WO2022041664A1 - 一种调色剂、溶菌酶含片及该溶菌酶含片的制备方法 - Google Patents

一种调色剂、溶菌酶含片及该溶菌酶含片的制备方法 Download PDF

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Publication number
WO2022041664A1
WO2022041664A1 PCT/CN2021/077412 CN2021077412W WO2022041664A1 WO 2022041664 A1 WO2022041664 A1 WO 2022041664A1 CN 2021077412 W CN2021077412 W CN 2021077412W WO 2022041664 A1 WO2022041664 A1 WO 2022041664A1
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Prior art keywords
lysozyme
toner
dextrin
pigment
granulator
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PCT/CN2021/077412
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English (en)
French (fr)
Inventor
沈贡民
刘群
金艳
莫凤君
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杭州国光药业股份有限公司
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Priority to US17/319,113 priority Critical patent/US20220062162A1/en
Publication of WO2022041664A1 publication Critical patent/WO2022041664A1/zh

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01017—Lysozyme (3.2.1.17)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • 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
    • A61K9/1682—Processes
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the application relates to the technical field of pharmaceutical processing, in particular to a toner; the application also relates to a lysozyme lozenge and a method for preparing the lysozyme lozenge.
  • a tablet refers to a round or shaped flaky solid supported by a drug substance and suitable excipients. Among them, most of the tablets are taken orally, buccally, and chewed. In order to improve children's willingness to take tablets, a certain amount of pigment is often added to the tablet to make the tablet have a brighter color.
  • the Chinese invention patent with the authorization announcement number of CN101829212B and the authorization announcement date of August 31, 2011 discloses a lozenge and a preparation method thereof, wherein a preparation method of a lozenge is specifically disclosed, and the method includes the following steps : Pulverize rock sugar, mix with Yunnan olive powder, hawthorn powder, dextrin, soluble starch and pulverized mint and mix them evenly; dissolve citric acid in water and dilute to citric acid solution; dissolve sodium carboxymethyl cellulose in water, dilute it into an aqueous solution of sodium carboxymethyl cellulose; dissolve the food flavor and food coloring in edible ethanol, respectively, to form a food flavor solution and a food coloring solution; dissolve the honey in water, stir evenly to form a honey dilution; dissolve the citric acid The solution, honey dilution, sodium carb
  • the pigment is directly dissolved in water, mixed with other materials, granulated, dried and pressed, and the color of the obtained tablet is adjusted by the pigment.
  • the color and luster of the tablets prepared by the above method were not uniform, and some of the tablets would have spot morphology formed by the non-uniform color and luster, commonly known as the phenomenon of "flower tablets", which affected the uniformity of the tablets. sex.
  • the first purpose of the invention of the present application is to provide a toner, which helps to make the overall color of the tablet uniform in the process of tablet processing, and is not easy to produce "flowers”. Phenomenon.
  • the second object of the invention of the present application is to provide a lysozyme lozenge, in which the distribution of the pigment is relatively uniform, so that the overall appearance is relatively uniform.
  • the third object of the present application is to provide a method for preparing the above-mentioned lysozyme lozenges.
  • the lysozyme lozenges prepared by the preparation method have better uniformity and help to reduce the "flowers" in the lysozyme lozenges. The phenomenon occurs, so that the color and luster of the lysozyme lozenges are uniform inside and outside.
  • a toner prepared by the following method:
  • step S2 Weigh the dextrin, atomize and spray the pigment suspension obtained in step S1 on the dextrin, keep stirring while spraying, after the pigment suspension is sprayed, add additional water, and continue to stir until it is formed , to obtain pigment wet material;
  • step S3 Dry and pulverize the pigment wet material in step S2 to obtain a toner; wherein, the particle size of the toner after pulverization is not greater than 120 meshes.
  • the pigment is first dispersed in water, then atomized and sprayed onto the dextrin.
  • the pigment can be dispersed more uniformly by dextrin adsorbing the pigment and serving as the carrier of the pigment. Regardless of whether the pigment is soluble in water or not, it can achieve a relatively uniform dispersion after being adsorbed by dextrin.
  • the obtained pigment wet material is subsequently dried and pulverized to form a powdery toner.
  • step S2 when the pigment suspension is atomized and sprayed on the dextrin, the system is kept at an air pressure of 0.5-10 kPa.
  • the atomized liquid formed by the atomization of the pigment suspension can be more uniformly mixed with dextrin, so that the prepared toner has better uniformity.
  • the color of the particles is more uniform, thereby further reducing the possibility of flower chips in subsequent use.
  • step S2 the flow rate of atomization is 700-1000mL/min, and the atomization pressure is 0.1-0.2mPa.
  • the present application can be further configured as: the pigment is a mixed system of ⁇ -carotene and tartrazine, and the mass ratio of the ⁇ -carotene to tartrazine is (3-6):1;
  • the dextrin is white dextrin, and the mass ratio of the pigment to the dextrin is (0.01-0.05):1.
  • ⁇ -Carotene is insoluble in water, and tartrazine is easily soluble in water, and the two are coordinated with each other to achieve a more bright and bright color.
  • Dextrin is the product obtained by preliminary hydrolysis of starch, and its surface contains many hydroxyl groups, so it has good compatibility with the above two pigments, can carry the two pigments more evenly, and can mix the two pigments evenly.
  • the mass ratio of pigment and filler is set to (0.01 ⁇ 0.05):1, and the mass ratio of ⁇ -carotene and tartrazine in the pigment is (3 ⁇ 6):1. Within this range, it is easy to achieve uniform mixing of pigments, so it is more It helps to improve the uniformity of tablet color when the toner is used in tablet processing.
  • lysozyme buccal tablets the preparation raw materials of which include the following mass parts:
  • Sweetener 10 to 20 servings
  • Lysozyme 15 to 25 parts
  • Toner 20 to 30 parts
  • Adhesive 300 to 400 parts
  • the toner is any one of the above toners;
  • the filler is a mixture of dextrin and sucrose, and the mass parts of the dextrin are: 130-185 parts;
  • the sweetener is mannitol,
  • the adhesive included a 10% solution of povidone K30.
  • the filler is a mixture of dextrin and sucrose, and the dextrin has good adsorption performance, and has good adsorption performance for materials such as lysozyme, toner and sweetener.
  • Sucrose has a viscosity-promoting effect, which can make materials such as dextrin, lysozyme, toner and sweetener more fully mixed.
  • hydrogen bonds are easily formed between sucrose and dextrin, so during processing, sucrose will adhere to the surface of dextrin and coat the dextrin, so that the surface of the prepared lozenge has a sweet taste.
  • Mannitol can be better adsorbed in dextrin and covered by dextrin, and mannitol has high sweetness and refreshing taste, which is helpful to efficiently adjust the taste of the lysozyme lozenge.
  • the sucrose and dextrin in the filler can be uniformly mixed with the toner, so that the toner is not easy to agglomerate and agglomerate during the mixing process, which helps to further improve the toner
  • the uniformity of dispersion in the prepared lozenge improves the uniformity of color and luster of the lysozyme lozenge, and makes the lysozyme lozenge less likely to cause the phenomenon of "flowers" due to toner or pigment agglomeration.
  • the prepared lysozyme lozenges have relatively high strength, are easy to form, and are not easily broken into powder or granules.
  • the adhesive further contains 5-12 parts by mass of citric acid.
  • citric acid can not only play the role of seasoning, make the taste of lysozyme lozenges relatively mild and delicious, but also play the role of anti-oxidation and prolong the shelf life of lysozyme lozenges.
