CN110051851A - A kind of combination of sodium-glucose co-transporter -2 inhibitor and maniod ebish flower extract - Google Patents
A kind of combination of sodium-glucose co-transporter -2 inhibitor and maniod ebish flower extract Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
Abstract
The present invention relates to the combinations of a kind of sodium - glucose co-transporter -2 inhibitor and maniod ebish flower extract, -2 inhibitor of sodium - glucose co-transporter be selected from canagliflozin, Dapagliflozin, En Gelie is net, Yi Gelie is net, glug column only, tofogliflozin it is one or more, it can be used for treating chronic kidney disease, especially diabetic nephropathy has the function of synergy.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of -2 inhibitor of sodium-glucose co-transporter and sunset abelmoschus flower
The combination of extract.
Background technique
Chronic kidney disease (CKD), also referred to as chronic renal disease, clinic in, be diagnosed as glomerulonephritis, latent nephritis,
Pyelonephritis, Henoch Schonlein purpura nephritis, lupus erythematosus nephritis, gout kidney, nephrotic syndrome, membranous nephropathy, nephrotic syndrome, sugar
Urinate sick nephrosis, hypertensive nephropathy, polycystic kindey, etc., when the morbidity delay of these nephrosis is refractory, the time more than three months, patient
There is exception in urine and relevant physiochemical indice, and Renal Paphology, iconography note abnormalities or the glomerulus of kidney effectively filters
Rate is lower than 60%, all can be collectively referred to as " chronic kidney disease ".The diagnosis of chronic kidney disease is often known to screening that there are kidney problems risks
Crowd result.
The identification of chronic kidney disease can pass through blood test, such as creatinine.The creatinine of higher concentration indicates lower glomerulus
Filtration rate, and thereby indicate that reduced kidney excretion waste ability.
The amount that two kidneys generate filtrate in unit time is known as glomerular filtration rate (eGFR), glomerular filtration rate and kidney blood plasma
The ratio of flow is known as filtration frasction.
In clinic, CKD was divided into for 5 phases, wherein 1 phase was the kidney damage of the normal GFR (mL/min/1.73m2) with >=90
Wound；2 phases were the injury of kidney that there is slight GFR to reduce (GFR60-89)；3 phases were that GFR moderate reduces (GFR30-59)；4 phases were GFR
Severe reduces (GFR15-29)；And 5 the phase be kidney failure (GFR < 15 or dialysis).5 phase CKD are commonly referred to as end-stage renal disease (ESRD)
And it is synonymous with out-of-date term chronic renal failure (CKF) or chronic renal failure (CRF).
Albuminuria can also be the mark of kidney trouble.Albuminuria is the illness in urine there are albumin.Healthy individuals
Kidney can filter albumin.When kidney normally can not filter macromolecular (such as albumin) from urine, albumin can be secreted
Into urine, and the usually excessive symptom of injury of kidney or Salt intake.In clinic, urinary albumin can be surveyed by test strips
Amount, or directly measured as the protein content secreted in the total volume of urine acquired during 24 hours.
Albuminuria has been divided into 3 classes, and wherein the reflection of A1 class normally increases to slight without albuminuria, albumin；The reflection of A2 class
Microalbuminuria, albumin moderate increase；A3 class reflects High-grade Proteinuria, and albumin severe increases.
Diabetes are for there are the raised medical terminologys of blood-glucose.Suffer from person with diabetes or pancreas cannot be generated
Island element, generates very little insulin or cannot respond insulin, accumulate in blood so as to cause glucose.Diabetes
Most common form is diabetes B.Diabetes can also refer to gestational diabetes, type 1 diabetes or autoimmune diabetes.
Type-2 diabetes mellitus (Non-Insulin Dependent Diabetes Mellitus or NIDDM) is that one kind is related to abnormal glucose metabolism and pancreas islet
Element is resisted and the metabolic disorder of long-term complications, the long-term complications are related to eyes, kidney, nerve and blood vessel.
Type-2 diabetes mellitus is characterized in that following clinical symptom or symptom: plasma glucose concentration persistently increases or high blood
Sugar；Polyuria；More thirsty diseases and/or polyphagia；Chronic microvascular complication such as retinopathy, nephrosis and neuropathy；With it is big
Vascular complication, such as hyperlipemia and hypertension, this can lead to blindness, end-stage renal disease, amputation and myocardial infarction.
Albuminuria can also occur in the patient with long-term diabetes (I (1) type or II (2) patients with type Ⅰ DM).
When glomerulus has abnormal high permeability to albumin, thus kidney leaks a small amount of albumin into urine, can go out
Existing microalbuminuria.When urinary albumin level during when patient 24 is small is in the range of 30mg to 300mg, then it can indicate
Microalbuminuria as nephrosis illness.
