Sugar-coated tablet preparation and preparation method thereof

Abstract

The invention provides a sugar-coated tablet preparation. The sugar-coated tablet preparation sequentially comprises a tablet core, a hydrophobic layer, a powder coating layer and an optional coloring layer from inside to outside. The invention also provides a method for preparing the sugar-coated tablet preparation. The estradiol valerate sugar-coated tablet disclosed by the invention has a good moisture-proof effect and has an in-vitro dissolution curve similar to that of a reference preparation 'Gabale', and after the estradiol valerate sugar-coated tablet is placed for a period of time, active pharmaceutical substances stably exist, and the content of impurities in a medicine meets related requirements.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sugar-coated tablet preparation and a preparation method thereof. BACKGROUND

[0002] Estradiol valerate is a long-acting estradiol derivative, i.e. the valerate ester of estradiol, which has estradiol activity after liver deacidification. It is an artificially synthesized chemically modified estrogen. Oral estrogen can increase the level of estrogen in the female body and promote endometrial growth. Estradiol valerate tablets belong to estrogen preparations and have the effects of supplementing the body's estrogen level and improving endometrial growth. They are mainly used for treating estrogen deficiency symptoms such as menstrual disorders, premature ovarian failure, menopause, hot flashes, and irritability.

[0003] At present, estradiol valerate tablets are combined with progestogens to establish an artificial menstrual cycle for supplementing the main estrogen deficiency related to natural or artificial menopause, vasomotor disorders (hot flashes), reproductive urological to nutritional disorders (vulvar and vaginal atrophy, dyspareunia, urinary incontinence), and mental disorders (sleep disorders, weakness).

[0004] Estradiol valerate tablets were first developed by Schering AG in Germany, and the trade name is "provera". The specification is 1 mg. The chemical generic reference preparation catalog (the tenth batch) issued by the State Drug Administration is a generic reference preparation. The reference preparation is a sugar-coated film coating. Although the modern film coating process is simple, it is difficult to achieve the effects of moisture-proof of the tablet core and consistency of the in-vitro dissolution curve.

[0005] Therefore, there is an urgent need in the art for an estradiol valerate sugar-coated tablet with the effects of moisture-proof of the tablet core and consistency of the in-vitro dissolution curve similar to the reference preparation. SUMMARY

[0006] In view of the problems in the prior art, the present application provides a sugar-coated tablet preparation and a preparation method thereof.

[0007] In a first aspect, the present application provides a sugar-coated tablet preparation, which comprises, in order from inside to outside, a tablet core, a hydrophobic layer, and a powder coating layer.

[0008] The hydrophobic layer comprises a first binder.

[0009] The powder coating layer comprises a second binder, a first structural support material, a first plasticizer, and a first anti-adhesive.

[0010] In a second aspect, the present application provides a preparation method of a sugar-coated tablet preparation, which comprises the following steps:

[0011] 1) preparing a hydrophobic film-forming solution for preparing a hydrophobic layer:

[0012] dissolving the first adhesive in the dispersing solvent under stirring to obtain the hydrophobic film forming solution;

[0013] 2) preparing a first suspension for preparing a sugar coating layer:

[0014] dissolving the first structural support material in boiling water to obtain a first solution;

[0015] lowering the temperature of the first solution to 50-65℃, and adding the second adhesive, the first plasticizer, and the first anti-sticking agent into the first solution in sequence under stirring at a stirring speed of 500-2000 rpm to obtain a first intermediate suspension;

[0016] maintaining the temperature of the first intermediate suspension at 50-65℃, and homogenizing the first intermediate suspension at a homogenization speed of 500-2000 rpm for 20-40 min to obtain the first suspension;

[0017] 3) preparing a sugar-coated tablet preparation:

[0018] a) wrapping the tablet core with the hydrophobic film forming solution to form a hydrophobic layer on the outer surface of the tablet core;

[0019] b) wrapping the tablet core with the first suspension to form a sugar coating layer on the outer surface of the hydrophobic layer.

[0020] In summary, the present application provides a sugar-coated tablet preparation and a preparation method thereof, which has one or more of the following beneficial effects:

[0021] 1) the sugar-coated tablet of the present application, such as estradiol valerate sugar-coated tablet, has good moisture-proof effect;

[0022] 2) the sugar-coated tablet of the present application, such as estradiol valerate sugar-coated tablet, has similar in-vitro dissolution curve as the reference preparation “progest”;

[0023] 3) the sugar-coated tablet of the present application, such as estradiol valerate sugar-coated tablet, is placed for 6 months after packaging, and it is found that the drug active substance is stable and the impurity content in the drug meets the relevant requirements. BRIEF DESCRIPTION OF DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the specific embodiments of the present application, the drawings in the specific embodiments will be briefly introduced as follows.

[0025] Figure 1 The appearance of the reference preparation “progest” at 0 days and 30 days under 75% RH environment humidity is shown.

[0026] Figure 2Appearance of estradiol valerate sugar-coated tablets prepared in Example 1 at 0 days and 30 days under 75% RH environmental humidity is shown.

[0027] Figure 3 Appearance of estradiol valerate sugar-coated tablets prepared in Example 2 at 0 days and 30 days under 75% RH environmental humidity is shown.

[0028] Figure 4 Appearance of estradiol valerate sugar-coated tablets prepared in Example 3 at 0 days and 30 days under 75% RH environmental humidity is shown.

[0029] Figures 5-8 Results of particle size distribution in the powder coating suspension prepared in Example 10 at different homogenization speeds are shown. DETAILED DESCRIPTION

[0030] Hereinafter, the present application will be described in detail. It is to be understood that the following description is only by way of illustration of the present application and is not intended to limit the scope of the present application. The scope of the present application is defined with the appended claims. And, it is understood by those skilled in the art that the technical solutions of the present application can be modified without departing from the spirit and principle of the present application. If not specifically indicated, the technical means used in the examples are the conventional means well known to those skilled in the art.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs. The following definitions are provided to better define the present application.

[0032] In the context of the present application, many embodiments use the expressions "comprising", "including" or "consisting essentially of". The expressions "comprising", "including" or "consisting essentially of" are to be interpreted as open-ended expressions, meaning that not only the elements, components, components, method steps, etc. specifically listed after the expressions are included, but also other elements, components, components, method steps, etc. are included. In addition, in this context, the expressions "comprising", "including" or "consisting essentially of" can also be interpreted as closed expressions in some cases, meaning that only the elements, components, components, method steps, etc. specifically listed after the expressions are included, and any other elements, components, components, method steps, etc. are not included. At this time, the expression is equivalent to the expression "consisting of".

[0033] If not otherwise specified, all steps mentioned in the present application can be carried out in sequence or randomly, unless the context requires a sequence. For example, when it is mentioned that "the method comprises steps (a) and (b)", it means that the method can be carried out by first carrying out step (a) and then carrying out step (b), or by first carrying out step (b) and then carrying out step (a), unless the context requires that step (a) must be carried out before step (b). For another example, when it is mentioned that "the method can further comprise step (c)", it means that step (c) can be added to the method in any sequence, specifically, the method can be carried out in the following sequence of steps: steps (a), (b) and (c), steps (a), (c) and (b), steps (c), (a) and (b); steps (c), (b) and (a).

[0034] It should be noted that, for the numerical values or numerical ranges mentioned herein, unless the context clearly dictates, the term "about" is defined. In the present text, the term "about" for a numerical value means ±5%, for example ±4%, ±3%, ±2%, or ±1%, and for a numerical range, the term "about" means ±5%, for example ±4%, ±3%, ±2%, or ±1% of the upper and lower limits of the numerical range.

[0035] In the present text, sometimes the ordinal numbers "first", "second", "third" and the like are used to modify or qualify elements, components, assemblies, method steps, solutions, solvents, temperatures, systems and the like. It should be noted that in the present text these expressions are used only to distinguish the elements, components, assemblies, method steps, solutions, solvents, temperatures, systems and the like they modify or qualify, without any intention to limit their sequence or importance.

[0036] As mentioned before, the present application aims to provide a sugar-coated tablet, for example estradiol valerate sugar-coated tablets, having a tablet core moisture protection and a similar effect on the in vitro dissolution profile of the reference formulation.

[0037] Therefore, in a first aspect, the present application provides a sugar-coated tablet formulation comprising, from the inside out, a tablet core, a hydrophobic layer comprising a first binder, a powder coating layer comprising a second binder, a first structural support material, a first plasticizer, a first anti-sticking agent.

