KR20170038990A - Methods for Manufacturing Cocrystal of Choline alfoscerate and Curcumin - Google Patents
Methods for Manufacturing Cocrystal of Choline alfoscerate and Curcumin Download PDFInfo
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Abstract
Description
The present invention relates to novel curcumin co-crystals of choline alfoscerate with improved stability, hygroscopicity and taste, and a process for their preparation.
The development of modern medicine has led to an extension of the average life expectancy of mankind, while the social cost of rapid aging has also increased. The increase in the number of elderly people suffering from degenerative brain diseases, such as adult diseases, especially dementia, is becoming an important problem to be managed by the state and society beyond the individual category.
Choline alfoscerate (alpha-GPC) is a compound of the formula [(2R) -2,3-dihydroxypropyl] 2-trimethylazanium ethyl phosphate, which is an acetylcholine insoluble in Alzheimer's patients It is a substance that supplies raw choline, and it is widely used as a typical dementia treatment with donepezil, Rivastigmine and the like. Acetylcholinesterase inhibitors (ChEI), such as donepezil or ribastigmine, increase the efficiency of acetylcholine by inhibiting the degradation of the neurotransmitter acetylcholine. These drugs are commonly used for the treatment of Alzheimer's or vascular dementia. They are effective in slowing the onset of dementia or alleviating symptoms, but they are not effective in long-term administration. In this case, choline alfoscerate It is well known that it is helpful to prevent the deterioration of such an effect.
In Korea, choline alfoscerate is listed as a prescription drug, while in the US and Europe, it is marketed as dietary supplements. In the United States, it is classified as GRAS (generally recognized as safe) (safety) is an established substance. The clinical dose of choline alfoscerate is 400 mg to 1,200 mg per day for adults and 400 mg for soft capsules or tablets in Korea.
On the other hand, choline alfoscerate has the following physico-chemical disadvantages, which result from the properties of the material itself as a raw material.
1) The taste of the raw material itself is very high
2) The liquid raw material is decomposed when stored for a long time.
2) High hygroscopicity (absorbs moisture easily in the atmosphere)
3) The present commercial formulations such as soft capsules and tablets are weak to heat and moisture (melting or deformation occurs at 30 degrees or more and are susceptible to moisture as well as raw materials)
As prior arts for solidifying the raw drug of choline alfoscerate, Korean Patent No. 10-1287422 discloses an I-form of choline alfoscerate, Korean Patent No. 10-1287423 discloses a choline alfoscerate II-type crystal, Korean Patent Publication No. 10-2013-0063520 discloses a method for producing I-form crystals of glyceryl choline alfoscerate, and Korean Patent Publication No. 10-2013-0063521 discloses a method for producing choline alfoscerate II-type crystals. .
In addition, the present inventors have disclosed in International Application No. PCT / KR2015-000446 the Form III and Form IV crystal forms of choline alfoscerate, which are different from the above-mentioned crystal form of the present invention, and a method for producing the same.
In the case of producing the crystalline solid, the crystalline solid material has advantages over the conventional liquid raw material, but any crystalline solid material can not sufficiently inhibit the formation of the gel formation by absorbing moisture in the atmosphere. This is because choline alfoscerate is a zwitterionic substance and has good affinity with water molecules, so that moisture in the atmosphere is absorbed very quickly to form hydrate. For this reason, choline alfoscerate as a raw material drug is usually supplied as liquid Gel form (choline alfoscerate containing water at 13-17%) or crystalline powder having 99% or more solids content as atmospheric contact It is supplied in a vacuum packed and nitrogen filled form. It is obvious that the crystalline solid technology to date can not sufficiently control the problem of moisture absorption that can occur during the storage, transportation, formulation of the drug substance, and storage of the finished product.
On the other hand, commercially available formulations of choline alfoscerate also have the following problems.
1) In the case of a soft capsule using a liquid raw material, there is a possibility that the active ingredient will migrate to a water-soluble soft gelatin capsule over time, a separate soft capsule manufacturing facility is required at the time of manufacture, and the possibility of microbial deterioration of the soft capsule preparation is reduced The gelatin capsules are weak to moisture and heat, and may be delayed in disintegration during storage. Especially, in patients with older age, in which the ability to swallow is low, it is inconvenient to take.
