CN101642562A - Preparation method of pharmaceutical preparation and injection of exenatide acetate - Google Patents
Preparation method of pharmaceutical preparation and injection of exenatide acetate Download PDFInfo
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- CN101642562A CN101642562A CN200910194746A CN200910194746A CN101642562A CN 101642562 A CN101642562 A CN 101642562A CN 200910194746 A CN200910194746 A CN 200910194746A CN 200910194746 A CN200910194746 A CN 200910194746A CN 101642562 A CN101642562 A CN 101642562A
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Abstract
The invention relates to a preparation method of pharmaceutical preparation and injection of exenatide acetate. The exenatide acetate pharmaceutical preparation is a stable liquid formulation appliedto a plurality of dosing manners. Per 100ml of the pharmaceutical preparation contains at least the exenatide acetate of 0.005-0.4g, preservative of 0.1-0.75g, appropriate amount of buffer and isotonic agent, wherein the preservative is chosen from one or two of chlorobutanol and phenethyl alcohol, with pH value of the pharmaceutical preparation being 3.0-7.0. The preparation method has the following steps: dissolving auxiliary materials of the preservative, the isotonic agent and the buffer according to prescription amount by using water for injection, and immigrating the dissolving solutioninto batching pot; taking the auxiliary solution or the water for injection to dissolve the exenatide acetate; and replenishing the water for injection to total volume and uniformly stirring; filtering the pharmaceutical preparation for degerming by using filter membrane of 0.22mu m to produce the exenatide acetate injection. The invention has the advantages that the preservative of chlorobutanolhas the dual effects of bacteriostasis and local pain relieving; and the exenatide acetate completes the stability examination of high temperature, hard light, long-term experiment and speed-up experiment, thus having stable quality and fitting for long-term storage.
Description
Technical field
The invention belongs to medical technical field, especially a kind of Exenatide injection and preparation method thereof.
Background technology
Diabetes are that what to be caused by Different types of etiopathogenises is the metabolism disorder of feature with the chronic hyperglycemia, and hyperglycemia is mainly caused by the defective of insulin secretion or effect.At present the therapeutic goal of type 2 diabetes mellitus is blood glucose is reached or near normal level, based on Diet Therapy and physical training, to give Drug therapy according to the different state of an illness.Common drug all might cause the untoward reaction of health, therefore, need develop the treatment approach of better blood sugar control for the type 2 diabetes mellitus patient.
Exenatide (claims Yi Xina peptide or Yi Kena peptide again, Exenatide) be the exendin-4 of synthetic, be the analog of a kind of human glucagon-like-peptide-1 (GLP-1), the aminoacid sequence of its aminoacid sequence and GLP-1 partially overlaps, so it has identical physiological function with GLP-1.After Exenatide and pancreas GLP-1 receptors bind, the beta Cell of islet excreting insulin be can stimulate, thereby type ii diabetes patient's empty stomach and post-prandial glycemia reduced, slow down the carrying out property decline of beta Cell of islet function.Because so the glucose regulating action of Exenatide simulation GLP-1 is the incretin agonist that is otherwise known as.
In addition, Exenatide also can be regulated type ii diabetes patient's blood sugar level from other number of ways, and promotes to lose weight.This medicine is mainly used in the well type ii diabetes patient of blood sugar control of metformin and/or sulfonylureas drugs for diabetes clinically.Its advantage is that blood sugar reducing function is strong, and untoward reaction is few, better tolerance.
Chinese patent application number 00804847.9 discloses a kind of Exendin agonist peptide formulations and medication thereof, point out a kind of comprise 0.005% to 0.4%w/v exendin-4, buffer agent, etc. the antiseptic of osmolality regulator and 0.005%-1.0%w/v, used antiseptic is selected from metacresol, phenol, benzylalcohol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of stable Exenatide pharmaceutical formulation, to satisfy the needs of clinical treatment.
Another technical problem to be solved by this invention is to provide a kind of preparation method of Exenatide injection.
The present invention solves the problems of the technologies described above the technical scheme of being taked: a kind of Exenatide pharmaceutical formulation, this pharmaceutical formulation is applicable to the stable liquid dosage form of multiple mode administration, wherein, this pharmaceutical formulation of every 100ml is included as the Exenatide of 0.005～0.4g, the antiseptic of 0.1～0.75g, an amount of buffer agent and isotonic agent at least, wherein, described antiseptic is selected from one or both in chlorobutanol, the phenethanol, and the pH value of described pharmaceutical formulation is 3.0～7.0.
