CN104998251A - Intestinal absorption promoting liraglutide salt for preparing oral enteric-coated preparations - Google Patents
Intestinal absorption promoting liraglutide salt for preparing oral enteric-coated preparations Download PDFInfo
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Abstract
The invention discloses an intestinal absorption promoting liraglutide salt for preparing oral enteric-coated preparations, and belongs to the field of medicines. The liraglutide salt is selected from salts formed through reacting liraglutide with sodium caprate, potassium caprate, benzene sulfonic acid, sodium dodecyl benzene sulfonate, potassium dodecyl benzene sulfonate, sodium octanoate, potassium octanoate, sodium laurate, potassium laurate, sodium oleate and potassium oleate.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt with short intestinal absorption effect prepared for oral enteric preparation, obviously improve Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral organism-absorbing availability.Application in treating diabetes.
Background technology
Diabetes are commonly encountered diseases, frequently-occurring disease, its prevalence just along with the raising of people's living standard, aged tendency of population, living-pattern preservation and increasing sharply.The existing diabetics more than 9,000 ten thousand of China according to statistics, wherein type ii diabetes patient accounts for about 90%, and the morbidity of type ii diabetes is just tending to become younger.Diabetes have become the third-largest noninfectious after intentions angiopathy and tumor, bring white elephant to society and economy.Therefore find the medicine of blood sugar lowering and control diabetic complication safely and effectively significant.
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], English general Liraglutide by name, it is a kind of human glucagon-like-peptide-1 analog of synthetic, be made up of 31 amino acid residues, its aminoacid 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-y-glutamyl))-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is replaced by arginine by natural GLP-1 molecule the 34th lysine; 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.This medicine is developed by Novo Nordisk Co., Ltd of Denmark, and in July, 2009 goes on the market in European Union first.In January, 2010, go on the market in Japan.On January 25th, 2010, FDA (FDA) ratifies Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] goes on the market in the U.S..On April 13rd, 2011, obtain the approval of Chinese food Drug Administration, be used for the treatment of Adult type II diabetes.On October 9th, 2011, formally in Discussion on Chinese Listed.The trade name " Nuo Heli " of this medicine, after being applicable to metformin alone or the treatment of sulfonylurea drugs maximum tolerable dose, blood glucose still controls not good patient, with metformin or sulfonylurea drugs use in conjunction, effectively can control blood glucose.At present, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] obtains U.S. FDA approval on the 23rd for fat-reducing in December in 2014.The current administering mode of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] all adopts subcutaneous administrations.
Oral administration is easy to most received administering mode.But concerning a lot of medicine, the absorption efficiency of oral administration is also bad.The bioactive macromolecules such as such as albumen, polypeptide, polysaccharide, nucleic acid, usually can not oral administration due to factors such as enzymatic degradation, absorption difference or instability.In enteric cavity, physiological environment is complicated, and the total amount of medicine in enteric cavity also can be reduced to gastrointestinal excretion by blood plasma due to hydrolysis, metabolism, gastrointestinal enzyme degraded and medicine.Therefore, oral still have many problems need solve.
Salify improves one of drug molecule physicochemical property, the effective means improving its druggability, can change the dissolubility of medicine, improve its compliance, improve its stability, reduce its untoward reaction.Because Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] contains palmityl side chain, lipotropy is comparatively strong, and hydrophilic is poor, so in order to improve its dissolubility, the present invention have studied Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt.
When the medicine of intestinal permeation enhancers and permeability difference is taken jointly, can increase medicine by property, and then improve its bioavailability.The absorption of medicine is commonplace method (B.J.Aungst, J.Pharm.Sci., 2000,89 (4): 429-442) to adopt absorption enhancer to promote.
At present, intestinal absorption enhancers has a lot of type, and wherein medium-chain fatty acid and salt thereof are conventional classes, and it mainly comprises sodium caprylate, Capric acid sodium salt, lauric acid sodium, sodium laurate and enuatrol etc.Wherein, Capric acid sodium salt is a kind of low toxicity and effective absorption enhancer, and is used for clinical as suppository, is a kind of absorption enhancers going through to use in medicine.Its short absorption mechanism is mainly by the combination with film, the structure of film is produced disorderly, produce chelation with the various ions at intercellular tight junction place simultaneously, cause actin filament to shrink and temporarily open epithelial tight connection, regulate close-connected aperture penetration enhancement, increase paracellular transport.The enterocyte damage that this chelation of Capric acid sodium salt is caused has reversibility, and can recover rapidly after drug withdrawal, toxicity is less, and Capric acid sodium salt promotes that medicine is definite at the assimilation effect of intestinal.(Capric acid sodium salt strengthens berberine to type ii diabetes therapeutical effect and study on mechanism, 2011, Jilin University, Lv Xiaoyan)
Whether Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] can oral application, whether oral administration biaavailability can be improved after Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salify, whether can be prepared into enteric coated preparation carries out oral, prior art is not reported, for this reason, the present invention by Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] with intestinal absorption enhancers in conjunction with salify, using Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt as active constituents of medicine, prepare a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] enteric coated preparation, achieve beyond thought effect.
