Andrographolide anhydrous swallow granule and its preparation method

Abstract

The application belongs to the technical field of medicine, and particularly relates to a andrographolide anhydrous swallowing granule and a preparation method thereof. The andrographolide anhydrous swallowing granule is formed by mixing drug-containing microcapsules and flavoring auxiliaries. The drug-containing microcapsules are prepared by centrifugal hot melt spraying technology from andrographolide and high-melting-point capsule materials. The high-melting-point capsule materials are one or more of Brazil palm wax, hydrogenated castor oil, microcrystalline wax, rice bran wax and sugarcane wax. The flavoring auxiliaries are fillers, sweeteners, essences and pH regulators. The prepared granule has the characteristics of small particle size, smooth surface, good fluidity, no grit feeling, no sticky teeth feeling and easy swallowing. Moreover, the granule has a significant taste masking effect, no bitterness, moderate sweetness and moderate fragrance, which helps to improve patient compliance, and is particularly suitable for old people and children patients who have difficulty in swallowing. The centrifugal hot melt spraying technology adopted by the application is simple in process, low in cost, green and pollution-free, and suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a andrographolide anhydrous swallowing granule and a preparation method thereof. BACKGROUND

[0002] Andrographolide is a natural diterpene lactone compound existing in Andrographis Herba, which has the effects of clearing heat and resolving toxins and anti-bacterial and anti-inflammatory, and can be used to treat upper respiratory tract infection and bacterial dysentery. Andrographolide is also known as "natural antibiotic" due to its low drug resistance, and has a high clinical application value. However, andrographolide is known as "the king of bitter taste", and a small amount of oral administration can produce extremely strong bitter taste, and even cause adverse reactions such as vomiting, which seriously reduces the patient compliance and limits its clinical application. Therefore, it is of great significance to mask the bitter taste of andrographolide.

[0003] The andrographolide preparations that have been marketed mainly include capsules, tablets and drop pills. Among them, the capsules are not conducive to swallowing by the elderly, children and other patients due to their large size. The tablets are also difficult to be accepted by patients due to their strong bitter taste and poor swallowing. The drop pills have a small size and are convenient to swallow, but still have obvious bitter taste when taken orally, and the drop pills are easy to swell due to the use of polyethylene glycol as a excipient, and are adhered in the oral cavity, so the bitter taste lasts for a long time, and the patient experience is poor. In summary, the existing andrographolide preparations on the market have the disadvantages of difficult swallowing, poor taste and strong bitter taste, which seriously reduces the patient compliance and is not conducive to clinical treatment. Therefore, it is urgent to develop andrographolide preparations with easy swallowing and good taste to meet the clinical needs.

[0004] In the prior art, andrographolide granules are coated with a stomach-soluble and enteric-soluble polymer material, mixed with a taste-correcting excipient, and then prepared into a dry suspension (CN110507636A, CN111297825A), but the water-soluble film coating is easy to dissolve, and the coating is easy to break during swallowing, and the teeth may also be stuck, which eventually leads to the release of the drug in the oral cavity, and the patient will still feel a strong bitter taste. In addition, andrographolide is mixed with a low-melting-point lipid excipient in CN105581985A, heated and melted, granulated by hot melt spraying technology, mixed with a suspending agent, a flavoring agent and the like, and then administered in the form of a dry suspension. However, the low-melting-point lipid excipient has limited taste-masking effect; and the dry suspension needs to be taken with additional water, which causes a small amount of drug to be released in advance, and there is still a bitter taste when taken. In addition, due to the low density of the low-melting-point excipient, a large amount of suspending agent needs to be added in the prescription to achieve the suspending effect, so the corresponding suspension has a certain viscosity, and a small amount of drug will adhere to the oral cavity when taken, and the bitter taste will last for a long time.

[0005] Therefore, the selection of appropriate excipients and the application of appropriate preparation technology are the key to obtaining andrographolide preparations with convenient administration, good taste and high patient compliance. SUMMARY

[0006] The present application is to solve the problems of the existing preparation of andrographolide, such as difficult to swallow, strong bitter taste, and inconvenient to take, and proposes a preparation method of andrographolide anhydrous swallowing granules: andrographolide is uniformly mixed with high-melting-point encapsulating materials, and after being heated and melted, drug-containing microcapsules are prepared by centrifugal hot melt spraying technology; then the drug-containing microcapsules are uniformly mixed with taste-correcting excipients, and the andrographolide anhydrous swallowing granules are obtained. The surface of the drug-containing microcapsules prepared by the present application is a continuous physical barrier composed of high-melting-point encapsulating materials, which can effectively slow down the release of the drug in the oral cavity, efficiently mask the bitter taste, and also improve the stability of the drug; the drug-containing microcapsules also have the characteristics of small particle size, smooth surface, high roundness, and good flowability, and have excellent swallowability. In addition, due to the addition of taste-correcting excipients, the andrographolide anhydrous swallowing granules have a pleasant sweet taste and fragrance; and the filler in the taste-correcting excipients can quickly dissolve in the mouth, stimulate saliva secretion, and help the drug-containing microcapsules to be quickly swallowed. In addition, this technology is simple to operate, low in cost, and can be continuously produced, and does not require the use of organic solvents in the preparation process, which is a new way of green industrial production.

[0007] Specifically, the present application is realized through the following technical solutions:

[0008] In a first aspect, the present application provides an andrographolide anhydrous swallowing granule, which comprises:

[0009] a. Drug-containing microcapsules: the drug-containing microcapsules are composed of andrographolide and high-melting-point encapsulating materials;

[0010] b. Taste-correcting excipients: the taste-correcting excipients are composed of a filler, a sweetener, a flavoring, and a pH regulator, and in the andrographolide anhydrous swallowing granule, the andrographolide is 1-70% by mass percentage, the high-melting-point encapsulating materials are 15-60% by mass percentage, the filler is 15-60% by mass percentage, the sweetener is 0.1-1% by mass percentage, the flavoring is 0.1-2% by mass percentage, the pH regulator is 0.1-2% by mass percentage, and the sum of the mass percentages of the components is 100%.

