Multi-unit sustained release tablet and preparation method thereof

Abstract

The invention relates to a sustained-release tablet capable of avoiding sudden release of a medicine after being taken together with an alcoholic beverage, the sustained-release tablet comprises a sustained-release tablet core and an anti-sudden-release material coating layer wrapping the sustained-release tablet core, and the anti-sudden-release material is composed of a polysaccharide substance and a cellulose derivative, the polysaccharide substance is selected from one or more of guar gum, xanthan gum and Arabic gum, the cellulose derivative is selected from one or more of hydroxypropyl methylcellulose, ethyl cellulose and hydroxyethyl cellulose, and the weight ratio of the polysaccharide substance to the cellulose derivative is 1: 1-10: 1. The sustained-release tablet disclosed by the invention has an excellent burst release resisting effect when being taken together with an alcoholic beverage, and the clinical medication safety and effectiveness of a preparation are improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a multi-unit sustained-release tablet and a preparation method thereof. Background Art

[0002] Compared with oral immediate-release preparations, oral modified-release preparations usually contain higher drug doses and different excipient ingredients, which can release drugs slowly, controllably or in a predictable manner. If the active drug ingredients are unexpectedly released from the preparation in whole or in large part quickly, resulting in a large accumulation of high-dose drugs in the body in a short period of time, it may cause problems with drug safety and efficacy.

[0003] In order to reduce the risk of sudden release of drugs in oral modified-release preparations, membrane-coated preparations can use film-forming materials that are not easily soluble in alcohol, such as ethyl acrylate-methyl methacrylate copolymer, cellulose acetate, etc. Frame-based preparations can use frame materials that are not easily soluble in alcohol, such as polyethylene oxide, chitosan, carbomer, beeswax, etc.

[0004] For sustained-release multi-unit delivery preparations such as sustained-release pellet tablets, most of the prescriptions use ethyl cellulose or acrylic resin as the matrix and are prepared by coating. The sustained-release tablets prepared by this technology after tablet compression will have a serious burst release phenomenon when taken with alcoholic beverages. Although the existing method can form a coating system with alcohol resistance, the preparation method of such preparations is usually complicated, and the water dispersion system has poor storage stability. At present, there are no reports on sustained-release pellet tablets with simple preparation process and excellent anti-burst release effect when taken with alcoholic beverages. Summary of the invention

[0005] To solve the above technical problems, the present invention includes the following aspects:

[0006] The first aspect of the present invention provides a sustained-release tablet for avoiding sudden drug release after taking with alcoholic beverages, the sustained-release tablet comprising a sustained-release tablet core and a coating layer of an anti-burst release material wrapped around the sustained-release tablet core, the anti-burst release material being composed of a polysaccharide substance and a cellulose derivative, and the weight ratio of the polysaccharide substance to the cellulose derivative being 1:1-10:1.

[0007] Preferably, the polysaccharide is selected from one or more of guar gum, xanthan gum and gum arabic. More preferably, the polysaccharide is selected from one or more of guar gum and xanthan gum. Further preferably, the polysaccharide is guar gum.

[0008] Preferably, the cellulose derivative is selected from one or more of hydroxypropyl methylcellulose, ethyl cellulose, and hydroxyethyl cellulose. More preferably, the cellulose derivative is selected from one or more of hydroxypropyl methylcellulose and ethyl cellulose. Further preferably, the cellulose derivative is hydroxypropyl methylcellulose. Further preferably, the cellulose derivative is hydroxypropyl methylcellulose E5.

[0009] Preferably, the weight ratio of the polysaccharide to the cellulose derivative is 1:1-9:1, for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.

[0010] Preferably, the weight percentage of the polysaccharide in the sustained-release tablet is 1-10%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0011] Preferably, the weight percentage of the cellulose derivative in the sustained-release tablet is 0.1-5%, for example 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%.

[0012] Preferably, the sustained-release tablet core comprises sustained-release coated pellets, and the sustained-release coated pellets comprise: (a) a blank pellet core, (b) a drug coating layer wrapped around the blank pellet core, and (c) a sustained-release coating layer wrapped around the drug coating layer.

[0013] Preferably, the blank pill core is selected from one or more of sucrose, starch, lactose, and microcrystalline cellulose. More preferably, the blank pill core material is selected from one or more of sucrose and starch. Further preferably, the blank pill core is a sucrose pill core. Further preferably, the blank pill core is a 30-35 mesh sucrose pill core.

[0014] Preferably, the weight percentage of the blank pellet core in the sustained-release tablet is 1-40%, such as 1-5%, 5-10%, 10-15%, 15-20%, 25-30%, 30-35%, 35-40%.

[0015] Preferably, the drug coating layer comprises an active ingredient and a first binder.

[0016] Preferably, the active ingredient is selected from one or more of diltiazem hydrochloride, tolterodine tartrate, tramadol hydrochloride, and oxycodone hydrochloride. More preferably, the active ingredient is diltiazem hydrochloride or tolterodine tartrate.

[0017] Preferably, the weight percentage of the active ingredient in the sustained-release tablet is 1-40%.

