CN104069485A - A liraglutide in-situ gel preparation and a preparing method thereof - Google Patents
A liraglutide in-situ gel preparation and a preparing method thereof Download PDFInfo
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Abstract
The invention relates to the field of medicine preparations, in particular, the invention relates to a liraglutide in-situ gel preparation and a preparing method thereof. The liraglutide in-situ gel preparation comprises liraglutide, an in-situ gel material and an organic solvent. Based on g/g/mL, the mass volume ratio of the liraglutide, the in-situ gel material and the organic solvent is (0.5-1.5):(2-6):(14-30). The liraglutide in-situ gel preparation has a function of sustained release and avoids peak and valley phenomena of plasma concentrations. The medicine function time is long and the number of times of taking the medicine is reduced, thus largely alleviating pain of patients and improving compliance of patients. The liraglutide in-situ gel preparation is nonirritant to skin and connective tissues. The preparing method is simple, suitable for large-scale production, high in medicine loading capacity and low in cost.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation and preparation method thereof.
Background technology
Due to the change of growth in the living standard, dietary structure, the factors such as rhythm of life and few moving life style of sitting that day is becoming tight more, whole world onset diabetes rate rapid development, diabetes have become the chronic disease of the third-largest serious threat human health after tumor, cardiovascular pathological changes.Current global diabetics has exceeded 1.2 hundred million people, the Chinese patients people the second in the world of living in groups, and the onset diabetes rate of China is up to 9.6%, and in future 50 years, diabetes will be serious public health problems of China.Diabetes are divided into gestational diabetes, specificity diabetes, type i diabetes and type ii diabetes.Wherein, type ii diabetes has another name called non-insulin-dependent diabetes mellitus, and feature is that human body self can produce insulin, but cell cannot react to it, and the effect of insulin is had a greatly reduced quality.In diabetes mellitus in China crowd, taking type ii diabetes as main, proportion reaches 93.7%, therefore prevents and the medicine for the treatment of type ii diabetes has the market demand widely.
Type ii diabetes mainly, by oral or subcutaneous injection antidiabetic drug treatment, mainly comprises metformin, sulfonylurea drugs and GLP-1 (GLP-1) analog etc. for the antidiabetic drug of type ii diabetes.
Wherein, GLP-1 analog is the focus of antidiabetic drug research in recent years.GLP-1 analog can improve by many approach type ii diabetes patient's metabolism disorder, and approach mainly comprises: concentration of glucose dependency insulin secretion accelerating; Suppress the secretion of glucagon after the meal, reduce the release of glycogen; Strengthen the sensitivity of insulin; The emptying of stomach of slowing down; Appetite-suppressing, loses weight.Wherein, the insulin secretion accelerating of GLP-1 analog and glucagon suppression secretory action have blood sugar concentration dependency, in the time that blood sugar concentration recovers normal, promoting insulin secretion weakens, therefore, accept for a long time GLP-1 analog Drug therapy, can not cause hypoglycemic generation, thereby improved the safety of medication.
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] (liraglutide) is the GLP-1 analog medicine of Novo Nordisk Co.,Ltd of Denmark research and development, and is gone on the market in the U.S. by FDA approval on January 25th, 2010.The chemistry of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is expressed as Arg
34lys
26-[N-ε-(γ-Glu-(N-hexadecanoyl))]-GLP-1
7-37, molecular formula is C
172h
265n
43o
51, relative molecular mass 3751.2, CAS registration number is 204656-20-2, is made up of 31 amino acid residues, molecular formula is suc as formula shown in I.The 34th lysine of GLP-1 is replaced with arginine by Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] compared with natural GLP-1 molecular structure; and glutamic acid and 16 carbon palmityl fatty acid side chains on the 26th lysine, are connected; there is 97% homology with natural GLP-1; make it in retaining natural effect, extend its acylate and protein binding time, overcome the easily shortcoming of degraded of natural GLP-1.
Formula I
Because diabetes are chronic diseases, need long-term treatment, and existing Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] preparation is normal injection agent, the peak valley phenomenon that is prone to blood drug level, drug treating time is short, needs drug administration by injection every day, be administered to for a long time patient and brought very large misery and inconvenient, cause patient's compliance very poor, be badly in need of clinically a kind of long-acting and Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] preparation with slow releasing function to alleviate patient's misery, improve patient's compliance.Therefore, for the clinical long-acting slow-release preparation that a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is provided has important practical significance.
