Compound sulfate solid preparation for intestinal tract cleaning as well as preparation method and application of compound sulfate solid preparation

Abstract

The invention discloses a compound sulfate solid preparation for cleaning intestinal tracts as well as a preparation method and application of the compound sulfate solid preparation. The invention provides a brand-new compound sulfate solid preparation, which effectively solves the technical problems of poor compressibility (difficult tabletting, sticking, top cracking and waist cracking), poor flowability, fragility, large tablet weight difference and the like of the existing sulfate solid preparation, and also has at least more than one of the following advantages: easy swallowing and good compliance; the taste is good; the disintegration is fast, the effect is fast, and the adverse reaction is less; the problems of intestinal foam and solution turbidity can be solved; the product quality is stable; the process is simple and stable, can realize industrial large-scale continuous production, and has no process defects such as oil spots.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, especially the field of pharmaceutical preparations for intestinal cleansing before colonoscopy, and specifically relates to a novel compound sulfate solid preparation, its preparation method and uses. Background Art

[0002] Colonoscopy is considered an efficient method for early detection of colorectal cancer (CRC) and resection of precancerous polyps, which can significantly reduce the incidence and mortality of colorectal cancer. Adequate intestinal cleansing is crucial for examining the entire colonic mucosa during colonoscopy. Insufficient bowel preparation will reduce the adenoma detection rate, increase the risk of complications after colonoscopy, and prolong the operation time.

[0003] Currently, a variety of laxatives have been developed to improve the effect of intestinal cleansing, including 4L high-volume polyethylene glycol (PEG), 2L low-volume PEG + ascorbic acid (ASC). However, both PEG-based preparations still require patients to drink 3 to 4L of solution. Therefore, the availability of low-volume preparations is very important for intestinal cleansing. Oral sulfate solution (OSS) with less water intake has similar safety and effectiveness compared with 4L PEG or 2L PEG / ASC drugs, and has a shorter withdrawal time and total examination time. However, the high-concentration sulfate in oral sulfate solution (OSS) has an obvious irritating taste, poor taste, and poor tolerance of patients.

[0004] Based on this, oral sulfate tablets (OST) have been developed. OST is comparable to OSS in terms of intestinal cleansing effect. Since OST is a film-coated tablet and can be directly swallowed with water during use, it can avoid the irritating taste of high-concentration sulfate in OSS and shows better tolerance. Currently, there are two commonly used oral sulfate tablets (OST) on the market, which are (USA, Braintree Laboratories Inc) and (South Korea, Pharmbio Korea Inc). However, the existing OST tablets have many deficiencies: (1) The tablet size is large and the compliance is poor. Up to 9*18mm, 2g / tablet, 12 tablets are taken orally at one time; It is 8.2 * 17.2 mm in length, 1.5 g per tablet, and 14 tablets are taken orally at one time. It is large in size and difficult to swallow. Some patients will crush or chew the tablets in order to swallow them, resulting in poor taste and compliance. (2) There are technical problems such as poor compressibility (difficult to be pressed into tablets, sticking to the punch, top cracking, waist cracking), poor fluidity, easy to be brittle and broken, and large variation in tablet weight. Since the main component of oral sulfate tablets (OST) is inorganic salt and the content ratio is large, the compressibility of the material is poor, and problems such as top cracking and waist cracking frequently occur during tableting. The upper part of the tablet separates from the main body and falls off as a lid, or the tablet splits into horizontal layers and peels off. In addition, the powder of the tablet is easily adhered to the punch surface, resulting in defects on the tablet surface; poor fluidity and large variation in tablet weight; and the large tablets prepared are easy to be brittle and broken, which is not conducive to film coating, etc. (3) Slow disintegration, slow onset, and large side effects. Since the disintegration time of oral sulfate (OST) tablets on the market is long, the dissolution rate of sulfate in the body is slow. On the one hand, it prolongs the defecation time; on the other hand, sulfate tablets are easy to accumulate in the stomach and have a local stimulating effect on the gastric mucosa, which may cause a relatively high incidence of gastric distension, erosive gastritis / gastric ulcer. (4) It is impossible to simultaneously solve the problems of intestinal foam and solution turbidity. During the endoscopic examination process, there is a 32% - 57% chance of encountering foam. The existing marketed preparations have no defoaming effect after disintegration. Although the preparation adds simethicone and can improve the foam to a certain extent, the solution has high turbidity after dissolution, which may affect the observation of the digestive tract mucosa and lesions.

[0005] Therefore, there is an urgent need for a new solid preparation that can solve as many of the above problems as possible (preferably solve the above problems simultaneously), aiming to better improve patient compliance, solve the long-existing technical problems such as compressibility, fluidity, friability, and reproducibility of such preparations, increase the disintegration speed, enhance the intestinal cleansing ability, reduce adverse reactions, and reduce intestinal foam and turbidity problems. Summary of the Invention

[0006] In order to improve the above problems, small-sized traditional tablets were studied in the early stage. However, during the research process, it was found that problems such as frequent lamination, top cracking, and adhesion still occurred, including poor compressibility, poor friability, and large variation in tablet weight.

[0007] The inventor was the first to discover that the novel solid preparation containing dimethicone and colloidal silica of the present invention can effectively solve the technical problems existing in the existing sulfate solid preparations, such as poor compressibility (difficult to press into tablets, sticking to punches, top cracking, waist cracking), poor fluidity, easy friability, large tablet weight variation, etc. At the same time, it also has one or more of the following advantages: easy to swallow, good compliance; good taste; fast disintegration, fast onset, and few adverse reactions; can take into account the solution of intestinal foam and solution turbidity problems; stable product quality; simple and stable process, can be continuously produced on a large scale industrially; no process defects such as oil spots; more preferably, it can solve the above problems simultaneously.

[0008] In view of this, the present invention provides a novel compound sulfate solid preparation, and the solid preparation comprises the following components: anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone and colloidal silica.

[0009] 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.

[0010] In one embodiment of the present invention, the total weight percentage content of dimethicone and colloidal silica in the solid preparation (if there is a coating, based on the uncoated preparation) is 0.05% to 5%; preferably, the total weight percentage content of dimethicone and colloidal silica in the solid preparation (if there is a coating, based on the uncoated preparation) is 0.1% to 2.1%; more preferably, the total weight percentage content of dimethicone and colloidal silica in the solid preparation (if there is a coating, based on the uncoated preparation) is 0.6% to 1.5%; most preferably, the total weight percentage content of dimethicone and colloidal silica in the solid preparation (if there is a coating, based on the uncoated preparation) is 1.0% to 1.2%; for example, the total weight percentage content of dimethicone and colloidal silica in the solid preparation (if there is a coating, based on the uncoated preparation) is 1.1%.

[0011] In one embodiment of the present invention, the weight percentage content of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is: anhydrous sodium sulfate 50.0% to 95.0%, preferably 60.0% to 90.0%, more preferably 65.0% to 85.0%, most preferably 70.0% to 80.0%, for example 72%, 73%, 74%, 74.2%, 75% or 76%.

[0012] In a certain embodiment of the present invention, the weight percentage of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is as follows: anhydrous magnesium sulfate 5.0% - 20.0%, preferably 7.0% - 15.0%, more preferably 8.0% - 14.0%, most preferably 9.0% - 13.0%, for example 10%, 11%, 11.2% or 12%.

[0013] In a certain embodiment of the present invention, the weight percentage of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is as follows: potassium chloride 5.0% - 20.0%, preferably 7.0% - 12.0%, more preferably 8.0% - 11.0%, still preferably 9.0% - 10.0%, for example 9.3%, 9.4% or 9.5%.

[0014] In a certain embodiment of the present invention, the weight percentage of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is as follows: dimethicone 0.1% - 3.0%, preferably 0.4% - 1.8%, more preferably 0.6% - 1.6%, most preferably 0.8% - 1.5%, for example 0.9%, 0.92%, 1%, 1.05%, 1.1% or 1.2%.

[0015] In a certain embodiment of the present invention, the weight percentage of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is as follows: colloidal silicon dioxide 0.005% - 1.0%, preferably 0.01% - 0.4%, more preferably 0.02% - 0.2%, most preferably 0.04% - 0.15%, for example 0.05%, 0.1%, 0.12%, 0.14%, 0.16% or 0.18%.

