KR101772759B1 - Stabilised amorphous form of 20(R)-ginsenoside Rg3, a method for making the same, and a pharmaceutical preparation comprising the same - Google Patents
Stabilised amorphous form of 20(R)-ginsenoside Rg3, a method for making the same, and a pharmaceutical preparation comprising the same Download PDFInfo
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- KR101772759B1 KR101772759B1 KR1020150136373A KR20150136373A KR101772759B1 KR 101772759 B1 KR101772759 B1 KR 101772759B1 KR 1020150136373 A KR1020150136373 A KR 1020150136373A KR 20150136373 A KR20150136373 A KR 20150136373A KR 101772759 B1 KR101772759 B1 KR 101772759B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract
The amorphous 20 (R) -ginsenoside Rg3 solid dispersion containing the 20 (R) -ginnenoside Rg3 and the amide compound of the present invention is thermodynamically stable and has excellent dissolution characteristics even under high temperature conditions. Also, the process for producing the 20 (R) -ginnenoside Rg3 solid dispersion of the present invention can secure the convenience of manufacture and the safety of workers by using a grinding method such as grinding and ball milling which is relatively simple and does not require any special chemical equipment .
Description
The present invention relates to a stabilized amorphous 20 (R) -ginnenoside Rg3, a process for its preparation and a preparation containing the same, and more particularly to a process for the preparation of 20 (R) -ginnenoside Rg3 (R) -ginsenoside Rg3 solid dispersion obtained by co-grinding an amide compound of the formula (I), a process for its preparation and a preparation containing the same.
Red ginseng processed with ginseng and ginseng contains unique saponins present only in ginseng saplings and exhibits a unique pharmacological activity. To date, 34 saponins have been known. Among the 34 kinds of ginseng saponins, ginsenoside Rg3 has been reported to have various therapeutic effects such as platelet aggregation inhibiting action, cancer metastasis inhibiting action, anticancer action, anticancer drug resistance inhibition, blood circulation improving action, (R) -ginsenoside Rg3 and 20 (S) -ginenoside Rg3. Among them, 20 (R) -ginsenoside Rg3 has stable chemical properties and strong tumor suppression and transposing action, but its solubility in water is very low and its bioavailability is also very low, Performance is inhibited. In general, amorphous forms are considered a possible strategy for solubility enhancement, since amorphous forms of the material are known to have better solubility characteristics than crystalline forms of the same material. However, since the unstable amorphous active component undergoes transition to a stable crystalline form, a manufacturing method capable of stabilizing the amorphous form is required.
Studies using hydroxypropyl-β-cyclodextrin, PLLA, PLGA and liposome capsules have been reported to improve water solubility and pharmacological activity of ginsenoside Rg3. This exhibits improved properties by dispersing the active ingredient in a solid matrix or carrier of high molecular weight to prevent them from forming a crystal lattice. In the preparation of solid dispersions, the more active ingredients are further diluted in the solid dispersion medium, the more amorphous they are formed. Due to the high molecular weight of the solid dispersion medium, the size and dosage of solid dispersions containing amorphous active ingredients are substantially , Which can be a major drawback for patients who need to take it.
The present inventors have studied how to prevent crystal lattice formation while minimizing the amount of solid dispersion medium used to provide stabilized amorphous 20 (R) -ginnenoside Rg3. Surprisingly, amides used for pharmaceuticals (R) -ginsenoside Rg3 solid dispersion having improved elution properties through co-grinding with a compound of the present invention.
Accordingly, the present invention provides amorphous 20 (R) -ginenoside Rg3, which has improved solubility characteristics of 20 (R) -gincenoside Rg3 and is stable under high temperature conditions, a process for producing the same, and a process for producing the amorphous 20 (R) To provide a pharmaceutical preparation containing senoside Rg3.
The present invention provides an amorphous 20 (R) -ginenoside Rg3 solid dispersion comprising 20 (R) -ginenoside Rg3 and an amide compound.
The solid dispersion of the present invention is a stabilized amorphous 20 (R) -ginnenoside Rg3 solid obtained by co-grinding 20 (R) -ginnenoside Rg3 with an amide compound used for medicine Is a dispersant. In the present invention, the "amorphous 20 (R) -ginnenoside Rg3" refers to any diffraction peak associated with the diffraction peak characteristically present in the crystalline 20 (R) -ginnenoside Rg3 in the X- Quot; refers to the 20 (R) -ginsenoside Rg3 solid form that does not show. The term "stabilized amorphous 20 (R) -ginnenoside Rg3" as used herein also means that 20 (R) -ginnenoside Rg3 is maintained in amorphous form after storage for one month at 100 DEG C do.