[0018] Preferably, the weight percentage of diltiazem hydrochloride in the sustained-release tablet is 20-40%. More preferably, the weight percentage of diltiazem hydrochloride in the sustained-release tablet is 25-35%. Further preferably, the weight percentage of diltiazem hydrochloride in the sustained-release tablet is 30-35%.

[0019] Preferably, the weight percentage of the tolterodine tartrate in the sustained-release tablet is 0.5-5%. More preferably, the weight percentage of the tolterodine tartrate in the sustained-release tablet is 1-3%. Further preferably, the weight percentage of the tolterodine tartrate in the sustained-release tablet is 1-2%.

[0020] Preferably, the first binder is selected from one or more of hypromellose, hydroxypropyl cellulose, and povidone. More preferably, the first binder is selected from one or more of hypromellose E5, hydroxypropyl cellulose EXF, and povidone K29 / 32. Further preferably, the first binder is hypromellose E5 or povidone K29 / 32.

[0021] Preferably, the weight percentage of the first binder in the sustained-release tablet is 1-10%. More preferably, the weight percentage of the first binder in the sustained-release tablet is 3-8%. Further preferably, the weight percentage of the first binder in the sustained-release tablet is 4-7%.

[0022] Preferably, the sustained-release coating layer comprises a sustained-release material, a plasticizer and optionally an anti-adhesive agent.

[0023] Preferably, the sustained-release material is selected from one or more of ethyl cellulose, polyacrylic acid resin, and hydroxypropyl methylcellulose. More preferably, the sustained-release material is selected from one or more of ethyl cellulose and polyacrylic acid resin. Further preferably, the sustained-release material is ethyl cellulose, Eudragit RS or Eudragit RL. Further preferably, the sustained-release material is ethyl cellulose with a viscosity of 7 mPa.s. Further preferably, the sustained-release material is a composition of Eudragit RS and Eudragit RL in a weight ratio of 1:1-4:1. Further preferably, the sustained-release material is a composition of Eudragit RS and Eudragit RL in a weight ratio of 2:1-4:1. Further preferably, the sustained-release material is a composition of Eudragit RS and Eudragit RL in a weight ratio of 4:1.

[0024] Preferably, the weight percentage of the sustained-release material in the sustained-release tablet is 1-10%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0025] Preferably, the plasticizer is selected from one or more of triethyl citrate, diethyl phthalate, and dibutyl sebacate. More preferably, the plasticizer is selected from one or more of triethyl citrate and diethyl phthalate. Further preferably, the plasticizer is triethyl citrate or diethyl phthalate.

[0026] Preferably, the weight percentage of the plasticizer in the sustained-release tablet is 0.1-3%. More preferably, the weight percentage of the plasticizer in the sustained-release tablet is 0.2-2%. Further preferably, the weight percentage of the plasticizer in the sustained-release tablet is 0.5-2%.

[0027] Preferably, the anti-adherent is selected from one or more of talc, silicon dioxide, and magnesium stearate. More preferably, the anti-adherent is selected from one or more of talc and silicon dioxide. Further preferably, the anti-adherent is talc.

[0028] Preferably, the weight percentage of the anti-adhesive agent in the sustained-release tablet is 1-5%. More preferably, the weight percentage of the anti-adhesive agent in the sustained-release tablet is 2-4%. Further preferably, the weight percentage of the anti-adhesive agent in the sustained-release tablet is 2-3%.

[0029] Preferably, the sustained-release tablet core further comprises a filler, a second binder and a lubricant.

[0030] Preferably, the filler is selected from one or more of lactose, microcrystalline cellulose, starch, and mannitol. More preferably, the filler is selected from one or more of lactose and microcrystalline cellulose. Further preferably, the filler is microcrystalline cellulose. Further preferably, the filler is microcrystalline cellulose M102.

[0031] Preferably, the weight percentage of the filler in the sustained-release tablet is 30-50%. More preferably, the weight percentage of the filler in the sustained-release tablet is 30-45%. Further preferably, the weight percentage of the filler in the sustained-release tablet is 35-45%.

[0032] Preferably, the second binder is selected from one or more of hypromellose, hydroxypropyl cellulose, and povidone. More preferably, the second binder is selected from one or more of hypromellose E5, hydroxypropyl cellulose EXF, and povidone K29 / 32. Further preferably, the second binder is hypromellose E5 or povidone K29 / 32.

[0033] Preferably, the weight percentage of the second binder in the sustained-release tablet is 1-10%. More preferably, the weight percentage of the second binder in the sustained-release tablet is 3-8%. Further preferably, the weight percentage of the second binder in the sustained-release tablet is 4-6%.

[0034] Preferably, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, and talc. More preferably, the lubricant is selected from one or more of magnesium stearate and silicon dioxide. Further preferably, the lubricant is magnesium stearate or silicon dioxide.

[0035] Preferably, the weight percentage of the lubricant in the sustained-release tablet is 0.1-1%. More preferably, the weight percentage of the lubricant in the sustained-release tablet is 0.2-0.8%. Further preferably, the weight percentage of the lubricant in the sustained-release tablet is 0.4-0.6%.

