CN1913879A - Compositions and methods for treating diabetes - Google Patents

Abstract

The subject invention provides compositions and methods for treating diabetes in patients. In a preferred embodiment, the invention provides compositions methods for treating diabetes and/or preventing or alleviating complications associated with diabetes. Specifically exemplified herein is the concurrent administration of a cysteamine compound with at least one additional therapeutic agent to prevent and/or treat diabetes as well as prevent and/or treat complications associated with diabetes. In a preferred embodiment, oral administration of cysteamine hydrochloride with Metformin to a patient diagnosed with diabetes can substantially regulate the patient's glucose metabolism and insulin sensitivity.

Description

The compositions and the method that are used for the treatment of diabetes

The cross-reference of related application

The application requires the interests of U.S. Provisional Application sequence number 60/531,119 that December in 2003 submitted on the 19th and the U.S. Provisional Application sequence number of submitting on July 27th, 2,004 60/591,709.

Background of invention

Diabetes are a kind of incurable chronic diseases.Current, 6.3% of about 18,200,000 people or U.S. population suffers from diabetes.Although after diagnosing about 13,000,000 cases, estimate at 5,200,000 people and do not know that they suffer from diabetes.As lethal the 6th main cause of disease in 2000, estimate 13,200,000,000 dollars of the annual cost of diabetes U.S. sanitary health care systems.NationalDiabetes Information Clearinghouse, NIH Publication No.04-3892, in November, 2003.The ratio economic cost relevant with diabetes be the decline, serious health complications/consequence of quality of life more seriously, with the death relevant with diabetes.

12,000 to 24,000 the newly-increased cases of having an appointment every year, diabetes are the main causes of blind new case among 20-74 year adult.Diabetes still are the main cause of end stage kidney disease, cause annual about 44% new case.Only in calendar year 2001,42,800 people that just have an appointment are because diabetes and begin treatment end stage kidney disease (renal failure).The diabetics of about 60-70% has slight diabetes nerve infringement to severe form, and it can cause lower extremity amputation in severe form.In fact, the atraumatic lower extremity amputation more than 60% is carried out diabetics.At 2002-2003, diabetics is carried out about 82,000 routine atraumatic lower extremity amputation.The probability that diabetics suffers stroke is high 2 to 4 times.In addition, suffers from the adult of diabetes than high about 2 to 4 times of the adult deaths from heart disease rate that does not have diabetes.

Diabetes are that a stack features is the disease of hyperglycemia level, and it produces defective, insulin action defective by insulin or both cause.Because diabetes reach the several years and all can not be diagnosed, so many people only know that just they suffer from diabetes in that one of life-threatening complication of suffering from diabetes is back.Although the cause of disease of diabetes is still unknown, generally acknowledge the h and E factor, all be important factor as obesity with lacking exercise.

When the immune system of health was destroyed the pancreatic cell that produces hormone insulin (its blood sugar regulation level), one group of diabetes-type i diabetes (perhaps insulin-dependent diabetes or juvenile onset diabetes) took place.Type i diabetes takes place in child and adolescence usually; Yet this seizure of disease can take place at any age.Type i diabetes account for diabetes all diagnosed SARS cases about 5 to 10%.The risk factor of type i diabetes comprises autoimmune, h and E factor.The individual need that is diagnosed as type i diabetes passes through to inject or the pump insulin delivery every day.

Another organizes diabetes---and type 2 diabetes mellitus (perhaps noninsulindependent diabetes or maturity-onset diabetes) is the metabolic disease that health can not be enough or suitably utilized insulin to cause.This disease begins with insulin resistance usually, and cell can not correctly use insulin in insulin resistance, and along with the demand of insulin raises, pancreas loses the ability that produces insulin gradually.Type 2 diabetes mellitus is the modal form of this disease, accounts for the 90-95% of diabetes.Because old American increases and bigger obesity prevalence and sedentary lifestyle, type 2 diabetes mellitus is near popular ratio.

Gestational diabetes refers to the glucose intolerance of a kind of form of diagnosing in the anemia of pregnant woman.At phenolics, gestational diabetes need be treated with normalization mother blood sugar level and be avoided complication among the baby.The women who suffers from the certain percentage (5-10%) of gestational diabetes suffers from type 2 diabetes mellitus after pregnancy.Suffering from the chance of suffering from diabetes among the women 5-10 afterwards of gestational diabetes is 20-50%.

Hyperinsulinemia refers to the excessive generation insulin of pancreatic cell.Usually, because insulin resistance causes hyperinsulinemia, it is by the disease of cell to the Drug resistance definition of insulin action.State/disease as insulin resistance defined above is, wherein the insulin of normal amount produces subnormal biology (metabolism) reaction.For example, in the diabetics of insulinize, whenever the therapeutic dose of insulin surpasses the insulin secretion speed among the normal person, all thinks to have insulin resistance.

Impaired glucose stable state (perhaps metabolism) refers to such situation, and wherein blood sugar level is than higher in the normal individual but enough height and can not be classified as diabetes whether.Think have two classes in the future diabetes and the risk factor of cardiovascular disease.When glucose level was 140 to 199mg/dl behind 2 hours oral glucose tolerance tests, impaired glucose tolerance reduction (IGT) took place.IGT is the main hazard factor of type 2 diabetes mellitus and is present among about 11% adult, among perhaps about 2,000 ten thousand Americans.The people of about 40-45%65 year or over-65s suffers from type 2 diabetes mellitus or IGT.When but glucose levels were greater than 110 less than 126mg/dl after 8 hours the fasting plasma glucose test, impaired fasting glucose (IFG) took place.

Hyperglycemia is the common feature of diabetes, is reduced and the increase of liver generation glucose causes by the glucose utilization of liver and peripheral tissues.Glucokinase (GK) is the main glucose phosphorylation enzyme in liver and the pancreas beta cell, plays an important role in the blood sugar regulation homeostasis.Obviously, in type 2 diabetes mellitus (Caro, people such as J.F., Hormone metabolic Res., 27; 19-22,1995) level of (Barzilai, N. and Rossetti, L.J.Biol.Chem., 268:25019-25025,1993) this enzyme reduces and in some diabetes animal models.

Having proposed many pharmaceutical compositions and method is used for the treatment of and/or cures diabetes.For example, alleviating in the diabetes a kind of method of hyperglycemia comprises and increases liver GK activity (VanSchaftingen, people such as E., Adv.Enzyme Regul.32:133-148,1992).The research that relates to the transgenic diabetic mice has shown that the GK copy number of increase causes the liver glucose metabolism that increases and reduces plasma glucose levels (Ferre, T. wait the people, Proc.Natl.Acad.Sci.USA, 93:7225-7230 (1996a) and FASEB J., 10:1213-1218, (1996b); Niswender, people such as K.D., J.Biol.Chem., 272:22570-22575 (1997)), show that it is effective increasing liver GK hyperglycemia in alleviating diabetes.In addition, Hariharan, people such as N. (Diabetes 46:11-16 (1997)) have illustrated and have increased liver GK and improve the glucose homeostasis and cause losing weight in the transgenic mice.

A plurality of research groups have been illustrated glucokinase and have been regulated albumen (" GKRP ") in conjunction with the GK in the liver cell nuclear and can therefore bring into play function in vivo to regulate GK activity (Brown, people such as K.S., Diabetes 46:179-186,1997; De la Iglesia, people such as N., FEBS Left.456:332-338,1999; Fernandez-Novell, people such as J.M., FEBS Left.459:211-214,1999).Cherrington and colleague (Shiota, people such as M., Diabetes 47:867-873,1998) in experiment, illustrated in the environment in vivo should mechanism dependency.In these researchs, a small amount of fructose (thereby its change into fructose-1-phosphate in liver will increase the GK that dissociates) has significantly increased clean liver glucose utilization, is similar to see from fasting to the as fed transition.

U.S. Patent number 5,714,519 (hereinafter being called ' 519 patent) disclosed in one day uses panthethine (see claim 1-18 with predetermined space; 5 hurdles, 6-15 is capable) or the method for cysteamine (16-22 is capable for see claim 19-27,5 hurdles) control hyperinsulinemia or insulin resistance.Unfortunately, the panthethine of discloseder dosage or cysteamine (for example, 500mg cysteamine) are deleterious to the people in ' 519 patent that exists.In fact, the cysteamine of this type of dosage or panthethine can also cause undesirable gastrointestinal symptoms, as the acid output that increases or even ulcer (Srivastava, P.K.﹠amp; L.Field, " Organic disulfides and related substances.38.Some disulfide and trisulfide sulfinate salts as antiradiation drugs, " JMed Chem, 18 (8): 798-802 (1975)).In addition, as the instruction of ' 519 patent, be helpless to the compliance of patient to therapeutic scheme for using necessary special time.

