CN104415326A - Liraglutide-containing pharmaceutical preparation composition and preparation method thereof - Google Patents
Liraglutide-containing pharmaceutical preparation composition and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of preparation of medicines and discloses a liraglutide-containing pharmaceutical preparation composition. The pharmaceutical preparation composition comprises therapeutically effective liraglutide and pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable carriers consist of a buffer solution, a pH-value adjusting agent and an excipient for improving the stability. The pharmaceutical preparation composition contains no preservative and has good stability at a room temperature. In addition, the invention further discloses a preparation method of the pharmaceutical preparation composition and a therapeutically-effective liraglutide-containing freeze-dried powder injection prepared from the pharmaceutical preparation composition.
Description
Technical field
The present invention relates to field of medicine preparing technology, be specifically related to a kind of pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and preparation method thereof, and the lyophilized injectable powder of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] containing treatment effective dose prepared by it.
Background technology
In recent years, along with the fast development of economy, living standards of the people improve constantly, and the sickness rate of some diseases also there occurs change thereupon.Wherein the rising of onset diabetes rate and outstanding the showing of becoming younger of patient give prominence to.Estimate that more than the 20 years old diabetes number of patients in the whole nation is more than 2,000 ten thousand at present, patients with impaired glucose tolerance number is more than 3,000 ten thousand, and wherein more than 90% is type 2 diabetes mellitus.All the time, global scientist is in the new way constantly exploring complete treatment diabetes.Have on earth and there is no a kind of medicine, the multiple demand of patient-effectively can control blood glucose to raise can be met, risk of hypoglycemia can be reduced again, avoid body weight to increase, and solve the problems such as the continuous exhaustion of islet beta cell function, Secondary cases drug failure.Nowadays, GLP-1(glicentin-1) appearance of class medicine allows type 2 diabetes mellitus patient see new hope.
GLP-1 is secreted by intestinal cell, can promote a parahormone of insulin secretion.After people eats feed thing, intestinal is upset and will secretes this hormone, thus reduces blood glucose.Be used for clinical to GLP-1 be made medicine, scientist has carried out revising accurately to the peptide chain of human body GLP-1, its half-life has just extended to 13 hours from 2 minutes like this, the long-acting people GLP-1 analog made thus, " Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] " (commodity are called promise and power) by name.
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] (Liraglutide) is the novel type 2 diabetes mellitus medicine researched and developed by Novo Nordisk A/S company; have reduction blood glucose, lose weight, promote the multiple effect such as pancreatic cell regeneration and cardiovascular system protection, potential applicability in clinical practice is wide.It is a kind of acidylate glucagon-like-peptide-1 (GLP-1) receptor stimulating agent; molecular formula is C172H265N43O51; relative molecular mass 3751; this medicine ratifies listing in the U.S. in January, 2010; listing dosage form is injection, and commodity are called promise and power (Victoza), and every day only need use once; when blood sugar level is too high, it is played a role by stimulation insulin releasing and appetite-suppressing.Zoopery confirms, promise and power can reduce β apoptosis, increases β cell regeneration, thus β cell quantity is increased, in theory likely delay the progress of the course of disease and the generation of complication.This medicine feature integrating multi-effect is not available for traditional diabetes medicament, and therefore, the appearance of the GLP-1 class medicine being representative with promise and power, has important milestone significance in type 2 diabetes mellitus treatment field.
