CN110812344A - Pharmaceutical composition for treating diabetes complicated with angina pectoris and preparation method thereof - Google Patents
Pharmaceutical composition for treating diabetes complicated with angina pectoris and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition for treating diabetes complicated with angina pectoris, which comprises a slow release part and a quick release part, wherein the slow release part comprises ranolazine, ranolazine hydrochloride or pharmaceutical salt of ranolazine, and the quick release part comprises acarbose. The pharmaceutical composition disclosed by the invention realizes the treatment of complicated symptoms of diabetes complicated with angina pectoris, can play the roles of two drugs simultaneously, and can play a synergistic treatment effect.
Description
FIELD
The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition for treating diabetes complicated with angina.
Background
Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by a defect in insulin secretion or an impaired biological action, or both. Hyperglycemia occurring in diabetes over a long period of time leads to various complications such as chronic damage to various tissues, particularly eyes, kidneys, heart, blood vessels, nerves, dysfunction, and the like.
Diabetes complications can be classified into acute and chronic types according to their difference in pathology and urgency.
Causes of acute complications of diabetes mellitus: the disease causes are mainly hyperglycemia caused by severe deficiency of insulin activity and improper rise of glycemic hormone, and the metabolic disturbance of sugar, fat and protein is caused, so that the balance of water, electrolyte and acid-base of the body is disordered.
The etiology of chronic complications of diabetes mellitus, chronic complications are the main causes of disability and death of diabetes mellitus, and mainly comprise ① macrovascular complications such as cerebrovascular, cardiovascular and lower limb vascular lesions and the like, ② microvascular complications such as renal lesions and fundus lesions, ③ neuropathy including sensory nerves responsible for sensory perception, motor nerves which govern physical activity, and autonomic neuropathy which governs visceral, vascular and endocrine functions and the like.
The more serious diabetic complications mainly comprise diabetic complication cardiovascular complications: including microangiopathy, cardiomyopathy and autonomic neuropathy of the heart and great vessels, leading to death of diabetic patients. Coronary heart disease is the main macrovascular complication of diabetes, and researches show that the death risk of the coronary heart disease of diabetic patients is 3-5 times higher than that of non-diabetic patients. The pathological mechanism of the medicine is atherosclerosis, and the risk factors of the diseases include hyperglycemia, high systolic pressure, high cholesterol, high low density lipoprotein increase, high density lipoprotein decrease, age, sex, smoking and family history.
The diabetic heart disease comprises diabetic cardiac microangiopathy, macroangiopathy, cardiomyopathy, heart autonomic nerve dysfunction and the like, and the coronary artery disease of a diabetic patient is often diffuse and severe in stenosis degree, and can be manifested as angina pectoris, acute coronary syndrome, severe patients who can suffer from myocardial infarction, cardiogenic shock, sudden death and the like. It is noted that, since diabetic patients often have autonomic neuropathy, asymptomatic coronary heart disease is common or manifested as atypical symptoms such as fatigue, labored breathing difficulties, gastrointestinal symptoms, etc. It is also known that serious cardiac rhythm disorders, cardiogenic shock and sudden death occur unconsciously due to various stresses, infections, operative anesthesia, etc. Heart disease is the most common cause of death in diabetics.
According to studies, about 80% of patients with coronary heart disease have associated carbohydrate metabolism abnormalities, of which more than 50% have associated diabetes, while more than 50% of newly diagnosed patients with diabetes have coronary heart disease, and therefore, the two diseases often appear in the same patient, at which time the risk of cardiovascular events is significantly increased, and in many patients diabetes associated with angina pectoris, especially stable angina, is more common than other types of diabetic complications.
The main purposes of the current treatment of diabetes mellitus combined with angina pectoris are: preventing myocardial infarction and sudden death, and improving survival; relieving symptoms and ischemic attack, and improving life quality. In selecting a therapeutic drug, in addition to consideration of improving prognosis and relieving symptoms, blood glucose and other risk factors should be actively controlled.