[0016] In a certain embodiment of the present invention, the weight percentage content of each component in the solid preparation (i.e., the weight percentage content of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone and colloidal silicon dioxide in the solid preparation) (if there is a coating, based on the uncoated preparation) is as follows: anhydrous sodium sulfate 50.0% - 95.0%, anhydrous magnesium sulfate 5.0% - 20.0%, potassium chloride 5.0% - 20.0%, and dimethicone and colloidal silicon dioxide 0.05% - 5% (based on the total weight of dimethicone and colloidal silicon dioxide); preferably, the weight percentage content of each component in the solid preparation (if there is a coating, based on the uncoated preparation) is: anhydrous sodium sulfate 60.0% - 90.0%, anhydrous magnesium sulfate 7.0% - 15.0%, potassium chloride 7.0% - 12.0%, and dimethicone and colloidal silicon dioxide 0.1% - 2.1% (based on the total weight of dimethicone and colloidal silicon dioxide); more preferably, the weight percentage content of each component in the solid preparation (if there is a coating, based on the uncoated preparation) is: anhydrous sodium sulfate 65.0% - 85.0%, anhydrous magnesium sulfate 8.0% - 14.0%, potassium chloride 8.0% - 11.0%, and dimethicone and colloidal silicon dioxide 0.6% - 1.5% (based on the total weight of dimethicone and colloidal silicon dioxide); most preferably, the weight percentage content of each component in the solid preparation (if there is a coating, based on the uncoated preparation) is: anhydrous sodium sulfate 70.0% - 80.0%, anhydrous magnesium sulfate 9.0% - 13.0%, potassium chloride 9.0% - 10.0%, and dimethicone and colloidal silicon dioxide 1.0% - 1.2% (based on the total weight of dimethicone and colloidal silicon dioxide); for example, the weight percentage content of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is: anhydrous sodium sulfate 74.2%, anhydrous magnesium sulfate 11%, potassium chloride 9.4%, and dimethicone and colloidal silicon dioxide 1.1% (based on the total weight of dimethicone and colloidal silicon dioxide) or the weight percentage content of the components in the solid preparation (if there is a coating, based on the uncoated preparation) is: anhydrous sodium sulfate 74%, anhydrous magnesium sulfate 11.2%, potassium chloride 9.4%, and dimethicone and colloidal silicon dioxide 1.1% (based on the total weight of dimethicone and colloidal silicon dioxide).

[0017] In a certain embodiment of the present invention, the sum of the weight percentage content of anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone and colloidal silicon dioxide in the solid preparation (if there is a coating, based on the uncoated preparation) is less than or equal to 100%.

[0018] In a certain embodiment of the present invention, the solid preparation further comprises a water-soluble lubricant and / or a water-soluble binder; preferably, the weight percentage content 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% - 2.5% and / or water-soluble binder 1.0% - 5.0%; more preferably, the weight percentage content 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% - 2.0% and / or water-soluble binder 2.0% - 3.0%; for example, the weight percentage content of the water-soluble lubricant (if there is a coating, based on the uncoated preparation) is 1.5% and / or the weight percentage content of the water-soluble binder (if there is a coating, based on the uncoated preparation) is 2.8%.

[0019] In a certain embodiment of the present invention, the solid preparation further comprises a water-soluble binder and does not include a water-soluble lubricant; preferably, the weight percentage content of the water-soluble binder (if there is a coating, based on the uncoated preparation) is 1.5% - 7.5%; more preferably, the weight percentage content of the water-soluble binder (if there is a coating, based on the uncoated preparation) is 3.0% - 5.0%; for example, the weight percentage content of the water-soluble binder (if there is a coating, based on the uncoated preparation) is 4.3%.

[0020] In a certain embodiment of the present invention, the water-soluble lubricant is selected from one or more of sodium caprylate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol monostearate, and polyethylene glycol lauryl ether.

[0021] In a certain 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, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, and sodium alginate, such as polyethylene glycol 4000.

[0022] In a certain embodiment of the present invention, the sum of the weight percentage contents of sodium sulfate anhydrous, magnesium sulfate anhydrous, potassium chloride, dimethicone, colloidal silicon dioxide, water-soluble lubricant, and water-soluble binder (if there is a coating, based on the uncoated preparation) is less than or equal to 100%.

[0023] In a certain embodiment of the present invention, the sum of the weight percentage contents of sodium sulfate anhydrous, magnesium sulfate anhydrous, potassium chloride, dimethicone, colloidal silicon dioxide, and water-soluble binder (if there is a coating, based on the uncoated preparation) is less than or equal to 100%.

[0024] In a certain embodiment of the present invention, the uncoated components of the solid preparation are composed of the sodium sulfate anhydrous, magnesium sulfate anhydrous, potassium chloride, dimethicone, colloidal silicon dioxide, water-soluble lubricant, and water-soluble binder.

[0025] In one embodiment of the present invention, the non-coated 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.

[0026] In one embodiment of the present invention, the solid preparation further comprises a water-soluble film coating.

[0027] In one embodiment of the present invention, the water-soluble coating layer is one or more of a polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic resin, polyvinyl acetal diethylaminoacetate, and polyethylene glycol.

[0028] In one embodiment of the present invention, the water-soluble film coating is IR.

[0029] In one embodiment of the present invention, the mass percentage of the water-soluble coating layer 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%.

[0030] In one embodiment of the present invention, the solid preparation is a spherical solid preparation.

[0031] 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; even more preferably, the size of the spherical solid preparation is 5 to 8 mm (such as 5 to 7 mm).

[0032] In one embodiment of the present invention, the spherical solid preparation may or may not contain an intermediate zone.

[0033] In one embodiment of the present invention, the spherical solid preparation contains an intermediate zone; the diameter of the intermediate zone is 2 to 10 mm; more preferably, the diameter of the intermediate zone is 3 to 9 mm; even 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, 6.5 mm);

[0034] In one embodiment of the present invention, 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; preferably, the hemispherical diameter of the spherical solid preparation is 4 to 8 mm; more preferably, the hemispherical diameter of the spherical solid preparation is 5 to 8 mm (such as 5 to 7 mm, 6.5 mm).

[0035] In one embodiment of the present invention, the spherical solid preparation comprises a middle zone and an edge (i.e., the part where the middle zone protrudes relative to the hemisphere), 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 - 2 mm; more preferably, the cross-sectional width of the edge is 0.1 - 1 mm; even more preferably, the cross-sectional width of the edge is 0.1 - 0.5 mm; for example, the cross-sectional width of the edge is 0.20 mm or 0.16 mm.

[0036] In one embodiment of the present invention, the spherical solid preparation comprises a middle zone, and the thickness of the middle zone is 1 - 5 mm; preferably, the thickness of the middle zone is 1.5 - 4.5 mm; more preferably, the thickness of the middle zone is 2 - 4 mm; for example, the thickness of the middle zone is 2.5 mm or 3 mm.

[0037] In one embodiment of the invention, the arc depth of the spherical solid preparation 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.

[0038] In one embodiment of the present invention, the ratio of the arc depth to the hemisphere diameter of the upper and lower punches of the mold used in pressing the spherical solid preparation is 0.2 - 0.5; more preferably, the ratio of the arc depth to the hemisphere diameter is 0.2 - 0.4; most preferably, the ratio of the arc depth to the hemisphere diameter is 0.2 - 0.3; for example, the ratio of the arc depth to the hemisphere diameter is 0.29 or 0.3.

[0039] In the present invention, the arc depth is the longitudinal depth of the hemisphere.

[0040] In one embodiment of the present invention, the middle zone is a band with substantially the same thickness; preferably, the middle zone is a band with the same thickness.

[0041] 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.

[0042] In one embodiment of the present invention, the spherical solid preparation is a pill or a spherical tablet.

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

[0044] In the present invention, the spherical tablet comprises an upper hemisphere, a lower hemisphere and a middle zone. The middle zone is located in the middle of the spherical tablet and is a band with substantially the same thickness. The upper and lower hemispheres are located on the two end faces of the middle zone, and the sizes and shapes of the two hemispheres are substantially the same. The diameter of the middle zone is larger than the diameter of the hemisphere.

[0045] In a certain embodiment of the present invention, the diameter of the middle zone of the spherical tablet is 2 - 10 mm; more preferably, the diameter of the middle zone is 3 - 9 mm; even more preferably, the diameter of the middle zone is 4 - 8 mm; most preferably, the diameter of the middle zone is 5 - 8 mm (such as 5 - 7 mm or 6.5 mm);

[0046] In a certain embodiment of the present invention, the hemispherical diameter of the spherical tablet is 2 - 10 mm; preferably, the hemispherical diameter of the spherical tablet is 3 - 9 mm; preferably, the hemispherical diameter of the spherical tablet is 4 - 8 mm; more preferably, the hemispherical diameter of the spherical tablet is 5 - 8 mm (such as 5 - 7 mm or 6.5 mm).

[0047] In a certain embodiment of the present invention, the spherical tablet comprises a middle zone and an edge (i.e., the part where the middle zone protrudes relative to the hemispherical body), and the cross-sectional width of the edge (i.e., the difference between the diameter of the middle zone and the hemispherical diameter) is 0.1 - 2 mm; more preferably, the cross-sectional width of the edge is 0.1 - 1 mm; even more preferably, the cross-sectional width of the edge is 0.1 - 0.5 mm; for example, the cross-sectional width of the edge is 0.20 mm or 0.16 mm.

