MXPA06011442A - Sustained-release oral molsidomine composition for treating atherosclerosis - Google Patents

Abstract

The present invention is applicable in the pharmaceutical industry and relates to the use of molsidomine or a pharmaceutically acceptable salt thereof, particularly in the form of a sustained-release solid oral composition effective for 24 hours, for producing a drug for preventing or controlling atherosclerosis.

Description

ORAL COMPOSITION OF MOLSIDOMINE OF PROLONGED RELEASE FOR THE TREATMENT OF ATHEROSCLEROSIS DESCRIPTIVE MEMORY The present invention aims to present a new therapeutic use of molsidomine and its pharmaceutically acceptable salts, particularly under an oral galenic form of prolonged release, effective for 24 hours, for the prevention or treatment of atherosclerosis. Atherosclerosis is a progressive condition of the arteries that compromises the blood supply of organs located downstream. In this way, the atheroma plaques that appear on the wall of the coronary arteries can cause a restriction in the irrigation of the heart (ischemia), which can lead to a myocardial infarction, the main cause of death in the industrialized countries. Risk factors such as hypercholesterolemia or hypertension stimulate the formation of atherosclerotic lesions. In the case of hypercholesterolemia, the mechanism that leads to the formation of these lesions can be summarized in the manner described below. Low density lipoproteins (usually known as LDL) accumulate in the intima (inner wall of the artery) where they oxidize, becoming Ox-LDL. The presence of these oxidized molecules in the intima propitiate the synthesis and expression of adhesion molecules such as ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) on the surface of the endothelium . These adhesion molecules have the characteristic of fixing the monocytes that come from the blood circulation, which infiltrate the vascular wall and transform into macrophages. These macrophages absorb Ox-LDL (phagocytosis) and thus slowly transform into lipid-saturated foam cells. On the other hand, these macrophages release cytokines that provoke a local inflammatory reaction, which favors an even more important concentration of monocytes. The smooth muscle cells multiply and move on the intima. They secrete collagen, elastic fibers and proteoglycans, which leads to a progressive thickening of the lesions. The foam cells also synthesize a factor related to the organic tissues that contributes to the deposition of fibrins in the atheromatous plaque. As a result, increasingly severe endothelial lesions occur. Also, as a result of the above, adhesion molecules and, in particular, ICAM-1, are involved in the formation process of atherosclerotic lesions.

