CN112315944B - Preparation method of potassium dehydroandrographolide succinate enteric dry suspension - Google Patents
Preparation method of potassium dehydroandrographolide succinate enteric dry suspension Download PDFInfo
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- CN112315944B CN112315944B CN202011423468.3A CN202011423468A CN112315944B CN 112315944 B CN112315944 B CN 112315944B CN 202011423468 A CN202011423468 A CN 202011423468A CN 112315944 B CN112315944 B CN 112315944B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of medicines, and particularly relates to a preparation method of potassium dehydroandrographolide succinate enteric dry suspension. The specific technical scheme is as follows: a preparation method of potassium dehydroandrographolide succinate enteric dry suspension comprises the following steps: adding the crosslinked gelatin microspheres into an absolute ethyl alcohol solution in which dehydroandrographolide succinate is dissolved, then dropwise adding a 10-25% potassium bicarbonate solution, crystallizing potassium dehydroandrographolide succinate in the gelatin microspheres, filtering, washing and drying to obtain gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals; then, an agar layer, an enteric layer and a flavoring layer are wrapped outside the gelatin microsphere-loaded potassium dehydroandrographolide succinate crystal in sequence, and agar particles are adhered between the enteric layer and the flavoring layer. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension provided by the invention effectively avoids adverse reactions possibly caused by injection in an intestinal administration mode and is convenient for children or people who have difficulty in taking medicine.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of potassium dehydroandrographolide succinate enteric dry suspension.
Background
The andrographolide is dehydroandrographolide disuccinate monopotassium salt formed by dehydroandrographolide and hydroxyl esterification, is white-like to yellowish crystalline powder in appearance, is insoluble in water, and is dissolved in diluted ethanol and 1% sodium bicarbonate solution; wherein the dehydroandrographolide succinate is intermediate of potassium dehydroandrographolide succinate. Clinically, Chuanhuning is widely used for treating viral diseases such as hyperpyrexia, respiratory tract infection, children autumn diarrhea, parotitis and the like.
At present, the most common types of potassium dehydroandrographolide succinate preparations are injection, sodium chloride infusion solution and sterile powder for injection, but the purity requirement of injection on the drugs is high, and if the drugs contain excessive impurities, adverse reactions such as anaphylactic reaction, thrombocytopenia and the like can occur, so that great hidden danger is brought to the safe medication of patients. Therefore, in order to avoid adverse reactions, the potassium dehydroandrographolide succinate is prepared into an oral preparation by adopting an intestinal administration mode, the administration is convenient, the pain of patients is not increased by the intestinal administration, and the potassium dehydroandrographolide succinate is particularly suitable for children and patients who can not take medicines or are difficult to take medicines.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of potassium dehydroandrographolide succinate enteric dry suspension, which effectively avoids possible adverse reactions of injection medication in an intestinal administration mode and is convenient for children or people who have difficulty in taking medicine.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the invention discloses a preparation method of potassium dehydroandrographolide succinate enteric dry suspension, which comprises the following steps: adding the crosslinked gelatin microspheres into an absolute ethanol solution in which dehydroandrographolide succinate is dissolved, then dropwise adding a 10-25% potassium bicarbonate solution, crystallizing potassium dehydroandrographolide in the gelatin microspheres, filtering, washing and drying to obtain gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals; then, an agar layer, an enteric layer and a flavoring layer are wrapped outside the gelatin microsphere-loaded potassium dehydroandrographolide succinate crystal in sequence, and agar particles are adhered between the enteric layer and the flavoring layer.
Preferably, the particle size of the gelatin microsphere is 1-12 μm, and the particle size of the agar particle is nano-scale.
Preferably, the crosslinking process of the gelatin microspheres is as follows: and (3) carrying out microwave heating treatment on the gelatin microspheres, wherein the treatment temperature is 245-260 ℃, and the treatment time is 8-15 min.
Preferably, the gelatin microspheres are added into an absolute ethyl alcohol solution dissolved with dehydroandrographolide succinate, the mixture is stirred and then stands for 10-20 min, the addition amount of the potassium bicarbonate solution is determined until no bubble is generated in a reaction system, the reaction of the potassium bicarbonate and the dehydroandrographolide succinate is carried out under the water bath condition of sound wave vibration, the water bath temperature is 20-35 ℃, and the vibration frequency is 1000-5000 Hz.
Preferably, the mass-volume ratio of the dehydroandrographolide succinate to the absolute ethyl alcohol is 0.3-15 g/mL, and the mass ratio of the gelatin microspheres to the dehydroandrographolide succinate is 8-15: 2-3.
