WO2011152657A2 - Acetyl-l-carnitine malate, process for preparing the same, and pharmaceutical composition comprising the same - Google Patents

Acetyl-l-carnitine malate, process for preparing the same, and pharmaceutical composition comprising the same Download PDF

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WO2011152657A2
WO2011152657A2 PCT/KR2011/004002 KR2011004002W WO2011152657A2 WO 2011152657 A2 WO2011152657 A2 WO 2011152657A2 KR 2011004002 W KR2011004002 W KR 2011004002W WO 2011152657 A2 WO2011152657 A2 WO 2011152657A2
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acetyl
carnitine
malate
pharmaceutical composition
inner salt
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French (fr)
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WO2011152657A3 (en
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Kyoung Soo Kim
Young Jun Park
Hyun-Nam Song
Dong Youn Kim
Joon Woo Kim
Kyoung-Suk Cho
Keewon Yu
Hyuk Jin Kwon
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Celltrion Chemical Research Institute
Celltrion Pharm, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups

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  • the present invention relates to acetyl-L-carnitine malate, a process for preparing the same, and a pharmaceutical composition comprising the same. More particularly, the present invention relates to acetyl-L-carnitine malate having good stability against heat and moisture, high water-solubility, and non-hygroscopicity, a process for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient.
  • Acetyl-L-carnitine is an endogenous mitochondrial inner membrane compound, the acetylated ester of L-carnitine, and superior to L-carnitine in terms of bioavailability.
  • the exact mechanisms of action of acetyl-L-carnitine are unknown, but it is reported that acetyl-L-carnitine acts as a precursor to acetyl coenzyme A and cholinergic enhancer in the mitochondria.
  • Acetyl-L-carnitine has been shown to be neuroprotective in in vitro and animal studies and to increase cerebral blood flow in patients with cerebrovascular disease. Therefore, acetyl-L-carnitine is used for treating primary degenerative disease or secondary degenerative disease due to cerebrovascular disease, and is represented by the following formula (II).
  • acetyl-L-carnitine is used in various diseases such as Alzheimer's disease, dysthymia, attention deficit hyperactivity disorder (fragile syndrome), male infertility, multiple sclerosis, neuropathy, peripheral nerve and facial nerve paralysis, and Peyronie's disease.
  • Acetyl-L-carnitine is usually prepared in the form of acetyl-L-carnitine chloride of the following formula (IV) by reacting L-carnitine chloride of the following formula (III) with acetyl chloride according to the known process as shown in the following Reaction Scheme 1.
  • the acetyl-L-carnitine chloride has very high hygroscopicity, it causes many difficulties in the processes of storing the compound, formulating it, and packaging and storing the finished product.
  • the finished product is packaged in a blister pack to block out moisture, it deteriorates even under normal moisture conditions.
  • Acetyl-L-carnitine inner salt of formula (II), desalted form of acetyl-L-carnitine chloride, has low stability as well as very high hygroscopicity. Thus, it is more difficult to use it for preparing a drug.
  • desalting with an anionic exchange resin is necessary as described in US Patent No. 6,693,215, which is incorporated in its entirety here by reference.
  • the desalting with an anionic exchange resin requires complicated processes, and the acetyl-L-carnitine inner salt is obtained in aqueous solution, which has to be solidified through further processes such as lyophilization.
  • L-carnitine is produced as a side-product during the desalting, it is very difficult to control the quality of the finished product.
  • acetyl-L-carnitine is in the form of inner salt or unstable acid addition salts, it decomposes more rapidly to release triethylamine.
  • US Patent No. 4,602,039 which is incorporated in its entirety here by reference, discloses acetyl-L-carnitine inner salt, aspartate, citrate, phosphate, fumarate, lactate, maleate, oxalate, sulfurate, and orotate.
  • US Patent No. 5,952,379 which is incorporated in its entirety here by reference, teaches acetyl-L-carnitine mucate of the following formular (V), which is the most commonly used besides the acetyl-L-carnitine chloride.
  • the present inventors have researched to develop a novel acid addition salt of acetyl-L-carnitine which has good formulation properties such as stability against heat and moisture and non-hygroscopicity, and found that acetyl-L-carnitine malate has good moisture and thermal stability, very low hygroscopicity, and high water-solubility.
  • An object of the present invention is, therefore, to provide acetyl-L-carnitine malate having superior stability, non-hygroscopicity, and high water-solubility.
  • Another object of the present invention is to provide a process for preparing the acetyl-L-carnitine malate.
  • Further object of the present invention is to provide a pharmaceutical composition comprising the acetyl-L-carnitine malate as an active ingredient.
  • the present invention relates to acetyl-L-carnitine malate of the following formula (I).
  • the acetyl-L-carnitine malate according to one embodiment of the present invention is particularly a crystalline acetyl-L-carnitine malate, more particularly, a crystalline acetyl-L-carnitine malate showing an X-ray powder diffraction (XRPD) pattern characterized by peaks having I/I o values of at least 10% (I is the intensity of each peak; I o is the intensity of the highest peak) at diffraction angles (2 ⁇ ) of 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 15.1 ⁇ 0.2, 15.5 ⁇ 0.2, 16.3 ⁇ 0.2, 18.0 ⁇ 0.2, 18.2 ⁇ 0.2, 19.2 ⁇ 0.2, 20.7 ⁇ 0.2, 20.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, 23.3 ⁇ 0.2, 23.8 ⁇ 0.2, 24.4 ⁇ 0.2 24.7 ⁇ 0.2, 25.1 ⁇ 0.2, 25.7 ⁇ 0.2, 26.3 ⁇ 0.2, 27.8 ⁇ 0.2, 28.4 ⁇ 0.2, 30.2 ⁇ 0.2, 30.6 ⁇ 0.2, 31.0 ⁇ 0.2, 32.6
  • the acetyl-L-carnitine malate according to the present invention has overcome the problem of high hygroscopicity that the known inner salt and acid addition salts of acetyl-L-carnitine have, and contains malic acid, one of the safest organic acids to have pharmaceutically favorable advantages.
