A matrine sustained-release solid dispersion and a preparation method thereof

Abstract

The present application relates to the technical field of solid dispersion, and discloses a solid dispersion of matrine and a preparation method thereof.The solid dispersion of matrine comprises matrine and hydroxypropyl methyl cellulose with a mass ratio of 1:4-1:5.In vitro experimental research shows that the solid dispersion can effectively prolong the drug release time of matrine and effectively improve the bioavailability of matrine, thereby reducing the number of drug administration, reducing the adverse reactions caused by multiple drug administration, enhancing the patient compliance, and further ensuring the drug safety and effectiveness without organic solvents in the preparation process, so that the solid dispersion of matrine has a wide application prospect in the field of drug preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of solid dispersion technology, in particular to a matrine sustained-release solid dispersion and a preparation method thereof. BACKGROUND

[0002] Matrine (MAT) has the structural formula as shown in formula (I), which is a quinoline alkaloid extracted from the dried roots, plants and fruits of Sophora flavescens Ait. in the Leguminosae family, and has a molecular formula of C 15 H 24 N2O, a relative molecular mass of 248.37, and is an important active ingredient of traditional Chinese medicines (such as Sophora flavescens and Salvia miltiorrhiza) and is used for treating intestinal inflammation, skin inflammation, breast cancer and other diseases.

[0003]

[0004] Formula (I)

[0005] Matrine is extremely soluble in water and belongs to Class I drugs with high solubility and high permeability in the Biopharmaceutics Classification System (BCS). The currently disclosed solid preparations of matrine generally have a short half-life (3.66±0.13h), low bioavailability, need multiple dosing, and are prone to causing liver and kidney toxicity and other problems. Although some documents report that matrine is prepared into sustained-release preparations with various sustained-release matrix materials or additional agents, which to some extent improve the dissolution rate of the solid preparation of matrine, the preparation method is complex and the preparation composition is complex, and the ability to improve the blood drug concentration and bioavailability is limited. Therefore, there is an urgent need for a new method to improve the drug release time of matrine and improve its bioavailability. SUMMARY

[0006] In view of the problems of short half-life, fast metabolism and low bioavailability of the existing matrine, the present application provides a matrine sustained-release solid dispersion and a preparation method thereof, which can significantly prolong the drug release time of matrine and effectively improve its bioavailability and drug safety.

[0007] To achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0008] In a first aspect, the present application provides a matrine sustained-release solid dispersion, comprising matrine and a sustained-release carrier, wherein the mass ratio of the matrine to the sustained-release carrier is 1:4 to 1:5, and the sustained-release carrier is hydroxypropyl methyl cellulose.

[0009] Compared with the prior art, the matrine sustained-release solid dispersion provided by the application realizes stable and slow release of matrine by using hydroxypropyl methyl cellulose as a sustained-release carrier to package matrine, 60% to 77% of the matrine is released in 2 h in a phosphate buffer solution with pH = 6.8, no burst release occurs, 70% to 82% of the matrine is released in 6 h, 93% to 96% of the matrine is released in 12 h, and the drug release is basically complete in 24 h, the matrine has obvious stable and slow release characteristics, and the C max , T max , t 1 / 2 and AUC 0-48 are increased by about 1 times, 3 times, 2 times and 2 times respectively, the bioavailability is obviously improved, the bioavailability of matrine is increased by about 1.2 times, so that various adverse effects of multiple daily dosing can be reduced, especially the adverse effects on the liver and kidney, the drug safety and the patient's medication compliance are improved, and the application has high practical value in the pharmaceutical field.

[0010] It should be noted that the matrine in the matrine sustained-release solid dispersion exists in an amorphous state. The solid in the amorphous solid form of the application means that it is in a non-crystalline state.

[0011] Further, the mass ratio of the matrine to the sustained-release carrier is 1:5.

[0012] Further, the hydroxypropyl methyl cellulose is E-type hydroxypropyl methyl cellulose.

[0013] The type and addition ratio of the preferred sustained-release carrier are beneficial to further improve the sustained-release effect and bioavailability of matrine.