Summary of the invention
The invention provides the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt with short intestinal absorption effect prepared for oral enteric preparation, object is, by Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and intestinal absorption enhancers salify, to improve the absorption of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in intestinal, improves blood drug level, improve bioavailability, thus can be widely used in clinical.The technical method that the present invention adopts is:
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.
The Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt that the present invention obtains adds suitable pharmaceutic adjuvant as starch, dextrin, lactose, microcrystalline Cellulose, Pulvis Talci, cross-linking sodium carboxymethyl cellulose mix homogeneously, can be made into the preparations such as corresponding tablet, capsule, granule, pellet, preferably oral enteric preparation, preparation of the present invention is using Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt of the present invention as active constituents of medicine, oral drug preparation is prepared into according to galenic pharmacy routine techniques, particularly oral enteric preparation, as tablet, granule superscribe enteric coating, capsule adopts enteric coated capsule etc.
Invention has been a large amount of study of pharmacy and drug effect animal experiment study.Research shows, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation stability of the present invention is good, and drug loading is large, and influence factor's experimental condition is without obvious degradation, gathering, and in body, safety is good.Preparation method of the present invention is simple, and process conditions are easy to control, are suitable for large-scale industrial production, and are easy to obtain stay-in-grade product, and differences between batches are little, are convenient to quality control.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.
Containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] caprate oral enteric preparation bioavailability apparently higher than Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] oral formulations, bioavailability is 31%.
In order to the convenience illustrated, now special words all in literary composition is explained, all understands by following content without when specified otherwise:
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt refers to 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, the salt that potassium oleate is formed, when this patent Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] be 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 any one compound formed complex or mixture also referred to as Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt.
Hpmc: hydroxypropyl emthylcellulose
Beneficial effect of the present invention is further illustrated below by way of experimental data:
The study on the stability of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation
Each 3 parts of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt pref of Example 2, embodiment 3, embodiment 4, embodiment 5 preparation, 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 embodiment 2-4 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 1, 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 15 days, 10 days principal agent content balances
As seen from the above table, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation stability of embodiment 2, embodiment 3, embodiment 4 preparation 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] non-salify oral enteric preparation predominant amount prepared by embodiment 5 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 take embodiment 2, embodiment 3, embodiment 4, embodiment 5 prepare Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] enteric coated preparation 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 2 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].In different Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation 60min, the contrast of principal agent burst size trend refers to Fig. 1.
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 3 group and administrations
Bioavailability contrast in table 4 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 5 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.The trend contrast of different dosing group blood sugar lowering rate refers to Fig. 2.
Figure of description:
Principal agent burst size trend contrast in Fig. 1 different Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt oral enteric preparation 60min
The trend contrast of Fig. 2 different dosing group blood sugar lowering rate
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:
Below in conjunction with embodiment, the present invention is further explained.Should be understood that, following examples only for explaining the present invention, instead of limit the scope of the invention.
The preparation of embodiment 1, 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: CN 103864918 A) 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.
Embodiment 2 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt oral enteric preparation
Main formula
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt 1g
Trehalose 5g
Preparation method:
1) add microcrystalline Cellulose and the Pulvis Talci weight ratio 8:1 of recipe quantity, adopt the standby celphere of centrifugal granulator mechanism.
Take the microcrystalline Cellulose of recipe quantity, Pulvis Talci, use three-dimensional mixer to mix 30 minutes, get half and be placed in centrifugal pellet processing machine, second half is positioned in loader, getting appropriate purified water is positioned in liquid-supplying bucket, opens centrifugal pellet processing machine, unlocking turntable, air feed, spraying, treat that on rotating disk, piller made by material, open for powder, until the material in loader is finished, close spraying, for powder, discharging, last closing machine.By the ball core made, be placed in fluid bed dryer, open machine, open air feed, adjustment parameter, dried after 20 minutes, opened heating, till oven dry, and discharging, closing machine.14 orders and 40 mesh sieves sieve is used to get qualified ball core.