The Substitute Indexes of microalbuminuria are the ratios of the creatinine levels and albumin and kreatinin in serum.White egg
White/creatinine ratio (ACR) and microalbuminuria are defined as ACR >=3.5mg/mmol (women) or >=2.5mg/mmol
(male), or in the case where two kinds of substances press mass measurement, it is defined as ACR in 30 μ g albumin/mg kreatinin and 300
Between μ g albumin/mg kreatinin.
Microalbuminuria can be the development of nephrosis and the important prognostic marker of process, for suffering from diabetes or hypertension
Patient for it is particularly true.Microalbuminuria is also that the index of subclinical cardiovascular disease, function of vascular endothelium be not complete
Mark and the risk factors for forming phlebothrombosis.
Nephrosis (DN) is one of microvascular complication of diabetes, and it is characterized in that albuminuria continues
In the presence of and renal function gradually fail.An important factor for hyperglycemia is nephrosis breaking-out and process propulsion.
People have fully understood the spy of the Clinical course of the diabetes in patients nephrosis with T1DM (type 1 diabetes)
Sign.Originally, it can be observed that excessively filtering and being increased with glomerular filtration rate (GFR) increase and renal plasma flow.Analysis
It was found that the illness that the patient with T1DM excessively filters if it exists, then can be such that microalbuminuria or a large amount of albuminurias occurs
Risk increase to twice or more.There is GFR after the stage and decline and microalbuminuria occurs (to be defined as >=30mg/
The urinary albumin excretion of its (or 20 μ g/min) and < 300mg/24h (or 200 μ g/min of <)), this can be with the raising of blood pressure.
Later in disease process, as GFR continues to decline, it then will appear apparent albuminuria (that is, a large amount of albuminurias) and (determined
Justice is the urinary albumin excretion of > 300mg/ days), this is associated with hypertension exacerbation.Finally, ESKD (end-stage renal disease) process
It promotes, to need renal replacement therapy.
For suffering from the patient of diabetes B (T2DM), Clinical course be it is changeable, main cause is multiple kidney damage
Wound, this not only includes hyperglycemia, but also including vascular pathological, so as to cause Ischemic kieney injury.However, other common attributes can
It can promote the patient with T2DM that injury of kidney occurs, including the horizontal excessive filtration of single nephron, proximal tubular glucose
Toxicity, and stimulation due to enhancing of the sodium glucose into renal tubular cell cotransports to renal tubular cell growth.
Research is and cardiovascular it has proven convenient that albuminuria is the biological marker for predicting nephrosis process
(CV) risk factors.Urinary albumin excretion increase and GFR reduce also independently with suffer from T2DM patient in cardiovascular prognosis
It is associated with the risk of both kidney prognosis, but there is no the evidence to interact between these risk factors.Albuminuria moderately rises
It is high also associated with the quickening of nephrosis process.
Do not have particular treatment be explicitly shown out slow down chronic kidney disease deteriorate and severe CKD need renal replacement therapy, can relate to
And dialysis form, but ideal form is kidney transplant.
Sunset abelmoschus flower is the dry flower of Malvaceae gumbo platymiscium sunset abelmoschus root Abelmoschus Manihot (L.) Medic,
Sunset abelmoschus flower is recorded in " good help book on Chinese herbal medicine " earliest, widely distributed, resourceful, and Compendium of Material Medica is recorded: its spend smell it is sweet, it is cold,
It is sliding, nontoxic, cure mainly urine leaching and expedite the emergence of, control all malignant sore pus and be not recovered long person, make that end applies i.e. more, be persons particularly liable to develop skin infection's key medicine, the subcutaneous ulcer that disappears is swollen,
Immersion oil applies burn etc..In modern medicine, the principle active component of sunset abelmoschus flower is flavones ingredient, at present to chemical component
Research also focuses on Flos abelmoschi manihot total flavones (Total flavone of A, TFA) and monomer.Research, which has shown that have, reduces egg
Albiduria mitigates erythrocyturia, mitigates interstitial disease of renal tubule, eliminates oxygen radical, improves Abelmoschus manihot, promotes people
The transhipment and removing of CIC ELISA (CIC) adjust cellular immune function, inhibit humoral immune reaction degree, to subtract
Light people CIC ELISA (CIC) mediated injury of kidney, improves renal function, achievees the purpose that treat chronic nephritis (CKD).
List marketing recent two decades, main active are sunset abelmoschus flower ethanol extract to Huang Kui capsule, are used for CKD
Clinical application, Huang Kui capsule be every 0.5g (being equivalent to medicine materical crude slice 2g), take orally, one time 5,3 times a day.Sunset abelmoschus flower is mentioned
Take being used in combination for object and -2 inhibitor of sodium-glucose co-transporter, still shortage correlative study.
Therefore, have for can in patients, especially there are the patients of kidney trouble risk (such as with 1 type or 2
The patient of patients with type Ⅰ DM) in slow down chronic kidney disease deteriorate or progress method, the unsatisfied medicine of drug and pharmaceutical composition
Demand.