Summary of the invention
In view of this, the invention provides a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation and preparation method thereof.This Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation has slow releasing function, has avoided the peak valley phenomenon of blood drug level, and drug treating time is long, reduce medication number of times, greatly alleviate patient's misery, improved patient's compliance, and to skin and connective tissue nonirritant; The preparation method of this Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation is simple, is beneficial to large-scale production, and Drug loading capacity is high, and cost is low.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation, formed by Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], situ-gel material and organic solvent;
In g/g/mL, the mass volume ratio of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], situ-gel material and organic solvent is (0.5～1.5) ︰ (2～6) ︰ (14～30).
In-situ gel preparation be macromolecular material with solution or semi-solid state administration after, stimulate to external world (as temperature, pH, ionic species and concentration, light and special chemical substance etc.) to respond at medicine-feeding part, there is the reversible conversion of dispersion or conformation, thus the semisolid or the solid preparation that form.In-situ gel preparation is solution state before injection, after injection, can flow into and be filled in interstice, after injection, can there is in vivo solution gel phase transformation, form gelatin polymer, medicine slowly discharges along with the continuous degraded of gelatin polymer, corrosion, thereby reach the effect of slow release, extended the release cycle, reduced adverse effect.
As preferably, situ-gel material is a kind of or both the above mixture in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material or biodegradable situ-gel material.
In embodiment more provided by the invention, situ-gel material is biodegradable situ-gel material.
In other embodiment provided by the invention, situ-gel material is the mixture of a kind of and biodegradable situ-gel material in thermosensitive in situ gel material, pH sensitive in situ gels research material or ionic strength sensitive in situ gels research material.
As preferably, biodegradable situ-gel material is selected from PEO-PPO, PLA, PLGA, PLA-PEG, PLGA-PEG, PNIPA or SAIB.
Preferably, biodegradable situ-gel material is selected from PLA or PLGA.
As preferably, the number-average molecular weight of PLGA is 10000～40000D.
As preferably, in PLGA, the mol ratio of lactic acid and hydroxyacetic acid is 75 ︰ 25 or 50 ︰ 50.
As preferably, thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87, methylcellulose, hypromellose, chitosan derivatives, PLA-PEG, PLGA-PEG, hydroxyethyl-cellulose, polycaprolactone-polyethylene glycol block copolymer or PNIPA.
Preferably, thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87, methylcellulose, PLA-PEG, PLGA-PEG, polycaprolactone-polyethylene glycol block copolymer or PNIPA.
More preferably, thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87 or methylcellulose.
As preferably, pH sensitive in situ gels research material is selected from CAP, HPMCP, carbomer or chitosan.
Preferably, pH sensitive in situ gels research material is selected from CAP or carbomer.
As preferably, ionic strength sensitive in situ gels research material is selected from alginate or gellan gum.
As preferably, organic solvent is selected from NMP, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, ethanol, 2-arsenic pyrrolidone or Allyl carbonate.
Preferably, organic solvent is selected from NMP, ethyl lactate, glycerol formal, ethanol or 2-Pyrrolidone.
More preferably, organic solvent is NMP.
As preferably, the administering mode of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation is subcutaneous injection or intramuscular injection.
The present invention also provides a kind of preparation method of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation, comprises the steps:
Situ-gel material is dissolved in organic solvent, obtains polymer solution;
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is mixed with polymer solution, is to stir 30～35min under 30 DEG C, the rotating speed condition that is 150～250rpm in temperature, through sterilizing, to obtain final product.
