CN104548096B - A kind of pharmaceutical composition and preparation method thereof containing GLP-1 analog and DPP-4 inhibitor - Google Patents
A kind of pharmaceutical composition and preparation method thereof containing GLP-1 analog and DPP-4 inhibitor Download PDFInfo
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Abstract
The invention belongs to field of medicine preparing technology, disclose the pharmaceutical composition and preparation method thereof of a kind of glucagon-like-peptide-1 (GLP-1) analog containing therapeutically effective amount and dipeptidyl peptidase-4 (DPP-4) inhibitor.Type-2 diabetes mellitus can effectively be prevented, slow down and be treated to the composition, it is particularly possible to the effectively concentration of control blood glucose, therefore can be used for treatment disease relevant to blood sugar concentration raising.In addition, composition of the invention can reduce the dosage of GLP-1 analog and DPP-4 inhibitor, so that their side effect be effectively reduced, the tolerance level of patient is improved.
Description
Technical field
The present invention relates to field of medicine preparing technology, and in particular to a kind of containing GLP-1 analog and DPP-4 inhibitor
Pharmaceutical composition and preparation method thereof.
Background technique
Glucagon-like-peptide-1 (GLP-1) is secreted by intestinal cell, and a parahormone of insulin secretion can be promoted.People
After eating food, enteron aisle, which is stimulated, will secrete this hormone, to reduce blood glucose.It is used in order to which drug is made in GLP-1
Clinic, scientist accurately modify the peptide chain of human body GLP-1, its half-life period so has just extended to 13 from 2 minutes
A hour, thus manufactured long-acting people GLP-1 analog, entitled " Liraglutide ".
Liraglutide is a kind of drug for treating type-2 diabetes mellitus that danish novo nordisk is developed, is GLP-1
Receptor stimulating agent, it is primary per injection day by day as a kind of subcutaneous injection formulation, good reduction blood glucose can be played and weight is made
With.Its peptide sequence is H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Le u-Glu-Gly-
Gln-Ala-Ala-Lys(N-ε-(N-α-Palmitoyl-L-γ-glutamyl))-Glu-Phe-Ile-Ala-Trp-Leu-
Val-Arg-Gly-Arg-Gly-OH.Liraglutide is in FDA approval listing in 2010, trade name promise and power (Victoza).System
Agent specification is 18mg/ml.
DPP-IV inhibitor is by inhibiting the activity of DPP-IV to promote beta Cell of islet to generate pancreas in raising GLP-1 concentration
While the element of island, Glucagon concentrations are reduced, to reduce blood glucose.Different from conventional oral hypoglycemic agent, DPP-IV inhibits
The appearance nothing of agent controls blood glucose suspected of II diabetic and provides new selection.
DPP-IV inhibitor can be individually used for treatment type II diabetes, can also combine with other conventional oral diabetes medicaments
It uses.Clinical research shows: being applied alone DPP-IV inhibitor that can reduce postprandial blood sugar and HbA1c, improves islet beta cell function, mention
Sensibility of the high body to insulin.DPP-IV inhibitor has good blood sugar decreasing effect, and adverse reaction is slight, will not
Cause weight gain and oedema, causes risk of hypoglycemia also very small.