Research finds, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is easily by various such environmental effects, and as more responsive to humiture, illumination etc., related substance and macromolecule protein can change along with the prolongation of holding time.Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection in the market must its stability of guarantee in lucifuge and under the condition of low temperature, and this causes in actual therapeutic, there is a lot of problem.First, be difficult to ensure low-temperature dark condition in long-distance transport.Secondly, diabetes spp is in chronic disease, need long-term even life-long therapy, the disposable injection clamped bottle of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection on market is packed, implement after being combined with some injecting apparatus during use to inject, because of simple to operate, dosage is accurate, certain injection knowledge training is carried out to patient and can complete injection voluntarily, therefore, thing followed problem is, most patient conveniently, medicine certainly will be taken home and carry out self administer, now, cannot ensure medicine cryopreservation, also cannot ensure that medicine is finished using before the deadline, these behaviors also just cannot ensure qualified medicine, the medicine that patient uses may cause bad stability because being subject to the impact of the environmental condition such as humiture and illumination for a long time, thus have impact on safety and the effectiveness of medicine, there is potential safety hazard in these behaviors.Moreover, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection in the market with the addition of antiseptic phenol, corrosiveness is had to tissue when consumption is large, also human body can be caused poisoning, the propylene glycol added in addition, may produce haemolysis during large usage quantity, thus should strictly control its consumption when using these adjuvants, for this chronic disease, may there is potential safety hazard in the medicine that long-term taking contains these adjuvants.If possible, replace with the better adjuvant of safety as far as possible.
Summary of the invention
The present invention is directed to the above-mentioned defect existed in prior art, provide a kind of pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] on the one hand, it comprises the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] for the treatment of effective dose and pharmaceutically acceptable carrier, this pharmaceutically acceptable carrier comprises the excipient of buffer, pH adjusting agent and increase stability, this pharmaceutical preparations composition does not comprise antiseptic, and possesses good stability at ambient temperature.
In a preferred embodiment of the present invention, the concentration of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in pharmaceutical preparation is 0.1mg/ml ~ 3.0mg/ml, is more preferably 0.3 ~ 1.0mg/ml, most preferably is 0.9mg/ml.
In a preferred embodiment of the present invention, buffer is selected from one or two or more kinds in sodium ascorbyl phosphate or ammonium salt, acetic acid sodium salt or ammonium salt, sodiocitrate or ammonium salt, be more preferably one or two or more kinds in sodium ascorbyl phosphate, acetic acid sodium salt and sodiocitrate, most preferably be sodium ascorbyl phosphate.
The concentration of buffer in pharmaceutical preparation is preferably 0.1mg/ml ~ 5.0mg/ml, is more preferably 0.5mg/ml ~ 3.0mg/ml, most preferably is 1.0mg/ml ~ 2.0mg/ml.
In a preferred embodiment of the present invention, pH adjusting agent is sodium hydroxide or hydrochloric acid, and adjust ph is preferably 6.5 ~ 9.0, is more preferably 7.0 ~ 8.5, most preferably is 7.9 ~ 8.4.
In a preferred embodiment of the present invention, the excipient of increase stability is selected from one or two or more kinds in Polyethylene Glycol, polypropylene glycol, HPMC, gelatin, mannitol, amino acids (glycine, alanine, serine, threonine, tryptophan, histidine, arginine, phenylalanine, leucine, isoleucine, aspartic acid, lysine, glutathion, sodium glutamate, methionine), hyaluronic acid, lecithin, phosphoglyceride, tween 80, poloxamer, collagen protein, fibroin, sucrose, fructose, glucose; One or two or more kinds in preferred mannitol, amino acids (glycine, alanine, phenylalanine, leucine, isoleucine, aspartic acid, lysine, glutathion, sodium glutamate, methionine), tween 80, poloxamer, glucose; More preferably one or two or more kinds in mannitol, glycine, methionine, tween 80.
The concentration increasing the excipient of stability is preferably 0.5% ~ 20% with weight/volume, is more preferably 1% ~ 10%, most preferably is 5%.
The present invention additionally provides the method preparing pharmaceutical preparations composition of the present invention on the other hand, and it comprises the steps:
1, take buffer and the excipient of recipe quantity, dissolve with appropriate water for injection, coarse filtration;
2, collection filtrate is poured into and is weighed up in the container of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], injects water to close to dosing amount (amount of reserved adjust ph), stirring and dissolving;
3, after pH value being adjusted to desired value by pH adjusting agent, standardize solution, stirring and evenly mixing, slightly considers, ultrafiltration;
4, intermediate measurement requirement parameter is got, qualified rear fill, sterilizing.
