COMPOSITION FOR TREATING A PATIENT SUFFERING FROM ULCERATIVE COLITIS, AND USE OF THE COMPOSITION AS A DRUG

Abstract

The invention relates to a composition for treating a patient suffering from a bowel disease associated with chronic inflammations, the composition comprising at least one DNAzyme which specifically inhibits the expression of GATA-3. A further aspect of the invention relates to the use of such a composition as a drug.

Claims

1. A composition for treating a patient suffering from a bowel disease associated with chronic inflammations, the composition comprising at least one DNAzyme which specifically inhibits the expression of GATA-3.

2. The composition as claimed in claim 1, characterized in that the DNAzyme has the sequence hgd40 (GTGGATGGAggctagctacaacgaGTCTTGGAG).

3. The composition as claimed in either of claims 1 and 2, characterized in that the concentration of the DNAzyme in the composition is between 0.75 mg/ml and 75 mg/ml.

4. The composition as claimed in any of the preceding claims, characterized in that the composition is in the form of an aqueous solution.

5. The composition as claimed in any of the preceding claims, characterized in that the composition comprises at least one salt.

6. The composition as claimed in claim 5, characterized in that the salt is sodium chloride and/or potassium chloride and/or a phosphate.

7. The composition as claimed in any of the preceding claims, characterized in that the composition is suitable for rectal administration.

8. The composition as claimed in any of the preceding claims, characterized in that the composition is, in the case of a desired therapy period of n days, administered over an administration period of not more than n days, especially an administration period of not more than $\frac{n}{2}$ days.

9. The use of the composition as claimed in any of claims 1 to 9 as a drug for treating a patient suffering from a bowel disease associated with chronic inflammations.

10. The use as claimed in claim 9, characterized in that the composition is administered in the form of a suppository.

11. The use as claimed in claim 10, characterized in that the composition is administered in the form of an enema and/or a rectal foam.

12. The use as claimed in any of claims 9 to 11, characterized in that the composition is administered such that the administered dose of the DNAzyme is between 10 mg and 500 mg per patient per day.

13. The use as claimed in any of claims 9 to 12, characterized in that the composition is, in the case of a desired therapy period of n days, administered over an administration period of not more than n days, especially an administration period of not more than $\frac{n}{2}$ days.

14. The composition as claimed in any of claims 1 to 8 for use in the treatment of a patient suffering from a bowel disease associated with chronic inflammations.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0021] FIG. 1 shows mean values of total MAYO scores from a series of experiments to test the composition according to the invention in a graph;

[0022] FIG. 2 shows mean values of total MAYO scores from the series of experiments from FIG. 1 in a table;

[0023] FIG. 3 shows mean values of sigmoid endoscopic MAYO scores from a series of experiments to test the composition according to the invention as a bar chart; and

[0024] FIG. 4 shows mean values of endoscopic MAYO scores from the series of experiments from FIG. 3 in a table.

DETAILED DESCRIPTION OF THE INVENTION

[0025] A person skilled in the art is aware that downregulation of expression can be understood to mean either a partial inhibition or a complete inhibition of the expression. In any case, the expression is significantly reduced in comparison with the natural expression level.

[0026] In this connection, what can be provided according to a preferred embodiment is that the DNAzyme has the sequence hgd40 (GTGGATGGAggctagctacaacgaGTCTTGGAG) (SEQ ID No. 1). This sequence exhibits particularly high enzyme activity and cleaves GATA-3 mRNA with very high specificity and with high efficiency. Consequently, a DNAzyme having the sequence hgd40 is outstandingly suitable for specific and effective treatment of bowel diseases which are Th2-dependent, i.e., which correspond to an increased GATA-3 level. However, DNAzymes having other sequences with which the expression of GATA-3 can likewise be specifically inhibited are also conceivable.

[0027] According to an advantageous embodiment of the invention, what is provided is that the concentration of the DNAzyme in the composition is between 0.75 mg/ml and 75 mg/ml. What is especially provided in this connection is that the concentration of the DNAzyme in the composition is approx. 7.5 mg/ml. Such a concentration proves to be particularly efficient. DNAzyme concentrations of under 0.75 mg/ml may be associated with a high loss of action of the composition. At the same time, the risk of toxicity, which may exist when administering the composition, may increase in the case of concentrations of over 75 mg/ml. With respect to absolute amounts, what can be provided according to the invention is that the DNAzyme hgd40 is administered in a dose of from 10 mg to 500 mg per patient per day. What can be especially provided is a dose which is between 50 mg and 250 mg per patient per day. Surprisingly, such a composition has the result that a positive effect of the active ingredient can also still be observed weeks after administration of the composition. The composition is therefore outstandingly suitable for treating a patient suffering from a bowel disease associated with chronic inflammations because DNAzymes administered in this way display their action over a long period of time. The composition according to the invention thus leads to a high degree of remission in the patients treated with the composition.