Concrete, the content of Exenatide is 0.005,0.01,0.015,0.02 in this pharmaceutical formulation of every 100ml, 0.025,0.03,0.035,0.04,0.045,0.05,0.055,0.06,0.065,0.07,0.075,0.08,0.085,0.09,0.095,0.1,0.15,0.2,0.25,0.3,0.35 or 0.4g;
The preferred chlorobutanol of the present invention is cooked antiseptic, and chlorobutanol is safe and reliable, and has antibacterial and the local analgesia dual function.
Concrete, the content of antiseptic is 0.1,0.15,0.2,0.25 in this pharmaceutical formulation of every 100ml, 0.3,0.35,0.4,0.45,0.5,0.55,0.6,0.65,0.7 or 0.75g;
The pH value of pharmaceutical formulation can be 3.0,6.5,4,4.5,5,5.5,6,6.5 or 7.0.
On the such scheme basis, described stable liquid dosage form is an injection, and pharmaceutical formulation is the Exenatide injection, and water for injection is no less than 75% of volume ratio.
On the basis of such scheme, the content of described Exenatide is 0.005g/100ml～0.1g/100ml.
On the basis of such scheme, described antiseptic content is 0.1g/100ml～0.5g/100ml.
On the basis of such scheme, the pH value of injection is preferably 4.0～6.0, and preferred pH value is 4.0～5.0, and most preferably pH value 4.5.
On the basis of such scheme, described isotonic agent content is 1g/100ml～10g/100ml, is a kind of or its combination in mannitol, sorbitol, inositol, glycerol, xylitol, Polyethylene Glycol, galactose, arabinose and the lactose.
On the basis of such scheme, described isotonic agent is a mannitol.
Concrete, isotonic agent content is 1,2,2.5,3,3.5,4,4.5,5,5.5,6,7,8,9 or 10g/100ml, be preferably 2～6g/100ml.
On the basis of such scheme, described buffer content is 0.02g/100ml～0.5g/100ml, is acetate buffer.
Concrete, the content of buffer agent can be 0.02,0.05,0.1,0.15,0.2,0.23,0.25,0.27,0.28,0.3,0.35,0.4,0.45 or 0.5g/100ml, and acetate buffer is specially glacial acetic acid-sodium acetate trihydrate buffer solution.
The invention provides a kind of preparation method, comprise the steps: at above-mentioned Exenatide injection
The first step: press recipe quantity with adjuvant antiseptic, isotonic agent and buffer agent, successively with water for injection dissolving and immigration material-compound tank;
Second step: after treating adjuvant dissolving fully, get adjuvant solution or water for injection with Exenatide dissolving and immigration material-compound tank, stirring and evenly mixing;
The 3rd step: add water for injection to cumulative volume, stirring and evenly mixing makes pH value at 3.0～7.0 medicinal liquid;
The 4th step: medicinal liquid with 0.22 μ m membrane filtration degerming, is made the Exenatide injection.
The invention has the beneficial effects as follows:
Exenatide injection formulation of the present invention, through check, indexs such as its character, discriminating, related substance, content all comply with relevant regulations, and wherein used antiseptic chlorobutanol has antibacterial and the local analgesia dual function;
Exenatide injection formulation with the present invention's preparation has carried out the stability experiment under the different condition, high temperature (40 ℃) test 10 days, highlight test 10 days, long term test (2-8 ℃) 8 months and 6 months study on the stability of accelerated test (25 ℃) have now been finished, the result shows that this product is not less than existing stability of formulation, has the characteristics of steady quality, suitable long term storage.
The specific embodiment
The following example only is used to further describe the preparation method of the present invention and Exenatide injection, and scope of the present invention can not be interpreted as only being made of the following example.
Embodiment 1
The Exenatide injection comprises following component:
The preparation method of Exenatide injection, press following step:
The first step: press recipe quantity with adjuvant chlorobutanol (antiseptic), mannitol (isotonic agent), glacial acetic acid and sodium acetate trihydrate (buffer agent), successively with water for injection dissolving and immigration material-compound tank, stirring and dissolving, the water for injection consumption should be at more than 75% of medicinal liquid cumulative volume;
Second step: after treating adjuvant dissolving fully, again Exenatide is dissolved with water for injection and the immigration material-compound tank, stir;
The 3rd step: add water for injection to cumulative volume, mixing is surveyed the medicinal liquid pH value about 4.5;
The 4th step: with the membrane filtration degerming of medicinal liquid with 0.22 μ m, make the Exenatide injection, product detects packing.
