A pharmaceutical composition for preventing or treating arteriosclerosis and use thereof

Abstract

The present application relates to the technical field of medicine, and in particular to a medicine composition for preventing or treating arteriosclerosis and application thereof. The medicine composition for preventing or treating arteriosclerosis comprises terazosin or a pharmaceutically acceptable salt thereof and an angiotensin II receptor antagonist. The medicine composition for preventing or treating arteriosclerosis and application thereof provided by the present application can reduce the hardness of arteries while avoiding adverse effects on blood pressure.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition for the prevention or treatment of arteriosclerosis and its application. Background Technology

[0002] Arteriosclerosis is the main pathological basis of cardiovascular and cerebrovascular diseases, and its incidence is increasing year by year with age and changes in lifestyle. Arteriosclerosis is mainly manifested as thickening, hardening and loss of elasticity of the arterial wall, which leads to narrowing of the vascular lumen, affects blood flow and increases the risk of cardiovascular and cerebrovascular diseases. Age is one of the main risk factors for the occurrence and development of cardiovascular and cerebrovascular diseases, and vascular degenerative changes play a leading role in this process. Vascular degenerative changes refer to the physiological and pathological process of functional and structural aging and degeneration of blood vessels with age and the combined effect of other factors (Zhang Yucong, Zhang Cuntai, "Emphasis on the Assessment and Prevention of Vascular Aging", Chinese Journal of Geriatrics, 2020, 39(08)10.3760 / cma.j.issn.0254-9026.2020.08.001). Vascular degenerative diseases vary depending on the target organ. When cardiac damage occurs, aging and degeneration of the aorta increase left ventricular afterload, leading to ventricular remodeling, left ventricular dysfunction, and ultimately heart failure. In kidney damage, the renal microarteries are the first to be affected, causing glomerular damage and subsequently developing into end-stage renal diseases such as chronic renal failure. In brain damage, aging blood vessels cause arteriosclerosis, exacerbating damage to the cerebral microcirculation, reducing oxygen supply and leading to stroke, cognitive decline, and other central nervous system diseases. Morphologically, aging blood vessels are characterized by increased collagen fiber deposition, increased and disordered elastic fibers, disorganized smooth muscle cell arrangement, and intimal indentation. Functionally, aging blood vessels exhibit increased stiffness, decreased sensitivity to vasodilators, increased sensitivity to vasoconstrictors, and reduced angiogenesis. Vascular aging increases susceptibility to hypertension and atherosclerosis (Zhang C, Tao J; Cardiovascular Group, Society of Geriatrics, Chinese Medical Association. Expert consensus on clinical assessment and intervention of vascular aging in China (2018). AgingMed (Milton). 2018 Nov 30;1(3):228-237. doi: 10.1002 / agm2.12049. PMID:31942501; PMCID: PMC6880715.).

[0003] Existing treatments are mostly focused on controlling blood pressure and blood lipids, but there are few drugs that directly treat arteriosclerosis (especially vascular aging-related arteriosclerosis). Summary of the Invention

[0004] To address the aforementioned problems in the prior art, the present invention provides a pharmaceutical composition for the prevention or treatment of arteriosclerosis and its application, offering a new solution for the treatment of arteriosclerosis and improving the quality of life for patients.

[0005] Based on this, the present invention has the following technical solution:

[0006] In a first aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of arteriosclerosis, characterized in that it comprises: terazosin or a pharmaceutically acceptable salt thereof, and an angiotensin II receptor antagonist.

[0007] Terazosin, an α1-adrenergic receptor blocker, achieves vasodilation and blood pressure reduction by blocking α1-adrenergic receptors, and is therefore widely used clinically to treat benign prostatic hyperplasia and hypertension. This invention unexpectedly discovered that terazosin has a synergistic effect with angiotensin II receptor antagonists; combined use can significantly reduce vascular stiffness, providing a new approach to the treatment of arteriosclerosis.

[0008] This invention also found that not all α1-adrenergic receptor blockers have the effect of reducing vascular stiffness in synergy with angiotensin II receptor antagonists.

[0009] Preferably, the mass ratio of the terazosin or its pharmaceutical salt to the angiotensin II receptor antagonist is 1:240-480.

