Sustained-release formulation containing acetone extract of Gamboge resin

Abstract

To provide a sustained-release preparation.SOLUTION: The sustained-release preparation contains, based on the total weight of the preparation, an active ingredient comprising an acetone extract of gamboge resin in an amount of 25.00 wt.% to 31.25 wt.%, sodium lauryl sulfate in an amount of 4 wt.% to 25 wt.%, hydroxypropyl methylcellulose in an amount of 15.63 wt.% to 23.44 wt.%, microcrystalline cellulose in an amount of 6.25 wt.% to 13.38 wt.%, silicon dioxide in an amount of 0.63 wt.% to 1.56 wt.%, magnesium stearate in an amount of 0.63 wt.% to 1.56 wt.%, lactose in an amount of 25.00 wt.% to 40.13 wt.%, and dextrose in an amount of 5.00 wt.% to 7.81 wt.%.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to a sustained-release formulation containing an acetone-extracted product of gamboge resin.

Background Art

[0002] Gamboge resin is a gum-resin secreted by plants of the genus Garcinia in the family Guttiferae. It has long been used as a raw material for plant dyes and pigments. In some regions, such as India and Thailand, gamboge resin is also used as a folk medicine.

[0003] Garcinia (gamboge), mainly called "gamboge", is a kind of evergreen tree that grows in tropical regions. The main species growing in India is Garcinia morella Desv, while the main species growing in Thailand is Garcinia hanburyi Hook. Before the flowering period, the bark is spirally cut at a height of 2 meters from the ground, and the exuded resin is collected. Generally, the resin is heat-dried and solidified to obtain gamboge resin.

[0004] According to Traditional Chinese Medicine (TCM), gamboge is considered to have anti-inflammatory, detoxifying, hemostatic, and antiparasitic effects. Since 1934, there have been many reports on the components of gamboge resin.

[0005] It is now known that many compounds can be isolated from extracts of gamboge resin. For example, morellin, morellic acid, gambogic acid, morellinol, isomorellin, isomorelic acid, isogambogic acid, isomorelinol, neogambogic acid, deoxymorellin, dihydroisomorellin, α-guttiferin, β-guttiferin, gambogenic acid, deoxygambogenin, gambogellic acid, epigambogic acid, epiisogambogic acid Examples include isogambogenic acid and 30-hydroxygambogic acid.

[0006] Acetone extracts of gamboge resin and compounds obtained therefrom have been reported to have activity that inhibits the proliferation of tumor / cancer cells, as well as analgesic and anti-inflammatory effects. For example, Reference 1 describes an acetone extract derived from gamboge resin, and nine compounds further purified from the acetone extract, including formoxanthone A, which was a novel compound at the time, and eight known compounds: betulin, betulinic acid, morelic acid, isomorelic acid, gambacnic acid, isogambogic acid, isomorelinol, and deoxymorelin.

[0007] The aforementioned acetone extract and nine purified compounds have been shown to have an inhibitory effect on the proliferation of tumor / cancer cells such as liver cancer cells (HepG2), lung cancer cells (A549), breast cancer cells (MCF-7), colon cancer cells (HT-29), leukemia cells (HL-60), and lymphoma cancer cells (U937).

[0008] Reference 2 disclosed 17 novel compounds and 5 fractionated products obtained from an acetone extract of gamboge resin at the time. These 17 novel compounds and 5 fractionated products were demonstrated to have activity that inhibits the proliferation of tumor / cancer cells. Furthermore, the acetone extract and the 5 fractionated products obtained therefrom were demonstrated to have analgesic and anti-inflammatory effects.

[0009] Considering the above, there is a need for the development of a sustained-release formulation containing acetone extract of gamboge resin for medical applications. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] U.S. Patent No. 7138428 [Patent Document 2] U.S. Patent Application Publication No. 2011 / 0305784 [Overview of the project] [Problems that the invention aims to solve]

[0011] The applicant provides a sustained-release formulation that can mitigate at least one of the drawbacks of the prior art. [Means for solving the problem]

