TWI657825B - Pharmaceutical compositions and methods of treating cardiovascular disease - Google Patents

Abstract

The present invention provides a combination drug comprising two, three or more independent compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H _1- Receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist, or one or more of the active compounds is rich in isotopes (isotopes are not enriched in Less than 50%). The present invention also provides a combination medicine and method of using for treating, preventing or ameliorating cardiovascular disease in a subject, which comprises administering a combination medicine of two, three or four independent compounds to a subject in need, each of which Compounds are phosphodiesterase inhibitor, adenosine receptor antagonist, calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor Antagonist or β ₂ -adrenergic receptor agonist.

Description

Combination medicine for treating cardiovascular disease, and preparation and use method thereof

The present invention provides a combination drug comprising two or more independent compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and a histamine H ₁ -receptor, respectively. An agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenergic receptor agonist, or one or more of its active compounds is rich in isotopes (isotope enrichment is not less than 50%). The invention also includes a method for using the drug to treat, prevent or reduce cardiovascular disease in a subject. These methods include administering to a subject a combination of two or more independent compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H ₁ -A receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenergic receptor agonist.

[Cross-reference to related patent applications]

The present application claims U.S. Provisional Patent Application No. 62 / 652,812 filed on April 4, 2018 and U.S. Patent Application filed on May 7, 2018 (Official, Fast Track) Priority No. 15973132, the disclosure of each of which is incorporated herein by reference in its entirety.

Cardiovascular disease is a type of disease involving the heart or cardiovascular vessels (Mendis et al., Global Atlas on Cardiovascular Disease Prevention and Control-World Health Organization, World Heart Federation, and World Stroke Organization 2011). Cardiovascular diseases include coronary heart disease such as angina pectoris and myocardial infarction (commonly known as heart disease), stroke, hypertension heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, heart valve disease, carditis, aorta Tumors, peripheral arterial disease, and venous thrombosis (Mendis et al., Global Atlason Cardiovascular Disease Prevention and Control-World Health Organization, World Heart Federatio, and World Stroke Organization 2011). Cardiovascular disease caused 17.3 million deaths (31.5%) in 2013, up from 12.3 million (25.8%) in 1990 (Lancet 2014, 385, 117-171). In the United States, 11% of people between the ages of 20 and 40 have cardiovascular disease, 37% of people between the ages of 40 and 60 and 71% of people between the ages of 60 and 80 , 85% of people over 80 years of age (Go et al., Circulation 2013, 127, e6-e245).

A major form of arrhythmia is bradycardia or slowness. Bradycardia can cause fainting, dizziness, malaise, general weakness, excessive fatigue, chest pain, and memory loss. Some researchers have tried some drugs for therapeutic research (Alboni et al., Am. J. Cardiol., 1990, 65, 1037-1039; Ling et al., Ann. Pharmacother., 1998, 32, 837-839; Benditt et al., Am. J. Cardiol., 1983, 52, 1223-229). Due to the adverse side effects of the drug selected, these test drug candidates cannot be routinely used for a long time. As a result, there are currently no medicines in the world approved by the medical regulations that can be used to treat bradycardia. Treatment options for chronic symptomatic bradycardia are limited to implanting a pacemaker into the patient. It is estimated that the pacemaker implantation rate in the United States and Europe and other developed countries is about 50-60 / 100,000 people per year. According to a global survey released in 2009, about 1 million people use pacemakers in the 61 countries surveyed (about 740,000 are newly implanted). By 2028, it is estimated that more than 700,000 new pacemakers will be implanted in the United States alone. According to US National Health Statistics Reports 2011, 41, 1-16, clinically determined bradycardia (abnormally slow heart rate, RP resting pulse rate (RPR) <60 beats / minute) in the United States for 10 years The average prevalence rate between 1999 and 2008 was 15.2% for men and 6.9% for women. Because human heart rate is negatively related to age, the number of patients with bradycardia who need to use a pacemaker will continue to increase as the global elderly population increases. In addition, due to the adverse side effects and high cost of pacemakers, many patients with bradycardia are either unable or unwilling to choose a treatment method for implanting pacemakers.

As mentioned above, the current medical treatment for bradycardia requires surgically installed pacemakers. The first use of an embedded pacemaker was in Sweden in 1958. Since then, this method of treating abnormal heart rhythms has spread throughout the world. In recent years, as the quality of pacemakers has improved, the effect of pacemakers in treating bradycardia has also greatly increased. Unfortunately, pacemakers also have some limitations or defects. For example, a pacemaker needs to be surgically implanted in the body, and sometimes an installed pacemaker needs to be removed due to an infection. In addition, pacemakers may not provide a normal physiological heart rate response to exercise or normal contraction patterns. If the heart rate response is inadequate or uncomfortable during exercise, patients may experience significant symptoms related to insufficient cardiac output. In addition, a single right ventricular pacemaker may cause significant left ventricular dysfunction and worsening heart failure in some patients. Implantation of a dual ventricular pacemaker can improve left ventricular failure associated with right ventricular pacing, but this procedure is time consuming, difficult, and not always feasible due to technical issues. As recently observed, the pacemaker's pacing leads may fail and may be subject to periodic recalls by regulatory agencies such as the FDA. Finally, pacemaker implantation, replacement, and monitoring are expensive. Due to the lack of effective arrhythmic drugs to replace current treatments, doctors and patients can only use pacemakers when necessary. However, due to the aforementioned potential complications, many patients with bradycardia delay or abandon the use of pacemakers and live with bradycardia symptoms and the associated potentially fatal risks. Therefore, there is an unmet need for effective drugs and treatments for treating bradycardia.

In order to overcome the deficiencies or deficiencies associated with current bradycardia treatments, the present invention provides effective combination drugs and methods of administration for treating bradycardia and related cardiovascular diseases.

The combination drug provided by the present invention comprises: (a) two or more independent compound drugs, each of which is (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, and (ii) a calcium channel blocker A deterrent, (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist or a histamine H ₃ -receptor antagonist, or (iv) a β ₂ -adrenergic receptor agonist, Or one or more of the active compounds are rich in isotopes (isotope enrichment is not less than 50%); and (b) pharmaceutically acceptable excipients (also known as excipients).

The combination drug provided by the present invention comprises: (a) three or more independent compound drugs, each of which is (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, and (ii) a calcium channel blocker Agent, (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist or a histamine H ₃ -receptor antagonist, or (iv) a β ₂ -adrenergic receptor agonist, or One or more of the active compounds are rich in isotopes (isotope enrichment is not less than 50%); and (b) pharmaceutically acceptable excipients (also known as excipients).

The combination drugs provided by the present invention also include a combination of the following independent drugs: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, (ii) a calcium channel blocker, and (iii) a histamine H ₁ -receptor Agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist, or (iv) β ₂ -adrenergic receptor agonist, or one or more of the active compounds is rich in isotopes (isotopically rich Set no less than 50%).

The present invention provides a pharmaceutical composition also comprises a combination of the following separate medicament: (i) a phosphodiesterase inhibitor, or an adenosine receptor antagonist, (ii) a calcium channel blocker, and (iii) a histamine H ₁ - receiving Agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

The combination drugs provided by the present invention include a combination of the following independent drugs: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, (ii) a calcium channel blocker, and (iii) a β ₂ -adrenergic receptor Agonist.

The combination drugs provided by the present invention also include a combination of the following independent drugs: (i) phosphodiesterase inhibitor or adenosine receptor antagonist, (ii) histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonists or antagonists of the histamine H ₃ receptor, and (iii) β ₂ - adrenoreceptor agonist.

The combination drugs provided by the present invention also include a combination of the following independent drugs: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, (ii) a calcium channel blocker, and (iii) a histamine H ₁ -receptor Agonists, histamine H ₂ -receptor agonists or histamine H ₃ -receptor antagonists, and (iv) β ₂ -adrenergic receptor agonists.

The combination medicine provided by the present invention comprises: (a) two or more independent compounds, wherein each compound is: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In one embodiment, Its compound is theophylline, aminophylline or its isotopic variant (isotopic enrichment is not less than 50%), and its content is about 5-90% by weight or about 5-35% by weight; (ii) calcium channel resistance Excipient, in another embodiment, the compound is nifedipine or its isotopic variant (isotope enrichment is not less than 50%), and its content is about 1-20% or about 1-5 by weight percentage %; (Iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, in another embodiment, the compound is betahist dihydrochloride Ting or its isotope variant (isotope enrichment is not less than 50%), and its content is about 0.1-20% or about 0.5-5% by weight percentage; or (iv) β ₂ -adrenergic receptor agonist In another embodiment, the compound is albuterol, levosalbutamol hydrochloride or its isotope variant (isotope enrichment is not less than 50%). From about 0.01 to 5%, or about 0.1-0.5%; and a pharmaceutically (b) a pharmaceutically acceptable excipient (also called excipients).

The combination medicine provided by the present invention comprises: (a) three or more independent compounds, wherein each compound is: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In one embodiment, The compound is theophylline, aminophylline or its isotopic variant (isotope enrichment is not less than 50%), and its content is about 5-90% or about 5-35% based on weight percentage; (ii) calcium channel resistance Excipient, in another embodiment, the compound is nifedipine or its isotopic variant (isotope enrichment is not less than 50%), and its content is about 1-20% or about 1-5 by weight percentage %; (Iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, in another embodiment, the compound is betahist dihydrochloride Ting or its isotope variant (isotope enrichment is not less than 50%), and its content is about 0.1-20% or about 0.5-5% by weight percentage; or (iv) β ₂ -adrenergic receptor agonist In another embodiment, the compound is albuterol, levosalbutamol hydrochloride or its isotope variant (isotope enrichment is not less than 50%), calculated by weight percentage In an amount of about 0.01 to 5%, or about 0.1-0.5%; and a pharmaceutically (b) a pharmaceutically acceptable excipient (also called excipients).

The invention provides a method for treating, preventing or ameliorating a cardiovascular disease in a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and a calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

The invention provides a method for treating, preventing or improving symptomatic sinus bradycardia in a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, Histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist, or one or more of the active compounds is rich in isotopes (Isotopic enrichment is not less than 50%).

The present invention provides methods for treating, preventing or improving stroke in a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and a calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

The present invention provides a method for treating, preventing or improving cerebrovascular thrombosis in a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and a calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

The present invention provides a method for treating, preventing or improving arrhythmia in a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist-calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

The present invention provides a method for increasing the heart rate of a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and a calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

The present invention provides a method for increasing the cardiac output of a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and a calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

The present invention provides a method for increasing cerebral blood flow in a subject. The method is to administer an effective dose of a combination drug comprising two or more independent compounds to a patient in need, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and a calcium channel blocker, respectively. , A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist or a β ₂ -adrenergic receptor agonist, or one or more of these active compounds is rich in Isotopes (not less than 50% enrichment).

In order to facilitate the understanding of the contents of this patent, the terms used in the present invention are described or defined.

In general, the terms used in the present invention and the laboratory methods and procedures described are common knowledge well known in the fields of medicinal chemistry, biochemistry, biology, and pharmacology. Unless specifically defined, all scientific and technological terms used in the present invention have the same meaning as the terms in the related scientific and technological fields.

The term "recipient" or "recipient" refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse this. The terms "subject", "patient", or "patient" are used interchangeably in the present invention. In one embodiment, a mammalian recipient, such as a human recipient embodiment, is specifically a patient or patient.

The terms "treatment", "therapeutic action" and "treatment regimen" are meant to include alleviating or eliminating a physiological disorder, disease, or disorder, or one or more symptoms associated with a disease or disorder, or alleviating or removing their causes.

The terms "prevention," "preventive action," and "prevention regimen" are meant to include delaying and / or excluding physiological dysfunction, disease or disorder, and / or complications associated with the disorder, blocking the physical dysfunction of the subject , Disease or condition, or reduce the risk of a physical disorder, disease, or condition in a subject.

The term "therapeutically effective dose" means the pharmaceutically acceptable amount of the individual compounds contained. Where practical, the amount used is sufficient to prevent or treat a patient's condition, disease, or to a certain extent alleviate the development of the symptoms of one or more diseases. The term "therapeutically effective dose" also refers to a pharmaceutically acceptable amount of a compound sufficient to elicit a biological or medical response from a biomolecule (eg, protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human. These biological or medical responses are of interest to drug researchers, veterinarians, doctors, or clinicians.

The term "sub-therapeutic effective dose" refers to a compound or component in which the pharmaceutically acceptable amount of the compound is less than the effective dose used alone.

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable auxiliary material or carrier, such as a liquid , Solid fillers, diluents, solvents or packaging materials. In one embodiment, each component is compatible with the other ingredients of the pharmaceutical formulation and is suitable for contact with tissues or organs of a subject, such as a human or animal. "Pharmaceutically acceptable" when used refers to complications that have no or little toxicity, irritation, allergic reactions, immunogenicity, or other problems. It has a more reasonable benefit than risk (see reference: Remington: The Science and Practice of Pharmacy, 22nd ed .; Allen Ed .: Philadelphia, PA 2012; Handbook of Pharmaceutical Excipients, 7th ed .; Rowe et al. ,, Eds .; The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd ed .; Ash and Ash Eds .; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed .; Gibson Ed .; CRC Press LLC: Boca Raton, FL, 2009).

The term "about" or "approximately" refers to an error acceptable to a particular parameter value in the art. It depends on how this value is measured or determined. In some embodiments, the term "about" or "approximately" means that its standard deviation is within 1, 2, 3, or 4. In other embodiments, the terms "about" or "approximately" mean between 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3 Within a given value or range of%, 1%, 0.5%, or 0.05%.

The terms "active ingredient", "active pharmaceutical ingredient", "API" and "active substance" are used interchangeably in this patent. It refers to the administration of a single or multiple drugs together with one or more pharmaceutically acceptable excipients for the treatment, prevention or amelioration of one or more symptoms of a disease, disease or condition in a subject. As used in this patent, "active ingredient", "active pharmaceutical ingredient", "API", and "active substance" may be metabolites of the compounds described in this patent, and / or their isotopic variants (isotopic enrichment of not less than 50 %), And / or its optical isomers.

The term "isotopically enriched group" or "isotopically enriched (isotope enrichment of not less than 50%)" refers to a compound containing an unnatural proportion of isotopes at one or more atoms constituting such a compound. In certain embodiments, isotopically enriched compounds contain one or more isotopes in unnatural proportions, including hydrogen ( ¹ H), deuterium ( ² H), tritium ( ³ H), carbon-11 ( ¹¹ C), carbon -12 ⁽¹² C), the carbon -13 ⁽¹³ C), carbon -14 ⁽¹⁴ C), nitrogen -13 ⁽¹³ N), nitrogen -14 ⁽¹⁴ N), nitrogen -15 ⁽¹⁵ N), oxygen - 14 ( ¹⁴ O), oxygen-15 ( ¹⁵ O), oxygen-16 ( ¹⁶ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), fluorine-17 ( ¹⁷ F), fluorine-18 ( ¹⁸ F), phosphorus -31 ⁽³ 1P), phosphorus -32 ⁽³² P), phosphorus -33 ⁽³³ P), sulfur -32 ⁽³² S), sulfur -33 ⁽³³ S), sulfur -34 ⁽³⁴ S ), Sulfur-35 ( ³⁵ S), sulfur-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine -81 ( ⁸¹ Br), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I), and iodine-131 ( ¹³¹ I), but not limited to this. In certain other embodiments, the isotopically enriched compound is in a stable form, ie, non-radioactive. In other embodiments, isotopically enriched compounds contain one or more isotopes in unnatural proportions, including hydrogen ( ¹ H), deuterium ( ² H), carbon-12 ( ¹² C), carbon-13 ( ¹³ C ) nitrogen -14 ⁽¹⁴ N), nitrogen -15 ⁽¹⁵ N), oxygen -16 ⁽¹⁶ O), oxygen -17 ⁽¹⁷ O), oxygen -18 ⁽¹⁸ O), fluorine -17 ⁽¹⁷ F), phosphorus -31 ( ³¹ P), sulfur-32 ( ³² S), sulfur-33 ( ³³ S), sulfur-34 ( ³⁴ S), sulfur-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), and iodine-127 ( ¹²⁷ I), but are not limited thereto. In certain embodiments, the isotopically enriched compound is in an unstable form, i.e., is radioactive. In other embodiments, the isotope-enriched compound contains one or more isotopes in an unnatural ratio, including tritium ( ³ H), carbon-11 ( ¹¹ C), carbon-14 ( ¹⁴ C), nitrogen-13 ( ¹³ N), oxygen -14 ⁽¹⁴ O), oxygen -15 ⁽¹⁵ O), fluorine -18 ⁽¹⁸ F), phosphorus -32 ⁽³² P), phosphorus -33 ⁽³³ P), sulfur -35 ⁽³⁵ S) chlorine -36 ⁽³⁶ Cl), iodine -123 ⁽¹²³ I), iodine -125 ⁽¹²⁵ I), iodine -129 ⁽¹²⁹ I) and iodine -131 ⁽¹³¹ I), but is not limited thereto. It should be understood that in the compounds provided by the present invention, any hydrogen may be ² H, or any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N, or any oxygen may be ¹⁸ O. Judgment and application can be made where feasible based on the capabilities of those with ordinary knowledge in the art.

In certain embodiments, "optically active" and "enantiomerically active" means that the set of compound molecules has more than, not less than about 50%, not less than about 70%, No less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than "Optically active" and "enantiomerically active" substance contents of about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the total amount of the mixture of enantiomers in question is one of the enantiomers and has an optically active compound at a content of about 95% or more and another compound at a content of about 5 % Or less of the enantiomers.

In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the compound with respect to its chiral center. (+) And (-) are used to indicate the optical rotation of the compound, that is, the direction in which the plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is left-handed, that is, the compound rotates the plane of polarized light to the left or to the left. The prefix (+) indicates that the compound is right-handed, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the optical rotation signs (+) and (-) are independent of the absolute configurations R and S of the compound.

The term "isotopic enrichment" refers to the percentage, which means that an element of a common isotope (such as the ¹ H isotope) at a given position is replaced with its less common isotopic element (such as D for ² H) . As used in the present invention, when an atom at a particular position in a molecule is designated as a particularly less common isotope, it should be understood that the abundance of that isotope at that position is much greater than its natural abundance.

The term "isotopic enrichment factor" refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a particular isotope.

The term "hydrogen" or the symbol "H" refers to the composition of naturally occurring hydrogen isotopes, which includes hydrogen ( ¹ H), deuterium ( ² H or D), and tritium ( ³ H). In their natural abundance content, The natural abundance of hydrogen over 99.98% is the most common hydrogen isotope. Deuterium is a less common hydrogen isotope with a natural abundance of about 0.0156%.

The term ^"2 H or deuterium enrichment" refers to the percentage of hydrogen in the molecule at a given position is deuterium ⁽² H) replaced. For example, a 1% deuterium ( ² H) enrichment at a given position means that 1% of the molecules in a given sample contain deuterium ( ² H) at the specified position. Since the natural distribution of deuterium is about 0.0156% on average, the average deuterium enrichment at any position in compounds synthesized using non-enriched raw materials is about 0.0156%. As used in the present invention, when an element at a specific position in an isotope-enriched compound is designated to contain deuterium, it should be understood that the abundance of deuterium ( ² H) at that position in the compound is much greater than its natural abundance (0.0156%). ).

The term "carbon" or the symbol "C" refers to the composition of naturally occurring carbon isotopes, which includes the natural abundance of carbon-12 ( ^12C ) and carbon-13 ( ^13C ). The natural abundance of carbon-12 is the most common carbon isotope of over 98.89%. Carbon-13 is a less common carbon isotope with a natural abundance of about 1.11%.

The term "carbon-13 enrichment" or " ^13C enrichment" refers to the percentage of carbon atoms incorporated at a given position in a carbon-13 molecule. For example, a given position of carbon-13 is enriched at 10%, which means that 10% of the molecules in a given sample contain carbon-13 at the specified position. Because the average natural distribution of carbon-13 is approximately 1.11%, the average carbon-13 enrichment at any position in compounds synthesized using non-enriched raw materials is approximately 1.11%. As used in the present invention, when a specific position in an isotope-enriched compound is determined to have carbon-13, this should be understood as the abundance of carbon-13 at that position in the compound is significantly greater than its natural abundance (1.11% ).

The term "solvent compound" refers to a complex or aggregate formed from one or more solute molecules (such as compounds provided by the present invention) and one or more solvent molecules, which are present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. When the solvent is water, the solvent compound is a hydrate. Examples of the hydrate include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

The phrase "its isotopic variant (with an isotopic enrichment of not less than 50%); or a pharmaceutically acceptable salt, solvent compound, hydrate or drug precursor thereof" has the same meaning as the phrase: (i) where Isotopic variants of the referenced compounds (isotopic enrichment of not less than 50%); or (ii) pharmaceutically acceptable salts, solvent compounds, hydrates, or prodrugs of the compounds mentioned therein; or ( iii) isotopic variants of the compounds mentioned therein (isotope enrichment is not less than 50%); pharmaceutically acceptable salts, solvent compounds, hydrates or precursors of drugs.

Composition and pharmacology of combination drugs

In one embodiment, the present invention provides a combination drug for treating symptomatic sinus bradycardia. In some embodiments, the present invention provides a combination drug comprising two or more independent compounds, each compound in the pharmaceutical composition is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel Blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist, or one or more of these activities The compound is rich in isotopes (isotope enrichment is not less than 50%).

The combination drug of two or more active pharmaceutical ingredients (API) for treating cardiovascular disease (such as bradycardia) disclosed by the present invention has unexpected special effects. Specifically, without being bound by theory, the principle of the combination drug is to take advantage of the addition or synergy of the second or subsidiary function of each independent drug, such as increasing heart rate or increasing cardiac output The role of quantity. These auxiliary functions may be undesired side effects of related drugs already recognized on the market when used alone. Through scientific research and reasonable combination, their auxiliary functions have become effective functions of the combination drugs provided by the present invention. The combination drug can stimulate and enhance a desired therapeutic effect on the heart, such as an increase in heart rate of the heart or an increase in blood output to the heart; and this desired therapeutic effect can be used to treat many cardiovascular diseases, such as cardiac output Heart failure and bradycardia associated with abnormal blood volume or bradycardia. The combination drug disclosed by the present invention, on the basis of ensuring the efficacy, each active ingredient also uses the principle of the minimum effective amount in the combination drug to reduce adverse side effects. Without being bound by theory, the combination of two or more active pharmaceutical ingredients (APIs) provided by the present invention also takes advantage of the special properties of its different components to offset its associated adverse side effects, such as cardiac oxygen consumption Increase or decrease in blood pressure of the recipient. As a result, by taking the combination medicine provided by the present invention, the recipient can obtain the desired therapeutic effect on the heart, including the increase in the heart rate and cardiac output of the recipient without any adverse side effects, or adverse side effects. Minimized, for example, avoiding an increase or decrease in cardiac oxygen consumption and an increase or decrease in blood pressure when the active ingredient is administered alone less. The combination medicine of two or more active pharmaceutical ingredients provided by the present invention, each of which has the same desired effect of new heart rate and cardiac output, and the undesired effect of each independent pharmaceutical active ingredient Can be offset by the side effect of another active ingredient in the combination drug. In addition, on the basis of ensuring the efficacy of the drug, the amount of each active ingredient in the combined drug is brought to a minimum effective dose through a synergistic effect, thereby further reducing the side effects of each active ingredient.

In one embodiment, the present invention provides a combination drug comprising two independent compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H _1- Receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination drug provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (ii) a calcium channel blocker. In another embodiment, the combination drug provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (ii) a histamine H ₁ -receptor agonist, a histamine H _2- Receptor agonist or histamine H ₃ -receptor antagonist. In yet another embodiment, the combination medicament provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (ii) a β ₂ -adrenergic receptor agonist. In yet another embodiment, the combination medicament provided by the present invention comprises (i) a calcium channel blocker; and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist. In yet another embodiment, the combination medicament provided by the present invention comprises (i) a calcium channel blocker; and (ii) a β ₂ -adrenergic receptor agonist. In yet another embodiment, the combination medicament provided by the present invention comprises (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist; and (ii ) β ₂ -adrenergic receptor agonist. In yet another embodiment, the present invention provides a combination drug comprising three independent compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H _1- Receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the present invention provides a pharmaceutical composition comprising (i) a phosphodiesterase inhibitor, or an adenosine receptor antagonist; (ii) a calcium channel blocker; and (iii) a histamine H ₁ - receptors An agonist, a histamine H ₂ -receptor agonist or a histamine H ₃ -receptor antagonist. In another embodiment, the combination medicament provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) a calcium channel blocker; and (iii) a β ₂ -adrenergic receptor Body agonist. In yet another embodiment, the combination drug provided by the present invention comprises (i) a calcium channel blocker; (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -A receptor antagonist; and (iii) a β ₂ -adrenergic receptor agonist. In yet another embodiment, the combination drug provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonists or histamine H ₃ - receptor antagonist; and (iii) β ₂ - adrenoreceptor agonist. In yet another embodiment, the present invention provides a combination drug comprising four independent compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H ₁ -A receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenergic receptor agonist.

In one embodiment, the combination drug provided by the present invention comprises: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) a calcium channel blocker; (iii) a histamine H ₁ -receptor Agonists, histamine H ₂ -receptor agonists or histamine H ₃ -receptor antagonists; and (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist is a solid. In other embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist is a crystalline solid. In some other embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist is an amorphous solid.

In certain embodiments, the calcium channel blocker is a solid. In certain embodiments, the calcium channel blocker is a crystalline solid. In certain embodiments, the calcium channel blocker is an amorphous solid.

In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is a solid. In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is a crystalline solid. In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is an amorphous solid.

In certain embodiments, the β ₂ -adrenergic receptor agonist is a solid. In certain embodiments, the β ₂ -adrenergic receptor agonist is a crystalline solid. In certain embodiments, the β ₂ -adrenergic receptor agonist is an amorphous solid.

In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker in a combination drug provided by the present invention ranges from about 1 to about 180, About 2 to about 100, about 2 to about 50, or about 2 to about 20. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker in a combination drug provided by the present invention ranges from about 1 to about 180. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker in a combination drug provided by the present invention ranges from about 2 to about 100. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker in a combination drug provided by the present invention ranges from about 2 to about 50. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker in a combination drug provided by the present invention ranges from about 2 to about 20. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker in the combination drug provided by the present invention is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, or about 20.

In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor in a combination drug provided by the present invention agonists or histamine H ₃ - receptor antagonist in a weight ratio range from about 2 to about 200, from about 4 to about 100, from about 5 to about 50 or about 10 to about 30. In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- receptor agonists or histamine H ₃ - receptor antagonist in a weight ratio ranging from about 2 to about 200. In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- receptor agonists or histamine H ₃ - receptor antagonist in a weight ratio ranging from about 4 to about 100. In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- receptor agonists or histamine H ₃ - receptor antagonist in a weight ratio ranging from about 5 to about 50. In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- receptor agonists or histamine H ₃ - receptor antagonist in a weight ratio ranging from about 10 to about 30. In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- The weight ratio of the receptor agonist or histamine H ₃ -receptor antagonist is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 30 .

