CN105079793A - Liraglutide and metformin hydrochloride compound preparation applicable to oral administration - Google Patents
Liraglutide and metformin hydrochloride compound preparation applicable to oral administration Download PDFInfo
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- CN105079793A CN105079793A CN201510424152.9A CN201510424152A CN105079793A CN 105079793 A CN105079793 A CN 105079793A CN 201510424152 A CN201510424152 A CN 201510424152A CN 105079793 A CN105079793 A CN 105079793A
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Abstract
The invention discloses a liraglutide and metformin hydrochloride compound preparation applicable to oral administration, wherein the compound preparation is prepared from liraglutide or pharmaceutically acceptable salt, metformin hydrochloride, accessories and the like. The finished product has indexes of effectively and synergistically lowering blood sugar, glycosylated hemoglobin and the like.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of oral compound preparation that can be used for oral Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride, include but not limited to oral enteric compound preparation.
Background technology
Diabetes have become the chronic disease of the 3rd serious harm human health after tumor, cardiovascular and cerebrovascular disease in the world.Type ii diabetes is many-sided to body harm, but mainly endangers the heart, brain, kidney, blood vessel, nerve, skin etc.According to national survey report, the earliest, at most and the most serious, type ii diabetes has the course of disease patient of more than 10 years in spot in the world for the complication of China type ii diabetes people, the complication that the people of more than 78% has degree different.
(1) type ii diabetes is to the harm of kidney: due to hyperglycemia, hypertension and hyperlipidemia, and Microcirculation of Renal Glomeruli filtration pressure is abnormal to be raised, and promotes diabetic nephropathy to occur and development.Early manifestation is albuminuria, edema, and late period, renal failure occurred, and is the topmost causes of death of diabetes.
(2) type ii diabetes can cause heart change: diabetes can cause angina pectoris, myocardial infarction, even die suddenly.
(3) diabetic ophthalmopathy is caused: diabetics is except arteriosclerosis, Retinopathy of Hypertension and senile cataract, and diabetic retinopathy and diabetic cataract are the main manifestations that diabetes endanger eyeball.The lighter's visual deterioration, severe one can cause blind.In the U.S., diabetes are the blind main reasons of more than 20 years old patient, and in addition, diabetes can also cause glaucoma and other oculopathy.
(4) diabetic foot is caused: main based on lower limb atherosclerosis, diabetics raises due to blood glucose, peripheral angiopathy can be caused, local organization is caused to reduce and hypoperfusion the sensitivity of impairment factor, when extraneous factor damage local organization or local infection, comparatively more easily there is local tissue ulceration in common people, the modal position of this danger is exactly foot, therefore is called diabetic foot.Clinical manifestation is lower limb pain, festers, and serious blood supply insufficiency can cause acral necrosis.In this case, amputation will be inevitable, cause maimed person.According to statistics, the amputation rate of diabetes patient is 5 times of non-diabetic people, and 40%II diabetes mellitus type and 20% diabetics diabetic foot can occur.
(5) other diabetic complications: type ii diabetes also can concurrent respiratory tract and urinary tract infection, pulmonary tuberculosis, skin infection and periodontitis etc.Concurrent metabolism disorder as ketoacidosis, hyperosmolar coma, hypoglycemic coma.
The Victoza main component of the exploitation of Novo Nordisk Co., Ltd of Denmark, development is Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]; natural GLP-1 molecule the 34th lysine is replaced by arginine; on 26th lysine, increase by is by 16 carbon palmityl fatty acid side chains of glutamate-induced; make it while reservation innate efficacy, extend its acylate and protein binding time, overcome the shortcoming that GLP-1 easily degrades.Due to this molecular changes, patient only needs every day 1 subcutaneous injection just can play good blood sugar reducing function.Have in Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] clinical practice and reduce blood glucose and HbA
1Clevel, improve islet beta cell function and reduce systolic pressure, lose weight, adjust fat to protect the effects such as cardiovascular system.On January 25th, 2010, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is used for the treatment of type ii diabetes by FDA approval, this product can separately as the second line treatment medicine of type ii diabetes, also can with other oral antidiabetic drug conbined usage, but the treatment of type i diabetes can not be used for as insulin substitutes.