Xi Gelieting is a kind of novel antidiabetic drug dipeptidyl peptidase-4 (DPP-4) inhibitor, and human body itself reduction can be improved
The ability of too high blood glucose level is a kind of drug for treating type-2 diabetes mellitus of United States Merck company development, acquisition FDA in 2006
Approval listing.Trade name Jie Nuowei.Its structure are as follows:
Vildagliptin is a kind of DPP-4 inhibitor researched and developed by Novartis Co., Ltd, Switzerland, in acquisition EMA approval in 2 months 2008
City, structure are as follows:
Saxagliptin is a kind of DPP-4 inhibitor of Bristol-Myers Squibb Co., U.S. research and development, obtains FDA in July, 2009
Approval listing, structure are as follows:
Li Nalieting is a kind of DPP-4 inhibitor of German Boehringer Ingelheim drugmaker research and development, obtains in May, 2011
Obtain FDA approval listing, structure are as follows:
Egelieting is a kind of DPP-4 inhibitor of Japanese Takeda Pharmaceutical Company Limited's research and development, obtains FDA approval in January, 2013
Listing, structure are as follows:
Gigue column spit of fland is a kind of DPP-4 inhibitor of LG Life Sciences, South Korea research and development, and in June, 2012 is in South Korea
City, structure are as follows:
Teneligliptin is a kind of DPP-4 inhibitor of Mitsubishi Tian Bian drugmaker research and development, and in August, 2012 is in Japan
Listing, structure are as follows:
Liraglutide is subcutaneous administrations once a day at present, although Liraglutide peptide sequence is repaired by side chain hexadecanoic acid
Decorations, extend half-life period, but since Liraglutide belongs to GLP-1, can be degraded rapidly by DPP-4 enzyme in human body, cause to need
It to inject daily once, gastrointestinal side effect etc. causes larger pain to patient.
Since DPP- VIII and DPP- Ⅸ and DPP-4 belong to same enzyme family, DPP-IV inhibitor is inhibiting DPP-IV
While, it is also possible to inhibiting effect is generated to these enzymes.
Type-2 diabetes mellitus is chronic and progressive disease, due to complicated pathologic, physiologic, is related to insulin resistance and pancreas
Island element secretes the dual endocrine defects being damaged.The treatment of type-2 diabetes mellitus typically begins with diet and exercise, then
Carry out the single current system method of oral antidiabetic.For many patients, these schemes cannot be controlled fully during long-term treatment
Blood glucose leads to the requirement of the combination therapy after diagnosis within several years.However, two or more oral antidiabetic drugs
There may be complexity and the therapeutic scheme for being difficult to follow for many patients for common prescription.
Remedies for diabetes is primarily present following problems at present: unsatisfactory curative effect, and HbA1c is increased with disease progression；It is low
Blood glucose；Patient's cardiovascular risk is high.It is when business therefore, it is necessary to find the pharmaceutical preparation of highly-safe, high curative effect and low-risk
It is anxious.
Summary of the invention
The present invention in view of the above defects of the prior art, on the one hand provides a kind of pharmaceutical composition, it includes
Glucagon-like-peptide-1 (GLP-1) analog of therapeutically effective amount, the dipeptidyl peptidase-4 (DPP-4) of therapeutically effective amount inhibit
Agent, pH adjusting agent, isotonic regulator and preservative.
In a preferred embodiment of the present invention, GLP-1 analog is Liraglutide or its salt, and DPP-4 inhibitor is selected from
One of Xi Gelieting, vildagliptin, saxagliptin, Li Nalieting, Egelieting, teneligliptin and gigue column spit of fland or its can
One of medicinal salt, more preferably Xi Gelieting, saxagliptin, Li Nalieting and Egelieting or its pharmaceutical salt,
Be further preferably one of Xi Gelieting, saxagliptin and Li Nalieting or its pharmaceutical salt, most preferably Xi Gelieting and
One of Li Nalieting or its pharmaceutical salt.
In pharmaceutical composition of the invention, pharmaceutical salt is selected from phosphate, hydrochloride, sulfate, hydrosulphuric acid salt, lemon
Lemon hydrochlorate, tartrate, acetate, benzoate, malate, maleate, fumarate, glutamate and aspartic acid
Salt.
In a preferred embodiment of the present invention, the dosage of GLP-1 is the 20%-100% that the dosage of GLP-1 is used alone,
The dosage of DPP-4 inhibitor is the 20%-100% that DPP-4 is used alone and inhibits agent dose；The dosage of GLP-1 is more preferably 0.1-
10mg/ml is further preferably 0.1-5mg/ml, most preferably 0.2-3.6mg/ml；The dosage of DPP-4 inhibitor is more preferably
0.1mg-100mg/ml is further preferably 0.25-50mg/ml, most preferably 0.25-20mg/ml.
In pharmaceutical composition of the invention, pH adjusting agent is selected from hydrochloric acid, acetate buffer solution, phosphate buffer, citric acid
Buffer, sodium hydroxide, sodium carbonate, sodium bicarbonate and disodium hydrogen phosphate are preferably selected from disodium hydrogen phosphate, sodium carbonate and hydroxide
Sodium.
