Compositions for use in treating cervical cell abnormalities

Abstract

The present invention provides a pharmaceutical composition containing a selenium-containing compound and a pharmaceutically acceptable acid selected from citric acid, acetic acid, malic acid, carbonic acid, sulfuric acid, nitric acid, hydrochloric acid, fruit acids, and mixtures thereof for use in reducing the progression of cervical cell abnormalities in a female patient, wherein the patient is p16-positive and Ki-67-positive in at least the cervical region. The composition is applied intravaginally.

Description

Technical Field

[0001] The present invention relates to a composition for use in the treatment of cervical cell abnormalities.

Background Art

[0002] Cervical smear screening (also known as Pap test or Pap smear) is a widely used technique for detecting potential pre-cancerous and cancerous processes in the cervix of female patients. Typically, cervical cell abnormalities are classified according to the Bethesda System (see Nayar R, Wilbur D. The Bethesda System for Reporting Cervical Cytology, Definitions, Criteria, and Explanatory Notes. Springer; 2015 (Non-Patent Document 1)). Such abnormalities include, inter alia, atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells that cannot exclude HSIL (ASC-H), atypical glandular cells (AGC), low-grade squamous intraepithelial lesions (LSIL) and, in particular, high-grade squamous intraepithelial lesions (HSIL). These abnormalities can be improved but are known to deteriorate over time. In this context, remission is defined as a complete recovery from abnormal cytological smear findings, regression is defined as an improvement in cytological smear findings (e.g., from HSIL to LSIL or ASC-US, or from LSIL to ASC-US), persistence is defined as no change in cytological smear findings, and progression is defined as a deterioration in cytological smear findings (e.g., from ASC-US to ASC-H or LSIL, or from ASC-H to LSIL or from LSIL to HSIL).

[0003] Depending on the severity of the cervical cell abnormalities, and often after a period of "careful follow-up" to assess whether the abnormalities will remit or spontaneously regress (or, conversely, persist or progress), surgical intervention is recommended in accordance with general treatment guidelines. Typical procedures include cone biopsy, cryotherapy, loop electrosurgery (LEEP), or large loop resection of the cervical deformity zone (LLETZ). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Nayar R, Wilbur D. The Bethesda System for Reporting Cervical Cytology, Definitions, Criteria, and Explanatory Notes. Springer; 2015 [Overview of the project] [Problems that the invention aims to solve]

[0005] Since any surgical intervention carries certain health risks, non-surgical interventions are needed to reduce the rate of progression of cervical cell abnormalities, either to reduce the need for surgery or, if such intervention is still necessary, to at least reduce the invasiveness of surgery.

[0006] Therefore, an object of the present invention is to provide a non-surgical treatment that reduces the rate of progression of cervical cell abnormalities. [Means for solving the problem]

[0007] The present invention relates to a pharmaceutical composition comprising a selenite-containing compound and a pharmaceutically acceptable acid selected from citric acid, acetic acid, malic acid, carbonic acid, sulfuric acid, nitric acid, hydrochloric acid, fruit acids (e.g., malic acid, citric acid, tartaric acid, oxalic acid, and fumaric acid, particularly citric acid) and mixtures thereof. The composition is intended for use in reducing the progression of cervical cell abnormalities (typically determined by cervical smear screening) in female patients. The composition is applied to the patient vaginally. In a particularly preferred embodiment, the patient is p16-positive and Ki-67-positive (i.e., p16 / Ki-67 double-positive) in at least the cervical region, and / or at least a portion of the cervical cell abnormalities are p16-positive and Ki-67-positive (i.e., p16 / Ki-67 double-positive). [Brief explanation of the drawing]