Metformin hydrochloride is as a line antidiabetic drug, its pharmacological action mainly recovers insulin to the inhibitory action of adenylate cyclase activity by liver plasma membrane G-protein, to reduce hepatic gluconeogenesis and hepatic glucose output, promote the anerobic glycolysis of myocyte's glucose, increase the peripheral tissues such as muscle to the picked-up of glucose, thus strengthen the sensitivity of tissue to insulin, and to normal person without blood sugar reducing function, safety is good, also has ameliorate body quality, reduces the effect of blood fat and alleviation hyperinsulinemia.
The amount ranges that metformin hydrochloride is conventional is 500mg--2000mg, and dosage is large, untoward reaction: 1. common are: have metallic taste in nausea,vomiting,diarrhea, mouth.2. sometimes there is weak, tired, dizzy, erythra.3., although lactic acidosis incidence rate is very low, should note.Clinical manifestation is vomiting, stomachache, Hyperventilation, mind obstacle, and in blood, lactic acid concn increases and uremia, ketoacidosis or salicylism can not be used to explain.4. can reduce intestinal absorption vitamin B12, make hemoglobin reduction, produce macrocytic anemia, also can cause malabsorption.Clinical conventional treatment type ii diabetes dosage regimen metformin hydrochloride and Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection use in conjunction.
Only have the injection of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] to go on the market in the market, but the patient compliance of injection is poor, causes suffering to patient.The present invention has prepared Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride compound preparation.Compound preparation has many advantages: by the complementary action between mechanism of drug action to improve curative effect; Because each one-component consumption reduces, the toxic and side effects of medicine is reduced; The compound preparation of fixed mixing ratio, be conducive to the compliance improving patient, this point is particularly important to long-term chronic disease.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and natural GLP-1 different, the degraded of two kinds of peptidase metabolic enzymes is all stablized and plasma half-life 13 hours after subcutaneous administration.The pharmacokinetics figure of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] makes it to be suitable for 1 administration every day, is self companion's delayed absorption, plasma protein combination and the result to DPP-IV and NEP metabolic degradation stability.Because after the administration of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] persistent, plasma half-life reaches 13h, compound preparation administration every day 1 time, reaches medication object easily.Efficiently solve the misery of drug administration by injection, reduce the clinical dosage of metformin hydrochloride, thus reduce the untoward reaction of metformin hydrochloride generation.
Whether Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral application can there is no report at present, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is prepared salify by the present invention, using Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt as active constituents of medicine, prepare a kind of enteric coated preparation together with metformin, achieve Synergistic and improve the beyond thought effect of bioavailability.
Summary of the invention:
The invention discloses and a kind ofly can be used for oral Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride compound preparation.
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt of the present invention is that Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and intestinal absorption enhancers react the salt formed, and described intestinal absorption enhancers is selected from: Capric acid sodium salt, Capric acid potassium salt, benzenesulfonic acid, dodecylbenzene sodium sulfonate, Potassium dodecylbenzenesulfonate, sodium caprylate, potassium octanoate, sodium laurate, potassium laurate, enuatrol, potassium oleate.Preferred Capric acid sodium salt, Capric acid potassium salt.
The method of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] of the present invention and intestinal absorption enhancers salify is, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and intestinal absorption enhancers turn salt prepare salify through efficiently preparing liquid phase, and both mol ratios are 1:0.1-5.
Described preparation method preferably as: by Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and caprate salify, both mol ratios are 1:0.1-5, preferred 1:0.5-2.5.
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt of the present invention, preferred Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate.
For this reason, the invention provides and a kind ofly can be used for oral compound medicinal formulation, its active component is Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride, wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt is selected from: the salt that Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and Capric acid sodium salt, Capric acid potassium salt, benzenesulfonic acid, dodecylbenzene sodium sulfonate, Potassium dodecylbenzenesulfonate, sodium caprylate, potassium octanoate, sodium laurate, potassium laurate, enuatrol, potassium oleate are formed
The part by weight of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride is 0.5 ~ 9:250.Preferably, the part by weight of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride is 1 ~ 5:250.Most preferred, the part by weight of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride is 3:250.
Compound medicinal formulation of the present invention, described preparation is enteric coated preparation.Include but not limited to enteric coated tablet, enteric coated capsule, enteric coated micropill, enteric coated particles.
