WO2018010406A1 - 一种二氧化硅药用微球的制备及在制药领域的应用 - Google Patents
一种二氧化硅药用微球的制备及在制药领域的应用 Download PDFInfo
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- WO2018010406A1 WO2018010406A1 PCT/CN2017/070891 CN2017070891W WO2018010406A1 WO 2018010406 A1 WO2018010406 A1 WO 2018010406A1 CN 2017070891 W CN2017070891 W CN 2017070891W WO 2018010406 A1 WO2018010406 A1 WO 2018010406A1
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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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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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
- A61K47/02—Inorganic compounds
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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
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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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
-
- 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
- A61K9/5078—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 with drug-free core
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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
- A61K9/5089—Processes
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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
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Definitions
- the present invention relates to a medicinal microsphere of silica, a process for its preparation and medicinal purification, and the use of a silica medicinal microsphere in the field of a particle coating formulation of less than 150 ⁇ m.
- the medicinal blank pellet core is the mother core necessary for the preparation of the pellet preparation.
- the blank pellet core commonly used in the pellet preparation mainly includes: sugar pellet (sucrose type), microcrystalline cellulose pellet core, starch pellet core, lactose pellet core. , silica pellet core, etc., mainly used in micropellet medicine, coating, its particle size range is 300-800 ⁇ m, and different types of pellet core stability, bulk density, friability, can not be applied to less than Coating of 150 ⁇ m granule preparation, existing blank pellet core ( ⁇ 150 ⁇ m) has many defects when using wuster coating technology, because the existing blank pellet core ( ⁇ 150 ⁇ m) itself has small particle size and large specific surface area.
- the oral preparations of less than 150 ⁇ m have a wide range of clinical applications and needs, and are especially suitable for oral or dysphagia in children and the elderly.
- the development of pharmaceutical excipients that can overcome the above shortcomings has positive economic and social benefits.
- silica As an inert material, silica has been widely used in food and pharmaceutical fields. There are many reports on the preparation of silica microspheres. By controlling the purity, particle size distribution, bulk density and friability of silica microspheres. Roundness, good physical properties and medicinal safety, suitable for wuster package Coating technology to achieve less than 150 ⁇ m particle coating preparation technology has not seen any report, the combination of the two innovations in the physical properties of silica microspheres control combined with wuster coating technology requirements, the realization of silica medicinal microsphere breakthrough application.
- the medicinal microspheres for silica of the present invention are obtained by using high-purity silica as a raw material, obtained by melting or grinding, and purified to meet the requirements of pharmaceutical excipients.
- the preparation method of the silica medicinal microspheres of the present invention comprises the following steps:
- the silica microspheres are first washed with a strong acid, and then the strongly acidified pellet core suspension is neutralized with a strong base to a pH of 6-7, washed, dried, and sieved to obtain a silica drug. Use microspheres.
- silica microspheres are silica microspheres formed in a molten state
- the silica microspheres are silica microspheres formed by grinding a natural crystal ore by a ball mill, wherein the purity of the silica in the raw natural crystal ore reaches 90.0% or more.
- the strong acid is selected from any one or more of sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid, and the concentration of the strong acid is 1-10%.
- the strong base is selected from any one or more of sodium hydroxide and potassium hydroxide.
- the method for preparing the medicinal microspheres of the present invention comprises the following steps:
- the medicinal microspheres prepared by the invention are novel pharmaceutical excipients, the main component of which is silica, and meets the requirements of the Chinese Pharmacopoeia, has no toxic and side effects, and the purity of the silica should reach above 90.0%, chloride, sulfuric acid Salt, iron salt, arsenic salt and heavy metals shall comply with the Pharmacopoeia.
- the microsphere silica content is not less than 99.0%, the chloride is not more than 0.1%, the sulfate is not more than 0.5%, the iron salt is not more than 0.015%, and the heavy metal is not more than 30 parts per million.
- the silica medicinal microspheres of the present invention should have a particle size ranging from 40 to 250 ⁇ m, more preferably from 50 to 100 ⁇ m.
- the silica medicinal microspheres of the invention should have a high bulk density in the particle size range, and are suitable for the wuster coating, and the density thereof should be 1.2-1.6 g/cm 3 , so that the particle size range of the coated pellet core is increased.
- the medicinal microspheres of silica of the invention have high hardness, low breakage rate during coating, high product yield, and coating yield of over 90%.
- the silica medicinal microspheres of the invention have high roundness and surface critical stability in the range of 10-12°, which can make the core medicine and the functional coating more uniform.
- the medicinal microspheres of the present invention are controlled by process parameters in the preparation process to have a narrow particle size distribution, which makes the drug-loading and functional coating more uniform.
- Another object of the present invention is to provide the use of the silica medicinal microspheres for the preparation of a coating formulation having a particle size of less than 150 ⁇ m.
- the medicinal microspheres of silica are applied to the pharmaceutical field, and as a blank core of the wuster coating, the coating process of the granule preparation of less than 150 ⁇ m is achieved, and the taste masking, sustained release and controlled release are achieved. Based on its suitable particle size distribution, higher bulk density, mechanical strength, and roundness, the yield of the particle coating of less than 150 ⁇ m can be greatly improved, and the coating yield is over 90%.
- the invention has the following advantages:
- the medicinal microspheres of silica have no toxic and side effects, meet the requirements of the Chinese Pharmacopoeia, have no absorption in the body, have no biological activity, and are completely applicable to the human body;
- the silica medicinal microspheres adopt a unique microsphere technology to make the roundness of the microspheres better, so that in the fluidized bed wuster medicine and coating process, the coating is uniform, and it is easy to form a continuous film, reducing Loss of coating;
- the medicinal microspheres of silica have high bulk density (suitable density) and narrow particle size distribution, and are suitable for fluidized bed wuster coating, especially suitable for particle coating of less than 150 ⁇ m (pill after completion of coating) Particle size is 100-150 ⁇ m);
- the silica medicinal microspheres have high hardness, high mechanical strength, low breakage rate during the coating process, almost no loss in the collision of the coating, and the coating yield is very high, which is very suitable for less than 150 ⁇ m particle coating preparation;
- the fine particle preparation prepared from the medicinal microspheres of silica has no gritty feeling in the oral cavity and is suitable for swallowing; it can be swallowed together with soft food such as cheese, pudding, jam, etc., and the compliance is good;
- the preparation of less than 150 ⁇ m particles of small particle size is conducive to the preparation of oral dry suspension or suspension preparations, suitable for children and the elderly and other people who have difficulty in oral and swallowing.
- the wuster coating refers to: the fluidized bed bottom spray device, also known as the Wurster system, developed by Professor Dale Wuster, is an important breakthrough in the coating technology, making it possible to coat small particle size materials. With the development of technology, it is possible to coat powders as small as 50 ⁇ m.
- silica microspheres prepared by melting or crystal minerals with a purity of 99.0% of silica.
- silica microspheres prepared by melting or crystal minerals with a purity of 99.0% of silica.