[0038] The first adhesive is used to form a uniform film layer, to enhance the adhesion of the hydrophobic layer to the tablet core. The second adhesive helps to uniformly disperse other ingredients, to form a uniform film layer, to enhance the adhesion of the powder coating layer to the hydrophobic layer. The first structural support material serves as a basic framework for subsequent superimposition of other functional coatings, giving the tablet a glossy and beautiful appearance. The first plasticizer can improve the mechanical properties of the film, increase the flexibility and hydrophilicity of the film, and reduce brittleness. The first anti-adhesive agent is used to reduce the adhesion between the coating liquid and the equipment, improve the spraying efficiency, reduce the adhesion after drying of the coating layer, make the tablet surface smoother and easier to separate, and its white powdery characteristics can improve the hiding power of the coating layer, helping to cover the color of the tablet core or the peculiar smell of the drug.

[0039] In a preferred embodiment, the first adhesive is one or more selected from povidone K90, hydroxypropyl methylcellulose and hydroxypropyl cellulose. In a more preferred embodiment, the first adhesive is povidone K90.

[0040] In another embodiment, the second adhesive is one or more selected from povidone K90, hydroxypropyl methylcellulose and hydroxypropyl cellulose. In a preferred embodiment, the second adhesive is povidone K90.

[0041] In another embodiment, the first structural support material is one or more selected from sucrose, mannitol, xylitol and sorbitol. In a preferred embodiment, the first structural support material is sucrose.

[0042] In another embodiment, the first plasticizer is one or more selected from polyethylene glycol, glycerol, propylene glycol and triethyl citrate. In a preferred embodiment, the first plasticizer is polyethylene glycol 6000.

[0043] In another embodiment, the first anti-adhesive agent is talc and / or calcium carbonate. In a preferred embodiment, the first anti-adhesive agent is calcium carbonate.

[0044] In a further embodiment, the sugar-coated tablet formulation further comprises a coloring layer as the outermost layer. The coloring layer comprises a second structural support material, a second plasticizer, a second anti-adhesive agent and a coloring agent. The second structural support material, the second plasticizer, the second anti-adhesive agent can be independently selected from the substance options of the first structural support material, the first plasticizer, the first anti-adhesive agent given above for the powder coating layer, and have the same functions as them, respectively. Further details thereof can be referred to the specific description above, which will not be repeated here.

[0045] In one embodiment, the colorant is selected from one or more of yellow iron oxide, red iron oxide, and blue iron oxide. In a preferred embodiment, the colorant is yellow iron oxide.

[0046] In a still further embodiment, the coloring layer further comprises a third binder, which can be selected from one or more of povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[0047] In a preferred embodiment, the sugar-coated tablet formulation is an estradiol valerate sugar-coated tablet formulation, the tablet core comprising estradiol valerate. In a further preferred embodiment, the tablet core further comprises a diluent (e.g., lactose), a disintegrant (e.g., corn starch), a fourth binder (e.g., povidone K25), a lubricant (e.g., either or a combination of talc and magnesium stearate).

[0048] In one embodiment, the first binder, the second binder, and the third binder can be the same or different. For example, the first binder, the second binder, and the third binder are the same; or, the first binder and the second binder are the same but different from the third binder; or, the first binder, the second binder, and the third binder are all different; and the like. In a preferred embodiment, the first binder, the second binder, and the third binder are all povidone K90.

[0049] Likewise, the first and second structural support materials, the first and second plasticizers, and the first and second anti-tacking agents can also be the same or different, respectively. In a preferred embodiment, the first and second structural support materials are the same, both being sucrose; the first and second plasticizers are the same, both being polyethylene glycol; and the first and second anti-tacking agents are the same, both being calcium carbonate.

[0050] In one embodiment, the hydrophobic layer is prepared from a hydrophobic film-forming solution, which comprises 3% to 5% (e.g., 3%, 3.5%, 4%, 4.5%, 5%, or any value in between) of the first binder, by weight percentage of the hydrophobic film-forming solution.

[0051] In one embodiment, the sugar-coating layer is prepared from a first suspension, the particle size D 90 of the particles in the first suspension is 5 to 100 μm, and the viscosity is less than 700 mPa·S. The inventors of the present application have found through repeated tests that the particle size distribution and the viscosity of the first suspension affect the moisture-proof effect and the in-vitro dissolution profile of the sugar-coated tablet formulation. In a specific embodiment, the particle size D 90may be 5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, or any value therebetween. In a preferred embodiment, the particle size D 90 is 5-50 μm. In a more preferred embodiment, the particle size D 90 is 5-15 μm. In a specific embodiment, the viscosity of the first suspension is 700 mPa-S, 600 mPa-S, 500 mPa-S, 400 mPa-S, or any value therebetween. In a preferred embodiment, the viscosity of the first suspension is 550-650 mPa-S, for example 550 mPa-S, 570 mPa-S, 590 mPa-S, 610 mPa-S, 630 mPa-S, 650 mPa-S, or any value therebetween.

[0052] In a preferred embodiment, the first suspension comprises, by weight percentage of the first suspension:

[0053] First structural support material: 27-60% (e.g., 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or any value therebetween);

[0054] Second binder: 0.2-0.4% (e.g., 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, or any value therebetween);

[0055] First plasticizer: 2.7-4.5% (e.g., 2.7%, 3%, 3.5%, 4%, 4.5%, or any value therebetween);

[0056] First anti-tacking agent: 16-26% (e.g., 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, or any value therebetween).

[0057] In an embodiment, the colored layer is prepared from a second suspension, the particle size D 90 is 5-100 μm and the viscosity is less than 700 mPa-S. The inventors of the present application have found through repeated testing that the particle size distribution and viscosity of the second suspension also affect the moisture resistance and in-vitro dissolution profile of the sugar-coated tablet formulation. In a specific embodiment, the particle size D 90may be 5 μιη, 10 μιη, 20 μιη, 30 μιη, 40 μιη, 50 μιη, 60 μιη, 70 μιη, 80 μιη, 90 μιη, 100 μιη, or any value in between. In a preferred embodiment, the particle size D 90 may be 5-50 μιη. In a more preferred embodiment, the particle size D 90 may be 5-15 μιη. In a specific embodiment, the viscosity of the second suspension is 700 mPa-S, 600 mPa-S, 500 mPa-S, 400 mPa-S, or any value in between. In a preferred embodiment, the viscosity of the second suspension is 550-650 mPa-S, such as 550 mPa-S, 570 mPa-S, 590 mPa-S, 610 mPa-S, 630 mPa-S, 650 mPa-S, or any value in between.

[0058] In a preferred embodiment, the second suspension comprises, by weight percentage of the second suspension:

[0059] second structural support material: 27-60% (e.g., 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or any value in between);

[0060] third binder: 0-0.4%, such as 0.2-0.4% (e.g., 0%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, or any value in between);

[0061] second plasticizer: 2.7-4.5% (e.g., 2.7%, 3%, 3.5%, 4%, 4.5%, or any value in between);

[0062] second anti-tack agent: 16-26% (e.g., 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, or any value in between);

[0063] colorant: 0.3-0.5% (e.g., 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, or any value in between).

[0064] In one embodiment, the hydrophobic layer is 2% to 5% (e.g., 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or any value in between) by weight of the core, the powder coating layer is 40% to 50% (e.g., 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or any value in between) by weight of the core, and the coloring layer is 60% to 75% (e.g., 60%, 62%, 64%, 66%, 68%, 70%, 72%, 75%, or any value in between) by weight of the core.

[0065] It is understood that the sugar-coated tablet formulation of the present application can include one or more (e.g., two, three, etc.) layers of the hydrophobic layer, the powder coating layer, and the coloring layer, but from the cost perspective, if a single layer can achieve the technical effects, it is preferred to include only one of the layers.

[0066] In a second aspect, the present application provides a method for preparing a sugar-coated tablet formulation, the method comprising the steps of:

[0067] 1) preparing a hydrophobic film-forming solution for preparing a hydrophobic layer:

[0068] dissolving the first binder in the dispersion solvent under stirring to obtain a hydrophobic film-forming solution;

[0069] 2) preparing a first suspension for preparing a powder coating layer:

[0070] dissolving the first structure-supporting material in boiling water to obtain a first solution;

[0071] lowering the temperature of the first solution to 50°C to 65°C, and sequentially adding the second binder, the first plasticizer, and the first anti-sticking agent into the first solution under stirring at a stirring speed of 500 rpm to 2000 rpm to obtain a first intermediate suspension;

[0072] maintaining the temperature of the first intermediate suspension at 50°C to 65°C, and homogenizing the first intermediate suspension at a homogenization speed of 500 rpm to 2000 rpm for 20 min to 40 min to obtain a first suspension;

[0073] 3) preparing a sugar-coated tablet formulation:

[0074] a) wrapping a core with the hydrophobic film-forming solution to form a hydrophobic layer on the outer surface of the core;

[0075] b) wrapping the core with the hydrophobic layer on the outer surface with the first suspension to further form a powder coating layer on the outer surface of the hydrophobic layer.