[0010] In this invention, the mass ratio of the terazosin or its pharmaceutical salt to the angiotensin II receptor antagonist can be any ratio selected from 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400, 1:410, 1:420, 1:430, 1:440, 1:450, 1:460, 1:470, and 1:480, or any two of the above ratios being a range of values ​​with endpoints.

[0011] This invention reveals that terazosin, as the main active ingredient, promotes vascular smooth muscle relaxation and reduces vascular resistance by blocking α1-adrenergic receptors, thereby reducing arterial stiffness to a certain extent. Angiotensin II receptor antagonists, as an adjuvant ingredient, reduce myocardial oxygen consumption and improve cardiac function by inhibiting excessive sympathetic nerve activation, further protecting the cardiovascular system. When used in combination at the aforementioned dosages, both ingredients produce a synergistic effect, effectively reducing arterial stiffness, stabilizing blood pressure, and improving the prognosis of patients with arteriosclerosis.

[0012] Preferably, the angiotensin II receptor antagonist includes one or more of sartan medoxomil, valsartan or its extended-release formulation, and irbesartan or its extended-release formulation; more preferably, the angiotensin II receptor antagonist is a sartan medoxomil; and even more preferably, alisartan medoxomil.

[0013] In this invention, alisartan medoxomil selectively binds to angiotensin II receptors, blocking angiotensin II-induced vasoconstriction and promoting aldosterone secretion, thereby lowering blood pressure. This type of drug can steadily and effectively lower blood pressure, reverse or improve myocardial remodeling, improve insulin resistance in hypertensive patients, and promote uric acid excretion, thus significantly reducing the risk of cardiovascular and stroke events.

[0014] In a preferred embodiment of the present invention, the pharmaceutical composition is a mixture of terazosin or its pharmaceutical salt and alisartan ester.

[0015] Preferably, the pharmaceutical salts of the terazosin include terazosin hydrochloride and / or terazosin phosphate.

[0016] It is well known to those skilled in the art that the daily dose of terazosin for treating hypertension is above 2 mg. However, this invention has discovered that low doses of terazosin or its pharmaceutically acceptable salts can be used to prevent or treat arteriosclerosis, thereby effectively preventing or treating hypertension and other cardiovascular diseases. Furthermore, low doses of terazosin have less impact on blood pressure, avoiding the side effects that may occur with conventional or high doses.

[0017] Preferably, the daily dose of terazosin or its pharmaceutical salt is 0.5 to 1.0 mg, for example, any value among 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, and 1.0 mg, or a range of values ​​with any two of the above values ​​as endpoints.

[0018] In a preferred embodiment of the present invention, the daily dose of terazosin is 0.5 mg, taken once daily. For specific patient groups, such as the elderly or those with weak constitutions, it may be taken before bedtime.

[0019] Preferably, the daily dose of the angiotensin II receptor antagonist is 80-240 mg, for example, it can be any value among 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, and 240 mg, or a range of values ​​with any two of the above values ​​as endpoints.

[0020] As a preferred embodiment of the present invention, the daily dose of alisartan medoxomil is a low dose within the conventional dose range, and the dose can be adjusted according to the specific condition of the patient, preferably 240 mg per day.

[0021] In this invention, compared with traditional antihypertensive drugs, low-dose terazosin has a smaller effect on blood pressure. Alisartan medoxomil, as an adjuvant drug, achieves the effect of lowering blood pressure and reducing the risk of further development of arteriosclerosis. By using low-dose terazosin in combination with the above-mentioned dose of alisartan medoxomil, it is possible to simultaneously reduce arterial stiffness and hypertension levels, which helps improve the prognosis of patients with arteriosclerosis, reduce the risk of cardiovascular and cerebrovascular diseases, and improve the quality of life of patients.

[0022] Preferably, the arteriosclerosis is vascular aging-related arteriosclerosis.

[0023] Specifically, healthy large arteries possess strong buffering capacity, providing a stable blood flow to microvessels even during cardiac contraction and relaxation and intermittent ejection, thus protecting microvessels from the harmful effects of pressure fluctuations. However, with age and under the influence of various cardiovascular risk factors, blood vessels age, resulting in structural remodeling and functional impairment, primarily characterized by increased vascular stiffness. Compared to atherosclerosis, vascular aging-induced atherosclerosis differs significantly in mechanism and leads to more extensive structural remodeling of the vessel wall. In the absence of atherosclerosis, vascular aging primarily causes intimal thickening, especially a significant increase in intima-media thickness (IMT), and also leads to endothelial cell damage and dysfunction, resulting in a significant reduction in nitric oxide (NO)-dependent vasodilation. Structural remodeling and functional impairment interact, ultimately leading to the atherosclerosis described in this invention.