  • the preparation method for preparing the above-mentioned lysozyme lozenge comprises the following steps:
  • P1 get described filler, sweetener, lysozyme, toner, citric acid, weigh and sieve for subsequent use;
  • step P3 under the condition of keeping stirring, in the granulator, add binder to the premixed composition obtained in step P3, obtain paste composition;
  • step P4 in a granulator, the paste composition obtained in step P3 is cut into granules to obtain a wet product;
  • step P5 The wet product obtained in step P4 is subjected to the procedures of granulation, drying and tablet pressing to obtain lysozyme buccal tablets.
  • the filler, sweetener, lysozyme and toner are fully mixed first. Since both the filler and the toner contain dextrin, during the mixing process, the filler and the flavor can form relatively Uniform mixing structure, not easy to agglomerate or agglomerate flavoring agents.
  • the flavoring agent, sweetener and lysozyme are fully mixed in the system, the binder is added, and the material is formed into granules by stirring and cutting. The color is uniform, and there is basically no "flowering" phenomenon.
  • Step P2 is as follows: first add dextrin, lysozyme and toner into the granulator, and after fully stirring, add sucrose and mannitol into the granulator , continue to stir and mix evenly to obtain a premixed composition.
  • dextrin, lysozyme and toner are first mixed, and dextrin is used as the main filler, which is the same as the main component in the toner, so it is easier to form a homogeneous system when mixing.
  • sucrose and mannitol sucrose and mannitol can be bonded to dextrin by the mutual adsorption of hydroxyl groups to form a coating structure, thereby forming a uniform system, which is helpful for the prepared lysozyme lozenges to be more uniform.
  • step P2 while adding sucrose and mannitol to the granulator, add 50-80 parts by mass of purified sucrose and mannitol to the granulator by atomization. Water; sucrose, mannitol and purified water are uniformly added to the granulator within 20-40s.
  • water is added during the process of adding sucrose to form a syrup with a certain viscosity, and the materials such as dextrin, lysozyme powder and toner formed in the system can be preliminarily bonded and stereotypes. Since the water is added by atomization, the dextrin can be fully removed from the water during the adding process, which helps the surface of the dextrin to adsorb sucrose more evenly, thereby improving the overall strength and uniformity of the formed lysozyme lozenges.
  • step P3 after adding adhesive
  • the mixture formed by mass parts of 75 to 150 parts of 10% povidone K30 solution and 5 to 12 parts of citric acid was added to the granulator within 1 to 2 minutes, and then the mass parts were added.
  • a part of the binder is firstly added, and a certain amount of citric acid is mixed, which is conducive to the uniform mixing of solid materials such as citric acid and dextrin, and is coated by the binder.
  • the binder is then continued to be added to shape the lozenge.
  • the paste composition prepared by the above process is mixed relatively evenly, and can form a stable coating structure during the cutting process, so that the obtained lysozyme buccal tablet has a uniform inner and outer mouthfeel.
  • the present application includes at least one of the following beneficial technical effects:
  • a toner which can improve the dispersibility of the pigment when preparing the tablet by mixing the pigment into a pigment suspension and atomizing and spraying it in the dextrin to make powder, thereby making the After the tablet is processed, the color uniformity is better, and the phenomenon of "flowering" is not easy to occur.
  • a lysozyme lozenge which has the above-mentioned toner added and has better color uniformity.
  • Embodiment 1 a kind of toner, is prepared by following steps:
  • the pigment is added with purified water to prepare a suspension with a mass fraction of 10%, stir evenly, and prepare a pigment suspension;
  • step S2 Weigh the dextrin, atomize the pigment suspension obtained in step S1 at a pressure of 0.1 mPa and a flow rate of 700 mL/min and spray it on the dextrin under normal pressure, and keep it at 8 r/s while spraying
  • the dextrin was stirred at the speed of 100 °C, and after the pigment suspension was sprayed, 2.5 g of purified water was added, and the stirring was continued for 5 min to form a pigment wet material;
  • step S3 drying the pigment wet material in step S2 at a temperature of 75 ⁇ 5° C. in a hot air circulation oven, pulverizing in a pulverizer, and passing through a 120-mesh sieve to obtain a toner.
  • the pigment is a mixed system of 0.4g beta-carotene and 0.1g tartrazine, the added amount of purified water in the pigment suspension is 5g, the dextrin is white dextrin, and the added amount of dextrin is 25g.
  • Embodiment 2 a kind of toner, is prepared by following steps:
  • step S2 Weigh the dextrin, atomize the pigment suspension obtained in step S1 with a pressure of 0.2 mPa and a flow rate of 1000 mL/min and spray it on the dextrin under normal pressure, and keep it at 8 r/s while spraying
  • the dextrin was stirred at the speed of 100 °C, and after the pigment suspension was sprayed, 2.5 g of purified water was added, and the stirring was continued for 5 min to form a pigment wet material;
  • step S3 drying the pigment wet material in step S2 at a temperature of 75 ⁇ 5° C. in a hot air circulation oven, pulverizing in a pulverizer, and passing through a 120-mesh sieve to obtain a toner.
  • the pigment is a mixed system of 0.4g beta-carotene and 0.1g tartrazine, the addition amount of purified water in the pigment suspension is 5g, and the addition amount of dextrin is 25g.
  • Example 3 a toner, the difference from Example 1 is that the pigment is a mixed system of 0.6g beta-carotene and 0.2g tartrazine, and the amount of dextrin added is 15g.
  • Example 4 a toner, the difference from Example 1 is that the pigment is a mixed system of 0.45g beta-carotene and 0.075g tartrazine, and the amount of dextrin added is 45.5g.
  • Example 5 A toner that differs from Example 1 in that tartrazine is replaced with the same amount of beta-carotene.
  • Example 6 A toner that differs from Example 1 in that ⁇ -carotene is replaced with an equal amount of tartrazine.
  • Embodiment 7 a toner, is prepared by the following steps:
  • the pigment is added with purified water to prepare a suspension with a mass fraction of 10%, stir evenly, and prepare a pigment suspension;
  • step S2 Weigh the dextrin, under the pressure environment of 0.5kPa, atomize the pigment suspension obtained in step S1 with a pressure of 0.1mPa and a flow rate of 700mL/min and spray it on the dextrin, and keep it while spraying
  • the dextrin was stirred at a speed of 8r/s, after the pigment suspension was sprayed, 2.5g of purified water was added additionally, and the stirring was continued for 5 minutes to form a pigment wet material;
  • step S3 drying the pigment wet material in step S2 at a temperature of 75 ⁇ 5° C. in a hot air circulation oven, pulverizing in a pulverizer, and passing through a 120-mesh sieve to obtain a toner.
  • the pigment is a mixed system of 0.4g beta-carotene and 0.1g tartrazine, the addition amount of purified water in the pigment suspension is 5g, and the addition amount of dextrin is 25g.
  • Example 8 a toner, differs from Example 7 in that the air pressure environment in step S2 is 2 kPa.
  • Example 9 a toner, differs from Example 7 in that the air pressure environment in step S2 is 6 kPa.
  • Example 10 a toner, differs from Example 7 in that the atmospheric pressure environment in step S2 is 10 kPa.
  • Comparative Example 1 A toner, the difference from Example 1 is that in step S3, after the pigment wet material is dried and pulverized, it is used directly without being screened by a 120-mesh sieve.
  • Embodiments 11 to 20 lysozyme lozenges, comprising the following components:
  • Lysozyme 20g
  • Adhesive 350g
  • the toners in Examples 11 to 20 are the toners prepared in Examples 1 to 10, respectively.
  • the binder is a mixture of 342g 10% povidone K30 solution and 8g citric acid
  • the filler is a mixture of 300g sucrose and 140g dextrin
  • the sweetener is mannitol .