[0048] In a certain embodiment of the present invention, the thickness of the middle zone of the spherical tablet is 1 - 5 mm; preferably, the thickness of the middle zone is 1.5 - 4.5 mm; more preferably, the thickness of the middle zone is 2 - 4 mm; for example, the thickness of the middle zone is 2.5 mm, 3 mm.

[0049] In a certain embodiment of the invention, the arc depth of the spherical tablet 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.

[0050] In a certain embodiment of the present invention, the ratio of the arc depth to the hemispherical diameter of the upper and lower punches of the tablet press mold used for pressing the spherical tablet is 0.2 - 0.5; more preferably, the ratio of the arc depth to the hemispherical diameter is 0.2 - 0.4; most preferably, the ratio of the arc depth to the hemispherical diameter is 0.2 - 0.3; for example, the ratio of the arc depth to the hemispherical diameter is 0.29 or 0.3.

[0051] In a certain embodiment of the present invention, the spherical solid preparation is a pill, and the size of the pill is 2 - 10 mm; preferably, the size of the pill is 3 - 9 mm; preferably, the size of the pill is 4 - 8 mm; more preferably, the size of the pill is 5 - 8 mm (such as 5 - 7 mm or 6.5 mm).

[0052] In a certain embodiment of the present invention, the weight of a single unit solid preparation of the solid preparation is 50 to 600 mg; preferably, the weight of a single unit solid preparation of the solid preparation is 100 to 500 mg; more preferably, the weight of a single unit solid preparation of the solid preparation is 150 to 400 mg; still more preferably, the weight of a single unit solid preparation of the solid preparation is 200 to 400 mg, and most preferably, the weight of a single unit solid preparation of the solid preparation is 350 to 400 mg (for example, 200 to 375 mg).

[0053] In a certain embodiment of the present invention, the solid preparation does not contain a disintegrant.

[0054] In a certain embodiment of the present invention, the solid preparation is prepared by dry granulation and tabletting or direct tabletting.

[0055] In a certain embodiment of the present invention, no water is added during the preparation of the solid preparation.

[0056] In a certain embodiment of the present invention, the colloidal silica and dimethicone composition are separately prepared during the preparation of the solid preparation.

[0057] In a certain embodiment of the present invention, the colloidal silica and dimethicone are added in the form of a composition during the preparation of the solid preparation.

[0058] In a certain embodiment of the present invention, the colloidal silica and dimethicone are mixed and then mixed with other components during the preparation of the solid preparation.

[0059] In a certain embodiment of the present invention, the dimethicone is separately sprayed onto other materials and mixed during the preparation of the solid preparation.

[0060] In a certain embodiment of the present invention, the solid preparation is administered orally.

[0061] The present invention provides a method for preparing a solid preparation, and the solid preparation is prepared by dry granulation and tabletting or direct tabletting.

[0062] In a certain embodiment of the present invention, the method for preparing the solid preparation includes the following steps:

[0063] (1) Sieving anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride; preferably, the mesh number of the sieve is 20 - 80 mesh, more preferably 20 - 60 mesh, further preferably 20 - 40 mesh, for example, 40 mesh;

[0064] (2) Mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride with a water-soluble binder to obtain mixture I;

[0065] (3) Mixing colloidal silica and dimethicone to obtain mixture II;

[0066] (4) Mix mixture I and mixture II to obtain mixture III;

[0067] (5) Add a water-soluble lubricant to mixture III and mix to obtain mixture IV;

[0068] (6) Use a tableting die to press mixture IV into tablets, and optionally coat them to obtain the product.

[0069] In one embodiment of the present invention, the preparation method of the solid preparation comprises the following steps:

[0070] (1) Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride; preferably, the mesh number of the sieve is 20 - 80 mesh, more preferably 20 - 60 mesh, and further preferably 20 - 40 mesh, such as 40 mesh;

[0071] (2) Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride with a water-soluble binder to obtain mixture I;

[0072] (3) Mix colloidal silica and dimethicone to obtain mixture II;

[0073] (4) Mix mixture I and mixture II to obtain mixture III;

[0074] (5) Use a tableting die to press mixture III into tablets, and optionally coat them to obtain the product.

[0075] In one embodiment of the present invention, the preparation method of the solid preparation comprises the following steps:

[0076] (1) Sieve 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, such as 40 mesh;

[0077] (2) Detect the particle size distribution of anhydrous sodium sulfate, crush potassium chloride, and screen potassium chloride material with a particle size distribution similar to that of anhydrous sodium sulfate;

[0078] (3) Crush the water-soluble binder and then sieve it;

[0079] (4) Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride to obtain mixture I;

[0080] (5) Then add the water-soluble binder and colloidal silica to mixture I and mix to obtain mixture II;

[0081] (6) Spray dimethicone into mixture II using a spray gun to granulate and obtain mixture III;

[0082] (7) Screen and size the mixture III;

[0083] (8) After sizing is completed, mix using a mixing barrel to obtain mixture IV;

[0084] (9) Using a tableting die, press mixture IV into tablets, and optionally perform coating to obtain the product.

[0085] In one embodiment of the present invention, the method for preparing the solid preparation comprises the following steps:

[0086] (1) Screen anhydrous sodium sulfate and anhydrous magnesium sulfate, and the optional mesh number of the sieve is 20 - 80 mesh, more preferably 20 - 60 mesh, further preferably 20 - 40 mesh, for example 40 mesh;

[0087] (2) Detect the particle size distribution of anhydrous sodium sulfate, crush potassium chloride, and screen to obtain potassium chloride material with a particle size distribution similar to that of anhydrous sodium sulfate;

[0088] (3) Crush the water-soluble binder and then screen it;

[0089] (4) Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride to obtain mixture I;

[0090] (5) Then add the water-soluble binder and colloidal silica to mixture I and mix to obtain mixture II;

[0091] (6) Use a spray gun to spray dimethicone into mixture II for granulation to obtain mixture III;

[0092] (7) Screen and size the mixture III;

[0093] (8) After sizing is completed, mix using a mixing barrel to obtain mixture IV;

[0094] (9) Add a water-soluble lubricant mixture to obtain mixture V;

[0095] (10) Using a tableting die, press mixture V into tablets, and optionally perform coating to obtain the product.

[0096] In one embodiment of the present invention, when tableting, the hemispherical diameter of the upper and lower punches of the tableting die 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 (for example 5 - 7 mm), and the ratio of the arc depth to the hemispherical diameter is 0.2 - 0.3.

[0097] In the present invention, the hemispherical diameters of the upper and lower punches of the tablet press die refer to the diameters of the outermost edges of the punches.

[0098] The present invention provides a mixture containing anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, dimethicone, and colloidal silica, or 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, for preparing the solid preparation described in the present invention.

[0099] In a certain embodiment of the present invention, the mixture contains particles of anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride. As determined by screening analysis, the weight percentage of particles with a particle size less than 125 μm is in the range of 1% to 20%, more preferably in the range of 4% to 18%, still more preferably in the range of 7% to 15%; the weight percentage of particles with a particle size in the range of 125 μm to 150 μm is in the range of 3% to 17%, more preferably in the range of 5% to 15%, still more preferably in the range of 7% to 13%; the weight percentage of particles with a particle size in the range of 150 μm to 180 μm is in the range of 10% to 28%, more preferably in the range of 12% to 25%, still more preferably in the range of 14% to 22%; the weight percentage of particles with a particle size in the range of 180 μm to 250 μm is in the range of 30% to 55%, more preferably in the range of 32% to 50%, still more preferably in the range of 34% to 45%; the weight percentage of particles with a particle size in the range of 250 μm to 355 μm is in the range of 6% to 21%, more preferably in the range of 8% to 19%, still more preferably in the range of 10% to 17%; the weight percentage of particles with a particle size in the range of 355 μm to 600 μm is in the range of 2% to 14%, more preferably in the range of 2% to 12%, still more preferably in the range of 2% to 10%; and the weight percentage of particles with a particle size greater than 600 μm is in the range of 0.1% to 0.9%, more preferably in the range of 0.1% to 0.7%, still more preferably in the range of 0.1% to 0.5%, each based on the total weight of the particles.

[0100] In a certain embodiment of the present invention, the upper and lower punches of the tablet press die used during tableting are hemispherical.

[0101] In a certain embodiment of the present invention, no water is added during the preparation process of the solid preparation.

[0102] In a certain embodiment of the present invention, the above-mentioned solid preparation has an intestinal cleansing effect.

[0103] The present invention provides the use of the above-mentioned solid preparation or the solid preparation prepared by the above-mentioned preparation method in the preparation of a pharmaceutical preparation for intestinal cleansing.

[0104] The present invention provides a solid preparation for intestinal cleansing or a solid preparation prepared by the above-mentioned preparation method.

