Compound sulfate solid formulation for intestinal tract cleaning and preparation method therefor and use thereof

Abstract

A compound sulfate solid formulation for intestinal tract cleaning and a preparation method therefor and use thereof. Provided is a brand-new compound sulfate solid formulation. This novel solid formulation effectively addresses the technical challenges associated with existing sulfate solid formulations, such as poor compressibility (difficulty in tablet formation, sticking, capping, and laminating), poor fluidity, high friability, and significant tablet weight variation, and meanwhile it has at least one or more of the following advantages: easy swallowing and good compliance; good taste; fast disintegration and fast onset of action with fewer adverse reactions; the ability to simultaneously address intestinal foam and solution turbidity issues; stable product quality; simple and stable process, being suitable for industrial large-scale continuous production, and free of process defects such as oil spots.

Description

A compound sulfate solid preparation for intestinal cleansing, and its preparation method and use

[0001] This application claims the benefit of Chinese patent application No. 2023118677078, filed December 30, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of pharmaceutical preparations, in particular to the field of pharmaceutical preparations for intestinal cleansing before colonoscopy, and specifically relates to a novel compound sulfate solid preparation and a preparation method and use thereof. Background Art

[0003] Colonoscopy is considered a highly effective method for early detection of colorectal cancer (CRC) and removal of precancerous polyps, significantly reducing CRC morbidity and mortality. Adequate bowel cleansing is crucial for examining the entire colonic mucosa during colonoscopy. Inadequate bowel preparation reduces adenoma detection rates and increases the risk of post-colonoscopy complications and procedural duration.

[0004] Currently, a variety of laxatives have been developed to improve the effect of intestinal cleansing, including 4L high-volume polyethylene glycol (PEG) and 2L low-volume PEG + ascorbic acid (ASC). Both PEG-based preparations still require patients to drink 3 to 4L of solution. Therefore, the availability of small-volume preparations is very important for intestinal cleansing. Oral sulfate solution (OSS) with less water intake has similar safety and efficacy to 4L PEG or 2L PEG / ASC drugs, and has shorter withdrawal time and total examination time. However, the high concentration of sulfate in oral sulfate solution (OSS) has a significant pungent taste, poor taste, and poor patient tolerance.

[0005] Based on this, oral sulfate tablets (OST) were developed. OST is comparable to OSS in terms of intestinal cleansing effect. Since OST is a film-coated tablet, it can be swallowed directly with water when used, avoiding the pungent taste of OSS's high concentration of sulfate and showing better tolerance. Currently, there are two types of oral sulfate tablets (OST) commonly used on the market, namely (Braintree Laboratories Inc, USA) and (South Korea, Pharmbio Korea Inc.) However, existing OST tablets have many shortcomings: (1) The tablet size is large and the compliance is poor. Up to 9*18mm, 2g / tablet, 12 tablets per oral dose; The tablet is 8.2*17.2mm long, 1.5g / tablet, and 14 tablets are taken orally at one time. The large size makes it difficult to swallow; some patients crush and chew the tablets in order to swallow them, resulting in a poor taste and poor compliance. (2) There are technical difficulties such as poor compressibility (difficult to compress into tablets, sticking to the punch, top cracking, waist cracking), poor fluidity, easy to break, and large tablet weight variation. Since the main component of oral sulfate tablets (OST) is inorganic salt, and the content accounts for a large proportion, the compressibility of the material is poor. During tableting, problems such as top cracking and waist cracking frequently occur. The upper half of the tablet separates from the main body and falls off as a cover, or the tablet splits into horizontal layers and peels off. In addition, the powder of the tablet is prone to sticking to the punch surface, resulting in defects on the tablet surface; poor fluidity, large tablet weight variation; and the large tablets produced are easy to break, which is not conducive to coating. (3) Slow disintegration, slow onset of effect, and large side effects. Due to the long disintegration time of oral sulfate (OST) tablets on the market, the dissolution rate of sulfate in the body is slow, which prolongs the time of defecation; on the other hand, sulfate tablets are easy to accumulate in the stomach, causing local irritation to the gastric mucosa, which may cause gastric distension, erosive gastritis / gastric ulcers. (4) It is impossible to solve the problems of intestinal foam and solution turbidity. During the endoscopic examination, there is a 32% to 57% chance of encountering foam. The existing marketed preparations There is no defoaming effect after disintegration, although the preparation The addition of simethicone can improve the foam to a certain extent, but the solution has high turbidity after dissolution, which may affect the observation of the gastrointestinal mucosa and lesions.

[0006] Therefore, there is an urgent need for a new solid preparation that solves as many of the above problems as possible (preferably solving the above problems simultaneously), aiming to better improve patient compliance, solve the long-standing technical problems of this type of preparation such as compressibility, flowability, friability, reproducibility, etc., increase the disintegration rate, enhance the intestinal cleansing ability, reduce adverse reactions, and reduce intestinal foam and turbidity problems. Summary of the Invention

[0007] In order to improve the above problems, research on small-sized traditional tablets was conducted in the early stage. However, it was found during the research process that many problems such as cracking, capping, adhesion, poor compressibility, poor friability, and large differences in tablet weight still frequently occurred.

[0008] The inventors were the first to discover that the novel solid preparation containing dimethicone and colloidal silicon dioxide of the present invention can effectively solve the technical problems of existing sulfate solid preparations, such as poor compressibility (difficult to compress into tablets, sticking, top cracking, waist cracking), poor fluidity, brittleness, and large tablet weight differences. At the same time, it also has one or more of the following advantages: easy to swallow and good compliance; good taste; rapid disintegration, rapid onset, and few adverse reactions; can solve the problems of intestinal foam and solution turbidity; stable product quality; simple and stable process, which can be industrialized for large-scale continuous production; no process defects such as oil spots; and better can solve the above problems at the same time.

[0009] In view of this, the present invention provides a novel compound sulfate solid preparation, which comprises the following components: anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone and colloidal silicon dioxide.

[0010] In one embodiment of the present invention, the mass ratio of dimethicone to colloidal silica is 1:1 to 30:1; preferably, the mass ratio of dimethicone to colloidal silica is 3:1 to 25:1; more preferably, the mass ratio of dimethicone to colloidal silica is 5:1 to 21:1; most preferably, the mass ratio of dimethicone to colloidal silica is 8:1 to 15:1; for example, the mass ratio of dimethicone to colloidal silica is 5:1, 10:1 or 21:1.

[0011] In a certain embodiment of the present invention, the combined weight percentage of dimethicone and colloidal silica in the solid preparation (if coated, calculated relative to the uncoated preparation) is 0.05% to 5%; preferably, the combined weight percentage of dimethicone and colloidal silica (if coated, calculated relative to the uncoated preparation) is 0.1% to 2.1%; more preferably, the combined weight percentage of dimethicone and colloidal silica (if coated, calculated relative to the uncoated preparation) is 0.6% to 1.5%; most preferably, the combined weight percentage of dimethicone and colloidal silica (if coated, calculated relative to the uncoated preparation) is 1.0% to 1.2%; for example, the combined weight percentage of dimethicone and colloidal silica (if coated, calculated relative to the uncoated preparation) is 1.1%.

[0012] In one embodiment of the present invention, the weight percentage of the components in the solid preparation (if coated, relative to the uncoated preparation) is: 50.0% to 95.0% of anhydrous sodium sulfate, preferably 60.0% to 90.0%, more preferably 65.0% to 85.0%, and most preferably 70.0% to 80.0%, for example 72%, 73%, 74%, 74.2%, 75% or 76%.

[0013] In one embodiment of the present invention, the weight percentage of the components in the solid preparation (if coated, relative to the uncoated preparation) is: anhydrous magnesium sulfate 5.0% to 20.0%, preferably 7.0% to 15.0%, more preferably 8.0% to 14.0%, most preferably 9.0% to 13.0%, for example 10%, 11%, 11.2% or 12%.

[0014] In one embodiment of the present invention, the weight percentage of the components in the solid preparation (if coated, calculated relative to the uncoated preparation) is: potassium chloride 5.0% to 20.0%, preferably 7.0% to 12.0%, more preferably 8.0% to 11.0%, and further preferably 9.0% to 10.0%, for example 9.3%, 9.4% or 9.5%.

[0015] In one embodiment of the present invention, the weight percentage of the components in the solid preparation (if coated, relative to the uncoated preparation) is: dimethicone 0.1% to 3.0%, preferably 0.4% to 1.8%, more preferably 0.6% to 1.6%, most preferably 0.8% to 1.5%, for example 0.9%, 0.92%, 1%, 1.05%, 1.1% or 1.2%.

[0016] In one embodiment of the present invention, the weight percentage of the components in the solid preparation (if coated, calculated relative to the uncoated preparation) is: colloidal silicon dioxide 0.005% to 1.0%, preferably 0.01% to 0.4%, more preferably 0.02% to 0.2%, most preferably 0.04% to 0.15%, for example 0.05%, 0.1%, 0.12%, 0.14%, 0.16% or 0.18%.