Preferably, 35-70 parts of potassium dehydroandrographolide succinate crystals, 4-20 parts of agar layer, 7-45 parts of enteric layer, 0.01-5 parts of flavoring layer and 0.5-10 parts of agar particles are loaded on the gelatin microspheres in parts by weight.
Preferably, the enteric layer is one or a mixture of more of cellulose acetate phthalate, acrylic resin II, acrylic resin III, hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate; the flavoring layer is one or more of aspartame, sodium cyclamate, stevioside, citric acid, orange flavor and pineapple flavor.
Preferably, the agar layer, the enteric layer, the agar particles and the flavor modifying layer are coated by a rotary vibration atomizing device, and the coating parameters of the enteric layer and the flavor modifying layer are 50-100 r/min of rotation speed, the temperature of a coating liquid is 30 +/-5 ℃, the spraying speed is 10-40 mL/min, and the atomizing pressure is 0.1-0.4 MPa.
Preferably, the agar layer, and/or the agar particles, have coating parameters of: under the condition of continuous vibration, intermittent rotation is adopted, the rotating speed is 50-70 r/min, the rotating speed is 3-5 s per rotation, the stop time is 2-3 s, the rotating speed is gradually reduced in the rotating process, and the rotating speed is gradually reduced by 0.2-0.5 r per second; and spraying agar solution and/or agar particles in the process of stopping, stopping once, spraying for 4-6 times totally, and rotating in a mode of 2-4 times of rotation speed decreasing after spraying, wherein the stopping is not in the middle.
Preferably, the rotary vibration atomizing device comprises a mixing cylinder with an opening at the top, a cylinder cover buckled at the top of the mixing cylinder and a plurality of sector plates hinged at the bottom of the mixing cylinder, the sector plates form a bottom plate of the mixing cylinder, a supporting tube with a hollow inner part is arranged at the top of the cylinder cover, a rotary telescopic cylinder is arranged at the top of the supporting tube, the material mixing device with temperature control extends into the cylinder cover through a hose, the end part of the material mixing device is connected with a spray head, a funnel-shaped annular mixing seat is arranged on the inner side wall of the mixing cylinder, and the annular mixing seat is contacted with the surface of the sector plates;
the mixing cylinder is detachably arranged on the base, the bottom of the base is provided with a motor, a plurality of limiting seats with clamping grooves are arranged on the edge surrounding the base, the outer side wall of the mixing cylinder is provided with clamping blocks which are the same in number as the limiting seats and are matched with the clamping grooves, the center of the upper surface of the base is provided with a funnel-shaped storage tank, and the side wall of the base is provided with a discharge hole communicated with the bottom of the storage tank; the fan-shaped plate is connected with a connecting piece near the circle center, and the other end of the connecting piece is connected in the storage tank.
The invention has the following beneficial effects:
according to the invention, gelatin microspheres are crosslinked in a microwave heating mode, so that the solubility of gelatin in water is increased slightly, and then the crosslinked gelatin microspheres are added into a preparation system of potassium dehydroandrographolide succinate by using a reaction principle that dehydroandrographolide succinate reacts with potassium bicarbonate to generate potassium dehydroandrographolide succinate, so that generated potassium dehydroandrographolide succinate crystals are crystallized in the gelatin microspheres, and then an agar layer, an enteric layer and agar particles are sequentially coated. When the potassium dehydroandrographolide succinate enteric dry suspension prepared by the preparation method is taken, the dry suspension is added into boiling water, the gelatin microspheres and the agar layer are melted at high temperature, and the potassium dehydroandrographolide succinate is in a micro-liquid environment after the gelatin microspheres and the agar layer are melted; and the taste-modifying layer and the agar granules positioned on the outermost layer are melted, so that the dry suspension is suspended in the aqueous solution. When the water temperature is reduced to be less than 40 ℃, the gelatin microspheres and the agar layer form gel, after the gelatin microspheres and the agar layer are taken, the potassium dehydroandrographolide succinate in the gel system can be released more quickly after the enteric layer is melted under the action of intestinal juice, so that the intestinal tract can be better used. Meanwhile, the invention discloses a rotary atomizing device which can coat gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals more uniformly at a low rotating speed, and also solves the problems that the gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals are not easy to disperse in agar solution and are not uniformly mixed when being directly stirred and mixed with the agar solution.
