Non-Patent Document 1 reports anti-human papillomavirus activity, Non-Patent Document 2 reports anti-HBV activity, Non-Patent Document 3 reports anti-HIV activity, and Non-Patent Document 4 reports anti-human herpes simplex virus activity, anti-human cytomegalovirus activity, and anti-human adenovirus activity).

[0080] [ka]

[0081] (Anti-human papillomavirus activity) Hela S3 cells (human cervical cancer cell line) carrying the genome of human papillomavirus type 18 were seeded on a plate, and after 24 hours of culture, the above-mentioned compound was added to a final concentration of 30 μM. After 3 days of culture, the cells were harvested to obtain mRNA and cell lysate. Using the obtained mRNA as a template, real-time RT-PCR was performed using HPV18 E6 primer or GAPDH primer to calculate the induction ratio of E6 gene expression rate. As a result, it was confirmed that the above-mentioned compound reduces the expression of E6 gene, that is, inhibits the transcription of the E6 gene of human papillomavirus, thereby inhibiting viral proliferation.

[0082] In addition, the cell lysate obtained above was developed by SDS-PAGE, and the expression of p53 was evaluated by Western blotting using an anti-p53 antibody. As a result, it was confirmed that the compound significantly increased the expression level of p53. This indicates that the compound reduces viral proteins and inhibits the degradation of cell cycle proteins through its activity of inhibiting the proliferation of papillomavirus, and is therefore effective in restoring normal cell function.

[0083] The above compounds have been reported to inhibit CDK9, which is essential for the expression of human papillomavirus. Based on the mechanism of action, they are also expected to have antiviral activity against other types of human papillomavirus, such as human papillomavirus 6 and 11.

[0084] (Anti-herpes simplex virus activity) The inhibitory effect on herpes simplex virus type 2 (HSV-2) proliferation was confirmed by plaque assay. Vero cells (African green monkey kidney cells) were seeded on a plate and incubated overnight. The day after cell seeding, the Vero cells were infected with HSV-2, and a cell culture medium containing the above compound was added and cultured for 24 hours. Then, a cell lysate was obtained. In order to measure the amount of HSV-2 contained in the obtained cell lysate, the obtained cell lysate was again infected into Vero cells for 1 hour and cultured in a cell culture medium containing γ-globulin for 48 hours. After 48 hours of culture, the cells were fixed and stained with crystal violet, and the cell morphology was observed under a phase contrast microscope, and the number of plaques derived from cell death due to HSV-2 infection was counted. As a result, it was confirmed that the above compound has an inhibitory effect on the proliferation of herpes simplex virus.

[0085] Example 2: Preparation of the pharmaceutical composition of the present invention The granular formulation of the present invention was prepared according to the manufacturing process shown below. (Step 1: Core particle mixture preparation step) Core particle raw materials including crystalline cellulose having a needle-like and / or roughly cylindrical shape (CEOLUS UF-702, average particle size 90 μm, manufactured by Asahi Kasei Corporation) and pharma- ceutically acceptable roughly spherical additives (lactose hydrate (SuperTab (registered trademark), average particle size 120 μm, manufactured by DFE Pharma) and corn starch (official corn starch, average particle size 15 μm, manufactured by Nihon Shokuhin Kako Co., Ltd.) were each sieved through a 355 μm sieve and placed in a bag to premix, and then the mixture was put into a fluidized bed granulator to produce a core particle mixture (primary particles). (Step 2: Drug mixture preparation step) The active ingredient, compound (Ia), was dissolved or suspended in a mixture of a nonionic surfactant (polysorbate 80) and a solvent (ethanol) to obtain a drug mixture. (Step 3: Core particle preparation step) Using a fluidized bed granulator, the drug mixture obtained in step (2) was sprayed onto the core particle mixture (primary particles) obtained in step (1) to obtain core particles having the drug liquid adhering to the primary particles. (Step 4: Final step of preparing granular formulation) Using a fluidized bed granulator, the coating layer solution was sprayed onto the core particles obtained in step (3) and dried at 60°C to obtain a granular preparation of the present invention in which the core particles were coated with the coating layer solution. Next, (Process 5: Tableting process) The granular preparation prepared by the above process was mixed with additives (excipient, flow agent, excipient, and lubricant in arbitrary amounts). The resulting mixture was compressed into a vaginal tablet, which is a vaginal insert.

[0086] (Preparation of vaginal tablets for small animals) Using the above manufacturing method, pharmaceutical compositions having the formulations shown in the following table were manufactured as vaginal tablets (each tablet weighing 80 mg) for testing using small animals.

[0087] [Table 1]

[0088] (Preparation of vaginal tablets for human administration) Using the above manufacturing method, pharmaceutical compositions having the formulations shown in the table below were produced as vaginal tablets (each tablet weighing 800 mg) for administration to humans.

