Sustained-release preparation 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 technology]

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

[0003] Garcinia cambogia, commonly known as "gamboge," is an evergreen tree that grows in tropical regions. The main species grown in India is Garcinia morella Desv, while the main species grown in Thailand is Garcinia hanburyi Hook. Before flowering, the bark is cut open in a spiral pattern two meters above ground level, and the exuding resin is collected. This resin is generally heat-dried to solidify and become gamboge resin.

[0004] According to Traditional Chinese Medicine (TCM), gamboge may have anti-inflammatory, detoxifying, hemostatic, and parasitic effects. Since 1934, many studies have documented the properties of gamboge resin.

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

[0006] It has been reported that an acetone extract of gamboge resin and compounds obtained therefrom have the activity of inhibiting the growth of tumor / cancer cells, as well as analgesic and anti-inflammatory effects. For example, Cited Document 1 describes an acetone extract 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, morellic acid, isomorellic acid, gambogic acid, isogambogic acid, isomorellinol, and deoxymorelin.

[0007] The acetone extract and nine purified compounds have been demonstrated to have the effect of inhibiting the proliferation of tumor / cancer cells, including 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] Cited Document 2 then disclosed 17 new compounds and 5 fractionated products obtained from an acetone extract of gamboge resin. These 17 new compounds and 5 fractionated products were demonstrated to have activity in inhibiting tumor / cancer cell proliferation. In addition, the acetone extract and its 5 fractionated products were demonstrated to have analgesic and anti-inflammatory effects.

[0009] In view of the foregoing, there is a need for the development of sustained release formulations containing acetone extract of gamboge resin for medical use. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Patent No. 7,138,428 [Patent Document 2] US Patent Application Publication No. 2011 / 0305784 Summary of the Invention [Problem to be solved by the invention]

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

[0012] In order to achieve the above object, the present invention provides a pharmaceutical preparation comprising: an active pharmaceutical ingredient (API) containing an acetone extract of gamboge resin in an amount 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 15.63wt% to 23.44wt%, Microcrystalline cellulose with a content of 6.25 wt% to 13.38 wt%, Silicon dioxide with a content of 0.63wt% to 1.56wt%; Magnesium stearate with a content of 0.63wt% to 1.56wt% Lactose content of 25.00wt% to 40.13wt% and a dextrose content of 5.00 wt% to 7.81 wt%. [Brief explanation of the drawings]

[0013] Other features and advantages of the present disclosure will become apparent from the following detailed description of the embodiments, taken in conjunction with the accompanying drawings, in which it is noted that various features may not be drawn to scale. [Figure 1] 1 shows the HPLC elution profile of TSB-9-W1, an acetone extraction product of gamboge resin in Example 2 below. [Figure 2] 1 is a graph showing the change over time in the in vitro dissolution rate of the tablet of the present invention and TSB-9-W1, an acetone extraction product of gamboge resin in Example 4 below. DETAILED DESCRIPTION OF THE INVENTION

[0014] It will be clearly understood that for purposes of this specification the word "including" means "including but not limited to" and the word "comprises" has a corresponding meaning. Where a prior art publication is referred to herein, it should be understood that such reference is not an admission that the publication forms 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 meaning commonly understood by one skilled in the art to which this invention belongs. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is not limited to the methods and materials described herein.

[0015] For purposes of this specification and claims, unless otherwise stated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, quantities, characteristics, and other numerical values ​​used in this specification and claims are to be understood as being modified in all instances by the term "about," even if the term "about" is not expressly stated in conjunction with a value, amount, or range.

[0016] Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and claims are not, and need not be, exact, but may be approximations and / or desired magnitudes or magnitudes reflecting tolerances, conversion factors, rounding off, measurement error and the like, as well as other factors known to those skilled in the art depending upon the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term "about" when referring to a value can mean encompassing a variation from the specified amount of ±100% in fractional forms, ±50% in fractional forms, ±20% in fractional forms, ±10% in fractional forms, ±5% in fractional forms, ±1% in fractional forms, ±0.5% in fractional forms, or ±0.1% in fractional forms, as such variations are appropriate for performing the disclosed methods or using the disclosed compositions.