[0014] In a second aspect, the application provides a preparation method of a matrine sustained-release solid dispersion, which comprises the following steps:

[0015] Mixing matrine and a sustained-release carrier in proportion, dry ball milling, to obtain a matrine sustained-release solid dispersion.

[0016] As a specific embodiment of the application, the preparation method of the matrine sustained-release solid dispersion specifically comprises the following steps:

[0017] Putting the sustained-release carrier into a centrifuge tube, then adding matrine, mixing uniformly, to obtain a dispersion powder; adding zirconia beads into the centrifuge tube, putting the centrifuge tube into a ball mill, taking out the sample after ball milling, to obtain a matrine sustained-release dispersion, and placing it in a drying box for standby.

[0018] Further, the rotation speed of the dry ball milling is 600 r / min to 1800 r / min.

[0019] Further, the time of the dry ball milling is 20 min to 180 min.

[0020] The preparation method of the matrine sustained-release solid dispersion provided by the present application is simple in operation, good in reproducibility, and low in production cost, and no toxic or low-toxic organic solvent is involved in the preparation process, further ensuring the effectiveness and safety of the drug, and being suitable for the large-scale production of the matrine sustained-release solid dispersion.

[0021] In a third aspect, the present application further provides a pharmaceutical composition comprising the matrine sustained-release solid dispersion.

[0022] In a fourth aspect, the present application further provides a pharmaceutical preparation comprising the matrine sustained-release solid dispersion according to any one of the above or the pharmaceutical composition.

[0023] Further, the pharmaceutical preparation further comprises a pharmaceutically acceptable pharmaceutical excipient.

[0024] Further, the dosage form of the pharmaceutical preparation comprises tablets, capsules, granules, pills, powders or suspensions.

[0025] It should be noted that the matrine sustained-release solid dispersion provided by the present application can be prepared into various dosage forms by using conventional preparation processes in the art to facilitate the patients of different types to take. The present application does not specially limit the preparation method of each dosage form, and the existing technology can be used.

[0026] In view of the problem that the half-life of matrine is very short, resulting in the need for multiple dosing to maintain effective drug concentration, the present application provides a matrine solid dispersion. In vitro experimental studies show that the solid dispersion can effectively prolong the drug release time of matrine and effectively improve the bioavailability of matrine, thereby reducing the number of dosing, reducing the adverse reactions caused by multiple dosing, enhancing the patient compliance, and at the same time, the matrine solid dispersion is prepared by using dry ball milling, the preparation method is simple, the preparation efficiency is high, and the preparation process does not involve organic solvents, further ensuring the safety and effectiveness of the drug, and having a wide application prospect in the field of pharmaceutical preparations. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor on the basis of these drawings.

[0028] Figure 1 is the powder X-ray diffraction (PXRD) pattern of matrine in Example 1 of the present application;

[0029] Figure 2is a powder X-ray diffraction (PXRD) pattern of hydroxypropyl methylcellulose in Example 1 of the present invention;

[0030] Figure 3 is a powder X-ray diffraction (PXRD) pattern of the sustained-release solid dispersion of matrine obtained in Example 1 of the present invention;

[0031] Figure 4 is a powder X-ray diffraction (PXRD) pattern of the sustained-release solid dispersion of matrine obtained in Example 2 of the present invention;

[0032] Figure 5 is a powder X-ray diffraction (PXRD) pattern of the hydroxypropyl methylcellulose matrine powder obtained in Comparative Example 1 of the present invention;

[0033] Figure 6 is a powder X-ray diffraction (PXRD) pattern of the methacrylic acid-ethyl acrylate copolymer matrine powder obtained in Comparative Example 2 of the present invention;

[0034] Figure 7 is a powder X-ray diffraction (PXRD) pattern of the ethyl cellulose matrine solid dispersion obtained in Comparative Example 3 of the present invention;

[0035] Figure 8 is a differential scanning calorimetry (DSC) pattern of matrine in Example 1 of the present invention;

[0036] Figure 9 is a differential scanning calorimetry (DSC) pattern of hydroxypropyl methylcellulose in Example 1 of the present invention;

[0037] Figure 10 is a differential scanning calorimetry (DSC) pattern of the sustained-release solid dispersion of matrine obtained in Example 1 of the present invention;