  • the malic acid used in the present invention is very safe since it has a LD 50 (lethal dose causing death in 50% of rats on oral administration) of 4730 mg/kg ( see Handbook of Pharmaceutical Salts , p293 (2008), which is incorporated in its entirety here by reference), and has a relatively low molecular weight of 134.09 g/mol to be favorably used to give an acid addition salt.
  • the acetyl-L-carnitine malate according to the present invention has superior stability against heat and moisture and high water-solubility at a wide pH range including stomach, intestine and blood pH conditions to be used as a biologically active substance in various fields.
  • the present invention further relates to a process for preparing the acetyl-L-carnitine malate, which comprises the steps of:
  • the acetyl-L-carnitine inner salt of the above formula (II) is prepared as a white solid by reacting acetyl-L-carnitine chloride of the above formula (IV) with trialkylamine in an organic solvent to desalt the acetyl-L-carnitine chloride. If necessary, the acetyl-L-carnitine inner salt can be recrystallized to give a crystalline acetyl-L-carnitine inner salt with higher purity.
  • the organic solvent may include one or more selected from alcohols such as methanol, ethanol, isopropanol, 1-butanol and 1-hexanol; and chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane.
  • the organic solvent may be a mixed solvent of ethanol and dichloromethane, for example, in the volume ratio of 1:10 to 1:40.
  • the trialkylamine may include one or more selected from triethylamine, N,N-diethylmethylamine, N,N-diisopropylethylamine, and 1-methylpyrrolidine.
  • the trialkylamine may be particularly triethylamine, and used in the amount of 2 to 5 equivalents, particularly 3 to 4 equivalents, based on the acetyl-L-carnitine chloride of the above formula (IV).
  • the reaction temperature may be 20 to 30 °C
  • the reaction time may be 3 to 24 hours, particularly 5 to 10 hours.
  • the acetyl-L-carnitine inner salt of the above formula (II) prepared as a white solid may be filtered, washed, and dried under reduced pressure. Further, the filtered white solid may be recrystallized, if necessary, to give a crystalline acetyl-L-carnitine inner salt with higher purity.
  • Step 2 Prepartion of acetyl-L-carnitine malate
  • the acetyl-L-carnitine malate is prepared by reacting the acetyl-L-carnitine inner salt of the above formula (II) with malic acid of the above formula (VI) in an organic solvent.
  • the acetyl-L-carnitine malate can be recrystallized to give a crystalline acetyl-L-carnitine malate.
  • the present process may further optionally include the step of:
  • the malic acid may be used in the amount of about 1 equivalent based on the acetyl-L-carnitine inner salt.
  • the organic solvent may include one or more selected from alcohols such as methanol, ethanol, isopropanol, 1-butanol and 1-hexanol.
  • the precipitating solvent may include one or more selected from alcohols such as ethanol, isopropanol, 1-butanol and 1-hexanol; ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and isopropyl acetate; and chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane.
  • alcohols such as ethanol, isopropanol, 1-butanol and 1-hexanol
  • ethers such as tetrahydrofuran and dioxane
  • nitriles such as acetonitrile
  • ketones such as acetone and 2-butanone
  • esters such as ethyl acetate and isopropyl acetate
  • chlorinated hydrocarbons such as dichloromethane, chlor
  • the reaction time may be 30 minutes to 3 hours, and the reaction temperature may be 20 to 60 °C.
  • the process for preparing the acetyl-L-carnitine malate may further include washing and drying the solid obtained after filtering.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the acetyl-L-carnitine malate together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be used for treating or preventing primary degenerative disease, secondary degenerative disease due to cerebrovascular disease, Alzheimer's disease, dysthymia, attention deficit hyperactivity disorder (fragile syndrome), male infertility, multiple sclerosis, neuropathy, peripheral nerve or facial nerve paralysis, or Peyronie's disease.
  • the pharmaceutical composition of the present invention may optionally include biologically active substances, in addition to the acetyl-L-carnitine malate.
  • the pharmaceutical composition according to the present invention can be formulated as tablets, capsules, granules, powders, emulsions, suspensions, syrups, etc.
  • the above various forms of the pharmaceutical composition can be prepared in a manner well known in the art using a pharmaceutically acceptable carrier(s) which are usually used for each form.
  • the pharmaceutically acceptable carriers include excipient, filler, extender, binder, disintegrator, lubricant, preservative, antioxidant, isotonic agent, buffer, coating agent, sweetening agent, dissolvent, base, dispersing agent, wetting agent, suspending agent, stabilizer, colorant, flavoring agent, etc.
  • the pharmaceutical composition of the present invention may contain 10 to 90 wt%, particularly 20 to 70 wt% of the inventive acetyl-L-carnitine malate depending on the form thereof.
  • the particular dosage of the pharmaceutical composition can be varied with species of mammals including a human-being, administration route, body weight, gender, age, severity of disease, judgment of doctor, etc.
  • administration route for example, 1 to 50 mg of the active ingredient is administered per kg of body weight a day for oral use.
  • the total daily dosage can be administered once or over several times depending on the severity of disease, judgment of doctor, etc.
  • the acetyl-L-carnitine malate of the present invention has good moisture and thermal stability, high water-solubility, and much lower hygroscopicity as compared with the known acid addition salts of acetyl-L-carnitine.
  • the acetyl-L-carnitine malate can be effectively used for preparing a pharmaceutical composition.
