CN102442918B - Stable levocarnitine compound - Google Patents
Stable levocarnitine compound Download PDFInfo
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- CN102442918B CN102442918B CN201110343682.2A CN201110343682A CN102442918B CN 102442918 B CN102442918 B CN 102442918B CN 201110343682 A CN201110343682 A CN 201110343682A CN 102442918 B CN102442918 B CN 102442918B
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Abstract
The invention specifically relates to a levocarnitine sesquihydrate, which belongs to the technical field of medicines. The levocarnitine sesquihydrate obtained in the invention contains one and a half crystal water and has the advantages of a high purity and good stability, having non-obvious moisture absorption and weight gain even under the condition of high humidity. The invention also relates to application of the levocarnitine sesquihydrate in preventing and mitigating myocardial damage, in mitigating and alleviating symptoms of chest pain, in treating coronary heart disease, angina pectoris, heart failure, myocardial infarction and cerebral infarction, in auxiliary treatment of renal disease, chronic pulmonary heart disease, male sterility, acquired immune deficiency syndrome, intermittent claudication, as well as acute and chronic hepatitis, cirrhosis, chronic hepatic insufficiency, muscular atrophy, diabetes and bad postpartum uterus contraction, etc.
Description
Technical field
The invention belongs to medical technical field, be specifically related to levocarnitine hydrate and preparation method thereof, the invention still further relates to and use this hydrate prevention and alleviate myocardial damage, alleviate and alleviate pectoralgia symptom, treatment coronary heart disease, stenocardia, in heart failure, myocardial infarction, cerebral infarction, to kidney disease, chronic pulmonary heart disease, masculine sterility, acquired immune deficiency syndrome (AIDS), intermittent claudications etc. also have good therapeutic action, and acute, chronic hepatitis, liver cirrhosis, chronic hepatic insufficiency, amyotrophy, diabetes, bad assisting therapy of uterine contraction in postpartum etc.
Background technology
Vitamin BT (carnitine) was found first by two Russian scientists in 1905 in muscle extract, its molecular structural formula is 3-hydroxyl-4-nitrogen-front three aminobutyric acid, have left-handed and two kinds of existence forms of dextrorotation, but only levo form has to the useful physiological action of human body or pharmacological action.Levo form, levocarnitine, claims again levo-carnitine (L-carnitine), chemistry is by name: (R)-3-carboxyl-2-hydroxy-n, N, N-trimethylammonium-1-propanaminium hydroxide inner salt, molecular formula: C7H15NO3, structural formula is as follows:
Levocarnitine structural formula
Levocarnitine (levo-carnitine), is a kind of special acid being extensively present in body tissue, is the essential cofactor of fatty acid metabolism, can promote lipid acid through generate energy, closely related with organ, the tissue metabolism of body.The shortage of levocarnitine can cause the various intermediate product accumulation oxypathy of energy supply obstacle and fatty acid metabolism, occurs the symptoms such as myocardium pathology, irregular pulse, organism fatigue.
This product safety coefficient is quite large, and oral LD50 can not do.LD50 and the amino acid similarity of the subcutaneous or abdominal injection of injection liquid, it is not yet seen irreversible lesion report.
1993, the Committee of Experts of united States food and drug administration (FDA) thought that levocarnitine is " generally recognized as safe is nontoxic ".Within 1994, German Ministry of Health regulation carnitine usage quantity is without set upper limit.1996, the 16 national foodstuff additive technical committee for standardization (TCST) of China, allowed to use levocarnitine in beverage, milky-drinks, biscuit, solid beverage, milk powder.At present, existing 22 countries and regions add levocarnitine in infant formula in the world.Levocarnitine, through security for all countries test, proves safe, and unique side effect is exactly transience diarrhoea.Now, levocarnitine has been incorporated into the multi-section pharmacopeia such as American Pharmacopeia, European Pharmacopoeia, in global widespread use.