[0011] Preferably, in the andrographolide anhydrous swallowing granule, the andrographolide is 1-35% by mass percentage, the high-melting-point encapsulating materials are 20-50% by mass percentage, the filler is 30-50% by mass percentage, the sweetener is 0.1-0.5% by mass percentage, the flavoring is 0.1-1% by mass percentage, the pH regulator is 0.1-1% by mass percentage, and the sum of the mass percentages of the components is 100%.

[0012] As an optional mode in the above-mentioned andrographolide anhydrous swallowing granule, the high-melting-point encapsulating materials have a melting point not lower than 80℃, and the high-melting-point encapsulating materials are one or more of Brazil palm wax, hydrogenated castor oil, microcrystalline wax, rice bran wax, and sugarcane wax.

[0013] As an optional mode in the above-mentioned andrographolide anhydrous swallowing granule, the filler is one or more of sucrose, lactose, mannitol, maltodextrin, and isomalt.

[0014] As an optional way in the above andyandrographolide dry swallow granules, the sweetener is one or more of neotame, aspartame, stevioside, acesulfame potassium, sucralose, glycyrrhizin, neohesperidin, and the flavoring agent is one or more of strawberry flavor, vanilla flavor, cherry flavor, banana flavor, chocolate flavor, mixed berry flavor, orange flavor, lemon flavor, pineapple flavor, and mint flavor.

[0015] As an optional way in the above andyandrographolide dry swallow granules, the pH regulator is one or more of citric acid, potassium citrate, lactic acid, tartaric acid, and malic acid.

[0016] In a second aspect, the present application provides a preparation method of the above andyandrographolide dry swallow granules of the first aspect, which comprises the following steps:

[0017] a. uniformly mixing the high-melting-point encapsulating material with the andyandrographolide powder, heating and melting, and stirring at a constant temperature to uniformly disperse the andyandrographolide;

[0018] b. spraying the molten suspension prepared in step a into a low-temperature gas stream through a rotary atomizer, controlling the temperature of the inlet and outlet air, and collecting and sieving to obtain the drug-containing microcapsules;

[0019] c. uniformly mixing the drug-containing microcapsules with the flavoring auxiliary material to obtain the andyandrographolide dry swallow granules.

[0020] As an optional way in the above preparation method of the andyandrographolide dry swallow granules, in step a, the andyandrographolide powder has been sieved through a 150-mesh screen with a mesh size of 100 μm, and the constant temperature is 80-120°C.

[0021] As an optional way in the above preparation method of the andyandrographolide dry swallow granules, in step b, the rotary atomizer rotates at a speed of 15,000-25,000 rpm, the temperature of the inlet air of the low-temperature gas stream is 10-15°C, and the temperature of the outlet air is controlled below 50°C.

[0022] Preferably, the rotary atomizer rotates at a speed of 18,000-22,000 rpm, and the temperature of the outlet air is not more than 40°C.

[0023] As an optional way in the above preparation method of the andyandrographolide dry swallow granules, in step b, the drug-containing microcapsules D 50 are less than 100 μm.

[0024] As an optional way in the above preparation method of the andyandrographolide dry swallow granules, in step c, the flavoring auxiliary material has been sieved through a 100-mesh screen with a mesh size of 150 μm.

[0025] Preferably, the prepared andrographolide anhydrous swallowing granules are screened to remove large particles and fine powder, preferably 80-200 mesh, more preferably 100-150 mesh.

[0026] Compared with the prior art, the present application has the following beneficial effects:

[0027] The present application obtains drug-containing microcapsules by mixing andrographolide with high-melting-point capsule materials, melting, and then using centrifugal hot-melt spraying technology. After screening, the drug-containing microcapsules are mixed with flavoring auxiliaries to prepare andrographolide anhydrous swallowing granules. Compared with fluidized bed granulation, coating, centrifugal coating granulation, cyclodextrin inclusion, gel micro-pellets, and hot-melt extrusion, the drug-containing microcapsules obtained by the method are smaller, have good roundness and smooth surface, are smooth to swallow without grittiness and stickiness in the mouth. At the same time, the microcapsules have low dissolution in the oral cavity and better taste masking effect. Moreover, due to the addition of flavoring auxiliaries, the microcapsules have a pleasant sweet and fragrant taste, which is easy for patients to accept, and are suitable for patients such as the elderly and children who have difficulty swallowing. In addition, the production process is simple and convenient, the production time is short, and the production can be continuous, which is convenient for scale-up. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 Fig. 1 is a dissolution test data graph of Examples 1-3.

[0029] Figure 2 Fig. 2 is a dissolution test data graph of Examples 4-6.

[0030] Figure 3 Fig. 3 is a dissolution test data graph of Examples 7-9.

[0031] Figure 4 Fig. 4 is a dissolution test data graph of Examples 10-13.

[0032] Figure 5 Fig. 5 is a dissolution test data graph of Examples 14-19.

[0033] Figure 6 Fig. 6 is a dissolution test data graph of Examples 20-25.

[0034] Figure 7 Fig. 7 is a polarizing microscope graph of raw drug and drug-containing microcapsules of Example 20. DETAILED DESCRIPTION

[0035] The preferred embodiments of the present application are described below, and it should be understood that the preferred embodiments described herein are only used to illustrate and explain the present application, and are not used to limit the present application. If the specific technology or condition is not specified in the examples, the technology or condition is performed according to the technology or condition described in the literature in the art, or according to the product instruction. If the reagent or instrument is not specified by the manufacturer, it is a conventional product that can be purchased through a regular channel.

