CN101325959A - Combination therapy for controlled carbohydrate digestion - Google Patents
Combination therapy for controlled carbohydrate digestion Download PDFInfo
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Abstract
Compositions that include combinations of agents that inhibit carbohydrate degradation, decrease formation or severity of intestinal gas, and/or modulate insulin signalling or blood glucose levels are described. Methods of administering these compositions are also described, for example, to reduce or prevent post-prandial glucose spikes.
Description
The α alpha-glucosidase inhibitors is to suppress digestive enzyme such as amylase, saccharase, maltase and limit dextrinase, to reduce the chemical compound of starch and sugar digestion.The disaccharide of these enzyme catalysis enteral resolves into monosaccharide.By slowing down this process, the α alpha-glucosidase inhibitors reduces acute post-prandial hyperglycemia.The example of α alpha-glucosidase inhibitors comprises acarbose, miglitol and voglibose, and (N-1 (1,3-dihydroxy-2-propyl group) derivant that replaces of valienamine (valiolamine) and N-thereof (referring to, U.S.5 for example, 004,838), the false amino sugar that N-replaces (referring to, for example US 4,595,678)).
Acarbose is the zymoid inhibitor of glucosidase in a kind of small intestinal, also is the inhibitor of pancreatic alpha amylase.Acarbose is O-4,6-dideoxy-4-[(1S, and 4R, 5S, 6S)-4,5,6-trihydroxy-3-(methylol)-2-cyclohexene-1-base is amino]-α-D-glucopyranosyl-(1 → 4)-O-α-D-glucopyranosyl (1 → 4)-D-Glucopyranose..This inhibitor can obtain (referring to German patent specification 2,209,832 by fermentation actinoplanes (Actinoplanes) species, German patent specification 2,209,834, German patent specification 2,064,092), and can from fermentation broth, separate.Purification process for this purpose (referring to German patent specification 2,347,782 and German patent specification 2,719,912) has been described.U.S.4,904,769 have described the method for the highly purified preparation of preparation acarbose.Also referring to, U.S.6 for example, 150,568.
As the inhibitor of α glucosidase, acarbose is a carbohydrate digestion, for instance, and the example of the active inhibitor of carbohydrase.The typical inhibitor of other of carbohydrate digestion comprises that voglibose (valienamine), miglitol and its N-substitutive derivative (see, for example, the U.S. 5,004,838) and N-replace vacation-amino sugar (see, for example, the U.S. 4,595,678).
By suppressing glucosidase, the digestion of acarbose delays complex carbohydrate and the absorption of glucose subsequently cause the less rising of blood sugar concentration after the meal.Acarbose can reduce GLPP (PPG) peak.
On the one hand, of the present disclosure being characterised in that regulated insulin signaling conduction or blood sugar level, for example, and the method for post-prandial glucose and/or fasting glucose level.This method comprises: give two or more in the following material of experimenter: (i) suppress first medicament of carbohydrate degradation, (ii) reduce by second medicament of the formation of intestinal gas or seriousness and (iii) regulate the 3rd medicament of insulin signaling conduction or blood sugar level, preferably give all above-mentioned three kinds of medicaments, for example, the combination of above-mentioned three kinds of medicaments.The administration that can customize these medicaments is to reduce or to prevent postprandial glucose spikes.
" unite and give " as used herein and mean two or more medicaments in the identical time or in certain intervals, give the experimenter, have every kind of medicament overlapping to patient's effect like this.Preferably, the administration of described medicament is spaced apart fully and is close together, so that obtain combined effect.This interval can be the interval in a few minutes, several hours, several days or several weeks.Usually, but described medicament is the while biological utilisation in the experimenter, and is for example, detectable.First medicament, second medicament and the 3rd medicament can give with random order, perhaps to comprise two or more one or more dosage form administrations in the described medicament.In preferred embodiments, one of described at least medicament, for example the administration of first medicament is at another kind of medicament for example in a few minutes, 1,2,3 or 4 hour of second medicament or the 3rd medicament administration, perhaps or even carry out in 1 day or 2 days.In some cases, combination can obtain collaborative result, that is, greater than add and the result, for example than adding and result greatly at least 20,50,70 or 100%.
For some embodiment, two kinds of medicaments formulated together be particularly advantageous, for example, in single pill (for example, tablet or gel).Provide the use of the single pill of moderate dose (for example, being used for adult or child) can improve compliance and be easy to administration.
In preferred embodiments, first medicament, second medicament and the 3rd medicament are formulated as single pill (for example, tablet, gel or other dosage device) jointly, are used for administration together.In another embodiment, give α alpha-glucosidase inhibitors and the 3rd medicament (for example chlorine returns benzoic acid class medicine) in ante cibum, and (for example giving second medicament after the meal
Or simethicone).For example, can one day twice or three administrations, for example, required according to the quantity and the capacity of having meal.
Described method can be regulated the carbohydrate utilization in experimenter's gastrointestinal tract.Typically, the experimenter is the human experimenter.The experimenter has normal or off-note, for example, and about metabolic characteristics, for example, the experimenter of normal or unusual glucose tolerance.For example, the experimenter can have normal blood glucose response.In another example, the experimenter is that glucose does not tolerate for standard or has glucose tolerance reduction (IGT).In another example, the experimenter suffers from diabetes, for example, and type ii diabetes or the trouble diabetes are arranged, for example, the risk of type ii diabetes.In another example also, the experimenter suffers from big vascular obstacle or dysbolismus, for example, and X syndrome or the big vascular obstacle of suffering from or dysbolismus are arranged, for example, the risk of X syndrome.The experimenter is normally human, for example, and adult or child.
Typically, so that second medicament is preferentially at the specific part of intestinal, for example the mode that works in the ileum gives this second medicament.
In one embodiment, give first medicament and second medicament simultaneously.For example, first medicament and second medicament is formulated together.In another embodiment, give first medicament and second medicament in the different time.For example, can before the meal or during, for example give first medicament, and can give second medicament after the meal with initial a bite.Can combine with every meal and give first medicament and second medicament, for example before every meal, for example, one day about two, three or four times.
In one embodiment, give first medicament and the 3rd medicament simultaneously.For example, first medicament and the 3rd medicament is formulated together.In another embodiment, give first medicament and the 3rd medicament in the different time.