Cysteamine itself is not very stable chemical compound.Usually, cysteamine disappears when being applied to health (a few minutes) very fast.Therefore, will be crucial for the cysteamine of preparation stable form, the cysteamine of described stable form will be in the purpose zone by the correct metabolism of health to reach optimum therapeuticing effect.

Current two kinds of pharmacology's forms that are used for blood sugar lowering are blood sugar lowering (anti--diabetes) agent and insulins.Insulin displacement is current to be finished and based on the restriction that lacks insulin or insulin action in the diabetes by injection.Oral antidiabetic in chemically irrelevant and their blood sugar lowering mechanism with insulin with directly the metathetical effect of insulin is different.According to the needs of diabetic individual, orally-taken blood sugar reducing agent and insulin are current to be used separately in treatment or collaborative mutually the use.More than one oral therapeutics of some body and functions, with or obtain optimal treatment without insulin.

Owing to the front, need the new therapeutic treatment of diabetes; Be particularly useful for eliminating or alleviating the symptom relevant with diabetes.

The invention summary

The theme invention provides the compositions and the method for treatment diabetes, and said composition has alleviated the many unwanted side effect relevant with the conventional therapy agent that is used for the treatment of diabetes usually with method.In preferred embodiments, the invention provides unique compositions and method, symptom that they are used for the treatment of and/or prevent diabetes is relevant with diabetes and prevention or delay diabetes relevant complication, situation or advancing of disease.

The invention provides compositions, its comprise cysteamine compound and known in treating diabetes effective at least a extra therapeutic agent (hereinafter being called " additional therapeutic agent ").Special in this article illustration be to use cysteamine compound and at least a additional therapeutic agent simultaneously with prevention or treatment diabetes; And/or reduce or seriousness, intensity and/or persistent period of at least a complication that elimination is relevant with diabetes, and alleviate the unwanted side effect relevant usually with using described additional therapeutic agent separately.The compositions and methods of the invention are especially effective aspect horizontal at blood sugar lowering.

The therapeutic agent of this paper definition refers to treatment diabetes and related indication those therapeutic agents of diabetes or the therapeutic scheme of being suitable for known to the skilled.The example of therapeutic agent includes, but not limited to the medical compounds based on gene; Insulin; Sulphanylureas (for example, glibenclamide, glipizide, glimepiride, tolbutamide, chlorpropramide); Insulin succagoga (for example, repaglinide, Nateglinide); Alpha-glucosidase inhibitor (for example, acarbose, miglitol); Biguanide (for example, metformin); And thiazolidinediones (for example, rosiglitazone, piaglitazone); Meglitinides and D-phenylalanine.These available therapeutic agents do not become for many years substantially, have realized that their limitation when they use (for example, not using cysteamine compound simultaneously) separately.

In using method, before diabetes diagnosis or after the diagnosis cysteamine compound and at least a additional therapeutic agent are applied to the patient simultaneously with treatment diabetes or diabetes related symptoms.In related embodiment, cysteamine compound is used to prevent and/or treat the relevant complication of diabetes or diabetes simultaneously with at least a additional therapeutic agent that is selected from medical compounds, insulin, sulphanylureas, biguanide, Alpha-glucosidase inhibitor, thiazolidinediones, meglitinides and D-phenylalanine based on gene.Can use the extra therapeutic agent of the extra expection that shows effect with prevent diabetes to comprise according to the theme invention, but be not limited to following scheme: physical training (promptly, suitably sports, every day is half an hour at least), the diet that improves takes in (that is, reducing sugar takes in) and loses weight.According to theme invention, compositions of the present invention at any time (as in the undetermined time) use to cause therapeutic effect.

Be the unwanted side effect relevant with using the conventional therapy agent below: (1) is by using sulphanylureas (promptly, tolbutamide and glipizide) or meglitinide with the more insulins of stimulating pancreas beta cell secretion, and/or when sulphanylureas or meglitinide become invalid, increase the blood plasma level of insulin by insulin injection, increase insulin concentration to sufficiently high level to stimulate glucagon sex organization; (2) administration of insulin or insulin succagoga (sulphanylureas or meglitinide) can cause dangerous low-level plasma glucose, and can take place because even the insulin resistance level that causes of higher plasma insulin level raise; (3) can not make up with other treatment and treat diabetes (that is, need when combination sulfonylurea drugs and other diabetes medicaments clinical cautiously); (4) uncomfortable (that is, weight increase, fluid retention increase, the rising of low-density lipoprotein white level, flatulence and diarrhoea).

According to the present invention, find that first the patient is used cysteamine compound can increase glucose transporter expression and adiponectin level.Thereby the glucose transporter that increases is expressed and the adiponectin level can improve patient's insulin sensitivity and make cysteamine compound and extra therapeutic agent be used for guaranteeing enhanced therapeutic effect in highly useful mode, will can not observe this therapeutic effect with using cysteamine compound or described additional therapeutic agent separately.

Also according to theme invention, to have observed and the patient is used cysteamine compound influence other biological and learn factor, it can represent or develop into complication or situation that diabetes are correlated with.For example, according to the present invention, have been found that the patient is used the level that cysteamine compound can influence C-peptide among the patient, insulin like growth factor, blood uric acid, free fatty, adiponectin, triglyceride, high density lipoprotein (HDL), low density lipoprotein, LDL (LDL) and Microalbuminuria.Particularly, to the patient use cysteamine compound can: reduce type-1 insulin like growth factor (IGF-1), reduce C-peptide level, reduce free fatty acid levels, reduce serum uric acid level, rising adiponectin level, triglyceride reducing level, the LDL level that reduces, rising HDL level and reduce the Microalbuminuria level.Because the complication that all these biological factors are all relevant with diabetes or the diagnosis of situation and/or development is relevant (sees Reist, people such as GC, " Changes in IGF activities in human diabeticvitreous; " Diabetes, 53 (9): 2428-35 (Sept.2004); Janssen JA and Lamberts, SW, " The role of IGF-I in the development of cardiovascular disease intype 2 diabetes mellitus:is prevention possible? " Eur J Endocrinol., 146 (4): 467-77 (2002); Chakrabarti, people such as S, " C-peptide and retinalmicroangiopathy in diabetes, " Exp Diabesity Res., 5 (1): 91-6 (Jan-Mar2004); Gottsater, A. wait the people, " Plasma adiponectin and serum advancedglycated end-products increase and plasma lipid concentrations decreasewith increasing duration of type 2diabetes; " Eur J Endocrinol., 151 (3): 361-6 (Sept 2004); Tseng, CH., " Independent association of uric acidlevels with peripheral arterial disease in Taiwanese patients with Type 2diabetes, " Diabet Med., 21 (7): 724-9 (July 2004); Liese, people such as AD, " Microalbuminuria; central adiposity and hypertension in the non-diabeticurban population of the MONICA Augsburg survey 1994/95; " J HumHypertens., 15 (11): 799-804 (2001); And Wollesen, F. wait the people, " Peripheralatherosclerosis and serum lipoprotein (a) in diabetes; " Diabetes Care., 22 (1): 93-8 (1999)), so cysteamine compound is used together separately or with extra treatment chemical compound can treat relevant complication of diabetes and situation as described.

When cysteamine compound and at least a additional therapeutic agent were used simultaneously, these materials provided together than the more favourable therapeutic effect of any one form substance for delivery separately.Biguanide is generally used for treating noninsulindependent diabetes or type 2 diabetes mellitus.The inventor has been surprisingly found out that biguanide, and the combination with cysteamine compound causes controlling than the better glucemia that only can realize with biguanide or cysteamine compound as metformin.This beneficial effect is especially effective in the patient who is diagnosed as diabetes, heritability diabetes, 1 type and type 2 diabetes mellitus and gestational diabetes.

In another embodiment, provide the compositions that comprises cysteamine compound and at least a additional therapeutic agent.In related embodiment, this based composition can also comprise " clathrate host material " (inclusion compound host material), it is fixed as the enclose complex with gas, liquid or chemical compound, thereby this complex can discharge (promptly subsequently with solid form processing and included composition (as cysteamine compound), by being exposed to alkaline environment, by solvent action or by fusion).