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

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

[0019] As used herein, the term "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 an extended period of time. In some embodiments, the sustained-release formulation can gradually release the drug over a period of at least 12 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 therefore has therapeutic value.

[0021] According to the present invention, the active ingredient (API) has a mean particle size of about 10 μm.

[0022] According to the present invention, the acetone extract of gamboge resin can be produced by a method including the following steps a to d. In step a, gamboge resin is ground into powder to obtain gamboge resin powder, and then the gamboge resin powder is extracted with acetone to obtain a first extract. In step b, the first extract is sonicated 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-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 carried out at a temperature in the range of 20°C to 35°C. In some embodiments, in step c, the filtration is performed using filter paper with a pore size in the range of 3 μm to 6 μm.

[0024] According to the present invention, when the acetone extract of gamboge resin is analyzed by high performance liquid chromatography (HPLC), the high performance liquid chromatography (HPLC) elution profile shown in FIG. 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 made into a tablet.

[0026] In accordance with the present invention, the sustained release formulations can be manufactured into tablets using direct compression or dry granulation, both of which are well known to those skilled in the art.

[0027] Examples of the present invention will now be described, and it should be understood that these examples are illustrative and explanatory and should not be construed as limiting the present invention. [Example]

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

[0029] Example 2. High-Performance Liquid Chromatography (HPLC) Analysis Testing Procedure: The dry powder of the acetone extract TSB-9-W1 of gamboge resin obtained in Example 1 was dissolved in an appropriate amount of acetonitrile to obtain a test sample of the acetone extract TSB-9-W1 having 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, an acetone extraction product of gamboge resin. As shown in Figure 1, 13 major peaks (i.e., peak 1 to peak 13) appear between retention times of 0 and 70 minutes, indicating that TSB-9-W1, an acetone extraction product of gamboge resin, contains 13 major compounds.

[0032] Example 3. Preparation of hydrophobic long-acting tablets containing acetone-extracted product TSB-9-W1 Test materials: The ingredients and their amounts for producing hydrophobic long-acting tablets (used as pharmaceuticals) containing the acetone extraction product TSB-9-W1 are shown in Table 2.

[0033] [Table 2]

[0034] Testing Procedure: First, the acetone-extracted product TSB-9-W1 obtained in Example 1 was pulverized to an average particle size of 10 μm (as API). SLS, hydroxypropyl methylcellulose K4M, microcrystalline cellulose 102, silicon dioxide, magnesium stearate, lactose, and dextrose were each sieved through a 40-mesh sieve (mesh No. 40, Kuang Yang Co., Ltd., Taiwan). The acetone-extracted product TSB-9-W1 having 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, which was then compressed into a lump using a rotary tablet press (manufacturer: Chuang Pao Special Precision Industry Co., Ltd., Taiwan, model number: CB-747). The mass was then crushed into powder, and the crushed powder was sieved using a 20-mesh sieve (mesh NO. 20, Kuang Yang Co., 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 tablet obtained had dimensions of 0.9 cm (width) x 1.6 cm (length) x 0.515 cm (height) and weighed 640 mg.

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

[0036] Testing Procedure: The in vitro dissolution rates of three tablets containing the acetone-extracted 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). Each of the three tablets was placed in 900 mL of a 0.25% SLS solution (pH 6.8) using 50 mM sodium phosphate monobasic solution as the solvent and stirred at 37 ± 0.5°C with a paddle speed of 50 rpm for 24 hours. During the stirring period, 5 mL of the resulting dissolution solution for each of the three tablets was collected at irregular intervals (approximately every 0.5 to 3 hours). The filtrate was collected as the test solution using a 0.45 μm porosity filter (manufacturer: Pall Corporation, USA). The obtained test solution was measured at 360 nm (A) using a UV-VIS spectrophotometer (UV-VIS spectrophotometer, manufacturer: Shishin Technology Co., Ltd., China, model number: SP-8001). 360 The absorbance was measured at a wavelength of 1000 nm. Furthermore, 200 mg of the acetone-extracted product TSB-9-W1 obtained in Example 1 was dissolved in 900 mL of a 0.25% SLS solution (pH 6.8) using 50 mM sodium dihydrogen phosphate solution as the solvent, and the same dissolution test was carried out.