2) In the case of refining using solid materials, the size of the tablets is increased due to excessive use of adsorbates and excipients for the solidification of the raw materials, and when a specific solidified crystalline solid material is used, a considerable excess amount of the coating polymer is used The tablets made by this method are also different in size from soft capsules. On the other hand, since it is difficult to completely block the moisture absorption between the raw material of the adsorbate and the crystalline solid raw material, it is vulnerable to moisture and heat and thus is difficult to store. In addition, taking the drug is still inconvenient in patients with older age with reduced ability to swallow.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
The present inventors sought to develop a technique for improving the stability, hygroscopicity and bitter taste of choline alfoscerate. As a result, the inventors of the present invention have remarkably improved stability and hygroscopicity, while at the same time ensuring bitter taste shielding by producing a novel cocrystal of choline alfoscerate and curcumin, thereby completing the present invention.
It is an object of the present invention to provide a process for producing co-crystallins of choline alfoscerate and curcumin. This is because, as described above, the provision of a raw material drug (API) having optimized physical properties for the development of foaming agents, powders, oral disintegrants, and troch candy preparations which are not greatly affected by the volume of the API (API) .
Another object of the present invention is to provide novel choline alfoscerate and choline alfoscerate curcumin cocrystal which are improved in stability and hygroscopicity and have a bitter taste.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
The inventors of the present invention have made extensive efforts to develop a technique for improving the stability, hygroscopicity and bitter taste of choline alfoscerate. As a result, it has been found that choline alfoscerate curcumin cocrystal And the hygroscopicity was remarkably improved, and at the same time, a new crystal was obtained in which the bitter taste was shielded.
More specifically, the present inventors conducted studies in order to solve the problems of the above-mentioned choline alfoscerate raw material medicines and choline alfoscerate commercial preparations:
(I) development of a formulation that is not affected by the size of the formulation to overcome issues such as difficulty swallowing (foaming agents, powders, oral disintegration (ODT), etc.);
(Ii) Significant improvement of the hygroscopicity problem of existing raw materials;
(Iii) ensuring proper properties for the new formulation to be developed.
As a result, the present inventors propose choline alfoscerate and a novel cocrystal of curcumin as an optimal API (ingredient drug) for the development of new pharmaceutical preparations and a method for producing the same. The co-crystal of the present invention has a unique new crystal form and is thermodynamically stable and does not cause crystal transition depending on storage conditions such as aging. On the other hand, the problem of hygroscopicity which the conventional simple crystal type solids can not overcome is resolved. In addition, since it is difficult to apply to capsules or tablets due to the increase in volume compared to conventional drug substances, it is not a problem for foaming agents, powders, oral disintegrants, and troch candy formulations which are not affected by the size of the preparation. On the other hand, an important part of these preparations is that the taste of the drug substance itself affects the ease of taking, and pure choline alfoscerate has a bitter taste. Taste masking was successfully achieved through the sensory evaluation, and a taste of acceptable level was obtained by sensory evaluation.
The co-crystallization technique, that is, the technique of producing a cocrystal, is applied for the purpose of improving the solubility and the oral absorption rate for a poorly soluble substance and a substance having a low bioabsorption rate in the pharmaceutical or food field, or in some cases, decreasing the moisture absorption or solubility The co-crystals are based on the binding force of hydrogen bonds and intermolecular bonds (π-π stacking interaction) between drugs (raw materials) and Cocrystal formers . In the present invention, curcumin is used as the co-crystal former.
The chemical formula of choline alfoscerate and curcumin used in the present invention is as follows.
Formula 1
(2)
Curcumin is an antioxidant and antiinflammatory substance that contains 5-10% in the root of ganghwang (ugum). It has been used for thousands of years as a medicine, a food preservative and a natural pigment, and has been used for cardiovascular diseases, Alzheimer's disease , Metabolic diseases, depression. It is a substance reported to be effective in various kinds of diseases and fatigue. However, the water solubility of curcumin is very low (less than 0.6 μg / mL) and the bioavailability by oral administration is very low (Oral Bioavailability 1% or less). For these reasons, curcumin has limitations in its application as a medical application or as a functional food .
In order to solve the problems of strong hygroscopicity and bitter taste of choline alfoscerate, the present inventors have found that, as a co-crystallizer, co-crystals are formed using curcumin, which has a relatively low hygroscopicity and can shield a bitter taste, It is possible to complement each other 's weak points.
Hereinafter, the method for preparing choline alfoscerate and curcumin according to the present invention will be described in detail.