The invention provides a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation and preparation method thereof.This Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation is made up of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], situ-gel material and organic solvent; In g/g/mL, the mass volume ratio of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], situ-gel material and organic solvent is (0.5～1.5) ︰ (2～6) ︰ (14～30).The present invention has measured the release of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation in the time of 1d, 3d, 5d, 7d, 14d, 21d, 28d by experiment, result shows that this Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation has slow releasing function, avoid the peak valley phenomenon of blood drug level, more than drug treating time reaches 28d, only need monthly medication 1 time, reduce medication number of times, greatly alleviated patient's misery, improved patient's compliance; Be injected into 1 week, 2 weeks, the 4 weeks rear pathological sections of observing in test mice body by the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] situ-gel that the present invention is made, compared with blank group, skin and the connective tissue of test group mice are clear, thin film epithelium is column, cilium exists, have no chronic inflammatory cell infiltration, result shows that this Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation is to skin and connective tissue nonirritant; The preparation method of this Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation comprises: situ-gel material is dissolved in organic solvent, obtains polymer solution; Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is mixed with polymer solution, is to stir 30～35min under 30 DEG C, the rotating speed condition that is 150～250rpm in temperature, through sterilizing, to obtain final product, and preparation method is simple, is beneficial to large-scale production, and Drug loading capacity is high, and cost is lower.As can be seen here, this Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation has slow releasing function, has avoided the peak valley phenomenon of blood drug level, and drug treating time is long, has reduced medication number of times, has greatly alleviated patient's misery, has improved patient's compliance; The preparation method of this Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation is simple, is beneficial to large-scale production, and Drug loading capacity is high, and cost is low.
Brief description of the drawings
The cumulative in vitro releasing curve diagram of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation being provided by embodiment 1 in embodiment 17 is provided Fig. 1;
Fig. 2 is provided by the homogeneity of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation cumulative in vitro release being provided by embodiment 1～3 in embodiment 17; Wherein, line 1 shows the cumulative in vitro release profiles of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1 provides, line 2 shows the cumulative in vitro release profiles of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 2 provides, and line 3 shows the cumulative in vitro release profiles of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 3 provides;
Fig. 3 shows the pathological section figure that embodiment 18 provides; Wherein, Fig. 3 (a) shows the pathological section figure of blank group, and Fig. 3 (b) shows that embodiment 1 provides Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation subcutaneous injection to enter the pathological section figure after 1 week in experiment mice body;
Fig. 4 shows the pathological section figure that embodiment 18 provides; Wherein, Fig. 4 (a) shows the pathological section figure of blank group, and Fig. 4 (b) shows that embodiment 1 provides Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation subcutaneous injection to enter the pathological section figure after 2 weeks in experiment mice body;
Fig. 5 shows the pathological section figure that embodiment 18 provides; Wherein, Fig. 5 (a) shows the pathological section figure of blank group, and Fig. 5 (b) shows that embodiment 1 provides Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation subcutaneous injection to enter the pathological section figure after 4 weeks in experiment mice body.
Detailed description of the invention
The invention discloses a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation and preparation method thereof, those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
The abbreviation concrete meaning using in description and claims is as follows:
Abbreviation and English implication
PEO-PPO polyoxyethylene polyoxypropylene block copolymer
PLA polylactic acid
PLGA PLGA
PLA-PEG polylactic acid-polyethylene glycol block copolymer
PLGA-PEG polylactic-co-glycolic acid-polyethyleneglycol block copolymer
PNIPA poly-N-isopropyl acrylamide
SAIB acetic acid-isopropylformic acid. sucrose vinegar
HPMCP HP-55
NMP N-methyl adjoins pyrrolidone
In Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation provided by the invention and preparation method thereof, raw materials used medicine and reagent all can be buied by market.