  • P1 take by weighing filler, sweetener, lysozyme, toner, citric acid according to the above ratio, weigh and sieve for subsequent use;
  • step P3 Add a binder to the premixed composition obtained in step P3 in the granulator under the condition of maintaining stirring, and stir at a speed of 7r/s for 15min, so that the material is basically in a soft state, and a paste-like composition is obtained thing
  • step P5 Spread the wet product obtained in step P4 evenly on the stainless steel baking tray, and send the drying rack into the RXH-27-C hot air circulation oven. After closing the oven door, turn on the power switch of the oven, and at the same time turn on the control panel of the oven. Automatic temperature control switch, adjust the oven temperature at 75 °C, after the oven temperature reaches 75 °C, timed drying for 4 hours. Then put the dried granules through a 20-mesh sieve into the cavity of the YK-160 rocking granulator, and turn on the YK-160 rocking granulator to an appropriate speed.
  • Example 21 the lysozyme lozenge, differs from Example 11 in that it includes the following components:
  • Adhesive 400g;
  • the filler is a mixture of 395g of 10% povidone K30 solution and 5g of citric acid as a binder, a mixture of 270g of sucrose and 130g of dextrin as a filler, and a sweetener of mannitol.
  • Example 22 the lysozyme lozenge, differs from Example 11 in that it includes the following components:
  • Lysozyme 25g
  • Adhesive 300g;
  • the filler is the mixture of 288g 10% povidone K30 solution and 12g citric acid as the binder, the filler is the mixture of 270g of sucrose and 130g of dextrin, and the sweetener is mannitol.
  • Example 23 the lysozyme lozenge, differs from Example 17 in that it includes the following components:
  • Adhesive 400g;
  • the filler is a mixture of 395g of 10% povidone K30 solution and 5g of citric acid as a binder, a mixture of 270g of sucrose and 130g of dextrin as a filler, and a sweetener of mannitol.
  • Example 24 the lysozyme lozenge, differs from Example 17 in that it includes the following components:
  • Lysozyme 25g
  • Adhesive 300g;
  • the filler is a mixture of 288g 10% povidone K30 solution and 12g citric acid as a binder, a mixture of 270g of sucrose and 130g of dextrin as a filler, and a sweetener of mannitol.
  • Example 25 the lysozyme lozenge, differs from Example 17 in that the adhesive is a povidone K30 solution with a mass fraction of 350 g and 10%.
  • Example 26 lysozyme lozenge, differs from Example 17 in that step P2 is as follows: first add dextrin, lysozyme and toner into the granulator, stir at 7r/s for 10min, and then Sucrose and mannitol were added to the granulator, and the stirring was continued for 10 min to obtain a premixed composition.
  • Example 27 lysozyme lozenges, differ from Example 26 in that step P2 is as follows: first add dextrin, lysozyme and toner into the granulator, stir at 7r/s for 5min, and then Sucrose and mannitol were added to the granulator, and stirring was continued for 5 min to obtain a premixed composition.
  • Example 28 lysozyme lozenges, differ from Example 26 in that step P2 is as follows: first add dextrin and lysozyme into the granulator, stir at 7r/s for 10min, then mix sucrose, mannitol and The toner was added to the granulator, and the stirring was continued for 10 min to obtain a premixed composition.
  • Example 29, lysozyme lozenges differ from Example 26 in that step P2 is as follows: first add dextrin and sucrose into the granulator, stir for 10min at a rotating speed of 7r/s, then mix lysozyme, mannitol and The toner was added to the granulator, and the stirring was continued for 10 min to obtain a premixed composition.
  • Example 30 lysozyme lozenge, differs from Example 26 in that step P2 is as follows: first add dextrin, lysozyme and toner into the granulator, stir for 10min at a rotating speed of 7r/s, Then add sucrose and mannitol into the granulator, at the same time spray 50g of water into the granulator by atomization, the atomization pressure is 0.1kPa, sucrose, mannitol and water are added evenly within 20s, and continue to stir after the addition is complete. 10min to obtain a premixed composition.
  • Example 31 lysozyme lozenges, differ from Example 26 in that step P2 is as follows: first add dextrin, lysozyme and toner into the granulator, and stir for 10 min at a rotating speed of 7r/s, Then add sucrose and mannitol into the granulator, and spray 80g of water into the granulator by atomization at the same time.
  • the atomization pressure is 0.1kPa.
  • the sucrose, mannitol and water are added evenly within 40s, and the stirring is continued after the addition is completed. 10min to obtain a premixed composition.
  • Example 32 lysozyme lozenges, differ from Example 26 in that step P2 is as follows: first, add dextrin, lysozyme and toner into the granulator, and stir for 10 min at a rotating speed of 7r/s, Then add sucrose and mannitol into the granulator, pour 50 g of water into the granulator, and continue stirring for 10 minutes after the addition to obtain a premixed composition.
  • Example 33 the lysozyme lozenge, differs from Example 31 in that in step P3, in the process of adding the adhesive, 75 parts of 10% povidone K30 solution was mixed with 5 parts of citric acid, And uniformly added to the granulator within 1min, and then added 215 parts by mass of 10% povidone K30 solution into the granulator, and stirred at a speed of 7r/s for 20min.
  • Example 34 the lysozyme lozenge, differs from Example 33 in that, in step P3, in the process of adding the adhesive, 150 parts of 10% povidone K30 solution and 12 parts of citric acid were mixed first, And evenly added into the granulator within 1min, and then added 138 parts by mass of 10% povidone K30 solution into the granulator, and stirred at a speed of 12r/s for 10min.
  • Comparative Example 2 the lysozyme lozenge, differs from Example 11 in that the toner prepared in Comparative Example 1 is used as the toner.
  • Example 3 the lysozyme lozenge, differs from Example 11 in that it includes the following components:
  • Lysozyme 20g
  • Adhesive 350g
  • the toner is the toner prepared in Example 1, the binder is a mixture of 342g 10% povidone K30 solution and 8g citric acid in parts by mass, the filler is 440g sucrose, and the sweetener is Mannitol.
  • lysozyme lozenges including the following components:
  • Lysozyme 20g
  • Adhesive 350g
  • the toner is the toner prepared in Example 1, the binder is a mixture of 342g 10% povidone K30 solution and 8g citric acid in parts by mass, the filler is 440g dextrin, and the sweetener for mannitol.
  • filler Add filler, sweetener, lysozyme and pigment into the granulator, stir and mix well; the filler is a composition formed by 165g dextrin and 300g sucrose, and the pigment is 0.4g beta-carotene and 0.1g lemon The composition formed by mixing yellow and yellow, and the sweetener is mannitol.
  • step 2 Add a binder to the composition obtained in step 1, and stir at a speed of 7r/s for 10min, so that the material is basically in a soft state; wherein, the binder is povidone K30 with a mass portion of 342g10% A mixture of the solution and 8 g of citric acid.
  • the cutter speed is 25r/s
  • the material obtained in step 2 is cut into pellets
  • the cutting time is 60s.
  • step 4 Spread the wet product obtained in step 3 evenly on the stainless steel baking tray, and send the drying rack into the RXH-27-C hot air circulation oven.
  • Automatic temperature control switch adjust the oven temperature at 75 °C, after the oven temperature reaches 75 °C, timed drying for 4 hours.
  • friability test according to the method in the 0923 tablet friability test method in "Chinese Pharmacopoeia” 2015 edition, the friability of the above-mentioned lysozyme buccal tablets was tested.
  • the specific detection method is as follows: take 10 lysozyme lozenges, blow off the surface powder with a hair dryer, weigh them and place them in the CS-2 tablet friability tester, set the rotation speed to 25r/min, and rotate 100 times. Remove, blow off powder, weigh and measure weight loss.