Summary of the invention
The present invention relates to the groups of a kind of sodium-glucose co-transporter -2 (SGLT-2) inhibitor and maniod ebish flower extract
It closes, for treating (chronic) nephrosis, especially diabetic nephropathy.
The invention further relates to a kind of SGLT-2 inhibitor in preparation and maniod ebish flower extract combination therapy CKD (chronic renal
Disease) application that is especially in the drug of diabetic nephropathy or a kind of maniod ebish flower extract be in preparation and SGLT-2 inhibitor
Application in the drug of combination therapy chronic kidney disease especially diabetic nephropathy.
The SGLT-2 inhibitor is a kind of hypoglycemic medicine, including but not limited to Canagliflozin (canagliflozin),
Dapagliflozin (Dapagliflozin), Empagliflozin (En Gelie is net), Ipragliflozin (Yi Gelie is net),
Luseogliflozin (glug column are net) and Tofogliflozin (tofogliflozin) etc., preferably canagliflozin.
The combination of SGLT2 inhibitor (preferably canagliflozin) and maniod ebish flower extract of the present invention, it is (slow for CKD
Property nephrosis) patient, the patient is the CKD with 3 phases, 4 phases or 5 phases measured with GFR, optionally can be with one kind or more
The other active substance combinations of kind use.
The present invention relates to the combination comprising certain SGLT2 inhibitor (preferably canagliflozin) and maniod ebish flower extract or medicines
Certain medical applications of compositions, for example, for treat and/or prevent metabolic disease, particularly diabetes B and/or with
Its relevant illness (such as diabetic complication), including the trouble with (chronic) nephrosis, renal insufficiency or kidney function damage
Person especially has with (chronic) kidney function damage patient of GFR 3 phases, 4 phases or 5 phases measured；Its optionally with it is a kind of or
A variety of other active substance combinations use.Other active materials include that antidiabetic treatment agent and/or angiotensins turn
Change enzyme (ACE) inhibitor or angiotensin-ii receptor retarding agent (ARB))
In addition, being used for and maniod ebish flower extract the present invention relates to certain SGLT2 inhibitor (preferably canagliflozin)
Combination, such as there is diabetes B and microalbuminuria or Macroalbuminuria for treating, with or without kidney function damage
The diabetes B of patient, and treatment, reduce following disease, postpone following disease morbidity and/or the following disease of delay into
Exhibition: diabetic nephropathy, chronic kidney disease, albuminuria, such as microalbuminuria or Macroalbuminuria, kidney function damage, depending on
Nethike embrane disease, neuropathy, study or memory or cognitive disorder or decline, nervus retrogression or cognitive disorder are for example dull-witted, and/or big
The vascular complication such as heart or cerebrovascular events such as apoplexy or myocardial infarction, such as the patient with CKD (chronic kidney disease), it is special
Be not have 3 phases, 4 phases or 5 phases (chronic) kidney function damage patient, optionally with one or more other active materials
It is applied in combination.
The present invention relates to SGLT2 inhibitor (preferably canagliflozin), combined with maniod ebish flower extract for treat and/
Or prevention metabolic disease (including metabolic disease is delayed to be in progress or postpone metabolic disease morbidity), especially diabetes are (special
It is not diabetes B) and/or relative illness (such as diabetic complication, especially diabetes chronic nephrosis)；Including
(chronic) nephrosis, renal insufficiency or kidney function damage (kidney function damage) patient, especially with 3 phases, 4 phases or 5 phases
(chronic) kidney function damage patient optionally uses with one or more other active substance combinations.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
Application of the combination of hollyhock flower extract in the drug that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy,
Or a kind of maniod ebish flower extract is in preparation and SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetic nephropathy
Application in drug, wherein SGLT-2 inhibitor is preferably canagliflozin.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
The combination of hollyhock flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Using or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetogenous nephrosis
Application in the drug or pack of disease, wherein the mass ratio of SGLT-2 inhibitor and maniod ebish flower extract is 1:1~200, excellent
1:10~150, preferably 1:15~100, preferably 1:20~60 are selected as, more preferably 1:30~60 can be 1:20,1:30 or 1:
60, wherein SGLT-2 inhibitor is preferably canagliflozin.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
The combination of hollyhock flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Using or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetogenous nephrosis
Application in the drug or pack of disease, the Hyperoside mass ratio that wherein SGLT-2 inhibitor contains with maniod ebish flower extract are
100:1.5~225, preferably 100:15~150, preferably 100:20~120.It can be 100:40,100:75,100:120.100:
40,100:75,100:120, wherein SGLT-2 inhibitor is preferably canagliflozin.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
The combination of hollyhock flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Using or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetogenous nephrosis
In the drug of disease or the application of pack, wherein SGLT-2 inhibitor and maniod ebish flower extract mass ratio are 50mg~200mg:
0.1~10g, preferably 50mg~100mg:1~7.5g, preferably 50mg~100mg:2.0~6.0g can be 50mg:0.6g,
50mg:1.6g,50mg:2.0g；Or 100mg:1.2g, 100mg:3g, 100mg:4g, 100mg:6g, wherein SGLT-2 inhibits
Agent is preferably canagliflozin.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
The combination of hollyhock flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Using or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetogenous nephrosis
Application in the drug or pack of disease, the Hyperoside mass ratio wherein contained in SGLT-2 inhibitor and maniod ebish flower extract
It is excellent for 50mg~100mg:1~250mg, the preferred 50mg~100mg:20 of preferably 50mg~100mg:15~150mg~120mg
50mg~100mg:40~120m g is selected, can be 50mg:20mg, 50mg:37mg, 50mg:60mg；Or 100mg:45mg,
100mg:90mg,100mg:120mg。
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
The combination of hollyhock flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Using or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetogenous nephrosis
Application in the drug or pack of disease, can be SGLT-2 inhibitor and maniod ebish flower extract forms composition, further may be used
Including pharmaceutically acceptable auxiliary material, the available pharmaceutical preparation of pharmacy is made.The pharmaceutical preparation includes but is not limited to tablet, glue
Wafer, granule etc..