[0089] [Table 2]

[0090] (Example 3) Dissolution test of active ingredient in vaginal tablet Vaginal tablets (each tablet weighing 800 mg) containing 50 mg of compound (Ia) and 20 mg (2.5% relative to the total vaginal tablet weight), 40 mg (5.0%), 60 mg (7.5%), or 80 mg (10%) of polysorbate 80 (PS80) were produced based on the formulation of the 50 mg tablet described in Example 2. In addition, vaginal tablets not containing polysorbate 80 were produced in the same manner as a control.

[0091] One vaginal tablet was placed in a φ20×50 mm (approximately 3 mL) stainless steel tube packed with glass beads (φapproximately 0.7 mm). Water was pumped into the stainless steel tube at 37°C and 0.007 mL / min, and samples were taken every 120 minutes to detect the eluted compounds. The results are shown in Figure 2. No elution of compounds was observed in tablets that did not contain polysorbate 80, while elution increased depending on the amount of polysorbate 80 in the tablets that contained polysorbate 80.

[0092] Next, the effect of the content of compound (Ia) in the vaginal tablet on dissolution was examined. Based on the formulation of the 50 mg tablet described in Example 2, vaginal tablets (800 mg per tablet) containing 60 mg of polysorbate 80 (PS80) and 10 mg, 25 mg, or 50 mg of compound (Ia) were manufactured. In accordance with the section on the dissolution test method of the Japanese Pharmacopoeia General Test Method, 700 mL of McIlvaine's buffer solution (pH 4.0) diluted as the test liquid was used, and the test was performed at 50 revolutions per minute by the paddle method. The results are shown in Figure 3. From the above results, it was confirmed that the incorporation of polysorbate 80 resulted in rapid dissolution of the compound.

[0093] Example 4: Stability test of active ingredient in vaginal tablet Based on the formulation of the 50 mg tablet described in Example 2, vaginal tablets (800 mg per tablet) were manufactured with a compound (Ia) content of 50 mg and a polysorbate 80 (PS80) content of 20 mg (2.5% relative to the total vaginal tablet weight), 60 mg (7.5%), or 80 mg (10%). The ratio of polysorbate to compound (Ia) in each tablet is PS80 2.5% tablet (0.4 times), PS80 7.5% tablet (1.2 times), or PS80 10% tablet (1.6 times). After storing each tablet for 3 weeks under 60°C and humidity conditions, the decomposition products were measured and the stability was examined. The results are shown in Figure 4. In the figure, RRT0.6, RRT0.7, RRT2.4, and RRT2.8 indicate different decomposition products. The content of polysorbate 80 was stable in all cases with only a slight increase in the amount of decomposition products.

[0094] In order to confirm the effect of the ratio of compound (Ia) to polysorbate on stability, the storage stability of the compound suspended in a polysorbate solution was tested. Specifically, polysorbate 80 was dissolved in 2 g of ethanol, the compound was dispersed, and the mixture was dried under reduced pressure for 3 hours, then left at 40°C for 3 hours to remove the ethanol and prepare a sample. The following three samples were prepared. Compound: polysorbate 80 (ratio of polysorbate to compound) = (I) 12.5 mg / 60 mg (4.8 times); (II) 25 mg / 60 mg (2.4 times); (III) 50 mg / 60 mg (1.2 times). Each sample was stored at 40°C for 4 weeks, and then analyzed to detect decomposition products. The results are shown in Figure 5. At the ratios of (I) and (II), related substances (decomposition products) were significantly detected.

[0095] Next, the effect of the ratio of compound (Ia) to polysorbate in the vaginal tablet on stability was examined. Based on the formulation of the 25 mg tablet described in Example 2, vaginal tablets (800 mg per tablet) were manufactured with a compound (Ia) content of 25 mg and a polysorbate 80 (PS80) content of 30 mg (1.2 times the compound: tablet B) or 60 mg (2.4 times the compound: tablet A). Accelerated stability test (40°C ± 2°C / 75% RH ± 5% RH) was performed on each tablet, and the purity was measured after one month. The results are shown in the table below.

[0096] [Table 3] Tablet B contained significantly less related substances (decomposition products) than tablet A.

[0097] Example 5: Vaginal tablet administration test using rats The vaginal tablet for small animals prepared in Example 2 was administered vaginally to rats, and absorption (transfer) into plasma, cervical and vaginal tissues was confirmed. The study was designed and performed in accordance with ethical standards for animal experiments. Rats were restrained by hand under no anesthesia, and vaginal tablets were placed deep in the rat vagina (close to the cervix) using a vaginal administration device. The vaginal tablets were administered into the rat vagina once or repeatedly once a day for 5 days, and blood, cervical and vaginal tissues were collected to analyze the concentration of compound (Ia) in each tissue.