  • Comparative Example 3 the filler in the preparation process of lysozyme is only sucrose, so the effect on the toner is poor, resulting in more unevenness in the produced lysozyme lozenges.
  • the filler in Comparative Example 4 is only dextrin, and the lack of sucrose's adhesion and dispersing effect will lead to uneven dispersion of toner, sweetener, lysozyme and other materials in the dextrin during the mixing process of the toner and the filler. As a result, some uneven spots remain on the surface of the prepared lysozyme lozenges. And the lack of the adhesion promoting effect of sucrose will lead to a decrease in the strength of lysozyme and an increase in friability.
  • Comparative Example 5 the pigment is directly mixed with other raw materials to prepare lysozyme lozenges.
  • the distribution uniformity of the pigment in the lysozyme lozenge is poor, the pigment itself is easy to agglomerate, and it is difficult to uniformly distribute the pigment only by stirring. In the whole system, therefore, compared with Examples 11-16, the lysozyme lozenges prepared in Comparative Example 5 have poor uniformity.
  • Example 11 The lysozyme lozenges prepared in Example 11 and Examples 17-25 were tested in Experiment 1 and Experiment 2, and the results are shown in Table 2.
  • step S2 was performed under normal pressure.
  • step S2 was performed under low pressure.
  • the principle may be that under the low pressure state, during the atomization of the pigment suspension, the droplets are not easy to agglomerate, which helps to make the atomized droplets more uniformly dispersed in the dextrin , thereby improving the uniformity of the prepared toner.
  • Example 25 citric acid is not contained in the adhesive, and its mouthfeel is poor, and will affect the shelf life of the obtained lysozyme lozenges.
  • Example 17 The lysozyme lozenges prepared in Example 17 and Examples 26 to 34 were tested in Experiment 1 and Experiment 2, and the results are shown in Table 3.
  • Embodiments 26 to 29 compared with Embodiment 17, in Embodiments 26 to 29, the order of adding materials was adjusted.
  • the method of firstly processing dextrin, lysozyme and toner into the granulator for mixing, and then adding sucrose and mannitol can improve the quality of the prepared lysozyme lozenges. Color uniformity (as shown in Examples 26 and 27).
  • Example 28 dextrin and lysozyme were mixed first, and then sucrose, toner and sweetener were added, and the toner was unevenly dispersed in the sucrose, resulting in poor color uniformity.
  • Example 29 the dextrin and sucrose were mixed first, followed by the addition of lysozyme, mannitol and toner. Due to the mutual attraction effect between dextrin and sucrose, after mixing dextrin and sucrose, other materials tend to agglomerate when added, resulting in poor color uniformity of the prepared lysozyme lozenges.
  • Examples 30 to 31 purified water was sprayed into the system by atomization while adding sucrose.
  • purified water can dissolve part of sucrose and form syrup, and enhance the mutual adsorption effect of dextrin and sucrose, so that the system changes from powder to slightly viscous paste, which is added to the granulator at this time.
  • the pigments, mannitol and other materials will be positioned by the surrounding dextrin, and then it is not easy to agglomerate due to mutual adsorption during the stirring process.