[0028] It is also advantageous when the composition is in the form of an aqueous solution. Producing such a solution is economical and simple. In addition, an aqueous solution does not have increased toxicity, meaning that it is suitable for use in therapeutics.

[0029] A further advantage arises from the design variant according to which the composition comprises at least one salt. What is especially provided in this connection is that the salt is sodium chloride and/or potassium chloride and/or a phosphate. According to the invention, it is intended that the hgd40 be present in a dissolved state in PBS for use, and so the composition is essentially a phosphate-buffered saline solution (PBS) containing the DNAzyme as active ingredient. However, other buffers common in biochemistry are also conceivable. In addition, further additives such as, for example, EDTA can be added.

[0030] According to an advantageous further development of the invention, what is provided is that the composition is suitable for rectal administration. This has the advantage that the DNAzyme active ingredient hgd40 can act directly at the site of inflammation, namely at the surface mucosa of the large intestine. There, active ingredient is taken up by the inflamed mucosa. The result is a rapid and efficient action of the therapeutic. However, oral forms of administration such as, for example, capsules, pills or tablets are also conceivable.

[0031] As a further feature of the composition, what can be provided is that the composition is, in the case of a desired therapy period of n days, administered over an administration period of not more than n days. What can be intended in this connection is that the administration period comprises, in the case of a desired therapy period of n days, not more than

[00001]$\frac{3n}{4}$

days of the desired therapy period. What can be especially provided is an administration period of not more than

[00002]$\frac{n}{2}$

days of the desired therapy period. Said therapy period is to be understood to mean the period during which a patient suffering from a bowel disease associated with chronic inflammations is to be treated (i.e., during which the active ingredient of the composition is to act in the patient and therefore control the disease symptoms).

[0032] Such a dosing scheme, in which the composition is, in the case of a desired therapy period of n days, to be administered over an administration period of not more than n days, is possible not least because the composition leads to a high degree of remission in the treated patients. This in turn results in the advantageous effect of a patient not having to be treated longer than necessary. This is desirable because it provides relief for the patient to be treated.

[0033] A further aspect of the invention consists in the use of the composition as a drug for treating a patient suffering from a bowel disease associated with chronic inflammations. The composition can also be referred to as SB012 when it is used as a drug. What can be especially provided in this connection by the invention is that the composition is administered in the form of a suppository. Alternatively, what can be provided is that the composition is administered in the form of an enema or a rectal foam. Advantageously, the composition SB012 can thus be used to treat affected patients either as a drug within a supportive therapy or in the course of a therapy of its own. What especially arises, then, from the form of the composition or the drug as suppository, enema or rectal foam is a simple and rapid administrability of the drug. Consequently, the drug can be administered on an outpatient basis and, if necessary, even without the help of skilled staff.

[0034] In a preferred use variant, the composition is administered such that the administered dose of the DNAzyme is between 10 mg and 500 mg per patient per day. What can be especially provided in this connection is a dose which is between 50 mg and 250 mg per patient per day. Surprisingly, such use of the composition has the result that a positive effect of the active ingredient can also still be observed weeks after administration of the composition. Said use is therefore outstandingly suitable for treating a patient suffering from a bowel disease associated with chronic inflammations because DNAzymes administered in this way display their action over a long period of time. The preferred use thus leads to a high degree of remission in the patients treated with the composition.

[0035] In addition, what can be provided in the use according to the invention is that the composition is, in the case of a desired therapy period of n days, administered over an administration period of not more than n days. What can be intended in this connection is that the administration period comprises, in the case of a desired therapy period of n days, not more than

[00003]$\frac{3n}{4}$

days of the therapy period. What can be especially provided is an administration period of not more than

[00004]$\frac{n}{2}$

days of the desired therapy period. The reason for this is the high degree of remission of the composition. A drug administered according to such a dosing scheme, i.e., in which the drug is, in the case of a desired therapy period of n days, administered over an administration period of preferably not more than

[00005]$\frac{n}{2}$

days, has the positive effect of a patient suffering from a bowel disease associated with chronic inflammations not having to be treated longer than necessary. A shorter administration period minimizes the stress on the patients to be treated and is therefore advantageous.

[0036] The above-described advantages and effects arise especially when using the composition according to the invention in the treatment of a patient suffering from a bowel disease associated with chronic inflammations.

[0037] Further features, details and advantages of the invention become apparent from the wording of the claims and from the following description of exemplary embodiments and figures.

[0038] In one embodiment, the composition containing the DNAzyme hgd40 is present in a pharmacologically compatible carrier together with excipients and/or fillers or as a solvent.

