Patent Publication Number: US-10322157-B2

Title: Method of treatment of drug-resistance diabetes mellitus

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention is directed to a method of treatment of diabetes mellitus; in particular, to a method of treatment of drug-resistance diabetes. 
     2. Description of Related Art 
     The application of Chinese herbal medicine in treatment of cancer attracts significant attentions for a long time. In recent years, the Chinese herbal medicine is also gradually applied to treatment of some metabolic diseases, too. 
     Diabetes mellitus (or diabetes) is a metabolic disease, whose typical symptoms include high blood sugar levels over a prolonged period, and being difficult to maintain the normal value. Other diabetic syndromes and complications include but are not limited to polyphagia, polydipsia, polyuria, blurry vision, headache, fatigue, slow healing of wound, cardiovascular disease, stroke, chronic renal disease, foot ulcer, and retinopathy. 
     In present time, there is no effective medicine to cure diabetes but the general treatment simply ameliorates the conditions, including administration of hypoglycemic drug, improving diet, lifestyle, and weight loss. Regular diabetes drugs include Biguanides, Thiazolidinediones, Sulfonylureas, and Glycosurics. The effect of these medicines comprises improving sensitivity to insulin, increasing the amount of secretion of insulin, or increasing the excretion of sugar. 
     After intake of drug for a long period, the efficiency and the effective time of the drug might be decrease. This means that the subject of intake might acquire tolerance to the drug and have to consume more dose amount or increased frequency of intake to maintain the original pharmaceutical effect. After the tolerance is acquired, withdrawal symptoms might come after drug abstinence. Even if the alternative drug is administered, the blood sugar is still above the normal value. Therefore, it is necessary to develop new diabetes drug that can prevent drug tolerance and dependency without any withdrawal symptoms occurring. 
     SUMMARY OF THE INVENTION 
     One of the objectives of the present application is to provide a method for the treatment of diabetes mellitus. 
     Another objective of the present application is to provide a method of treatment of drug-resistance diabetes mellitus. 
     The method of treatment of drug-resistance diabetes mellitus, comprising administering a therapeutically effective amount of a Chinese herbal medicine to a subject in need; 
     wherein the Chinese herbal medicine is an extract of a first mixture comprising raw oyster shell powder, raw Os Draconis, Haematitum, Magnetitum, radix Achyranthis Bidentatae, rhizoma Dioscoreae, radix Paeoniae Rubra, radix Rehmanniae, and semen Platycladi. 
     In a preferred embodiment of the present invention, the preparation of the Chinese herbal medicine comprises following steps: 
     providing the first mixture; mixing the first mixture and water to form a second mixture; 
     heating the second mixture to obtain a crude extract; and 
     filtering the crude extract and retaining the liquid, to obtain the Chinese herbal medicine. 
     In a preferred embodiment of the present invention, the Chinese herbal medicine is the extract of the first mixture comprising 4-6 parts by weight of raw oyster shell powder, 4-6 parts by weight of raw Os Draconis, 7-9 parts by weight of Haematitum, 2-4 parts by weight of Magnetitum, 4-6 parts by weight of radix Achyranthis Bidentatae, 4-6 parts by weight of rhizoma Dioscoreae, 4-6 parts by weight of radix Paeoniae Rubra, 4-6 parts by weight of radix Rehmanniae, and 3-5 parts by weight of semen Platycladi. 
     In a preferred embodiment of the present invention, the part by weight of the first mixture is 3.75 gram per part for a daily dose. 
     In a preferred embodiment of present invention, the first mixture further comprises  Poria, Alisma  rhizome, rhizoma Gastrodiae, Herba Ephedrae, radix Rhubarb, rhizoma Drynariae, gypsum powder, radix Panax notoginseng, Rhizoma Coptidis, cortex Mori, or Radish seed, or the combination thereof. 
     In a preferred embodiment of present invention, the drug resistance is the resistance to Glimepiride, Pioglitazone, Glucobose, Metformin, Atorvastatin, or Zolpidem. 