In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 1 To about 1000, about 10 to about 500, about 20 to about 400, or about 40 to about 300. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 1 To about 1000. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 10 To about 500. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 20 To about 400. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 40 To about 300. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention is about 40, About 60, about 80, about 100, about 120, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -The receptor antagonist has a weight ratio ranging from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10. In certain embodiments, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -The weight ratio of the receptor antagonist ranges from about 1 to about 50. In certain embodiments, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -The weight ratio of the receptor antagonist ranges from about 1 to about 40. In certain embodiments, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -The weight ratio of the receptor antagonist ranges from about 1 to about 20. In certain embodiments, the present invention provides (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H _{3 in a} pharmaceutical composition -The weight ratio of the receptor antagonist ranges from about 1 to about 10. In certain embodiments, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -The weight ratio of the receptor antagonist is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5 , About 8, about 8.5, about 9, about 9.5, or about 10. In certain embodiments, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -The weight ratio of the receptor antagonist is about 2, about 2.2, about 2.4, about 2.6, about 2.8, about 3, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.

In certain embodiments, the weight ratio of (i) calcium channel blocker to (ii) β ₂ -adrenoreceptor agonist in the combination drug provided by the present invention ranges from about 1 to about 100, about 5 to about 50 Or about 5 to about 30. In certain embodiments, the weight ratio of (i) a calcium channel blocker to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 1 to about 100. In certain embodiments, the weight ratio of (i) a calcium channel blocker to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 5 to about 50. In certain embodiments, the weight ratio of (i) a calcium channel blocker to (ii) a β ₂ -adrenergic receptor agonist in a combination drug provided by the present invention ranges from about 5 to about 30. In certain embodiments, the weight ratio of (i) calcium channel blocker to (ii) β ₂ -adrenergic receptor agonist in the combination drug provided by the present invention is about 5, about 6, about 7, about 8 About 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 28, about 29, or about 30.

In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of the β ₂ -adrenergic receptor agonist ranges from about 1 to about 100, about 1 to about 50, about 1 to about 30, or about 1 to about 20. In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of the β ₂ -adrenergic receptor agonist ranges from about 1 to about 100. In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of the β ₂ -adrenergic receptor agonist ranges from about 1 to about 50. In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of the β ₂ -adrenergic receptor agonist ranges from about 1 to about 30. In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of the β ₂ -adrenergic receptor agonist ranges from about 1 to about 20. In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of β ₂ -adrenergic receptor agonist is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the combination medicaments provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 1 to about 1200, about 1 to about 1000, about 1 to about 800, About 1 to about 600, about 2 to about 300, or about 10 to about 200 mg. In certain embodiments, the combination drugs provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 1 to about 1200 mg. In certain embodiments, the combination medicament provided by the present invention comprises a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 1 to about 1000 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 1 to about 800 mg. In certain embodiments, the combination medicine provided by the present invention comprises a phosphodiesterase inhibitor or an adenosine receptor antagonist The amount of the antagonist ranges from about 1 to about 600 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 2 to about 300 mg. In certain embodiments, the combination medicament provided by the present invention comprises a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 10 to about 200 mg. In certain embodiments, the combination drugs provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount of about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg. In certain embodiments, the combination medicament provided by the present invention comprises a calcium channel blocker in an amount ranging from about 0.1 to about 200, about 0.1 to about 100, about 0.2 to about 80, about 1 to about 50 or about 1 To about 30 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 0.1 to about 200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 0.1 to about 100 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 0.2 to about 80 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 1 to about 50 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount of about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, About 20, about 22, about 24, about 26, about 28, or about 30 mg.

In certain embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 0.1 to About 200, about 0.1 to about 100, about 0.1 to about 60, about 0.2 to about 50, about 0.5 to about 40, or about 1 to about 30 mg. In some embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, and the amount thereof ranges from about 0.1 To about 200 mg. In some embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, and the amount thereof ranges from about 0.1 To about 100 mg. In some embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, and the amount thereof ranges from about 0.1 To about 60 mg. In certain embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, and the amount thereof ranges from about 0.2 To about 50 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 0.5 To about 40 mg. In some embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 1 To about 3 mg. In certain embodiments, the combination medicine provided by the present invention comprises a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount of about 1, About 5, about 10, about 15, about 20, about 25, or about 30 mg.

In certain embodiments, the combination medicament provided by the present invention comprises a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.01 to about 60, about 0.01 to about 40, about 0.05 to about 30, about 0.05 to about 20. About 0.1 to about 10 or about 0.1 to about 5 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.01 to about 60 mg. In certain embodiments, the combination medicament provided by the present invention comprises a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.01 to about 40 mg. In certain embodiments, the combination medicament provided by the present invention comprises a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.05 to about 30 mg. In certain embodiments, the combination drugs provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.05 to about 20 mg. In certain embodiments, the combination drugs provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.1 to about 10 mg. In certain embodiments, the combination drugs provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.1 to about 5 mg. In certain embodiments, the combination medicament provided by the present invention comprises a β ₂ -adrenergic receptor agonist in an amount of about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5 , About 4, about 4.5, or about 5 mg.

In certain embodiments, the combination medicament provided by the present invention comprises a phosphodiesterase inhibitor or an adenosine receptor antagonist, and the amount thereof ranges from about 1 to about 90, about 2 to about 80, about 5 to 60 or about 5 to about 35%. In certain embodiments, the combination drugs provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 1 to about 90%. In certain embodiments, the combination drugs provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 2 to about 80%. In certain embodiments, the combination drugs provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 5 to about 60%. In certain embodiments, the combination drugs provided by the present invention comprise a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount ranging from about 5 to about 35%. In some implementations In an example, the combination medicine provided by the present invention comprises a phosphodiesterase inhibitor or an adenosine receptor antagonist in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, About 45, about 50, about 55, or about 60%.

In some embodiments, the combination medicament provided by the present invention comprises a calcium channel blocker, and its amount ranges from about 0.1 to about 30, about 0.5 to about 20, or about 1 to about 10%, based on the weight percentage. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 0.1 to about 30%. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 0.5 to about 20%. In certain embodiments, the combination medicaments provided by the present invention comprise a calcium channel blocker in an amount ranging from about 1 to about 10%. In certain embodiments, the combination medicament provided by the present invention comprises a calcium channel blocker in an amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or About 10%.

In some embodiments, the combination medicine provided by the present invention comprises a H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist. At about 0.02 to about 30, about 0.05 to about 20, about 0.1 to about 15 or about 0.2 to about 10%. In certain embodiments, the combination drugs provided by the present invention comprise a H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 0.02 to about 30%. In certain embodiments, the combination medicaments provided by the present invention comprise a H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 0.05 to about 20%. In certain embodiments, the combination medicament provided by the present invention comprises a H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 0.1 to about 15%. In certain embodiments, the combination medicament provided by the present invention comprises a H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount ranging from about 0.2 to about 10%. In some embodiments, the combination medicine provided by the present invention comprises a H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in an amount of about 0.2, about 0.5 About 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 8.5 9.0, about 9.5, or about 10%.

In certain embodiments, the combination medicine provided by the present invention comprises a β ₂ -adrenergic receptor agonist, and the amount thereof is in a range of about 0.005 to about 10, about 0.01 to about 8, and about 0.02 to about 6 in terms of weight percentage. Or about 0.05 to about 5%. In certain embodiments, the combination medicaments provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.005 to about 10%. In certain embodiments, the combination medicaments provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.01 to about 8%. In certain embodiments, the combination medicaments provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.02 to about 6%. In certain embodiments, the combination medicaments provided by the present invention comprise a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.05 to about 5%. In certain embodiments, the combination medicament provided by the present invention comprises a β ₂ -adrenergic receptor agonist in an amount of about 0.05, about 0.1, about 1, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5 , About 4.0, about 4.5, or about 5%.

Phosphodiesterase inhibitor or adenosine receptor antagonist

In some embodiments, the active ingredient (API) included in the combination medicine provided by the present invention is a phosphodiesterase (PDE) inhibitor and / or an adenosine receptor antagonist. Phosphodiesterase inhibitors and adenosine receptor antagonists are commonly used in the treatment of chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary disease (COPD) and asthma. Phosphodiesterase inhibitors or adenosine receptor antagonists have another function (also known as a second effect), which is to increase heart rate and cardiac output. The molecular mechanism of action of the active ingredient phosphodiesterase inhibitor and / or adenosine receptor is (i) competitively and non-selectively inhibiting phosphodiesterase, which increases intracellular cyclic adenylate (cAMP), protein Protein kinase A (PKA), inhibits tumor necrosis factor-α (TNF-α), inhibits leukotriene synthesis, and reduces inflammation and innate immunity; and (ii) non-selectively antagonizes adenosine receptors, almost equally antagonize a _1, a ₂ and a ₃ receptors, its molecular mechanism of action explains many of the heart. By inhibiting phosphodiesterase, cyclic cAMP hydrolysis is reduced, thereby promoting endogenous epinephrine and controlling the release of norepinephrine. Adenosine receptor antagonists can antagonize adenosine and prevent excessive release of adenosine, thereby increasing cAMP in myocardial cells and stimulating an increase in heart rate (HR) and cardiac output. When a recipient receives two or more combination drugs provided by the present invention, the undesired side effect of one active ingredient (API) in the combination drug can be offset by the side effect of the other active ingredient. Through the mutual elimination of their side effects, reduce the consumption of oxygen and minimize the undesired side effects of this active ingredient, including myocardial contractility, myocardial metabolism, and its consumption of oxygen is minimized or even eliminated, meanwhile, by A combination medicine using two or more compounds provided by the present invention includes, but is not limited to, the desired therapeutic effect is enhanced, heart rate and cardiac output are increased.

The invention discloses a method for treating cardiovascular diseases (such as bradycardia). Combinations of one, three or more compounds have unexpected special effects. Phosphodiesterase (PDE) inhibitors and / or adenosine receptor antagonists are good active ingredients in combination drugs that can be used to treat bradycardia, while avoiding or minimizing the associated adverse side effects.

In certain embodiments, the phosphodiesterase (PDE) inhibitor is a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent thereof Compound. In certain embodiments, the phosphodiesterase inhibitor is a methylxanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof . In certain embodiments, the phosphodiesterase inhibitor is caffeine, doxofylline, dihydroxypropylline, tachyophylline, paraxanthine, pentoxifylline, theobromine, theophylline, Or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the phosphodiesterase inhibitor is aminophylline, caffeine, doxofylline, dihydroxypropylline, choline theophylline, paraxanthine, pentoxifylline, cocoa Alkali or theophylline. In certain embodiments, the phosphodiesterase inhibitor is aminophylline, caffeine, doxofylline, dihydroxytheophylline, oxaphylline, pentoxifylline, or theophylline. In certain embodiments, the phosphodiesterase inhibitor is aminophylline. In certain embodiments, the phosphodiesterase inhibitor is caffeine. In certain embodiments, the phosphodiesterase inhibitor is doxofylline. In certain embodiments, the phosphodiesterase inhibitor is dihydroxypropylline. In certain embodiments, the phosphodiesterase inhibitor is tatrotheline. In certain embodiments, the phosphodiesterase inhibitor is pentoxifylline. In certain embodiments, the phosphodiesterase inhibitor is theophylline.

In certain embodiments, the phosphodiesterase inhibitor is a non-selective phosphodiesterase inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a competitive non-selective phosphodiesterase inhibitor. In certain embodiments, the non-selective phosphodiesterase inhibitor is caffeine, paraxanthine, pentoxifylline, theophylline, theophylline, theophylline, or an isotope variant (isotope enrichment is not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-1 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a selective phosphodiesterase-1 inhibitor. In certain embodiments, the phosphodiesterase-1 inhibitor is vinpocetine or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-2 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a selective phosphodiesterase-2 inhibitor. In certain embodiments, the phosphodiesterase-2 inhibitor is EHNA (erythro-9- (2-hydroxy-3-nonyl) adenine), BAY 60-7550 (2-[(3,4-Dimethoxyphenyl) methyl ] -7-[(1 R ) -1-hydroxyethyl] -4-phenylbutyl] -5-methyl-imidazo [5,1- f ] [1,2,4] triazin-4 (1 H ) -one), Oxindole (oxindole), PDP (9- (6-phenyl-2-oxohex-3-yl) -2- (3,4-dimethoxybenzyl) -purin-6-one), or its isotopic variant (isotopically rich Set not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-3 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-3 selection Sexual inhibitor. In certain embodiments, the phosphodiesterase-3 inhibitor is anagrelide, cilostazol, enoxidone, emicone, milrinone, pimobendan, or an isotope variant (isotope Enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-4 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a selective phosphodiesterase-4 inhibitor. In certain embodiments, the phosphodiesterase-4 inhibitor is pamodrolast, drovervirin, ibudilast, luteolin, messimlin, piramilast, roflumilast Teflon, Rolipram, or an isotope variant (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-5 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a selective phosphodiesterase-5 inhibitor. In certain embodiments, the phosphodiesterase-5 inhibitor is avanafil, dipyridamole, icariin, sildenafil, tadalafil, udinafil, vardenafil , Or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the phosphodiesterase-5 inhibitor is 4-methylpiperazine, pyrazolopyrimidine-7-1, or an isotopic variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-7 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a selective phosphodiesterase-7 inhibitor. In certain embodiments, the phosphodiesterase-7 inhibitor is a quinazoline, or an isotopic variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound.

In certain embodiments, the phosphodiesterase inhibitor is a phosphodiesterase-10 inhibitor. In certain embodiments, the phosphodiesterase inhibitor is a selective phosphodiesterase-10 inhibitor. In certain embodiments, the phosphodiesterase-10 inhibitor is papaverine, or an isotope variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is adibendan, amipizone, anagrelide, apremilast, afrylline ), Atizram (atizoram), avanafil, befuraline, bemarinone, bemoradan, benafentrine , Bucladesine, buflomedil, buquineran, CC-1088, carbazeran, catramilast, cilomilast, Cilostazol, cilostazol, crisaborole (AN2728), dipuridamole, drrotaverin, enoximone, etamiphyllin, exophyllin Ibudilast, inamrinone, luteolin, mesembrenone, metescufylline, midaxifylline, milrinone , Motapizone, papaverine, parogrelil, pelrinone, spray tea Pentifylline, pentoxifylline, perbufylline, piclamilast, pimefylline, Pimobendan, Piroximone, Proxodan, Prophylline, Pumafentrine, Roflumilast, Rolipram (rolipram), sildenafil, tadalafil, theophylline, udenafil, vardenafil, vinpocetine, or Its isotopic variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is AN2728, abitriptan, aminophylline, aminophylline dihydrate, amiloride, avertin, a Tirastron, benfuralin, bemarinone hydrochloride, bemolendon, benafentriazine, bradoxine, teflomedil, butraquine, CC-1088, cabalazole , Catorastel, Imatinib, Imidazolidine Hydrochloride, Imitriptyline, Imitone Lactate, Isbufylline, Imatinib Hydrochloride, Imatinib Hydrochloride, Imatinib Hydrochloride, imatinib hydrochloride, imatinib hydrochloride, imatinib hydrochloride, imatinib hydrochloride, telmisarin, milrinone, milrinone lactate, malayalam , Nanamidone, antipyrine, nitropromazine, ogamilast, ogamilast sodium, opolinone, oxagrelate, oxarelin, papaverine, papaverine hydrochloride Base, papaverine sulfate, pioglitazone, priezone hydrochloride, pentoxifylline, promylcholine, picoxetine, pimexitin, piracetam, pyridoxine Ximin, Procodant, Promethamphetamine, Prometholamine, Quinazinone, Quinazoline, Ramostil, Retiridone, Roflumilast, Rolipram, Ronamilast , Saterinone, senazodan, Siguazodan, theophylline, tofimilast, trapidil, vesnarinone, zardaverine, or its isotopic variant (isotope Enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the phosphodiesterase inhibitor is aminotadalafil, avanafil, mifeadine, dasantafil, gisadenafil (5- [2-Ethoxy-5- (4- ethylpiperazin-1-yl) sulfonyl-pyridin-3-yl] -3-ethyl-2- (2-methoxyethyl) -4H-pyrazolo [4,3-d] pyrimidin-7-one) Phenafil, milotina, sildenafil, sildenafil citrate, tadalafil, udinafil, vardenafil, vardenafil dihydrochloride, vardenafil III Hydrate or Zoplast.

In certain embodiments, the adenosine receptor antagonist is a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the adenosine receptor antagonist is a methylxanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof . In certain embodiments, the adenosine receptor antagonist is caffeine, paraxanthine, pentoxifylline, theophylline, theophylline, theophylline, or an isotope variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound. In certain embodiments, the adenosine receptor antagonist is aminophylline, caffeine, doxofylline, diprophylline, oxophylline, paraxanthine, pentoxifylline, theobromine, or Theophylline. In certain embodiments, the adenosine receptor antagonist is aminophylline. In certain embodiments, the adenosine receptor antagonist is theophylline.

In certain embodiments, the adenosine receptor antagonist is a non-selective adenosine receptor antagonist. In certain embodiments, A ₁ adenosine receptor antagonist is an antagonist. In certain embodiments, the adenosine receptor antagonist is an A ₂ antagonist. In certain embodiments, A ₃ adenosine receptor antagonist is an antagonist. In certain embodiments, the adenosine receptor antagonist is an antagonist of A _1, A _2, and A ₃ receptors.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; And (ii) one or more independent compounds, each of which is a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist Agent or β ₂ -adrenergic receptor agonist.

In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof A compound; and (ii) a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenergic receptor agonist Agent.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; And (ii) a calcium channel blocker. In another embodiment, the combination drug comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and ( ii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist. In yet another embodiment, the combination medicament comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and ( ii) β ₂ -adrenergic receptor agonist.

In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof compound; and (ii) two compounds, wherein each compound is independently calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist, a histamine H ₃ - receptor antagonist Agent or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (ii) a calcium channel blocker; and (iii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist. In another embodiment, the combination drug comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) ) Calcium channel blockers; and (iii) β ₂ -adrenergic receptor agonists. In yet another embodiment, the combination drug comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) ) A histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist; and (iii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof compound; and (ii) three compounds, wherein each compound independent of calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist, a histamine H ₃ - receptor antagonist Or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination medicine provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. (Ii) a calcium channel blocker; (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist; and (iv) β _2- Adrenaline receptor agonist.

In certain embodiments, the xanthine compound is methylxanthine. In certain embodiments, the xanthine compound is caffeine, doxofylline, diprophylline, taurine, paraxanthine, pentoxifylline, theobromine, theophylline, or isotopic variants Isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the xanthine compound is aminophylline, caffeine, doxofylline, diprophylline, choline theophylline, paraxanthine, pentoxifylline, theobromine, or theophylline. In certain embodiments, the xanthine compound is aminophylline. In certain embodiments, the xanthine compound is theophylline.

In certain embodiments, the xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is a solid. In certain embodiments, the xanthine compound, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is a crystalline solid. In certain embodiments, the xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is an amorphous solid.

In certain embodiments, in the combination medicine provided by the present invention, the weight ratio of the xanthine compound to the calcium channel blocker ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 To about 20. In some embodiments, in the combination medicine provided by the present invention, the weight ratio of the xanthine compound to the calcium channel blocker ranges from about 1 to about 180. In some embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the combination medicine provided by the present invention ranges from about 2 to about 100. In certain embodiments, in the combination medicine provided by the present invention, the weight ratio of the xanthine compound to the calcium channel blocker is about 2, about 4, about 6, about 8, about 10, about 12, about 14, About 16, about 18, or about 20.

In certain embodiments, (i) a xanthine compound and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor in a combination drug provided by the present invention The weight ratio of the somatic antagonist ranges from about 2 to about 200, from about 4 to about 100, from about 5 to about 50, or from about 10 to about 30. In certain embodiments, (i) a xanthine compound and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H _3- The weight ratio of the receptor antagonist is about 10, about 12, about 14, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, About 27, about 28, about 29, or about 30.

In certain embodiments, the weight ratio of the xanthine compound to the β ₂ -adrenergic receptor agonist in the combination medicine provided by the present invention ranges from about 1 to about 1000, about 10 to about 500, about 20 to about 400, or About 40 to about 300. In certain embodiments, the weight ratio of the xanthine compound to the β ₂ -adrenergic receptor agonist in the combination drug provided by the present invention is about 40, about 60, about 80, about 100, about 120, about 140, about 140 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the combination medicament provided by the present invention comprises a xanthine compound in an amount ranging from about 1 to about 1200, about 1 to about 1000, about 1 to about 800, about 1 to about 600, about 2 to about 300 or about 20 to about 200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 1 to about 1200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 1 to about 1000 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 1 to about 800 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 1 to about 600 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount of about 2 to about 300 mg. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 10 to about 200 mg. In certain embodiments, the combination medicament provided by the present invention comprises a xanthine compound in an amount of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100 About 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg.

In certain embodiments, the combination medicament provided by the present invention comprises a xanthine compound, and the amount thereof ranges from about 1 to about 90, about 2 to about 80, about 5 to about 60, or about 5 to about 35 in terms of weight percent. %. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 1 to about 90%. In certain embodiments, the combination medicament provided by the present invention comprises a xanthine compound in an amount The range is from about 2 to about 80%. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 5 to about 60%. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 5 to about 35%. In certain embodiments, the combination medicaments provided by the present invention comprise a xanthine compound in an amount ranging from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35%.

Calcium channel blocker

In some embodiments, the active ingredient (API) included in the combination drug provided by the present invention is a calcium channel blocker. Calcium channel blockers are commonly used to treat hypertension. By blocking the calcium channel, its active ingredients can relax the coronary system and prevent coronary spasm (thus dilating the main coronary arteries in normal and ischemic areas), and further reduce the use of oxygen, reducing the arterial pressure by expanding the peripheral arteries, thereby Reduces total peripheral resistance to heart work. Without being bound by theory, the side effects of this active ingredient, including inhibition of myocardial contractility and reduced myocardial metabolism, can be offset or maximized by the side effects of another active ingredient in the combination drug, such as a phosphodiesterase inhibitor. At the same time, by using a combination drug of two or more compounds provided by the present invention, the desired therapeutic effect is enhanced, and the heart rate and cardiac output are increased, but not limited thereto.

The combination medicine of two or more compounds for treating cardiovascular disease (such as bradycardia) disclosed by the present invention has unexpected special curative effect. Calcium channel blocker is a very good active ingredient in the combination medicine and can be used for treatment. Bradycardia, while avoiding or minimizing associated adverse side effects.

In certain embodiments, the calcium channel blocker is amlodipine, aridipine, aradipine, bannidipine, benidipine, cinidipine, clevidipine, diltiazem, ififipine, felodipine, Nilvadipine, Nisoldipine, Nixandipine, Prandipine, Pregabalin, Verapamil, Ziconotide, or their isotopic variants (isotope enrichment is not less than 50%), or pharmaceutically acceptable Accepted salts, hydrates or solvent compounds. In certain embodiments, the calcium channel blocker is tepril, flunarizine, forpirin, miberadil, nidipine or an isotope variant thereof (isotope enrichment is not less than 50% ), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the calcium channel blocker is dihydropyridine or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the calcium channel blocker is amlodipine, aridipine, aradipine, bannidipine, benidipine, cinidipine, clevidipine, ififipine, felodipine, ila Dipine, Laxidipine, Lecardipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Prandipine, or their isotopic variants (isotopic enrichment Not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the calcium channel blocker is amlodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is aradipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is atidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compounds. In certain embodiments, the calcium channel blocker is bannidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is benidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is phenylpyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is cinidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is clevidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is diltiazem, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is ififipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is felodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is fentiline, or an isotopic variant thereof (whose isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is flunarizine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is Firth Pilin, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is galapamil, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is irradipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is lacidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is lercanidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is manidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is mibeladil, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is nicardipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is nifedipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is nilvadipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is nimodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a drug thereof A scientifically acceptable salt, hydrate or solvent compound. In certain embodiments, the calcium channel blocker is nisoldipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is nitrendipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is pradipine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is verapamil, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the calcium channel blocker is zicoronide, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In some embodiments, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) one or more compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, respectively , Histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; And (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof compound; and (ii) a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist. In yet another embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) β ₂ -adrenergic receptor agonists.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, Histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist Agent. In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) β ₂ -adrenergic receptor agonists. In yet another embodiment, the combination drug provided by the present invention comprises (i) dihydropyridine or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (ii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist; and (iii) β ₂ - adrenoreceptor agonist.

In yet another embodiment, the combination drug provided by the present invention comprises (i) dihydropyridine or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; And (ii) three compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, and histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist ; And (iv) a β ₂ -adrenergic receptor agonist.

In certain embodiments, the dihydropyridine is amlodipine, alandipine, aradidipine, bannidipine, benidipine, cinidipine, clevidipine, clonidipine, daclidipine, diazepam Misone, ifodipine, erodipine, alaprofen, felodipine, flulotin, venidipine, nicardipine, nimodipine, nisoldipine, nitropine Dipine, oladipine, osodipine, palonidine, prandipine, digoxin, tramadol hydrochloride, tenidipine, ticadipine, tiazadipine, telmidipine, ticadipine, or an isotope variant (Isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the dihydropyridine is amlodipine, aridipine, azelnidipine, barnidipine, benidipine, cinidipine, clevidipine, ififipine, felodipine Dipine, Irradipine, Laxidipine, Lecardipine, L-Amlodipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pradipine , Or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In certain embodiments, the dihydropyridine is amlodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is aradipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is atenidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is barnidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is benidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is cinidipine, or an isotope variant thereof (isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the dihydropyridine is clevidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is ififipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is felodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is irradipine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is lacidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is lercanidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is levamlodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is Manidipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is nicardipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is nifedipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvate thereof Thing. In certain embodiments, the dihydropyridine is nilvadipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is nimodipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is nisoldipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is nitrendipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the dihydropyridine is pradipine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In certain embodiments, the dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound component thereof is a solid. In certain embodiments, the dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is a crystalline solid. In certain embodiments, the dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is an amorphous solid.

In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) dihydropyridine in a combination drug provided by the present invention ranges from about 1 to about 180, about 2 To about 100 or about 2 to about 20. In certain embodiments, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist in a combination drug provided by the present invention and (ii) the weight ratio of dihydropyridine is about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, (i) dihydropyridine and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor in a combination drug provided by the present invention The weight ratio of the somatic antagonist ranges from about 0.1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10. In certain embodiments, (i) dihydropyridine and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor in a combination drug provided by the present invention The weight ratio of the body antagonist ranges from about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, About 8, about 8.5, about 9, about 9.5, or about 10. In certain embodiments, (i) dihydropyridine and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor in a combination drug provided by the present invention The weight ratio of the antagonist is about 2, about 2.2, about 2.4, about 2.6, about 2.8, about 3, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.

In some embodiments, the weight ratio of dihydropyridine to β ₂ -adrenergic receptor agonist in the pharmaceutical combination provided by the present invention ranges from about 1 to about 100, about 5 to about 50, or about 5 to about 30. . In certain embodiments, the weight ratio of dihydropyridine to β ₂ -adrenergic receptor agonist in the pharmaceutical combination provided by the present invention is about 5, about 6, about 7, about 8, about 9, about 10, About 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27 , About 28, about 29, or about 30.

In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount ranging from about 0.1 to about 200, about 0.1 to about 100, about 0.2 to about 80, about 1 to about 50, or about 1 to about 30 mg. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount ranging from about 0.1 to about 200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount of about 0.1 to about 100 mg. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount ranging from about 0.2 to about 80 mg. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount ranging from about 1 to about 50 mg. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount ranging from about 1 to about 30 mg. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount of about 1, about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18 , About 20, about 22, about 24, about 26, about 28, or about 30 mg.