[0036] The andrographolide raw material in the following examples is passed through a 150-mesh sieve, and the percentages (%) mentioned are mass percentages.

[0037] Example 1:

[0038] This example provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0039] S1, 200 g of andrographolide and 800 g of microcrystalline cellulose are weighed and uniformly mixed to obtain a mixture, which is reserved.

[0040] S2, the above mixture is placed in a fluidized bed, and an appropriate amount of 5% polyvinylpyrrolidone K30 aqueous solution is top-sprayed for granulation, then dried, sieved, and 60-100 mesh granules are collected for reservation.

[0041] S3, the above granules are coated with 5% Eudragit E100 ethanol solution using a fluidized bed, then dried, sieved, and 60-100 mesh granules are collected, which are obtained. The coating weight gain is 15%.

[0042] Example 2:

[0043] This example provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0044] S1, 200 g of andrographolide and 800 g of microcrystalline cellulose are weighed and uniformly mixed to obtain a mixture, which is reserved.

[0045] S2, the above mixture is placed in a fluidized bed, and an appropriate amount of 5% polyvinylpyrrolidone K30 aqueous solution is top-sprayed for granulation, then dried, sieved, and 60-100 mesh granules are collected for reservation.

[0046] S3, the above granules are coated with 5% Eudragit E100 ethanol solution using a fluidized bed, then dried, sieved, and 60-100 mesh granules are collected, which are obtained. The coating weight gain is 15%.

[0047] Example 3:

[0048] This example provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0049] S1, 200 g of andrographolide and 800 g of microcrystalline cellulose are weighed and uniformly mixed to obtain a mixture, which is reserved.

[0050] S2, place the above mixture in a fluidized bed, top spray 5% polyvinylpyrrolidone K30 aqueous solution for granulation, dry, screen, collect 60-100 mesh particles, ready for use.

[0051] S3, using a fluidized bed, bottom spray 5% ethyl cellulose N50 ethanol solution to coat the above particles, then dry, screen, collect 60-100 mesh particles, obtained. The coating weight gain is 15%.

[0052] Example 4:

[0053] The embodiment provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0054] S1, take 100g andrographolide, 200g sucrose and mix evenly to obtain a mixture, ready for use.

[0055] S2, place the above mixture in a centrifugal granulator, spray 5% polyvinylpyrrolidone K30 aqueous solution to prepare andrographolide-sucrose drug-containing pellet cores, the spraying speed is 5rpm, the atomization pressure is 0.5MPa, and the centrifugal speed is 200rpm.

[0056] S3, after the preparation of the pellet cores, continue to spray 5% polyvinylpyrrolidone K30 aqueous solution, and use a feeder to spray 100g of microcrystalline cellulose powder for powder layering coating, and the feeding speed is 15-20g / min.

[0057] S4, take the above obtained particles, dry, then pass through a 40 mesh sieve to remove large blocks of adhesion, and place in a fluidized bed, bottom spray 5% Eudragit E100 ethanol solution for coating, dry, screen, collect 30-80 mesh particles, obtained. The coating weight gain is 15%.

[0058] Example 5:

[0059] The embodiment provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0060] S1, take 200g andrographolide, 400g sucrose and mix evenly to obtain a mixture, ready for use.

[0061] S2, place the above mixture in a centrifugal granulator, spray 5% polyvinylpyrrolidone K30 aqueous solution to prepare andrographolide-sucrose drug-containing pellet cores, the spraying speed is 5rpm, the atomization pressure is 0.5MPa, and the centrifugal speed is 200rpm.

[0062] S3, after the preparation of the core, continue to spray 5% polyvinylpyrrolidone K30 aqueous solution, and use the feeder to spray 100 g of microcrystalline cellulose powder, carry out powder layering coating, and the feeding speed is 15-20 g / min.

[0063] S4, after drying the obtained granules, remove the large blocks adhered through a 40-mesh sieve, and place them in a fluidized bed, spray an appropriate amount of 5% hydroxypropyl methyl cellulose K4M ethanol solution from the bottom to coat, dry, sieve, and collect 30-80 mesh granules, thereby obtaining the coated granules. The coating weight gain is 15%.

[0064] Example 6:

[0065] The embodiment provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0066] S1, weigh 200 g of andrographolide and 400 g of sucrose, and mix them uniformly to obtain a mixture, which is used for standby.

[0067] S2, place the mixture in a centrifugal granulator, spray an appropriate amount of 5% polyvinylpyrrolidone K30 aqueous solution to prepare andrographolide-sucrose drug-containing core, the spraying speed is 5 rpm, the atomization pressure is 0.5 MPa, and the centrifugal speed is 200 rpm.

[0068] S3, after the preparation of the core, continue to spray 5% polyvinylpyrrolidone K30 aqueous solution, and use the feeder to spray 100 g of microcrystalline cellulose powder, carry out powder layering coating, and the feeding speed is 15-20 g / min.

[0069] S4, after drying the obtained granules, remove the large blocks adhered through a 40-mesh sieve, and place them in a fluidized bed, spray an appropriate amount of 5% hydroxypropyl methyl cellulose K4M ethanol solution from the bottom to coat, dry, sieve, and collect 30-80 mesh granules, thereby obtaining the coated granules. The coating weight gain is 15%.

[0070] Example 7:

[0071] The embodiment provides a preparation method of andrographolide coated granules. Specifically, the preparation method comprises the following steps:

[0072] S1, weigh 200 g of andrographolide and 400 g of sucrose, and mix them uniformly to obtain a mixture, which is used for standby.

