CN106822158B - Salidroside for preventing and treating obstructive sleep apnea induced hypertension - Google Patents

Abstract

The invention provides application of salidroside or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating obstructive sleep apnea induced hypertension, wherein the salidroside or pharmaceutically acceptable salts thereof is present in the medicament in a therapeutically effective amount. The invention also provides application of salidroside or pharmaceutically acceptable salts thereof in preparing health care products for preventing obstructive sleep apnea induced hypertension, wherein the salidroside or pharmaceutically acceptable salts thereof exist in the health care products in a preventive effective amount.

Description

Salidroside for preventing and treating obstructive sleep apnea induced hypertension

Technical Field

The invention relates to the field of obstructive sleep apnea induced hypertension treatment, in particular to application of salidroside in preparation of medicines and health-care products for preventing and treating obstructive sleep apnea induced hypertension.

Background

Obstructive Sleep Apnea (OSA) is a common chronic disease characterized by complete or partial upper airway obstruction caused by pharyngeal stenosis and airway relaxation, and is mainly characterized by snoring during night sleep, disappearance or limitation of respiratory airflow, resulting in intermittent hypoxia and sleep fragmentation, thus causing daytime sleepiness and possibly involving multiple organs and multiple systems such as respiration, circulation, metabolism and the like. In the united states, about 26% of adults suffer from varying degrees of OSA; 2016, sleep white skin book shows: 20.4% of adults in China have OSA, and with the prevalence of obesity, the incidence of OSA tends to increase year by year.

There is increasing research evidence that OSA is an independent risk factor for the development and progression of hypertension. Epidemiological investigation shows that the incidence of hypertension in patients with OSA is 50%, and the incidence of OSA in patients with hypertension is 30%^[1]The incidence rate of the intractable hypertension patient combined with the OSA is up to 83 percent^[2](ii) a The probability of hypertension of the moderate and severe OSA patients after 4 years is 3 times higher than that of the patients without OSA^[3]. OSA has been listed as one of the causes of secondary hypertension in the seventh report of the American Committee for the prevention, treatment and evaluation of hypertension^[4]. The hypertension guideline published by the European hypertension society/European Heart disease society (ESH/ESC) of 2013 also indicates that OSA is one of the causes of development of refractory hypertension^[5]。

OSA is characterized by Chronic Intermittent Hypoxia (CIH) as a core pathological feature, which is characterized by long-term and repeated hypoxia-reoxygenation caused by collapse and blockage of the upper airway during sleep, and the disappearance of intermittent oronasal respiratory airflow lasting for more than 10 seconds, so that the body has intermittent hypoxia and sleep structure disorder. OSA-mode CIH differs from acute hypoxia or chronic hypoxia mainly in the difference in frequency and duration of hypoxia and the presence or absence of reoxygenation events, which are essential differences from acute hypoxia caused by cardiovascular accidents, chronic hypoxia caused by chronic obstructive pulmonary disease and high altitude hypoxia. It has been shown that oxidative stress and inflammatory reactions caused by hypoxia-reoxygenation may cause more significant damage to the cardiovascular system than persistent chronic hypoxia^[6]。

The development of animal models further confirms the causal relationship between the OSA-mode CIH and hypertension. At present, adult male rodents (rats and mice) are mainly selected for establishing an OSA (oxygen deficiency syndrome) induced hypertension and cardiovascular disease model, and the adult male rodents can automatically control gas input and have high-precision oxygen concentration in real timeAn animal three-gas incubator (widely used instruments such as OxyCyler model A84system of BioSpherix corporation, USA) with good detection and sealing performance can change the oxygen concentration in the incubator from 5% -10% to the air oxygen concentration (21%) by inputting different gases such as nitrogen, oxygen, etc. The daily treatment for 8-12h for 4-12 weeks can observe cardiovascular pathological changes such as intermittent decrease and recovery of arterial oxygen partial pressure (PO2) and oxygen saturation (SaO2), blood pressure increase, oxidative stress, inflammation, vascular endothelial injury, and arterial plaque formation^[10-14]. Research shows that the OSA mode CIH mainly stimulates vascular endothelial cells, smooth muscle cells and macrophages to release ROS, activates oxidative stress, starts generation and release of various cytokines, promotes generation and development of an inflammatory process, leads to endothelial dysfunction and vascular remodeling, enhances vasoconstriction and finally leads to hypertension^[15]. Meanwhile, the hypertension induced by CIH is closely related to the aspects of central and peripheral nervous systems, transcription factors and the like^[10,16]。