- silica microspheres prepared by melting or crystallites with a purity of 99.9% of silica.
- 1kg of silica microspheres (100-120 mesh) prepared by ball mill grinding, put into 10% hydrochloric acid solution, stir for 1h. , standing, decanting the supernatant, adding 1 mol / L sodium hydroxide to the remaining silica microsphere concentrate to adjust to pH 7, filtered, washed with purified water, dried and sieved to obtain 120 Silica microspheres.
- the azithromycin-containing pellets are prepared, the barrier layer is coated, and the azithromycin taste-masking pellets are prepared by coating the sustained-release layer, and the auxiliary materials are added according to the characteristics of the dry suspension, and the mixture is uniformly mixed.
- Azithromycin-containing pellets 300 g of silica microspheres (particle size: 0.075-0.10 mm), 150 g (100 mesh) of azithromycin, 10 g of HPMC (E5), 5 g of talc, 2000 mL of 85% ethanol.
- Preparation of drug-containing pellets Take 300-200 mesh silica microspheres (particle size: 0.15-0.12mm) 300g, put into a fluidized bed coating machine, and apply the coating to the silica microspheres by using the bottom spray coating. Set the blast frequency to 25 Hz, the inlet air temperature to 45 ° C, the nozzle diameter to 1.0 mm, the atomization pressure to 0.15 MPa, the peristaltic pump fluid speed to 5 r/min, the material temperature to 35 ° C, and the peristaltic pump to be turned on.
- the peristaltic pump is stopped, and the fluid is continuously removed for 20 minutes, and then taken out in a blast drying oven at 50 ° C for 2 hours, taken out, and sieved to obtain a drug-containing pellet.
- Separation layer solution preparation 20 g of hypromellose was added to 500 mL of purified water under stirring, and dissolved until clarification.
- Separation layer preparation using a fluidized bed coating machine bottom spray coating to isolate the drug-containing pellet core, taking the prescribed amount of the isolation pellet into the fluidized bed coating machine, setting the blast frequency to 25 Hz, the inlet air The temperature is 45 °C, the nozzle diameter of the spray gun is 1.0mm, the atomization pressure is set to 0.16MPa, the pumping speed of the peristaltic pump is 5r/min, and the temperature of the material to 40°C, the peristaltic pump is turned on to pump the liquid, after the coating of the isolation solution is completed. Stop the peristaltic pump pump fluid, continue to fluidize for 20 minutes, take it out, place it in a blast drying oven at 50 °C for 2h, take it out, sift it, and pass the test to isolate the pellet.
- taste masking layer solution 150 g of Eudragit E100 and 15 g of triethyl citrate were added, and 1500 mL of a 90% ethanol solution was added, dissolved to clarification, and 15 g of talc powder was added to prepare a taste masking layer coating liquid.
- Preparation of taste-masking pellets The isolation pellets were put into a fluidized bed coating machine, and the blasting frequency was set to 25 Hz, the inlet air temperature was 45 ° C, the nozzle diameter of the spray gun was 1.0 mm, the atomization pressure was set to 0.15 MPa, and the peristaltic pump was used. The pumping speed is 5r/min. After the material temperature reaches 40°C, open the peristaltic pump to pump the liquid. After the masking solution is finished, stop the peristaltic pump pumping fluid, continue to fluidize for 20 minutes, take it out, and place it in the blast drying oven. Placed at 50 ° C for 2 h, taken out, passed through 100 and 120 mesh sieve, that is, azithromycin taste masked pellets.
- the cefprozil-containing drug-containing pellets are prepared, the barrier layer is coated, and the sustained release layer is coated to obtain particles of less than 150 ⁇ m, and the auxiliary materials are added according to the characteristics of the dry suspension, and the mixture is uniformly mixed.
- Cefprozil-containing pellets 200 g of silica microspheres (particle size: 0.12-0.15 mm), 125 g of cefprozil (micronized to 10 ⁇ m), 20 g of povidone, 5 g of talc, 2000 mL of 60% ethanol.
- the preparation process of the chemical solution 20.0 g of povidone was added to 2000 mL of 60% ethanol under stirring, dissolved to clarification, 125 g of cefprozil was added, stirring was continued for 1 h, 5 g of talc powder was added, and the mixture was stirred for 15 minutes to obtain a drug-containing solution.
- Preparation of drug-containing pellets 200 g of 100-120 mesh silica microspheres (particle size: 0.15-0.12 mm) were placed in a fluidized bed coating machine, and the silica microspheres were coated with a bottom spray coating.
- the blast frequency to 20 Hz, the inlet air temperature to 45 ° C, the nozzle nozzle diameter to 1.0 mm, the atomization pressure to 0.15 MPa, the peristaltic pump pumping speed to 5 r/min, the material temperature to 30 ° C, and the peristaltic pump to be turned on.
- the coating of the perfusion solution is stopped, the peristaltic pump is stopped, and the fluid is further removed for 20 minutes, and then placed in a blast drying oven at 50 ° C for 2 hours, taken out, and sieved to obtain a drug-containing pellet.
- Separation layer solution preparation 20 g of hypromellose was added to 400 mL of purified water under stirring, and dissolved to clarification.
- Separation layer preparation using a fluidized bed coating machine bottom spray coating to isolate the drug-containing pellet core, taking the prescribed amount of the isolation pellet into the fluidized bed coating machine, setting the blast frequency to 20 Hz, and entering the air
- the temperature is 45 ° C
- the spray gun nozzle diameter is 1.0mm
- the atomization pressure is set to 0.16MPa
- the peristaltic pump pumping speed is 6r/min
- the material temperature is 40°C.
- the peristaltic pump is turned on to pump the liquid. After the isolation solution coating is completed, the peristaltic pump is stopped.
- the liquid is further fluidized for 15 minutes, taken out, placed in a blast drying oven at 50 ° C for 2 h, taken out, sieved, and passed the test to obtain the isolated pellets.
- sustained-release layer solution 50 g of Eudragit RS100 and 5 g of triethyl citrate were added, 400 mL of a 90% ethanol solution was added, dissolved to clarification, and 5 g of talc powder was added to prepare a sustained-release layer coating liquid.
- Preparation of sustained-release pellets The isolated pellets were put into a fluidized bed coating machine, and the blasting frequency was set to 20 Hz, the inlet air temperature was 45 ° C, the nozzle diameter of the spray gun was 1.0 mm, the atomization pressure was set to 0.15 MPa, and the peristaltic pump was used. The pumping speed is 5r/min. After the material temperature reaches 40°C, open the peristaltic pump to pump the liquid. After the coating of the slow-release solution is completed, stop the peristaltic pump pump fluid, continue to fluidize for 20 minutes, take it out, and place it in the blast drying oven. After being placed at 50 ° C for 2 h, it was taken out and passed through a sieve of 80 and 110 mesh to obtain a cefprozil sustained-release pellet.
- cefprozil sustained-release sustained-release pellets were added with 8 g of talc powder, 10 g of mannitol and 15 g of fruit flavor, and uniformly mixed.