Ⅰ. Method for preparing co-crystals using solid choline alfoscerate and curcumin
According to one aspect of the present invention, the present invention provides a process for preparing a cocrystal comprising Choline alfoscerate and Curcumin, comprising the steps of:
(a) mixing and stirring crystalline IV solid choline alfoscerate and curcumin;
(b) cooling the resultant of step (a), followed by re-mixing and stirring; And
(c) drying the resultant of step (b) to obtain a co-crystal.
A solid choline alfoscerate and a method for producing a co-crystallized choline alfoscerate curcumin cocrystal will be described step by step as follows:
Step (a): mixing and stirring of solid choline alfoscerate with curcumin
First, the process of the present invention involves mixing and stirring the choline alfoscerate in solid form with curcumin. Said solid choline alfoscerate is a crystalline form IV solid choline alfoscerate which can be prepared by the method of preparation of International Application No. PCT / KR2015-000446.
According to an embodiment of the present invention, the step (a) is performed at a speed of 250 rpm to 1000 rpm for 5 minutes to 60 minutes, more preferably at 600 rpm to 800 rpm for 10 minutes to 30 minutes . According to a particular embodiment of the invention, step (a) is carried out at room temperature for 30 minutes at 750 rpm.
Step (b): Re-mixing and stirring
Next, the resultant product of step (a) is cooled to room temperature and then re-mixed and stirred.
According to an embodiment of the present invention, in the step (b), the remixing and stirring are performed at a speed of 250 rpm to 1000 rpm for 5 to 180 minutes.
The step (b) may further include the step of adding a solvent to the resultant of step (a) before the re-mixing and stirring. The solvent of step (b) is selected from the group consisting of acetone, methanol, ethanol, butanol, isopropyl alcohol, ethyl acetate, methylene chloride, water, more preferably acetone, ethanol, methanol, Ethanol. The solvent is added in a catalytic amount. The amount of solvent used is preferably about 0.01 to 0.02 times the weight of the total mixed material, and co-crystals are formed quickly and stably by adding a solvent.
If a solvent is added in step (b), the re-mixing and stirring are carried out at a speed of 250 rpm to 1000 rpm for 5 to 60 minutes, preferably 600 to 800 rpm for 10 to 30 minutes. According to a particular embodiment of the invention, if a solvent is added in step (b), the re-mixing and stirring are carried out for 20 minutes at a rate of 750 rpm.
Step (c): Drying
Finally, the result of step (b) is dried to obtain a co-crystal.
According to one embodiment of the present invention, the drying temperature is between 20 ° C and 75 ° C, more preferably, vacuum drying is performed at 45 ° C for 4 hours to 6 hours.
Figure 3 shows that the crystalline type IV choline alfoscerate having an endothermic temperature of 142 占 폚 forms a co-crystal transition to choline alfoscerate curcumin cocrystal with an endothermic temperature of 63 占 폚; Figure 4 shows the final transition to choline alfoscerate-curcumin cocrystal with an endothermic temperature of 63 [deg.] C. Figure 5 is 1 H NMR showing that the molar ratio of choline alfoscerate curcumin cocrystal is 1: 1.
On the other hand, the choline alfoscerate curcumin co-crystals prepared by the above steps (a) to (c) had diffraction angles of 2θ of 5.1 ± 0.2 °, 7.9 ± 0.2 °, and 8.9 ± 0.2 ° in powder X-ray diffraction (PXRD) 18.2 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 24.7 ± 0.2 °, 12.3 ± 0.2 °, 14.6 ± 0.2 °, 15.2 ± 0.2 °, , And 27.4 ± 0.2 ° (FIG. 9), respectively, and shows an endothermic peak at an endothermic onset temperature of 60 ° ± 2 ° C. and an endothermic temperature of 63 ° ± 3 ° C. in a differential scanning calorimetry (DSC) 4).
Ⅱ. Method for preparing co-crystals using liquid choline alfoscerate and curcumin
According to another aspect of the present invention, the present invention provides a method for preparing a cocrystal comprising Choline alfoscerate and Curcumin, comprising the steps of:
(a) mixing and stirring liquid choline alfoscerate and curcumin;
(b) cooling the resultant of step (a), followed by re-mixing and stirring; And
(c) drying the resultant of step (b) to obtain a co-crystal.
The process for preparing a co-crystal using liquid choline alfoscerate and curcumin will be described step by step as follows:
Step (a): mixing and stirring of solid choline alfoscerate with curcumin
First, choline alfoscerate in liquid form and curcumin are mixed at room temperature and stirred.