The existing treatment medicines mainly comprise 1 medicine for relieving symptoms and improving ischemia, such as β receptor retarder, nitrate medicine and calcium antagonist, 2 medicine for improving prognosis, such as aspirin, statins and angiotensin converting enzyme inhibitor (ACE I), and 3 Chinese patent medicine for improving thirst and thoracic obstruction.
However, the current therapeutic drugs show that the therapeutic effect is not ideal, and the effect is not ideal only from the aspect of treating diabetes or angina pectoris.
In addition, ranolazine is the first choice of drugs for treating angina at present, has a unique action mechanism, has the effects of resisting myocardial ischemia, arrhythmia and heart failure, is approved by FDA in 2006-1 month, and is a ranolazine sustained-release film coated tablet with specifications of 500mg and 1000 mg. Ranolazine is a piperazine derivative that acts by partially inhibiting fatty acid metabolism, i.e., reducing fatty acid oxidation, and inducing glucose metabolism, and because glucose metabolism is more effective than fatty acid metabolism, it enables the heart to utilize oxygen more efficiently, because the regulatory mechanism of cardiac metabolism tends to convert energy metabolism substrates into glucose during myocardial ischemia, thereby increasing the efficiency of oxygen utilization. Glucose is now used as a substrate for energy metabolism and its utilization is increased because to produce the same energy, fatty acid oxidation requires more oxygen than glucose metabolism. Clinical tests and animal experiments show that the medicine can obviously improve the symptoms of angina patients and improve the exercise tolerance of the patients, and animals also find that the medicine can fully increase the cardiac ejection fraction and the myocardial oxygen consumption is reduced along with the increase of the ejection fraction. In view of the novel mechanism of action described above, oral ranolazine does not cause a slowing in heart rate and a drop in blood pressure. Can also prevent lactic acidosis and greatly enhance the use safety. The medicine is taken as the first choice medicine for treating angina pectoris at present.
SUMMARY
In one aspect, the present disclosure relates to a pharmaceutical composition for arteriosclerosis complicated with angina pectoris, which comprises a sustained-release part comprising ranolazine, ranolazine hydrochloride or a pharmaceutically acceptable salt of ranolazine, and an immediate-release part comprising acarbose.
In another aspect, the present disclosure relates to a method of preparing a pharmaceutical composition comprising the steps of
Dissolving the sustained-release part in an alkali solution, and granulating to obtain sustained-release granules;
mixing the immediate release portion with the sustained release granules.
Detailed description of the invention
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. Unless otherwise required by the disclosure, throughout the specification and the appended claims, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".
Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment, and furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
Definition of
In the present disclosure, the term "granulation" refers to a process of improving the flowability of a powder such that finer particles agglomerate into coarse powder aggregates. Granulation is the operation of processing the materials in the state of powder, melt, aqueous solution, etc. into granules with certain shape and size.
In the present disclosure, the term "acarbose" refers to a novel oral hypoglycemic agent. Competitively inhibits the glycoside hydrolase in the intestinal tract.
In the present disclosure, the term "microcrystalline cellulose" refers to a purified, partially depolymerized cellulose, white, odorless, tasteless, crystalline powder composed of porous microparticles, primarily used as a filler.
In the present disclosure, the term "corn starch" refers to a naturally occurring resistant starch, primarily used as a bulking agent.
In the present disclosure, the term "colloidal silicon dioxide" refers to a glidant in an amount that has a significant effect on the flowability of the blend, thereby affecting the production efficiency of dry granulation.
In the present disclosure, the term "ethyl methacrylate copolymer" refers to a novel acrylic resin, which has the advantages of stable physical and chemical properties, no toxicity, no irritation, etc., and is mainly used as a coating material for sustained and controlled release preparations, and related substances are mainly monomer components of methacrylic acid and ethyl acrylate.
In the present disclosure, the term "hydroxypropylmethylcellulose" has thermal gelling properties, aqueous solution has surface activity, high transparency, stable performance, and is mainly used as an adhesive.
In the present disclosure, the term "magnesium stearate" refers to a white, light, non-gritty fine powder, which is used primarily as a lubricant, with appropriate amounts of lubricant providing anti-sticking, flow-enhancing, and lubricating properties, but excess lubricant can soften the tablet, resulting in a decrease in tablet hardness, an increase in friability, and the hydrophobic magnesium stearate can also result in a delay in disintegration and a decrease in dissolution of the tablet.