[0017] In one embodiment of the present invention, the weight percentage of each component in the solid preparation (i.e., the weight percentage of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone and colloidal silicon dioxide in the solid preparation) (if coated, calculated relative to the uncoated preparation) is: anhydrous sodium sulfate 50.0% to 95.0%, anhydrous magnesium sulfate 5.0% to 20.0%, potassium chloride 5.0% to 20.0%, and dimethicone and colloidal silicon dioxide 0.05% to 5% (calculated based on the total weight of dimethicone and colloidal silicon dioxide); preferably, the solid preparation The weight percentage of each component (if coated, based on the uncoated preparation) is: anhydrous sodium sulfate 60.0% to 90.0%, anhydrous magnesium sulfate 7.0% to 15.0%, potassium chloride 7.0% to 12.0%, and dimethicone and colloidal silicon dioxide 0.1% to 2.1% (based on the total weight of dimethicone and colloidal silicon dioxide); More preferably, the weight percentage of each component in the solid preparation (if coated, based on the uncoated preparation) is: anhydrous sodium sulfate 65.0% to 85.0%, anhydrous magnesium sulfate 8.0% to 14.0%, potassium chloride 8 .0% to 11.0%, and 0.6% to 1.5% of dimethicone and colloidal silicon dioxide (based on the total weight of dimethicone and colloidal silicon dioxide); most preferably, the weight percentage of each component in the solid preparation (if coated, based on the uncoated preparation) is: anhydrous sodium sulfate 70.0% to 80.0%, anhydrous magnesium sulfate 9.0% to 13.0%, potassium chloride 9.0% to 10.0%, and 1.0% to 1.2% of dimethicone and colloidal silicon dioxide (based on the total weight of dimethicone and colloidal silicon dioxide); for example, the components in the solid preparation are The weight percentages of the components in the solid preparation (if coated, calculated relative to the uncoated preparation) are: 74.2% anhydrous sodium sulfate, 11% anhydrous magnesium sulfate, 9.4% potassium chloride, and 1.1% dimethicone and colloidal silicon dioxide (calculated based on the total weight of dimethicone and colloidal silicon dioxide) or the weight percentages of the components in the solid preparation (if coated, calculated relative to the uncoated preparation) are: 74% anhydrous sodium sulfate, 11.2% anhydrous magnesium sulfate, 9.4% potassium chloride, and 1.1% dimethicone and colloidal silicon dioxide (calculated based on the total weight of dimethicone and colloidal silicon dioxide).

[0018] In one embodiment of the present invention, the sum of the weight percentages of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone and colloidal silicon dioxide in the solid preparation (if coated, calculated relative to the uncoated preparation) is less than or equal to 100%.

[0019] In one embodiment of the present invention, the solid preparation further comprises a water-soluble lubricant and / or a water-soluble adhesive; preferably, the weight percentage of the water-soluble lubricant and / or the water-soluble adhesive (if coated, calculated relative to the uncoated preparation) is: 0.5% to 2.5% of the water-soluble lubricant and / or 1.0% to 5.0% of the water-soluble adhesive; more preferably, the weight percentage of the water-soluble lubricant and / or the water-soluble adhesive (if coated, calculated relative to the uncoated preparation) is: 1.0% to 2.0% of the water-soluble lubricant and / or 2.0% to 3.0% of the water-soluble adhesive; for example, the weight percentage of the water-soluble lubricant (if coated, calculated relative to the uncoated preparation) is 1.5% and / or the weight percentage of the water-soluble adhesive (if coated, calculated relative to the uncoated preparation) is 2.8%.

[0020] In one embodiment of the present invention, the solid preparation further includes a water-soluble adhesive but does not include a water-soluble lubricant; preferably, the weight percentage of the water-soluble adhesive (if coated, calculated relative to the uncoated preparation) is 1.5% to 7.5%; more preferably, the weight percentage of the water-soluble adhesive (if coated, calculated relative to the uncoated preparation) is 3.0% to 5.0%; for example, the weight percentage of the water-soluble adhesive (if coated, calculated relative to the uncoated preparation) is 4.3%.

[0021] In one embodiment of the present invention, the water-soluble lubricant is selected from one or more of sodium octanoate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, polyoxyethylene monostearate and polyoxyethylene lauryl alcohol.

[0022] In one embodiment of the present invention, the water-soluble binder is selected from one or more of polyethylene glycol (polyethylene glycol 3350 / 4000 / 6000 / 8000), hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, carboxymethyl cellulose and sodium alginate, such as polyethylene glycol 4000.

[0023] In one embodiment of the present invention, the sum of the weight percentages of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone, colloidal silica, water-soluble lubricant and water-soluble adhesive (if coated, calculated relative to the uncoated formulation) is less than or equal to 100%.

[0024] In one embodiment of the present invention, the sum of the weight percentages of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone, colloidal silica and water-soluble binder (if coated, calculated relative to the uncoated formulation) is less than or equal to 100%.

[0025] In one embodiment of the present invention, the non-coating components of the solid preparation are composed of the anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone, colloidal silicon dioxide, a water-soluble lubricant and a water-soluble adhesive.

[0026] In one embodiment of the present invention, the non-coating components of the solid preparation are composed of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone, colloidal silicon dioxide and a water-soluble binder.

[0027] In one embodiment of the present invention, the solid preparation further comprises a water-soluble film coating.

[0028] In one embodiment of the present invention, the water-soluble coating layer is one or more of polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, acrylic resin, polyvinyl acetal diethylamino acetate, and polyethylene glycol.

[0029] In one embodiment of the present invention, the water-soluble film coating is

[0030] In one embodiment of the present invention, the mass percentage of the water-soluble coating layer relative to the uncoated preparation is 0.1wt% to 5.0wt%; more preferably, the mass percentage of the water-soluble film coating relative to the uncoated preparation is 1.0wt% to 3.0wt%.

[0031] In one embodiment of the present invention, the solid preparation is a spherical solid preparation.

[0032] In one embodiment of the present invention, the size of the spherical solid preparation is 2 to 10 mm; preferably, the size of the spherical solid preparation is 3 to 9 mm; more preferably, the size of the spherical solid preparation is 4 to 8 mm; further preferably, the size of the spherical solid preparation is 5 to 8 mm (e.g., 5 to 7 mm).

[0033] In one embodiment of the present invention, the spherical solid preparation may or may not contain an intermediate zone.

[0034] In one embodiment of the present invention, the spherical solid preparation comprises a middle zone; the diameter of the middle zone is 2 to 10 mm; more preferably, the diameter of the middle zone is 3 to 9 mm; further preferably, the diameter of the middle zone is 4 to 8 mm; most preferably, the diameter of the middle zone is 5 to 8 mm (e.g., 5 to 7 mm, 6.5 mm);

[0035] In a certain embodiment of the present invention, the hemisphere diameter of the spherical solid preparation is 2 to 10 mm; preferably, the hemisphere diameter of the spherical solid preparation is 3 to 9 mm; preferably, the hemisphere diameter of the spherical solid preparation is 4 to 8 mm; more preferably, the hemisphere diameter of the spherical solid preparation is 5 to 8 mm (e.g., 5 to 7 mm, 6.5 mm).

[0036] In one embodiment of the present invention, the spherical solid preparation comprises a middle band and an edge (i.e., the portion of the middle band protruding relative to the hemisphere), and the cross-sectional width of the edge (i.e., the difference between the diameter of the middle band and the diameter of the hemisphere) is 0.1 to 2 mm; more preferably, the cross-sectional width of the edge is 0.1 to 1 mm; further preferably, the cross-sectional width of the edge is 0.1 to 0.5 mm; for example, the cross-sectional width of the edge is 0.20 mm or 0.16 mm.

[0037] In one embodiment of the present invention, the spherical solid preparation comprises an intermediate zone, and the thickness of the intermediate zone is 1 to 5 mm; preferably, the thickness of the intermediate zone is 1.5 to 4.5 mm; more preferably, the thickness of the intermediate zone is 2 to 4 mm; for example, the thickness of the intermediate zone is 2.5 mm or 3 mm.

[0038] In one embodiment of the invention, the arc depth of the spherical solid preparation is 1 to 5 mm; preferably, the arc depth is 1.5 to 4.5 mm; more preferably, the arc depth is 1.8 to 2.2 mm or the arc depth is 2 to 4 mm; for example, the arc depth is 1.80 mm or 2.04 mm.

[0039] In one embodiment of the present invention, the arc depth / hemispherical diameter ratio of the upper and lower punches of the mold used for compressing the spherical solid preparation is 0.2 to 0.5; more preferably, the arc depth / hemispherical diameter ratio is 0.2 to 0.4; most preferably, the arc depth / hemispherical diameter ratio is 0.2 to 0.3; for example, the arc depth / hemispherical diameter ratio is 0.29 and 0.3.

[0040] In the present invention, the arc depth is the longitudinal depth of the hemisphere.