In pharmaceutical composition of the invention, isotonic regulator is selected from propylene glycol, mannitol, sodium chloride, glucose, fruit
Sugar, magnesium chloride, polyethylene glycol, glycerol, lactose, galactolipin and xylitol, are preferably selected from mannitol and propylene glycol.
In pharmaceutical composition of the invention, preservative be selected from anesin, benzoic acid and its salt, sorbic acid and its
One of salt, metacresol, phenol or combination, preferably one of anesin, metacresol, phenol or combination, it is more excellent
It is selected as anesin.
In a preferred embodiment of the present invention, the dosage of preservative is 1-10mg/ml, and the dosage of isotonic regulator is 5-
20mg/ml, pH range are 7.0-9.0, preferably 7.5-8.5, more preferably 7.8-8.4.
In a preferred embodiment of the present invention, pharmaceutical composition of the invention is injection dosage form, dosage form
Preferably peace cuts open bottle or prefilled injection pen.
Another aspect of the present invention additionally provides the method for preparing pharmaceutical composition of the present invention, includes the following steps:
1, the preservative and isotonic regulator for weighing recipe quantity, are added in material-compound tank；
2, appropriate water for injection is added to be completely dissolved；
3, it takes appropriate water for injection to be completely dissolved the GLP-1 analog of recipe quantity and DPP-4 inhibitor, is added to above-mentioned
In material-compound tank；
4, with water for injection constant volume；
5, it adjusts and arrives target ph；
6, using 0.22 μm of membrane filtration degerming, injection is made in packing.
In a preferred embodiment of the present invention, the dosage of composition is prepared into 1 time a day or at a suitable time
The suitable dose at interval exists, such as 3 days 2 times or 2 days 1 time.
In a preferred embodiment of the present invention, the preparation of composite injection aseptically carries out.
Compared with GLP-1 analog or DPP-4 inhibitor is used alone, it is of the invention comprising GLP-1 analog and
The pharmaceutical composition of DPP-4 inhibitor can significantly improve blood glucose.Inhibit for GLP-1 analog or DPP-4 is used alone
Agent, usual dosage is higher, enteron aisle side effect is larger, patient's poor resistance, all patients can not be made to reach control blood glucose purpose.
And with the sustainable development of diabetes, diabetic will appear many complication, such as arterial sclerosis, pedopathy (foot
Gangrene, amputation), nephrosis (renal failure, uremia), eye disease (smudgy, blindness), encephalopathy (cerebrovascular disease), heart
Disease, skin disease, venereal disease etc..Compared with independent medication, pharmaceutical composition of the invention can effectively control blood sugar concentration, make blood glucose
Level drops to 6% level or more.It follows that II type sugar can effectively be prevented, slow down and be treated to pharmaceutical composition of the invention
Urine disease, it is particularly possible to the effectively concentration of control blood glucose, therefore can be used for treatment disease relevant to blood sugar concentration raising.Together
When, since the GLP-1 activity of GLP-1 analog is utilized in pharmaceutical composition of the invention, patient can also be effectively reduced
Weight.
In addition, composition of the invention can reduce the dosage of GLP-1 analog and DPP-4 inhibitor, to have
Effect reduces their side effect, improves the tolerance level of patient.
Specific embodiment
Below by embodiment, the present invention is described in further detail, it is intended to limit this for illustrating rather than
Invention.It should be pointed out that those skilled in the art, it without departing from the principle of the present invention, can also be to this hair
Bright some improvement and modification can also be carried out, these improvement and modification are similarly fallen under the scope of the present invention.