In the present invention, the amide compound may be any amide compound used for medicinal purposes. For example, it may be an amide compound having a molecular weight of 300 or less, which is a solid at normal temperature and preferably contains saccharin, nicotinamide, glycol Amide, caffeine or a mixture thereof, most preferably saccharin. However, examples of the amide compound are not limited to those described above. In the present invention, the amide compound functions as a dispersion medium which improves the solubility while uniformly distributing the 20 (R) -ginnenoside Rg3. It minimizes the thermodynamic deformation of 20 (R) -ginsenoside Rg3 by external temperature and moisture, thereby securing the stability of the amorphous form.
In the present invention, the solid dispersion may be prepared by mixing 20 (R) -ginenoside Rg3 with an amide compound in various ratios, preferably 20 (R) -ginenoside Rg3 and 1: 0.1 to 1:10 molar ratio. More preferably in a molar ratio of 1: 0.5 to 1: 3. However, the mixing ratio of 20 (R) -ginsenoside Rg3 and the amide compound is not limited to the above.
In the present invention, the solid dispersion containing the 20 (R) -ginenoside Rg3 and the amide compound exhibits excellent solubility characteristics as compared with the crystalline form of 20 (R) -ginnenoside Rg3, and as a result, the improved bioavailability .
The present invention also provides a process for preparing an amorphous 20 (R) -ginnenoside Rg3 solid dispersion comprising co-grinding 20 (R) -ginnenoside Rg3 with an amide compound .
In the present invention, the co-milling step may be carried out using various methods known in the art. For example, it can be performed by a method such as a grinding method and a ball milling method which are relatively simple and do not require a special chemical apparatus.
In one embodiment of the present invention, the co-milling step comprises:
20 (R) -ginsenoside Rg3 and amide compound into agate induction and mixing; And
And grinding the mixture into an agate paddle.
In yet another embodiment of the present invention, the co-milling step comprises the steps of: introducing 20 (R) -ginnenoside Rg3, an amide compound and a milling ball into a milling port; And
And rotating the milling pot at the roller. At this time, the milling port can be rotated on the roller at a speed of 100 rpm to 500 rpm, preferably at 250 rpm. However, the rotation speed is not limited thereto.
The present invention provides a pharmaceutical formulation comprising an amorphous 20 (R) -ginenoside Rg3 solid dispersion comprising 20 (R) -ginsenoside Rg3 and an amide compound.
In the present invention, the pharmaceutical preparation may be formulated by a conventional formulation method including a carrier, adjuvant or diluent commonly used as an excipient together with the solid dispersion, and may be administered orally or parenterally. have. The carrier may be any inert, non-toxic, pharmaceutically acceptable carrier.
In the present invention, the effective daily dose of the pharmaceutical preparation is from 1 mg to 1000 mg on an adult basis. The dose may be adjusted depending on the patient's age, weight, sex, dosage form, health condition, It may be administered once to several times per day.
The pharmaceutical preparations of the present invention exhibit excellent dissolution characteristics and have improved bioavailability. Therefore, it can be effectively used as a preparation having excellent effects of 20 (R) -ginsenoside Rg3 such as cancer prevention, cancer metastasis suppression, immune function improvement, fatigue recovery, memory improvement, pain relief and wound healing.
The amorphous 20 (R) -ginsenoside Rg3 solid dispersion containing the 20 (R) -ginnenoside Rg3 and the amide compound of the present invention is thermodynamically stable and has excellent dissolution characteristics even under high temperature conditions. Also, the process for producing the 20 (R) -ginnenoside Rg3 solid dispersion of the present invention can secure the convenience of manufacture and the safety of workers by using a grinding method such as grinding and ball milling which is relatively simple and does not require any special chemical equipment .
1 is a powder XRD diffraction pattern of a crystalline 20 (R) -ginnenoside Rg3 used as a raw material for an amorphous 20 (R) -ginchenoid Rg3 solid dispersion according to the present invention.
2 shows a powder XRD diffraction pattern of an amorphous 20 (R) -ginchenoid Rg3 solid dispersion according to Example 1 of the present invention.
FIG. 3 is a powder XRD diffraction pattern of saccharin used as a dispersion medium of an amorphous 20 (R) -ginsenoside Rg3 solid dispersion according to Example 1 of the present invention.
Figure 4 shows the amorphous 20 (R) -ginsenoside Rg3 solid dispersion according to Example 2 of the present invention and the powder XRD diffraction pattern measured after 8 weeks of storage at 100 deg.