[0076] In one embodiment, the first binder is selected from one or more of povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. In a preferred embodiment, the first binder is povidone K90.

[0077] In one embodiment, the dispersing solvent is selected from one or more of ethanol, purified water, and glycerol. In a preferred embodiment, the dispersing solvent is anhydrous ethanol.

[0078] In a preferred embodiment, the preparation conditions of the hydrophobic film forming solution are as follows: dissolution temperature: room temperature, e.g., 20-35°C; stirring speed: 50 rpm-200 rpm; stirring time: 20 min-40 min. In a specific embodiment, the preparation conditions of the hydrophobic film forming solution further comprise standing degassing time: 15 min-30 min.

[0079] In one embodiment, the first structural support material is selected from one or more of sucrose, mannitol, xylitol, and sorbitol.

[0080] In one embodiment, the second binder is selected from one or more of povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. In a preferred embodiment, the second binder is povidone K90.

[0081] In one embodiment, the first plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, and triethyl citrate. In a preferred embodiment, the first plasticizer is polyethylene glycol 6000.

[0082] In one embodiment, the first anti-tack agent is talc and / or calcium carbonate. In a preferred embodiment, the first anti-tack agent is calcium carbonate.

[0083] In a specific embodiment, the stirring speed of the first intermediate suspension can be 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, 1100 rpm, 1200 rpm, 1300 rpm, 1400 rpm, 1500 rpm, 1600 rpm, 1700 rpm, 1800 rpm, 1900 rpm, 2000 rpm, or any value therebetween. In a preferred embodiment, the stirring speed of the first intermediate suspension is 1500 rpm.

[0084] In one embodiment, the first intermediate suspension has a viscosity of less than 700 mPa-S. In one preferred embodiment, the first intermediate suspension has a viscosity of 550-650 mPa-S.

[0085] In one embodiment, the particle size Dv50 of the particles in the first suspension is 5-100 μm. In one preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-50 μm. In one more preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-15 μm. 90 In one embodiment, the particle size Dv50 of the particles in the first suspension is 5-100 μm. In one preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-50 μm. In one more preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-15 μm. 90 In one embodiment, the particle size Dv50 of the particles in the first suspension is 5-100 μm. In one preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-50 μm. In one more preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-15 μm. 90 In one embodiment, the particle size Dv50 of the particles in the first suspension is 5-100 μm. In one preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-50 μm. In one more preferred embodiment, the particle size Dv50 of the particles in the first suspension is 5-15 μm.

[0086] In one preferred embodiment, the sugar-coated tablet formulation is an estradiol valerate sugar-coated tablet formulation, the tablet core comprising estradiol valerate. In one further preferred embodiment, the tablet core further comprises a diluent (e.g. lactose), a disintegrant (e.g. corn starch), a fourth binder (e.g. povidone K25), a lubricant (e.g. either or a combination of talc and magnesium stearate).

[0087] In one further embodiment, the sugar-coated tablet formulation prepared by the present method further comprises a coloring layer as the outermost layer. Accordingly, the method further comprises the following steps:

[0088] 4) preparing a second suspension for preparing the coloring layer:

[0089] dissolving the second structural support material in boiling water, thereby obtaining a second solution;

[0090] reducing the temperature of the second solution to 50-65 °C, and adding a second plasticizer, a second anti-tacking agent, a coloring agent, and optionally a third binder, in sequence, to the second solution at a stirring speed of 500-2000 rpm, thereby obtaining a second intermediate suspension;

[0091] maintaining the temperature of the second intermediate suspension at 50-65 °C, and homogenizing the second intermediate suspension at a homogenization speed of 500-2000 rpm for 20-40 min, thereby obtaining a second suspension; and

[0092] The method further comprises, in step 3) of preparing the sugar-coated tablet formulation:

[0093] c) coating the outer surface of the tablet core with the second suspension to form a tablet core with a hydrophobic layer and a sugar coating layer, to further form a coloring layer on the outer surface of the sugar coating layer.

[0094] In one embodiment, the second structuring material is selected from one or more of sucrose, mannitol, xylitol and sorbitol.

[0095] In one embodiment, the second plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol and triethyl citrate. In a preferred embodiment, the second plasticizer is polyethylene glycol 6000.

[0096] In one embodiment, the second anti-tacking agent is talc and / or calcium carbonate. In a preferred embodiment, the first anti-tacking agent is calcium carbonate.

[0097] In one embodiment, the coloring agent is selected from one or more of yellow iron oxide, red iron oxide and blue iron oxide. In a preferred embodiment, the coloring agent is yellow iron oxide.

[0098] In one embodiment, the third binder is selected from one or more of povidone K90, hydroxypropyl methylcellulose and hydroxypropyl cellulose. In a preferred embodiment, the third binder is povidone K90.

[0099] In one specific embodiment, the stirring speed of the second intermediate suspension can be 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, 1100 rpm, 1200 rpm, 1300 rpm, 1400 rpm, 1500 rpm, 1600 rpm, 1700 rpm, 1800 rpm, 1900 rpm, 2000 rpm, or any value in between. In a preferred embodiment, the stirring speed of the second intermediate suspension is 1500 rpm.

[0100] In one specific embodiment, the homogenization speed of the second intermediate suspension can be 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, 1100 rpm, 1200 rpm, 1300 rpm, 1400 rpm, 1500 rpm, 1600 rpm, 1700 rpm, 1800 rpm, 1900 rpm, 2000 rpm, or any value in between. In a preferred embodiment, the homogenization speed of the second intermediate suspension is 1800 rpm.

[0101] In one embodiment, the particle size D90of the particles in the second suspension is from 5 to 100 pm. 90 In one preferred embodiment, the particle size D90of the particles in the second suspension is from 5 to 50 pm. 90 In one more preferred embodiment, the particle size D90of the particles in the second suspension is from 5 to 15 pm. 90 In one embodiment, the viscosity of the second suspension is less than 700 mPa-S. In one preferred embodiment, the viscosity of the second suspension is from 550 to 650 mPa-S.

[0102] The inventors of the present application found that the homogenization speed during the preparation of the first suspension and the second suspension affects the particle size and the viscosity of the suspensions, and in turn, the moisture resistance and the dissolution performance of the sugar-coated tablet formulation. The inventors found through repeated tests that the suspensions obtained at a homogenization speed of 500 rpm to 2000 rpm can be used to prepare sugar-coated tablet formulations with excellent moisture resistance and dissolution performance. In addition, the homogenization speed also affects the dispersibility of the suspensions; a lower homogenization speed leads to uneven dispersion of the suspensions, which in turn leads to uneven coating of the tablet cores and the shedding of the coating; a higher homogenization speed leads to splashing of the suspensions, causing waste and fluctuations in the temperature of the suspensions; a homogenization speed of 500 rpm to 2000 rpm leads to good dispersibility of the suspensions without splashing and wall sticking.

[0103] The material selection and the role of the first, second and third binders, the first and second structural support materials, the first and second plasticizers, the first and second anti-tacking agents of the present aspect are the same as those described in the first aspect of the present application, and further details can be referred to the specific description above, which will not be repeated here.

[0104] In one embodiment, the hydrophobic film-forming solution comprises 3% to 5% (e.g., 3%, 3.5%, 4%, 4.5%, 5%, or any value therebetween) of the first binder, based on the weight percentage of the hydrophobic film-forming solution;

[0105] The first suspension comprises, based on the weight percentage of the first suspension:

[0106] The first structural support material: 27% to 60% (e.g., 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or any value therebetween);

[0107] The second binder: 0.2% to 0.4% (e.g., 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, or any value therebetween);

[0108] First plasticizer: 2.7% to 4.5% (e.g., 2.7%, 3%, 3.5%, 4%, 4.5%, or any value in between);

[0109] First anti-tacking agent: 16% to 26% (e.g., 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, or any value in between);

[0110] The second suspension comprises, by weight percentage of the second suspension:

[0111] Second structural support material: 27% to 60% (e.g., 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or any value in between);

[0112] Third binder: 0% to 0.4%, e.g., 0.2% to 0.4% (e.g., 0%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, or any value in between);

[0113] Second plasticizer: 2.7% to 4.5% (e.g., 2.7%, 3%, 3.5%, 4%, 4.5%, or any value in between);

[0114] Second anti-tacking agent: 16% to 26% (e.g., 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, or any value in between);

[0115] Colorant: 0.3% to 0.5% (e.g., 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, or any value in between).