[0098] Each sample was collected as follows: (Blood collection from the jugular vein) Blood was collected from the jugular vein of three randomly selected mice immediately before administration on the second, third, fourth and fifth days of repeated administration. (Total blood collection and extraction of each tissue and preparation of plasma and tissue homogenates) On the first day of administration, plasma, cervical tissues and vaginal tissues were collected from three mice in each group at 7 time points (0.5, 1, 2, 4, 6, 8, and 24 hours) and on the last day of repeated administration, plasma, cervical tissues and vaginal tissues were collected at 8 time points (0.5, 1, 2, 4, 6, 8, 24, and 72 hours) and stored at -80°C. Influenza inhalation anesthesia was administered, and blood was collected from the abdominal aorta after laparotomy. Plasma was stored at -80°C until the concentration was measured. After blood collection, the blood was promptly exsanguinated, and the entire uterine tissue was removed from the vaginal tissue and washed with saline from the uterine side. The excess part of the uterus and the vagina were cut off, and the entire cervical tissue was washed again with saline, and after lightly wiping off the moisture, it was immediately frozen on dry ice and stored at -80°C. The uterine tissue was cut off, and the vaginal opening of the remaining vagina was cut off, washed with saline, and after lightly wiping off the moisture, it was immediately frozen on dry ice and stored at -80°C. Each of the excised frozen tissues was mixed with 5 times the amount of physiological saline and crushed with a bead grinder using a metal crusher to prepare homogenates, which were stored at -80°C until the concentration was measured.

[0099] (Concentration measurement in sample) The compound concentration in each sample was quantified using LC-MS / MS. The results of a single administration are shown in Figure 6, and the results of repeated administration are shown in Figure 7. As a result of the above, when the vaginal tablet of the present invention was administered intravaginally to rats, transfer into the blood was observed, and excellent transfer into the cervical and vaginal tissues was confirmed.

[0100] (Example 6) Vaginal administration test of vaginal tablets to humans The vaginal tablets for human use (10 mg tablets and 25 mg tablets) prepared in Example 2 were administered to humans. Human vaginal tablets (10 mg tablet and 25 mg tablet) manufactured in Example 2 were administered to a total of 12 healthy women aged 20 years or older and younger than 50 years old (6 women in each dose group) by manually inserting one 10 mg tablet and one 25 mg tablet into the vagina. Blood was collected using EDTA-containing vacuum blood collection tubes before administration, and 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after administration, and on the 7th day after administration, and plasma was separated. The drug concentration in the separated plasma was measured by LC / MS / MS. The results are shown in Figure 8. In addition, PK parameters were calculated as follows. max is the maximum blood concentration for each subject, T max is the time to reach the maximum blood concentration, and AUC 0-Day8 was calculated by the trapezoidal rule from the blood concentration transition from before administration (0 hours on Day 1) to the 7th day after administration (Day 8), and the average value and standard deviation for each dose group were calculated. The results are shown below.

[0101] [Table 4] As a result, the vaginal tablet of the present invention was confirmed to have the ability to transfer the active ingredient into the blood.In addition, since the drug was detected in the blood even after 24 hours or more after administration, it was considered that the active ingredient transfers to the intravaginal tissues such as the vagina and cervix, which are the administration site and the target tissues, and then transfers into the blood.Therefore, as in Example 5, when the vaginal tablet of the present invention is administered intravaginally to humans, transfer into the blood was observed, and excellent transfer into the cervix and vaginal tissues was confirmed.

[0102] The above detailed description is merely illustrative of the objects and subject matter of the present invention and is not intended to limit the scope of the appended claims. Various modifications and substitutions to the described embodiments will be apparent to those skilled in the art from the teachings set forth herein without departing from the scope of the appended claims. [Industrial Applicability]

[0103] The pharmaceutical compositions of the present invention are useful for the prevention and / or treatment of viral intravaginal or peri-vaginal diseases.

Claims

1. The following general formula (I) 【Chemistry 1】 [Wherein W represents S or O] or a hydrate thereof, wherein the compound is selected from the group consisting of an aniline derivative represented by the formula (I): The pharmaceutical composition is a pharmaceutical composition in the form of a vaginal insert (e.g., vaginal tablet, vaginal capsule, or vaginal suppository) containing a granular preparation comprising a core particle containing the compound, needle-shaped and / or roughly columnar crystalline cellulose, a pharma- ceutically acceptable roughly spherical additive, and a nonionic surfactant, and a coating layer coating the core particle, A pharmaceutical composition, wherein the core particle has a void between the crystalline cellulose and the additive.

