KR20150063040A - Metadoxine for use in the treatment of liver diseases, and metadoxine extended release formulations - Google Patents

Abstract

The present invention relates to the use of metadoxine for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic fatty liver disease (NASH) and for the improvement of survival in severe alcoholic hepatitis patients, ≪ / RTI >

Description

METADOXINE FOR USE IN THE TREATMENT OF LIVER DISEASES AND METADOXINE EXTENDED RELEASE FORMULATIONS FOR USE IN THE TREATMENT OF LIVER DISEASE,

The present invention relates to novel therapeutic uses of meta-xanthine and novel agents comprising meta-xanthine which are made for new indications and especially once-a-day dosing.

5-oxo-L-proline compound having 5-hydroxy-6-methylpyridine-3,4-dimethanol (1: 1); also referred to herein as MTD) is a synthetic compound having the following formula:

Metadoxine in the form of conventional immediate release (IR) tablets containing 500 mg of active ingredient is currently marketed for the treatment of chronic and acute alcoholic and alcoholic liver disease (ALD). Because the half-life of the drug is one hour, multiple administrations in the form of tablets or solutions for oral or parenteral administration are required within 24 hours.

Although pharmaceutical technology for obtaining an extended release drug has been known in the past, there is no known extended release drug of metadoxine. In fact, the inventors have found that there is a significant difficulty in the preparation of metadoxin preparations that can be administered only once per day, and in particular have faced problems related to biological equivalence. Various attempts to produce meta-xoxine with other known polymers in a sustained-release system have shown that the desired result, i.e., a composition that can be administered once a day and has biological equivalence to the plasma concentration obtained with existing compositions sold on the market I did not provide it. As a matter of fact, nowadays, in dosage units containing 500 mg of active ingredient, an average of approximately 1000 mg of active ingredient is presently administered twice / thrice daily and the therapeutic haematic level of metadoxin is maintained It is considered that the administration is necessary.

In addition, a common disease of a person taking metadoxine at a dosage of 500 mg twice daily is sleep disturbance at night. This may be due to the high accumulation of metadoxine in the second dose administered at night.

Although metadoxin has been investigated for pharmacological effects on liver, especially fatty liver, the possibility of metadoxin for the prevention and / or treatment of nonalcoholic fatty liver disease (NAFLD) and especially nonalcoholic fatty liver disease (NASH) There has been no clinical evidence to measure the effect.

In addition to long-term excess alcohol use, fat accumulation in the liver leads to NAFLD and NASH fatty liver disease. NAFLD and NASH have been implicated in insulin resistance and metabolic syndrome, and may be effective in first-line treatment of weight loss and other insulin resistance states such as oral antidiabetic agents (eg, type 2 diabetes). NASH is a major cause of unexplained cirrhosis of the liver.

A first object of the present invention is to provide a novel treatment method of NAFLD and NASH.

A second object of the present invention is to provide a new administration scheme for the treatment and / or prevention of metadoxin (MTD), particularly NAFLD and NASH.

A third object of the present invention is to provide a method for the treatment of metadoxin (MTD) for the reduction of mortality in patients with severe alcoholic hepatitis (SAH).

The fourth object of the present invention is to provide a novel oral preparation and therapeutic regimen for meta-cortisone that eliminates the need for multiple daily doses to improve the patient's condition of reception, To eliminate sleep disturbances that occur during the night.

Thus, according to a first aspect, the present invention relates to a new use of metadoxine (MTD) for the prophylaxis and treatment of NAFLD and NASH. With respect to the first aspect of the present invention, metadoxine can be administered in the form of a pharmaceutical composition for oral administration (tablets, capsules, tablets, feces or syrups) or in the form of a parenterally administered solvent.

As used herein, the terms "NAFLD" and "NASH " do not include NAFLD and NASH that are derived, associated or associated with liver fibrosis.

The pharmaceutical composition is preferably administered in an amount of 250 mg to 2,500 mg per day, advantageously 500 mg to 1,500 mg per day, most preferably about 1,000 mg to 1,500 mg per day, but is preferably administered in an amount of from about 1,000 mg to about 1,500 mg per day, Different doses may be selected by the physician depending on the weight and general clinical condition as well as the diagnostic status of NAFLD / NAS.