In certain embodiments, the combination medicament provided by the present invention comprises dihydropyridine, and its content ranges from about 0.1 to about 30, about 0.5 to about 20, or about 1 to about 10%, based on weight percent. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine, the content of which ranges from about 0.1 to about 30%. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount ranging from about 0.5 to about 20%. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine, the content of which ranges from about 1 to about 10%. In certain embodiments, the combination medicaments provided by the present invention comprise dihydropyridine in an amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 %.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) optionally two or more Various compounds, each of which is a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenoreceptor agonist, respectively.

In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) dihydropyridine, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) histamine H _1- Agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) dihydropyridine, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) a histamine H ₁ -receptor An agonist, a histamine H ₂ -receptor agonist or a histamine H ₃ -receptor antagonist. In another embodiment, the combination drug comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) ) Dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) two compounds of each The compounds are histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, histamine H ₃ -receptor antagonists, or β ₂ -adrenoreceptor agonists, respectively.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) dihydropyridine, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) histamine H ₁ -receptor agonism Agents, histamine H ₂ -receptor agonists or histamine H ₃ -receptor antagonists; and (iv) β ₂ -adrenergic receptor agonists.

In some embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the combination drug provided by the present invention ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 to about 20. In certain embodiments, a combination drug provided by the present invention The weight ratio of mesoxanthine compound to dihydropyridine ranges from about 1 to about 180. In some embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the combination medicine provided by the present invention ranges from about 2 to about 100. In some embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the combination medicine provided by the present invention ranges from about 2 to about 50. In some embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the combination drug provided by the present invention is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18 or about 20.

Histamine H ₁ -Receptor agonist, histamine H ₂ -Receptor agonist or histamine H ₃ -Receptor antagonist

In some embodiments, the combination medicine provided by the present invention contains the active ingredient histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist. Histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H ₃ -receptor antagonists can be used to treat vertigo in general cases. Similar to phosphodiesterase inhibitors, adenosine receptor antagonists or calcium channel blockers, when such drugs are administered alone, they interact with histamine H ₁ -receptor agonists, histamine H ₂ -receptors agonists or histamine H ₃ - receptor antagonist various undesirable side effects associated generates and pharmaceutically acceptable impact. Without being bound by theory, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H ₃ -receptor antagonists mainly have two potential molecular mechanisms of action. First, some histamine H ₃ -receptor antagonists can stimulate histamine H ₁ -receptors, causing local vasodilation and permeability. Secondly, the antagonism of histamine H ₃ -receptors can cause the release of histamine, acetylcholine, norepinephrine, serotonin and γ-aminobutyric acid (GABA) in nerve endings, causing vasodilation Including lowering blood pressure. These undesired side effects can be offset by the side effects of another active ingredient in the combination drug provided by the present invention, such as the β ₂ -adrenergic receptor agonist provided by the present invention. As a result, unwanted side effects of this active ingredient are offset or maximized by another active ingredient in the combination drug, such as salbutamol or levosalbutamol. At the same time, by using a combination drug of two or more compounds provided by the present invention, it includes enhanced desired therapeutic effects, increased heart rate and cardiac output, and dilation of peripheral arterioles and veins, but is not limited thereto .

The combination drugs of two or more compounds disclosed in the present invention for treating cardiovascular disease (such as bradycardia) have unexpected special therapeutic effects. Histamine H ₁ -receptor agonist, histamine H ₂ -receptor Somatic agonists or histamine H ₃ -receptor antagonists are good active ingredients in combination drugs that can be used to treat bradycardia, while avoiding or minimizing the associated adverse side effects.

In certain embodiments, the histamine H ₁ -receptor agonist is Histamine trifluoromethyl toluidide (HTMT), 2-pyridylethylamine, 2-thiazolylethylamine , Or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist is betahistine, betaxazole, isoamyl An amine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist is bezole, or an isotope variant thereof (isotopically rich Set not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is isopentyl amine, or isotopic variations (isotope Enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In certain embodiments, the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist is 4-methylhistamine, tampapril (dimaprit), isopropylaniline, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is A-349821, ABT-239, betamethasone Division Tintin, bumimabamine, ciprofloxacin, clobenpropit, conessine, failproxifan, impentamine, iodophenpropit, irdabisant, ratio Pitolisant, thioperamide, VUF-5681 (4- [3- (1 H -imidazol-4-yl) propyl) piperidine), or its isotopic variant (isotope enrichment is not low) At 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is betahistine, or isotopic variations ( Isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is Betahistine hydrochloride.

In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is betahistine metabolites. In certain embodiments, the metabolite is 2- (2-aminoethyl) pyridine, 2- (2-hydroxyethyl) pyridine ) Or pryidylacetic acid. In certain embodiments, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is 2- (2-aminoethyl) pyridine, 2- (2-hydroxyethyl) pyridine or pyridylacetic acid.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (ii) one or more separate compounds, wherein each compound are phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers or β ₂ - adrenergic Receptor agonist.

In another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers or β ₂ -adrenergic receptor agonists.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; and (ii) phosphodiesterase inhibitors or adenosine receptor antagonists. In another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) calcium channel blockers. In yet another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) β ₂ -adrenergic receptor agonists.

In yet another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, or a β ₂ -adrenergic receptor, respectively Agonist.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) calcium channel blockers. In another embodiment, the pharmaceutical composition provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) β ₂ -adrenergic receptor agonists. In yet another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) calcium channel blockers; and (iii) β ₂ -adrenergic receptor agonists.

In yet another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compounds; and (ii) three compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, or a β ₂ -adrenergic receptor agonist Agent.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate, or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; (iii) calcium channel blockers; and (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, the betahistine, or a metabolite thereof, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is solid. In certain embodiments, the betahistine, or a metabolite thereof, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is Crystalline solid. In certain embodiments, the betahistine, or a metabolite thereof, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof is Amorphous solid.

In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) betahistine or a metabolite thereof in a pharmaceutical combination provided by the present invention ranges from about 2 To about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30. In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) betahistine or a metabolite thereof in the pharmaceutical combination provided by the present invention is about 10, About 12, about 14, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30.

In certain embodiments, the weight ratio of (i) calcium channel blocker to (ii) betahistine or its metabolite in the combination drug provided by the present invention ranges from about 1 to about 50, about 1 to about 40 , About 1 to about 20 or about 1 to about 10. In certain embodiments, the weight ratio of (i) a calcium channel blocker to (ii) betahistine or a metabolite thereof in a combination drug provided by the present invention is about 1, about 1.5, about 2, about 2.5, About 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10. In certain embodiments, the weight ratio of (i) a calcium channel blocker to (ii) betahistine or a metabolite thereof in a combination drug provided by the present invention is about 2, about 2.2, about 2.4, about 2.6, About 2.8, about 3, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.

In certain embodiments, the weight ratio of (i) betahistine or its metabolite to (ii) β ₂ -adrenergic receptor agonist in the combination medicine provided by the present invention ranges from about 1 to about 100, about 1 to about 50, about 1 to about 30, or about 1 to about 20. In certain embodiments, the weight ratio of (i) betahistine or its metabolite to (ii) β ₂ -adrenergic receptor agonist in the combination drug provided by the present invention is about 1, about 2, about 3 About 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.1 to about 200, about 0.1 to about 100, about 0.1 to about 60, and about 0.2 to about 50. About 0.5 to about 40 or about 1 to about 30 mg. In certain embodiments, the combination drug provided by the present invention comprises betahistine or its metabolism And its content ranges from about 0.1 to about 200 mg. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.1 to about 100 mg. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount of about 0.1 to about 60 mg. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.2 to about 50 mg. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.5 to about 40 mg. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 1 to about 30 mg. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount of about 1, about 2, about 4, about 6, about 8, about 10, about 12, about 14, About 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 30 mg.

In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof, and its content ranges from about 0.02 to about 30, about 0.05 to about 20, about 0.1 to about 15 or About 0.2 to about 10%. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof, and its content ranges from about 0.02 to about 30%. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.05 to about 20%. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.1 to about 15%. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof in an amount ranging from about 0.2 to about 10%. In certain embodiments, the combination medicament provided by the present invention comprises betahistine or a metabolite thereof, which The content is about 0.2, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, About 8.0, about 8.5, about 9.0, about 9.5, or about 10%.

In one embodiment, the combination medicine provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (whose isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) ) Optionally one or more of these compounds, each compound being a calcium channel blocker or a β ₂ -adrenergic receptor agonist, respectively.

In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) Calcium channel blocker or β ₂ -adrenergic receptor agonist.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a calcium channel Blocker. In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) β ₂ -adrenergic receptor agonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) Two compounds, each of which is a calcium channel blocker or a β ₂ -adrenergic receptor agonist, respectively.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) Betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salts, hydrates, or solvent compounds; (iii) calcium channels Blockers; and (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, the xanthine compound in the combination medicine provided by the present invention The weight ratio of the substance to betahistine or its metabolite ranges from about 2 to about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30. In certain embodiments, the weight ratio of the xanthine compound to betahistine or its metabolite in the combination medicine provided by the present invention is about 10, about 12, about 14, about 16, about 17, about 18, about 19 , About 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) Betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salts, hydrates, or solvent compounds; and (iii) any One or more compounds are selected, and each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, or a β ₂ -adrenergic receptor agonist, respectively.

In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) Phosphodiesterase inhibitors, adenosine receptor antagonists and / or β ₂ -adrenergic receptor agonists.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) Betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salts, hydrates, or solvent compounds; and (iii) phosphate Diesterase inhibitor or adenosine receptor antagonist. In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) β ₂ -adrenergic receptor agonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) Two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, or a β ₂ -adrenergic receptor agonist, respectively.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof (Ii) Betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salts, hydrates, or solvent compounds; (iii) diphosphate Esterase inhibitors or adenosine receptor antagonists; and (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, the weight ratio of dihydropyridine to betahistine or its metabolites in the combination drugs provided by the present invention ranges from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10. In certain embodiments, the weight ratio of dihydropyridine to betahistine or its metabolites in the combination drugs provided by the present invention ranges from about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4. About 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10. In certain embodiments, the weight ratio of dihydropyridine to betahistine or its metabolites in the combination drugs provided by the present invention is about 2, about 2.2, about 2.4, about 2.6, about 2.8, about 3.0, about 3.2 , About 3.4, about 3.6, about 3.8, or about 4.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) dihydropyridine, or its isotopic variant (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) betahistine, or its metabolism Or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; or (iv) an optional β ₂ -adrenergic receptor agonist.

β ₂ -Adrenergic receptor agonist

In some embodiments, the combination medicine provided by the present invention contains an active ingredient β ₂ -adrenergic receptor agonist. In general, β ₂ -adrenergic receptor agonists are used to treat asthma. Similar to phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H ₃ -receptor antagonists Agents, when such drugs are administered alone, various undesirable side effects with β ₂ -adrenergic receptor agonists can occur and affect their medicinal properties. Its active ingredient is a racemic mixture of salbutamol and R-salbutamol. The main mechanism of action of this active ingredient includes (i) the (R) -enantiomer (L-salbutamol) is responsible for pharmacological activity, and (ii) the (S) -enantiomer can block the metabolic pathway, but is not limited thereto. In addition, this active ingredient has the effect of increasing heart rate and cardiac output. This active ingredient is called a short-acting β ₂ -adrenergic receptor agonist and was originally used to relieve bronchospasm. In addition, the active ingredient can stimulate the heart's B ₁ receptor. The myocardium also has B ₂ receptors. This active ingredient can increase the heart rate by stimulating the B ₁ and B ₂ receptors. Side effects of this active ingredient include elevated blood pressure. By using a combination drug of two or more compounds provided by the present invention, the side effect of this active ingredient can be offset or minimized by the side effect of another component in the combination drug. At the same time, by using a combination drug of two or more compounds provided by the present invention, the desired therapeutic effect is enhanced, and the heart rate and cardiac output are increased, but not limited thereto.

The present invention discloses, discloses and provides a combination drug of two or more independent contents for treating cardiovascular diseases (such as bradycardia) with unexpected special therapeutic effects, β ₂ -adrenergic receptor agonist It is a very good active pharmaceutical ingredient in a combination drug that can be used to treat bradycardia, while avoiding or maximally reducing the adverse side effects associated with it.

In one embodiment, the β ₂ -adrenergic receptor agonist is a short-acting β ₂ -agonist. In another embodiment, the β ₂ -adrenergic receptor agonist is a long-acting β ₂ -agonist. In yet another embodiment, the β ₂ -adrenergic receptor agonist is a super long-acting β ₂ -agonist.

In certain embodiments, the β ₂ -adrenergic receptor agonist is Shuchuanning, Bambuterol, Bitoterol, Clenbuterol, Finoterol, Formoterol, Indene Datrol, isoproterenol, levosalbutamol, oxenaline, odadrol, piobuterol, procaterol, ritodrine, salbutamol, terbutaline, vilantrol, or their isotopes A variant (isotope enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. In certain embodiments, the β ₂ -adrenergic receptor agonist is salbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or Solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is bambuterol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is Bitoterol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is clenbuterol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is fenoterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, hydrated Substance or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is formoterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is indacaterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is isoproterenol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is levosalbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate thereof. Or solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is oxinalin, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound.

In certain embodiments, the β ₂ -adrenergic receptor agonist is ordatrol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is piobutrolol, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is procaterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, hydrated Substance or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is ritodrine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, hydrated Substance or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is salbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or Solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is terbutaline, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is Velantrol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound.

In certain embodiments, the β ₂ -adrenergic receptor agonist is afomodrol, buphenine, doxamine, adrenaline, isoserine, isoprenaline, left Salbutamol, osinalin, salmeterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof. In certain embodiments, the β ₂ -adrenergic receptor agonist is afomoterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof. , Hydrate or solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is styrene butadiene, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt or hydrate thereof. Or solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is dobexamine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In some embodiments, the β ₂ -adrenergic receptor agonist is epinephrine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate thereof. Or solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is isophylline, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, hydrated Substance or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is isoproterenol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is levousartanbutanol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds. In certain embodiments, the β ₂ -adrenergic receptor agonist is oxinalin, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound. In certain embodiments, the β ₂ -adrenergic receptor agonist is salmeterol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, hydrated Substance or solvent compound.

In one embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50) %), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) one or more compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker breaking agent, a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) acceptable 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (ii) phosphodiesterase inhibitor, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ - receiving Agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In one embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) a calcium channel blocker. In yet another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H _3- receptor Body antagonist.

In yet another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist. In yet another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor Body antagonist.

In one embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (iii) a calcium channel blocker. In another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (iii) a histamine H ₁ -receptor agonist , Histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist. In yet another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) a calcium channel blocker; and (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonists or histamine H ₃ - receptor antagonist.

In another embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) three compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker breaking agent, a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In one embodiment, the combination drug provided by the present invention comprises (i) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (the isotopic enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (iii) a calcium channel blocker; and (iv) a group Amine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In certain embodiments, the albuterol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmacological agent thereof The acceptable salts, hydrates or solvent compounds are solids. In certain embodiments, the albuterol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmacological agent thereof An acceptable salt, hydrate or solvent compound is a crystalline solid. In certain embodiments, the albuterol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutical agent thereof An acceptable salt, hydrate or solvent compound is an amorphous solid.

Ingredient formula and products

In certain embodiments, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) salbutamol or levosalbutamol in the combination medicine provided by the present invention ranges from about 1 to about 1,000, about 10 to about 500, about 20 to about 400, or about 40 to about 300. In certain embodiments, the weight ratio of (i) phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) salbutamol or levosalbutamol in the combination medicine provided by the present invention is about 40, about 60, about 70 , About 80, about 90, about 110, about 120, About 130, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the weight ratio of (i) calcium channel blocker to (ii) salbutamol in the combination drugs provided by the present invention ranges from about 1 to about 100, about 5 to about 50, or about 5 to about 30. In certain embodiments, the weight ratio of (i) calcium channel blocker to (ii) salbutamol or levosalbutamol in the combination medicament provided by the present invention is about 5, about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 30.

In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of salbutamol or levosalbutamol ranges from about 1 to about 100, about 1 to about 50, about 1 to about 30, or about 1 to about 20. In certain embodiments, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist in a combination drug provided by the present invention and (ii) The weight ratio of salbutamol or levosalbutamol is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, About 15, about 16, about 17, about 19, or about 20.

In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol (micronized or non-micronized) in a range of about 0.01 to about 60, about 0.01 to about 40, about 0.05 to about 30, About 0.05 to about 20, about 0.1 to about 10, or about 0.1 to about 5 mg. In certain embodiments, the combination medicaments provided by the present invention comprise salbutamol or levosalbutamol, and the content ranges from about 0.01 to about 60 mg. In certain embodiments, the combination medicaments provided by the present invention comprise salbutamol or levoxacin Butaminol is present in an amount ranging from about 0.05 to about 30 mg. In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol in an amount ranging from about 0.05 to about 20 mg. In certain embodiments, the combination medicaments provided by the present invention comprise salbutamol or levosalbutamol in an amount ranging from about 0.1 to about mg. In certain embodiments, the combination medicaments provided by the present invention comprise salbutamol or levosalbutamol in a range of about 0.1 to about 5 mg. In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol, and its weight content is about 0.1, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, About 4.5 or about 5 mg.

In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol, and its content ranges from about 0.005 to about 10, about 0.01 to about 8, about 0.02 to about 6, about 0.05 to about 0.05, based on weight percent. 5%. In some embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol, and its content ranges from about 0.005 to about 10%. In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol, and its content ranges from about 0.01 to about 8%. In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol, and its content ranges from about 0.02 to about 6%. In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol, and its content ranges from about 0.05 to about 5%. In certain embodiments, the combination medicament provided by the present invention comprises salbutamol or levosalbutamol in an amount of about 0.1, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.0, about 4.5 or about 5%.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; and (iii) any one or more compounds, wherein each compound is a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or Histamine H ₃ -receptor antagonist.

In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent Compounds; and (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (iii) calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; and (iii) calcium channel blockers. In another embodiment, the pharmaceutical composition provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or Solvent compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotope enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (iii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (iii) two compounds, each of which is a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , hydrate or solvate; (iii) calcium channel blockers; and (iv) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In certain embodiments, the combination medicaments provided by the present invention comprise (i) xanthine compounds and (ii) salbutamol or levosalbutamol in a weight ratio ranging from about 1 to about 1000, about 10 to about 500, and about 20 to about 400. Or about 40 to about 300. In certain embodiments, the combination medicament provided by the present invention comprises (i) a xanthine compound and (ii) albuterol or levosalbutamol in a weight ratio of about 40, about 60, about 80, about 100, about 120, about 140, About 160, about 180, about 200, about 220, about 240, about 260, about 28, or about 300.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , A hydrate or a solvent compound; and (iii) optionally one or more independent compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, Histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; and (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (Isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In another embodiment, the combination medicine provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (iii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iv) histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists or groups Amine H ₃ -receptor antagonist.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; and (iii) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In another embodiment, the pharmaceutical composition provided by the present invention comprises (i) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or Solvent compounds; (ii) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (iii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (iii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, and a histamine H ₂ - agonists or histamine H ₃ - receptor antagonist.

In one embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; (iii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iv) histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists or histamines H ₃ -receptor antagonist.

In certain embodiments, the weight ratio of (i) dihydropyridine to (ii) salbutamol or levosalbutamol in the combination drug provided by the present invention ranges from about 1 to about 100, about 5 to about 50, or about 5 to about 30 . In some embodiments, the weight ratio of (i) dihydropyridine to (ii) salbutamol or levosalbutamol in the combination medicine provided by the present invention is about 5, about 10, about 12, about 14, about 16, about 18, About 20, about 22, about 24, about 26, about 28, or about 30.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotope enrichment is not low) At 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) optionally one or more compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, respectively Agent or calcium channel blocker.

In another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or Its pharmaceutically acceptable salt, hydrate or solvent compound.

In yet another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a phosphodiesterase inhibitor, an adenosine receptor antagonist or a calcium channel blocker.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compound; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isomer thereof Variants (isotope enrichment of not less than 50%), or pharmaceutically acceptable salts, hydrates or solvent compounds thereof; and (iii) phosphodiesterase inhibitors or adenosine receptor antagonists. In another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a calcium channel blocker.

In yet another embodiment, the combination medicine provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist or a calcium channel blocker, respectively.

In one embodiment, the combination drug provided by the present invention comprises (i) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compound; (ii) salbutamol, or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates or solvent compounds; (iii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iv) calcium channel blockers.

In certain embodiments, the weight ratio of (i) betahistine or its metabolite to (ii) salbutamol or levosalbutamol in the combination medicine provided by the present invention ranges from about 1 to about 100, about 1 to about 50, About 1 to about 30 or about 1 to about 20. In certain embodiments, the weight ratio of (i) betahistine or its metabolite to (ii) salbutamol or levosalbutamol in the combination medicine provided by the present invention is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof ; (Ii) dihydropyridine, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) salbutamol, or an enantiomer Or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iv) may select histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salts, hydrates, or solvent compounds; (iii) salbutamol , Or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant (isotopic The enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iv) an optional calcium channel blocker.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) betahistine, or its metabolites, or its isotopic variants (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salts, hydrates, or solvent compounds; (iii) salbutamol , Or an enantiomer, or a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent thereof Compounds; and (iv) an optional phosphodiesterase inhibitor or adenosine receptor antagonist.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (ii) dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; (iii) betahistine, or Metabolites, or isotopic variants thereof (isotopes enriched not less than 50%), or pharmaceutically acceptable salts, hydrates or solvent compounds thereof; and (iv) salbutamol, or an enantiomer, or an enantiomer A mixture of isomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In one embodiment, the xanthine compound is aminophylline or theophylline. In another embodiment, the dihydropyridine is nifedipine.

In one embodiment, the combination medicine provided by the present invention comprises aminophylline or Theophylline. In another embodiment, the combination medicament provided by the present invention comprises nifedipine. In yet another embodiment, the combination medicament provided by the present invention comprises betahistine or betahistine hydrochloride. In yet another embodiment, the combination medicament provided by the present invention comprises salbutamol, salbutamol hydrochloride, levosalbutamol or levosalbutamol hydrochloride.

In one embodiment, the combination medicine provided by the present invention comprises (i) aminophylline or theophylline and (ii) nifedipine.

In another embodiment, the combination medicament provided by the present invention comprises (i) aminophylline or theophylline and (ii) betahistine or betahistine hydrochloride.

In yet another embodiment, the combination drug provided by the present invention comprises (i) aminophylline or theophylline and (ii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) nifedipine and (ii) betahistine or betahistine hydrochloride.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) nifedipine and (ii) salbutamol, salbutamol hydrochloride, levosalbutamol or levosalbutamol hydrochloride.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) betahistine or betahistine hydrochloride and (ii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride.

In one embodiment, the combination medicine provided by the present invention comprises (i) aminophylline or theophylline; (ii) nifedipine; and (iii) betahistine or betahistine hydrochloride.

In another embodiment, the combination medicine provided by the present invention comprises (i) ammonia Theophylline or theophylline; (ii) nifedipine; and (iii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride.

In yet another embodiment, the combination medicament provided by the present invention comprises (i) nifedipine; (ii) betahistine or betahistine hydrochloride; and (iii) salbutamol, salbutamol hydrochloride, levosalbutamol, or hydrochloric acid L-salbutamol.

In one embodiment, the combination medicament provided by the present invention comprises (i) aminophylline or theophylline; (ii) nifedipine; (iii) betahistine or betahistine hydrochloride; and (iv) Salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride.

In certain embodiments, the aminophylline is a solid. In certain embodiments, the aminophylline is a crystalline solid. In certain embodiments, the aminophylline is an amorphous solid. In certain embodiments, the theophylline is a solid. In certain embodiments, the theophylline is a crystalline solid. In certain embodiments, the theophylline is an amorphous solid.

In certain embodiments, the nifedipine is a solid. In certain embodiments, the nifedipine is a crystalline solid. In certain embodiments, the nifedipine is an amorphous solid.

In some embodiments, the weight ratio of theophylline to nifedipine in the combination medicine provided by the present invention ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 to about 20. In some embodiments, the weight ratio of theophylline to nifedipine in the combination medicine provided by the present invention ranges from about 1 to about 180. In some embodiments, the weight ratio of theophylline to nifedipine in the combination medicine provided by the present invention ranges from about 2 to about 100. In some embodiments, the weight ratio of theophylline to nifedipine in the combination medicine provided by the present invention ranges from about 2 to about 50. In certain embodiments, the set provided by the invention The weight ratio of theophylline to nifedipine in the drug combination ranges from about 2 to about 20. In some embodiments, the weight ratio of theophylline to nifedipine in the combination medicine provided by the present invention is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18 Or about 20.

In certain embodiments, the weight ratio of theophylline to betahistine in the combination drugs provided by the present invention ranges from about 2 to about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30. In some embodiments, the weight ratio of theophylline to betahistine in the combination medicine provided by the present invention is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 30.

In certain embodiments, the weight ratio of theophylline to salbutamol or levosalbutamol in the combination medicaments provided by the present invention ranges from about 1 to about 1,000, about 10 to about 500, about 20 to about 200, or about 40 to about 300. In some embodiments, the weight ratio of theophylline to salbutamol or levosalbutamol in the combination medicine provided by the present invention is about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the weight ratio of nifedipine to betahistine in the combination medicine provided by the present invention ranges from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10 . In certain embodiments, the weight ratio of nifedipine to betahistine in the combination medicine provided by the present invention is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, About 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, the weight ratio of betahistine to salbutamol or levosalbutamol in the combination drugs provided by the present invention ranges from about 1 to about 100, about 5 to about 50, about 5 to about 30, or about 1 to about 20. In some embodiments, the weight ratio of betahistine to salbutamol or levosalbutamol in the combination medicine provided by the present invention is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8 , About 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 1200, about 1 to about 1000, about 1 to about 800, about 1 to about 600, about 2 to about about 300 or about 10 to about 200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 1200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 1000 milligrams. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 800 mg. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 600 mg. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 300 mg. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount ranging from about 1 to about 200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in an amount of about 10, about 20, about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180 or About 200 mg.

In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline, the content of which ranges from about 1 to about 1200, about 1 to about 1000, about 1 to about 800, about 1 to about 600, about 2 to about 300 or about 10 to about 200 mg. In certain embodiments, the combination medicament provided by the present invention comprises aminophylline, the content of which ranges from about 1 to about 1200 Mg. In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline in an amount ranging from about 1 to about 1000 mg. In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline in an amount ranging from about 1 to about 800 mg. In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline, which content ranges from about 1 to about 600 mg. In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline, the content of which ranges from about 2 to about 300 mg. In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline in an amount ranging from about 10 to about 200 mg. In certain embodiments, the combination medicaments provided by the present invention comprise aminophylline in an amount of about 10, about 20, about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180 Or about 200 mg.

