CN102258463A - Stable sodium folinate injection - Google Patents
Stable sodium folinate injection Download PDFInfo
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- CN102258463A CN102258463A CN 201110200820 CN201110200820A CN102258463A CN 102258463 A CN102258463 A CN 102258463A CN 201110200820 CN201110200820 CN 201110200820 CN 201110200820 A CN201110200820 A CN 201110200820A CN 102258463 A CN102258463 A CN 102258463A
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Abstract
The invention relates to stable sodium folinate injection. The stable sodium folinate injection contains effective ingredients of folinate or pharmaceutically-acceptable salts thereof and water for injection, and also contains a stabilizing agent, and the weight ratio of the effective ingredients to the stabilizing agent is (0.0001:1)-(5:1), and the injection adopts a pH regulating agent to adjust the pH value to be 6.5-8.5. According to the stable sodium folinate injection, the stable preparation of folinate in high-concentration physiologically-compatible isotonic solution becomes possible.
Description
Technical field
The present invention relates to go up the preparation of acceptable salt as the aqueous solution for injection of effective ingredient, particularly a kind of stable sodium folinate injection with folinic acid or its pharmacology.
Background technology
Folinic acid is that another name is the known compound of 5-formoxyl tetrahydrofolic acid.The calcium salt of this chemical compound goes on the market for many years abroad, is mainly used in clinically and the 5-fluorouracil drug combination, and as the synergist of its treatment gastric cancer, colorectal cancer, can also be as the excessive cure of separating of methotrexate.Calcium folinate is owing to the existence of calcium ion, and poor solubility has certain limitation in clinical treatment.Show as: during clinical application, need 1% calcium folinate solution is dissolved in 0.9% the sodium chloride isosmotic solution, increased the medication total amount and with the incoherent ionic weight of treatment; Calcium folinate must slowly instil, otherwise the increase meeting health risk of plasma calcium ion concentration; The calcium ion of too much no therapeutical effect directly in injection enters body, produces unnecessary side effect to meetings such as human hearts; Sedimentary calcium easily stops up tube for transfusion can't carry out treatment smoothly.
Because the active component of calcium folinate is a folinic acid, calcium ion and drug action are irrelevant, so replace calcium folinate with leucovorin sodium, not only uncorrelated impurity is few in consumption minimizing and the preparation, and clinical application effect is better than calcium folinate.Because leucovorin sodium is to factor sensitivities such as temperature, pH value, oxygen, stability is poor.In order to improve the stability of leucovorin sodium, pharmaceutical industry is many at present makes oral formulations and freeze dried powder with leucovorin sodium.But not only onset speed of oral formulations is slower than ejection preparation, and is inferior to ejection preparation because gastrointestinal absorbs the saturated curative effect that makes, and a large amount of when using leucovorin sodium if the patient needs, and oral formulations obviously can not satisfy clinical demand.For freeze dried powder because the restriction of preparation method, employing be aseptic filtration, the cost of preparation is higher, freeze dried powder is mixed with injection and introduces antibacterial easily in process of clinical application simultaneously, safety aspect existing problems.From the safety aspect, the terminal sterilization of injection more can meet the requirement of safe medication.
There is pharmacy corporation to begin to prepare the leucovorin sodium ejection preparation for this reason, for example the Chinese patent publication number be CN1799546 disclosed be exactly a kind of leucovorin sodium ejection preparation, but from its product quality and stability data, described method can not satisfy the requirement of long preservation stability.Therefore, improve sodium folinate injection stability, the injection products of excellent in stability is provided, meet clinical needs is the technical barrier that pharmaceutical industry makes great efforts to capture always.
Though at present existing a lot of documents openly improve the method for tetrahydrofolic acid class related preparations stability, all do not obtain satisfied result.For example CN03121530.0 is described, stablizes the solution of calcium levofolinate as antioxidant by adding an amount of sodium pyrosulfite.
As described in CN200480017791.3, stablize and contain 5, the preparation of 10-methylene tetrahydrofolate calcium by in prescription, adding a large amount of sodium citrates.
As described in CN200510098679.3, stablize the aqueous solution that contains calcium levofolinate as antioxidant by the ascorbic acid that adds 0.005～1 weight/volume %.
As described in CN200910077804.0, stablize the aqueous solution preparation of calcium levofolinate by in prescription, adding antioxidant and chelating agen.
The applicant has carried out long term studies to the long-time stability of sodium folinate injection, and unexpected the discovery adds the stabilizing agent such as the sodium citrate of appropriate amount under certain pH condition, can significantly improve the quality and the stability of sodium folinate injection.
Summary of the invention
The present invention is directed to above-mentioned situation, aim to provide the simple sodium folinate injection of a kind of prescription, avoided leucovorin sodium because of the existence of hyperpyrexia, low pH and oxygen causes decomposing, help long term store, impurity content is low, clinical practice safety.
The beat all discovery of the present invention, use sodium citrate, citric acid or similar stabilizing agent such as sodium acetate simultaneously by regulating pH value to an alkaline range, can significantly improve the stability of folinic acid in the aqueous solution, unexpectedly, this stabilisation is to realize under the situation that does not have antioxidant.