The pharmaceutical composition preferably comprises one or more pharmaceutically acceptable carriers and is prepared according to methods well known to those of ordinary skill in the art.

Thus, according to the present invention, meta-coxin is a metabolic syndrome that is known to be a contributing factor to the onset of NAFLD, which can be easily caused by subjects, for example, progression of NASH to cirrhosis and ultimately death, Can be used to treat NAFLD and NASH and to prevent NASH in subjects.

According to a first aspect of the present invention there is also provided a method for the treatment of NAFLD and NASH and for the prevention of NASH comprising administering to a subject in need of an effective amount of metadoxin.

As used herein, "subject" refers to an animal, particularly a mammal, more particularly a human.

According to a second aspect, the present invention relates to a novel administration scheme, which comprises orally administering MTD once a day, in particular for the treatment and / or prevention of NASH.

According to a preferred embodiment of the second aspect of the invention, the MTD composition is administered once a day in the morning, advantageously after breakfast.

According to a third aspect, the present invention relates to the use of MTD to provide a novel therapeutic regimen for the treatment of severe alcoholic hepatitis (SAH), wherein the survival rate of the patient is significantly increased. Patients are treated with corticosteroids (eg, prednisone) alone, depending on the practice. Combined therapy with MTD and corticosteroids increases patient survival by more than 300% over 90 days (68% versus 20%) compared to single therapy with corticosteroid alone. Thus, single treatment with corticosteroids causes 80% of SAH patients to die on the 90th day, while combination therapy with MTD causes a significant reduction of 32% in 90 days.

It is well known that once-a-day dosing improves patient acceptance and, as a result, results in improved outcomes, several medications, including MTD, are often given twice or thrice daily, In particular, given that patients with metabolic syndrome are taking multidrug therapy, there is no way to predict if a single dose will have the same clinical effect.

According to a second aspect of the present invention, the MTD is administered in the form of an oral composition according to a dosage regimen which provides a daily dosage of about 1,000 mg to 1,500 mg of the active ingredient, for example, 1,000 mg, 1,250 mg or 1,500 mg do.

According to a third aspect of the present invention, a 1,500 mg daily dose MTD is co-administered with a corticosteroid (e.g., prednisone) to patients with severe alcoholic hepatitis (SAH) to improve the survival rate of the patients. Compared with prednisone monotherapy, the combination of prednisone and 1,500 mg MTD for 1 day for 30 days proved to significantly improve patient survival at 90 days (68% versus 20%). Therefore, MTD can be concluded to be a life-sustaining drug that increases survival rate to more than 300% at 90 days.

According to a preferred embodiment of this aspect of the invention, the metadoxine is administered in combination with at least one pharmaceutically acceptable carrier to provide a capsule containing from about 750 mg to about 1500 mg, for example from 1000 mg to 1500 mg, , Especially in the form of tablets or coated pellets (microspheres) of a divided oral tablet or sugar.

According to another preferred embodiment of this aspect of the invention, the oral composition is a once-a-day extended release pharmaceutical formulation, which may be prepared according to any known process.

According to another preferred embodiment of this aspect of the invention, the combination therapy of MTD with prednisone is carried out by the combination of 40 mg of prednisone and 1,000 mg to 1,500 mg of MTD, in particular 40 mg of active ingredient prednisone, And a prolonged release layer containing from 1,000 mg to 1,500 mg of MTD. Advantageously, this combination is a fixed dose combination of 40 mg of prednisone and 1,000 mg of MTD, or 40 mg of prednisone and 1500 mg of MTD. Such combinations are prepared by methods well known in the art and include pharmaceutically acceptable excipients. According to another preferred embodiment of this aspect of the invention, the composition is administered once a day, preferably in the morning after breakfast.

Alternatively, the extended release pharmaceutical formulation may contain an MTD of 500 mg to 1000 mg, advantageously 750 mg of MTD, and may be administered twice a day.

As a further alternative, the extended release pharmaceutical formulation may comprise 500 mg to 1000 mg of MTD and approximately 20 mg of prednisone, advantageously 750 mg of MTD and 20 mg of prednisone, administered twice daily .