The liquid choline alfoscerate of step (a) has a moisture content of 18% or less, more preferably a water content of 8% -14%, and most preferably a moisture content of 10% -12%. Outside this range, there is a problem that the yield of co-crystallization is greatly reduced.
According to an embodiment of the present invention, the step (a) is carried out at a speed of 250 rpm to 1200 rpm for 20 to 120 minutes, preferably 600 rpm to 800 rpm. According to a particular embodiment of the invention, it is carried out at 750 rpm for 30 minutes.
Step (b): Re-mixing and stirring
Then, the resultant product of step (a) is cooled to room temperature, and then mixed and stirred again.
According to an embodiment of the present invention, the step (b) is performed at a speed of 250 rpm to 1200 rpm for 20 to 120 minutes, preferably 600 rpm to 800 rpm for 30 to 60 minutes. According to a particular embodiment of the invention, it is carried out at 750 rpm for 30 minutes.
Step (c): Drying
Finally, the result of step (b) is dried to obtain a co-crystal.
The drying temperature is 20 ° C to 75 ° C, more preferably, vacuum drying is performed at 45 ° C for 6 hours to 10 hours.
Figure 6 shows that choline alfoscerate and curcumin form a choline alfoscerate curcumin cocrystal having an endothermic temperature of 68 캜 while forming a co-crystal and then transition to a co-crystal having an endothermic temperature of 63 캜 have.
On the other hand, the choline alfoscerate-curcumin co-crystals prepared by the above steps (a) to (c) had a 2? Diffraction angle of 5.1 ± 0.2 °, 7.9 ± 0.2 °, 8.9 ± 0.2 18.2 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 24.7 ± 0.2 °, 12.3 ± 0.2 °, 14.6 ± 0.2 °, 15.2 ± 0.2 °, ° and 27.4 ± 0.2 °, respectively, and shows an endothermic peak at an endothermic onset temperature of 60 ° ± 2 ° C. and an endothermic temperature of 63 ° ± 3 ° C. in a differential scanning calorimetry (DSC) analysis (see FIG. 6).
Ⅲ. Crystallization method using liquid choline alfoscerate and curcumin in organic solvent phase
According to another aspect of the present invention, the present invention provides a method for preparing a cocrystal comprising Choline alfoscerate and Curcumin, comprising the steps of:
(a) mixing and stirring liquid choline alfoscerate and curcumin in the presence of an organic solvent;
(b) concentrating the result of step (a); And
(c) stirring the resultant of step (b) in the presence of an organic solvent and drying to obtain a co-crystal.
The process for preparing a co-crystal using liquid choline alfoscerate and curcumin in the presence of an organic solvent will be described in detail step by step as follows:
Step (a): mixing and stirring of liquid choline alfoscerate with curcumin
First, choline alfoscerate in liquid form and curcumin are mixed and stirred in the presence of an organic solvent. More specifically, after the liquid choline alfoscerate is stirred in the presence of an organic solvent, curcumin is added and mixed and stirred.
According to an embodiment of the present invention, the liquid choline alfoscerate has a moisture content of 18% or less, preferably a moisture content of 8% to 14%, and most preferably a moisture content of 10% to 12%. Outside this range, there is a problem that the yield of co-crystallization is greatly reduced.
The organic solvent of step (a) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, methylene chloride, chloroform, Acetone, ethyl acetate, ethanol, methanol, methylene chloride or acetonitrile, more preferably ethanol, acetone, methylene chloride or acetonitrile, more preferably selected from the group consisting of methanol, ethanol, Ethyl acetate or acetonitrile, most preferably ethanol. The volume of the usable solvent is 5-20 times, preferably 8-15 times, and most preferably 10 times by weight of the choline alfoscerate used.
According to one embodiment of the present invention, the step (a) is carried out by stirring liquid choline alfoscerate in the presence of an organic solvent, adding curcumin and stirring. At this time, stirring is performed at 600 rpm or more, preferably 600 rpm to 900 rpm for 20 to 120 minutes, more preferably 800 rpm for 30 to 60 minutes.
Step (b): Concentration
And then concentrating the product of step (a).
According to an embodiment of the present invention, the concentration of said mixing step (b) is conducted under vacuum and is concentrated until no more ethanol is present. According to one embodiment of the present invention, the concentration is carried out at 20 ° C to 75 ° C, more preferably at 45 ° C in vacuum concentration.
Step (c): Stirring And drying
Finally, an organic solvent is added to the resultant of the step (b), stirred, and then dried.