Drawings
FIG. 1 is a schematic structural view of the present invention;
FIG. 2 is an enlarged view of a portion A of FIG. 1;
FIG. 3 is a view taken along line A-A of FIG. 1;
FIG. 4 is a schematic structural view of a sector plate;
fig. 5 is a bottom view of the cartridge cover 2;
in the figure: the device comprises a mixing barrel 1, a barrel cover 2, a sector plate 3, a supporting pipe 4, a rotary telescopic cylinder 5, a material mixing device 6, a hose 7, a spray head 8, an annular mixing seat 9, a base 10, a motor 11, a clamping groove 12, a limiting seat 13, a clamping block 14, a storage tank 15, a discharge hole 16, a connecting piece 17, a first magnet 18, an arc-shaped clamping plate 19, a limiting frame 20, a sealing gasket 21, a second magnet 22, a guide groove 23, a shell 24, a guide plate 25, a ball 26 and an annular groove 27.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise indicated, the technical means used in the examples are conventional means well known to those skilled in the art.
1. The invention discloses a preparation method of potassium dehydroandrographolide succinate enteric dry suspension, which comprises the following specific preparation processes: loading potassium dehydroandrographolide succinate crystals on the crosslinked gelatin microspheres, and then wrapping an agar layer, an enteric layer, agar particles and a taste-modifying layer outside the gelatin microsphere loaded potassium dehydroandrographolide succinate crystals in sequence, namely the potassium dehydroandrographolide succinate enteric dry suspension prepared by the invention takes the crosslinked gelatin microsphere loaded potassium dehydroandrographolide succinate crystals as a core and agar as a shell to prepare a potassium dehydroandrographolide succinate embedded precursor with a core-shell structure; the outer layer of the precursor is sequentially coated with an enteric layer and a flavoring layer, and agar particles are adhered between the enteric layer and the flavoring layer. The particle size of the gelatin microsphere is 1-12 mu m, the particle size of the agar particle is nano-scale, and the preferable particle size is 50-200 nm. The particle size of the gelatin microsphere is 10 mu m, and the particle size of the agar particle is 150 nm.
The gelatin microspheres are limited in application because gelatin is unstable in water environment and is easily dissolved. Therefore, in order to increase the stability of the gelatin microspheres in an aqueous environment, the gelatin microspheres are crosslinked to reduce the solubility thereof, and the crosslinked gelatin microspheres can still swell in water. The invention adopts a heating denaturation mode to realize the crosslinking of gelatin, so that carboxyl and adjacent amino of gelatin molecules are dehydrated to form intermolecular amido bond, and the two molecules are connected through covalent bonds. The gelatin microsphere is prepared by the prior art, and the particle size is controlled to be 10 mu m.
The specific crosslinking process of the gelatin microsphere is as follows: and (3) carrying out microwave heating treatment on the gelatin microspheres, wherein the treatment temperature is 150-250 ℃, the treatment time is 8-15 min, and preferably 250 ℃, and the treatment time is 10 min. After the crosslinked gelatin microspheres are detected, the content of amino and carboxyl is greatly reduced (the detection is carried out by adopting the existing method and is not described again).
The potassium dehydroandrographolide succinate enteric dry suspension disclosed by the invention comprises the following components, by weight, 35-70 parts of potassium dehydroandrographolide succinate crystals are loaded on gelatin microspheres, 4-20 parts of agar layers, 7-45 parts of enteric layers, 0.01-5 parts of flavor-modifying layers and 0.5-10 parts of agar particles.
Wherein the enteric layer is one or a mixture of more of cellulose acetate phthalate, acrylic resin II, acrylic resin III, hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate; the flavoring layer is one or more of aspartame, sodium cyclamate, stevioside, citric acid, orange flavor and pineapple flavor.
The weight gain of the agar layer is controlled to be 15-30% of the weight of the gelatin microsphere loaded potassium dehydroandrographolide succinate crystal, and the weight gain of the enteric layer is controlled to be 15-50% of the weight of the precursor.
The process of loading the potassium dehydroandrographolide succinate crystals on the gelatin microspheres comprises the following steps: dissolving dehydroandrographolide succinate in absolute ethyl alcohol, adding the crosslinked gelatin microspheres, stirring, standing for 10-20 min, and loading the dehydrated andrographolide succinate as much as possible into the gelatin microspheres; slowly dripping 10-25% of potassium bicarbonate solution, reacting under the water bath condition of sound wave vibration until no bubbles are generated, namely, no potassium bicarbonate solution is dripped when no bubbles are generated, cooling and crystallizing, filtering, washing with ethanol, and drying to obtain the gelatin microsphere loaded potassium dehydroandrographolide succinate crystal. The mass-volume ratio of the dehydroandrographolide succinate to the absolute ethyl alcohol is 0.3-15 g/mL, the mass ratio of the gelatin microspheres to the dehydroandrographolide succinate is 8-15: 2-3, the water bath temperature is 20-35 ℃, the vibration frequency is 1000-5000 Hz, bubbles generated after the reaction of the dehydroandrographolide succinate in the gelatin microspheres and potassium bicarbonate are discharged through vibration, the dehydroandrographolide succinate generated after the reaction stays in the gelatin microspheres, and the gelatin microspheres are crystallized after cooling.