[0008] [Figure 1] This figure shows the difference between cervical smear specimens at the time of the initial check-up and at the third visit. In the interim analysis, the progression rate was significantly reduced in the treatment group treated with the present invention compared to the untreated control group (0.0% in the treatment group, 20.7% in the control group). "At the time of the initial check-up": at the time of the patient's first screening; "At the third visit": 3 × 28 days after treatment once a day. [Figure 2] This figure shows the difference between cervical smear specimens at the initial screening and at the fourth visit. Compared to the untreated control group, the treatment group treated with the present invention maintained a significantly reduced rate of progression even several months after the completion of the treatment (1.9% in the treatment group vs. 19.3% in the control group). "At initial screening": at the time of the patient's first screening; "at fourth visit": 6 months after the initial screening. [Figure 3] This figure shows the improvement in the p16 / Ki-67 status. A much greater rate of remission from p16 / Ki-67 bi-strain positivity was observed in the treatment group treated with the present invention, even several months after the end of treatment. "p16 / Ki-67 -": Negative as measured by the established CINtec® PLUS test (Roche, Switzerland). "p16 / Ki-67 +": Positive as measured by the established CINtec® PLUS test (Roche, Switzerland). [Figure 4A] This figure compares patients who were p16 / Ki-67 negative at baseline (Figure 4A) with patients who were p16 / Ki-67 positive at baseline (Figure 4B). Patients in both groups benefited from the treatment of the present invention in terms of their p16 / Ki-67 status, that is, by maintaining a p16 / Ki-67 negative status or by returning to a p16 / Ki-67 negative status. Surprisingly, in the group of patients who were p16 / Ki-67 positive at baseline (Figure 4B), the proportion of patients who achieved benefit in terms of their p16 / Ki-67 status with the treatment of the present invention during the observation period was much higher when each treatment group was compared to each control group. "p16 / Ki-67 -": Negative as measured by the established CINtec® PLUS test (Roche, Switzerland). "p16 / Ki-67 +": Positive as measured by the established CINtec® PLUS test (Roche, Switzerland). [Figure 4B] This figure compares patients who were p16 / Ki-67 negative at baseline (Figure 4A) with patients who were p16 / Ki-67 positive at baseline (Figure 4B). Patients in both groups benefited from the treatment of the present invention in terms of their p16 / Ki-67 status, that is, by maintaining a p16 / Ki-67 negative status or by returning to a p16 / Ki-67 negative status. Surprisingly, in the group of patients who were p16 / Ki-67 positive at baseline (Figure 4B), the proportion of patients who achieved benefit in terms of their p16 / Ki-67 status with the treatment of the present invention during the observation period was much higher when each treatment group was compared to each control group. "p16 / Ki-67 -": Negative as measured by the established CINtec® PLUS test (Roche, Switzerland). "p16 / Ki-67 +": Positive as measured by the established CINtec® PLUS test (Roche, Switzerland). [Modes for carrying out the invention]

[0009] In the course of this invention, it was surprisingly found that the pharmaceutical composition is not only effective in increasing the remission and regression of cervical cell abnormalities, but also in significantly reducing the progression of cervical cell abnormalities. This was confirmed by controlled clinical trials (see Example 2).

[0010] Pharmaceutical compositions have been previously disclosed for use in other therapeutic indications, but these disclosures do not anticipate or suggest the present invention. US2003 / 0180387A1 relates to a method for increasing the antioxidant capacity of a selenium-containing aqueous solution. It is disclosed that a preparation comprising a pharmaceutically acceptable or food-compatible form of selenium, i.e., selenic acid, and a pharmaceutically acceptable or food-compatible acid selected from citric acid, acetic acid, malic acid, carbonate, various fruit acids and mixtures thereof, may be used to prevent or treat herpes simplex infection, among many other indications. However, this document does not disclose vaginal application, nor that the target organ is the cervix, nor the therapeutic indications of the present invention.

[0011] US2005 / 0048134A1 relates to the use of selenate-containing compounds administered topically or orally. Treatment or prevention of papillomavirus infections, particularly in the genital area, is disclosed as one of many indications. However, this document does not disclose vaginal application, nor does it disclose that the target organ is the cervix, nor are the therapeutic indications of the present invention disclosed.