[0038] Figure 11 is a differential scanning calorimetry (DSC) pattern of the sustained-release solid dispersion of matrine obtained in Example 2 of the present invention;

[0039] Figure 12 is a differential scanning calorimetry (DSC) pattern of ethyl cellulose in Comparative Example 3 of the present invention;

[0040] Figure 13 is a differential scanning calorimetry (DSC) pattern of the ethyl cellulose matrine solid dispersion obtained in Comparative Example 3 of the present invention;

[0041] Figure 14 is a graph of the in-vitro dissolution curve of matrine in Example 1 of the present invention;

[0042] Figure 15is the in-vitro dissolution curve diagram of the matrine sustained-release solid dispersion obtained in the embodiment 1 of the present application;

[0043] Figure 16 is the in-vitro dissolution curve diagram of the matrine sustained-release solid dispersion obtained in the embodiment 2 of the present application;

[0044] Figure 17 is the in-vitro dissolution curve diagram of the ethyl cellulose matrine solid dispersion obtained in the comparative example 3 of the present application;

[0045] Figure 18 is the blood concentration change curve diagram of the matrine sustained-release solid dispersion obtained in the embodiment 1 of the present application. DETAILED DESCRIPTION

[0046] In order to make the objects, technical solutions and advantages of the present application clearer, the present application is further described in detail below with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the present application.

[0047] Embodiment 1

[0048] The embodiment of the present application provides a matrine sustained-release solid dispersion, and the mass ratio of matrine (MAT) and E-type hydroxypropyl methyl cellulose (HPMC-E5) is 1:5.

[0049] The preparation method of the above matrine sustained-release solid dispersion is as follows:

[0050] 0.05g HPMC-E5 is added into a 2mL centrifuge tube, then 0.01g matrine is added, mixed uniformly, zirconium oxide beads are added into the centrifuge tube, the centrifuge tube is placed into a ball mill, and ball milling is carried out at a rotating speed of 1200r / min for 1h to obtain a matrine sustained-release dispersion, which is placed in a drying box for standby.

[0051] Embodiment 2

[0052] The embodiment of the present application provides a matrine sustained-release solid dispersion, and the mass ratio of matrine (MAT) and E-type hydroxypropyl methyl cellulose (HPMC-E5) is 1:4.

[0053] The preparation method of the above matrine sustained-release solid dispersion is as follows:

[0054] 0.04g HPMC-E5 is added into a 2mL centrifuge tube, then 0.01g matrine is added, mixed uniformly, zirconium oxide beads are added into the centrifuge tube, the centrifuge tube is placed into a ball mill, and ball milling is carried out at a rotating speed of 1800r / min for 20min to obtain a matrine sustained-release dispersion, which is placed in a drying box for standby.

[0055] Embodiment 3

[0056] The embodiment of the present application provides a matrine sustained-release solid dispersion, and a mass ratio of matrine (MAT) and E-type hydroxypropyl methyl cellulose (HPMC-E5) is 1:4.5.

[0057] The preparation method of the matrine sustained-release solid dispersion is as follows:

[0058] 0.045g of HPMC-E5 is added into a 2mL centrifuge tube, then 0.01g of matrine is added, and the mixture is uniformly mixed, zirconium oxide beads are added into the centrifuge tube, the centrifuge tube is placed into a ball mill, and ball milling is performed at a rotating speed of 600r / min for 180min, so that the matrine sustained-release dispersion is obtained, and the matrine sustained-release dispersion is placed in a drying box for standby.

[0059] Comparative Example 1

[0060] The present comparative example is different from the embodiment 1 only in that a mass ratio of matrine and HPMC-E5 is replaced by 1:3, and other preparation processes are consistent with those of the embodiment 1, and details are not described herein again.

[0061] Comparative Example 2

[0062] The present comparative example is different from the embodiment 1 only in that HPMC-E5 is replaced by an equal amount of methacrylic acid-ethyl acrylate copolymer (Methacrylic Acid-Ethyl Acrylate Copolymer, ME), and other preparation processes are consistent with those of the embodiment 1, and details are not described herein again.