- the content of cefprozil in the sustained-release dry suspension of cefprozil was measured, and the amount of the sample was calculated according to the content test result. Fill it up. Capsules can be opened before use and can be taken with cheese, pudding, jam and other foods.
- Roxithromycin-containing pellets silica microspheres (particle size: 0.10-0.12 mm) 200 g, roxithromycin 100 g, hypromellose 35 g, talc powder 5 g, 70% ethanol 2000 mL.
- Preparation of drug-containing pellets 200 g of 130-150 mesh silica microspheres (particle size: 0.12-0.10 mm) was placed in a centrifugal granulation coating machine, and the rotation speed of the turntable was set to 200 r-300 r/min, and the blast frequency was 5 Hz. -50Hz, inlet air temperature is 40°C-60°C, spray gun nozzle diameter is 0.8mm, atomization pressure is set to 0.01-0.05MPa, open peristaltic pump for pumping, peristaltic pump pumping liquid speed is 5r-15r/min After the surface of the blank pellet core is wetted, the automatic feeding device is turned on, and the frequency of the feeder is set to 5r-20r/min.
- the peristaltic pump is stopped, and the pellet containing the pellet is further rotated for 10 minutes to 30 minutes, and then taken out and placed on the drum.
- the air drying oven is placed at 50 ° C for 2-6 hours, taken out, sieved, and passed the test to obtain the drug-containing pellets.
- Separation layer solution preparation 20 g of hypromellose was added to 400 mL of purified water under stirring to dissolve, and then clarified, and then 5 g of talc powder was added, and the mixture was stirred for use.
- Separation layer preparation the drug-containing pellets were put into a high-efficiency coating machine, and the nozzle diameter of the spray gun was set to 1.0 mm, the atomization pressure of the spray gun was 1.4 bar-2.0 bar, the needle valve pressure was 4.0 bar, and the inlet air temperature was adjusted to 40-60 ° C.
- the outlet air temperature is 30-50 °C
- the main engine speed is 10-25r/min
- the inlet air volume is 500-900m 3 /h
- the outlet air volume is 1000-2900m 3 /h
- the negative pressure in the pot is about -0.1KPa
- the material temperature is up to 30-45 °C
- adjust the peristaltic pump pumping speed to the isolation layer solution the pumping speed is 5r/min-25r/min to the end of the coating solution solution, take out, dry at 50 °C for 2h-6h, take out, sieve, and pass the inspection. I will get it later.
- taste masking layer solution Take 50g of polyacrylic acid resin IV, add 400mL of 95% ethanol solution, dissolve to clarification, add 6g of talc powder, stir evenly, and make a taste masking layer coating liquid.
- Preparation of taste masking layer Take the drug-containing pellets (including the separation layer) into the high-efficiency coating machine, set the nozzle diameter of the spray gun to 1.0mm, the spray gun atomization pressure to 1.4bar-2.0bar, the needle valve pressure to 4.0bar, and adjust Inlet air temperature 40-60 °C, outlet air temperature 30-50 °C, main engine speed 10-25r/min, inlet air volume 500-900 3 /h, outlet air volume 1000-2900 3 /h, negative pressure in the pot is about -0.1KPa, the temperature of the material to 30-45 ° C, adjust the pumping speed of the peristaltic pump pumping solution, the pumping speed is 5r/min-25r/min to the end of the coating solution, take out, dry at 50 °C for 2h- 6h, taken out, passed through 80 mesh and 120 mesh sieve, after the test passed, roxithromycin taste masked pellets.
- the lincomycin-containing drug-containing pellets are prepared, the coating layer is coated, and the sustained-release pellets are prepared by coating the sustained-release layer, and then uniformly mixed with appropriate characteristic auxiliary materials.
- Lincomycin-containing pellets silica microspheres (particle size: 0.12-0.10 mm) 200 g, lincomycin 150 g, povidone 20 g, talc powder 5 g, 60% ethanol 2000 mL.
- the preparation process of the chemical solution adding 20.0 g of povidone to 2000 mL of 60% ethanol under stirring, dissolving until clarification, adding 150 g of lincomycin (over 100 mesh sieve), stirring for 1 h, adding 5 g of talc powder, stirring for 15 min, Have a liquid medicine.
- Preparation of drug-containing pellets take 130-150 mesh silica microspheres (particle size: 0.12-0.10mm) 200g, put into a fluidized bed coating machine, use the bottom spray coating to apply the blank pellet core, set The blast frequency is 15Hz-25Hz, the inlet air temperature is 40°C-60°C, the nozzle diameter is 1.0mm, the atomization pressure is set to 0.15MPa-0.20MPa, and the peristaltic pump pumping speed is 3r-15r/min. After the temperature reaches 30-50 °C, open the peristaltic pump to pump the solution.
- Separation layer solution preparation 20 g of hypromellose was added to 400 mL of purified water under stirring, and dissolved to clarification.
- Separation layer preparation using a fluidized bed coating machine bottom spray coating to isolate the drug-containing pellet core, taking a prescribed amount of the drug-containing pellet core into a fluidized bed coating machine, setting the blast frequency to 15 Hz - 25 Hz,
- the inlet air temperature is 40°C-50°C
- the spray gun nozzle diameter is 1.0mm
- the atomization pressure is set to 0.15MPa-0.20MPa
- the peristaltic pump pumping speed is 3r-15r/min
- the material temperature is 40°C
- the peristaltic pump is turned on.
- sustained-release layer solution 50 g of Eudragit RS100 and 5 g of triethyl citrate were added, 400 mL of a 90% ethanol solution was added, dissolved to clarification, and 5 g of talc powder was added to prepare a sustained-release layer coating liquid.
- the drug-containing pellets (including the separator) are put into a fluidized bed coating machine, and the blasting frequency is set to 15 Hz to 25 Hz, the inlet air temperature is 40 ° C to 50 ° C, and the nozzle diameter of the spray gun is 1.0 mm.
- the atomizing pressure is set to 0.15MPa-0.20MPa, peristaltic pump pumping speed is 3r-15r/min, after the material temperature reaches 40°C, open the peristaltic pump to pump the liquid.
- stop the peristaltic pump pump and continue to fluidize for 10min. After -30min, take it out and place it in a blast drying oven at 50 °C for 2h-6h, take it out, pass the 75 mesh and 115 mesh sieve, and pass the test to obtain the sustained release pellet.
- talc powder 8g to lincomycin sustained-release pellets, mix with mannitol 10g, fruit flavor 15g, sodium benzoate 15g, mix well, and fill.
- Clarithromycin-containing pellets 300 g of silica microspheres (particle size: 0.10-0.12 mm), 250 g of clarithromycin (micronized to 10 ⁇ m), 60 g of hydroxypropylcellulose, 12 g of talc, 2200 mL of 60% ethanol .
