Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups

Definitions

• the present invention relates to reduced coenzyme Q10, which is useful as a supplement material, and in particular to its crystals and preparations.
• Coenzyme Q is an essential component found in a wide range of living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport chain in living cells. In humans, the main component is coenzyme Q10, which has 10 repeating side chains of coenzyme Q, and in the body, approximately 40-90% of it normally exists in the reduced form.
• Coenzyme Q10 has been reported to have a wide range of physiologically active effects, including activating energy production through mitochondrial activation, activating cardiac function, stabilizing cell membranes, and protecting cells through its antioxidant properties, and is used as a pharmaceutical and supplement ingredient.
• Patent Document 1 Traditionally, most of the coenzyme Q10 used in supplements and the like has been oxidized coenzyme Q10, but since reduced coenzyme Q10 has higher oral absorbability than oxidized coenzyme Q10 (Patent Document 1), the use of reduced coenzyme Q10 is becoming more widespread.
• reduced coenzyme Q10 is easily oxidized by oxygen in the air, so supplements that contain reduced coenzyme Q10 as the main ingredient are mainly available in the form of soft capsules, such as gelatin capsules filled with oils containing reduced coenzyme Q10.
• Patent Document 2 reports that a solid composition containing reduced coenzyme Q10 can be stabilized by coating it with a coating medium such as shellac, gelatin, or gum arabic.
• the inventors have produced a tablet-type supplement using Form II crystals of reduced coenzyme Q10, and have been able to suppress oxidation during processing and obtain a formulation with a high reduced coenzyme Q10 content. However, it has been confirmed that further improvement in oxidation stability is desirable in consideration of the distribution and storage of the formulation.
• the present invention aims to provide reduced coenzyme Q10 crystals and preparations with excellent oxidative stability.
• reduced coenzyme Q10 crystals also known as Form II crystals
• crystals with higher melting points exhibit higher oxidation stability, leading to the completion of the various forms of the present invention shown below.
• a crystal of reduced coenzyme Q10 which has a maximum melting point of 53.0°C or higher when measured by differential scanning calorimetry (DSC) at a heating rate of 1°C/min.
• a solid preparation containing crystals of reduced coenzyme Q10 A formulation in which the maximum melting point (y) (°C) when measured by differential scanning calorimetry (DSC) on 30 ⁇ 1 mg of the formulation at a heating rate of 1°C/min and the amount (x) (mg) of reduced coenzyme Q10 crystals contained in 30 ⁇ 1 mg of the formulation satisfy the following formula (1):
• the present invention provides crystals and formulations of reduced coenzyme Q10 that have excellent oxidation stability and can be used in various forms of supplements.
• 1 is a graph showing the relationship between the melting point and oxidation rate of reduced coenzyme Q10 crystals as an approximate straight line.
• reduced coenzyme Q10 exists in two types of crystal polymorphism: Form I and Form II. Specifically, a crystal form of reduced coenzyme Q10 with a melting point of around 48°C and characteristic peaks at diffraction angles (2 ⁇ 0.2°) of 3.1°, 18.7°, 19.0°, 20.2°, and 23.0° in powder X-ray (Cu-K ⁇ ) diffraction is called Form I crystal, and a crystal form of reduced coenzyme Q10 with a melting point of around 52°C and characteristic peaks at diffraction angles (2 ⁇ 0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-K ⁇ ) diffraction is called Form II crystal.
• the melting point of the crystals means the melting point measured by differential scanning calorimetry (DSC) with a sample amount of 8 ⁇ 1 mg.
• Oxidation rate (%/day) (100 - relative QH ratio after storage)/number of days of storage
• the "QH ratio” means the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10 present in the crystals, and is a value calculated by the following formula.
• QH ratio (%) reduced coenzyme Q10 content / (oxidized coenzyme Q10 content + reduced coenzyme Q10 content)
• the "relative QH ratio after storage” is a value obtained by relativizing the QH ratio after storage based on the above-mentioned QH ratios measured before and after storage, with the QH ratio before storage being set at 100. Specifically, it is calculated by the following formula.
• Relative QH ratio after storage (%) QH ratio after storage / QH ratio before storage ⁇ 100
• the melting point of the crystal of the present invention is a maximum melting point of 53.0°C or higher when measured at a heating rate of 1°C/min, and more preferably 53.1°C or higher, 53.2°C or higher, 53.3°C or higher, or 53.4°C or higher.
• the melting point As long as the crystals of the present invention can be handled/stored as a solid without any problems, there is no particular upper limit to the melting point, but the maximum melting point when measured at a heating rate of 1°C/min is, for example, 55.0°C or less, preferably 54.5°C or less, more preferably 54.0°C or less, and even more preferably 53.5°C or less.
• the oxidation rate is 0.35 or less, as described above, and more preferably 0.30 or less, 0.28 or less, 0.26 or less, 0.24 or less, or 0.23 or less.
• any crystal that is a reduced coenzyme Q10 crystal and exhibits the melting point and/or oxidation rate described above belongs to the crystals of the present invention, but it is preferable that the crystal exhibits an XRD diffraction pattern characteristic of Form II crystals.