In one embodiment, first medicament is a glucosidase, for example, and the inhibitor of alpha-Glucosidase.For example, first medicament comprises:
Formula (I)
Each R
1Be H, C independently
1-C
6Alkyl, C (O) R
3Or aryl alkyl;
R
2Be C
1-C
6Alkyl;
Each R
3Be C independently
1-C
6Alkyl or aryl,
X, Y and Z are NR independently of one another
4Or O; And
Each R
4Be H, alkyl or aryl alkyl independently.
In some preferred embodiments, X is NR
4, NH for example.In some preferred embodiments, Y and Z are O.In some preferred embodiments, at least 3
R1 part is H, for example, and each R
1Be H.In some preferred embodiments, R
2It is methyl.
The example of preferred moieties comprises methyl, ethyl and propyl group.The example of preferred aryl groups moieties comprises benzyl and phenethyl.Preferred C (O) R
3The example of part comprises acetyl group.
Term " alkyl " refers to hydrocarbon chain, and it can be a straight or branched, comprises the carbon number of indicating.For example, C
1-C
10Show that group can have 1-10 (comprising end value interior) carbon atom therein.Term " aryl alkyl " refers to the alkyl that replaces with aryl.Term " aryl " refers to the monocycle of 6-carbon, the bicyclo-of 10-carbon or the trinucleated aromatic ring of 14-carbon, and wherein 0,1,2,3 or 4 of each ring atom can be substituted the base replacement.The example of aromatic yl group comprises phenyl, naphthyl or the like.
Voglibose (a kind of disaccharide) is a kind of intestinal Alpha-glucosidase inhibitor.Voglibose suppresses alpha-Glucosidase.These enzymes are decomposed into monosaccharide at enteral catalysis disaccharide.By slowing down this process, voglibose reduces acute post-prandial hyperglycemia.
In preferred embodiments, first medicament is an acarbose.In another embodiment, first medicament is voglibose, miglitol or the like.Miglitol is a deoxidization nojirimycin derivative, and chemically is being called 3,4,5-piperidines triol, and 1-(2-ethoxy)-2-(methylol)-, [2R-(2 α, 3 β, 4 α, 5 β)].It can prepare from white to the pale yellow powder.It has 207.2 molecular weight.The miglitol water soluble, and the pKa value is 5.9.Its empirical formula is C
8H
17NO
5
In another embodiment, first medicament is from the chemical compound of natural existence source as extracting in the Salacia prinoides (Willd.) DC. platymiscium (for example, Salacia prinoides (Willd.) DC., salacia reticulata (Salacia reticulata) or Salacia oblonga).For example, first medicament is:
(salacinol), or:
(kotalanol)。These chemical compounds are representational naturally occurring α alpha-glucosidase inhibitors.In other example, described chemical compound can be the chemical compound that extracts from Cinnamomum zeylanicum Bl. (Cinnamomumzeylanicum), Fructus Artocarpi Heterophylli (Artocarpus heterophyllus), Tinosooracordifolia (Tinosporacordifolia) or Lignum pterocarpi indici (Pterocarpus marsupium).
In one embodiment, second medicament comprises the enzyme of digested carbohydrate.Can give numerous second different medicaments, for example, the mixture of the enzyme of digested carbohydrate.Exemplary enzyme comprises α tilactase, α glucosidase and β glucosidase.Typical example is
In another embodiment, second medicament comprises it maybe can being defoamer, for example simethicone.Exemplary defoamer is not by the defoamer of intestinal absorption.
Can prepare second medicament preferentially to send the distal location of second medicament to colon.For example, second medicament can be formulated as the compositions of time-delay release or the compositions of position dependent release.The example of location-dependent release compositions comprises the preparation that pH sensitive formulation and enzyme trigger.In one embodiment, second medicament is prepared by enteric encapsulation.
In one embodiment, the 3rd medicament is the insulin secretion enhancers that promotes from the pancreatic beta cell excreting insulin.The example of insulin secretion enhancers is a sulfonylureas, for example, tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N[(1-pyrrolidinyl amino (pyrolidinylamino)) carbonyl]-benzsulfamide (adopted name: glycopyramide) or its ammonium salt, glibenclamide, gliclazide, 1-butyl-3-metanilyl urea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepide, glybuthiazole, glibuzole, glyhexamide, 2-benzenesulfonamido-5-(.beta.-methoxyethoxy)pyrimidine, glypinamide, Phenbutamide, metahexamide or the like, or its esters.Insulin secretion enhancers also comprises N-[4-(1-Methylethyl) cyclohexyl] carbonyl]-D-phenylalanine (AY-4166), (2S)-2-benzyl-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) calcium propionate dihydrate (KAD-1229) and glimepiride (Hoe 490).
In one embodiment, the 3rd medicament is a for example metformin of biguanides
Metformin hydrochloride or long-acting QD metformin
In one embodiment, the 3rd medicament is an euglycemic agent, for example rosiglitazone or pioglitazone.Other typical insulin sensitizer comprises 4-[4-[2-(5-methyl-2-Ben Ji oxazole-4-yl) ethyoxyl] benzyl] isoxazole alkyl-3; 5-diketone (JTT-501) or its salt; 5-[[3; 4-dihydro-2-(phenyl methyl)-2H-1-.alpha.-5:6-benzopyran-6-yl] methyl]-2; englitazone) or its salt (particular certain cancers) 4-thiazolidinedione (adopted name:; 5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl] phenyl] methyl]-2; 4-thiazolidinedione (adopted name: darglitazone/CP-86325) or its salt (particular certain cancers); 5-[2-(5-methyl-2-phenyl-4-oxazolyl methyl) benzofuran-5-ylmethyl]-2; 4-oxazolidinedione (CP-92768) or its salt; 5-(2-naphthyl sulfonyl)-2; 4-thiazolidinedione (AY-31637) or its salt; the 4-[(2-naphthyl) methyl]-3H-1; 2; 3; 5-Evil thiadiazoles-2-oxide (AY-30711) or its salt; 5-[[6-(2-fluorobenzene methyl oxygen base)-2-naphthyl] methyl]-2; 4-thiazolidinedione (MCC-555) or its salt; [5-[(2; 4-dioxo Thiazolidine-5-yl) methyl]-2-methoxyl group-N-[[4-(trifluoro acute pyogenic infection of nails base) phenyl] methyl] benzamido (AHG-255) or its salt; 4-[1-(3; 5; 5; 8; 8-pentamethyl-5; 6; 7; 8-naphthane-2-yl) vinyl] benzoic acid (LGD1069) or its salt; 6-[1-(3; 5; 5; 8; 8-pentamethyl-5; 6; 7; 8-naphthane-2-yl) cyclopropyl] nicotinic acid (LGD 100268) or its salt; 1; two [the 4-[(3 of 4-; 5-dioxo-1; 2; 4-oxadiazole alkane-2-yl) methyl] phenoxy group]-2-butylene (YM-440) or its salt, or the like.