Fig. 5 shows a powder XRD diffraction pattern of an amorphous 20 (R) -ginenoside Rg3 solid dispersion according to Example 3 of the present invention.
6 shows a powder XRD diffraction pattern of nicotinamide used as a dispersion medium of an amorphous 20 (R) -ginenoside Rg3 solid dispersion according to Example 3 of the present invention.
7 is a powder XRD diffraction pattern of an amorphous 20 (R) -ginchenoid Rg3 solid dispersion according to Example 4 of the present invention.
8 is a powder XRD diffraction pattern of a glycolamide used as a dispersion medium of an amorphous 20 (R) -ginenoside Rg3 solid dispersion according to Example 4 of the present invention.
9 is a powder XRD diffraction pattern of an amorphous 20 (R) -ginchenoid Rg3 solid dispersion according to Example 5 of the present invention.
10 is a powder XRD diffraction pattern of caffeine used as a dispersing medium for an amorphous 20 (R) -ginenoside Rg3 solid dispersion according to Example 5 of the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
Crystalline 20 (R) -ginsenoside Rg3 used in embodiments of the present invention is available from Chengdu Biofurify Phytochemicals Ltd. (Chengdu, China), and the amide compound purchased from Sigma-Aldrich (St. Louis, MO, USA) was used.
< Example 1> Grinding method Amorphous 20 (R) -ginsenoside Rg3 -saccharin solid Dispersion preparation
40 mg (0.05 mmol) of crystalline 20 (R) -ginsenoside Rg3 and 27.4 mg (0.15 mmol) of saccharin were precisely weighed and placed in agate mortar, mixed appropriately and ground for 30 minutes with agar pestle. The results were confirmed by powder XRD analysis of the 20 (R) -ginsenoside Rg3 solid dispersion prepared by recovering the powder prepared after 30 minutes. The powder XRD diffraction pattern was obtained using a Rigaku miniflex 600 X-ray diffractometer using Cu-K alpha with 0.154 nm as a solid phase detector. Bragg angles (2 [theta]) ranging from 5 to 35 [deg.] Were measured under the conditions of a step size of 0.02 [deg.] And a scan speed of 10 [deg.] / Min after each powder sample was stacked on a silica mount with a flat surface. In the following examples, powder XRD analysis was performed in the same manner.
FIG. 1 shows a powder XRD diffraction pattern of crystalline 20 (R) -ginenoside Rg3 used as a raw material, and FIG. 2 shows a powder XRD diffraction pattern of an amorphous 20 (R) -ginchenoid Rg3 solid dispersion prepared by the above- FIG. 3 shows a powder XRD diffraction pattern of saccharin used as a dispersion medium. Comparing FIG. 1, FIG. 3 and FIG. 2, it can be confirmed that an amorphous 20 (R) -ginnenoside Rg3 solid dispersion was prepared by the above method.
< Example 2> Ball milling Amorphous 20 (R) -ginsenoside by Method Rg3 -saccharin Solid dispersion Manufacturing and Thermal Stability Test
The ball-milling method was used for scale-up for solubility and thermal stability. Specifically, 785 mg (1 mmol) of the same crystalline 20 (R) -ginchenoid Rg3 as used in Example 1 and 91.5 mg (0.5 mmol) of saccharine were precisely weighed and placed in a 250 ml zirconia milling port. Here, a zirconia ball was inserted and tightly sealed. The milling pot was placed on a roller and milled at a rotation speed of 250 rpm. After 72 hours of milling, the powder in the pot was withdrawn and powder XRD analysis was performed immediately after manufacture and after 2 weeks, 4 weeks, and 8 weeks storage at 100 ° C, respectively.
FIG. 4 shows powder XRD patterns at 2 weeks, 4 weeks, and 8 weeks after storage of the amorphous 20 (R) -ginnenoside Rg3 solid dispersion prepared by the above method and immediately after storage at 100 ° C. 4, amorphous 20 (R) -glycinoside Rg3 solid dispersion was successfully prepared by ball milling, and 20 (R) -ginsenoside Rg3 was amorphous even after storage at high temperature for a long time, .
< Example 3> Grinding method Amorphous 20 (R) -ginsenoside Rg3 - Nicotinamide Solid dispersion Produce
40 mg (0.05 mmol) of the same crystalline 20 (R) -ginchenoid Rg3 as used in Example 1 and 13.8 mg (0.15 mmol) of nicotinamide were precisely weighed and placed in agar mortar and mixed appropriately. Respectively. After 30 minutes, the powder was recovered and powder XRD analysis of the amorphous 20 (R) -ginsenoside Rg3 solid dispersion was confirmed.