[0073] S2, place the mixture in a centrifugal granulator, spray an appropriate amount of 5% polyvinylpyrrolidone K30 aqueous solution to prepare andrographolide-sucrose drug-containing core, the spraying speed is 5 rpm, the atomization pressure is 0.5 MPa, and the centrifugal speed is 200 rpm.

[0074] S3, place the soft material into the extrusion spheronizer to prepare the pellets. The extrusion speed is 40 rpm, the spheronization speed is 800 rpm, the extrusion screen aperture is 300 μm, and after drying, the 40-80 mesh pellets are screened and collected for use. Take 500 g of the pellets and coat them in a fluidized bed with 5% Eudragit E100 ethanol solution, screen and collect the 40-80 mesh pellets, and the coated pellets are obtained. The coating weight gain is 15%.

[0075] Example 8

[0076] This example provides a preparation method of andrographolide coated pellets. Specifically, the preparation method comprises the following steps:

[0077] S1, take 200 g of andrographolide and 800 g of microcrystalline cellulose, mix them evenly, and obtain a mixture for use.

[0078] S2, place the mixture into a wet mixing granulator, mix and stir for 5 min, and under the stirring state, add an appropriate amount of 5% polyvinylpyrrolidone K30 aqueous solution to prepare a soft material.

[0079] S3, place the soft material into the extrusion spheronizer to prepare the pellets. The extrusion speed is 40 rpm, the spheronization speed is 800 rpm, the extrusion screen aperture is 300 μm, and after drying, the 40-80 mesh pellets are screened and collected for use. Take 500 g of the pellets and coat them in a fluidized bed with 5% Eudragit E100 ethanol solution, screen and collect the 40-80 mesh pellets, and the coated pellets are obtained. The coating weight gain is 15%.

[0080] Example 9

[0081] This example provides a preparation method of andrographolide coated pellets. Specifically, the preparation method comprises the following steps:

[0082] S1, take 200 g of andrographolide and 800 g of microcrystalline cellulose, mix them evenly, and obtain a mixture for use.

[0083] S2, place the mixture into a wet mixing granulator, mix and stir for 5 min, and under the stirring state, add an appropriate amount of 5% polyvinylpyrrolidone K30 aqueous solution to prepare a soft material.

[0084] S3, place the soft material into the extrusion spheronizer to prepare the pellets. The extrusion speed is 40 rpm, the spheronization speed is 800 rpm, the extrusion screen aperture is 300 μm, and after drying, the 40-80 mesh pellets are screened and collected for use. Take 500 g of the pellets and coat them in a fluidized bed with 5% Eudragit E100 ethanol solution, screen and collect the 40-80 mesh pellets, and the coated pellets are obtained. The coating weight gain is 15%.

[0085] Example 10

[0086] The embodiment provides a preparation method of andrographolide-cyclodextrin powder. Specifically, the preparation method comprises the following steps:

[0087] S1, 20g of β-cyclodextrin is dissolved in water under the condition of 40°C; 5g of andrographolide is dissolved in ethanol, and then dripped into the β-cyclodextrin aqueous solution; and the inclusion is carried out under the condition of 40°C and an ultrasonic frequency of 50KHz for 2h.

[0088] S2, after the ultrasonic treatment of the above solution is completed, the solution is filtered through a 0.45μm microporous filter membrane, and freeze-dried for 48h to obtain freeze-dried powder.

[0089] S3, the freeze-dried powder is taken out, sieved, and the powder with a mesh size of 80 or less is collected, and the andrographolide-cyclodextrin powder is obtained.

[0090] Embodiment 11:

[0091] The embodiment provides a preparation method of andrographolide-cyclodextrin powder. Specifically, the preparation method comprises the following steps:

[0092] S1, 20g of hydroxypropyl-β-cyclodextrin is dissolved in water under the condition of 40°C; 5g of andrographolide is dissolved in ethanol, and then dripped into the hydroxypropyl-β-cyclodextrin aqueous solution; and the inclusion is carried out under the condition of 40°C and an ultrasonic frequency of 50KHz for 2h.

[0093] S2, after the ultrasonic treatment of the above solution is completed, the solution is filtered through a 0.45μm microporous filter membrane, and freeze-dried for 48h to obtain freeze-dried powder.

[0094] S3, the freeze-dried powder is taken out, sieved, and the powder with a mesh size of 80 or less is collected, and the andrographolide-cyclodextrin powder is obtained.

[0095] Embodiment 12:

[0096] The embodiment provides a preparation method of andrographolide-cyclodextrin powder. Specifically, the preparation method comprises the following steps:

[0097] S1, 20g of sulfobutyl ether-β-cyclodextrin is dissolved in water under the condition of 40°C; 5g of andrographolide is dissolved in ethanol, and then dripped into the sulfobutyl ether-β-cyclodextrin aqueous solution; and the inclusion is carried out under the condition of 40°C and an ultrasonic frequency of 50KHz for 2h.

[0098] S2, after the ultrasonic treatment of the above solution is completed, the solution is filtered through a 0.45μm microporous filter membrane, and freeze-dried for 48h to obtain freeze-dried powder.

[0099] S3, the freeze-dried powder is taken out, sieved, and the powder with a mesh size of 80 or less is collected, and the andrographolide-cyclodextrin powder is obtained.

[0100] Embodiment 13:

[0101] The embodiment provides a preparation method of andrographolide gel micro-pellets. Specifically, the preparation method comprises the following steps:

[0102] S1, sodium alginate solution is prepared by dissolving sodium alginate in water according to the ratio of sodium alginate:andrographolide:water=2g:0.5g:100g, and then andrographolide is added and uniformly stirred to obtain a drug-containing stock solution.

[0103] S2, 3g of calcium chloride is weighed and dissolved in 100g of water to uniformly stir to obtain a calcium chloride solution.