According to the invention, the agar layer is wrapped and/or the agar particles are adhered to each other in a rotary vibration atomization mode, agar solution and/or agar particles are sprayed out in an atomization mode under the action of rotary vibration, the surface of the gelatin particle loaded potassium dehydroandrographolide succinate crystal is wrapped with the agar layer, and/or the agar particles are adhered to the outside of the enteric layer. The coating parameters of the agar layer and/or the agar particles are as follows: under the condition of continuous vibration, the vibration frequency is 1000-1500 Hz, intermittent rotation is adopted, the rotating speed is 50-70 r/min, the rotating speed is 3-5 s per rotation, the stopping time is 2-3 s, the rotating speed is gradually reduced in the rotating process, and the rotating speed is reduced by 0.2-0.5 per second; and in the process of stopping, spraying the agar solution and/or the agar particles, stopping once, wherein the spraying speed is the agar solution, and/or the agar particles are 0.5-4 parts by weight per time per second, spraying is completed for 4-6 times totally, and rotating in a mode of 2-4 times of rotation speed reduction after spraying is completed, wherein the rotation speed reduced in each second is still 0.2-0.5 r, and the process is not stopped in the middle. The agar layer and the agar particles are wrapped by adopting the steps, so that the finally prepared particles are uniform in shape, the thickness of the wrapped agar layer is uniform, and the agar particles are uniformly distributed on the surface of the enteric-coated layer. It should be noted that: and in the process of spraying the agar solution or the agar particles, the agar solution or the agar particles is sprayed for 4-6 times on average.
In the invention, the wrapping of the agar layer and the adhesion of the agar particles are carried out by adopting the rotary vibration atomization device disclosed by the invention. The agar solution disclosed by the invention is formed by mixing agar and boiling water, the mass ratio of the agar to the boiling water (more than or equal to 95 ℃) is 1-2: 5-20, and the agar solution is stored for later use at the temperature of more than or equal to 45 ℃. In order to accelerate the agar solution to better wrap and form the gelatin microsphere-loaded potassium dehydroandrographolide succinate crystal, the ratio of agar to boiling water is preferably 2:7, and different ratios can be selected according to actual needs.
The preparation process of the potassium dehydroandrographolide succinate enteric dry suspension is carried out in a rotary vibration atomization device. The method specifically comprises the following steps: adding gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals into a rotary vibration atomization device, coating agar solution by adopting the equipment parameters, then preparing the raw material of an enteric layer into enteric coating liquid with the solid content of 3-15% by using pure water or 20-85% ethanol solution, coating in the rotary vibration atomization device, wherein the rotating speed is 50-100 r/min, the temperature of the coating liquid is 30 +/-5 ℃, the spraying speed is 10-40 mL/min, and the atomization pressure is 0.1-0.4 MPa, and finally preparing potassium dehydroandrographolide succinate enteric particles; when the enteric coating is not completely dried, adhering agar particles in a rotary vibration atomization device by adopting the process parameters of the agar coating, wherein the agar particles do not need to be insulated; and finally, adding pure water into the raw materials for the taste-modifying layer, melting, coating the taste-modifying layer by adopting the process parameters of coating the enteric layer, and drying to obtain the potassium dehydroandrographolide succinate enteric dry suspension.
2. Referring to fig. 1 to 5, the rotary vibration atomizing device disclosed in the present invention includes a housing 24, a mixing barrel 1 disposed in the housing 24 and having an opening at the top, a barrel cover 2 fastened to the top of the mixing barrel 1, and a plurality of sector plates 3 hinged to the bottom of the mixing barrel 1, wherein the plurality of sector plates 3 form a bottom plate of the mixing barrel 1, an operation hole is opened on a side wall of the housing 24, and an edge of the sector plate 3 is hinged to the bottom of the mixing barrel 1, and specifically, the operation hole may be: the edge of the sector plate 3 is provided with a gap, the bottom of the mixing drum 1 is provided with a rotating shaft, and the rotating shaft is rotatably connected to two ends of the gap, so that the sector plate 3 can rotate around the rotating shaft. In order to avoid the contact between the adjacent sector plates 3 from being loose and the leakage of materials from gaps between the adjacent sector plates 3, first magnets 18 are arranged on the contact surfaces of the adjacent sector plates 3, and the length of each first magnet 18 is smaller than the radius of the sector plate 3.
