FR2956976A1 - Composition, useful for preventing and/or treating complications of diabetes, where the complications are retinopathy and neuropathy, and reducing myocardial infarction and stroke, comprises delapril and manidipine - Google Patents

Abstract

Composition (I) comprises delapril, manidipine or their salts. ACTIVITY : Antidiabetic; Ophthalmological; Neuroprotective; Cardiovascular-Gen.; Cardiant; Cerebroprotective; Vasotropic. MECHANISM OF ACTION : Angiotensin converting enzyme (ACE) inhibitor.

Description

USE OF ACTIVE INGREDIENTS IN COMBINATION FOR THE TREATMENT OF DIABETES COMPLICATIONS

Field of the Invention The present invention relates to the use of a pharmaceutical composition for the prevention and treatment of diabetes complications. In particular, the invention relates to the use of a pharmaceutical composition which comprises delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt, for use in the prevention and treatment of diabetes complications.

State of the Prior Art Diabetes mellitus type 1 is characterized by the absence or marked reduction of endogenous insulin secretion and accounts for about 10% of diabetes cases, whereas type 2 diabetes mellitus is characterized by a variable association of reduced pancreatic hormone secretion and peripheral resistance to insulin action and accounts for approximately 90% of all diabetes cases. Diabetes mellitus, in its different forms, affects 2-5% of the European population.

According to the World Health Organization, more than 170 million people in the world suffer from diabetes, and this number will increase to 370 million by 2030. In particular, the increase is due to the increase of diabetics. 2. In recent years it has become clear that modest levels of hyperglycaemia are also significantly associated with the development of chronic complications (micro- and / or macro-angiopathic complications) of the disease. The main chronic complications of diabetes include, for example, cardio- and cerebrovascular diseases, retinopathy, nephropathy, neuropathy.

Retinopathy and diabetic nephropathy are the leading causes, respectively, of blindness and uremia in subjects under 50 years of age. Recent estimates indicate that after twenty years of diabetic disease, almost all people with type 1 diabetes and over 60% of those with type 2 diabetes develop some degree of retinopathy.

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, and its predominance and severity, as demonstrated by the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WEDSR), is closely related to duration of diabetes as well as the degree of metabolic control. Retinopathy is rare during the first 2-3 years of diagnosis in subjects with type 1 diabetes, while in subjects with type 2 diabetes, a significant proportion (up to 30%) of patients with retinopathy moment of diagnosis.

This fact is related to the presence in these patients of hyperglycemia long before the diagnosis. Diabetic retinopathy is clinically distinct in two stages: 1) nonproliferative retinopathy (in turn distinct into three subgroups: mild, moderate or severe); 2) proliferative retinopathy. In addition, macular edema may be present in each of these stages. Careful graduation of the non-proliferative form is extremely important since progression to the proliferative form is closely related to the severity of the non-proliferative framework.

In addition, WESDR has shown that progression of retinopathy is based on baseline retinopathy. Retinal lesions may be present without any visual disturbances. Alterations of the sight are manifested only when the macula is concerned (sits precisely of the distinct vision).

Diabetes Control and Complication Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) have shown that intensive management of diabetes, in order to achieve the closest possible glycemic compensation to normal, can prevent and delay progression. retinopathy in diabetic subjects. Similarly, all risk factors (for example, cardiovascular events, high blood pressure, cigarette smoke, dyslipidemia, duration of diabetes, metabolic control), which alter the frequency of onset and progression of Diabetic retinopathy, which could contribute to worsening the retinal situation, must be carefully controlled.