In one embodiment, the 3rd medicament is to increase the medicament that insulin produces, for example, and the meglitinides medicine, for example, Nateglinide, repaglinide or Mitiglinide.For example, the 3rd medicament is the chemical compound of following formula:
Wherein A represents heterocyclic group, 3 to 8-unit's group of naphthene base or phenyl groups, and it can have one or more substituent groups, and this substituent group is selected from halogen atom, has the low alkyl group of 1 to 6 carbon atom and has the lower alkoxy groups of 1 to 6 carbon atom;
B represents the amino group of dicyclo, and it can have 1 or 2 unsaturated bond, and condition is that B combines with the carbon atom of carbonyl on nitrogen-atoms;
R represents hydrogen atom or mutually combines the formation chemical bond;
R
1The expression hydrogen atom, have the low alkyl group of 1 to 6 carbon atom or have the aralkyl of 7 to 10 carbon atoms; When having asymmetric carbon atom, be its enantiomer and its racemic mixture.When having geometric isomer, this chemical compound can have every kind of geometric isomer, its E-isomer, its Z-isomer, its cis-isomer and its trans-isomer and its pharmaceutically acceptable salt class.
The example of formula (I) chemical compound comprises those that are expressed from the next:
Wherein Y represents halogen atom, has the low-grade alkyl group of 1 to 6 carbon atom or has the lower alkoxy groups of 1 to 6 carbon atom, and n represents 0,1 or 2, and other group defines suc as formula (I);
Wherein Y and n as defined above and Z represent ethylidene group or vinylene group;
Wherein Y and n as defined above and Z represent that ethylidene group or ethenylidene group and other group define suc as formula (I);
And its enantiomer and its racemic mixture and its pharmaceutically acceptable salt class;
Wherein use the C of (S) labelling to represent the carbon atom of S-configuration and its pharmaceutically acceptable salt class.
In one embodiment, the medicament that increases the insulin generation is: (E)-and 2-benzal-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, (E)-2-benzal-3-(cis-3a, 4,7,7a-tetrahydrochysene-2-iso-dihydro-indole-group carbonyl)-propanoic acid, (E)-2-benzal-3-(trans-decahydro-2-isoquinolyl carbonyl) propanoic acid, (E)-2-benzal-3-(trans-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, (E)-2-(4-methyl benzal)-3-(cis-3a, 4,7,7a-tetrahydrochysene-2-iso-dihydro-indole-group carbonyl) propanoic acid, (E)-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-methyl benzal) propanoic acid, (E)-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-isopropyl benzal)-propanoic acid, (E)-2-(4-chlorine benzal)-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, (E)-2-(2-fluoro benzal)-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, (E)-2-(2-ethyoxyl benzal)-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, (E)-2-(2, the 6-dichlorin benzylidene)-3-(cis-six hydrogen-2-iso-dihydro-indole-group) propanoic acid, (E)-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-thenylidene) propanoic acid, (E)-2-cyclohexylmethylene-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, 2-benzyl-3-(trans six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, 2-benzyl-3-(trans-six hydrogen-1-indolinyl carbonyl) propanoic acid, 2-benzyl-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-propanoic acid, (S)-2-benzyl-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, (R)-2-benzyl-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, 2-benzyl-3-(cis-3a, 4,7,7a-tetrahydrochysene-2-iso-dihydro-indole-group carbonyl) propanoic acid, 3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(4-methylbenzene methyl) propanoic acid, 3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-methyl-benzyl) propanoic acid, 3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-mehtoxybenzyl) propanoic acid, 3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-propoxyl group benzyl)-propanoic acid, 2-(2,6-dimethyl benzene methyl)-3-(cis-six-hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, 3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl)-2-(2-thenyl) propanoic acid and 2-cyclohexyl methyl-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid, and most preferred is (S)-2-benzyl-3-(cis-six hydrogen-2-iso-dihydro-indole-group carbonyl) propanoic acid.
The 3rd medicament is normally by suppressing the medicament that carbohydrate degradation mechanism in addition plays a role.
Described method can comprise uses acarbose or the first other medicament, for example, the acarbose of effective dose or first medicament, for example, with second medicament combination, with the combination of the 3rd medicament, or with the second and the 3rd the two combination of medicament.Can use these methods, for example, treat or prevent metabolism disorder, for example, metabolism syndrome (for example, X syndrome), obesity, diabetes or the like." metabolism disorder " refers to those skilled in the art wherein will detect a kind of obstacle that the physiology changes among the experimenter, and this changes and changes at least a material, for instance, and the metabolism of carbohydrate or fat.
Metabolism syndrome (for example, the X syndrome insulin resistance relevant with syndrome) shows among the patient who has one group of metabolic risk factors.These factors comprise: central obesity (excess fats tissue be in abdominal part and on every side), atherogenic dyslipidemia (dyslipidemia) (high triglyceride of blood fat fat imbalance-mainly be and low HDL cholesterol-its promote the assembly of speckle on arterial wall); The not anti-disease of insulin resistance or glucose (for example, health can not suitably use insulin or blood glucose); Short thrombosis (prothrombotic) state (for example, high fibrinogen in the blood or plasminogen activator inhibitor [1]); Elevated blood pressure (130/85mmHg or higher); And short inflammatory conditions (the high sensitivity c reactive protein that for example, raises in the blood).Overweight/obesity, health inertia and inherited genetic factors can promote this syndrome.The people who suffers from metabolism syndrome have the trouble coronary heart disease of increase, with arterial wall on speckle assemble the relevant other diseases (for example, apoplexy and peripheral blood vessel) and the risk of type 2 diabetes mellitus.Metabolism syndrome can be the insulin resistance that is closely related.
In one embodiment, metabolism disorder is diabetes, for example type 2 diabetes mellitus.For example, the patient can be normal (for example, with respect to blood sugar level), and its glucose tolerance reduces (IGT), so-called prediabetes experimenter or diabetic subjects.The patient may have on an empty stomach hyperglycemia, for example, and the patient who does not have diabetic character and have the fasting glucose level of 100-125 milligram/dL in others.The example of diabetes comprises insulin-dependent diabetes and noninsulindependent diabetes.For example this method comprises to suffering from diabetes or having the patient who suffers from risk of diabetes to use combination of compounds described here.In some instances, can identify that the patient has the danger of development diabetes by glucose tolerance reduction (IGT) or empty stomach hyperglycemia are arranged.
