CN105853347A - Levocarnitine composition and preparation method thereof - Google Patents
Levocarnitine composition and preparation method thereof Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a levocarnitine composition and a preparation method thereof. The composition is prepared from the following components: 200g of levocarnitine, 0.02-0.10g of egg yolk lecithin, 0.005-0.015g of resveratrol, a proper amount of pH regulator and water for injection which is added until the total volume is 1000ml. The composition has excellent thermal stability, and the content of pyrolyzed impurity 2(5H)-furanone generated in a high-temperature sterilization process can be greatly reduced.
Description
Technical field
The present invention relates to the compositions of a kind of levocarnitine, specifically, relate to a kind of containing levocarnitine, white Herba chenopodii
Reed alcohol and the compositions of Ovum Gallus domesticus Flavus lecithin, belong to pharmaceutical technology field.
Background technology
Levocarnitine, also known as L-carnitine, chemical name is: (R)-3-carboxyl-2-hydroxy-n, N, N-trimethyl-1-
Third ammonium hydroxide, is a kind of special acid being widely present in when injected organism tissue, be the mankind and animal required
Nutrient substance, is biostearin nutrient, is equivalent to vitamin B complex.Levocarnitine is a kind of essential nutrients,
Its function is closely related with the metabolism of organs of living beings and tissue.It was found that with exogenous L-carnitine in treatment
A little diseases, can improve clinical symptoms.As far back as the sixties, D, VBT has been used for clinic as stomach medicine, mainly uses
In aid digestion, appetite stimulator.Research later finds that only VBT works, and D-carnitine has antagonism, right
Organism is unfavorable, is the most gradually substituted by L-carnitine.
L-carnitine can be widely used for the treatment of various ischemic heart desease, for shock, acute and chronic cardiac insufficiency,
Myocarditis, arrhythmia have preferably effect..The Renal Failure Patients that nephropathy and diabetes cause is saturating due to long-term blood
Analysis causes carnitine to lack, and it is required that these patients supplement carnitine.Carnitine can be used for the auxiliary treatment of hepatopath,
Its mechanism is the ammonia concentration that carnitine can reduce hepatopath, reduces portal hypertension, reduces esters and accumulates in liver,
Levocarnitine can with blood fat reducing, lose weight, treat angiopathy.Its another one important function is for performing the operation
Or gastrointestinal fistula malignant tumor accepts patient and the neonate that total parenteral nutrition is supported.Along with the development of science, left
Carnitine has new achievement in research in terms of nourishing healthy, defatting beauty, therapeutic treatment and feedstuff interpolation, has wide
Wealthy market prospect.The levocarnitine reagent of the injection sold in the market generally uses following preparation method:
In preparing container, adding appropriate water for injection, after adding levocarnitine dissolving, regulation medicinal liquid pH value is to allowing
Scope, add to the full amount of water for injection, add activated carbon decolorizing, filter to the most clear and bright, with sintered glass filter with
Membrane filter, and under stream of nitrogen gas, carry out embedding, carry out sterilizing the most under the high temperature conditions.In such biography
During controlling is standby, owing to levocarnitine is the most unstable, autoclaving process can generate high temperature
Analyte, this can affect the drug safety of injection reagent, there is the probability of harmful to human safety.
CN03100541.1 discloses a kind of by levocarnitine or its physiologically acceptable salt and vitamin B6 group
The compound injection become, decreases patient and causes owing to vomiting and loss of appetite cause B6 to lack at therapeutic process
Side reaction, turn avoid twice injection levocarnitine and vitamin B6, the misery brought to patient and use respectively
On inconvenience.
CN03147716.X discloses a kind of levocarnitine and coenzyme Q10 compound preparation, has reached levocarnitine with auxiliary
The coordinative role of enzyme Q10, be used alone with two kinds of medicines compared with, there is more preferable therapeutic effect, use economy side
Just.
CN200710021408.7 discloses the medicine of a kind of levocarnitine or derivatives thereof preparation treatment hyperuricemia
Thing, described derivant is selected from acetyl levocarnitine, propionyl-L-carnitine and their pharmaceutically useful salt and left card Buddhist nun
The pharmaceutically useful salt in spit of fland, said composition can effectively be treated hyperuricemia and have related disorders, and having hypotoxicity.
CN200810183214.1 discloses a kind of levocarnitine injection submicron emulsion preparation and preparation method, it is provided that
The submicron emulsion lyophilized formulations of a kind of levocarnitine used for intravenous injection, this Emulsion can be directly used for intravenous injection, stability
Well.
CN201010215998.9 relates to a kind of pharmaceutical composition comprising levocarnitine and hydroxy benzene sulfonate, can be effective
Ground is for treating and/or preventing the various disease affecting renal function and/or disease.
Above-described invention does not the most solve the thermal stability problems of Levocarnitine Injection determined.