- the preparation process of the chemical solution 50.0 g of hydroxypropylcellulose was added to 2000 mL of 60% ethanol under stirring, dissolved to clarification, 250 g of clarithromycin was added, stirring was continued for 1 hour, 10 g of talc powder was added, and the mixture was stirred for 15 minutes to obtain a drug-containing solution.
- Preparation of drug-containing pellets 300 g of 130-150 mesh silica microspheres (particle size: 0.12-0.10 mm), put into a fluidized bed coating machine, and spray coated with a fluidized bed coater to the blank pills
- the core is applied to the medicine, and the rotation speed of the rotary disk is set to 100-200r/min, the slit width is 2-5mm, the blast frequency is 15Hz-25Hz, the inlet air temperature is 40°C-60°C, the nozzle diameter is 1.0mm, and the atomization pressure is Set to 0.15MPa-0.20MPa, the peristaltic pump pumping speed is 3r-15r/min, open the peristaltic pump to pump the liquid, and wait until the blank pellet core and the auxiliary material are glued. Stop the peristaltic pump pump liquid, continue to rotate for 10 minutes, take it out, place it in a blast drying oven at 50 °C for 2-6h, take it out, sift through it, and pass the test to obtain the drug-
- Separation layer solution preparation 25 g of hypromellose was added to 500 mL of purified water under stirring to dissolve, and then talc powder 5 g, and stirred well.
- Separation layer preparation using a fluidized bed coating machine bottom spray coating to isolate the drug-containing pellet core, taking a prescribed amount of the drug-containing pellet core into a fluidized bed coating machine, setting the blast frequency to 15 Hz - 25 Hz,
- the inlet air temperature is 40°C-50°C
- the spray gun nozzle diameter is 1.0mm
- the atomization pressure is set to 0.15MPa-0.20MPa
- the peristaltic pump pumping speed is 3r-15r/min
- the material temperature is 40°C
- the peristaltic pump is turned on.
- sustained-release layer solution 80 g of Eudragit L100-55 and 8 g of triethyl citrate were added, 1000 mL of a 95% ethanol solution was added, dissolved to clarification, and 13 g of talc powder was added to prepare an enteric layer coating liquid.
- enteric layer The drug-containing pellets (including the separation layer) are put into a fluidized bed coating machine, and the blasting frequency is set to 15 Hz to 25 Hz, the inlet air temperature is 40 ° C to 50 ° C, and the nozzle diameter of the spray gun is 1.0 mm.
- the atomization pressure is set to 0.15MPa-0.20MPa, the peristaltic pump pumping speed is 3r-15r/min, and the material temperature is to 40°C.
- the peristaltic pump is turned on to pump the liquid. After the coating of the drug solution is completed, the peristaltic pump is stopped. Continue to fluidize for 10min-30min, take it out, place it in a blast drying oven at 50°C for 2h-6h, take it out, pass through 75 mesh and 110 mesh sieve, and pass the test to obtain enteric pellet.
- the content of clarithromycin in the clarithromycin enteric pellets was measured, and the loading amount of the pellets in the capsule was calculated according to the detection result of the clarithromycin content, and the filling was performed.