Compound medicinal formulation of the present invention, wherein also containing pharmaceutic adjuvant.Described pharmaceutic adjuvant comprises: filler, disintegrating agent, binding agent, lubricant; Described filler comprises silica sol and is selected from following one or more: Icing Sugar, lactose, corn starch, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, Sorbitol, mannitol, for the metformin hydrochloride of every 250 weight portions, the amount of filler is 15 ~ 150 weight portions; Described disintegrating agent be selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose sodium, polacrilin potassium one or more, for the metformin hydrochloride of every 250 weight portions, the amount of disintegrating agent is 5 ~ 50 weight portions; Described binding agent is selected from one or more in polyvidone, sodium carboxymethyl cellulose, polyvinylpyrrolidone or hypromellose, and for the metformin hydrochloride of every 250 weight portions, the amount of binding agent is 5 ~ 50 weight portions; Described lubricant is selected from the one in magnesium stearate, Macrogol 4000-8000, micropowder silica gel, Pulvis Talci, and for the metformin hydrochloride of every 250 weight portions, the amount of lubricant is 2 ~ 20 weight portions.Described pharmaceutic adjuvant also comprises solubilizing agent, and described solubilizing agent is selected from poloxamer, tween.
The present invention also comprises the preparation method of compound medicinal formulation of the present invention, and the method comprises the following steps:
A each material is crushed to acceptable granularity in pharmacy by () respectively;
B () prepares granule I: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and solubilizing agent, appropriate binding agent are dissolved in appropriate water and make solution, by this spray solution in appropriate filler, abundant mix homogeneously, be dried to moisture lower than 5% granule, again this dried particles is ground to form granularity and be less than 80 object fine powders, obtain granule I;
C () prepares granule II: metformin hydrochloride, remainder binder, filler and appropriate mix lubricant is even, is wetting agent pelletize with water, dry, obtains granule II;
D () be mixed and preparations shaping eventually: granule I, granule II, disintegrating agent, surplus lubricant and surplus filler are fully mixed, the mixture obtained is compound preparation; Optionally this compound preparation is loaded in enteric capsule shell, to be pressed into tablet enteric coated or make and comprise but do not limit enteric coated micropill, enteric coated particles etc., make enteric compound preparation.
The most preferred compound medicinal formulation of the present invention, active component is wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt and metformin hydrochloride, and wherein metformin hydrochloride is 250 weight portions, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt 3 weight portion.
Beneficial effect of the present invention is further illustrated below by way of experimental data:
Carry out evaluating drug effect to different dosing group by the index such as glycolated hemoglobin and blood glucose, different dosing group comprises: the compound preparation group of the embodiment of the present invention 1; Metformin hydrochloride administration group 1 (250mg); Metformin hydrochloride administration group 2 (500mg); The embodiment of the present invention 2 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt oral formulations group; Blank group.
Metformin hydrochloride tablet: trade name: Dihua tang ding; Lot number 8017426, source: Australian Ai Hua great pharmaceutical factory
Drug effect scheme is as follows:
Laboratory animal: ZDF rat (Beijing Vital River Experimental Animals Technology Co., Ltd. SPF level)
Experiment equipment: blood glucose meter, balance, blood sugar test paper
Preparatory work of experiment: monitoring fasting glucose before the administration of ZDF rat, reaches and meets after diabetes glucose standard by fasting blood sugar random packet.
Experimental procedure: experiment is divided into 5 groups, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt of embodiment 1 and metformin hydrochloride compound preparation group (3mg:250mg), metformin hydrochloride administration group 1 (250mg), metformin hydrochloride administration group 2 (500mg), embodiment 2 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral formulations group, blank group.Often organize 10 animals.Metformin hydrochloride administration group 1, dosage is 2.1mg/100g, metformin hydrochloride administration group 2, dosage is 4.2mg/100g, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] matched group, and dosage is 26 μ g/100g, tested material group dosage is metformin 2.1mg/100g+ Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] 26 μ g/100g, successive administration 5 weeks.
Testing index: 1 every four days monitoring body weight
2 every seven days monitoring fasting glucose
Administration at 3 five weekends terminates rear rat aorta and gets whole blood, and centrifuging and taking serum is frozen for subsequent use.Detect glycolated hemoglobin.
Result:
Table 1 different dosing group is average blood sugar (mmol/L) situation of change after 5 weeks
Table 2 different dosing group is mean glycated haemoglobin (g/L) situation of change after 5 weeks
Conclusion: the change of blank administration group average blood sugar, mean glycated haemoglobin is not obvious, and metformin hydrochloride administration group 1 (250mg), Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral formulations group have certain change; Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt and metformin hydrochloride compound preparation group and give metformin hydrochloride administration group 2 (500mg), average blood sugar, mean glycated haemoglobin have significant change, mean glycated haemoglobin, in range of normal value, is starkly lower than other administration groups.