Embodiment 1: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 300mg anesin, 1500mg are weighed
Mannitol is added in material-compound tank after 150mL water for injection stirring and dissolving is added；Weigh 30mg Liraglutide, 3000mg phosphoric acid
Xi Gelieting (to the west of Ge Lieting calculate) is added the dissolution of 50mL water for injection, is added in above-mentioned Agitation Tank solution, stirring and dissolving
It is clarified to solution, 0.1N sodium hydroxide is added, the pH value for adjusting solution is 8.0, remaining injection water constant volume is supplemented, using 0.22
μm membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 2: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 3000mg anesin is weighed,
2500mg propylene glycol is added in material-compound tank after 150mL water for injection stirring and dissolving is added；1080mg Liraglutide is weighed,
3000mg phosphoric acid Xi Gelieting (to the west of Ge Lieting calculate) is added the dissolution of 50mL water for injection, is added to above-mentioned Agitation Tank solution
In, stirring and dissolving to solution is clarified, and 0.1N sodium hydroxide is added, and the pH value for adjusting solution is 8.4, and it is fixed to supplement remaining injection water
Hold, using 0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 3: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 3000mg anesin is weighed,
2500mg propylene glycol is added in material-compound tank after 150mL water for injection stirring and dissolving is added；600mg Liraglutide is weighed,
600mg phosphoric acid Xi Gelieting (to the west of Ge Lieting calculate) is added the dissolution of 50mL water for injection, is added to above-mentioned Agitation Tank solution
In, stirring and dissolving to solution is clarified, and 0.1N sodium hydroxide is added, and the pH value for adjusting solution is 8.4, and it is fixed to supplement remaining injection water
Hold, using 0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 4: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 3000mg anesin is weighed,
5000mg propylene glycol is added in material-compound tank after 150mL water for injection stirring and dissolving is added；600mg Liraglutide is weighed,
600mg phosphoric acid Xi Gelieting (to the west of Ge Lieting calculate) is added the dissolution of 50mL water for injection, is added to above-mentioned Agitation Tank solution
In, stirring and dissolving to solution is clarified, and appropriate 10% aqueous sodium carbonate is added, and the pH value for adjusting solution is 7.6, supplements remaining note
Jetting amount constant volume, using 0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 5: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 1500mg phenol, 4000mg sweet dew are weighed
Alcohol is added in material-compound tank after 150mL water for injection stirring and dissolving is added；Weigh 600mg Liraglutide, the western lattice of 600mg phosphoric acid
Spit of fland (to the west of Ge Lieting calculate) is arranged, the dissolution of 50mL water for injection is added, is added in above-mentioned Agitation Tank solution, stirring and dissolving is to molten
Liquid clarification, is added appropriate 10% aqueous sodium carbonate, and the pH value for adjusting solution is 7.6, supplements remaining injection water constant volume, uses
0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 6: the preparation of Liraglutide and Li Nalieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 2000mg metacresol is weighed, 6000mg is sweet
Reveal alcohol, after 150mL water for injection stirring and dissolving is added, is added in material-compound tank；Weigh 300mg Liraglutide, 600mg Li Nalie
Spit of fland (is calculated) with Li Nalieting, and the dissolution of 50mL water for injection is added, is added in above-mentioned Agitation Tank solution, stirring and dissolving to solution
Appropriate 10% aqueous sodium carbonate is added in clarification, and the pH value for adjusting solution is 8.2, supplements remaining injection water constant volume, uses
0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 7: the preparation of Liraglutide and saxagliptin injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 2000mg metacresol is weighed, 6000mg is sweet
Reveal alcohol, after 150mL water for injection stirring and dissolving is added, is added in material-compound tank；Weigh 300mg Liraglutide, 600mg Sha Gelie
Spit of fland (is calculated) with saxagliptin, and the dissolution of 50mL water for injection is added, is added in above-mentioned Agitation Tank solution, stirring and dissolving to solution
Appropriate 10% aqueous sodium carbonate is added in clarification, and the pH value for adjusting solution is 8.0, supplements remaining injection water constant volume, uses
0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 8: the preparation of Liraglutide and Egelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 2000mg metacresol is weighed, 6000mg is sweet
Reveal alcohol, after 150mL water for injection stirring and dissolving is added, is added in material-compound tank；Weigh 300mg Liraglutide, 600mg benzoic acid
Egelieting (is calculated) with Egelieting, and the dissolution of 50mL water for injection is added, is added in above-mentioned Agitation Tank solution, stirring and dissolving
It is clarified to solution, appropriate 10% aqueous sodium carbonate is added, the pH value for adjusting solution is 8.4, remaining injection water constant volume is supplemented,
Using 0.22 μm of membrane filtration degerming；Packing is into injection pen, every 3ml, and totally 100.
