Andrographolide preparation and preparation method thereof

Abstract

The invention relates to the technical field of medicine, and discloses an andrographolide preparation and a preparation method thereof.The andrographolide preparation comprises andrographolide and an auxiliary material, the andrographolide comprises raw materials with strong diffraction peaks at the positions of 12.9 + / -0.2 degrees and 25.5 + / -0.2 degrees in an X diffraction pattern expressed by the angle of 2 theta, and the auxiliary material comprises a penetration enhancer. According to the andrographolide preparation in the scheme, the andrographolide raw material with the specific crystal form is adopted, the andrographolide preparation can be directly and rapidly dissolved out in a medium during dissolution rate inspection, additives such as a surfactant and enzyme are not needed, the dissolution process is simplified, and operation is convenient; the preparation in the scheme is higher in stability, and can still keep better properties, content and dissolution rate after high temperature, high humidity and illumination influence factors; moreover, the permeability of the active ingredients is improved by introducing the penetration enhancer, so that the medicine can enter blood circulation more effectively, and the medicine effect is improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to an andrographolide preparation and a preparation method thereof. Background Art

[0002] Andrographis paniculata, also known as spring lotus and autumn willow, and bitter gall grass, is a plant of the Acanthaceae family. It tastes bitter, is cold in nature, and enters the lung, stomach, large intestine, and small intestine meridians. It is mainly used to treat exogenous wind-heat, lung heat cough and asthma, etc. Diterpenoid lactones are the main active ingredients in andrographolide preparations. They are effective monomers extracted from andrographolide. They are pure Chinese medicine preparations with pharmacological effects of clearing away heat, detoxifying, anti-inflammatory and anti-infective. They can inhibit and reduce the increase in body temperature caused by pneumococci and hemolytic streptococci, and while enhancing the body's immune function, they effectively regulate the expression of inflammatory signaling pathways and reduce lung tissue damage caused by lung inflammation. They can be used clinically to treat pneumonia and upper respiratory tract infections, etc. Andrographolide preparations overcome the shortcomings of strong hydrophobicity and low dissolution of andrographolide tablets, improve bioavailability, and improve efficacy accordingly.

[0003] Dissolution test refers to the speed and degree of drug dissolution from solid preparations such as tablets in a specified solvent. It is an important indicator for solid preparation quality control. When performing dissolution curve tests on andrographolide preparations on the market, 0.01% to 1% or more (W / V) of surfactants or enzymes and other substances need to be added to the dissolution medium to help andrographolide dissolve from the pills to increase the average dissolution content. For example, patent CN103145661B discloses a new crystal form of andrographolide. Solid preparations such as soft capsules prepared from the new crystal form mentioned in this patent use 0.1% sodium dodecyl sulfate solution as the dissolution medium when performing dissolution tests, and the dissolution process is relatively complicated.

[0004] Moreover, the properties, content and solubility of traditional andrographolide preparations will be adversely affected after being subjected to high temperature (60°C ± 2°C), high humidity (25°C, 90% ± 5%) and light (total illumination of the light source is not less than 1.2×106Lux·hr, near-ultraviolet energy is not less than 200W·hr / m2).

[0005] In addition, traditional andrographolide drugs have the problem of insufficient permeability of active ingredients, which makes it difficult for the drugs to effectively enter the blood circulation, reducing the drug effect. In response to the above problems, this application is proposed. Summary of the invention

[0006] The purpose of the present invention is to provide an andrographolide preparation and a preparation method thereof, wherein the solubility and dissolution rate of andrographolide are improved by using a specific crystal form of andrographolide, the dissolution process is simplified, and the andrographolide can be quickly dissolved from a dripping pill without adding any additives during a dissolution test, and the stability of the andrographolide preparation is improved, and the permeability of the active ingredient is improved by introducing a permeation enhancer, thereby solving the problem of insufficient permeability of the active ingredient of traditional andrographolide drugs.

[0007] The present invention is achieved through the following technical solutions.

[0008] The invention discloses an andrographolide preparation, comprising andrographolide and auxiliary materials. The andrographolide comprises a raw material having strong diffraction peaks at 12.9°±0.2° and 25.5°±0.2° in an X-ray diffraction spectrum represented by a 2θ angle. Such andrographolide raw material can be directly and rapidly dissolved in a medium during a dissolution test without the need for additives such as surfactants and enzymes. The auxiliary materials comprise a permeation promoter for improving the permeability of active ingredients in andrographolide. The andrographolide preparation has no obvious changes in properties, content and solubility after being subjected to high temperature, high humidity and light influence factors.