[0041] In a certain embodiment of the present invention, the intermediate belt is in the shape of a belt with substantially the same thickness; preferably, the intermediate belt is in the shape of a belt with substantially the same thickness.

[0042] In one embodiment of the present invention, the cross-section of the spherical solid preparation is circular or quasi-circular; preferably, the cross-section of the spherical solid preparation is circular.

[0043] In one embodiment of the present invention, the spherical solid preparation is a pill or a spherical tablet.

[0044] In one embodiment of the present invention, the spherical solid preparation is a spherical tablet.

[0045] In the present invention, the spherical tablet comprises an upper and lower hemisphere and an intermediate zone, wherein the intermediate zone is located in the middle of the spherical tablet and is in the shape of a band with substantially the same thickness; the upper and lower hemispheres are located on the two end surfaces of the intermediate zone, and the two hemispheres are substantially the same in size and shape; and the diameter of the intermediate zone is greater than the diameter of the hemispheres.

[0046] In one embodiment of the present invention, the diameter of the middle zone of the spherical piece is 2 to 10 mm; more preferably, the diameter of the middle zone is 3 to 9 mm; further preferably, the diameter of the middle zone is 4 to 8 mm; most preferably, the diameter of the middle zone is 5 to 8 mm (e.g., 5 to 7 mm or 6.5 mm);

[0047] In one embodiment of the present invention, the hemispherical diameter of the spherical tablet is 2 to 10 mm; preferably, the hemispherical diameter of the spherical tablet is 3 to 9 mm; preferably, the hemispherical diameter of the spherical tablet is 4 to 8 mm; more preferably, the hemispherical diameter of the spherical tablet is 5 to 8 mm (for example, 5 to 7 mm or 6.5 mm).

[0048] In one embodiment of the present invention, the spherical piece includes a middle band and an edge (i.e., the portion of the middle band protruding relative to the hemisphere), and the cross-sectional width of the edge (i.e., the difference between the diameter of the middle band and the diameter of the hemisphere) is 0.1 to 2 mm; more preferably, the cross-sectional width of the edge is 0.1 to 1 mm; further preferably, the cross-sectional width of the edge is 0.1 to 0.5 mm; for example, the cross-sectional width of the edge is 0.20 mm or 0.16 mm.

[0049] In one embodiment of the present invention, the thickness of the middle zone of the spherical piece is 1 to 5 mm; preferably, the thickness of the middle zone is 1.5 to 4.5 mm; more preferably, the thickness of the middle zone is 2 to 4 mm; for example, the thickness of the middle zone is 2.5 mm or 3 mm.

[0050] In one embodiment of the invention, the arc depth of the spherical piece is 1-5 mm; preferably, the arc depth is 1.5-4.5 mm; more preferably, the arc depth is 1.8-2.2 mm or the arc depth is 2-4 mm; for example, the arc depth is 1.80 mm or 2.04 mm.

[0051] In one embodiment of the present invention, the arc depth / hemispherical diameter ratio of the upper and lower punches of the tableting mold used for tableting the spherical tablets is 0.2 to 0.5; more preferably, the arc depth / hemispherical diameter ratio is 0.2 to 0.4; most preferably, the arc depth / hemispherical diameter ratio is 0.2 to 0.3; for example, the arc depth / hemispherical diameter ratio is 0.29 or 0.3.

[0052] In one embodiment of the present invention, the spherical solid preparation is a pill, and the size of the pill is 2 to 10 mm; preferably, the size of the pill is 3 to 9 mm; preferably, the size of the pill is 4 to 8 mm; more preferably, the size of the pill is 5 to 8 mm (e.g., 5 to 7 mm or 6.5 mm).

[0053] In a certain embodiment of the present invention, the weight of the solid preparation per unit solid preparation is 50 to 600 mg; preferably, the weight of the solid preparation per unit solid preparation is 100 to 500 mg; more preferably, the weight of the solid preparation per unit solid preparation is 150 to 400 mg; further preferably, the weight of the solid preparation per unit solid preparation is 200 to 400 mg, and most preferably, the weight of the solid preparation per unit solid preparation is 350 to 400 mg (e.g., 200 to 375 mg).

[0054] In one embodiment of the present invention, the solid preparation does not contain a disintegrant.

[0055] In one embodiment of the present invention, the solid preparation is prepared by dry granulation or direct tableting.

[0056] In one embodiment of the present invention, no water is added during the preparation of the solid preparation.

[0057] In one embodiment of the present invention, colloidal silicon dioxide and dimethicone composition are prepared separately during the preparation of the solid preparation.

[0058] In one embodiment of the present invention, colloidal silicon dioxide and dimethicone are added in the form of a composition during the preparation of the solid preparation.

[0059] In one embodiment of the present invention, during the preparation of the solid preparation, colloidal silicon dioxide and dimethicone are mixed and then mixed with other components.

[0060] In one embodiment of the present invention, during the preparation of the solid preparation, dimethicone is sprayed separately onto other materials for mixing.

[0061] In one embodiment of the present invention, the solid preparation is administered orally.

[0062] The present invention provides a method for preparing a solid preparation. The solid preparation is prepared by dry granulation tableting or direct tableting.

[0063] In one embodiment of the present invention, the method for preparing the solid preparation comprises the following steps:

[0064] (1) sieving anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride; preferably, the mesh size is 20-80 mesh, more preferably 20-60 mesh, and further preferably 20-40 mesh, for example, 40 mesh;

[0065] (2) mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride with a water-soluble binder to obtain a mixture I;

[0066] (3) mixing colloidal silica and dimethicone to obtain a mixture II;

[0067] (4) mixing mixture I with mixture II to obtain mixture III;

[0068] (5) adding a water-soluble lubricant to the mixture III and mixing them to obtain a mixture IV;

[0069] (6) Using a tabletting die, compress the mixture IV into tablets, and optionally coat the tablets to obtain the product.

[0070] In one embodiment of the present invention, the method for preparing the solid preparation comprises the following steps:

[0071] (1) sieving anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride; preferably, the mesh size is 20-80 mesh, more preferably 20-60 mesh, and further preferably 20-40 mesh, for example, 40 mesh;

[0072] (2) mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride with a water-soluble binder to obtain a mixture I;

[0073] (3) mixing colloidal silica and dimethicone to obtain a mixture II;

[0074] (4) mixing mixture I with mixture II to obtain mixture III;

[0075] (5) Using a tabletting die, compress the mixture III into tablets, and optionally coat the tablets to obtain the product.

[0076] In one embodiment of the present invention, the method for preparing the solid preparation comprises the following steps:

[0077] (1) sieving anhydrous sodium sulfate and anhydrous magnesium sulfate, preferably with a mesh size of 20-80 mesh, more preferably 20-60 mesh, further preferably 20-40 mesh, for example 40 mesh;

[0078] (2) detecting the particle size distribution of anhydrous sodium sulfate, crushing potassium chloride, and screening potassium chloride material with a particle size distribution similar to that of anhydrous sodium sulfate;

[0079] (3) crushing the water-soluble adhesive and sieving it;

[0080] (4) mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride to obtain a mixture I;

[0081] (5) adding a water-soluble binder and colloidal silica to the mixture I and mixing to obtain a mixture II;

[0082] (6) using a spray gun to spray dimethicone into the mixture II, and granulating to obtain a mixture III;

[0083] (7) sieving the mixture III;

[0084] (8) After granulation, the mixture is mixed in a mixing tank to obtain mixture IV;

[0085] (9) Using a tabletting die, compress the mixture IV into tablets, and optionally coat the tablets to obtain the product.

[0086] In one embodiment of the present invention, the method for preparing the solid preparation comprises the following steps:

[0087] (1) sieving anhydrous sodium sulfate and anhydrous magnesium sulfate, wherein the mesh size of the sieve is 20-80 mesh, more preferably 20-60 mesh, and further preferably 20-40 mesh, for example 40 mesh;

[0088] (2) detecting the particle size distribution of anhydrous sodium sulfate, crushing potassium chloride, and screening potassium chloride material with a particle size distribution similar to that of anhydrous sodium sulfate;

[0089] (3) crushing the water-soluble adhesive and sieving it;

[0090] (4) mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride to obtain a mixture I;

[0091] (5) adding a water-soluble binder and colloidal silica to the mixture I and mixing to obtain a mixture II;

[0092] (6) using a spray gun to spray dimethicone into the mixture II, and granulating to obtain a mixture III;

[0093] (7) sieving the mixture III;

[0094] (8) After granulation, the mixture is mixed in a mixing tank to obtain mixture IV;

[0095] (9) adding the water-soluble lubricant mixture to obtain a mixture V;

[0096] (10) Using a tabletting die, the mixture V is compressed into tablets, and optionally coated.