[0105] The present invention provides the use of a solid preparation prepared by the above-mentioned solid preparation or the above-mentioned preparation method for intestinal cleansing.

[0106] Unless otherwise specified, the terms used in this application have the following definitions. For terms not covered below, the definitions are as commonly understood by those skilled in the art to which the present invention pertains.

[0107] Term Definitions

[0108] "Spherical": The shape is spherical or quasi-spherical.

[0109] "Spherical solid preparation": A solid preparation with a "spherical" appearance, and its cross-section is circular or quasi-circular; it may or may not contain an intermediate zone;

[0110] "Intermediate zone": A belt with substantially the same thickness in the middle of the spherical solid preparation, as Figure 1 shown.

[0111] "Spherical tablet": A "spherical" tablet containing an intermediate zone.

[0112] "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 die hemisphere diameter is the diameter of the outermost edge of the die, that is, the diameter of the intermediate zone of the solid preparation), "intermediate zone thickness" (i.e., the longitudinal height of the intermediate zone), "intermediate zone diameter" (i.e., the diameter of the cross-section of the intermediate 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 where the intermediate zone protrudes relative to the hemisphere), "cross-sectional width of the edge" (i.e., the difference between the intermediate zone diameter and the hemisphere diameter): as Figure 1 shown.

[0113] "Solid preparation": It may or may not contain a coating.

[0114] "Weight percentage content": If the solid preparation contains a coating, it is calculated based on the uncoated preparation.

[0115] On the basis of not violating the common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0116] The reagents and raw materials used in the present invention are all commercially available.

[0117] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0118] (1) The present invention provides a novel compound sulfate solid preparation, which can effectively solve the technical problems existing in sulfate solid preparations for a long time, such as poor compressibility (difficult to press into tablets, sticking to punches, top-cracking, waist-cracking), poor fluidity, easy brittleness, and large variation in tablet weight. The prepared material has good fluidity and compressibility, no top-cracking, waist-cracking, or sticking to punches, high hardness, strong earthquake resistance and wear resistance, small variation in tablet weight, which is beneficial to subsequent operations such as film coating, and has good uniformity and reproducibility.

[0119] (2) The novel compound sulfate solid preparation of the present invention has no problem of bad taste of liquid preparations, and has a good taste; compared with conventional sulfate tablets, the size is greatly reduced, the tablet shape design has a regular appearance shape and 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 the number of tablets taken is less; moreover, the geometric shape is similar to that of small candies, which can give patients a certain degree of psychological suggestion, is easily accepted by patients, and improves compliance.

[0120] (3) The novel compound sulfate solid preparation of the present invention can effectively shorten the disintegration time, has a quick onset, reduces the residence time in the stomach, and reduces adverse reactions such as gastric ulcer and flatulence.

[0121] (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 the field of vision, improves the efficiency of colonoscopy, shortens the observation time, reduces the pain of patients, and overcomes the deficiencies of existing marketed preparations.

[0122] (5) The product quality of the novel compound sulfate solid preparation of the present invention is stable, and there are no obvious changes in the properties, ion content, disintegration time, and dissolution rate during long-term storage.

[0123] (6) The process of the novel compound sulfate solid preparation of the present invention is simple and stable, can be industrially produced on a large scale, and has no process defects such as oil spots. More preferably, water can be not added during the preparation process of the present invention, which is more beneficial to the stability of the preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0124] Figure 1 Schematic diagram of the spherical preparation of the present invention

[0125] Figure 2 Schematic diagram of the spherical preparation of the present invention

[0126] Figure 3 Appearance diagrams of the spherical preparation of the present invention (Example 1) and ordinary tablets (Comparative Examples 6 and 7)

[0127] Figure 4 The preparation of the present invention (Example 1) and marketed preparations Appearance diagram

[0128] Figure 5The preparation of the present invention (Example 6) and the marketed preparation Appearance diagram

[0129] Figure 6 The preparation of the present invention (Example 1) and the marketed preparation Diagram of defoaming effect and clarity of the solution after disintegration

[0130] Figure 7 The preparation of the present invention (Example 6) and the marketed preparation Diagram of defoaming effect and clarity of the solution after disintegration Detailed implementation mode

[0131] The implementation scheme of the present invention will be described in detail below in combination with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are adopted. For the reagents or instruments not specified in the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0132]

Example 1

[0133]

[0134]

[0135] The spherical tablets are prepared by direct compression, including the following steps:

[0136] Pretreatment:

[0137] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride, and the sieve mesh is 20-40 meshes.

[0138] Mixing:

[0139] ① Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride with polyethylene glycol 4000, pour them into a high-shear mixing granulator in sequence, and mix for 20 minutes to obtain mixture I;

[0140] ② Mix colloidal silicon dioxide and dimethicone to obtain mixture II;

[0141] ③ Mix mixture I and mixture II to obtain mixture III;

[0142] ④ Add sodium octanoate to mixture III and mix for 20 minutes to obtain mixture IV;

[0143] ⑤ Check the angle of repose, bulk density, and particle size distribution of mixture IV.

[0144] Tabletting:

[0145] ① In a tablet press, use a tablet press die with upper and lower punches being hemispherical, a hemispherical diameter of 6 mm, and an arc depth / hemispherical diameter ratio of 0.3 to press the mixture Ⅳ into tablets;

[0146] ② Check for process defects such as adhesion and top cracking during the tablet pressing process;

[0147] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0148] Film coating:

[0149] ① Weigh the prescribed amount IR, mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the desired weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air, and cool the small spherical tablets;

[0150] ② Check the disintegration time of the tablets.

[0151]

Example 2 - 3

[0152]

[0153] The specific preparation method is as follows:

[0154] Pretreatment:

[0155] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride through a sieve with a mesh size of 20 - 40 meshes.

[0156] Mixing:

[0157] ① Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride with polyethylene glycol 4000, pour them into a high - shear mixing granulator pot in sequence, and mix for 20 min to obtain mixture Ⅰ;

[0158] ② Mix colloidal silicon dioxide and dimethicone to obtain mixture Ⅱ;

[0159] ③ Mix mixture Ⅰ and mixture Ⅱ to obtain mixture Ⅲ;

[0160] ④ Then add sodium caprylate to mixture Ⅲ and mix for 20 min to obtain mixture Ⅳ;

[0161] ⑤ Check the angle of repose, bulk density, and particle size distribution of mixture Ⅳ.

[0162] Tablet pressing:

[0163] ① In a tablet press, use a tablet press die with upper and lower punches being hemispherical, a hemispherical diameter of 6 mm, and an arc depth / hemispherical diameter ratio of 0.3 to press the mixture Ⅳ into tablets;

[0164] ② Check for process defects such as adhesion and top cracking during the tabletting process;

[0165] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0166] Film coating:

[0167] ① Weigh the prescription amount IR, mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the desired weight gain range. Once enough film coating is applied, stop the coating, turn off the hot air supply of the inlet air, and cool the small spherical tablets;

[0168] ② Check the disintegration time of the tablets.

[0169]

Example 4

[0170]

[0171] The specific preparation method is as follows:

[0172] Pretreatment:

[0173] ① Sieve anhydrous sodium sulfate and anhydrous magnesium sulfate through a sieve with a mesh size of 20 - 40 meshes;

[0174] ② Detect the particle size distribution of anhydrous sodium sulfate;

[0175] ③ After potassium chloride is pulverized by a universal pulverizer for 10 s, it is sieved to select potassium chloride with a particle size distribution similar to that of anhydrous sodium sulfate; ④ After polyethylene glycol 4000 is pulverized by a universal pulverizer for 10 s, it is passed through a 60 - mesh sieve;

[0176] Mixing:

[0177] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and the selected potassium chloride into a high - shear mixing granulator pot for mixing for 10 min to obtain mixture Ⅰ;

[0178] ② Then add polyethylene glycol 4000 and colloidal silicon dioxide to mixture Ⅰ and mix for 10 min to obtain mixture Ⅱ;

[0179] ③ Use a spray gun to spray dimethicone into mixture Ⅱ for granulation to obtain mixture Ⅲ;

[0180] ④ Screen mixture Ⅲ through a sieve with a mesh size of 0.81 mm;

[0181] ⑤ After the screening is completed, use a conical mixing barrel to mix for 10 min to obtain mixture Ⅳ;

[0182] ⑥ Add sodium caprylate and mix for 10 min to obtain mixture V;

[0183] ⑦ Check the angle of repose, bulk density, and particle size distribution of mixture V.

[0184] Tabletting:

[0185] ① In a tabletting machine, use a tabletting die with upper and lower punches being hemispherical, the hemispherical diameter of the punch (i.e., the outermost diameter) being 6 mm, and the ratio of arc depth to hemispherical diameter being 0.3 to tablet the mixture Ⅳ;

[0186] ② Check whether there are process defects such as sticking and capping during the tabletting process;

[0187] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0188] Film coating:

[0189] ① Weigh the prescribed amount IR, mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the desired weight gain range, stop coating once enough film coating is applied, close the hot air supply of the inlet air, and cool the small spherical tablets;

[0190] ② Check the disintegration time of the tablets.