[0063] Comparative Example 3

[0064] The present comparative example provides a matrine solid dispersion, which comprises matrine and ethyl cellulose (Ethyl cellulose, EC) with a mass ratio of 1:9.

[0065] The preparation process is consistent with that of the embodiment 1, and details are not described herein again.

[0066] Sample determination and structure characterization

[0067] The sample powders prepared in the embodiment 1 to the embodiment 2 and the comparative example 1 to the comparative example 3 are determined and characterized, and specific methods are as follows:

[0068] 1. Powder X-ray diffraction (PXRD)

[0069] Powder X-ray diffraction (PXRD) is performed by using a TD-3700 X-ray diffractometer (Dandong Tongda Science and Technology Co., Ltd.), and before the sample is determined, silicon sample calibration is performed, and after the sample is determined, the sample is determined.

[0070] Measurement conditions: Cu Kα radiation 1.54056 Å, tube voltage 45 kV, tube current 40 mA, scanning range 5°~35°, scanning step interval 0.02°, scanning speed 1 sec per step.

[0071] X-ray diffraction of matrine powder as follows Figure 1 As shown, its powder X-ray diffraction exhibits crystal diffraction peaks at diffraction angles of 2θ = 7.4 ± 0.2°, 11.6 ± 0.2°, 14.1 ± 0.2°, 17.5 ± 0.2°, 19.7 ± 0.2°, and 22.9 ± 0.2°.

[0072] Powder X-ray diffraction of hydroxypropyl methylcellulose tested under the same conditions is as follows: Figure 2 As shown, it does not have crystal form diffraction peaks.

[0073] Powder X-ray diffraction of matrine sustained-release solid dispersion prepared in Example 1 under the same testing conditions is as follows: Figure 3 As shown in the figure, the crystal diffraction peaks of matrine disappear, proving that matrine is in an amorphous state in the solid dispersion.

[0074] Powder X-ray diffraction of matrine sustained-release solid dispersion prepared in Example 2 under the same testing conditions is as follows: Figure 4 As shown in the figure, the crystal diffraction peaks of matrine disappear, proving that matrine is in an amorphous state in the solid dispersion.

[0075] Powder X-ray diffraction of the sample powder prepared under the same conditions as Comparative Example 1 is as follows: Figure 5 As shown in the figure, the crystal diffraction peaks of matrine still exist, indicating that matrine did not become amorphous under this method.

[0076] Powder X-ray diffraction of the powder in Comparative Example 2, tested under the same conditions, is as follows: Figure 6 As shown, the crystal diffraction peaks of matrine still exist, indicating that matrine did not become amorphous under this method.

[0077] Powder X-ray diffraction of the powder in Comparative Example 3, tested under the same conditions, is as follows: Figure 7 As shown, the crystal diffraction peaks of matrine disappear, proving that matrine is in an amorphous state in the solid dispersion.

[0078] contrast Figures 1 to 7 It can be seen that the sample powders prepared in Examples 1-2 and Comparative Example 3 are amorphous drugs, namely matrine sustained-release solid dispersions, while Comparative Example 1 and Comparative Example 2 did not form solid dispersions.

[0079] 2. Differential Scanning Calorimetry (DSC)

[0080] Differential scanning calorimetry (DSC) was performed on florfenicol, hydroxypropyl methylcellulose acetate succinate and the florfenicol solid dispersion prepared in Example 1.

[0081] DSC 3 differential scanning calorimeter (Mettler Toledo, Switzerland) was used. The sample (matrine, hydroxypropyl methylcellulose, ethyl cellulose, the sample powder prepared in Examples 1-2 and Comparative Example 3) was placed in an aluminum crucible. The determination conditions were as follows: temperature range 25-100℃, heating rate 10℃ / min, nitrogen protection, nitrogen flow rate 50mL / min.

[0082] The differential scanning calorimetry diagram of matrine is shown in Figure 8 The sharp absorption peak of matrine at 86.1℃ is the melting point peak.

[0083] The differential scanning calorimetry diagram of hydroxypropyl methylcellulose is shown in Figure 9 There is no obvious endothermic peak, indicating that it is amorphous.