For example, chemical compound as herein described can give the experimenter with the treatment effective dose and reduce glyconeogenesis, improves glucemia (glycemic) control (for example, reducing fasting glucose) or makes insulin sensitivity normalization.This chemical compound can suffer from the experimenter of diabetes or obesity.
Insulin dependent diabetes mellitus (IDDM) (type 1 diabetes) is a kind of autoimmune disease, and wherein insulitis causes the destruction of the J-cell of pancreas.When the type 1 diabetes clinical episodes, the β cell of a considerable amount of generation insulins is destroyed, only has 15%-40% still can produce insulin (people such as McCulloch,, Diabetes 40:673-679 in 1991).Beta cell failure cause to every day injection of insulin lifelong dependence and the acute and late complication that is exposed to this disease.
Type 2 diabetes mellitus is the impaired metabolic disease of a kind of glucose homeostasis, is characterised in that the too high or hyperglycemia of blood glucose, as showing as the damaged property insulin action of insulin resistance, damaged property insulin secretion or both results.The patient who suffers from type 2 diabetes mellitus has and insulin resistance and/or impaired relevant abnormal carbohydrate, lipid and the protein metabolism of insulin secretion.This disease causes the β cytoclasis and the last absolute insulin deficit of pancreas.During no insulin, there is high glucose level in the blood.That the long term effect of high blood-glucose comprises is blind, renal failure and to the bad blood circulation at these positions, and it can cause foot and ankle excision.Preventing that the patient from reaching in this seriousness, earlier detection is crucial.The patient that great majority suffer from diabetes suffers from non-insulin-dependent diabetes mellitus, is referred to as type 2 diabetes mellitus at present.
The inhibitor of acarbose or other alpha-glucosidase activity can be united use with second medicament or the 3rd medicament or the two, treat or prevent big vascular obstacle, for example atherosclerosis, apoplexy, peripheral blood vessel, myocardial infarction and renal vascular.For example, this method can be used for multiple experimenter, for example be used for the normal subjects, be used to have this obstacle hereditary inducement the experimenter or be used to have the symptom that shows this obstacle or the experimenter of medical history, for example, suffered from the heart attack the experimenter or be diagnosed as experimenter with this obstacle.
Acarbose has side effect, comprises flatulence and stomachache.The acarbose treatment has gastrointestinal (GI) side effect, comprises gastrointestinal gas, abdominal pain and diarrhoea.This side effect is by a lot of patient experience mistakes, particularly when treatment beginning and higher dosage.When excessive indigested carbohydrate enters the bottom of small intestinal, do not decomposed fully, thereby, when producing carbon dioxide, cause this side effect probably by bacterial metabolism by the enzyme in the intestinal down.
By beginning with low dosage and slowly progressively increasing dosage, can regulate side effect to a certain degree, for example in the process of several months.In addition, some side effect can be gone down in time at least, because the endogenous enzyme level of patient's intestinal bottom is raised, causes less carbohydrate to be utilized by intestinal flora.The seriousness of this side effect alleviates, and does not influence the effect of acarbose, because the carbohydrate of taking in is still delayed to enter blood flow.Further alleviate the discomfort of side effect, for example in during the interval (before the patient is in the dosage of expectation, can span several weeks to the interval of several months) that acarbose dosage just progressively increases with alleviate social and health.By improving compliance, on the basis of " planning to treat ", alleviate the effect that side effect also can improve acarbose.
Disclosed herein is to be used for alleviating acarbose or to suppress carbohydrate degradation, for example, and the whole bag of tricks of the other medicament side effect of alpha-glucosidase activity.
On the other hand, the method for using acarbose to the experimenter that is characterised in that of the present disclosure.This method comprises: unite to the experimenter with the medicament that reduces the formation of intestinal gas or its seriousness and use acarbose, this medicament is so that the mode administration that medicament preferentially plays a role in intestinal or colon.This method also can comprise uses the 3rd medicament, for example, regulates the medicament of insulin signaling conduction or blood sugar level, for example, and by changing insulin secretion or insulin sensitivity.
The example that reduces the medicament of intestinal gas formation comprises the enzyme of digested carbohydrate.Can use the multiple second different medicament, for example, the mixture of digested carbohydrate enzyme.Typical enzyme comprises α tilactase, alpha-Glucosidase and β-Pu Tangganmei.The example that reduces the medicament of intestinal gas seriousness comprises defoamer, for example, and simethicone.
Can be formulated to preferentially deliver the agent to the colon distal location.For example, medicament is formulated as time-delay release composition or position dependence release composition prepare.The example of position dependence release composition comprises pH sensitive formulation and enzyme triggering property preparation.In one embodiment, second medicament is prepared by enteric encapsulation.
In one embodiment, reduce the medicament of intestinal gas formation and use after meal, and acarbose is to carry out administration before the meal.
On the other hand, the method for using acarbose to the experimenter that is characterised in that of the present disclosure.This method comprises: unite to the experimenter with defoamer and use acarbose.Can use acarbose and defoamer to the experimenter just before the meal at each, at interval for example, at least 10,20,30 or 50 days.In one embodiment, at the interval, during 30 days of beginning, the dosage of acarbose increases with one or more increments for instance.In one embodiment, at the interval, during 30 days of beginning, the dosage of defoamer reduces with one or more decrements for instance.At interval, use for instance after the beginning 30 days of acarbose and defoamer, use acarbose, without defoamer.
On the other hand, the method that is characterised in that the blood sugar regulation level of the present disclosure.This method comprises: unite to the experimenter with the medicament that reduces formation of intestinal gas or seriousness and use acarbose, this medicament is so that the mode administration that medicament preferentially plays a role in intestinal or colon.
On the other hand, the method that is characterised in that treatment or prevent diabetes or diabetes associated disorders of the present disclosure.This method comprises: unite to the experimenter who suffers from diabetes, IGT or empty stomach hyperglycemia with the medicament that reduces formation of intestinal gas or seriousness and use acarbose, this medicament is so that the mode administration that medicament preferentially plays a role in intestinal or colon.
On the other hand, big vascular obstacle, the method for apoplexy, myocardial infarction or peripheral vascular disease are for instance treated or prevented to of the present disclosure being characterised in that.This method comprises: unite to the experimenter with the medicament that reduces formation of intestinal gas or seriousness and (for example use the α alpha-glucosidase inhibitors, acarbose), this medicament is so that the mode administration that medicament preferentially plays a role in intestinal or colon, and at least a symptom or the procatarxis of big whereby vascular obstacle are improved.Typical medicament comprises sugared lyases (for example, alpha-galactosidase or β-Pu Tangganmei) and defoamer, for example, and simethicone.