CN200910017768.9 discloses a kind of levocarnitine liposomes injection, it is characterised in that by active component
Levocarnitine, soybean lecithin, cholesterol, antioxidant and pharmaceutically acceptable carrier composition, use preferably
PH gradient method is prepared for the injection of a kind of excellent in stability.
CN201110191392.0 discloses a kind of levo-carnitine for injection, this patent buffering with cushioning effect
Salt regulates (sodium dihydrogen phosphate forms buffer salt ion pair with sodium hydroxide) pH of levocarnitine solution, it is to avoid left
The pH acute variation of carnitine, improves the stability of Levocarnitine Injection determined, improves the safety of product.
Above-mentioned invention uses different schemes, improves the stability of Levocarnitine Injection determined by controlling acid-base value,
But technique is relative complex, the non-natural substances of introducing is more.
CN201110202892.X relate to a kind of injection containing levocarnitine and the lyophilized powder of mannitol, overcome note
Penetrate and hold givey problem by levocarnitine compositions skeleton and lyophilizing micro structure, ensured redissolution performance.
By using freeze dried powder, it is to avoid Levocarnitine Injection determined is deposited in liquid form, the asking of poor heat stability
Topic.But it is many to prepare lyophilized powder processing step, power consumption is high, and the program is not directly to solve the heat of injection surely
Qualitative question.
Generally there is the shortcoming of poor heat stability in Levocarnitine Injection determined at present, produces impurity after its decomposes
2 (5H)-furanones.2 (5H)-furanones, call 2-butylene-4-lactone, and its structural formula is:
2 (5H)-furanones are a kind of endogenous saccharic acids, can cause satiety.Lumbar injection, intravenous injection, Intraventricular note
Penetrate, after gastric infusion, feed suppression can be caused.It addition, 2 (5H)-furanones can be on Hypothalamic Stimulation-hypophysis-kidney
Gland axle and Sympathetic Nerve are neural, affect immunoloregulation function.Therefore should be reduced as far as in the middle of pharmacy procedure
The content of 2 (5H)-furanones, reduces issuable untoward reaction during medication.
In view of this, the special proposition present invention.
Summary of the invention
In order to overcome the defect of poor heat stability set forth above, reduce the content of objectionable 2 (5H)-furanones,
The present invention provides the compositions of a kind of levocarnitine, and said composition has heat stability, thus greatly reduces bad
The content of impurity 2 (5H)-furanone.
For achieving the above object, the technical solution used in the present invention is:
A kind of compositions of levocarnitine, wherein, described pharmaceutical composition is injection, and its composition is as follows:
Under study for action, by adding a small amount of resveratrol and Ovum Gallus domesticus Flavus lecithin, it has unexpectedly been found that prepared left card
Buddhist nun spit of fland injection has good heat stability, uses injection prepared by technical solution of the present invention through too high
After temperature sterilizing, the content of impurity 2 (5H)-furanone significantly subtracts compared with the common left card Buddhist nun's injection sold on market
Few.
Above-described resveratrol is polyphenol compound, and its structural formula is:
It is mainly derived from the plants such as Semen arachidis hypogaeae, Fructus Vitis viniferae (red wine), Rhizoma Polygoni Cuspidati, Fructus Mori, is a kind of biological the strongest
Natural polyphenol class material, has excellent pharmacologically active and health care, additionally it is possible to prevent some anaphylaxis.
Ovum Gallus domesticus Flavus lecithin has Adjust-blood lipid, improves memory, improves liver metabolism obstacle, improves hypoxia-bearing capability etc.
Effect, is conventional excipient substance.
Above-described two kinds of materials all can commercially buy the product of pharmaceutic adjuvant requirement purity.
Preferably, the composition of described levocarnitine compositions is as follows:
Or, the composition of described levocarnitine compositions is as follows:
Described levocarnitine compositions is prepared by following method:
1) weigh levocarnitine, Ovum Gallus domesticus Flavus lecithin, resveratrol according to described consumption, add water for injection, dissolve；
2) adding pH adjusting agent, regulation pH is to acid, and water for injection adds to full dose；
3) add activated carbon decolorizing, filter, embedding, sterilizing,.
Preferably, described step 1) carry out as follows:
Weigh the resveratrol of described consumption, add water for injection and make it be completely dissolved, add the yellow lecithin of described consumption,
Stirring and dissolving, is eventually adding levocarnitine 200g so that it is be completely dissolved.
Described pH adjusting agent is the hydrochloric acid of 0.1mol/L.
Preferably, described step 2) regulation pH4.8～5.9.
The present invention has investigated the injection of the most different pH of regulation rear impurities A under identical sterilization time
The changes of contents of (2 (5H)-furanone).Result shows, control injection pH in the range of 4.8～5.9, warp
After spending high temperature sterilize certain time, the content of impurity 2 (5H)-furanone is less.