Clinical application: levocarnitine is a kind of nutritive substance that is similar to vitamins, can prevent and alleviate myocardial damage, alleviates and alleviate pectoralgia symptom is the active drug for the treatment of coronary heart diseases and angina pectoris, heart failure, myocardial infarction, cerebral infarction.To kidney disease (chronic renal failure Anemia, hemodialysis associated hypotension), (AIDS, intermittent claudication etc. also have good therapeutic action for chronic pulmonary heart disease, masculine sterility, acquired immune deficiency syndrome (AIDS), and the bad assisting therapy of acute, chronic hepatitis, liver cirrhosis, chronic hepatic insufficiency, amyotrophy, diabetes, postpartum uterine contraction etc., become a kind of medicine that has important clinical value, had a extensive future.
The less stable of levocarnitine, especially water absorbability is stronger, and affected it and used, thus be made into pharmacy acceptable salt, as sodium salt, hydrochloride, nitrate, tartrate, fumaric acid, mucate etc., but still have certain defect.
The levocarnitine sesquialter hydrate crystal that the present invention obtains on the basis of great many of experiments, has advantages of: purity is high, maximum contaminant is less than 1 ‰; Good stability, even moisture absorption weightening finish is also not obvious under high humidity.
Summary of the invention
One object of the present invention, discloses a kind of levocarnitine times semihydrate.
Another object of the present invention, discloses the preparation method of levocarnitine times semihydrate.
Another object of the present invention, discloses the drug regimen that comprises levocarnitine times semihydrate
Thing.
The invention also discloses levocarnitine times semihydrate as a kind of widespread use that is similar to the nutritive substance of vitamins.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of levocarnitine times semihydrate (shown in formula I),
（Ⅰ）
Karl Fischer method (Karl Fischer method) is in a kind of all kinds of chemical processes of measuring moisture in material, and, the most accurately method the most single-minded to water, has been listed in the standard method of moisture determination in many materials, organic compound especially, reliable results.Through 6 batches of mensuration, the moisture that described invention compound contains is between 14.26%-14.45% (weight percent).In levocarnitine times semihydrate, the theoretical content of water is 14.36%, can assert that invention compound contains a hypocrystalline water.
This levocarnitine sesquialter hydrate crystal, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value are as follows, see Fig. 1.
| Peak number | 2 θ angles (°) measured value | D() measured value | Intensity | I/I 0 |
| 1 | 5.060 | 17.4499 | 2203 | 7 |
| 2 | 5.620 | 15.7123 | 12458 | 37 |
| 3 | 9.340 | 9.4610 | 3274 | 10 |
| 4 | 10.120 | 8.7335 | 3604 | 11 |
| 5 | 11.240 | 7.8656 | 33567 | 100 |
| 6 | 11.920 | 7.4184 | 4001 | 12 |
| 7 | 12.580 | 7.0306 | 2170 | 6 |
| 8 | 13.500 | 6.5535 | 2177 | 6 |
| 9 | 14.500 | 6.1037 | 1780 | 5 |
| 10 | 14.960 | 5.9170 | 6152 | 18 |
| 11 | 15.240 | 5.8090 | 9301 | 28 |
| 12 | 15.980 | 5.5416 | 3207 | 10 |
| 13 | 16.880 | 5.2481 | 11466 | 34 |
| 14 | 17.540 | 5.0521 | 4439 | 13 |
| 15 | 18.120 | 4.8916 | 12096 | 36 |
| 16 | 18.480 | 4.7972 | 4581 | 14 |
| 17 | 18.740 | 4.7312 | 2469 | 7 |
| 18 | 19.500 | 4.5485 | 6628 | 20 |
| 19 | 20.180 | 4.3967 | 1127 | 3 |
| 20 | 20.960 | 4.2348 | 3111 | 9 |
| 21 | 21.640 | 4.1033 | 2152 | 6 |
| 22 | 22.200 | 4.0010 | 18463 | 55 |
| 23 | 22.780 | 3.9004 | 19747 | 59 |
| 24 | 23.260 | 3.8210 | 2257 | 7 |
| 25 | 23.820 | 3.7324 | 5414 | 16 |
| 26 | 24.240 | 3.6687 | 2816 | 8 |
| 27 | 24.480 | 3.6333 | 2370 | 7 |
| 28 | 25.080 | 3.5477 | 5078 | 15 |
| 29 | 25.620 | 3.4741 | 3260 | 10 |
| 30 | 25.860 | 3.4424 | 3702 | 11 |
| 31 | 26.180 | 3.4011 | 2834 | 8 |
| 32 | 26.560 | 3.3533 | 1633 | 5 |
| 33 | 27.220 | 3.2734 | 1247 | 4 |
| 34 | 27.840 | 3.2019 | 1985 | 6 |
| 35 | 28.340 | 3.1466 | 3217 | 10 |
| 36 | 29.560 | 3.0194 | 1714 | 5 |