Last aspect of the present invention additionally provides the lyophilized injectable powder of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] containing treatment effective dose prepared by pharmaceutical preparations composition of the present invention.When medicine per injection after lyophilizing uses, the sterilized water for injection of 1ml or 0.9% sodium chloride injection or 5% glucose solution dissolve.
Of the present invention containing in the pharmaceutical preparations composition of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], buffer can provide a suitable environment, avoids the degraded relevant with pH to reach good stability; Excipient all adopts conventional and human body to be easy to the composition accepted, and has the effects such as antioxidant, isoosmotic adjusting agent, solubilizing agent, effectively can reduce the increase of related substance and macromolecule protein content, improve medicine stability.Meanwhile, in pharmaceutical preparations composition of the present invention, the antiseptic such as phenol are not comprised, do not add the propylene glycol easily causing haemolysis, therefore pharmaceutical preparations composition of the present invention i.e. stable but also safety, and facilitate patient yet, can preserve by room temperature, be suitable for actual clinical and use.
Detailed description of the invention
Below by embodiment, the present invention is described in further detail, is intended to non-limiting the present invention for illustration of the present invention.It should be pointed out that to those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and fall into too within protection scope of the present invention.
Embodiment 1: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 100mg sodium hydrogen phosphate of recipe quantity, 3g mannitol and 2g tween 80, dissolve with 200ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 100mg Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 6.5 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 2: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 1g sodium citrate of recipe quantity, 7g Polyethylene Glycol and 3g collagen protein, dissolve with 300ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 500mg Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 7.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 3: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 1.42g sodium hydrogen phosphate of recipe quantity, 35g glycine and 15g methionine, dissolve with 400ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 900mg Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 8.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 4: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 5g Ammonium biphosphate of recipe quantity, 160g tryptophan and 40g sucrose, dissolve with 600ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 3g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 9.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 5: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 5mg ammonium acetate of recipe quantity, 20g alanine and the soft phospholipid of 10g, dissolve with 200ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 300mg Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 7.5 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 6: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 3g Diammonium citrate of recipe quantity, 40g gelatin and 40g fructose, dissolve with 400ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 1.5g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 8.3 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 7: the preparation of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
1, preparation prescription (in 1000ml)
2, preparation technology
Take the 4g sodium hydrogen phosphate of recipe quantity, 100g sodium glutamate and 50g polypropylene glycol, dissolve with 600ml water for injection, coarse filtration, collect filtrate to pour in the container weighing up 2.5g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inject water to close to dosing amount (amount of reserved adjust ph) 900ml, stirring and dissolving, be 8.1 with sodium hydroxide or hydrochloric acid conditioning solution pH value, 1000ml is settled to, stirring and evenly mixing, coarse filtration with water for injection, ultrafiltration, get middle body examination requirement parameter, qualified rear fill, sterilizing.
Embodiment 8: the preparation of lyophilized injectable powder
Adopt conventional method that the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] prepared in embodiment 1-7 is prepared into lyophilized injectable powder.Use 1ml sterilized water for injection or 0.9% sodium chloride injection or 5% glucose injection to dissolve after lyophilizing, every day injects once, per injection one.
Embodiment 9: the Detection of Stability of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
In order to detect the stability of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] prepared by the present invention, embodiment 9 has carried out the test of accelerated test, long term test and strong illumination.
1, accelerated test
Carrying out accelerated test according to 2010 editions Chinese Pharmacopoeia XIXC crude drug and pharmaceutical preparation stability test guideline (two), its objective is the chemistry by accelerating medicine or physical change, inquire into the stability of medicine.Example 2,3,6 three batch sample is appropriate, get the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection liquid samples that market is bought appropriate, respectively at 40 ± 2 DEG C, accelerate 6 months under the condition of relative humidity 75% ± 5%, in the point in time sampling one-time detection of duration of test the 0th, 1,2,3,6 the end of month, detect by stability high spot reviews project, test item is appearance character, pH value, clarity, related substance and macromolecule protein content, and testing result is as shown in table 1.