[0037] The A obtained for each of the acetone-extracted product TSB-9-W1 and the three tablets containing the acetone-extracted product TSB-9-W1 was 360 The value of each A 360The values ​​were converted into concentrations of the acetone-extracted product TSB-9-W1 (i.e., API) in mg / mL according to a standard curve previously prepared using standards of different known concentrations of the acetone-extracted product TSB-9-W1 (i.e., API), and the total dissolved amounts (mg) of TSB-9-W1 (i.e., API) for the acetone-extracted product TSB-9-W1 and the three tablets containing the acetone-extracted product TSB-9-W1 of the present invention at different time points were calculated.

[0038] The dissolution rates (%) of the acetone-extracted product TSB-9-W1 and the three tablets containing the acetone-extracted product TSB-9-W1 of the present invention were calculated by substituting the total dissolved amount of API and the initial weight of API (i.e., 200 mg) into the following formula 1.

[0039]

number

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

[0041] The dissolution rates of the three tablets thus obtained at each time point were averaged to determine the average dissolution rate of the tablets of the present invention at each time point. The average dissolution rates of the tablets of the present invention (i.e., sustained-release formulations) at each time point and the dissolution rate of the acetone-extracted product TSB-9-W1 were plotted against time to generate corresponding dissolution profiles.

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

[0043] According to the above results, the sustained-release preparation of the present invention can effectively and sustainably release the acetone extraction products of gamboge resin.

[0044] For purposes of explanation, numerous specific details have been set forth above to facilitate a thorough understanding of the embodiments. However, it will be apparent to one skilled in the art that one or more other embodiments may be practiced without these specific details. Furthermore, in the description of "one embodiment" or "an embodiment" herein, all references to "one embodiment" or "an embodiment" accompanied by an ordinal number or other designation should be understood to include specific aspects, structures, and features of the present invention. Furthermore, although multiple variations may be incorporated into one embodiment, drawing, or description thereof, this is for the purpose of streamlining the description and understanding the multifaceted aspects of the present disclosure. Furthermore, one or more features or specific embodiments of one embodiment may, where appropriate, be combined with one or more features or specific embodiments of other embodiments in the implementation of the present disclosure.

[0045] While the foregoing describes what are considered to be exemplary embodiments of the present invention, it is understood that the invention is not limited to the disclosed embodiments, but rather is intended to encompass all modifications and equivalents as various configurations falling within the spirit and scope of the broadest interpretation. [Industrial Applicability]

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

Claims

1. Based on the total weight of the formulation, an active ingredient comprising an acetone extract of gamboge resin in an amount of 25.00 wt % to 31.25 wt %; sodium lauryl sulfate having a content of 4 wt% to 25 wt%; Hydroxypropyl methylcellulose having a content of 15.63 wt% to 23.44 wt%; Microcrystalline cellulose having a content of 6.25 wt% to 13.38 wt%; Silicon dioxide having a content of 0.63 wt% to 1.56 wt%; magnesium stearate having a content of 0.63 wt% to 1.56 wt%; Lactose having a content of 25.00 wt% to 40.13 wt%; A sustained-release formulation comprising 5.00 wt% to 7.81 wt% dextrose.

2. The acetone extract of gamboge resin is Step a) of grinding gamboge resin into powder to obtain gamboge resin powder, and then extracting the gamboge resin powder with acetone to obtain a first extract; Step b: sonicating the first extract to obtain a second extract; Step c) filtering the second extract to obtain a filtrate; 2. The sustained-release formulation according to claim 1, wherein the sustained-release formulation is produced by a method comprising the steps of: concentrating the filtrate to remove acetone;

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

3.

4. 3. The sustained-release preparation according to claim 2, wherein in step b, the ultrasonic treatment is carried out at a temperature in the range of 20°C to 35°C.

5. 3. The sustained-release preparation according to claim 2, wherein in step c, the filtration is carried out using filter paper having a pore size in the range of 3 μm to 6 μm.

6. 2. The sustained-release formulation of claim 1, wherein the acetone extract of gamboge resin has a high performance liquid chromatography elution profile as shown in FIG.

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