Below in conjunction with embodiment, further set forth the present invention:
The preparation of embodiment 1 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation
Take 25g PLGA(Mn=10000, LA:GA=75:25), add in 100mL nmp solvent, mix, be mixed with polymer solution, then add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7.0g, heated at constant temperature stirs (30 DEG C of temperature, 200rpm) 30min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 2 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 30g PLGA(Mn=15000, LA:GA=50:50), add in 100mL nmp solvent, mix, be mixed with polymer solution, then add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7.5g, heated at constant temperature stirs (30 DEG C of temperature, 250rpm) 30min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 3 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 25g PLGA(Mn=20000, and 4g poloxamer188 LA:GA=50:50), be dissolved in 110mL NMP, mix, be mixed with polymer solution, then add 6.5g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], heated at constant temperature stirs (30 DEG C of temperature, 150rpm) 35min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 4 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 20g PLGA(Mn=25000, and 5g poloxamer188 LA:GA=50:50), be dissolved in 130mL NMP, mix, be mixed with polymer solution, then add 6.0g Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], heated at constant temperature stirs (30 DEG C of temperature, 150rpm) 30min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 5 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 15g PLGA(Mn=40000, LA:GA=50:50), after adding 120mL nmp solvent to dissolve, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7.0g, heated at constant temperature stirs (30 DEG C of temperature, 250rpm) 35min, form translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 6 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 16g PEO-PPO, add after 70mL triacetin dissolution with solvents, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 4g, heated at constant temperature stirs (30 DEG C of temperature, 160rpm) 30min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 7 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 18g PLA, add after 120mL ethyl lactate dissolution with solvents, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 4.5g, heated at constant temperature stirs (30 DEG C of temperature, 170rpm) 32min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 8 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 20g PNIPA, add after 105mL glycerol formal dissolution with solvents, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 5g, heated at constant temperature stirs (30 DEG C of temperature, 180rpm) 33min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 9 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 8g PLURONICS F87, after adding 56mL benzyl benzoate to dissolve, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 6g, heated at constant temperature stirs (30 DEG C of temperature, 190rpm) 34min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 10 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 24g methylcellulose, after adding 125mL dimethyl sulfoxine to dissolve, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 6g, heated at constant temperature stirs (30 DEG C of temperature, 200rpm) 30min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 11 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 20g chitosan derivatives and 8g PLA, add after 135mL acetone solution, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7g, heated at constant temperature stirs (30 DEG C of temperature, 210rpm) 32min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 12 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 30g CAP, add after 145mL dissolve with ethanol, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7.5g, heated at constant temperature stirs (30 DEG C of temperature, 220rpm) 33min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 13 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 30g hypromellose and 6g PLGA, after adding 180mL2-ketopyrrolidine to dissolve, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 3g, heated at constant temperature stirs (30 DEG C of temperature, 230rpm) 34min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 14 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 30g alginate, after adding 120mL Allyl carbonate to dissolve, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7.5g, heated at constant temperature stirs (30 DEG C of temperature, 240rpm) 35min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 15 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Take 15g gellan gum and 6g PLA, after adding 105mL ethyl lactate to dissolve, add Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] crude drug 7g, heated at constant temperature stirs (30 DEG C of temperature, 200rpm) 30min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The mensuration of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] content in embodiment 16 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations
Get the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1～3 makes, measure medicament contg according to medicine assay method.Concrete grammar is: the about 25mg of content that precision takes mix homogeneously under loading amount item, put in 100mL measuring bottle, and add dissolve with methanol and be diluted to scale, shake up, as need testing solution.Another precision takes Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] reference substance 50mg, puts in 50mL measuring bottle, adds mobile phase and dissolves and be quantitatively diluted to scale, shakes up.Precision measures 5mL, puts in 50mL measuring bottle, is quantitatively diluted to scale by mobile phase, shakes up, in contrast product solution.Precision measures reference substance solution and the each 20 μ L of need testing solution, and injection liquid chromatography, records chromatogram respectively, with calculated by peak area, obtains the sign content of medicine by external standard method, and measurement result is in table 1.
The assay result of table 1 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
As shown in Table 1, the sign content of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1～3 makes, between 94.4%～95.7%, all meets national drug content standard.The meansigma methods of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation sign content prepared by embodiment 1 is the RSD(relative standard deviation of 95.4%, 3 batch) be 0.26%; The meansigma methods of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation sign content prepared by embodiment 2 is that the RSD of 95.3%, 3 batch is 0.42%; The meansigma methods that Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation prepared by embodiment 3 indicates content is that the RSD of 94.8%, 3 batch is 0.43%, and result shows that the stability of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation of same batch is high.
Get Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 4～15 makes and carry out the mensuration of medicament contg, the result that result and embodiment 1～3 record is close, show that the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 4～15 makes all meets national drug content standard, the stability of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation of same batch is high.
The mensuration of embodiment 17 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation releases
Get the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1～9 makes, measure release according to drug release determination method.Concrete grammar is: precision takes Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation (being equivalent to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] 25mg), be injected in release medium (PBS=7.4), solvent diffuse, after solid block to be formed, being placed in 37 ± 0.1 DEG C of constant temperature oscillation instrument vibrations discharges, rotating speed 100rpm, respectively at 1 day, 3 days, 5 days, 7 days, 14 days, 21 days, sampling in 28 days, and the release medium more renewing after sampling, with high performance liquid chromatography calculating cumulative release percentage ratio, with release time (day) and cumulative release amount (%), draw curved figure release profiles, the results are shown in Table 2, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation release curve chart that embodiment 1 provides as shown in Figure 1, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation release that embodiment 1～3 is provided is drawn release curve chart, result as shown in Figure 2.