[0084] The differential scanning calorimetry diagram of the matrine sustained-release solid dispersion prepared in Example 1 is shown in Figure 10 There is no obvious endothermic peak, indicating that it is amorphous.

[0085] The differential scanning calorimetry diagram of the matrine sustained-release solid dispersion prepared in Example 2 is shown in Figure 11 There is no obvious endothermic peak, indicating that it is amorphous.

[0086] The differential scanning calorimetry diagram of ethyl cellulose is shown in Figure 12 There is no obvious endothermic peak, indicating that it is amorphous.

[0087] The differential scanning calorimetry diagram of the matrine sustained-release solid dispersion prepared in Comparative Example 3 is shown in Figure 13 There is no obvious endothermic peak, indicating that it is amorphous.

[0088] It can be seen from the comparison Figures 8 to 13 that the products prepared in Examples 1-2 and Comparative Example 3 are amorphous drugs, i.e. matrine sustained-release solid dispersions.

[0089] 3. In vitro dissolution experiment

[0090] In vitro dissolution experiments were performed on matrine, the matrine sustained-release solid dispersions prepared in Examples 1-2 and Comparative Example 3. The specific method is as follows:

[0091] The experiment was conducted using an RCZ-8 intelligent dissolution tester (Shanghai Huanghai Pharmaceutical Instruments Co., Ltd.). Phosphate buffer (pH 6.8) was selected as the dissolution medium, the rotation speed was 100 rpm, and the temperature was 37.0 ± 0.5℃. Appropriate amounts of matrine and the matrine sustained-release solid dispersion powder prepared in Examples 1-2 and Comparative Example 3 were added to pH 6.8 phosphate buffer, respectively. Timing was initiated from the moment the powder came into contact with the medium. 1 mL of solution was collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h, and an equal volume of medium was immediately added. The absorbance was measured using a UV-6850 ultraviolet spectrophotometer (JENWAY, USA), and the cumulative dissolution rate of the drug at each time point was calculated in triplicate. The cumulative dissolution results for each sample powder are shown in Table 1.

[0092] Table 1. Cumulative dissolution rate of matrine sustained-release solid dispersion / %

[0093]

[0094] The results of the dissolution test of matrine are as follows: Figure 14 As shown, it accumulated a dissolution rate of up to 100.9% and reached equilibrium in 0.25 hours, which can be interpreted as complete release.

[0095] The dissolution test results of the matrine sustained-release solid dispersion prepared in Example 1 are as follows: Figure 15 As shown, the cumulative dissolution rate was 45.63% at 0.25h, 63.22% at 2h, and over 80% at 8h. It reached equilibrium after 12h, at which point the cumulative dissolution rate was 96.01%, thus prolonging the drug release time.

[0096] The dissolution test results of the matrine sustained-release solid dispersion prepared in Example 2 are as follows: Figure 16 As shown, the cumulative dissolution rate was 62.33% at 0.25h and reached 93.79% at 12h, thus reaching equilibrium.

[0097] The dissolution test results of the matrine sustained-release solid dispersion prepared in Comparative Example 3 are as follows: Figure 17 As shown, the cumulative dissolution rate was 56.29% at 0.25h, 86.65% at 2h, and 95.22% at 6h, which can be considered as complete release.

[0098] The results showed that the sustained-release solid dispersions of matrine prepared in Examples 1-2 and Comparative Example 3 all had varying degrees of sustained-release effect compared with matrine in vitro dissolution results, but the sustained-release effect of Example 1 was the best.

[0099] 4. Pharmacokinetics test

[0100] Eighteen male SD rats aged 7-8 weeks, weighing 250±20g, were purchased from Spiford (Beijing) Biotechnology Co., Ltd. After one week of acclimatization, they were randomly divided into three groups: the matrine group (MAT group), the matrine sustained-release solid dispersant group obtained in Example 1, and the matrine sustained-release solid dispersant group obtained in Comparative Example 3. All rats had free access to water and food during this period, but were fasted for 12 hours before the experiment.