In a further embodiment, theme invention provides and has been used to alleviate and/or compositions and the method for seriousness, intensity and/or the persistent period of at least a complication that elimination is relevant with diabetes.Invent according to theme, by using cysteamine compound and at least a additional therapeutic agent, can alleviate and/or eliminate complication, situation or the disease relevant usually, as background diabetic retinopathy, macular edema, cataract, necrobiosis lipoidica, diabetic dermatopathy, fungal infection, congestive heart failure, kidney disease, diabetic neuropathy with diabetes.

Other advantages of theme invention comprise the development of prevent diabetes.According to theme invention, do not develop or develop into lesser extent when lacking described cysteamine compound and additional therapeutic agent thereby use metabolism diabetes that cysteamine compound and at least a additional therapeutic agent can change the patient before diabetes diagnosis or during outbreak simultaneously.By strengthening insulin sensitivity (promptly, express by the glucose transporter that increases), the compositions and methods of the invention can treat and/or prevent the diabetes symptom relevant with diabetes and treat and/or prevent diabetes relevant complication or situation.According to the present invention, have abnormal glucose metabolism or insulin resistance and still (for example do not have full-blown diabetes, in obesity) the glucose utilization and the insulin resistance of experimenter's raising that (that is, the cysteamine of viewed glucose transporter and adiponectin and lipid metabolism is regulated) causes because the cysteamine activity will not develop into diabetes.

According to theme invention, diagnosis there are diabetes or suffer the daily dose of the cysteamine compound that the patient of the complication relevant with diabetes, situation or disease uses to arrive the cysteamine compound of about 400mg/kg weight in patients (BW) cysteamine (perhaps 600mg/kg BW Mercaptamine) or equimolar amounts for about 0.1mg.Preferably, according to the present invention, the patient is used the daily dose of the cysteamine compound of about 30mg/kg BW cysteamine or equimolar amounts.The dosage of additional therapeutic agent is based on will cause desirable amount of replying when using simultaneously with cysteamine compound.

The accompanying drawing summary

Fig. 1 has shown the metabolic pathway of cysteamine.

Fig. 2 has shown the composition of cysteamine as coenzyme A.

Fig. 3-5 has shown the result of the oral glucose tolerance test that mouse model is carried out, and shows the effectiveness of system and method for the present invention.

Fig. 6 has shown the result of the hungry blood plasma glucose test that mouse model is carried out, and has shown the effectiveness of the system and method for theme invention.

Fig. 7-10 has shown the result from the serological test that mouse model is carried out, and has shown the effectiveness of the system and method for theme invention.

Detailed Description Of The Invention

The theme invention provides treatment to be diagnosed as the patient's of diabetes method.The present invention provides cysteamine compound and at least a additional therapeutic agent to be used for the treatment of the useful therapeutic combination of diabetes first.In preferred embodiments, the invention provides by using cysteamine compound and metformin simultaneously and treat and/or prevent the development of diabetes and the compositions and the method for the complication relevant with diabetes.

Term used herein " diabetes " is intended to refer to all diabetic conditions, includes, but not limited to diabetes, heritability diabetes, type 1 diabetes, type 2 diabetes mellitus and gestational diabetes.Term " diabetes " refers to that also feature is the chronic disease that the relative or absolute deficiency of insulin causes glucose intolerance.Type 1 diabetes is also referred to as insulin-dependent diabetes (IDDM) and for example comprises juvenile diabetes.1 type mainly is because the destruction of pancreatic beta cell.Type 2 diabetes mellitus is also referred to as noninsulindependent diabetes (NIDDM) and characteristic is that impaired after the meal insulin discharges.Insulin resistance also can be a factor that causes taking place type 2 diabetes mellitus.The heritability diabetes are that it disturbs the function and the adjusting of β cell owing to suddenly change.

The feature of diabetes used herein is that the fasting glucose level is greater than or equal to behind about 130mg/dl or the about 75g glucose load of dosage forms for oral administration or the plasma glucose levels of assessment after about after the meal 2 hours is greater than or equal to about 180mg/dl.Understand as the technical staff, be used to identify that the feature of glucose can change and newest standards, can be used for definition as the disclosed newest standards of World Health Organization (WHO) (World HealthOrganization) provides diabetes as this paper.

Term " diabetes " also is intended to comprise to suffer from hyperglycemia, comprises chronic hyperglycemia, hyperinsulinemia, impaired glucose homeostasis or those individualities of toleration and insulin resistance.Plasma glucose levels comprises in the hyperglycemia individuality, for example, greater than as the concentration of glucose of the normal level measured by the reliable diagnostic indicator.This type of hyperglycemia is individual dangerous or tend to produce the obvious clinical symptoms of diabetes.

Term used herein " diabetic complication " refers to the common medical science/clinical problem that takes place in being diagnosed as the patient of diabetes.As this paper expection, diabetic complication comprises because diabetes change the medical science/clinical problem that causes in blood vessel and/or the nerve.These problems comprise, but be not limited to, dermatosis (promptly, bacterial infection, fungal infection, diabetic dermatopathy, necrobiosis lipoidica, diabetic vesicle (diabeticorum) (promptly, BD), dermexanthesis xanthomatosis (eruptivexanthomatosis), allergic skin reaction, the sclerosis of finger/toe, DGA and acanthosis nigricans), gum disease, ocular disorders (promptly, glaucoma, cataract, retinopathy, kidney disease), neuropathy (promptly, the systematicness neuropathy, tip systematicness polyneuropathy, nearside neuropathy (proximal neuropathy), femoral neuropathy, neuropathic anthropathy, the cranial nerve disease, plant (authonomic) neuropathy, pressuring nerve disease and diabetic muscular dystrophy), gout and cardiovascular disease/disease (that is hypertension,, heart disease, heart attack, apoplexy).

Biology described in term used herein " patient ", comprises mammal, and described biology is provided according to compositions of the present invention.The mammalian species of being benefited from disclosed Therapeutic Method includes, but not limited to ape, chimpanzee, orangutan, people, monkey; With the animal (that is, house pet) of domestication, as Canis familiaris L., cat, mice, rat, Cavia porcellus and hamster.

" using simultaneously " used herein refers to use at least a extra therapeutic agent (for example, insulin and/or blood sugar lowering chemical compound) that is suitable for treating diabetes.For example, at least a extra therapeutic agent can mix with cysteamine compound to be provided, as in pharmaceutical composition; Perhaps additional therapeutic agent and cysteamine can provide with the chemical compound that separates, as continuously, simultaneously or the separated drug compositions of using at different time.Preferably, if be used for the treatment of the cysteamine compound of diabetes and extra therapeutic agent is used separately, they are not to use at a distance of the so long time so that this cysteamine compound and additional therapeutic agent can not interact so.

As used herein, the reference of " cysteamine compound " is comprised the prodrug of cysteamine, multiple cysteamine salt (as Mercaptamine and cysteine phosphate) and cysteamine, its for example can be in health metabolism easily to produce cysteamine.Analog, derivant, conjugate and the metabolite (as cystamine) that also comprise cysteamine in the theme scope of invention, they can treat and/or alleviate the relevant complication of diabetes as described in this article.Multiple analog, derivant, conjugate and the metabolite of cysteamine be known and can easily used and comprised by those skilled in the art, for example, and U.S. Patent number 6,521,266,6,468, the chemical compound, compositions and the delivering method that provide in 522 and 5,714,519.

As this paper expection, cysteamine compound comprises pantothenic acid.Pantothenic acid is the vitamin of natural generation, and it changes into coenzyme A in mammalian body, and it is the material important to many physiological reactions.Cysteamine is the component of coenzyme A, increases the circulation cysteamine that the coenzyme A level causes the increase level.Alkali metal salt is as the formation of magnesium orthophosphate and magnesium sulfite (Epsom salts) enhancing coenzyme A.In addition, Reducing agent strengthens the decomposition of coenzyme A to cysteamine as the existence of citric acid.Thereby pantothenic acid and alkali-metal combination cause the coenzyme A generation that increases and follow the cysteamine of increase to produce.

Therefore, in an embodiment of theme invention, the advantage of using cysteamine compound and at least a additional therapeutic agent when proposing as this paper can be by promoting through natural metabolic process, as realizing (seeing Fig. 1 and 2) through the effect of coenzyme A or as the endogenous generation cysteamine of the metabolite of cysteine.This can be by for example, uses pantothenic acid simultaneously and at least a extra therapeutic agent is realized.