[0104] S3, the drug-containing stock solution is dropped into the calcium chloride solution at a rate of 15mL / min by using a microsyringe, so that the sodium alginate and calcium ions are fully cross-linked to form calcium alginate gel micro-pellets, and then the micro-pellets are washed, filtered, dried and collected to obtain 40-mesh micro-pellets.

[0105] Embodiment 14:

[0106] The embodiment provides a preparation method of andrographolide-lipid granules. Specifically, the preparation method comprises the following steps:

[0107] S1, 200g of andrographolide and 400g of carnauba wax are weighed and uniformly mixed to obtain a mixture, which is used for standby.

[0108] S2, the mixture is transferred to a hot melt double-screw extruder feeder, the feeding speed is set to 1kg / h, the screw rotation speed is set to 80rpm, the extrusion temperature is set to 95 DEG C, and the extrusion screen aperture is set to 300μm.

[0109] S3, the extruded granules are collected, sieved, and 30-80-mesh granules are collected, thereby obtaining the andrographolide-lipid granules.

[0110] Embodiment 15:

[0111] The embodiment provides a preparation method of andrographolide-lipid granules. Specifically, the preparation method comprises the following steps:

[0112] S1, 200g of andrographolide and 400g of hydrogenated castor oil are weighed and uniformly mixed to obtain a mixture, which is used for standby.

[0113] S2, the mixture is transferred to a hot melt double-screw extruder feeder, the feeding speed is set to 1kg / h, the screw rotation speed is set to 80rpm, the extrusion temperature is set to 95 DEG C, and the extrusion screen aperture is set to 300μm.

[0114] S3, the extruded granules are collected, sieved, and 30-80-mesh granules are collected, thereby obtaining the andrographolide-lipid granules.

[0115] Embodiment 16:

[0116] The embodiment provides a preparation method of andrographolide-lipid particles. Specifically, the preparation method comprises the following steps:

[0117] S1, 200g of andrographolide, 400g of microcrystalline wax are weighed and uniformly mixed to obtain a mixture, which is reserved.

[0118] S2, the mixture is transferred to a hot melt double screw extruder feeder, the setting is that the feeding speed is 1kg / h, the screw rotation speed is 80rpm, the extrusion temperature is 95℃, and the extrusion screen aperture is 300μm.

[0119] S3, the extruded particles are collected, screened, and 30-80 mesh particles are collected, thereby obtaining the andrographolide-lipid particles.

[0120] Embodiment 17:

[0121] The embodiment provides a preparation method of andrographolide-lipid particles. Specifically, the preparation method comprises the following steps:

[0122] S1, 200g of andrographolide, 400g of microcrystalline wax are weighed and uniformly mixed to obtain a mixture, which is reserved.

[0123] S2, the mixture is transferred to a hot melt double screw extruder feeder, the setting is that the feeding speed is 1kg / h, the screw rotation speed is 80rpm, the extrusion temperature is 95℃, and the extrusion screen aperture is 300μm.

[0124] S3, the extruded particles are collected, screened, and 30-80 mesh particles are collected, thereby obtaining the andrographolide-lipid particles.

[0125] Embodiment 18:

[0126] The embodiment provides a preparation method of andrographolide-lipid particles. Specifically, the preparation method comprises the following steps:

[0127] S1, 200g of andrographolide, 400g of microcrystalline wax are weighed and uniformly mixed to obtain a mixture, which is reserved.

[0128] S2, the mixture is transferred to a hot melt double screw extruder feeder, the setting is that the feeding speed is 1kg / h, the screw rotation speed is 80rpm, the extrusion temperature is 95℃, and the extrusion screen aperture is 300μm.

[0129] S3, the extruded particles are collected, screened, and 30-80 mesh particles are collected, thereby obtaining the andrographolide-lipid particles.

[0130] Embodiment 19:

[0131] The embodiment provides a preparation method of andrographolide-lipid particles. Specifically, the preparation method comprises the following steps:

[0132] S1, take 200g andirogine, 400g octadecanol and mix evenly to obtain a mixture, which is used as needed.

[0133] S2, transfer the mixture to a hot melt double screw extruder feeder, set the feeding speed to 1kg / h, the screw rotation speed to 80rpm, the extrusion temperature to 70℃, and the extrusion screen aperture to 300μm.

[0134] S3, collect the extruded particles, sieve, and collect the 30-80 mesh particles, thus obtaining the andirogine microcapsules.

[0135] Example 20

[0136] The example provides a preparation method of andirogine microcapsules. Specifically, the preparation method comprises the following steps:

[0137] S1, take 200g andirogine, 400g carnauba wax and mix evenly to obtain a mixture, which is used as needed.

[0138] S2, melt the mixture to 95℃ and continuously stir to disperse the andirogine evenly, thus obtaining a molten mixture.

[0139] S3, atomize the molten mixture through a rotary atomizer and spray it into a cold air stream, set the rotary atomizer rotation speed to 21000rpm, and the cold air stream temperature to 10℃, at this time the air outlet temperature is 29℃.

[0140] S4, after gas-solid separation, collect and sieve, and collect the andirogine microcapsules with a particle size of less than 100 mesh, thus obtaining the andirogine microcapsules.

[0141] Example 21

[0142] The example provides a preparation method of andirogine microcapsules. Specifically, the preparation method comprises the following steps:

[0143] S1, take 200g andirogine, 400g hydrogenated castor oil and mix evenly to obtain a mixture, which is used as needed.

[0144] S2, melt the mixture to 95℃ and continuously stir to disperse the andirogine evenly, thus obtaining a molten mixture.

[0145] S3, atomize the molten mixture through a rotary atomizer and spray it into a cold air stream, set the rotary atomizer rotation speed to 21000rpm, and the cold air stream temperature to 10℃, at this time the air outlet temperature is 26℃.