On the other hand, the pharmaceutical preparation that is characterised in that two or more (for example, whole three kinds) that comprise in the following medicament of the present disclosure: suppress active first medicament of carbohydrase, reduce second medicament of formation of intestinal gas or seriousness and regulate the 3rd medicament of insulin signaling conduction or blood sugar level.Said preparation can be liquid, semisolid or solid.Example comprises tablet or gel.
For example, first medicament is an acarbose.The example of second medicament comprises sugared lyases (for example, alpha-galactosidase or β-Pu Tangganmei), helps to discharge from gastrointestinal tract the medicament or the defoamer of gas.Preparation can comprise first medicament and second medicament, first medicament and the 3rd medicament, three of all of the second and the 3rd medicament or first medicament, second medicament and the 3rd medicament.
The example of preparation is listed in the table below:
Alpha-galactosidase can be from non-human organism, the biology of nonmammalian for example, for example, from aspergillus niger (Aspergillus niger).Mammal (for example people), enzyme also can use.Exemplary compositions is
It is the mixture of about four kinds of enzymes.Exemplary component can comprise one or more in xylitol, invertase, disodium citrate, gelatin and the potassium sorbate.
Defoamer can be based on the defoamer of silicone.Exemplary defoamer comprises: the ANTIFOAM FG-10 that DowCorning produces
TMComprise hydrocarbon-siliceous copolymer, hydrophobic filler, organic silicone surfactant, hydrocarbon carrier oil and the optional compositions that comprises silicone oil (referring to, US4 for example, 514,319), the compositions of the fluid hydrocarbon ils that comprise the mineral oil that contains dispersive hydrophobic solid particle, contains hydrophobic silica (referring to, for example US 3,714,068); Comprise the polyoxyethylene-polypropylene copolymer that contains dispersive hydrophobic silica compositions (referring to, for example US 3,959,176); Comprise the compositions that contains as the water-insoluble polyalkylene of the muriatic non-silicone of the alkoxyl silicone of water-repelling agent (referring to, for example British Patent No. 1,166,877); Comprise the compositions that is dispersed in broken polyolefin polymer of fine powder in the organic liquid or polyester (referring to, U.S.3 for example, 705,859); Comprise silicone oil-silica composite and organic silicone compound compositions (referring to, for example US 3,691,091); And comprise with the compositions of the silicone-diol copolymer of silicone oil and silica bound (referring to, for example US 3,865,544).US 5,458, and 886 have described some useful defoamer, comprise the defoamer that contains titanium dioxide.Said preparation can also comprise one or more in calcium silicates and the water-soluble agglomerated maltodextrin.Referring to, US5 for example, 073,384.
Defoamer can comprise, for example the high surface area silica of one or more polydimethylsiloxane of 92-98 percentage by weight and 2-8 percentage by weight (50m at least
2/ g) mixture.
Exemplary defoamer is a simethicone.Simethicone is described in NATIONALFORMULARY, the 14th edition, American Pharmaceutical Association, Washington, D.C., in 1975, the 648 pages, for being no less than 93% and no more than 99% dimethyl polysiloxane and being no less than the mixture of 4% and no more than 4.5% silicon dioxide.Other feature descriptions of simethicone are on page or leaf shown in the above-mentioned publication of mentioning, described content is incorporated herein by reference at this.Dimethyl polysiloxane is called as polysiloxanes or organopolysiloxane sometimes.Can also use relevant mixture, for example the another kind of mixture of polydimethylsiloxane and high surface area silica.
Simethicone can exist with respect to the different proportion of first medicament (for example, acarbose), is about 10: 1 to 2: 1 or 1: 1 or about 1: 2 to 1: 7 based on weight by weight for example.
In one embodiment, preparation other forms of being formulated as tablet, gel or being suitable for absorbing.For example, first medicament and second medicament are separated in the tablet the inside.Second medicament can be contained in internal layer, and first medicament can be contained in skin.Said preparation can comprise first medicament of 10-20 milligram (for example, about 12.5 milligrams), 20-40 milligram (for example, about 25 milligrams), 40-65 milligram (for example, about 50 milligrams) or 80-120 milligram (for example, 100 milligrams).US 5,456, and 920 describe a kind of illustrative methods of producing tablet.
Another aspect, the disclosure are characterised in that a kind of kit, and it comprises: comprise and suppress active first medicament of carbohydrate digestion, for example pharmaceutical composition of acarbose; Comprise the formation that reduces intestinal gas or seriousness second medicament (for example, alpha-Glucosidase or simethicone) pharmaceutical composition and regulate the 3rd medicament of insulin signaling conduction or blood sugar level.Another aspect, the disclosure are characterised in that a kind of kit, and it comprises: a plurality of compartments, each compartment comprises the pharmaceutical composition of one or more units.First subclass of these a plurality of compartments comprises the compositions of first dosage of a plurality of units, and second subclass of these a plurality of compartments comprises the compositions of second dosage of a plurality of units.Pharmaceutical composition comprises and suppresses active first medicament of carbohydrate digestion and reduce the formation of intestinal gas or second medicament of seriousness.
Preferably give acarbose or other alpha-glucosidase inhibitors, so that it reduces the carbohydrate degradation of colon portions of proximal, for example glucosidase activity.Yet it is useful keeping the ability of the carbohydrate (for example, using glucosidase activity) of digestion colon distal part.Therefore, the carbohydrate in the colon distal portions is utilized by bacteria flora less.
First medicament (for example, reducing the medicament of carbohydrate degradation, for example acarbose) and/or second medicament can be mixed with one or both the release that various ways respectively or jointly controls this medicament.Second medicament can be the chemical compound (for example, the commercial chemical compound of buying) that reduces intestinal gas.Special example comprises
And simethicone.
Can make any preparation be suitable for preparing one of first medicament and second medicament or both.For example, one of preparation of describing in the following patent documentation so is fit to: US 4,863, and 744 have described and transmit medicine to the transmission system of pH greater than 3.5 selected environment for use, for example, and the gastrointestinal regional after the stomach.US 2004-0062804 has described the accent release dosage form, comprises the slow releasing pattern that is used for simethicone.US 2003-0108743 has described the method that Pharmaceutical sausage discharges.US 5,637, and 319 have described and are used for drug delivery to the gastrointestinal different parts, comprise the controlled release formulations for oral administration of the bottom of intestinal or colon.