[0097] In a certain embodiment of the present invention, the hemispherical diameter of the upper and lower dies of the tableting mold used during tableting is 2 to 10 mm, and the arc depth / hemisphere diameter ratio is 0.2 to 0.5; preferably, the hemispherical diameter is 3 to 9 mm, and the arc depth / hemisphere diameter ratio is 0.2 to 0.5; more preferably, the hemispherical diameter is 4 to 8 mm, and the arc depth / hemisphere diameter ratio is 0.2 to 0.4; most preferably, the hemispherical diameter is 5 to 8 mm (for example, 5 to 7 mm), and the arc depth / hemisphere diameter ratio is 0.2 to 0.3.

[0098] In the present invention, the hemispherical diameter of the upper and lower punches of the tabletting mold refers to the diameter of the outermost edge of the punch.

[0099] The present invention provides a mixture containing anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride, dimethicone and colloidal silicon dioxide for preparing the solid preparation of the present invention, mixture III or mixture IV in the preparation method of the present invention, or mixture IV or mixture V in the preparation method of the present invention.

[0100] In one embodiment of the present invention, the mixture comprises particles of anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride, wherein the weight proportion of particles with a particle size of less than 125 μm is in the range of 1% to 20%, more preferably in the range of 4% to 18%, and even more preferably in the range of 7% to 15%, as determined by sieve analysis, and the weight proportion of particles with a particle size of 125 μm to 150 μm is in the range of 3% to 17%, more preferably in the range of 5% to 15%, and even more preferably in the range of 7% to 13%, and the weight proportion of particles with a particle size of 150 μm to 180 μm is in the range of 10% to 28%, more preferably in the range of 12% to 25%, and even more preferably in the range of 14% to 22%, and the weight proportion of particles with a particle size of 180 μm to 250 μm is in the range of 10% to 28%, more preferably in the range of 12% to 25%, and even more preferably in the range of 14% to 22%. % and 0.1 % respectively, based on the total weight of the particles.

[0101] In one embodiment of the present invention, the upper and lower punches of the tableting die used in tableting are hemispherical.

[0102] In one embodiment of the present invention, no water is added during the preparation of the solid preparation.

[0103] In one embodiment of the present invention, the solid preparation has an intestinal cleansing effect.

[0104] The present invention provides a use of the solid preparation or the solid preparation prepared by the preparation method in preparing a pharmaceutical preparation for intestinal cleansing.

[0105] The present invention provides the above solid preparation for intestinal cleansing or the solid preparation prepared by the above preparation method.

[0106] The present invention provides the solid preparation or the solid preparation prepared by the preparation method for intestinal cleansing.

[0107] Unless otherwise specified, the terms used in this application have the following definitions. Definitions of terms not mentioned below are as commonly understood by those skilled in the art to which the present invention belongs.

[0108] Definition of terms

[0109] "Spherical": The shape is spherical or spherical.

[0110] “Spherical solid dosage form”: a solid dosage form that is “spherical” in appearance and has a circular or quasi-circular cross-section; it may or may not contain a central zone;

[0111] “Middle band”: a band with substantially the same thickness located in the middle of the spherical solid preparation, as shown in FIG1 .

[0112] "Spherical tablets": "spherical" tablets containing a central zone.

[0113] "Hemisphere diameter" (i.e., the diameter of the cross section of the hemisphere; if it is quasi-circular, it is the maximum diameter of the cross section; the hemisphere diameter of the die is the diameter of the outermost edge of the die, i.e., the diameter of the middle zone of the solid preparation), "middle zone thickness" (i.e., the longitudinal height of the middle zone), "middle zone diameter" (i.e., the diameter of the cross section of the middle zone; if it is quasi-circular, it is the maximum diameter of the cross section), "arc depth" (i.e., the longitudinal depth of the hemisphere), "edge" (i.e., the part of the middle zone protruding relative to the hemisphere), and "cross-sectional width of the edge" (i.e., the difference between the diameter of the middle zone and the diameter of the hemisphere): as shown in Figure 1.

[0114] "Solid dosage form": may or may not be coated.

[0115] “Weight percentage”: If the solid preparation contains a coating, it shall be calculated based on the uncoated preparation.

[0116] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0117] The reagents and raw materials used in the present invention are commercially available.

[0118] Compared with the prior art, the present invention has the following beneficial effects:

[0119] (1) The present invention provides a novel compound sulfate solid preparation, which can effectively solve the long-standing technical problems of sulfate solid preparations, such as poor compressibility (difficult to compress into tablets, sticking, cracking, and splitting), poor fluidity, brittleness, and large differences in tablet weight. The prepared material has good fluidity and compressibility, no cracking, splitting, or sticking, high hardness, strong shock and wear resistance, small differences in tablet weight, which is conducive to subsequent operations such as coating, and good uniformity and reproducibility.

[0120] (2) The novel compound sulfate solid preparation of the present invention does not have the bad taste problem associated with liquid preparations and has a good taste. Compared with conventional sulfate tablets, the size is greatly reduced, the tablet design has a regular shape, good fluidity, and is easy to swallow, which can solve the problem of dysphagia. Compared with ordinary tablets of the same diameter, it is easier to swallow and requires a smaller dosage. Moreover, the geometric shape is similar to that of small candies, which can bring a certain degree of psychological suggestion to patients, making it easy for patients to accept and improve compliance.

[0121] (3) The novel compound sulfate solid preparation of the present invention can effectively shorten the disintegration time, has a rapid onset of action, reduces the residence time in the stomach, and reduces adverse reactions such as gastric ulcers and flatulence.

[0122] (4) The novel compound sulfate solid preparation of the present invention can simultaneously solve the problems of intestinal foam and solution turbidity, which is beneficial to the clarity of vision, improves the efficiency of colonoscopy, shortens the observation time, reduces the pain of patients, and overcomes the shortcomings of existing marketed preparations.

[0123] (5) The novel compound sulfate solid preparation of the present invention has stable product quality, and there is no significant change in long-term storage properties, ion content, disintegration time, and dissolution rate.

[0124] (6) The novel compound sulfate solid preparation of the present invention has a simple and stable process, can be industrialized and mass-produced, and is free of process defects such as oil spots. Furthermore, water can be omitted during the preparation process, which further facilitates the stability of the preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0125] FIG1 is a schematic diagram of a spherical preparation of the present invention.

[0126] FIG2 is a schematic diagram of a spherical preparation of the present invention.

[0127] FIG3 is an appearance diagram of the spherical preparation of the present invention (Example 1) and conventional tablets (Comparative Examples 6 and 7).

[0128] Figure 4 The preparation of the present invention (Example 1) and the marketed preparation Appearance picture.

[0129] Figure 5 The preparation of the present invention (Example 6) and the marketed preparation Appearance picture.

[0130] Figure 6 The preparation of the present invention (Example 1) and the marketed preparation Diagram of defoaming effect and clarity of solution after disintegration.

[0131] Figure 7 The preparation of the present invention (Example 6) and the marketed preparation Diagram of defoaming effect and clarity of solution after disintegration. DETAILED DESCRIPTION

[0132] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are only intended to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0133] [Example 1]

[0134] The spherical tablets are prepared by direct compression, comprising the following steps:

[0135] Preprocessing:

[0136] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride with a sieve size of 20 to 40 meshes.

[0137] mix:

[0138] ① Mix sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, pour them into a high shear mixing granulator in sequence, and mix for 20 minutes to obtain mixture I;

[0139] ② mixing colloidal silica and dimethicone to obtain a mixture II;

[0140] ③ Mixing mixture I with mixture II to obtain mixture III;

[0141] ④ Sodium octanoate was added to mixture III and mixed for 20 minutes to obtain mixture IV;

[0142] ⑤ Check the angle of repose, bulk density, and particle size distribution of mixture IV.

[0143] Tablet pressing:

[0144] ① In a tablet press, use a tableting die with hemispherical upper and lower dies, a hemispherical diameter of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3 to compress mixture IV into tablets;

[0145] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0146] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0147] Film coating:

[0148] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0149] ② Check the tablet disintegration time.

[0150] [Example 2-3]

[0151] The specific preparation method is as follows:

[0152] Preprocessing:

[0153] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride with a sieve size of 20 to 40 meshes.

[0154] mix:

[0155] ① Mix sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, pour them into a high shear mixing granulator in sequence, and mix for 20 minutes to obtain mixture I;

[0156] ② mixing colloidal silica and dimethicone to obtain a mixture II;

[0157] ③ Mixing mixture I with mixture II to obtain mixture III;

[0158] ④ Sodium octanoate was added to mixture III and mixed for 20 minutes to obtain mixture IV;

[0159] ⑤ Check the angle of repose, bulk density, and particle size distribution of mixture IV.

[0160] Tablet pressing:

[0161] ① In a tablet press, use a tableting die with hemispherical upper and lower dies, a hemispherical diameter of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3 to compress mixture IV into tablets;

[0162] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0163] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0164] Film coating:

[0165] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0166] ② Check the tablet disintegration time.