| 37 | 30.760 | 2.9043 | 4240 | 13 |
| 38 | 31.320 | 2.8537 | 1201 | 4 |
| 39 | 32.020 | 2.7928 | 3263 | 10 |
| 40 | 34.220 | 2.6182 | 1478 | 4 |
| 41 | 35.640 | 2.5170 | 1080 | 3 |
| 42 | 36.720 | 2.4454 | 1666 | 5 |
| 43 | 37.600 | 2.3902 | 1135 | 3 |
| 44 | 39.000 | 2.3076 | 1116 | 3 |
| 45 | 41.420 | 2.1782 | 1980 | 6 |
| 46 | 44.640 | 2.0282 | 1081 | 3 |
| 47 | 45.280 | 2.0010 | 1393 | 4 |
| 48 | 47.880 | 1.8983 | 1301 | 4 |
In the present invention, the mensuration of 2 θ values is used light source, and precision is ± 0.2 °, therefore represents that above-mentioned got value has allowed certain reasonably limit of error, and its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) appendix VI C first method, the fusing point recording is 183.1 ℃-184.6 ℃.
Another object of the present invention, discloses the preparation method of levocarnitine hydrate crystal, by levocarnitine is dissolved in Virahol-acetonitrile-heated in water solution, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that levocarnitine adds in the mixed solution of 4-5 times of (weight or measurement (WM) ratio) Virahol-acetonitrile-water=7-5:3-2:2-1, is heated to 70 ℃-75 ℃, filtered while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hour, crystallization, filter, drying obtains.
Levocarnitine used can obtain easily by commercial sources.
Another object of the present invention, provides the composition that comprises the levocarnitine hydrate that levocarnitine hydrate crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.
The amount of the active ingredient containing in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, 1%～40%(weight that the weight range of active compound is composition).
The present invention also provides levocarnitine hydrate manufacturing treatment myocardial damage, alleviates and alleviate pectoralgia symptom, treatment coronary heart diseases and angina pectoris, heart failure, myocardial infarction, cerebral infarction; Kidney disease, chronic pulmonary heart disease, masculine sterility, acquired immune deficiency syndrome (AIDS), intermittent claudication, and the application in the bad medicine of acute, chronic hepatitis, liver cirrhosis, chronic hepatic insufficiency, amyotrophy, diabetes, postpartum uterine contraction.
stability test
Contriver is studied the chemical stability of crystal formation of the present invention, and investigation condition is high temperature (60 ℃ ± 2 ℃), strong illumination (4500Lx ± 500lx), and (92.5%, RH) investigate index is outward appearance, content and related substance to high humidity.
Result: under high light, high temperature, super-humid conditions from 0-10 days, outward appearance, related substance, content do not change, and illustrates that chemical stability is good, manufacture and the standing storage of applicable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in levocarnitine:
Result: at 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), levocarnitine has moisture absorption weightening finish, to moist lability.
figure of description:
Fig. 1, the X-ray diffractogram of levocarnitine sesquialter hydrate crystal;
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Levocarnitine used in the present invention obtains from commercial channels, purity 99.1% (HPLC normalization method), and its chemical structure, through proton nmr spectra, ultimate analysis confirmation, proves that chemical structure is correct.
The moisture recording by karl Fischer method is 0.42%.
embodiment 1
In the 2000ml reaction flask of stirring, thermometer, condenser is housed, add Virahol-acetonitrile-water (5:3:2) mixed solution of 200 grams of levocarnitines and 1000ml, start stirring, be heated to 70 ℃-75 ℃, treat all molten clear, filtered while hot.Filtrate naturally cools to room temperature, then is incubated 8 hours, and crystallization filters, and through indoor seasoning, obtains 181.6 grams of levocarnitine white crystals, and fusing point is 183.1 ℃-184.6 ℃, content 99.36%, specific optical rotation [а]
20 dfor-31.1(c=1, H
2o).Through karl Fischer method, measure the moisture that contains 14.30% (weight percent).