The organic solvent of step (c) of the present invention may be selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, methylene chloride, chloroform, More preferably toluene, acetone, ethyl acetate, ethanol, methanol, methylene chloride or acetonitrile, more preferably selected from the group consisting of benzene, ethylene glycol, propylene glycol, butylene glycol and acetonitrile, Ethanol, acetone, ethyl acetate or acetonitrile, and most preferably ethanol. The volume of the usable solvent is 2-10 times, preferably 4-8 times, most preferably 6 times by weight of the choline alfoscerate used.
The agitation time and speed are from 5 minutes to 120 minutes at 250 rpm to 800 rpm, and more preferably from 40 minutes to 80 minutes at 400 rpm to 600 rpm. According to a particular embodiment of the present invention, stirring of step (c) is carried out at 500 rpm for 60 minutes.
On the other hand, the drying temperature is 20 ° C to 75 ° C, more preferably 45 ° C for 4 hours to 6 hours.
FIG. 7 shows choline alfoscerate curcumin coocrystal having an endothermic temperature of 142.degree. Figure 9 is 1 H NMR showing that the molar ratio of choline alfoscerate curcumin cocrystal is 2: 5.
On the other hand, the choline alfoscerate-curcumin co-crystals prepared by the above steps (a) to (c) had diffraction angles of 2.8 ± 0.2 °, 14.5 ± 0.2 °, and 17.2 ± 0.2 ° in powder X-ray diffraction (PXRD) (A), 18.1 ± 0.2 °, 18.8 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 27.7 ± 0.2 °, 25.6 ± 0.2 ° and 29 ± 0.2 ° ), An endothermic peak at 140 ° C ± 2 ° C and an endothermic temperature of 142 ° C ± 3 ° C in differential scanning calorimetry (DSC) analysis (see FIG. 7).
According to another aspect of the present invention, the present invention provides a novel cocrystal comprising the following Formula 1 (choline alfoscerate) and Formula 2 (curcumin).
Formula 1
(2)
The present inventors have attempted to prepare choline alfoscerate curcumin cocrystal under various conditions. As a result, it was confirmed that choline alfoscerate curcumin cocrystal having a quantitative molar ratio can be prepared by controlling the solvent, the mixing speed and the stirring time in an environment where specific conditions are maintained Respectively.
According to one aspect of the present invention, there is provided a choline alfoscerate-curcumin cocrystal wherein the choline alfoscerate-curcumin has a one-to-one molar ratio. The co-crystals were characterized by a powder X-ray diffraction (PXRD) analysis of 2? Diffraction angles of 5.1 ± 0.2 °, 7.9 ± 0.2 °, 8.9 ± 0.2 °, 12.3 ± 0.2 °, 14.6 ± 0.2 °, 15.2 ± 0.2 °, 17.2 ± 0.2 (Fig. 9), and the peak of the differential scanning calorie (Fig. 9) was observed at 18.2 ± 0.2 °, 18.9 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 24.7 ± 0.2 ° and 27.4 ± 0.2 ° DSC) analysis shows an endothermic peak at an endothermic start temperature of 60 캜 2 캜 and an endothermic temperature of 63 캜 3 캜.
According to another aspect of the present invention, there is provided a choline alfoscerate curcumin cocrystal wherein aloserate-curcumin has a composition of 2 to 5 at a molar ratio. The co-crystals were analyzed by powder X-ray diffraction (PXRD) analysis at 2? Diffraction angles of 8.8 ± 0.2 °, 14.5 ± 0.2 °, 17.2 ± 0.2 °, 18.1 ± 0.2 °, 18.8 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 (DSC) analysis showed a peak at an endothermic start temperature of 140 ° C ± 2 ° C and an endothermic temperature of 142 ° C (FIG. 10), and a peak at 23.3 ± 0.2 °, 27.7 ± 0.2 °, 25.6 ± 0.2 ° and 29 ± 0.2 ° Indicates an endothermic peak at 3 ° C.
Thus, the inventors have confirmed that choline alfoscerate curcumin cocrystal is a novel crystalline form through powder X-ray diffraction (PXRD) analysis and differential scanning calorimetry (DSC) analysis
The choline alfoscerate curcumin co-crystal of the present invention uses the above-mentioned " choline alfoscerate-curcumin co-crystal preparation method " of the present invention, and the common content between the two is " .