Due to the unique and important factor of CIH, the development of OSA-induced hypertension is different from the classical essential hypertension and the secondary hypertension caused by other factors, thus leading to the specificity of its treatment method relative to other types of hypertension. In addition, hypertension in patients with OSA also has a nighttime "reverse spoon" feature^[9]"reverse spoon" hypertension has more severe organ damage and cardiovascular adverse event consequences than other types of hypertension.

Currently, the clinical treatment means for OSA-induced hypertension mainly include traditional antihypertensive drug therapy, Continuous Positive Airway Pressure (CPAP) therapy or a combination of the two, surgery, and the like. In clinical research, it is found that although similar endothelium-dependent diastolic dysfunction appears in hypertension induced by OSA and hypertension caused by other reasons, the effect of treating hypertension patients accompanied by OSA by using a blood pressure lowering drug is poor. The traditional antihypertensive drugs such as ACEI and beta-receptor blocker have limited curative effect, cause laryngopharynx inflammation, increase weight of patients and aggravate qi-goingEdema and obstruction of the tract^[17]. Diuretics, while effective in reducing pharyngeal edema, interfere with carbohydrate metabolism over prolonged periods of time^[18]. At present, no obvious antihypertensive drug is repeatedly proved to be effective on OSA-induced hypertension^[19-20]. CPAP treatment can control blood pressure in such patients to some extent. Meanwhile, compared with other hypertension patients, the effect of treating the blood pressure reduction by using the CPAP is more obvious for intractable hypertension patients^[2,7,8]. However, although the CPAP has obvious effect, the curative effect of the CPAP depends on the compliance of patients, the price of the apparatus is high, the use is inconvenient, the nasopharynx part is uncomfortable, the breath holding feeling is felt, the noise of the machine is large, and the application and popularization of the CPAP are seriously influenced^[21]. The requirement of the snore operation is strict, and the ideal blood pressure reducing effect cannot be achieved.

At present, no medicine capable of definitely preventing and treating OSA induced hypertension is reported. Therefore, aiming at the unique pathogenesis of OSA-induced hypertension, the development of safe and effective prevention and treatment drugs for OSA-induced hypertension is urgent.

Salidroside (Sali) is an important tyrosol compound with chemical name of 2- (4-hydroxyphenyl) ethyl-beta-D-glucoside and molecular formula of C₁₇H₂₀O₇(relative molecular mass 300.3, CAS registry number 10338-51-9, structural formula shown in figure 1), colorless transparent needle crystal at room temperature, melting point 158-160 deg.C, and water-soluble substances such as ethanol, n-butanol, etc. The compound is a characteristic monomer component of a medicinal plant rhodiola rosea, and can be extracted from roots and stems of the plant and synthesized by other ways. The traditional Chinese medicine holds that rhodiola rosea has the effects of resisting anoxia and fatigue, and modern pharmacological research also proves that rhodiola rosea and characteristic monomer component salidroside have the effects of resisting oxidation, inflammation and tumor and improving atherosclerosis^[22]Improving chronic hypoxia induced pulmonary hypertension^[23]Protection of chronic intermittent hypoxia-induced myocardial apoptosis^[24]And the like, and has wide application prospect.

Chinese patent application publication No. CN103463115A discloses the use of salidroside in the preparation of a medicine for preventing and treating hypertension, and its only example uses Spontaneous Hypertension Rat (SHR) as an animal model, which is a classic animal model simulating essential hypertension, and there is no mention of OSA-induced hypertension, a special hypertension type. In view of the significantly different responsiveness of essential hypertension and OSA-induced hypertension to antihypertensive drugs, the unique pathological features of CIH faced by OSA-induced hypertension, and the associated teachings of the prior art (as described above), it is for a sufficient reason to be certain that the authors of this patent do not realize that salidroside can be used to treat OSA-induced hypertension.

Disclosure of Invention

In one aspect, the invention provides the use of salidroside or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of obstructive sleep apnea-induced hypertension, wherein salidroside or a pharmaceutically acceptable salt thereof is present in said medicament in a therapeutically effective amount.