  • ⁇ -carotene which is insoluble in water, can be more uniformly distributed in the lysozyme lozenge during the above process.
  • adding all the water directly would cause the dextrin to rapidly agglomerate to form agglomerates during processing, which would affect the effect of subsequent stirring, thereby causing uneven texture and uneven color of the lysozyme lozenges.
  • Example 33 and Example 34 further in the process of adding the binder, first add a part of the mixture of 10% povidone K30 solution and citric acid, and then add the remaining 10% povidone K30 Adding the solution to the system helps to coat the citric acid uniformly, so that the citric acid can have a relatively uniform distribution state inside and on the surface of the lozenge, so that the overall taste of the lozenge is relatively uniform.
  • pigments and dextrins are first prepared into toners, and then together with fillers, binders, sweeteners, lysozyme and other materials through a wet granulator to prepare lysozyme buccal tablets.
  • the pigment distribution in the toner can be made more uniform, and the phenomenon of "flowers" produced in the prepared lysozyme lozenges can be reduced.
  • dextrin, toner and lysozyme powder are added first, and then sucrose and sweetener are added, which helps to further improve the color uniformity of the prepared lysozyme buccal tablets.

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Abstract

一种调色剂、包含该调色剂的溶菌酶含片以及该溶菌酶含片的制备方法。其中，通过将色素加纯化水配制成色素混悬液，再将色素混悬液雾化喷洒至糊精上，充分混合后干燥粉碎可得该调色剂。

Description

一种调色剂、溶菌酶含片及该溶菌酶含片的制备方法 技术领域
本申请涉及药物加工的技术领域，尤其是涉及一种调色剂；本申请还涉及溶菌酶含片及该溶菌酶含片的制备方法。
背景技术
依照中国药典，片剂是指原料药物和适宜的辅料支撑的圆形或异形的片状固体。其中，大部分片剂采用口服、含服、咀嚼服用的方式进行服用。为了提高儿童的片剂服用意愿，常会在片剂中添加一定量的色素，使片剂带有较为鲜艳的色泽。
在现有技术中，一般会将色素直接加入片剂的原料中，共同进行制粒，通过色素调整含片的色泽。例如，授权公告号为CN101829212B，授权公告日为2011年8月31日的中国发明专利公开了一种含片及其制备方法，其中具体公开了一种含片的制备方法，该方法包括以下步骤：将冰糖粉碎，与滇橄榄粉、山楂粉、糊精、可溶性淀粉及粉碎后的薄荷进行混合并均勻；将柠檬酸溶于水中，稀释为柠檬酸溶液；将羧甲基纤维素钠溶于水中，稀释为羧甲基纤维素钠水溶液；将食用香精和食用色素分别溶于食用乙醇中，形成食用香精溶液与食用色素溶液；将蜂蜜溶于水中，搅拌均匀形成蜂蜜稀释液；将柠檬酸溶液、蜂蜜稀释液、羧甲基纤维素钠水溶液、食用香精溶液、食用色素溶液先后加入到由冰糖粉、滇橄榄粉、山楂粉、糊精、可溶性淀粉及薄荷粉混合后的混合粉中进行混合，整粒并烘干后进行压片。
在上述过程中，色素直接溶解于水中后与其他物料共同混合整粒烘干压片，并通过色素对制得的片剂的色泽进行调节。但是在实际操作中发现，通过上述方法制得的片剂内外色泽不均一，部分片剂上会存在色泽不均匀所形成的的斑点形貌，俗称“花片”现象，影响了片剂的均一性。
发明内容
针对现有技术存在的不足，本申请的第一个发明目的是提供一种调色剂，在用于片剂加工的过程中有助于使片剂整体色泽均一，不易产生“花片”的现象。
本申请的第二个发明目的是提供一种溶菌酶含片，其中色素的分布较为均匀，使得整体形貌较为均匀。
本申请的第三个发明目的是提供上述溶菌酶含片的制备方法，通过该制备方法制备得到的溶菌酶含片具有较好的均匀度，有助于减少溶菌酶含片中“花片”的现象发 生，使溶菌酶含片内外色泽均匀。
本申请的第一个目的是通过以下技术方案得以实现的：一种调色剂，通过如下方法制备得到：
S1、将色素加纯化水配制成混悬液，搅拌均匀，配制成色素混悬液；
S2、称取糊精，将步骤S1中得到的色素混悬液雾化并喷洒在糊精上，在喷洒的同时保持搅拌，色素混悬液喷洒完毕后，再额外加入水，继续搅拌至成型，得到色素湿料；
S3、将步骤S2中的色素湿料干燥并粉碎，得到调色剂；其中，粉碎后调色剂的粒度目数不大于120目。
在上述技术方案中，先将色素分散于水中，再雾化并喷洒至糊精上。通过糊精吸附色素并作为色素的载体，可以使色素更加均匀地分散。无论色素是否溶于水，在经过糊精的吸附后，均可以实现较为均匀的分散。随后将得到的色素湿料干燥并粉碎后，即可形成粉末状的调色剂。上述调色剂在片剂制备的工艺中，将粉状与片剂中的辅料混合并搅拌均匀后，可以实现较好的混合效果，进而提高制得的片剂的色泽均匀程度，有助于减少片剂加工时产生的花片现象。
本申请在一较佳示例中可以进一步配置为：在步骤S2中，在色素混悬液雾化并喷洒于糊精上时，保持体系处于0.5～10kPa的气压下进行。
在上述技术方案中，在低压的状态下，色素混悬液雾化形成的雾化液可以更加均匀地与糊精混合，从而使制得的调色剂具有更好的均匀性，粉碎后得到的颗粒色泽更加均一，从而在后续使用中进一步减少产生花片的可能性。
本申请在一较佳示例中可以进一步配置为：步骤S2中，雾化的流量为700～1000mL/min，雾化压力为0.1～0.2mPa。
本申请在一较佳示例中可以进一步配置为：所述色素为β-胡萝卜素和柠檬黄的混合体系，所述β-胡萝卜素与柠檬黄的质量比为(3～6):1；所述糊精为白糊精，所述色素与糊精的质量比为(0.01～0.05):1。
β-胡萝卜素不溶于水，柠檬黄易溶于水，二者相互协调，可以实现较为鲜艳亮丽的色泽。糊精是淀粉初步水解得到的产物，其表面含有较多羟基，因此对于上述两种色素均有较好的相容性，能够较为均匀地对两种色素进行承载，且可以使两种色素混合均匀。设置色素和填料的质量比为(0.01～0.05):1，色素中β-胡萝卜素与柠檬黄的质量比为(3～6):1，在该范围内容易实现色素的均匀混合，因此更加有助于该调色剂在运用于片剂加工时提高片剂色泽的均匀度。
本申请的第二个发明目的是通过以下技术方案得以实现的：溶菌酶含片，其制备原料包括如下质量份的物料：
填料：400～525份；
甜味剂：10～20份；
溶菌酶：15～25份；
调色剂：20～30份
粘合剂：300～400份；