[0167] [Example 4]

[0168] The specific preparation method is as follows:

[0169] Preprocessing:

[0170] ① Sieve anhydrous sodium sulfate and anhydrous magnesium sulfate with a sieve size of 20-40 mesh;

[0171] ② Detect the particle size distribution of anhydrous sodium sulfate;

[0172] ③ After potassium chloride is crushed with a universal grinder for 10 seconds, it is sieved to select potassium chloride with a particle size distribution similar to that of anhydrous sodium sulfate;

[0173] ④ Grind polyethylene glycol 4000 with a universal grinder for 10 seconds and then pass it through a 60-mesh sieve;

[0174] mix:

[0175] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate and sieved potassium chloride into a high shear mixing granulator and mix for 10 minutes to obtain mixture I;

[0176] ② Then, polyethylene glycol 4000 and colloidal silicon dioxide were added to mixture I and mixed for 10 minutes to obtain mixture II;

[0177] ③ Using a spray gun, spray dimethicone into the mixture II and granulate to obtain a mixture III;

[0178] ④ Sieve the mixture III through a 0.81 mm sieve;

[0179] ⑤ After granulation, use a conical mixing barrel to mix for 10 minutes to obtain mixture IV;

[0180] ⑥ Add sodium octanoate and mix for 10 minutes to obtain a mixture V;

[0181] ⑦ Check the angle of repose, bulk density and particle size distribution of the mixture V.

[0182] Tablet pressing:

[0183] ① In a tablet press, mixture IV was compressed into tablets using a tabletting die with hemispherical upper and lower dies, a hemispherical diameter (i.e., outermost diameter) of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3;

[0184] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0185] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0186] Film coating:

[0187] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0188] ② Check the tablet disintegration time.

[0189] [Example 5]

[0190] The specific preparation method is as follows:

[0191] Preprocessing:

[0192] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride with a sieve size of 20 to 40 meshes.

[0193] mix:

[0194] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride into a high shear mixing granulator and mix for 10 minutes to obtain mixture I;

[0195] ② Then, polyethylene glycol 4000 and colloidal silicon dioxide were added to mixture I and mixed for 10 minutes to obtain mixture II;

[0196] ③ Using a spray gun, spray dimethicone into the mixture II and granulate to obtain a mixture III;

[0197] ④ Sieve the mixture III through a 0.81 mm sieve;

[0198] ⑤ After granulation, use a conical mixing barrel to mix for 10 minutes to obtain mixture IV;

[0199] ⑥ Check the angle of repose, bulk density, and particle size distribution of mixture IV.

[0200] Tablet pressing:

[0201] ① In a tablet press, use a tablet pressing die with hemispherical upper and lower dies, a hemispherical diameter (outermost diameter of the die) of 7 mm, and an arc depth / hemisphere diameter ratio of 0.291 to press into spherical tablets;

[0202] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0203] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0204] Film coating:

[0205] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0206] ② Check the tablet disintegration time.

[0207] [Example 6]

[0208] The specific preparation method is as follows:

[0209] Preprocessing:

[0210] ① Sieve anhydrous sodium sulfate and anhydrous magnesium sulfate with a sieve size of 20-40 mesh;

[0211] ② Detect the particle size distribution of anhydrous sodium sulfate;

[0212] ③ After potassium chloride is crushed with a universal grinder for 10 seconds, it is sieved to select potassium chloride with a particle size distribution similar to that of anhydrous sodium sulfate;

[0213] ④ Grind polyethylene glycol 4000 with a universal grinder for 10 seconds and then pass it through a 60-mesh sieve;

[0214] mix:

[0215] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate and sieved potassium chloride into a high shear mixing granulator and mix for 10 minutes to obtain mixture I;

[0216] ② Then, polyethylene glycol 4000 and colloidal silicon dioxide were added to mixture I and mixed for 10 minutes to obtain mixture II;

[0217] ③ Using a spray gun, spray dimethicone into the mixture II and granulate to obtain a mixture III;

[0218] ④ Sieve the mixture III through a 0.81 mm sieve;

[0219] ⑤ After granulation, use a conical mixing barrel to mix for 10 minutes to obtain mixture IV;

[0220] ⑥ Check the angle of repose, bulk density, and particle size distribution of mixture IV.

[0221] Tablet pressing:

[0222] ① In a tablet press, use a tablet pressing die with hemispherical upper and lower dies, a hemispherical diameter (outermost diameter of the die) of 7 mm, and an arc depth / hemisphere diameter ratio of 0.291 to press into spherical tablets;

[0223] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0224] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0225] Film coating:

[0226] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0227] ② Check the tablet disintegration time.

[0228] [Examples 7-8]

[0229] The specific preparation method is as follows:

[0230] Preprocessing:

[0231] ① Sieve anhydrous sodium sulfate and anhydrous magnesium sulfate with a sieve size of 20-40 mesh;

[0232] ② Detect the particle size distribution of anhydrous sodium sulfate;

[0233] ③ After potassium chloride is crushed with a universal grinder for 10 seconds, it is sieved to select potassium chloride with a particle size distribution similar to that of anhydrous sodium sulfate;

[0234] ④ Grind polyethylene glycol 4000 with a universal grinder for 10 seconds and then pass it through a 60-mesh sieve.

[0235] mix:

[0236] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate and sieved potassium chloride into a high shear mixing granulator and mix for 10 minutes to obtain mixture I;

[0237] ② Then, polyethylene glycol 4000 and colloidal silicon dioxide were added to mixture I and mixed for 10 minutes to obtain mixture II;

[0238] ③ Using a spray gun, spray dimethicone into the mixture II and granulate to obtain a mixture III;

[0239] ④ Sieve the mixture III through a 0.81 mm sieve;

[0240] ⑤ After granulation, use a conical mixing barrel to mix for 10 minutes to obtain mixture IV;

[0241] ⑥ Check the angle of repose, bulk density and particle size distribution of mixture IV particles.

[0242] Tablet pressing:

[0243] ① In a tablet press, use a tablet pressing die with hemispherical upper and lower dies, a hemispherical diameter (outermost diameter of the die) of 7 mm, and an arc depth / hemisphere diameter ratio of 0.291 to press into spherical tablets;

[0244] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0245] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0246] Film coating:

[0247] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0248] ② Check the tablet disintegration time.

[0249] [Comparative Example 1]

[0250] According to patent publication (announcement) No. CN112292136A (trade name: ) published prescription composition, pressed into the spherical tablets of the present invention, as shown in the following table:

[0251] The specific preparation method is as follows:

[0252] Preprocessing:

[0253] Sieve anhydrous sodium sulfate, potassium sulfate and anhydrous magnesium sulfate with a sieve size of 20 to 40 mesh.

[0254] mix:

[0255] ① Weigh anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate, and copovidone, pour them into a high shear mixing granulation pot in sequence, and mix for 20 minutes to obtain mixture I;

[0256] ② Weigh simethicone and add it to Mixture I, mixing for 10 minutes. Pour the mixture into a cone-shaped granulator with a 0.99 mm screen and a rotation speed of 1000 rpm. After granulation, pour it into a single-arm fixed hopper mixer and mix for 10 minutes to obtain Mixture II.

[0257] ③ Check the angle of repose and bulk density of mixture II.

[0258] Tablet pressing:

[0259] ① In a tablet press, use a tableting die with hemispherical upper and lower dies, a hemispherical diameter of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3 to compress mixture II into tablets;

[0260] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0261] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0262] Film coating:

[0263] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0264] ② Check the tablet disintegration time.

[0265] [Comparative Example 2]

[0266] According to patent publication (announcement) No. US10143656B1 (trade name: ) published prescription composition, pressed into the spherical tablets of the present invention, as shown in the following table:

[0267] The specific preparation method is as follows:

[0268] Preprocessing:

[0269] Sieve anhydrous sodium sulfate, magnesium sulfate and potassium chloride with a sieve size of 20 to 40 mesh.

[0270] mix:

[0271] ① Weigh anhydrous sodium sulfate, magnesium sulfate, potassium chloride, and polyethylene glycol 8000, pour them into a high-shear mixing granulation pot in sequence, and mix for 20 minutes to obtain mixture I;

[0272] ② Weigh sodium octanoate and add it to mixture I, mix for 10 minutes to obtain mixture II;

[0273] ③ Check the angle of repose and bulk density of mixture II.

[0274] Tablet pressing:

[0275] ① In a tablet press, use a tableting die with hemispherical upper and lower dies, a hemispherical diameter of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3 to compress mixture II into tablets;

[0276] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0277] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0278] Film coating:

[0279] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0280] ② Check the tablet disintegration time.

[0281] [Comparative Examples 3-5]

[0282] The preparation method of Reference Example 1 was used, except that no dimethicone or colloidal silica was added (Comparative Example 3), no colloidal silica was added (Comparative Example 4), and no dimethicone was added (Comparative Example 5). The specific preparation methods are as follows:

[0283] mix:

[0284] ① Mix sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, pour them into a high shear mixing granulator in sequence, and mix for 20 minutes to obtain mixture I;

[0285] ② Mixing dimethicone (Comparative Example 4) / colloidal silica (Comparative Example 5) with mixture I to obtain mixture II (except Comparative Example 3);

[0286] ③ Sodium octanoate was added to mixture II (Comparative Example 4 or Comparative Example 5) or mixture I (Comparative Example 3), and mixed for 20 minutes to obtain mixture III;

[0287] ④ Check the angle of repose and bulk density of mixture III.