In certain embodiments, the combination medicament provided by the present invention comprises nifedipine (micronized or non-micronized), and its content ranges from about 0.1 to about 200, about 0.1 to about 100, about 0.2 to about 80, about 1 to about 50, about 1 to about 30, or about 1 to about 20 mg. In certain embodiments, the combination medicament provided by the present invention comprises nifedipine in an amount ranging from about 0.1 to about 200 mg. In certain embodiments, the combination medicament provided by the present invention comprises nifedipine in an amount ranging from about 0.1 to about 100 mg. In certain embodiments, the combination medicament provided by the present invention comprises nifedipine in an amount ranging from about 0.2 to about 80 mg. In certain embodiments, the combination medicament provided by the present invention comprises nifedipine in an amount ranging from about 1 to about 50 mg. In certain embodiments, the combination medicament provided by the present invention comprises nifedipine in an amount ranging from about 1 to about 30 mg. In some embodiments, the combination medicament provided by the present invention comprises nifedipine in an amount ranging from about 1 to about 20 mg. In some embodiments, this The combination medicament provided by the invention contains nifedipine in an amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, About 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg.

In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in a weight ratio ranging from about 1 to about 90, about 2 to about 80, about 5 to about 60, or about 5 to about 35%. In some embodiments, the combination medicament provided by the present invention comprises theophylline in a weight ratio ranging from about 1 to about 90%. In certain embodiments, the combination medicaments provided by the present invention comprise theophylline in a weight ratio ranging from about 2 to about 80%. In some embodiments, the combination medicament provided by the present invention comprises theophylline in a weight ratio ranging from about 5 to about 60%. In some embodiments, the combination medicine provided by the present invention comprises theophylline in a weight ratio ranging from about 5 to about 35%. In some embodiments, the combination medicine provided by the present invention comprises theophylline in a weight ratio of about 5%, about 10%, about 20%, about 30%, or about 35%.

In certain embodiments, the combination medicament provided by the present invention comprises nifedipine in a weight ratio ranging from about 0.1 to about 30, about 0.5 to about 20, or about 1 to about 10%. In some embodiments, the combination medicine provided by the present invention comprises nifedipine in a weight ratio ranging from about 0.1 to about 30%. In some embodiments, the combination medicine provided by the present invention comprises nifedipine in a weight ratio ranging from about 0.5 to about 20%. In some embodiments, the combination medicine provided by the present invention comprises nifedipine in a weight ratio ranging from about 1 to about 10%. In some embodiments, the combination medicine provided by the present invention comprises nifedipine in a weight ratio of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or About 10%.

In one embodiment, the combination medicament provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, the content of which ranges from about 10 to about 200 mg; and (ii) a calcium channel blocker Its content is about 1 to about 20 mg. In another embodiment, the combination medicament provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, and its content ranges from about 5% to about 35% by weight; and ( ii) Calcium channel blockers, based on weight percent, range from about 1 to about 10%.

In one embodiment, the pharmaceutical combination provided by the present invention comprises (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, in a content range At about 1 to about 30 mg; and (ii) a β ₂ -adrenergic receptor agonist in an amount ranging from about 0.1 to about 5 mg. In another embodiment, the combination drug provided by the present invention comprises (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, in weight percent It is calculated to be in the range of about 0.2 to about 10%; and (ii) the β ₂ -adrenergic receptor agonist, in the range of about 0.05 to about 5% by weight.

In one embodiment, the combination medicine provided by the present invention comprises (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In one embodiment, the content of theophylline, aminophylline or its hydrochloride is A range, calculated as a weight percentage, of about 5 to about 90% or about 10 to about 35%; (ii) a calcium channel blocker, in one embodiment of which the content of nifedipine ranges from about 1 to about 20% Or about 1 to about 5%; (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist, in one embodiment thereof betahist Ting, or its metabolite, or its hydrochloride is in the range of about 1 to about 20% or about 1 to about 5%; (iv) a β ₂ -adrenergic receptor agonist, in one embodiment of albuterol, Levosalbutamol or its hydrochloride content ranges from about 0.05 to about 5% (by weight) or from about 0.1 to about 0.5%; and (v) a pharmaceutically acceptable excipient, in one embodiment, a pharmaceutically acceptable Excipients are diluents, adhesives, disintegrating agents, glidants, lubricants, preservatives, or mixtures thereof.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound, Its content ranges from about 10 to about 200 milligrams; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof, The content range is from about 1 to about 20 milligrams; (iii) Betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%) or its pharmaceutically acceptable salt, its content range At about 1 to about 20 mg; and (iv) salbutamol, levosalbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%) or a pharmaceutically acceptable salt thereof, in an amount ranging from about 0.1 to about 5 Mg. In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds, calculated in weight percent, in the range of about 5 to about 90%; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound, the content of which ranges from about 1 to about 20%; (iii) betahistine, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacologically Acceptable salts in the range of about 0.1 to about 20%; and (iv) salmeterol, Levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt thereof, ranges from about 0.05 to about 5%.

In one embodiment, the combination medicine provided by the present invention comprises (i) theophylline in an amount ranging from about 10 to about 200 mg; (ii) nifedipine in an amount ranging from about 1 to about 20 mg; (iii) ) Betahistine or its hydrochloride in an amount ranging from about 0.1 to about 20 mg; and (iv) salbutamol, levosalbutamol or its hydrochloride in an amount ranging from about 0.1 to about 5 mg. In one embodiment, the combination medicament provided by the present invention comprises (i) theophylline in a content range of about 5 to about 90% by weight; (ii) nifedipine in a content range of about 1 to about 20%; (iii) betahistine or its hydrochloride in a range of about 0.1 to about 20%; and (iv) salbutamol, levosalbutamol or its hydrochloride in a range of about 0.05 to about 5 %.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof And its content ranges from about 10 to about 200 milligrams; and (ii) dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof Its content ranges from about 1 to about 20 mg. In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof And its content ranges from about 5 to about 90%; and (ii) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof Its content ranges from about 1 to about 20%.

In one embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound, Its content ranges from about 10 to about 200 milligrams; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof, The content ranges from about 1 to about 20 mg; and (iii) betahistine, or a metabolite thereof, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, The content ranges from about 1 to about 20 mg. In another embodiment, the combination drug provided by the present invention comprises (i) a xanthine compound, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds, calculated in weight percent, in the range of about 5 to about 90%; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound, the content of which ranges from about 1 to about 20%; and (iii) betahistine, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutical The acceptable salt ranges from about 0.1 to about 20%.

In one embodiment, the combination medicine provided by the present invention comprises (i) theophylline in an amount ranging from about 10 to about 200 mg; (ii) nifedipine in an amount ranging from about 1 to about 20 mg; (iii) ) Betahistine or its hydrochloride, the content of which ranges from about 0.1 to about 20 milligrams; in another embodiment, the combination drug provided by the present invention comprises: (i) theophylline, in terms of weight percent, its content The range is from about 5 to about 90%; (ii) nifedipine, whose content ranges from about 1 to about 20%; (iii) betahistine or its hydrochloride, whose content ranges from about 0.1 to about 20% .

In one embodiment, the combination drug provided by the present invention comprises (i) theophylline in an amount ranging from about 10 to about 200 mg; (ii) nifedipine in an amount ranging from about 1 to about 20 mg; and ( iii) salbutamol, levosalbutamol, or its hydrochloride salt, in an amount ranging from about 0.1 to about 5 mg. In another embodiment, the pharmaceutical composition provided by the present invention comprises: (i) theophylline, in a weight percent range of about 5 to about 90%; (ii) nifedipine, in a content range of about 1 to about 20%; (iii) salbutamol, levosalbutamol, or a hydrochloride salt thereof, the content of which ranges from about 0.05 to about 5%.

In one embodiment, the combination medicine provided by the present invention comprises (i) theophylline in an amount ranging from about 10 to about 200 mg; (ii) betahistine or its hydrochloride in an amount ranging from about 0.1 to About 20 mg; (iii) salbutamol, levosalbutamol, or a hydrochloride salt thereof in an amount ranging from about 0.1 to about 5 mg. In another embodiment, the combination medicament provided by the present invention comprises (i) theophylline, and its content ranges from about 5 to about 90% by weight percentage; (ii) betahistine or its hydrochloride, which The content ranges from about 0.1 to about 20%; (iii) salbutamol, levosalbutamol or its hydrochloride, and the content ranges from about 0.05 to about 5%.

In certain embodiments, the combination medicaments provided by the present invention comprise a diluent, an adhesive, a disintegrant, a glidant, a lubricant, a preservative, or a mixture thereof. In certain embodiments, the combination medicaments provided by the present invention comprise a diluent, a binder, a disintegrant, a glidant, a lubricant, and a preservative.

In certain embodiments, the combination medicament provided by the present invention has a diluent content ranging from about 10 to about 60, about 10 to about 50, about 10 to about 45 or about 10 to about 35%, based on the weight percentage. . In certain embodiments, combinations provided by the invention The amount of diluent in the drug is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, or about 35%.

In some embodiments, the content of the binder in the combination medicine provided by the present invention ranges from about 10 to about 65, about 10 to about 50, about 10 to about 45, or about 10 to about 35, based on the weight percentage. %. In some embodiments, the content of the binder in the combination medicine provided by the present invention is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, or about 35%.

In certain embodiments, the combination medicament provided by the present invention has a disintegrant content in a range of about 1 to about 5% or about 1 to about 3% based on weight percent. In certain embodiments, the combination medicine provided by the present invention has a disintegrant content of about 1%, about 1.5%, about 2%, about 2.5%, or about 3%.

In certain embodiments, the combination drug provided by the present invention has a glidant content ranging from about 0.01 to about 0.5% or about 0.02 to about 0.3%, calculated on a weight percentage basis. In certain embodiments, the combination drug provided by the present invention has a glidant content of about 0.02, about 0.05, about 0.10, about 0.15, about 0.20, about 0.25, or about 0.3%.

In certain embodiments, the combination medicament provided by the present invention has a lubricant content ranging from about 0.05 to about 0.8 or about 0.1 to about 0.5% based on weight percent. In certain embodiments, the combination medicine provided by the present invention has a lubricant content of about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, or about 0.5%.

In certain embodiments, the combination medicament provided by the present invention has a preservative content ranging from about 0.1 to about 2 or about 0.2 to about 1% based on weight percent. in In some embodiments, the combination medicine provided by the present invention has a preservative content of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1%.

In certain embodiments, the combination medicine provided by the present invention comprises a diluent, and its content ranges from about 10 to about 65% by weight percentage; a binder, its content ranges from about 10 to about 65%; a disintegrant Its content ranges from about 1 to about 5%; glidants, its content ranges from about 0.01 to about 0.5%; lubricants, its content ranges from about 0.05 to about 0.8%; and preservatives, its content ranges from about 0.1 to about 2%.

In some embodiments, the combination medicine provided by the present invention comprises a diluent, whose content ranges from about 50 to about 450 mg; a binder, whose content ranges from about 50 to about 450 mg; a glidant, whose content ranges from About 1 to about 25 milligrams; lubricants in a range of about 0.1 to about milligrams; and preservatives in a range of about 0.5 to about 5 milligrams.

In certain embodiments, the combination medicaments provided by the present invention comprise a diluent, an adhesive, a disintegrant, a glidant, a lubricant, a preservative, or a mixture thereof. In certain embodiments, the combination medicaments provided by the present invention comprise a diluent, a binder, a disintegrant, a glidant, a lubricant, and a preservative.

In some embodiments, the diluent of the combination drug provided by the present invention is microcrystalline cellulose, lactose or corn starch. In certain embodiments, the diluent of the combination drug provided by the present invention is microcrystalline cellulose. In some embodiments, the combination drug provided by the present invention has a mannitol as a binder. In certain embodiments, the disintegrating agent of the combination drug provided by the present invention is sodium starch glycolate or crospovidone. In certain embodiments, the disintegrating agent of the combination medicine provided by the present invention is sodium starch glycolate. In some implementations In the example, in the combination drug provided by the present invention, the glidant is colloidal silica. In certain embodiments, the combination medicament provided by the present invention has a lubricant of magnesium stearate. In certain embodiments, the combination drug provided by the present invention has a preservative of citric acid.

In some embodiments, the combination drug provided by the present invention has a diluent of microcrystalline cellulose; a binder is mannitol; a disintegrant is sodium starch glycolate; a glidant is colloidal silicon dioxide; a lubricant It is magnesium stearate; the preservative is citric acid.

Without being bound by theory, the present invention provides a combination drug of two or more active pharmaceutical ingredients, the principle of which is to use the addition of the same other therapeutic effect (also known as the second therapeutic effect) of each active ingredient And mutual synergistic effects, such as the effect of accelerating heart rate or increasing cardiac output (that is, the undesired side effects of related drugs on the market when administered alone). It is formulated into medicine through scientific research and reasonable combination. For example, one of the side effects of theophylline is a faster heartbeat, accompanied by an increase in oxygen consumption. One of the side effects of nifedipine is also a faster heartbeat, accompanied by a reduction in oxygen consumption. Therefore, theophylline and nifedipine are paired together to achieve the desired increase in heart rate without significantly affecting oxygen consumption. By the same principle, one of the side effects of betahistine is faster heartbeat and lower blood pressure. One of the side effects of L-salbutamol is a faster heartbeat and increased blood pressure. Thus, the combination of betahistine and levosalbutamol is combined to achieve the desired increase in heart rate without having a significant effect on blood pressure.

The compounds in the combination drugs provided by the present invention are intended to cover all possible stereoisomers unless a specific stereochemistry is specified. When the compound provided by the present invention contains an alkenyl group, the compound may exist as one or a mixture of geometric cis / trans (or Z / E) isomers. Where structural isomers can be converted to each other, compounds It can exist as a single tautomer or as a mixture of tautomers. This can take the form of a proton tautomeric form in a compound containing, for example, an imino, keto, or oxime group, or a so-called valence tautomerism in a compound containing an aromatic moiety.

The compound in the combination drug provided by the present invention may be an enantiomer, such as a single enantiomer, or a single diastereomer, or may be a stereoisomeric mixture or a mixture of enantiomers, such as A racemic mixture of two enantiomers or a mixture of two or more diastereomers. Therefore, those of ordinary skill in the art will recognize that for compounds that undergo epimerization in vivo, the administration of the compound in the ( R ) form is equivalent to the administration of the compound in the ( S ) form. Conventional techniques for the preparation / separation of individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from achiral starting materials or resolution of enantiomeric mixtures, such as chiral chromatography, recrystallization , Resolution, diastereomeric salt formation or derivation into diastereomeric adducts, and then separation.

When the compound in the combination drug provided by the present invention contains an acidic or basic moiety, it can also be used as a pharmaceutically acceptable salt. (See Berge et. Al., J. Pharm. Sci. 1977, 66, 1-19 and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed .; Wiley-VCH and VHCA, Zurich, 2011 ).

Suitable acids for the preparation of pharmaceutically acceptable salts include acetic acid, 2,2-dichloroacetic acid, tritiated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzene Formic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S ) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexylsulfamic acid, cyclic Hexanesulfamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactic acid, gentisic acid , Glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+) -L-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene -2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid Acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-a (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, The composition of a water-soluble resin and carbon valeric acid but not limited thereto.

Suitable bases for preparing pharmaceutically acceptable salts include inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; containing L-arginine, phenethylbenzylamine, Benzathine penicillin, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, equal primary, secondary, tertiary, and quaternary aliphatics And aromatic amines, ethanolamines, ethylamines, ethylenediamines, isopropylamines, N-methylglucamines, hammamines, (2-hydroxyethyl) -morpholines, methylamines, piperidines, piperazines, propylamines, Pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinine ring, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucosamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol and tromethamine, but are not limited thereto.

The compound provided by the present invention can also be used as a precursor of a drug, for example, a functional derivative of the compound, such as Compound-1, can be easily converted into its parent compound in vivo. Prodrugs are often useful because, in some cases, they It may be easier to administer than the parent compound. For example, they can be biologically active by oral administration, while their parent compounds are not. Compared to the parent compound, the solubility of the prodrug in the combination drug can also be increased. Prodrugs can be converted into their parent drugs through a variety of mechanisms, including enzymatic processes and metabolic hydrolysis. (See Harper, Progress in Drug Research 1962, 4, 221-2294; Morozowich et al. In "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application, "Roche Ed., APHA Acad. Pharm. Sci. 1987;" Design of Prodrugs, "Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv .Drug Delivery Rev. 1999, 39,183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179- 96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1 996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996 , 19,241-273; Stella et al., Drugs 1985, 29,455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507).

The combination medicine provided by the present invention can be formulated into various dosage forms for oral, parenteral and local administration. The combination drug can also be formulated into sustained release dosage forms, including delayed, extended, extended, sustained, pulsed, controlled, accelerated, fast, targeted, programmed release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those having ordinary skill in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc .: New York, NY, 2008).

In one embodiment, the combination medicine provided by the present invention can be formulated into a dosage form for oral administration. In one embodiment, the oral combination medicine provided by the present invention further comprises one or more pharmaceutically acceptable excipients. In one embodiment, the oral combination medicine provided by the present invention can also be formulated into a capsule. In another embodiment, the oral combination medicine provided by the present invention can also be formulated into a tablet.

In another embodiment, the combination medicament provided by the present invention can be formulated into a dosage form for parenteral administration. In one embodiment, the combination medicament provided by the present invention may Formulated into a dosage form for intravenous administration. In another embodiment, the combination medicament provided by the present invention can be formulated into a dosage form for intramuscular administration. In yet another embodiment, the combination medicament provided by the present invention can be formulated into a dosage form for subcutaneous administration.

In yet another embodiment, the combination medicament provided by the present invention can be formulated into a dosage form for topical administration.

In some embodiments, the combination drug provided by the present invention may be a single-administration dosage form or a multiple-administration dosage form. The single-dose dosage form provided by the present invention refers to discrete single-units that are physically suitable for administration to humans and animals, and can be packaged separately as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired effective treatment and the required pharmaceutical excipients. Examples of single-dose dosage forms include ampoules, syringes, individually packaged tablets and capsules. The dosage form for a single administration may also be a single administration or multiple administrations. Multiple-dose dosage forms are multiple identical single-dose dosage forms packaged in a single package, administered in separate unit dosage forms. Examples of multiple-dose dosage forms include bottled tablets or capsules.

The combination medicine provided by the present invention can be administered at one time or multiple times at certain time intervals. Based on knowledge and experience, the precise dose of treatment and the duration of its medication can vary depending on the age, weight and disease status of the patient being treated, and can be learned from outside or in vitro using experience using known testing protocols or by extrapolation And ok. It is further understood that, for any particular individual, the dosage should be administered according to the needs of the individual, or the dosage regimen of the administration should be adjusted over time under professional judgment and supervision.

In certain embodiments, one or more of the active compounds in the combination drug provided by the present invention is micronized.

A. Oral medicine

The combination medicament provided by the present invention for oral administration may be in a solid, semi-solid or liquid dosage form. As used herein, oral administration also includes oral, lingual and sublingual administration. Suitable oral dosage forms include tablets, instant tablets, chewable tablets, capsules, pills, sticks, dragees, lozenges, cachets, pills, medicinal chewing gum, bulk powder, effervescent tablets, or non-foaming Teng powder or granules, oral sprays, solutions, emulsions, suspensions, glutinous rice paper capsules, powders, elixirs and syrups are not limited thereto. In addition to the active ingredients, the combination drugs provided by the present invention may contain one or more pharmaceutically acceptable excipients including a binder, a filler, a diluent, a disintegrant, a wetting agent, a lubricant, a glidant, and a colorant. , Dye migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources, but are not limited thereto.

The purpose of the binders or granulations described herein is to impart cohesiveness to the tablets to ensure that they remain intact after compression. Suitable binders or granulators include starches such as corn starch, potato starch and pregelatinized starch (e.g. STARCH 1500), gelatin, sugars (e.g. sucrose, glucose, dextrose, molasses and lactose), natural and synthetic gums ( Such as acacia, alginic acid, alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethyl cellulose , Methylcellulose, polyvinylpyrrolidone (PVP), aluminum magnesium silicate (Veegum), larch arabinogalactan, tragacanth powder and guar gum), cellulose (such as ethyl cellulose, acetate fiber Cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl fiber (HPC), hydroxypropylmethyl cellulose (HPMC), microcrystalline cellulose (e.g. AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA)) and mixtures thereof, but are not limited thereto. Suitable fillers described herein include talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose binders, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof, but Not limited to this. The amount of the binder or filler in the combination medicine provided by the present invention varies according to the type of the preparation, and it is easy for those skilled in the art to recognize it. In the combination medicament provided by the present invention, the weight ratio of the binder or the filler may be about 50% to about 99%.

Suitable diluents include, but are not limited to, calcium hydrogen phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when they are present in sufficient amounts, can impart some compressed tablet properties that enable them to disintegrate in the mouth by chewing. This compressed tablet can be used as a chewable tablet. The amount of the diluent in the combination medicine provided by the present invention varies according to the type of the preparation, and can be easily discerned by those with ordinary knowledge in the art.

Suitable disintegrants described herein include agar, bentonite, cellulose (such as methyl cellulose and carboxymethyl cellulose), wood products, natural sponges, cation exchange resins, alginic acid, and gums (such as guar and Veegum HV). ), Citrus pulp, cross-linked cellulose (such as croscarmellose), cross-linked polymer (such as crospovidone), cross-linked starch, calcium carbonate, microcrystalline cellulose (such as starch sodium glycolate) , Polakrin potassium, starch (such as corn starch, potato starch, tapioca starch and pregelatinized starch), clay, algin and other Our mixture, but not limited to this. The amount of the disintegrant in the combination medicine provided by the present invention varies according to the type of the preparation, and can be easily identified by those skilled in the art. The content of the disintegrant in the combination medicine provided by the present invention may be about 0.5 to about 15% or about 1 to about 5% by weight percentage.

Suitable lubricants described herein include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, glycols such as glyceryl behenate and polyethylene glycol (PEG)), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, Ethyl laurate, agar, starch, stone pine, silica or silicone (e.g. AEROSIL ^® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL ^® (Cabot Co. of Boston, MA)) and their A mixture, but not limited to this. In the combination medicine provided by the present invention, the weight ratio of the lubricant may be about 0.1% to about 5%.

Suitable described herein glidants include colloidal silicon ^{dioxide, CAB-O-SIL ® (} Cabot Co.of Boston, MA) , and asbestos-free talc, but is not limited thereto. Suitable colorants include, but are not limited to, any approved, certified water-soluble FD & C dyes, and water-insoluble FD & C dyes suspended in alumina hydrate, as well as lakes and mixtures thereof. Color lakes are a combination formed by adsorbing water-soluble dyes to hydrated oxides of heavy metals, resulting in insoluble forms of the dyes. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants (e.g., fruits) and synthetic blends of compounds that produce pleasant tastes (e.g., mint and methyl salicylate). Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerol, and artificial sweeteners (such as saccharin and aspartame). Suitable emulsifiers include gelatin, gum arabic, tragacanth, bentonite and surfactants (e.g. polyoxyethylene sorbitan monooleate (TWEEN ^® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ^® 80) and triethanolamine oleate), but are not limited thereto. Suitable suspending and dispersing agents include sodium carboxymethyl cellulose, pectin, tragacanth, magnesium aluminum silicate, acacia, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methyl paraben and propyl paraben, benzoic acid, sodium benzoate, and alcohols. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids used in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

Many carriers and excipients described herein can perform multiple functions, even in the same formulation.

The combination medicaments provided by the present invention which can be used for oral administration can be made into tablets, ground tablets, chewable lozenges, fast-dissolving tablets, multiple tablets or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are tablets coated with a substance that acts against gastric acid and dissolves or disintegrates in the intestine. The coating protects the active ingredient from the effects of the gastric acid environment. Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are sugar-coated tablets that may be beneficial in covering unpleasant tastes or odors and protecting The tablets are free from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multi-compressed tablets are tablets made from more than one compression cycle, including layered tablets as well as compression-coated or dry-coated tablets.

The tablet dosage form provided by the present invention can be made by combining one or more active ingredients in powder, crystalline or granular form with one or more carriers and excipients. Adjuvants used include binders, disintegrating agents, controlled release polymers, lubricants, diluents and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

The combination medicine for oral administration provided by the present invention can be made into a soft capsule or a hard capsule, which can be made of gelatin, methyl cellulose, starch or calcium alginate. Hard capsules, also known as dry-filled capsules (DFCs), consist of two parts, one sliding over the other, thus completely blocking its active ingredients. Soft elasric capsule (SEC) is a soft spherical shell, such as a gelatin shell, which is plasticized by adding glycerin, sorbitol or similar polyols. Soft gelatin shells can contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl and propyl parabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include propylene carbonate, vegetable oil or triglyceride solutions and suspensions. Capsules containing this solution can be prepared as described in U.S. Pat. Nos. 4,328,245, 4,409,239, and 4,410,545. These capsules may also be coated to alter or maintain dissolution of the active ingredient as known to those of ordinary skill in the art.

The combination medicaments for oral administration provided by the present application can be liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of pellets in another liquid, which can be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde (such as acetaldehyde diethyl acetal) and a water-miscible solvent having one or more hydroxyl groups (such as Propylene glycol and ethanol). Tinctures are clear, sweet and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugar, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be used with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example, to facilitate dilution with water.

Other useful liquid and semi-solid dosage forms described herein include those containing the active ingredients and dialkylated mono- or polyalkylene glycols provided by the present application, including 1,2-dimethoxymethane, diethylene glycol Glyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether Ether, where 350, 550, and 750 refer to the average molecular weight of polyethylene glycol, but are not limited thereto. These formulations may include one or more antioxidants, such as butylared hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, Ethanolamine, lecithin, cerebral phospholipid, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

The combination drugs provided for oral administration provided by the present application can also be provided in the form of liposomes, micelles, microspheres, or nano systems. Micellar dosage forms can be prepared as described in US Patent No. 6,350,458.

The combination medicament for oral administration provided by the present application can be provided as a non-effervescent or effervescent, granule and powder, and reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable excipients for use in effervescent granules or powders may include organic acids and carbon dioxide sources.

Colorants and flavoring agents can be used in all of the above dosage forms.

The combination drugs for oral administration provided by the application of the present invention can be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

B. Parenteral medication

The combination drugs provided by the present application can be administered parenterally by injection, infusion or implantation, or used for local or systemic implantation. The parenteral administration used in the application of the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

The combination medicament provided by the present application for parenteral administration can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes formulated for use in liquids , Microspheres, nanosystems, and solid forms prior to injection. Such dosage forms can be prepared according to conventional methods known to those with ordinary knowledge in the field of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, supra).

The combination drugs described herein that can be designed for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including water-soluble carriers, water-soluble carriers, non-aqueous carriers, antimicrobial growth antimicrobial agents, or Preservatives, stabilizers, solubilizers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, chelating agents, cryoprotectants, lyophilization protectants, Thickener, pH adjuster, and inert gas, but are not limited thereto.

Suitable aqueous carriers described herein include water, saline, physiological saline, or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, right Rotary sugar and lactated Ringer's injection, but not limited to this. Suitable non-aqueous carriers include plant-derived fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain glycerin from coconut oil. Triesters as well as palm seed oil, but are not limited thereto. Suitable water-miscible carriers described herein include ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl -2-Pyrrolidone, N, N-dimethylacetamidine, and dimethylsulfine, but are not limited thereto.