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention or the SGLT-2 inhibitor and Huang
The combination of hollyhock flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Using or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetogenous nephrosis
Application in the drug or pack of disease, it is also possible to SGLT-2 inhibitor and group after maniod ebish flower extract respectively independent packaging
It is combined, wherein GLT-2 inhibitor may include pharmaceutically acceptable auxiliary with maniod ebish flower extract independent packaging back
Material, is made the available pharmaceutical preparation of pharmacy.
The combination of this SGLT-2 inhibitor of the present invention and maniod ebish flower extract or the SGLT-2 inhibitor with
The combination of maniod ebish flower extract is in the drug or pack that preparation combination therapy CKD (chronic kidney disease) is especially diabetic nephropathy
Application or a kind of maniod ebish flower extract preparation with SGLT-2 inhibitor combination therapy chronic kidney disease especially diabetes
The drug of nephrosis or the application in pack, it can further include other one or more other active materials, as blood vessel is tight
Open plain converting Enzyme (ACE) inhibitor Losartan, Irbesartan, Olmesartan etc..
In addition the present invention also provides a kind of treats the related to nephrosis especially diabetic nephropathy of mammal in need
Method, this method include for the mammal provide it is a effective amount of include SGLT2 inhibitor (preferably canagliflozin) with Huang
The combination of hollyhock flower extract；The combination further may include and other any one or more other active substance combinations
It uses, such as ACR inhibitor.
The maniod ebish flower extract, preferably sunset abelmoschus flower chromocor extract, main component are Flavonoid substances, are contained
Hyperoside is no less than 11.5mg/g, further no less than 12.5mg/g, further preferably 1.5-1.9%；Further
, general flavone contains Hyperoside, isoquercitrin, quercetin-3'-glucoside, gossypitrin -8- in the maniod ebish flower extract
The ingredients such as O- β-D-Glucose aldehydic acid glycosides, myricetin, Quercetin, in extract general flavone content in terms of Hyperoside no less than
11.5mg/g。
Maniod ebish flower extract of the present invention, preferably flavones content are 15% or more, including 25% or more, preferably 30%
More than, further preferred 50% or more.
The maniod ebish flower extract is ethanol extract, preferably the extract of 50-95% alcohol reflux extraction, into one
Step is preferably the extract that 80-95% alcohol reflux extracts, the extract still more preferably extracted for 955 alcohol refluxs.Institute
It states maniod ebish flower extract to prepare by the following method: taking sunset abelmoschus flower medicinal material, ethyl alcohol heating and refluxing extraction filters, filtrate concentration,
It is dry.The ethanol extract is sunset abelmoschus flower chromocor extract, and main component is Flavonoid substances, is no less than containing Hyperoside
11.5mg/g, further no less than 12.5mg/g, further preferably 1.5-1.9%；.
Maniod ebish flower extract of the present invention can be prepared by the following method: take sunset abelmoschus flower medicinal material, ethyl alcohol heats back
Stream extracts, filtration, filtrate concentration, dry.Further, preferably prepare by the following method: sunset abelmoschus flower is with 85%~95%
Ethyl alcohol, refluxing extraction 1~3 time, 1~2 hour every time, filtering, merging filtrate recycle ethyl alcohol, concentration filtrate to specific gravity 1.20~
1.35, concentrate stands 24~48 hours at 0 DEG C~4 DEG C, and the oil reservoir of removal refrigeration liquid adjusts pH value 6.0~7.0, concentration, thin layer
Rapid draing or vacuum drying are to get maniod ebish flower extract.