[0012] US2013 / 0323328A1 (also published as WO2012 / 109685A1) relates to a pharmaceutical formulation containing selenite or a selenite-containing compound for the treatment of cervical dysplasia or carcinoma. However, this document does not describe, at least, the therapeutic indications of the present invention.

[0013] In a particularly preferred embodiment of the present invention, the cervical cell abnormalities to be treated are selected from ASC-US, ASC-H, AGC, LSIL, and HSIL, preferably from ASC-US, ASC-H, AGC, and LSIL, more preferably from ASC-US, ASC-H, and AGC, even more preferably from ASC-US and ASC-H, and particularly from ASC-US, all according to the Bethesda System (see also the above description and book).

[0014] In embodiments, patients have a cervical cell abnormality selected from ASC-US, ASC-H, AGC, LSIL, and HSIL, preferably from ASC-US, ASC-H, AGC, and LSIL, more preferably from ASC-US, ASC-H, and AGC, even more preferably from ASC-US and ASC-H, and particularly from ASC-US, which is determined in particular by cervical smear screening (particularly of the said region of the cervix).

[0015] In a preferred embodiment, the progression of the cervical cell abnormality is at least one of the following: a change from ASC-US to ASC-H, a change from ASC-US to AGC, a change from ASC-US to LSIL, a change from ASC-US to HSIL, a change from ASC-H to AGC, a change from ASC-H to LSIL, a change from ASC-H to HSIL, a change from AGC to LSIL, a change from AGC to HSIL, and a change from LSIL to HSIL. Preferably, the changes are from ASC-US to ASC-H, ASC-US to AGC, and ASC-U The changes include at least one of the following: a change from S to LSIL, a change from ASC-H to HSIL, a change from ASC-H to AGC, a change from ASC-H to LSIL, or a change from ASC-H to HSIL; more preferably, at least one of the following: a change from ASC-US to ASC-H, a change from ASC-US to AGC, a change from ASC-US to LSIL, and a change from ASC-US to HSIL, particularly at least one of the following: a change from ASC-US to ASC-H and a change from ASC-US to LSIL (or as defined above). Preferably, such changes are determined after at least 30 days, preferably at least 60 days, more preferably at least 90 days, even more preferably at least 120 days, even more preferably at least 150 days, or even more preferably at least 180 days, following an initial screening which may be performed, for example, when initiating the process of the present invention.

[0016] In the context of the present invention, reducing progression is defined as not including increasing remission or increasing regression.

[0017] p16(p16 INK4ap16 (also known as cyclin-dependent kinase inhibitor 2A) is a protein encoded by the CDKN2A gene in humans. Overexpression of p16 is a biomarker of increased cervical cancer risk. Ki-67 (also known as KI-67 or MKI67) is a protein encoded by the MKI67 gene in humans. Ki-67 is a biomarker of cell proliferation. Both of these biomarkers can be tested using the commercially available CINtec® PLUS test (Roche, Switzerland), which is approved as a cytological assay (see, for example, "CINtec® PLUS Immunocytochemistry as a Tool for Cytological Diagnosis of Glandular Lesions of the Cervix," Ravarino, A et al. (2012), American Journal of Clinical Pathology, 138(5), 652-656). p16 / Ki-67 dual-staining is also disclosed in "p16 / Ki-67 dual-stain cytology in the triage of ASCUS and LSIL Papanicolaou cytologies obtained from a potentially or mildly abnormal Papanicolaou cytological study in Europe:", Schmidt, Dietmar et al., Cancer cytology 119.3(2011):158-166.