Suitable antimicrobial or preservative agents described herein include phenol, cresol, mercury formulations, benzyl alcohol, chlorobutanol, methyl paraben, and propyl paraben, thimerosal, benzalkonium chloride (e.g. benzyl Sodium chloride), methyl- and propyl-parabens and sorbic acid, but are not limited thereto. Suitable isotonic agents described herein include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffering agents described herein include, but are not limited to, phosphate and citrate. Suitable antioxidants described herein are those described in the present application, including bisulfite and sodium metabisulfite. Suitable local anesthetics described herein include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents as described herein are those described in the application of the present invention, including, but not limited to, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Suitable emulsifiers described herein are those described in this application and include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable chelating agents described herein include, but are not limited to, ethylenediaminetetraacetic acid. Suitable pH adjusting agents described herein include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents described herein include cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl Ether 7-β-cyclodextrin (CAPTISOL ^® , CyDex, Lenexa, KS), but is not limited thereto.

When the combination drug provided by the application is formulated for multiple administration, the parenteral preparation for multiple administration must contain a certain concentration of an antimicrobial agent such as a bacteriostatic or fungistatic agent. All parenteral preparations must be sterile, as is known and practiced in the art.

In one embodiment, the combination drug for parenteral administration can be a ready-to-use sterile solution. In another embodiment, the combination drug is a sterile dry soluble product, including a lyophilized powder and a subcutaneous injection tablet, which is reconstituted with a carrier before use. In yet another embodiment, the combination drug is provided as a ready-to-use sterile suspension. In yet another embodiment, the combination drug is provided as a sterile dry insoluble product and reconstituted with a carrier prior to use. In yet another embodiment, the combination drug is in a ready-to-use sterile milk Available in liquid form.

The combination drug provided for parenteral administration provided by the present application can be formulated into an immediate release or modified release dosage form, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

The combination medicament provided by the present invention for parenteral administration can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implantation depot. In one embodiment, the combination drug provided by the present invention is dispersed in a solid internal matrix surrounded by an external polymer film that is insoluble in body fluids but allows the active ingredients in the combination drug to diffuse through.

Suitable inner matrices described herein include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber , Polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as acrylic acid Hydrogels with methacrylate, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, but are not limited thereto.

Suitable outer polymer films described herein include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chlorine Butadiene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, Ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers The chloride copolymer is not limited thereto.

C. External use

The combination medicine provided by the present invention may be applied topically to the skin, orifice or mucous membrane. As used herein, topical administration includes (internal) dermis, conjunctiva, intracorneal, intraocular, eye, ear, transdermal, nasal, vaginal, urethral, respiratory and rectal administration.

The combination drugs provided by the present invention can be formulated into any dosage form suitable for local or systemic administration, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusters, dressings Agents, tinctures, lotions, suspensions, tinctures, pastes, foams, films, aerosols, lavages, sprays, suppositories, bandages and skin patches. The external preparation of the combination drug provided by the present invention may further include liposomes, micelles, microspheres, nano systems and mixtures thereof.

The pharmaceutically acceptable carriers and excipients in the external preparation provided by the present invention include an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, an antimicrobial agent or a preservative for antimicrobial growth, a stabilizer, a dissolution promoter, Isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickeners and inerts Gas, but not limited to this.

The mode of administration of the pharmaceutical compositions of the present invention may also be provided by electroporation, iontophoresis, phonophoresis, ultrasound therapy, or microneedle or needle-free injection, e.g. POWDERJECTTM (Chiron Corp., Emeryville, CA ) , and BIOJECT ^TM ( Bioject Medical Technologies Inc., Tualatin, OR).

The combination medicine provided by the present invention may be in the form of ointment, cream and gel Style. Suitable ointment carriers include oily or hydrocarbon carriers, including lard, benzoated lard, olive oil, cottonseed oil, and other oils, white petrolatum, emulsifiable or absorbent carriers (e.g., hydrophilic petrolatum, hydroxystearate glycerol) Esters and anhydrous lanolin), dehydratable carriers (such as hydrophilic ointments, water-soluble ointment carriers containing polyethylene glycols of different molecular weights), emulsified carriers, oil-in-water (W / O) emulsions, or water-in-oil (O / W) Emulsion containing cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). These carriers have an emollient effect, but usually require the addition of antioxidants and preservatives.

Suitable cream bases described herein may be oil-in-water or water-in-oil. Suitable cream carriers can be washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "internal" phase, which usually consists of petrolatum and a fatty alcohol such as cetyl alcohol or stearyl alcohol. The water phase usually, but not necessarily, exceeds the volume of the oil phase, and often contains a humectant. The emulsifier in a cream formulation may be a non-ionic, anionic, cationic or amphoteric surfactant.

The gels described herein are semi-solid suspension-type systems. Single-phase gels contain organic macromolecules that are distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers (such as carbomers, polyalkylene carboxy and CARBOPOL ^®), hydrophilic polymers (such as polyethylene oxide, polyoxyethylene - polyoxypropylene copolymers, and poly Vinyl alcohol), cellulose polymers (such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and methyl cellulose), Gum (such as tragacanth and xanthan gum, sodium alginate, and gelatin), but are not limited thereto. To prepare a homogeneous gel, a dispersant such as an alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing and / or stirring.

The combination medicine provided by the present invention can be administered rectally, urethra, vagina, or intravaginally, with suppositories, vaginal suppositories, sugar coatings, cataplasms, or poultices, pastes, powders, dressings , Cream, ointment, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms can be prepared using conventional methods such as Remington: The Science and Practice of Pharmacy, supra.

Rectal, urethral, and vaginal suppositories described herein are solids that are inserted into the body holes, which are solid at ordinary temperatures but melt or soften at body temperatures to release the active ingredients in the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or vehicles, such as sclerosing agents which produce a melting point near body temperature. When formulated with the combination drug provided by the present invention, the antioxidants of the present invention can be used, including Bisulfite and sodium metabisulfite. Suitable carriers include cocoa butter (cocoa butter), glycerol-gelatin, carbon wax (polyoxyethylene glycol), cetyl wax, paraffin wax, white wax, and yellow wax, as well as monoglycerides, diglycerides, and triglycerides of fatty acids. Mixtures and hydrogels, such as, but not limited to, polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vectors can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. Rectal and vaginal suppositories typically have a content of about 2 to about 3 grams.

The combination medicine provided by the present invention can be used for ophthalmic administration, and can be in the form of a solution, a suspension, an ointment, an emulsion, a gel-forming solution, a solution powder, a gel, an eye insertion agent, and an implant.

The combination medicament provided by the present invention can be administered to the breath in the nose or by inhalation Way of administration. The combination drug can be provided in the form of an aerosol or a solution. A pressurized container, a pump, a sprayer, or an atomizer can be used, such as an atomizer or atomizer that uses electrodynamic kinetics to produce a fine mist. Propellants such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane combination. Combination drugs can also be provided as dry powders and nasal drops for insufflation, either alone or in combination with an inert carrier such as lactose or phospholipids. For intranasal use, the powder may contain bioadhesives, including chitosan or cyclodextrin.

Solutions described herein that can be used in pressurized containers, pumps, sprayers, nebulizers or sprayers can be formulated to contain ethanol, aqueous ethanol, or suitable alternatives for dispersing, solubilizing, or extending the release of the active ingredient provided by the present invention Reagents, propellants as solvents and / or surfactants, such as sorbitan trioleate, oleic acid or oligolactic acid.

The combination drugs provided by the present invention may be micronized to a size suitable for inhaled delivery, such as about 50 microns or less, or about 10 microns or less. The pulverization methods known to those skilled in the art can be used, such as spiral jet milling, fluid bed jet milling, supercritical fluid treatment to form nano particles, high-pressure homogenization, or spray drying.

The combination drugs provided by the present invention such as capsules for inhalers or insufflators, blister and cartridges can be formulated as a powder-containing mixture. Suitable powder bases, such as lactose or starch; and performance modifiers, such as L-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The combination drug for inhalation / intranasal administration provided by the present invention may further comprise suitable flavoring agents, such as menthol and menthol, and / or Sweeteners such as saccharin and sodium saccharin.

The combination medicament provided by the present invention for external administration can be formulated into dosage forms of immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

D. Improved release dosage form

The combination medicine provided by the present invention can be formulated into an improved release dosage form. As used herein, the term "controlled release" refers to a dosage form in which the release rate or release site of the active ingredient is different from the rate or release site of a rapid release dosage form administered by the same route. Modified release dosage forms include, but are not limited to, delayed, extended, elongated, sustained, pulsed, controlled, accelerated and fast, targeted, programmed release and gastrointestinal retention dosage forms. Various modified release devices and methods known to those having ordinary skill in the art can be used to prepare combined release dosage form combination drugs, which include matrix controlled release devices, osmotic controlled release devices, and multi-particle controlled release devices. , Ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof, but are not limited thereto. The release rate of the active ingredient can also be changed by changing the particle size and polymorphism of the active ingredient.

Examples of modified releases include those described in U.S. Pat. , 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, and 6,699,500, but are not limited thereto.

1. Media controlled release device and dosage form

The modified release dosage form of the combination drug provided by the present invention can be prepared by those with ordinary knowledge in the technical field by using a media controlled release device. (See: Takada et al. In "Encyclopedia of Controlled Drug Delivery," Vol. 2, Maththiowitz Ed., Wiley, 1999).

In certain embodiments, the modified release dosage forms of the combination drugs provided by the present invention may be formulated using an erodible medium, which may be a water-swellable, erodible, or soluble polymer, including synthetic polymers, and occurs naturally Polymers and derivatives such as polysaccharides and proteins, but are not limited to this.

Materials described herein that can be used to form erodible media include chitin, chitosan, dextran and amylopectin, gum arabic, sycamore gum, locust bean gum, tragacanth gum, carrageenan, India Gum gum, guar gum, xanthan gum and hard glucan; starches such as dextrin and maltodextrin; hydrocolloids if gum; phospholipids such as lecithin, alginate, propylene glycol alginate, gelatin, collagen; fiber Such as ethyl cellulose (EC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose trimellitate (CAT) , Hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinic acid (HPMCAS), hydroxypropyl methyl cellulose acetate Triesters (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone, Copolymers of polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, ethacrylic acid, or methacrylic acid (EUDRAGIT, Rohm America, Inc., Piscataway, NJ), poly (2-hydroxyl (Ethyl-methacrylate), polylactide, copolymers of L-glutamic acid and L-glutamic acid ethyl ester, degradable lactic acid-glycolic acid copolymer, poly-D-(-)-3- Hydroxybutyric acid; and other acrylic derivatives, such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and ( Trimethylaminoethyl) methacrylate chloride, but is not limited thereto.

In certain embodiments, the combination medicaments provided by the present invention are formulated with a non-erodible medium. The active ingredient dissolves or diffuses in the inert medium, and is slowly released mainly by diffusion of the inert-based medium. Suitable materials for non-aggressive media include insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated Polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloroacetate, vinylidene chloride , Vinyl chloride copolymer of ethylene and propylene, ionomer polyethylene terephthalate butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, Ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane and silicone carbonate copolymer; hydrophilic polymerization Compounds such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides, but are not limited thereto.

In the medium controlled release system described herein, the required release power can be controlled. For example, by the type of polymer used, the viscosity of the polymer, the particle size of the polymer and / or active ingredient, the active ingredient (s) and polymer, and other excipients or carriers in the composition.

The modified release dosage form of the combination drug provided by the present invention can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation, then compression, granulation, and compression.

2. Penetration controlled release device and dosage form

The modified release dosage form of the combination drug provided by the present invention can be manufactured using an osmotic controlled release device, which includes a single-chamber system, a dual-chamber system, an asymmetric membrane technology (AMT), and an extrusion core system (ECS), But it is not limited to this. Generally, these devices have at least two components: (a) a core containing the active ingredient; and (b) a semi-permeable membrane with at least one delivery port that encapsulates the core. A semi-permeable membrane is used to control the inflow of water from the aqueous environment to the inner core, thereby releasing the drug through the extrusion port.

In addition to the active ingredients described herein, the core of the osmotic device optionally includes a penetrant, which can transfer moisture from the environment of use to the core of the device. One class of penetrants is water-swellable hydrophilic polymers, which are also known as "penetrating polymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as penetrants include hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG) ), Poly (2-hydroxyethyl methacrylate), polyvinylpyrrolidone (PVP), PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer, hydrophobic PVA / PVP copolymer monomers, such as methyl methacrylate and vinyl acetate, hydrophilic polyurethane containing large polyethylene oxide blocks, Croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose ( (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate, but are not limited thereto.

Another class of osmotic agents described herein are zymogens, which are capable of absorbing water to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable penetrants include inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; glucose, Inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, xylitol and other sugars; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, decyl Diacids, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof, but are not limited thereto.

As described herein, penetrants with different dissolution rates can be used to influence the rate at which the active ingredient dosage form begins to be delivered. For example, amorphous sugars such as MANNOGEM ^™ EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery within the first few hours to quickly produce the desired therapeutic effect, and then gradually and continuously release the remaining amount over an extended period of time To maintain the desired level of therapeutic or preventive effect. In this case, the active ingredient is released at such a rate to replace the amount of active ingredient that is metabolized and excreted.

The core described herein may also include a variety of other Excipients and carriers to enhance the performance of the dosage form, or to promote the stability or processability of the dosage form.

The materials described herein that can be used to form semi-permeable membranes include various grades of acrylic resins, vinyl resins, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable at physiologically relevant pH values and Water-insoluble, or easily becomes water-insoluble through chemical changes such as crosslinking. Examples of suitable polymers that can be used to form the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, butyl acetate Cellulose (CAB), urethane CA, carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloride Acetate, CA ethyl oxalate, CA mesylate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, ethyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (hydroxyethyl vinyl acetate), starch, dextran, dextrin, shell Glycans, collagen, gelatin, polyolefins, polyethers, polyfluorenes, polyethers, polystyrenes, polyvinyl halides, polyacrylic acids, vinyl esters and ethers, natural waxes and synthetic waxes.

The drug semipermeable membrane described herein may also be a hydrophobic microporous membrane, in which the pores are substantially filled with gas and are not wetted by an aqueous medium, but are permeable to water vapor, as disclosed in US Patent No. 5,798,119. This hydrophobic but water vapor permeable membrane is typically made of materials such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polyfluorene, polyetherfluorene, polystyrene, Polyethylene halide, Polyvinyl It is composed of fluoroethylene, polyvinyl ester and ether, hydrophobic polymer of natural wax and synthetic wax.

The delivery ports on the semipermeable membrane of the drug described herein can be formed into a post-coating by mechanical or laser drilling. One or more delivery ports may also be formed in situ by erosion of a plug of a water-soluble material, or rupture of a thinner portion of the membrane on an indentation in the core. In addition, the delivery port may be formed during the coating process, as disclosed in US Pat. Nos. 5,612,059 and 5,698,220, of the type of coating layer in an asymmetric case.

The total amount and release rate of the active ingredients released by the drugs described herein can be substantially regulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

The osmotic controlled-release dosage forms of the combination medicaments of the present invention may further include additional conventional excipients or carriers described herein to facilitate the performance or processing of the formulation.

The osmotic controlled-release dosage forms of the combination drugs according to the present invention can be prepared according to conventional methods and techniques known to those having ordinary knowledge in the art (see Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In certain embodiments, the combination drug provided by the present invention can be formulated as an AMT controlled release dosage form, the core active ingredients of which are coated with an asymmetric osmotic membrane and the activity of the core with other pharmaceutically acceptable excipients or carriers The ingredients are coated with an asymmetric osmotic membrane. See US Patent No. 5,612,059 and WO 2002/17918. AMT controlled release dosage forms can be based on conventional methods and techniques known to those having ordinary skill in the art. Surgical preparation, including direct compression, dry granulation, wet granulation and dip coating.

In some embodiments, the combination drug provided by the present invention can be formulated as an ESC controlled-release dosage form, the core active ingredient of which is coated with an osmotic membrane, such as hydroxyethyl cellulose and other pharmaceutically acceptable excipients or carriers.

3. Multi-particle controlled release device and dosage form

The controlled release dosage form of the combination drug provided by the present invention can be made into a multi-particle controlled release agent, which comprises a plurality of particles, granules, or particles having a diameter ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Small pills. Such multiparticulates can be prepared by methods known to those of ordinary skill in the art, including wet and dry granulation, extrusion / spheronization, rolling, melt solidification, and seeding by spraying. For examples, see Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994 and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers described herein can be blended with the combination drugs provided by the present invention to help process and form multiparticulates. The resulting particles may themselves constitute multi-particulate devices or may be coated with various film-forming materials such as enteric polymers, water-swellable and water-soluble polymers. Multiparticulates can be further processed into capsules or tablets.

4. Targeted drugs

The combination drugs provided by the present invention can also be formulated for targeted administration to specific tissues, receptors or other areas of the body of the recipient to be treated, including liposomes, reseal red blood cells and antibody-based delivery systems. Examples include those disclosed in U.S. patents, such as U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874, but are not limited thereto.

How to use combination drugs

In one embodiment, the present invention provides a method for treating, preventing or ameliorating one or more symptoms of cardiovascular disease in a subject, which comprises administering to the subject a combination drug of two or more independent compounds, Each of these compounds is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, and a histamine H ₃ -Receptor antagonist or β ₂ -adrenergic receptor agonist.

In certain embodiments described herein, the cardiovascular disease is acute myocardial infarction, aortic aneurysm, atherosclerosis, atrial fibrillation, atrial flutter, cardiomyopathy, carditis, cerebrovascular disease, chest pain (angina), Congenital heart disease, coronary artery disease, endocarditis, hemorrhagic stroke, arrhythmia, heart attack, heart block, heart failure, hypertension heart disease, ischemic heart disease, ischemic stroke, Left ventricular dysfunction, myocardial fibrosis, myocardial infarction (heart attack), myocardial ischemia, myocarditis, peripheral arterial disease, peripheral vascular disease, rheumatic heart disease, stroke, heart valve disease or venous thrombosis.

In one embodiment described herein, the cardiovascular disease is a heart attack. In another embodiment, the cardiovascular disease is heart failure. In yet another embodiment, the cardiovascular disease is heart failure associated with abnormal cardiac output. In yet another embodiment, the cardiovascular disease is stroke. In yet another embodiment, the cardiovascular disease is arrhythmia. In yet another embodiment described herein, the cardiovascular disease is venous thrombosis.

In one embodiment described herein, the cardiovascular disease is arrhythmia. In another embodiment, the cardiovascular disease is bradycardia. In yet another embodiment, the cardiovascular disease is sinus bradycardia, sinus arrest, sinus exit block, atrioventricular (AV) block. In yet another embodiment, the cardiovascular disease is severe sinus bradycardia, sinoatrial block, sinus arrest, or bradycardia-tachycardia syndrome.

In certain embodiments described herein, the cardiovascular disease is cardiac block. In some embodiments, the cardiac block is an AV-block. In some embodiments, the AV-block is a primary, secondary, or tertiary AV-block. In some embodiments, the AV-blocking is a secondary Mobitz type I or Π.

In another embodiment, the present invention provides a method of treating, preventing or ameliorating one or more bradycardia symptoms in a subject, comprising administering to the subject a combination drug of two or more compounds, wherein each These compounds are phosphodiesterase inhibitor, adenosine receptor antagonist, calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor Body antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment described herein, bradycardia is atrial bradycardia, atrioventricular nodular bradycardia, infantile bradycardia, or ventricular bradycardia. In another embodiment, bradycardia is respiratory sinus arrhythmia, sinus bradycardia or pathological sinus bradycardia (SS) bradycardia.

In one embodiment described herein, bradycardia is asymptomatic bradycardia. In another embodiment, bradycardia is symptomatic bradycardia.

In one embodiment described herein, bradycardia is early bradycardia. in In another embodiment, bradycardia is severe bradycardia. In one embodiment, bradycardia is a symptomatic bradycardia due to a sick sinus symptom.

In certain embodiments described herein, bradycardia is associated with AV block. In some embodiments, bradycardia is associated with first-, second-, or third-degree atrioventricular block. In some embodiments, bradycardia is associated with a secondary Mohs type I or Π degree atrioventricular block.

In certain embodiments, a subject treated with a combination drug or method provided by the present invention may not have chronic obstructive pulmonary disease.

In certain embodiments, the resting pulse rate of a subject treated with a combination drug or method provided by the present invention may be increased from about 28 to 45 times per minute or from about 40 to 68 times.

In yet another embodiment, the invention provides a method of treating, preventing or ameliorating one or more stroke symptoms in a subject, the method comprising administering to the subject a combination drug of two or more compounds, wherein Each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, and a histamine H _3- Receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment described herein, the stroke is a hemorrhagic stroke. In another embodiment, the stroke is an ischemic stroke. In yet another embodiment, the stroke is a stroke associated with abnormal cardiac output. In yet another embodiment, the stroke is a stroke associated with bradycardia.

In yet another embodiment, the invention provides a method of treating, preventing or ameliorating one or more symptoms of cerebrovascular thrombosis in a subject, comprising administering to the subject a combination drug of two or more compounds, wherein Each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, and a histamine H _3- Receptor antagonist or β ₂ -adrenergic receptor agonist.

This article is not bound by any theory, and usually the heartbeat of the subject is slower during sleep at night. Patients with bradycardia are prone to thrombosis during sleep due to the slower heartbeat.

In yet another embodiment, the present invention provides treatment, prevention, or improvement of abnormal heart rhythm (e.g., heart rate) in a subject after cardiac surgery. 50 beats per minute (BPM) method comprising administering to a subject a combination drug of two or more compounds, wherein each compound is a phosphodiesterase inhibitor, adenosine, respectively Receptor antagonist, calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist .

In one embodiment, the subject treated with the combination drugs and methods provided by the present invention may have a normal heart rhythm. In one embodiment, the resting pulse rate (RPR) of the subject treated with the combination drugs and methods provided by the present invention can be increased from about 30 to about 60 per minute, and from about 35 to It can be increased from about 60 to about 60, from about 45 to 60, or from about 50 to about 60 times. In another embodiment, a subject treated with a combination drug and method provided by the present invention may have a resting pulse rate of about 30, about 32, about 34, about 36, about 40, about 42, about 46 per minute. , About 50, about 55, about 58, or about 60 times. In yet another embodiment, using this The subject after the combination drug or method provided by the invention has a resting pulse rate of about 30, about 32, about 34, about 36, about 40, about 42, about 46, about 50, about 52, about 54 per minute , About 56, about 58, about 60, about 64, about 65, about 67, about 68, about 69, or about 70 times.

In yet another embodiment, the present invention provides a method for increasing a subject's heart rate, which comprises administering to the subject a combination drug of two or more compounds, wherein each compound is a phosphodiesterase inhibitor, Adenosine receptor antagonist, calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor Agonist.

In one embodiment, the present invention provides a method for increasing the heart rate of a subject without significant changes in oxygen consumption by the subject. The method includes administering to the subject: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (ii) a calcium channel blocker.

In another embodiment, the present invention provides a method for increasing a subject's heart rate without significant changes in oxygen consumption by the subject, the method comprising administering to the subject: (i) a xanthine compound, Or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound; and (ii) dihydropyridine, or its isotopic variant (isotope enrichment is not low) At 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In yet another embodiment, the present invention provides a method for increasing a subject's heart rate without significant changes in oxygen consumption by the subject, the method comprising administering to the subject: (i) theophylline, or Its isotopic variant (isotope enrichment is not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) nifedipine, or an isotope variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt, hydrate Or solvent compounds.

In yet another embodiment, the present invention provides a method for increasing a subject's heart rate without significant changes in oxygen consumption by the subject, the method comprising administering to the subject: (i) aminophylline or Theophylline; and (ii) nifedipine.

Without being bound by any theory, the phosphodiesterase inhibitor or adenosine receptor antagonist provided by the present invention can be formulated with a calcium channel blocker to counteract adverse side effects or minimize side effects. For example, theophylline has the side effect of increasing oxygen consumption, while nifedipine has the side effect of reducing oxygen consumption. They also all have the effect of increasing heart rate. Therefore, theophylline and nifedipine can be paired together to cause an increase in heart rate without significant changes in oxygen consumption.

In one embodiment, the present invention provides a method for increasing the heart rate of a subject without significant changes in the subject's blood pressure, the method comprising administering to the subject: (i) histamine H ₂ -subject agonists or histamine H ₃ - receptor antagonist; and (ii) β ₂ - adrenoreceptor agonist.

In another embodiment, the present invention provides a method for increasing a subject's heart rate without significant changes in the blood pressure of the subject, the method comprising administering to the subject: (i) betahistine, Or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound; and (ii) salbutamol, or its enantiomer, or its enantiomer Mixtures of isomers, or isotope variants thereof (with an isotopic enrichment of not less than 50%), or pharmaceutically acceptable salts, hydrates, or Solvent compounds.

In yet another embodiment, the present invention provides a method for increasing a subject's heart rate without significant changes in the subject's blood pressure, the method comprising administering to the subject: (i) betahistine salt Acid salt; and (ii) salbutamol hydrochloride or L-salbutamol hydrochloride.

Without being bound by any theory, the histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist can be paired with a β ₂ -adrenergic receptor agonist to counteract adverse side effects or Minimize side effects. For example, betahistine may have side effects that cause blood pressure to rise, while both albuterol and levosalbutamol may have side effects that cause blood pressure to drop. Betahistine, salbutamol, and levosalbutamol also all have effects that cause an increase in heart rate. Therefore, betahistine can be used in combination with salbutamol or levosalbutamol to cause an increase in heart rate without significant changes in blood pressure.

In one embodiment, after using the combination medicine or method provided by the present invention, the resting pulse rate of the subject can be increased by about 2 to about 20, about 5 to about 18, about 5 to about 15 or about 5 per minute. To about 10 times. In another embodiment, the resting pulse rate of the subject can be increased by about 5, about 6, about 7, about 8, about 9 or about 10 times per minute after treatment with the combination medicine or method provided by the present invention.

In yet another embodiment, the present invention provides a method of increasing the cardiac output of a subject, the method comprising administering to the subject a combination drug of two or more compounds, wherein each compound is separately Is a phosphodiesterase inhibitor, adenosine receptor antagonist, calcium channel blocker, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist .

In one embodiment, after treatment with the combination medicine or method provided by the present invention, the cardiac output of the recipient can be increased in a range of about 200 to about 2000, about 100 to about 1000, or about 100 to about 500 ml per minute. .

In yet another embodiment, the invention provides a method of increasing cerebral blood flow in a subject, the method comprising administering to the subject a combination drug of two or more compounds, wherein each compound is independent of phosphate diphosphate Esterase inhibitor, adenosine receptor antagonist, calcium channel blocker, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, after being treated with the combination medicine or method provided by the present invention, the cerebral blood flow of the subject can be increased in a range of about 200 to about 750, about 250 to about 600, or about 300 to about 500 ml per minute.

In one embodiment, the method provided by the present invention comprises administering two compounds to a subject, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H, respectively. ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the invention comprises administering to the subject: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (ii) a calcium channel blocker. In another embodiment, the present invention provides a method comprising administering to the subject drugs: (i) a phosphodiesterase inhibitor, or an adenosine receptor antagonist; and (ii) a histamine H ₁ - receptor agonists, Histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist. In yet another embodiment, the method provided by the invention comprises administering to the subject: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (ii) a β ₂ -adrenergic receptor agonist. In yet another embodiment, the present invention provides a method comprising administering to the subject drugs: (i) calcium channel blockers; and (ii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonistic Agent or histamine H ₃ -receptor antagonist. In yet another embodiment, the method provided by the invention comprises administering to the subject: (i) a calcium channel blocker; and (ii) a β ₂ -adrenergic receptor agonist. In yet another embodiment, the method provided by the invention comprises administering to the subject: (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor Antagonists; and (ii) β ₂ -adrenergic receptor agonists.