In fact, ICAM-1 is manifested in excess on the endothelium that covers the atheromatous plaques inside the coronary arteries and the human carotids. Recent clinical studies indicate that the severity of atherosclerosis is correlated with the soluble ICAM-1 rates (hereafter, ICAM-ls). On the other hand, in the atherosclerotic models performed on mice, it has been observed that the elimination of ICAM-1s contributes to protect the arteries against the progression of atherosclerosis. For this reason, the reduction in the rates of soluble ICAM-1 appears to be an effective means to restore normal endothelial functions and to prevent and / or moderate the progression of atherosclerosis. On the other hand, it is known in the art that molsidomine is a particularly useful compound in the preventive treatment of anginal crises in all its forms, which acts causing a relaxation of the vascular smooth muscle fiber, as well as an inhibition of the early phases of platelet activation. Molsidomine was marketed in the first instance essentially: - in the form of divisible immediate-release tablets dosed at 2 mg and 4 mg, generally administered three times a day in the treatment of angina or chest pain in effort, and four times a day in the treatment of angina at rest and angina in severe effort; subsequently - in the form of prolonged-release tablets with a dose of 8 mg, which will have to be administered twice a day for prophylactic and long-term treatment in the treatment of angina pectoris. Recently, molsidomine has been commercialized (particularly under the trade name of Coruno® in Belgium) in the form of prolonged-release solid oral composition, effective for 24 hours and in a dose of 16 mg, for the prevention and chronic long-term treatment of stable angina pectoris . The efficacy and tolerance of this composition have been demonstrated in short and long-term studies with a large number of patients. In this context, it was discovered in a surprising and totally unexpected manner that molsidomine, particularly in the form of an oral sustained release solid composition, effective for 24 hours, allows to restore endothelial functions and, consequently, to prevent the physiopathological processes that lead to to atherosclerosis and / or slow down its progress. Specifically, it was found that the daily administration of a galenic form of molsidomine with these characteristics produces a significant decrease in the amount of circulating soluble ICAM-1, which is considered as a biomarker of atherosclerosis and, in this way, in addition to its antianginal characteristics known in the art, molsidomine also inhibits the binding of monocytes on the endothelium and consequently ensure the restoration of endothelial functions, and prevent and / or moderate the progression of atherosclerosis. Thus, in accordance with a first aspect, the present invention aims at the use of molsidomine or one of its pharmaceutically acceptable salts, particularly the form of an effective prolonged-release oral composition for 24 hours, for manufacture of a medicament intended to prevent or attenuate the development of atherosclerosis. In the context of the present invention, molsidomine can be used under its free form, but it can also be used in the form of a pharmaceutically acceptable salt, such as for example a hydrochloride. In the description that follows, the term molsidomine will be used to designate both its free form and the salified form of this molecule. In general, in the treatment of atherosclerosis according to the invention, molsidomine will be administered orally, particularly in the form of prolonged-release tablets, effective for a period of 24 hours. The term "effective (effective) for 24 hours" used herein means that the amount of molsidomine released by the pharmaceutical form used is sufficient to lead to a therapeutic plasma concentration of at least 5 ng / ml, and preferably at least 10 ng / ml of plasma, for a period of about 24 hours. The effects of molsidomine in the treatment of atherosclerosis are particularly important in the context of a long-term treatment (at least six months). These effects are particularly noticeable in stable anginal patients. Particularly interesting results have been obtained in the treatment of atherosclerosis according to the invention by the administration of prolonged-release tablets dosed in 16 mg corresponding to the Coruno® pharmaceutical specialty, marketed in Belgium. This galenic form and its manufacturing process have been described in the international patent application WO 01/62256 incorporated herein by reference. In general, the galenic forms of molsidomine described in this international patent application are essentially characterized in that they present an in vitro dissolution rate [determined spectrophotometrically at 286 or at 311 nm in accordance with the method described in the European Pharmacopoeia, third edition ( or USP XXIV) at 50 turns per minute in 500 ml of a 0.1 N HCl medium, at 37 ° C] of: 15 to 25% molsidomine released after 1 hour 20 to 35% molsidomine released after 2 hours 50 a 65% molsidomine released after 6 hours 75 to 95% molsidomine released after 12 hours >85% molsidomine released after 18 hours > 90% molsidomine released after 24 hours; the plasma peak of molsidomine obtained in vivo occurs within 2.5 to 5 hours, preferably within 3 to 4 hours, after administration of the aforementioned form and having a value comprised between 25 and 40 mg / ml of plasma. In this context, "the plasma peak of molsidomine obtained in vivo" corresponds to the mean maximum concentration of molsidomine found in the plasma of at least 10 volunteers in good health. Under the context of the present invention, any galenic form similar to that described in this international patent application WO 01/62256 can be preferably used. In general, these galenic forms allow the administration of molsidomine in daily doses, preferably between 14 and 24 mg, and more preferably between 16 and 20 mg. Such galenic forms of molsidomine, which have a 24-hour release profile characterized by an absence of nearby peaks and over-marked valleys, are particularly useful in the treatment of atherosclerosis, by guaranteeing a constant and stable release of the molsidomine on the points affected by atherosclerosis. Consequently, the relatively slow and constant release of molsidomine with the absence of marked and nearby plasma peaks seems to be an important characteristic for obtaining the desired effect in the treatment of atherosclerosis. The use of molsidomine under its galenic forms of prolonged release is particularly interesting insofar as this compound does not induce a tolerance and that the safety of its use has been demonstrated in a large er of patients.

