CN107823148A - Levo-carnitine for injection freeze drying powder injection and preparation method thereof - Google Patents
Levo-carnitine for injection freeze drying powder injection and preparation method thereof Download PDFInfo
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- CN107823148A CN107823148A CN201711193931.8A CN201711193931A CN107823148A CN 107823148 A CN107823148 A CN 107823148A CN 201711193931 A CN201711193931 A CN 201711193931A CN 107823148 A CN107823148 A CN 107823148A
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- levocarnitine
- injection
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- drug solution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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Abstract
The invention provides a kind of levo-carnitine for injection freeze drying powder injection, and it is formed by levocarnitine drug solution is lyophilized, and the pH of the levocarnitine drug solution is 6.0 6.5, and the levocarnitine drug solution contains per 200mL：The 120g of levocarnitine 80, the 18g of sorbierite 12,8 12g methyl amimoacetic acids of glucose 4 8g, the 15g of vitamine D1 0, appropriate pH adjusting agent, and water surplus.Appropriate auxiliary material is added in the formula of this hair, it is possible to increase using the face shaping and gas porosity of freeze-drying prods of the present invention, and make the surface of product more smooth, while pharmaceutical properties are also more stable, are easy to the storage and transport of medicine.And preparation technology is simple, technical requirements are not high, the production cycle is relatively short, obtained product quality is stably and controllable, is advantageous to store for a long time.
Description
Technical field
The present invention relates to a kind of medicine and preparation method thereof, more particularly to a kind of levo-carnitine for injection freeze drying powder injection and
Its preparation method.
Background technology
Levocarnitine is also known as l-cn, is natural materials inside required in mammalian energy metabolism, its main work(
Can promote lipid metabolism, for various tissue ischemia anoxics, levocarnitine improves histoorgan by increasing energy production
Energy supply.Other functions of levocarnitine include the oxidation of medium long chain fatty acids, the oxidation of fatty acid peroxidase
Effect, to reference to coacetylase and free coenzyme both ratio cushioning effect and from letones, pyruvic acid, amino acid (including
Branched-chain amino acid) in produce energy, remove the toxicity of too high coacetylase, adjust ammonia density in blood.Levocarnitine is applied to Secondary cases
Carntine deficiency, it is mainly used in chronic kidney hypofunction long-term hemodialysis patients because of a series of syndromes, clinical table caused by carnitine shortage
Now such as muscle spasmus etc. in cardiomyopathy, skeletal myopathy, arrhythmia cordis, hyperlipidemia, and low blood pressure and dialysis.
The chemical name of levocarnitine is：(R) -3- carboxyls -2- hydroxy-ns, N, N- trimethyls -1- the third ammonium hydroxide are interior
Salt, it is readily soluble in water or ethanol, it is almost insoluble in acetone or ether, it is readily soluble in formic acid.At present, it is by approval listing
Levocarnitine Injection determined and freeze drying powder injection, if but these preparation standing times it is longer, color can turn to be yellow, by measure find
Be its dextrorotation product increase and easily degrade caused by, therefore listed preparation it is stored, the requirement of lucifuge have very strictly,
Even if dextrorotation product so, can not be still avoided to produce.Because dextrorotation product does not have drug effect substantially, and easily degrade, thus it is logical
Cross preparation technique and suppress conversion of the levocarnitine to dextrorotation product, this is particularly important.
CN101461782A discloses a kind of levocarnitine injection sub-micro emulsion formulation and preparation method, by weight,
Said preparation is made up of following component：Levocarnitine 0.5-1.0 parts, oil for injection 0.5-3.0 parts, emulsifying agent 1.0-5.0 parts, stably
Agent 0.05-1 parts, isotonic regulator 0-9 parts, appropriate pH value regulator, remaining is water for injection.
CN101637450A discloses a kind of levocarnitine liposomes injection, by active component levocarnitine, soybean ovum
Phosphatide, cholesterol, antioxidant and pharmaceutically acceptable carrier composition, the ratio of weight and number of wherein each component are：Levocarnitine 1
Part, soybean lecithin 3-15 parts, cholesterol 0.4-7.5 parts, antioxidant 0.02-1 parts.