In one embodiment, preparation comprises enteric coating.US 5,840, and 332 have described the exemplary preparation of transmission medicament to the digestive tract distal part.Transfer system allows to be sent to the position that duodenum, jejunum, ileum, ascending colon, transverse colon and descending colon transmit as medicine.The low stomach pH and the existence of gastric enzyme cause having developed enteric coatings.Such coatings protect gastric mucosa is not subjected to medicine irritation, and the protection medicine avoids because of gastric enzyme and/or low pH inactivation.Coating can adopt optionally, and insoluble substance makes.Exemplary enteric coating comprises methacrylic acid copolymer (EUDRAGITS
TM), cellulose acetate-phthalate, succinic acid cellulose acetate and styrene maleic acid copolymer (Ritschel, W.A., AngewanteBiopharmazie, Stuttgart (1973), 396-402 page or leaf; Agyilirah, people such as G.A. " Polymers for Enteric Coating Applications " in Polymers forControlled Drug Delivery, Tarcha, P.J.ed., CRC Press, (1991) BocaRaton, 39-66 page or leaf).
In one embodiment, second medicament is a protein, for example glucosidase or tilactase.This protein can crystalline form, crosslinked form or its combination provides.For example, US 6,541, and 606 have described a kind of exemplary stable protein crystals formulation.Another exemplary method is crosslinked enzyme crystal technology.Referring to, for example, people such as N.L.St.Clair, J.Am.Chem.Soc., 114, the 4314-4316 page or leaf (1992) and PCT/US91/05415.Crosslinked enzyme crystal can keep its activity usually and in the incompatible environment of enzyme function.Such environment comprises the exposure to protease, organic solvent, high temperature or extreme pH of prolongation.In such environment, it is insoluble, stable with activated that crosslinked enzyme crystal remains.
Usually, by with suitable aqueous solvent or contain suitable crystallizing agent such as the aqueous solvent of salt or organic solvent mix crystalline protein, obtain crystal.Solvent mixes with protein, and can stand to stir under the temperature that test is determined, described temperature is suitable for causing crystallization and is to keep activity of proteins and stability institute is acceptable.Solvent can randomly comprise cosolute such as bivalent cation, cofactor or chaotropic agent and buffer material and control pH.The needs of cosolute and concentration thereof are determined in test, to promote crystallization.
It is crosslinked to use reversible cross-linking agent to carry out parallel or successively.The cross-linked proteins of gained is crystalline to be characterised in that reactive multi-functional connector, incorporates into wherein as the group that separates triggering agent.Reactive functionalities participates in making the reactive amino acid side chain in the protein to connect together and trigger agent being made of key, and described key can rupture by changing one or more conditions (for example, pH, temperature or thermodynamic (al) water activity) in the surrounding.Key between cross-linking agent and the protein can be covalent bond or ionic bond or hydrogen bond.The variation of surrounding causes and triggers agent bond fission and proteinic dissolving.Therefore, when the crosslinked fracture in the protein crystal crosslinked with reversible like this cross-linking agent, the dissolving of protein crystal begins and therefore active release.The exemplary cross-linking agent of the cross-linked proteins in the crystal is described in US 6,541, in 606.
Protein crystal or preparation itself can be encapsulated, for example, forms microsphere in polymer coating.Crystal is suspended in the polymer support, and described carrier is dissolved in the organic solvent.Polymer solution can be to exist with such amount, and described amount provides about 0.02-about 20, the protein crystal of preferably about 0.1-about 2 and the weight ratio of polymer.Protein crystal can contact about 0.5 minute with the polymer in the solution to about 30 minutes a period of time, preferably about 1 minute to about 3 minutes.
After contacting like that, crystal becomes coating, and is called as newborn microsphere.When coating existed, newborn microsphere size increased.In a preferred embodiment, the crystal of the coating of suspension or newborn microsphere are transferred to containing in the surfactant aqueous solution of (being called emulsifying agent) of larger volume with polymer support and organic solvent.In this aqueous solution, the nascent microspheres of suspension immerses water, and organic solvent evaporates from polymer or spreads.At last, reach a bit, wherein polymer no longer dissolves, and forms precipitated phase, and its encapsulating protein matter crystal or preparation form compositions.In this process sclerosis stage, emulsifying agent can the minimizing system in the not interfacial surface tension between the homophase of material.Optionally, if the coating polymer has some intrinsic surface activitys, then can not need to add independent surfactant.Exemplary emulsifying agent comprises poly-(vinyl alcohol), surfactant and can reduce protein crystal or the crystal formulations of polymer coating and capillary other surfactants between the solution of polymer coating.
In one embodiment, crystal be comprise at least a or multiple
The crystal of the middle enzyme that exists.
Embodiment: give Alpha-glucosidase inhibitor (as acarbose) and carbohydrate lyases (CCE)
Alpha-glucosidase inhibitor (as acarbose) can be united with CCE and given, for example when beginning to have meal.Can give the minimizing possibility that these two kinds of medicaments make compensating effect, for example, prevent the inhibitor inactivator.Can use the arbitrary or two kinds of medicaments of time-delay delivery formulations preparation.For example, this medicament can be mixed with has different release characteristics, for example, discharge in the top of intestinal or proximal colon so that this characteristic helps inhibitor, and CCE for example discharges in distal colon at more following gastrointestinal tract.This design will promote acarbose to work the absorption of delay glucose on the top of intestinal, and CCE works in the bottom of intestinal and prevents that excessive carbohydrate from being digested by enterobacteria.In one embodiment, inhibitor is used for typical release by preparation and CCE is used for time-delay by preparation and discharges.
In another embodiment, CCE is used for pH sensitivity by preparation and discharges, and for example, reaches the distinctive specific pH level in bottom of intestinal like this up to CCE, and it just is released or activates.Release can be activated the triggerings such as dissolving of some coating on (that is, CCE-type medicament will be limited, and discharge or will activate it up to the enzyme of intestinal down or condition), molecule or the pill by time, pH, other enzymes.Also possible is makes the CCE sudden change so that enzymatic activity pH sensitivity more for example, in the activity that reduces under the acid pH, but has bigger relative activity under the pH of distal colon small acidity.In one embodiment, CCE be can from
The enzyme that obtains.