Furthermore, the cover 2 is funnel-shaped, the top of the cover 2 is provided with a hollow supporting tube 4 inside and communicated with the cover 2, the top of the supporting tube 4 is provided with a rotary telescopic cylinder 5, a material mixing device 6 with temperature control extends into the cover 2 through a hose 7, and the end part of the hose 7 extending into the cover 2 is connected with a spray head 8. The telescopic rotary cylinder 5 and the material mixing device 6 are arranged at the top of the shell 24, and the hose 7 and an output rod of the rotary telescopic cylinder 5 penetrate through the shell 24. The method specifically comprises the following steps: hose 7 stretches into in cover 2 through stay tube 4, and shower nozzle 8 is fixed in the junction of cover 2 and stay tube 4, avoids shower nozzle 8 to rock under the pressure effect, and the aperture size of shower nozzle 8 can be changed as required to the material blowout of adaptation different properties. The material mixing device 6 is provided with a temperature control system and can be used for adjusting and controlling the temperature, the material mixing device 6 can be used for preparing agar solution, enteric layer solution and flavoring layer solution, and the solutions are respectively sprayed into the mixing cylinder 1 through a pressure pump for coating; meanwhile, the agar particles can be sprayed under the action of a pressure pump.
Furthermore, in order to seal and open the mixing cylinder 1 by starting the rotary telescopic cylinder 5, a plurality of arc-shaped clamping plates 19 are transversely arranged on the edge of the mixing cylinder 1, preferably 3 arc-shaped clamping plates are arranged, meanwhile, arc-shaped limiting frames 20 with the same number as the arc-shaped clamping plates 19 are arranged on the edge of the bottom surface of the cylinder cover 2, the cross sections of the limiting frames 20 are C-shaped, the arc-shaped clamping plates 19 extend into the limiting frames 20, and the distance between the limiting frames 20 is greater than the arc length of the arc-shaped clamping plates 19. When the barrel cover 2 is rotated until the gap between the arc-shaped clamping plate 19 and the limiting frame 20 corresponds, the barrel cover 2 can be separated from the mixing barrel 1. When the mixing cylinder 1 is covered by the cylinder cover 2, in order to increase the contact tightness between the mixing cylinder 1 and the cylinder cover, a sealing gasket 21 is arranged on the edge of the top of the mixing cylinder 1, and the shape of the sealing gasket 21 is the same as that of the arc-shaped clamping plate 19 and the top of the mixing cylinder 1. When the nozzle 8 sprays the raw material into the mixing drum 1, a plurality of exhaust valves are arranged on the drum cover 2 in order to balance the pressure in the mixing drum 1.
Furthermore, an annular mixing seat 9 in a funnel shape is arranged on the inner side wall of the mixing cylinder 1, and the annular mixing seat 9 is in contact with the surface of the sector plate 3. In order to make the contact between the annular mixing seat 9 and the sector plate 3 more tight, a second magnet 22 is embedded on the plate surface of the annular plate 3. If the annular mixing seat 9 is made of metal, only the second magnet 22 needs to be embedded on the plate surface of the annular plate 3; if the annular mixing base 9 is made of a non-metallic material, a third magnet corresponding to the second magnet 22 needs to be embedded in the bottom of the annular mixing base 9. When the mixing cylinder 1 rotates, in order to make the particles more uniform through collision, a plurality of protrusions are arranged on the surface of the annular mixing seat 9 in a staggered manner. When the particulate matter enters into the clearance whereabouts between the protruding, can receive the impact of different angles to make the particulate matter more even, the better quality.
Further, in order to realize the rotation of the mixing drum 1, the mixing drum 1 is detachably disposed on the base 10, specifically: the bottom of the base 10 is provided with a motor 11, a plurality of limiting seats 13 with clamping grooves 12 are arranged on the edge surrounding the base 10, the tops of the clamping grooves 12 are open, clamping blocks 14 which are the same as the limiting seats 13 in number and are matched with the clamping grooves 12 are arranged on the outer side wall of the mixing drum 1, and the clamping blocks 14 are clamped into the clamping grooves 12 of the limiting seats 13, so that the mixing drum 1 is fixed on the base 10. It should be noted that: when the arc-shaped clamping plate 19 extends into the limiting frame 20, the distance between the limiting frame 20 and the arc-shaped clamping plate 19 is 3-5 cm. When the motor 11 drives the base 10 to rotate, the rotary telescopic cylinder 5 needs to be started in advance to enable the arc-shaped clamping plate 19 and the limiting frame 20 to be in a separated state, and at the moment, when the motor 11 drives the mixing drum 1 to rotate, the drum cover 2 can be kept still and cannot be influenced by the mixing drum 1.