CN1864673A discloses a kind of levo-carnitine for injection and preparation method thereof, and the formula composition of the injection is a left side
Carnitine 1000g or 500g；Mannitol 1400g or 700g；1mol/L hydrochloric acid solutions are appropriate；Water for injection add to 10000ml or
Add to 5000ml；Process is：1. weighing mannitol to put in material-compound tank, dissolving of blunging is penetrated in filling；2. into material-compound tank
Levocarnitine is added, stirring is completely dissolved levocarnitine, adds activated carbon, stirring and adsorbing, takes off charcoal, sampling, survey pH value, use
It is 6.0-6.5 that 1mol/L hydrochloric acid solution, which adjusts pH value, adds water for injection, surveys content, determines loading amount；3. with 0.15 μm of miillpore filter
Refined filtration, dispensed after detection solution clarity is qualified；4. freeze-drying：- 45 DEG C -- 40 DEG C of pre-freeze 3-5 hours, -10 DEG C of distillation 7-8
Hour, 10 DEG C of distillation 6-7 hours, last 50 DEG C of re-dries 5 hours；5. tamponade, Zha Gai, packaging, full inspection, storage.
CN101011373A discloses a kind of pharmaceutical composition containing levocarnitine and preparation method thereof, and its active component is
Levocarnitine, the active material in composite formula and corresponding auxiliary material are prepared by mixing into by the means for dissolving, being suspended, emulsifying
Fluid composition, soft capsule or emulsion are further prepared into, enhanced into the penetrating of the active component levocarnitine after human body
Property, the bioavilability for improving active component levocarnitine is high.
Found by retrieving prior art both domestic and external, upper no document produces to the dextrorotation for how avoiding levocarnitine at present
Thing increase proposes solution.
The content of the invention
In view of this, the technical problems to be solved by the invention are, overcome the deficiencies in the prior art, there is provided one
Kind of product quality is stably and controllable and simple levo-carnitine for injection freeze drying powder injection of operating procedure and preparation method thereof.
The first aspect of the invention is to provide a kind of levo-carnitine for injection freeze drying powder injection, and it is by levocarnitine medicine
Solution is lyophilized to be formed, and the pH of the levocarnitine drug solution is 6.0-6.5, and the levocarnitine drug solution contains per 200mL
Have：
Preferably, per 200mL, the levocarnitine drug solution contains：
Wherein, the pH adjusting agent is pharmaceutically acceptable pH adjusting agent, and the present invention is defined not to this, example
Such as, it can be hydrochloric acid, citric acid, tartaric acid, phosphoric acid, maleic acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate etc..
The second aspect of the invention is to provide a kind of preparation method of levo-carnitine for injection freeze drying powder injection, the preparation
Method comprises the following steps：
1. having weighed required component according to the formula in one side of the invention, dissolved simultaneously under the conditions of C level cleanliness factors
Stir；
Wherein, C levels cleanliness factor canonical reference《GMP (is revised) for 2010》In cleanliness factor level
Other standard, wherein the requirement to suspended particles and microorganism mainly has：
Suspended particles maximum allowable number/cubic meter：Static state 352000/2900, dynamic 352000/29000
Microorganism maximum allowable number：Flcating germ 100cfu/ cubic meters, settling bacteria 50cfu/4h, contact (Φ 55mm)
25cfu/ dish.
2. tune pH value range is 6.0-6.5, constant volume；
3. aseptic filtration 2-3 times, collect filtrate；
4. it is filling, freeze.
Preferably, the freeze-drying process is：Filling certified products are placed in cold freeze drying box, -40 DEG C of pre-freeze 2-5 hours, will
Below 30Pa is evacuated in case, sample is progressively warming up to -25 DEG C, and sample temperature is close to shelf temperature after sample water heading line off；
Sample is progressively warming up to 50 DEG C or so, and it is qualified to pressure test to be incubated, and terminates lyophilized.