  • the acetyl-L-carnitine inner salt containing no moisture can be easily and simply prepared with high purity by reacting the acetyl-L-carnitine chloride with trialkylamine in an organic solvent to desalt the acetyl-L-carnitine chloride, as compared with the known process desalting the acetyl-L-carnitine chloride with an anionic exchange resin, and the acetyl-L-carnitine malate can be prepared with high yield by reacting the obtained acetyl-L-carnitine inner salt with malic acid.
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the crystalline acetyl-L-carnitine malate obtained in Example 2.
  • XRPD X-ray powder diffraction
  • Fig. 2 is a differential scanning calorimeter (DSC) thermogram of the crystalline acetyl-L-carnitine malate obtained in Example 2.
  • the white solid formed was filtered and washed with 500 ml of dichloromethane.
  • the filtered white solid was dissolved in 70 ml of ethanol and 1050 ml of acetone was added thereto, followed by stirring at 0 to 5 °C for 1 hour.
  • the resulting white solid was filtered, washed with 500 ml of cooled acetone, and dried under vacuum at 40 °C for 24 hours to give 56.72 g of white crystalline acetyl-L-carnitine inner salt.
  • the yield was 66.89%, the purity was 99.3% or more (HPLC analysis), and the content of a side-product, L-carnitine was 0.1%.
  • the white crystals formed was filtered, washed with 10 ml of cooled ethanol, and dried under vacuum at 40 °C for 24 hours to give 16.11 g of white crystalline acetyl-L-carnitine malate. The yield was 95.51%.
  • the obtained crystalline acetyl-L-carnitine malate was subjected to X-ray powder diffraction (XRPD) and differential scanning calorimeter (DSC) analyses, and the results are shown in Figs. 1 and 2, respectively.
  • the white crystals formed was filtered, washed with 30 ml of cooled 2-butanone, and dried under vacuum at 40 °C for 24 hours to give 22.05 g of white crystalline acetyl-L-carnitine malate. The yield was 93.38%.
  • the white crystals formed was filtered, washed with 20 ml of cooled acetone, and dried under vacuum at 40 °C for 24 hours to give 19.23 g of white crystalline acetyl-L-carnitine malate. The yield was 81.44%.
  • Acetyl-L-carnitine mucate was prepared as follows in accordance with the process described in U.S. Patent No. 5,952,379, which is incorporated in its entirety here by reference.
  • the crystals formed was filtered, washed with 100 ml of acetone, and dried under vacuum at 40 °C for 24 hours to give 14.50 g of white crystalline acetyl-L-carnitine mucate. The yield was 94.08%.
  • the crystalline acetyl-L-carnitine malate obtained in Example 2 has distinctively characteristic peaks in the X-ray powder diffraction (XRPD) pattern.
  • the observed characteristic peaks shown in the XRPD pattern of Fig. 1 are listed in Table 1, wherein ‘2 ⁇ ’ is diffraction angle, ‘d’ is interplanar spacing, and 'I/I 0 ' is relative intensity of the peak.
  • the hygroscopicity of the acetyl-L-carnitine malate obtained in Example 2 was compared with those of the known acetyl-L-carnitine chloride (Edengene Chemical Ltd, China) and acetyl-L-carnitine mucate.
  • Each compound was exposed to the condition of a temperature of 40 °C and a relative humidity of 75 % for 2 hours, 8 hours, 24 hours and 3 days, and then the amount of moisture contained in the compound was measured with Karl-Fischer titrator.
  • the percentage amounts (weight %) of moisture contained in the active ingredients are listed in Table 2.
  • the acetyl-L-carnitine malate showed superior non-hygroscopicity even when exposed to the high humidity condition, as compared with the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate. Such a result suggests that the acetyl-L-carnitine malate of the present invention has good moisture stability to be effectively used for preparing a pharmaceutical composition without any problems in the processes of storing the compound, formulating it, and packaging and storing the finished product.
  • the moisture and thermal stability of an active ingredient in a pharmaceutical composition is an important factor on the perspective of the production process and long-term storage of the pharmaceutical composition.
  • the moisture and thermal stability of the acetyl-L-carnitine malate obtained in Example 2 was measured and compared with those of the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate.
  • each acetyl-L-carnitine acid addition salt was stored in a sealed state under an accelerated condition (a temperature of 40 °C and a relative humidity of 75 %), and after 0 (zero), 3, 7, 14 and 28 days, the remaining rate of the active ingredient was analyzed with high performance liquid chromatography (HPLC). The results are listed in Table 3.
  • the acetyl-L-carnitine malate showed the same or higher level of stability when exposed to the accelerated condition for 28 days, as compared with the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate. Such a result suggests that the acetyl-L-carnitine malate of the present invention has good chemical stability to be effectively used for preparing a pharmaceutical composition.
  • the water-solubility of an active ingredient in a pharmaceutical composition has effects on the dissolution rate and bioavailability of the pharmaceutical composition.
  • the solubility of the acetyl-L-carnitine malate obtained in Example 2 was measured and compared with those of the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate.
  • the solubility measurement was performed at a pH range for in vivo uptake, that is, at the stomach pH value of 1.2, the intestine pH value of 4.0 and the blood pH value of 6.8.
  • a pH range for in vivo uptake that is, at the stomach pH value of 1.2, the intestine pH value of 4.0 and the blood pH value of 6.8.
  • Each acetyl-L-carnitine acid addition salt was dissolved to saturation, the saturated solutions were analyzed with high performance liquid chromatography (HPLC), and the dissolved amounts were measured based on free acetyl-L-carnitine.
  • HPLC high performance liquid chromatography
  • the acetyl-L-carnitine malate showed good solubility at all pH values. Particularly, the solubility of the acetyl-L-carnitine malate was not as good as acetyl-L-carnitine chloride but sufficient to be used for a medicament, and much superior to the known acetyl-L-carnitine mucate.