Fig. 5 shows a powder XRD diffraction pattern of the amorphous 20 (R) -ginnenoside Rg3 solid dispersion prepared by the above method, and Fig. 6 shows a powder XRD diffraction pattern of nicotinamide used as a dispersion medium. Comparing FIG. 1, FIG. 6 and FIG. 5, it can be confirmed that an amorphous 20 (R) -ginnenoside Rg 3 solid dispersion was prepared by the above method.
< Example 4> Grinding method Amorphous 20 (R) -ginsenoside Rg3 - Glycolamide Solid dispersion Produce
40 mg (0.05 mmol) of the same crystalline type 20 (R) -ginchenoid Rg3 as used in Example 1 and 11.3 mg (0.15 mmol) of glycolamide were precisely weighed and placed in agar mortar and mixed appropriately. Respectively. After 30 minutes, the powder was recovered and powder XRD analysis of the amorphous 20 (R) -ginsenoside Rg3 solid dispersion was confirmed.
FIG. 7 shows a powder XRD diffraction pattern of an amorphous 20 (R) -ginnenoside solid dispersion prepared by the above method, and FIG. 8 shows a powder XRD diffraction pattern of a glycolamide used as a dispersion medium. 1, FIG. 8 and FIG. 7, it can be confirmed that an amorphous 20 (R) -ginnenoside Rg3 solid dispersion was prepared by the above method.
< Example 5> Grinding method Amorphous 20 (R) -ginsenoside Rg3 -Caffeine Solid dispersion Produce
40 mg (0.05 mmol) of crystalline 20 (R) -ginsenoside Rg3 and 29 mg (0.15 mmol) of caffeine were precisely weighed and placed in agate mortar, mixed appropriately and ground for 30 minutes with agate pestle. After 30 minutes, the powder was recovered and powder XRD analysis of the amorphous 20 (R) -ginsenoside Rg3 solid dispersion was confirmed.
FIG. 9 shows a powder XRD diffraction pattern of the amorphous 20 (R) -ginnenoside Rg3 solid dispersion prepared by the above method, and FIG. 10 shows a powder XRD diffraction pattern of caffeine used as a dispersion medium. Comparing FIG. 1, FIG. 10 and FIG. 9, it can be confirmed that an amorphous 20 (R) -glycinoside Rg 3 solid dispersion was prepared by the above method.
< Experimental Example 1> Solubility test
The following test was conducted to examine the solubility of the amorphous 20 (R) -ginsenoside Rg3 solid dispersion according to the present invention.
A suspension of about 20 mg of the solid dispersion prepared in Example 2 and the crystalline 20 (R) -ginenoside Rg3 powder prepared in Example 3 and 40 ml of the pH 6.8 buffer solution was placed in a shaking incubator at 37 ° C, and 12 (R) -ginnenoside Rg3 concentration in the solution was analyzed by HPLC (UFLC, Shimadzu, Japan) under the following conditions.
- Detector: UV-vis absorption spectrophotometer (wavelength: 203 nm)
Column: Shim-pack GIS-ODS, 5 占 퐉, 250 mm 占 4.6 mm
- mobile phase: water and acetonitrile (5: 5)
- Flow rate: 1.0 ml / min
The results obtained are presented in the table below and show the observed maximum solubility and 12 hour solubility.
[Table 1]
The results obtained showed a substantial increase in solubility. It can be seen that the solids dispersions prepared in Example 2 and Example 3 have a solubility three to six times higher than that of crystalline 20 (R) -ginnenoside Rg3. Importantly, this increase in solubility is maintained over a period of 12 hours, which provides time for the active ingredient to be absorbed before re-precipitation. Therefore, the effect of improving the bioabsorption rate can be expected.
Claims (11)
Wherein said co-grinding comprises the steps of:
1) adding crystalline 20 (R) -ginchenoid Rg3 and an amide compound to agar induction and mixing; And
2) grinding the mixture into agar pests.
Wherein said co-grinding comprises the steps of:
1) introducing crystalline 20 (R) -ginchenoid Rg3, amide compound and milling balls into a milling port; And
2) rotating the milling pot on the roller.
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| Title |
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| Chem. Pharm. Bull. 45(10) 1688-1693 (1997) Voㅣ. 45, No.10 |
| 논문1(ZHONGGUO ZHONG YAO ZA ZHI.,2013) |
| 논문2(CHINESE TRADITIONAL AND HERBAL DRUGS,2008) |
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