2) get recipe quantity purified water, more slowly add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt, stir, adjust ph to 8.15 with the sodium hydroxide solution of 1mol/L, dissolve for subsequent use completely to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt; Another preparation 8%Hpmc (W/W), 1% Pulvis Talci (W/W), aqueous trehalose.Join in material solution, stir, filter, for subsequent use.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, until coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
3) prepare 8%Hpmc (W/W) to join in appropriate purified water, stir evenly, then add 1% Pulvis Talci (W/W), stir evenly, filter, for subsequent use.Use fluidized-bed coating machine, will carry out coating containing pill layer piller, coating weight gain 10-15%, prepares sealing coat.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
4) take Ka Lekang coating materials (93f19255) slowly to join in purified water, stir about 2 hours, filters for subsequent use constantly, and use fluidized-bed coating machine, sealing coat piller is carried out coating, and coating weight gain 40-60%, prepares enteric layer.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
The preparation of embodiment 3 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate oral enteric preparation
Main formula
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate 1g
Trehalose 5g
Preparation method
1) add microcrystalline Cellulose and the Pulvis Talci weight ratio 8:1 of recipe quantity, adopt the standby celphere of centrifugal granulator mechanism.
Take the microcrystalline Cellulose of recipe quantity, Pulvis Talci, use three-dimensional mixer to mix 30 minutes, get half and be placed in centrifugal pellet processing machine, second half is positioned in loader, getting appropriate purified water is positioned in liquid-supplying bucket, opens centrifugal pellet processing machine, unlocking turntable, air feed, spraying, but the piller that on rotating disk, material is made, open for powder, until the material in loader is finished, close spraying, for powder, discharging, last closing machine.By the ball core made, be placed in fluid bed dryer, open machine, open air feed, adjustment parameter, dried after 20 minutes, opened heating, till oven dry, and discharging, closing machine.14 orders and 40 mesh sieves sieve is used to get qualified ball core.
2) get recipe quantity purified water, more slowly add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium caprylate, stir, adjust ph to 8.15 with the sodium hydroxide solution of 1mol/L, dissolve for subsequent use completely to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt; Another preparation 8%Hpmc (W/W), 1% Pulvis Talci (W/W), aqueous trehalose.Join in material solution, stir, filter, for subsequent use.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
3) prepare 8%Hpmc (W/W) to join in appropriate purified water, stir evenly, then add 1% Pulvis Talci (W/W), stir evenly, filter, for subsequent use.Use fluidized-bed coating machine, will carry out coating containing pill layer piller, coating weight gain 10-15%, prepares sealing coat.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
4) take Ka Lekang coating materials (93f19255) slowly to join in purified water, stir about 2 hours, filters for subsequent use constantly, and use fluidized-bed coating machine, sealing coat piller is carried out coating, and coating weight gain 40-60%, prepares enteric layer.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
The preparation of embodiment 4 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate oral enteric preparation
Main formula
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate 1g
Trehalose 5g
Preparation method
1) add microcrystalline Cellulose and the Pulvis Talci weight ratio 8:1 of recipe quantity, adopt the standby celphere of centrifugal granulator mechanism.
Take the microcrystalline Cellulose of recipe quantity, Pulvis Talci, use three-dimensional mixer to mix 30 minutes, get half and be placed in centrifugal pellet processing machine, second half is positioned in loader, getting appropriate purified water is positioned in liquid-supplying bucket, opens centrifugal pellet processing machine, unlocking turntable, air feed, spraying, but the piller that on rotating disk, material is made, open for powder, until the material in loader is finished, close spraying, for powder, discharging, last closing machine.By the ball core made, be placed in fluid bed dryer, open machine, open air feed, adjustment parameter, dried after 20 minutes, opened heating, till oven dry, and discharging, closing machine.14 orders and 40 mesh sieves sieve is used to get qualified ball core.
2) get recipe quantity purified water, more slowly add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate, stir, adjust ph to 8.15 with the sodium hydroxide solution of 1mol/L, dissolve for subsequent use completely to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sodium laurate; Another preparation 8%Hpmc (W/W), 1% Pulvis Talci (W/W), aqueous trehalose.Join in material solution, stir, filter, for subsequent use.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
3) prepare 8%Hpmc (W/W) to join in appropriate purified water, stir evenly, then add 1% Pulvis Talci (W/W), stir evenly, filter, for subsequent use.Use fluidized-bed coating machine, will carry out coating containing pill layer piller, coating weight gain 10-15%, prepares sealing coat.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
4) take Ka Lekang coating materials (93f19255) slowly to join in purified water, stir about 2 hours, filters for subsequent use constantly, and use fluidized-bed coating machine, sealing coat piller is carried out coating, and coating weight gain 40-60%, prepares enteric layer.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
Embodiment 5
Main formula
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] 1g
Trehalose 5g
Preparation method
1) add microcrystalline Cellulose and the Pulvis Talci weight ratio 8:1 of recipe quantity, adopt the standby celphere of centrifugal granulator mechanism.