     In a preferred embodiment of present invention, the treatment of the drug-resistance diabetes mellitus is the treatment of hyperglycemia, hyperlipidemia, and azotemia. 
     In a preferred embodiment of present invention, the Chinese herbal medicine is administered via oral administration, enteral administration, or intravenous injection. 
     In a preferred embodiment of present invention, the Chinese herbal medicine further comprises pharmaceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agents, thickening agent, or excipient, or the combination thereof. 
     Another objective of the present application provides a method of abstaining drug dependency of diabetes mellitus patient, comprising administering a therapeutically effective amount of Chinese herbal medicine to a subject in need; wherein the Chinese herbal medicine comprises the extract of a first mixture of raw oyster shell powder, raw Os Draconis, Haematitum, Magnetitum, radix Achyranthis Bidentatae, rhizoma Dioscoreae, radix Paeoniae Rubra, radix Rehmanniae, and semen Platycladi. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     The features of the present invention are set forth with particularity in the appended claims. A better understanding of the features and advantage thereof will be demonstrated by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are employed. 
     Certain Pharmaceutical and Medical Terminology 
     Unless otherwise specified, the following terms used in the specification and claims have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology can be employed. In this application, the use of “or” or “and” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Unless otherwise indicated, all materials employed in the present invention are available in the ordinary markets. 
     The term “diabetes” or “diabetes mellitus”, as used herein, refers to type 1 diabetes, type 2 diabetes, gestational diabetes, or diseases and conditions having typical signs or symptoms of diabetes mellitus. 
     The term “carrier” or “excipient”, as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues without interfering the effect of the treatment. 
     The term “diluent”, as used herein, refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. 
     The aforementioned vehicles can further comprise aromatics, buffering agents, binders, colorants, disintegrants, emulsifiers, extenders, flavor-improving agents, gellants, glidants, preservatives, skin-penetration enhancers, solubilizers, stabilizers, dispersing agents, suspending agents, sweeteners, tonicity agents, viscosity-increasing agents, or the combination thereof. 
     The term “pharmaceutically acceptable”, as used herein, refers to the compounds, formulations, composition, and/or dose form, within the scope of reasonable medical judgment, suitable for contacting with the suffered subject, without undue detrimental effect, toxicity, irritation, allergic response, or any conditions or complications on the general health of the subject being treated, and commensurate with a reasonable benefit/risk ratio. 
     The term “effective amount” or “therapeutically effective amount”, as used herein, refers to a sufficient amount of an agent or a compound being administered which will relieve one or more of the symptoms of the disease or condition being treated to some extent; the result thereof can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. 
     The term “enhance”, “enhancing”, or the like, as used herein, means to increase or prolong either in potency or duration of a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. 
     The term “treat,” “treating”, “treatment”, or the like, as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing disease progression, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving the condition caused by the disease or condition, or reducing the sign or symptoms of the disease or condition either prophylactically and/or therapeutically. 
     The term “resistance” or the like, as used herein, refers to the regression of the sensitivity to certain medicine, increment of therapeutically effective amount compared to the expected effect, after a series of course of treatment are taken by a subject in need. The term “drug-resistance” or the like, as used herein, is resistance to a single drug or multidrug resistance. 
     The term “tolerance”, as used herein, refers to the adaptive reaction or reduced reaction of cell, tissue, organisms to the drug after a series of course of treatment are taken by a subject in need, and leading to symptoms of withdrawal upon abruption or decrease in intake of medicine. 
     General Consideration for Combination Treatments 
     The term “combination therapy” or the like, as used herein, refers to giving or administering to a suffered subject at least two selected pharmaceuticals, further comprising a course of treatment, via the same or different routes simultaneously, concurrently or sequentially. 
     In general, the compositions described herein and, in embodiments where combinational therapy is employed based on the mode of action described herein, other agents do not have to be administered in the same pharmaceutical composition; and in some embodiments, because of different physical and chemical characteristics, they are administered by different routes. In some embodiments, the initial administration is made according to established protocols, and then, based upon the observed effects, the dosage, modes of administration and times of administration are modified by the skilled clinician. 