[0012] To achieve the above objective, the present invention, based on the total weight of the formulation, The active pharmaceutical ingredient (abbreviated as "API") contains an acetone extract of gamboge resin with a content of 25.00 wt% to 31.25 wt%, Sodium lauryl sulfate (abbreviated as "SLS") with a content of 4 wt% to 25 wt%, Hydroxypropyl methylcellulose with a content of 15.63 wt% to 23.44 wt%, Microcrystalline cellulose with a content of 6.25 wt% to 13.38 wt%, Silicon dioxide content of 0.63 wt% to 1.56 wt%, Magnesium stearate, with a content of 0.63 wt% to 1.56 wt%, Lactose content of 25.00 wt% to 40.13 wt%, The present invention provides a sustained-release formulation characterized by containing dextrose in an amount of 5.00 wt% to 7.81 wt%. [Brief explanation of the drawing]

[0013] Other features and advantages of this disclosure will become apparent by referring to the accompanying drawings and describing the details of the embodiments below. Note that various features may not be depicted to exact scale. [Figure 1] The HPLC elution profile of TSB-9-W1, the acetone extraction product of the gamboge resin from Example 2, is shown below. [Figure 2] This graph shows the time-dependent changes in the in vitro dissolution rate of the tablets of the present invention and TSB-9-W1, the acetone extraction product of the gamboge resin described in Example 4 below. [Modes for carrying out the invention]

[0014] For the purposes of this specification, it will be clearly understood that the word “includes” means “includes, but is not limited to,” and the word “includes” has a corresponding meaning. Where prior art publications are referenced herein, it should be understood that such references do not constitute an acknowledgment that such publications form part of the general knowledge in the art in Taiwan or any other country. Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this invention belongs. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that may be used in carrying out this invention. In fact, this invention is not limited to the methods and materials described herein.

[0015] For the purposes of this Specified and the Claims, unless otherwise stated, all numbers used herein, including amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, quantities, characteristics, and other numerical values, should be understood in all cases as being modified by the term "about," even if the term "about" is not explicitly indicated with the value, quantity, or range.

[0016] Therefore, unless the contrary is presented, the numerical parameters set forth in the following specification and claims are not and need not be exact, but may reflect tolerances, conversion factors, rounding off, measurement errors, etc., and may be approximate values and / or desired magnitudes or sizes, and may also reflect other factors known to those skilled in the art depending on the desired characteristics to be obtained by the presently disclosed subject matter. For example, the term “about” when referring to a value can mean a variation of ± 100% in some instances, ± 50% in some instances, ± 20% in some instances, ± 10% in some instances, ± 5% in some instances, ± 1% in some instances, ± 0.5% in some instances, or ± 0.1% in some instances from the specified amount, such that such variations are appropriate for carrying out the disclosed method or using the disclosed composition.

[0017] The present invention provides a sustained-release preparation. The sustained-release preparation includes an active ingredient (API) containing an acetone extract of copal resin with a content of 25.00 wt% to 31.25 wt% based on the total weight of the sustained-release preparation, sodium lauryl sulfate (SLS) with a content of 4 wt% to 25 wt%, hydroxypropyl methylcellulose with a content of 15.63 wt% to 23.44 wt%, microcrystalline cellulose with a content of 6.25 wt% to 13.38 wt%, silicon dioxide with a content of 0.63 wt% to 1.56 wt%, magnesium stearate with a content of 0.63 wt% to 1.56 wt%, lactose with a content of 25.00 wt% to 40.13 wt%, and dextrose with a content of 5.00 wt% to 7.81 wt%.

[0018] In an exemplary embodiment, based on the total weight of the sustained-release formulation, the sustained-release formulation includes an API with a content of 31.25 wt%, SLS with a content of 5 wt%, hydroxypropyl methylcellulose with a content of 18.75 wt%, microcrystalline cellulose with a content of 6.25 wt%, silicon dioxide with a content of 1.56 wt%, magnesium stearate with a content of 1.56 wt%, lactose with a content of 27.81 wt%, and dextrose with a content of 7.81 wt%.

[0019] As used herein, "sustained-release formulation" can be used interchangeably with other terms such as "controlled-release formulation" and refers to a formulation that maintains a constant drug concentration in the blood by gradually releasing the drug over a long period of time. In some embodiments, the sustained-release formulation can gradually release the drug over a period of at least 12 hours to 72 hours. In an exemplary embodiment, the sustained-release formulation can gradually release the drug over a period of at least 24 hours.

[0020] As used herein, "active ingredient" can be used interchangeably with other terms such as "active component" and "biologically active compound" and is understood to include any substance or material, or combination of substances and materials, that is pharmacologically active and thus has therapeutic value.

[0021] According to the present invention, the active ingredient (API) has an average particle diameter of about 10 μm.