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Abstract

The present invention relates to acetyl-L-carnitine malate, a process for preparing the same, and a pharmaceutical composition comprising the same. The acetyl-L-carnitine malate of the present invention has good stability, solubility, and non-hygroscopicity to be effectively used for preparing a pharmaceutical composition.

Description

ACETYL-L-CARNITINE MALATE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
The present invention relates to acetyl-L-carnitine malate, a process for preparing the same, and a pharmaceutical composition comprising the same. More particularly, the present invention relates to acetyl-L-carnitine malate having good stability against heat and moisture, high water-solubility, and non-hygroscopicity, a process for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient.
Acetyl-L-carnitine is an endogenous mitochondrial inner membrane compound, the acetylated ester of L-carnitine, and superior to L-carnitine in terms of bioavailability. The exact mechanisms of action of acetyl-L-carnitine are unknown, but it is reported that acetyl-L-carnitine acts as a precursor to acetyl coenzyme A and cholinergic enhancer in the mitochondria.
Acetyl-L-carnitine has been shown to be neuroprotective in in vitro and animal studies and to increase cerebral blood flow in patients with cerebrovascular disease. Therefore, acetyl-L-carnitine is used for treating primary degenerative disease or secondary degenerative disease due to cerebrovascular disease, and is represented by the following formula (II).
Figure PCTKR2011004002-appb-I000001
Also, acetyl-L-carnitine is used in various diseases such as Alzheimer's disease, dysthymia, attention deficit hyperactivity disorder (fragile syndrome), male infertility, multiple sclerosis, neuropathy, peripheral nerve and facial nerve paralysis, and Peyronie's disease.
Acetyl-L-carnitine is usually prepared in the form of acetyl-L-carnitine chloride of the following formula (IV) by reacting L-carnitine chloride of the following formula (III) with acetyl chloride according to the known process as shown in the following Reaction Scheme 1.
[Reaction Scheme 1]
Figure PCTKR2011004002-appb-I000002
However, since the acetyl-L-carnitine chloride has very high hygroscopicity, it causes many difficulties in the processes of storing the compound, formulating it, and packaging and storing the finished product. In particular, although the finished product is packaged in a blister pack to block out moisture, it deteriorates even under normal moisture conditions.
Acetyl-L-carnitine inner salt of formula (II), desalted form of acetyl-L-carnitine chloride, has low stability as well as very high hygroscopicity. Thus, it is more difficult to use it for preparing a drug. Moreover, to prepare the acetyl-L-carnitine inner salt, desalting with an anionic exchange resin is necessary as described in US Patent No. 6,693,215, which is incorporated in its entirety here by reference. However, the desalting with an anionic exchange resin requires complicated processes, and the acetyl-L-carnitine inner salt is obtained in aqueous solution, which has to be solidified through further processes such as lyophilization. Furthermore, since L-carnitine is produced as a side-product during the desalting, it is very difficult to control the quality of the finished product.
Also, if acetyl-L-carnitine is in the form of inner salt or unstable acid addition salts, it decomposes more rapidly to release triethylamine.
Therefore, many studies have been carried out to develop a novel acid addition salt of acetyl-L-carnitine to overcome the hygroscopicity and unstability of acetyl-L-carnitine inner salt and chloride.
US Patent No. 4,602,039, which is incorporated in its entirety here by reference, discloses acetyl-L-carnitine inner salt, aspartate, citrate, phosphate, fumarate, lactate, maleate, oxalate, sulfurate, and orotate. Also, US Patent No. 5,952,379, which is incorporated in its entirety here by reference, teaches acetyl-L-carnitine mucate of the following formular (V), which is the most commonly used besides the acetyl-L-carnitine chloride.
Figure PCTKR2011004002-appb-I000003
However, the known acid addition salts of acetyl-L-carnitine also have problems of inferior physiochemical properties such as unstability and hygroscopicity.
The present inventors have researched to develop a novel acid addition salt of acetyl-L-carnitine which has good formulation properties such as stability against heat and moisture and non-hygroscopicity, and found that acetyl-L-carnitine malate has good moisture and thermal stability, very low hygroscopicity, and high water-solubility.
An object of the present invention is, therefore, to provide acetyl-L-carnitine malate having superior stability, non-hygroscopicity, and high water-solubility.
Another object of the present invention is to provide a process for preparing the acetyl-L-carnitine malate.
Further object of the present invention is to provide a pharmaceutical composition comprising the acetyl-L-carnitine malate as an active ingredient.
The present invention relates to acetyl-L-carnitine malate of the following formula (I).
Figure PCTKR2011004002-appb-I000004
The acetyl-L-carnitine malate according to one embodiment of the present invention is particularly a crystalline acetyl-L-carnitine malate, more particularly, a crystalline acetyl-L-carnitine malate showing an X-ray powder diffraction (XRPD) pattern characterized by peaks having I/Io values of at least 10% (I is the intensity of each peak; Io is the intensity of the highest peak) at diffraction angles (2θ) of 11.9±0.2, 12.4±0.2, 13.2±0.2, 15.1±0.2, 15.5±0.2, 16.3±0.2, 18.0±0.2, 18.2±0.2, 19.2±0.2, 20.7±0.2, 20.9±0.2, 22.6±0.2, 23.0±0.2, 23.3±0.2, 23.8±0.2, 24.4±0.2 24.7±0.2, 25.1±0.2, 25.7±0.2, 26.3±0.2, 27.8±0.2, 28.4±0.2, 30.2±0.2, 30.6±0.2, 31.0±0.2, 32.6±0.2, 34.1±0.2, 35.8±0.2, 36.3±0.2, 37.2±0.2, 37.6±0.2, and 38.1±0.2.