Both DCCT and UKPDS have documented, for example, the association between poor metabolic compensation and retinopathy. It also seems clear that proteinuria is associated with retinopathy. The increase in blood pressure is a well-known risk factor for the development of macular edema and is associated with the presence of PDR (proliferative diabetic retinopathy). Some observations indicate an association between serum lipid levels, those present on the retina (hard exudates) and vision loss. Therefore, systemic control of blood pressure and serum lipids can be considered important in the management of diabetic retinopathy. Diabetic neuropathy is a debilitating disorder that occurs in 50% of people with diabetes. It is a complication that causes structural and functional damage to the Peripheral Nervous System in its components: somatic (sensory and motor nerve fibers), autonomic. In 1987, diabetic neuropathies were classified by Dick as: distal symmetrical polyneuropathy (sensory, autonomic, motor), distal symmetrical neuropathy and asymmetric neuropathy. The most common and typical form of neuropathy that affects diabetics is represented by symmetrical peripheral polyneuropathy. Peripheral diabetic neuropathy may present with pain, loss of sensation, and muscle weakness. Autonomic involvement may involve gastrointestinal, cardiovascular and genitourinary function. 25 Even in this case, the control of diabetes, in order to have glycemic compensation as close as possible to normal, and the control of risk factors (for example, cardiovascular events, high blood pressure, cigarette smoke, dyslipidemia , duration of diabetes, metabolic control), can prevent and delay the progression of the disease. Numerous studies have now conclusively demonstrated the fundamental etiopathogenic role of chronic hyperglycemia in the development and progression of the chronic complications of subjects suffering from diabetes. It follows that the maintenance of blood glucose levels as close as possible to normality values at the onset of diabetes and the control of risk factors are essential conditions for preventing the onset and progression of micro-complications. and macro-angiopathic. Risk factors that alter the frequency of onset and progression of diabetes complications, particularly diabetic retinopathy and neuropathy, are multiple and it is still necessary to identify new combinations of active ingredients to control the complications of diabetes. Risk factors and therefore reduce the occurrence and progression of chronic complications of diabetes. There is therefore still the need for new compositions useful in the prevention and / or treatment of complications of diabetes, particularly diabetic retinopathy and neuropathy.

Summary of the Invention The present invention relates to the use of delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt for the preparation of a pharmaceutical composition for the prevention and / or treatment of complications of diabetes. In a first preferred embodiment, the invention relates to the use of delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt for the preparation of a pharmaceutical composition for the prevention of diabetic neuropathy. In a second preferred embodiment, the invention relates to the use of delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt for the preparation of a pharmaceutical composition for the treatment of diabetic neuropathy.

In a third preferred embodiment, the invention relates to the use of delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt for the preparation of a pharmaceutical composition for the prevention of diabetic retinopathy. In a fourth preferred embodiment, the invention relates to the use of delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt for the preparation of a pharmaceutical composition for the treatment of diabetic retinopathy.

Summary of Figures Figure 1 shows in the top panel the Kaplan-Meier curves for the percentage of subjects with major cardiovascular events during administration of manidipine plus delapril, delapril or placebo.

The central panel and the bottom panel show the evolution of both systolic and diastolic pressure and the evolution of serum glycosylated hemoglobin (HbA1C) levels during the observation period according to the treatment groups. Figure 2 shows in the top panel the Kaplan-Meier curves for the percentage of subjects with progression of retinopathy during administration of manidipine plus delapril, delapril or placebo. The central panel and the bottom panel show the evolution of both systolic and diastolic pressure and the evolution of serum glycosylated hemoglobin (HbA1C) levels during the observation period according to the treatment groups.

Definitions The general term "complications" is intended to indicate, in addition to retinopathy and diabetic neuropathy, a range of conditions that may accompany diabetes, such as certain cardiovascular events, such as myocardial infarction and stroke. ictus, the diabetic foot, manifested by ulcerations and problems in the lower limbs, and complications during pregnancy, such as congenital malformations, high birth weight, up to a high risk of perinatal mortality . The general term "prevention" refers to the use of the drug to reduce the risk of developing diabetes complications.

By the general term "treatment" it is meant to indicate the use in order to reduce the incidence, to act with a protective effect against progression, to induce a regression of the complications of diabetes.

Detailed Description of the Invention The present invention relates to a pharmaceutical composition for use in the prevention and / or treatment of diabetic complications, which comprises delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt.