The present invention finds, in suitable alkaline pH scope 6.5～8.5, especially the pH scope is 7.0～8.5 o'clock, reduce the consumption of stabilizing agent sodium citrate gradually, can increase the stability of leucovorin sodium aqueous solution on the contrary, but when the amount of sodium citrate reduces to certain value, with the weight ratio of leucovorin sodium be 0.0005: 1 o'clock, the stability of aqueous solution has no longer changed with the variation of sodium citrate amount.
The present invention also finds, is 7.8 at pH especially, and the weight ratio of sodium citrate and leucovorin sodium is 0.0005: 1 o'clock, and the stability of aqueous solution is optimum.
Stabilizing agent citrate of the present invention can reduce the hydrolysis and the oxidation Decomposition of skeleton in 5-formoxyl tetrahydrofolic acid solution; reduce the formation of the amino glutamic acid of product such as neighbour, pterin and tetrahydrochysene pterin derivatives thus, have the stabilisation of the leucovorin sodium that can't expect that citrate causes in the alkaline pH scope to give citrate buffer unexpected synergism in the pH scope.On the one hand between citrate and folinic acid, complex between the counter ion counterionsl gegenions (salt) of citrate and folinic acid forms on the other hand, the stabilisation of folinic acid is made conclusive contribution, stoped the decomposition of the tetchy folinic acid of oxidation rotten thus.
The present invention makes the stabilization formulations of leucovorin sodium in the isosmotic solution of high concentration physiology compatibility become possibility through this.
Description of drawings
Fig. 1 sodium folinate injection process chart of the present invention.
The specific embodiment
Prescription
Principal agent: folinic acid
Stabilizing agent: sodium citrate:
Isoosmotic adjusting agent: sodium chloride
PH regulator agent: sodium hydroxide.Because the principal agent folinic acid is insoluble at neutrallty condition, transfer pH about 7.8 can dissolve fully with sodium hydroxide.
Solvent: water for injection.
Preparation technology
Whole process of preparation is carried out on clean bench.
Referring to Fig. 1, take by weighing sodium citrate, the sodium chloride of recipe quantity, place the 2500ml container of sterilizing, add the cold water for injection of 1400ml, after stirring and the dissolving, the folinic acid that takes by weighing recipe quantity adds wherein, and the about 420ml of sodium hydroxide that slowly drips 1mol/l under fully stirring in this suspension is to solution clarification (pH7.8).Add the 3g medicinal carbon, continue to stir 30 minutes, with 0.6 μ m filter membrane decarburization of process sterilization and with 0.22 μ m filter membrane aseptic filtration, add injection and wash filter with water, and add the injection water to 2000ml, measure projects such as pH value of solution, qualified back aseptic condition by the device fill of every 2ml in ampoule bottle, seal 121 ℃ of steam sterilizations 8 minutes.
Embodiment 1:pH is to the influence of stability
According to above-mentioned preparation technology's method, when regulating pH, transfer to pH value different in the following table 1, the preparation finished product, the impurity after preserving 10 days under 25 ℃ of conditions changes.
Studies show that, pH raises, the dissolubility of folinic acid rises, and pH reaches at 6.5 o'clock, and medicine dissolves fully, it during pH7.8 the theoretical value that folinic acid becomes the folinic acid disodium, reduce the stimulation to blood vessel when considering injecting drug use, pH is unsuitable too high, and above-mentioned experiment also proves, pH is controlled between 6.5 to 8.5, and sodium folinate injection is relatively more stablized.
Embodiment 2: sodium citrate is compared to the influence of stability with other stabilizing agents
The results are shown in following table
Prescription 1 is used the sodium citrate used as stabilizers, and prescription 2 is for adding phosphate-buffered salt, and prescription 3 usefulness tartaric acid replace the sodium citrate used as stabilizers.
From The above results, place after 10 days for 25 ℃, take temperature from containing, all descend to some extent, prescription 1 and prescription 3, the degree of decline is less, judges that therefore the variation of content is an acceptable under its condition of storage (2-8 ℃).
Embodiment 3: the sodium citrate of different proportion is to the influence of stability
The results are shown in following table
From The above results, the content of stabilizing agent sodium citrate and principal agent than within the specific limits 0.0001: 1～5: 1 linear, along with the minimizing stability of sodium citrate consumption decreases, but when not adding the stabilizing agent sodium citrate, the stability of aqueous solution preparation is poorer, and the sodium citrate of this explanation appropriate amount has a very important role as the long preservation of stabilizing agent to sodium folinate injection.Especially the weight ratio between principal agent and sodium citrate is that 1: 0.0005 stability is best.
Embodiment 5: sodium citrate and principal agent 0.0005: 1 o'clock, pH is to the influence of stability
The results are shown in following table
From The above results, be 0.0005: 1 o'clock at sodium citrate and principal agent ratio, the stability of pH leucovorin sodium aqueous solution preparation when 7.0-8.5 is better relatively, and especially working as pH is 7.8, and stability is best.