Accompanying drawing illustrates:
Fig. 1 different dosing group is average blood sugar situation of change after 5 weeks
Fig. 2 different dosing group is mean glycated haemoglobin situation of change after 5 weeks
Fig. 3 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt prepares spectrogram
Fig. 4 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt detects spectrogram
Spectrogram prepared by Fig. 5 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate
Fig. 6 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate detects spectrogram
Fig. 7 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate prepares spectrogram
Fig. 8 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate detects collection of illustrative plates
Detailed description of the invention:
Further illustrate the present invention below by specific embodiment/experimental example, but should be understood to, these embodiments and experimental example are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
Embodiment 1: prepare drug compound preparation
Formula:
Method for making:
A each material is crushed to acceptable granularity in pharmacy (granularity is less than 80 orders) by () respectively;
B () prepares granule I: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt and alkaline agent, solubilizing agent, binding agent are dissolved in the solution making 2/4 degree of saturation in appropriate water, by this spray solution, (exit is through the syringe of repacking, during outside extruding, solution can therefrom spray) in filler, abundant mix homogeneously, be dried to moisture lower than 2% granule, again this dried particles is ground to form granularity and be less than 80 object fine powders, obtain granule I (in this technique, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt yield of granule I is 96.7%);
C () prepares granule II: metformin hydrochloride, binding agent, filler and mix lubricant is even, is wetting agent pelletize, is dried to moisture lower than 2%, obtain granule II with water;
D () be mixed and preparations shaping eventually: granule I, granule II, disintegrating agent, lubricant and filler are fully mixed, the enteric coated mixture obtained is drug compound preparation of the present invention.
Embodiment 2: prepare Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt enteric coated preparation
Formula:
| Composition | Amount/mg | Prescription is resolved |
| Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt | 3 | Activating agent |
| Tween 80 | 0.5 | Solubilizing agent |
| Hypromellose | 3 | Binding agent |
| Arginine | 1 | Alkaline agent |
| Microcrystalline Cellulose | 18.9 | Filler |
| Cross-linking sodium carboxymethyl cellulose | 10.8 | Disintegrating agent |
Method for making:
Each material is crushed to respectively acceptable granularity in pharmacy (granularity is less than 80 orders); Prepare granule I: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt and alkaline agent, solubilizing agent, binding agent are dissolved in the solution making 1/2 degree of saturation in appropriate water, by this spray solution, (exit is through the syringe of repacking, during outside extruding, solution can therefrom spray) in filler, abundant mix homogeneously, be dried to moisture lower than 2% granule, again this dried particles is ground to form granularity and be less than 80 object fine powders, obtain granule, add the disintegrating agent of recipe quantity, mix lubricant is even, enteric coating makes Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt enteric coated preparation.
The preparation of embodiment 3, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate
The patent way (open application number: CN103864918A) of having applied for according to my company synthesizes Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude product, high-purity Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] concentrated solution is obtained after using preparative liquid chromatography to carry out purification, concentrated by rotary evaporation to crude product, the mobile phase re-used containing Capric acid sodium salt carries out turning Ficus caricaL in preparation liquid phase, obtain Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt solution, after concentrated by rotary evaporation, carry out lyophilizing, obtain Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt.
The preparation technology of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt is specific as follows:
Compound concentration be the Capric acid sodium salt aqueous solution of 0.1% as mobile phase A, acetonitrile is as Mobile phase B, and salt to be turned uses.
Turning salt equipment is the DAC150 high performance preparative liquid chromatography instrument that Beijing Chuangxin Tongheng Science and Technology Co., Ltd. produces.Column packing is the anti-phase C18 filler of great Cao (DAISO), specification SP-100-8-OOS-P.
First, the mobile phase water influent pipeline A of preparation liquid phase is put in the highly purified Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] concentrated solution of 3L salt to be turned, the ratio arranging mobile phase A is 95%, the mobile phase water influent pipeline B of preparation liquid phase is put in acetonitrile, the ratio arranging Mobile phase B is 5%, overall flow velocity is set as 600ml/min, and determined wavelength is chosen as 280nm.Sample injection time is 5 minutes.