[0009] Furthermore, the andrographolide preparation is preferably an andrographolide pill preparation, and can also be prepared into capsules, tablets and other preparations.

[0010] Furthermore, the andrographolide also includes a raw material having strong diffraction peaks at 4.8°±0.2°, 6.2°±0.2°, 28.2°±0.2°, and 39.9°±0.2° in the X-ray diffraction pattern expressed in 2θ angles.

[0011] Furthermore, the penetration enhancer includes one of polyoxyethylene castor oil and polyoxyethylene monostearate or a mixture of any two of them.

[0012] Furthermore, the penetration enhancer also includes one or a mixture of any of Tweens, poloxamer, chitosan, sodium taurocholate, sodium deoxycholate, glycocholic acid, and polyoxyethylene alkyl ether.

[0013] Furthermore, the auxiliary material also includes a matrix, and the matrix is ​​one of polyethylene glycols, sorbitan, polyoxyethylene sorbitan, sodium stearate, beta-cyclodextrin, glycerol gelatin, or a mixture of any of them.

[0014] Furthermore, the matrix includes at least two substances, the minimum proportion of each substance is 20%, the maximum proportion is 80%, and the preferred proportion of each substance is 30-70%, more preferably 40-60%.

[0015] Furthermore, the ratio of andrographolide to auxiliary materials is 3:1, that is, 25% andrographolide and 75% auxiliary materials.

[0016] Furthermore, the particle size of the andrographolide is in the range of 100 to 200 meshes, preferably 120 to 150 meshes, and more preferably 150 meshes.

[0017] A method for preparing an andrographolide preparation, used for the above-mentioned andrographolide preparation, specifically a method for preparing andrographolide dripping pills, comprising the following steps:

[0018] Preparation: Weigh a set amount of matrix and place it in a 70-75℃ water bath. After the matrix is ​​completely melted, add a set amount of andrographolide and penetration enhancer, mix thoroughly and keep warm for later use;

[0019] Dropping: Set the drip irrigation oil bath temperature of the pill machine to 70-75℃, the cooling temperature to 12-18℃, the nozzle heating temperature to 30-45℃, the drop distance to 6-8cm, the drop rate to 40-50 drops / min, the pill weight to 26mg, and control the dripping temperature according to the actual pill weight.

[0020] The beneficial effects of the present invention are as follows: the andrographolide preparation in the present scheme adopts andrographolide raw material with specific crystal form, which can be directly dissolved in the medium quickly during dissolution test, without the need for additives such as surfactants and enzymes, thereby simplifying the dissolution process and facilitating operation; the preparation in the present scheme has higher stability, and can still maintain better properties, content and solubility after being affected by high temperature, high humidity and light; and, in the present scheme, a penetration enhancer is introduced to improve the permeability of the active ingredient, so that the drug can enter the blood circulation more effectively and improve the drug effect; the preparation process of the andrographolide dripping pill preparation disclosed in the present scheme has strong operability and is easy to mass produce. DETAILED DESCRIPTION

[0021] The invention discloses an andrographolide preparation, in particular an andrographolide dripping pill preparation, which has the following prescription: 25% of andrographolide and 75% of auxiliary materials, and each bag of the dripping pills contains 0.15g of andrographolide.

[0022] The andrographolide raw material in the prescription has strong diffraction peaks at 4.8°±0.2°, 6.2°±0.2°, 12.9°±0.2°, 25.5°±0.2°, 28.2°±0.2°, 39.9°±0.2°, and 2θ by X-ray diffraction. Preferably, the andrographolide raw material has strong diffraction peaks at 6.2°±0.2°, 12.9°±0.2°, 25.5°±0.2°, 28.2°±0.2°, and 2θ by X-ray diffraction. More preferably, the andrographolide raw material has strong diffraction peaks at 12.9°±0 There are strong diffraction peaks at 25.5°±0.2°2θ and 25.5°±0.2°2θ. The pellets prepared by using this specific crystal form of andrographolide can be directly dissolved in the medium quickly during the dissolution test, without the need for additives such as surfactants and enzymes, and have better stability. After being subjected to high temperature (60℃±2℃), high humidity (25℃, 90%±5%) and light (total illumination of the light source is not less than 1.2×106Lux·hr, and near-ultraviolet energy is not less than 200W·hr / m2), there is still no obvious change in properties, content and solubility.