[0191]

Example 5

[0192]

[0193] The specific preparation method is as follows:

[0194] Pretreatment:

[0195] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride, with a sieve mesh of 20 - 40 meshes.

[0196] Mixing:

[0197] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride into a high - shear mixing granulator pot for mixing for 10 min to obtain mixture Ⅰ;

[0198] ② Then add polyethylene glycol 4000 and colloidal silicon dioxide to mixture Ⅰ and mix for 10 min to obtain mixture Ⅱ;

[0199] ③ Use a spray gun to spray dimethicone into mixture Ⅱ and granulate to obtain mixture Ⅲ;

[0200] ④ Screen mixture Ⅲ, with a sieve mesh of 0.81 mm;

[0201] ⑤After the whole granulation process, a conical mixing barrel is used for mixing for 10 minutes to obtain mixture Ⅳ;

[0202] ⑥Check the angle of repose, bulk density, and particle size distribution of mixture Ⅳ.

[0203] Tablet pressing:

[0204] ①In a tablet press, a spherical tablet is pressed using a tablet pressing die with upper and lower punches being hemispherical, the hemispherical diameter of the punch die (the outermost diameter of the punch die) being 7 mm, and the ratio of arc depth to hemispherical diameter being 0.291;

[0205] ②Check whether there are process defects such as adhesion and top cracking during the tablet pressing process;

[0206] ③Check the friability, weight variation, and disintegration time of the plain tablets.

[0207] Film coating:

[0208] ①Weigh the prescribed amount IR, and mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the desired weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air, and cool the small spherical tablets;

[0209] ②Check the disintegration time of the tablets.

[0210]

Example 6

[0211]

[0212] The specific preparation method is as follows:

[0213] Pretreatment:

[0214] ①Sieve anhydrous sodium sulfate and anhydrous magnesium sulfate, with the sieve mesh being 20 - 40 meshes;

[0215] ②Detect the particle size distribution of anhydrous sodium sulfate;

[0216] ③After potassium chloride is pulverized by a universal pulverizer for 10 s, it is sieved to select potassium chloride with a particle size distribution similar to that of anhydrous sodium sulfate; ④After polyethylene glycol 4000 is pulverized by a universal pulverizer for 10 s, it is passed through a 60 - mesh sieve;

[0217] Mixing:

[0218] ①Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and the selected potassium chloride into a high - shear mixing granulator pot for mixing for 10 minutes to obtain mixture Ⅰ;

[0219] ② Then, polyethylene glycol 4000 and colloidal silica were added to Mixture Ⅰ and mixed for 10 min to obtain Mixture Ⅱ;

[0220] ③ Dimethicone was spray-added to Mixture Ⅱ using a spray gun for granulation to obtain Mixture Ⅲ;

[0221] ④ The mixture Ⅲ was sized and sieved through a sieve with a mesh size of 0.81 mm;

[0222] ⑤ After sizing, a conical mixing barrel was used to mix for 10 min to obtain Mixture Ⅳ;

[0223] ⑥ The angle of repose, bulk density, and particle size distribution of Mixture Ⅳ were inspected.

[0224] Tablet pressing:

[0225] ① In a tablet press, a spherical tablet was pressed using a tablet press die with upper and lower punches being hemispherical, the hemispherical diameter of the punch (the outermost diameter of the punch) being 7 mm, and the ratio of arc depth to hemispherical diameter being 0.291;

[0226] ② Whether there are process defects such as adhesion and top cracking during the tablet pressing process was inspected;

[0227] ③ The friability, tablet weight variation, and disintegration time of the plain tablets were inspected.

[0228] Film coating:

[0229] ① Weigh the prescription amount IR, and mix it with an appropriate amount of purified water to prepare a coating solution. The plain tablets were kept at 25 - 35 °C, and the coating solution was continuously stirred during the coating process. The coating solution was sprayed onto the spherical tablets to obtain the required weight gain range, and once enough film coating was applied, the coating was stopped, the hot air supply of the inlet air was turned off, and the small spherical tablets were cooled;

[0230] ② The disintegration time of the tablets was inspected.

[0231]

Example 7 - 8

[0232]

[0233]

[0234] The specific preparation method is as follows:

[0235] Pretreatment:

[0236] ① Sodium sulfate anhydrous and magnesium sulfate anhydrous were sieved through a sieve with a mesh size of 20 - 40 mesh;

[0237] ② The particle size distribution of sodium sulfate anhydrous was detected;

[0238] ③ After pulverizing potassium chloride with a universal pulverizer for 10 s, perform screening to select potassium chloride with a particle size distribution similar to that of anhydrous sodium sulfate; ④ After pulverizing polyethylene glycol 4000 with a universal pulverizer for 10 s, pass it through a 60-mesh sieve.

[0239] Mixing:

[0240] ① Pour the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, and the selected potassium chloride into a high-shear mixing granulator pot for mixing for 10 min to obtain mixture I;

[0241] ② Then add polyethylene glycol 4000 and colloidal silica to mixture I and mix for 10 min to obtain mixture II;

[0242] ③ Use a spray gun to spray dimethicone into mixture II for granulation to obtain mixture III;

[0243] ④ Screen mixture III through a sieve with a mesh size of 0.81 mm;

[0244] ⑤ After the granulation is completed, use a conical mixing barrel to mix for 10 min to obtain mixture IV;

[0245] ⑥ Check the angle of repose, bulk density, and particle size distribution of the particles in mixture IV.

[0246] Tablet pressing:

[0247] ① In a tablet press, use a tablet pressing die with upper and lower punches being hemispherical, the hemispherical diameter of the punch (the outermost diameter of the punch) being 7 mm, and the ratio of the arc depth to the hemispherical diameter being 0.291 to press into spherical tablets;

[0248] ② Check whether there are process defects such as sticking and top cracking during the tablet pressing process;

[0249] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0250] Film coating:

[0251] ① Weigh the prescription amount IR, mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the desired weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air, and cool the small spherical tablets;

[0252] ② Check the disintegration time of the tablets.

[0253]

Comparative Example 1

[0254] According to the patent publication (announcement) number CN112292136A (trade name: )The published prescription composition is used to press the spherical tablets of the present invention, as shown in the following table:

[0255]

[0256] The specific preparation method is as follows:

[0257] Pretreatment:

[0258] Sieve anhydrous sodium sulfate, potassium sulfate, and anhydrous magnesium sulfate through a sieve with a mesh size of 20 - 40 meshes.

[0259] Mixing:

[0260] ① Weigh anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate, and copovidone, and pour them into a high - shear mixing granulator pot in sequence. Mix for 20 min to obtain mixture Ⅰ;

[0261] ② Weigh simethicone and add it to mixture Ⅰ. Mix for 10 min. Pour it into a conical crushing and sizing machine with a sieve mesh of 0.99 mm and a rotation speed of 1000 rpm. After sizing, pour it into a single - arm fixed hopper mixer and mix for 10 min to obtain mixture Ⅱ;

[0262] ③ Check the angle of repose and bulk density of mixture Ⅱ.

[0263] Tablet pressing:

[0264] ① In a tablet press, use a punch die with upper and lower punches being hemispherical, a hemispherical diameter of 6 mm, and an arc depth / hemispherical diameter ratio of 0.3 to press mixture Ⅱ into tablets;

[0265] ② Check whether there are process defects such as sticking and top - cracking during tablet pressing;

[0266] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0267] Film coating:

[0268] ① Weigh the prescription amount IR, and mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the required weight gain range. Once enough film coating is applied, stop coating, turn off the hot air supply of the inlet air, and cool the small spherical tablets;

[0269] ② Check the disintegration time of the tablets.

[0270]

Comparative Example 2

[0271] According to the prescription composition published in Patent Publication (Announcement) No. US10143656B1 (trade name: ), press the spherical tablets of the present invention, as shown in the following table:

[0272]

[0273] The specific preparation method is as follows:

[0274] Pretreatment:

[0275] Sieve anhydrous sodium sulfate, magnesium sulfate, and potassium chloride through a sieve with a mesh size of 20 - 40 meshes.

[0276] Mixing:

[0277] ① Weigh anhydrous sodium sulfate, magnesium sulfate, potassium chloride, and polyethylene glycol 8000, and pour them into a high - shear mixing granulator pot in sequence, and mix for 20 min to obtain mixture Ⅰ;

[0278] ② Weigh sodium caprylate and add it to mixture Ⅰ, and mix for 10 min to obtain mixture Ⅱ;

[0279] ③ Check the angle of repose and bulk density of mixture Ⅱ.