[0024] In some implementations, the routes of administration for terazosin or its pharmaceutical salts, as well as angiotensin II receptor antagonists, include oral administration, injection, etc., with oral administration being the optimal route.

[0025] In a second aspect, the present invention provides a medicament for the prevention or treatment of cardiovascular and cerebrovascular diseases, including the aforementioned medicament composition for the prevention or treatment of arteriosclerosis.

[0026] Thirdly, the present invention provides a medicament for the prevention or treatment of hypertension, comprising the aforementioned medicament composition for the prevention or treatment of arteriosclerosis.

[0027] In some embodiments, the drugs for preventing or treating arteriosclerosis, cardiovascular and cerebrovascular diseases, and hypertension may contain any pharmaceutically acceptable excipients.

[0028] In some embodiments, the pharmaceutically acceptable excipients mentioned above include, but are not limited to, at least one of ultrapure water, physiological saline, non-aqueous solvents, solubilizers, cosolvents, binders, disintegrants, colorants, preservatives, dispersants, plasticizers, isotonic adjusters, pH adjusters, antibacterial agents, antioxidants, and chelating agents, which are not limited herein.

[0029] In some embodiments, the dosage forms of the drugs for preventing or treating arteriosclerosis, cardiovascular and cerebrovascular diseases, and hypertension include, but are not limited to, injections, oral preparations, capsules, tablets, powders, or suspensions, etc., and are not limited thereto.

[0030] As one method to verify the effectiveness of the present invention, changes in arterial stiffness can be assessed by measuring the patient's pulse-wave velocity (PWV), and the impact on blood pressure can be assessed by measuring the patient's systolic and diastolic blood pressure. Furthermore, the effectiveness of the present invention can be further verified through animal experiments.

[0031] It should be noted that this invention is not only applicable to patients with arteriosclerosis, but can also be used to prevent the occurrence and development of arteriosclerosis, providing cardiovascular protection for a wider population.

[0032] Fourthly, the present invention provides the use of the pharmaceutical composition in any of the following aspects:

[0033] a) Prepare drugs for the prevention or treatment of arteriosclerosis;

[0034] b) Prepare drugs for the prevention or treatment of cardiovascular and cerebrovascular diseases;

[0035] c) Prepare drugs for the prevention or treatment of hypertension.

[0036] The present invention provides a pharmaceutical composition for the prevention or treatment of arteriosclerosis and its application, which can reduce arterial stiffness while avoiding adverse effects on blood pressure. Attached Figure Description

[0037] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0038] Figure 1 A bar chart illustrating the effect of the combined use of terazosin hydrochloride and alisartan medoxomil on the long-term intervention of blood pressure (systolic blood pressure) in experimental animals in an animal model, as provided in Example 1 of this invention.

[0039] Figure 2 A bar chart illustrating the effect of the combined use of terazosin hydrochloride and alisartan medoxomil on long-term blood pressure (diastolic pressure) in experimental animals in an animal model, as provided in Example 1 of this invention.

[0040] Figure 3 This is a schematic diagram (stained sections) showing the effect of combined administration of terazosin hydrochloride and allisartan medoxil on the morphological changes of vascular tissue in experimental animals in Example 1 of the present invention; wherein, Figure A represents the SHR group, Figure B represents the WKY group, Figure C represents the SHR terazosin hydrochloride group, Figure D represents the SHR allisartan isoproxil group, and Figure E represents the SHR terazosin hydrochloride + allisartan isoproxil group. Detailed Implementation

[0041] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0042] The term "combination therapy" as used in this article refers to the simultaneous administration of two active ingredients (i.e., terazosin and angiotensin II receptor antagonist) to a patient as defined in this article.

[0043] The term “treatment” as used in this article includes treatment that relieves, reduces or alleviates at least one symptom in a subject or achieves a delay in disease progression, or means to prevent, delay the onset (i.e., within a period of time prior to the clinical manifestation of the disease) and / or reduce the risk of disease development or disease exacerbation.

