COMPOSITION FOR USE IN A TREATMENT OF CERVICAL CELL ABNORMALITIES COMPRISING SELENITE COMPOUND AND ACID

Abstract

The present invention provides a pharmaceutical composition containing 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 and mixtures thereof, for use in reducing progression of cervical cell abnormalities in a female patient, wherein the patient is p16-positive and Ki-67-positive at least in a region of the cervix uteri. The composition is applied intravaginally.

Claims

1-15. (canceled)

16. A method for reducing progression of cervical cell abnormalities in a female patient, comprising the steps of obtaining a pharmaceutical composition containing 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 and mixtures thereof, and administering an effective amount of the composition to the patient, wherein the composition is applied intravaginally, wherein the patient has the cervical cell abnormalities, wherein the cervical cell abnormalities are p16-positive and Ki-67-positive.

17. The method of claim 16, wherein said cervical cell abnormalities are further defined as ASC-US, ASC-H, AGC, LSIL or HSIL.

18. The method of claim 16, wherein said cervical cell abnormalities are further defined as ASC-US or ASC-H.

19. The method of claim 16, wherein said cervical cell abnormalities are further defined as ASC-US.

20. The method of claim 16, wherein said administering is performed until the patient has become p16-negative and Ki-67-negative in the cervix uteri.

21. The method of claim 16, wherein the total selenium content is 0.01 mg-1.25 mg per 5 ml of the pharmaceutical composition.

22. The method of claim 21, wherein the total selenium content is 0.20 mg-0.30 mg per 5 ml of the pharmaceutical composition.

23. The method of claim 16, wherein the total selenium dose is 0.01 mg-1.25 mg per application.

24. The method of claim 23, wherein the total selenium dose is 0.20 mg-0.30 mg per application.

25. The method of claim 16, wherein said administering is performed at least once per day.

26. The method of claim 25, wherein said administering is performed for at least 30 days.

27. The method of claim 26, wherein said administering is performed for at least 90 days.

28. The method of claim 26, wherein said administering is discontinued during menstruation of the patient.

29. The method of claim 16, wherein said administering is performed once per day, wherein said administering is discontinued during menstruation of the patient.

30. The method of claim 16, wherein the progression of the cervical cell abnormalities in the patient is reduced.

31. The method of claim 16, wherein said administering is performed until the cervical cell abnormalities in the patient cannot be detected any more.

32. The method of claim 16, wherein said progression of cervical cell abnormalities comprises at least one of: change from ASC-US to ASC-H, change from ASC-US to AGC, change from ASC-US to LSIL, change from ASC-US to HSIL, change from ASC-H to AGC, change from ASC-H to LSIL, change from ASC-H to HSIL, change from AGC to LSIL, change from AGC to HSIL and change from LSIL to HSIL.

33. The method of claim 16, wherein said progression of cervical cell abnormalities comprises at least one of: change from ASC-US to ASC-H, change from ASC-US to AGC, change from ASC-US to LSIL, change from ASC-US to HSIL, change from ASC-H to AGC, change from ASC-H to LSIL and change from ASC-H to HSIL,

34. The method of claim 16, wherein said progression of cervical cell abnormalities comprises at least one of: change from ASC-US to ASC-H and change from ASC-US to LSIL.

35. The method of claim 16, wherein the pharmaceutical composition is present in the form of a gel, a suspension, an emulsion, a suppository such as gelatine capsules or gelatine-free capsules, a spray or a powder.

36. The method of claim 16, wherein the pharmaceutical composition further contains silicon dioxide.

37. The method of claim 16, wherein the pharmaceutical composition has a pH of between 4.0 and 2.5.

38. The method of claim 16, wherein the pharmaceutically acceptable acid is citric acid.

39. The method of claim 16, wherein the selenite-containing compound is sodium selenite.

40. The method of claim 16, wherein the human papillomavirus (HPV) infection status of the cervix uteri of the patient is either unknown or is not determined.

41. The method of claim 16, wherein the patient is further defined by at least one of: not having cancer, not having chronic viral disease other than optionally HPV infection, and not being immunosuppressed.

42. The method of claim 41, wherein the patient is further defined by not having cancer, not having chronic viral disease other than optionally HPV infection, and not being immunosuppressed.

43. A method for reducing progression of cervical cell abnormalities in a female patient, comprising the steps of obtaining a pharmaceutical composition containing 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 and mixtures thereof, wherein the pharmaceutical composition is a gel, has a pH of between 4.0 and 2.5 and further contains silicon dioxide, and administering an effective amount of the composition to the patient, wherein the composition is applied intravaginally, wherein the total selenium dose is 0.20 mg-0.30 mg per application, wherein the patient has the cervical cell abnormalities, wherein the cervical cell abnormalities are p16-positive and Ki-67-positive.