The features and advantages of the present invention are summarized as follows:
(a) The present invention provides choline alfoscerate curcumin cocrystal used as a therapeutic agent for dementia as a brain function improving agent and a method for producing the same.
(b) The choline alfoscerate curcumin cocrystal of the present invention can be used in the production of choline alfoscerate curcumin cocrystal in which the rate of formation of co-crystals and the composition ratio of co-crystals are different depending on the crystal form of choline alfoscerate, To form a co-crystal compound.
Figure 1 shows the results of differential scanning calorimetry (DSC) analysis of choline alfoscerate crystalline Form IV (International Application No. PCT / KR2015-000446) used in the present invention.
2 shows the results of differential scanning calorimetry (DSC) analysis of curcumin (Asta chemical, China) used in the present invention.
FIG. 3 shows the results of differential scanning calorimetry (DSC) analysis of the process for forming 1: 1 choline alfoscerate curcumin cocrystal according to an embodiment of the present invention (see Example 1).
4 shows the results of differential scanning calorimetry (DSC) analysis after formation of 1: 1 choline alfoscerate-curcumin cocrystal according to one embodiment of the present invention (see Examples 1 and 2) ).
FIG. 5 shows the 1 H NMR analysis results after formation of 1: 1 choline alfoscerate curcumin cocrystal according to one embodiment of the present invention (see Example 1 and Examples 2 and 3).
FIG. 6 shows the results of differential scanning calorimetry (DSC) analysis of the process for forming 1: 1 choline alfoscerate-curcumin cocrystal according to another embodiment of the present invention (see Example 3).
FIG. 7 shows the results of differential scanning calorimetry (DSC) analysis of 2: 5 choline alfoscerate curcumin cocrystal according to an embodiment of the present invention (see Example 4).
FIG. 8 shows the 1 H NMR analysis results of 2: 5 choline alfoscerate curcumin cocrystal according to an embodiment of the present invention (see Example 4).
FIG. 9 shows the powder X-ray diffraction (PXRD) analysis results of 1: 1 choline alfoscerate curcumin cocrystal according to an embodiment of the present invention.
FIG. 10 shows the powder X-ray diffraction (PXRD) analysis results of 2: 5 choline alfoscerate curcumin cocrystal according to another embodiment of the present invention.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Example
Example 1: solid choline Aloscerate and Curcumin Used co-crystal Produce
51.4 g of crystalline IV solid glycerylphosphorylcholine (GPC-1% or less) prepared according to the method of International Application No. PCT / KR2015-000446 previously obtained at 24 ° C and 73.6 g of 99% pure curcumin, purchased from China asta, And the mixture was stirred at 750 rpm for 30 minutes. After cooling to room temperature, 10 drops of ethanol (1% by weight) were added and further mixed at 750 rpm for an additional 20 minutes. Filtered and vacuum-dried at 45 ° C for 8 to 16 hours to quantitatively obtain 1: 1 choline alfoscerate curcumin cocrystal.
Powder X-ray diffraction ( PXRD ) analysis
Powder X-ray diffraction (PXRD) analysis showed that the 2? Diffraction angles were 5.1 ± 0.2 °, 7.9 ± 0.2 °, 8.9 ± 0.2 °, 12.3 ± 0.2 °, 14.6 ± 0.2 °, 15.2 ± 0.2 ° and 17.2 ± 0.2 ° , 18.2 ± 0.2 °, 18.9 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 24.7 ± 0.2 ° and 27.4 ± 0.2 °, respectively (FIG. The scanning range was 5 ° to 40 °, 2θ, and the scanning speed was 5 ° / min.
Differential scanning calorie ( DSC ) analysis
As a result of differential scanning calorimetry (DSC) analysis, an endothermic peak was observed at an endothermic initiation temperature of 60 ° C ± 2 ° C and an endothermic temperature of 63 ° C ± 3 ° C (FIG. 4). The temperature raising range was 20-195 占 폚, and the temperature raising rate was 5 占 폚 / min.
Example 2: solid choline Aloscerate and Curcumin Used Co-decision Manufacturing (no solvent catalyst)
51.4 g of crystalline IV solid glycerylphosphorylcholine (GPC-1% or less) prepared according to the method of International Patent Application No. PCT / KR2015-000446 at 24 ° C and 73.6 g of 99% pure curcumin purchased from China asta And the mixture was stirred at 750 rpm for 30 minutes. After cooling to room temperature, the mixture was further mixed for 3 hours at 750 rpm. Filtered and vacuum-dried at 45 ° C for 8 to 16 hours to obtain quantitative 1: 1 choline alfoscerate curcumin cocrystal.