Delavir, which is an angiotensin converting enzyme inhibitor, is the International Nonproprietary Name (INN) for N- [N - [(S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L -alanyl-N- (indan-2-yl) glycine. The pharmaceutically acceptable salt of delapril is preferably an acid addition salt of delapril, preferably delapril hydrochloride. According to the present invention, "delapril hydrochloride" means N- [N - [(S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl-N- (indan-2-yl) glycine hydrochloride. Delapir and its pharmaceutically acceptable salts can be easily prepared, for example, according to the methods described in US Pat. No. 4,822,818. Manidipine, a calcium antagonist, is the international non-proprietary name (INN) for 2- [4- (diphenylmethyl) -1-piperazynyl] ethyl methyl 1,4-dihydro-2,6-dimethyl-4- nitrophenyl) -3,5-pyridine-dicarboxylate. The pharmaceutically acceptable salt of manidipine is preferably an acid addition salt of manidipine, preferably manidipine dihydrochloride. According to the present invention, "manidipine hydrochloride" means 2- [4- (diphenylmethyl) -1-piperazynyl] ethyl methyl 1,4-dihydro-2,6-dimethyl-4- (mnitrophenyl) -3,5-dihydrochloride. pyridine-dicarboxylic acid. Manidipine and its pharmaceutically acceptable salts can be easily prepared according to the methods described in US Patent No. 4,892,875. The complications of diabetes may be micro- and / or macroangiopathic complications and in particular they include, for example, retinopathy and neuropathy. According to one aspect of the invention, the pharmaceutical compositions can be used in the prevention and / or treatment of diabetic complications, also on subjects suffering in addition to hypertension. The present invention relates to pharmaceutical compositions comprising a combination of the active ingredients per se, or in admixture with at least one pharmaceutically acceptable excipient or carrier.

These compositions are preferably administered orally. Pharmaceutical compositions for the prevention and / or treatment of diabetic complications comprising delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt as active ingredients may be formulated by conventional methods.

Preferred dosage forms are solid formulations for oral administration, such as, for example, powders, granules, tablets, pills and capsules. When the compositions are administered in tablet or pill form, the latter may be enteric coated. In the preparation of these compositions, the active ingredients may be mixed with at least one excipient or carrier, such as, for example, sucrose, lactose, cellulose, mannitol, maltose, dextran, starch, agar. alginate, chitin, chitosan, pectin, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer or glyceride. These formulations may further contain, as usual, other excipients or carriers. These excipients or subsequent supports may comprise an inert diluent, a lubricant such as magnesium stearate, a preservative such as paraben or sorbic acid, an antioxidant such as ascorbic acid, a-tocopherol, cysteine, an agent disintegrant, a binder, a densifying agent, a buffer, a sweetener, a flavoring agent and a perfuming agent. Other dosage forms may be liquid formulations for oral administration, including, for example, emulsions, syrups, elixirs, suspensions and solutions.

These formulations may contain an inert diluent such as water, which is conventionally used in the field of interest. The pharmaceutical formulations of the present invention are characterized by lower toxicity and may be used as animal drugs, particularly for mammals (eg, humans, dogs, rabbits, rats, mice) and may be used for the prevention and / or treatment of complications of diabetes, particularly retinopathy and neuropathy. The dose of active ingredients for each patient is determined by age, body mass, general health conditions, sex, diet, interval between doses, route of administration, rate of excretion, the combination ratio of the active ingredients and the conditions of the disease treated, taking into account these factors and / or other factors. Generally, in the case of a pharmaceutical composition containing delapril hydrochloride and manidipine hydrochloride administered to an adult human patient, the amounts of delaparin hydrochloride and manidipine hydrochloride in dosage unit form are 10 to 60 mg and from 1 to 20 mg, respectively. By the combination of delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt, the result has been to intensify the effects of each drug and to reduce the harmful effects thereof. The combined effect of the two active ingredients makes it possible to reduce the dose so that, in the pharmaceutical compositions of the invention, the amount of delaparin hydrochloride and of manidipine hydrochloride can be reduced by 15 to 30 mg and to 10 mg, respectively, per unit dose. Therefore, the amounts of the active ingredients in the composition are preferably 15 to 30 mg of delapril hydrochloride, preferably 30 mg, and 5 to 10 mg of manidipine hydrochloride, preferably 10 mg in the form of dosing unit. The dosage unit form is usually administered once a day, but it can be administered twice a day. The combination of these two active ingredients has been shown to reduce the incidence of cardiovascular events such as myocardial infarction and stroke. In addition, this combination has been shown to reduce the risk of development and to induce significant regression in mild-form peripheral neuropathy, and also to reduce the occurrence and significantly protect against progression of retinopathy. In the following experimental examples, the present invention is illustrated in more detail but without limitation.