The preparation method of maniod ebish flower extract of the present invention can be with are as follows: sunset abelmoschus flower with 95% ethyl alcohol, reflux
It extracts 2 times, 1 hour every time, filtering, merging filtrate recycled ethyl alcohol, filtrate was concentrated to specific gravity 1.20, concentrate is quiet at 0 DEG C~4 DEG C
It sets 24~48 hours, the oil reservoir of removal refrigeration liquid adjusts pH value 6.0, refrigeration liquid is slowly added in thin layer rapid draing roller trough,
Make until refrigeration liquid liquid level is just contacted with barrel surface in roller trough, preheating barrel surface temperature to 140 DEG C~150 DEG C,
Air pressure is 0.4~0.5Mpa, opens rollers roll start button, and drum speed is 3~3.5 minutes/turns, the medicinal extract liquid that will be rolled down
Body, which is coated on polyfluortetraethylene plate, to cool down, and material to be dried cooling becomes fragile, and breaks into pieces, is fitted into cleaning double-layer plastic bag to get
Maniod ebish flower extract.
The condition of above-mentioned thin layer rapid draing operation are as follows: preheating thin layer rapid draing barrel surface temperature to 135 DEG C~
160 DEG C, air pressure is 0.3~0.6Mpa, and drum rotation speed is 2~4.5 minutes/turns, and coated panel is plastic plate or stainless steel plate, plastics
Plate is selected from polyethylene version, PVC plastic flitch, PP plastic plate, PE plastic plate, polyfluortetraethylene plate, preferably polytetrafluoroethylene plate.
Maniod ebish flower extract of the present invention preferred the preparation method comprises the following steps: sunset abelmoschus flower with 95% ethyl alcohol, reflux
It extracts 2 times, 1 hour every time, filtering, merging filtrate recycled ethyl alcohol, filtrate was concentrated to specific gravity 1.20, concentrate is quiet at 0 DEG C~4 DEG C
It sets 24~48 hours, the oil reservoir of removal refrigeration liquid adjusts pH value 6.0, and it is dry after concentration, preferably it is slowly added to vacuum belt drier
Interior carry out vacuum belt type drying.
Vacuum belt drier used in the present invention has an advantage in that 1. rates of drying are fast；2. easy to operate easily-controllable: being convenient for
It continuous production and realizes that mass production automation is easy to control in time since power adjustable is whole and mertialess feature, is convenient for technique
The adjustment and determination of parameter；3. drying time is short；4. good product quality: compared with conventional drying methods, such as conventional vacuum drying,
It is dry since under vacuum occasion, heat is very difficult by convection current, can only conduct progress, and heating speed is slow, and energy consumption is high
Period is long, coking phenomenon easily occurs, influences product quality；Be dried under reduced pressure, due to medical fluid be not inside and outside it is dry simultaneously, medical fluid is inside and outside
The temperature difference is big, inside and outside heating occurs unevenly, easily agglomerates, influence product quality, and this drying mode overcomes conventional drying methods
Defect, rapid draing, product quality has raising by a relatively large margin.
The preparation of SGLT2 inhibitor (preferably canagliflozin) of the present invention, can refer to the prior art and is prepared, separately
Outside, these inhibitor, such as Canagliflozin (canagliflozin), Dapagliflozin (Dapagliflozin), Empagliflozin
(En Gelie is net), Ipragliflozin (Yi Gelie is net), Luseogliflozin (glug column are net) and Tofogliflozin
(tofogliflozin) etc. has listing in the world, can choose the existing dosage form of these inhibitor and mentions with sunset abelmoschus flower
Object (for example, exclusive kind Huang Kui capsule of Soviet Union's Chinese medicinal material industry) is taken to be combined.
The white egg of urine can be significantly reduced in the composition of SGLT-2 inhibitor and maniod ebish flower extract of the present invention
It is white.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention can effectively treat chronic kidney disease
Disease, especially diabetic nephropathy.
The combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention can be controlled effectively at lower doses
Treat chronic renal disease, especially diabetic nephropathy.
The advantages of combination of SGLT-2 inhibitor and maniod ebish flower extract of the present invention:
Its pathogenic process of DN is progressive, mechanism is complicated, and basis is glucose -lipid metabolism disorder, have oxidation say, inflammation is said, blood vessel is said
Deng, but the basic standard of DN morbidity diagnosis is that albuminuria occur, clinically, the goldstandard of nephropathy diagnosis (renal damage) is Urinary
Urine proteins are positive in liquid, secondly, serum creatinine and urea nitrogen are also the necessary index for reflecting renal function.
Therefore, the present invention is using Urine proteins, serum creatinine and urea nitrogen as core index, while observing maniod ebish flower extract pair
Animal pattern glycolipid metabolism, anti-oxidant, inflammation, fibrosis and other and renal function index of correlation influence.