[0116] It can be appreciated that the order of steps 1), 2), and 4) in the method is not limited, e.g., can be performed in the order of steps 1), 2), 4), in the order of steps 1), 4), 2), etc., or the three steps are performed simultaneously, followed by step 3). Alternatively, step 3) can be further split, e.g., step 1) can be performed first, followed by step a) of the hydrophobic layer overcoating in step 3); step 2) can be performed first, followed by step b) of the powder overcoating in step 3), etc.

[0117] Further, as described above, the sugar-coated tablet formulation can include one or more layers (e.g., two or three layers) of the hydrophobic layer, the powder overcoating, and the colorant layer. Correspondingly, each sub-step in step 3) can be repeated one or more times, e.g., two or three times, to provide multiple layers of the respective layer structure.

[0118] In one embodiment, the sugar-coated tablet preparation prepared by the method of the second aspect of the present application is the sugar-coated tablet preparation of the first aspect of the present application.

[0119] Examples

[0120] The concept and the technical effects of the present application will be described clearly and completely in combination with the examples and the drawings, so as to fully understand the purpose, features and effects of the present application. Obviously, the described examples are only a part of the examples of the present application, but not all the examples. Based on the examples of the present application, other examples obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0121] Example 1

[0122] In this example, the estradiol valerate sugar-coated tablets (1 mg) containing the ingredients shown in Table 1 were prepared, which included the tablet core, the powder coating layer and the coloring layer from inside to outside.

[0123] Table 1.

[0124]

[0125]

[0126] I. Preparation method of the tablet core:

[0127] 1) Sieving: Sieve the raw and auxiliary materials through a nylon screen (screen mesh size is 40 mesh).

[0128] 2) Weighing: Weigh the raw and auxiliary materials according to the batch prescription amount in the table.

[0129] 3) Pre-mixing: Add corn starch, povidone K25, estradiol valerate raw material and lactose into a 5L wet mixing granulator (model G50, Shenzhen Xinyite) in sequence and mix, and the mixing machine parameters are set as follows: the mixing machine speed is 100 rpm-400 rpm, the shear speed is 1000 rpm-2000 rpm, and the mixing time is 3 min-6 min. After mixing, stop the machine, and the pre-mixed powder is obtained.

[0130] 4) Granulation: Add 375 g-500 g of purified water to the pre-mixed powder and mix in the mixing machine, and the mixing machine parameters are set as follows: the mixing machine speed is 100 rpm-400 rpm, the shear speed is 1000 rpm-2000 rpm, and the mixing time is 1 min-5 min. After mixing, stop the machine, and the wet granules are obtained. Open the discharge port of the mixing machine, and set the mixing machine speed to 50 rpm-100 rpm to discharge all the wet granules.

[0131] 5) Drying: Pour the wet granules into a multifunctional fluidized bed (model WBF-2G, Chongqing Yingge). The setting parameters of the fluidized bed are as follows: inlet air temperature is 60℃, air volume is 50m 3 / h~80m 3 / h. When the material temperature reaches 45℃~50℃ and the outlet temperature reaches 35℃~40℃, dry it for 15min~30min, then stop the machine and discharge the material.

[0132] 6) Final Mixing: Transfer the dried granules to a final mixer (model GHJ1, Nanjing Huasha Drying Equipment Co., Ltd.) and add the prescribed amount of talc and magnesium stearate in sequence. Set the speed to 10-30 rpm and mix for 5-8 minutes. After mixing, stop the machine and discharge.

[0133] 7) Tablet Compression: Tablet cores were compressed using a rotary tablet press (model ZP10A, Beijing Xinlongli) at a weight of 80 mg per tablet. The tablet core hardness ranged from 20 kg to 40 kg.

[0134] 2. Preparation method of sugar coating film:

[0135] 1) Preparation method of powder coating: Heat the prescribed amount of purified water to a boiling state using an induction cooker, add the prescribed amount of sucrose and stir until the sucrose is completely dissolved, and continue heating to boil the solution for 5 minutes. When the temperature of the syrup solution drops to 50°C to 65°C, turn on the digital display electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.), add povidone K90 and polyethylene glycol 6000 in turn, stir at a speed of 1500rpm to dissolve them, add calcium carbonate, and continue stirring for 15 to 40 minutes to disperse it evenly. Use an imported Italian stirring homogenizer (model 120000001, IMA) to homogenize the suspended sugar coating solution at a homogenization speed of 1800rpm for 20 to 40 minutes and set aside.

[0136] 2) Preparation method of the coloring layer: Heat the prescribed amount of pure water to a boiling state using an induction cooker, add the prescribed amount of sucrose and stir until all the sucrose is dissolved, and continue heating to boil the solution for 5 minutes. When the temperature of the syrup solution drops to 50°C ~ 65°C, turn on the digital display electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.), add povidone K90 and polyethylene glycol 6000 in turn, stir at a speed of 1500rpm to dissolve them, then add calcium carbonate and yellow ferric oxide in turn, continue stirring for 15 minutes to disperse them evenly. Use an imported Italian stirring homogenizer (model 120000001, IMA) to homogenize the suspended sugar coating solution at a homogenization speed of 1800rpm for 20 to 40 minutes and set aside.

[0137] 3. Preparation method of estradiol valerate sugar-coated tablets:

[0138] 1) Take 2 kg of prepared estradiol valerate tablet cores and put them into the coating pan. Control the temperature of the tablet cores to be 35-50°C by preheating. Set the rotation speed of the coating pan to be 10-12 rpm, the atomization pressure to be 0.5-1.4 bar, the spraying time to be 1-3 s, the homogenization time to be 4-10 min, and the drying time to be 8 min. The weight gain of the coating is 40-50%, and the tablet cores wrapped with the powder coating are obtained.

[0139] 2) Continue to dry the tablet cores wrapped with the powder coating in the coating pan for 10-20 min, control the temperature to be 35-50°C, set the rotation speed of the coating pan to be 10-12 rpm, the atomization pressure to be 0.5-1.4 bar, the spraying time to be 1-3 s, the homogenization time to be 4-10 min, and the drying time to be 8 min. The weight gain of the coating is 60-75%, and the estradiol valerate sugar-coated tablets are obtained.

[0140] Example 2

[0141] In this example, estradiol valerate sugar-coated tablets (1 mg) containing the ingredients shown in Table 2 are prepared, which include, from inside to outside, a tablet core, a powder coating, and a coloring layer. Compared with Example 1, the amount of calcium carbonate used in this example is increased.

[0142] Table 2.

[0143]

[0144] I. Preparation method of the tablet core:

[0145] This step of this example is the same as that of Example 1.

[0146] II. Preparation method of the sugar-coated film:

[0147] 1) Preparation method of the powder coating: heat the batch prescription amount of pure water to boiling state using an electromagnetic oven, add the prescription amount of sucrose and stir until the sucrose is completely dissolved, continue to heat the solution to boiling state for 5 minutes. When the temperature of the sugar syrup solution decreases to 50-65°C, start the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.), add povidone K90 and polyethylene glycol 6000 in sequence, stir at a speed of 1500 rpm to dissolve them, then add calcium carbonate, and continue to stir for 15-40 min to make it uniformly dispersed. Use the Italian imported stirring homogenizer (model 120000001, IMA) to homogenize the suspension sugar coating solution at a homogenization speed of 1800 rpm for 20-40 min, and reserve it.

[0148] 2) The preparation method of the coloring layer: the batch prescription amount of pure water is heated to boiling state by electromagnetic oven, the prescription amount of sucrose is added and stirred until the sucrose is completely dissolved, the solution is continuously heated to boiling state for 5 minutes. When the temperature of the sugar syrup solution is reduced to 50-65°C, the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) is started, and povidone K90 and polyethylene glycol 6000 are added in sequence, and stirred at 1500 rpm to dissolve, then calcium carbonate and yellow iron oxide are added in sequence, and continue to stir for 15 min to make them uniformly dispersed. The suspension coating solution is homogenized by using the imported Italian stirring homogenizer (model 120000001, IMA) at a homogenization speed of 1800 rpm for 20-40 minutes, and is ready for use.