Preferably, the route of administration of the medicament is oral and/or parenteral.

Preferably, the parenteral routes include topical, buccal, sublingual, pulmonary, transdermal, transmucosal, and intravenous, subcutaneous, intraperitoneal, and/or intramuscular injection.

Preferably, the medicament further comprises a pharmaceutically acceptable excipient. Preferably, the pharmaceutically acceptable excipient is selected from diluents, solubilizers, alcohols, binders, controlled release polymers, enteric polymers, disintegrants, colorants, flavorants, sweeteners, antioxidants, preservatives, pigments, additives, fillers, suspending agents and/or surfactants.

Preferably, the pharmaceutical dosage form comprises tablets, pills, capsules, granules, powders, chewable gums, suspensions, emulsions, suppositories, solutions and/or liposomal injection suspensions.

Preferably, the salidroside or pharmaceutically acceptable salt thereof is administered at a dosage of 25-50mg/kg, such as 30-45mg/kg, 35-40 mg/kg.

Preferably, the pharmaceutically acceptable salts include salts derived from inorganic and/or organic acids. Preferably, the inorganic acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and/or nitric acid, and the organic acid comprises acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and/or isethionic acid.

In another aspect, the present invention provides the use of salidroside or a pharmaceutically acceptable salt thereof in the preparation of a health care product for the prevention of obstructive sleep apnea induced hypertension, wherein salidroside or a pharmaceutically acceptable salt thereof is present in said health care product in a prophylactically effective amount.

The inventor uses an animal three-gas incubator (the environmental oxygen concentration is 21% -5%, the 90 s/cycle is realized, and the 10 h/day) to simulate the chronic intermittent hypoxia state of a severe OSA patient, establishes an OSA combined hypertension mouse model, screens a large number of tested compounds, finds that salidroside can relieve the hypertension and endothelial function damage induced by CIH, has an action mechanism related to the improvement of the oxidative stress state of vascular endothelial cells induced by CIH, and has an application value for preventing and treating OSA-induced hypertension, thereby completing the invention.

Drawings

FIG. 1 shows the chemical structural formula of salidroside.

Figure 2 shows the effect of gavage administration of salidroside in the low (25mg/kg) and high (50mg/kg) dose groups on blood pressure in chronic intermittent hypoxic C57 mice (n-10). Nor, normal control group; CIH, model set; CIH + Sali (25mg/kg), Sal I, Sal II, and Sal II; CIH + Sali (50mg/kg), salidroside high dose group. P < 0.05, P < 0.01, compared to model control (t-test).

FIG. 3 shows the effect of gavage administration in the high dose group of salidroside (50mg/kg) on endothelium-dependent diastolic function in chronic intermittent hypoxia C57 mice. Nor, normal control group; CIH, model set; CIH + Sali (50mg/kg), salidroside high dose group. P < 0.05, compared to model control (t-test).

FIG. 4 shows the effect of gavage administration of salidroside in the low (25mg/kg) and high (50mg/kg) dose groups on blood pressure in chronic intermittent hypoxic apoE mice. Nor, normal control group; CIH, model set; CIH + Sali (25mg/kg), Sal I, Sal II, and Sal II; CIH + Sali (50mg/kg), salidroside high dose group. P < 0.01, P < 0.001, compared to model control (t-test).

FIG. 5 shows the effect of gavage administration in the salidroside high dose group (50mg/kg) on endothelium-dependent diastolic function in chronic intermittent hypoxic apoE mice. C57, C57 normal control group; nor, normal control group; CIH, model set; CIH + Sali (50mg/kg), salidroside high dose group. P < 0.05, compared to model control (t-test).

FIG. 6 shows the effect of salidroside low dose (10 μ M) and high dose (100 μ M) groups on chronic intermittent hypoxia-induced oxidative stress of Human Umbilical Vein Endothelial Cells (HUVECs) (ROS probe DCFH-DA). CIH, chronic intermittent hypoxia; blank, normal control group; CON, model group; sali 10. mu.M, salidroside Low dose group; sali 100. mu.M, salidroside high dose group. P < 0.05, compared to model control (t-test).