Term used herein " therapeutic dose " or " treatment effective dose " have guided the essential amount of desirable biological answer-reply.Invent according to theme, the treatment effective dose is treatment and/or alleviates diabetes and alleviate the seriousness of specific diabetes related complication (that is, retinopathy, glaucoma, cataract, heart disease, apoplexy, hypertension, neuropathy, dermatosis, gum disease or the like) or prevent the amount of essential cysteamine compound of described complication and at least a additional therapeutic agent.Described alleviating can be that the seriousness of complication alleviates 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%.

The present invention provides cysteamine compound and at least a additional therapeutic agent to be used for the treatment of the useful therapeutic combination of diabetes first.When cysteamine compound and at least a additional therapeutic agent were used simultaneously, these materials were advantageously brought into play function with than the bigger therapeutic effect of sending separately of any form.The compositions of the present invention that comprises cysteamine compound and at least a additional therapeutic agent especially is advantageously used in treatment diabetes and diabetes related complication, because this based composition can (need not used with the time limit scheduled time) at any time and use to cause therapeutic outcome (that is the reduction of glucose level).

Biguanide is generally used for treating noninsulindependent diabetes.The inventor is surprisingly found out that the biguanide (for example, metformin) and the combination of cysteamine compound cause than only using any therapeutic agent, as metformin and the better glucemia control of cysteamine compound.This beneficial effect is especially effective in the patient who is diagnosed as diabetes, heritability diabetes, 1 type and type 2 diabetes mellitus and gestational diabetes.

Special in this article illustration be to use Mercaptamine (and/or its analog, derivant and prodrug) and at least a additional therapeutic agent simultaneously to treat and/or prevent the outbreak of diabetes in patients; Perhaps alleviate seriousness, intensity or the persistent period of the diabetes related complication that takes place subsequently.Preferably, can carry out using in Mercaptamine and at least a additional therapeutic agent in the uncertain time.Invent according to theme, the diabetes related complication, as, but being not limited to, retinopathy, glaucoma, cataract, heart disease, hypertension, apoplexy, gum disease and dermatosis can be by using cysteamine compound and at least a additional therapeutic agent is treated, prevented and/or alleviates.

Other advantages of theme invention comprise the development that treats and/or prevents diabetes.Especially, can be before diabetes diagnosis or in use cysteamine (and/or its analog, derivant and prodrug) and at least a additional therapeutic agent simultaneously.Alternatively, cysteamine compound and one or more additional therapeutic agent can be used with the treatment diabetes simultaneously with other known therapies.

The alleged herein additional therapeutic agent of using simultaneously with cysteamine compound includes, but not limited to the medical compounds based on gene; Insulin; Sulphanylureas (that is, glibenclamide, glipizide, glimepiride, tolbutamide, chlorpropramide); Insulin succagoga (that is, repaglinide, Nateglinide); Alpha-glucosidase inhibitor (that is, acarbose, miglitol); Biguanide (that is metformin); And thiazolidinediones (that is, rosiglitazone, piaglitazone); The diet of meglitinides and D-phenylalanine, physical training, improvement is taken in and is lost weight.

In one embodiment, cysteamine compound is used with treatment type 1 diabetes, type 2 diabetes mellitus and relevant situation and symptom simultaneously with insulin.The hypertension that causes for type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, diabetes, obesity or to blood vessel, eyes, kidney, nerve, autonomic nervous system, skin, connective tissue or immune infringement can be used cysteamine compound and the blood sugar lowering chemical compound that replaces insulin simultaneously.

Alternatively, cysteamine compound and insulin and blood sugar lowering chemical compound are used the hypertension that causes with treatment type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, diabetes, obesity or simultaneously to blood vessel, eyes, kidney, nerve, autonomic nervous system, skin, connective tissue or immune infringement.

Compositions of the present invention can be used with multiple route of administration, for example comprises, the form of dosage forms for oral administration is as tablet, capsule or the like, perhaps by parenteral, intravenous, intramuscular, percutaneous, buccal, subcutaneous, suppository or other approach.This based composition generally is called " pharmaceutical composition " in this article.Usually, they can be unit dosage forms, promptly, the physically discrete unit of suitable single dose as human consumption, each unit contains the active component of scheduled volume, its as calculated with one or more pharmaceutically useful other compositions, that is, diluent or carrier are in conjunction with producing desirable therapeutic effect.

Can be according to the cysteamine compound of the known method preparation theme invention of the compositions that is used to prepare pharmaceutically useful and extra therapeutic agent.Preparation is described in many sources, and they are as well known to those skilled in the art and obtain easily.For example, and Remington ' s Pharmaceutical Science (Martin EW[1995] Easton Pennsylvania, Mack Publishing Company 19thed.) has described the preparation that can be used for the theme invention.The preparation that is suitable for parenteral administration comprises, for example, the agent of aqueous aseptic injectable solution, it can contain antioxidant, buffer agent, antibacterial and solute, and it makes receiver's the blood etc. of preparation and expection ooze; With aqueous and non-aqueous aseptic suspensoid, it can comprise suspending agent and thickening agent.Preparation may reside in unit dose or multi-dose container, for example, in the ampoule of sealing and the bottle, and can be kept under lyophilization (freeze dried) condition, only needs aseptic liquid carrier before use, for example, and water for injection.Can be from interim injection solution of preparation and suspensions such as sterile powder, granule, tablets.With understanding except the top composition of mentioning especially, for the type of described preparation, the preparation of theme invention can also comprise other conventional ingredients in this area.

According to theme invention, use can be by those skilled in the art current or expect that known any suitable method and technology finish in the time of cysteamine compound and at least a additional therapeutic agent.In preferred embodiments, the per os preparation preparation can apply for a patent and be dissolved in consumption of cysteamine compound and at least a additional therapeutic agent is as pill, lozenge, tablet, natural gum, beverage or the like.Before or after diagnosis of diabetes, consume then.

In certain embodiments of the invention, (for example use cysteamine compound and at least a additional therapeutic agent at the same time, the diet of physical training, improvement is taken in and is lost weight) assess patient to be to identify the danger of suffering from insulin-dependent diabetes (IDDM) before.Multiple label has been identified the important label before the clinical episodes of IDDM recently.Can include, but not limited to autoantibody (IAA) with the amynologic label thing that method known to the skilled being used for of detecting assessed asymptomatic patient's diabetes susceptibility at insulin; Glutamate decarboxylase (GAD); With autoantibody, as autoantibody at the islet cells member of the receptor type of the tyrosine phosphatase family that is called IA-2 at islet cells.Can identify that the method to the asymptomatic patient of diabetes susceptible includes but not limited to U.S. Patent number 6,391,651 and 6,316,209 according to this type of label that the theme invention is used by detecting.

According to the present invention, comprise as the cysteamine compound of the effective dose of active component and the compositions of at least a additional therapeutic agent and also comprise pharmaceutically useful carrier or the diluent that one or more are nontoxic.The example that is used for examples of such carriers of the present invention comprises ethanol, dimethyl sulfoxide, glycerol, silicon dioxide, aluminium oxide, starch, sorbitol, inositol, xylitol, D-xylose, mannitol, Powderd cellulose, microcrystalline Cellulose, Talcum, silica sol, calcium carbonate, magnesium carbonate, calcium phosphate, Aluminum calcium silicate., aluminium hydroxide, sodium starch phosphate, lecithin and carrier that is equal to and diluent.

In one embodiment, provide the compositions that comprises cysteamine compound, at least a additional therapeutic agent and carrier such as clathrate host material.Think by carrier is provided,, can stable cysteamine compound molecule safe delivery be arrived the patient not induce toxic dosage as the clathrate host material.In addition, the examples of such carriers material can comprise coating material (for example, enteric coating), and its permission is dissolved in alkaline environment with coating, in intestinal.

Can comprise those disclosed in the Application No. 20040033985 according to the clathrate host material that theme invention is used, be incorporated herein by reference this patent application is complete.The clathrate host material of expection comprises protein (as albumin), crown ether, polyoxyalkylene, polysiloxanes, zeolites, cholestyramine, cholestipol, colesevelam (colesevelam), colestimide, sevelamer (sevelamer), cellulose derivative, glucan derivative, starch, starch derivatives and its officinal salt.The cellulose derivative and the glucan derivative of expection comprise DEAE-cellulose, GE-cellulose, perhaps DEAE-Sephadex.Favourable starch or starch derivatives in the present composition comprises cyclodextrin with being included in, the starch of bringing back to life (retrograded starch), degradable starch, the combination of bring back to life starch and degradable starch, hydrophobic starch, amylase, starch-diethylamino ether, and starch-2-hydroxyl ether.