Surprisingly, it has been found that these agents are more acceptable than the usual agents for patients, since they should be administered twice a day, i.e., every 12 hours, but do not cause typical sleep disturbances.

According to a fourth aspect, the present invention relates to a novel oral preparation of MTD and the use of the therapeutic regimen.

According to a fourth aspect of the present invention, the MTD is administered in the form of a novel oral, once-a-day extended release pharmaceutical formulation, wherein about 1,000 mg to about 1,500 mg of metadoxine is administered in combination with a selected excipient and a pharmaceutically acceptable cellulosic derivative , A pharmaceutically acceptable methacrylate derivative, and a mixture thereof.

According to the present invention, "once-a-day extended release pharmaceutical formulation" holds the active ingredient for a longer period of time than the conventional composition in order to maintain the plasma concentration of the drug for 24 hours, , Slowly releasing pharmaceutical preparations. This formulation is also referred to herein as "TEET" (treatment efficiency enhancing technology) formulation.

The expression "pharmaceutically acceptable cellulosic derivatives" is intended to encompass a composition comprising a composition, for example, a pharmaceutically acceptable cellulosic, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT) Propyl methylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, mixtures thereof, and salts thereof. The term " derivative "

The expression "pharmaceutically acceptable methacrylate derivative" refers to the time required for the release of a drug from a composition, for example a copolymer methacrylic acid / methyl methacrylate, copolymer methacrylic acid / ethyl methacrylate, mixtures thereof, Lt; / RTI >

Preferred release modifier polymers according to the present invention are advantageously pharmaceutically acceptable cellulose derivatives selected from methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and mixtures thereof.

The release modulator polymer is used in an amount of 75 mg to 250 mg per tablet, preferably 100 mg to 175 mg, such as 100 mg, 125 mg, 150 mg or 175 mg, per administration unit, alone or in combination.

According to an advantageous embodiment of this aspect of the invention, the novel oral preparation comprises about 1,000 mg to 1,500 mg of metadoxine and 50 mg to 250 mg, preferably about 150 mg of one or more cellulose derivatives, for example methyl cellulose and Lt; RTI ID = 0.0 > hydroxypropylmethylcellulose. ≪ / RTI >

The formulations of the present invention may be formulated with excipients that are well known to those of ordinary skill in the art, such as lubricants, fillers, compression aids, plasticizers with or without additives such as lubricants, disintegrants, granulating agents, Other excipients are included.

Fillers and diluents include but are not limited to confectioner sugar, compressible sugar, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, Calcium sulfate, calcium phosphate or calcium trisphosphate, calcium sulfate, and the like.

Lubricants include, but are not limited to, those conventionally known in the art, such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate and magnesium stearate , Stearic acid, hardened vegetable oil, talc, and the like.

Glidants include, but are not limited to, silicon dioxide; 3 magnesium silicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicone hydrogel and the like.

Disintegrants include, but are not limited to, starch; Clay; cellulose; Alginate; sword; Cross-linked polymers such as cross-linked polyvinylpyrrolidone or crospovidone, cross-linked sodium carboxymethylcellulose or croscarmellose sodium, cross-linked calcium carboxymethylcellulose; Guar gum and the like.

Granulating agents include, but are not limited to, polyvinylpyrrolidone, microcrystalline cellulose, and the like.

Preferred formulations of the invention advantageously comprise, for example, from 5 mg to 200 mg, such as from 10 mg to 150 mg, advantageously 10 mg, 50 mg, 70 mg or 100 mg of one or more fillers, For example, talc, lactose or microcrystalline cellulose.

The agent may comprise an anti-fibrotic agent and / or one or more anti-oxidants.

The preferred formulations of the invention are preferably prepared in tablet form by mixing the active ingredient, the release modifier polymer (or mixture of polymers) and any other ingredients according to methods known in the art and compressing them with appropriate hardness .

According to a preferred embodiment of this aspect of the invention, the novel formulation is made of an intragranular part and an extragranular part. The active ingredient, the cellulose derivative and one or more additional excipients are present in the granular part, but the extragranular part may contain, for example, fillers and lubricants or lubricants, for example talc and magnesium stearate.