[0022] According to the present invention, the acetone extract of the gamboge resin can be produced by a method including the following steps a to d. In step a, after pulverizing the gamboge resin into powder to obtain gamboge resin powder, the gamboge resin powder is extracted with acetone to obtain a first extract. In step b, the first extract is subjected to sonication to obtain a second extract. In step c, the second extract is filtered to obtain a filtrate. In step d, the filtrate is concentrated to remove acetone.

[0023] In some embodiments, in step a, the weight-to-volume ratio (g / mL) of the gamboge resin powder to acetone is in the range of 1:2 to 1:3. In some embodiments, in step b, the ultrasonic treatment is performed at a temperature within the range of 20°C to 35°C. In some embodiments, in step c, the filtration process is carried out using filter paper with a pore size in the range of 3 μm to 6 μm.

[0024] According to the present invention, when an acetone extract of gamboge resin is analyzed by high-performance liquid chromatography (HPLC), a high-performance liquid chromatography (HPLC) elution profile as shown in Figure 1 is obtained.

[0025] According to the present invention, the sustained-release formulation can be made into a dosage form suitable for oral administration using techniques well known to those skilled in the art. Examples of dosage forms include, but are not limited to, tablets (e.g., coated tablets), granules, powders, capsules (e.g., coated capsules and pellet-filled capsules), pellets, and pills. In an exemplary embodiment, the sustained-release formulation is manufactured as a tablet.

[0026] According to the present invention, the sustained-release formulation can be manufactured into tablets using direct compression or dry granulation, which are well known to those skilled in the art.

[0027] The following describes embodiments of the present invention. It should be understood that these embodiments are illustrative and descriptive, and should not be construed as limiting the present invention. [Examples]

[0028] <Examples> Basic experimental materials: Example 1. Preparation of acetone extract TSB-9-W1 of Gamboge resin The acetone extract of gamboge resin, TSB-9-W1 (i.e., the active ingredient (API)), was prepared by a slightly modified method of the method described in Example 1 of U.S. Patent No. 7,138,428. First, gamboge resin was ground into a powder to obtain gamboge resin powder. This powder was then sieved using a sieve (mesh No. 40, Kuang Yang, Taiwan). The sieved gamboge resin powder was then impregnated in acetone (the weight-to-volume ratio of gamboge resin powder to acetone (g / mL) was 1:3) at room temperature for 12 hours to obtain the first extract. The first extract was then ultrasonically vibrated for 1 hour using an ultrasonic extraction device (manufacturer: Taiwan Supercritical Technology Co., Ltd., model: ES-600N) at an initial water temperature of 20°C to 35°C to obtain the second extract. The second extract was filtered using filter paper No. 1 with a pore size of 6 μm (manufacturer: ADVANTEC) to obtain the residue on the filter paper and the filtrate. Subsequently, the residue was subjected to the above-described acetone impregnation, ultrasonic vibration, and filtration treatments four times in a row. In the last four acetone impregnations, the weight-to-volume ratio (g / mL) of the residue to acetone was 1:2. After that, all the filtrate obtained from all five filtrations was collected and concentrated using a rotary evaporator (manufacturer: Hocon-Engineering Enterprise Co., Ltd., Taiwan, model: 16A8-19) to remove most of the acetone, and then a dry extract was obtained using a vacuum furnace (manufacturer: Dengyng Instrument Co., Ltd., Taiwan, model: DOV-40) at 40°C. Then, the dried extract was pulverized using a floor-standing pulverizer (manufacturer: Yu Chi Ling Co., Ltd., Taiwan; model number: FM) equipped with a sieve with a pore size of 0.2 mm to obtain a dried powder of the acetone extract TSB-9-W1 of Gamboge resin.

[0029] Example 2. High-performance liquid chromatography (HPLC) analysis Experimental procedure: The dried powder of the acetone extract TSB-9-W1 obtained in Example 1 was dissolved in an appropriate amount of acetonitrile to obtain a test sample of the acetone extract TSB-9-W1 with a concentration of 1 mg / mL. The test samples were subjected to high-performance liquid chromatography (HPLC) analysis using techniques well known to those skilled in the art. The operating parameters and conditions for performing the HPLC are summarized in Table 1 below.