Embodiment: give Alpha-glucosidase inhibitor (as acarbose)+simethicone
Simethicone or another kind of defoamer can be used to improve the influence of excess air in the intestinal.Defoamer can alleviate the foam of stomach or following intestinal, for example, and by the discharge of belch or discharge gastrointestinal tachypnea air inlet body.The defoamer of simethicone and other reduces surface tension, therefore breaks or destroys bubble.For example, simethicone is not by intestinal absorption, and also the unknown has disadvantageous side effect, for example, uses the conditioned disjunction medication.Simethicone can be at regular or controlled release formulation, for example, time-delay discharge or the pH dependent release formulation in.
Embodiment
An embodiment is characterised in that a kind of packing (for example, blister) that comprises a plurality of compartments.Each compartment can comprise the alpha-glucosidase inhibitors (for example, acarbose) of at least one unit dose.Compartment can be orderly, and for example, in the zone of low dosage in packing, medium is in another zone, and high dose is in the 3rd zone.For example, compartment can be to present successively, and is for example from left to right downward again, or ring-type presents, for example, and clockwise direction.Compartment can be to organize like this, so that compartment in the order early has low dosage (for example, 25 milligrams), the compartment in whole order centre position (for example has second dosage, 50 milligrams), the compartment at the order rear portion has the 3rd dosage (for example, 100 milligrams).Packing can be used to provide the alpha-glucosidase inhibitors of the dosage that increases gradually.
Can prepare unit dose, two meal that are used for expecting during the day-night cycle or each meal of breakfast, lunch and dinner.
Embodiment
Make a kind of 25 milligrams of acarbose, 20 milligrams of Mitiglinides and 300GaIU of containing
Tablet.It gives when can every day having meal for three times.For example, it can taken before the meal.
Embodiment
Make a kind of 0.2 milligram of voglibose, 20 milligrams of Mitiglinides and 300GaIU of containing
Tablet.It gives when can every day having meal for three times.For example, it can taken before the meal.
Other embodiments are within following claim.All patents, application and list of references are to be incorporated herein by reference in full in this article.
Claims (60)
1. method, it comprises:
Using (i) to the experimenter suppresses first medicament of carbohydrate degradation, (ii) reduces that intestinal gas forms or second medicament of seriousness and (iii) regulate the 3rd medicament of insulin signaling conduction or blood sugar level.
2. the process of claim 1 wherein that the 3rd medicament is a sulfonylureas.
3. the method for claim 2, wherein the 3rd medicament is tolbutamide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glibenclamide, gliclazide, 1-butyl-3-metanilyl urea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepide, glybuthiazole, glibuzole, glyhexamide, 2-benzenesulfonamido-5-(.beta.-methoxyethoxy)pyrimidine, glypinamide, Phenbutamide, metahexamide, or their salt.
4. the process of claim 1 wherein that the 3rd medicament is a biguanides.
5. the method for claim 4, wherein the 3rd medicament is a metformin
Metformin hydrochloride or long-acting QD metformin
6. the process of claim 1 wherein that the 3rd medicament is an euglycemic agent.
7. the method for claim 6, wherein the 3rd medicament is rosiglitazone or pioglitazone.
8. the method for claim 8, wherein the 3rd medicament increases insulin and produces.
9. the method for claim 8, wherein the 3rd medicament is a meglitinides.
10. the method for claim 8, wherein the 3rd medicament is a Nateglinide.
11. the method for claim 8, wherein the 3rd medicament is a repaglinide.
12. the method for claim 8, wherein the 3rd medicament is a Mitiglinide.
13. the method for claim 8, wherein the 3rd medicament is the chemical compound of following formula:
Wherein A represents heterocyclic group, 3 to 8-unit cycloalkyl or phenyl, and it can have one or more substituent groups, and this substituent group is selected from halogen atom, have the low alkyl group of 1 to 6 carbon atom and have the lower alkoxy of 1 to 6 carbon atom;
B represents the amino group of dicyclo, and it can have 1 or 2 unsaturated bond, and condition is that B combines with the carbon atom of carbonyl on nitrogen-atoms;
R represents hydrogen atom or mutually combines the formation chemical bond;
R
1The expression hydrogen atom, have the low alkyl group of 1 to 6 carbon atom or have the aralkyl of 7 to 10 carbon atoms; When having asymmetric carbon atom, be its enantiomer and racemic mixture.
14. the process of claim 1 wherein that first medicament comprises the inhibitor of alpha-Glucosidase.
15. the process of claim 1 wherein that first medicament comprises:
Formula (I)
Wherein, each R
1Be H, C independently
1-C
6Alkyl, C (O) R
3Or aryl alkyl;
R
2Be C
1-C
6Alkyl;
Each R
3Be C independently
1-C
6Alkyl or aryl,
X, Y and Z are NR independently of one another
4Or O; And
Each R
4Be H, alkyl or aryl alkyl independently.
16. the process of claim 1 wherein that first medicament comprises acarbose.
17. the process of claim 1 wherein that first medicament comprises voglibose.
18. the process of claim 1 wherein that first medicament comprises
(salacinol), or
(kotalanol) or
Other chemical compound that from Salacia prinoides (Willd.) DC. platymiscium (for example, Salacia prinoides (Willd.) DC. or long fruit Salacia prinoides (Willd.) DC.), extracts.
19. the method for arbitrary aforementioned claim, wherein second medicament comprises the mixture of the enzyme of the enzyme of digested carbohydrate or digested carbohydrate.
20. the method for claim 19, wherein second medicament comprises α tilactase or β glucosidase.
21. the method for claim 19, wherein second medicament is
22. the method for claim 19, wherein second medicament is formulated as delayed release compositions or position dependence release composition.
23. the method for claim 19, wherein second medicament is formulated as the enteric solubility capsule, or enzyme triggers release composition.
24. each method of claim 1 to 5, wherein second medicament comprises defoamer.
25. the method for claim 24, wherein second medicament comprises simethicone.
26. the method for arbitrary aforementioned claim, wherein the experimenter has normal blood glucose response.
27. the method for arbitrary aforementioned claim, wherein the experimenter is that glucose does not tolerate or glucose tolerance reduces (IGT) with respect to standard.
28. the method for arbitrary aforementioned claim, wherein the experimenter suffers from diabetes, big vascular obstacle or metabolism syndrome, and the danger of diabetes, big vascular obstacle or metabolism syndrome is perhaps arranged.
29. the method for arbitrary aforementioned claim, wherein second medicament is so that its mode that preferentially works in ileum is carried out administration.
30. the method for arbitrary aforementioned claim, wherein first medicament and second medicament are prepared together.