Embodiment 2
The Exenatide injection comprises following component:
The preparation method of Exenatide injection, press following step:
The first step: press recipe quantity with adjuvant chlorobutanol (antiseptic), mannitol (isotonic agent), glacial acetic acid and sodium acetate trihydrate (buffer agent), with water for injection dissolving and immigration material-compound tank, the water for injection consumption should be at more than 75% of medicinal liquid cumulative volume successively;
Second step: after treating adjuvant dissolving fully, it is an amount of to get adjuvant solution and water for injection, with Exenatide dissolving and immigration material-compound tank, stirs;
The 3rd step: add water for injection to cumulative volume, mixing is surveyed the medicinal liquid pH value about 4.5;
The 4th step: with the membrane filtration degerming of medicinal liquid with 0.22 μ m, make the Exenatide injection, product detects packing.
Embodiment 3
The Exenatide injection comprises following component:
The Exenatide injection prepares by following step:
The first step: press recipe quantity with adjuvant chlorobutanol (antiseptic), mannitol (isotonic agent), glacial acetic acid and sodium acetate trihydrate (buffer agent), with water for injection dissolving and immigration material-compound tank, the water for injection consumption should be at more than 75% of medicinal liquid cumulative volume successively;
Second step: after treating adjuvant dissolving fully, it is an amount of to get adjuvant solution and water for injection, with Exenatide dissolving and immigration material-compound tank, stirs;
The 3rd step: add water for injection to cumulative volume, mixing is surveyed the medicinal liquid pH value about 4.5;
The 4th step: with the membrane filtration degerming of medicinal liquid with 0.22 μ m, make the Exenatide injection, product detects packing.
Embodiment 4
The Exenatide injection comprises following component:
The Exenatide injection prepares by following step:
The first step: press recipe quantity with adjuvant phenethanol (antiseptic), mannitol (isotonic agent), glacial acetic acid and sodium acetate trihydrate (buffer agent), move into material-compound tank with the water for injection dissolving successively;
Second step: after treating adjuvant dissolving fully, again Exenatide is dissolved with water for injection and the immigration material-compound tank, stir;
The 3rd step: add water for injection to cumulative volume, mixing is surveyed the medicinal liquid pH value about 4.5;
The 4th step: with the membrane filtration degerming of medicinal liquid with 0.22 μ m, make the Exenatide injection, product detects packing.
Claims (9)
1, a kind of Exenatide pharmaceutical formulation, this pharmaceutical formulation is applicable to the stable liquid dosage form of multiple administration, it is characterized in that: this pharmaceutical formulation of every 100ml is included as the Exenatide of 0.005～0.4g, the antiseptic of 0.1～0.75g, an amount of buffer agent and isotonic agent at least, wherein, described antiseptic is selected from one or both in chlorobutanol, the phenethanol, and the pH value of described pharmaceutical formulation is 3.0～7.0.
2, Exenatide pharmaceutical formulation according to claim 1 is characterized in that: described stable liquid dosage form is an injection, and pharmaceutical formulation is the Exenatide injection, and water for injection is no less than 75% of volume ratio.
3, Exenatide pharmaceutical formulation according to claim 1 and 2 is characterized in that: the content of described Exenatide is 0.005g/100ml～0.1g/100ml.
4, Exenatide pharmaceutical formulation according to claim 1 and 2 is characterized in that: described antiseptic content is 0.1g/100ml～0.5g/100ml.
5, Exenatide pharmaceutical formulation according to claim 1 and 2 is characterized in that: the pH value of described pharmaceutical formulation is 4.0～5.0.
6, Exenatide pharmaceutical formulation according to claim 1 and 2, it is characterized in that: described isotonic agent content is 1g/100ml～10g/100ml, is a kind of or its combination in mannitol, sorbitol, inositol, glycerol, xylitol, Polyethylene Glycol, galactose, arabinose and the lactose.
7, Exenatide pharmaceutical formulation according to claim 6 is characterized in that: described isotonic agent is a mannitol.