Research through the invention finds that the pharmacological action of maniod ebish flower extract may anti-inflammatory with it, anti-oxidant, drop
Rouge, anti-fibrosis etc. are related.And due to sodium-glucose co-transporter -2 (SGLT-2) inhibitor such as canagliflozin, Da Ge
Column are net, En Gelie is net, Yi Gelie is net, glug arranges the treatment nephrosis effect of net, tofogliflozin etc. with sodium-glucose co-transporters egg
White -2 is related, when sunset abelmoschus root extract is joining treatment diabetogenous nephrosis with sodium-glucose co-transporter -2 (SGLT-2) inhibitor
When sick, collective effect, plays synergistic effect, such as reducing Urine proteins and improving nephrosis reason side through a variety of ways
Face plays significant therapeutic effect, provides a kind of new treatment means for clinical treatment diabetic nephropathy.
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments not limit model of the invention
It encloses.
The preparation of 1 maniod ebish flower extract of embodiment
Medicinal material sunset abelmoschus flower 4000g is taken, with the ethyl alcohol of 15 times of (mass/volume ratios) 95%, refluxing extraction 2 times, 1 is small every time
When, filtering, merging filtrate recycles ethyl alcohol, concentration filtrate to specific gravity 1.20, and concentrate stands 24 hours at 0 DEG C~4 DEG C, removes cold
The oil reservoir of liquid is hidden, pH value 6.0 is adjusted, is slowly added in vacuum belt drier, dry, pulverize after concentration, is packed into clean Double-layer Plastic
To get maniod ebish flower extract in material bag.
Extract Determination of Hyperoside by weight percentage is not less than 1.3%.Through multiple authentication, Determination of Hyperoside exists
1.5-1.9% or so.Moisture is no more than 10%.
The preparation of 2 maniod ebish flower extract of embodiment
Medicinal material sunset abelmoschus flower 3000g is taken, with the ethyl alcohol of 18 times of (mass/volume ratios) 85%, refluxing extraction 3 times, 2 is small every time
When, filtering, merging filtrate recycles ethyl alcohol, concentration filtrate to specific gravity 1.35, and concentrate stands 30 hours at 0 DEG C~4 DEG C, removes cold
The oil reservoir of liquid is hidden, pH value 7.0 is adjusted, is slowly added in vacuum belt drier, dry, pulverize after concentration, is packed into clean Double-layer Plastic
To get maniod ebish flower extract in material bag.
The content of extract Hyperoside by weight percentage is in 1.3-1.8% or so.Moisture is no more than 10%.
The preparation of 3 maniod ebish flower extract of embodiment
Raw medicinal material sunset abelmoschus flower 2000g of the present invention, 20 times of 90% ethyl alcohol of sunset abelmoschus flower, refluxing extraction 2 times, every time
2.5 hours, filtering, merging filtrate recycled ethyl alcohol, concentration filtrate to specific gravity 1.30, and concentrate stands 48 hours at 0 DEG C~4 DEG C,
The oil reservoir of removal refrigeration liquid, adjusts pH value 6.5, and refrigeration liquid is slowly added in thin layer rapid draing roller trough, make in slot liquid level with
Until barrel surface just contacts, barrel surface temperature is preheated to 150 DEG C, air pressure 0.5Mpa, opens rollers roll starting
Button, drum speed are 3.5 minutes/turns, and the medicinal extract liquid rolled down is coated on polyfluortetraethylene plate and is cooled down, material to be dried
Cooling becomes fragile, and crushes, and is fitted into clean double-layer plastic bag to get maniod ebish flower extract.
The content of extract Hyperoside by weight percentage is in 1.3-1.8% or so.Moisture is no more than 10%.
The preparation of 4 maniod ebish flower extract of embodiment
Take medicinal material sunset abelmoschus flower 3000g, 19 times 95% of ethyl alcohol of sunset abelmoschus flower, refluxing extraction 2 times, 1 hour every time, mistake
Filter, merging filtrate recycle ethyl alcohol, concentration filtrate to specific gravity 1.20, and concentrate stands 48 hours at 0 DEG C~4 DEG C, removal refrigeration liquid
Oil reservoir, adjust pH value 6.0, be slowly added in vacuum belt drier after concentration, dry, pulverize at 100 DEG C, be packed into clean double-deck
To get maniod ebish flower extract in polybag.
The content of extract Hyperoside by weight percentage is in 1.5-1.9% or so.Moisture is no more than 10%.