In another embodiment, the method provided by the present invention comprises administering three compounds to a subject, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine H, respectively. ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the invention comprises administering to the subject: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) a calcium channel blocker; and (iii) Histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist. In another embodiment, the method provided by the invention comprises administering to the subject: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) a calcium channel blocker; and (iii) ) β ₂ -adrenergic receptor agonist. In yet another embodiment, the present invention provides a method comprising administering to the subject a drug by: (i) a phosphodiesterase inhibitor, or an adenosine receptor antagonist; (ii) a histamine H ₁ - receptor agonist , A histamine H ₂ -receptor agonist or a histamine H ₃ -receptor antagonist; and (iii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering four compounds to a subject, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and histamine. H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the invention comprises administering to the subject: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) a calcium channel blocker; (iii) group Amine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist; and (iv) β ₂ -adrenergic receptor agonist.

In certain embodiments, in the method provided by the present invention, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a calcium channel blocker ranges from about 1 to about 180 , About 2 to about 100, about 2 to about 50, or about 2 to about 20. In some embodiments, in the method provided by the present invention, the weight ratio of (i) the phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) the calcium channel blocker is about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, in the methods provided by the present invention, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- receptor agonists or histamine H ₃ - receptor antagonist in a weight ratio range from about 2 to about 200, from about 4 to about 100, from about 5 to about 50 or about 10 to about 30. In certain embodiments, in the methods provided by the present invention, (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist and (ii) a histamine H ₁ -receptor agonist, histamine H _2- The weight ratio of the receptor agonist or histamine H ₃ -receptor antagonist is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 30 .

In certain embodiments, in the methods provided by the invention, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist ranges from about 1 to about 1000, about 10 to about 500, about 20 to about 400, or about 40 to about 300. In certain embodiments, in the methods provided by the present invention, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) a β ₂ -adrenergic receptor agonist is about 40 About 60, about 80, about 100, about 120, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, in the methods provided by the present invention, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H The weight ratio of the ₃ -receptor antagonist ranges from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10. In certain embodiments, in the methods provided by the present invention, (i) a calcium channel blocker and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H The weight ratio of the ₃ -receptor antagonist is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, in the methods provided by the present invention, the weight ratio of (i) calcium channel blocker to (ii) β ₂ -adrenergic receptor agonist ranges from about 1 to about 100, about 5 to About 50 or about 5 to about 30. In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the calcium channel blocker to (ii) the β ₂ -adrenergic receptor agonist is about 5, about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 20.

In certain embodiments, in the methods provided by the present invention, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist with (ii) The weight ratio of β ₂ -adrenergic receptor agonists ranges from about 1 to about 100, about 1 to about 50, about 1 to about 30, or about 1 to about 20. In certain embodiments, in the methods provided by the present invention, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist with (ii) The weight ratio of β ₂ -adrenergic receptor agonist is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, About 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the methods provided by the present invention include administering to a subject a phosphodiesterase inhibitor or adenosine receptor antagonist in an amount that is less than when the drug is administered alone. In certain embodiments, the methods provided by the invention include administering a phosphodiesterase inhibitor or adenosine receptor antagonist to a subject in a daily dosage range of about 1 to about 1200, about 5 to about 1000, About 10 to about 800 or about 20 to about 600 mg. In certain embodiments, the methods provided by the invention include administering a phosphodiesterase inhibitor or adenosine receptor antagonist to a subject in a daily dosage range of about 1 to about 1200 mg. In certain embodiments, the methods provided by the invention include administering a phosphodiesterase inhibitor or adenosine receptor antagonist to a subject in a daily dosage range of about 5 to about 1000 milligrams. In certain embodiments, the methods provided by the invention include administering a phosphodiesterase inhibitor or adenosine receptor antagonist to a subject in a daily dosage range of about 10 to about 800 mg. In certain embodiments, the methods provided by the present invention comprise administering a phosphodiesterase inhibitor or adenosine receptor antagonist to a subject in a daily amount ranging from about 1 to about 600 mg. In certain embodiments, the methods provided by the invention include administering to a subject a phosphodiesterase inhibitor or adenosine receptor antagonist in a daily amount of about 20, about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, or about 600 mg .

In certain embodiments, the methods provided by the present invention include administering a calcium channel blocker to a subject in an amount less than the amount of the drug administered alone. In certain embodiments, the methods provided herein include administering a calcium channel blocker to a subject in an amount ranging from about 1 to about 200, about 1 to about 100, or about 2 to about 60 mg per day. In certain embodiments, the methods provided herein include administering a calcium channel blocker to a subject in an amount ranging from about 1 to about 200 mg per day. In certain embodiments, the methods provided herein include administering a calcium channel blocker to a subject in an amount ranging from about 1 to about 100 mg per day. In certain embodiments, the methods provided herein include administering a calcium channel blocker to a subject in an amount ranging from about 2 to about 60 mg per day. In certain embodiments, the methods provided herein include administering a calcium channel blocker to a subject in an amount of about 2, about 5, about 10, about 15, about 20, about 25, about 30, About 35, about 40, about 45, about 50, about 55, or about 60 mg.

In certain embodiments, the present invention provides a method comprising administering to the subject a histamine H drug in ₁ - agonists, histamine H ₂ - agonists or histamine H ₃ - receptor antagonist drugs The amount is lower than when this medicine is administered alone. In certain embodiments, the present invention provides a method comprising administering to the subject a histamine H drug in ₁ - agonists, histamine H ₂ - agonists or histamine H ₃ - receptor antagonist daily. The dosage ranges from about 0.1 to about 100, about 0.5 to about 50, or about 1 to about 30 mg. In certain embodiments, the present invention provides a method comprising administering to the subject a histamine H drug in ₁ - agonists, histamine H ₂ - agonists or histamine H ₃ - receptor antagonist daily. Dosage ranges from about 0.1 to about 100 mg. In certain embodiments, the present invention provides a method comprising administering to the subject a histamine H drug in ₁ - agonists, histamine H ₂ - agonists or histamine H ₃ - receptor antagonist daily. Dosage ranges from about 0.5 to about 50 mg. In certain embodiments, the present invention provides a method comprising administering to the subject a histamine H drug in ₁ - agonists, histamine H ₂ - agonists or histamine H ₃ - receptor antagonist daily. Dosage ranges from about 1 to about 30 mg. In certain embodiments, the present invention provides a method comprising administering to the subject a histamine H drug in ₁ - agonists, histamine H ₂ - agonists or histamine H ₃ - receptor antagonist daily. The dosage is about 1, about 2, about 4, about 6, about 5, about 5, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26 , About 28 or about 30 mg.

In certain embodiments, the methods provided by the invention include administering a beta ₂ -adrenergic receptor agonist to a subject in a dose that is less than when the drug is administered alone. In certain embodiments, the methods provided by the present invention include administering a beta ₂ -adrenergic receptor agonist to a subject in a dosage ranging from about 0.1 to about 50, about 0.1 to about 20, or about 0.1 per day To about 10 mg. In certain embodiments, the methods provided by the invention include administering a beta ₂ -adrenergic receptor agonist to a subject in a dosage ranging from about 0.1 to about 50 milligrams per day. In certain embodiments, the methods provided by the invention include administering a beta ₂ -adrenergic receptor agonist to a subject in a dosage ranging from about 0.1 to about 20 mg per day. In certain embodiments, the methods provided by the invention include administering a beta ₂ -adrenergic receptor agonist to a subject in a dosage ranging from about 0.1 to about 10 mg per day. In certain embodiments, the methods provided by the invention include administering a beta ₂ -adrenergic receptor agonist to a subject in a dosage range of about 0.1, about 0.2, about 0.5, about 1, about 1.5 per day About 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about 9 or about 10 mg.

In some embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist in the method provided by the present invention is administered once daily (QD) or divided into multiple doses, for example, twice daily. (BID), three times daily (TID), four times daily (QID), five times daily or six times daily. In certain embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist in the method provided by the present invention is administered once daily. In certain embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist in the method provided by the present invention is administered twice daily. In certain embodiments, the phosphodiesterase inhibitor or adenosine receptor antagonist in the method provided by the present invention is administered three times a day. In certain embodiments, a phosphodiesterase inhibitor or adenosine receptor antagonist in a method provided by the invention is administered four times a day.

In some embodiments, the calcium channel blocker in the method provided by the present invention is administered once daily (QD) or divided into multiple doses, for example, twice daily (BID) and three times daily (TID), four times daily (QID), five times daily or six times daily. In certain embodiments, a calcium channel blocker in a method provided by the invention is administered once daily. In certain embodiments, the calcium channel blocker in the methods provided by the present invention is administered twice daily. In certain embodiments, the calcium channel blocker in the methods provided by the invention is administered three times daily. In certain embodiments, the calcium channel blocker in the methods provided by the present invention is administered four times a day.

In certain embodiments, the present invention provides a method for the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is administered once daily (QD) Alternatively, the daily dose is divided into multiple administrations, such as twice daily administration (BID), three daily administrations (TID), four daily administrations (QID), five daily administrations, or six daily administrations. In certain embodiments, the present invention provides the method, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is administered once daily administration . In certain embodiments, the present invention provides the method, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is administered twice daily. In certain embodiments, the present invention provides the method, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is administered three times a day. In certain embodiments, the present invention provides the method, the histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is administered four times a day.

In some embodiments, in the method provided by the present invention, a β ₂ -adrenergic receptor agonist is administered once daily (QD) or divided into multiple doses, for example, twice daily (BID), Three times daily (TID), four times daily (QID), five times daily or six times daily. In certain embodiments, a β ₂ -adrenergic receptor agonist in a method provided by the invention is administered once daily. In certain embodiments, a β ₂ -adrenergic receptor agonist in a method provided by the invention is administered twice daily. In certain embodiments, a β ₂ -adrenergic receptor agonist in a method provided by the invention is administered three times daily. In certain embodiments, a β ₂ -adrenergic receptor agonist in a method provided by the invention is administered four times daily.

In certain embodiments, methods In the methods provided by the present invention, phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H _2- The receptor agonist or histamine H ₃ -receptor antagonist may be administered simultaneously with the β ₂ -adrenergic receptor agonist or sequentially in any order of the components. In certain embodiments, the phosphodiesterase inhibitor and / or adenosine receptor antagonist in the method provided by the present invention can be administered simultaneously with the calcium channel blocker. In some embodiments, the phosphodiesterase inhibitor and / or adenosine receptor antagonist and the calcium channel blocker in the method provided by the present invention can be administered simultaneously as a single pharmaceutical component. In certain embodiments, the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist in the method provided by the present invention and β ₂ -adrenergic receptor Somatic agonists are administered together at the same time. In certain embodiments, the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist in the method provided by the present invention and β ₂ -adrenergic receptor Somatic agonists are administered sequentially simultaneously in the form of a single pharmaceutical component. In certain embodiments, the phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptors in the methods provided by the present invention Somatic agonists or histamine H ₃ -receptor antagonists are administered simultaneously with β ₂ -adrenergic receptor agonists. In certain embodiments, the phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptors in the methods provided by the present invention Somatic agonists or histamine H ₃ -receptor antagonists can be administered simultaneously with β ₂ -adrenergic receptor agonists in the form of a single pharmaceutical component.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (ii) one or more compounds, wherein each compound are calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonists, group Amine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; and (ii) calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, histamine H ₃ -receptor antagonists or β _2- Adrenaline receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; and (ii) a calcium channel blocker. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , hydrate, or solvate thereof; and (ii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist. In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) β ₂ -adrenergic receptor agonists.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; and (ii) two compounds, each of which is a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, and a histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) calcium channel blockers; and (iii) histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H ₃ -receptor antagonists . In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; (ii) calcium channel blockers; and (iii) β ₂ -adrenergic receptor agonists. In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist; and (iii) β ₂ -adrenal Receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) three compounds, each of which is a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, and histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) calcium channel blockers; (iii) histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists or histamine H ₃ -receptor antagonists; And (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the method provided by the present invention ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 to about 20 . In some embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the method provided by the present invention ranges from about 1 to about 180. In some embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the method provided by the present invention ranges from about 2 to about 100. In some embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the method provided by the present invention ranges from about 2 to about 50. In some embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the method provided by the present invention ranges from about 2 to about 20. In certain embodiments, the weight ratio of the xanthine compound to the calcium channel blocker in the method provided by the present invention is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16 , About 18 or about 20.

In certain embodiments, (i) a xanthine compound and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor in a method provided by the present invention The weight ratio of the antagonist ranges from about 2 to about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30. In certain embodiments, in the methods provided by the present invention, (i) a xanthine compound and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H _3- The weight ratio of the receptor antagonist is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, or about 30.

In certain embodiments, in the methods provided by the present invention, the weight ratio of the xanthine compound to the β ₂ -adrenergic receptor agonist ranges from about 1 to about 1000, about 10 to about 500, and about 20 to about 400. Or about 40 to about 300. In certain embodiments, in the method provided by the present invention, the weight ratio of the xanthine compound to the β ₂ -adrenergic receptor agonist ranges from about 40, about 60, about 80, about 100, about 120, about 140 , About 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the methods provided by the present invention include administering a xanthine compound, or an isotope variant thereof (isotopically enriched to not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent to a subject The compound is administered in an amount lower than that when the drug is administered alone. In certain embodiments, the methods provided by the present invention include administering a xanthine compound to a subject at a daily dosage ranging from about 1 to about 1200, about 5 to about 1000, about 10 to about 800, or about 20 to About 600 mg. In certain embodiments, the methods provided by the present invention include administering a xanthine compound to a subject in a daily dosage ranging from about 1 to about 1200 mg. In certain embodiments, the methods provided by the present invention comprise administering a xanthine compound to a subject in a daily dosage ranging from about 5 to about 1000 milligrams. In certain embodiments, the methods provided by the invention include administering a xanthine compound to a subject in a range of about 10 to about 800 milligrams per day. In certain embodiments, the methods provided by the invention include administering a xanthine compound to a subject in a daily dosage ranging from about 20 to about 600 mg. In certain embodiments, the methods provided by the invention include administering a xanthine compound to a subject at a daily dosage of about 20, about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, or about 600 Mg.

In certain embodiments, the xanthine compound in the method provided by the present invention is administered once daily (QD) or divided into multiple doses, for example, twice daily (BID), three times daily (TID ), Four times daily (QID), five times daily or six times daily. In certain embodiments, the xanthine compounds in the methods provided by the invention are administered once daily. In certain embodiments, the xanthine compounds in the methods provided herein are administered twice daily. In certain embodiments, the xanthine compounds in the methods provided by the invention are administered three times daily. In certain embodiments, the xanthine compounds in the methods provided by the invention are administered four times daily.

In certain embodiments, methods In the methods provided by the present invention, xanthine compounds, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H _3- Receptor antagonists can be administered simultaneously with the β ₂ -adrenergic receptor agonist or sequentially in any order of the components. In certain embodiments, the xanthine compounds in the methods provided by the present invention can be administered simultaneously with the calcium channel blocker. In some embodiments, the xanthine compound and the calcium channel blocker in the method provided by the present invention can be administered sequentially in the form of a single pharmaceutical component. In certain embodiments, the xanthine compound and the calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor in the method provided by the present invention Somatic antagonists or β ₂ -adrenergic receptor agonists are administered together at the same time. In certain embodiments, the xanthine compound and the calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor in the method provided by the present invention Somatic antagonists or β ₂ -adrenergic receptor agonists can be administered sequentially simultaneously in the form of a single pharmaceutical component.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) one or more compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; and (ii) phosphodiesterase inhibitors, adenosine receptor antagonists, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, histamine H _3- Receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) phosphodiesterase inhibitors or adenosine receptor antagonists. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , hydrate, or solvate thereof; and (ii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist. In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; and (ii) β ₂ -adrenergic receptor agonists.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; and (ii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, and histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrates or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H ₃ -receptor antagonist. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) β ₂ -adrenergic receptor agonists. In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist; and (iii) a β ₂ -adrenergic receptor Body agonist.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compounds; and (ii) three compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, and a histamine H ₂ -receptor Agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; (iii) histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists or histamines H ₃ -receptor antagonists; and (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, in the method provided by the present invention, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) dihydropyridine ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 to about 20. In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) the dihydropyridine is about 2, about 4, about 6 , About 8, about 10, about 12, about 14, about 16, about 18, or about 20.

In certain embodiments, in the methods provided by the present invention, (i) dihydropyridine and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H _3- The weight ratio of the receptor antagonist ranges from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10. In certain embodiments, (i) dihydropyridine and (ii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor in a method provided by the present invention The weight ratio of the antagonist is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8 , About 8.5, about 9, about 9.5, or about 10.

In certain embodiments, in the method provided by the present invention, the weight ratio of dihydropyridine to β ₂ -adrenergic receptor agonist ranges from about 1 to about 100, about 1 to about 50, or about 5 to about 30 . In certain embodiments, the weight ratio of dihydropyridine to β ₂ -adrenergic receptor agonist in the method provided by the present invention is about 5, about 10, about 11, about 12, about 13, about 14, about 15 , About 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30.

In certain embodiments, the methods provided by the present invention include administering to a subject a dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or The amount of the solvent compound is less than the amount of the drug when it is administered alone. In certain embodiments, the methods provided by the invention include administering dihydropyridine to a subject in a daily dosage range of about 0.5 to about 200, about 1 to about 100, or about 2 to about 60 mg. In certain embodiments, the methods provided by the present invention include administering dihydropyridine to a subject in a daily dosage ranging from about 0.5 to about 200 mg. In certain embodiments, the methods provided by the present invention include administering dihydropyridine to a subject in a daily dosage ranging from about 1 to about 100 milligrams. In certain embodiments, the methods provided by the present invention include administering dihydropyridine to a subject in a daily dosage ranging from about 2 to about 50 mg. In certain embodiments, the methods provided by the present invention include administering a dihydropyridine to a subject at a daily dosage of about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg.

In some embodiments, the dihydropyridine in the method provided by the present invention can be administered once daily (QD) or divided into multiple doses, for example, twice daily. (BID), three times daily (TID), four times daily (QID), five times daily or six times daily. In certain embodiments, the dihydropyridine in the methods provided by the invention is administered once daily. In certain embodiments, the dihydropyridine in the methods provided by the invention is administered twice daily. In certain embodiments, the dihydropyridine in the methods provided by the invention is administered three times daily. In certain embodiments, the dihydropyridine in the methods provided by the invention is administered four times daily.

In certain embodiments, the method provided by the present invention, dihydropyridine and phosphodiesterase inhibitor, adenosine receptor antagonist, histamine H ₁ -receptor agonist, histamine H ₂ -receptor An agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenergic receptor agonist may be administered simultaneously together or sequentially in any order of the components. In certain embodiments, the dihydropyridine and the phosphodiesterase inhibitor or adenosine receptor antagonist in the method provided by the present invention are administered simultaneously. In certain embodiments, the dihydropyridine and the phosphodiesterase inhibitor or adenosine receptor antagonist in the method provided by the present invention can be administered sequentially as a single pharmaceutical component simultaneously. In certain embodiments, the dihydropyridine and phosphodiesterase inhibitors, adenosine receptor antagonists, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists in the methods provided by the present invention Agents, histamine H ₃ -receptor antagonists or β ₂ -adrenergic receptor agonists are administered simultaneously. In certain embodiments, the dihydropyridine and phosphodiesterase inhibitors, adenosine receptor antagonists, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists in the methods provided by the present invention agent, a histamine H ₃ - receptor antagonist or β ₂ - adrenoreceptor agonist may be in the form of a single pharmaceutical component while the administered sequentially.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) optionally One or more compounds, each of which is a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenoreceptor agonist .

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , A hydrate or a solvent compound; and (ii) dihydropyridine, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; (ii) dihydropyridine, or an isotopic variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) group Amine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, histamine H ₃ -receptor antagonist, or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , A hydrate or a solvent compound; (ii) dihydropyridine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) β ₂ -adrenaline receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) ) Two compounds, each of which is a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor antagonist, or a β ₂ -adrenoreceptor agonist .

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound; (ii) dihydropyridine, or its isotopic variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) each of these receptor agonist, a histamine H ₂ - - - H ₃ histamine receptor agonist or receptor antagonist compounds are histamine H _1; and (iv) β ₂ - adrenoreceptor agonist.

In certain embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the method provided by the present invention ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 to about 20. In certain embodiments, in the method provided by the present invention, The weight ratio of the purine compound to the dihydropyridine ranges from about 1 to about 180. In certain embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the method provided by the present invention ranges from about 2 to about 100. In some embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the method provided by the present invention ranges from about 2 to about 50. In certain embodiments, the weight ratio of the xanthine compound to the dihydropyridine in the method provided by the present invention ranges from about 2 to about 20. In certain embodiments, the weight ratio of xanthine compound to dihydropyridine in the method provided by the present invention is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18 or about 20.

In certain embodiments, the method provided by the present invention, a dihydropyridine and a xanthine compound, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, a histamine H ₃ -receptor Antagonists or β ₂ -adrenergic receptor agonists can be administered simultaneously together or sequentially in any order of the components. In certain embodiments, the dihydropyridine and the xanthine compound in the method provided by the present invention are administered simultaneously. In certain embodiments, the dihydropyridine and the xanthine compound in the method provided by the present invention are administered sequentially in the form of a single pharmaceutical component. In certain embodiments, dihydropyridine and xanthine compounds, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, histamine H ₃ -receptor antagonists in the methods provided by the present invention Agents or β ₂ -adrenergic receptor agonists may be administered together at the same time. In certain embodiments, dihydropyridine and xanthine compounds, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, histamine H ₃ -receptor antagonists in the methods provided by the present invention The agent or β ₂ -adrenergic receptor agonist is administered simultaneously and sequentially as a single pharmaceutical component.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacological agent thereof Acceptable salt, hydrate, or solvent compounds; and (ii) one or more compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, or β _2- Adrenergic receptor agonist.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates, or solvent compounds; and (ii) phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, and β ₂ -adrenergic receptor agonists.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacological agent thereof Acceptable salts, hydrates or solvent compounds; and (ii) phosphodiesterase inhibitors or adenosine receptor antagonists. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound; and (ii) a calcium channel blocker. In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound; and (ii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, or β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacological agent Acceptable salts, hydrates or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) calcium channel blockers. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) β ₂ -adrenergic receptor agonists. In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound; (ii) a calcium channel blocker; and (iii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) three compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, or β ₂ -Adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacological agent thereof Acceptable salts, hydrates or solvent compounds; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; (iii) calcium channel blockers; and (iv) β ₂ -adrenergic receptors Agonist.

In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the phosphodiesterase inhibitor adenosine receptor antagonist to (ii) betahistine ranges from about 2 to about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30. In certain embodiments, in the method provided by the present invention, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) betahistine is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, About 29 or about 30.

In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the calcium channel blocker to (ii) betahistine ranges from about 1 to about 50, about 1 to about 40, about 1 To about 20 or about 1 to about 10. In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the calcium channel blocker to (ii) betahistine is about 1, about 1.5, about 2, about 2.5, about 3, About 3.5, about 4, about 4.5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, in the methods provided by the present invention, the weight ratio of (i) betahistine to (ii) β ₂ -adrenergic receptor agonist ranges from about 1 to about 100, about 1 to about 50. About 1 to about 30 or about 1 to about 20. In certain embodiments, the weight ratio of (i) betahistine to (ii) β ₂ -adrenergic receptor agonist in the method provided by the present invention is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the methods provided by the invention include administering betahistone, or a metabolite thereof, or an isotope variant thereof (isotopically enriched to not less than 50%), or a pharmaceutically acceptable The amount of the salt, hydrate or solvent compound is less than the amount of the drug when it is administered alone. In certain embodiments, the methods provided by the invention include administering betahistine to a subject in a daily dosage range of about 0.1 to about 100, about 0.5 to about 50, or about 1 to about 20 mg. In certain embodiments, the methods provided by the invention include administering betahistine to a subject in a daily dosage ranging from about 0.1 to about 100 milligrams. In certain embodiments, the methods provided by the invention include administering betahistine to a subject in a daily amount of about 0.5 to about 50 mg. In certain embodiments, the methods provided by the invention include administering betahistine to a subject in a daily dosage ranging from about 1 to about 20 milligrams. In certain embodiments, the methods provided by the invention include administering betahistine to a subject in a daily dosage of about 1, about 2, about 3, about 4, about 5, about 6, about 8, About 10, about 12, about 14, about 16, about 18, or about 20 mg.

In some embodiments, the method of the present invention can be used once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily ( TID), four times daily (QID), five times daily or six times daily. In certain embodiments, betahistine in the methods provided by the invention is administered once daily. In certain embodiments, betahistine in the methods provided by the invention is administered twice daily. In certain embodiments, betahistine in the methods provided by the invention is administered three times daily. In certain embodiments, betahistine in the methods provided by the invention is administered four times daily.

In certain embodiments, the method provided by the present invention is a betahistine with a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and / or a β ₂ -adrenergic receptor agonist. It may be applied simultaneously together or sequentially in any order of the components. In certain embodiments, the betahistine and the β ₂ -adrenergic receptor agonist in the method provided by the present invention are administered simultaneously. In certain embodiments, the betahistine and β ₂ -adrenergic receptor agonist in the method provided by the present invention are administered sequentially in the form of a single pharmaceutical component. In certain embodiments, betahistine and phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, and / or β ₂ -adrenergic receptor agonists in the methods provided by the present invention However, they are applied together at the same time. In certain embodiments, betahistine and phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, and / or β ₂ -adrenergic receptor agonists in the methods provided by the present invention They are administered simultaneously in the form of a single pharmaceutical component.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; And (iii) optionally one or more compounds, wherein each compound is a calcium channel blocker or a β ₂ -adrenergic receptor agonist, respectively.

In another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; and (ii) betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compound; (ii) Betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound ; And (iii) a calcium channel blocker or a β ₂ -adrenergic receptor agonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) betahistine, or a metabolite thereof or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) Calcium channel blockers. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compound; (ii) Betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound ; And (iii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or Solvent compounds; and (iii) two compounds, each of which is a calcium channel blocker or a β ₂ -adrenergic receptor agonist, respectively.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; (iii) calcium channel blockers; and (iv) β ₂ -adrenergic receptor agonists.

In certain embodiments, the weight ratio of the xanthine compound to betahistone in the method provided by the present invention ranges from about 2 to about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30 . In certain embodiments, the weight ratio of the xanthine compound to the betatine in the method provided by the present invention is about 10, about 12, about 14, about 16, about 17, about 18, about 19, about 20, About 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30.

In certain embodiments, the methods provided by the present invention, the betahistine and the xanthine compound, the calcium channel blocker or the β ₂ -adrenergic receptor agonist can be administered together simultaneously or in any of the components. Apply sequentially. In certain embodiments, the betahistine in the method provided by the present invention is administered simultaneously with a xanthine compound, a calcium channel blocker, or a β ₂ -adrenergic receptor agonist. In certain embodiments, the betahistine and xanthine compounds, calcium channel blockers, or β ₂ -adrenergic receptor agonists in the methods provided by the present invention are administered sequentially as a single pharmaceutical component .