Embodiment 9: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 200g anesin is weighed, 600g is sweet
Reveal alcohol, after 15L water for injection stirring and dissolving is added, is added in material-compound tank；Weigh 30g Liraglutide, 45g phosphoric acid Xi Gelieting
(to the west of Ge Lieting calculate) is added the dissolution of 5L water for injection, is added in above-mentioned Agitation Tank solution, stirring and dissolving is clear to solution
Clearly, appropriate 0.1N sodium hydrate aqueous solution is added, the pH value for adjusting solution is 8.4, supplements remaining injection water constant volume, crosses and filter out
Bacterium；Packing is into injection pen, every 3ml, and totally 10000.
Embodiment 10: the preparation of Liraglutide and Xi Gelieting injection
1, formula of liquid is injected
2, preparation process
In ten thousand grades of toilets and on clean indoor hundred-grade super-clean workbench, 300g anesin is weighed, 450g is sweet
Reveal alcohol, after 15L water for injection stirring and dissolving is added, is added in material-compound tank；Weigh 75g Liraglutide, 45g phosphoric acid Xi Gelieting
(to the west of Ge Lieting calculate) is added the dissolution of 5L water for injection, is added in above-mentioned Agitation Tank solution, stirring and dissolving is clear to solution
Clearly, appropriate 0.1N sodium hydrate aqueous solution is added, the pH value for adjusting solution is 8.4, supplements remaining injection water constant volume, crosses and filter out
Bacterium；Packing is into injection pen, every 3ml, and totally 10000.
Embodiment 11: Detection of Stability
Liraglutide and DPP-4 prepared by 1-10 of the embodiment of the present invention inhibits remover liquid injection respectively in strong light hot conditions
Lower 40 DEG C are placed 5 days and 10 days, then separately sampled, detect the variation of its purity, solution clarity and bacterial growth situation, detection
The results are shown in Table 1.
Table 1 is provided by the invention to penetrate liquid Detection of Stability
As shown in Table 1, the Li Lalu that the embodiment of the present invention 1, embodiment 3, embodiment 6, embodiment 7 and embodiment 10 provide
Peptide inhibits Liraglutide purity decrease speed in remover liquid injection most slow with DPP-4.
The Liraglutide and DPP-4 for taking the embodiment of the present invention 1, embodiment 6 and embodiment 10 to provide inhibit remover liquid injection to exist
2-8 DEG C of temperature under 60% holding conditions of relative humidity, further detects the long-term steady of Liraglutide injection provided by the invention
Qualitative, solution clarity variation and bacterial growth situation, testing result are as shown in table 2.
2 Liraglutide of table and DPP-4 inhibit remover liquid injection study on the stability result
As shown in Table 2, Liraglutide and DPP-4 inhibitor that the embodiment of the present invention 1, embodiment 6 and embodiment 10 provide
Injection is qualified in content, clarity and bacterial growth situation after storage 12 months, and quality is stablized.
The testing result for the Liraglutide injection that other embodiments of the invention provide is similarly.
Comprehensive Tables 1 and 2 is it is found that Liraglutide injection provided by the invention is with good stability, buffer pH tune
Section system maintains the pH of Liraglutide injection provided by the invention between 6~7.5, and it is most suitable to guarantee that Liraglutide is stored in
Under the conditions of pH；And the use of bacteriostatic agent grow bacterium can not, the degradation so as to avoid bacterium to Liraglutide；Show pH tune
Section agent and the use of bacteriostatic agent ensure that the stability of Liraglutide.
Embodiment 12: hypoglycemic effect detection
The Liraglutide and Xi Gelieting injection for taking the embodiment of the present invention 10 to provide, carry out hypoglycemic effect detection, take city
The Liraglutide injection and Jie Nuowei (phosphoric acid Xi Gelieting piece) sold are as control.