[0149] III. The preparation method of estradiol valerate sugar-coated tablets:

[0150] 1) 2 kg of prepared estradiol valerate tablet cores are weighed and put into the coating pan, the temperature of the tablet cores is controlled to 35-50°C by preheating, the rotation speed of the coating pan is set to 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The coating weight is increased by 40-50%, and the tablet cores wrapped with the powder coating layer are obtained.

[0151] 2) The tablet cores wrapped with the powder coating layer are continuously dried in the coating pan for 10-20 min, the temperature is controlled to 35-50°C, the rotation speed of the coating pan is set to 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The coating weight is increased by 60-75%, and the estradiol valerate sugar-coated tablets are obtained.

[0152] Example 3

[0153] In this example, estradiol valerate sugar-coated tablets (1 mg specification) containing the ingredients shown in Table 3 are prepared, which include tablet cores, a hydrophobic layer, a powder coating layer and a coloring layer from inside to outside.

[0154] Table 3.

[0155]

[0156]

[0157] I. The preparation method of the tablet cores:

[0158] This step of the example is the same as that of Example 1.

[0159] II. The preparation method of the sugar-coated film:

[0160] 1) The preparation method of the hydrophobic layer: at room temperature, the prescribed amount of povidone K90 was added to 50% ethanol solution, and the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) was started to stir until completely dissolved, the stirring speed was 50-200 rpm, the stirring time was 20-40 min, and the static degassing time was 15-30 min.

[0161] 2) The preparation method of the sugar coating layer: the batch prescription amount of pure water was heated to boiling state by electromagnetic oven, the prescribed amount of sucrose was added and stirred until the sucrose was completely dissolved, and the solution was continuously heated to boiling state for 5 minutes. When the temperature of the sugar syrup solution decreased to 50-65°C, the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) was started, and polyethylene glycol 6000 and povidone K90 were added in sequence. After stirring at a speed of 1500 rpm to dissolve them, calcium carbonate was added, and the stirring was continued for 15-40 min to make them uniformly dispersed. The suspension sugar coating solution was homogenized by using the imported Italian stirring homogenizer (model 120000001, IMA) at a homogenization speed of 1800 rpm for 20-40 min, and was ready for use.

[0162] 3) The preparation method of the coloring layer: the batch prescription amount of pure water was heated to boiling state by electromagnetic oven, the prescribed amount of sucrose was added and stirred until the sucrose was completely dissolved, and the solution was continuously heated to boiling state for 5 minutes. When the temperature of the sugar syrup solution decreased to 50-65°C, the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) was started, and polyethylene glycol 6000 and povidone K90 were added in sequence. After stirring at a speed of 1500 rpm to dissolve them, calcium carbonate and yellow iron oxide were added in sequence, and the stirring was continued for 15 min to make them uniformly dispersed. The suspension sugar coating solution was homogenized by using the imported Italian stirring homogenizer (model 120000001, IMA) at a homogenization speed of 1800 rpm for 20-40 min, and was ready for use.

[0163] III. The preparation method of estradiol valerate sugar-coated tablets:

[0164] 1) 2 kg of prepared estradiol valerate tablets were weighed and put into the coating pan, the tablet core temperature was controlled to 35-50°C by preheating, the rotation speed of the coating pan was set to 10-12 rpm, the atomization pressure was 0.5-1.4 bar, the spraying time was 1-3 s, the homogenization time was 4-10 min, and the drying time was 8 min. The coating weight was increased by 2-5%, and the tablet core wrapped with the hydrophobic layer was obtained.

[0165] 2) Continue to dry the tablet core wrapped with the hydrophobic layer in the coating pan for 10-20 min, control the temperature at 35-50°C, set the rotation speed of the coating pan at 10-12 rpm, the atomization pressure at 0.5-1.4 bar, the spraying time at 1-3 s, the homogenization time at 4-10 min, and the drying time at 8 min. The weight gain of the coating is 40-50%, and the tablet core wrapped with the powder coating is obtained.

[0166] 3) Continue to dry the tablet core wrapped with the powder coating in the coating pan for 10-20 min, control the temperature at 35-50°C, set the rotation speed of the coating pan at 10-12 rpm, the atomization pressure at 0.5-1.4 bar, the spraying time at 1-3 s, the homogenization time at 4-10 min, and the drying time at 8 min. The weight gain of the coating is 60-75%, and the estradiol valerate sugar-coated tablet is obtained.

[0167] Example 4

[0168] In this example, estradiol valerate sugar-coated tablets (1 mg) containing the ingredients shown in Table 4 are prepared, which include, from inside to outside, a tablet core, a hydrophobic layer, a powder coating layer, and a coloring layer. The difference between this example and Example 3 is that the ingredients of the hydrophobic layer are different.

[0169] Table 4.

[0170]

[0171]

[0172] I. Preparation method of the tablet core:

[0173] This step of this example is the same as that of Example 1.

[0174] II. Preparation method of the sugar-coated film:

[0175] 1) Preparation method of the hydrophobic layer: At room temperature, add the prescribed amount of povidone K90 to a 50% glycerol aqueous solution, and start a digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) to stir until completely dissolved, at a stirring speed of 50-200 rpm and a stirring time of 20-40 min, and then stand for 15-30 min for degassing.

[0176] 2) The preparation method of the sugar coating layer: the batch prescription amount of pure water is heated to boiling state by electromagnetic oven, the prescription amount of sucrose is added and stirred until the sucrose is completely dissolved, the solution is continuously heated to boiling state for 5 minutes. When the temperature of the syrup solution is reduced to 50-65℃, the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) is started, and the polyethylene glycol 6000 and povidone K90 are added in sequence, and stirred at 1500 rpm to dissolve them, then the calcium carbonate is added, and stirred for 15-40 min to disperse uniformly. The suspension sugar coating solution is homogenized by using the imported stirring homogenizer (model 120000001, IMA) at a homogenization speed of 1800 rpm for 20-40 minutes, ready for use.

[0177] 3) The preparation method of the color coating layer: the batch prescription amount of pure water is heated to boiling state by electromagnetic oven, the prescription amount of sucrose is added and stirred until the sucrose is completely dissolved, the solution is continuously heated to boiling state for 5 minutes. When the temperature of the syrup solution is reduced to 50-65℃, the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) is started, and the polyethylene glycol 6000 and povidone K90 are added in sequence, and stirred at 1500 rpm to dissolve them, then the calcium carbonate, yellow iron oxide are added in sequence, and stirred for 15 min to disperse uniformly. The suspension sugar coating solution is homogenized by using the imported stirring homogenizer (model 120000001, IMA) at a homogenization speed of 1800 rpm for 20-40 minutes, ready for use.

[0178] III. The preparation method of estradiol valerate sugar-coated tablets:

[0179] 1) 2 kg of prepared estradiol valerate tablets are weighed and put into the coating pan, the tablet core temperature is controlled to 35-50℃ by preheating, the rotation speed of the coating pan is set to 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The coating weight gain is 2%-5%, and the tablet core wrapped with the hydrophobic layer is obtained.

[0180] 2) The tablet core wrapped with the hydrophobic layer is continuously dried in the coating pan for 10-20 min, the temperature is controlled to 35-50℃, the rotation speed of the coating pan is set to 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The coating weight gain is 40%-50%, and the tablet core wrapped with the sugar coating layer is obtained.

[0181] 3) Continue to dry the tablet core wrapped with the powder coating layer in the coating pan for 10-20 min, control the temperature at 35-50°C, set the rotation speed of the coating pan at 10-12 rpm, the atomization pressure at 0.5-1.4 bar, the spraying time at 1-3 s, the homogenization time at 4-10 min, and the drying time at 8 min. The over-coating weight gain is 60-75%, and the estradiol valerate sugar-coated tablets are obtained.

[0182] Example 5

[0183] In this example, estradiol valerate sugar-coated tablets (1 mg) containing the ingredients shown in Table 5 are prepared, which include, from inside to outside, a tablet core, a hydrophobic layer, a powder coating layer, and a coloring layer. The difference between this example and Example 3 is that the ingredients of the hydrophobic layer are different.

[0184] Table 5.

[0185]

[0186]

[0187] I. Preparation method of the tablet core:

[0188] This step of this example is the same as Example 1.

[0189] II. Preparation method of the sugar-coated film:

[0190] 1) Preparation method of the hydrophobic layer: At room temperature, add the prescribed amount of gelatin to water, and start the digital electric mixer (Model NE-60A, Suzhou Jiulian Technology Co., Ltd.) to stir until completely dissolved, at a stirring speed of 50-200 rpm and a stirring time of 20-40 min, and then stand for 15-30 min for degassing.