Invent according to theme, preferred clathrate host material comprises, but be not limited to, cyclodextrin and/or its derivant (for example, methyl beta-schardinger dextrin-(M-β-CD), hydroxypropyl (HP-β-CD), ethoxy beta-schardinger dextrin-(HE-β-CD), cyclodextrin polymer, ethyl beta-schardinger dextrin-(E-β-CD) and branched cyclodextrin.It will be appreciated by those skilled in the art that mixture, the cyclodextrin that can use any cyclodextrin or cyclodextrin according to the present invention, perhaps modified cyclodextrin.Cyclodextrin can be from WackerBiochem Inc., Adrian, Michigan or Cerestar USA, Hammond, Indiana and obtain from other distributors.Forming inclusion complex protection composition (for example, cysteamine compound) with cyclodextrin or its derivant avoids evaporation loss, oxygen attack, acid, visible light and ultraviolet light and avoids intramolecularly and intermolecular reaction.

The general chemical formula of cyclodextrin is (C ₆O ₅H ₉) _nThe content of the clathrate host material in the theme invention compositions can be about 1 to 80wt%.Preferably, the content of clathrate host material can be about 1 to 60wt% in the present composition.The actual amount of used clathrate host material will depend on to a great extent and be used to prepare the cysteamine compound of the present composition and the actual content of additional therapeutic agent.

For using of this type of dosage of being provided for desirable therapeutic treatment, compositions of the present invention will comprise about 1% to about 99% at least a cysteamine compound usually, and at least a additional therapeutic agent and carrier and/or diluent are formed the remainder of total composition.Used dosage can be based on age, body weight, health or the sex of the individuality that will treat and is become.

Invent according to theme, the patient who is diagnosed as insulin resistance is used cysteamine compound and at least a additional therapeutic agent simultaneously preferably to make blood sugar level remain in the normal acceptable scope (to accept 90-130mg/dL after the fasting as ADA (American Diabetes Association)).

For some embodiment, when extra therapeutic agent is insulin, the preferred daily dose that comprises the compositions of cysteamine compound and insulin be about 0.1 to 400mg/kg body weight (BW) cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 0.1 to 50.0 units/kg BW insulin.Preferably, daily dose and insulin that will about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) be applied to the patient simultaneously.

When additional therapeutic agent be sulphanylureas (for example, glimepiride, glynase, glibenclamide, Glucotrol (Glucotrol) XL, Glucotrol, chlorpropamide, tolbutamide or tolazamide) time, the preferred daily dose that comprises the compositions of cysteamine compound and sulphanylureas is about 0.1 to 400mg/kg or 600mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 0.1 to 3,000mg sulphanylureas.Preferably, the daily dose and the sulphanylureas of about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) are applied to the patient simultaneously.

When biguanide (for example, metformin) and cysteamine compound were used simultaneously, the preferred dose of every kind of therapeutic agent was about 0.1 to 400mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 0.1 to 3,000mg biguanide.Preferably, daily dose and biguanide that will about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) be applied to the patient simultaneously.

For wherein (for example with at least a Alpha-glucosidase inhibitor, acarbose, miglitol) embodiment used simultaneously with cysteamine compound, the preferred daily dose of every kind of therapeutic agent is about 0.1 to 400mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 10 to 1,000mg Alpha-glucosidase inhibitor.Preferably, the daily dose and the Alpha-glucosidase inhibitor of about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) are applied to the patient simultaneously.

For wherein (for example with thiazolidinediones, rosiglitazone, pioglitazone) embodiment used simultaneously with cysteamine compound, the preferred daily dose of every kind of therapeutic agent is about 0.1 to arrive the 200mg thiazolidinediones to 400mg/kgBW cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 0.1.Preferably, the daily dose and the thiazolidinediones of about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) are applied to the patient simultaneously.

When meglitinide (for example, repaglinide) and cysteamine compound were used simultaneously, the preferred dosage of every kind of therapeutic agent was about 0.1 to arrive the 100mg meglitinide to 400mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 0.1.Preferably, the daily dose and the meglitinide of about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) are applied to the patient simultaneously.

For additional therapeutic agent wherein be the D-phenylalanine (for example, Nateglinide) embodiment, the preferred dosage that comprises the compositions of cysteamine compound and D-phenylalanine is about 0.1 to 400mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) and about 10 to 1,000mg D-phenylalanine.Preferably, daily dose and D-phenylalanine that will about 30mg/kg BW cysteamine (the perhaps cysteamine compound of equimolar amounts) be applied to the patient simultaneously.

More preferably, when with every day less than about 40mg/kg body weight, preferred every day is less than 2, when the daily dose of 000mg metformin is used simultaneously, be applied to the patient with the daily dose that causes desirable cysteamine of replying less than about 30mg/kg BW or littler (the perhaps cysteamine compound of equimolar amounts).Desirable seriousness, persistent period or intensity of replying the complication that can comprise that (1) is relevant with diabetes reduces; (2) adjusting during the metabolism of glucose is replied; (3) elimination of diabetes related complication; (4) the related indication treatment of diabetes or diabetes and/or alleviate; (5) outbreak of prevent diabetes and/or diabetes related complication, symptom or situation in symptom or asymptomatic patient are arranged.

Be to illustrate the embodiment that is used to implement step of the present invention below.These embodiment should be interpreted as qualification.Unless otherwise indicated, all percents all are by weight and all solvent mixture ratios all are by volume.

Embodiment 1

With 19 weight is that the male Goto-Kakizaki Wistar rat (GK rat) of 300 ± 20g remains in the steel cage every cage 3-4 rat.Per 2 days replacing cages.Indoor temperature and relative humidity remain on 23 ± 3 ℃ and 65 ± 1% respectively.Food and drinking water is provided.Allow the GK rat to adapt to 1 month.When the GK rat all shows diabetic symptom (that is, frequent feed, frequent drinking-water, frequent urination and high plasma glucose and insulin resistance), they are divided into 3 groups at random: 7 rats in the matched group; Every group of 6 rats among treatment group I and the II.

In earlier stage:

Tested preceding 1 day, and when 17:00, removed all feedstuffs, but do not remove drinking water from all groups.At second day 9:30; Measure the hungry plasma glucose of all GK rats.At 10:00, carry out glucose tolerance test (2g/kg BW) and measure the plasma glucose levels of all GK rats.At the 3rd day, to the GK rat oral administration of salt solution (2ml/ rat) of matched group and to the GK rat oral of treatment group I and II group use metformin solution (17mg/kg body weight (BW), every day at 9:30 once, each 2ml).Carry out this scheme in ensuing a couple of days.At the 9th day, measure hungry plasma glucose and once more all GK rats in all groups are carried out oral glucose tolerance test.

Mid-term:

At the 9th day, the scheme of GK rat changed dosage forms for oral administration metformin and Mercaptamine (metformin 17mg/kg BW, Mercaptamine 15mg/kgBW) in the treatment II group, continue 6 days, and the scheme of matched group and treatment I group remains unchanged.This scheme was carried out 6 days.

Late period:

After the change scheme 6 days, measure hungry plasma glucose and carry out the glucose tolerance test, and all the GK rats in all groups are collected blood and tissue samples (liver, duodenum, pancreas, fat and muscle).With blood sample be kept at 4 ℃ 3 hours and centrifugal 10 minutes with 3500 rev/mins.Then, collect serum and be kept at-20 ℃.Tissue sample is in case collection just places liquid nitrogen then-80 ℃ of preservations.

The glucose tolerance test of being carried out comprises the step of the hungry GK rat that spends the night.Second day 9:30 measures hungry plasma glucose.At 10:00, carry out the dosage forms for oral administration (2g/kgBW) of glucose solution.Collecting blood sample by the tail vein at 0,0.5,1,2 and 3 hour carries out with the plasma glucose test apparatus then.

The serology method of testing comprises by reflexive measures the mensuration serum insulin levels; With measure cholesterol, free fatty and triglyceride with known test kit and scheme.