[0146] S4, after gas-solid separation, collect and sieve, and collect the andirogine microcapsules with a particle size of less than 100 mesh, thus obtaining the andirogine microcapsules.

[0147] Example 22:

[0148] This embodiment provides a preparation method of andrographolide microcapsules. Specifically, the preparation method comprises the following steps:

[0149] S1, 200g of andrographolide and 400g of microcrystalline wax were weighed and uniformly mixed to obtain a mixture, which was prepared for use.

[0150] S2, the mixture was heated to 90°C for melting and continuous stirring to uniformly disperse the andrographolide, thereby obtaining a molten mixture.

[0151] S3, the molten mixture was atomized by a rotary atomizer and sprayed into a cold air stream, the rotary atomizer was set to rotate at a speed of 21000 rpm, and the cold air stream was set to have a temperature of 10°C, and at this time, the air outlet temperature was 25°C.

[0152] S4, after gas-solid separation, the andrographolide microcapsules with a particle size of 100 mesh or less were collected by sieving.

[0153] Example 23:

[0154] This embodiment provides a preparation method of andrographolide microcapsules. Specifically, the preparation method comprises the following steps:

[0155] S1, 200g of andrographolide and 400g of glyceryl monostearate were weighed and uniformly mixed to obtain a mixture, which was prepared for use.

[0156] S2, the mixture was heated to 85°C for melting and continuous stirring to uniformly disperse the andrographolide, thereby obtaining a molten mixture.

[0157] S3, the molten mixture was atomized by a rotary atomizer and sprayed into a cold air stream, the rotary atomizer was set to rotate at a speed of 21000 rpm, and the cold air stream was set to have a temperature of 10°C, and at this time, the air outlet temperature was 25°C.

[0158] S4, after gas-solid separation, the andrographolide microcapsules with a particle size of 100 mesh or less were collected by sieving.

[0159] Example 24:

[0160] This embodiment provides a preparation method of andrographolide microcapsules. Specifically, the preparation method comprises the following steps:

[0161] S1, 200g of andrographolide and 400g of glyceryl monostearate were weighed and uniformly mixed to obtain a mixture, which was prepared for use.

[0162] S2, the mixture was heated to 85°C for melting and continuous stirring to uniformly disperse the andrographolide, thereby obtaining a molten mixture.

[0163] S3, the above molten mixture is atomized by a rotary atomizer and sprayed into a cold gas stream, the rotary atomizer is set at a speed of 21000 rpm, and the cold gas stream is at a temperature of 10℃, at this time the air temperature is 21℃.

[0164] S4, after gas-solid separation, collection, screening, and collection of drug-containing microcapsules with a size of 100 mesh or less, are obtained.

[0165] Example 25:

[0166] The embodiment provides a preparation method of andrographolide microcapsules. Specifically, the preparation method comprises the following steps:

[0167] S1, 200g of andrographolide and 400g of octadecanol are weighed and uniformly mixed to obtain a mixture, which is ready for use.

[0168] S2, the above mixture is heated to 70℃ to melt and continuously stirred to uniformly disperse the andrographolide, to obtain a molten mixture.

[0169] S3, the above molten mixture is atomized by a rotary atomizer and sprayed into a cold gas stream, the rotary atomizer is set at a speed of 21000 rpm, and the cold gas stream is at a temperature of 10℃, at this time the air temperature is 19℃.

[0170] S4, after gas-solid separation, collection, screening, and collection of drug-containing microcapsules with a size of 100 mesh or less, are obtained.

[0171] Example 26:

[0172] A certain amount of andrographolide preparation described in Examples 1-25 is taken and subjected to particle size, angle of repose and Hausner ratio determination, respectively, and the results are shown in Table 1:

[0173] Table 1: Particle size, angle of repose and Hausner ratio determination results

[0174]

[0175]

[0176] According to Table 1, compared with other examples, the drug-containing microcapsules described in Examples 20-25 have smaller particle size, D 50 are all less than 80μm; and the angle of repose is smaller, in the range of 35-40°, the Hausner ratio is between 1.14-1.21, and the flowability is excellent. In summary, the drug-containing microcapsules prepared by centrifugal hot melt spraying (Examples 20-25) have the advantages of small particle size and good flowability.

[0177] Example 27:

[0178] The capsule materials (carnauba wax, hydrogenated castor oil, microcrystalline wax, glycerin monostearate, glycerin behenate and octadecanol) described in Examples 20-25 were taken in an appropriate amount for melting point determination, and the results are shown in Table 2.

[0179] Table 2 Melting point determination results

[0180]

[0181] According to Table 2, the melting points are ranked from high to low as follows: carnauba wax > hydrogenated castor oil > microcrystalline wax > glycerin monostearate > glycerin behenate > octadecanol. In the present application, the capsule materials with a melting point not lower than 80°C are classified as high-melting-point capsule materials.

[0182] Example 28:

[0183] Since andrographolide has poor thermal stability and is prone to ring opening in the presence of moisture, an influencing factor experiment was performed. The andrographolide preparations described in Examples 1-25 were taken in an appropriate amount, and placed under high temperature (60°C±2°C), high humidity (RH 90%±5%) and strong light (4500lx±500lx) conditions for 10 days. Samples were taken at 0, 5 and 10 days for content determination, and the remaining percentage of andrographolide content in each preparation was calculated. The results are shown in Table 3.

[0184] Table 3 Stability determination results under high temperature, high humidity and strong light conditions

[0185]

[0186]

[0187] According to Table 3, compared with other examples, the drug-containing microcapsules prepared using the centrifugal hot melt spray technology (Examples 20-25) can effectively reduce the influence of light, moisture and heat on the drug due to the protective effect of the capsule materials, thus the drug degradation is less and the stability is significantly improved. Moreover, when high-melting-point capsule materials are used (Examples 20-22), the drug is more stable.