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; And (iii) optionally one or more compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist, or a β ₂ -adrenergic receptor agonist, respectively.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compound; and (ii) betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent Compound.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or Solvent compounds; and (iii) phosphodiesterase inhibitor adenosine receptor antagonists and β ₂ -adrenergic receptor agonists.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; And (iii) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrate or solvent compound; (ii) Betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound ; And (iii) a β ₂ -adrenergic receptor agonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or Solvent compounds; and (iii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, or a β ₂ -adrenergic receptor agonist, respectively.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) betahistine, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent thereof Compounds; (iii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iv) β ₂ -adrenergic receptor agonists.

In some embodiments, the weight ratio of dihydropyridine to betahistone in the method provided by the present invention ranges from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10. In certain embodiments, the dihydropyridine and The weight ratio of betahistine is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, About 8, about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, the methods provided by the present invention, Betahistine and phosphodiesterase inhibitors, adenosine receptor antagonists, dihydropyridines, and β ₂ -adrenergic receptor agonists are simultaneously They are applied together or sequentially in any order of the components. In some embodiments, the betahistine and the phosphodiesterase inhibitor, adenosine receptor antagonist, dihydropyridine, and β ₂ -adrenergic receptor agonist are administered simultaneously in the method provided by the present invention. . In certain embodiments, the betahistine and phosphodiesterase inhibitors, adenosine receptor antagonists, dihydropyridines, and β ₂ -adrenergic receptor agonists in the methods provided by the present invention The drug components are administered sequentially.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) dihydropyridine, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound; (iii) times Statin, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iv) optional β _2- Adrenaline receptor agonist.

In certain embodiments, methods. In the methods provided by the present invention, betahistine and xanthine compounds, dihydropyridines, or β ₂ -adrenergic receptor agonists can be administered together simultaneously or in any order of components. Apply sequentially. In certain embodiments, the betahistine in the method provided by the present invention is administered simultaneously with a xanthine compound, dihydropyridine, and a β ₂ -adrenergic receptor agonist. In certain embodiments, the betahistine and xanthine compounds, dihydropyridine, and β ₂ -adrenergic receptor agonist in the methods provided by the present invention are administered sequentially in the form of a single pharmaceutical component.

In one embodiment, the present invention provides a method comprising administering to the subject: (i) albuterol, or an enantiomer, a mixture of enantiomers, or levobuterol, or an isotope variant thereof ( Isotope enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) one or more compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor, respectively antagonists, calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (isotope Enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) phosphodiesterase inhibitor, adenosine receptor antagonist, calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope thereof A variant (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In another embodiment, the method provided by the invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or Isotope variants (isotope enrichment is not less than 50%), or pharmaceutically acceptable salts, hydrates or solvent compounds thereof; and (ii) calcium channel blockers. In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or Isotopic variants (isotope enrichment of not less than 50%), or pharmaceutically acceptable salts, hydrates or solvent compounds thereof; and (ii) histamine H ₁ -receptor agonists, histamine H ₂ -receptors agonists or histamine H ₃ - receptor antagonist.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotopic modification thereof (Isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (ii) two compounds, each of which is a phosphodiesterase inhibitor, adenosine, respectively receptor antagonists, calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (Isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (iii) a calcium channel blocker断 剂。 Breaking agent. In another embodiment, the method provided by the invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or Isotopic variants (isotope enrichment of not less than 50%), or pharmaceutically acceptable salts, hydrates or solvent compounds thereof; (ii) phosphodiesterase inhibitors or adenosine receptor antagonists; and (iii) Histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist. In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or isotopic variations (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate; (ii) a calcium channel blocker; and (iii) a histamine H ₁ - receptor agonistic agents, histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or Isotopic variants (isotope enrichment of not less than 50%), or pharmaceutically acceptable salts, hydrates or solvent compounds thereof; and (ii) three compounds, each of which is a phosphodiesterase inhibitor, a glycoside receptor antagonists, calcium channel blockers, histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

The method provided by the present invention comprises administering to the subject: (i) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (isotopically enriched Less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; (iii) a calcium channel blocker; and (iv ) Histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In certain embodiments, in the methods provided by the present invention, (i) the weight of a phosphodiesterase inhibitor or adenosine receptor antagonist and (ii) albuterol or levosalbutamol The ratio ranges from about 1 to about 1000, about 10 to about 500, about 20 to about 200, or about 50 to about 200. In certain embodiments, in the methods provided by the present invention, the weight ratio of (i) a phosphodiesterase inhibitor or adenosine receptor antagonist to (ii) albuterol or levosalbutamol is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200.

In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the calcium channel blocker to (ii) salbutamol or levosalbutamol ranges from about 1 to about 100, about 5 to about 50, or about 5 To around 20. In certain embodiments, in the method provided by the present invention, the weight ratio of (i) the calcium channel blocker to (ii) salbutamol or levosalbutamol is about 5, about 6, about 7, about 8, about 9, About 10, about 11, about 12, about 13, about 14, about 15, about 16, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, in the methods provided by the present invention, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist with (ii) The weight ratio of salbutamol or levosalbutamol ranges from about 1 to about 100, about 1 to about 50, about 1 to about 30, or about 1 to about 20. In certain embodiments, in the methods provided by the present invention, (i) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist with (ii) The weight ratio of salbutamol or levosalbutamol is between about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14 , About 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the methods provided by the invention include administering albuterol, or an enantiomer thereof, a mixture of enantiomers thereof, or levosalbutine to a subject The amount of amine alcohol, or its isotopic variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound, is less than the amount when this drug is administered alone. In certain embodiments, the method provided by the present invention comprises administering albuterol or levosalbutamol (micronized or non-micronized) to a subject in a daily dosage range of about 0.1 to about 50, about 0.2 to about 20, or about 0.5 to about 10 mg. In certain embodiments, the methods provided herein include administering albuterol or levosalbutamol to a subject in a daily dosage range of about 0.1 to about 50 mg. In certain embodiments, the methods provided by the present invention include administering albuterol or levosalbutamol to a subject at a daily dosage ranging from about 0.2 to about 20 mg. In certain embodiments, the methods provided by the present invention include administering albuterol or levosalbutamol to a subject in a daily dosage ranging from about 0.5 to about 10 mg. In certain embodiments, the method provided by the present invention comprises administering an albuterol or levosalbutamol to a subject at a daily dosage of about 0.1, about 0.2, about 0.5, about 1, about 1.5, about 2, about 2.5, About 3, about 3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about 9 or about 10 mg.

In some embodiments, in the method provided by the present invention, salbutamol or levosalbutamol may be administered once daily (QD) or divided into multiple doses, such as twice daily (BID), three times daily ( TID), four times daily (QID), five times daily or six times daily. In some embodiments, the salbutamol or levosalbutamol in the methods provided by the present invention is administered once daily. In certain embodiments, the salbutamol or levosalbutamol in the methods provided by the present invention is administered twice daily. In certain embodiments, the methods of the present invention provide salbutamol or levosalbutamol who are administered three times daily. In certain embodiments, albuteramine in the methods provided by the present invention Alcohol or levosalbutamol is said to be administered four times daily.

In certain embodiments, the method provided by the present invention, the salbutamol or levosalbutamol and phosphodiesterase inhibitor, adenosine receptor antagonist, calcium channel blocker, histamine H ₁ -receptor agonist, Histamine H ₂ -receptor agonists or histamine H ₃ -receptor antagonists may be administered simultaneously together or sequentially in any order of the components. In some embodiments, the albuterol or levosalbutamol in the method provided by the present invention is simultaneously with the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist Apply together. In some embodiments, the albuterol or levosalbutamol in the method provided by the present invention is simultaneously with the histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -receptor antagonist They are administered sequentially as a single pharmaceutical component. In certain embodiments, the present invention provides a method of albuterol or levalbuterol with phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ - receptor agonist, group The amine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist may be administered together at the same time. In certain embodiments, the present invention provides a method of albuterol or levalbuterol with phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, histamine H ₁ - receptor agonist, group Amine H ₂ -receptor agonists or histamine H ₃ -receptor antagonists are administered sequentially in the form of a single pharmaceutical component simultaneously.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotope enrichment of not less than 50%) , Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) optionally one or more compounds, wherein each compound is a calcium channel blocker, a histamine H ₁ -receptor agonist, a group Amine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; and (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or L-salbutamol, or its isotopic variant (isotope enrichment of not less than 50%) , Or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotope enrichment of not less than 50%), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a calcium channel blocker, a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H _3- Receptor antagonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or an enantiomer, a mixture of enantiomers, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound; and (iii) a calcium channel blocker. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotope enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (iii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotopic enrichment of not less than 50% ), Or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; and (iii) two compounds, each of which is independent of a calcium channel blocker, a histamine H ₁ -receptor agonist, and histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) albuterol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) a calcium channel blocker; and (iv) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist, or a histamine H ₃ -receptor antagonist.

In certain embodiments, in the methods provided by the present invention, (i) xanthine The weight ratio of the compound to (ii) salbutamol or levosalbutamol ranges from about 1 to about 1,000, about 10 to about 500, about 20 to about 400, or about 40 to about 300. In certain embodiments, the weight ratio of (i) xanthine compound to (ii) salbutamol or levosalbutamol in the method provided by the present invention is about 40, about 60, about 80, about 100, about 120, about 140, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the method In the method provided by the present invention, salbutamol, or levosalbutamol and a calcium channel blocker, histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H _{The 3} -receptor antagonists can be administered simultaneously together or sequentially in any order of the components. In certain embodiments, the salbutamol or levosalbutamol and xanthine compounds, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists or groups in the methods provided by the present invention Amine H ₃ -receptor antagonists are administered simultaneously. In certain embodiments, the salbutamol or levosalbutamol and xanthine compounds, calcium channel blockers, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists or groups in the methods provided by the present invention Amine H ₃ -receptor antagonists are administered sequentially in the form of a single pharmaceutical component simultaneously.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotope enrichment of not less than 50%) , Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) optionally one or more compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and histamine H, respectively ₁ -receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In another embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotopic enrichment of not less than 50 %), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotopic enrichment of not less than 50% ), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a phosphodiesterase inhibitor, an adenosine receptor antagonist, a histamine H ₁ -receptor agonist, a histamine H _2- Receptor agonist or histamine H ₃ -receptor antagonist.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotope enrichment of not less than 50%) , Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a phosphodiesterase inhibitor or an adenosine receptor antagonist. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof , Hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotope enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (iii) a histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In yet another embodiment, the method provided by the present invention comprises administering to the subject: (i) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable Salt, hydrate or solvent compound; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotopic enrichment of not less than 50% ), Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist, and histamine H _1- Receptor agonist, histamine H ₂ -receptor agonist or histamine H ₃ -receptor antagonist.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) albuterol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (iv) a histamine H ₁ -receptor agonist, a histamine H _2- Receptor agonist or histamine H ₃ -receptor antagonist.

In certain embodiments, the weight ratio of (i) dihydropyridine to (ii) salbutamol or levosalbutamol in the method provided by the present invention ranges from about 1 to about 100, about 5 to about 50, or about 10 to about 20. In some embodiments, the weight ratio of (i) dihydropyridine to (ii) salbutamol or levosalbutamol in the method provided by the invention is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the present invention provides methods, the albuterol or levalbuterol with phosphodiesterase inhibitors, adenosine receptor antagonists, dihydropyridine, histamine H ₁ - receptor agonist, a histamine The H ₂ -receptor agonist or histamine H ₃ -receptor antagonist may be administered simultaneously together or sequentially in any order of the components. In certain embodiments, the salbutamol or levosalbutamol and phosphodiesterase inhibitors, adenosine receptor antagonists, dihydropyridines, histamine H ₁ -receptor agonists, histamine H in the methods provided by the present invention ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is administered together simultaneously. In certain embodiments, the salbutamol or levosalbutamol and phosphodiesterase inhibitors, adenosine receptor antagonists, dihydropyridines, histamine H ₁ -receptor agonists, histamine H in the methods provided by the present invention ₂ - receptor agonist or a histamine H ₃ - receptor antagonist is simultaneously in the form of a single pharmaceutical composition is administered sequentially.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacologically Acceptable salts, hydrates or solvent compounds; (ii) Salbutamol, or its enantiomers, or a mixture of enantiomers, or L-salbutamol, or its isotopic variant (isotope enrichment is not less than 50%), or pharmaceutically acceptable Salt, hydrate or solvent compound; and (iii) optionally one or more compounds, wherein each compound is a phosphodiesterase inhibitor, an adenosine receptor antagonist or a calcium channel blocker, respectively.

In another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates or solvent compounds; and (ii) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (isotopically enriched Not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates or solvent compounds; (ii) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (isotopically enriched Less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a phosphodiesterase inhibitor, an adenosine receptor antagonist or a calcium channel blocker.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmacological agent thereof Acceptable salts, hydrates or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or L-salbutamol, or its isotopic variant (isotope enrichment is not low) 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a phosphodiesterase inhibitor or gland Glycoside receptor antagonist. In another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates, or solvent compounds; (ii) salbutamol, or its enantiomers, or a mixture of enantiomers, or levosalbutamol, or its isotopic variant (isotopically enriched Not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) a calcium channel blocker.

In yet another embodiment, the method provided by the present invention comprises administering to a subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or Pharmaceutically acceptable salts, hydrates or solvent compounds; (ii) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (isotopically enriched Less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; and (iii) two compounds, each of which is a phosphodiesterase inhibitor, an adenosine receptor antagonist or calcium Channel blocker.

In one embodiment, the method provided by the present invention comprises administering to the subject: (i) betahistone, or a metabolite thereof, or an isotopic variant thereof (isotope enrichment is not less than 50%), or A pharmaceutically acceptable salt, hydrate or solvent compound thereof; (ii) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (isotopic enrichment Not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) a phosphodiesterase inhibitor or an adenosine receptor antagonist; and (iv) a calcium channel blocker.

In some embodiments, (i) betahistine and (ii) The weight ratio of salbutamol or levosalbutamol ranges from about 1 to about 100, about 1 to about 50, about 1 to about 20, or about 1 to about 10. In certain embodiments, the weight ratio of (i) betahistine to (ii) salbutamol or levosalbutamol in the method provided by the present invention is about 1, about 2, about 3, about 4, about 5, about 6, About 7, about 8, about 9 or about 10.

In certain embodiments, methods In the methods provided by the present invention, salbutamol or levosalbutamol and phosphodiesterase inhibitors, adenosine receptor antagonists, calcium channel blockers, and betahistine can be administered together or at the same time. The components are applied sequentially in any order. In certain embodiments, the salbutamol or levosalbutamol in the methods provided by the present invention are administered simultaneously with betahistine. In some embodiments, the salbutamol or levosalbutamol in the methods provided by the present invention are currently administered sequentially with betahistine simultaneously in the form of a single pharmaceutical component. In certain embodiments, the albuterol or levosalbutamol in the methods provided by the present invention is administered simultaneously with a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, and betahistine. In certain embodiments, the salbutamol or levosalbutamol in the methods provided by the present invention are simultaneously administered as a single drug component with a phosphodiesterase inhibitor, adenosine receptor antagonist, calcium channel blocker, and betahistine. And applied sequentially.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound; (ii) dihydropyridine, or its isotopic variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) salbutamol, or Its enantiomer, or a mixture of enantiomers, or levosalbutamol, or its isotope variant (isotope enrichment of not less than 50%), or its pharmaceutically acceptable salt, hydrate, or solvent compound; and (iv) optionally histamine H ₁ - receptor agonist, a histamine H ₂ - receptor agonist or a histamine H ₃ - receptor antagonist.

In certain embodiments, the method provided by the present invention, the salbutamol or levosalbutamol is combined with a xanthine compound, dihydropyridine, an optional histamine H ₁ -receptor agonist, an amine H ₂ -receptor agonist, or Histamine H ₃ -receptor antagonists may be administered simultaneously together or sequentially in any order of the components. In certain embodiments, the salbutamol or levosalbutamol and xanthine compounds, dihydropyridines, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H in the methods provided by the present invention _{The 3} -receptor antagonists are administered simultaneously. In certain embodiments, the salbutamol or levosalbutamol and xanthine compounds, dihydropyridines, histamine H ₁ -receptor agonists, histamine H ₂ -receptor agonists, or histamine H in the methods provided by the present invention ₃ -receptor antagonists are administered sequentially in the form of a single pharmaceutical component simultaneously.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound; (ii) betahistine, or its metabolite, or its isotopic variant (isotope enrichment is not less than 50%), or its pharmaceutically acceptable salt, hydrate or solvent compound; (iii) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (iv) an optional calcium channel blocker.

In certain embodiments, the salbutamol or Salbutamol and xanthine compounds, calcium channel blockers or betahistine can be administered simultaneously together or sequentially in any order of the components. In certain embodiments, the albuterol or levosalbutamol in the method provided by the present invention is administered simultaneously with a xanthine compound, a calcium channel blocker, and betahistine. In certain embodiments, the albuterol or levosalbutamol in the method provided by the present invention is administered sequentially with a xanthine compound, a calcium channel blocker, and betahistine in the form of a single pharmaceutical component.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) dihydropyridine, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, A hydrate or a solvent compound; (ii) betahistine, or a metabolite thereof, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof; (iii) salbutamol, or an enantiomer thereof, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable Salts, hydrates or solvent compounds; and (iv) optional phosphodiesterase inhibitors or adenosine receptor antagonists.

In certain embodiments, the salbutamol or levosalbutamol in the method provided by the present invention can be administered together with a phosphodiesterase inhibitor, an adenosine receptor antagonist, dihydropyridine, or betahistine in a component They are applied sequentially in any order. In certain embodiments, the salbutamol or levosalbutamol in the method provided by the present invention is administered simultaneously with a phosphodiesterase inhibitor, an adenosine receptor antagonist, dihydropyridine or betahistine. In some embodiments, the salbutamol or levosalbutamol and the phosphodiesterase inhibitor, adenosine receptor antagonist, dihydropyridine or betahistine are simultaneously in the form of a single pharmaceutical component in the method provided by the present invention. Apply sequentially.

In one embodiment, the method provided by the present invention comprises administering to a subject: (i) a xanthine compound, or an isotopic variant thereof (isotopically enriched not less than 50%), or a pharmaceutically acceptable salt thereof, Hydrate or solvent compound; (ii) dihydropyridine, or an isotopic variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof; (iii) betahist Ting, or its metabolite, or its isotopic variant (with an isotopic enrichment of not less than 50%), or its pharmaceutically acceptable salt, hydrate, or solvent compound; and (iv) salbutamol, or its enantiomer Isomers, or a mixture of enantiomers thereof, or levosalbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound thereof.

In certain embodiments, the albuterol or levosalbutamol and the xanthine compound, dihydropyridine, or betahistine in the methods provided by the present invention can be administered simultaneously or sequentially in any order of the components. In some embodiments, the albuterol or levosalbutamol in the method provided by the present invention is administered simultaneously with a xanthine compound, dihydropyridine, or betahistine. In some embodiments, the albuterol or levosalbutamol in the method provided by the present invention is administered sequentially with a xanthine compound, dihydropyridine, or betahistine in the form of a single pharmaceutical component.

In one embodiment, the method provided by the invention comprises administering aminophylline or theophylline to a subject. In another embodiment, the present invention provides a method comprising administering nifedipine to a subject. In yet another embodiment, the present invention provides a method comprising administering betahistone or betahistine hydrochloride to a subject. In yet another embodiment, the method provided by the present invention comprises administering an albuterol, albuterol hydrochloride, a levbutalol or a levarterol hydrochloride to a subject.

In one embodiment, the method provided by the invention comprises administering (i) aminophylline or theophylline and (ii) nifedipine to a subject. In another embodiment, the present invention provides a method comprising administering (i) aminophylline or theophylline to a subject; and (ii) betahistine or betahistine hydrochloride. In yet another embodiment, the method provided by the present invention comprises administering (i) aminophylline or theophylline to a subject; and (ii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride. In yet another embodiment, the present invention provides a method comprising administering (i) nifedipine to a subject; and (ii) betahistine or betahistine hydrochloride. In yet another embodiment, the method provided by the invention comprises administering (i) nifedipine to a subject; and (ii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride. In yet another embodiment, the method provided by the invention comprises administering (i) betahistine or betahistine hydrochloride to a subject; and (ii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride.

In one embodiment, the invention provides a method comprising administering (i) aminophylline or theophylline to a subject; (ii) nifedipine; and (iii) betahistine or betahistine hydrochloride. In another embodiment, the method provided by the present invention comprises administering (i) aminophylline or theophylline to a subject; (ii) nifedipine; and (iii) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride . In yet another embodiment, the method provided by the invention comprises administering (i) aminophylline or theophylline to a subject; (ii) betahistine or betahistine hydrochloride; and (iii) salbutamol, Salbutamol hydrochloride, levosalbutamol or levosalbutamol hydrochloride.

In one embodiment, the method provided by the present invention comprises administering (i) aminophylline or theophylline to a subject; (ii) nifedipine; (iii) betahistine or betahistine hydrochloride; And (iv) salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride.

In some embodiments, the weight ratio of theophylline to nifedipine in the method provided by the present invention ranges from about 1 to about 180, about 2 to about 100, about 2 to about 50, or about 2 to about 20. In some embodiments, in the method provided by the present invention, the weight ratio of theophylline to nifedipine ranges from about 1 to about 180. In some embodiments, in the method provided by the present invention, the weight ratio of theophylline to nifedipine ranges from about 2 to about 100. In some embodiments, in the method provided by the present invention, the weight ratio of theophylline to nifedipine ranges from about 2 to about 50. In some embodiments, in the method provided by the present invention, the weight ratio of theophylline to nifedipine ranges from about 2 to about 20. In certain embodiments, in the method provided by the present invention, the weight ratio of theophylline to nifedipine is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18 Or about 20.

In certain embodiments, in the method provided by the present invention, the weight ratio of theophylline to betahistine ranges from about 2 to about 200, about 4 to about 100, about 5 to about 50, or about 10 to about 30. In certain embodiments, in the method provided by the present invention, the weight ratio of theophylline to betahistine is about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, About 26, about 28, or about 30.

In certain embodiments, in the method provided by the present invention, the weight ratio of theophylline to salbutamol or levosalbutamol ranges from about 1 to about 1,000, about 10 to about 500, about 20 to about 400, or about 40 to about 300. In certain embodiments, in the method provided by the present invention, the weight ratio of theophylline to salbutamol or levosalbutamol is about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180, about 180, about 200, about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, in the method provided by the present invention, the weight ratio of nifedipine to betahistine ranges from about 1 to about 50, about 1 to about 40, about 1 to about 20, or about 1 to about 10 . In some embodiments, in the method provided by the present invention, the weight ratio of nifedipine to betahistine is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, About 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.

In some embodiments, in the method provided by the present invention, the weight ratio of nifedipine to salbutamol or levosalbutamol ranges from about 1 to about 100, about 5 to about 50, or about 5 to about 20. In some embodiments, in the method provided by the present invention, the weight ratio of nifedipine to salbutamol or levosalbutamol is about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 , About 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, in the method provided by the present invention, the weight range ratio of betahistine to salbutamol or levosalbutamol ranges from about 1 to about 100, about 1 to about 50, about 1 to about 30 or about 1 to about 20. In certain embodiments, in the method provided by the present invention, the weight ratio of betahistine to salbutamol or levosalbutamol is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8 , About 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the method provided by the present invention comprises administering aminophylline to a subject in an amount that is less than when the drug is administered alone. In certain embodiments, the methods provided by the present invention include administering aminophylline (micronized or non-micronized) to a subject, the daily dosage of which ranges from about 1 to about 1200, about 1 to about 1000, about 1 to about 800, about 1 to about 600, about 1 to about 400, about 1 to about 300, about 1 to about 200, about 1 to about 100, about 1 to about 90, about 1 to about 80, about 1 to about 70, About 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, or about 1 to about 10 mg / day.

In certain embodiments, the methods provided by the present invention include administering theophylline (micronized or non-micronized) to a subject in a dosage that is less than when the drug is administered alone. In certain embodiments, the methods provided by the present invention include administering theophylline to a subject in a daily dosage range of about 1 to about 1200, about 1 to 1000, about 5 to about 800, or about 10 to about 600 Mg / day. In certain embodiments, the methods provided by the invention include administering theophylline to a subject in a daily dosage range of about 1 to about 1200 mg / day. In certain embodiments, the methods provided by the invention include administering theophylline to a subject in a daily dosage range of about 1 to about 1000 mg / day. In certain embodiments, the methods provided by the present invention include administering theophylline to a subject in a daily dosage ranging from about 5 to about 800 mg / day. In certain embodiments, the methods provided by the present invention include administering theophylline to a subject at a daily dosage ranging from about 20 to about 600 mg / day. In certain embodiments, the methods provided by the present invention include administering theophylline to a subject at a daily dosage of about 20, about 50, about 75, about 100, about 125, about 150, about 175, about 200 About 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, or about 600 mg / day.

In certain embodiments, the methods provided by the present invention include administering nifedipine (micronized or non-micronized) to a subject in a dose that is less than when the drug is administered alone The amount. In certain embodiments, the methods provided by the present invention include administering nifedipine to a subject at a daily dosage ranging from about 0.1 to about 200, about 1 to about 100, or about 2 to about 60 mg / day. In certain embodiments, the methods provided by the present invention include administering nifedipine to a subject at a daily dosage ranging from about 0.1 to about 200 mg / day. In certain embodiments, the methods provided by the present invention include administering nifedipine to a subject at a daily dosage ranging from about 1 to about 100 mg / day. In certain embodiments, the methods provided by the present invention include administering nifedipine to a subject at a daily dosage ranging from about 2 to about 60 mg / day. In certain embodiments, the methods provided by the present invention include administering nifedipine to a subject at a daily dosage of about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg / day.

In certain embodiments, the methods provided by the invention include administering (i) aminophylline or theophylline, (ii) nifedipine, (iii) betahistine, and (iv) salbutamol or left Salbutamol; wherein the content of aminophylline or theophylline ranges from about 1 to about 1000 mg / day, the content of nifedipine ranges from about 0.1 to about 180 mg / day, and the content of betahistine ranges from about 1 to about 100 mg / day, and salbutamol or levosalbutamol levels range from about 0.1 to about 32 mg / day.

In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, and (iii) betahistine may be administered simultaneously or in any of the components. Apply sequentially. In certain embodiments, in the methods provided by the invention, (i) aminophylline or theophylline, (ii) nifedipine, and (iii) betahistine are administered simultaneously. In certain embodiments, in the method provided by the present invention, (i) aminophylline or tea The base, (ii) nifedipine, and (iii) betahistine are administered sequentially as a single pharmaceutical component.

In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, and (iii) salbutamol or levosalbutamol can be administered together simultaneously or in any order of components And applied sequentially. In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, and (iii) salbutamol or levosalbutamol are administered simultaneously. In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, and (iii) salbutamol or levosalbutamol are administered sequentially as a single pharmaceutical component.

In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) betahistine and (iii) salbutamol, salbutamol levosalbutamol, or levosalbutamol hydrochloride can be administered simultaneously. Or, they can be applied sequentially in any order of the components. In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) betahistine and (iii) salbutamol, salbutamol hydrochloride, levosalbutamol or levosalbutamol . In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) betahistine and (iii) salbutamol, salbutamol hydrochloride, levosalbutamol or levosalbutamol hydrochloride as a single drug The components are applied sequentially.

