A pharmaceutical composition for treating renal hypertension

Abstract

The present invention relates to a pharmaceutical composition for treating renal hypertension. The pharmaceutical composition comprises neferine or a pharmaceutically acceptable salt thereof and Gastrodia elata polysaccharide. The two have a synergistic effect in reducing renal hypertension and preventing renal atrophy, significantly improving drug efficacy and promising development into an effective drug for treating renal hypertension.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a pharmaceutical composition for treating renal hypertension. Background Art

[0002] Renal hypertension is a common cause of secondary hypertension caused by unilateral or bilateral stenosis of the main or branch renal arteries, resulting in reduced renal blood flow and, consequently, renal ischemia. Renal parenchymal hypertension is mostly caused by renal vascular sclerosis. The clinical manifestations and progression of renal hypertension are more severe than those of essential hypertension. It is a special type of refractory hypertension with an extremely poor prognosis and increasing disability and mortality rates.

[0003] Drug therapy is the cornerstone and first choice for hypertension treatment, including renin-angiotensin-aldosterone system blockers, calcium channel blockers (CCBs), diuretics, beta-blockers, and alpha-blockers. Although each antihypertensive drug has its own mechanism of action, the pathogenesis of renal hypertension is complex, often requiring the combined use of two or more antihypertensive drugs to achieve a positive effect. Common treatment options include angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) plus a CCB, an ACEI or ARB plus a thiazide diuretic, or a CCB plus a thiazide diuretic. However, this is only an ideal scenario; in clinical practice, adverse reactions often occur, including elevated blood lipids, water and sodium retention, ankle swelling, cough, facial flushing, and dizziness.

[0004] Research on the use of traditional Chinese medicine in treating hypertension is increasing. Modern pharmacological and clinical studies have shown that many traditional Chinese medicines and their ingredients have antihypertensive effects. Antihypertensive traditional Chinese medicine ingredients are primarily classified into the following categories: alkaloids: nitrogen-containing organic compounds with significant physiological activity. Many traditional Chinese medicines are rich in alkaloids. Examples of antihypertensive agents include berberine (berberine), ligustrazine, rhynchophylline, and liesinine (including methyl neferine and isoliensinine); flavonoids: most are derivatives of the 2-phenylchromone nucleus, with common substituents including -OH, -OCH3, and terpenoid side chains. Examples of antihypertensive agents include safflower yellow, apigenin, and total flavonoids from ginkgo biloba leaves; and saponins: a class of glycosides widely found in the plant kingdom, whose aqueous solutions produce a persistent, soap-like foam upon shaking. Antihypertensive saponins include ginsenoside Rb1, astragaloside, and sapindus saponin. Polysaccharides are natural high-molecular-weight polymers containing aldehyde or ketone groups, formed by glycosidic bonds linking ten or more monosaccharides. Examples of these antihypertensive agents include Lycium barbarum polysaccharides, Astragalus polysaccharides, and Gastrodia elata polysaccharides. Other antihypertensive agents include terpenes, quinones, coumarins, lignins, and amino acids, such as Cassia anthraquinone glycosides, peucedanum coumarin, and sesamin. However, single traditional Chinese medicine ingredients often have insufficient antihypertensive effects, particularly for renal hypertension. Therefore, the development of more effective drugs for this condition is necessary. Summary of the Invention

[0005] In view of the above problems existing in the prior art, the present invention provides a pharmaceutical composition for treating renal hypertension, which is composed of neferine as a monomer of traditional Chinese medicine alkaloids and gastrodia polysaccharide as an active ingredient of traditional Chinese medicine polysaccharides.

[0006] Therefore, the present invention provides a pharmaceutical composition comprising neferine or a pharmaceutically acceptable salt thereof and gastrodia polysaccharide, wherein the mass ratio of neferine or a pharmaceutically acceptable salt thereof to gastrodia polysaccharide is (0.5-8):1.

[0007] In one embodiment of the present invention, the mass ratio of neferine or a pharmaceutically acceptable salt thereof to Gastrodia elata polysaccharide is (1-3):1.

[0008] In one embodiment of the present invention, the mass ratio of neferine or a pharmaceutically acceptable salt thereof to Gastrodia elata polysaccharide is 1:1.