Influence of 5 maniod ebish flower extract of embodiment to DN rat
SD rat, male, SPF grades, 80.10 are only used as normal group, remaining 70 are combined STZ with high-sugar-fat-diet
(streptozotocin) replicates Diabetic Nephropathy model, and the successful rat of modeling is randomly divided into 7 groups, every group 10, grouping with
Administration design is as follows:
Model group: volume distilled water is given in stomach-filling after modeling；
Model+canagliflozin canagliflozin 5mg/kg group: canagliflozin 5mg/kg is given in stomach-filling after modeling；
Model+canagliflozin canagliflozin 10mg/kg group: canagliflozin 10mg/kg is given in stomach-filling after modeling；
Model+maniod ebish flower extract 0.3g/kg group: maniod ebish flower extract 0.3g/kg is given in stomach-filling after modeling；
Model+maniod ebish flower extract 0.6g/kg group: maniod ebish flower extract 0.6g/kg is given in stomach-filling after modeling；
Model+canagliflozin 10mg/kg+ maniod ebish flower extract 0.3g/kg group: canagliflozin is given in stomach-filling after modeling
10mg/kg+ maniod ebish flower extract 0.3g/kg；
Model+canagliflozin 10mg/kg+ maniod ebish flower extract 0.6g/kg group: canagliflozin is given in stomach-filling after modeling
10mg/kg+ maniod ebish flower extract 0.6g/kg；
Reserved Normal group (referred to as normal group): isometric distilled water stomach-filling is set simultaneously；
Each group rat every morning gastric infusion is primary after grouping, and continuous 12 weeks.During administration, rat ad lib drink
Water；Control rats are raised with normal diet, remaining each group rat is raised with high lipid food.Wherein maniod ebish flower extract be by
Embodiment 1 is prepared, and Determination of Hyperoside is 1.5%.
After administration, the urine for 24 hours of each rat is collected using metabolic cage, is carried out quantity of proteinuria for 24 hours and is detected；Rat
After carbon dioxide narcosis, abdominal aorta bloodletting, the left kidney of anatomical acquisition, 10% neutral formalin fixed, and carries out disease after HE dyeing
Reason detection.
The influence of 5.1 pairs of DN rats quantity of proteinuria for 24 hours
The result shows that quantity of proteinuria is apparently higher than control group to model group rats for 24 hours, and has statistics after administration in 12 weeks
It learns meaning (P < 0.01)；Quantity of proteinuria is decreased obviously and has statistical significance each administration group for 24 hours；Canagliflozin and yellow another name for Sichuan Province
The quantity of proteinuria for 24 hours of sunflower extract high dose is lower with model group than low dose group effect respectively and statistically significant；Two
A administering drug combinations group is compared with being administered alone group, and quantity of proteinuria is decreased obviously and has statistical significance for 24 hours, and see Table 1 for details.
The influence to DN rat quantity of proteinuria for 24 hours in 12 weeks is administered in table 1
*: compared with the control group, p < 0.05；#: compared with model group, p < 0.05；★: with model+canagliflozin 10mg/
Kg group compares, p < 0.05；☆: compared with model+maniod ebish flower extract 0.6g/kg group, p < 0.05；◇: with model+card lattice
Arrange net 10mg/kg+ maniod ebish flower extract 0.3g/kg group, p < 0.05.
The influence of 5.2 pairs of DN rat kidney
The result shows that: compared with normal group, model group and each administration group, it is thin that obvious mesentery in various degree occurs in rat kidney
Born of the same parents' hyperplasia and matrix increase, interstitial inflammation cellular infiltration and atrophy, glomerulosclerosis or fibrosis, renal cells denaturation
With fall off；After pharmaceutical intervention, canagliflozin group proliferation of mesangial cells and matrix increase be improved significantly, and 10g/kg group is excellent
In 5g/kg group；Maniod ebish flower extract group is significantly improved, and 0.6g/kg group is better than 0.3g/kg group；Drug combination group
It has shown as or unconspicuous pathological change, has been better than canagliflozin and maniod ebish flower extract group, and model+canagliflozin
10mg/kg+ maniod ebish flower extract 0.6g/kg group is better than model+canagliflozin 10mg/kg+ maniod ebish flower extract 0.3g/kg
Group in detail, is shown in Table 2.
Table 2DN rat kidney pathological examination
Note: A proliferation of mesangial cells and matrix increase；B interstitial inflammation cellular infiltration, atrophy；C glomerulosclerosis or fiber
Change；The denaturation of D renal cells falls off；"/" without；"+/ " is unobvious；"+" has；" ++ " is more apparent；" +++ " is apparent.
In summary: with canagliflozin, maniod ebish flower extract, which is used alone, to be compared, and canagliflozin and sunset abelmoschus flower extract
Object use in conjunction mitigates kidney injury to can more effectively reduce diabetic nephropathy rats quantity of proteinuria for 24 hours.
Claims (10)
1. a kind of combination of sodium-glucose co-transporter -2 inhibitor and maniod ebish flower extract.