The acetyl-L-carnitine malate according to the present invention has overcome the problem of high hygroscopicity that the known inner salt and acid addition salts of acetyl-L-carnitine have, and contains malic acid, one of the safest organic acids to have pharmaceutically favorable advantages. The malic acid used in the present invention is very safe since it has a LD50 (lethal dose causing death in 50% of rats on oral administration) of 4730 mg/kg (see Handbook of Pharmaceutical Salts, p293 (2008), which is incorporated in its entirety here by reference), and has a relatively low molecular weight of 134.09 g/mol to be favorably used to give an acid addition salt.
Also, the acetyl-L-carnitine malate according to the present invention has superior stability against heat and moisture and high water-solubility at a wide pH range including stomach, intestine and blood pH conditions to be used as a biologically active substance in various fields.
The present invention further relates to a process for preparing the acetyl-L-carnitine malate, which comprises the steps of:
(i) desalting acetyl-L-carnitine chloride of the following formula (IV) by reacting it with trialkylamine in an organic solvent to give acetyl-L-carnitine inner salt of the following formula (II); and
(ii) reacting the acetyl-L-carnitine inner salt with malic acid of the following formula (VI) in an organic solvent.
Figure PCTKR2011004002-appb-I000005
Figure PCTKR2011004002-appb-I000006
Figure PCTKR2011004002-appb-I000007
The process for preparing the acetyl-L-carnitine malate of the present invention is described in more detail below.
Step 1: Prepartion of acetyl-L-carnitine inner salt
The acetyl-L-carnitine inner salt of the above formula (II) is prepared as a white solid by reacting acetyl-L-carnitine chloride of the above formula (IV) with trialkylamine in an organic solvent to desalt the acetyl-L-carnitine chloride. If necessary, the acetyl-L-carnitine inner salt can be recrystallized to give a crystalline acetyl-L-carnitine inner salt with higher purity.
In one embodiment, the organic solvent may include one or more selected from alcohols such as methanol, ethanol, isopropanol, 1-butanol and 1-hexanol; and chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane. Particularly, the organic solvent may be a mixed solvent of ethanol and dichloromethane, for example, in the volume ratio of 1:10 to 1:40.
In one embodiment, the trialkylamine may include one or more selected from triethylamine, N,N-diethylmethylamine, N,N-diisopropylethylamine, and 1-methylpyrrolidine. The trialkylamine may be particularly triethylamine, and used in the amount of 2 to 5 equivalents, particularly 3 to 4 equivalents, based on the acetyl-L-carnitine chloride of the above formula (IV).
In one embodiment, the reaction temperature may be 20 to 30 ℃, and the reaction time may be 3 to 24 hours, particularly 5 to 10 hours.
The acetyl-L-carnitine inner salt of the above formula (II) prepared as a white solid may be filtered, washed, and dried under reduced pressure. Further, the filtered white solid may be recrystallized, if necessary, to give a crystalline acetyl-L-carnitine inner salt with higher purity.
Step 2: Prepartion of acetyl-L-carnitine malate
The acetyl-L-carnitine malate is prepared by reacting the acetyl-L-carnitine inner salt of the above formula (II) with malic acid of the above formula (VI) in an organic solvent.
If necessary, the acetyl-L-carnitine malate can be recrystallized to give a crystalline acetyl-L-carnitine malate. In one embodiment, the present process may further optionally include the step of:
(a) evaporating the reaction solution under reduced pressure, and adding a precipitating solvent to the obtained residue with stirring, followed by filtering the solid formed;
(b) lowering the temperature of the reaction solution with stirring, followed by filtering the solid formed; or
(c) adding a precipitating solvent to the reaction solution with stirring, followed by filtering the solid formed.
In one embodiment, the malic acid may be used in the amount of about 1 equivalent based on the acetyl-L-carnitine inner salt.
In one embodiment, the organic solvent may include one or more selected from alcohols such as methanol, ethanol, isopropanol, 1-butanol and 1-hexanol.
In one embodiment, the precipitating solvent may include one or more selected from alcohols such as ethanol, isopropanol, 1-butanol and 1-hexanol; ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and isopropyl acetate; and chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane.
In one embodiment, the reaction time may be 30 minutes to 3 hours, and the reaction temperature may be 20 to 60 ℃.
In one embodiment, the process for preparing the acetyl-L-carnitine malate may further include washing and drying the solid obtained after filtering.
The present invention further relates to a pharmaceutical composition comprising the acetyl-L-carnitine malate together with a pharmaceutically acceptable carrier. In particular, the pharmaceutical composition of the present invention can be used for treating or preventing primary degenerative disease, secondary degenerative disease due to cerebrovascular disease, Alzheimer's disease, dysthymia, attention deficit hyperactivity disorder (fragile syndrome), male infertility, multiple sclerosis, neuropathy, peripheral nerve or facial nerve paralysis, or Peyronie's disease.
In one embodiment, the pharmaceutical composition of the present invention may optionally include biologically active substances, in addition to the acetyl-L-carnitine malate.
The pharmaceutical composition according to the present invention can be formulated as tablets, capsules, granules, powders, emulsions, suspensions, syrups, etc. The above various forms of the pharmaceutical composition can be prepared in a manner well known in the art using a pharmaceutically acceptable carrier(s) which are usually used for each form. Examples of the pharmaceutically acceptable carriers include excipient, filler, extender, binder, disintegrator, lubricant, preservative, antioxidant, isotonic agent, buffer, coating agent, sweetening agent, dissolvent, base, dispersing agent, wetting agent, suspending agent, stabilizer, colorant, flavoring agent, etc.
In one embodiment, the pharmaceutical composition of the present invention may contain 10 to 90 wt%, particularly 20 to 70 wt% of the inventive acetyl-L-carnitine malate depending on the form thereof.
The particular dosage of the pharmaceutical composition can be varied with species of mammals including a human-being, administration route, body weight, gender, age, severity of disease, judgment of doctor, etc. By way of example, 1 to 50 mg of the active ingredient is administered per kg of body weight a day for oral use. The total daily dosage can be administered once or over several times depending on the severity of disease, judgment of doctor, etc.