[0188] Example 29:

[0189] The products described in Examples 1-25 were taken in an appropriate amount (containing 150 mg of andrographolide). According to the second method of General 0931 in the 2020 edition of Chinese Pharmacopoeia, the paddle method was used with 900 mL of phosphate buffer solution (pH 6.8) as the dissolution medium, simulating the oral environment, setting the rotation speed to 100 rpm and the temperature to 37°C. 10 mL of sample was taken at 1 min for dissolution determination, and the results are shown in Table 4.

[0190] According to Table 4, the drug-containing microcapsules prepared by the centrifugal hot melt spraying technology (Examples 20-25) have a small drug dissolution rate in the simulated saliva medium at 1 min, all less than 1.5%, indicating a good taste masking effect. When high melting point encapsulating materials are used (Examples 20-22), the andrographolide dissolution rate is not more than 0.5%, and the taste masking effect is more significant.

[0191] Example 30:

[0192] Take the andrographolide described in Examples 1-25 (containing 150 mg of andrographolide) in an appropriate amount. Randomly number the samples of Examples 1-25, and select 10 volunteers to evaluate the taste. First, orally administer the above preparation and keep it in the mouth for 120 seconds, then spit it out and rinse the mouth with pure water for 10 times until there is no bitter taste in the mouth. Evaluate the next sample after 3 minutes. The evaluation indicators include bitter intensity, bitter appearance time point, grittiness, and tooth stickiness. The bitter intensity is indicated by a score ranging from 0 to 5, with a lower score representing weaker bitterness. Among them, the bitter level of andrographolide raw material is defined as 5 points, and no obvious bitterness after tasting is 0 points. The results are shown in Table 4.

[0193] Table 4 Dissolution rate and taste evaluation results of andrographolide preparations

[0194]

[0195]

[0196] According to Table 4, the drug-containing microcapsules prepared by the centrifugal hot melt spraying technology (Examples 20-25) have no grittiness and tooth stickiness, and have good swallowing properties. Compared with other examples, the taste masking effect is more significant, with bitter appearance time greater than 80 seconds and bitter intensity score less than 1.5. In addition, the results show that the drug-containing microcapsules prepared using high melting point encapsulating materials (Examples 20-22) have lower bitter intensity (bitter intensity score less than 1.0) and longer bitter appearance time (bitter appearance time greater than 100 seconds), proving that high melting point encapsulating materials have more obvious taste masking effect.

[0197] Example 31:

[0198] Take the products described in Examples 1-25 in an appropriate amount (containing 150 mg of andrographolide). According to the second method of Chapter 0931 of the 2020 edition of Chinese Pharmacopoeia, the paddle method is used, with 900 mL of pH 1.2 phosphate buffer containing 0.5% sodium dodecyl sulfate as the dissolution medium, the rotation speed is set to 100 rpm, and the temperature is 37°C. Take 10 mL at 15, 30, 60, 120, 180, 240, 360 min, then supplement the same volume of medium, and determine the dissolution rate of andrographolide. The results are shown in Table 4. Figures 1-6 ​

[0199] According to the Figures 1-6 It is known that the dissolution of the drug-containing microcapsules prepared by the centrifugal hot melt spray technique (Examples 20-25) can reach 80%, and the dissolution is good compared with other embodiments.

[0200] Example 32:

[0201] The embodiment provides a preparation method of andrographolide anhydrous swallowing granules. Specifically, the drug-containing microcapsules in Example 20 are uniformly mixed with appropriate flavoring auxiliaries to obtain the andrographolide anhydrous swallowing granules.

[0202] The prescription of the andrographolide anhydrous swallowing granules is as follows:

[0203] Drug-containing microcapsules: 10 g

[0204] Sucrose: 9.8 g

[0205] Neotame: 0.05 g

[0206] Citric acid: 0.1 g

[0207] Example 33:

[0208] The embodiment provides a preparation method of andrographolide anhydrous swallowing granules. Specifically, the drug-containing microcapsules in Example 20 are uniformly mixed with appropriate flavoring auxiliaries to obtain the andrographolide anhydrous swallowing granules.

[0209] The prescription of the andrographolide anhydrous swallowing granules is as follows:

[0210] Drug-containing microcapsules: 10 g

[0211] Sucrose: 9.8 g

[0212] Sucralose: 0.05 g

[0213] Citric acid: 0.1 g

[0214] Example 34:

[0215] The embodiment provides a preparation method of andrographolide anhydrous swallowing granules. Specifically, the drug-containing microcapsules in Example 20 are uniformly mixed with appropriate flavoring auxiliaries to obtain the andrographolide anhydrous swallowing granules.

[0216] The prescription of the andrographolide anhydrous swallowing granules is as follows:

[0217] Drug-containing microcapsules: 10 g

[0218] Sucrose: 9.8 g

[0219] Aspartame: 0.05 g

[0220] Citric acid: 0.1 g

[0221] Example 35:

[0222] This example provides a preparation method of andrographolide anhydrous swallowing granules. Specifically, the drug-containing microcapsules described in Example 20 are mixed with an appropriate amount of flavoring aids, and andrographolide anhydrous swallowing granules are obtained.

[0223] The prescription of andrographolide anhydrous swallowing granules is as follows:

[0224] Drug-containing microcapsules: 10 g

[0225] Sucrose: 9.8 g

[0226] Neotame: 0.05 g

[0227] Strawberry flavor: 0.1 g

[0228] Citric acid: 0.1 g

[0229] Example 36:

[0230] This example provides a preparation method of andrographolide anhydrous swallowing granules. Specifically, the drug-containing microcapsules described in Example 20 are mixed with an appropriate amount of flavoring aids, and andrographolide anhydrous swallowing granules are obtained.