Detailed Description

Hereinafter, the present invention will be described in more detail with reference to specific examples, but the scope of the present invention will not be limited thereto.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications mentioned herein are incorporated herein by reference in their entirety for all purposes including describing and disclosing the chemicals, instruments, statistical analyses and methods reported in the publications that might be used in connection with the invention. All references cited in this specification should be considered as indicative of the level of skill in the art. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

As used herein, "pharmaceutically acceptable" includes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complication commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" include derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; acidic residues such as bases or organic salts of carboxylic acids; and so on. Thus, the term "acid addition salt" includes the corresponding salt derivatives of the parent compound that have been prepared by addition of an acid. Pharmaceutically acceptable salts include, for example, the conventional salts or the quaternary ammonium salts of the parent compound formed from inorganic or organic acids. For example, such conventional salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic and the like.

As used herein, a drug is prepared according to acceptable Pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences (Remington Pharmaceutical Sciences), 17 th edition, Alfonoso R.Gennaro, Mack Publishing Company, Easton, Pa (1985). Pharmaceutically acceptable carriers include those that are compatible with the other ingredients of the formulation and are biologically acceptable.

As used herein, the terms "include" and "comprise" are open-ended terms and should be interpreted to mean "including, but not limited to. These terms encompass the more limiting terms "consisting essentially of … …" and "consisting of … …". It should also be noted that the terms "comprising" and "including" and "characterized by" and "having" may be used interchangeably.

As used herein, no specific numerical designation includes singular or plural referents unless the context clearly dictates otherwise. In addition, no specific number of designations, the terms "one or more" and "at least one" may be used interchangeably.

When a range of values is provided, it is understood that each intervening value, and any combination or subcombination of intervening values, between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the recited range of values.

As used herein, "administering" refers to introducing a compound into the body of a subject, preferably into the systemic circulation of a subject, as described in more detail below. Examples include, but are not limited to, oral, topical, buccal, sublingual, pulmonary, transdermal, transmucosal, and subcutaneous, intraperitoneal, intravenous, and intramuscular injections, or in the form of liquid or solid medicaments that pass through the alimentary canal.

As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. By "therapeutically effective amount" of a compound is meant the amount of a therapeutic agent that provides a therapeutic benefit in the treatment or management of the disease or disorder, alone or in combination with other therapies. The term "therapeutically effective amount" can encompass an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or increases the therapeutic efficacy of another therapeutic agent. The "therapeutically effective amount" will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

As used herein, a "prophylactically effective amount" of a compound is an amount sufficient to provide a prophylactic benefit prior to the onset or occurrence of an underlying disease or condition, or to delay or minimize the onset or occurrence of one or more symptoms associated with the disease or condition. By "prophylactically effective amount" of a compound is meant an amount of prophylactic agent that provides a prophylactic benefit, alone or in combination with other prophylactic therapies, before the occurrence or onset of the underlying disease or condition. The "prophylactically effective amount" will vary with the compound, the type of disease to be prevented, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

As used herein, the term "treating" includes overcoming, alleviating, reducing, relieving or ameliorating an injury, disease or condition. The term "prevention" refers to the prevention of the underlying intended injury, disease or disorder to some extent. In certain instances, the term "treating" also includes "preventing".

As used herein, "subject" includes mammals and non-mammals. "mammal" refers to any member of the mammalia class, including but not limited to humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs, livestock such as rabbits, dogs, and cats; laboratory animals include rodents such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term "subject" does not indicate a particular age or gender. The main subjects to which the present invention is directed are humans treated with or receiving hemodialysis. The term "subject" is used interchangeably herein with the terms "patient" or "individual".

The compounds of the present invention may be administered orally or parenterally, in pure form or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents or encapsulating materials. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression characteristics in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, low melting waxes and ion exchange resins.