After sample introduction, the elution program of preparation liquid phase is arranged as follows:
| Time min | Flow velocity ml/min | A pump (Capric acid sodium salt/water) | B pump (acetonitrile) | Determined wavelength |
| 0-3 | 600 | 95-95 | 5-5 | 280nm |
| 3-70 | 600 | 80-40 | 20-60 | 280nm |
| 70-75 | 600 | 40-40 | 60-60 | 280nm |
| 75-80 | 600 | 5-5 | 95-95 | 280nm |
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt is prepared spectrogram and is referred to Fig. 3.
Collection method
| Collect liquid title | Collect voltage (ordinate value) |
| Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] turns saline solution | 500mv (before summit)-500mv (after summit) |
At 45 DEG C, distilling under reduced pressure is carried out to the 4L Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt solution collected, obtains Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt after concentrated and turn salt concentrated solution, after using 0.22 micron of poly (ether sulfone) film aseptic filtration, carry out lyophilizing.Obtain 5.8g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt, outward appearance is white fluffy powder, and liquid phase purity is 100%, and the mol ratio of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and Capric acid sodium salt is 1:2.3.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt detects spectrogram and refers to Fig. 4.
The preparation technology of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate is specific as follows:
Compound concentration be the sodium laurate aqueous solution of 0.1% as mobile phase A, acetonitrile is as Mobile phase B, and salt to be turned uses.
Turning salt equipment is the DAC150 high performance preparative liquid chromatography instrument that Beijing Chuangxin Tongheng Science and Technology Co., Ltd. produces.Column packing is the anti-phase C18 filler of great Cao (DAISO), specification SP-100-8-OOS-P.
First, the mobile phase water influent pipeline A of preparation liquid phase is put in the highly purified Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] concentrated solution of 3L salt to be turned, the ratio arranging mobile phase A is 95%, the mobile phase water influent pipeline B of preparation liquid phase is put in acetonitrile, the ratio arranging Mobile phase B is 5%, overall flow velocity is set as 600ml/min, and determined wavelength is chosen as 280nm.Sample injection time is 5 minutes.
After sample introduction, the elution program of preparation liquid phase is arranged as follows:
| Time min | Flow velocity ml/min | A pump (sodium laurate/water) | B pump (acetonitrile) | Determined wavelength |
| 0-3 | 600 | 95-95 | 5-5 | 280nm |
| 3-70 | 600 | 80-40 | 20-60 | 280nm |
| 70-75 | 600 | 40-40 | 60-60 | 280nm |
| 75-80 | 600 | 5-5 | 95-95 | 280nm |
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate is prepared spectrogram and is referred to Fig. 5.
Collection method
| Collect liquid title | Collect voltage (ordinate value) |
| Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] turns saline solution | 500mv (before summit)-500mv (after summit) |
At 45 DEG C, distilling under reduced pressure is carried out to the 4L Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate solution collected, obtains Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate after concentrated and turn salt concentrated solution, after using 0.22 micron of poly (ether sulfone) film aseptic filtration, carry out lyophilizing.Obtain 5.7g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate, outward appearance is white fluffy powder, and liquid phase purity is 100%, and the mol ratio of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and sodium laurate is 1:1.9.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate Product checking spectrogram refers to Fig. 6.
The preparation technology of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate is specific as follows:
Compound concentration be the sodium caprylate aqueous solution of 0.1% as mobile phase A, acetonitrile is as Mobile phase B, and salt to be turned uses.
Turning salt equipment is the DAC150 high performance preparative liquid chromatography instrument that Beijing Chuangxin Tongheng Science and Technology Co., Ltd. produces.Column packing is the anti-phase C18 filler of great Cao (DAISO), specification SP-100-8-OOS-P.
First, the mobile phase water influent pipeline A of preparation liquid phase is put in the highly purified Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] concentrated solution of 3L salt to be turned, the ratio arranging mobile phase A is 95%, the mobile phase water influent pipeline B of preparation liquid phase is put in acetonitrile, the ratio arranging Mobile phase B is 5%, overall flow velocity is set as 600ml/min, and determined wavelength is chosen as 280nm.Sample injection time is 5 minutes.