[0044] As used in this article, “prevention” includes prevention of at least one symptom associated with or caused by a state, disease, or disorder that is being prevented.

[0045] As used herein, the term "synergistic" refers to the effect of at least two therapeutic agents, namely terazosin hydrochloride as defined herein and alisartan medoxomil as defined herein, such that the effect is greater than the sum of the individual effects of each drug administered. This effect may, for example, be the slowing of disease or the progression of its symptoms. The synergistic effect can be calculated as shown in the examples.

[0046] As used in this article, the terms "subject" or "patient" include animals at risk of or with existing cardiovascular disease or symptoms, including hypertension and arteriosclerosis. Examples of subjects include mammals such as humans, dogs, pigs, rabbits, rats, mice, and transgenic nonhuman animals.

[0047] As used herein, the terms “pharmaceutical acceptable” or “medicinal…” are defined as compounds, materials, compositions, and / or dosage forms that are suitable for use in the tissues of subjects (e.g., human or non-human mammals) to the extent reasonably medically permissible without excessive toxicity, irritation, allergic reactions, and / or other complications, and in proportion to a reasonable benefit / risk ratio.

[0048] Unless otherwise specified, all raw materials used in the examples and comparative examples are commercially available conventional raw materials, and the technical means used are conventional means well known to those skilled in the art.

[0049] Example 1: Detection of the effect of long-term intervention with terazosin hydrochloride combined with alisartan cilexetil on arteriosclerosis

[0050] Table 1. Equivalent dose ratios between humans and animals based on body surface area.

[0051]

[0052] Dosage conversion between rats and humans:

[0053] The clinical human dose is X mg / kg, which can be converted to a rat dose as follows:

[0054] The dosage for rats = X mg / kg × 70kg × 0.018 / 200g

[0055] = X mg / kg × 70kg × 0.018 / 0.2kg

[0056] =6.3 X mg / kg

[0057] That is, based on the dose per unit body weight, the equivalent dose for rats is 6.3 times that for humans.

[0058] Based on this example, the human dose of terazosin hydrochloride is 0.5 mg / day, which translates to a rat dose of 6.3 × (0.5 / 70) = 0.045 mg / kg / day. Similarly, the rat dose of alisartan medoxomil is 6.3 × (240 / 70) = 21.6 mg / kg / day.

[0059] Spontaneously hypertensive rats (SHR) were selected as the model animals for arteriosclerosis (SHR group), and Wistar-Kyoto rats (WKY) were selected as the control model without arteriosclerosis (WKY group). SHR rats were treated with drugs including terazosin hydrochloride alone (SHR terazosin hydrochloride group), allisartan isoproxil alone (SHR allisartan isoproxil group), and terazosin hydrochloride + allisartan isoproxil (SHR terazosin hydrochloride + allisartan isoproxil group), with 8 rats in each group. All drugs were administered via force-feeding after being dissolved in 0.5% sodium carboxymethyl ester. The dosage was calculated based on the body surface area coefficient according to the clinical dosage designed in this invention (see Table 2). The specific dosage of allisartan isoproxil was 21.6 mg / kg / day. A long-term intervention of 3 months was conducted. After treatment, the pulse wave velocity (PWV) and blood pressure of the rats were measured and statistically analyzed.

[0060] Table 2

[0061]

[0062] Jin Zhengjun's Q-value method for calculating composition interactions: Q=E a+b / (E a +E b -E a ×E b ), where E a+b E is the average value of the data when components A and B are combined. a and E b These are the average values ​​of components A and B when used alone. In the formula, the numerator represents the "measured combined effect," the denominator represents the "expected combined effect," and Q is the ratio of the two. Q < 0.85 indicates an antagonistic effect, 0.85 ≤ Q < 1.15 indicates an additive effect, and Q ≥ 1.15 indicates a synergistic effect. Here, the measured values ​​are converted into effects that can intuitively reflect the drug's action. The calculation formula is: E i =(1-P i / P 模型组 )×100%, P i P represents the measured values ​​for each group.模型组 These are the measured values ​​for the model group.