Oral formulations are preferred and the present invention has the advantage over related products of being readily absorbed by a mammal at sufficient levels to render the compounds of the present invention orally active as therapeutic agents. Formulations for oral or injectable use are based on solutions with sufficient solubility to allow the therapeutic agent to pass into the stomach or in an injectable medium. Suitable pharmaceutical formulations include, but are not limited to, tablets, pills, capsules, sachets, granules, powders, chewable gums, suspensions, emulsions, suppositories, and solutions. Preferred embodiments for oral use are all varieties of tablets and capsules. A preferred embodiment for injection or infusion is a solution free of microorganisms. The formulations may include diluents, binders, dispersants, surfactants, lubricants, coating materials, flavoring agents, coloring agents, controlled release formulations, sweeteners, or any other pharmaceutically acceptable additives such as gelatin, sodium starch glycolate, lactose, starch, talc, magnesium stearate, microcrystalline cellulose, povidone, hydrogenated or unsaturated oils, polyethylene glycols, syrups or other aqueous solutions, as appropriate and necessary. When the formulation is a tablet or capsule or the like, the formulation may be presented in a pre-measured unit dose form or in a multi-dose container from which the appropriate unit dose may be extracted.

As used herein, an "oral dosage form" may include a capsule (i.e., a solid oral dosage form comprised of a shell and a fill), wherein the shell is comprised of a single sealed shell or two half shells that fit together and are sometimes sealed with a band, and wherein the capsule shell may be made of gelatin, starch, or cellulose or other suitable material, may be soft or hard, and filled with a solid or liquid ingredient that may be poured or extruded. Oral dosage forms may also be capsules or coated pellets in which the drug is enclosed within a rigid or flexible dissolvable container or "shell" made of a suitable form of gelatin. The drug itself may take the form of granules to which varying amounts of coating have been applied, or delayed release coated capsules in which the drug is enclosed within a hard or soft soluble container or "shell" made of a suitable form of gelatin. Furthermore, the capsules may be covered in a specified coating which releases the drug or drugs in a manner that at least allows for a reduction in the frequency of administration compared to the drug or drugs present as conventional dosage forms.

The oral dosage form may also be a delayed release capsule in which the drug is enclosed in a hard or soft soluble container made of a suitable form of gelatin and which releases the drug (or drugs) at other times than immediately after administration, and thus the enteric coated article is a delayed release dosage form. Delayed release pellet capsules, in which the drug is enclosed in a rigid or flexible container or "shell," are also useful. In these cases, the drug itself takes the form of particles to which an enteric coating has been applied, thus delaying the release of the drug until it passes into the intestine. Delayed release capsules and film coated delayed release capsules are also useful.

Furthermore, the capsules are covered in a defined film coating which releases the drug or drugs in a manner which at least allows for a reduction in the frequency of administration compared to the drug or drugs present as conventional dosage forms. Gelatin-coated capsules (solid dosage forms in which the drug is enclosed within a rigid or flexible dissolvable container made of a suitable form of gelatin; by a taping process, the capsules are coated with an additional layer of gelatin to form an integral seal), liquid-filled capsules (a solid dosage form in which the drug is enclosed within a shell of dissolvable gelatin that is plasticized by the addition of a polyol such as sorbitol or glycerol, and thus has a slightly thicker consistency than a hard-shell capsule).

Other forms include pills (small round solid dosage forms containing a pharmaceutical agent intended for oral administration), powders (intimate mixtures of dry finely divided drugs and/or chemicals that may be intended for oral or external use), elixirs (clear, flavorful sweetened aqueous alcoholic liquids containing dissolved pharmaceutical agents; it is intended for oral use), masticants (sweetened and flavored insoluble plastic materials of various shapes that release the drug substance into the oral cavity when chewed), syrups (oral solutions containing high concentrations of sucrose or other sugars; the term is also intended to include any other liquid dosage forms prepared in a sweet and viscous medium, including oral suspensions), tablets (solid dosage forms containing a pharmaceutical agent with or without suitable diluents for chewing), chewable tablets (solid dosage forms containing a pharmaceutical agent with or without suitable diluents for chewing, which produces a pleasant tasting residue in the oral cavity that is easy to swallow and that does not leave a bitter or unpleasant aftertaste), coated or delayed release tablets, dispersible tablets, effervescent tablets, delayed release tablets, film coated tablets or film coated delayed release tablets, wherein the tablets are formulated such that the contained drug can be made available for a prolonged period of time after ingestion.

In other forms, tablets for solution, tablets for suspension, multilayer tablets, delayed release multilayer tablets may be provided, wherein the tablets are formulated to at least allow for a reduction in the frequency of administration compared to drugs present as conventional dosage forms. Orally disintegrating tablets, orally disintegrating delayed release tablets, dissolvable tablets, sugar coated tablets, osmotic tablets, and the like are also suitable.