[0101] Drug administration and sampling

[0102] The aqueous solutions of the MAT group, the matrine sustained-release solid dispersion group obtained in Example 1, and the matrine sustained-release solid dispersion group obtained in Comparative Example 3 were administered to rats by gavage at a dose of 70 mg / kg. Approximately 0.5 mL of blood was then collected from the orbital venous plexus at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, and 48 h, respectively. The blood samples were placed in centrifuge tubes containing heparin sodium, centrifuged at 6000 r / min for 10 min, and 200 μL of plasma was collected and stored at -20℃. The content of matrine in the blood was then determined. The results are shown in Table 2.

[0103] Table 2 Pharmacokinetic parameters of Example 1 and Comparative Example 3 (n=6)

[0104]

[0105] Note: Different lowercase letters in the superscript of peer data indicate significant differences. P <0.05); different capital letters on the shoulder insignia indicate extremely significant differences ( P <0.01); the same letter or no letter on the shoulder label indicates no significant difference ( P >0.05).

[0106] Depend on Figure 11 The results showed that the MAT group was completely detected within 24 hours, while the Example 1 group was completely detected within 48 hours. Table 2 shows the peak concentration (C0) of the MAT group within 24 hours. max Peak time (T) max ), half-life (t) 1 / 2 ) and area under the curve (AUC) 0-48 The concentrations were (5.47±0.21) μg / mL, (1.33±0.29) h, (3.42±0.50) h, and (37.24±1.37) μg·h / mL, respectively; C of group 1 in Example 1 max T max t 1 / 2 and AUC 0-48(8.96±0.47) μg / mL, (4.00±0.02) h, (8.01±1.54) h and (85.13±4.89) μg·h / mL. The peak concentration (C max ), time to peak (T max ), half-life (t 1 / 2 ) and area under the curve (AUC 0-48 ) of Example 1 were 1.64, 3.01, 2.34 and 2.29 times of MAT, respectively. The C max , T max , t 1 / 2 and AUC 0-48 of Example 1 were significantly increased compared with the MAT group and the Comparative Example 3 group (P<0.01). The bioavailability of the matrine solid dispersion prepared in Example 1 was 1.29 times of matrine, and the bioavailability of the matrine solid dispersion prepared in Example 1 was 0.37 times of that of Comparative Example 3. P <0.01). The bioavailability of the matrine solid dispersion prepared in Example 1 was 1.29 times of matrine, and the bioavailability of the matrine solid dispersion prepared in Example 1 was 0.37 times of that of Comparative Example 3.

[0107] The matrine prepared in Example 3 can achieve the same technical effects as Example 2.

[0108] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement or improvement within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A sustained-release solid dispersion of matrine, characterized in that, It includes matrine and a sustained-release carrier, wherein the mass ratio of matrine to sustained-release carrier is 1:4 to 1:5, and the sustained-release carrier is hydroxypropyl methylcellulose.

2. The matrine sustained-release solid dispersion as described in claim 1, characterized in that, The mass ratio of matrine to the sustained-release carrier is 1:

5.

3. The matrine sustained-release solid dispersion as described in claim 1, characterized in that, The hydroxypropyl methylcellulose is type E hydroxypropyl methylcellulose.

4. A method for preparing the matrine sustained-release solid dispersion according to any one of claims 1 to 3, characterized in that, Includes the following steps: Matrine and a sustained-release carrier were mixed in a certain proportion and then dry-milled to obtain a sustained-release solid dispersion of matrine.

5. The method for preparing the sustained-release solid dispersion of matrine as described in claim 4, characterized in that, The rotational speed of the dry ball mill is 600 r / min to 1800 r / min.

6. The method for preparing the sustained-release solid dispersion of matrine as described in claim 4, characterized in that, The dry ball milling time is 20 min to 180 min.

7. A pharmaceutical composition, characterized in that, Includes the matrine sustained-release solid dispersion as described in any one of claims 1 to 3.

8. A pharmaceutical preparation, characterized in that, Includes the matrine sustained-release solid dispersion according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 7.

9. The pharmaceutical preparation according to claim 8, characterized in that, It also includes pharmaceutically acceptable excipients.

10. The pharmaceutical formulation as described in claim 8 or 9, characterized in that, The dosage forms of the pharmaceutical preparations include tablets, capsules, granules, pills, powders, or suspensions.

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