[0280] Tabletting:

[0281] ① In a tabletting machine, use a tabletting die with upper and lower punches being hemispherical, the hemispherical diameter being 6 mm, and the ratio of arc depth to hemispherical diameter being 0.3 to tablet mixture Ⅱ;

[0282] ② Check whether there are process defects such as sticking and capping during the tabletting process;

[0283] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0284] Film coating:

[0285] ① Weigh the prescription amount IR, and mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the required weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air and cool the small spherical tablets;

[0286] ② Check the disintegration time of the tablets.

[0287]

Comparative Examples 3 - 5

[0288]

[0289] Prepared according to the method of Reference Example 1, with the only difference being that dimethicone or colloidal silica is not added (Comparative Example 3), colloidal silica is not added (Comparative Example 4), and dimethicone is not added (Comparative Example 5). The specific preparation method is as follows:

[0290] Mixing:

[0291] ① Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, and pour them into a high-shear mixing granulator pot in sequence, mix for 20 min to obtain mixture Ⅰ;

[0292] ② Mix dimethicone (Comparative Example 4) / colloidal silica (Comparative Example 5) with mixture Ⅰ to obtain mixture Ⅱ; (except for Comparative Example 3);

[0293] ③ Then add sodium caprylate to mixture Ⅱ (Comparative Example 4 or Comparative Example 5) or mixture Ⅰ (Comparative Example 3), mix for 20 min to obtain mixture Ⅲ;

[0294] ④ Check the angle of repose and bulk density of mixture Ⅲ.

[0295] Tabletting:

[0296] ① In a tabletting machine, use a tabletting die with upper and lower punches being hemispherical, the hemispherical diameter being 6 mm, and the ratio of arc depth to hemispherical diameter being 0.3 to tablet mixture Ⅲ;

[0297] ② Check whether there are process defects such as sticking and capping during the tabletting process;

[0298] ③ Check the friability, tablet weight variation and disintegration time of the plain tablets.

[0299] Film coating:

[0300] ① Weigh the prescription amount IR, mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the required weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air and cool the small spherical tablets;

[0301] ② Check the disintegration time of the tablets.

[0302]

Comparative Examples 6 - 7

[0303]

[0304] Prepared according to the method of Reference Example 1, with the only difference being the different punches. The punch of Comparative Example 6 is a 17 mm * 10 mm ordinary tablet punch and the punch of Comparative Example 7 is a 6 mm ordinary tablet punch. The specific preparation method is as follows:

[0305] Pretreatment:

[0306] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate and potassium chloride, and the sieve mesh is 20 - 40 meshes.

[0307] Mixing:

[0308] ① Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride with polyethylene glycol 4000, pour them into a high-shear mixing granulator pot in sequence, and mix for 20 min to obtain mixture I;

[0309] ② Mix colloidal silica with dimethicone to obtain mixture II;

[0310] ③ Mix mixture I with mixture II to obtain mixture III;

[0311] ④ Then add sodium caprylate to mixture III and mix for 20 min to obtain mixture IV;

[0312] ⑤ Check the angle of repose and bulk density of mixture IV.

[0313] Tabletting:

[0314] ① Use a rotary tabletting machine to tablet, the punching dies are 17 mm * 10 mm ordinary tablet punches (Comparative Example 6) and 6 mm ordinary tablet punches (Comparative Example 7), and tablet mixture IV;

[0315] ② Check whether there are process defects such as sticking and capping during the tabletting process;

[0316] ③ Check the friability, tablet weight variation, and disintegration time of the plain tablets.

[0317] Film coating:

[0318] ① Weigh the prescription amount IR, mix it with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the required weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air and cool the small tablets;

[0319] ② Check the disintegration time of the tablets.

[0320]

Comparative Example 8

[0321]

[0322]

[0323] Prepared by referring to the method of Example 1, the difference is only that the dimethicone + colloidal silica composition is replaced by simethicone, and the specific preparation method is as follows:

[0324] Pretreatment:

[0325] Sieve anhydrous sodium sulfate, anhydrous magnesium sulfate, and potassium chloride, and the sieve mesh is 20 - 40 meshes.

[0326] Mixing:

[0327] ① Mix the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and polyethylene glycol 4000, and pour them into a high-shear mixing granulator pot in sequence, mix for 20 min to obtain mixture Ⅰ;

[0328] ② Mix simethicone with mixture Ⅰ, mix for 20 min to obtain mixture Ⅱ;

[0329] ③ Then add sodium caprylate to mixture Ⅱ, mix for 20 min to obtain mixture Ⅲ;

[0330] ④ Check the angle of repose and bulk density of mixture Ⅲ.

[0331] Tabletting:

[0332] ① In a tabletting machine, use a tabletting die with upper and lower punches being hemispherical, the hemispherical diameter of the punch die (the outermost diameter of the punch die) being 6 mm, and the ratio of arc depth / hemispherical diameter being 0.3 to tablet mixture Ⅲ;

[0333] ② Check whether there are technological defects such as sticking and capping during the tabletting process;

[0334] ③ Check the friability, tablet weight variation and disintegration time of the plain tablets.

[0335] Film coating:

[0336] ① Weigh the prescription amount IR, mix with an appropriate amount of purified water to prepare a coating solution. Keep the plain tablets at 25 - 35 °C and continue to stir the coating solution during the coating process. Spray the coating solution onto the spherical tablets to obtain the required weight gain range, stop coating once enough film coating is applied, turn off the hot air supply of the inlet air and cool the small spherical tablets;

[0337] ② Check the disintegration time of the tablets.

[0338] I. Research on the effects of the solid preparation of the present invention

[0339] 1.1 Granule fluidity experiment

[0340] (1) Angle of repose

[0341] The angle of repose is the stable three-dimensional angle (relative to the horizontal base) formed when the material presents in a conical shape. Add an excessive amount of the powder to be tested (the material corresponding to checking the angle of repose in the preparation steps of the examples and comparative examples) into a container with a chassis of a fixed diameter In the device, when the powder flows out from the central hole at the bottom of the container, a smooth moving inclined plane (the vertical shear plane is triangular), measure the radius of the disc and the height of the powder, and calculate the angle of repose, Tanθ = height / radius.

[0342] (2) Carr index

[0343] Take about 50 g of the material (the material corresponding to the inspection of bulk density in the preparation steps of the examples and comparative examples), weigh it accurately, gently add it to a 100 mL graduated cylinder, record the loose volume, install the graduated cylinder on a vibrator, set the number of vibrations to 500 times, the amplitude to 3 ± 0.3 mm, record the tapped volume after the vibration stops, and calculate the bulk density, tapped density and Carr's index. The calculation formula of Carr's index = (tapped density - bulk density) / tapped density * 100%.

[0344] Table 1 Results of fluidity experiment

[0345] item Particle fluidity (angle of repose) Particle fluidity (Carr index) Example 1 29° 12％ Example 2 32° 21％ Example 3 31° 19％ Example 4 27° 13％ Example 5 30° 12％ Example 6 28° 12％ Example 7 31° 16％ Example 8 32° 15％ Comparative Example 1 52° 37％ Comparative Example 2 59° 42％ Comparative Example 3 52° 32％ Comparative Example 4 39° 36％ Comparative Example 5 43° 29％ Comparative Example 6 29° 12％ Comparative Example 7 27° 12％ Comparative Example 8 48° 29％

[0346] The patented formulation (Comparative Example 1) and The patented formulation (Comparative Example 2) has poor particle fluidity; although in Comparative Example 8, simethicone is used to replace colloidal silica and dimethicone, the fluidity still cannot be effectively improved. The solid preparation particles of the present invention have good fluidity and meet the requirements of the preparation.

[0347] Without adding dimethicone and colloidal silica (Comparative Example 3) or only adding one of them alone (Comparative Examples 4 and 5), good fluidity of the material cannot be guaranteed. The combined use of dimethicone and colloidal silica in the present invention can effectively improve the fluidity.

[0348] 1.2 Tableting situation and friability experiment

[0349] Observe the sticking and capping situations during the tableting process.

[0350] Take several tablets of the preparation (the material corresponding to the inspection of friability in the preparation steps of the examples and comparative examples), and make their total weight about 6.5 g. Blow off the powder falling off the tablets with a hair dryer, and accurately weigh the total weight and record it as the weight before rolling. Then place it in a friability tester (model: FT-2000AE) cylinder and roll it 100 times. Take it out, blow off the powder falling off the tablets with a hair dryer, and accurately weigh the total weight and record it as the weight after rolling.

[0351] Friability = (weight before rolling - weight after rolling) / weight before rolling × 100%.

[0352] The experimental results are shown in Table 2.