During the early stage of this embodiment, mid-term and late period in all groups the per os glucose tolerance test result of GK rat respectively table 1,2 and 3 and Fig. 3,4 and 5 in show.Change of hungry plasma glucose levels shows in table and summarizes in Fig. 6 in during those.These results show that only the dosage forms for oral administration of metformin has reduced duodenum plasma glucose levels and insulin resistance to a certain extent.Yet, when metformin and Mercaptamine are used simultaneously, observe beat all improved result.Especially, when using metformin and Mercaptamine, plasma insulin and free fatty acid levels (indication diabetes) are lower than the level (seeing Fig. 7-10) of only using metformin (perhaps cysteamine compound).In addition, stop metformin/Mercaptamine after, the plasma insulin of reduced levels and free fatty will keep the longer time than the situation of only using metformin or cysteamine compound.

The glucose tolerance test that table 1-carried out in early stage
							Hungry	0.5 hour	1 hour	2 hours	3 hours
Matched group	5.87	15.57	15.37	10.91	7.31
						Treatment I	6.08	15.74	16.76	11.4	7.82
Treatment II	6.02	15.28	16.7	11.38	7.6

Table interim glucose tolerance test of carrying out among the 2-(behind the dosage forms for oral administration metformin 6 days)
							Hungry	0.5 hour	1 hour	2 hours	3 hours
Matched group	5.03	17.04	18.46	11.5	8.59
						Treatment I	4.98	15.68	15.93	10.55	8.5
Treatment II	5.03	15.65	15.8	10.55	8.37

The glucose tolerance test that table 3-carried out in late period (behind dosage forms for oral administration metformin+Mercaptamine 6 days)
							Hungry	0.5 hour	1 hour	2 hours	3 hours
Matched group	5.27	12.83	14.57	10.81	7.52
						Treatment I	4.57	12.98	13.42	8.6	6.67
Treatment II	4.77	11.75	12.37	8.17	6

Embodiment 2-uses metformin (to be higher than the dosage among the embodiment 1) simultaneously and cysteamine compound is expressed glucose metabolism in the diabetes rat, glucose transporter and the influence of adiponectin level

With 36 36 week age, body weight 321-323g Goto-Kakizaki Wistar (GK) rat (buying) from Shanghai Slaccas Laboratory Animal Center independent cage, adapt to animal facility.Food and water arbitrarily are provided.

36 GK rats are divided into 4 groups based on body weight (BW) and plasma glucose levels.(contrast is n=10) by gavage saline treatment (2ml/ rat) for group 1; (DC n=6) handles with Mercaptamine (22.5mg/kg BW in the 2ml tap water) by gavage group 2; (metformin, Met n=10) handle (34mg/kg BW in the 2ml tap water) by gavage with metformin to group 3; (Met+DC n=10) handled preceding 10 days with metformin 34mg/kg in the 2ml tap water group 4 in BW/ days, added that with the Mercaptamine 22.5mg/kg BW in the 2ml tap water metformin 34mg/kg BW handled back 10 days then.All animals are all handled when 10:10, coprocessing 20 days.

Four treated animals all remain in the different cages that have the metal mesh opening bottom in the same room (23 ± 3 ℃ of temperature, relative humidity 65 ± 1%), and the metal mesh opening bottom is in order to reduce the coprophagy in the whole experiment.Before carrying out glucose tolerance test with rat from evening 10:00 to the 09:30 overnight fast.Handle with the glucose 2g/kg BW in the 2ml tap water that rat carries out glucose tolerance test and behind glucose injection, collected blood from the tail vein in 0.5,1,2 and 3 hour at 09:30.(Roche Diagnostics, Basel Switzerland) measure plasma glucose concentration by Glucotrendr2 equipment.By radioimmunoassay (Insulin RIA Kit, NO:0410 buy from Shanghai RadioimmunoassayResearch Institution) plasma insulin concentration.Be displayed in Table 4 influence, be displayed in Table 5 influence, be displayed in Table 6 influence different tissues to plasma insulin and adiponectin level to plasma glucose levels." p " value is the comparison with matched group.

The glucose tolerance test of Mercaptamine (DC) and/or metformin in the table 4-GK diabetes rat (meansigma methods ± STD, mmol/L)
								N	Fasting	0.5 hour	1 hour	2 hours	3 hours
Contrast
		10	5.56±0.22	15.78±1.96	15.32±1.58	11.52±1.45	8.85±0.8
DC								6	5.80±0.36	16.68±1.1	15.68±0.8	11.00±0.8	8.33±0.64
	Metformin	10	5.53±0.53	15.24±1.34	13.98±0.95 *	9.62±0.83 *	7.71±1.37 *
Metformin+DC								10	5.46±0.46	14.07±1.84+	12.44±0.96 *	7.71±0.83 *	6.35±0.73 *

For the group of using metformin, (p＜0.05 is expressed as in the table 4 at 1 hour, 2 hours and the result that obtained in 3 hours and matched group significant difference ^*).When Mercaptamine and metformin were used simultaneously, (p＜0.05 was expressed as in the table 4 at 1 hour, 2 hours and result who obtained in 3 hours and the matched group of only using metformin significant difference ^*).For using metformin and Mercaptamine simultaneously, the result who obtained at 0.5 hour compares and reduces (p=0.059, be expressed as in the table 4+) with matched group.

Table 5-Mercaptamine (DC) and/or metformin to the influence of insulin (IU/L) in the GK diabetes rat and adiponectin (ng/ml) (meansigma methods ± STD, mmol/L)
					Meansigma methods ± STD	Contrast	CYS	Metformin	Metformin+DC
The fasting insulin	20.69±1.67	22.46±2.65	18.75±3.98	21.08±4.37
					?P		0.132	0.23	0.82
Adiponectin	3922±528	4318±590	3917±416	3743±366
					?P		0.034	0.971	0.206

Taking in the back about glucose only to use the result of glucose level of group of metformin significantly different with the statistics as a result of matched group separately with 3 hours time points at 1 hour, 2 hours from table 5.Only Mercaptamine does not influence glucose level or insulin level in the GK diabetes rat.Use that metformin causes reducing but be not the significant insulin level of statistics.Yet, when metformin and Mercaptamine are used simultaneously,, all observe improve (special when comparing) that reduces glucose level at all time points with the therapeutic effect of only using metformin except the fasting time point.Observing cysteamine significantly increases adiponectin, but only metformin but can not significantly increase adiponectin.

Influence (the meansigma methods ± STD), be expressed as the change multiple of comparing with control level that table 6-Mercaptamine (DC) and/or metformin or combination are expressed glucose transporter (glut4) in the different tissues of GK diabetes rat
					DC	Metformin	Metformin+DC
Liver	3.77±3.15	2.43±1.85	2.8±1.0
				p	0.002	0.31	0.04
Muscle	1.5±0.74	1.38±0.67	1.31±0.75
				p	0.001	0.152	0.633
Adipose cell	2.7±1.16	2.14±1.39	3.49±2.37
				p	0.005	0.095	0.095

As shown in table 6, cysteamine compound (as Mercaptamine) can significantly increase the expression of total glut4 in the liver, muscle, adipose cell of GK rat.Compare with muscle, in liver and adipose cell, should increase bigger.Metformin has also increased, but be not significantly increased the institute of measuring in a organized way in the total expression of glut4.Yet when metformin and cysteamine compound were used simultaneously, total glucose transporter (glut4) expression levels was further strengthened.

Embodiment 3-cysteamine compound use influence to diabetes rat

National diabetes reference center in China carries out the randomized test of little open label.Recruitment is diagnosed as 60 patients (age is 30 to 75 years old) of two kinds of sexes of type ii diabetes.All experimenters know the inside story and agree and participate in.WHO standard diagnosing diabetes based on setting in 1999.In addition, the standard below selected patient satisfies: (1) was less than the diabetic history in 5 years; (2) fasting plasma glucose levels is 7-14mmol/L; (3) serum triglyceride level is 2.5mmol/L or higher; (4) urine protein is drained to 30mg/ days or higher; (5) do not take in lipotropism class medicine and ACE inhibitor in the past in one month.Patient with following situation gets rid of outside this research: the malfunction of (1) heart, liver and/or kidney; (2) acute diabetes complication and/or any acute cardiovascular complication are arranged in the past in 3 months; (3) pregnancy or suckling.