     In the embodiment herein, therapeutically-effective dosages vary when the drugs are used in treatment combinations. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease, disorder, or condition being treated and so forth. 
     The term “combination” or the like, as used herein, means a product that results from combining more than one active pharmaceutical and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active pharmaceuticals are administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active pharmaceuticals are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the pharmaceuticals in the body of the patient. The latter may also be applied to cocktail therapy, e.g. the administration of three or more active ingredients. 
     The dose forms of the Chinese herbal medicine provided in the present invention include but are not limit to solution, emulsion, suspension, powder, tablet, pill, lozenge, troche, chewing gum, capsule, or any dose form which is suitable for the Chinese herbal medicine provided herein. 
     The present invention provides a method of treatment of drug-resistance diabetes mellitus, comprising administering a therapeutically effective amount of Chinese herbal medicine to a subject in need; wherein the Chinese herbal medicine is an extract of a first mixture comprising raw oyster shell powder, raw Os Draconis, Haematitum, Magnetitum, radix Achyranthis Bidentatae, rhizoma Dioscoreae, radix Paeoniae Rubra, radix Rehmanniae, and semen Platycladi. 
     In an embodiment, the Chinese herbal medicine can be co-administered with another pharmaceutical composition according to the method of treatment of drug-resistance diabetes mellitus. In a specific embodiment, the Chinese herbal medicine and another pharmaceutical composition are administered simultaneously, concurrently or sequentially. 
     In an embodiment of the present invention, the pharmaceutical composition said above comprises the pharmaceuticals for treating diabetes disclosed in the prior art, which include, but are not limited to, insulin and the modifiers thereof; biguanide such as metformin, pheformin, and buformin; thiazolidinediones such as rosiglitazone, pioglitazone, and troglitazone; sulfonylurea such as glimepiride, glyburide, glipizide, glipizide, chloropropamide, and tolbutamide; meglitinides such as repaglinide, nateglinide; α-glucosidase inhibitors such as miglitol, acarbose, and voglibose; HMG CoA reductase inhibitor such as mevastatin, lovastatin, simvastatin, atorvastatin, and pitavastatin; SGLT2 inhibitor such as Dapagliflozin, Empagliflozin, Canagliflozin, Ipragliflozin, and Tofogliflozin; DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin, alogliptin, and teneligliptin. 
     The method according to the present invention is the treatment of diabetes mellitus and the complications, syndromes, metabolic disorder, or conditions, including but not limited to type 1 diabetes, type 2 diabetes, gestational diabetes, beta cell genetic deficiency, diabetic ketoacidosis, atherosclerosis, cardiovascular diseases, high blood sugar, hypertension, hyperlipidemia, obesity, acute or chronic renal failure, retinopathy, diabetic foot ulcer, insulin resistance, albuminuria, hyperuricemia, swollen, decreased glucose tolerance. In particular, the method is the treatment of drug-resistance diabetes mellitus. 
     The foregoing scopes are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages, indication, administration, and intake may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. 
     Preparation of the Chinese Herbal Material and the Chinese Herbal Medicine. 
     The present invention is directed to an use of Chinese herbal medicine, which includes the extract of a first mixture that mixes the following components: 5 parts by weight of raw oyster shell powder, 5 parts by weight of raw long gu(Os Draconis) powder, 8 parts by weight of Haematitum (Hematite) powder, 3 parts by weight of Magnetitum powder, 5 parts by weight of radix Achyranthis Bidentatae ( Achyranthes bidentata ), 5 parts by weight of rhizoma Dioscoreae ( Dioscorea opposita ), 5 parts by weight of radix Paeoniae Rubra, 5 parts by weight of radix Rehmanniae ( Rehmannia glutinosa ), and 4 parts by weight of semen Platycladi ( Platycladus orientalis ); wherein it is a daily dose of the Chinese herbal medicine when the part by weight of the first mixture is 3.75 g per part. 