[0191] 2) Preparation method of the powder coating layer: Heat the prescribed amount of pure water to boiling state using an electromagnetic oven, add the prescribed amount of sucrose and stir until completely dissolved, continue to heat to boiling state for 5 min. When the temperature of the sugar syrup solution drops to 50-65°C, start the digital electric mixer (Model NE-60A, Suzhou Jiulian Technology Co., Ltd.), and add polyethylene glycol 6000 and povidone K90 in sequence, stir at a speed of 1500 rpm until dissolved, then add calcium carbonate and continue to stir for 15-40 min to make it uniformly dispersed. Use the Italian imported stirring homogenizer (Model 120000001, IMA) to homogenize the suspension sugar coating solution at a homogenization speed of 1800 rpm for 20-40 min, and reserve for use.

[0192] 3) The preparation method of the coloring layer: the batch prescription amount of pure water is heated to boiling state by electromagnetic oven, the prescription amount of sucrose is added and stirred until the sucrose is completely dissolved, and the solution is continuously heated to boiling state for 5 minutes. When the temperature of the sugar syrup solution is reduced to 50-65°C, the digital electric mixer (model NE-60A, Suzhou Jiulian Technology Co., Ltd.) is started, and the polyethylene glycol 6000 and povidone K90 are added in sequence, and stirred at 1500 rpm to dissolve them, and then the calcium carbonate and yellow iron oxide are added in sequence, and continue to stir for 15 min to make them uniformly dispersed. The suspension coating solution is homogenized by using the imported stirring homogenizer (model 120000001, IMA) at a homogenization speed of 1800 rpm for 20-40 minutes, and is ready for use.

[0193] III. The preparation method of estradiol valerate sugar-coated tablets:

[0194] 1) 2 kg of prepared estradiol valerate tablet cores are put into the coating pan, the temperature of the tablet cores is controlled to be 35-50°C by preheating, the rotation speed of the coating pan is set to be 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The weight gain of the coating is 2%-5%, and the tablet cores wrapped with the hydrophobic layer are obtained.

[0195] 2) The tablet cores wrapped with the hydrophobic layer are continuously dried in the coating pan for 10-20 min, the temperature is controlled to be 35-50°C, the rotation speed of the coating pan is set to be 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The weight gain of the coating is 40%-50%, and the tablet cores wrapped with the powder coating layer are obtained.

[0196] 3) The tablet cores wrapped with the powder coating layer are continuously dried in the coating pan for 10-20 min, the temperature is controlled to be 35-50°C, the rotation speed of the coating pan is set to be 10-12 rpm, the atomization pressure is 0.5-1.4 bar, the spraying time is 1-3 s, the homogenization time is 4-10 min, and the drying time is 8 min. The weight gain of the coating is 60%-75%, and the estradiol valerate sugar-coated tablets are obtained.

[0197] Example 6

[0198] In this example, estradiol valerate sugar-coated tablets (1 mg specification) containing the ingredients shown in Table 6 are prepared, which include tablet cores, a hydrophobic layer, a powder coating layer, and a coloring layer from inside to outside. The difference between this example and Example 3 is that the ingredients of the hydrophobic layer are different.

[0199] Table 6.

[0200]

[0201]

[0202] I. Preparation method of the core:

[0203] This step of the present embodiment is the same as that of Example 1.

[0204] II. Preparation method of the sugar-coated film:

[0205] 1) Preparation method of the hydrophobic layer: at room temperature, add the prescribed amount of hydroxypropyl cellulose into 50% ethanol aqueous solution, and start the digital electric mixer (Model No. NE-60A, Suzhou Jiulian Technology Co., Ltd.) to stir until completely dissolved, the stirring speed is 50-200 rpm, the stirring time is 20-40 min, and the static degassing time is 15-30 min.

[0206] 2) Preparation method of the powder-coated layer: heat the prescribed amount of pure water to boiling state using an electromagnetic oven, add the prescribed amount of sucrose and stir until completely dissolved, continue heating to boiling state for 5 min. When the temperature of the syrup solution drops to 50-65°C, start the digital electric mixer (Model No. NE-60A, Suzhou Jiulian Technology Co., Ltd.), add polyethylene glycol 6000 and povidone K90 in sequence, stir to dissolve at a speed of 1500 rpm, then add calcium carbonate and continue stirring for 15-40 min to make it uniformly dispersed. Use the imported Italian stirring homogenizer (Model No. 120000001, IMA) to homogenize the suspension sugar-coated solution at a homogenization speed of 1800 rpm for 20-40 min, and reserve.

[0207] 3) Preparation method of the colored layer: heat the prescribed amount of pure water to boiling state using an electromagnetic oven, add the prescribed amount of sucrose and stir until completely dissolved, continue heating to boiling state for 5 min. When the temperature of the syrup solution drops to 50-65°C, start the digital electric mixer (Model No. NE-60A, Suzhou Jiulian Technology Co., Ltd.), add polyethylene glycol 6000 and povidone K90 in sequence, stir to dissolve at a speed of 1500 rpm, then add calcium carbonate and yellow iron oxide in sequence, and continue stirring for 15 min to make it uniformly dispersed. Use the imported Italian stirring homogenizer (Model No. 120000001, IMA) to homogenize the suspension sugar-coated solution at a homogenization speed of 1800 rpm for 20-40 min, and reserve.

[0208] III. Preparation method of estradiol valerate sugar-coated tablets:

[0209] 1) Take 2 kg of prepared estradiol valerate tablet cores and put them into the coating pan. Control the temperature of the tablet cores to be 35-50°C by preheating. Set the rotation speed of the coating pan to be 10-12 rpm, the atomization pressure to be 0.5-1.4 bar, the spraying time to be 1-3 s, the homogenization time to be 4-10 min, and the drying time to be 8 min. The weight gain of the coating is 2-5%, and the tablet cores wrapped with the hydrophobic layer are obtained.

[0210] 2) Continue to dry the tablet cores wrapped with the hydrophobic layer in the coating pan for 10-20 min, control the temperature to be 35-50°C, set the rotation speed of the coating pan to be 10-12 rpm, the atomization pressure to be 0.5-1.4 bar, the spraying time to be 1-3 s, the homogenization time to be 4-10 min, and the drying time to be 8 min. The weight gain of the coating is 40-50%, and the tablet cores wrapped with the powder coating layer are obtained.

[0211] 3) Continue to dry the tablet cores wrapped with the powder coating layer in the coating pan for 10-20 min, control the temperature to be 35-50°C, set the rotation speed of the coating pan to be 10-12 rpm, the atomization pressure to be 0.5-1.4 bar, the spraying time to be 1-3 s, the homogenization time to be 4-10 min, and the drying time to be 8 min. The weight gain of the coating is 60-75%, and the estradiol valerate sugar-coated tablets are obtained.

[0212] Example 7

[0213] This example compares the in-vitro dissolution data of the reference preparation “Progynova” and the estradiol valerate sugar-coated tablets prepared in Examples 1-6.

[0214] Take 12 pieces of the reference preparation and the self-prepared estradiol valerate sugar-coated tablets in Examples 1-6 respectively, and follow the dissolution determination method (Chinese Pharmacopoeia 2020 Edition Part II Appendix X C Second Method) to operate. Use 0.3% sodium dodecyl sulfate solution 900 mL as the dissolution medium, the rotation speed is 50 revolutions per minute, sample at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min respectively as the test solution. Precisely take about 10 mg of estradiol valerate reference substance, put it into a 50 mL volumetric flask, dissolve and dilute to the mark with methanol solution, shake well, precisely take 2 mL, put it into a 50 mL volumetric flask, dilute to the mark with 0.3% sodium dodecyl sulfate, shake well, as the control solution. Follow the chromatographic conditions (octadecylsilane-bonded silica gel as the filler, with acetonitrile-water (70:30) as the mobile phase, and the detection wavelength is 280 nm) under the content determination, precisely take 100 μL of the test solution and the control solution respectively, inject into the liquid chromatograph, and record the chromatogram. Calculate the dissolution rate at each time point, and the results are shown in Table 7.