The patient is divided into 4 groups at random, every group of 15 patients.The experimenter of matched group does not use antidiabetic medicine.Only the group of cysteamine (DC) is treated with 540mg/ days cysteamine hydrochloric acid.In only metformin (Met) is organized, during two months, keep the dosage of metformin constant.For DC+Met group, the patient remains on the metformin of the same dose of their initial application, comprises extra 100mg/ days cysteine hydrochloride.All patients carry out 2 months treatment, and collect when on-test, after 1 month and after 2 months and measuring samples is used for analyzing.

Table 7-Mercaptamine is to the influence of lipid in the diabetics and insulin
									Before the treatment	n	After the treatment	n	Pairing difference	95％CI	p
IGF ? ?	49.36± 5.75	10 ? ?	44.37± 7.28	10 ? ?	4.99±5.12 ?	1.33～8.65 ? ?	0.013 ? ?
								FINS ? ?	35.39± 14.43	6 ? ?	13.25±6.36 ? ?	6 ? ?	22.14± 19.39	1.79～42.5 ? ?	0.038 ? ?
? FCP	? 739±183	? 7	? 557±119	? 7	? 182±164	? 30.1～333.9	? 0.026
								? FBS	? 7.52±1.57	? 11	? 8.21±2.43	? 11	? -0.69±2.11	? -2.11～0.72	? 0.301
HOMA	11.94±4.62	6	5.43±3.19	6	6.51±4.94	1.32～11.7	0.023
								UA	389±50.98	11	359±60.16	11	29.5±37.87	4.07～54.95	0.027
24 hours Microalbuminurias	42.73± ? 31.33	8 ? ?	30.97± ? 25.12	8 ? ?	11.77± ? 40.73	-22.28～45.82 ? ?	0.441 ? ?

As shown in table 7, use cysteamine hydrochloric acid and significantly reduced fasting insulin (FINS), HOMA (homeostasis model evaluation) and blood uric acid (UA) level.Compare, when only using metformin, only among the IGF-1 reduction is arranged.These results show and can use cysteamine compound to improve insulin resistance to the patient.In addition, the result shows that using Mercaptamine has significantly reduced type-1 insulin like growth factor among the patient (IGF1), C peptide (CP) and Microalbuminuria (obviously but be not on the statistics significant), and this prompting cysteamine compound can be separately or made up with additional therapeutic agent and to be used for the treatment of or complication and Syndrome that prevent diabetes is relevant.Abbreviation FBS represents fasting serum glucose.

Embodiment 4-preparation

New compositions of the present invention comprises 1 and arrives 95wt% cysteamine compound and 1 to the 80wt% carrier, as the clathrate host material.In some embodiments, the therapeutic effect of the compositions of the present invention additional therapeutic agent that also comprises doses when guaranteeing to use simultaneously with cysteamine compound.

In this embodiment, the clathrate host material mainly comprises cyclodextrin and/or its derivant, and it is selected from methyl beta-schardinger dextrin-(M-β-CD), hydroxypropyl (HP-β-CD), ethoxy beta-schardinger dextrin-(HE-β-CD), cyclodextrin polymer, ethyl beta-schardinger dextrin-(E-β-CD) and branched cyclodextrin.And the work content that contains clathrate host material in the compositions of cysteamine is 1 to 80wt%, and can also use optimised working region is 1 to 60wt%, and more preferably working range is 10 to 40wt% clathrate host material.The actual amount of used clathrate host material will depend on and be used for preparing the compositions cysteamine compound that contains cysteamine and the actual content of additional therapeutic agent.

In certain embodiments, compositions prepared in accordance with the present invention is a granule agent form, and each granule preferably has and is essentially 0.28 to 0.90mm diameter.Use Microencapsulation Method to prepare these granules.This method relates to uses the macromolecular substances with enclose character.Operable a kind of material is above-mentioned clathrate host material (it mainly comprises cyclodextrin).The clathrate host material is a macromolecular substances, and it is involved in the molecule of cysteamine and/or additional therapeutic agent as minute ascus, thus cysteamine compound in the compositions and/or therapeutic agent are protected and with on every side light, heat, air and water separation from.Thereby preserved the stability of cysteamine compound.The clathrate host material that is used for Microencapsulation Method preferably has the cyclic polysaccharide chemical compound of 6 to 12 glucose molecules, and it is by reacting cyclodextrin FscM (glycosidtransferase) and starch to generation in the presence of bacillus cereus (Bacillus).Use acute, subacute and chronic toxicity test is carried out multiplely studies show that described macromolecular substances can reduce the toxic level among the patient.After the micro encapsulation process, each granule can be used one deck and the preferred above-mentioned coating material coating of multilamellar at least.

Be how to prepare above-mentioned examples of formulations below for cysteamine compound.In the reactor that adds cover (jacketed reactor) of the agitator that connects politef and the coating of equipment politef, mainly with nitrogen as air, add the 75wt% Mercaptamine solution in the 4080g ethanol.The purity of used cysteamine, fusing point and combustion residue (burning residue) preferably be respectively 98% or more than, 66-70 ℃ and 0.05% or below.Under nitrogen protection, add 1200g beta-schardinger dextrin-(The quality of ss-cyclodextrin is the requirement according to food additive) to reactor similarly then.Particularly, butt purity is higher than 98%; The weight saving that drying causes is less than 10.0%; Combustion residue is less than 0.2%; The content of heavy metal is less than 10ppm; Arsenic content is less than 2ppm).Then mixture was heated 3 hours at 40 ℃.Stop heating then and continue to stir 2 hours, afterwards with product behind vacuum drying under 40-50 ℃ the temperature, products therefrom is milled and sieves by sieve (for example, 40 meshes) filter.All parts that can contact with the composition of compositions of equipment will be preferably by the rustless steel manufacturing.

In the grooved blender, under the protection of dry environment, add 4200g (butt) cysteamine compound, 2600g filler and the 1200g disintegrating agent and the 1700g adhesive of experience enclose process as described.Then these compositions are fully mixed, and can add the dehydrated alcohol mixing with it then of Sq.The soft material that the representative of gained mixture has suitable hardness, thus it can gently hold the formation ball by palm.Then can be by touching with the spherical mixture fragmentation of gained.Under nitrogen protection by granulator with granulating mixture after, the agent of gained granule imports fluidized bed dryer immediately, and is dry under 40-50 ℃ the temperature in vacuum environment basically then.

Then by a kind of method with following formulation enteric coating material: Cellulose Acetate Phthalate 8.0g, polyethylene terephthalate 2.4ml, ethyl acetate 33.0ml and isopropyl acetate 33.6ml.Top gained granule is used one deck at least under nitrogen protection, the still preferred above-mentioned enteric coating material of multilamellar is coating equably.This enteric coating material is only solvable at alkaline environment.This can prevent cysteamine compound in advance from the compositions escape, and at this moment it is still in patient's stomach.As previously mentioned, cysteamine compound can stimulate the gastric mucosa of patient's stomach unfriendly.

To contain then cysteamine compositions the gained granule under the 40-50 ℃ of temperature in basic vacuum desiccator bone dry.Then, remove all solvents.Allow gained granule cool to room temperature then, microcapsule is mixed with the flavoring agent or the fumet of appropriate amount by the cantilever double spiral agitator.The compositions that contains cysteamine is a microcapsule, and there are Mercaptamine and cyclodextrin in its inside, its outside coating enteric coating material.

The compositions that is produced will demonstrate little granule (perhaps microgranule) shape, and it has smooth surface, good flowing property, and mixes with multiple animal feed easily.The diameter of each granule of compositions is preferably 0.28 to 0.90mm.Said composition also has advantages of excellent stability.Have been found that with compositions with the plastic bag packaging of sealing and nice and cool, dark and exsiccant local preserve 1 year after, their character remains unchanged.

Compositions and cysteamine compound with above-mentioned particular configuration self have been compared many functional advantage.At first, the activity of cysteamine compound that contains in the said composition and/or additional therapeutic agent obtains preserving after said composition is produced.Secondly, said composition will not cause the side effect of any significant stomach to the patient.The 3rd, the activity of said composition is not only during preservation preserved, and the more important thing is that when by gastrointestinal tract in the intestinal that arrives the patient time, the activity of compositions also obtains preservation.

This paper with reference to or all patents, patent application and the publication quoted all intactly (comprise figure and table) and be incorporated herein by reference, up to they not with the conflicting degree of clearly instruction of this description.

To understand embodiment described herein and embodiment only is used to illustrate purpose and will point out multiple modification or change and they will be included in the application's the spirit and scope to those skilled in the art.

Claims (48)

1. treat the method for diabetes, wherein said method comprises cysteamine compound and at least a additional therapeutic agent of the patient being used simultaneously effective dose.