     In addition, the first mixture can optionally include at least one of the following components or the combination of at least two thereof: 
     4-6 parts by weight of  Poria  ( Wolfiporia cocos ), 4-6 parts by weight of Rhizoma Alismatis ( Alisma orientalis ), 3-5 parts by weight of rhizoma Gastrodiae ( Gastrodia elata ), 1-3 parts by weight of Herba Ephedrae ( Ephedra sinica ), 0-3 parts by weight of radix Rhubarb ( Rheum palmatum, R. tanguticum , or  R. officinale ), 4-6 parts by weight of rhizoma Drynariae ( Drynaria fortunei ), 3-5 parts by weight of gypsum (CaSO4.2H2O) powder, 2-4 parts by weight of Radix Panax notoginseng, 7-9 parts by weight of rhizoma Coptidis ( Coptis chinensis, C. deltoidea , or  C. teeta ), 7-9 parts by weight of cortex Mori ( Morus alba ), 7-9 parts by weight of Semen Raphani ( Raphanus sativus ). 
     The preparation method of the Chinese herbal medicine is provided as following. 
     The components of the first mixture are heated and extracted in a solvent; wherein the component of the first mixture can be optionally grinded before extraction to achieve the best extraction outcome, except that raw long gu powder, Haematitum powder, and Magnetitum powder should be extracted in powder. The preferred solvent of the extraction is water, ethanol, DMSO (Dimethyl sulfoxide), or the combination thereof. 
     In a preferred embodiment of the present invention, the components of the daily dose of the Chinese herbal medicine are dissolved in 1,600 ml water to obtain a second mixture; the second mixture is decocted at 100-120° C. for 1 hour and then the residue of decoction is filtered out to obtain the liquid extract. Preferably; the liquid extract is equally divided into 3 doses for ter in die administration. Preferably, the the second mixture is decocted at 100-120″C for 1 hour and then the volume of the liquid extract after filtration is 450 ml. 
     Furthermore, the preparation method of the Chinese herbal medicine can include the step of concentration as follows: after the residue of the extract is filtered out, the liquid extract is condensed by vacuum or low pressure concentration under the condition of 50-60° C. and 20-40 torr, in order to obtain the condensate; preferably, the volume of the condensate is 1/10-1/20 volume of the liquid extract. 
     Furthermore, the corn starch used as an excipient is added to the condensate to obtain Chinese herbal paste; wherein the quantity of the corn starch depends on the stability of condensate; wherein the paste is optionally subject to granulation by spray-drying method. 
     Example 1: Patient 1 
     The diabetes patient in example 1 was diagnosed to have the condition including GLU(AC): 186, Total Cholesterol (T Chole):168, T G: 89, GOT/GPT=31/32; the patient had taken several diabetes drugs to alleviate the symptoms of diabetes, including Glimepiride, Pioglitazone, Glucobose, Metformin, Atorvastatin, and Zolpidem. 
     The treatment for the patient in example 1 comprised: daily administration of the daily dose of the Chinese herbal medicine according to the present invention for a period of 14 consecutive days; specifically, a daily dose of Chinese herbal medicine was equally divided for ter in die administration. 
     After the 14 days course of treatment (administering daily dose for each day), the outcome of the condition of the diabetes patient included: 
     GLU(AC) reduced to 126-137 approximately, while the GLU(AC) was about 145 for 3 days in the course of treatment; T Chole reduced to 150; TG reduced to 65; GOT/GPT-18/19. During the course of treatment, the patient solely took 2 kinds of the aforementioned drugs in the morning but not in the afternoon and evening. At the end of the course of treatment, the patient stopped taking any drugs but the Chinese herbal medicine of the present invention without any withdrawal symptoms occurring. The Chinese herbal medicine of the present invention was able to substitute the drugs of diabetes and achieve the purpose of alleviating diabetic condition as well as abstaining drug dependence without suffering from withdrawal symptoms. 
     Example 2: Patient 2 
     The diabetes patient in example 2 was diagnosed to have the condition including GLU(AC): 156, BUN/CR: 26.8/1.1; the patient had taken several diabetes drugs to alleviate the symptoms of diabetes, including Glimepiride, Pioglitazone, Glucobose, Metformin, Atorvastatin, and Zolpidem. 