[0288] Tablet pressing:

[0289] ① In a tablet press, use a tableting die with hemispherical upper and lower dies, a hemispherical diameter of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3 to compress mixture III into tablets;

[0290] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0291] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0292] Film coating:

[0293] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0294] ② Check the tablet disintegration time.

[0295] [Comparative Examples 6-7]

[0296] The preparation method of reference example 1 is different only in the die. The die of comparative example 6 is a 17mm*10mm ordinary sheet punch and the die of comparative example 7 is a 6mm ordinary sheet punch. The specific preparation method is as follows:

[0297] Preprocessing:

[0298] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride with a sieve size of 20 to 40 meshes.

[0299] mix:

[0300] ① Mix sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, pour them into a high shear mixing granulator in sequence, and mix for 20 minutes to obtain mixture I;

[0301] ② mixing colloidal silica and dimethicone to obtain mixture II;

[0302] ③ Mixing mixture I with mixture II to obtain mixture III;

[0303] ④ Sodium octanoate was added to mixture III and mixed for 20 minutes to obtain mixture IV;

[0304] ⑤ Check the angle of repose and bulk density of mixture IV.

[0305] Tablet pressing:

[0306] ① Using a rotary tablet press, the mixture IV was compressed into tablets using a 17 mm * 10 mm common tablet punch (Comparative Example 6) and a 6 mm common tablet punch (Comparative Example 7);

[0307] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0308] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0309] Film coating:

[0310] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare the coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small tablets to cool.

[0311] ② Check the tablet disintegration time.

[0312] [Comparative Example 8]

[0313] The preparation method of reference example 1 is as follows, except that the dimethicone + colloidal silica composition is replaced with simethicone.

[0314] Preprocessing:

[0315] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride with a sieve size of 20 to 40 meshes.

[0316] mix:

[0317] ① Mix sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, pour them into a high shear mixing granulator in sequence, and mix for 20 minutes to obtain mixture I;

[0318] ② Mixing simethicone with mixture I for 20 min to obtain mixture II;

[0319] ③ Sodium octanoate was added to mixture II and mixed for 20 minutes to obtain mixture III;

[0320] ④ Check the angle of repose and bulk density of mixture III.

[0321] Tablet pressing:

[0322] ① In a tablet press, mixture III was compressed into tablets using a tabletting die with hemispherical upper and lower dies, a hemispherical diameter (outermost diameter of the die) of 6 mm, and an arc depth / hemisphere diameter ratio of 0.3;

[0323] ② Check whether there are any process defects such as adhesion and capping during tableting;

[0324] ③ Check the brittleness, weight difference and disintegration time of the tablets.

[0325] Film coating:

[0326] ①Weigh the prescription amount Mix with an appropriate amount of purified water to prepare a coating solution. Keep the tablets warm at 25-35°C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to achieve the desired weight gain range. Once sufficient film coating is applied, stop coating, turn off the hot air supply to the inlet air, and allow the small spherical tablets to cool.

[0327] ② Check the tablet disintegration time.

[0328] 1. Study on the Effect of the Solid Preparation of the Present Invention

[0329] 1.1 Particle flowability test

[0330] (1) Angle of repose

[0331] The angle of repose is the stable three-dimensional angle (relative to a horizontal base) formed when a material presents itself as a cone. An excess of the powder to be tested (the material used to test the angle of repose in the preparation steps of the Examples and Comparative Examples) is added to a container with a fixed-diameter bottom plate. As the powder flows out of the center hole at the bottom of the container, a sliding slope (a triangular vertical shear plane) forms at the opening of the bottom plate inside the container, allowing the powder to flow out. The radius of the disk and the height of the powder are measured, and the angle of repose is calculated: Tanθ = height / radius.

[0332] (2) Carr Index

[0333] Weigh approximately 50 g of the material (the material corresponding to the bulk density test in the preparation steps of the Examples and Comparative Examples) and gently add it to a 100 mL graduated cylinder. Record the bulk volume. Mount the cylinder on a vibrator and set the vibration frequency to 500 times with an amplitude of 3 ± 0.3 mm. After the vibration stops, record the tapped volume and calculate the bulk density, tapped density, and Carr's index. Carr's index calculation formula = (tap density - bulk density) / tapped density * 100%; the experimental results are shown in Table 1.

[0334] Table 1 Fluidity test results

[0335] Patented prescription (Comparative Example 1) and The particles of the patented formulation (Comparative Example 2) had poor fluidity; even though simethicone was used in place of colloidal silicon dioxide and dimethicone in Comparative Example 8, fluidity was still not effectively improved. The particles of the solid preparation of the present invention had good fluidity and met the formulation requirements.

[0336] Without adding dimethicone and colloidal silicon dioxide (Comparative Example 3) or adding only one of them (Comparative Examples 4 and 5), good fluidity of the material cannot be guaranteed. The combined use of dimethicone and colloidal silicon dioxide in the present invention can effectively improve fluidity.

[0337] 1.2 Tableting conditions and friability test

[0338] Observe the adhesion and capping during tableting.

[0339] Take several tablets of the preparation (the corresponding materials for friability testing in the preparation steps of the Examples and Comparative Examples) to a total weight of approximately 6.5 g. Use a hair dryer to blow away any powder that falls off the preparation, and accurately weigh the total weight, recording it as the weight before rolling. Then place the tablets in the cylinder of a friability tester (Model: FT-2000AE) and roll them 100 times. Remove the tablets, blow away any powder that falls off the preparation with a hair dryer, and accurately weigh the total weight, recording it as the weight after rolling.

[0340] Crumbliness = (weight before rolling - weight after rolling) / weight before rolling × 100%.

[0341] The experimental results are shown in Table 2.

[0342] Table 2 Tablet adhesion, capping and friability test results

[0343] Note: +++: Very high frequency; ++: High frequency; +: Frequent (shows defects); -: No defects

[0344] Patented prescription (Comparative Example 1) and The patented formula (Comparative Example 2) exhibited a high frequency of defects such as adhesion and capping during tableting, and the product produced had poor friability, making it impossible to ensure tablet integrity during the coating process and transportation of the finished product.

[0345] The tableting processes of the formulations without dimethicone and colloidal silicon dioxide (Comparative Example 3), without colloidal silicon dioxide (Comparative Example 4), and without dimethicone (Comparative Example 5) all had adhesion and capping defects, and the friability was poor. The addition of simethicone to the patented formulation, and the replacement of the dimethicone + colloidal silica composition of the present invention with simethicone (Comparative Example 8), also failed to completely resolve the problems of sticking, capping defects, and poor friability. The combined use of dimethicone and colloidal silica (Examples 1-8) of the present invention effectively resolved the problems of sticking, capping, and friability, ensuring smooth manufacturing of the formulation.

[0346] Comparative Examples 6 and 7, using the same formulation and conventional tablet dies, exhibited adhesion and capping defects, regardless of size. Furthermore, the friability was significantly increased, failing to meet subsequent coating requirements. The spherical shape of the solid preparation of the present invention allows for stable and complete compression molding with good friability, facilitating subsequent coating processes and the transportation and storage of finished products, while maintaining the same tablet diameter and weight.

[0347] 1.3 Tablet weight difference experiment

[0348] Randomly take 20 tablets (the materials corresponding to the tablet weight difference inspection in the preparation steps of the Examples and Comparative Examples), accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet separately, and compare the weight of each tablet with the average tablet weight.

[0349] Tablet weight difference lower limit = (minimum weight among 20 tablets - average tablet weight) / average tablet weight × 100%;

[0350] Upper limit of tablet weight variation = (maximum weight among 20 tablets - average tablet weight) / average tablet weight × 100%;

[0351] The experimental results are shown in Table 3.

[0352] Table 3 Tablet weight difference experimental results

[0353] in accordance with Patented prescription (Comparative Example 1) and The tablets prepared by the patented prescription (Comparative Example 2) had large differences in tablet weight and could not meet the requirements of the continuous preparation process.

[0354] Tablets compressed by the formulations not containing dimethicone and colloidal silicon dioxide (Comparative Example 3), not containing colloidal silicon dioxide (Comparative Example 4), not containing dimethicone (Comparative Example 5), and replacing the dimethicone + colloidal silicon dioxide composition of the present invention with simethicone (Comparative Example 8) also failed to guarantee a qualified tablet weight difference.

[0355] The tablets with the same formulation compressed using the punching die for ordinary tablets (Comparative Examples 6 and 7) had large differences in tablet weight, especially for large-sized tablets, where the differences were significant.