[0039] The composition can then, for example, be produced and administered in the form of suppositories, drops, mouth spray, nasal spray, pills, tablets, film-coated tablets, layered tablets, suppositories, gels, ointments, syrup, powders for inhalation, granules, emulsions, dispersions, microcapsules, capsules, powders, or solutions for injection. Moreover, the group of pharmacologically compatible carriers encompasses formulations such as layered tablets for the controlled and/or continuous release of the active ingredient and also microencapsulations as a specific dosage form.

[0040] Such formulations are highly suited for rectal administration. However, other forms of administration can also be provided, such as, for example, inhalation or intravenous, intraperitoneal, intramuscular, subcutaneous, mucocutaneous, oral, transdermal, topical, buccal, intradermal, intragastric, intracutaneous, intranasal, intrabuccal, percutaneous or sublingual administration.

[0041] The addition of excipients improves the pharmaceutical properties of the composition for the specific use. Examples of pharmacologically compatible excipients that can be used are lactose, starch, sorbitol, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol and the like. The aforementioned carriers can consist of such an excipient to an extent of up to 95% (w/w). To prepare suppositories, preference is given to using low-melting waxes, fatty acid esters and/or glycerides.

[0042] When processing small to very small amounts, fillers are usually required, which ensure that the composition according to the invention receives the necessary size/mass and can be used without any problems. The filler used is a substance from the group comprising starches (corn, potato and wheat starch), lactose, glucose, mannitol, sorbitol and fructose.

[0043] Furthermore, disintegrants, colorants, flavorings and/or binders can be additionally added to the composition. The disintegrants used are substances from the group comprising starches (corn, potato and wheat starch, sodium carboxymethyl starch), natural and synthetic gums such as, for example, locust bean gum, karaya, guar, tragacanth, agar, cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, alginates, aluminas, bentonites, PVP (polyvinylpyrrolidone), Carbopol and magnesium peroxide. These constituents can be used in amounts of up to 30% (w/w). Disintegrants ensure good compressibility of the composition by improving particle adhesion. They also facilitate later disintegration, for instance in the gastrointestinal tract. They work by absorbing moisture, increasing capillarity and swelling, or evolving gases and effervescing under the influence of moisture, or by increasing the wettability of the tablets as a hydrophilization agent. Binders ensure cohesion in granules and, alongside applied pressure, tablet strength.

[0044] Liquid formulations encompass solutions, suspensions, sprays and emulsions, such as, for example, aqueous solutions for injection or solutions based on water and propylene glycol for parenteral injections.

[0045] Lubricants can also be provided. Lubricants are an umbrella term for flow agents, lubrication agents and mold-release agents. Flow agents generally improve flow properties by reducing frictional and adhesive forces between particles of bulk materials. They reduce interparticle friction and reduce surface moisture.

[0046] The lubricants used can be substances from the group comprising boric acid, stearates (e.g., magnesium stearate, calcium stearate, potassium stearate), stearic acid, high-melting waxes and water-soluble substances from the group comprising sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and amino acids (e.g., leucine). Lubricants can be used in amounts of up to 15% (w/w).

[0047] FIGS. 1 to 4 are each based on the same series of experiments. In the series of experiments, patients were treated with a DNAzyme which has the sequence GTGGATGGAggctagctacaacgaGTCTTGGAG (hgd40) (SEQ ID No. 1) and which specifically inhibits or downregulates the expression of GATA-3. However, treatment with other DNAzymes which specifically inhibit or downregulate the expression of GATA-3 is also conceivable. In parallel to the treatment with the DNAzyme hgd40, a PBS buffer solution was administered to a control group. Said control group consequently did not receive a DNAzyme.

[0048] FIG. 1 and FIG. 2 both depict the same results. In FIG. 1, mean values of total MAYO scores from the aforementioned series of experiments to test the composition according to the invention are shown in a graph. In FIG. 2, mean values of total MAYO scores from the series of experiments from FIG. 1 are depicted in a table. The MAYO score is used especially in clinical studies as an index for determining the disease activity of ulcerative colitis. This four-level index includes the stool frequency, the severity of rectal bleedings, the endoscopic assessment of the mucosa and the overall assessment by a physician. In the graph, the mean value of the MAYO scores of patients from the series of experiments (Y-axis) is plotted against the duration of treatment in days (X-axis).

[0049] In the series of experiments that corresponds to the MAYO scores shown in FIG. 1 and FIG. 2, patients were treated with a DNAzyme which has the sequence GTGGATGGAggctagctacaacgaGTCTTGGAG (SEQ ID No. 1) and which specifically inhibits or downregulates the expression of GATA-3 (FIGS. 1 and 2, hgd40). In parallel to the treatment with the DNAzyme hgd40, a PBS buffer solution was administered to a control group (FIGS. 1 and 2, Placebo). The control group consequently did not receive a DNAzyme. The period in which the patients and the control group were treated with the active ingredient and with the placebo, respectively, is highlighted in gray in FIG. 1 (28 days). The MAYO scores were measured three times: 7 days before the start of the administration period (7), 28 days after the start of the administration period (28) and 28 days after the end of the administration period (56).