其中，调色剂为上述调色剂中的任意一种；所述填料为糊精和蔗糖的混合物，所述糊精的质量份为：130～185份；所述甜味剂为甘露醇，所述粘合剂包括10％聚维酮K30溶液。
在上述技术方案中，填料为糊精和蔗糖的混合物，糊精具有较好的吸附性能，对于溶菌酶、调色剂和甜味剂等物料具有较好的吸附性。蔗糖具有助黏效果，可以使糊精、溶菌酶、调色剂和甜味剂等物料更加充分地混合。另外，蔗糖与糊精之间容易形成氢键，因此在加工过程中蔗糖会粘附于糊精的表面，并对糊精进行包覆，从而使制得的含片表面具有甜味。甘露醇可以较好地吸附于糊精中并被糊精包覆，且甘露醇具有较高的甜度和清爽的口感，有助于高效调节该溶菌酶含片的口感。在将调色剂与填料混合的过程中，填料中的蔗糖和糊精可以与调色剂均匀混合，进而使调色剂在混合过程中不易团聚和结块，有助于进一步提高调色剂在制得的含片中的分散均匀程度，从而提高溶菌酶含片的色泽均匀程度，使溶菌酶含片中不易因调色剂或色素团聚而产生“花片”的现象。另外，由于色素在溶菌酶含片中分布较为均匀，因此制备得到的溶菌酶含片的强度也相对较高，容易成型，不易碎裂形成粉状或颗粒状。
本申请在一较佳示例中可以进一步配置为：所述粘合剂中还含有质量份为5～12份的枸橼酸。
在上述技术方案中，枸橼酸既可以起到调味的作用，使溶菌酶含片的口感较为温和可口，也可以起到抗氧化、延长溶菌酶含片的保质期的作用。
本申请的第三个发明目的是通过以下技术方案得以实现的：用于制备上述溶菌酶含片的制备方法，包括如下步骤：
P1、取所述填料、甜味剂、溶菌酶、调色剂、枸橼酸，称量过筛备用；
P2、向制粒机中加入填料、甜味剂、溶菌酶和调色剂，充分搅拌，得到预混组合物；
P3、在保持搅拌的条件下在制粒机中向步骤P3中得到的预混组合物中加入粘合剂，得 到膏状组合物；
P4、在制粒机中将步骤P3中得到的所述膏状组合物切割为颗粒状，得到湿品；
P5、将步骤P4中得到的湿品通过整粒、干燥、压片程序，得到溶菌酶含片。
在上述技术方案中，先对填料、甜味剂、溶菌酶和调色剂进行充分地混合，由于填料和调色剂中均含有糊精，因此在混合过程中，填料和调味剂可以形成较为均匀的混合结构，不易使调味剂团聚或结块。当调味剂、甜味剂和溶菌酶在体系中充分混合完毕后，再加入粘合剂，并通过搅拌和切分使物料形成颗粒状，通过压片整形后即可使溶菌酶含片的内外色泽均一，基本无“花片”现象产生。
本申请在一较佳示例中可以进一步配置为：步骤P2具体如下：先将糊精、溶菌酶和调色剂加入制粒机中，充分搅拌均匀后，再将蔗糖和甘露醇加入制粒机中，继续搅拌混合均匀，得到预混组合物。
在上述技术方案中，先将糊精、溶菌酶和调色剂混合，糊精作为主要填料，其与调色剂中的主要成分相同，因此在混合时，更加容易形成均相体系。随后加入蔗糖和甘露醇后，蔗糖和甘露醇可以羟基的相互吸附作用粘合于糊精上，形成包覆结构，进而形成均匀的体系，有助于制得的溶菌酶含片更加均匀。
本申请在一较佳示例中可以进一步配置为：在步骤P2中，在将蔗糖和甘露醇加入制粒机的同时，向制粒机中以雾化的方式加入质量份为50～80的纯化水；蔗糖、甘露醇和纯化水在20～40s内均匀添加至制粒机中。
在上述技术方案中，在加入蔗糖的过程中同时加入水，可以形成有一定粘性的糖浆，并通过糖浆对体系中形成的糊精、溶菌酶粉和调色剂等物料进行初步的粘合和定型。由于水以雾化的方式加入，因此加入过程中糊精可以充分地与水解除，有助于糊精表面更加均匀地吸附蔗糖，进而提高成型后的溶菌酶含片的整体强度和均匀性，既有助于提高溶菌酶含片中的色泽均匀度，减少“花片”的现象发生，也有助于本申请在一较佳示例中可以进一步配置为：在步骤P3中，在加入粘合剂的过程中，先在1～2min内将质量份为75～150份的10％聚维酮K30溶液和质量份为5～12份的枸橼酸形成的混合物加入制粒机中，再加入质量份为138～320份的10％聚维酮K30溶液，继续搅拌10～20min，搅拌速度为7～12r/s，得到膏状组合物。
在上述技术方案中，先将部分粘合剂加入其中，并掺入了一定量的枸橼酸，有利于枸橼酸与糊精等固体物料均匀混合，并被粘合剂包覆。随后继续加入粘合剂，使含片成型。上述过程制备得到的膏状组合物混合较为均匀，且在切割的过程中可以形成稳定 的包覆结构，从而使制得的溶菌酶含片内外口感均一。
综上所述，本申请包括以下至少一种有益技术效果：
1.在本申请中，提供了一种调色剂，通过将色素配制成色素混悬液并雾化喷洒于糊精中制成粉末，可以提高色素在制备片剂时的分散性，从而使片剂加工后色泽的均匀度更佳，不易产生“花片”的现象。
2.在本申请中，提供了一种溶菌酶含片，添加了上述调色剂，具有更好的色泽均匀度。
3.在本申请中，提供了上述溶菌酶含片的制备方法，制备得到的溶菌酶含片色泽均匀，少有“花片”的现象发生。
具体实施方式
以下通过具体实施例对上述技术方案进行进一步阐述。
实施例1，一种调色剂，通过如下步骤制备得到：
S1、将色素加纯化水配制成质量份数为10％的混悬液，搅拌均匀，配制成色素混悬液；
S2、称取糊精，在常压下将步骤S1中得到的色素混悬液以0.1mPa的压强和700mL/min的流量雾化并喷洒在糊精上，在喷洒的同时保持以8r/s的速度对糊精搅拌，色素混悬液喷洒完毕后，再额外加入2.5g纯化水，继续搅拌5min至成型，得到色素湿料；
S3、将步骤S2中的色素湿料在热风循环烘箱中以75±5℃的温度烘干，并在粉碎机中粉碎，过120目筛，得到调色剂。
其中，色素为0.4gβ-胡萝卜素和0.1g柠檬黄的混合体系，色素混悬液中纯化水的加入量为5g，糊精为白糊精，糊精的加入量为25g。
实施例2，一种调色剂，通过如下步骤制备得到：
S1、将色素加纯化水配制成混悬液，搅拌均匀，配制成色素混悬液；
S2、称取糊精，在常压下将步骤S1中得到的色素混悬液以0.2mPa的压强和1000mL/min的流量雾化并喷洒在糊精上，在喷洒的同时保持以8r/s的速度对糊精搅拌，色素混悬液喷洒完毕后，再额外加入2.5g纯化水，继续搅拌5min至成型，得到色素湿料；
S3、将步骤S2中的色素湿料在热风循环烘箱中以75±5℃的温度烘干，并在粉碎机中粉碎，过120目筛，得到调色剂。
其中，色素为0.4gβ-胡萝卜素和0.1g柠檬黄的混合体系，色素混悬液中纯化水的加入量为5g，糊精的加入量为25g。
实施例3：一种调色剂，与实施例1的区别在于：色素为0.6gβ-胡萝卜素和0.2g 柠檬黄的混合体系，糊精的加入量为15g。
实施例4：一种调色剂，与实施例1的区别在于：色素为0.45gβ-胡萝卜素和0.075g柠檬黄的混合体系，糊精的加入量为45.5g。
实施例5：一种调色剂，与实施例1的区别在于，用等量β-胡萝卜素替代柠檬黄。
实施例6：一种调色剂，与实施例1的区别在于，用等量柠檬黄替代β-胡萝卜素。
实施例7，一种调色剂，通过如下步骤制备得到：
S1、将色素加纯化水配制成质量份数为10％的混悬液，搅拌均匀，配制成色素混悬液；
S2、称取糊精，在0.5kPa的气压环境下，将步骤S1中得到的色素混悬液以0.1mPa的压强和700mL/min的流量雾化并喷洒在糊精上，在喷洒的同时保持以8r/s的速度对糊精搅拌，色素混悬液喷洒完毕后，再额外加入2.5g纯化水，继续搅拌5min至成型，得到色素湿料；
S3、将步骤S2中的色素湿料在热风循环烘箱中以75±5℃的温度烘干，并在粉碎机中粉碎，过120目筛，得到调色剂。
其中，色素为0.4gβ-胡萝卜素和0.1g柠檬黄的混合体系，色素混悬液中纯化水的加入量为5g，糊精的加入量为25g。
实施例8，一种调色剂，与实施例7的区别在于，步骤S2的气压环境为2kPa。
实施例9，一种调色剂，与实施例7的区别在于，步骤S2的气压环境为6kPa。
实施例10，一种调色剂，与实施例7的区别在于，步骤S2的气压环境为10kPa。
对比例1：一种调色剂，与实施例1的区别在于，在步骤S3中，色素湿料干燥粉碎完毕后，不经过120目筛筛分直接使用。
实施例11～20，溶菌酶含片，包括如下组分物料：
溶菌酶：20g；
填料：440g；
甜味剂：15g；
调色剂：25g；
粘合剂：350g；
其中，实施例11～20中的调色剂分别为实施例1～10中制得的调色剂。