[0030] [Table 1]

[0031] result: Figure 1 shows the HPLC elution profile of TSB-9-W1, the acetone extract product of Gamboge resin. As shown in Figure 1, 13 major peaks (i.e., peaks 1 to 13) appeared during retention times from 0 to 70 minutes, indicating that TSB-9-W1, the acetone extract product of Gamboge resin, contains 13 major compounds.

[0032] Example 3. Preparation of hydrophobic, long-acting tablets containing the acetone extraction product TSB-9-W1 Experimental materials: Table 2 shows the ingredients and their amounts for producing hydrophobic, long-acting tablets (used as pharmaceuticals) containing the acetone extract product TSB-9-W1.

[0033] [Table 2]

[0034] Experimental procedure: First, the acetone extract product TSB-9-W1 obtained in Example 1 was ground (as API) to an average particle size of 10 μm. SLS, hydroxypropyl methylcellulose K4M, microcrystalline cellulose 102, silicon dioxide, magnesium stearate, lactose, and dextrose were each sieved using a 40-mesh sieve (mesh NO. 40, Kuang Yang Co., Ltd., Taiwan). Then, the acetone extract product TSB-9-W1 with an average particle size of 10 μm, the sieved SLS, the sieved hydroxypropyl methylcellulose K4M, the sieved microcrystalline cellulose 102, the sieved lactose, and the sieved dextrose were mixed to obtain a first mixture, and this first mixture was compressed into a mass using a rotary tablet press (manufacturer: Chuang Pao Special Precision Industry Co., Ltd., Taiwan, model: CB-747). The mass was then crushed into a powder, and the crushed powder was sieved using a sieve with a mesh number of 20 (mesh No. 20, Kuang Yang Co., Ltd., Taiwan). The crushed powder was then mixed with sieved silicon dioxide and sieved magnesium stearate to obtain a second mixture. The second mixture was compressed into tablets using the rotary tablet press described above. Each resulting tablet had dimensions of 0.9 cm (width) × 1.6 cm (length) × 0.515 cm (height) and a weight of 640 mg.

[0035] Example 4. Dissolution test of tablets containing acetone extract product TSB-9-W1 A dissolution test was performed on the tablets obtained in Example 3 (i.e., sustained-release formulations) to evaluate the in vitro release profile of the acetone extract product TSB-9-W1 released from the tablets. For comparison, a similar dissolution test was performed on the acetone extract product TSB-9-W1 obtained in Example 1.

[0036] Experimental procedure: The in vitro dissolution rates of three tablets, each containing the acetone extraction product TSB-9-W1 (i.e., API), were evaluated using a USP dissolution apparatus II machine (manufacturer: Tianda Tianfa Technology Co., Ltd., China, model number: RC806D). First, each of the three tablets was placed in 900 mL (pH 6.8) of a 0.25% SLS solution using 50 mM sodium phosphate monobasic solution as the solvent, and stirred at a paddle speed of 50 rpm at 37 ± 0.5 °C for 24 hours. During the stirring period, 5 mL of the dissolved solution obtained from each of the three tablets was collected irregularly (approximately every 0.5 to 3 hours), and the filtrate was collected as the test solution using a 0.45 μm porosity filter (manufacturer: Pall Corporation, USA). The obtained test solution was then analyzed using a UV-VIS spectrophotometer (manufacturer: Shishin Technology Co., Ltd., China, model number: SP-8001) at 360 nm (A 360 The absorbance was measured at the wavelength of ). Furthermore, 200 mg of the acetone extract product TSB-9-W1 obtained in Example 1 was dissolved in 900 mL (pH 6.8) of a 0.25% SLS solution using 50 mM sodium dihydrogen phosphate as the solvent, and the same dissolution test was performed.

[0037] Then, A obtained from each of the acetone extract product TSB-9-W1 and the three tablets containing the acetone extract product TSB-9-W1 360 The values ​​of each A 360The values ​​were converted to concentrations of the acetone extract product TSB-9-W1 (i.e., API) expressed in mg / mL, according to a pre-prepared standard curve using standards of different known concentrations of the acetone extract product TSB-9-W1 (i.e., API) relative to the given values. The total dissolved amount (mg) of TSB-9-W1 (i.e., API) in each of the three tablets containing the acetone extract product TSB-9-W1 of the present invention was then calculated at different time points.

[0038] The solubility (%) of the acetone extract product TSB-9-W1 and the three tablets containing the acetone extract product TSB-9-W1 of the present invention was calculated by substituting the total amount of API dissolved and the initial weight of API (i.e., 200 mg) into Equation 1 below.