According to yet another aspect, the present invention comprises a process for the preparation of the tablets of the present invention, comprising:

(a) mixing the metadoxine with a release modifier polymer, optionally with a filler;

(b) pre-compressing the mixture (a);

(c) pulverizing the compressed mixture in (b);

(d) optionally mixing the ground mixture in (c) with other desired excipients;

(e) compressing the mixture (d).

According to another preferred embodiment, the compression in step (b) is carried out to obtain a tablet hardness of 7 Kg / cm ² to 9 Kg / cm ² .

According to a further preferred embodiment, in step (d) a lubricant and / or a filler are mixed.

The formulations of the present invention may also be prepared in the form of pellets (microspheres) coated onto capsules.

The formulations of the present invention have undergone various tests to evaluate their bioavailability in addition to their solubility profile and stability.

It can be concluded through the tests performed that the formulations of the invention, in particular the preferred formulations in tablet form as defined above, are stable and have an optimal dissolution profile to maintain the hematin concentration of meta- there was.

In addition, the bioavailability test performed with the preferred formulations in tablet form as defined above provided excellent results and improved efficacy of treatment compared to conventional formulations of metadoxin (e.g., 500 mg twice daily) . Therefore, the preparations of the present invention are suitable for administration once a day instead of twice or three times a day of the conventional preparation.

Alternatively, the same extended release pharmaceutical formulation may comprise 500 mg to 1000 mg of MTD, advantageously 750 mg of MTD, and may be administered twice a day.

As described above, these preparations surprisingly do not cause typical sleep disturbances even when administered at night.

All of the new extended prolonged release formulations may advantageously further comprise a corticosteroid reagent, preferably prednisone, in an amount of 40 mg per day, i.e., about 40 mg of prednisone or 1 When administered twice daily, approximately 20 mg of prednisone may be included.

Representative agents according to preferred embodiments of this aspect of the invention are reported in the experimental part of the specification.

The novel agents of the present invention, which are life-saving agents for significantly increasing the survival rate of patients with SAH, can be used for the treatment and prevention of hepatic degeneration of all causes, i.e. for the treatment of NAFLD, for the treatment and prevention of NASH, as well as for the treatment of chronic alcohol intoxication .

Thus, new agents can be used to improve liver function, promote fatty liver regeneration, and reduce the incidence of diabetes, regardless of the cause of the pathology.

New agents may also be administered to subjects suffering from metabolic syndrome and / or obesity and / or diabetes to prevent NAFLD and NASH.

Applicants have conducted extensive clinical studies and have found that metazoansin is very effective in the treatment of NASH. Details of the clinical protocols and results are reported in the experimental part of this specification.

As can be seen, oral administration of 1000 mg of metadoxine daily significantly improved the condition of the subjects treated in conjunction with fatty liver and degenerative inflammation.

In another clinical study conducted in patients with severe alcoholic hepatitis (SAH), 30-day combination therapy with 1,500 mg MTD and 40 mg prednisone daily significantly improved patient survival compared to prednisone monotherapy . Survival rates were assessed at 30 and 90 days. The survival rate at 30 days was 74.3% vs. 45.7% (p = 0.02) in the MTD group; The survival rate was 68.6% vs. 20% (p = 0.0001) at 90 days.

Experimental part

Example 1

Prolonged release once daily Methadoxine tablets 1,000 mg

Example 2

Metered-dose 1,500 mg extended release tablet

Example 3

Extended release methadoxine tablets 750 mg

Example 4

A fixed dose combination of metadoxin 750 mg and prednisone 20 mg combined with an extended release tablet

Example 5

Clinical study of NASH

A total of 134 patients were enrolled in a double-blind, randomized, placebo-controlled multicenter study. Patients were randomly assigned to two groups receiving metadoxin (75 patients) or placebo (59 patients) and were treated for 16 weeks. Nine patients in the metadoxin group discontinued treatment before completion of the study and eight patients stopped in the placebo group.