Male and healthy SD rat 50, weight 200g~250g are taken, cleaning grade.It randomly selects and wherein 10 is only used as normally
Group, feeding basal feed, with 1.5mL water for injection stomach-filling.After remaining rat adaptable fed 5d, that is, start feeding feeding high in fat
Material cooperates normal diet, and after 7 days, overnight fast, normal group of next day replaces streptozotocin to be injected intraperitoneally with physiological saline,
It is remaining (to be prepared with the sterile citrate buffer solution of 0.1mol/L, pH value 4.5) with streptozotocin with 50mg/kg intraperitoneal injection,
Tail is cut after 72 hours surveys blood glucose, the modeling Success Flag using fasting blood-glucose > 11.1mmol/L as diabetes rat.
After modeling success, it is divided into normal group A；Model control group B；Phosphoric acid Xi Gelieting piece is administered orally daily morning and evening twice
Administration group C, each 2mgKg-1；Liraglutide and Xi Gelieting injection the nape of the neck subcutaneous administration administration group D once a week, often
Secondary 0.4mgKg-1；Liraglutide injection the nape of the neck subcutaneous administration administration group E, each 0.6mgKg once a day-1.Administration
The 0th week afterwards, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks collection tail veins detected blood glucose value with blood glucose meter, and each data of this experiment are adopted
Processing analysis is carried out with SPSS16.0 software, each group compares to be examined using t, and testing result is as shown in table 3.
3 experimental rat blood glucose value (mmol/L) of table
| Group | Number of animals | Before injection | Injection 1 week | Injection 2 weeks | Injection 3 weeks | Injection 4 weeks | Injection 5 weeks | Injection 6 weeks |
| A group | 10 | 5.1±1.0 | 5.2±1.1 | 5.3±1.5 | 5.3±1.3 | 5.5±2.0 | 5.6±2.5 | 5.4±1.4 |
| B group | 10 | 15.8±3.1 | 18.0±3.5 | 20.3±4.0 | 23.7±3.8 | 24.6±4.4 | 26.0±2.5 | 28.7±3.3 |
| C group | 10 | 17.3±2.2 | 13.8±1.3 | 12.2±1.2 | 9.8±2.0 | 8.7±1.4 | 7.6±1.7 | 6.0±2.1 |
| D group | 10 | 17.5±1.5 | 9.6±2.0 | 7.9±2.5 | 6.8±1.1 | 6.0±1.0 | 5.2±1.5 | 4.8±1.0 |
| E group | 10 | 17.4±2.0 | 12.7±1.0 | 11.0±1.0 | 8.4±2.4 | 7.0±1.1 | 6.0±1.6 | 5.6±1.3 |
As shown in Table 3, compared with A group, there is significant difference in B group P < 0.01；Compared with B group, C, D, E group P < 0.01 have
Significant difference；Compared with C group, D, E group P > 0.05, there was no significant difference, and total hypoglycemic effect is suitable.But it can from upper table
Out, Liraglutide and Xi Gelieting injection and Liraglutide injection hypoglycemic effect will be slightly faster than oral phosphoric acid Xi Gelieting.
As can also be seen from Table 3, although Liraglutide provided by the invention and Xi Gelieting injection and commercially available existing drop
Sugared injection is compared, and hypoglycemic effect is suitable, all has significant hypoglycemic effect.But Liraglutide provided by the invention and western lattice
Column spit of fland injection hypoglycemic speed is slightly faster than commercially available oral phosphoric acid Xi Gelieting piece and Li Lula peptide injection.
The Liraglutide and DPP-4 that other embodiments of the invention provide inhibit the testing result and embodiment 10 of remover liquid injection
Result it is similar.
Claims (7)
1. a kind of pharmaceutical composition, which is characterized in that it includes the glucagon-like-peptide-1 of therapeutically effective amount (GLP-1) is similar
Dipeptidyl peptidase-4 (DPP-4) inhibitor, pH adjusting agent, isotonic regulator and the preservative of object, therapeutically effective amount；The GLP-
1 analog is Liraglutide or its salt；The DPP-4 inhibitor is Xi Gelieting or its pharmaceutical salt；The agent of the GLP-1
Amount is 2.5mg/ml, and the dosage of the DPP-4 inhibitor is 1.5mg/ml；The isotonic regulator is 15mg/ml mannitol；
The preservative is the anesin of 10mg/ml；The pH adjusting agent is sodium hydroxide, and the composition pH is 8.4.