In the present disclosure, the term "opadry" refers to a film coating material used to meet the coating needs of different tablet types.
In the present disclosure, the term "purified water" refers to water for medical use prepared by distilling drinking water, ion exchange, reverse osmosis or other suitable method, without any additives.
In the present disclosure, the term "mesh" refers to the unit of measure, and the unit of measure mesh size refers to the size of the particles of the feedstock, generally expressed as the maximum length of the particles. The mesh is the size representing the mesh size of a standard screen. In the taylor standard sieve, the so-called mesh is the number of sieve openings in a 1 inch length and is simply called mesh.
Detailed Description
In one aspect, the present disclosure relates to a pharmaceutical composition for arteriosclerosis complicated with angina pectoris, which comprises a sustained-release part comprising ranolazine, ranolazine hydrochloride or a pharmaceutically acceptable salt of ranolazine, and an immediate-release part comprising acarbose.
In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is about 5:1 to 20: 1.
In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is about 8:1 to 12: 1.
In certain embodiments, illustrative examples of pharmaceutically acceptable salts of ranolazine that can be used in the present disclosure include, but are not limited to, hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate and glutamate salts of ranolazine.
In certain embodiments, the sustained release portion further comprises microcrystalline cellulose and an ethyl methacrylate copolymer.
In certain embodiments, the immediate release portion further comprises microcrystalline fiber, corn starch, colloidal silicon dioxide, and magnesium stearate.
In certain embodiments, the pharmaceutical composition is a tablet, capsule, or granule.
In certain embodiments, the tablet is a bilayer tablet.
In certain embodiments, the capsule is a bi-directional release capsule.
In certain embodiments, the granule is a bi-directional release granule.
In another aspect, the present disclosure relates to a method of preparing a pharmaceutical composition comprising the steps of
Dissolving the sustained-release part in an alkali solution, and granulating to obtain sustained-release granules;
mixing the immediate release portion with the sustained release granules.
In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is 5:1 to 20: 1.
In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is 8:1 to 12: 1.
In certain embodiments, illustrative examples of pharmaceutically acceptable salts of ranolazine that can be used in the present disclosure include, but are not limited to, hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate and glutamate salts of ranolazine.
In certain embodiments, the sustained release portion further comprises microcrystalline cellulose and an ethyl methacrylate copolymer.
In certain embodiments, the immediate release portion further comprises microcrystalline fiber, corn starch, colloidal silicon dioxide, and magnesium stearate.
In certain embodiments, illustrative examples of alkali solutions that can be used in the present disclosure include, but are not limited to, sodium hydroxide solution, potassium carbonate solution, sodium carbonate solution, potassium hydrogen carbonate solution, sodium methoxide solution, and sodium ethoxide solution.
In some embodiments, the granulating further comprises mixing the sustained release portion with a high speed granulator.
In certain embodiments, the mixing time is about 5 to 8 min.
In some embodiments, the step of stirring is further included after the slow release portion is dissolved in the alkaline solution.
In certain embodiments, the stirring time is about 3 to 5 min.
In certain embodiments, a drying step is included after granulation.
In certain embodiments, the drying temperature is about 30 ℃ to 100 ℃.
In certain embodiments, the drying temperature is about 0 ℃ to 80 ℃.
In certain embodiments, the drying temperature is about 60 ℃.
In certain embodiments, the drying time is from about 30 to 50 minutes, or the pellet moisture is controlled to be 3.0% or less.
In certain embodiments, greater than 70% of the sustained release particles in the sustained release granules have a particle size of about 20 mesh to 80 mesh.
In some embodiments, mixing the immediate release portion with the sustained release granules further comprises making the immediate release portion into a tablet, capsule or granule.
In certain embodiments, the tablet is a bilayer tablet.
In certain embodiments, the capsule is a bi-directional release capsule.
In certain embodiments, the granule is a bi-directional release granule.
In certain embodiments, further comprising coating the tablet.
In certain embodiments, the coating is performed using opadry.