[0215] Table 7. In-vitro dissolution data of the reference preparation “Progynova” and the estradiol valerate sugar-coated tablets prepared in Examples 1-6

[0216]

[0217] According to the data in Table 7, the similarity factor f2 of the preparations prepared in Examples 1-6 and the reference preparation are all greater than 50%, which indicates that the preparations prepared in Examples 1-6 are all usable from the perspective of dissolution curves. However, in the six examples, the similarity factor f2 of Example 2 in which calcium carbonate is added as an excipient and Example 5 in which the hydrophobic layer is a gelatin aqueous solution is lower than that of the other examples, which is not preferred, and it is presumed that this is due to the following reasons: in Example 2, the amount of calcium carbonate added in the sugar coating layer is increased, which makes the sugar coating film dissolve faster and the calcium carbonate that has fallen off accumulates at the bottom; in Example 5, the hydrophobic layer is a gelatin aqueous solution, which significantly accelerates in-vitro dissolution, and gelatin is an animal-derived excipient, which is not recommended for use in the product. In contrast, Examples 3, 4 and 6 in which the hydrophobic layer is added are the most preferred.

[0218] Example 8

[0219] This example compares the properties of the reference preparation "Proge" and the estradiol valerate sugar-coated tablets prepared in Examples 1-3 before being placed in a 75% RH humidity environment and after being placed in a 75% RH humidity environment for 30 days. The results are shown in Figure 1, in which the left photograph (A) in each figure is the property of the product observed at 0 days and the right photograph (B) is the property of the product observed after being placed in a 75% RH humidity environment for 30 days. Figures 1-4

[0220] The results show that the reference preparation has no significant change in appearance after being placed in a high-humidity 75% RH environment for 30 days; Figure 1 The preparation of Example 1 is obtained by directly spraying the sugar coating layer and the coloring layer on the tablet core, and although the process is simple, the sugar-coated tablets crack after being placed in a high-humidity environment for 30 days, and the properties do not meet the requirements of the quality standards; Figure 2 The preparation of Example 2 is obtained by directly spraying the sugar coating layer and the coloring layer on the tablet core, and although the hydrophobic excipient calcium carbonate is added in the sugar coating layer and the coloring layer relative to Example 1, which can fill the tablet weight and lubrication, the protective effect of calcium carbonate on the tablet core in a high-humidity environment is not significantly improved, Figure 3 The preparation of Example 3 is obtained by spraying the hydrophobic layer, the sugar coating layer and the coloring layer on the tablet core, and the sugar-coated tablets of the preparation have no significant change after being placed in a high-humidity environment for 30 days. Figure 4

[0221] Example 9

[0222] This example compares the related substance content of the reference preparation "Proge" and the estradiol valerate sugar-coated tablets prepared in Example 3 after being packaged for 6 months.​​

[0223] The pentaoestradiol sugar-coated tablets prepared in Example 3 were packaged using an aluminum plastic packaging machine and stored at an accelerated condition temperature of 40°C ± 2°C and relative humidity of 75% ± 5% for 6 months, together with the reference preparation "Proge". The temperature and relative humidity were controlled to be ± 2°C and ± 5% respectively during storage. The related substances of the pentaoestradiol sugar-coated tablets were determined on day 0 and after 6 months of storage.

[0224] Table 8. Related substance information of the reference preparation "Proge" and the pentaoestradiol sugar-coated tablets prepared in Example 3 after 6 months of storage

[0225]

[0226] ND: not detect, not detected

[0227] EP-ZG: 3-hydroxyestra-1, 3, 5(10), 6-tetraen-17β-pentanoate EP-ZC: 3-hydroxyestra-1, 3, 5(10), 9(11)-tetraen-17β-pentanoate

[0228] According to the data in Table 8, the amounts of estradiol and 6-ketoestradiol in the reference preparation "Proge" and the pentaoestradiol sugar-coated tablets prepared in Example 3 after 6 months of storage were very small, indicating that pentaoestradiol in the two preparations was stable and little decomposition or reaction occurred. The single impurity content was < 0.5%, which met the relevant standards for pharmaceutical products.

[0229] Example 10

[0230] In this example, pentaoestradiol sugar-coated tablets (1 mg) containing the ingredients shown in Table 3 were prepared at different homogenization speeds. The pentaoestradiol sugar-coated tablets comprise, from the inside to the outside, a tablet core, a hydrophobic layer, a powder coating layer and a coloring layer. Specifically, the preparation method of this example was the same as that of Example 3, except that different homogenization speeds (including 400 rpm, 500 rpm, 1500 rpm, 2000 rpm and 2500 rpm) were used during preparation of the powder coating layer.

[0231] In this example, the inventors tested the effects of the homogenization speed during preparation of the powder coating layer on the particle size distribution, viscosity and dispersibility of the powder coating suspension, and further tested the effects on the moisture resistance of the sugar-coated tablet preparation and the in vitro dissolution curve.

[0232] Take about 20 mL of the powder coating suspension, and according to the dynamic viscosity determination method (Chinese Pharmacopoeia General 0633 Third Method), use a rotary viscometer (model: Rotavisco-vi complete, Guangzhou Equipment Co., Ltd.), No. 2 rotor, 20 revolutions per minute, adjust the temperature to 25 ± 0.1 ℃, and determine the dynamic viscosity of the powder coating suspension. The relationship between the homogenization speed during the preparation of the powder coating and the viscosity and dispersibility of the powder coating suspension is shown in Table 9, wherein the dispersibility is based on the subjective evaluation of the experimental personnel.

[0233] Table 9.

[0234]

[0235] Note: “-” indicates no dispersibility, no vortex in the center of the solution; “+” indicates good dispersibility, no splashing; “++” indicates over-dispersion.

[0236] According to the data in Table 9, when the homogenization speed is low, the powder coating suspension is not uniformly dispersed, and the viscosity is high, which will cause the coating on the tablet core to be uneven and fall off; when the homogenization speed is high, the powder coating suspension is over-dispersed, which is easy to cause loss of the suspension and fluctuation of the suspension temperature; the viscosity of the powder coating suspension prepared at a homogenization speed of 500-2000 rpm has no obvious difference, tends to be stable, and has good dispersibility, no splashing and no sticking to the wall, so that the coating on the tablet core is uniform.

[0237] According to the particle size and particle size distribution determination method (Chinese Pharmacopoeia 2020 Edition Fourth General 0982 Third Method), use a Malvern 3000 laser particle size analyzer, take about 20 mL of the powder coating suspension, add a saturated aqueous solution, shake and ultrasonic clean with an ultrasonic cleaner for 1 minute, then use an ultrasonic cell pulverizer at 30% power for 5 minutes (external ice water bath, ultrasonic 1 second stop 1 second), and use the laser particle size analyzer to determine that the light shielding rate of the detector is in the range of 6%-18%, the circulation speed is 2000 revolutions per minute, and the method is checked according to the law. According to the method, the powder coating suspension prepared at a homogenization speed of 1500 rpm was determined for particle size distribution twice, and the results are shown in Figure 5 and Figure 6 The D 50 of the particles in the powder coating suspension was 3.9 μm, and the D 90 was 8.8 μm. In addition, the powder coating suspension prepared at a homogenization speed of 400 rpm was determined for particle size distribution twice according to the method, and the results are shown in Figure 7 and Figure 8 The D 50 of the particles in the powder coating suspension was 50 μm, and the D 90 was 140 μm.

[0238] The dissolution curves and the storage conditions under high humidity of the estradiol valerate sugar-coated tablets prepared in this embodiment are further tested. The results show that the estradiol valerate sugar-coated tablets prepared at the homogenization speeds of 500 rpm, 1500 rpm and 2000 rpm have similar in-vitro dissolution curves to the reference preparation, and after being placed in a high humidity environment for 30 days, these sugar-coated tablets have no significant changes; while the estradiol valerate sugar-coated tablets prepared at the homogenization speeds of 400 rpm and 2500 rpm have obvious cracks after being placed in a high humidity environment for 30 days.

[0239] In summary, by comparing the particle size distribution, viscosity and dispersibility of the powder-coating layer suspensions prepared at different homogenization speeds, and the moisture-proof performance and in-vitro dissolution curves of the sugar-coated tablet preparations obtained therefrom, it can be concluded that the suspensions prepared at the homogenization speeds of 500 rpm to 2000 rpm can be used to prepare sugar-coated tablet preparations with excellent moisture-proof performance and dissolution performance.

[0240] The sugar-coated tablet preparation and the preparation method thereof provided by the present application are described in detail above, and the principles and implementation manners of the present application are described by using specific embodiments in this document, and the above embodiment descriptions are only used to help understand the method of the present application and its core idea; meanwhile, for those skilled in the art, according to the idea of the present application, the specific implementation manners and application ranges will be changed, and in summary, the content of the present description should not be understood as a limitation of the present application.