[0353] Table 2 Results of tableting sticking, capping situations and friability experiment

[0354] item adhesion top cracking friability Example 1 - - 0.30％ Example 2 - - 0.35％ Example 3 - - 0.30％ Example 4 - - 0.33％ Example 5 - - 0.26％ Example 6 - - 0.21％ Example 7 - - 0.28％ Example 8 - - 0.26％ Comparative Example 1 ++ +++ 1.20％ Comparative Example 2 +++ +++ 0.60％ Comparative Example 3 ++ +++ 1.20％ Comparative Example 4 ++ + 0.60％ Comparative Example 5 + - 0.40％ Comparative Example 6 ++ ++ 2.80％ Comparative Example 7 + + 1.50％ Comparative Example 8 + + 1.69％

[0355] Note: +++: Very highly frequent; ++: Highly frequent; +: Frequent (showing defects); -: No defects

[0356] Patent prescription (Comparative Example 1) and During the tabletting process of the patent prescription (Comparative Example 2), defects such as high-frequency sticking and capping occurred, and the produced products had poor friability, unable to ensure the integrity of the tablets during the coating process and finished product transportation.

[0357] In the tabletting processes of the prescriptions without dimethicone and colloidal silica (Comparative Example 3), without colloidal silica (Comparative Example 4), and without dimethicone (Comparative Example 5), there were sticking and capping process defects, and the friability was not good. According to The simethicone added in the patent prescription, replacing the dimethicone + colloidal silica composition of the present invention (Comparative Example 8), also could not completely solve the problems of sticking, capping defects, and poor friability. The combined use of dimethicone and silica in the present invention (Examples 1-8) effectively solved the problems of sticking, capping, and friability, ensuring the smoothness of the process during the preparation of the preparation.

[0358] When using the same prescription to press tablets with ordinary tablet dies (Comparative Examples 6 and 7), whether large-sized or small-sized, there were sticking and capping defects. In addition, the friability increased significantly, unable to meet the subsequent coating requirements. The spherical shape of the solid preparation of the present invention can be stably and completely pressed into shape under the same tablet diameter and tablet weight, with good friability, which is beneficial to the subsequent coating process and the transportation and storage of the finished product.

[0359] 1.3 Tablet weight variation test

[0360] Randomly take 20 tablets (the materials for checking tablet weight variation 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. Compare the weight of each tablet with the average tablet weight.

[0361] Lower limit of tablet weight variation = (the smallest weight among the 20 tablets - average tablet weight) / average tablet weight × 100%;

[0362] Upper limit of tablet weight variation = (the largest weight among the 20 tablets - average tablet weight) / average tablet weight × 100%;

[0363] The experimental results are shown in Table 3.

[0364] Table 3 Experimental results of tablet weight variation

[0365]

[0366]

[0367] According to Patent prescription (Comparative Example 1) and Tablets prepared with the patented prescription (Comparative Example 2) had a large variation in tablet weight, failing to meet the requirements of continuous tablet manufacturing processes.

[0368] Tablets pressed with the prescription without dimethicone and colloidal silica (Comparative Example 3), the prescription without colloidal silica (Comparative Example 4), the prescription without dimethicone (Comparative Example 5), and the replacement of dimethicone + colloidal silica composition of the present invention with simethicone (Comparative Example 8) also could not ensure qualified tablet weight variation.

[0369] Tablets pressed with the same prescription using the dies for ordinary tablets (Comparative Examples 6 and 7) had a large variation in tablet weight, especially for large-sized tablets, with a significant difference.

[0370] 1.4 Disintegration Time Experiment

[0371] Using an intelligent disintegration tester (model ZB-1E), add 900 ml of disintegration medium (purified water) to a beaker, then place it in the disintegration tester and heat it in a water bath to a temperature of 37°C ± 1°C. Place the tablets (the materials for checking the disintegration time in the preparation steps of the examples and comparative examples) in the glass tubes of the disintegration tester basket respectively, start the disintegration tester for inspection, record the disintegration time each time, and calculate the mean value by summarization. For Examples 1-4 and Comparative Examples 1-8, add 10 tablets (total 2 g) to each glass tube; for Examples 5-8, add 5 tablets (total 1.875 g) to each glass tube.

[0372] The experimental results are shown in Table 4-1 or Table 4-2.

[0373] Table 4-1 Disintegration Time Experiment Results of Examples 1-4 and Comparative Examples 1-8

[0374]

[0375]

[0376] Table 4-2 Disintegration Time Experiment Results of Examples 5-8

[0377]

[0378] According to the patented prescription (Comparative Example 1) and the tablets prepared with the patented prescription (Comparative Example 2), as well as the tablets pressed with the prescription without dimethicone and colloidal silica (Comparative Example 3), the prescription without colloidal silica (Comparative Example 4), the prescription without dimethicone (Comparative Example 5), and the replacement of dimethicone + colloidal silica composition of the present invention with simethicone (Comparative Example 8) had a longer disintegration time. There were oil spots on the tablets of Comparative Example 1 and Comparative Example 8 during tableting with simethicone. The combined use of dimethicone and colloidal silica in the present invention has better disintegration performance.

[0379] Tablets compressed with the die of ordinary tablets (Comparative Examples 6 and 7) of the same prescription showed slow disintegration, and the solid preparation of the present invention had better disintegration performance than ordinary tablets of the same size.

[0380] 1.5 Detection of particle size distribution

[0381] Take the 600μm, 355μm, 250μm, 180μm, 150μm, 125μm sieves and the chassis respectively, and stack them in the order of the large-aperture sieve on the upper layer and the small-aperture sieve on the lower layer. The bottom layer is equipped with a chassis, and the top layer is covered. Take about 100g of particles (the materials corresponding to the detection of particle size distribution in the preparation steps of the examples and comparative examples) and place them in the top sieve, cover it, install all the sieves on the sieve shaker (model: As200 basic B), set the amplitude to 75Hz, and the time to 5min. After the end, weigh the weight of each sieve and the chassis respectively, and calculate the particle size distribution by calculating the powder ratio. As shown in Table 5, this table shows the particle size distribution of the examples.

[0382] Table 5 Detection results of particle size distribution

[0383]

[0384]

[0385] 1.6 Stability test

[0386] The compound sulfate spherical tablets prepared in Example 1 and Example 6 were subjected to an accelerated test (40°C, RH75%) according to the guiding principles of the stability test of the Chinese Pharmacopoeia. Referring to the pharmacopoeia method, the disintegration time (disintegration medium: purified water), dissolution rate (dissolution medium: purified water, sampling at 15 minutes, 75rpm), and the content of each ion were detected, and the appearance was observed. The results are shown in Table 6.

[0387] Table 6 Stability test results of the compound sulfate spherical tablets prepared in Example 1 and Example 6

[0388]

[0389] The compound sulfate spherical tablets prepared in Example 1 and Example 6 of the present invention showed excellent stability in the accelerated test (40°C, RH75%) for 6 months, and there were no obvious changes in each index compared with day 0.

[0390] II. The solid preparation of the present invention (Example 1 / Example 6) and the conventional oral sulfate tablet preparation Comparison

[0391] 2.1 Appearance

[0392] The schematic diagram of the spherical preparation of the present invention is as Figure 1-2 shown.

[0393] The appearance comparison between the spherical preparation (Example 1) and the ordinary tablets (Comparative Examples 6 and 7) of the present invention is as follows Figure 3 shown.

[0394] For the spherical preparations of Examples 1-4 of the present invention, it was measured that the diameter of the middle zone of the spherical tablets was 6 mm, the diameter of the hemisphere was 5.60 mm, the width of the edge cross-section was 0.20 mm, the thickness of the middle zone was 2.30 - 2.70 mm, and the arc depth was 1.80 mm.

[0395] For the spherical preparations of Examples 5-8 of the present invention, it was measured that the diameter of the middle zone of the spherical tablets was 7 mm, the diameter of the hemisphere was 6.68 mm, the width of the edge cross-section was 0.16 mm, the thickness of the middle zone was 2.80 - 3.20 mm, and the arc depth was 2.04 mm.

[0396] The appearance comparison between Example 1 of the present invention and the conventional oral sulfate tablet preparation is as follows Figure 4 shown; the appearance comparison between Example 6 of the present invention and the conventional oral sulfate tablet preparation is as follows Figure 5 shown.

[0397] 2.2 Disintegration time

[0398] Using an intelligent disintegration tester (model ZB-1E), add 900 ml of disintegration medium into a beaker, and then place it in the disintegration tester for water bath heating to a temperature of 37°C ± 1°C. Place the tablets into 6 glass tubes of the disintegration tester basket respectively. For Example 1, add 10 tablets (total 2 g) to each glass tube, and for Example 6, add 5 tablets (total 1.875 g) to each glass tube. (2 g) and (1.5 g) Add 1 tablet to each glass tube. Start the disintegration tester, and simultaneously detect the disintegration time of the preparations in the 6 glass tubes. Record the disintegration time of each tablet ( and ) or each time (Examples 1 and 6), and summarize and calculate the mean value.

[0399] The experimental results are shown in Table 7.