Take the microcrystalline Cellulose of recipe quantity, Pulvis Talci, use three-dimensional mixer to mix 30 minutes, get half and be placed in centrifugal pellet processing machine, second half is positioned in loader, getting appropriate purified water is positioned in liquid-supplying bucket, opens centrifugal pellet processing machine, unlocking turntable, air feed, spraying, treat the piller that on rotating disk, material is made, open for powder, until the material in loader is finished, close spraying, for powder, discharging, last closing machine.By the ball core made, be placed in fluid bed dryer, open machine, open air feed, adjustment parameter, dried after 20 minutes, opened heating, till oven dry, and discharging, closing machine.14 orders and 40 mesh sieves sieve is used to get qualified ball core.
2) get recipe quantity purified water, more slowly add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], stir, adjust ph to 8.15 with the sodium hydroxide solution of 1mol/L, dissolve for subsequent use completely to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]; Another preparation 8%Hpmc (W/W), 1% Pulvis Talci (W/W), aqueous trehalose.Join in material solution, stir, filter, for subsequent use.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
3) prepare 8%Hpmc (W/W) to join in appropriate purified water, stir evenly, then add 1% Pulvis Talci (W/W), stir evenly, filter, for subsequent use.Use fluidized-bed coating machine, will carry out coating containing pill layer piller, coating weight gain 10-15%, prepares sealing coat.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
4) take Ka Lekang coating materials (93f19255) slowly to join in purified water, stir about 2 hours, filters for subsequent use constantly, and use fluidized-bed coating machine, sealing coat piller is carried out coating, and coating weight gain 40-60%, prepares enteric layer.
Use fluidized-bed coating machine, ball core is positioned in fluidized-bed coating machine, open air feed, heating, adjustment parameter, open spraying, till coating materials has sprayed, after continue heating again 30 minutes, closing machine, discharging.
Claims (10)
1. an Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt, it is characterized in that, be 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.
2. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt according to claim 1, is characterized in that, be selected from: 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.
3. the pharmaceutical preparation containing any one Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt of claim 1 or 2.
4. pharmaceutical preparation according to claim 3, is characterized in that, is enteric coated preparation.
5. pharmaceutical preparation according to claim 4, is characterized in that, dosage form is selected from: enteric coatel tablets, enteric coated capsule, enteric coated granule or enteric coated micropill.
6. the preparation method of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt according to claim 1, it is characterized in that, by Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] be selected from: the compound of 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 turns salt be prepared from through efficiently preparing liquid phase.
7. preparation method according to claim 6, it is characterized in that, wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] be selected from: the mol ratio of the compound of 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 is 1:0.1-5.
8. preparation method according to claim 7, it is characterized in that, wherein Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] be selected from: the mol ratio of the compound of 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 is 1:0.5-2.5.
9. preparation method according to claim 6, it is characterized in that, described preparation method step is as follows: use preparative liquid chromatography to carry out purification to 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 concentrated by rotary evaporation, re-use containing being 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, the mobile phase of potassium oleate carries out turning Ficus caricaL in preparation liquid phase, obtain Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] saline solution, lyophilizing is carried out after concentrated by rotary evaporation, obtain Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] salt.
10. preparation method according to claim 6, is characterized in that, described preparation method step is as follows:
Compound concentration is that the Capric acid sodium salt aqueous solution of 0.1% is as mobile phase A, acetonitrile is as Mobile phase B, 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%, and overall flow velocity is set as 600ml/min, and determined wavelength is chosen as 280nm.Sample injection time is 5 minutes, after sample introduction, arranges as follows by the elution program of preparation liquid phase:
collect:
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, carry out lyophilizing after using 0.22 micron of poly (ether sulfone) film aseptic filtration, obtain 5.8g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] Capric acid sodium salt.
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| US12002595B2 (en) | 2016-09-29 | 2024-06-04 | The Regents Of The University Of California | Separation of metal ions by liquid-liquid extraction |
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| JP7018210B2 (en) | 2016-09-06 | 2022-02-10 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Preparation of hydroxypyridonate actinide / lanthanide in vitro remover |
| JP2022044699A (en) * | 2016-09-06 | 2022-03-17 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Formulations of hydroxypyridonate actinide/lanthanide decorporation agents |
| US11684614B2 (en) | 2016-09-06 | 2023-06-27 | The Regents Of The University Of California | Formulations of hydroxypyridonate actinide/lanthanide decorporation agents |
| JP7391403B2 (en) | 2016-09-06 | 2023-12-05 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Hydroxypyridonate actinide/lanthanide extracorporeal removal agent formulation |
| US12002595B2 (en) | 2016-09-29 | 2024-06-04 | The Regents Of The University Of California | Separation of metal ions by liquid-liquid extraction |
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