[0023] The particle size range of andrographolide in the prescription is 100-200 mesh, preferably 120-150 mesh, more preferably 150 mesh.

[0024] The matrix in the prescription is one or a mixture of any several of polyethylene glycols (such as PEG4000, PEG6000), sorbitan, polyoxyethylene sorbitan, sodium stearate, beta-cyclodextrin, and glycerol gelatin; preferably one or a mixture of any several of polyethylene glycols, sorbitan glycosides, and glycerol gelatin; more preferably one or a mixture of any several of polyethylene glycols.

[0025] In this embodiment, the matrix in the prescription preferably uses two substances, wherein the proportion of matrix 1 can be 20-80%, preferably 30-70%, more preferably 40-60%; the proportion of matrix 2 can be 20-80%, preferably 30-70%, more preferably 40-60%.

[0026] The penetration enhancer is one or any combination of Tweens, poloxamers, polyoxyethylene castor oil, chitosan, sodium taurocholate, sodium deoxycholate, glycocholic acid, polyoxyethylene alkyl ether, and polyoxyethylene monostearate; preferably one or a mixture of any combination of Tweens, poloxamers, polyoxyethylene castor oil, and polyoxyethylene monostearate; more preferably one or a mixture of any combination of polyoxyethylene castor oil and polyoxyethylene monostearate.

[0027] The preparation process of andrographolide preparation is as follows:

[0028] 1. Preparation: Weigh the prescribed amount of matrix and place it in a 70-75℃ water bath. After the matrix is ​​completely melted, add the prescribed amount of andrographolide and permeation enhancer, mix well, and keep warm for later use.

[0029] 2. Dropping: Set the drip irrigation oil bath temperature of the pill machine to 70-75°C, the cooling temperature to 12-18°C, the nozzle heating temperature to 30-45°C, the drop distance to 6-8cm, the drop rate to 40-50 drops / min, the pill weight to 26mg, and control the dripping temperature according to the actual pill weight.

[0030] The indicators of the andrographolide pills prepared using the above prescription and preparation method are compared with those of the traditional andrographolide preparations as follows:

[0031] Parameter table of embodiments:

[0032]

[0033]

[0034] Comparative parameter table:

[0035]

[0036] According to the prescription composition of the embodiment and the comparative example, the pills were prepared, 0.6 grams per bag, and the influencing factors were investigated. The properties, roundness, content and dissolution were investigated. Among them, the dissolution of the pills of comparative examples 1 to 3 and the commercially available medicine required the addition of 1% surfactant sodium dodecyl sulfate (SDS) in the medium.

[0037] Table of test results of each sample determination index:

[0038]

[0039]

[0040]

[0041]

[0042]

[0043] It can be seen from the test result table of the test indicators of each sample that the dropping pills of the embodiments of the present invention are directly dissolved in the medium, while the dropping pills in Comparative Examples 1 to 3 and the commercially available medicine need to add 1% surfactant sodium dodecyl sulfate (SDS) to the medium, otherwise andrographolide cannot be dissolved in the medium and the dissolution content cannot be detected.

[0044] From the above test results, it can be seen that the test results of the embodiment of the andrographolide dripping pill of the present invention are better than those of the comparative example. The influencing factors show that the specific crystal form and reasonable particle size range of andrographolide have a great influence on the dissolution of the dripping pills, and the embodiment shows faster and more convenient dissolution; the reasonable matrix ratio also has a great influence on the properties of the dripping pills, and the dripping pills prepared in the embodiment show better roundness and more stable properties.

[0045] Therefore, only the pellets prepared using the specific crystalline form of andrographolide raw material in the prescription can be directly dissolved rapidly in the medium during the dissolution test without the need for additives such as surfactants and enzymes.

[0046] The inspection method is as follows:

[0047] 1. Content determination: Determine by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0048] Chromatographic conditions and system suitability test: octadecylsilane bonded silica gel is used as filler; methanol-water (50:50) is used as mobile phase; detection wavelength is 225nm. The theoretical plate number calculated based on andrographolide peak should be no less than 4000.