[0356] 1.4 Disintegration time experiment

[0357] Use an intelligent disintegration instrument (model ZB-1E), add 900ml of disintegration medium (purified water) to a beaker, then place the disintegration instrument in a water bath and heat to a temperature of 37°C ± 1°C. Place the tablets (materials for checking the disintegration time of the corresponding tablets in the preparation steps of the examples and comparative examples) in the glass tubes of the disintegration instrument basket, start the disintegration instrument for inspection, record the disintegration time each time, and calculate the average value. In Examples 1-4 and Comparative Examples 1-8, 10 tablets (2g in total) were added to each glass tube, and 5 tablets (1.875g in total) were added to each glass tube of Examples 5-8.

[0358] The experimental results are shown in Table 4-1 or Table 4-2.

[0359] Table 4-1 Disintegration time test results of Examples 1-4 and Comparative Examples 1-8

[0360] Table 4-2 Experimental results of disintegration time of Example 5-8

[0361] in accordance with Patented prescription (Comparative Example 1) and Tablets prepared using the patented formulation (Comparative Example 2), as well as formulations without simethicone and colloidal silicon dioxide (Comparative Example 3), without colloidal silicon dioxide (Comparative Example 4), without simethicone (Comparative Example 5), and with simethicone substituted for the simethicone + colloidal silicon dioxide composition of the present invention (Comparative Example 8), had longer disintegration times. Simethicone tablets in Comparative Examples 1 and 8 had oily spots when pressed. The combination of simethicone and colloidal silicon dioxide in the present invention exhibited superior disintegration properties.

[0362] The tablets compressed with the same prescription using the punch die of ordinary tablets (Comparative Examples 6 and 7) disintegrated slowly. The solid preparation of the present invention has better disintegration performance than ordinary tablets of the same size.

[0363] 1.5 Particle size distribution detection

[0364] Take 600μm, 355μm, 250μm, 180μm, 150μm, 125μm sieves and chassis respectively, and stack them in the order of upper large-aperture sieve and lower small-aperture sieve. The bottom layer is equipped with a chassis, and the top layer is covered. Take about 100g of particles (materials for detecting particle size distribution corresponding to the preparation steps of the embodiments and comparative examples) and place them in the top layer of sieve, cover them, and install all sieves on a sieving instrument (model: As200basicB), set the amplitude to 75Hz, and the time is 5min. After the end, weigh each sieve and chassis weight respectively, and obtain the particle size distribution by calculating the powder proportion. As shown in Table 5, the table shows the particle size distribution of the embodiment.

[0365] Table 5 Particle size distribution test results

[0366] 1.6 Stability test

[0367] The compound sulfate spherical tablets prepared in Examples 1 and 6 were subjected to accelerated testing (40°C, RH 75%) according to the Chinese Pharmacopoeia Stability Testing Guidelines. Disintegration time (disintegration medium: purified water), dissolution rate (dissolution medium: purified water, sampling every 15 minutes, 75 rpm), and ion content were measured using the pharmacopoeial method. Properties were also observed. The results are shown in Table 6.

[0368] Table 6 Stability test results of compound sulfate spherical tablets prepared in Example 1 and Example 6

[0369] The compound sulfate spherical tablets prepared in Example 1 and Example 6 of the present invention showed excellent stability in an accelerated test (40° C., RH 75%) for 6 months, with no significant changes in various indicators compared with day 0.

[0370] 2. Solid Preparations of the Present Invention (Example 1 / Example 6) and Conventional Oral Sulfate Tablet Preparations contrast

[0371] 2.1 Appearance

[0372] The schematic diagram of the spherical preparation of the present invention is shown in Figure 1-2.

[0373] FIG3 shows a comparison of the appearance of the spherical preparation of the present invention (Example 1) and conventional tablets (Comparative Examples 6 and 7).

[0374] The spherical preparations of Examples 1-4 of the present invention were measured to have a middle band diameter of 6 mm, a hemisphere diameter of 5.60 mm, an edge cross-sectional width of 0.20 mm, a middle band thickness of 2.30-2.70 mm, and an arc depth of 1.80 mm.

[0375] The spherical preparations of Examples 5-8 of the present invention were measured to have a middle zone diameter of 7 mm, a hemisphere diameter of 6.68 mm, an edge cross-sectional width of 0.16 mm, a middle zone thickness of 2.80-3.20 mm, and an arc depth of 2.04 mm.

[0376] Example 1 of the present invention and conventional oral sulfate tablet preparation Appearance comparison, as shown in Figure 4; Example 6 of the present invention and conventional oral sulfate tablet preparation The appearance comparison is shown in Figure 5.

[0377] 2.2 Disintegration time

[0378] Using an intelligent disintegration instrument (model ZB-1E), add 900 ml of disintegration medium to a beaker, then place the beaker in the disintegration instrument and heat it in a water bath to 37°C ± 1°C. Place the tablets in the 6 glass tubes of the disintegration instrument's hanging basket. For Example 1, add 10 tablets (2 g in total) to each glass tube, and for Example 6, add 5 tablets (1.875 g in total) to each glass tube. (2g) and (1.5g) Add 1 tablet to each glass tube. Start the disintegration instrument and test the disintegration time of the preparations in 6 glass tubes at the same time. Record the time of each tablet ( and ) or each time (Examples 1 and 6) disintegration time, and calculate the mean value.

[0379] The experimental results are shown in Table 7.

[0380] Table 7 Example 1, Example 6 and conventional preparations Disintegration time comparison

[0381] The spherical tablets of the present invention can completely disintegrate within 5 minutes, and the disintegration effect is greatly improved, which can further reduce the residence time of the preparation in the stomach and reduce the occurrence of adverse reactions such as gastritis / gastric ulcer.

[0382] 2.3 Clarity

[0383] After the tablets are completely disintegrated in a disintegrator at room temperature (37°C ± 1°C), they are immediately inspected visually. To evaluate the defoaming effect, a surfactant is added to the solution, and the solution is stirred with a glass rod to produce foam. The solution is then allowed to stand for 5 minutes and the state of the solution is observed to evaluate the effectiveness of the defoaming agent.

[0384] The preparation of the present invention (Example 1) and the marketed preparation The comparison of the defoaming effect and clarity of the solution after disintegration is shown in Figure 6.

[0385] The preparation of the present invention (Example 6) and the marketed preparation The comparison of the defoaming effect and clarity of the solution after disintegration is shown in Figure 7.

[0386] During endoscopic examination, there is a 32% to 57% chance of encountering intestinal foam, which affects the observation effect and examination time of the digestive tract mucosa and lesions. 12 tablets*2g / tablet has obvious foam and no defoaming effect; Although 14 tablets * 1.5g / tablet can reduce foam to a certain extent, it has high turbidity. The solid preparations of the present invention (Examples 1 and 6) have a significant defoaming effect and are significantly clearer than the marketed preparations.

[0387] It should be understood that the above embodiments are only for further illustration and explanation of the present invention and do not limit the present invention. Those skilled in the art may make various adjustments or changes based on the present invention and still fall within the scope of the claims of the present invention.

Claims

1. A compound sulfate solid preparation, characterized in that, The solid preparation comprises the following components: Sodium sulfate anhydrous, magnesium sulfate anhydrous, potassium chloride, dimethicone and colloidal silicon dioxide.

2. The solid preparation according to claim 1, wherein The mass ratio of the dimethicone to the colloidal silicon dioxide is 1:1 to 30:

1. Preferably, the mass ratio of the dimethicone to the colloidal silicon dioxide is 3:1 to 25:1; more preferably, the mass ratio of the dimethicone to the colloidal silicon dioxide is 5:1 to 21:1; most preferably, the mass ratio of the dimethicone to the colloidal silicon dioxide is 8:1 to 15:

1.

3. The solid preparation according to claim 1 or 2, characterized in that, The total weight percentage content of the dimethicone and the colloidal silicon dioxide in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is 0.05% to 5%; preferably, the total weight percentage content of the dimethicone and the colloidal silicon dioxide in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is 0.1% to 2.1%; more preferably, the total weight percentage content of the dimethicone and the colloidal silicon dioxide in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is 0.6% to 1.5%; most preferably, the total weight percentage content of the dimethicone and the colloidal silicon dioxide in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is 1.0% to 1.2%.

4. The solid preparation according to any one of claims 1 to 3, characterized in that, The weight percentage content of the components in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is as follows: 50.0% to 95.0% of sodium sulfate anhydrous, 5.0% to 20.0% of magnesium sulfate anhydrous, 5.0% to 20.0% of potassium chloride, and 0.05% to 5% (calculated based on the total weight of the dimethicone and the colloidal silicon dioxide) of the dimethicone and the colloidal silicon dioxide; preferably, the weight percentage content of the components in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is as follows: 60.0% to 90.0% of sodium sulfate anhydrous, 7.0% to 15.0% of magnesium sulfate anhydrous, 7.0% to 12.0% of potassium chloride, and 0.1% to 2.1% (calculated based on the total weight of the dimethicone and the colloidal silicon dioxide) of the dimethicone and the colloidal silicon dioxide; more preferably, the weight percentage content of the components in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is as follows: 65.0% to 85.0% of sodium sulfate anhydrous, 8.0% to 14.0% of magnesium sulfate anhydrous, 8.0% to 11.0% of potassium chloride, and 0.6% to 1.5% (calculated based on the total weight of the dimethicone and the colloidal silicon dioxide) of the dimethicone and the colloidal silicon dioxide; most preferably, the weight percentage content of the components in the solid preparation (if there is a coating, calculated based on the uncoated preparation) is as follows: 70.0% to 80.0% of sodium sulfate anhydrous, 9.0% to 13.0% of magnesium sulfate anhydrous, 9.0% to 10.0% of potassium chloride, and 1.0% to 1.2% (calculated based on the total weight of the dimethicone and the colloidal silicon dioxide) of the dimethicone and the colloidal silicon dioxide.