Examples 1. "DEMAND" study A study called the "DElapril and MAnidipine for Neuroprotection in Diabetes" APPLICATION was conducted to compare the effects of the combination treatment of Delapril with Manidipine with the effects of Delapril alone or a placebo, in combination with particularly on retinopathy and peripheral neuropathy. DEMAND is a multicentre, randomized, placebo-controlled, double-blind study. The study was carried out on 380 subjects aged 40 years or older, hypertensive, suffering from type 2 diabetes mellitus for less than 25 years, with a urinary excretion rate of albumin of less than 200 μg / minute (normoalbuminurics less than 20 μg / minute to microalbuminuric acid equal to or greater than 20 μg / minute but less than 200 μg / minute) in at least two of three consecutive sterile samples, all night, with a serum creatinine concentration of not more than 1.5 mg per deciliter (133 μmon / liter). Arterial hypertension was defined as an untreated systolic blood pressure of 130 mmHg or greater or a diastolic blood pressure of 85 mmHg or greater, or the need for antihypertensive therapy to maintain systolic and diastolic blood pressure. below these values.

Targeted blood pressure was set at 120/80 mmHg. The subjects were randomly divided into three groups and each group was respectively subjected to one of the following treatments: - Delapril 30 mg daily + Manidipine 10 mg daily; or - Delapril 30 mg daily; or - Placébo. Subjects continued to take the usual medications for diabetes, including a low-sodium diet (less than 100 mEq / day). A glycosylated hemoglobin level of less than 7% was recommended for all subjects. 1.1 Assessment of Cardiovascular Events In a sample of 126 patients, combination therapy with Manidipine and Delapril was shown to reduce the incidence of cardiovascular events such as myocardial infarction and stroke. significantly with respect to delapril and placebo (Fig. 1). In Figure 1, the indices show: Unadapted risk ratios between delapril plus manidipine and placebo and the adapted risk ratios corresponding to 2 smoking habit, smoking habit, baseline and follow-up average arterial pressure, and smoking habit, baseline and HbAl C follow-up. These results are all significant. While the risk ratios between delapril and placebo have all been shown to be insignificant. 1.2 Evaluation of Retinopathy The study was conducted to evaluate the incidence of new retinopathies, confirmed in two consecutive fundus assessments on subjects without evidence of retinal disease at the start of the study. .

In addition, regression of retinopathy was assessed in subjects with known retinal disease at the start of the study. All the subjects who consented to the fundoscopic evaluation were evaluated at the central level, the changes of the retina were evaluated by an oculist, not informed of the data of the study.

Indirect binocular ophthalmoscopy was performed using a L-0185 cracking lamp biomicroscope (magnification 10x and 16x) and manual lenses (magnification 90x). Images of four standard 30 ° fields from each eye were taken through the dilated pupils in stereo pairs (lateral to the macula, macula, disc and nasal) with a Canon CF 60 UV photocamera on the bottom of the eye ( Tokyo, Japan). The severity of retinal changes was classified from an apparent absence of retinopathy, to mild to moderate pre-proliferative retinopathy, and to proliferative retinopathy. The eye with the most serious affection was used for statistical analysis. The new occurrence of retinopathy was diagnosed when any degree of retinopathy was observed in two consecutive one-year assessments of distances in eyes with non-apparent basal retinopathy. The progression or regression of retinopathy was defined as an increase or a decrease in degree, respectively, in two consecutive evaluations, relative to the baseline value.

1.2.1 Evaluation of the occurrence of retinopathy Combination therapy was found to be able to reduce the incidence of new cases of retinopathy in subjects who showed no change in the retina 30 at the start of the study. In subjects with type 2 diabetes with arterial hypertension and normo- or micro-albuminuria, the combined treatment of Delapril with Manidipine reduces the incidence of retinopathy compared to Delapril alone and placebo.