Detection of the effects of molsidomine in the treatment of atherosclerosis 1) Characteristics of the study population and experimental scheme The favorable effects of molsidomine in the treatment of atherosclerosis have been demonstrated by a long-term clinical study conducted on 172 patients with stable angina pectoris. This study consisted of three consecutive phases: - a preliminary seven-day study under placebo; - a double-blind, randomized, double-blind, double-placebo, four-week study, during which the patients received an alternating (two times two weeks) formulation based on molsidomine in a dose of 8 mg currently sold in Belgium under the commercial name of Corvatard® (2 daily doses) and a formulation based on molsidomine in a dose of 16 mg and effective for 24 hours, currently marketed in Belgium under the trade name Coruno® (1 dose) daily); - a 12-month study during which 172 patients received a formulation based on molsidomine dosed at 16 mg, currently marketed in Belgium under the trade name of Coruno®. This study can be illustrated schematically in Figure 3. In Figure 3, and in the description that follows, the abbreviation "bid" (for the Latin term "bis in die") is used to characterize the administration of molsidomine in a dose of 8 mg in two daily doses, and the abbreviation "oad" (for the English term "eleven a day") is used to characterize the administration of molsidomine in a dose of 16 mg once a day. It should be noted that during the second phase of the study, concomitant or simultaneous use of other antianginal drugs was prohibited, with the exception of sublingual isosorbide dinitrate (s.l.) (ISDN) 5 mg tablets, which could be consumed ad libitum to relieve the symptoms of angina pain. On the other hand, during the third phase of the study, the concomitant use of beta-blockers and / or calcium antagonists was allowed, while the use of oral nitrates and sildenafil remained prohibited. Molsidomine 16 mg o.a.d. It should be taken orally every morning for 1 year. The study was carried out in accordance with the guidelines on clinical research for antianginal drugs provided by the CPMP, following good clinical practice (stage 4), as applied in the European Community. In the course of this study, the weekly frequency of anginal attacks was observed and recorded, as well as the weekly frequency of consumption of ISDN tablets s.l. in a dose of 5 mg. On the other hand, and above all, ICAM-1s concentrations were measured at the conclusion of each of the three phases of the study, the baseline being the first measurement. Specifically, the concentrations of ICAM-1s were measured and determined in the following manner. Blood samples were taken (5 ml) and placed in non-heparinized tubes. These samples were stored at room temperature, and were subsequently centrifuged. The serum was separated and immediately frozen at -20 ° C until the moment of analysis. Circulating 1CAM-1 was determined using a commercially available ELISA test (marketed by R &D Systems Europe). 2. Statistical analyzes Descriptive statistics (means, standard deviation or standard, and percentages) were used to characterize the demography and other parameters of the patient population of the study. Dispersion analyzes were made for the repeated measurements, with time as a classification criterion, followed by post-hoc Bonferroni tests when these were significant, to evaluate the evolution of the weekly frequency of the anginal attacks, the weekly consumption of the tablets nitrados sl and the rates of circulating ICAMs during the short-term (second phase) and long-term (third phase) periods of the study. Likewise, Student t tests or ANOVA tests were used to a classification criterion to evaluate the effects of sex, alcohol consumption, whether or not they were smokers, as well as the concomitant or simultaneous use of medications, on the rate of ICAMs measured at the end of each phase of the study (baseline, preliminary study under placebo, after a four-week treatment and after a one-year treatment). Dispersion analyzes were made on repeated measurements to evaluate the effects of the same risk factors on the evolution of ICAM-1s rates. In addition, Pearson correlation coefficients were calculated to detect the possible links between the ICAM-1s rates and the demographic variables contained or the risk factors. The same method was used to evaluate the correlations between the variations in the rates of ICAM-1s and changes in risk factors.

On the other hand, four pages of changes in ICAM-1 s rates were determined after one year of treatment. An ANOVA test was made with a classification criterion, followed, when it was significant, of adjusted post-hoc Bonferroni tests, to determine the effects of the changes in the ICAM-1s rates, in the 4 categories defined in this way. (4 pages) on the observed changes (from the baseline to the end of the one-year treatment) in the weekly frequency of anginal attacks and the consumption of ISDN tablets. 3. Results The demographic characteristics of the population in the baseline (after the preliminary study under placebo), are detailed in Table 1 below.