8, Exenatide pharmaceutical formulation according to claim 1 and 2 is characterized in that: described buffer content is 0.02g/100ml～0.5g/100ml, is acetate buffer.
9,, it is characterized in that comprising the steps: at the preparation method of the described Exenatide injection of one of claim 2 to 8
The first step: press recipe quantity with adjuvant antiseptic, isotonic agent and buffer agent, successively with water for injection dissolving and immigration material-compound tank;
Second step: after treating adjuvant dissolving fully, get adjuvant solution or water for injection with Exenatide dissolving and immigration material-compound tank, stirring and evenly mixing;
The 3rd step: add water for injection to cumulative volume, stirring and evenly mixing makes pH value at 3.0～7.0 medicinal liquid;
The 4th step: medicinal liquid with 0.22 μ m membrane filtration degerming, is made the Exenatide injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN200910194746A CN101642562A (en) | 2009-08-28 | 2009-08-28 | Preparation method of pharmaceutical preparation and injection of exenatide acetate |
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| CN200910194746A CN101642562A (en) | 2009-08-28 | 2009-08-28 | Preparation method of pharmaceutical preparation and injection of exenatide acetate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102100906A (en) * | 2011-02-18 | 2011-06-22 | 深圳翰宇药业股份有限公司 | Medicinal preparation of exenatide and preparation method thereof |
| CN108042794A (en) * | 2018-01-05 | 2018-05-18 | 北京博康健基因科技有限公司 | Stabilization formulations of Exendin-4 and preparation method thereof |
| CN110038118A (en) * | 2013-04-16 | 2019-07-23 | 石药集团百克(山东)生物制药有限公司 | The medicinal composition for injections of Gluca Gen sample peptide-1 receptor stimulant |
| US11771773B2 (en) * | 2016-10-14 | 2023-10-03 | Jiangsu Hansoh Pharmaceutical Group Co., Ltd. | Pharmaceutical preparation containing polyethylene gylcol loxenatide and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1384755A (en) * | 1999-01-14 | 2002-12-11 | 安米林药品公司 | Novel exendin agonist formulations and methods administration thereof |
| US20050215475A1 (en) * | 2003-05-30 | 2005-09-29 | John Ong | Transmucosal delivery of peptides and proteins |
| CN101366692A (en) * | 2007-08-15 | 2009-02-18 | 江苏豪森药业股份有限公司 | Stable Exenatide formulation |
| CN101670096A (en) * | 2008-09-11 | 2010-03-17 | 杭州九源基因工程有限公司 | Medicinal preparation containing exenatide |
-
2009
- 2009-08-28 CN CN200910194746A patent/CN101642562A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1384755A (en) * | 1999-01-14 | 2002-12-11 | 安米林药品公司 | Novel exendin agonist formulations and methods administration thereof |
| US20050215475A1 (en) * | 2003-05-30 | 2005-09-29 | John Ong | Transmucosal delivery of peptides and proteins |
| CN101366692A (en) * | 2007-08-15 | 2009-02-18 | 江苏豪森药业股份有限公司 | Stable Exenatide formulation |
| CN101670096A (en) * | 2008-09-11 | 2010-03-17 | 杭州九源基因工程有限公司 | Medicinal preparation containing exenatide |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102100906A (en) * | 2011-02-18 | 2011-06-22 | 深圳翰宇药业股份有限公司 | Medicinal preparation of exenatide and preparation method thereof |
| CN110038118A (en) * | 2013-04-16 | 2019-07-23 | 石药集团百克(山东)生物制药有限公司 | The medicinal composition for injections of Gluca Gen sample peptide-1 receptor stimulant |
| US11771773B2 (en) * | 2016-10-14 | 2023-10-03 | Jiangsu Hansoh Pharmaceutical Group Co., Ltd. | Pharmaceutical preparation containing polyethylene gylcol loxenatide and preparation method thereof |
| CN108042794A (en) * | 2018-01-05 | 2018-05-18 | 北京博康健基因科技有限公司 | Stabilization formulations of Exendin-4 and preparation method thereof |
| CN108042794B (en) * | 2018-01-05 | 2022-01-25 | 北京博康健基因科技有限公司 | Stable preparation of recombinant insulinotropic hormone secretagogue and preparation method thereof |
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Application publication date: 20100210 |