Example 3: liquid choline Aloscerate and Curcumin Used co-crystal Produce
57.6 g of liquid glycerylphosphorylcholine (GPC-moisture 12%) purchased from China asta at 24 ° C and 73.6 g of 99% pure curcumin purchased from Asta China were added to the high-speed mixer and stirred at 750 rpm for 30 minutes. After cooling to room temperature, the mixture was further stirred at 750 rpm for an additional 30 minutes. Filtered and vacuum-dried at 45 ° C for 8 to 16 hours to quantitatively obtain 1: 1 choline alfoscerate curcumin cocrystal.
Powder X-ray diffraction ( PXRD ) analysis
Powder X-ray diffraction (PXRD) analysis showed that the 2? Diffraction angles were 5.1 ± 0.2 °, 7.9 ± 0.2 °, 8.9 ± 0.2 °, 12.3 ± 0.2 °, 14.6 ± 0.2 °, 15.2 ± 0.2 ° and 17.2 ± 0.2 ° , 18.2 ± 0.2 °, 18.9 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 °, 24.7 ± 0.2 ° and 27.4 ± 0.2 °, respectively (FIG. The scanning range was 5 to 40 degrees, 2?, And the scanning speed was 5 deg / min.
Differential scanning calorie ( DSC ) analysis
As a result of differential scanning calorimetry (DSC) analysis, an endothermic peak was observed at an endothermic initiation temperature of 60 ° C ± 2 ° C and an endothermic temperature of 63 ° C ± 3 ° C (FIG. 4). The temperature raising range was 20-195 占 폚, and the temperature raising rate was 5 占 폚 / min.
Example 4: Choline using solvent Aloscerate and Curcumin Used co-crystal Produce
57.6 g of L-α-glycerylphosphoryl choline (GPC-12% moisture) liquid at 24 ° C. was dissolved in 575 ml of ethanol at 50 ° C., and then 57.6 g of sodium sulfate was added. Thereafter, the mixture was cooled to 25 ° C, stirred for 1 hour, and then filtered under reduced pressure (56.7 ml of ethanol was washed) to remove sodium sulfate. The removed GPC solution was mixed with 73.6 g of 99% pure curcumin purchased from asta, China, in 736 ml of acetone and then suspended in the solution. Thereafter, the mixture was stirred at room temperature for 1 hour at a water bath temperature of 45 DEG C and 800 rpm. Thereafter, the mixture was concentrated in vacuo at a water bath temperature of 45 ° C to obtain yellow crystals. 275 ml of ethanol was added thereto, followed by stirring at 500 rpm at 24 DEG C for 1 hour. Thereafter, filtration under reduced pressure (washing with 55 ml of ethanol) followed by vacuum drying at 45 ° C for 8 to 16 hours yielded 2: 5 choline alfoscerate curcumin cocrystal (yield: 68%) .
Powder X-ray diffraction ( PXRD ) analysis
Powder X-ray diffraction (PXRD) analysis showed that the 2? Diffraction angles were 8.8 ± 0.2 °, 14.5 ± 0.2 °, 17.2 ± 0.2 °, 18.1 ± 0.2 °, 18.8 ± 0.2 °, 21.2 ± 0.2 °, 22.8 ± 0.2 ° , 23.3 ± 0.2 °, 27.7 ± 0.2 °, 25.6 ± 0.2 ° and 29 ± 0.2 °, respectively (FIG. 10). The scanning range was 5 to 35 ° , 2?, And the scanning speed was 6 deg / min.
Differential scanning calorie ( DSC ) analysis
As a result of differential scanning calorimetry (DSC) analysis, an endothermic peak was observed at an endothermic start temperature of 140 ° C ± 2 ° C and an endothermic temperature of 142 ° C ± 3 ° C (FIG. 7). The temperature raising range was 20-195 占 폚, and the temperature raising rate was 5 占 폚 / min.
Test Example 1: choline Alfoscerate - Curcumin Co-decision Taste comparison evaluation
The choline alfoscerate-curcumin co-crystals and choline alfoscerate solid crystals (crystalline form IV solid glyceryl phosphoryl choline, prepared according to International Application No. PCT / KR2015-000446) prepared in Example 1, A sensory test was conducted to compare and evaluate the taste. A 0.01 M aqueous solution was prepared for each material, and then 0.5 mL was taken in a brown vial. After that, 10 adult men were used as the experimental group, and each of them was tasted at intervals of 30 minutes. The subjects who were subjected to the sensory test did not know what the taste material was first and the taste material afterwards. After tasting the first substance, they drank 200 mL of water and tasted the next substance after 30 minutes. The results are shown in Table 1 below.