TABLE 1 Demographic characteristics and baseline of the patients who participated in the study TABLE 1 (CONTINUED) ET = standard or standard deviation As shown in table 1, the patients in the study were 56.2 ± 8.3 years old (mean ± standard deviation), mostly males (68.0%) and suffered stable angina pectoris for 4.4 ± 4.5 years. years on average. During the first phase of the study under placebo, which precedes the active treatments, the weekly frequencies of the anginal attacks and the consumption of ISDN tablets were respectively 3.7 ± 3.8 crises / week and 2.5 ± 3.2 tablets / week. While concomitant use of antianginal drugs was allowed during this phase of the study, 67.4% of patients did not take any other medication in addition to molsidomine, and 29.1% of patients did not ingest beta-blockers. Figure 1 shows the evolution of the weekly frequency of anginal attacks and the consumption of sublingual nitrate tablets during the second and third phases of the study. The results were presented in the form of means ± errors over the mean (SEM); ANOVA tests for repeated measurements, p < 0.001; Bonferroni post-hoc tests: ** comparisons against the baseline, p < 0.0001; £ comparison between 4 weeks and a year, p = 0.002; NS comparison between 4 weeks and a year, p = 0.105. As shown in Figure 1, significant global decreases were detected in the weekly frequency of anginal attacks and in the consumption of nitrated tablets s.l. (p <0.0001; ANOVA) throughout the study. Regarding the frequency of anginal attacks, the differences were significant between the baseline and the 4-week treatment (p <0.001, Bonferroni) as well as between the baseline and the one-year treatment. of duration (p < 0.0001; Bonferroní). The differences were equally significant between the 4-week treatment and the one-year treatment (p = 0.002, Bonferroni). On the other hand, with regard to the consumption of sl nitrated tablets, the differences were significant between the baseline and the 4-week treatment (p <0.0001, Bonferroni) as well as between the baseline and the one-year treatment (p <0.0001; Bonferroni). Table 2 below shows the concentrations of ICAM-1s (ng / ml) measured during the short-term periods (second phase) as well as the long-term (third phase) of the study, in order to determine particularly the influence of sex, alcohol consumption, tobacco addiction and concomitant medications, on the evolution of circulating ICAM-1 rates.