[0009] In one embodiment of the present invention, the pharmaceutically acceptable salt of neferine refers to a pharmaceutically acceptable salt formed by neferine and a pharmaceutically acceptable acid selected from the following: hydrochloride, hydrobromide, sulfate, nitrate, perchlorate, fumarate, maleate, phosphate, glycolate, lactate, salicylate, succinate, toluene sulfate, tartrate, acetate, citrate, methanesulfonate, formate, benzoate, malonate and benzenesulfonate, but not limited thereto.

[0010] In one embodiment of the present invention, the pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable excipients or carriers.

[0011] Furthermore, in the above-mentioned pharmaceutical composition, the pharmaceutically acceptable excipient or carrier is selected from at least one of excipients, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, antioxidants, adsorbents, filter aids, and release retardants.

[0012] The excipients of the present invention include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as hypromellose, sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; and agar.

[0013] The diluents of the present invention include, but are not limited to, mannitol, sorbitol, calcium dihydrogen phosphate dihydrate, microcrystalline cellulose and powdered cellulose.

[0014] The disintegrants of the present invention include, but are not limited to, modified starch, modified cellulose polymer or one of polycarboxylic acids, such as crosslinked sodium hydroxymethylcellulose, hypromellose, sodium starch glycolate, polacrilin potassium and hydroxymethylcellulose calcium.

[0015] The binder described in the present invention includes, but is not limited to, one or more of carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymers and salts thereof, vinyl pyrrolidone-vinyl acetate copolymer, gelatin, guar gum, reduced gum, partially hydrolyzed starch, low-substituted hydroxypropyl cellulose, povidone or copovidone.

[0016] The surfactants described in the present invention can be anionic, cationic, or neutral surfactants. Anionic surfactants include sodium lauryl sulfate, sodium dodecyl sulfate, sodium oleyl sulfate, and sodium laurate mixed with stearate and talc. Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters.

[0017] The wetting agents of the present invention include, but are not limited to, poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivatives and polyoxyethylene stearate.

[0018] The antioxidants of the present invention include, but are not limited to, α-tocopherol, γ-tocopherol, L-ascorbic acid and its sodium or calcium salt, ascorbyl palmitate, butylated hydroxytoluene and butylated hydroxyanisole.

[0019] The pharmaceutical composition of the present invention is presented in a unit dosage form such as a tablet, pill, capsule, powder, granule, suspension, oral liquid, aerosol or liquid spray, drops, ampoule, autoinjector device or suppository; a dosage form for oral parenteral, intranasal, sublingual or rectal administration or for inhalation or spray administration. The preferred pharmaceutical dosage form is an oral preparation, more preferably a tablet prepared by compression.

[0020] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making sugar-coated pills, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0021] Pharmaceutically, the content of the active ingredient in the pharmaceutical composition of the present invention should be in the range of 0.05 to 90 weight %, preferably 0.1 to 50 weight % of the entire composition.

[0022] For adult patients, the pharmaceutical composition of the present invention can be administered orally or parenterally in a single dose of 0.001 to 500 mg once daily or divided into several doses. This dosage can be appropriately increased or decreased depending on the type of disease being treated, the patient's age, weight, and symptoms.

[0023] Another aspect of the present invention provides use of the pharmaceutical composition of the present invention in preparing a medicament for preventing or treating hypertension, especially renal hypertension.

[0024] Beneficial effects

[0025] The present invention provides a pharmaceutical composition for treating renal hypertension, comprising neferine or a pharmaceutically acceptable salt thereof and Gastrodia elata polysaccharide. Both neferine and Gastrodia elata polysaccharide have a certain antihypertensive effect. The present invention finds that the two compounds have a synergistic effect in reducing renal hypertension and preventing renal atrophy, significantly improving the effectiveness of preventing and treating renal hypertension. The composition has both practical value and industrial application value. DETAILED DESCRIPTION

[0026] The present invention is described in more detail below to facilitate understanding of the present invention.

[0027] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions.

[0028] Example 1: Pharmaceutical composition of the present invention

[0029] 1 Experimental methods

[0030] 46 SPF-grade SD rats weighing 200 ± 20 g, half male and half female (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were fed adaptively for one week. 38 of them were intraperitoneally injected with 3% sodium pentobarbital. The skin at the abdominal incision was disinfected with ethanol. The left renal artery was isolated about 2 cm below the left hypochondrium with a glass rod at a distance of about 1 cm from the rat spine. The left renal artery was ligated when the skin at the incision was sutured. To prevent infection, penicillin was injected intraperitoneally after suturing to establish the model. The tail artery pressure of the rats was measured at week 4 after modeling. If the tail artery pressure was higher than 160 mmHg (1 mmHg = 0.133 kPa), the animal model was successfully established. A total of 34 rats were successfully modeled in the experiment, and 32 of them were randomly selected and divided into model group, neferine group, gastrodia polysaccharide group and neferine + gastrodia polysaccharide group, with 8 rats in each group. They were gavage-administered according to the following regimen, once a day, for 6 consecutive weeks; the 8 rats in the normal group did not undergo modeling treatment.