The acetyl-L-carnitine malate of the present invention has good moisture and thermal stability, high water-solubility, and much lower hygroscopicity as compared with the known acid addition salts of acetyl-L-carnitine. Thus, the acetyl-L-carnitine malate can be effectively used for preparing a pharmaceutical composition.
Also, according to the process for preparing the acetyl-L-carnitine malate of the present invention, the acetyl-L-carnitine inner salt containing no moisture can be easily and simply prepared with high purity by reacting the acetyl-L-carnitine chloride with trialkylamine in an organic solvent to desalt the acetyl-L-carnitine chloride, as compared with the known process desalting the acetyl-L-carnitine chloride with an anionic exchange resin, and the acetyl-L-carnitine malate can be prepared with high yield by reacting the obtained acetyl-L-carnitine inner salt with malic acid.
Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the crystalline acetyl-L-carnitine malate obtained in Example 2.
Fig. 2 is a differential scanning calorimeter (DSC) thermogram of the crystalline acetyl-L-carnitine malate obtained in Example 2.
The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.
Example 1: Preparation of acetyl-L-carnitine inner salt
100.00 g (417.19 mmol) of acetyl-L-carnitine chloride was added to 1020 ㎖ of a mixed solution of ethanol and dichloromethane (1:33, v/v), followed by stirring for 10 minutes. To the reaction solution was slowly added 178 ㎖ (1251.56 mmol) of triethylamine, followed by stirring at 20 to 25 ℃ for 6 hours.
The white solid formed was filtered and washed with 500 ㎖ of dichloromethane. The filtered white solid was dissolved in 70 ㎖ of ethanol and 1050 ㎖ of acetone was added thereto, followed by stirring at 0 to 5 ℃ for 1 hour. The resulting white solid was filtered, washed with 500 ㎖ of cooled acetone, and dried under vacuum at 40 ℃ for 24 hours to give 56.72 g of white crystalline acetyl-L-carnitine inner salt. The yield was 66.89%, the purity was 99.3% or more (HPLC analysis), and the content of a side-product, L-carnitine was 0.1%.
1H NMR (400 MHz, D2O) :δ= 5.47 ~ 5.52 (m, 1 H), 3.72 ~ 3.78 (m, H), 3.49 ~ 3.52 (d, 1 H), 3.09 (s, 9 H), 2.51 ~ 2.56 (d, 1 H), 2.37 ~ 2.42 (d, 1 H), 2.03 (s, 3 H)
Example 2: Preparation of acetyl-L-carnitine malate
10.16 g (50.00 mmol) of acetyl-L-carnitine inner salt obtained in Example 1 was added to 40 ㎖ of ethanol, followed by stirring for 10 minutes. To the reaction solution was slowly added 6.70 g (50.00 mmol) of malic acid dissolved in 40 ㎖ of ethanol. The resulting reaction solution was cooled to 0 ℃, and further stirred for 2 hours.
The white crystals formed was filtered, washed with 10 ㎖ of cooled ethanol, and dried under vacuum at 40 ℃ for 24 hours to give 16.11 g of white crystalline acetyl-L-carnitine malate. The yield was 95.51%. The obtained crystalline acetyl-L-carnitine malate was subjected to X-ray powder diffraction (XRPD) and differential scanning calorimeter (DSC) analyses, and the results are shown in Figs. 1 and 2, respectively.
M.P. : 125 ~ 128 ℃
1H NMR (400MHz, DMSO-d6) : δ = 5.48 ~ 5.53 (m, 1 H), 4.34 ~ 4.37 (m, 1 H), 3.73 ~ 3.79 (m, 1 H), 3.53 (d, 1 H), 3.07 (s, 9 H), 2.53 ~ 2.78 (m, 4 H), 2.02 (s, 3 H)
Example 3: Preparation of acetyl-L-carnitine malate
14.23 g (70.00 mmol) of acetyl-L-carnitine inner salt obtained in Example 1 was added to 50 ㎖ of methanol, followed by stirring for 10 minutes. To the reaction solution was slowly added 9.38 g (70.00 mmol) of malic acid, followed by stirring at 20 to 25 ℃ for 1 hour. The reaction solution was distilled under reduced pressure, and 70 ml of 2-butanone was added to the residue, followed by stirring for 1 hour.
The white crystals formed was filtered, washed with 30 ㎖ of cooled 2-butanone, and dried under vacuum at 40 ℃ for 24 hours to give 22.05 g of white crystalline acetyl-L-carnitine malate. The yield was 93.38%.
Example 4: Preparation of acetyl-L-carnitine malate
14.23 g (70.00 mmol) of acetyl-L-carnitine inner salt obtained in Example 1 was added to 50 ㎖ of methanol, followed by stirring for 10 minutes. To the reaction solution was slowly added 9.38 g (70.00 mmol) of malic acid, followed by stirring for 1 hour. To the reaction solution was added 20 ㎖ of acetone, followed by stirring for 1 hour.
The white crystals formed was filtered, washed with 20 ㎖ of cooled acetone, and dried under vacuum at 40 ℃ for 24 hours to give 19.23 g of white crystalline acetyl-L-carnitine malate. The yield was 81.44%.
Comparative Example 1: Preparation of acetyl-L-carnitine mucate
Acetyl-L-carnitine mucate was prepared as follows in accordance with the process described in U.S. Patent No. 5,952,379, which is incorporated in its entirety here by reference.
10.16 g (49.99 mmol) of acetyl-L-carnitine inner salt obtained in Example 1 was dissolved in 4 ㎖ of water. To the reaction solution was added 5.25 g (24.98 mmol) of mucic acid, followed by stirring. To the reaction solution was added 100 ㎖ of acetone, followed by stirring for 1 hour.