TABLE 2 Evolution of ICAM-1s concentrations (ng / ml) during the short-term and long-term periods of the study, and influence of sex, alcohol consumption, tobacco addiction and concomitant medications * / * = statistical probability against baseline / against results at 4 weeks; Bonferroni post-hoc tests * = p < 0.05; ** = p < 0.01; *** = p = 0.001; £ = p < 0.0001; NS = not significant p > 0.05; NA = not applicable; ET = standard deviation As indicated in Table 2, 4-week treatment with molsidomine (16 mg o.a.d or 8 mg b.i.d.) had no effect on the rates of circulating ICAM-1s. However, after 12 months of a daily molsidomine intake of 16 mg oad, the ICAM-1s rates decreased significantly (p <0.001) (around 10%), compared to the baseline values before the cross study. Rates of circulating ICAM-1s tend to be higher among women than among men. However, the interaction with sex was not significant (p = 0.914) by ANOVA, indicating that the decrease in ICAM-1s during the one-year treatment with molsídomina is globally parallel for both sexes. Alcohol users tend to have lower ICAM-ls rates than non-alcohol users. All the differences were not significant and the evolution of the ICAM-1s rate during the one-year treatment was globally parallel in the two groups (p = 0.149). Smokers had a tendency to have higher ICAM-ls rates than non-smokers or former smokers, but, again, the evolution of the ICAM-1s rate was globally the same whatever the habits of tobacco consumption ( p = 0.192). The use of concomitant medications such as statins, beta-blockers or both drugs in combination had no influence on the rate of ICAM-1s. All the differences were not significant and the evolution in the rate of ICAM-1s was independent of the type of concomitant medication absorbed during the period of one year of treatment (p = 0.598). At the baseline, no correlation was detected between the ICAM-1s concentrations and the demographic factors or risk factors, such as age (r = -0.068), weight (r = -0.079), duration of stable angina (r = 0.042), the weekly frequency of anginal attacks (r = 0.137), the weekly frequency of consumption of ISDN sl tablets (r = 0.124), diastolic blood pressure (r = 0.051), systolic blood pressure (r = 0.097) or heart rate (r = 0.176). The same conclusions could be reached with regard to correlations between variations in ICAM-1 rates and changes in demographic factors and risk factors after a one-year treatment with molsidomine (data not presented). Figure 2 also illustrates the decrease in the weekly frequency of consumption of ISDN tablets as a function of the variation in the rate of circulating ICAM-1 s after a one-year treatment with molsidomine in doses of 16 mg oad; the ICAM-1s change categories correspond to the 4 pages of the distribution. The results are presented in the form of means ± errors over the mean (SEM); ANOVA p = 0.031; * Bonferroni post-hoc tests p = 0.038. In Figure 2, with the distribution in sheets of the changes in the ICAM-1s rates during the third phase of the study, it is further illustrated that the effect of the change in the rate of ICAM-1 s on the evolution of the frequency of the Consumption of ISDN sl tablets it is significant (p = 0.031). The post-hoc Bonferroni tests demonstrated that the reduction in ISDN consumption between the start and the end of the third phase of the study (12 months later) was more pronounced in the group with a greater decrease in ICAM-1 s (fourth distribution page) (p = 0.038). The same trend was registered with respect to the change in the weekly frequency of anginal crises, but the differences between the 4 pages of changes of ICAM-1s were not significant (p = 0.072) (data not shown). 4. Discussion The present study allows us to evaluate the effect of short-term (4 weeks) and long-term (one year) treatment with molsidomine of 16 mg o.a.d. in patients with stable angina pectoris. The results obtained show surprisingly that, after one year of administration of this galenic form, the significant antianginal effects, measured previously after a 4-week treatment, persist, and that the rates of circulating ICAM-1s, proinflammatory marker of endothelial dysfunction and therapeutic objective potential in the pathology of atherosclerosis, are reduced in a sensitive manner. At the beginning of the study, after a preliminary period of seven days of placebo, the ICAM-1 rates were comparable to the values obtained in other studies with patients suffering from coronary heart disease or stable angina. Women and smokers have a tendency to have higher rates than men and non-smokers or former smokers, confirming the observations of previous studies. Short-term treatment (4 weeks) with molsidomine had no effect on circulating ICAM-1s rates. Among patients who presented stable angina, the efficacy of the 4-week antianginal treatment was nonetheless significant, since the number of anginal attacks and the consumption of sublingual nitrates decreased. After 12 months of ingesting molsidomine daily in a dose of 16 mg o.a.d., the ICAM-1s rates were significantly lower. This decrease was independent of other parameters such as sex, alcohol consumption, tobacco addiction or concomitant medications. After one year, the antianginal effects of molsidomine were maintained or even improved, and the most pronounced decrease in the consumption of sublingual nitrates was observed among the patients who had the greatest decrease in ICAM-1s rates (fourth page). In conclusion, the reduction of the ICAM-1s marker after a one-year daily treatment with molsidomine at a dose of 16 mg o.a.d. indicates that this compound, in addition to its antianginal function, favors a less activated state of the endothelium and, thanks to this fact, allows to prevent and / or moderate the progress of atherosclerosis, particularly in patients who have stable angina pectoris.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - Use of molsidomine or one of its pharmaceutically acceptable salts, in the form of an effective prolonged release oral composition for 24 hours, for the manufacture of a medicament intended to prevent or attenuate the development of atherosclerosis.

2. The use claimed in claim 1 of an effective extended release oral composition for 24 hours, further characterized in that this composition has an in vitro dissolution rate, measured spectrophotometrically at 286 or 311 nm in accordance with the method described in the European Pharmacopoeia, third edition (or USP XXIV) at 50 vpm in 500 ml of a 0.1 N HCl medium, at 37 ° C, of: 15 to 25% of molsidomine released after 1 hour, 20 to 35% of molsidomine released after 2 hours, 50 to 65% of molsidomine released after 6 hours, 75 to 95% molsidomine released after 12 hours, > 85% molsidomine released after 18 hours, > 90% molsidomine released after 24 hours; the plasma peak of molsidomine obtained in vivo occurs between 2.5 to 5 hours, preferably between 3 to 4 hours, after administration of the aforementioned form and having a value that is between 25 and 40 ng / ml of plasma.

3. The use claimed in claims 1 or 2, wherein the aforementioned oral composition includes, per unit dose intended to be administered daily, between 14 and 24 mg, and preferably, 16 mg of molsidomine.

4. The use claimed in one of claims 1 to 3, wherein the aforementioned solid oral composition is administered to patients suffering from angina pectoris.