- the preparation method of the present invention is preferably obtained after extensive screening, and the screening process is as follows:
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Abstract
一种二氧化硅微球,以高纯度的二氧化硅为原料,通过熔融或研磨方式获得,并经过纯化达到药用辅料要求,具有很好的圆整度和机械强度,粒径范围为40-250μm,堆密度范围为1.2-1.6g/cm3,将其应用到制药领域,作为wuster包衣用空白丸芯,实现小于150μm颗粒制剂的包衣过程,达到掩味、缓释及控释。基于其合适的粒径分布,较高的堆密度、机械强度、圆整度,可极大提高小于150μm颗粒包衣的收率,包衣收率在90%以上。
Description
本发明涉及一种二氧化硅药用微球,它们的制备和药用纯化方法,以及二氧化硅药用微球在小于150μm颗粒包衣制剂领域的应用。
药用空白丸芯是制备生产微丸制剂必需的母核,目前,微丸制剂常用的空白丸芯主要包括:糖丸(蔗糖型)、微晶纤维素丸芯、淀粉丸芯、乳糖丸芯、二氧化硅丸芯等,主要应用于微丸上药、包衣,其粒径范围在300-800μm,且不同的类型丸芯稳定性、堆密度、脆碎度不同,根本无法应用于小于150μm颗粒制剂的包衣,现有的空白丸芯(≤150μm)在使用wuster包衣技术时,存在很多缺陷,由于现有的空白丸芯(≤150μm)本身的粒径小,比表面积大,且颗粒本身存在不规则性和不均匀性,包衣难度大,包衣增重量大,破碎率高,产品收率很低,有些空白丸芯根本无法实现,包衣颗粒也存在不均匀性,应用于掩味、缓控释制剂时不能达到令人满意的效果,如掩味不均匀,释放不均匀,甚至突释或者破碎等情况。这极大的限制了wuster包衣技术在小于150μm颗粒制药领域的应用。而小于150μm颗粒口服制剂在临床上有着广泛应用和需求,特别适用于儿童、老年人的等口服或者吞咽困难人群。开发能够克服上述缺点的药用辅料有着积极的经济价值和社会效益。
二氧化硅作为惰性材料,已经广泛应用于食品和制药领域,二氧化硅微球的制备技术也有很多公开报道,而通过控制二氧化硅微球的纯度、粒径分布,堆密度、脆碎度、圆整度,使之具有良好的物理性能和药用安全性,适用wuster包
衣技术实现小于150μm颗粒包衣制备技术尚未见任何报道,二者的结合创新在于对二氧化硅微球的物理性能控制与wuster包衣技术要求结合,实现了二氧化硅药用微球突破性应用。
发明内容
本发明的目的是提供一种二氧化硅药用微球的制备方法。
本发明所述二氧化硅药用微球,是以高纯度的二氧化硅为原料,通过熔融或研磨方式获得,并经过纯化达到药用辅料要求。
具体的,本发明所述的二氧化硅药用微球的制备方法,包括以下步骤:
将二氧化硅微球先通过强酸进行洗涤,然后将强酸化后的丸芯悬混液用强碱进行中和至pH至6-7,再进行洗涤后烘干,筛分制得二氧化硅药用微球。
其中,所述二氧化硅微球为熔融状态下形成的二氧化硅微球,
或者,所述二氧化硅微球为天然水晶矿通过球磨机研磨形成的二氧化硅微球,其中原料天然水晶矿中二氧化硅纯度达到90.0%以上。
其中,所述强酸选自:硫酸、盐酸、磷酸、硝酸中的任意一种或几种,所述强酸的浓度为1-10%。
其中,所述强碱选自:氢氧化钠、氢氧化钾中的任意一种或几种。
优选的,本发明所述的二氧化硅药用微球的制备方法,包括以下步骤:
取熔融状态下形成的二氧化硅微球,或者取天然水晶矿通过球磨机研磨形成的二氧化硅微球,投入到5-10%的盐酸溶液中,搅拌1-2h,静置,倾去上清液,将剩余的二氧化硅微球浓缩液中加1-5mol/L氢氧化钠调节至pH=7,过滤,采用纯化水进行洗涤,烘干后过筛即得二氧化硅药用微球。
本发明制备得到的二氧化硅药用微球为新型药用辅料,其主要成分为二氧化硅,且符合中国药典要求,无毒副作用,二氧化硅纯度应达到90.0%以上,氯化物、硫酸盐、铁盐、砷盐、重金属均应符合药典规定。
优选的,该微球二氧化硅含量不得低于99.0%、氯化物不得大于0.1%、硫酸盐不得大于0.5%、铁盐不得大于0.015%、重金属不得大于百万分之三十。
本发明的二氧化硅药用微球的粒径范围应在40-250μm,更加优选50-100μm。
本发明的二氧化硅药用微球在粒径范围应具有较高的堆密度,适合wuster包衣,其密度应该在1.2-1.6g/cm3,使包衣的丸芯粒径范围增大,能实现50-100μm颗粒的wuster包衣。
本发明的二氧化硅药用微球具有较高的硬度,在包衣过程中破碎率低,产品收率高,包衣收率在90%以上。
本发明的二氧化硅药用微球具有较高的圆整度,表面临界稳定性在10-12°范围,可以使丸芯上药和功能性包衣更均匀。
本发明的二氧化硅药用微球通过制备过程中的工艺参数控制,使其具有较窄的粒径分布,使载药和功能性包衣更均匀。
本发明的另一目的是提供该二氧化硅药用微球在制备粒径小于150μm的包衣制剂中的应用。
二氧化硅药用微球应用到制药领域,作为wuster包衣用空白丸芯,实现小于150μm颗粒制剂的包衣过程,达到掩味、缓释及控释。基于其合适的粒径分布,较高的堆密度、机械强度、圆整度,可极大提高小于150μm颗粒包衣的收率,包衣收率在90%以上。
本发明与现有同类产品相比较,具有以下优点:
1、该二氧化硅药用微球无毒副作用,符合中国药典要求,体内无吸收,无生物活性,完全适用于人体;
2、该二氧化硅药用微球采用独特的微球技术使其圆整度好,使其在流化床wuster上药和包衣过程中,包衣均匀,易形成连续性衣膜,减少包衣损失;
3、该二氧化硅药用微球具有较高的堆密度(密度适宜)和较窄的粒径分布,适合流化床wuster包衣,特别适合小于150μm颗粒包衣(包衣完成后微丸粒径在100-150μm);
4、该二氧化硅药用微球具有较高的硬度,机械强度高,在包衣过程中破碎率低,包衣的相互碰撞中几乎不会损失,包衣收率非常高,非常适合小于150μm颗粒包衣制剂;
5、由该二氧化硅药用微球制备的细微粒制剂在口腔中无砂砾感,适宜吞服;可以与奶酪、布丁、果酱等软食一同吞服,顺应性好;
6、制备的小于150μm颗粒成品粒径小、利于制备口服干混悬剂或混悬液制剂,适宜于于儿童和老年人等口服和吞咽有困难人群。
其中,所述wuster包衣是指:流化床底喷装置也称为Wurster系统,由Dale Wuster教授研制,是包衣技术的一次重要突破,使对小粒径物料的包衣成为可能。随着技术的发展,已经可以对小至50μm的粉末进行包衣。
以下通过实施例进一步说明本发明,但不作为对本发明的限制。
实施例1二氧化硅微球的制备
取熔融制备的二氧化硅微球或二氧化硅纯度达到99.0%的水晶矿采用球磨机研磨制备的二氧化硅微球(80目)1kg,投入到10%的盐酸溶液中,搅拌1h,静置,
倾去上清液,将剩余的二氧化硅微球浓缩液中加1mol/L氢氧化钠调节至pH=7,过滤,采用纯化水进行洗涤,烘干后过筛即得80目二氧化硅微球。
实施例2二氧化硅微球的制备
取熔融制备的二氧化硅微球或或二氧化硅纯度达到99.9%的水晶矿采用球磨机研磨制备的二氧化硅微球(100-120目)1kg,投入到10%的盐酸溶液中,搅拌1h,静置,倾去上清液,将剩余的二氧化硅微球浓缩液中加1mol/L氢氧化钠调节至pH=7,过滤,采用纯化水进行洗涤,烘干后过筛即得120目二氧化硅微球。
实施例3阿奇霉素干混悬剂的制备方法
先制备阿奇霉素含药微丸,包衣隔离层,再包衣缓释层制得阿奇霉素掩味微丸,根据干混悬剂的特性添加辅料,混合均匀,即可。