[0018] In the course of the present invention, it was found that the treatments of the present invention are particularly effective in reducing the progression of cervical cell abnormalities when they are associated with the biomarkers p16 and Ki-67. Therefore, in a preferred embodiment of the present invention, the patient is p16-positive, preferably p16-positive and Ki-67-positive, in at least the cervical region (and / or at least a portion of the cervical cell abnormalities are p16-positive and / or Ki-67-positive). Preferably, the pharmaceutical composition is applied to the patient until the patient becomes p16-negative, preferably p16-negative and Ki-67-negative, in the said region (and / or until at least a portion of the cervical cell abnormalities are p16-negative and / or Ki-67-negative).

[0019] One skilled in the art knows how to evaluate whether the region of the cervix (or at least a part of the cellular abnormality) is p16-positive, for example, by performing a biopsy in that region and using a p16 assay (such as an immunohistochemical assay) known in the art. Preferably, when at least one cell, preferably at least two adjacent cells, more preferably at least three adjacent cells, even more preferably at least five adjacent cells, particularly at least ten adjacent cells obtained from a biopsy sample of the cervical region overexpress p16 compared to healthy control tissue such as healthy adjacent cells in the biopsy sample, it is defined as p16-positive, and preferably each of the said cells is an epithelial cell. Conversely, such a biopsy sample is preferably defined as p16-negative when each cell less than 10, preferably less than 5, more preferably less than 3, even more preferably less than 2, particularly no cell overexpresses p16 compared to healthy control tissue such as healthy adjacent cells in the biopsy sample, and preferably each of the said cells is an epithelial cell.

[0020] Furthermore, one skilled in the art also knows how to evaluate whether the region of the cervix (or at least a part of the cellular abnormality) is Ki-67-positive, for example, by performing a biopsy in that region and using a Ki-67 assay (such as an immunohistochemical assay) known in the art. Preferably, when at least one cell, preferably at least two adjacent cells, more preferably at least three adjacent cells, even more preferably at least five adjacent cells, particularly at least ten adjacent cells obtained from a biopsy sample of the cervical region overexpress Ki-67 compared to healthy control tissue such as healthy adjacent cells in the biopsy sample, it is defined as Ki-67-positive, and preferably each of the said cells is an epithelial cell. Conversely, such a biopsy sample is preferably defined as Ki-67-negative when less than 1, preferably less than 5, more preferably less than 3, even more preferably less than 2, particularly no cell overexpresses Ki-67 compared to healthy control tissue such as healthy adjacent cells in the biopsy sample, and preferably each of the said cells is an epithelial cell.

[0021] Particularly preferably, "p16 positive and Ki-67 positive" is defined as a positive result in the established CINtec® PLUS test (Roche, Switzerland) as disclosed in the CINtec® PLUS Interpretation Guide (Roche, 2016). In this interpretation guide, a positive result is defined as the presence of at least one double-stained cervical epithelial cell (cytoplasmic staining is brown (p16) and nuclear staining is red (Ki-67)).

[0022] In the process of the present invention, it has been found that the composition of the present invention is already effective at surprisingly low concentrations of selenium. Therefore, in a further preferred embodiment, the total selenium content of the pharmaceutical composition is 0.01 mg to 1.25 mg, preferably 0.025 mg to 1.00 mg, more preferably 0.05 mg to 0.75 mg, still more preferably 0.10 mg to 0.50 mg, even more preferably 0.15 mg to 0.40 mg, particularly 0.20 mg to 0.30 mg per 5 ml of the composition. It is clear that "total selenium content" does not mean that selenium must be present as elemental selenium in the composition. As an example, 0.83 mg of sodium selenite as the only selenium-containing compound per 5 ml of the composition corresponds to a total selenium content ("selenium equivalent content") of 0.25 mg per 5 ml.

[0023] Also, it has been found that the selenium dose per application is low and can still be effective. According to a further preferred embodiment, the total selenium dose is 0.01 mg to 1.25 mg, preferably 0.025 mg to 1.00 mg, more preferably 0.05 mg to 0.75 mg, even more preferably 0.10 mg to 0.50 mg, even more preferably 0.15 mg to 0.40 mg, particularly 0.20 mg to 0.30 mg per application. It is clear that "total selenium dose" does not mean that selenium must be present as elemental selenium in the dose. As an example, 0.83 mg of sodium selenite as the only selenium-containing compound in the applied dose unit corresponds to a total selenium dose ("selenium equivalent dose") of 0.25 mg per application.