The material storage tank 15 is arranged in the center of the upper surface of the base 10 and is funnel-shaped, the side wall of the base 10 is provided with a discharge hole 16 communicated with the bottom of the material storage tank 15, and the discharge hole 16 is inclined from the bottom of the material storage tank 15 to the outer side wall of the base 10, so that materials are easy to discharge. The sector plate 3 is connected with a connecting piece 17 near the circle center, and the other end of the connecting piece 17 is connected in the storage tank 15. The connecting piece 17 can be a connecting rod which is respectively hinged with the sector plate 3 and the bottom of the storage tank 15, and can also be objects such as strings and metal wires. When the cylinder cover 2 is buckled with the mixing cylinder 1, when the rotary telescopic cylinder 5 drives the mixing cylinder 1 to move upwards, the connecting piece 17 enables the sector plates 3 to rotate for a certain angle around the hinged position with the mixing cylinder 1, so that materials in the mixing cylinder 1 can fall into the storage tank 15 through the gaps between the sector plates 3 and are discharged through the discharge hole 16. When resetting, the arrangement of the magnet enables the sector plate 3 to be well restored.
Furthermore, in order to enable the materials to well fall towards the material storage groove 15, a plurality of material guide grooves 23 extending towards the circle center of the sector plate 3 are formed in the surface of the sector plate 3, and the guide grooves 23 are inclined towards the circle center of the sector plate 3 by the annular mixing seat 9, so that the materials can fall conveniently.
Furthermore, in order to ensure the stability of the motor 11 with the base 10 and the mixing drum 1 during the rotation process, a plurality of guide plates 25 are arranged on the inner wall of the housing 24, the end parts of the guide plates 25 are rotatably provided with balls 26, an annular groove 27 is arranged on the circumference of the base 10, and the balls 26 are arranged in the annular groove 27 and are in contact with the inner wall of the annular groove 27. Of course, the guide plate 25 may be annular, and the balls 26 are embedded on the inner wall of the guide plate 25 and extend into the annular groove 27 to contact the inner wall thereof, thereby increasing the stability of the base 10 during rotation.
The rotary telescopic cylinder 5 and the motor 11 are controlled by a controller, and the operation parameters disclosed in the method 1 are only required to be carried out when the method is used. When the material loading, only need open cover 2, through the handle hole to mixing drum 1 in pour the material can. In the invention, when the base 10 drives the mixing drum 1 to rotate, the materials are transferred to the surface of the annular mixing seat 9 under the action of centrifugal force and collide with the bulges at different angles, so that the coating layer of the materials is more uniform and compact, and the coating effect is prevented from being poor due to the falling of coating raw materials. And the mixing cylinder 1 is in the process of being lifted by the rotary telescopic cylinder 5 and is in linkage structure with the stroke of the connecting piece 17, so that the plurality of fan-shaped plates 3 are opened, and the coated potassium dehydroandrographolide succinate enteric dry suspension enters the discharge hole 16 through the storage tank 15 to be discharged and collected.
The invention is further illustrated by the following specific examples.
Example 1 drug Loading Performance of gelatin microspheres on Potassium dehydroandrographolide succinate
1. After the gelatin microsphere loaded potassium dehydroandrographolide succinate crystal is prepared by the method 1, the drug loading and encapsulation rate of the gelatin microsphere are measured, and the method specifically comprises the following steps: and grinding the gelatin microsphere-loaded potassium dehydroandrographolide succinate crystal, dissolving the ground gelatin microsphere-loaded potassium dehydroandrographolide succinate crystal in 50% ethanol solution, measuring the absorbance value of the solution by using an ultraviolet spectrophotometer, and comparing the absorbance value with a drug concentration-absorbance standard curve, so that the drug concentration is calculated, and the drug content in the microsphere is calculated. The input amount of the potassium dehydroandrographolide succinate is calculated according to a theoretical value calculated after the input dehydroandrographolide succinate half-ester and potassium bicarbonate are completely reacted, free potassium dehydroandrographolide succinate in the filtrate is the sum of the value calculated after the amount of the dehydroandrographolide succinate in the filtrate and the potassium bicarbonate are completely reacted and the value of the potassium dehydroandrographolide succinate which is not loaded, and the result is shown in the following table 1.
The drug loading capacity (%) is (the weight of the put potassium dehydroandrographolide succinate drug-free potassium dehydroandrographolide succinate drug)/gelatin microsphere is multiplied by 100 percent
The encapsulation ratio (%) (the amount of the applied potassium dehydroandrographolide succinate-free potassium dehydroandrographolide succinate) per the amount of the applied potassium dehydroandrographolide succinate × 100%
TABLE 1 drug loading and encapsulation efficiency of gelatin microspheres
The results in table 1 show that when the mass ratio of gelatin microspheres to dehydroandrographolide succinate is 5:1, the loading of gelatin microspheres to potassium dehydroandrographolide succinate approaches to saturation; with the increase of the using amount of the potassium dehydroandrographolide succinate, the drug loading on the gelatin microspheres cannot be increased.