Preferably, described step 3) in sterilizing carry out in accordance with the following methods:
In 100 DEG C of steam, sterilization time 10～30min.Use such sterilizing methods, guarantee abundant sterilizing
While, decrease energy consumption as far as possible, and reduce the content producing impurity.
Preferably, the temperature of the described water for injection for dissolving is 38 DEG C～40 DEG C.Process of the test finds,
Utilize the water for injection in this temperature range to dissolve the injection prepared more stable, after placement, be not easily formed big particle diameter
Microgranule, can improve the quality of injection further, keeps phase homogeneity, is used for injecting safer.
Use levocarnitine compositions prepared by the method for the present invention in autoclaving process, there is preferably heat steady
Qualitative, greatly reduce the content of pyrolytic thing impurity, for improving quality and the drug safety of medicine, tool
There is important meaning.
Detailed description of the invention
Below by enumerating part specific embodiment to further illustrate the present invention.Embodiments discussed below is only
Facilitate a better understanding of invention, not as a limitation of the invention.
Embodiment 1:
Prescription:
Preparation technology:
1) weigh resveratrol 0.005g, add 38 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.02g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 4.8, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 10min in 100 DEG C of flowing steams,.
Embodiment 2:
Prescription:
Preparation technology:
1) weigh resveratrol 0.01g, add 39 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.04g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 5.0, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 15min in 100 DEG C of flowing steams,.
Embodiment 3:
Prescription:
Preparation technology:
1) weigh resveratrol 0.008g, add 40 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.04g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 5.2, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 20min in 100 DEG C of flowing steams,.
Embodiment 4:
Prescription:
Preparation technology:
1) weigh resveratrol 0.01g, add 38 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.06g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 5.5, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 20min in 100 DEG C of flowing steams,.
Embodiment 5:
Prescription:
Preparation technology:
1) weigh resveratrol 0.015g, add 39 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.08g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 5.6, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 30min in 100 DEG C of flowing steams,.
Embodiment 6:
Prescription:
Preparation technology:
1) weigh resveratrol 0.012g, add 40 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.1g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 5.9, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 20min in 100 DEG C of flowing steams,.
Embodiment 7:
Prescription:
Preparation technology:
1) weigh resveratrol 0.015g, add 40 DEG C of water for injection 750ml and make it be completely dissolved, add Ovum Gallus domesticus Flavus lecithin
0.1g, stirring and dissolving, it is eventually adding levocarnitine 200g so that it is be completely dissolved；
2) adding appropriate pH adjusting agent, regulation pH is 5.5, continues to connect injection water to full dose；
3) add injection activated carbon decolorizing, filter to the most clear and bright, with membrane filtration, and embedding under stream of nitrogen gas, finally in
Sterilizing 15min in 100 DEG C of flowing steams,.
Test example 1, medicine high-temperature stability are tested
Test specimen:
The levocarnitine compositions of preparation in this programme embodiment；
Comparative sample is the Levocarnitine Injection determined (Racal) that Changzhou Lanling Pharmaceutical Co., Ltd. produces, specification 5ml:1g,
Traditional Chinese medicines quasi-word H20000543.
Control sample levocarnitine compositions and the market purchasing of the preparation in each embodiment come, at different high temperature
Test under steam sterilizing time, then measure the high-temperature stability of each sample, specifically, be to pass through HPLC
Method measures the content of high-temperature process rear impurity A (described impurity A is 2 (5H)-furanones), and method is as follows: accurate
Measure the test liquid body 1ml in each embodiment, in 100ml volumetric flask, be diluted to graduation mark, shake up, stand-by；With
On market, sale Levocarnitine Injection determined is as comparison, uses same dilution process to prepare.Various kinds after preparation
Product, test according to following chromatographic condition:
Chromatographic column: YMC-PackNH2250*4.6mmI.DS-5 μm, 12nm
Flowing phase: acetonitrile 0.05mol/L phosphate buffer proportioning is 65:35
Detection wavelength: 205nm
Flow velocity: 1ml/min
Column temperature: 25 DEG C
Sample size: 2 μ l
The integral area of the chromatographic peak according to chromatograph test determines that the content of impurity A, test data are shown in Table 1.
The content (%) of the impurity A measured after table 1, sterilizing
By the result of the test of test 1 it can be seen that levocarnitine prepared in each embodiment in the present invention combines
Thing has good heat stability.With on market sell Levocarnitine Injection determined compared with, through high-temperature process it
The Impurity A content of rear generation substantially reduces, and medicine quality improves significantly.
Test example 2, the selection of compositions pH
This test example has investigated the impact on compositions character of the pH regulator scope of compositions, has mainly investigated regulation extremely
After the compositions sterilizing of different pH, the changes of contents of impurities A (2 (5H)-furanone), is specifically shown in Table 2.