Table 1 accelerated test result
2, long term test
Carrying out long term test according to 2010 editions Chinese Pharmacopoeia XIXC crude drug and pharmaceutical preparation stability test guideline (two), carry out under close to the actual storage requirement of medicine, its objective is that the effect duration for formulating medicine provides foundation.Example 2,3,6 three batch sample is appropriate, get the sample that market is bought appropriate, place 30 months respectively at long-term under the condition of temperature 25 ± 2 DEG C, relative humidity 60% ± 10%, respectively at the point in time sampling one-time detection of 0,3,6,9,12,18,24,30 month, detect by stability high spot reviews project.Test item is appearance character, content, pH value, visible foreign matters, related substance and macromolecule protein content, and testing result is as shown in table 2.
Table 2 long-term test results
3, strong illumination test
Strong illumination test is carried out according to 2010 editions Chinese Pharmacopoeia XIXC crude drug and pharmaceutical preparation stability test guideline (two), Example 2, 3, 6 three batch samples are appropriate, get the sample that market is bought appropriate, often criticize that to divide equally be 2 groups, packages groups and exposed group, be place 10 days under the condition of 4500lx ± 500lx in illumination by sample, in the 5th day and sampling in the 10th day, with the testing result contrast of 0 day sample, detect by stability high spot reviews project, test item is appearance character, content, pH value, visible foreign matters, related substance and macromolecule protein content, testing result is as shown in table 3.
Table 3 strong illumination is tested
4, result and conclusion
From accelerated test, long-term experiment and strong illumination experiment data can draw, the embodiment of the present invention 2,3,6 prepare sample inspection target every under each condition with 0 time data compared with, all there is no significant change, illustrate that sample of the present invention is more stable.Compared with sample prepared by commercial samples and the present invention, related substance and macromolecule protein content obviously increase, and illustrate that sample prepared by the present invention is more stable than commercial samples in each condition.
Embodiment 10: the safety of the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] detects
Safer in order to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] pharmaceutical preparations composition prepared by the present invention is described, the present invention has carried out the test of zest, anaphylaxis and hemolytic according to the method for " Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline ".
1, medicine-feeding part irritation test
Irritation test be whether cause redness, hyperemia, ooze out after the location contacts such as blood vessel, muscle, skin, the mucosa tested material of observing animal, the local response such as degeneration or necrosis.
(1) by test product: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample prepared by embodiment 3 and commercial samples.
(2) laboratory animal: white big ear rabbit, healthy without wound, body weight 1.7 ~ 3.0kg, male and female half and half, often organize 3 by random point 3 groups.
(3) medication: all adopt consubstantiality left and right sides self-contrast method, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample test sample 0.5ml of left side thoracic wall subcutaneous tissue injection embodiment 3 preparation of A group three rabbit, right side thoracic wall subcutaneous tissue injecting normal saline solution 0.5ml; The left side thoracic wall subcutaneous tissue injection commercial samples 0.5ml of B group three rabbit, right side thoracic wall subcutaneous tissue injecting normal saline solution 0.5ml; The Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample test sample 0.5ml of left side thoracic wall subcutaneous tissue injection embodiment 3 preparation of C group three rabbit, right side thoracic wall subcutaneous tissue injection commercial samples 0.5ml.Test equal successive administration 7 days for three groups.
(4) result is observed: single-dose irritation test usually, within 48-96 hour, carries out perusal to animal and injection site upon administration; At the end of observation period, medicine-feeding part histopathological examination is carried out to Some Animals.
(4) evaluation of result: the result according to perusal and histopathological examination shows, after 7 days A group rabbit left and right sides thoracic wall subcutaneous tissue all there is not redness, hyperemia, ooze out, the local response such as degeneration or necrosis; All there is the local response such as redness, hyperemia in various degree in the left side thoracic wall subcutaneous tissue of B group rabbit and the right side thoracic wall subcutaneous tissue of C group rabbit, shows sample of the present invention to rabbit without local irritant effect, more safer than commercial samples.