[0024] To enhance efficacy, the pharmaceutical composition is preferably applied at least once a day, preferably for at least 30 days, more preferably for at least 60 days, and even more preferably for at least 90 days.

[0025] It has been found that applying the composition only once a day is suitable for achieving efficacy. Since this further reduces the risk of side effects compared to applying it several times a day, a further preferred embodiment relates to the pharmaceutical composition of the present invention for use, in which the composition is applied once a day, preferably for at least 30 days, more preferably for at least 60 days, and even more preferably for at least 90 days.

[0026] The application of the pharmaceutical composition may be interrupted during the patient's menstrual period.

[0027] Pharmaceutical compositions for use according to the present invention may further contain additional suitable ingredients and / or pharmaceutically acceptable excipients.

[0028] Preferably, the pharmaceutical composition for use according to the present invention contains a selenite in the form of sodium selenite (mostly existing as a pentahydrate compound that begins to release crystal water at 40°C).

[0029] In a more preferred embodiment of the present invention, the composition contains one or more acids in an amount of 1 mg to 10 g of acid, more preferably 10 mg to 5 g of acid, and particularly 100 mg to 1 g of acid per 100 g of composition (especially when the acid is added in its solid form). Alternatively, the acid may be added in its liquid form (for example, together with water, i.e., as an aqueous solution). Water and aqueous solutions containing further components may be added to the composition according to the present invention in an amount of 0 to about 99.9 g, preferably 50 to 99 g, and particularly 80 to 98 g per 100 g of composition.

[0030] In a more preferred embodiment, the composition exists in the form of a gel, suspension, emulsion, suppository such as a gelinose capsule or gelatin-free capsule, a spray, or a powder.

[0031] When existing in gel form, the pharmaceutical composition for use according to the present invention preferably contains a gelling agent. Both inorganic and organic aqueous gelling agents can be used as gelling agents. Particularly preferred gelling agents are cellulose derivatives, especially carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and especially hydroxyethylcellulose. Preferably, the gelling agent, especially hydroxyethylcellulose, is used in a total concentration of 0.1 g to 30 g, more preferably 0.5 g to 5 g, and especially 1 g to 3 g per 100 g of the composition.

[0032] A more particularly preferred embodiment of the composition for use according to the present invention is to include silicon dioxide, particularly highly dispersed silicon dioxide, as a technical suspension medium and / or adsorbent, for example, according to International Publication No. 2001 / 85852 A1, especially when the composition exists in the form of a gel. Preferably, an amount of SiO2 of 100 mg to 50 g, more preferably 500 mg to 10 g, and particularly 1 g to 5 g per 100 g of composition is used.

[0033] The compositions for use according to the present invention preferably have a pH value of less than 7.0, more preferably less than 5.0, and particularly between 4.0 and 2.5.

[0034] Advantageously, the composition may contain further excipients and / or further active ingredients, particularly buffers, colorants, stabilizers, preservatives, carriers, or combinations thereof. Preferred examples of preservatives are potassium sorbate and sodium benzoate.

[0035] Furthermore, the composition may further contain additional activators such as antibiotics, antivirals, antifungals, pain inhibitors, anti-inflammatory agents, or combinations thereof.

[0036] The present invention also provides a method for reducing the progression of cervical cell abnormalities in female patients (preferably patients who are p16-positive and Ki-67-positive in at least the cervical region), - To obtain a pharmaceutical composition as defined herein; and -Administering an effective amount of the composition to the patient, wherein the composition is applied to the vagina. This relates to the method of administration, including the method of administration.

[0037] Typically, the patient requires the treatment of the present invention.