(1)阿奇霉素含药微丸制备过程
阿奇霉素含药微丸组方:二氧化硅微球(粒径:0.075-0.10mm)300g,阿奇霉素150g(100目),HPMC(E5)10g,滑石粉5g,85%乙醇2000mL。
药液制备过程:在搅拌下向85%乙醇2000mL中加入HPMC(E5)10.0g,溶解至澄清,加入阿奇霉素150g,继续搅拌1h,加入滑石粉5g,搅拌15min,得含药溶液。
含药微丸制备:取150-200目二氧化硅微球(粒径:0.15-0.12mm)300g,投入流化床包衣机,采用底喷雾化包衣对二氧化硅微球进行上药,设置鼓风频率为25Hz、进风温度为45℃、喷枪喷嘴直径为1.0mm、雾化压力设置为0.15MPa、蠕动泵泵液速度为5r/min、待物料温度至35℃、打开蠕动泵进行泵液,上药溶
液包衣完成后,停止蠕动泵泵液,继续流化20min后取出,置于鼓风干燥箱中50℃放置2h,取出,过筛,即得含药微丸。
(2)阿奇霉素掩味微丸的制备
A.隔离微丸包隔离层
隔离层溶液制备:搅拌状态下向纯化水500mL中加入羟丙甲纤维素20g,溶解至澄清。
隔离层制备:采用流化床包衣机底喷雾化包衣对含药丸芯进行隔离包衣,取处方量的隔离微丸投入流化床包衣机中,设置鼓风频率为25Hz,进风温度为45℃,喷枪喷嘴直径为1.0mm,雾化压力设置为0.16MPa,蠕动泵泵液速度为5r/min,待物料温度至40℃,打开蠕动泵进行泵液,隔离溶液包衣完成后,停止蠕动泵泵液,继续流化20min后取出,置于鼓风干燥箱中50℃放置2h,取出,过筛,检验合格即得隔离微丸。
B.隔离微丸包掩味层
掩味层溶液制备:取150g尤特奇E100,柠檬酸三乙酯15g,加入1500mL的90%乙醇溶液,溶解至澄清,加入滑石粉15g,制成掩味层包衣液。
掩味微丸制备:将隔离微丸投入流化床包衣机中,设置鼓风频率为25Hz,进风温度为45℃,喷枪喷嘴直径为1.0mm,雾化压力设置为0.15MPa,蠕动泵泵液速度为5r/min,待物料温度至40℃,打开蠕动泵进行泵液,掩味溶液包衣完成后,停止蠕动泵泵液,继续流化20min后取出,置于鼓风干燥箱中50℃放置2h,取出,过100和120目筛,即得阿奇霉素掩味微丸。
(3)阿奇霉素干混悬剂的制备
将阿奇霉素掩味微丸,加入滑石粉10g,与甘露醇30g,水果香精20g,苯甲酸钠20g,黄原胶40g,混合均匀,检查合格后即得阿奇霉素干混悬剂。
实施例4头孢丙烯缓释胶囊制备方法
先制备头孢丙烯含药微丸,包衣隔离层,再包衣缓释层制得小于150μm颗粒,根据干混悬剂的特性添加辅料,混合均匀,即可。
(1)头孢丙烯含药微丸制备过程
头孢丙烯含药微丸组方:二氧化硅微球(粒径:0.12-0.15mm)200g,头孢丙烯125g(微粉至10μm),聚维酮20g,滑石粉5g,60%乙醇2000mL。
药液制备过程:在搅拌下向60%乙醇2000mL中加入聚维酮20.0g,溶解至澄清,加入头孢丙烯125g,继续搅拌1h,加入滑石粉5g,搅拌15min,得含药溶液。含药微丸制备:取100-120目二氧化硅微球(粒径:0.15-0.12mm)200g,投入流化床包衣机,采用底喷雾化包衣对二氧化硅微球进行上药,设置鼓风频率为20Hz、进风温度为45℃、喷枪喷嘴直径为1.0mm、雾化压力设置为0.15MPa、蠕动泵泵液速度为5r/min、待物料温度至30℃、打开蠕动泵进行泵液,上药溶液包衣完成后,停止蠕动泵泵液,继续流化20min后取出,置于鼓风干燥箱中50℃放置2h,取出,过筛,即得含药微丸。
(2)头孢丙烯缓释微丸的制备
A.隔离微丸包隔离层
隔离层溶液制备:搅拌状态下向纯化水400mL中加入羟丙甲纤维素20g,溶解至澄清。
隔离层制备:采用流化床包衣机底喷雾化包衣对含药丸芯进行隔离包衣,取处方量的隔离微丸投入流化床包衣机中,设置鼓风频率为20Hz,进风温度为45℃,
喷枪喷嘴直径为1.0mm,雾化压力设置为0.16MPa,蠕动泵泵液速度为6r/min,待物料温度至40℃,打开蠕动泵进行泵液,隔离溶液包衣完成后,停止蠕动泵泵液,继续流化15min后取出,置于鼓风干燥箱中50℃放置2h,取出,过筛,检验合格即得隔离微丸。
B.隔离微丸包缓释层
缓释层溶液制备:取50g尤特奇RS100,柠檬酸三乙酯5g,加入400mL的90%乙醇溶液,溶解至澄清,加入滑石粉5g,制成缓释层包衣液。
缓释微丸制备:将隔离微丸投入流化床包衣机中,设置鼓风频率为20Hz,进风温度为45℃,喷枪喷嘴直径为1.0mm,雾化压力设置为0.15MPa,蠕动泵泵液速度为5r/min,待物料温度至40℃,打开蠕动泵进行泵液,缓释溶液包衣完成后,停止蠕动泵泵液,继续流化20min后取出,置于鼓风干燥箱中50℃放置2h,取出,过80和110目筛,即得头孢丙烯缓释微丸。
(3)头孢丙烯缓释胶囊的制备
将头孢丙烯缓释缓释微丸,加入滑石粉8g,与甘露醇10g,水果香精15g,混合均匀,检测头孢丙烯缓释干混悬剂中的头孢丙烯含量,根据含量检测结果计算装样量,填装即可。使用前,可将胶囊打开,其内含物可与奶酪、布丁、果酱等食物同时服用。
实施例5采用二氧化硅微球制备罗红霉素干混悬剂
先制备罗红霉素含药微丸,包衣隔离层,再包衣掩味层制得罗红霉素掩味微丸,再根据干混悬剂的特性添加辅料,混合均匀,即得罗红霉素干混悬剂。
(1)罗红霉素含药微丸制备过程
罗红霉素含药微丸组方:二氧化硅微球(粒径:0.10-0.12mm)200g,罗红霉素100g,羟丙甲纤维素35g,滑石粉5g,70%乙醇2000mL。
药液制备过程:在搅拌下向70%乙醇2000mL中加入羟丙甲纤维素35.0g,溶解至澄清,加入罗红霉素(过100目筛)100g,继续搅拌1h,加入滑石粉5g,搅拌15min,得含药溶液。
含药微丸制备:取130-150目二氧化硅微球(粒径:0.12-0.10mm)200g投入离心造粒包衣机中,设置转盘转速为200r-300r/min、鼓风频率为5Hz-50Hz、进风温度为40℃-60℃、喷枪喷嘴直径为0.8mm、雾化压力设置为0.01-0.05MPa、打开蠕动泵进行泵液、蠕动泵泵入药液速度为5r-15r/min,待空白丸芯表面润湿后,打开自动加料装置,加料器频率设为5r-20r/min、加料完成后,停止蠕动泵泵液,含药丸芯继续转动10min-30min后取出,置于鼓风干燥箱中50℃放置2-6h,取出,过筛,检验合格即得含药微丸。
(2)罗红霉素掩味微丸的制备
A.含药微丸包隔离层
隔离层溶液制备:搅拌状态下向纯化水400mL中加入羟丙甲纤维素20g溶解至澄清后、再加入滑石粉5g,搅拌均匀备用。
隔离层制备:含药微丸投入高效包衣机中,设置喷枪喷嘴直径为1.0mm、喷枪雾化压力为1.4bar-2.0bar、针阀压力为4.0bar、调节进风温度40-60℃、出风温度30-50℃、主机转速10-25r/min、进风风量500-900m3/h、出风风量1000-2900m3/h、锅内负压约为-0.1KPa、待物料温度至30-45℃、调节蠕动泵泵液速度包隔离层溶液,泵液速度为5r/min-25r/min至包隔离衣溶液结束,取出,50℃干燥2h-6h,取出,过筛,检验合格后即得。
B.隔离微丸包掩味层
掩味层溶液制备:取50g聚丙烯酸树脂IV,加入400mL的95%乙醇溶液,溶解至澄清,加入6g滑石粉,搅拌均匀,制成掩味层包衣液。