The measurement result of table 2 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation release
From table 2, Fig. 1 and Fig. 2, the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1～9 provides has obvious slow releasing function, has avoided the peak valley phenomenon of drug level, and drug treating time is long, has reduced administration number of times, and has good homogeneity.
Get the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 10～15 makes and carry out drug release determination, the result that result and embodiment 1～9 record is close, show that the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 10～15 provides has obvious slow releasing function equally, avoid the peak valley phenomenon of drug level, drug treating time is long, reduce administration number of times, and there is good homogeneity.
Embodiment 18 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparations are to skin and the irritating detection of connective tissue
Experimental animal: the new zealand white rabbit of growing up, body weight is at 2.0～2.5kg.
Test method: the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation subcutaneous injection that embodiment 1 is made enters in experimental animal body, after 1 week, 2 weeks and 4 weeks, take the method for auricular vein injection air to put to death to new zealand white rabbit, cut skin of neck, perusal cervical region, the tissue of then getting skin of neck length and width and be lcm × 2cm left and right carries out HE dyeing.Dyeing course: be placed in 10% formalin fixing (24 hours), carry out routine paraffin wax embedding and section, rear hematoxylin, Yihong (HE) dyeing, be placed in paraffin section on microscope slide and dewax, and obtains tissue slice.Under light microscopic, (X20) observes tissue slice, and observed result is as shown in Fig. 3, Fig. 4, Fig. 5.
From Fig. 3, Fig. 4, Fig. 5, compared with blank, the skin of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation after 1 week, 2 weeks and 4 weeks and connective tissue are without significant change, organizational structure is clear, thin film epithelium is column, cilium exists, and has no chronic inflammatory cell infiltration, shows that Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1 makes is to skin and connective tissue nonirritant.
Get Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 2～15 makes and adopt the pathological change of above-mentioned test method detection of skin and connective tissue, result is as similar in the result of the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 1 makes, and shows that Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation that embodiment 2～15 makes is to skin and the same nonirritant of connective tissue.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. an Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation, is characterized in that, is made up of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], situ-gel material and organic solvent;
In g/g/mL, the mass volume ratio of described Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], described situ-gel material and described organic solvent is (0.5～1.5) ︰ (2～6) ︰ (14～30).
2. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 1, it is characterized in that, described situ-gel material is a kind of or both the above mixture in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material or biodegradable situ-gel material.
3. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 2, is characterized in that, described biodegradable situ-gel material is selected from PEO-PPO, PLA, PLGA, PLA-PEG, PLGA-PEG, PNIPA or SAIB.
4. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 2, is characterized in that, described biodegradable situ-gel material is selected from PLA or PLGA.
5. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 2, it is characterized in that, described thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87, methylcellulose, hypromellose, chitosan derivatives, PLA-PEG, PLGA-PEG, hydroxyethyl-cellulose, polycaprolactone-polyethylene glycol block copolymer or PNIPA.
6. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 2, is characterized in that, described pH sensitive in situ gels research material is selected from CAP, HPMCP, carbomer or chitosan.
7. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 2, is characterized in that, described ionic strength sensitive in situ gels research material is selected from alginate or gellan gum.
8. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 1, it is characterized in that, described organic solvent is selected from NMP, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, ethanol, 2-arsenic pyrrolidone or Allyl carbonate.
9. Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation according to claim 1, is characterized in that, the administering mode of described Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation is subcutaneous injection or intramuscular injection.
10. a preparation method for the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in-situ gel preparation as described in claim 1～9 any one, is characterized in that, comprises the steps:
Described situ-gel material is dissolved in described organic solvent, obtains polymer solution;
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is mixed with described polymer solution, is to stir 30～35min under 30 DEG C, the rotating speed condition that is 150～250rpm in temperature, through sterilizing, to obtain final product.
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| CN113304104A (en) * | 2021-05-11 | 2021-08-27 | 四川大学 | Intelligent temperature-sensitive slow-release gel and preparation method thereof |
| CN116172943B (en) * | 2023-02-15 | 2024-01-26 | 上海市肿瘤研究所 | Injectable sustained-release gel preparation and application thereof |
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