2. pharmaceutical composition according to claim 1, which is characterized in that wherein pharmaceutical salt is selected from phosphate, hydrochloric acid
Salt, sulfate, hydrosulphuric acid salt, citrate, tartrate, acetate, benzoate, malate, maleate, fumaric acid
Salt, glutamate, aspartate.
3. pharmaceutical composition according to claim 1, which is characterized in that it is injection dosage form, and dosage form is that peace is cutd open
Bottle or prefilled injection pen.
4. the method for preparing pharmaceutical composition of any of claims 1-3 includes the following steps: that (1) weighs prescription
The preservative and isotonic regulator of amount, are added in material-compound tank；(2) appropriate water for injection is added to be completely dissolved；(3) appropriate note is taken
It penetrates and is completely dissolved the GLP-1 analog of recipe quantity and DPP-4 inhibitor with water, be added in above-mentioned material-compound tank；(4) with injection
With water constant volume；(5) it adjusts and arrives target ph；(6) 0.22 μm of membrane filtration degerming is used, injection is made in packing.
5. the preparation method of pharmaceutical composition according to claim 4, wherein the dosage of the composition be 1 time a day or
The suitable dose of person at appropriate time intervals exists.
6. the preparation method of pharmaceutical composition according to claim 5, which is characterized in that the time interval is 3 days 2 times
Or 2 days 1 time.
7. the preparation method of pharmaceutical composition according to claim 4, wherein the preparation of composite injection is sterile
Under the conditions of carry out.
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| US20190060410A1 (en) * | 2015-05-13 | 2019-02-28 | Xiaoni LIU | Pharmaceutical Formulation Comprising GLP-1 Analogue and Preparation Method Thereof |
| CN106310237A (en) * | 2016-08-22 | 2017-01-11 | 卢连伟 | Compound hypoglycemic preparation containing liraglutide and preparation method thereof |
| CN108096227A (en) * | 2018-01-25 | 2018-06-01 | 河北科技大学 | The molten film preparation in Egelieting oral cavity |
| CN114350547B (en) * | 2021-12-17 | 2023-05-16 | 四川省医学科学院·四川省人民医院 | Bifidobacterium lactis strain B-622 and application thereof in preparation of medicines for treating diabetes |
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| CN101357924A (en) * | 2007-08-01 | 2009-02-04 | 山东轩竹医药科技有限公司 | Dipeptidase-IV inhibitor compound |
| CN101495502A (en) * | 2006-05-26 | 2009-07-29 | 百时美施贵宝公司 | N-terminally modified GLP-1 receptor modulators |
| CN101595109A (en) * | 2006-11-20 | 2009-12-02 | 百时美施贵宝公司 | As 7 of inhibitors of dipeptidyl IV, 8-dihydro-1,6-naphthyridine-5 (6H)-ketone and related bicyclic compounds and method |
| CN102946875A (en) * | 2010-05-05 | 2013-02-27 | 贝林格尔.英格海姆国际有限公司 | Combination therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101495502A (en) * | 2006-05-26 | 2009-07-29 | 百时美施贵宝公司 | N-terminally modified GLP-1 receptor modulators |
| CN101595109A (en) * | 2006-11-20 | 2009-12-02 | 百时美施贵宝公司 | As 7 of inhibitors of dipeptidyl IV, 8-dihydro-1,6-naphthyridine-5 (6H)-ketone and related bicyclic compounds and method |
| CN101357924A (en) * | 2007-08-01 | 2009-02-04 | 山东轩竹医药科技有限公司 | Dipeptidase-IV inhibitor compound |
| CN102946875A (en) * | 2010-05-05 | 2013-02-27 | 贝林格尔.英格海姆国际有限公司 | Combination therapy |
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