A protocol analysis of a group of 82 patients who underwent paired biopsy (n = 82) before and after treatment showed that metadocin 1000 mg / day was significantly effective in reducing fatty liver (fat accumulation in the liver). Reduced fatty liver has been reported in 34 patients (73.9%) of the metadoxin group compared with 25% of the placebo group (p <0.01). The mean change in the baseline was -0.76 ± 0.92 for metadoxine compared to 0.00 ± 0.76 for placebo (p <0.01). The mean change at baseline is -1.00 [-1.0, 0.0] for metadoxine compared to 0.00 [-0.75, 0.0] for placebo (p <0.01)

In the placebo group, 58.8% of the patients in the metadoxin group had a reduction in metamorphic inflammation with a difference of 12% compared to 46.9%. The difference (p = 0.331) is not statistically significant, but there is a significant improvement in the metadoxin group, which indicates that recovery takes a long time and requires long-term, if possible, up to one year of therapy.

The treatment objective analysis of the completed group is shown in the following table.

Table 1a: Patient's baseline characteristics

Table 1 b: Distribution of Symptoms

Table 1c: Baseline distribution of laboratory parameters

Table 1d: Baseline distribution of vital signs and physical examination

Table 1e: Distribution of reference value results

Data were expressed as mean ± SD, center [25%, 75%] or N (%).

Insulin resistance was calculated using a homeostatic model for insulin resistance (HOMA-IR) according to the following formula: [glucose (mg / dL) x insulin (uU / mL)] /

Metamorphosis stage of metamorphosis

ITT Analysis:

74 patients were included in the results analysis.

▶ 34 patients reached the baseline and underwent a final biopsy study

· One patient is uncertain

Forty patients did not perform a final biopsy study and considered the worst case as "no improvement".

· Two people do not follow up

· 4 people without reaction

· 3 others

· 31 completed the study but no final biopsy

PP analysis:

Thirty-four patients were included in the results analysis.

Results of degenerative inflammation in the placebo group

ITT Analysis:

59 patients were included in the results analysis.

▶ Thirty-two patients reached baseline and underwent a final biopsy study

27 did not perform a final biopsy study and considered the worst case as "no improvement".

· No one follow-up

· 5 people without reaction

· 2 others

· 19 completed the study but no final biopsy

PP analysis:

Thirty-two patients were included in the results analysis.

Results of the Metabolism Phase

ITT Analysis:

75 patients were included in the results analysis.

▶ Forty-six patients reached the baseline and underwent a final lipectomy test.

Twenty-nine did not perform a final biopsy study and considered the worst case as "no improvement."

· No two follow-up actions

· 4 No reaction

· 3 others

· 20 completed the study but no final biopsy

PP analysis:

Forty-six patients were included in the results analysis.

Results of the placebo phase of the placebo

ITT Analysis:

59 patients were included in the results analysis.

▶ 36 patients reached the baseline and conducted a final lipectomy test study.

Twenty-three did not undergo a final biopsy study and considered the worst case as "no improvement."

· No one follow-up action

· 5 people without reaction

· 2 others

· 15 completed the study, but no final biopsy.

PP analysis:

36 patients were included in the results analysis

Table 2: Primary efficacy analysis

Data were expressed as mean ± SD, center [25%, 75%] or N (%).

We used Student Independent Sample (t) test and Whitney Whitney test respectively to test the mean change at baseline and the median change at baseline.

The ITT analysis included replacing 50 patients who did not undergo liver biopsy and 17 patients who did not follow up with the worst outcome from baseline. One patient was excluded because the histological score was unknown at baseline.

The P-value for percent improvement was calculated using Pearson's chi-square method.

Table 3: Side effects reported weekly by intervention

Example 6

Clinical study of SAH

Severe alcoholic hepatitis (SAH) is a disease with a high mortality rate of up to 50% after 2 months without treatment. Standard treatments include corticosteroids, such as 1 day 40 mg of prednisone is used. A randomized, open clinical trial has been conducted to investigate the clinical benefit of meta-coxin for improving the survival rate of patients with SAH.