[0038] Particularly preferably, the human papillomavirus (HPV) infection status of the patient's cervix, preferably the entire cervix, is unknown or undetermined. In addition, or instead, the area of ​​the cervix, preferably the entire cervix, is not infected with any of the HPV selected from HPV16, HPV18, HPV31, HPV33, and HPV58 (preferably none of the five).

[0039] HPV infection can be specifically detected by methods such as polymerase chain reaction (PCR), transcription-mediated amplification (TMA) assays of biopsy specimens such as cervical smears, or other known methods, since the genome sequences of HPV16, HPV18, HPV31, HPV33, and HPV58 are known. The genome sequences of these HPV types are published, for example, in the National Center for Biotechnology Information (NCBI) GenBank under the following accession numbers: K02718.1 (HPV16), X05015.1 (HPV18), J04353.1 (HPV31), M12732.1 (HPV33), and D90400.1 (HPV58).

[0040] In this specification, the patient receiving treatment of the present invention is preferably 20 years of age or older, preferably 30 years of age or older, more preferably 40 years of age or older, and even more preferably 50 years of age or older. The patient is a human being.

[0041] The treatment of the present invention has been found to be less effective in immunosuppressed patients. Therefore, the patient is preferably not immunosuppressed. In addition, or instead, the patient is preferably not cancer and / or chronic viral disease (or chronic viral disease other than HPV infection).

[0042] In this specification, the term “overexpressed” or similar with respect to gene (product) A typically means, for example, that the expression level of A in a biopsy sample (e.g., measured by Western blotting or immunohistochemistry) is at least 1.2 times (i.e., at least 20% increase), preferably at least 1.4 times, more preferably at least 1.6 times, even more preferably at least 1.8 times, and particularly at least 2.0 times higher than the expression level of a suitable control (such as healthy tissue of the same type).

[0043] The present invention will be further illustrated by the following drawings and embodiments, but will not be limited thereto. [Examples]

[0044] <Pharmaceutical composition used to reduce the progression of cervical cell abnormalities> The composition is an aqueous vaginal gel having the following components (per 5 ml of gel): Highly dispersed silicon dioxide 10.00 mg Citric acid 24.80 mg Sodium selenite 0.83 mg (Equivalent to 0.25 mg of selenium) Sodium benzoate 2.50 mg Potassium sorbate 5.00 mg Hydroxyethylcellulose 100.00 mg Water (maximum 5ml) [Examples]

[0045] <Controlled Clinical Trial> This study was a 3 × 28 day randomized, open-label, multicenter study of once-daily treatment with the composition of Example 1 in female patients aged 25-60 years, without chronic viral disease, cancer, or immunosuppressive treatment. The daily dose applied vaginally was 5 ml of the composition.

[0046] Participants were recruited from three facilities. Cervical smear specimens were collected according to standard procedures known in the art, stored in a specific liquid environment called SurePath® (Becton & Dickinson), and evaluated according to the Bethesda classification. The samples were further analyzed using the CINtec® PLUS cytology kit (Roche, Switzerland).

[0047] Interim analyses were conducted with approximately 50% of patients (N=111; 50% evaluable per group) approximately 3 months after the trial (see Figure 1). Final evaluations were conducted with a larger number of patient groups at the end of the trial and 3 months after the end of treatment (see Figures 2 and 3).

[0048] <Result> The evaluated data demonstrate clearly improved outcomes in the patients in the treatment group for all measured parameters. Only minor adverse events were reported.

[0049] Compared to the untreated control group, the progression rate was significantly reduced in the treatment group treated with the present invention (see Figure 1, 0.0% in the treatment group vs. 20.7% in the control group), and remained significantly reduced even after the completion of treatment (see Figure 2, 1.9% in the treatment group vs. 19.3% in the control group).

[0050] Furthermore, a significantly higher remission rate from p16 / Ki-67 double staining positivity was observed in the treatment group treated with the present invention compared to the untreated control group (see Figure 3).