• the crystals of the present invention are preferably crystals that exhibit characteristic peaks at diffraction angles (2 ⁇ 0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-K ⁇ ) diffraction.
• the crystals of the present invention can be obtained efficiently by incorporating, for example, a procedure for temporarily increasing the temperature in the crystallization tank to dissolve a portion of the precipitated crystals in the crystallization process (cooling crystallization method) of reduced coenzyme Q10 Form II crystals.
• Crystallization of Form II crystals of coenzyme Q10 can be carried out, for example, by adding Form II crystals previously obtained as seed crystals to an ethanol solution containing reduced coenzyme Q10, and then cooling. It is preferable to appropriately control the cooling rate, since if the cooling rate is too fast, there is a risk of Form I crystals being mixed in.
• One method for obtaining the crystals of the present invention is to add an operation for dissolving some of the precipitated crystals in the above crystallization process. Specifically, at a certain point after an increase in turbidity in the crystallization tank, i.e., after crystal precipitation has been confirmed, the temperature in the crystallization tank is increased to dissolve some of the precipitated crystals. "Partial dissolution of the crystals" can be detected by a decrease in turbidity (however, it does not become zero). After some of the crystals have been dissolved, the temperature in the crystallization tank is lowered again, and cooling crystallization is resumed.
• the degree of temperature rise is not particular limitations on the degree of temperature rise as long as all of the precipitated crystals do not dissolve, but if the turbidity change is used as an indicator, and assuming that the turbidity does not become 0, it is preferable that the turbidity decrease is about 350 to 8,000 FTU, and if the temperature inside the tank is used as an indicator, the temperature rise is about 0.5 to 6.5°C.
• This temperature increase (partial dissolution of the precipitated crystals) operation usually only needs to be done once, but it may be carried out two or more times if necessary.
• the reduced coenzyme Q10 crystals precipitated through the above-mentioned process are subjected to solid-liquid separation treatment by filtration or centrifugation, and then dried, in the same manner as conventional reduced coenzyme Q10 crystals, and are isolated and recovered as the crystals of the present invention.
• solid-liquid separation and drying conditions that are well known as methods for solid-liquid separation and drying methods for reduced coenzyme Q10 crystals can be applied.
• One embodiment of the formulation of the present invention is a solid formulation containing crystals of reduced coenzyme Q10, and the maximum melting point (y) (°C) measured by differential scanning calorimetry (DSC) at a heating rate of 1°C/min for 30 ⁇ 1 mg of the formulation and the amount (x) (mg) of reduced coenzyme Q10 crystals contained in 30 ⁇ 1 mg of the formulation satisfy the following formula (1).
• the melting point of reduced coenzyme Q10 crystals observed by DSC tends to be lower in a preparation containing reduced coenzyme Q10 crystals than in a preparation containing reduced coenzyme Q10 crystals alone.
• the inventors have found through multiple experiments that a formulation satisfying the above formula (1) has excellent oxidation stability of reduced coenzyme Q10 and can be applied to various forms of supplements and the like.
• a formulation satisfying the above requirements can be obtained, for example, by using the reduced coenzyme Q10 crystal of the present invention as the reduced coenzyme Q10 crystal. That is, as another embodiment of the formulation of the present invention,
• the solid preparation include a solid preparation containing crystals of reduced coenzyme Q10.
• the maximum melting point (y) (°C) of the formulation is not particularly limited, but is, for example, 51.5°C or higher, and more preferably 51.6°C or higher, 51.7°C or higher, 51.8°C or higher, or 51.9°C or higher.
• the maximum melting point (y) (°C) of the formulation is, for example, 54.0°C or lower, preferably 53.5°C or lower, more preferably 53.0°C or lower, and even more preferably 52.5°C or lower.
• the reduced coenzyme Q10 crystals in the formulation show a pattern characteristic of Form II crystals.
• the reduced coenzyme Q10 crystals in the formulation show characteristic peaks at diffraction angles (2 ⁇ 0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-K ⁇ ) diffraction.
• the formulation of the present invention contains components other than reduced coenzyme Q10 crystals, but there are no particular limitations on the components other than reduced coenzyme Q10 crystals, and the components other than reduced coenzyme Q10 crystals may be appropriately selected depending on the use of the formulation, etc. Furthermore, there are no particular limitations on the method for producing the formulation of the present invention, and it may be produced using a known method depending on the use of the formulation, etc.
• Ingredients other than reduced coenzyme Q10 crystals include lubricants, base materials, etc.
• Lubricants include magnesium stearate, calcium stearate, sucrose fatty acid esters, etc.
• Base materials include microcrystalline cellulose, crystalline cellulose, maltitol, starch, HPC (hydroxypropyl cellulose), palatinose, etc.
• the amount of reduced coenzyme Q10 crystals contained in the formulation is not particularly limited, and can be appropriately selected according to the application, etc., as long as it does not interfere with the processing of the formulation.