Claims

1. A sugar-coated tablet preparation, comprising, from the inside out, a core, a hydrophobic layer, a powder coating layer, and an optional coloring layer; The hydrophobic layer comprises a first binder; preferably, the first binder is one or more selected from povidone K90, hydroxypropyl methylcellulose and hydroxypropyl cellulose; more preferably, the first binder is povidone K90; The sub-coat layer comprises a second binder (e.g., one or more selected from povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose), a first structural support material (e.g., one or more selected from sucrose, mannitol, xylitol, and sorbitol), a first plasticizer (e.g., one or more selected from polyethylene glycol, glycerol, propylene glycol, and triethyl citrate, preferably polyethylene glycol 6000), and a first anti-adhesive agent (e.g., talc and / or calcium carbonate, preferably calcium carbonate); The colored layer comprises a second structural support material (for example, one or more selected from sucrose, mannitol, xylitol and sorbitol), a second plasticizer (for example, one or more selected from polyethylene glycol, glycerol, propylene glycol and triethyl citrate, preferably polyethylene glycol 6000), a second anti-adhesive agent (for example, talc and / or calcium carbonate, preferably calcium carbonate), a colorant (for example, one or more selected from yellow iron oxide, red iron oxide and blue iron oxide, preferably yellow iron oxide), and an optional third binder (for example, one or more selected from povidone K90, hydroxypropyl methylcellulose and hydroxypropyl cellulose); Preferably, the tablet core comprises estradiol valerate; preferably, the tablet core further comprises a diluent (e.g., lactose), a disintegrant (e.g., corn starch), a fourth binder (e.g., povidone K25), and a lubricant (e.g., any one of talc and magnesium stearate, or a combination thereof).

2. The sugar-coated tablet preparation according to claim 1, wherein the hydrophobic layer is prepared from a hydrophobic film-forming solution, and the hydrophobic film-forming solution contains 3% to 5% of the first binder based on the weight percentage of the hydrophobic film-forming solution.

3. The sugar-coated tablet preparation according to claim 1 or 2, wherein the powder coating layer is prepared from a first suspension, and the particle size D in the first suspension is 90 The particle size is 5 to 100 μm, preferably 5 to 50 μm, more preferably 5 to 15 μm, and the viscosity of the first suspension is less than 700 mPa·s, preferably 550 to 650 mPa·s; Preferably, the first suspension comprises, by weight percentage of the first suspension: first structural support material: 27% to 60%; Second adhesive: 0.2% to 0.4%; First plasticizer: 2.7% to 4.5%; First anti-adhesive agent: 16% to 26%.

4. The sugar-coated tablet preparation according to any one of claims 1 to 3, wherein the colored layer is prepared from a second suspension, and the particle size D in the second suspension is 90 The particle size is 5 to 100 μm, preferably 5 to 50 μm, more preferably 5 to 15 μm, and the viscosity of the second suspension is less than 700 mPa·S, preferably 550 to 650 mPa·S; Preferably, the second suspension comprises, by weight percentage, Secondary structural support material: 27% to 60%; Third adhesive: 0% to 0.4%; Second plasticizer: 2.7% to 4.5%; Second anti-adhesive agent: 16% to 26%; Colorant: 0.3%~0.5%.

5. The sugar-coated tablet preparation according to any one of claims 1 to 4, wherein the hydrophobic layer accounts for 2% to 5% of the weight of the tablet core, the powder coating layer accounts for 40% to 50% of the weight of the tablet core, and the coloring layer accounts for 60% to 75% of the weight of the tablet core.

6. A method for preparing a sugar-coated tablet preparation, comprising the following steps: 1) Preparation of a hydrophobic film-forming solution for preparing a hydrophobic layer: dissolving a first binder (e.g., one or more selected from the group consisting of povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, preferably povidone K90) in a dispersing solvent (e.g., one or more selected from the group consisting of ethanol, purified water, and glycerol, preferably anhydrous ethanol) under stirring to obtain the hydrophobic film-forming solution; Preferably, the preparation conditions of the hydrophobic film-forming solution are as follows: Dissolving temperature: 20~35℃; Stirring speed: 50rpm~200rpm; Stirring time: 20min~40min; 2) Preparing the first suspension for preparing the powder coating layer: dissolving a first structural support material (e.g., one or more selected from sucrose, mannitol, xylitol, and sorbitol) in boiling water to obtain a first solution; Lowering the temperature of the first solution to 50° C. to 65° C., and sequentially adding a second binder (e.g., one or more selected from povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, preferably povidone K90), a first plasticizer (e.g., one or more selected from polyethylene glycol, glycerol, propylene glycol, and triethyl citrate, preferably polyethylene glycol 6000), and a first anti-adhesive agent (e.g., talc and / or calcium carbonate, preferably calcium carbonate) to the first solution at a stirring speed of 500 rpm to 2000 rpm, thereby obtaining a first intermediate suspension; The temperature of the first intermediate suspension is maintained at 50° C. to 65° C., and the first intermediate suspension is homogenized at a homogenization speed of 500 rpm to 2000 rpm (preferably 1800 rpm) for 20 min to 40 min to obtain a first suspension; preferably, the particle size D in the first suspension is 90 The particle size is 5 to 100 μm, preferably 5 to 50 μm, more preferably 5 to 15 μm, and the viscosity of the first suspension is less than 700 mPa·s, preferably 550 to 650 mPa·s; 3) Preparation of sugar-coated tablets: a) coating the tablet core with the hydrophobic film-forming solution to form a hydrophobic layer on the outer surface of the tablet core; b) coating the tablet core having a hydrophobic layer formed on the outer surface with the first suspension to further form a subbing layer on the outer surface of the hydrophobic layer; Preferably, the tablet core comprises estradiol valerate, and preferably further comprises a diluent (such as lactose), a disintegrant (such as corn starch), a fourth binder (such as povidone K25), and a lubricant (such as any one of talc and magnesium stearate or a combination thereof).

7. The method according to claim 6, further comprising: 4) Preparation of the second suspension for preparing the colored layer: dissolving a second structural support material (e.g., one or more selected from sucrose, mannitol, xylitol, and sorbitol) in boiling water to obtain a second solution; Lowering the temperature of the second solution to 50° C. to 65° C., and sequentially adding a second plasticizer (e.g., one or more selected from polyethylene glycol, glycerol, propylene glycol, and triethyl citrate, preferably polyethylene glycol 6000), a second anti-adherent (e.g., talc and / or calcium carbonate, preferably calcium carbonate), a colorant (e.g., one or more selected from yellow iron oxide, red iron oxide, and blue iron oxide, preferably yellow iron oxide), and an optional third binder (e.g., one or more selected from povidone K90, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, preferably povidone K90) to the second solution at a stirring speed of 500 rpm to 2000 rpm to obtain a second intermediate suspension; maintaining the temperature of the second intermediate suspension at 50° C. to 65° C. and homogenizing the second intermediate suspension at a homogenization speed of 500 rpm to 2000 rpm (preferably 1800 rpm) for 20 min to 40 min to obtain a second suspension; and The method further comprises, in step 3) preparing the sugar-coated tablet preparation: c) coating the tablet core having a hydrophobic layer and a subcoating layer formed on the outer surface thereof with the second suspension to further form a colored layer on the outer surface of the subcoating layer; Preferably, the particle size D in the second suspension is 90 The particle size is 5 to 100 μm, preferably 5 to 50 μm, more preferably 5 to 15 μm. The viscosity of the first suspension is less than 700 mPa·S, preferably 550 to 650 mPa·S.

8. The method according to claim 6 or 7, wherein: The hydrophobic film-forming solution comprises 3% to 5% of the first binder in terms of weight percentage of the hydrophobic film-forming solution; Measured by weight percentage of the first suspension, the first suspension comprises: First structural support material: 27% to 60%; Second adhesive: 0.2% to 0.4%; First plasticizer: 2.7% to 4.5%; First anti-adhesive agent: 16% to 26%; Calculated by weight percentage of the second suspension, the second suspension comprises: Secondary structural support material: 27% to 60%; Third adhesive: 0% to 0.4%; Second plasticizer: 2.7% to 4.5%; Second anti-adhesive agent: 16% to 26%; Colorant: 0.3%~0.5%.

9. The method according to any one of claims 6 to 8, wherein the hydrophobic layer, the subcoat layer and the coloring layer are each applied independently, wherein: Based on the weight of the core tablet, the weight gain of the hydrophobic layer is 2% to 5%, the weight gain of the powder coating layer is 40% to 50%, and the weight gain of the coloring layer is 60% to 75%.

10. The method according to any one of claims 6 to 9, wherein the sugar-coated tablet preparation is the sugar-coated tablet preparation according to any one of claims 1 to 5.

Images