The protective effect of Delapril + Manidipine against the development of new retinopathies has been shown to be independent of blood pressure control, but appears to depend in part on improved metabolic control. Of the 258 subjects with centralized endoscopic evaluation, 208 had no retinopathy and 50 had retinal alterations at the time of inclusion in the study. Of the subjects without retinal disease, 3 (4.5 percent) in combination therapy with manidipine plus delapril developed retinopathy compared with 6 (9 percent) in delalpine alone and 9 (15). percent) with the placebo. The risk ratio ("hazard ratio") between combined treatment and placebo was significant (Figure 2). It was significant even after adjusting the baseline and monitoring mean arterial pressure. While the risk ratio (hazard ratio) between delapril and placebo was not significant (Figure 2). Blood pressure monitoring changes from baseline did not differ between treatment groups, while HbA1C glycosylated hemoglobin decreased to a greater extent (p = 0.001) in the combined treatment compared with placebo (Figure 2). In FIG. 2, the indices show: The unadapted risk ratios between delapril plus manidipine and placebo and between delapril and placebo. The other risk ratios between delapril plus manidipine and placebo were adjusted to baseline and mean arterial pressure monitoring, and baseline and HbA1 monitoring.

1.2.2 Evaluation of the progression of retinopathy The protective effect of Delapril + Manidipine against the progression of retinopathy can be partly attributed to the increase in metabolic control compared with placebo. Deltapril administered alone showed no appreciable effect on changes in the retina. Glycosylated hemoglobin was measured using ion-exchange high resolution liquid chromatography (HPLC) (range of normality, 3.53 to 5.21%).

Table 1 shows the progression of retinopathy according to the percentage of HbAl C. Table 1 Baseline Monitoring Absolute Change Delapril 5.6 ± 1.2 5.8 ± 1.0 + 0.2 ± 0.9 Del. + Man. 5.8 ± 1.7 5.6 ± 0.9 - 0.3 ± 1.5 P = 0.06 * Placebo 5.6 ± 1.3 5.7 ± 0.7 + 0.1 ± 0, 8 P = 0.06 * * ANCOVA model

Improvement in metabolic control and, to a varying extent, in blood pressure control appear to influence retinopathy and peripheral neuropathy through the combined effect of treatment.

Since anti-diabetic treatment was similar between treatment groups, the changes observed in glycosylated hemoglobin levels can be explained by a direct effect of manidipine, in combination with delapril, probably caused by improved sensitivity. to insulin through the activation of the peroxisome proliferator activated gamma receptor in adipocytes (Oshimura, J Hyperten 2007, 25). Combination subjects less frequently required treatment with beta-blockers or diuretics than those treated with placebo to lower their blood pressure to the target value. Thus, the improvement in metabolic control observed on combination therapy could also be explained by a reduced need for drugs that reduce insulin sensitivity.

1.3 Assessment of neuropathy The prevalence, degree and progression of neuropathy were assessed in a cohort of subjects (200) treated with Delapril + Manidipine, Delapril or placebo for three years. The subjects enlisted in DEMAND had mild diabetes and neuropathy.

The diagnosis and degree of peripheral neuropathy was assessed using the validated TNS (Total Neuropathy Score) scale (Table 2) with the following characteristics: - it is a composite scale that combines: ^ the symptoms (sensory, motor and autonomic), signs (sensitivity to puncture and vibration, force and tendon reflexes), vibratory threshold measured with sensory and quantitative tests, and study of nerve conduction (sural and peroneal extent) ; - it is designed to note the "length-dependent" evolution of neuropathy; - it has a greater diagnostic sensitivity compared to previous scales (eg NIS); - score> 2 = neuropathy.

Quantitative sensory testing was performed at the first metatarsal phalanx of the big toe, with the Computed-Assisted Sensory Examinator (CASE IV) device (WR Medical Electronics Co., Stillwater, MN). The data were compared to the normative ranges provided by the software. Nerve driving studies were conducted in a warm room at a temperature maintained between 25 and 28 ° C and a controlled skin temperature using a key point. The magnitude of the motor action potential of the peroneal nerve (SAP) (normal> 4 mV) and the magnitude of the sural nerve (CMAP) antidomic action potential (peak-to-peak value, normal> 6 μV) were recorded in the dominant leg using a stimulating surface and recording electrodes with standard positioning. All assessments were centralized and performed by the same reviewers for the entire study period.