A total of 217 patients were selected from 70 patients who participated in the clinical study. Patients were randomly assigned to two treatment groups. Thirty-five patients in group 1 received a standard single-dose regimen of 40 mg prednisone daily for 30 days. 35 patients in group 2 received combination therapy with prednisone 40 mg daily and metadoxine 500 mg three times daily for 30 days. Survival rates were evaluated at 30 days and 90 days, respectively. Significant improvements were observed in patients receiving metadoxin:

The survival rate was 74.3% at 30 days (p = 0.02) in the combination therapy group (prednisone and metadoxine) compared with 45.7% in the single treatment group (prednisone alone)

The survival rate was 68.6% at 90 days (p = 0.0001) in the combination therapy group (prednisone and metadoxine) compared to 20% in the single treatment group (prednisone alone)

Metadoxin also reduced the incidence and progression of complications (encephalopathy and jaundice syndrome).

Claims (27)

Metadoxin for use in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic fatty liver disease (NASH). To increase the survival rate of patients with severe alcoholic hepatitis (SAH), metadocin for use in combination with corticosteroids. 3. The method of claim 2,
The corticosteroid is prednisone, metadoxine. 4. The method according to any one of claims 1 to 3,
Wherein the medicament is administered in an amount of 250 mg to 2,500 mg per day. 5. The method of claim 4,
Wherein the medicament is administered in an amount of about 1,000 mg to 1,500 mg per day. 6. The method of claim 5,
Wherein the medicament is administered once a day in the morning. 7. The method according to any one of claims 1 to 6,
Meta-coxin for use in the prevention of NASH in subjects with metabolic syndrome and / or obesity and / or diabetes. A pharmaceutical composition comprising at least 1,000 mg to 1,500 mg of metadoxine in combination with at least a pharmaceutically acceptable excipient. An extended release pharmaceutical composition comprising 750 mg to 1,500 mg of metadoxine in combination with a polymer, at least an excipient selected from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable methacrylate derivative, a mixture thereof, and the like. 10. The method of claim 9,
Wherein the cellulose derivative is hydroxypropyl methylcellulose. 11. The method according to any one of claims 8 to 10,
Wherein said hydroxypropylmethylcellulose is present in an amount of from 50 mg to 250 mg. The method according to any one of claims 8 to 11,
Further comprising a plasticizer having at least one lubricant, a filler, a compression aid, a lubricant, a disintegrant, a granulating agent, an adsorbent, and a moisture barrier layer. 13. The method according to any one of claims 8 to 12,
Wherein the pharmaceutical composition is an extended release pharmaceutical formulation once a day. 14. The method according to any one of claims 8 to 13,
Said pharmaceutical composition having the following composition.

14. The method according to any one of claims 8 to 13,
A pharmaceutical composition having the following composition.

14. The method according to any one of claims 9 to 13,
Said pharmaceutical composition having the following composition.

17. The method according to any one of claims 8 to 16,
A pharmaceutical composition comprising coated pellets (microspheres) encapsulated in a capsule. 17. The method according to any one of claims 8 to 16,
A pharmaceutical composition further comprising an immediate release layer comprising a corticosteroid. 16. The method according to claim 14 or 15,
40 mg of prednisone. 17. The method of claim 16,
20 mg of prednisone. 21. The method according to claim 19 or 20,
Wherein the two layers are optionally divided into a pharmaceutically acceptable excipient and a second elongated release layer comprising an immediate release layer comprising prednisone and a second extended release layer comprising metadoxine, &Lt; / RTI &gt; 22. The method according to any one of claims 8 to 21,
A pharmaceutical composition for use in the treatment and prevention of hepatic degeneration of all causes. 23. The method of claim 22,
A pharmaceutical composition for use in the treatment and / or prevention of NASH and alcoholic hepatic steatosis. 24. The method of claim 23,
A pharmaceutical composition for use in the prevention of NASH in a subject suffering from metabolic syndrome and / or obesity and / or diabetes. 25. The method of claim 24,
A pharmaceutical composition for use in the improvement of the survival rate of patients with SAH, wherein the metacercoxy is used as a combination therapy with a corticosteroid. 26. The method of claim 25,
Wherein the corticosteroid is prednisone. The method according to any one of claims 8, 14, 15, and 19,
Wherein the pharmaceutical composition is administered once a day.