2. Directly adopting the crosslinked gelatin microspheres to directly adsorb the potassium dehydroandrographolide succinate, and measuring the drug loading rate and the encapsulation efficiency of the gelatin microspheres. For comparison with the data in table 1 of the present invention, the amount of andrographolide was also calculated directly from the dehydroandrographolide succinate half-ester when the drug loading and encapsulation efficiency measurements were made. The method specifically comprises the following steps: gelatin microspheres and dehydroandrographolide succinate are weighed according to the mass ratio of the gelatin microspheres to the dehydroandrographolide succinate shown in table 1, and andrographolide succinate is prepared according to the method 1 disclosed by the invention, except that no gelatin microspheres are added in the preparation process. Then, dissolving the prepared potassium dehydroandrographolide succinate in 50% ethanol solution, adding gelatin microspheres, stirring at room temperature for 20-25 min, standing for 30-1 h, filtering, and measuring the potassium dehydroandrographolide succinate content in the filtrate, thereby calculating the drug loading rate and the encapsulation efficiency, wherein specific results are shown in table 2 below.
TABLE 2 Effect of drug loading on drug loading
The results in table 2 show that the effect of loading potassium dehydroandrographolide succinate in gelatin microspheres by adsorption is not ideal, the drug molecules on the gelatin microspheres are easy to elute, and the loading of the drug and the gelatin microspheres is not stable.
Example 2
1. The specific mixture ratio of the multi-group potassium dehydroandrographolide succinate enteric dry suspension prepared by the method 1 and the equipment 2 is shown in the following table 3, the coating parameters of the enteric layer and the taste-modifying layer are shown in the following table 4, and the coating parameters of the agar layer and the agar particles are shown in the following table 5.
TABLE 3 raw material proportions (parts by weight)
TABLE 4 enteric and flavor layer coating parameters
TABLE 5 coating parameters of agar layer and agar particles
2. The potassium dehydroandrographolide succinate enteric dry suspension is prepared by adopting the raw material proportion and the process parameters shown in the tables 3-5, and the weight increasing conditions of an agar layer and an enteric layer are shown in the following table 6 after the preparation is finished. Meanwhile, the potassium dehydroandrographolide succinate enteric dry suspension prepared by adopting the process parameters shown in the table 5 is full and uniform in particles, only a small amount of uncoated raw materials exist at the bottom, the waste of the raw materials is less, gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals can be well coated, and the medicine can not be released in gastric juice.
TABLE 6 weight gain of agar and enteric layers
3. Taking 3g of each potassium dehydroandrographolide succinate enteric dry suspension prepared by the invention, respectively adding into 15mL of boiling water, standing to the temperature of 30-40 ℃, respectively pouring into hydrochloric acid solution with the pH value of 1.5 for 2h, filtering, then placing in phosphate buffer solution with the pH value of 6.8 for 45min, respectively sampling in 30min, 60min, 90min, 120min, 135min, 145min, 155min and 165min time periods to determine the cumulative release degree, parallelly performing 3 tests on each group, and taking the average value, wherein the result is shown in the following table 7. The comparative experiments in table 7 were: the data in Table 4 are directly adopted to wrap an agar layer, an enteric layer and a flavoring layer, and agar particles are directly adhered in a stirring mode. The potassium dehydroandrographolide succinate enteric dry suspension prepared by the method has uneven particles, more uncoated raw materials exist at the bottom, so that the raw materials are wasted, and the situation that the gelatin microsphere loaded potassium dehydroandrographolide succinate crystals are not well coated so that the medicine is released in the stomach possibly exists, so that the medicine reaching the intestinal tract is reduced, and the treatment effect is influenced.
TABLE 7 cumulative release results for potassium dehydroandrographolide succinate enteric dry suspension
As can be seen from table 7, the suspension prepared in group 1 began to release in hydrochloric acid solution of potassium dehydroandrographolide succinate, probably because the enteric layer was less coated, causing the drug to be released after it was partially dissolved in hydrochloric acid solution.