[0063] Based on this calculation, the drug's effect in reducing PWV is shown in Table 3:

[0064] Table 3. Therapeutic effects of terazosin hydrochloride combined with alisartan medoxomil on arteriosclerosis

[0065]

[0066] The results showed that the PWV of rats in the combined treatment group was significantly lower than that in other groups (p<0.01), and systolic and diastolic blood pressure were more stable during long-term treatment. This further validated the long-term efficacy of the combination of terazosin and alisartan medoxomil in reducing arterial stiffness and controlling blood pressure, and demonstrated a synergistic effect in treating arterial stiffness.

[0067] The bar chart showing the effects of different drugs on long-term blood pressure (systolic blood pressure) in animal models is shown below. Figure 1 The bar chart showing the effects of different drugs on long-term interventional blood pressure (diastolic blood pressure) in animal models is shown below. Figure 2 A schematic diagram showing the effects of different drugs on the morphological changes of vascular tissue in experimental animals (stained sections) is shown below. Figure 3 Figure A represents the SHR group, Figure B represents the WKY group, Figure C represents the SHR Terazosin hydrochloride group, Figure D represents the SHR Allisartanisoproxil group, and Figure E represents the SHR Terazosin hydrochloride + Allisartan isoproxil group.

[0068] The present invention found that when the ratio of terazosin hydrochloride to alisartan medoxomil is 1:240, its effect is comparable to that of the combination of the two in Example 1 when the ratio is 1:480.

[0069] Example 2

[0070] The only difference between this embodiment and the SHR Terazosin hydrochloride + Allisartan isoproxil group in Example 1 is that alisartan ester is replaced with an equivalent dose of perindopril tert-butylamine.

[0071] The results showed that the antihypertensive effect of an equivalent dose of perindopril tert-butylamine was weaker than that of alisartan cilexetil; a double dose of perindopril tert-butylamine was required to achieve the same effect in reducing pulse wave volume (PWV). This demonstrates that the synergistic effect of terazosin hydrochloride and alisartan cilexetil in reducing arteriosclerosis is more significant than that of terazosin hydrochloride and other angiotensin II receptor antagonists.

[0072] Example 3

[0073] The only difference between this embodiment and the SHR Terazosin hydrochloride + Allisartan isoproxil group in Example 1 is that the daily dose of alisartan medoxomil is 3.6 mg / kg / day, and the mass ratio of alisartan medoxomil to terazosin hydrochloride is 80:1.

[0074] The results showed that the composition with this mass ratio did not have a significant blood pressure lowering effect; the composition with this mass ratio had no significant difference in reducing PWV compared with terazosin hydrochloride alone.

[0075] Example 4

[0076] The only difference between this embodiment and the SHR Terazosin hydrochloride + Allisartan isoproxil group in Example 1 is that the daily dose of terazosin hydrochloride is 0.45 mg / kg / day.

[0077] The results showed that the composition at this dosage had a significant antihypertensive effect; however, the composition at this dosage was less effective in reducing PWV than the composition at the indicated dosage, and there was no synergistic effect.

[0078] Comparative Example 1

[0079] The only difference between this embodiment and the SHR Terazosin hydrochloride + Allisartan isoproxil group in Example 1 is that terazosin hydrochloride is replaced with an equal amount of tamsulosin.

[0080] The results showed that the combination of these components lowered blood pressure, with the blood pressure reduction level being no different from that of alisartan medoxomil monotherapy; the effect of this combination in reducing PWV was also no different from that of alisartan medoxomil monotherapy. This demonstrates that not all α1-adrenergic receptor blockers can synergistically reduce arteriosclerosis with alisartan medoxomil.

[0081] Experimental Example 1

[0082] In animal experiments, aortic tissue from rats in Example 1 was used for pathological sections and EVG staining to assess morphological changes in vascular tissue. Results showed that the collagen fibers in the vascular wall of rats in the combined treatment group were neatly arranged and maintained elasticity, significantly improved compared to the SHR group, further demonstrating the protective effect of the combined use of terazosin and alisartan medoxomil on vascular tissue.

[0083] In summary, the present invention provides a combination composition for treating arteriosclerosis, comprising a low dose of terazosin and alisartan cilexetil, which can effectively reduce arterial stiffness while maintaining stable blood pressure, providing a new treatment option for arteriosclerosis. This combination composition has significant clinical efficacy and broad application prospects.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of arteriosclerosis, characterized in that, include: Terazosin hydrochloride, and Alisartan ester; The mass ratio of terazosin hydrochloride to alisartan medoxomil is 1:240 or 1:480.

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