[0050] In FIG. 1, the MAYO scores in the table from FIG. 2 are depicted as a graph. What becomes impressively apparent here is that the mean value of the MAYO scores of the patients who were treated with hgd40 decreases to a significantly higher extent than the mean value of the MAYO scores from the control group. If, at the start of the series of experiments (7), the mean MAYO score of the treated patients is still approx. 8.4, it is, 28 days after the start of the administration period, already approx. 6.5. At the end of the series of experiments (56), the mean MAYO score of the patients treated with hgd40 is approx. 5.0 (cf. FIG. 2). Overall, a decrease in the mean MAYO score of the patients of approx. 3.4 can thus be observed. In comparison, the mean MAYO score of the control group only decreases by approx. 1.0 (from 10.0 to 9.0; FIG. 2).

[0051] The results depicted in FIG. 1 and FIG. 2 impressively demonstrate that the composition according to the invention is suitable for treating a patient suffering from a bowel disease associated with chronic inflammations.

[0052] What is particularly advantageous in this connection is that a positive effect of the active ingredient can also still be observed over a period of at least 28 days after the end of the last administration of the composition. This effect becomes apparent from the fact that the MAYO scores of the treated patients also still decrease after day 28 (last day of the administration period) over a period of at least four further weeks. The composition according to the invention therefore surprisingly leads to a high degree of remission in the treated patients.

[0053] FIG. 3 and FIG. 4 are based on the same series of experiments as in FIG. 1 and FIG. 2. However, the results corresponding to FIG. 3 and FIG. 4 were obtained from other points of view. In FIG. 3, the mean values of sigmoid endoscopic MAYO scores are depicted as a bar chart. The associated measurement data can be seen in FIG. 4. A person skilled in the art understands the term sigmoid to mean the last part of the large intestine in humans, the colon sigmoideum. In the case of the endoscopic MAYO score, endoscopic findings are assessed with respect to disease-typical characteristics.

[0054] Analogously to FIGS. 1 and 2, in the series of experiments that corresponds to the endoscopic MAYO scores shown in FIG. 3 and FIG. 4, patients were treated with a DNAzyme which has the sequence GTGGATGGAggctagctacaacgaGTCTTGGAG (SEQ ID No. 1) and which specifically inhibits or downregulates the expression of GATA-3 (FIG. 3 and FIG. 4, hgd40). However, treatment with other DNAzymes which specifically inhibit or downregulate the expression of GATA-3 is also conceivable in the case of FIG. 3 and FIG. 4. In parallel to the treatment with the DNAzyme hgd40, PBS buffer solution was administered to a control group (FIG. 3 and FIG. 4, Placebo). Said control group consequently did not receive a DNAzyme. The period in which the patients and the control group were treated with the active ingredient and with the placebo, respectively, was 28 days. The MAYO scores were measured twice: 7 days before the start of the administration period (7) and on the 28th and last day of the administration period (28).

[0055] The bar charts in FIG. 3 provide an overview of the overall course of the series of experiments. Depicted in dark gray are the bars corresponding to the endoscopic MAYO scores of the control group (FIG. 3, Placebo). The white bars in FIG. 3 correspond to the MAYO scores of the patients who were treated with hgd40 (FIG. 3, hgd40). In FIG. 3, what is then compared in each case is the mean value of the MAYO scores at the first time point (7 days before the start of the administration period;7) with the mean value of the MAYO scores at the end of the administration period (28th day of the administration period; 28). No significant difference can be seen here in the case of the control group (cf. FIG. 3, gray bars). The mean value of the MAYO scores was approx. 2.6 on day7 and approx. 2.5 on day 28 (cf. FIG. 4, Placebo).

[0056] This contrasts with the findings of the patients treated with hgd40. In the case of the patients treated with hgd40, MAYO scores were likewise given at the first time point (7) and at the end of the administration period (28th day). The mean values of these MAYO scores are compared in FIG. 3 (FIG. 3, white bars). What can be clearly seen here in the group of patients treated with hgd40 is that there is a significant difference between the mean value of day7 and the mean value of day 28. The mean MAYO score is thus reduced from approx. 2.2 (day7) to approx. 1.5 (FIG. 4, hgd40).

[0057] The results depicted in FIGS. 1 to 4 thus impressively demonstrate that the composition according to the invention comprising at least one DNAzyme which specifically inhibits the expression of GATA-3 is suitable for treating a patient suffering from a bowel disease associated with chronic inflammations. In particular, the results show that the complaints which usually occur in connection with chronic inflammatory bowel diseases can be reduced effectively. At the same time, the results in FIGS. 1 and 2 especially show that the composition ensures improved remission.