44. A method comprising obtaining a cervical smear from a female patient, analysing the cervical smear, wherein said analysing shows that the patient has cervical cell abnormalities, wherein the cervical cell abnormalities are p16-positive and Ki-67-positive, obtaining a pharmaceutical composition containing 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 and mixtures thereof, and administering an effective amount of the composition to the patient, wherein the composition is applied intravaginally.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The present invention is further illustrated by the following figures and examples, without being restricted thereto.

[0045] FIG. 1: Difference in the cervical smear findings—Screening vs. 3.sup.rd visit. An interim analysis showed that compared to the non-treated control arm the progression rate was strongly reduced in the active arm treated with the inventive therapy (0.0% in the active arm vs. 20.7% in the control arm). “at Screening”: initial screening of the patient, “at 3.sup.rd Visit”: after 3×28 days of once-daily treatment.

[0046] FIG. 2: Difference in the cervical smear findings—Screening vs. 4.sup.th visit. Compared to the non-treated control arm the progression rate remained strongly reduced in the active arm treated with the inventive therapy even months after the treatment had ended (1.9% in the active arm vs. 19.3% in the control arm) “at Screening”: initial screening of the patient, “at 4.sup.th Visit”: six months after initial screening.

[0047] FIG. 3: Improvement of p16/Ki-67 status. A much larger remission rate from p16/Ki-67 double-stain positive was observed in the active arm treated with the inventive therapy, even months after the treatment had ended. “p16/Ki-67 −”: negative as determined with the established CINtec® PLUS test (Roche, Switzerland). “p16/Ki-67 +”: positive as determined with the established CINtec® PLUS test (Roche, Switzerland).

[0048] FIGS. 4A and 4B: Comparison between patients who were p16/Ki-67-negative at baseline (FIG. 4A) with patients who were p16/Ki-67-positive at baseline (FIG. 4B). Both groups of patients benefited from the inventive therapy also with respect to p16/Ki-67 status; i.e. by maintaining the status of being p16/Ki-67-negative or by changing the status back to p16/Ki-67-negative. Surprisingly, for the group of patients who were p16/Ki-67-positive at baseline (FIG. 4B), the percentage of patients for whom the inventive therapy achieved a benefit with respect to p16/Ki-67 status during the observation period was much larger, when comparing the respective active arm to the respective control arm. “p16/Ki-67(−)”: negative as determined with the established CINtec® PLUS test (Roche, Switzerland). “p16/Ki-67(+)”: positive as determined with the established CINtec® PLUS test (Roche, Switzerland).

EXAMPLES

Example 1—Pharmaceutical Composition for use in Reducing Progression of Cervical Cell Abnormalities

[0049] The composition is an aqueous vaginal gel having the following ingredients (per 5 ml of gel):

TABLE-US-00001 highly dispersed silicon dioxide 10.00 mg citric acid 24.80 mg sodium selenite 0.83 mg (corresponds to 0.25 mg selenium equivalent) sodium benzoate 2.50 mg potassium sorbate 5.00 mg hydroxyethyl cellulose 100.00 mg water (up to 5 ml)

Example 2—Controlled Clinical Trial

[0050] The present trial was a randomized, prospective, open label with control group multicentre study of 3×28 days once a day treatment with the composition of example 1 (female patients, age 25-60 years, no chronic viral disease, cancer and immunosuppressive treatment). Daily dose was 5 ml of the composition, applied intravaginally.

[0051] The subjects were recruited in 3 centres. Cervical smears were collected according the standard procedure known in the art, preserved in a specific liquid milieu called SurePath® (Becton & Dickinson) and evaluated in accordance to the Bethesda classification. Samples were further analysed with the CINtec® PLUS cytology kit (Roche, Switzerland).

[0052] An interim analysis was conducted after about 50% of patients (N=111; 50% evaluable per arm) had completed about 3 months in the trial (see FIG. 1). Final evaluations with larger patient sets were conducted at the end of the trial, 3 months after the treatment had ended (see FIGS. 2 and 3).

Results

[0053] Evaluated data demonstrate a clearly improved outcome for patients in the active arm for all measured parameters. Only a few slight adverse events were reported.

[0054] Compared to the non-treated control arm the progression rate was strongly reduced in the active arm treated with the inventive therapy (see FIG. 1, 0.0% in the active arm vs. 20.7% in the control arm), and remained strongly reduced even months after the treatment had ended (see FIG. 2, 1.9% in the active arm vs. 19.3% in the control arm).

[0055] Further, compared to the non-treated control arm, a much larger remission rate from p16/Ki-67 double-stain positive was observed in the active arm treated with the inventive therapy (see FIG. 3).

[0056] In addition, for the group of patients who were p16/Ki-67-positive at baseline, the percentage of patients for whom the inventive therapy achieved a benefit with respect to p16/Ki-67 status during the observation period was particularly large (see FIGS. 4A and 4B), which came as a surprise.

[0057] These results demonstrate the exceptional suitability of the composition for the therapeutic indications mentioned herein.