Preferably, the aseptic filtration is successively by 0.45 μm of filtering and 0.22 μm of aseptic filtration twice.
Beneficial effects of the present invention are：
1st, the sorbierite in inventive formulation is a kind of caffolding agent, is provided the structural support for freeze-dried component, improves medicine
Stability.
2nd, the glucose in inventive formulation plays the function of cryoprotective agent in freezing process, can prevent activearm
Divide and deform, strengthen medicine stability.
3rd, the methyl amimoacetic acid in inventive formulation, bulk skeleton function is played, makes to be easy to dissolve after freezing to form clear and bright solution.
4th, the vitamin D in inventive formulation has antioxidation, improves medicine stability.
In the formula of the present invention, appropriate auxiliary material levocarnitine, sorbierite, glucose, methyl amimoacetic acid, vitamin are added
D etc., each component synergy, it is possible to increase using the face shaping and gas porosity of freeze-drying prods of the present invention, and make product
Surface is more smooth, and exterior quality significantly improves.Medicine stability also significantly improves simultaneously, is easy to the preservation and transport of medicine.
And preparation technology is simple, technical requirements are not high, the production cycle is relatively short, obtained product quality is stably and controllable, favorably
In long-term storage.
Embodiment
With reference to specific embodiment, the present invention is further illustrated, to more fully understand the present invention.
Embodiment 1
1st, prescription
2nd, production technology
Cleaning, the sterilizing of 2.1 control antibiotic glass bottles
Control antibiotic glass bottle is removed through outer packing, incoming to wash between baking bottle, is cleaned through bottle washing machine, compressed air drying,
Sterilized 5 minutes in 350 DEG C of hot air tunnel oven dryings, cooling.
Cleaning, the sterilizing of 2.2 butyl rubbers
Butyl rubber bung is removed through outer packing, incoming to wash between plug, through washing the cleaning of plug machine, in 121 DEG C of moist heat sterilizations 30
Minute, cooling is standby.
The sterilizing of 2.3 aluminium-plastic combined covers
Aluminium-plastic cap is removed through outer packing, is passed between aluminium lid sterilizing, 121 DEG C of hot air sterilizations 30 minutes in drying box, cooling,
It is standby.
2.4 match somebody with somebody liquid
Raw material, auxiliary material are passed to C level clean areas through outer packing dismounting, surface sterilization.Levocarnitine, sweet is weighed by recipe quantity
Reveal alcohol, the tert-butyl alcohol, dextran, sodium chloride, glycine to add in the water for injection of configuration full dose 90%, adding pH under stirring adjusts
Section agent, which is adjusted to PH6.0-6.5, dissolves main ingredient, adds to the full amount of water for injection, and adds 0.03% (w/v) activated carbon, stirs at room temperature
Absorption 15 minutes is mixed, carbon removal, successively degerming with 0.45 μm of miillpore filter and 0.22um filtering with microporous membrane, filtrate are filtered with stud
It is standby.
Wherein, C levels clean area canonical reference《GMP (is revised) for 2010》In C level cleanliness factors
Class criteria, wherein the requirement to suspended particles and microorganism mainly has：
Suspended particles maximum allowable number/cubic meter：Static state 352000/2900,352000/29000 microorganism of dynamic are maximum
Allow to count：Flcating germ 100cfu/ cubic meters, settling bacteria 50cfu/4h, contact (Φ 55mm) 25cfu/ dish.
It is 2.5 filling
Filtrate detection is qualified, canned in 10ml control antibiotic glass bottles, and pressure half is filled in.
2.6 freeze-drying
Filling certified products are placed in cold freeze drying box, -40 DEG C of pre-freeze 2-5 hours, below 30Pa, sample will be evacuated in case
Product are progressively warming up to -25 DEG C, and sample temperature is close to shelf temperature after sample water heading line off；Sample is progressively warming up to 50 DEG C or so,
Insulation is qualified to pressure test, terminates lyophilized.The full plug of pressure.
2.7 by dried frozen aquatic products Zha Gai, lamp inspection, labeling, packaging, and Product checking is qualified, finished product storage.