Table 2 - TNS PARAMETER 0 1 2 3 4 Symptoms None Symptoms Symptoms Symptoms Sensory symptoms limited to limited to extended above knee fingers of ankles or knees / elbows or hand or wrists elbows functionally feet hindered Symptoms None Mild Difficulty Necessary Paralysis Moderate Difficulty of Help- Assistance Symptoms 0 1 2 3 4 or 5 autonomic (n) Sensitivity to Normal Reduced to Reduced Reduced to pain fingers up to the top of the hands / feet wrists / elbows / elbows / knees ankles knees Sensitivity to Normal Reduced to reduced Reduced to vibration fingers from up to the top of the hands / feet wrists / elbows / elbows / knees ankles knees Sthenia Normal Light Hypostenia Hypostenia Paralysis moderate severe hyposthenia Reflexes Normal Achilles Achilles Achillesens Areflexia tendonless reduced absent absent and general reduced other Normal sensitivity ù 126 ù 150% 151 ù 200% 201 ù 300%> 300% ULN vibration (QST) 125% ULN ULN ULN ULN Scale SAP Normal 76 to 95% 51 to 75% LLN 26 to 50% LLN 0 to 25% LLN sural / reduced to LLN <5% LLN Scope to CMAP Normal 76 to 95% 51 to 75% LLN 26 to 50% LLN 0 to 25% LLN to fibula / reduced LLN <5% LLN 1.3.1 Evaluation of the TNS In the three groups treated as described above, the average of the TNS Delapril + Manidipine = 0 (p = 0.03 / placebo; Wilcoxon test) Delapril = 1 (p = 0.09 / placebo) Placébo = 3 As is evident from the above data, combined administration (Délapril + Manidipine) significantly reduced the TNS score at 3 years. 14 In particular, as seen in Table 2, TNS demonstrates that it is only with combined administration that it is possible to reach and maintain all parameters in normal values as well as the absence of any symptoms. 1.3.2 Evaluation of developmental and regression risk of neuropathy Blood pressure, HbAlC, mean (interquartile range) of TNS, and NER greater than 2 at baseline and at 3-year assessment in the general population of the study and in both groups, with or without peripheral neuropathy at inclusion, assigned to the study of drugs, are shown in Table 3.

At three years, 24 (34.8 percent) patients in combination treatment with manidipine plus delapril had a TNS greater than two compared to 26 (41.3 percent) in treatment with delapril alone and 39 (57 , 4 percent) with placebo. The odds ratio between the combined treatment and placebo, as well as between delapril and placebo are both significant, even after baseline adjustments of TNS, baseline and follow-up. mean arterial pressure, mean, and HbAlC monitoring (Table 4). Of the 166 subjects without neuropathy at the time of inclusion, 12 (23.5 percent) in combination therapy with manidipine plus delapril developed neuropathy at 3 years, compared with 13 (28.8 percent) with delapril alone and 17 (38.6 percent) with placebo. Of the 77 subjects with neuropathy at the time of inclusion, 6 (33.3 percent) combined treatment demonstrated a regression of neuropathy at 3 years compared to 5 (27.7 percent) with delagin alone. and 2 (8.3 percent) with placebo (Table 4).

The odds ratio between combined treatment and placebo was significant even after baseline adjustments of TNS, baseline and mean arterial pressure monitoring and mean and follow-up. HbAlC (Table 4). Patients should be treated with manidipine plus delapril to achieve a regression of neuropathy relative to placebo. On the contrary, the odds ratio between delapril alone and placebo did not reach the level of significance (Table 4).