Table 2, different pH compositions sterilizing after Impurity A content (%)
By above-mentioned result of the test, it is found that the pH of control injection is in the range of 4.8～5.9, through too high
After temperature sterilizing certain time, the content of impurity 2 (5H)-furanone is less.
So according to this test, by currently preferred pH regulator scope control 4.8～5.9.
Test example 3 and the stability test of 0.9% sodium chloride solution compatibility
Using 0.9% sodium chloride solution, with 1:5,1:10,1:20,1:30,1:50 ratio is diluted, and is placed in room
Under the conditions of temperature, the appearance characteristics of each solution after observing 4h, 6h, 8h, 9h, 10h respectively, if keep clarification shape
State.That observes the results are shown in Table 3.
Table 3 and 0.9% sodium chloride solution compatibility stability
Note: " " represents solution clarification and stablize
By compatibility mechanism it can be seen that the levocarnitine compositions prepared of the present invention and 0.9% sodium chloride according to upper
After stating ratio compatibility, it is respectively provided with the character of stable uniform, meets injection standard requirement.To in the present invention, other are implemented
Compositions in example, has all carried out the test of above-mentioned compatibility stability, it is thus achieved that result similar.
Test example 4,0～8h pH situation of change
The levocarnitine injection present invention prepared is noted with the sodium chloride solution of 0.9%, the glucose of 5% respectively
Penetrate liquid and carry out compatibility, the pH situation of change in 8h of the mixed solution after detection compatibility according to 1:30, be specifically shown in Table
4。
The pH situation of change of table 4,0～8h
According to result of the test it can be seen that the solution after utilizing levocarnitine compositions compatibility prepared by the present invention exists
The pH of 0～8h changes in the range of 4～9, meets the pH requirement of the injection that 2010 editions " Chinese Pharmacopoeias " specify.
This test has all carried out above-mentioned test to the multiple levocarnitine compositions of preparation in invention, and experimental result all accords with
Close the regulation of 2010 editions " Chinese Pharmacopoeias ".
Test example 5,0～8h solution insoluble particle situation of change
This experimental test the levocarnitine compositions of the present invention, levocarnitine compositions and the sodium chloride solution of 0.9%
Compatible solution, levocarnitine compositions and the glucose injection of 5%, particle diameter >=10 μm, grain in 0～8h solution
The insoluble number of particles situation of change of footpath >=25 μm.
Table 5,0～8h particulate matter situation of change (/ml)
2010 editions " Chinese Pharmacopoeia " specifies, in every 1ml injection, to must not exceed 25 containing 10 μm and above microgranule
Grain, must not exceed 3 containing 25 μm and above microgranule.The levocarnitine that as can be seen from Table 5 prepared by the present invention
Compositions, levocarnitine compositions with 0.9% sodium chloride solution compatible solution, levocarnitine compositions and 5%
The glucose injection insoluble particle in 8h all meets the requirements.
This test has all carried out above-mentioned test to the multiple levocarnitine compositions of preparation in invention, and experimental result all accords with
The regulation of 2010 editions " Chinese Pharmacopoeias ".
Claims (8)
1. the compositions of a levocarnitine, it is characterised in that the composition of described compositions is as follows:
Compositions the most according to claim 1, it is characterised in that the composition of described compositions is as follows:
Compositions the most according to claim 1, it is characterised in that the composition of described compositions is as follows:
4. the preparation method of the compositions described in a claim 1-3 any one, it is characterised in that described preparation
Method comprises the steps:
1) weigh levocarnitine, Ovum Gallus domesticus Flavus lecithin, resveratrol according to described consumption, add water for injection, dissolve；
2) adding pH adjusting agent, regulation pH is to acid, and water for injection adds to full dose；
3) add activated carbon decolorizing, filter, embedding, sterilizing,.
Preparation method the most according to claim 4, it is characterised in that described step 2) regulation acidity be 4.8～5.9.
Preparation method the most according to claim 4, it is characterised in that step 3) described in sterilizing be at 100 DEG C
In steam, sterilization time 10～30min.
7. according to the preparation method described in any one of claim 4-6, it is characterised in that step 1) described in injection
It it is 38 DEG C～40 DEG C by the temperature of water.
8. according to the preparation method described in any one of claim 4-7, it is characterised in that step 3) described in embedding
Carry out under nitrogen protection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109431991A (en) * | 2018-12-21 | 2019-03-08 | 江西润泽药业有限公司 | The Levocarnitine Injection determined and preparation method thereof that a kind of stability is high and toxic byproduct production quantity is small |
| CN116602915A (en) * | 2023-03-22 | 2023-08-18 | 哈尔滨誉衡制药有限公司 | Levocarnitine injection and preparation method thereof |
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