2. The compound is represented by the following formula (I-a): 【Chemistry 2】 2. The pharmaceutical composition according to claim 1, wherein the compound is selected from the group consisting of aniline derivatives represented by the following formula:

3. The pharmaceutical composition according to claim 1 or 2, wherein at least a portion of the compound and at least a portion of the nonionic surfactant are retained in the voids of the core particle.

4. 4. The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is contained in an amount not more than twice that of the compound.

5. 4. The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is contained in an amount 1.5 times or less relative to the compound.

6. 6. The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is contained in an amount of 1.5% by weight or more and less than 10% by weight based on the total weight of the pharmaceutical composition.

7. 6. The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is contained in an amount of 7 to 8% by weight based on the total amount of the pharmaceutical composition.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the nonionic surfactant is contained in an amount of 1.5% by weight or more and less than 10% by weight based on the total amount of the pharmaceutical composition, and in an amount of 1.5 times or less relative to the compound.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the non-ionic surfactant is a polysorbate.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pathogenic virus is human papillomavirus or herpes simplex virus.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the disease is cervical cancer or cervical intraepithelial neoplasia.

12. The pharmaceutical composition according to claim 11, wherein the disease is at least one disease selected from the group consisting of diseases diagnosed as LSIL, ASC-US, ASC-H, or HSIL according to the Bethesda classification, and diseases diagnosed as mild dysplastic cervical intraepithelial neoplasia (CIN1), moderate dysplastic cervical intraepithelial neoplasia (CIN2), or severe dysplastic cervical intraepithelial neoplasia (CIN3).

13. The pharmaceutical composition according to any one of claims 1 to 9, wherein the disease is genital warts.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the vaginal insert is in the form of a vaginal tablet.

15. 15. The pharmaceutical composition of claim 14, wherein the compound is a vaginal tablet contained in a dosage of 10 mg to 50 mg.

16. The pharmaceutical composition according to any one of claims 1 to 15, characterized in that the compound is administered to a patient in a dose of 10 mg to 50 mg per day.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the compound is administered to a patient at a dose of 10 mg to 50 mg per day for 1 to 5 weeks.

18. The following general formula (I) 【Chemistry 3】 [Wherein W represents S or O] or a hydrate thereof, the pharmaceutical composition for treating or preventing a disease caused in the vagina or around the vagina by a pathogenic virus is produced by the following steps: (a) mixing a core particle raw material containing crystalline cellulose having an acicular and / or substantially cylindrical shape and a pharma- ceutically acceptable substantially spherical additive to obtain a core particle mixture; (b) dissolving or suspending the compound in a mixture of a nonionic surfactant and a solvent to obtain a mixture; (c) contacting the core particle mixture obtained in step (a) with the mixed liquid obtained in step (b) to obtain core particles containing the compound, the acicular and / or roughly cylindrical crystalline cellulose, the roughly spherical additive, and the nonionic surfactant; (d) a step of coating and drying the core particles obtained in the step (c) to obtain a granular preparation comprising the core particles having voids formed between the crystalline cellulose and the substantially spherical additive and a coating layer coating the core particles; and (e) processing the obtained granular preparation to obtain a vaginal insert in the form of a vaginal tablet, a vaginal suppository, or a vaginal capsule; A manufacturing method comprising:

19. The compound is represented by the following formula (I-a): 【Chemistry 4】 or a hydrate thereof.

20. The method according to claim 18 or 19, wherein at least a portion of the compound and at least a portion of the nonionic surfactant are held in voids formed in the core particle.

21. The method according to any one of claims 18 to 20, wherein the step (e) is a step of compressing the granular preparation into a vaginal tablet.

22. The method according to any one of claims 18 to 21, wherein in the step (b), the nonionic surfactant is mixed in an amount that is 2 times or less than that of the compound.

23. The method according to any one of claims 18 to 21, wherein in the step (b), the nonionic surfactant is mixed in an amount 1.5 times or less relative to the compound.

24. The method according to any one of claims 18 to 23, wherein the nonionic surfactant is contained in an amount of 1.5% by weight or more and less than 10% by weight based on the total weight of the pharmaceutical composition.

25. The method according to any one of claims 18 to 23, wherein the nonionic surfactant is contained in an amount of 7 to 8% by weight based on the total amount of the pharmaceutical composition.

26. The method according to any one of claims 18 to 25, wherein the nonionic surfactant is a polysorbate.

27. The method according to any one of claims 18 to 26, wherein the pathogenic virus is human papillomavirus or herpes simplex virus.

28. The method according to any one of claims 18 to 26, wherein the disease is cervical cancer or cervical intraepithelial neoplasia.

29. The method for producing a product according to any one of claims 18 to 26, wherein the disease is genital warts.

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