掩味层制备:取的含药微丸(含隔离层)投入高效包衣机中,设置喷枪喷嘴直径为1.0mm、喷枪雾化压力为1.4bar-2.0bar、针阀压力为4.0bar、调节进风温度40-60℃、出风温度30-50℃、主机转速10-25r/min、进风风量500-9003/h、出风风量1000-29003/h、锅内负压约为-0.1KPa、待物料温度至30-45℃、调节蠕动泵泵液速度包掩味层溶液,泵液速度为5r/min-25r/min至包隔离衣溶液结束,取出,50℃干燥2h-6h,取出,过80目和120目筛,检验合格后即得罗红霉素掩味微丸。
(3)罗红霉素干混悬剂的制备
将罗红霉素掩味微丸,加入滑石粉5g,与甘露醇10g,水果香精5g,苯甲酸钠10g,黄原胶20g,混合均匀,检查合格后,即得罗红霉素干混悬剂。
实施例6林可霉素干混悬剂的制备
先制备林可霉素含药微丸,包衣隔离层,再包衣缓释层制得缓释微丸,再与适当特性辅料混合均匀即可。
(1)林可霉素含药微丸制备过程
林可霉素含药微丸组方:二氧化硅微球(粒径:0.12-0.10mm)200g,林可霉素150g,聚维酮20g,滑石粉5g,60%乙醇2000mL。
药液制备过程:在搅拌下向60%乙醇2000mL中加入聚维酮20.0g,溶解至澄清,加入林可霉素(过100目筛)150g,继续搅拌1h,加入滑石粉5g,搅拌15min,得含药液。
含药微丸制备:取130-150目二氧化硅微球(粒径:0.12-0.10mm)200g,投入流化床包衣机,采用底喷雾化包衣对空白丸芯进行上药,设置鼓风频率为15Hz-25Hz、进风温度为40℃-60℃、喷枪喷嘴直径为1.0mm、雾化压力设置为0.15MPa-0.20MPa、蠕动泵泵液速度为3r-15r/min、待物料温度至30-50℃、打开蠕动泵进行泵液,上药溶液包衣完成后,停止蠕动泵泵液,继续流化10min-30min后取出,置于鼓风干燥箱中50℃放置2-6h,取出,过筛,检验合格即得含药丸芯。
(2)林可霉素缓释微丸的制备
A.含药微丸包隔离层
隔离层溶液制备:搅拌状态下向纯化水400mL中加入羟丙甲纤维素20g,溶解至澄清。
隔离层制备:采用流化床包衣机底喷雾化包衣对含药丸芯进行隔离包衣,取处方量的含药丸芯投入流化床包衣机中,设置鼓风频率为15Hz-25Hz,进风温度为40℃-50℃,喷枪喷嘴直径为1.0mm,雾化压力设置为0.15MPa-0.20MPa,蠕动泵泵液速度为3r-15r/min,待物料温度至40℃,打开蠕动泵进行泵液,上药溶液包衣完成后,停止蠕动泵泵液,继续流化10min-30min后取出,置于鼓风干燥箱中50℃放置2h-6h,取出,过筛,检验合格即得隔离微丸。
B.隔离微丸包缓释层
缓释层溶液制备:取50g尤特奇RS100,柠檬酸三乙酯5g,加入400mL的90%乙醇溶液,溶解至澄清,加入滑石粉5g,制成缓释层包衣液。
缓释层制备:将含药微丸(含隔离层)投入流化床包衣机中,设置鼓风频率为15Hz-25Hz,进风温度为40℃-50℃,喷枪喷嘴直径为1.0mm,雾化压力设置为
0.15MPa-0.20MPa,蠕动泵泵液速度为3r-15r/min,待物料温度至40℃,打开蠕动泵进行泵液,上药溶液包衣完成后,停止蠕动泵泵液,继续流化10min-30min后取出,置于鼓风干燥箱中50℃放置2h-6h,取出,过75目和115目筛,检验合格即得缓释微丸。
(3)林可霉素干混悬剂的制备
林可霉素缓释微丸中加入滑石粉8g,与甘露醇10g,水果香精15g,苯甲酸钠15g,混合均匀,填装即可。
实施例7克拉霉素肠溶胶囊制备
先制备克拉霉素含药微丸,包衣隔离层,再包衣肠溶层制得肠溶微丸,再灌装胶囊即可。
(1)克拉霉素含药微丸制备过程
克拉霉素含药微丸组方:二氧化硅微球(粒径:0.10-0.12mm)300g,克拉霉素250g(微粉至10μm),羟丙纤维素60g,滑石粉12g,60%乙醇2200mL。
药液制备过程:在搅拌下向60%乙醇2000mL中加入羟丙纤维素50.0g,溶解至澄清,加入克拉霉素250g,继续搅拌1h,加入滑石粉10g,搅拌15min,得含药液。
含药微丸制备:取130-150目二氧化硅微球(粒径:0.12-0.10mm)300g,投入流化床包衣机,采用流化床包衣机侧喷雾化包衣对空白丸芯进行上药,设置转盘转速100-200r/min、狭缝宽度为2-5mm、鼓风频率为15Hz-25Hz、进风温度为40℃-60℃、喷枪喷嘴直径为1.0mm、雾化压力设置为0.15MPa-0.20MPa、蠕动泵泵液速度为3r-15r/min、打开蠕动泵进行泵液,待空白丸芯和辅料粘合完毕后,停
止蠕动泵泵液,继续转动10min后取出,置于鼓风干燥箱中50℃放置2-6h,取出,过筛,检验合格即得含药丸芯。
(2)克拉霉素肠溶微丸的制备
A.含药微丸包隔离层
隔离层溶液制备:搅拌状态下向纯化水500mL中加入羟丙甲纤维素25g溶解至澄清后,再滑石粉5g,搅拌均匀备用。
隔离层制备:采用流化床包衣机底喷雾化包衣对含药丸芯进行隔离包衣,取处方量的含药丸芯投入流化床包衣机中,设置鼓风频率为15Hz-25Hz,进风温度为40℃-50℃,喷枪喷嘴直径为1.0mm,雾化压力设置为0.15MPa-0.20MPa,蠕动泵泵液速度为3r-15r/min,待物料温度至40℃,打开蠕动泵进行泵液,上药溶液包衣完成后,停止蠕动泵泵液,继续流化10min-30min后取出,置于鼓风干燥箱中50℃放置2h-6h,取出,过筛,检验合格即得隔离微丸。
B.隔离微丸包肠溶层
缓释层溶液制备:取80g尤特奇L100-55,柠檬酸三乙酯8g,加入1000mL的95%乙醇溶液,溶解至澄清,加入滑石粉13g,制成肠溶层包衣液。
肠溶层制备:将含药微丸(含隔离层)投入流化床包衣机中,设置鼓风频率为15Hz-25Hz,进风温度为40℃-50℃,喷枪喷嘴直径为1.0mm,雾化压力设置为0.15MPa-0.20MPa,蠕动泵泵液速度为3r-15r/min,待物料温度至40℃,打开蠕动泵进行泵液,上药溶液包衣完成后,停止蠕动泵泵液,继续流化10min-30min后取出,置于鼓风干燥箱中50℃放置2h-6h,取出,过75目和110目筛,检验合格即得肠溶微丸。
(3)克拉霉素肠溶胶囊的制备
检测克拉霉素肠溶微丸中的克拉霉素含量,根据克拉霉素含量检测结果计算胶囊中的微丸装样量,灌装即可。
实施例8本发明微丸制备方法的筛选过程
本发明的制备方法经过大量筛选后,优选得到的,筛选过程如下:
实验结果显示,通过研磨法制备的微球效果最好,该方法制备的玻璃微球粒径均匀,良品率高,成本低,易于大批量生产等优点。
实施例9本发明的微丸和现有产品的比较
为了进一步说明本发明的有益效果,申请人将本发明产品与现有产品进行比较,结果如下:
Claims (10)
- 一种二氧化硅药用微球的制备方法,其特征在于,是以高纯度的二氧化硅为原料,通过熔融或研磨方式获得,并经过纯化达到药用辅料要求。
- 根据权利要求1所述的制备方法,其特征在于,包括以下步骤:将二氧化硅微球先通过强酸进行洗涤,然后将强酸化后的丸芯悬混液用强碱进行中和至pH至6-7,再进行洗涤后烘干,筛分制得二氧化硅药用微球,其中,所述二氧化硅微球为熔融状态下形成的二氧化硅微球,或者,所述二氧化硅微球为天然水晶矿通过球磨机研磨形成的二氧化硅微球,其中原料天然水晶矿中二氧化硅纯度达到90.0%以上。
- 根据权利要求1所述的制备方法,其特征在于,所述强酸选自:硫酸、盐酸、磷酸、硝酸中的任意一种或几种,所述强酸的浓度为1-10%,所述强碱选自:氢氧化钠、氢氧化钾中的任意一种或几种。
- 根据权利要求1所述的制备方法,其特征在于,包括以下步骤:取熔融状态下形成的二氧化硅微球,或者取天然水晶矿通过球磨机研磨形成的二氧化硅微球,投入到5-10%的盐酸溶液中,搅拌1-2h,静置,倾去上清液,将剩余的二氧化硅微球浓缩液中加1-5mol/L氢氧化钠调节至pH=7,过滤,采用纯化水进行洗涤,烘干后过筛即得二氧化硅药用微球。