31. the method for arbitrary aforementioned claim, wherein first medicament, second medicament and the 3rd medicament are prepared together.
32. each method of claim 1-29, wherein first medicament and the 3rd medicament are prepared together.
33. each method of claim 1-29, wherein first medicament and second medicament and every meal combine and use.
34. each method of claim 1-29, wherein first medicament and second medicament administration simultaneously.
35. each method of claim 1-29, wherein first medicament and second medicament are at different time administrations.
36. each method of claim 1-29, wherein first medicament and the 3rd medicament administration simultaneously.
37. each method of claim 1-29, wherein first medicament and the 3rd medicament are at different time administrations.
38. each method of claim 1-29, wherein second medicament is so that its mode administration of preferentially working in intestinal or colon.
39. a pharmaceutical preparation, it comprises:
First medicament that suppresses the α glucosidase activity;
Reduce second medicament of formation of intestinal gas or seriousness; And
The 3rd medicament that stimulates insulin to produce.
40. the pharmaceutical preparation of claim 39, wherein first medicament is an acarbose.
41. the pharmaceutical preparation of claim 39 or 40, wherein second medicament comprises sugared lyases.
42. the pharmaceutical preparation of claim 41, wherein sugared lyases is an alpha-galactosidase.
43. the pharmaceutical preparation of claim 39 or 40, wherein second medicament is the medicament that helps to discharge from gastrointestinal tract gas.
44. the pharmaceutical preparation of claim 39 or 40, wherein second medicament is a simethicone.
45. each pharmaceutical preparation of claim 39 to 44, it is formulated into tablet or gel.
46. each pharmaceutical preparation of claim 39 to 44, wherein first medicament and second medicament are separate in tablet.
47. the pharmaceutical preparation of claim 46, wherein second kit is contained in internal layer and first kit is contained in skin.
48. first medicament that it contains 20-40 milligram, 40-65 milligram or 80-120 milligram is wrapped in the pharmaceutical preparation of claim 45.
49. each pharmaceutical preparation of claim 39 to 48, wherein the 3rd medicament is a sulfonylureas.
50. each pharmaceutical preparation of claim 39 to 48, wherein the 3rd medicament is tolbutamide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glibenclamide, gliclazide, 1-butyl-3-metanilyl urea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepide, glybuthiazole, glibuzole, glyhexamide, 2-benzenesulfonamido-5-(.beta.-methoxyethoxy)pyrimidine, glypinamide, Phenbutamide, metahexamide or their salt.
51. each pharmaceutical preparation of claim 39 to 48, wherein the 3rd medicament is a biguanides.
52. each pharmaceutical preparation of claim 39 to 48, wherein the 3rd medicament is a metformin
Metformin hydrochloride or long-acting QD metformin
53. each pharmaceutical preparation of claim 39 to 48, wherein the 3rd medicament is an euglycemic agent.
54. the pharmaceutical preparation of claim 53, wherein the 3rd medicament is rosiglitazone or pioglitazone.
55. each pharmaceutical preparation of claim 39 to 48, wherein the 3rd medicament increases insulin and produces.
56. the pharmaceutical preparation of claim 55, wherein the 3rd medicament is the meglitinides medicine.
57. the pharmaceutical preparation of claim 55, wherein the 3rd medicament is Nateglinide, repaglinide or Mitiglinide.
58. the pharmaceutical preparation of claim 55, wherein the 3rd medicament is the chemical compound of following formula:
Wherein A represents heterocyclic group, 3 to 8-unit cycloalkyl or phenyl, and it can have one or more substituent groups, and this substituent group is selected from halogen atom, have the low alkyl group of 1 to 6 carbon atom and have the lower alkoxy of 1 to 6 carbon atom;
B represents the amino group of dicyclo, and it can have 1 or 2 unsaturated bond, and condition is that B combines with the carbon atom of carbonyl on nitrogen-atoms;
R represents hydrogen atom or mutually combines the formation chemical bond;
R
1The expression hydrogen atom, have the low alkyl group of 1 to 6 carbon atom or have the aralkyl of 7 to 10 carbon atoms; When having asymmetric carbon atom, be its enantiomer and racemic mixture.
59. a pharmaceutical preparation, it comprises:
(i) acarbose;
(ii) simethicone; And
(iii) meglitinides medicine.
60. the pharmaceutical preparation of claim 59, wherein said meglitinides medicine is Nateglinide, repaglinide or Mitiglinide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71753605P | 2005-09-14 | 2005-09-14 | |
| US60/717,536 | 2005-09-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101325959A true CN101325959A (en) | 2008-12-17 |
Family
ID=37865568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800425151A Pending CN101325959A (en) | 2005-09-14 | 2006-09-13 | Combination therapy for controlled carbohydrate digestion |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1931359A4 (en) |
| CN (1) | CN101325959A (en) |
| CA (1) | CA2622558A1 (en) |
| WO (1) | WO2007033292A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7888382B2 (en) | 2005-04-20 | 2011-02-15 | Kissei Pharmaceutical Co., Ltd. | Combined pharmaceutical preparation for treatment of type 2 diabetes |
| EP1948150A4 (en) * | 2005-11-07 | 2010-04-14 | Elixir Pharmaceuticals Inc | Combinations of metformin and meglitinide |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3543999A1 (en) * | 1985-12-13 | 1987-06-19 | Bayer Ag | HIGH PURITY ACARBOSE |
| US4898986A (en) * | 1986-09-09 | 1990-02-06 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
| EP1796687A2 (en) * | 2004-09-14 | 2007-06-20 | Elixir Pharmaceuticals, Inc. | Combination therapy for controlled carbohydrate digestion |
| US20060229261A1 (en) * | 2005-04-12 | 2006-10-12 | John Devane | Acarbose methods and formulations for treating chronic constipation |
-
2006
- 2006-09-13 WO PCT/US2006/035761 patent/WO2007033292A2/en active Application Filing
- 2006-09-13 CN CNA2006800425151A patent/CN101325959A/en active Pending
- 2006-09-13 CA CA002622558A patent/CA2622558A1/en not_active Abandoned
- 2006-09-13 EP EP06803558A patent/EP1931359A4/en not_active Withdrawn
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| Publication number | Publication date |
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| EP1931359A2 (en) | 2008-06-18 |
| WO2007033292A3 (en) | 2007-06-28 |
| EP1931359A4 (en) | 2009-04-01 |
| CA2622558A1 (en) | 2007-03-22 |
| WO2007033292A2 (en) | 2007-03-22 |
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Open date: 20081217 |