Example 1
The embodiment discloses a pharmaceutical composition for treating diabetes complicated with angina pectoris, the dosage form of the pharmaceutical composition is a double-layer tablet, and the preparation consists of the following components:
| composition (I) | Dosage/tablet |
| Ranolazine | 500mg |
| Acarbose | 50mg |
| Microcrystalline cellulose | 80mg |
| Corn starch | 60mg |
| Colloidal silica | 2mg |
| Ethyl methacrylate copolymer | 40mg |
| Hydroxypropyl methylcellulose | 8mg |
| Sodium hydroxide | 1.5mg |
| Magnesium stearate | 8.5mg |
| Opadry | 35mg |
| Purified water | 0.25mg |
The preparation process comprises the following steps:
1. the ranolazine, microcrystalline cellulose and ethyl methacrylate copolymer in the formula are uniformly mixed by a high-speed granulator.
2. Dissolving sodium hydroxide in purified water, adding into the above uniformly mixed materials, stirring, and granulating.
3. Drying at 60 deg.C to obtain sustained release granule.
4. Mixing acarbose, microcrystalline fiber, corn starch and colloidal silicon dioxide uniformly by using a high-speed granulator, adding magnesium stearate, and uniformly mixing by using a three-dimensional mixer for later use.
5. Firstly pressing the sustained-release granules and the acarbose mixed powder into a double-layer tablet, wherein the average main pressure of a tablet press is controlled to be 5.0-11.0 KN during tabletting, the tabletting rotating speed is set to be less than or equal to 30.0rpm, sampling is carried out to check the properties, weight difference, hardness and friability of the tablet core, the quality of the tablet core is confirmed to meet the requirements, and tabletting is carried out according to the confirmed tabletting parameters.
6. Coating with Opadry.
Example 2
The embodiment discloses a pharmaceutical composition for treating diabetes complicated with angina pectoris, the dosage form of the pharmaceutical composition is a double-layer tablet, and the preparation consists of the following components:
| composition (I) | Dosage/tablet |
| Ranolazine | 500mg |
| Acarbose | 62mg |
| Microcrystalline cellulose | 80mg |
| Corn starch | 60mg |
| Colloidal silica | 2mg |
| Ethyl methacrylate copolymer | 40mg |
| Hydroxypropyl methylcellulose | 8mg |
| Sodium hydroxide | 1.5mg |
| Magnesium stearate | 8.5mg |
| Opadry | 35mg |
| Purified water | 0.25mg |
The preparation process comprises the following steps:
1. the ranolazine, microcrystalline cellulose and ethyl methacrylate copolymer in the formula are uniformly mixed by a high-speed granulator.
2. Dissolving sodium hydroxide in purified water, adding into the above uniformly mixed materials, stirring, and granulating.
3. Drying at 60 deg.C to obtain sustained release granule.
4. Mixing acarbose, microcrystalline fiber, corn starch and colloidal silicon dioxide uniformly by using a high-speed granulator, adding magnesium stearate, and uniformly mixing by using a three-dimensional mixer for later use.
5. The sustained-release granules and the acarbose mixed powder are firstly pressed into a double-layer tablet.
6. Coating with Opadry.
Example 3
The embodiment discloses a pharmaceutical composition for treating diabetes complicated with angina pectoris, which is a dosage form capsule and consists of the following components:
the preparation process comprises the following steps:
1. the ranolazine, microcrystalline cellulose and ethyl methacrylate copolymer in the formula are uniformly mixed by a high-speed granulator.
2. Dissolving sodium hydroxide in purified water, adding into the above uniformly mixed materials, stirring, and granulating.
3. Drying at 60 deg.C to obtain sustained release granule.
4. Mixing acarbose, microcrystalline fiber, corn starch and colloidal silicon dioxide uniformly by using a high-speed granulator, adding magnesium stearate, and uniformly mixing by using a three-dimensional mixer for later use.
5. And then the materials are mixed evenly.
6. And filling the mixed material into hard capsules to obtain capsules.
Test data
The formulations prepared in examples 1-3 of the invention were tested for release profile using a suitable assay to simulate in vivo release conditions.