[0031] Table 1: Animal grouping and dosing information (n=8)

[0032]

[0033] *Neferine was purchased from Chengdu Pusi Biotechnology Co., Ltd. with a purity of ≥98%; Gastrodia elata polysaccharide was purchased from Baoji Cosmece Plant Polysaccharide Development Co., Ltd. with a purity of ≥98%.

[0034] 2. Result Collection

[0035] The tail artery pressure of the rats was measured before modeling, after modeling, and 2 hours after the last administration (6 weeks). The rats were sacrificed, and the hearts and kidneys were quickly separated. The surface fat, connective tissue, and blood vessels were cleaned. The left and right kidneys were weighed after being rinsed with 4°C sodium chloride solution. Statistical analysis was performed using SPSS 22.0 software, and the data were expressed as mean ± standard deviation. The values in the same column are shown in Tables 2 and 3.

[0036] Table 2: Comparison of rat tail artery pressure

[0037]

[0038] Table 3: Comparison of left and right kidney mass in rats

[0039]

[0040]

[0041] The results of Tables 2 and 3 show that after successful modeling, compared with the blank group, the tail artery pressure of the model rats increased significantly, and the left kidney mass and the left and right kidney mass ratio decreased significantly; after treatment, the tail artery pressure of the rats decreased significantly, and the left kidney mass and the left and right kidney mass ratio increased significantly, indicating that it has a therapeutic effect on renal hypertension. Compared with the same amount of neferine or gastrodia polysaccharide, the therapeutic effect of the neferine and gastrodia polysaccharide composition of the present invention is significantly better, indicating that the two achieve a synergistic effect.

[0042] Example 2: Tablet composition

[0043]

[0044] Preparation method:

[0045] The first step is to sieve neferine, gastrodia polysaccharide, hydroxypropyl methylcellulose and lactose and set them aside; prepare povidone K30 ethanol solution as a binder and set them aside.

[0046] The second step is to weigh the prescribed amount of neferine, gastrodia polysaccharide, hypromellose and lactose, mix them, add the prescribed amount of binder to granulate, and after drying, add the prescribed amount of magnesium stearate and mix evenly.

[0047] The third step is tableting.

[0048] Step 4: Coating: Prepare a coating solution (oxygen-proof and light-proof) using the prescribed amount of colored film coating agent. Place the plain tablets in a coating pan, spray with the film coating, and dry. Each tablet contains 30 mg of neferine and 30 mg of Gastrodia elata polysaccharide.

[0049] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition comprising neferine or a pharmaceutically acceptable salt thereof and Gastrodia elata polysaccharide, wherein: The mass ratio of neferine or its pharmaceutically acceptable salt to Gastrodia elata polysaccharide is 1:

1.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutically acceptable salt of neferine is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, perchlorate, fumarate, maleate, phosphate, glycolate, lactate, salicylate, succinate, tartrate, acetate, citrate, methanesulfonate, formate, benzoate, malonate and benzenesulfonate.

3. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients or carriers.

4. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutically acceptable excipient or carrier is selected from at least one of a propellant, a solubilizer, a cosolvent, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, a flavoring agent, a preservative, a suspending agent, a coating material, a fragrance, an anti-adhesive agent, an integrator, a penetration enhancer, a pH regulator, a buffer, a plasticizer, a surfactant, a foaming agent, a defoaming agent, a thickener, a inclusion agent, a humectant, an absorbent, a diluent, a flocculant and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retardant.

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutically acceptable excipient or carrier is selected from at least one of an excipient and an emulsifier.

6. The pharmaceutical composition according to claim 1, characterized in that The dosage form of the pharmaceutical composition is at least one of tablets, pills, capsules, powders, granules, suspensions, oral liquids, aerosols or liquid sprays, drops, and suppositories.

7. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for preventing or treating hypertension.

8. The use according to claim 7, characterized in that The medicament is used for preventing or treating renal hypertension.

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