在实施例11～20中，粘合剂为质量分数为342g10％的聚维酮K30溶液和8g枸 橼酸组成的混合物，填料为300g蔗糖和140g糊精组成的混合物，甜味剂为甘露醇。
实施例11～20中溶菌酶含片的制备步骤如下：
P1、按照上述比例称取填料、甜味剂、溶菌酶、调色剂、枸橼酸，称量过筛备用；
P2、向制粒机中加入填料、甜味剂、溶菌酶和调色剂，以5r/s的速度搅拌4min，得到预混组合物；
P3、在保持搅拌的条件下在制粒机中向步骤P3中得到的预混组合物中加入粘合剂，以7r/s的速度搅拌15min，使物料基本成软材状态，得到膏状组合物
P4、开启制粒机中的切刀，切刀转速为25r/s，在制粒机中将步骤P3中得到的膏状组合物进行切割，切割时间为60s，得到湿品；
P5、将步骤P4中得到的湿品均匀地平摊在不锈钢烘盘上，烘架送入RXH-27-C热风循环烘箱，关好烘箱门后，打开烘箱电源开关，同时打开烘箱控制面板上的自动控温开关，调节烘箱温度在75℃，烘箱温度达到75℃后，计时干燥4小时。随后将烘干完毕的颗粒过20目筛装入YK-160摇摆颗粒机腔内，开启YK-160摇摆制粒机至适当速度。把已烘干的颗粒倒入YK-160摇摆颗粒机料斗内，慢慢开启进料开关，并控制较慢的进料速度。整粒完成后，将得到的颗粒压片，从而完成溶菌酶含片。
实施例21，溶菌酶含片，与实施例11的区别在于，包括如下组分物料：
溶菌酶：15g；
填料：400g；
甜味剂：10g；
调色剂：20g；
粘合剂：400g；
其中，填料为粘合剂为质量分数为395g10％的聚维酮K30溶液和5g枸橼酸组成的混合物，填料为270g蔗糖和130g糊精组成的混合物，甜味剂为甘露醇。
实施例22，溶菌酶含片，与实施例11的区别在于，包括如下组分物料：
溶菌酶：25g；
填料：525g；
甜味剂：20g；
调色剂：30g；
粘合剂：300g；
其中，填料为粘合剂为质量分数为288g10％的聚维酮K30溶液和12g枸橼酸组成的混 合物，填料为270g蔗糖和130g糊精组成的混合物，甜味剂为甘露醇。
实施例23，溶菌酶含片，与实施例17的区别在于：包括如下组分物料：
溶菌酶：15g；
填料：400g；
甜味剂：10g；
调色剂：20g；
粘合剂：400g；
其中，填料为粘合剂为质量分数为395g10％的聚维酮K30溶液和5g枸橼酸组成的混合物，填料为270g蔗糖和130g糊精组成的混合物，甜味剂为甘露醇。
实施例24，溶菌酶含片，与实施例17的区别在于，包括如下组分物料：
溶菌酶：25g；
填料：525g；
甜味剂：20g；
调色剂：30g；
粘合剂：300g；
其中，填料为粘合剂为质量分数为288g10％的聚维酮K30溶液和12g枸橼酸组成的混合物，填料为270g蔗糖和130g糊精组成的混合物，甜味剂为甘露醇。
实施例25，溶菌酶含片，与实施例17的区别在于，粘合剂为质量分数为350g10％的聚维酮K30溶液。
实施例26，溶菌酶含片，与实施例17的区别在于，步骤P2具体如下：先将糊精、溶菌酶和调色剂加入制粒机中，以7r/s的转速搅拌10min，再将蔗糖和甘露醇加入制粒机中，继续搅拌10min，得到预混组合物。
实施例27，溶菌酶含片，与实施例26的区别在于，步骤P2具体如下：先将糊精、溶菌酶和调色剂加入制粒机中，以7r/s的转速搅拌5min，再将蔗糖和甘露醇加入制粒机中，继续搅拌5min，得到预混组合物。
实施例28，溶菌酶含片，与实施例26的区别在于，步骤P2具体如下：先将糊精、溶菌酶加入制粒机中，以7r/s的转速搅拌10min，再将蔗糖、甘露醇和调色剂加入制粒机中，继续搅拌10min，得到预混组合物。
实施例29，溶菌酶含片，与实施例26的区别在于，步骤P2具体如下：先将糊精和蔗糖加入制粒机中，以7r/s的转速搅拌10min，再将溶菌酶、甘露醇和调色剂加入 制粒机中，继续搅拌10min，得到预混组合物。
实施例30，溶菌酶含片，与实施例26的区别在于，步骤P2具体如下：先将先将糊精、溶菌酶和调色剂加入制粒机中，以7r/s的转速搅拌10min，再将蔗糖和甘露醇加入制粒机中，同时以雾化的方式相制粒机中喷洒50g水，雾化压力为0.1kPa，蔗糖、甘露醇和水在20s内均匀添加，添加完毕后继续搅拌10min，得到预混组合物。
实施例31，溶菌酶含片，与实施例26的区别在于，步骤P2具体如下：先将先将糊精、溶菌酶和调色剂加入制粒机中，以7r/s的转速搅拌10min，再将蔗糖和甘露醇加入制粒机中，同时以雾化的方式相制粒机中喷洒80g水，雾化压力为0.1kPa，蔗糖、甘露醇和水在40s内均匀添加，添加完毕后继续搅拌10min，得到预混组合物。
实施例32，溶菌酶含片，与实施例26的区别在于，步骤P2具体如下：先将先将糊精、溶菌酶和调色剂加入制粒机中，以7r/s的转速搅拌10min，再将蔗糖和甘露醇加入制粒机中，并向制粒机中倒入50g的水，添加完毕后继续搅拌10min，得到预混组合物。
实施例33，溶菌酶含片，与实施例31的区别在于，在步骤P3中，在加入粘合剂的过程中，先将75份10％聚维酮K30溶液与5份枸橼酸混合，并在1min内均匀加入至制粒机中，再将质量份为215份的10％聚维酮K30溶液加入制粒机中，以7r/s的速度搅拌20min。
实施例34，溶菌酶含片，与实施例33的区别在于，在步骤P3中，在加入粘合剂的过程中，先将150份10％聚维酮K30溶液与12份枸橼酸混合，并在1min内均匀加入至制粒机中，再将质量份为138份的10％聚维酮K30溶液加入制粒机中，以12r/s的速度搅拌10min。
针对实施例11～34中制备得到的溶菌酶含片，设置如下对比例，进行比对。
对比例2，溶菌酶含片，与实施例11的区别在于，调色剂选用对比例1中制备得到的调色剂。
对比例3，溶菌酶含片，与实施例11的区别在于，包括如下组分物料：
溶菌酶：20g；
填料：440g；
甜味剂：15g；
调色剂：25g；
粘合剂：350g；
其中，调色剂为实施例1中制备得到的调色剂，粘合剂为质量份为342g10％的聚维酮K30溶液和8g枸橼酸组成的混合物，填料为440g蔗糖，甜味剂为甘露醇。
对比例4，溶菌酶含片，包括如下组分物料：
溶菌酶：20g；
填料：440g；
甜味剂：15g；
调色剂：25g；
粘合剂：350g；
其中，调色剂为实施例1中制备得到的调色剂，粘合剂为质量份为342g10％的聚维酮K30溶液和8g枸橼酸组成的混合物，填料为440g糊精，甜味剂为甘露醇。
对比例5，溶菌酶含片，其制备工艺包括下列步骤：
1、将填料、甜味剂、溶菌酶、色素加入制粒机中，充分搅拌混合均匀；其中，填料为165g糊精和300g蔗糖形成的组合物，色素为0.4gβ-胡萝卜素和0.1g柠檬黄混合形成的组合物，甜味剂为甘露醇。
2、向步骤1中得到的组合物中加入粘合剂，并以7r/s的速度搅拌10min，使物料基本成软材状态；其中，粘合剂为质量份为342g10％的聚维酮K30溶液和8g枸橼酸组成的混合物。
3、开启制粒机中的切刀，切刀转速为25r/s，将步骤2中得到的物料切割成颗粒，切割时间为60s。
4、将步骤3中得到的湿品均匀地平摊在不锈钢烘盘上，烘架送入RXH-27-C热风循环烘箱，关好烘箱门后，打开烘箱电源开关，同时打开烘箱控制面板上的自动控温开关，调节烘箱温度在75℃，烘箱温度达到75℃后，计时干燥4小时。随后将烘干完毕的颗粒过20目筛装入YK-160摇摆颗粒机腔内，开启YK-160摇摆制粒机至适当速度。把已烘干的颗粒倒入YK-160摇摆颗粒机料斗内，慢慢开启进料开关，并控制较慢的进料速度。整粒完成后，将得到的颗粒压片，从而完成溶菌酶含片。
针对实施例11～34及对比例2～5，设置如下实验对其各方面性质进行测定。
实验1、外观标准，采用目测的方式，每组实施例及对比例取100片样品进行检验，检验标准：溶菌酶含片片形一致、片面光洁、边缘整齐，表面和内部色泽均匀。
实验2、脆碎度实验，依照《中国药典》2015版中0923片剂脆碎度检查法中的方法，对上述溶菌酶含片的脆碎度进行检测。具体检测方法如下：取10篇溶菌酶含片， 用吹风机吹去表面脱落粉末后称重并置于CS-2片剂脆碎度测试仪中，设置转动速度为25r/min，转动100次后取出，吹去粉末，称重，测定重量损失。