[0039]

number

[0040] In the formula, A=dissolution rate (%) B = Total dissolution amount (mg) of the acetone extract product TSB-9-W1 and the API in each tablet of the present invention. C = Initial weight of the API (i.e., 200 mg) of the acetone extract product TSB-9-W1 and each tablet of the present invention.

[0041] The average dissolution rate of the tablets of the present invention at each time point was determined by averaging the dissolution rates of the three tablets obtained in this manner. The average dissolution rate of the tablets of the present invention (i.e., sustained-release formulation) at each time point and the dissolution rate of the acetone extraction product TSB-9-W1 were plotted against time to create corresponding dissolution profiles.

[0042] result: Figure 2 shows the changes in in vitro solubility of the tablets of the present invention (i.e., sustained-release formulation) and the acetone extract product TSB-9-W1. As shown in Figure 2, the solubility of the acetone extract product TSB-9-W1 was over 90% two hours after the start of the dissolution test, while the average solubility of the tablets of the present invention (i.e., sustained-release formulation) was only 16.1% two hours after the start of the dissolution test. Furthermore, the average solubility of the tablets of the present invention (i.e., sustained-release formulation) increased slowly throughout the entire period, reaching only around 80% at the end of the 24-hour dissolution test. In summary, the tablets of the present invention (i.e., sustained-release formulation) can effectively and sustainably release the acetone extract product TSB-9-W1 (i.e., API).

[0043] Based on the results described above, the sustained-release formulation of the present invention can effectively and continuously release the acetone extraction product of the gamboge resin.

[0044] In the above, many specific details have been provided to facilitate a full understanding of the embodiments for illustrative purposes. However, it will be apparent to those skilled in the art that one or more other embodiments can be implemented without specific details. Furthermore, in descriptions of "one embodiment" or "one example" in this specification, it should be understood that all descriptions accompanied by ordinal numbers or other designations may be included in specific implementations of the invention having a particular aspect, structure, or feature. Moreover, in this description, multiple variations are sometimes incorporated into a single embodiment, drawing, or description thereof, for the purpose of streamlining this description and to illustrate the multifaceted nature of this disclosure. Additionally, one or more features or specific examples in one embodiment may, where appropriate, be implemented in conjunction with one or more features or specific examples in other embodiments of this disclosure.

[0045] Although the above describes exemplary embodiments of the present invention, the present invention is not limited to the disclosed embodiments and encompasses all modifications and equivalent configurations as various configurations included in the broadest spirit and scope of interpretation. [Industrial applicability]

[0046] The sustained-release formulation of the present invention is suitable for formulations containing an acetone extract of gamboge resin.

Claims

1. Based on the total weight of the formulation, The active ingredient contains an acetone extract of Gamboge resin in an amount of 25.00 wt% to 31.25 wt%, Sodium lauryl sulfate with a content of 4 wt% to 25 wt%, Hydroxypropyl methylcellulose with a content of 15.63 wt% to 23.44 wt%, Microcrystalline cellulose with a content of 6.25 wt% to 13.38 wt%, Silicon dioxide with a content of 0.63 wt% to 1.56 wt%, Magnesium stearate with a content of 0.63 wt% to 1.56 wt%, Lactose with a content of 25.00 wt% to 40.13 wt%, A sustained-release formulation characterized by containing dextrose in an amount of 5.00 wt% to 7.81 wt%.

2. The acetone extract of the aforementioned gamboge resin is Step a involves grinding the gamboge resin into a powder to obtain gamboge resin powder, and then extracting the gamboge resin powder with acetone to obtain a first extract. Step b involves ultrasonically treating the first extract to obtain a second extract, Step c involves filtering the second extract to obtain a filtrate, The sustained-release formulation according to claim 1, characterized in that it is produced by a method comprising step d, which involves concentrating the filtrate to remove acetone.

3. The sustained-release formulation according to claim 2, characterized in that, in step a, the weight-to-volume ratio of the gamboge resin powder to acetone is within the range of 1:2 to 1:

3.

4. The sustained-release formulation according to claim 2, characterized in that, in step b, the ultrasonic treatment is performed at a temperature within the range of 20°C to 35°C.

5. The sustained-release formulation according to claim 2, characterized in that, in step c, the filtration treatment is performed using filter paper having a pore size in the range of 3 μm to 6 μm.

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