5. The solid preparation according to any one of claims 1-4, characterized in that, The solid preparation further comprises a water-soluble lubricant and / or a water-soluble binder; preferably, the weight percentage of the water-soluble lubricant and / or the water-soluble binder (if there is a coating, based on the uncoated preparation) is: water-soluble lubricant 0.5% to 2.5% and / or water-soluble binder 1.0% to 5.0%; more preferably, the weight percentage of the water-soluble lubricant and / or the water-soluble binder (if there is a coating, based on the uncoated preparation) is: water-soluble lubricant 1.0% to 2.0% and / or water-soluble binder 2.0% to 3.0%.

6. The solid preparation according to any one of claims 1-4, characterized in that, The solid preparation further comprises a water-soluble binder and does not include a water-soluble lubricant; preferably, the weight percentage of the water-soluble binder (if there is a coating, based on the uncoated preparation) is 1.5% to 7.5%; more preferably, the weight percentage of the water-soluble binder (if there is a coating, based on the uncoated preparation) is 3.0% to 5.0%.

7. The solid preparation according to claim 5 or 6, characterized in that, The water-soluble lubricant is one or more of sodium caprylate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol monostearate, polyethylene glycol lauryl alcohol; and / or, the water-soluble binder is one or more of polyethylene glycol (polyethylene glycol 3350 / 4000 / 6000 / 8000), hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, sodium alginate.

8. The solid preparation according to any one of claims 1-7, characterized in that, The solid preparation further comprises a water-soluble film coating; preferably, the mass percentage of the water-soluble film coating relative to the uncoated preparation is 0.1 wt% to 5.0 wt%, more preferably, the mass percentage of the water-soluble film coating relative to the uncoated preparation is 1.0 wt% to 3.0 wt%; and / or, the water-soluble coating layer is one or more of polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic resin, polyvinyl acetal diethylaminoacetate, polyethylene glycol.

9. The solid preparation according to any one of claims 1-8, characterized in that, The solid preparation is a spherical solid preparation; preferably, the spherical solid preparation is a spherical tablet.

10. The solid preparation according to any one of claims 1-9, characterized in that, The size of the spherical solid preparation is 2 to 10 mm; preferably, the size of the spherical solid preparation is 3 to 9 mm; more preferably, the size of the spherical solid preparation is 4 to 8 mm; still more preferably, the size of the spherical solid preparation is 5 to 8 mm (such as 5 to 7 mm).

11. The solid preparation according to any one of claims 1-10, characterized in that, The spherical solid preparation contains or does not contain an intermediate zone; preferably, it contains an intermediate zone, and the diameter of the intermediate zone is 2 to 10 mm; more preferably, the diameter of the intermediate zone is 3 to 9 mm; still more preferably, the diameter of the intermediate zone is 4 to 8 mm; most preferably, the diameter of the intermediate zone is 5 to 8 mm (such as 5 to 7 mm); and / or, the hemispherical diameter of the spherical solid preparation is 2 to 10 mm; preferably, the hemispherical diameter of the spherical solid preparation is 3 to 9 mm; more preferably, the hemispherical diameter of the spherical solid preparation is 4 to 8 mm; still more preferably, the hemispherical diameter of the spherical solid preparation is 5 to 8 mm (such as 5 to 7 mm); And / or, the spherical solid preparation comprises a middle zone and an edge (i.e., the part where the middle zone protrudes relative to the hemispheres), and the cross-sectional width of the edge (i.e., the difference between the diameter of the middle zone and the diameter of the hemisphere) is 0.1 to 2 mm; more preferably, the cross-sectional width of the edge is 0.1 to 1 mm; even more preferably, the cross-sectional width of the edge is 0.1 to 0.5 mm; And / or, the spherical solid preparation comprises a middle zone, and the thickness of the middle zone is 1 to 5 mm; preferably, the thickness of the middle zone is 1.5 to 4.5 mm; more preferably, the thickness of the middle zone is 2 to 4 mm; And / or, the arc depth of the spherical solid preparation is 1 to 5 mm; preferably, the arc depth is 1.5 to 4.5 mm; more preferably, the arc depth is 1.8 to 2.2 mm or the arc depth is 2 to 4 mm; And / or, the ratio of the arc depth of the upper and lower punches of the mold used when pressing the spherical solid preparation to the hemisphere diameter is 0.2 to 0.5; more preferably, the ratio of the arc depth to the hemisphere diameter is 0.2 to 0.4; most preferably, the ratio of the arc depth to the hemisphere diameter is 0.2 to 0.

3.

12. The solid preparation according to any one of claims 1-11, characterized in that, The weight of the unit solid preparation of the solid preparation is 50 to 600 mg; preferably, it is 100 to 500 mg; more preferably, it is 150 to 400 mg; more preferably, it is 200 to 400 mg (such as 200 to 300 mg).

13. The solid preparation according to any one of claims 1-12 or a method for preparing the same, characterized in that, The solid preparation is prepared by direct tableting or dry granulation tableting.

14. The preparation method according to claim 13, characterized in that, The method comprises the following steps: (1) Sieving anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride, and preferably the mesh number of the sieve is 20 - 80 mesh, more preferably 20 - 60 mesh, and further preferably 20 - 40 mesh; (2) Mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride with a water-soluble binder to obtain mixture I; (3) Mixing colloidal silica and dimethyl silicone oil to obtain mixture II; (4) Mixing mixture I and mixture II to obtain mixture III; (5) Optionally, adding a water-soluble lubricant to mixture III for mixing to obtain mixture IV; (6) Using a tableting mold, pressing mixture III (when no water-soluble lubricant is contained) or mixture IV (when a water-soluble lubricant is contained) into tablets, and optionally performing coating to obtain the product; Preferably, the hemisphere diameter of the upper and lower punches of the tableting mold used for tableting is 2 to 10 mm, and the ratio of the arc depth to the hemisphere diameter is 0.2 to 0.5; preferably, the hemisphere diameter is 3 to 9 mm, and the ratio of the arc depth to the hemisphere diameter is 0.2 to 0.5; more preferably, the hemisphere diameter is 4 to 8 mm, and the ratio of the arc depth to the hemisphere diameter is 0.2 to 0.4; most preferably, the hemisphere diameter is 5 to 8 mm (such as 5 to 7 mm), and the ratio of the arc depth to the hemisphere diameter is 0.2 to 0.

3.

15. The preparation method according to claim 13, wherein The method comprises the following steps: (1) Sieving anhydrous sodium sulfate and anhydrous magnesium sulfate; preferably the mesh number of the sieve is 20 - 80 mesh, more preferably 20 - 60 mesh, and further preferably 20 - 40 mesh; (2) Detect the particle size distribution of anhydrous sodium sulfate, crush potassium chloride, and screen potassium chloride materials with a particle size distribution similar to that of anhydrous sodium sulfate; (3) Crush the water-soluble binder and then screen it; (4) Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and the screened potassium chloride to obtain Mixture I; (5) Then add the water-soluble binder and colloidal silica to Mixture I and mix to obtain Mixture II; (6) Spray dimethyl silicone oil into Mixture II, granulate to obtain Mixture III; (7) Screen the whole granules of Mixture III; (8) After the whole granulation is completed, mix to obtain Mixture IV; (9) Optionally, add a water-soluble lubricant mixture to obtain Mixture V; (10) Use a tablet press mold to press Mixture IV (when no water-soluble lubricant is contained) or Mixture V (when a water-soluble lubricant is contained) into tablets, and optionally coat them to obtain the product; Preferably, the hemispherical diameter of the upper and lower punches of the tablet press mold used during tableting is 2-10 mm, and the ratio of the arc depth to the hemispherical diameter is 0.2-0.5; preferably, the hemispherical diameter is 3-9 mm, and the ratio of the arc depth to the hemispherical diameter is 0.2-0.5; more preferably, the hemispherical diameter is 4-8 mm, and the ratio of the arc depth to the hemispherical diameter is 0.2-0.4; most preferably, the hemispherical diameter is 5-8 mm (such as 5-7 mm), and the ratio of the arc depth to the hemispherical diameter is 0.2-0.

3.

16. Use of the solid preparation according to any one of claims 1-13 or the solid preparation prepared by the preparation method according to any one of claims 13-15 in the preparation of a drug for intestinal cleansing.

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