Oral dosage form compositions may comprise the active pharmaceutical ingredient and one or more inactive excipients such as diluents, solubilizers, alcohols, binders, controlled release polymers, enteric polymers, disintegrants, colorants, flavoring agents, sweeteners, antioxidants, preservatives, pigments, additives, fillers, suspending agents, surfactants (e.g., anionic, cationic, amphoteric, or non-ionic), and the like. Various FDA-approved topical Inactive Ingredients can be found in The FDA's "Inactive Ingredients Database" (The Inactive Ingredients Database) containing Inactive Ingredients that The manufacturer intends to use for this purpose, wherein an Inactive ingredient may also be considered as an active ingredient in some cases according to The definition of active ingredient given in 21CFR 210.3(b) (7). Alcohol is a good example of an ingredient that can be considered active or inactive depending on the product formulation.

As used herein, dosage forms for parenteral administration include, but are not limited to, injectable liposomes that are composed of or form liposomes (lipid bilayer vesicles, typically composed of phospholipids, that are used to encapsulate active drug substances). Injection solutions intended for parenteral administration, comprising sterile preparations, are also suitable. Also suitable are emulsions consisting of sterile, pyrogen-free preparations, injectable emulsions or lipid complex injections intended for parenteral administration.

Other forms include powders for solution injection, which are sterile preparations intended to be reconstituted to form solutions for parenteral use; powders for suspension injection, which are sterile preparations, are reconstituted to form a suspension for parenteral use; lyophilized powders for injection of liposomal suspensions, which are sterile lyophilized preparations intended for reconstitution for parenteral use, which are formulated to allow the formation of liposomes upon reconstitution (lipid bilayer vesicles, typically composed of phospholipids, which are used to encapsulate active pharmaceutical substances within a lipid bilayer or in an aqueous space); freeze-dried powders for solution injection, which are dosage forms intended for solution prepared by lyophilization ("freeze-drying"), a process involving removal of water from the product in the frozen state at very low pressures.

This is intended for subsequent addition of liquid to produce a solution that meets the requirements of injection in all respects; lyophilized powders for injection suspensions which are liquid preparations intended for parenteral use containing a carrier suspended in a suitable fluid medium and in all respects meeting the requirements for a sterile suspension; medicaments intended for suspension are prepared by lyophilization ("freeze-drying"), a process involving removal of water from the product in the frozen state at very low pressure; injection solutions, which are liquid formulations containing one or more drugs dissolved in a suitable solvent or mixture of mutual solvents suitable for injection; injection solution concentrates, which are sterile preparations for parenteral use, produce solutions which, upon addition of suitable solvents, meet the requirements of injection in all respects.

Injection suspensions comprise a liquid formulation suitable for injection, which consists of solid particles dispersed throughout a liquid phase in which the particles are insoluble, which may also consist of an oil phase dispersed throughout an aqueous phase or an aqueous phase dispersed throughout an oil phase. Liposomal injection suspensions comprise liquid formulations suitable for injection, consisting of an oil phase dispersed throughout an aqueous phase, so as to form liposomes (lipid bilayer vesicles, typically composed of phospholipids, which are used to encapsulate active drug substances within a lipid bilayer or in an aqueous space). Ultrasonic injection suspensions comprise a liquid formulation suitable for injection, consisting of solid particles dispersed throughout a liquid phase in which the particles are insoluble. Furthermore, the product is sonicated while bubbling a gas through the suspension, which results in the formation of microspheres from the solid particles.

Parenteral carrier systems include one or more pharmaceutically suitable excipients, such as solvents and co-solvents, solubilizers, wetting agents, suspending agents, thickening agents, emulsifiers, chelating agents, buffers, pH adjusting agents, antioxidants, reducing agents, antimicrobial preservatives, extenders, protectants, tonicity adjusting agents and special additives. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.

Liquid carriers can be used in preparing formulations including solutions, suspensions, emulsions, syrups and elixirs. The compounds of the present invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colors, viscosity regulators, stabilizers or osmo-regulators. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier may also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions as sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection.