[0051] Furthermore, in the group of patients who were p16 / Ki-67 positive at baseline, the proportion of patients who achieved benefit in terms of p16 / Ki-67 status with the treatment of the present invention during the observation period was particularly high (see Figures 4A and 4B), which was surprising.

[0052] These results demonstrate the exceptional suitability of the compositions for the therapeutic indications described herein.

Claims

1. A pharmaceutical composition for use in reducing the progression of cervical cell abnormalities in female patients, comprising selenite and a pharmaceutically acceptable acid selected from citric acid, acetic acid, malic acid, carbonate, sulfuric acid, nitric acid, hydrochloric acid, tartaric acid, oxalic acid, fumaric acid and mixtures thereof, wherein the patient is evaluated as p16-positive and Ki-67-positive in at least the cervical region, and the composition is applied vaginally.

2. A pharmaceutical composition for use according to claim 1, wherein the cervical cell abnormality is selected from ASC-US, ASC-H, AGC, LSIL, and HSIL.

3. A pharmaceutical composition for use according to claim 1 or 2, which is applied to the patient until the area becomes p16 negative.

4. A pharmaceutical composition for use according to claim 1 or 2, which is applied until the patient becomes p16-negative and Ki-67-negative in the said region.

5. A pharmaceutical composition for use according to any one of claims 1 to 4, wherein the total selenium content is 0.01 mg to 1.25 mg per 5 ml of composition; and / or the total selenium dose is 0.01 mg to 1.25 mg per application.

6. A pharmaceutical composition for use according to any one of claims 1 to 4, wherein the total selenium content is 0.20 mg to 0.30 mg per 5 ml of composition; and / or the total selenium dose is 0.20 mg to 0.30 mg per application.

7. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein the composition is applied at least once a day, and the application is interrupted during the patient's menstruation.

8. A pharmaceutical composition for use according to any one of claims 1 to 7, wherein the composition is applied once a day, and the application is interrupted during the patient's menstruation.

9. A pharmaceutical composition for use according to any one of claims 1 to 8, wherein the application is interrupted for at least 30 days after treatment for at least 30 days.

10. A pharmaceutical composition for use according to any one of claims 1 to 9, wherein the progression of cervical cell abnormalities includes at least one of the following: a change from ASC-US to ASC-H, a change from ASC-US to AGC, a change from ASC-US to LSIL, a change from ASC-US to HSIL, a change from ASC-H to AGC, a change from ASC-H to LSIL, a change from ASC-H to HSIL, a change from AGC to LSIL, a change from AGC to HSIL, and a change from LSIL to HSIL.

11. A pharmaceutical composition for use according to any one of claims 1 to 10, wherein the composition exists in the form of a suppository such as a gel, suspension, emulsion, gelatin capsule or gelatin-free capsule, a spray or a powder.

12. A pharmaceutical composition for use according to any one of claims 1 to 11, wherein the composition further contains silicon dioxide.

13. A pharmaceutical composition for use according to any one of claims 1 to 12, wherein the composition has a pH of less than 7.

0.

14. A pharmaceutical composition for use according to any one of claims 1 to 13, wherein the pharmaceutically acceptable acid is citric acid.

15. A pharmaceutical composition for use according to any one of claims 1 to 14, wherein the selenite is sodium selenite.

16. A pharmaceutical composition for use according to any one of claims 1 to 15, wherein the human papillomavirus (HPV) infection status of the area of ​​the patient's cervix is ​​unknown or undetermined; or the area of ​​the cervix is ​​not infected with any HPV selected from HPV16, HPV18, HPV31, HPV33 and HPV58.

17. A pharmaceutical composition for use according to any one of claims 1 to 16, wherein the patient does not have cancer and / or a chronic viral disease other than HPV infection, or a chronic viral disease, and / or the patient is not immunosuppressed.

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