2, sensitivity test
Anaphylaxis is in the animal body set up sensitization, intravenous injection antigen, observes after antigen is combined with IgE antibody to cause mastocyte, basophil retting conditions, discharge active medium and the systemic anaphylaxis that causes.
(1) by test product: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample prepared by embodiment 3.
(2) laboratory animal: select body weight to be the Cavia porcellus of 300 ~ 400 grams, male, 16, originate as Shanghai Vaccine and Serum Institute, random point four groups, often organize 6, be set to feminine gender, positive controls, low dosage and high dose group.
(3) medication: negative control group is normal saline 0.5ml/; Positive controls is 0.4% bovine serum albumin 2mg/, and about 0.5ml/ only; Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample low dose group prepared by embodiment 3 is 0.018mg/kg, and every only injection 0.5ml test sample, is clinical maximal dose (0.9mg/ day is that standard body weight calculates with 50kg); Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample high dose group prepared by embodiment 3 is 0.036mg/kg, often only injects 0.5ml, is 2 times of clinical maximal dose.
(4) sensitization: adopt subcutaneous injection, the next day 1 time, totally 5 times.Within after final injection the 11st day, once excite, booster dose is 4 times amount of priming dose, administration volume 1-2ml, and namely negative control is normal saline 1.0ml/; Positive controls is 0.8% bovine serum albumin 1mg/ only (about 8mg/ only); Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample low dose group prepared by embodiment 3 is 0.018mg/kg, every only injection 0.5ml test sample; Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample high dose group prepared by embodiment 3 is 0.036mg/kg, often only injects 0.5ml.
(5) observe: during sensitization, observe the symptom of every animal every day.For the first time, last sensitization and excited measured the same day often to organize the body weight of every animal.When exciting, at once to 30 minute after intravenous injection, observes the reaction of every animal in detail by table 4 symptom, the appearance of symptom and extinction time.The longest observation 3 hours.
Table 4 symptoms of allergic
| 0 is normal | 7 rapid breathing | 14 instability of gait |
| 1 is restless | 8 urinate | 15 jump |
| 2 perpendicular hairs | 9 defecation | 16 pant |
| 3 tremble | 10 shed tears | 17 spasm |
| 4 disturb nose | 11 dyspnea | 18 rotate |
| 5 sneezes | 12 wheezing sounds | 19 Cheyne-Stokes respiration |
| 6 coughs | 13 purpuras | 20 is dead |
(6) evaluation of result: anaphylaxis occurrence degree can be judged by table 5.Calculate anaphylaxis incidence rate.Comprehensive descision is carried out according to anaphylaxis incidence rate and occurrence degree.
Table 5 whole body sensitization evaluation criterion
| 0 | - | Anaphylaxis is negative |
| 1-4 symptom | + | The weak positive of anaphylaxis |
| 5-10 symptom | ++ | Anaphylaxis is positive |
| 11-19 symptom | +++ | Anaphylaxis strong positive |
| 20 | ++++ | The extremely strong positive of anaphylaxis |
After booster injection, if when finding that there is symptoms of allergic, the non-sensitized guinea pig of desirable health 2, from the tested material of intravenous injection booster dose, observes the similar symptoms of allergic with or without causing due to tested material effect, reference when judging for result.
During hypersensitive test, the body weight change situation of experimental animal is as shown in table 6.
The weight of animals situation of change during Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample hypersensitive test prepared by table 6 embodiment 3
(7) conclusion (of pressure testing): above-mentioned result of the test shows, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] sample subcutaneous administration prepared by the present invention is without allergenic effect.
3, hemolytic test
(1) method: conventional external test tube method (observation method of naked eye).
(2) by test product: Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] pharmaceutical preparations composition sample prepared by embodiment 3 and commercial samples.