- 根据权利要求1所述的制备方法,其特征在于,包括以下步骤:取熔融制备的二氧化硅微球或二氧化硅纯度达到99.0%的水晶矿采用球磨机研磨制备的二氧化硅微球(80目)1kg,投入到10%的盐酸溶液中,搅拌1h,静置,倾去上清液,将剩余的二氧化硅微球浓缩液中加1mol/L氢氧化钠调节至pH=7,过滤,采用纯化水进行洗涤,烘干后过筛即得80目二氧化硅微球。
- 根据权利要求1所述的制备方法,其特征在于,包括以下步骤:取熔融制备的二氧化硅微球或或二氧化硅纯度达到99.9%的水晶矿采用球磨机研磨制备的二氧化硅微球(100-120目)1kg,投入到10%的盐酸溶液中,搅拌1h,静置,倾去上清液,将剩余的二氧化硅微球浓缩液中加1mol/L氢氧化钠调节至pH=7,过滤,采用纯化水进行洗涤,烘干后过筛即得120目二氧化硅微球。
- 根据权利要求1所述的制备方法,其特征在于,二氧化硅药用微球的粒径范围应在40-250μm,更加优选50-100μm,二氧化硅药用微球具有较高的堆密度,适合wuster包衣,其密度应该在1.2-1.6g/cm3,使包衣的丸芯粒径范围增大,能实现50-100μm颗粒的wuster包衣,二氧化硅药用微球具有较高的圆整度,表面临界稳定性在10-12°范围。
- 权利要求1所述的制备方法得到的二氧化硅药用微球,在制备粒径小于150μm的包衣制剂中的应用。
- 根据权利要求8所述的应用,其特征在于,二氧化硅药用微球作为作为wuster包衣用空白丸芯。
- 根据权利要求8所述的应用,其特征在于,包衣收率在90%以上。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1477532B1 (en) * | 2003-05-13 | 2011-05-25 | Shin-Etsu Chemical Co., Ltd. | Spherical silica-titania-based fine particles surface-treated with silane, production process therefor, and external additive for electrostatically charged image developing toner using same |
CN102727452A (zh) * | 2011-04-01 | 2012-10-17 | 成都康弘药业集团股份有限公司 | 一种含右佐匹克隆的颗粒及其制备方法 |
CN103539147A (zh) * | 2013-10-29 | 2014-01-29 | 昆明理工大学 | 一种二氧化硅分子筛的制备方法 |
CN106309405A (zh) * | 2016-09-28 | 2017-01-11 | 河南中帅医药科技股份有限公司 | 一种功能性细微丸的制备方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1299685C (zh) * | 2005-01-26 | 2007-02-14 | 上海大学 | 氟尿嘧啶载药微球及其制备方法 |
CN104644565B (zh) * | 2015-01-26 | 2017-06-30 | 海南华益泰康药业有限公司 | 一种盐酸多西环素含药小丸及其制备方法 |
CN105271267B (zh) * | 2015-11-04 | 2017-06-16 | 青岛美高集团有限公司 | 一种微米级二氧化硅微球及其生产方法 |
-
2016
- 2016-07-15 CN CN201610556389.7A patent/CN106177968A/zh active Pending
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2017
- 2017-01-11 WO PCT/CN2017/070891 patent/WO2018010406A1/zh active Application Filing
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2019
- 2019-01-15 US US16/247,605 patent/US20190142753A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1477532B1 (en) * | 2003-05-13 | 2011-05-25 | Shin-Etsu Chemical Co., Ltd. | Spherical silica-titania-based fine particles surface-treated with silane, production process therefor, and external additive for electrostatically charged image developing toner using same |
CN102727452A (zh) * | 2011-04-01 | 2012-10-17 | 成都康弘药业集团股份有限公司 | 一种含右佐匹克隆的颗粒及其制备方法 |
CN103539147A (zh) * | 2013-10-29 | 2014-01-29 | 昆明理工大学 | 一种二氧化硅分子筛的制备方法 |
CN106309405A (zh) * | 2016-09-28 | 2017-01-11 | 河南中帅医药科技股份有限公司 | 一种功能性细微丸的制备方法 |
Non-Patent Citations (3)
Title |
---|
CHEN, RONGFANG ET AL.: "Progress in Preparation Technology of Nanometre Spherical Silica", GUANGZHOU CHEMICAL INDUSTRY, vol. 42, no. 24, 31 December 2014 (2014-12-31), ISSN: 1001-9677 * |
LI, JUN ET AL.: "Current Status of Preparation Methods of Spherical Silica Micro-Powder", FOSHAN CERAMICS, no. 195, 30 November 2012 (2012-11-30), pages 35, ISSN: 1006-8236 * |
LIU, XUEQING ET AL.: "Preparation of Ultrafine Rice Husk Silica by Ball Milling Method", CHEMISTRY & BIOENGINEERING, vol. 28, no. 11, 30 November 2011 (2011-11-30), pages 66, ISSN: 1672-5425 * |
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US20190142753A1 (en) | 2019-05-16 |
CN106177968A (zh) | 2016-12-07 |
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