[0231] The prescription of andrographolide anhydrous swallowing granules is as follows:

[0232] Drug-containing microcapsules: 10 g

[0233] Sucrose: 9.8 g

[0234] Neotame: 0.05 g

[0235] SD orange flavor: 0.1 g

[0236] Citric acid: 0.1 g

[0237] Example 37:

[0238] This example provides a preparation method of andrographolide anhydrous swallowing granules. Specifically, the drug-containing microcapsules described in Example 20 are mixed with an appropriate amount of flavoring aids, and andrographolide anhydrous swallowing granules are obtained.

[0239] The prescription of andrographolide anhydrous swallowing granules is as follows:

[0240] Drug-containing microcapsules: 10 g

[0241] Sucrose: 9.8 g

[0242] Neotame: 0.05 g

[0243] Mint flavor: 0.1 g

[0244] Citric acid: 0.1g

[0245] Example 38:

[0246] Appropriate amounts of the anhydrous andrographolide granules described in Examples 33-37, each containing 150 mg of andrographolide, were taken and evaluated using the same method as in Example 30. In addition, sweetness and aroma were evaluated. The sweetness score ranged from 0 to 5, with lower scores indicating weaker sweetness; 0 points represented no sweetness. The aroma score ranged from 0 to 5, with lower scores indicating weaker aroma; 0 points represented no aroma. The results are shown in Table 5.

[0247] Table 5 Taste Evaluation Experiment

[0248]

[0249] As shown in Table 5, the anhydrous andrographolide granules (Examples 32-37) all had a good taste, with no gritty or sticky feeling, and almost no bitterness, with a moderate sweetness. In addition, the addition of flavoring (Examples 35-37) significantly enhanced the aroma of the preparations, making them even more palatable when taken.

[0250] Example 39:

[0251] An appropriate amount of andrographolide raw material and the andrographolide-carnauba wax-containing microcapsules described in Example 20 were observed under a polarizing microscope. The results are as follows: Figure 7 As shown.

[0252] Depend on Figure 7 It is evident that the drug-containing microcapsules described in Example 20, prepared using centrifugal hot-melt spray technology, can completely encapsulate the andrographolide raw material within the capsule material. The capsule shell forms a continuous and dense physical barrier, explaining the advantages of the drug-containing microcapsules, such as low dissolution and good taste masking effect. Furthermore, the high sphericity and smooth surface of the microcapsules explain their advantages of good flowability and swallowability.

[0253] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. Anhydrous Andrographolide Swallowable Granules, characterized in that, It comprises: a, drug-containing microcapsules: the drug-containing microcapsules are composed of andrographolide and high-melting-point capsule materials, and the preparation method of the drug-containing microcapsules is to uniformly mix andrographolide with high-melting-point capsule materials, heat and melt, and then prepare by centrifugal hot melt spraying technology; b, flavoring adjuvants: the flavoring adjuvants are composed of fillers, sweeteners, essences and pH regulators, and in the andrographolide anhydrous swallowing granules, andrographolide accounts for 1-35% by mass percentage, high-melting-point capsule materials account for 20-50% by mass percentage, fillers account for 30-50% by mass percentage, sweeteners account for 0.1-0.5% by mass percentage, essences account for 0.1-1% by mass percentage, and pH regulators account for 0.1-1% by mass percentage, and the sum of the mass percentages of the components is 100%, The high-melting-point capsule materials are one or more of carnauba wax, hydrogenated castor oil and microcrystalline wax.

2. The andrographolide anhydrous swallow granule according to claim 1, characterized in that: The fillers are one or more of sucrose, lactose, mannitol, maltodextrin and isomalt.

3. The andrographolide anhydrous swallow granule according to claim 1, characterized in that: The sweeteners are one or more of neotame, aspartame, stevioside, acesulfame potassium, sucralose, glycyrrhizin and neohesperidin, and the essences are one or more of strawberry essence, vanilla essence, cherry essence, banana essence, chocolate essence, mixed berry essence, orange essence, lemon essence, pineapple essence and mint essence.

4. The andrographolide anhydrous swallow granule according to claim 1, characterized in that: The pH regulators are one or more of citric acid, potassium citrate, lactic acid, tartaric acid and malic acid.

5. The process for preparing the andrographolide anhydrous swallow granule according to claim 1, characterized in that: The preparation method comprises the following steps: a, uniformly mix the high-melting-point capsule materials with the andrographolide powder, heat and melt, and stir at a constant temperature to uniformly disperse the andrographolide; b, spray the molten suspension prepared in step a into a low-temperature airflow through a rotary atomizer, control the inlet and outlet air temperature, and collect and sieve to obtain the drug-containing microcapsules; c, uniformly mix the drug-containing microcapsules with the flavoring adjuvants to obtain the andrographolide anhydrous swallowing granules.

6. The process for preparing the andrographolide anhydrous swallow granules according to claim 5, characterized in that: In step a, the andrographolide powder has been sieved through a 150-mesh screen with a mesh size of 100 μm, and the constant temperature is 80-120℃.

7. The process for preparing the andrographolide anhydrous swallow granules according to claim 5, characterized in that: In step b, the rotary atomizer rotates at a speed of 15,000-25,000 rpm, the inlet air temperature of the low-temperature airflow is 10-15℃, and the outlet air temperature is controlled below 50℃.

8. The process for preparing the andrographolide anhydrous swallow granules according to claim 5, characterized in that: In step b, the drug-containing microcapsules D 50 less than 100 μm.

9. The process for preparing the andrographolide anhydrous swallow granules according to claim 5, characterized in that: In step c, the flavoring adjuvants have been sieved through a 100-mesh screen with a mesh size of 150 μm.

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