Claims (5)
1. stable sodium folinate injection, contain effective ingredient and water for injection with folinic acid or its pharmaceutically acceptable salt, it is characterized in that, also contain and the stabilizing agent that with the effective ingredient weight ratio of folinic acid or its pharmaceutically acceptable salt is 0.0001: 1～5: 1, and injection to adopt the pH regulator agent to regulate pH value be 6.5～8.5.
2. stable sodium folinate injection as claimed in claim 1 is characterized in that, described folinic acid pharmaceutically acceptable salt is alkali metal salt or alkali salt.
3. stable sodium folinate injection as claimed in claim 1 is characterized in that, described stabilizing agent is selected from citric acid, sodium citrate or its mixture.
4. stable sodium folinate injection as claimed in claim 1 is characterized in that, described is leucovorin sodium with folinic acid or its pharmaceutically acceptable salt, and described stabilizing agent is a sodium citrate, and described pH regulator agent is a sodium hydroxide; The weight ratio of described sodium citrate and leucovorin sodium is 0.0001: 1～2: 1, and the pH value scope of injection is 7.0～8.5.
5. stable sodium folinate injection as claimed in claim 4 is characterized in that, the weight ratio of described sodium citrate and leucovorin sodium is 0.0005: 1, and the pH value scope of injection is 7.8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110200820 CN102258463A (en) | 2011-07-18 | 2011-07-18 | Stable sodium folinate injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110200820 CN102258463A (en) | 2011-07-18 | 2011-07-18 | Stable sodium folinate injection |
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| CN102258463A true CN102258463A (en) | 2011-11-30 |
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| CN 201110200820 Pending CN102258463A (en) | 2011-07-18 | 2011-07-18 | Stable sodium folinate injection |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2617422A1 (en) * | 2012-01-20 | 2013-07-24 | Isofol Medical AB | Anti-tumor activity of reduced folates like methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate |
| CN108902575A (en) * | 2018-07-24 | 2018-11-30 | 河北冀衡（集团）药业有限公司 | beverage and preparation method thereof |
| CN118059042A (en) * | 2024-04-17 | 2024-05-24 | 成都瑞尔医药科技有限公司 | Calcium folinate injection and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4931441A (en) * | 1988-11-09 | 1990-06-05 | Luitpold Pharmaceuticals, Inc. | Stabilized aqueous leucovorin calcium compositions |
| EP0755396B1 (en) * | 1994-04-05 | 2000-07-05 | Pharmachemie B.V. | Stable aqueous folinate solution |
| CN1748704A (en) * | 2004-09-15 | 2006-03-22 | 尼普洛株式会社 | Aqueous preparation for injection and its stabilizing method |
| CN1799546A (en) * | 2005-06-14 | 2006-07-12 | 凯基贸易有限公司 | Sodium folinate injection and preparation method thereof |
| CN1820753A (en) * | 2005-02-18 | 2006-08-23 | 徐文凯 | Freeze-dried powder injection containing leucovorin sodium and its preparing method |
| CN101780084A (en) * | 2009-01-20 | 2010-07-21 | 北京利乐生制药科技有限公司 | Injection composition using levo leucovorin or salt thereof as major ingredients |
-
2011
- 2011-07-18 CN CN 201110200820 patent/CN102258463A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4931441A (en) * | 1988-11-09 | 1990-06-05 | Luitpold Pharmaceuticals, Inc. | Stabilized aqueous leucovorin calcium compositions |
| EP0755396B1 (en) * | 1994-04-05 | 2000-07-05 | Pharmachemie B.V. | Stable aqueous folinate solution |
| CN1748704A (en) * | 2004-09-15 | 2006-03-22 | 尼普洛株式会社 | Aqueous preparation for injection and its stabilizing method |
| CN1820753A (en) * | 2005-02-18 | 2006-08-23 | 徐文凯 | Freeze-dried powder injection containing leucovorin sodium and its preparing method |
| CN1799546A (en) * | 2005-06-14 | 2006-07-12 | 凯基贸易有限公司 | Sodium folinate injection and preparation method thereof |
| CN101780084A (en) * | 2009-01-20 | 2010-07-21 | 北京利乐生制药科技有限公司 | Injection composition using levo leucovorin or salt thereof as major ingredients |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2617422A1 (en) * | 2012-01-20 | 2013-07-24 | Isofol Medical AB | Anti-tumor activity of reduced folates like methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate |
| CN104114174A (en) * | 2012-01-20 | 2014-10-22 | 伊索弗尔医药公司 | Anti-tumor activity of reduced folates like methylene-tetrahydrofolate |
| CN108902575A (en) * | 2018-07-24 | 2018-11-30 | 河北冀衡（集团）药业有限公司 | beverage and preparation method thereof |
| CN118059042A (en) * | 2024-04-17 | 2024-05-24 | 成都瑞尔医药科技有限公司 | Calcium folinate injection and preparation method thereof |
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Application publication date: 20111130 |