[0049] Preparation of reference solution: Take an appropriate amount of andrographolide reference substance, weigh accurately, and add methanol to make a solution containing 60 μg per 1 ml.

[0050] Preparation of test solution: Grind the product into powder, take about 80 mg, accurately weigh, add appropriate amount of methanol, ultrasonically treat (120W, 40kHz) for 25 minutes to disperse evenly, let it cool to room temperature, transfer to a 25ml volumetric flask, add methanol to dilute to the scale, shake well, filter, accurately measure 2ml of the filtrate, put it in a 25ml volumetric flask, add methanol to dilute to the scale, shake well, and obtain.

[0051] Determination method: Accurately pipette 5 μl of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0052] Each bag of this product contains andrographolide (C 20 H 30 O5) should be 90.0% to 110.0% of the labeled amount.

[0053] 2. Dissolution: Take 1 bag of this product and follow the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2), 1000 ml of purified water as the dissolution medium, the rotation speed is 75 revolutions per minute, operate according to the law, after 45 minutes, take an appropriate amount of solution, filter, and take the filtrate as the test solution.

[0054] Take an appropriate amount of andrographolide reference substance, weigh it accurately, add an appropriate amount of methanol to dissolve it, and quantitatively dilute it with the dissolution medium to make a solution containing about 0.15 mg of andrographolide per 1 ml as the reference substance solution. Determine it according to the method under the content determination item and calculate the dissolution amount of each bag. The limit is 75% of the labeled amount, which should meet the regulations.

[0055] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology in this field to understand the content of the present invention and implement it, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. An andrographolide preparation, characterized in that: The invention comprises andrographolide and auxiliary materials, wherein the andrographolide comprises a raw material having strong diffraction peaks at 12.9°±0.2° and 25.5°±0.2° in an X-ray diffraction spectrum represented by a 2θ angle, and the auxiliary materials comprise a penetration enhancer.

2. The andrographolide preparation according to claim 1, characterized in that: Andrographolide preparations include andrographolide dripping pill preparations.

3. The andrographolide preparation according to claim 1 or 2, characterized in that: The andrographolide also includes a raw material having strong diffraction peaks at 4.8°±0.2°, 6.2°±0.2°, 28.2°±0.2° and 39.9°±0.2° in an X-ray diffraction spectrum expressed in 2θ angles.

4. The andrographolide preparation according to claim 3, characterized in that: The penetration enhancer includes one of polyoxyethylene castor oil and polyoxyethylene monostearate or a mixture of any two of them.

5. The andrographolide preparation according to claim 4, characterized in that: The permeation enhancer also includes one or a mixture of any of Tweens, poloxamer, chitosan, sodium taurocholate, sodium deoxycholate, glycocholic acid, and polyoxyethylene alkyl ether.

6. The andrographolide preparation according to claim 4 or 5, characterized in that: The auxiliary materials also include a matrix, which is one of polyethylene glycols, sorbitan, polyoxyethylene sorbitan, sodium stearate, beta-cyclodextrin, glycerol gelatin, or a mixture of any of the above.

7. The andrographolide preparation according to claim 6, characterized in that: The matrix includes at least two substances, and the minimum proportion of each substance is 20% and the maximum proportion is 80%.

8. The andrographolide preparation according to claim 6, characterized in that: The ratio of andrographolide to auxiliary materials is 3:

1.

9. The andrographolide preparation according to claim 6, characterized in that: The particle size range of the andrographolide is 100-200 meshes.

10. A method for preparing an andrographolide preparation, for preparing the andrographolide preparation according to any one of claims 1 to 9, characterized in that: The following steps are involved: Preparation: Weigh a set amount of matrix and place it in a 70-75℃ water bath. After the matrix is ​​completely melted, add a set amount of andrographolide and penetration enhancer, mix thoroughly and keep warm for later use; Dropping: Set the drip irrigation oil bath temperature of the pill machine to 70-75℃, the cooling temperature to 12-18℃, the nozzle heating temperature to 30-45℃, the drop distance to 6-8cm, the drop rate to 40-50 drops / min, the pill weight to 26mg, and control the dripping temperature according to the actual pill weight.

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