Sterile solutions may also be administered intravenously. Oral administration can be in the form of liquid or solid compositions. The injectable form can be an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, such as sterile pyrogen-free water or a parenterally acceptable oil or liquid mixture, which may contain bacteriostats, antioxidants or other preservatives and stabilizers, buffers (preferably but not limited to a physiological pH range of 6.5-7.7), solutes that render the solution isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable additives. These forms will be presented in unit dosage form, such as ampoules or disposable injection devices, or in multi-dose form, such as bottles from which appropriate doses may be extracted, or in solid form or concentrates useful for the rapid preparation of injectable preparations. All formulations for injection are preferably sterile and pyrogen-free. Suppositories containing the compounds will also contain suitable carriers such as cocoa butter, polyethylene glycol or other carriers of the state of the art.

Preferably, the compositions of the present invention are in unit dosage form, for example in the form of tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In this form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage form may be a packaged composition, for example a packaged powder, a vial containing a liquid, an ampoule, a pre-filled syringe or a sachet. The unit dosage form may be, for example, a capsule or tablet itself, or it may be an appropriate number of any such compositions in packaged form.

In general, the active ingredient may be dissolved or suspended in a liquid medium, and may be granules (small particles or granules), pellets (small sterile solid substances of highly purified drug, with or without excipients, made by granule formation or by compression and molding) or delayed release coated pellets (a solid dosage form in which the drug itself takes the form of granules to which different amounts of coating have been applied and which release the drug or drugs in a manner that allows for a reduction in the frequency of administration compared to the drug or drugs present as conventional dosage forms).

Examples

Example 1: effect of Salidroside on hypertension induced by chronic intermittent hypoxia in C57BL/6J mice

40C 57BL/6J mice were randomly divided into 4 groups of 10 mice each, namely a normal control group, a model group, a salidroside low dose group (25mg/kg), and a salidroside high dose group (50mg/kg), wherein salidroside was purchased from Nanjing beta Biotech, Inc., cat # 10189 (same below). Except for the normal control group, each group was placed in an animal triple air incubator (Oxycycler Model A42; BioSpherix Instruments, Redfield, NY, USA) to simulate chronic intermittent hypoxic conditions in patients with obstructive sleep apnea by adjusting the hypoxic parameters to achieve an ambient oxygen concentration of 21% -5%, 90 seconds/cycle, 10 hours/day for 7 weeks. And simultaneously, the normal group and the model group are subjected to intragastric administration of distilled water, and each administration group is subjected to intragastric administration of 25mg/kg and 50mg/kg of salidroside respectively once a day for 7 weeks. Blood pressure was measured in mice using an animal blood pressure recorder and endothelial dependent diastolic function changes were measured using a vascular tonometer (DMT620M, DMT, Denmark).

The results show that C57 mice fed with chronic intermittent hypoxia for 7 weeks have significant increases in systolic pressure, diastolic pressure and mean pressure, and impaired endothelial-dependent diastolic function of aortic vessels. Salidroside 50mg/kg can significantly reduce C57 mouse systolic pressure, diastolic pressure and average pressure increased by chronic intermittent hypoxia induction, and Salidroside 25mg/kg has certain improving effect on chronic intermittent hypoxia-induced C57 blood pressure increase (figure 2). Salidroside 50mg/kg can significantly improve CIH-induced vascular endothelial dependent diastolic function injury in C57 mice (FIG. 3). The salidroside is prompted to obviously improve the hypertension and the vascular function damage of C57 mice caused by chronic intermittent hypoxia in an obstructive sleep apnea mode, and has a protective effect.

Example 2: effect of Salidroside on chronic intermittent hypoxia induced hypertension in apoE mice

40 apoE mice were randomly divided into 4 groups of 10 mice each, namely a normal control group, a model group, a salidroside low dose group (25mg/kg), and a salidroside high dose group (50 mg/kg). Except for the normal control group, each group was placed in an animal triple air incubator (Oxycycler Model A42; BioSpherix Instruments, Redfield, NY, USA) to simulate chronic intermittent hypoxic conditions in patients with obstructive sleep apnea by adjusting the hypoxic parameters to achieve an ambient oxygen concentration of 21% -5%, 90 seconds/cycle, 10 hours/day for 7 weeks. And simultaneously, the normal group and the model group are subjected to intragastric administration of distilled water, and each administration group is subjected to intragastric administration of 25mg/kg and 50mg/kg of salidroside respectively once a day for 7 weeks. In addition, 10C 57BL/6J mice were used as a C57 normal control group. Blood pressure was measured in mice using an animal blood pressure recorder and endothelial dependent diastolic function changes were measured using a vascular tonometer (DMT620M, DMT, Denmark).