[0400] Table 7 Comparison of disintegration time between Example 1, Example 6 and the conventional preparation Disintegration time comparison

[0401]

[0402] The spherical tablets of the present invention can be completely disintegrated within 5 minutes, and the disintegration effect has been 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.

[0403] 2.3 Clarity

[0404] At room temperature (37°C ± 1°C), after the tablets are completely disintegrated in the disintegrator, visual inspection is immediately carried out. Then, to investigate the defoaming effect, after adding a surfactant to the solution, stir the solution with a glass rod to form bubbles, and observe the state of the solution after the solution stands for 5 min to evaluate the effect of the defoaming agent.

[0405] 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 as Figure 6 shown.

[0406] 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 as Figure 7 shown.

[0407] During the endoscopic examination process, there is a 32% - 57% probability of encountering intestinal foam, which affects the observation effect and examination time of the digestive tract mucosa and lesions. Research has found that 12 tablets * 2 g / tablet have obvious foam and no defoaming effect; 14 tablets * 1.5 g / tablet can reduce foam to a certain extent, but it has high turbidity. The solid preparations of the present invention (Examples 1 and 6) have a significant defoaming effect, and the clarity is significantly better than that of the marketed preparation

[0408] It should be understood that the above embodiments are only for further illustration and explanation of the present invention, and do not constitute a limitation to the present invention. Those skilled in the art can 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: Anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride, simethicone and colloidal silicon dioxide.

2. The solid preparation according to claim 1, characterized in that 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.

3. The solid preparation according to claim 1 or 2, characterized in that The combined weight percentage of dimethicone and colloidal silicon dioxide 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 silicon dioxide (if coated, calculated relative to the uncoated preparation) is 0.1% to 2.1%; more preferably, the combined weight percentage of dimethicone and colloidal silicon dioxide (if coated, calculated relative to the uncoated preparation) is 0.6% to 1.5%; most preferably, the combined weight percentage of dimethicone and colloidal silicon dioxide (if coated, calculated relative to 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 of the components in the solid preparation (if coated, calculated relative to the uncoated preparation) is: 50.0% to 95.0% of anhydrous sodium sulfate, 5.0% to 20.0% of anhydrous magnesium sulfate, 5.0% to 20.0% of potassium chloride, and 0.05% to 5% of dimethicone and colloidal silicon dioxide (calculated based on the total weight of dimethicone and colloidal silicon dioxide); preferably, the weight percentage of the components in the solid preparation (if coated, calculated relative to the uncoated preparation) is: 60.0% to 90.0% of anhydrous sodium sulfate, 7.0% to 15.0% of anhydrous magnesium sulfate, 7.0% to 12.0% of potassium chloride, and 0.1% to 2.1% of dimethicone and colloidal silicon dioxide (calculated based on the total weight of dimethicone and colloidal silicon dioxide); more preferably The weight percentages of the components in the solid preparation (if coated, based on the uncoated preparation) are: 65.0% to 85.0% anhydrous sodium sulfate, 8.0% to 14.0% anhydrous magnesium sulfate, 8.0% to 11.0% potassium chloride, and 0.6% to 1.5% dimethicone and colloidal silicon dioxide (based on the combined weight of dimethicone and colloidal silicon dioxide); most preferably, the weight percentages of the components in the solid preparation (if coated, based on the uncoated preparation) are: 70.0% to 80.0% anhydrous sodium sulfate, 9.0% to 13.0% anhydrous magnesium sulfate, 9.0% to 10.0% potassium chloride, and 1.0% to 1.2% dimethicone and colloidal silicon dioxide (based on the combined weight of dimethicone and colloidal silicon dioxide).

5. The solid preparation according to any one of claims 1 to 4, characterized in that The solid preparation also includes 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, based on 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, based on 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.

6. The solid preparation according to any one of claims 1 to 4, characterized in that The solid preparation also includes a water-soluble adhesive, but does not include a water-soluble lubricant; preferably, the weight percentage of the water-soluble adhesive (if coated, relative to the uncoated preparation) is 1.5% to 7.5%; more preferably, the weight percentage of the water-soluble adhesive (if coated, relative to 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 octanoate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, polyoxyethylene monostearate, and polyoxyethylene lauryl alcohol; and / or the water-soluble adhesive is one or more of polyethylene glycol (polyethylene glycol 3350 / 4000 / 6000 / 8000), hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, carboxymethyl cellulose, and sodium alginate.

8. The solid preparation according to any one of claims 1 to 7, characterized in that The solid preparation also includes a water-soluble film coating; preferably, the mass percentage of the water-soluble film coating relative to the uncoated preparation is 0.1wt% to 5.0wt%, and more preferably, the mass percentage of the water-soluble film coating relative to the uncoated preparation is 1.0wt% to 3.0wt%; and / or, 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.

9. The solid preparation according to any one of claims 1 to 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 to 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; further preferably, the size of the spherical solid preparation is 5 to 8 mm (e.g., 5 to 7 mm).

11. The solid preparation according to any one of claims 1 to 10, characterized in that: The spherical solid preparation may or may not contain an intermediate zone; preferably, the spherical solid preparation 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; further 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 (e.g., 5 to 7 mm); And / or, 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; more preferably, the hemisphere diameter of the spherical solid preparation is 4 to 8 mm; further preferably, the hemisphere diameter of the spherical solid preparation is 5 to 8 mm (e.g., 5 to 7 mm); And / or, the spherical solid preparation comprises a middle zone and an edge (i.e., the portion of the middle zone protruding relative to the hemisphere), 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; further 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, 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 arc depth / hemispherical diameter ratio of the upper and lower punches of the mold used for compressing the spherical solid preparation is 0.2-0.5; more preferably, the arc depth / hemispherical diameter ratio is 0.2-0.4; most preferably, the arc depth / hemispherical diameter ratio is 0.2-0.

3.

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

13. The solid preparation or the preparation method thereof according to any one of claims 1 to 12, 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, preferably with a sieve mesh of 20-80 mesh, more preferably 20-60 mesh, and further preferably 20-40 mesh; (2) mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate, potassium chloride and a water-soluble binder to obtain a mixture I; (3) mixing colloidal silica and dimethicone to obtain a mixture II; (4) mixing mixture I with mixture II to obtain mixture III; (5) optionally, adding a water-soluble lubricant to the mixture III and mixing to obtain a mixture IV; (6) Using a tabletting mold, compressing mixture III (when not containing a water-soluble lubricant) or mixture IV (when containing a water-soluble lubricant) into tablets, and optionally coating them, to obtain; Preferably, the hemispherical diameter of the upper and lower dies of the tableting mold used for tableting is 2-10 mm, and the arc depth / hemisphere diameter ratio is 0.2-0.5; preferably, the hemispherical diameter is 3-9 mm, and the arc depth / hemisphere diameter ratio is 0.2-0.5; more preferably, the hemispherical diameter is 4-8 mm, and the arc depth / hemisphere diameter ratio is 0.2-0.4; most preferably, the hemispherical diameter is 5-8 mm (for example, 5-7 mm), and the arc depth / hemisphere diameter ratio is 0.2-0.

3.

15. The preparation method according to claim 13, characterized in that: The method comprises the following steps: (1) sieving anhydrous sodium sulfate and anhydrous magnesium sulfate; preferably, the mesh size of the sieve is 20-80 mesh, more preferably 20-60 mesh, and further preferably 20-40 mesh; (2) detecting the particle size distribution of anhydrous sodium sulfate, crushing potassium chloride, and screening potassium chloride materials with a particle size distribution similar to that of anhydrous sodium sulfate; (3) crushing the water-soluble adhesive and sieving it; (4) mixing the sieved anhydrous sodium sulfate, anhydrous magnesium sulfate and sieved potassium chloride to obtain a mixture I; (5) adding a water-soluble binder and colloidal silicon dioxide to the mixture I and mixing them to obtain a mixture II; (6) spraying dimethicone into mixture II and granulating to obtain mixture III; (7) sieving the mixture III; (8) After the granulation is completed, the mixture is mixed to obtain a mixture IV; (9) optionally, adding a water-soluble lubricant mixture to obtain a mixture V; (10) Using a tabletting mold, compressing mixture IV (when not containing a water-soluble lubricant) or mixture V (when containing a water-soluble lubricant) into tablets, and optionally coating them, to obtain; Preferably, the hemispherical diameter of the upper and lower dies of the tableting mold used for tableting is 2-10 mm, and the arc depth / hemisphere diameter ratio is 0.2-0.5; preferably, the hemispherical diameter is 3-9 mm, and the arc depth / hemisphere diameter ratio is 0.2-0.5; more preferably, the hemispherical diameter is 4-8 mm, and the arc depth / hemisphere diameter ratio is 0.2-0.4; most preferably, the hemispherical diameter is 5-8 mm (for example, 5-7 mm), and the arc depth / hemisphere diameter ratio is 0.2-0.

3.

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

Images