The dissolution test data of the drug-containing coated particles of examples 1-3 are shown in Table 1.
Table 1: data for the two drug release tests in examples 1-3 above
Results of pharmacodynamics experiments
1. Laboratory animals and groups
56 Wistar rats are randomized into 7 groups, each group comprises 8 rats, and the Wistar rats are divided into a model group, a blank group and a dosing group (a low dose group, a medium dose group and a high dose group), each group is injected with streptozotocin except the blank group, high-sugar and high-fat feed is given for 4 weeks after 10 weeks except the blank group, and simultaneously, small dose of streptozotocin is injected into the abdominal cavity for multiple times to cause insulin resistance and myocardial lesion, and dosing treatment is started at the 10 th week of modeling.
2. Administration plan
Except for the model group, each group was administered in the following specific manner.
| Group of | Classes of pharmaceutical compositions | Dosage of drug | Remarks for note |
| Blank group | — | 0 | Normal feeding without making mould |
| Model set | — | 0 | High-sugar and high-fat feed and its moulding |
| Single side 1 group | Ranolazine | 50mg | High-sugar and high-fat feed and its moulding |
| Single side 2 group | Acarbose | 5mg | High-sugar and high-fat feed and its moulding |
| Low dose group | Ranolazine + acarbose | 25mg+2.5mg | High-sugar and high-fat feed and its moulding |
| Middle dose group | Ranolazine + acarbose | 40mg+4.0mg | High-sugar and high-fat feed and its moulding |
| High dose group | Ranolazine + acarbose | 50mg+5.0mg | High-sugar and high-fat feed and its moulding |
3. Observation index
3.1 serum Nitric Oxide (NO), serum Endothelin (ET), serum lipid peroxide (MDA) and other related indexes
Note: comparison with model groups: p < 0.01, between-group comparison P > 0.05
3.2 Effect of drugs on blood glucose in rats of various groups
| Group of | n | Administration for 1 week | The administration is carried out for 2 weeks | Administration for 3 weeks |
| Blank group | 8 | 4.9±0.19 | 5.3±0.13 | 5.2±0.39 |
| Model set | 8 | 16.6±2.15 | 17.6±1.24 | 16.9±1.69 |
| Single side 1 group | 8 | 18.6±1.69 | 16.6±1.25 | 17.9±1.86 |
| Single side 2 group | 8 | 13.2±1.59 | 12.8±1.96 | 13.6±1.87 |
| Low dose group | 8 | 12.6±2.03* | 13.5±1.94* | 12.9±1.05* |
| Middle dose group | 8 | 11.6±1.22* | 12.6±1.07* | 11.9±1.23* |
| High dose group | 8 | 10.6±1.15* | 10.6±1.75* | 10.9±1.03* |
Note and model group comparison: p < 0.01, between-group comparison P > 0.05
As shown in pharmacodynamic experimental results, the dosage of ranolazine serving as a main drug can be greatly reduced compared with that of a single component group, and the compound component group with the reduced dosage can effectively exert the treatment effect, so that the side effect caused by the dosage effect of the drug can be reduced.
Therefore, the pharmaceutical composition disclosed in the disclosure realizes the treatment of complicated symptoms of diabetes complicated with angina pectoris, can exert the effects of two drugs at the same time, and can exert the treatment effect synergistically. The traditional Chinese medicine composition has the advantages of simple preparation and cost reduction, and can greatly reduce the medicine taking times so as to be more convenient to take.
From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the disclosure, and that such modifications or improvements are intended to be within the scope of the appended claims.
Claims (10)
1. A pharmaceutical composition for treating diabetes complicated with angina comprises a slow-release part and a quick-release part, wherein the slow-release part comprises ranolazine, ranolazine hydrochloride or the pharmaceutically acceptable salt of ranolazine, and the quick-release part comprises acarbose.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the sustained release portion to the immediate release portion is 5:1 to 20:1, more preferably 8:1 to 12:1, preferably the pharmaceutically acceptable salt of ranolazine is selected from the group consisting of hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate, glutamate or mixtures thereof of ranolazine.