The crystals formed was filtered, washed with 100 ㎖ of acetone, and dried under vacuum at 40 ℃ for 24 hours to give 14.50 g of white crystalline acetyl-L-carnitine mucate. The yield was 94.08%.
M.P. : 103 ~ 106 ℃
1H NMR (400MHz, DMSO-d6) : δ = 5.37 ~ 5.42 (m, 2 H), 3.97 (s, 2 H), 3.62 ~ 3.72 (m, 6 H), 3.09 (s, 18 H), 2.38 ~ 2.54 (m, 4 H), 2.04 (s, 6 H)
Experimental Example 1: X-ray structure analysis of crystalline acetyl-L-carnitine malate
As shown in Fig. 1, the crystalline acetyl-L-carnitine malate obtained in Example 2 has distinctively characteristic peaks in the X-ray powder diffraction (XRPD) pattern. The observed characteristic peaks shown in the XRPD pattern of Fig. 1 are listed in Table 1, wherein ‘2θ’ is diffraction angle, ‘d’ is interplanar spacing, and 'I/I0' is relative intensity of the peak.
Table 1
2θ d I/I0 2θ d I/I0
7.7861 11.35498 2.96 24.6855 3.60656 47.84
11.9359 7.41487 48.61 25.1419 3.54212 16.99
12.3881 7.14518 30.82 25.7410 3.46103 13.48
13.1699 6.72274 10.24 26.3356 3.38422 58.73
15.1460 5.84977 42.02 27.8164 3.20734 11.02
15.4994 5.71719 34.77 28.4482 3.13753 58.44
16.3008 5.43788 40.39 30.2128 2.95817 44.35
18.0027 4.92743 99.33 30.6423 2.91768 33.76
18.2193 4.86934 95.68 31.0289 2.88220 22.23
19.2141 4.61944 70.83 32.6464 2.74301 23.73
20.6840 4.29436 83.45 34.1360 2.62665 10.50
20.9049 4.24946 100 35.8482 2.50502 13.24
22.5958 3.93515 27.61 36.2864 2.47577 11.86
22.9903 3.86852 72.83 37.2331 2.41496 17.92
23.2728 3.82219 42.00 37.6007 2.39220 16.23
23.8428 3.73210 29.24 38.1403 2.35959 21.80
24.4359 3.64283 34.14 39.1468 2.30121 4.05
Experimental Example 2: Hygroscopicity test
The hygroscopicity of the acetyl-L-carnitine malate obtained in Example 2 was compared with those of the known acetyl-L-carnitine chloride (Edengene Chemical Ltd, China) and acetyl-L-carnitine mucate. Each compound was exposed to the condition of a temperature of 40 ℃ and a relative humidity of 75 % for 2 hours, 8 hours, 24 hours and 3 days, and then the amount of moisture contained in the compound was measured with Karl-Fischer titrator. The percentage amounts (weight %) of moisture contained in the active ingredients are listed in Table 2.
Table 2
Salts Initial 2 hours 8 hours 24 hours 3 days
acetyl-L-carnitine chloride 0.27 2.20 12.30 24.62 25.10
acetyl-L-carnitine mucate 4.31 7.60 9.46 10.61 25.56
acetyl-L-carnitine malate 0.27 0.53 1.04 1.12 3.79
As shown in Table 2, the acetyl-L-carnitine malate showed superior non-hygroscopicity even when exposed to the high humidity condition, as compared with the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate. Such a result suggests that the acetyl-L-carnitine malate of the present invention has good moisture stability to be effectively used for preparing a pharmaceutical composition without any problems in the processes of storing the compound, formulating it, and packaging and storing the finished product.
Experimental Example 3: Moisture and thermal stability test
The moisture and thermal stability of an active ingredient in a pharmaceutical composition is an important factor on the perspective of the production process and long-term storage of the pharmaceutical composition. Thus, the moisture and thermal stability of the acetyl-L-carnitine malate obtained in Example 2 was measured and compared with those of the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate.
Particularly, each acetyl-L-carnitine acid addition salt was stored in a sealed state under an accelerated condition (a temperature of 40 ℃ and a relative humidity of 75 %), and after 0 (zero), 3, 7, 14 and 28 days, the remaining rate of the active ingredient was analyzed with high performance liquid chromatography (HPLC). The results are listed in Table 3.
Table 3
Salts Initial 3 days 7 days 14 days 28 days
acetyl-L-carnitine chloride 100 99.98 99.92 99.87 99.77
acetyl-L-carnitine mucate 100 100.01 99.98 99.96 99.94
acetyl-L-carnitine malate 100 99.97 99.97 99.95 99.93
As shown in Table 3, the acetyl-L-carnitine malate showed the same or higher level of stability when exposed to the accelerated condition for 28 days, as compared with the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate. Such a result suggests that the acetyl-L-carnitine malate of the present invention has good chemical stability to be effectively used for preparing a pharmaceutical composition.
Experimental Example 4: Solubility test at in vivo pH range
The water-solubility of an active ingredient in a pharmaceutical composition has effects on the dissolution rate and bioavailability of the pharmaceutical composition. Thus, the solubility of the acetyl-L-carnitine malate obtained in Example 2 was measured and compared with those of the known acetyl-L-carnitine chloride and acetyl-L-carnitine mucate.
Particularly, the solubility measurement was performed at a pH range for in vivo uptake, that is, at the stomach pH value of 1.2, the intestine pH value of 4.0 and the blood pH value of 6.8. Each acetyl-L-carnitine acid addition salt was dissolved to saturation, the saturated solutions were analyzed with high performance liquid chromatography (HPLC), and the dissolved amounts were measured based on free acetyl-L-carnitine. The results are listed in Table 4.