In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, (iii) betahistine or betahistine hydrochloride, and (iv) ) Salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride can be applied together simultaneously or sequentially in any order of the components. In some embodiments, in In the method provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, (iii) betahistine or betahistine hydrochloride, and (iv) salbutamol, salbutamol hydrochloride, and levosalbutamol Or levosalbutamol hydrochloride is administered together. In certain embodiments, in the methods provided by the present invention, (i) aminophylline or theophylline, (ii) nifedipine, (iii) betahistine or betahistine hydrochloride, and (iv) ) Salbutamol, salbutamol hydrochloride, levosalbutamol, or levosalbutamol hydrochloride are administered sequentially as a single pharmaceutical component.

In certain embodiments, it includes administering to a subject a combination drug provided by the present invention. In certain embodiments, the combination drug is administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), four times daily (QID), five times daily or six times daily. In certain embodiments, the combination drugs provided by the present invention are administered once daily. In certain embodiments, the combination drugs provided by the present invention are administered twice daily. In certain embodiments, the combination drugs provided by the invention are administered three times daily. In certain embodiments, the combination drugs provided by the invention are administered four times daily. In certain embodiments, the combination drugs provided by the present invention are administered orally. In certain embodiments, the combination drug is administered as an oral capsule or tablet.

In certain embodiments, the method provided by the present invention, wherein the administration time comprises administering to the subject a combination drug containing each active ingredient before a meal. In certain embodiments, the methods provided by the present invention include administering to a subject a combination drug containing each active ingredient after a meal.

In certain embodiments, the method for treating cerebrovascular thrombosis provided by the present invention comprises administering to a subject a combination drug containing each active ingredient before bedtime. In certain embodiments, the method for treating cerebrovascular thrombosis provided by the present invention comprises administering a combination drug containing each active ingredient to a subject in the morning and before bedtime. In some embodiments, the method for treating cerebrovascular thrombosis provided by the present invention comprises administering to the subject in the morning, noon, and before bedtime a combination drug containing each active ingredient. In certain embodiments, the methods provided by the present invention for treating cerebrovascular thrombosis include administering a combination drug containing each active ingredient to a subject at about 6 am, 2 pm, and 10 pm. In certain embodiments, the method for treating cerebrovascular thrombosis provided by the present invention comprises administering to the subject about 4 to 8 am in the morning a combination drug containing each active ingredient. In some embodiments, the method for treating cerebrovascular thrombosis provided by the present invention comprises administering a combination medicine containing each active ingredient to a subject from noon to 4 pm. In some embodiments, the method for treating cerebrovascular thrombosis provided by the present invention comprises administering a combination drug containing each active ingredient to a subject from 8 pm to midnight during sleep time.

In certain embodiments, the recipient is a mammal. In certain embodiments, the recipient is a human.

The methods provided by the present invention are suitable and include a subject or patient of any age, although certain diseases or conditions are more common in certain age groups. Depending on the patient's disease and condition, the active compounds in the combination can be taken orally, parenterally (e.g. intramuscularly, intraperitoneally, intravenously, ICV, intracavity or infusion, subcutaneous injection or implantation), inhalation , Nasal, vaginal, rectal, sublingual or topical (e.g. transdermal or topical) routes of administration, and can be formulated alone or together in suitable dosage units suitable Administration is in the form of a pharmaceutically acceptable carrier for each route of administration.

However, it should be understood that for any particular subject or patient, the specific dosage and the frequency of a certain dosage may vary, and the dosage will depend on various factors, including the specific active ingredient used, the metabolism of the active ingredient Stability and duration of action, age, weight, general health, gender, diet, mode and time of administration, excretion rate in combination with other drugs, the severity of the patient's specific condition, and acceptable treatment.

In certain embodiments, the invention provides kits that can be used by a physician to simplify the way in which an active ingredient is administered. In certain embodiments, the kit provided by the present invention includes a container and a dosage form of the active combination drug provided by the present invention or a combination drug provided by the present invention comprising one or more components.

The kit provided by the present invention may further include a device that can be used for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringe drip bags, patches, and inhalers.

The kit provided by the present invention may further include a pharmaceutically acceptable carrier that can be used for the administration of one or more active ingredients. For example, if the active ingredient is provided in solid form and must be reconstituted for parenteral administration, the kit may contain a sealed container of a suitable carrier in which the active ingredient can be dissolved and formed into a sterile solution without particles, which is suitable for parenteral Dosing. Examples of pharmaceutically acceptable carriers include, but are not limited to, aqueous carriers, including but not limited to water for injection, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection Liquid and lactated Ringer injection; water-miscible carriers, including but not limited to ethanol, polyethylene glycol, and polypropylene glycol Alcohol; and non-aqueous carriers, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The method for treating cardiovascular disease and the combination medicine disclosed, disclosed and provided by the present invention will be further understood through the following examples, and are not limited thereto.

Examples

Example 1: Combination of two active ingredients

An example provided by the present invention. When using the prescription drugs aminophylline (a phosphodiesterase inhibitor and adenosine receptor antagonist commonly used to treat asthma) and clenbuterol (a beta ₂ agonist that can be used to treat asthma) to treat patients with bronchiectasis A significant increase in heart rate was observed in the combination of these two drugs. Observation of this unwanted side effect (significant increase in heart rate) was caused by the sharing of aminophylline and clenbuterol, leading to a hypothesis. The combination of aminophylline and clenbuterol may also be used for Treat bradycardia. To test this hypothesis, an experiment was designed and conducted. The experiment was initially given to a group of volunteers with a combination of aminophylline and clenbuterol hydrochloride. During the experiment, it was observed that after giving the two combination drugs for about 2-3 hours, the subject's heart rate increased by 5-6 times per minute. The effect can last for about 6 to 8 hours. For each patient in this example, an electrocardiogram (ECG) was used to monitor heart rate and AV for conduction abnormalities.

In the example provided by the present invention, although the observed increase in heart rate of 5-6 times per minute is not as great as that normally achieved with pacemaker implantation, the increase in heart rate by the two combination drugs is still significant. In particular, there are currently no approved drugs for treating bradycardia. These bradycardia patients do not have or cannot access Subject to a pacemaker. These two combination drugs were therefore tested in bradycardia patients, and in this example it was observed that the average heart rate of patients treated with these two combinations increased 5-6 times per minute.

Example 2: Combination of three active ingredients

The invention provides yet another example. To further improve the effective effect of the aminophylline and clenbuterol combination on heart rate, a number of active pharmaceutical ingredients were tested. Without being bound by theory, the hypothesis in this experiment is to add other drug varieties to this combination formula. The drug varieties have a mechanism of action (also known as side effects) similar to aminophylline and clenbuterol and can further increase heart rate and heart Output. The additive and synergistic effects of several drugs are used to enhance their therapeutic effects. The combination of oryzanol, nicotinamide or anisodamine with aminophylline and clenbuterol was tested in a volunteer group, but no further improvement was observed.

In yet another example provided by the present invention, nifedipine (calcium channel blocker) is selected and tested. Although the main indication of nifedipine is vasospasm angina pectoris and chronic stable angina pectoris, when nifedipine is used in combination with aminophylline and clenbuterol when tested on a volunteer group, its effects lead to heart rate The results are better than those of Example 1. The recipient's heart rate can increase 7-9 times per minute 2 to 3 hours after administration of the three combination drugs. The effect of increased heart rate can last for about 6 to 8 hours. Patients with symptomatic sinus bradycardia were then tested for a combined trial of the three drugs. It has been observed that the average heart rate of bradycardia patients can increase 7-9 times per minute.

Example 3: Combination of four active ingredients

The invention provides yet another example. During the treatment of vertigo patients, a significant increase in the heart rate of the patients after the administration of betahistine was observed. Although betahistine is often used to treat patients with disorders of balance or to relieve the symptoms of vertigo associated with Meniere's disease, it has not been used to treat bradycardia. Based on this observation, betahistine was selected as one of the potential APIs for bradycardia. Betastatin, aminophylline, clenbuterol, and nifedipine were then tested on a small number of healthy volunteers. The results of their recipients showed that the heart rate could increase 10 times or more per minute. The combination of the four drugs was then further tested in patients with bradycardia. Test results for bradycardia patients show that heart rate can increase 10 or more times per minute.

In the example provided by the present invention, during the combination test of the above four drugs on bradycardia patients, some patients observed some adverse side effects. These side effects include hand tremors and twitching gastrocnemius muscles. Therefore, further research determines how to avoid or reduce such side effects. After careful investigation, these side effects were found to be related to clenbuterol. To confirm this phenomenon, clenbuterol was replaced with salbutamol hydrochloride in a combination of the above four drugs. Since salbutamol hydrochloride has a similar effect on increasing heart rate. As a result, it was found that the replacement of clenbuterol with salbutamol hydrochloride significantly reduced or eliminated side effects (hand tremor and spastic gastrocnemius muscle). Electrocardiogram monitoring of the recipients showed that patients' heart rate could be increased by 10 or more times per minute with the improved combination of the four drugs. With this improvement, the therapeutic effect on patients with bradycardia is preserved, and adverse side effects can be minimized or eliminated.

In more examples provided by the present invention, the combination of the above four drugs has been further improved to achieve better curative effects, and the improvements include: (1) aminophylline by tea Alkaline substitution, this is because aminophylline causes the degradation of another active ingredient in the combination drug and affects the stability of the combination drug; (2) salbutamol (50% R-salbutamol and 50% S-salbutamol) is activated by L- Salbutamol (purity 100% R-salbutamol) is substituted because (S) -salbutamol is inert or has some side effects, only (R) -salbutamol is considered to have the required pharmacological activity; and (3) micronized theophylline and nitrate Bendipine is administered for the purpose of enhancing its biological absorption and utilization.

Example 4: Formulation development of a combination drug with four active ingredients

The preparation of the combination medicine provided by the present invention is prepared by research and development according to the current Good Manufacturing Practice (CGMPs). Its active ingredients include micronized theophylline (API-1), micronized nifedipine (API-2), betahistine dihydrochloride (API-3), and levosalbutamol hydrochloride (API-4). The preparation process includes firstly mixing L-salbutamol hydrochloride (API-4) with 10% (weight percent) of microcrystalline cellulose for 5 minutes. Micronized nifedipine (API-2) and 20% total microcrystalline cellulose were added and the resulting mixture was blended for 5 minutes. Betahistine dihydrochloride (API-3) and 30% microcrystalline cellulose were then added and the resulting mixture was mixed for 5 minutes. Micronized theophylline (API-1) and 40% microcrystalline cellulose were added and the resulting mixture was mixed for 5 minutes. Add mannitol, sodium starch glycolate, colloidal silica and citric acid, followed by magnesium stearate. The resulting mixture was mixed for an additional 5 minutes and formulated into capsules with a size of 000, 00, 0, 1, 2, 3, 4 or 5 and each micronized API was prepared by jet milling.

Example 5: Quality control of combination drugs

Various analytical methods for all active ingredients of the combination drugs provided by the present invention have been developed and fully qualified. It is mainly used to identify and quantify the active ingredients and their stability in the combined drugs. Follow US and global drug standards. A quantitative analysis method was developed for the identification and quantitative analysis of active ingredient-1 (API-1) and active ingredient-2 (API-2) by high performance liquid chromatography (HPLC). Yet another quantitative analysis method is also used for the identification and quantitative analysis of active ingredient-3 (API-3) and active ingredient-4 (API-4) by high performance liquid chromatography. The reference standards are United States Pharmacopeia (USP) grade reference standards for quantitative analysis and identification of combination drugs.

The solubility measurement of the combination drug provided by the present invention uses a solubility measurement device conforming to the US Pharmacopoeia. Distek 5100 dissolution device is used for the solubility determination of active ingredient-1 and active ingredient-2. The Hanson Sr8-Plus dissolution device is used to determine the solubility of Active Ingredient-3 and Active Ingredient-4.

Several batches of combination drugs provided by the present invention have been prepared. Stability studies of combination drugs were conducted in accordance with US and International Council for Harmonisation (ICH) guidelines. (1) Preferred conditions: 25 ℃ ± 2 ℃, relative humidity (RH) 60% ± 5%; (2) acceleration bar Pieces: 40 ℃ ± 2 ℃, relative humidity 75% ± 5%; or (3) intermediate conditions: 30 ℃ ± 2 ℃, relative humidity 65% ± 5%. Stability studies were performed under accelerated conditions at a temperature of 40 ° C ± 2 ° C and a relative humidity of 75% ± 5% for 6 months, and under the preferred conditions of a temperature of 25 ° C ± 2 ° C and a relative humidity of 60% ± 5%. 24 months. The combination has been stable for more than 2 years and therefore meets the guidelines of the US and International Drug Regulatory Commission.

Example 6: Animal cardiovascular evaluation of a combination of four active ingredients

In more examples provided by the present invention, the cardiovascular evaluation of a combination drug containing four active ingredients has been performed in an animal of a Beagle (a puppy). It is administered orally and tested and evaluated. The test animals selected were 5 male experimental non-naive beagle dogs, aged between about 1 year, 8 months to 1 year, and 11 months of age. Prior to selected animal testing studies, all animals were medically examined. Weigh animals regularly and observe general health and any signs of disease. Baseline cardiovascular telemetry monitoring (temperature, blood pressure, heart rate, and electrocardiogram) was performed. An electrocardiogram (ECG) atlas of the 24-hour baseline cardiovascular monitoring period of all animals was evaluated to exclude electrophysiological abnormalities of the heart and determine the suitability of the study. Blood samples were collected from all animals for pre-tests to assess clinical chemistry and hematology parameters. All animals selected for study were considered suitable for this experiment based on test evaluation.

In the example provided by the present invention, the experimental results of animal cardiovascular evaluation show that no relevant abnormal clinical signs were observed after the Beagle dog received the combination drug containing the four active ingredients provided by the present invention. Clinical observation signs include weight, body temperature, systolic blood pressure, diastolic blood pressure and mean arterial pressure, heart rate, RR interval, PR interval Period, WRS duration, QT interval and corrected QT interval, and electrocardiogram.

In the animal cardiovascular evaluation experiment provided by the present invention, at the test dose, after the beagle dogs were acutely orally administered the combination drug containing the four active ingredients of the present invention, there was no lethality, and the body temperature, QTc or ECG No qualitative aspects were associated with abnormal clinical signs or effects.

In the animal cardiovascular evaluation experiment provided by the present invention, the combination drug containing the four active ingredients at the test dose produces a dose-independent decrease in blood pressure and a slight increase in QRS duration. At all tested dose levels, a significant increase in dose-related heart rate was observed, which resulted in changes in ECG parameters (RR, PR, and QT) and heart rate.

Example 7: Formulation design of a combination drug with four active ingredients

The combination drug containing four active ingredients provided by the present invention, and several dosage forms thereof have been designed and prepared as shown in Table 2. Low-dose combination drugs are designed to treat early bradycardia; medium-dose combination drugs are designed to treat symptomatic sinus patients; and high-dose combination drugs are mainly used to treat Patients with severe symptoms of sinus or AV block.

Example 8: Cardiovascular Assessment of Four Active Ingredient Combination Drugs in Healthy Volunteers

In the example provided by the present invention, the cardiovascular evaluation of the combination drug of the four active ingredients in Example 7 was performed, and two healthy volunteers participated in the experiment. In order to obtain a baseline heart rate (HR), two volunteers performed heart rate tests at 7 am, 10 am, and 6 pm, rested for 10 minutes before each measurement, and recorded HR at each time point (3 per day). Time point), 3 consecutive days.

In the example provided by the present invention, the average value of the baseline measurement of the heart rate (HR) of each volunteer was calculated before the administration. Several oral formulations were tested. Each volunteer was orally administered three times a day at 7 o'clock, 15 o'clock, and 22 o'clock, taking 2 capsules each time. The dose range is as shown in the intermediate dose in Table 2 above. Each volunteer was administered for 3 consecutive days. The measured heart rate after dosing was the same as the time recorded at the baseline heart rate (7 o'clock, 10 o'clock, and 18 o'clock). Then calculate and record the average heart rate of each volunteer. In order to avoid interference with legacy drugs or have an impact on the next drug, the two volunteer recipients did not wait for 7 days after completing each type of preparation. The experimental results are summarized in Tables 3 to 5 below.

Table 3. Baseline heart rate of healthy volunteers

The experimental results provided by the present invention are shown in Table 4. The heart rate of healthy volunteers before administration was compared with that when receiving placebo, and the baseline heart rate (HR) per beat was compared with the measured value when receiving placebo. No significant change. However, as shown in Table 5 above, the heart rate of the healthy volunteer recipients before receiving the combination drug developed by the present invention is 15 times higher per minute (BPM) than that before the administration of the combination drug; the volunteer recipients The heart rate of 2 increases 18 times per minute (BPM).

Example 9: Cardiovascular assessment of a combination of four active drugs in patients with bradycardia

The present invention provides evaluation of a combination of four active drugs as shown in Example 3 in patients with bradycardia, and the results are summarized in Table 6 below. The combination of the four active drugs provided by the present invention is used to treat bradycardia patients, and bradycardia symptoms disappear or are reduced, including chest pain, chest tightness, confusion or memory problems, dizziness, fatigue, shortness of breath, and syncope are all improved .

Example 10: Clinical trial of a combination of four active ingredients in patients with symptomatic sinus bradycardia

A combination of four active ingredient drugs (shown in Table 2 above) provided by the present invention in a single incremental administration in patients with symptomatic sinus bradycardia has been performed. Its clinical trial is mainly to determine the safety of its composition and the maximum dose for administration. Patients with peptic ulcer disease, epilepsy, or arrhythmia were excluded from the clinical trial. Patients with asthma taking beta-agonists and / or theophylline are also excluded.

In the example provided by the present invention, a total of 18 patients in clinical trials were divided into six groups, whose age was about 18 to 80 years, and the average heart rate of the patients 50 times / minute. No random grouping. There are 3-4 patients with symptomatic sinus bradycardia in each group. Each patient received a combination drug containing four active ingredients as described in Example 7 orally.

In the example provided by the invention, on the day of dosing, the clinical trial subject was monitored with a Holter monitor for 2 hours to establish a baseline. After administration, the recipient was continuously monitored with a Holter monitor for at least 22 hours. Before the alkane is discharged, each patient also needs to perform 12-lead ECG monitoring.

In the example provided by the present invention, the clinical trial is started from the lowest dose There are 6 doses from the highest dose. The initial cohort is performed in a staggered manner to determine when there is no effect on blood pressure or heart rate. Go to the next recipient. Specifically, only one recipient was started on the first day of the trial, and then monitored by a Holter monitor and a 12-lead electrocardiogram. 24 hours after the first recipient was administered, if no significant adverse effects were observed In response, the second recipient begins 24 hours after the first recipient, the third recipient begins 24 hours after the second recipient, and so on. For clinical safety, each recipient in the cohort was monitored for an additional 7 days.

In the example provided by the present invention, the clinical trial uses standard clinical assessment and objective measures to monitor and evaluate the safety of the clinical trial. Safety and tolerability assessments of all patients including adverse reactions (AE), physical examination, vital signs (such as systolic / diastolic blood pressure, heart rate, respiratory rate, and temperature), clinical laboratory tests, digital dynamic ECG monitoring Data (ECG) and local tolerance assessment scale.

In the example provided by the invention, if little or no adverse effects are observed in the first cohort of the clinical trial, the clinical trial dose is increased to the next level. Once the effects on the heart rate and blood pressure of the subject are observed, the dose is increased in smaller steps to ensure that the dose is safe for the subject. Recipients can participate in clinical trials at multiple dose levels, and more than 7 days after the previous clinical trial administration, that is, the previous drug has been cleared. High doses are primarily designed for patients with atrioventricular block bradycardia and may not be suitable for patients with sinus bradycardia.

The above examples provide a complete disclosure for those skilled in the art and how to make and use them. They do not limit the scope of the disclosure of the present invention. Around. For those who have ordinary knowledge in the technical field to adopt the specific method disclosed above or modify the above-mentioned mode, the application should be within the scope of the patent application scope of the present invention. All publications, inventions, and invention applications cited herein are incorporated by reference into the present invention, as if each such publication, invention, or application was individually listed and incorporated by reference.

Claims (20)

A combination drug suitable for treating or ameliorating bradycardia or cardiovascular disease in a subject, the combination drug comprises: (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, and (ii) a calcium channel blocker Agent, (iii) a histamine H ₁ -receptor agonist, a histamine H ₂ -receptor agonist or a histamine H ₃ -receptor antagonist, (iv) a β ₂ -adrenergic receptor agonist, or a combination thereof One or more active compounds are rich in isotopes (isotope enrichment is not less than 50%); and (v) pharmaceutically acceptable excipients or excipients. A combination drug suitable for treating or ameliorating bradycardia or cardiovascular disease in a subject, wherein the combination drug includes: (a) any three of the following four independent compounds, wherein the independent compounds include: (i) Phosphodiesterase inhibitor or adenosine receptor antagonist, (ii) calcium channel blocker, (iii) histamine H ₁ -receptor agonist, histamine H ₂ -receptor agonist, or histamine H ₃ -A receptor antagonist, (iv) a β ₂ -adrenergic receptor agonist, or one or more of its active compounds is rich in isotopes (isotope enrichment is not less than 50%); and (b) a pharmaceutically acceptable excipient Or excipients. The combination drug according to item 1 or item 2 of the patent application scope, wherein the one or more active compounds are deuterated compounds (isotope enrichment is not less than 50%). The combination drug according to item 1 or item 2 of the scope of patent application, wherein the phosphodiesterase inhibitor or adenosine receptor antagonist is selected from the group consisting of abitriptan, amiloride, anagrelide, aspirin , Averin, Attilastron, Awanafil, Benfuralin, Bemarinin, Bemorandon, Benazepine Triazine, Bradixine, Buflomedil, Dibuturon, CC1088 , Cabalazol, captolastlast, cilostazol, roflumilast, rolipram, sildenafil, tadalafil, udinafil, vardenafil, vinpocetine, yellow Purine, methylxanthine, caffeine, doxofylline, diprophylline, aminophylline, choline theophylline, ptoflavin, oxaphylline, pentoxifylline, theobromine, theophylline, or theophylline Isotope variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate or solvent compound thereof. The combination drug according to item 1 or item 2 of the patent application scope, wherein the calcium channel blocker is selected from the group consisting of amlodipine, aradipine, aridipine, bannidipine, benidipine, cinidipine, Clevidipine, ifodipine, felodipine, irradipine, lacidipine, lercanidipine, manipipine, nicardipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pradipine , Dihydropyridine, clonidipine, daclidipine, dexamethasone, erodipine, flulotin, venidipine, nidipine, oladipine, osodipine, digoxin, levamidipine , Nifedipine, or an isotope variant thereof (with an isotopic enrichment of not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound. The combination drug according to item 1 or item 2 of the patent application scope, wherein the histamine H ₁ -receptor agonist, the histamine H ₂ -receptor agonist, or the histamine H ₃ -receptor The antagonist is selected from betazol, isoamylamine, betahistine, or a metabolite thereof, or an isotope variant (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent Compound. The combination drug according to item 1 or item 2 of the patent application scope, wherein the β ₂ -adrenergic receptor agonist is selected from the group consisting of salbutamol, bambuterol, bitoterol, clenbuterol, and non- Nototerol, formoterol, indacaterol, isoprenaline, oxinalin, odadrol, piobutrolol, procaterol, ritodrine, suchuanning, terbutaline , Vilantrol, levosalbutamol, or an isotope variant thereof (isotope enrichment is not less than 50%), or a pharmaceutically acceptable salt, hydrate, or solvent compound. The combination drug according to item 1 or item 2 of the patent application range, wherein the amount of the phosphodiesterase inhibitor or adenosine receptor antagonist ranges from 1 to 1000 mg, 1 to 800 mg, 1 to 600 mg, 2 to 500 mg, 10 to 300 mg, 10 to 200 mg, 10 to 100 mg, or 10 to 80 mg. The combination drug according to item 1 or item 2 of the patent application range, wherein the amount of the calcium channel blocker ranges from 0.1 to 150 mg, 0.1 to 100 mg, 0.2 to 60 mg, 1 to 30 mg, 1 to 20 mg or 1 to 10 mg. The combination drug according to item 1 or item 2 of the patent application scope, wherein the histamine H ₁ -receptor agonist, the histamine H ₂ -receptor agonist, or the histamine H ₃ -receptor The dosage of the antagonist is between 0.1 to 150 mg, 0.1 to 100 mg, 0.2 to 60 mg, 0.5 to 30 mg, 1 to 20 mg, or 1 to 10 mg. The combination drug according to item 1 or item 2 of the patent application range, wherein the amount of the β ₂ -adrenergic receptor agonist ranges from 0.01 to 60 mg, 0.05 to 40 mg, 0.05 to 20 mg, 0.1 To 10 mg, 0.1 to 5 mg, or 0.1 to 2 mg. The combination drug according to item 1 or item 2 of the scope of patent application, comprising: (i) theophylline, aminophylline or its isotopic variant (isotope enrichment is not less than 50%), calculated by weight percentage, which The dosage range is from 5 to 90% or 5 to 35%; (ii) nifedipine or its isotopic variant (isotope enrichment is not less than 50%), and its dosage range is from 1 to 20% by weight percentage Or 1 to 5%; (iii) Betahistine dihydrochloride, its metabolite or its isotopic variant (isotope enrichment is not less than 50%), and its amount ranges from 0.1 to 20 in weight percent % Or 1 to 5%; (iv) salbutamol hydrochloride, levosalbutamol hydrochloride or its isotope variant (isotope enrichment is not less than 50%), and its amount ranges from 0.01 to 5% or 0.1 to 0.5 in terms of weight percentage %; And (v) pharmaceutically acceptable excipients or excipients. The combination medicament according to item 1 or item 2 of the scope of patent application, wherein the pharmaceutical composition can be administered and administered in a single dose or multiple doses simultaneously, separately, or sequentially. The combination medicament according to item 1 or 2 of the scope of patent application, wherein the pharmaceutical composition can be formulated into a liquid, semi-liquid dosage form or solid dosage form. The combination drug according to item 1 or item 2 of the patent application scope, wherein the pharmaceutical composition can be formulated for oral, intravenous (IV) or intramuscular (IM) administration. The combination drug according to item 1 or 2 of the patent application scope, wherein the pharmaceutical composition can be formulated into an improved or extended release dosage form. Use of a combination medicine for preparing a medicine for treating or ameliorating abnormal heart rhythm and bradycardia of a recipient, comprising administering an effective dose to a recipient in need, as described in any one of claims 1 to 16 of the scope of patent application Combination drug as described above. Use of a combination drug in the preparation of a medicament for increasing the heart rate, cardiac output or cerebral blood flow of a subject, including administering an effective dose to a subject in need, such as any one of claims 1 to 16 of the scope of patent application The combination drug. Use of a combination drug for the manufacture of a medicament for treating or ameliorating a cardiovascular disease in a subject, comprising administering to a subject in need thereof an effective dose of a combination as described in any one of claims 1 to 16 of the scope of patent application drug. Use of the combination drug according to item 19 of the scope of patent application in the manufacture of a medicament for treating or improving cardiovascular disease in a subject, wherein the cardiovascular disease is bradycardia, symptomatic sinus bradycardia, ventricular Bradycardia, atrial bradycardia, arrhythmia, abnormal heart rhythm, cardiac block, atrioventricular block, heart failure, sinus arrest, or sinus exit block.