In the description of the present invention, it is to be understood that the terms "longitudinal", "lateral", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like, indicate orientations or positional relationships based on those shown in the drawings, are merely for convenience of description of the present invention, and do not indicate or imply that the referenced devices or elements must have a particular orientation, be constructed and operated in a particular orientation, and thus, are not to be construed as limiting the present invention.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (8)
1. A preparation method of potassium dehydroandrographolide succinate enteric dry suspension is characterized by comprising the following steps: the method comprises the following steps: adding the crosslinked gelatin microspheres into an absolute ethyl alcohol solution in which dehydroandrographolide succinate is dissolved, then dropwise adding a 10-25% potassium bicarbonate solution, crystallizing potassium dehydroandrographolide succinate in the gelatin microspheres, filtering, washing and drying to obtain gelatin microsphere-loaded potassium dehydroandrographolide succinate crystals; then wrapping an agar layer, an enteric layer and a taste-modifying layer outside the gelatin microsphere-loaded potassium dehydroandrographolide succinate crystal in sequence, and adhering agar particles between the enteric layer and the taste-modifying layer;
the mass-volume ratio of the dehydroandrographolide succinate to the absolute ethyl alcohol is 0.3-15 g/mL, and the mass ratio of the gelatin microspheres to the dehydroandrographolide succinate is 8-15: 2-3;
the agar layer, the enteric layer, the agar particles and the flavor modifying layer are coated by a rotary vibration atomization device, and the coating parameters of the enteric layer and the flavor modifying layer are 50-100 r/min of rotation speed, 30 +/-5 ℃ of coating liquid temperature, 10-40 mL/min of spraying speed and 0.1-0.4 MPa of atomization pressure.
2. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: the particle size of the gelatin microspheres is 1-12 microns, and the particle size of the agar particles is nano-scale.
3. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: the crosslinking process of the gelatin microsphere comprises the following steps: and (3) carrying out microwave heating treatment on the gelatin microspheres, wherein the treatment temperature is 245-260 ℃, and the treatment time is 8-15 min.
4. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: the gelatin microspheres are added into an absolute ethyl alcohol solution dissolved with dehydroandrographolide succinate, the mixture is stirred and then stands for 10-20 min, the addition amount of the potassium bicarbonate solution is determined until bubbles are not generated in a reaction system, the reaction of the potassium bicarbonate and the dehydroandrographolide succinate is carried out under the condition of a water bath with sound wave vibration, the temperature of the water bath is 20-35 ℃, and the vibration frequency is 1000-5000 Hz.
5. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: according to the weight parts, 35-70 parts of potassium dehydroandrographolide succinate crystal, 4-20 parts of agar layer, 7-45 parts of enteric layer, 0.01-5 parts of taste-modifying layer and 0.5-10 parts of agar particles are loaded on the gelatin microsphere.
6. The preparation method of potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: the enteric layer is one or a mixture of more of cellulose acetate phthalate, acrylic resin II, acrylic resin III, hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate; the flavoring layer is one or more of aspartame, sodium cyclamate, stevioside, citric acid, orange flavor and pineapple flavor.
7. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: the agar layer, and/or the agar particles, have coating parameters of: under the condition of continuous vibration, intermittent rotation is adopted, the rotating speed is 50-70 r/min, the rotating speed is 3-5 s per rotation, the stop time is 2-3 s, the rotating speed is gradually reduced in the rotating process, and the rotating speed is gradually reduced by 0.2-0.5 r per second; and in the process of the stop, spraying agar solution and/or agar particles, stopping once, spraying for 4-6 times totally, and rotating in a mode of 2-4 times of rotation speed decreasing gradually without stopping in the middle.
8. The preparation method of the potassium dehydroandrographolide succinate enteric dry suspension according to claim 1, wherein the preparation method comprises the following steps: the rotary vibration atomizing device comprises a mixing cylinder with an opening at the top, a cylinder cover buckled at the top of the mixing cylinder and a plurality of sector plates hinged at the bottom of the mixing cylinder, the sector plates form a bottom plate of the mixing cylinder, a supporting tube with a hollow inner part is arranged at the top of the cylinder cover, a rotary telescopic cylinder is arranged at the top of the supporting tube, the material mixing device with temperature control extends into the cylinder cover through a hose, the end part of the material mixing device is connected with a spray head, and a funnel-shaped annular mixing seat is arranged on the inner side wall of the mixing cylinder and is contacted with the surfaces of the sector plates;
the mixing cylinder is detachably arranged on the base, a motor is arranged at the bottom of the base, a plurality of limiting seats with clamping grooves are arranged on the edge surrounding the base, clamping blocks which are the same as the limiting seats in number and are matched with the clamping grooves are arranged on the outer side wall of the mixing cylinder, a funnel-shaped storage tank is arranged at the center of the upper surface of the base, and a discharge hole communicated with the bottom of the storage tank is arranged on the side wall of the base; the fan-shaped plate is connected with a connecting piece near the circle center, and the other end of the connecting piece is connected in the storage tank.
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