The X-ray diffractogram of this crystallization is shown in Fig. 1.Instrument model and condition determination: Rigaku D/max 2500 type diffractometers; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°.
Use standard and conventional technology, be combined the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only be illustrated for example, never mean that it limits the scope of the invention by any way.
embodiment 2
The granule that contains levocarnitine times semihydrate
Prescription: 100 grams of levocarnitine times semihydrates, 650 grams of lactose, 80 grams of polyvinylpolypyrrolidone, 50 grams of PEG-4000,88 grams of Vltra tearss, distilled water is appropriate, makes 1000 bags.
Technique: a PEG-4000 and levocarnitine times semihydrate is pulverized jointly, crosses 80 mesh sieves, mixes rear with being packed as granule after distilled water softwood processed, granulation, cryodrying with other material.
embodiment 3
The capsule that contains levocarnitine times semihydrate
Prescription: 50 grams of levocarnitine times semihydrates, propylene glycol 5ml, 200 grams of starch, make 1000.
Technique: by levocarnitine times semihydrate, starch, wetting with 15% aqueous solution of propylene glycol, the granulation of sieving after mixing, 60 ℃ are dry, whole grain, filled capsules.
embodiment 4
The tablet that contains levocarnitine times semihydrate
Prescription: 80 grams of levocarnitine times semihydrates, 210 grams of lactose, 25 grams of PEG-4000,6 grams of Magnesium Stearates, 30 grams of PVP K30s, 33 grams of croscarmellose sodiums, distilled water is appropriate, makes 1000.
Technique: a PEG-4000 and levocarnitine times semihydrate is pulverized jointly, crosses 80 mesh sieves, mixes rear with distilled water softwood processed with other material, 16 mesh sieve particle processed, put in loft drier in 40-45 ℃ dry, the whole grain of 16 mesh sieves, Magnesium Stearate adds in dry particle and mixes, compressing tablet.
Claims (6)
1. levocarnitine compound shown in formula I,
（Ⅰ）
By karl Fischer method, measure the moisture that described levocarnitine compound contains 14.26%-14.45% weight percent;
Described levocarnitine compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and D value,
Relative intensity be greater than 30 be:
Relative intensity be more than or equal to 10 be:
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of levocarnitine compound described in claim 1, by levocarnitine is dissolved in Virahol-acetonitrile-heated in water solution, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that levocarnitine adds in the mixed solution of 4-5 times of weight/volume Virahol-acetonitrile-water=7-5:3-2:2-1, be heated to 70 ℃-75 ℃, filtered while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hour, crystallization, filter, drying obtains.
4. a composition that contains the levocarnitine compound that levocarnitine compound claimed in claim 1 and one or more pharmaceutically acceptable carriers form.
5. the composition of levocarnitine compound claimed in claim 4, is characterized in that said composition is for the preparation of granule, Tablet and Capsula.
6. described in claim 1, pectoralgia symptom is alleviated and alleviated to levocarnitine compound, manufacturing treatment myocardial damage,, treatment coronary heart diseases and angina pectoris, heart failure, myocardial infarction, cerebral infarction; Kidney disease, chronic pulmonary heart disease, masculine sterility, acquired immune deficiency syndrome (AIDS), intermittent claudication, and the application in the bad medicine of acute, chronic hepatitis, liver cirrhosis, chronic hepatic insufficiency, amyotrophy, diabetes, postpartum uterine contraction.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1864673A (en) * | 2005-05-18 | 2006-11-22 | 曾列丹 | A levo-carnitine for injection and preparation method thereof |
| CN101564378A (en) * | 2009-05-19 | 2009-10-28 | 邵爱霞 | Levocarnitine oral solution and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006028068A1 (en) * | 2004-09-08 | 2006-03-16 | Wako Pure Chemical Industries, Ltd. | Methods of purifying l-carnitine |
| CN101875616B (en) * | 2010-06-12 | 2012-11-21 | 胡建荣 | Levocarnitine compound and new preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1864673A (en) * | 2005-05-18 | 2006-11-22 | 曾列丹 | A levo-carnitine for injection and preparation method thereof |
| CN101564378A (en) * | 2009-05-19 | 2009-10-28 | 邵爱霞 | Levocarnitine oral solution and preparation method thereof |
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