The results show that apoE mice fed with chronic intermittent hypoxia for 7 weeks have significantly increased systolic and mean blood pressure, and impaired endothelial-dependent diastolic function of aortic vessels. Salidroside 25mg/kg and Salidroside 50mg/kg can significantly reduce apoE mouse systolic pressure and average pressure induced by chronic intermittent hypoxia, and has certain dose dependence (FIG. 4). Salidroside 50mg/kg can significantly improve apoE mouse vascular endothelial dependent diastolic function injury caused by CIH (FIG. 5). The salidroside is suggested to significantly improve hypertension and vascular function damage in apoE mice caused by chronic intermittent hypoxia in the obstructive sleep apnea mode.

Example 3: effect of Salidroside on oxidative stress of Human Umbilical Vein Endothelial Cells (HUVECs) induced by chronic intermittent hypoxia

HUVEC cells at 1X 10⁴One cell/well was plated on a 24-well cell culture plate, incubated at 37 ℃ in an incubator for 18 hours, the medium was aspirated, the culture medium was added with the media containing salidroside at final concentrations of 10. mu.M and 100. mu.M, respectively, pre-incubated for 2 hours, placed in a cell aeroponic incubator (Oxycycler Model C42; BioSpherix Instruments, Redfield, NY, USA), the ambient oxygen concentration was adjusted to 21% -2% by adjusting the hypoxia parameter, 1 hour/cycle, and continued for 24 hours, and then the reactive oxygen species in the cells were detected using an ROS kit (s0033, Byunyun). The method is briefly described as follows: the medium was aspirated, cells were washed three times with PBS, and ROS fluorescence probe (DCFH-D) was addedA) Incubation at 37 ℃ for 30 min was followed by aspiration of the medium, three washes with PBS, photographing with an inverted fluorescence microscope under 488nm excitation light, and quantification of Image fluorescence intensity with Image-Pro Plus 6 software.

The results show that chronic intermittent hypoxia can induce the oxidative stress state of HUVECs cells, and the ROS generation is obviously increased, and salidroside 10 mu M and 100 mu M can obviously reduce the ROS content of HUVECs cells which are induced and increased by the chronic intermittent hypoxia, and the dosage dependence is certain (figure 6). The salidroside is suggested to improve the oxidative stress state of HUVECs caused by chronic intermittent hypoxia.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples that follow are intended to illustrate and not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention encompasses and claims those inventions resulting from combinations of features of the inventions cited herein and features of the cited prior art references (which complement features of the present invention). Similarly, it should be understood that any of the materials, features or articles described may be used in combination with any other materials, features or articles, and such combinations are considered to be within the scope of the present invention.

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Claims (7)

1. Use of salidroside or a pharmaceutically acceptable salt thereof as sole active ingredient for the manufacture of a medicament for the treatment of obstructive sleep apnea induced hypertension, wherein salidroside or a pharmaceutically acceptable salt thereof is present in said medicament in a therapeutically effective amount.

2. Use according to claim 1, wherein the route of administration of the medicament is oral and/or parenteral.

3. The use of claim 2, wherein the parenteral route comprises topical, buccal, sublingual, pulmonary, transdermal, transmucosal, and intravenous, subcutaneous, intraperitoneal, and/or intramuscular injection.

4. The use according to claim 1, wherein the medicament further comprises a solubilizer, a binder, a controlled-release polymer, a disintegrant, a colorant, a flavoring agent, an antioxidant, a filler, a suspending agent and/or a surfactant.

5. The use of claim 1, wherein the medicament is in a dosage form comprising a tablet, pill, capsule, granule, powder, chewable gum, suspension, emulsion, suppository, or solution.

6. The use according to claim 5, wherein the suspension is a liposomal injection suspension.

7. The use according to claim 1, wherein the salidroside or pharmaceutically acceptable salt thereof is administered at a dose of 25-50 mg/kg.

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