Total 16 Table 3 Absence of neuropathy at inclusion Inclusion neuropathy Placebo Placebo Manipulitis Isis Delapril + Delapril Manidipine + Delapril Manidipine Delapn'l P + Delapril e BP û mm Hg base 1 ... e.2 1. :) .. 9..31>.,. $ Y 115) 1571 14.4) .4. 14.305.4) 14.4.2 1: zi 1.4. $ ''. 3 () 4.1) 1M.A. (.1.5..4) 'M .2 (11 ... 3.Y1U (14.8r 149: 7 (le; 14 :: 13.23' 13 .n '1472 14. e BP - "ee.:5) basis e years) y2 he 53., 5 0..5) e me û mm Hg K t..4 basis 154), 551A.U.5) 55.5 e..2); 11.1) 55.1 0..5f "81: 5 (5.5) 51 .2;, -.?.: 5) 15e.5 YES) i (1 .8.6) e .5), 5'j .57.5 25 M 2. (.1) 51 Ue3 v) .2) 15 W..3 105.5 (.5.4 base 5 (1.1 5.70: 5) 5: 8 (1.2y., 541. 5503) 5.50.5e .5: 701) .4 5.90 .e.1 0.1 : 5: C1.1) 5.3.0 NS (IQR) base 1 3) 2 - 3: 1 e) »& - 5) 1 - .4) 3 0 2) 4 ffl 3) # 1.5 (C 4) §. (4-6 (4- (2 8) 5..5 (: 5 ,! n (% basis 15.25.1.) 2.4 (24..e 12 (n.5) @ 1 (2e..8) 15 1M 12; 55 iti 15 72; s are mean (SD) or median and interquartile range (IQR) or figure (%) ris: BP: blood pressure HbAlC: glycosylated hemoglobin, p <0.05 compared to placebo ( model ANCOVA), * p <L base value, #p <0.001 compared to the base value §p <0.0001 compared to the base value.) ar compared to delapril (model ANCOVA); & p <0.05 compared with placebo (Wilcoxon test): p <0.01 compared with logistics for baseline TNS), @ p <0.05 compared to placebo (logistic regression for baseline TNS).

Table 4 TE: 2 Adapted for baseline TNS: 'adapted for baseline TNS and baseline and monitoring of blood pressure shooting baseline TNS and baseline and follow-up of the glycosylated hemoglobin. Maniclipine plus clellapril compared to placebo Delayed compared to placed! "a.14- p ,, O ... OW Mn a + Lm mig 1rst 0.3T e 14 - -G O. '., h - ..- 5.50, ta - ps, 0.05.51 8.010 52.28), 5.1 t 0. '2 4 25.02:, p1 2: ICL.02-- e !.,. 5.4 to 10.87 e-4-, (0: 1 e2 C.3,: qO.'l 0.24 pl-p = 0 ... 0.554 e-.-.-.-. 0.52 '' (L27--, 21. p, OEO2 11, 30, OEO2): 0.40: t017- .0A e0, .0e u, 5. 25 --------------- ------------- --------------- ------ ------- Husband + EDF Mother ------------------- ------------ fibn + Del lie ehie lin de lie Man + Mg IkHe

Claims (10)

A pharmaceutical composition comprising delapril or its pharmaceutically acceptable salt and manidipine or its pharmaceutically acceptable salt for use in the prevention and / or treatment of complications of diabetes. 2- The pharmaceutical composition according to claim 1, wherein said complications are retinopathy and neuropathy. 3- The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of delapril is delapril hydrochloride and the pharmaceutically acceptable salt of manidipine is manidipine hydrochloride. 4. Pharmaceutical composition according to claim 3, wherein the delapril hydrochloride varies from 10 to 60 mg and the manidipine hydrochloride varies from 20 mg. 5. The pharmaceutical composition according to claim 4, wherein the delapril hydrochloride varies from 15 to 30 mg and the manidipine hydrochloride varies from 5 to 10 mg. 6. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is administered orally. 7- Pharmaceutical composition according to any one of claims 1-6, for use in the prevention of neuropathy. 8. A pharmaceutical composition according to any of claims 1-6 for use in the treatment of neuropathy. 9- Pharmaceutical composition according to any one of claims 1-6, for use in the prevention of retinopathy. 10-Pharmaceutical composition according to any one of claims 1-6, for use in the treatment of retinopathy. 18