Table 4
Salts Deionized Water (mg/ml) pH 1.2 (mg/ml) pH 4.0 (mg/ml) pH 6.8 (mg/ml)
acetyl-L-carnitine chloride 867.07 940.59 973.80 968.54
acetyl-L-carnitine mucate 16.24 12.57 20.17 13.51
acetyl-L-carnitine malate 729.03 704.76 432.28 693.13
As shown in Table 4, the acetyl-L-carnitine malate showed good solubility at all pH values. Particularly, the solubility of the acetyl-L-carnitine malate was not as good as acetyl-L-carnitine chloride but sufficient to be used for a medicament, and much superior to the known acetyl-L-carnitine mucate.

Claims (14)

  1. Acetyl-L-carnitine malate of the following formula (I):
    Figure PCTKR2011004002-appb-I000008
  2. The acetyl-L-carnitine malate of Claim 1, wherein the acetyl-L-carnitine malate is a crystalline form.
  3. The acetyl-L-carnitine malate of Claim 1, wherein the acetyl-L-carnitine malate is a crystalline form showing an X-ray powder diffraction (XRPD) pattern characterized by peaks having I/Io values of at least 10% (I is the intensity of each peak; Io is the intensity of the highest peak) at diffraction angles (2θ) of 11.9±0.2, 12.4±0.2, 13.2±0.2, 15.1±0.2, 15.5±0.2, 16.3±0.2, 18.0±0.2, 18.2±0.2, 19.2±0.2, 20.7±0.2, 20.9±0.2, 22.6±0.2, 23.0±0.2, 23.3±0.2, 23.8±0.2, 24.4±0.2 24.7±0.2, 25.1±0.2, 25.7±0.2, 26.3±0.2, 27.8±0.2, 28.4±0.2, 30.2±0.2, 30.6±0.2, 31.0±0.2, 32.6±0.2, 34.1±0.2, 35.8±0.2, 36.3±0.2, 37.2±0.2, 37.6±0.2, and 38.1±0.2.
  4. A pharmaceutical composition comprising the acetyl-L-carnitine malate of any one of Claims 1 to 3 together with a pharmaceutically acceptable carrier.
  5. The pharmaceutical composition of Claim 4, wherein the pharmaceutical composition is used for treating or preventing primary degenerative disease or secondary degenerative disease due to cerebrovascular disease.
  6. The pharmaceutical composition of Claim 4, wherein the pharmaceutical composition is used for treating or preventing Alzheimer's disease, dysthymia, attention deficit hyperactivity disorder (fragile syndrome), male infertility, multiple sclerosis, neuropathy, peripheral nerve or facial nerve paralysis, or Peyronie's disease.
  7. A process for preparing acetyl-L-carnitine malate of the following formula (I), which comprises the steps of:
    (i) desalting acetyl-L-carnitine chloride of the following formula (IV) by reacting it with trialkylamine in an organic solvent to give acetyl-L-carnitine inner salt of the following formula (II); and
    (ii) reacting the acetyl-L-carnitine inner salt with malic acid of the following formula (VI) in an organic solvent:
    Figure PCTKR2011004002-appb-I000009
    Figure PCTKR2011004002-appb-I000010
    Figure PCTKR2011004002-appb-I000011
    Figure PCTKR2011004002-appb-I000012
  8. The process of Claim 7, wherein the organic solvent in step (i) is a mixed solvent of ethanol and dichloromethane.
  9. The process of Claim 8, wherein the volume ratio of the ethanol to the dichloromethane is 1:10 to 1:40.
  10. The process of Claim 7, wherein the trialkylamine in step (i) is one or more selected from the group consisting of triethylamine, N,N-diethylmethylamine, N,N-diisopropylethylamine, and 1-methylpyrrolidine.
  11. The process of Claim 10, wherein the trialkylamine in step (i) is triethylamine.
  12. The process of Claim 7, wherein the process further comprises the step of recrystallizing the acetyl-L-carnitine inner salt obtained in step (i) to give a crystalline acetyl-L-carnitine inner salt.
  13. The process of Claim 7, wherein the organic solvent in step (ii) is one or more selected from the group consisting of methanol, ethanol, isopropanol, 1-butanol and 1-hexanol.
  14. The process of Claim 7, wherein the process further comprises the step of recrystallizing the acetyl-L-carnitine malate obtained in step (ii) to give a crystalline acetyl-L-carnitine malate.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103204782A (en) * 2013-04-25 2013-07-17 四川海思科制药有限公司 Levocarnitine compound
CN104177271A (en) * 2014-06-23 2014-12-03 海南好康舒药业有限公司 Method for preparing acetyl levocarnitine hydrochloride
CN105732407A (en) * 2016-02-02 2016-07-06 广东隆赋药业有限公司 Synthesis method of acetyl-L-carnitine inner salt

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WO2001068075A2 (en) * 2000-03-10 2001-09-20 Hill's Pet Nutrition Method for increasing intestinal absorption of fat soluble vitamins in post-menopausal women and lower animals
US20080249168A1 (en) * 2007-04-06 2008-10-09 Shuhua Gu Pharmaceutical composition for gout

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068075A2 (en) * 2000-03-10 2001-09-20 Hill's Pet Nutrition Method for increasing intestinal absorption of fat soluble vitamins in post-menopausal women and lower animals
US20080249168A1 (en) * 2007-04-06 2008-10-09 Shuhua Gu Pharmaceutical composition for gout

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103204782A (en) * 2013-04-25 2013-07-17 四川海思科制药有限公司 Levocarnitine compound
CN103204782B (en) * 2013-04-25 2014-12-31 四川海思科制药有限公司 Crystal form of chloracetyl-levocarnitine compound
CN104177271A (en) * 2014-06-23 2014-12-03 海南好康舒药业有限公司 Method for preparing acetyl levocarnitine hydrochloride
CN105732407A (en) * 2016-02-02 2016-07-06 广东隆赋药业有限公司 Synthesis method of acetyl-L-carnitine inner salt

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