After sample introduction, the elution program of preparation liquid phase is arranged as follows:
| Time min | Flow velocity ml/min | A pump (sodium caprylate/water) | B pump (acetonitrile) | Determined wavelength |
| 0-3 | 600 | 95-95 | 5-5 | 280nm |
| 3-70 | 600 | 80-40 | 20-60 | 280nm |
| 70-75 | 600 | 40-40 | 60-60 | 280nm |
| 75-80 | 600 | 5-5 | 95-95 | 280nm |
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate is prepared spectrogram and is referred to Fig. 7.
Collection method
| Collect liquid title | Collect voltage (ordinate value) |
| Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] turns saline solution | 500mv (before summit)-500mv (after summit) |
At 45 DEG C, distilling under reduced pressure is carried out to the 4L Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate solution collected, obtains Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate after concentrated and turn salt concentrated solution, after using 0.22 micron of poly (ether sulfone) film aseptic filtration, carry out lyophilizing.Obtain 4.3g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate, outward appearance is white fluffy powder, and liquid phase purity is 100%, and the mol ratio of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and sodium caprylate is 1:2.1.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate detects spectrogram and refers to Fig. 8.
Why the present invention uses Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt as active component, and being because Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt has good oral stability and bioavailability, is below regarding assay data:
Sample 1, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt oral enteric preparation
Sample 2, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate oral enteric preparation
The preparation of sample 3, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate oral enteric preparation
Sample 4, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral enteric preparation
Study on the stability
Sampling this, place 10 days under putting illumination (4500 ± 500) lx, high temperature (40 ± 2) DEG C and high humidity (70 ± 5) % condition respectively, sample respectively at when the 5th day, 10 days, observe its outward appearance, measure drug content.Each formulation aesthetics is without remarkable change, and sample 1-3 drug content etc. are without significant difference, and in preparation, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is without the phenomenon such as obvious degradation, gathering.Each preparation drug content data that when the 5th day, 10 days, sampling obtains are in table 3, and the percentage ratio that wherein drug content surveys drug content with experiment product actual measurement drug content and reference substance represents.
The each placement condition of table 35 days, 10 days principal agent content balances
As seen from the above table, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation stability is comparatively strong, and place 10 days under high temperature, high humidity, illumination condition, drug content is without remarkable minimizing.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral enteric preparation predominant amount declines obviously.After showing salify, preparation stability obviously increases.
The tablets in vitro test of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation
Precision takes the enteric coated preparation of sample 1-4 in different stripping rotors, add the phosphate buffer of pH6.8, trypsin, with 100 revs/min of stirrings under 37 DEG C of conditions, from solution, draw 1ml respectively at 15min, 30min, 45min, 60min and measure Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] content, calculate the cumulative release amount of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].The results are shown in following table, the percentage ratio that in table, burst size accounts for Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] content in sample formulation with the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] of accumulative release represents.
Principal agent burst size contrast in table 4 different Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation 60min
From table, stripping major part principal agent after the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation 60min of preparation, release action is obvious, and Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salify sample release principal agent amount is apparently higher than non-salify Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].
Adopt different Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation on the impact of bioavailability in body, respectively containing the oral enteric preparation of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt (caprate, caprylate, laruate) 6mg, trehalose 30mg in formula, and with blank group, subcutaneous injection group, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral enteric preparation group contrast.
Table 5 group and administrations
Bioavailability contrast in table 6 different Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] preparation body
Result shows: containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] caprate oral enteric preparation bioavailability apparently higher than other Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral formulations, bioavailability is 31%.
Adopt different Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation on the impact of db/db diabetic mice hypoglycemic effect, respectively containing the oral enteric preparation of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt (caprate, caprylate, laruate) 6mg, trehalose 30mg in formula.
Test unit is Harbin Medical University.This test adopts db/db diabetic mice, and weight range is (30 ± 10g); Animal origin is that country of Nanjing University genetic engineering mice resources bank (number: SCXK (Soviet Union) 2015-0001) by animal origin licence; Animal group technology adopts the completely random method of dividision into groups.
Experimental technique: the db/db mice meeting diabetes glucose requirement is divided into six groups, blank group, promise and power group, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral enteric preparation group, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] caprate oral enteric preparation group, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] caprylate oral enteric preparation group, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Laurel salt oral enteric preparation group often organize 10 mices, male and female half and half.Each group gives relative medicine, successive administration 5 weeks, blood glucose during monitoring administration, and blood glucose once to detect weekly (fasting 12 hours) on an empty stomach.Model control group subcutaneous administration is according to clinical administration dosage; Oral administration group dosage: according to promise and power description, people's maximal dose every day 1.8mg/70kg, amounting to into mouse dose is 1.8mg/70kg*8.95=0.23mg/kg.Test medicine calculates by bioavailability 20%, 0.23/0.2=1.15mg/kg, (calculate by 3.2mg principal agent/g, 1.15mg/kg is equivalent to 0.36g patent medicine/kg).