As shown in Table 1, it can be seen that the choline alfoscerate curcumin co-crystals were significantly improved in taste compared to the choline alfoscerate solid crystals. In addition, subjects who tasted the choline alfoscerate solid crystalline form stated that the taste bitter for 5 minutes or more had drifted from the mouth, while the subjects who had tasted the crystals did not retain the taste even if they responded a little bit at the moment of taste I do not know.
Test Example 2: Hygroscopicity comparative evaluation
Hygroscopicity is one of the important factors for the processing and storage among the physical properties required for choline alfoscerate to be used as a raw material drug. Therefore, the hygroscopicity of the novel crystalline choline alfoscerate curcumin cocrystal Were compared. In particular, choline alfoscerate is a substance directly linked to hygroscopicity stability. Even in the case of a solid crystal form, when it is left at room temperature for a long time, it easily absorbs atmospheric humidity and is converted into a liquid phase through a hydrate and a gel form. And since it is well known that choline alfoscerate converted into liquid phase degrades during long-term storage, a comparative assessment of this hygroscopicity can be an important criterion directly linked to stability. Hygroscopicity test As a control group, solid type choline alfoscerate (International Application No. PCT / KR2015-000446) of crystalline type IV having the most improved hygroscopicity known to date was used.
500 mg of a crystalline type IV choline alfoscerate (manufactured by Nippon Shokubai Co., Ltd. under the PCT / KR2015-000446 method) and 500 mg of a curcumin powder with a purity of 99% (Asta chemical purchased in China) were used. 500 mg of each of Choline alfoscerate curcumin cocrystal 1: 1 forming ratio material (Example 1) and 2: 5 forming ratio material (Example 4) was placed in a glass tube for hygroscopicity measurement and the mixture was incubated at 25 ° C for 12 hours After drying with nitrogen, the mass change rate of the sample after storage for 10 hours at relative humidity of 15%, 35%, 55%, and 75% was measured using a hygroscopicity measuring device (Hydrosorb 1000, model name of Quantachrome) . The values in Table 2 are the mass changes in% as a result of moisture absorption and the initial mass of each sample as zero.
As shown in Table 2, the crystalline type IV choline alfoscerate shows a relatively rapid increase in moisture absorption as the relative humidity increases. However, the compound produced in the present invention, choline alfoscerate curcumin cocrystal ) 1: 1 formation ratio material and 2: 5 formation ratio material exhibit a good moisture absorption at a full range of relative humidity. Therefore, it can be seen that the quality of the raw material can be stably guaranteed even when exposed to moisture. This is because, in comparison with the case where the conventional crystalline solid choline alfoscerate is used and the problem of moisture absorption in the storage and formulation process and the storage condition after preparation of the finished product is not completely solved, the crystalline choline alfoselate The new decision by Curcumin suggests that this hygroscopic problem can be solved. In particular, when compared with the relative increase in moisture absorption of conventional solid crystalline choline alfoscerate at a relative humidity of 35%, which is a relatively dry condition, the crystalline choline alfoselate and the new crystal of curcumin, Of the amount of the API is relatively greatly reduced, which can be regarded as a significant improvement in the hygroscopicity problem which was difficult to handle in storage, transport, formulation and storage of the API.
In this way, it is possible to manufacture choline alfoscerate curcumin cocrystal which is improved in stability, hygroscopicity and bitter taste shielding as a novel powdery crystalline powder which can be used as a brain function improver or a dementia treatment agent can do.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (20)
(a) mixing and stirring solid choline alfoscerate and curcumin;
(b) cooling the resultant of step (a), followed by re-mixing and stirring; And
(c) drying the resultant of step (b) to obtain a co-crystal.
(a) mixing and stirring liquid choline alfoscerate and curcumin;
(b) cooling the resultant of step (a), followed by re-mixing and stirring; And
(c) drying the resultant of step (b) to obtain a co-crystal.
(a) mixing and stirring liquid or solid choline alfoscerate and curcumin in the presence of an organic solvent;
(b) concentrating the result of step (a); And
(c) stirring the resultant of step (b) in the presence of an organic solvent and drying to obtain a co-crystal.
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