(3) preparation of blood cell suspension: get Sanguis Leporis seu oryctolagi (or Sanguis caprae seu ovis) several milliliters, puts into the conical flask jolting 10 minutes containing bead, or stirs blood with Glass rod, and removing Fibrinogen, makes defibrinated blood.Add 0.9% sodium chloride solution about 10 times amount, shake up, centrifugal 15 minutes of 1000-1500rpm, removing supernatant, the erythrocyte of precipitation washs 2-3 time as stated above with 0.9% sodium chloride solution again, to the not aobvious redness of supernatant.Gained erythrocyte is made into the suspension of 2% with 0.9% sodium chloride solution, is for experiment.
(4) preparation of tested material: unless otherwise specified, the clinical injection for administration in non-vascular, the Clinical practice concentration specified with each medicine operation instructions, as need testing solution after diluting with 0.9% sodium chloride solution 1: 3; The Clinical practice concentration specified using operation instructions for the injection of intravascular administration is as need testing solution.
(5) test method: get clean tube 7, be numbered, No. 1-5 pipe is test sample pipe, and No. 6 pipes are negative control pipe, and No. 7 pipes are positive control pipe.Add 2% red cell suspension, 0.9% sodium chloride solution or distilled water shown according to the form below successively, after mixing, the calorstat being placed in 37 DEG C ± 0.5 DEG C immediately carries out incubation, start to observe 1 time every 15 minutes, after 1 hour, observed 1 time every 1 hour, overview 3 hours.Various solution is added by the order of table 7.
Table 7 test tube is numbered and is added the situation of solution
| Test tube is numbered | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Normal saline (ml) | 2.0 | 2.1 | 2.2 | 2.3 | 2.4 | 2.5 | |
| Distilled water (ml) | 2.5 | ||||||
| Tested material (ml) | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 |
(6) result is observed: if the solution in test be clear and bright redness, acellular residual or have a small amount of erythrocyte residual at the bottom of pipe, shows have haemolysis to occur; As erythrocyte all sinks, supernatant fluid achromatism and clarity, shows to occur without haemolysis.If have brownish red or rufous flocculent deposit in solution, do not disperse after jolting, show have red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, true cohesion or pseudo agglutination can be judged by the following method further.If condensation product can be uniformly dispersed again after test tube vibration, or condensation product is placed on microscope slide, 2 0.9% sodium chloride solutions are dripped at coverslip edge, put basis of microscopic observation, cohesion erythrocyte can be pseudo agglutination by the person of breaking up, if condensation product is not shaken and falls apart or be not true cohesion by the person of breaking up on slide.
(7) result criterion: when negative control pipe occurs without haemolysis and cohesion, when positive control pipe has haemolysis to occur, if the solution in tested property management, in 3 hours, haemolysis and cohesion does not occur, then tested material can inject use; If the solution in tested property management, in 3 hours, haemolysis and (or) cohesion occurs, then tested material should not inject use.
(8) conclusion (of pressure testing): above-mentioned result of the test shows, No. 1 ~ 6, test tube in sample prepared by the present invention and commercial samples without haemolysis and agglutination phenomenon, test tube No. 7 complete hemolysis.Show that sample prepared by the present invention and commercial samples do not have haemolysis and agglutination to erythrocyte, can drug administration by injection.
Claims (10)
1. the pharmaceutical preparations composition containing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], it comprises the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] for the treatment of effective dose and pharmaceutically acceptable carrier, described pharmaceutically acceptable carrier comprises the excipient of buffer, pH adjusting agent and increase stability, described pharmaceutical preparations composition does not comprise antiseptic, and possesses good stability at ambient temperature.
2. pharmaceutical preparations composition according to claim 1, wherein the concentration of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in pharmaceutical preparation is 0.1mg/ml ~ 3.0mg/ml, preferably 0.3 ~ 1.0mg/ml, more preferably 0.9mg/ml.