The contrast of table 7 different dosing group hypoglycemic effect (blood glucose reduction rate)
Conclusion: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral enteric preparation group blood sugar lowering rate is not obvious; The use of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt significantly can improve the absorption of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] medicine at intestinal, improves blood drug level, improves the bioavailability of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], heighten the effect of a treatment.Wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] caprate oral enteric preparation group and subcutaneous injection group blood sugar lowering rate are substantially suitable, and effect is optimum.
Claims (10)
1. one kind can be used for oral compound medicinal formulation, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] containing effective dose or the acceptable salt of its pharmacy and metformin hydrochloride, wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt is selected from: the salt that Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and Capric acid sodium salt, Capric acid potassium salt, benzenesulfonic acid, dodecylbenzene sodium sulfonate, Potassium dodecylbenzenesulfonate, sodium caprylate, potassium octanoate, sodium laurate, potassium laurate, enuatrol, potassium oleate are formed, and the part by weight of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride is 0.5 ~ 9:250.
2. compound medicinal formulation according to claim 1, wherein the part by weight of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride is 1 ~ 5:250.
3. compound medicinal formulation according to claim 1, wherein the part by weight of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and metformin hydrochloride is 3:250.
4. compound medicinal formulation according to claim 1, described preparation is enteric coated preparation.
5. compound medicinal formulation according to claim 1, wherein also containing pharmaceutic adjuvant.
6. compound medicinal formulation according to claim 1, described pharmaceutic adjuvant comprises: filler, disintegrating agent, binding agent, lubricant; Described filler comprises silica sol and is selected from following one or more: Icing Sugar, lactose, corn starch, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, Sorbitol, mannitol, for the metformin hydrochloride of every 250 weight portions, the amount of filler is 15 ~ 150 weight portions; Described disintegrating agent be selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose sodium, polacrilin potassium one or more, for the metformin hydrochloride of every 250 weight portions, the amount of disintegrating agent is 5 ~ 50 weight portions; Described binding agent is selected from one or more in polyvidone, sodium carboxymethyl cellulose, polyvinylpyrrolidone or hypromellose, and for the metformin hydrochloride of every 250 weight portions, the amount of binding agent is 5 ~ 50 weight portions; Described lubricant is selected from the one in magnesium stearate, Macrogol 4000-8000, micropowder silica gel, Pulvis Talci, and for the metformin hydrochloride of every 250 weight portions, the amount of lubricant is 2 ~ 20 weight portions.
7. compound medicinal formulation according to claim 6, wherein said pharmaceutic adjuvant also comprises solubilizing agent, and described solubilizing agent is selected from poloxamer, tween.
8. compound medicinal formulation according to claim 4, includes but not limited to enteric coated tablet, enteric coated capsule, enteric coated micropill, enteric coated particles.
9. the preparation method of compound medicinal formulation described in claim 1, the method comprises the following steps:
A each material is crushed to acceptable granularity in pharmacy by () respectively;
B () prepares granule I: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] or the acceptable salt of its pharmacy and solubilizing agent, appropriate binding agent are dissolved in appropriate water and make solution, by this spray solution in appropriate filler, abundant mix homogeneously, be dried to moisture lower than 5% granule, again this dried particles is ground to form granularity and be less than 80 object fine powders, obtain granule I;
C () prepares granule II: metformin hydrochloride, remainder binder, filler and appropriate mix lubricant is even, is wetting agent pelletize with water, dry, obtains granule II;
D () be mixed and preparations shaping eventually: granule I, granule II, disintegrating agent, surplus lubricant and surplus filler are fully mixed, the mixture obtained is compound preparation; Optionally this compound preparation is loaded in enteric capsule shell, to be pressed into tablet enteric coated or make and comprise but do not limit enteric coated micropill, enteric coated particles etc., make enteric compound preparation.
10. compound medicinal formulation according to claim 1, active component is wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt and metformin hydrochloride, and wherein metformin hydrochloride is 250 weight portions, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt 3 weight portion.
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