• the amount of reduced coenzyme Q10 crystals contained in the formulation is usually 1 wt% or more, preferably 2 wt% or more, 5 wt% or more, or 10 wt% or more.
• the amount of reduced coenzyme Q10 crystals contained in the formulation is usually 30 wt% or less, preferably 25 wt% or less, 20 wt% or less, 15 wt% or less, or 10 wt% or less.
• QH reduced coenzyme Q10
• QH reaction solution 10 wt % of QH was dissolved in ethanol with a purity of 99.5 wt % or more
• 2 wt % of Form II type QH crystals separately prepared as seed crystals were added to the dissolved QH weight, and the crystal precipitation rate was controlled at a turbidity change rate of 15.8 FTU/min until it reached 10,000 FTU.
• Example 1 Crystals obtained by cooling crystallization with intermediate heating When the reaction solution (QH reaction solution) in which 10 wt% QH was dissolved in ethanol with a purity of 99.5 wt% or more was at 37 ° C., 8 wt% Form II type QH crystals were added as seed crystals relative to the dissolved QH weight, and the crystal precipitation rate was controlled at a turbidity change rate of 15.8 FTU/min until 10,000 FTU was reached.
• the temperature was raised to 38.5 ° C., and after confirming the decrease in turbidity, crystals were precipitated at a rate of 25 FTU/min up to 10,000 FTU again based on the turbidity value.
• the solution was cooled at 1 ° C./hr to 25 ° C. and 10 ° C./hr to 1 ° C.
• the QH crystals in the resulting reaction solution were obtained by vacuum filtration, and then vacuum dried for 24 hours to prepare dried QH crystals.
• Example 2 Crystals obtained by cooling crystallization with intermediate heating QH crystals were prepared in the same manner as in Example 1, except that after the heating and the decrease in turbidity were confirmed, the crystal precipitation rate was set to 15 FTU/min until the turbidity again reached 10,000 FTU.
• Example 3 QH crystals were prepared in the same manner as in Example 1, except that after confirming the crystal temperature increase and turbidity decrease obtained by cooling crystallization with intermediate temperature increases, the crystal precipitation rate was set to 15 FTU/min until the turbidity again reached 10,000 FTU.
• the resulting QH crystals were subjected to DSC melting point measurement under the same conditions as in Comparative Example 1, and the maximum melting point was 53.4°C. (Example 4, Comparative Example 3)
• the QH crystals prepared in Examples 1 to 3 and Comparative Examples 1 and 2 were stored in a thermostatic chamber at 40° C. and 75% RH for about one month.
• the reduced coenzyme Q10 content and oxidized coenzyme Q10 content in the crystals were measured by HPLC (high performance liquid chromatography) before and after storage, and the QH ratio, relative QH ratio after storage, and oxidation rate, which will be described below, were calculated based on the measurement results.
• QH ratio means the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10 present in the crystal, and is calculated by the following formula.
• QH ratio (%) reduced coenzyme Q10 content / (oxidized coenzyme Q10 content + reduced coenzyme Q10 content)
• the "relative QH ratio after storage” is a value obtained by relativizing the QH ratio after storage to the QH ratio before storage, which is set to 100, based on the above-mentioned QH ratios measured before and after storage, and is calculated by the following formula.
• Relative QH ratio after storage (%) QH ratio after storage / QH ratio before storage ⁇ 100
• the "oxidation rate” is the change (decrease) in the relative QH ratio during the storage period divided by the number of days of storage, and is calculated using the following formula.
• Oxidation rate (%/day) (100-relative QH ratio after storage)/number of days of storage
• the measurement results for the crystals prepared in each Example and Comparative Example are summarized in the following Table 1.
• the approximation line of the melting point and oxidation rate prepared from the results in Table 1 is shown in FIG.
• Example 5 The QH crystals obtained in Example 1 (maximum melting point: 53.1° C.), magnesium stearate, and microcrystalline cellulose were mixed in the ratios shown in Table 2 below to obtain a powdered preparation.
• Example 6 5 mg of the QH crystals (maximum melting point temperature: 53.1° C.) obtained in Example 1, 2 mg of magnesium stearate, and 93 mg of each of the base materials shown in Table 3 below were mixed to obtain a powdered preparation (powders containing 5 wt % QH).
• HPC means hydroxypropyl cellulose.
• the upper and/or lower limit values of the numerical ranges described in this specification can be arbitrarily combined to define a preferred range.
• the upper and lower limit values of the numerical ranges can be arbitrarily combined to define a preferred range
• the upper limit values of the numerical ranges can be arbitrarily combined to define a preferred range
• the lower limit values of the numerical ranges can be arbitrarily combined to define a preferred range.

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• 2024
  • 2024-03-27 JP JP2025511038A patent/JPWO2024204380A1/ja active Pending
  • 2024-03-27 WO PCT/JP2024/012301 patent/WO2024204380A1/ja not_active Ceased
  • 2024-03-27 CN CN202480019999.6A patent/CN120835873A/zh active Pending

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