对实施例11～16及对比例2～5进行实验1和实验2，得到的实验结果如表1所示。
表1：实施例11～16及对比例2～5相关性状表征
Figure PCTCN2021077412-appb-000001
通过上述实验数据可知，在实施例11～16的技术方案中，通过先将色素和糊精制成调色剂，有助于在后续生产溶菌酶含片的过程中，使调色剂与填料混合更加均匀，进而提高制得的溶菌酶含片的色泽均匀度。对比例2中，由于调色剂在加工完成后未过筛分，因此有少量团聚的调色剂在后续加工过程中混杂于溶菌酶含片内，导致溶菌酶含片的脆碎度提高，且容易出现斑点。
对比例3中，溶菌酶制备过程中填料仅为蔗糖，因此对于调色剂的效果较差，导致生产得到的溶菌酶含片中含有较多不均匀的现象。对比例4中填料仅为糊精，缺少蔗糖的助黏和分散作用会导致调色剂和填料在混合过程中，调色剂、甜味剂、溶菌酶等物料在糊精中分散不均匀，进而导致制备得到溶菌酶含片表面残留有部分不均匀的斑点。且缺少蔗糖的助黏效果会到导致溶菌酶的强度降低，脆碎度升高。
对比例5中，直接将色素与其他原料混合并制备溶菌酶含片，在上述过程中，溶菌酶含片中色素的分布均匀度较差，色素本身容易团聚，仅通过搅拌难以将色素均匀分布到整个体系中，因此，相较于实施例11～16，对比例5中制备得到的溶菌酶含片均匀度较差。
对实施例11与实施例17～25中制得的溶菌酶含片进行实验1和实验2的检测，得到结果如表2所示。
表2：实施例11及实施例17～25相关性状表征
Figure PCTCN2021077412-appb-000002
在上述实施例中，实施例11、实施例21和实施例22在制备调色剂的过程中，步骤S2是在常压下进行的。而实施例17～20以及实施例23和实施例24在制备调色剂的过程中，步骤S2是在低压下进行的。通过对比上述数据可知，相较于实施例11、21和22，在低压下进行色素混悬液的雾化喷洒操作，有助于提高制得的溶菌酶含片的均匀度。推测其原理可能是在低压状态下，色素混悬液雾化过程中，液滴与液滴之间不容易团聚，进而有助于使雾化后的小液滴更加均匀地分散于糊精中，从而提高制得的调色剂的均匀性。
实施例25中，在粘合剂中不含有枸橼酸，其口感较差，且会影响制得的溶菌酶 含片的保质期。
对实施例17与实施例26～34中制得的溶菌酶含片进行实验1和实验2的检测，得到结果如表3所示。
表3：实施例17及实施例26～34相关性状表征
Figure PCTCN2021077412-appb-000003
在上述实施例中，相较于实施例17，实施例26～29中，对加入物料的顺序进行了调整。通过表4中的数据可知，采用先加工糊精、溶菌酶和调色剂加入到制粒机中进行混合，再将蔗糖和甘露醇加入的方法，可以提高制得的溶菌酶含片的的色泽均匀度(如实施例26、27所示)。而实施例28中，先将糊精和溶菌酶混合，再将蔗糖、调色剂和甜味剂加入，调色剂在蔗糖中分散不均匀，进而导致色泽均匀度较差。在实施例29中，先将糊精和蔗糖混合，再将溶菌酶、甘露醇和调色剂加入。由于糊精和蔗糖之间有相互吸引的效果，因此糊精和蔗糖混合后，其他物料加入时容易团聚，进而导致制得的溶菌酶含片色泽均匀度不佳。
实施例30～31中，在加入蔗糖的同时以雾化的方式相体系中喷洒纯化水。在喷洒纯化水时，纯化水可以使部分蔗糖溶解并形成糖浆，并使糊精和蔗糖相互吸附效果增强，从而使体系从粉状变为稍有粘性的膏状，此时加入制粒机中的色素、甘露醇等物料 在加入制粒机的过程中会受到周围糊精的定位作用，进而在搅拌过程中不易因相互吸附而团聚。尤其是难溶于水的β-胡萝卜素，在上述过程中可以更加均匀地分布于溶菌酶含片中。在实施例32中，直接将水全部加入，会导致加工过程中糊精快速团聚形成结块状，影响后续搅拌的效果，进而导致溶菌酶含片质地不均，色泽不均匀。
在实施例33和实施例34中，进一步地在加入粘合剂的过程中，先加入一部分10％的聚维酮K30溶液和枸橼酸的混合物，再将剩余的10％的聚维酮K30溶液加入到体系中，有助于均匀地对枸橼酸进行包覆，使枸橼酸可以在含片内部和表面具有较为均匀的分布状态，从而使含片整体口感较为均匀。
综上所述，在本申请中，通过将色素和糊精先行配制成调色剂，再与填料、粘合剂、甜味剂、溶菌酶等物料通过湿法制粒机制备成溶菌酶含片，可以提高色素在溶菌酶含片中的分布均匀度。通过将色素悬液低压下雾化喷入糊精中，可以使调色剂中色素分布更加均匀，减少制得的溶菌酶含片中产生的“花片”的现象。另外，在制粒过程中，先将糊精、调色剂和溶菌酶粉加入，再将蔗糖、甜味剂加入，有助于进一步提高制备得到的溶菌酶含片的色泽均匀度。
本具体实施方式的实施例均为本申请的较佳实施例，并非依此限制本申请的保护范围，故：凡依本申请的原理所做的等效变化，均应涵盖于本申请的保护范围之内。

Claims (10)

  1. 一种调色剂，其特征在于，通过如下方法制备得到：
    S1、将色素加纯化水配制成混悬液，搅拌均匀，配制成色素混悬液；
    S2、称取糊精，将步骤S1中得到的色素混悬液雾化并喷洒在糊精上，在喷洒的同时保持搅拌，色素混悬液喷洒完毕后，再额外加入水，继续搅拌至成型，得到色素湿料；
    S3、将步骤S2中的色素湿料干燥并粉碎，得到调色剂；其中，粉碎后调色剂的粒度目数不大于120目。
  2. 根据权利要求1所述的一种调色剂，其特征在于，在步骤S2中，在色素混悬液雾化并喷洒于糊精上时，保持体系处于0.5～10kPa的气压下进行。
  3. 根据权利要求2所述的一种调色剂，其特征在于，步骤S2中，雾化的流量为700～1000mL/min，雾化压力为0.1～0.2mPa。
  4. 根据权利要求1所述的一种调色剂，其特征在于，所述色素为β-胡萝卜素和柠檬黄的混合体系，所述β-胡萝卜素与柠檬黄的质量比为(3～6):1；所述糊精为白糊精，所述色素与糊精的质量比为(0.01～0.05):1。
  5. 溶菌酶含片，其特征在于，其制备原料包括如下质量份的物料：
    填料：400～525份；
    甜味剂：10～20份；
    溶菌酶：15～25份；
    调色剂：20～30份
    粘合剂：300～400份；
    其中，调色剂为如权利要求1～4中所述的调色剂中的任意一种；所述填料为糊精和蔗糖的混合物，所述糊精的质量份为：130～185份；所述甜味剂为甘露醇，所述粘合剂包括10％聚维酮K30溶液。
  6. 根据权利要求5所述的溶菌酶含片，其特征在于，所述粘合剂中还含有质量份为5～12份的枸橼酸。
  7. 用于制备如权利要求5～6中任意一条中所述的溶菌酶含片的制备方法，其特征在于，包括如下步骤：
    P1、取所述填料、甜味剂、溶菌酶、调色剂、枸橼酸，称量过筛备用；
    P2、向制粒机中加入填料、甜味剂、溶菌酶和调色剂，充分搅拌，得到预混组合物；
    P3、在保持搅拌的条件下在制粒机中向步骤P3中得到的预混组合物中加入粘合剂，得到膏状组合物；
    P4、在制粒机中将步骤P3中得到的所述膏状组合物切割为颗粒状，得到湿品；
    P5、将步骤P4中得到的湿品通过整粒、干燥、压片程序，得到溶菌酶含片。
  8. 根据权利要求7所述的溶菌酶含片的制备方法，其特征在于，步骤P2具体如下：先将糊精、溶菌酶和调色剂加入制粒机中，充分搅拌均匀后，再将蔗糖和甘露醇加入制粒机中，继续搅拌混合均匀，得到预混组合物。
  9. 根据权利要求8所述的溶菌酶含片的制备方法，其特征在于，在步骤P2中，在将蔗糖和甘露醇加入制粒机的同时，向制粒机中以雾化的方式加入质量份为50～80的纯化水；蔗糖、甘露醇和纯化水在20～40s内均匀添加至制粒机中。
  10. 根据权利要求7所述的溶菌酶含片的制备方法，其特征在于，在步骤P3中，在加入粘合剂的过程中，先在1～2min内将质量份为75～150份的10％聚维酮K30溶液和质量份为5～12份的枸橼酸形成的混合物加入制粒机中，再加入质量份为138～320份的10％聚维酮K30溶液，继续搅拌10～20min，搅拌速度为7～12r/s，得到膏状组合物。
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