Embodiment 2
The present embodiment is that prescription is different from the difference of embodiment 1, and the prescription of the present embodiment is as follows：
Embodiment 3
The present embodiment is that prescription is different from the difference of embodiment 1, and the prescription of the present embodiment is as follows：
Study on the stability
By the levocarnitine freeze-dried powder obtained by 1-3 of the embodiment of the present invention and reference substance (take levocarnitine 0.5g, it is sterile
Embedding is in glass tube vial), place under the conditions of 60 DEG C, strong light (4500lx ± 500lx), sampled respectively at the 5th day, 10 days respectively
Calibrating, as a result compared with 0 day, the stability result for investigating sample is shown in Table 1.
Table 1
As seen from the above table, levocarnitine freeze-dried powder of the invention has good stability.
The specific embodiment of the present invention is described in detail above, but it is intended only as example, it is of the invention and unlimited
It is formed on particular embodiments described above.To those skilled in the art, it is any to the equivalent modifications that carry out of the present invention and
Substitute also all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and
Modification, all should be contained within the scope of the invention.
Claims (5)
1. a kind of levo-carnitine for injection freeze drying powder injection, it is characterised in that it is formed by levocarnitine drug solution is lyophilized, should
The pH of levocarnitine drug solution is 6.0-6.5, and the levocarnitine drug solution contains per 200mL：
2. levo-carnitine for injection freeze drying powder injection according to claim 1, it is characterised in that per the 200mL left card Buddhist nuns
Spit of fland drug solution contains：
3. a kind of preparation method of levo-carnitine for injection freeze drying powder injection, it is characterised in that the preparation method includes following step
Suddenly：
1. weighing good required component according to formula in claim 1 or 2, dissolve and stir under the conditions of C level cleanliness factors；
2. tune pH value range is 6.0-6.5, constant volume；
3. aseptic filtration 2-3 times, collect filtrate；
4. it is filling, freeze.
4. preparation method according to claim 3, it is characterised in that the freeze-drying process is：Filling certified products are placed in
In cold freeze drying box, -40 DEG C of pre-freeze 2-5 hours, below 30Pa will be evacuated in case, sample is progressively warming up to -25 DEG C, treats sample
Sample temperature is close to shelf temperature after waterline disappears；Sample is progressively warming up to 50 DEG C or so, and it is qualified to pressure test to be incubated, and terminates to freeze
It is dry.
5. preparation method according to claim 3, it is characterised in that the aseptic filtration for successively by one time 0.45 μm
Filtering and 0.22 μm of aseptic filtration twice.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711193931.8A CN107823148A (en) | 2017-11-24 | 2017-11-24 | Levo-carnitine for injection freeze drying powder injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711193931.8A CN107823148A (en) | 2017-11-24 | 2017-11-24 | Levo-carnitine for injection freeze drying powder injection and preparation method thereof |
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| CN107823148A true CN107823148A (en) | 2018-03-23 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117503609A (en) * | 2024-01-05 | 2024-02-06 | 康贝音生物医药科技(海南)有限公司 | Preparation process of levocarnitine for injection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103622922A (en) * | 2013-11-27 | 2014-03-12 | 海南通用康力制药有限公司 | Preparation method of levocarnitine freeze-dried powder for injection |
-
2017
- 2017-11-24 CN CN201711193931.8A patent/CN107823148A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103622922A (en) * | 2013-11-27 | 2014-03-12 | 海南通用康力制药有限公司 | Preparation method of levocarnitine freeze-dried powder for injection |
Non-Patent Citations (1)
| Title |
|---|
| 傅超美等主编: "《药用辅料学》", 31 October 2008, 中国中医药出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117503609A (en) * | 2024-01-05 | 2024-02-06 | 康贝音生物医药科技(海南)有限公司 | Preparation process of levocarnitine for injection |
| CN117503609B (en) * | 2024-01-05 | 2024-04-16 | 康贝音生物医药科技(海南)有限公司 | Preparation process of levocarnitine for injection |
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