2. combination described in claim 1, it is characterised in that -2 inhibitor of sodium-glucose co-transporter and sunset abelmoschus flower
Extract is compound, further may include pharmaceutically acceptable auxiliary material, the pharmaceutical preparation pharmaceutically received is made.
3. combination described in claim 1, it is characterised in that -2 inhibitor of sodium-glucose co-transporter and sunset abelmoschus flower
Extract is respectively combined after independent packaging.
4. combination described in claim 1, it is characterised in that wherein -2 inhibitor of sodium-glucose co-transporter and yellow another name for Sichuan Province
Sunflower extract independent packaging back may include pharmaceutically acceptable auxiliary material, and pharmaceutically acceptable pharmaceutical preparation is made；
The combination can further include other one or more other active materials, such as Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe.
5. maniod ebish flower extract is especially in preparation with -2 inhibitor combination therapy chronic kidney disease of sodium-glucose co-transporter
The drug of diabetic nephropathy or the application in pack.
6. the combination of -2 inhibitor of sodium-glucose co-transporter and maniod ebish flower extract is special in preparation treatment chronic kidney disease
It is the application in the drug or pack of diabetic nephropathy.
7. application described in combination described in claim 1-4 or 5-6, it is characterised in that the sodium-glucose co-transporter-
2 inhibitor be selected from canagliflozin, Dapagliflozin, En Gelie is net, Yi Gelie is net, glug column only, tofogliflozin it is one or more,
It preferably is selected from canagliflozin.
8. application described in combination described in claim 1-4 or 5-6, it is characterised in that the sodium-glucose co-transporter-
The mass ratio of 2 inhibitor and maniod ebish flower extract is 1:1~200, preferably 1:10~150, preferably 1:15~100, preferably
1:20~60, further preferably 1:20,1:30 or 1:60；It is also preferred that -2 inhibitor of sodium-glucose co-transporter with
Mass ratio 50mg~200mg:0.1~10g of maniod ebish flower extract, preferably 50mg~100mg:1~7.5g, preferably 50mg~
100mg:2.0~6.0g, further preferably 50mg:0.6g, 50mg:1.6g, 50mg:2.0g；Or 100mg:1.2g,
100mg:3g, 100mg:4g, 100mg:6g；It is preferred that -2 inhibitor of sodium-glucose co-transporter and sunset abelmoschus flower extract
The Hyperoside mass ratio contained in object is 100:1.5~225, preferably 100:15~150, preferably 100:20~120；Further
Preferably 100:40,100:75,100:120；Further preferred -2 inhibitor of sodium-glucose co-transporter and Huang simultaneously
The Hyperoside mass ratio contained in hollyhock flower extract be 50mg~100mg:1~250mg, preferably 50mg~100mg:15~
Preferred 50mg~the 100mg:20 of 150mg~120mg, preferably 50mg~100mg:40~120mg can be 50mg:20mg,
50mg:37mg,50mg:60mg；Or 100mg:45mg, 100mg:90mg, 100mg:120mg.
9. application described in combination described in claim 1-4 or 5-6, it is characterised in that the maniod ebish flower extract mainly at
It is divided into Flavonoid substances, preferably flavones content is 15% or more, including 25% or more, preferably 30% or more, further preferably
50% or more；It is preferred that the maniod ebish flower extract, which contains Hyperoside, is no less than 11.5mg/g, it is further to be no less than
12.5mg/g, further preferably 1.5-1.9%；Further, general flavone contains Hypericum Chinense in the maniod ebish flower extract
Glycosides, isoquercitrin, quercetin-3'-glucoside, gossypitrin -8-O- β-D-Glucose aldehydic acid glycosides, myricetin, Quercetin etc. at
Point, general flavone content is no less than 11.5mg/g in terms of Hyperoside in extract.
10. application described in combination described in claim 1-4 or 5-6, it is characterised in that the maniod ebish flower extract is second
What the extract that alcohol extracting thing, preferably 50-95% alcohol reflux are extracted, further preferably 80-95% alcohol reflux extracted
Extract, the extract still more preferably extracted for 95% alcohol reflux；It is preferred that the maniod ebish flower extract is by such as lower section
Method preparation: sunset abelmoschus flower medicinal material, ethyl alcohol heating and refluxing extraction, filtration, filtrate concentration, drying are taken；The further preferably described yellow another name for Sichuan Province
Sunflower extract is prepared by the following method: 85%~95% ethyl alcohol of sunset abelmoschus flower, refluxing extraction 1~3 time, 1~2 is small every time
When, filtering, merging filtrate recycles ethyl alcohol, concentration filtrate to specific gravity 1.20~1.35, and concentrate stands 24~48 at 0 DEG C~4 DEG C
Hour, the oil reservoir of removal refrigeration liquid adjusts pH value 6.0~7.0, concentration, thin layer rapid draing or vacuum belt type drying are to get yellow another name for Sichuan Province
Sunflower extract.
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