2. according to the process of claim 1 wherein that diet that described additional therapeutic agent is selected from medical compounds based on gene, insulin, sulphanylureas, insulin succagoga, Alpha-glucosidase inhibitor, biguanide, meglitinides, thiazolidinediones, D-phenylalanine, physical training, improvement takes in and lose weight.

3. according to the process of claim 1 wherein that the effective dose of described cysteamine compound that the patient is used is less than about 400mg/kg body weight or equimolar amounts.

4. according to the method for claim 3, wherein the effective dose of the described cysteamine compound that the patient is used is about 30mg/kg body weight or equimolar amounts.

5. according to the process of claim 1 wherein that described cysteamine compound is selected from the prodrug of cysteamine, cysteamine salt, cysteamine, cysteamine analog, cysteamine derivant, cysteamine conjugate and cysteamine metabolite.

6. according to the method for claim 5, wherein said cysteamine compound is Mercaptamine, cysteamine phosphate, pantothenic acid or cystamine.

According to the process of claim 1 wherein described cysteamine compound and additional therapeutic agent per os, parenteral, intravenous, intramuscular, percutaneous, by buccal approach, subcutaneous or use by suppository.

8. according to the process of claim 1 wherein that described additional therapeutic agent is a biguanide.

9. method according to Claim 8, wherein said additional therapeutic agent is a metformin.

10. according to the method for claim 9, wherein the effective dose of metformin is that every day is less than about 40mg/kg body weight.

11. according to the process of claim 1 wherein that described additional therapeutic agent is insulin and blood sugar lowering chemical compound.

12. reduce the method for seriousness, intensity and/or the persistent period of the complication relevant with diabetes, wherein said method comprises cysteamine compound and at least a additional therapeutic agent of the patient being used simultaneously effective dose, and the effective dose of wherein said cysteamine compound is less than the 400mg/kg body weight.

13. according to the method for claim 12, wherein the described cysteamine compound that the patient is used is that effective dose is about 30mg/kg body weight or equimolar amounts.

14. according to the method for claim 12, the diet that wherein said additional therapeutic agent is selected from medical compounds based on gene, insulin, sulphanylureas, insulin succagoga, Alpha-glucosidase inhibitor, biguanide, meglitinides, thiazolidinediones, D-phenylalanine, physical training, improvement is taken in and is lost weight.

15. according to the method for claim 12, wherein said cysteamine compound is selected from prodrug, cysteamine analog, cysteamine derivant, cysteamine conjugate and the cysteamine metabolite of cysteamine, cysteamine salt, cysteamine.

16. according to the method for claim 15, wherein said cysteamine compound is Mercaptamine, cysteamine phosphate, pantothenic acid or cystamine.

17. according to the method for claim 12, wherein said cysteamine compound and additional therapeutic agent per os, parenteral, intravenous, intramuscular, percutaneous, by buccal approach, subcutaneous or use by suppository.

18. according to the method for claim 12, wherein said additional therapeutic agent is a biguanide.

19. according to the method for claim 18, wherein said additional therapeutic agent is a metformin.

20. according to the method for claim 19, wherein the effective dose of metformin is that every day is less than about 40mg/kg body weight.

21. according to the method for claim 12, wherein said additional therapeutic agent is insulin and blood sugar lowering chemical compound.

22. according to the method for claim 12, wherein relevant with diabetes complication is selected from dermatosis, bacterial infection, fungal infection, diabetic dermatopathy, necrobiosis lipoidica, the diabetic vesicle, the dermexanthesis xanthomatosis, allergic skin reaction, the sclerosis of finger/toe, DGA, acanthosis nigricans, gum disease, ocular disorders, glaucoma, cataract, retinopathy, kidney disease, neuropathy, the systematicness neuropathy, tip systematicness polyneuropathy, the nearside neuropathy, femoral neuropathy, neuropathic antrhropathy, the cranial nerve disease, the vegetative nerve disease, pressuring nerve disease and diabetic muscular dystrophy, gout, cardiovascular disease/disease, hypertension, heart disease, heart attack, and apoplexy.

23. the method for prevent diabetes or the outbreak of diabetes related complication, wherein said method comprises cysteamine compound and at least a additional therapeutic agent of the patient being used simultaneously effective dose, and wherein the effective dose of cysteamine compound is less than the 400mg/kg body weight.

24. according to the method for claim 23, wherein the effective dose of the cysteamine compound that the patient is used is about 30mg/kg body weight or equimolar amounts.

25. according to the method for claim 23, the diet that wherein said additional therapeutic agent is selected from medical compounds based on gene, insulin, sulphanylureas, insulin succagoga, Alpha-glucosidase inhibitor, biguanide, meglitinides, thiazolidinediones, D-phenylalanine, physical training, improvement is taken in and is lost weight.

26. according to the method for claim 23, wherein said cysteamine compound is selected from prodrug, cysteamine analog, cysteamine derivant, cysteamine conjugate and the cysteamine metabolite of cysteamine, cysteamine salt, cysteamine.

27. according to the method for claim 26, wherein said cysteamine compound is Mercaptamine, cysteamine phosphate, pantothenic acid or cystamine.

28. according to the method for claim 23, wherein said cysteamine compound and additional therapeutic agent per os, parenteral, intravenous, intramuscular, percutaneous, by buccal approach, subcutaneous or use by suppository.

29. according to the method for claim 23, wherein said additional therapeutic agent is a biguanide.

30. according to the method for claim 29, wherein said additional therapeutic agent is a metformin.

31. according to the method for claim 30, wherein the effective dose of metformin is that every day is less than about 40mg/kg body weight.

32. according to the method for claim 31, wherein said additional therapeutic agent is insulin and blood sugar lowering chemical compound.

33. compositions, it comprises at least a additional therapeutic agent of the cysteamine compound and the effective dose of effective dose.

34. according to the compositions of claim 33, wherein said additional therapeutic agent is selected from medical compounds, insulin, sulphanylureas, insulin succagoga, Alpha-glucosidase inhibitor, biguanide, meglitinides, thiazolidinediones and the D-phenylalanine based on gene.

35. according to the compositions of claim 33, it also comprises the clathrate host material.

36. according to the compositions of claim 35, wherein said clathrate host material is selected from cyclodextrin, M-β-CD, HP-β-CD, HE-β-CD, cyclodextrin polymer, E-β-CD and branched cyclodextrin.

37. according to the compositions of claim 33, wherein the effective dose of cysteamine compound is less than the 400mg/kg body weight.

38. according to the compositions of claim 37, wherein the effective dose of the cysteamine compound that the patient is used is about 30mg/kg body weight or equimolar amounts.

39. according to the compositions of claim 33, wherein said additional therapeutic agent is a biguanide.

40. according to the compositions of claim 39, wherein said additional therapeutic agent is a metformin.

41. according to the compositions of claim 40, the effective dose of wherein said additional therapeutic agent is that every day is less than about 40mg/kg body weight.

42. regulate the method for at least a biological factor among the patient who is diagnosed as diabetes, it comprises cysteamine compound and at least a additional therapeutic agent of the patient being used simultaneously effective dose, wherein said biological factor is selected from: type-1 insulin like growth factor, C peptide, free fatty, blood uric acid, adiponectin, glucose transporter, triglyceride, low density lipoprotein, LDL, and high density lipoprotein.

43. according to the method for claim 42, wherein said biological factor influences insulin sensitivity.

44. according to the method for claim 43, the described biological factor that wherein influences insulin sensitivity is a glucose transporter.

45. method according to claim 42, wherein said biological factor is the development of diabetes in patients related complication or situation or the factor in the diagnosis, wherein uses described diabetes related complication or situation among described cysteamine compound and the additional therapeutic agent treatment patient simultaneously.

46. according to the method for claim 42, wherein said biological factor is the development of diabetes in patients or the factor in the diagnosis, wherein uses the diabetes among described cysteamine compound and the additional therapeutic agent treatment patient simultaneously.

47. the method for the outbreak of diabetes or diabetes related complication among the prevention asymptomatic patient, it comprises:

Be evaluated at the existence of label among the patient before the clinical episodes of diabetes; With

This patient is used cysteamine compound and at least a additional therapeutic agent simultaneously.

48. according to the method for claim 47, wherein said label is selected from autoantibody (IAA) at insulin, at the autoantibody (ICA) of islet cells, and glutamate decarboxylase (GAD).

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