3. pharmaceutical preparations composition according to claim 1 and 2, wherein said buffer is selected from one or two or more kinds in sodium ascorbyl phosphate or ammonium salt, acetic acid sodium salt or ammonium salt, sodiocitrate or ammonium salt, be preferably one or two or more kinds in sodium ascorbyl phosphate, acetic acid sodium salt and sodiocitrate, be more preferably sodium ascorbyl phosphate.
4. pharmaceutical preparations composition according to claim 1 and 2, wherein said pH adjusting agent is sodium hydroxide or hydrochloric acid, and adjust ph is 6.5 ~ 9.0, is preferably 7.0 ~ 8.5, is more preferably 7.9 ~ 8.4.
5. pharmaceutical preparations composition according to claim 1 and 2, the excipient of wherein said increase stability is selected from Polyethylene Glycol, polypropylene glycol, HPMC, gelatin, mannitol, amino acids (glycine, alanine, serine, threonine, tryptophan, histidine, arginine, phenylalanine, leucine, isoleucine, aspartic acid, lysine, glutathion, sodium glutamate, methionine), hyaluronic acid, lecithin, phosphoglyceride, tween 80, poloxamer, collagen protein, fibroin, sucrose, fructose, one or two or more kinds in glucose, one or two or more kinds in preferred mannitol, amino acids (glycine, alanine, phenylalanine, leucine, isoleucine, aspartic acid, lysine, glutathion, sodium glutamate, methionine), tween 80, poloxamer, glucose, more preferably one or two or more kinds in mannitol, glycine, methionine, tween 80.
6. pharmaceutical preparations composition according to claim 3, wherein the concentration of buffer in pharmaceutical preparation is 0.1mg/ml ~ 5.0mg/ml, preferred 0.5mg/ml ~ 3.0mg/ml, more preferably 1.0mg/ml ~ 2.0mg/ml.
7. pharmaceutical preparations composition according to claim 4, the regulated quantity that wherein proportioning of pH adjusting agent is adjusted to 6.5 ~ 9.0 with preparation pH value is advisable.
8. pharmaceutical preparations composition according to claim 5, the concentration wherein increasing the excipient of stability with weight/volume for 0.5% ~ 20%, preferably 1% ~ 10%, more preferably 5%.
9. the method for the pharmaceutical preparations composition of preparation according to any one of claim 1-8, it comprises the steps:
(1) take buffer and the excipient of recipe quantity, dissolve with appropriate water for injection, coarse filtration;
(2) collection filtrate is poured into and is weighed up in the container of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], injects water to close to dosing amount (amount of reserved adjust ph), stirring and dissolving;
(3) after pH value being adjusted to desired value by pH adjusting agent, standardize solution, stirring and evenly mixing, slightly considers, ultrafiltration;
(4) intermediate measurement requirement parameter is got, qualified rear fill, sterilizing.
10. the lyophilized injectable powder of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] containing treatment effective dose prepared by the pharmaceutical preparations composition described in claim 1-8.
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| CN105126082A (en) * | 2015-09-22 | 2015-12-09 | 齐鲁制药有限公司 | Polypeptide drug preparation and preparation method thereof |
| CN105777858A (en) * | 2016-03-22 | 2016-07-20 | 威特曼生物科技（南京）有限公司 | Composite stabilizer of various antibodies and application method of composite stabilizer |
| CN105999272A (en) * | 2015-07-20 | 2016-10-12 | 汪蕾 | Application of glucagon-like peptde-1 receptor agonist to preparation of pulmonary hypertension treating medicine |
| WO2017147783A1 (en) * | 2016-03-01 | 2017-09-08 | 深圳翰宇药业股份有限公司 | Pharmaceutical composition and manufacturing method thereof |
| WO2022178737A1 (en) * | 2021-02-25 | 2022-09-01 | 杭州九源基因工程有限公司 | Treatment method for stable liraglutide pharmaceutical preparation |
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Application publication date: 20150318 |