     The treatment for the patient in example 2 comprised: daily administration of the daily dose of the Chinese herbal medicine according to the present invention for a period of 14 consecutive days; specifically, a daily dose of Chinese herbal medicine was equally divided for ter in die administration. Particularly, the daily dose of the Chinese herbal medicine in example 2 was the extract of the first mixture; wherein the first mixture additionally included 5 parts by weight of  Poria  and 5 parts by weight of  Alisma  rhizoma. 
     After the 14 days treatment (administering daily dose for each day), the outcome of the condition of the diabetes patient included: 
     GLU(AC) reduced to 91-129 approximately; BUN/CR reduced to 15.4/0.9. During the course of treatment, the patient did not take any of the aforementioned drugs. At the end of the course of treatment, the patient stopped taking any drugs but the Chinese herbal medicine according to the present invention without any withdrawal symptoms occurring. The Chinese herbal medicine according to the present invention was able to substitute the drugs of diabetes and achieve the purpose of alleviating diabetic condition as well as abstaining drug dependence without suffering from withdrawal symptoms. 
     Example 3: Patient 3 
     The diabetes patient in example 3 was diagnosed to have the condition including GLU(AC): 186; the patient had taken several diabetes drugs to alleviate the symptoms of diabetes, including Glimepiride, Pioglitazone, Glucobose, Metformin, Atorvastatin, and Zolpidem. 
     The treatment for the patient in example 3 comprised: daily administration of the daily dose of the Chinese herbal medicine of the present invention for a period of 14 consecutive days; specifically; a daily dose of Chinese herbal medicine was equally divided for ter in die administration. Particularly, the daily dose of the Chinese herbal medicine in example 3 was the extract of the first mixture; wherein the rhizoma Coptidis and the cortex Mori of the first mixture were both increased to 25 parts by weight; wherein the first mixture additionally included 0.5 parts by weight of radix Rhubarb, 2 parts by weight of Herba Ephedrae, and 3 parts by weight of Radix Panax notoginseng. 
     After the 14 days course of treatment (administering daily dose for each day), the outcome of the condition of the diabetes patient included: 
     GLU(AC) reduced to 130-160 approximately. During the course of treatment, the patient solely took 2 kinds of the aforementioned drugs in the morning but not in the afternoon and evening. At the end of the course of treatment, the patient stopped taking any drugs but the Chinese herbal medicine according to the present invention without any withdrawal symptoms occurring. The Chinese herbal medicine according to the present invention was able to substitute the drugs of diabetes and achieve the purpose of alleviating diabetic condition as well as abstaining drug dependence without suffering from withdrawal symptoms. 
     Example 4: Patient 4 
     The diabetes patient in example 4 was diagnosed to have the condition including GLU(AC): 207; the patient had taken several diabetes drugs to alleviate the symptoms of diabetes, including Glimepiride, Pioglitazone, Glucobose, Metformin, Atorvastatin, and Zolpidem. 
     The treatment for the patient in example 4 comprised: daily administration of the daily dose of the Chinese herbal medicine according to the present invention for a period of 14 consecutive days; specifically, a daily dose of Chinese herbal medicine was equally divided for ter in die administration. Particularly, the daily dose of the Chinese herbal medicine in example 3 was the extract of the first mixture; wherein the first mixture additionally included 5 parts by weight of rhizoma Drynariae, 2 parts by weight of gypsum powder. 
     After the 32 days course of treatment (administering daily dose for each day), the outcome of the condition of the diabetes patient included: 
     GLU(AC) reduced to 113-129 approximately. During the course of treatment, the patient solely took 2 kinds of the aforementioned drugs in the morning but not in the afternoon and evening. At the end of the course of treatment, the patient stopped taking any drugs but the Chinese herbal medicine according to the present invention without any withdrawal symptoms occurring. The Chinese herbal medicine according to the present invention was able to substitute the drugs of diabetes and achieve the purpose of alleviating diabetic condition as well as abstaining drug dependence without suffering from withdrawal symptoms. 
     While the preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents are covered thereby.