3. The pharmaceutical composition according to claim 1 or 2, wherein the sustained release portion further comprises microcrystalline cellulose and ethyl methacrylate copolymer, preferably the immediate release portion further comprises quercetin, microcrystalline fiber, corn starch, colloidal silicon dioxide and magnesium stearate.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is a tablet, capsule or granule, preferably the tablet is a bilayer tablet, preferably the capsule is a dual release capsule, preferably the granule is a dual release granule.
5. The preparation method of the pharmaceutical composition comprises the following steps
Dissolving the sustained-release part in an alkali solution, and granulating to obtain sustained-release granules;
mixing the immediate release portion with the sustained release granules.
6. A method of preparing a pharmaceutical composition according to claim 5, wherein the extended release portion comprises ranolazine, ranolazine hydrochloride or a pharmaceutically acceptable salt of ranolazine, the immediate release portion comprises quercetin, preferably the weight ratio of the extended release portion to the immediate release portion is 10:1 to 20:1, preferably 12:1 to 15:1, preferably the pharmaceutically acceptable salt of ranolazine is selected from the group consisting of hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-toluenesulfonate, glutamate and mixtures thereof, preferably the extended release portion further comprises microcrystalline cellulose and ethyl methacrylate copolymer, preferably the immediate release portion further comprises quercetin, microcrystalline fiber, corn starch, colloidal silicon dioxide and magnesium stearate, preferably the alkaline solution is selected from the group consisting of sodium hydroxide solution, sodium hydroxide, sodium, Potassium hydroxide solution, potassium carbonate solution, sodium carbonate solution, potassium bicarbonate solution, sodium methoxide solution, sodium ethoxide solution, or a mixture thereof.
7. The method for preparing the pharmaceutical composition according to claim 5 or 6, wherein the slow release part is mixed by a high speed granulator before granulation, preferably the mixing time is 5 to 8min, preferably the slow release part is dissolved in the alkali solution and then the stirring step is included, preferably the stirring time is 3 to 5min, preferably the drying step is included after granulation, preferably the drying temperature is 30 ℃ to 100 ℃, more preferably 40 ℃ to 80 ℃, even more preferably 60 ℃, preferably the drying time is 30 to 50min, or the moisture of the granules is controlled to be less than or equal to 3.0%.
8. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 5 to 7 wherein more than 70% of the extended release particles have a particle size of 20 to 80 mesh.
9. The preparation method of the pharmaceutical composition according to any one of claims 5 to 8, wherein the mixing of the immediate release part and the sustained release granules further comprises the step of preparing the mixture into tablets, capsules or granules, preferably the tablets are double-layer tablets, preferably the capsules are bidirectional release capsules, and preferably the granules are bidirectional release granules.
10. A process for the preparation of a pharmaceutical composition according to claim 9, which further comprises coating the tablet, preferably with opadry.
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| CN1823795A (en) * | 2005-12-30 | 2006-08-30 | 刘展欣 | Medicinal composition for treating diabetes and its preparation method |
| US20060205727A1 (en) * | 2005-03-11 | 2006-09-14 | Wayne Kaesemeyer | Combination therapy for endothelial dysfunction, angina and diabetes |
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| CN101678017A (en) * | 2007-05-31 | 2010-03-24 | Cv医药有限公司 | Method of treating diabetes |
| US20130102555A1 (en) * | 2002-05-21 | 2013-04-25 | Gilead Sciences, Inc. | Method of treating diabetes |
| CN103285398A (en) * | 2013-06-28 | 2013-09-11 | 青岛黄海制药有限责任公司 | Compound preparation containing DPP-IV (dipeptidyl peptidase-IV) inhibitor and type-II diabetes medicine and preparation method thereof |
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| US20130102555A1 (en) * | 2002-05-21 | 2013-04-25 | Gilead Sciences, Inc. | Method of treating diabetes |
| US20060205727A1 (en) * | 2005-03-11 | 2006-09-14 | Wayne Kaesemeyer | Combination therapy for endothelial dysfunction, angina and diabetes |
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Address after: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant after: Zhuohe Pharmaceutical Group Co.,Ltd. Address before: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant before: Zhuohe Pharmaceutical Group Co.,Ltd. |
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