[0036] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 546.3 mg microcrystalline cellulose M102, 60.7 mg povidone K29 / 32 and 6.1 mg magnesium stearate, the sustained-release coated pellets comprise 48.6 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 420 mg diltiazem hydrochloride and 91 mg povidone K29 / 32, the sustained-release coating layer comprises 34 mg ethyl cellulose and 7.3 mg triethyl citrate, and the anti-burst release material coating layer comprises 67.4 mg guar gum and 67.4 mg hydroxypropyl methylcellulose E5.

[0037] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 546.3 mg microcrystalline cellulose M102, 60.7 mg povidone K29 / 32 and 6.1 mg magnesium stearate, the sustained-release coated pellets comprise 48.6 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 420 mg diltiazem hydrochloride and 91 mg povidone K29 / 32, the sustained-release coating layer comprises 34 mg ethyl cellulose and 7.3 mg triethyl citrate, and the anti-burst release material coating layer comprises 79.2 mg guar gum and 26.4 mg hydroxypropyl methylcellulose E5.

[0038] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 546.3 mg microcrystalline cellulose M102, 60.7 mg povidone K29 / 32 and 6.1 mg magnesium stearate, the sustained-release coated pellets comprise 48.6 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 420 mg diltiazem hydrochloride and 91 mg povidone K29 / 32, the sustained-release coating layer comprises 34 mg ethyl cellulose and 7.3 mg triethyl citrate, and the anti-burst release material coating layer comprises 51.1 mg guar gum and 12.8 mg hydroxypropyl methylcellulose E5.

[0039] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 546.3 mg microcrystalline cellulose M102, 60.7 mg povidone K29 / 32 and 6.1 mg magnesium stearate, the sustained-release coated pellets comprise 48.6 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 420 mg diltiazem hydrochloride and 91 mg povidone K29 / 32, the sustained-release coating layer comprises 34 mg ethyl cellulose and 7.3 mg triethyl citrate, and the anti-burst release material coating layer comprises 22.3 mg guar gum and 2.5 mg hydroxypropyl methylcellulose E5.

[0040] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 123.7 mg microcrystalline cellulose M102, 15.4 mg povidone K29 / 32 and 1.5 mg silicon dioxide, the sustained-release coated pellets comprise 102.8 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 4 mg tolterodine tartrate and 15.4 mg hydroxypropyl methylcellulose E5, the sustained-release coating layer comprises 24 mg Eudragit RS, 6.2 mg Eudragit RL, 5.8 mg diethyl phthalate and 8.9 mg talc, and the anti-burst release material coating layer comprises 17.1 mg guar gum and 17.1 mg hydroxypropyl methylcellulose E5.

[0041] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 123.7 mg microcrystalline cellulose M102, 15.4 mg povidone K29 / 32 and 1.5 mg silicon dioxide, the sustained-release coated pellets comprise 102.8 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 4 mg tolterodine tartrate and 15.4 mg hydroxypropyl methylcellulose E5, the sustained-release coating layer comprises 24 mg Eudragit RS, 6.2 mg Eudragit RL, 5.8 mg diethyl phthalate and 8.9 mg talc, and the anti-burst release material coating layer comprises 23.4 mg guar gum and 3.3 mg hydroxypropyl methylcellulose E5.

[0042] Preferably, the sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer, the sustained-release tablet core comprises sustained-release coated pellets, 123.7 mg microcrystalline cellulose M102, 15.4 mg povidone K29 / 32 and 1.5 mg silicon dioxide, the sustained-release coated pellets comprise 102.8 mg sucrose pellet cores, a drug coating layer and a sustained-release coating layer, the drug coating layer comprises 4 mg tolterodine tartrate and 15.4 mg hydroxypropyl methylcellulose E5, the sustained-release coating layer comprises 24 mg Eudragit RS, 6.2 mg Eudragit RL, 5.8 mg diethyl phthalate and 8.9 mg talc, and the anti-burst release material coating layer comprises 5.7 mg guar gum and 0.6 mg hydroxypropyl methylcellulose E5.

[0043] The second aspect of the present invention provides a method for preparing the above-mentioned sustained-release tablet, the method comprising the following steps:

[0044] (1) dissolving a prescribed amount of active ingredient and a first binder in a solvent to prepare a drug-containing coating solution;

[0045] (2) slowly spraying the drug-containing coating solution prepared in step (1) onto the prescribed amount of blank pellets in a fluidized bed coating machine to prepare drug-containing immediate-release pellets;

[0046] (3) dissolving a prescribed amount of sustained-release material, a plasticizer, and an optional anti-adhesive agent in an organic solvent to prepare a sustained-release coating solution;

[0047] (4) slowly spraying the sustained-release coating solution prepared in step (3) onto the drug-containing immediate-release pellets prepared in step (2) in a fluidized bed coating machine to prepare sustained-release coated pellets;

[0048] (5) mixing the sustained-release coated pellets prepared in step (4) with a prescribed amount of a filler, a second binder, and a lubricant in a mixer;

[0049] (6) placing the mixture of step (5) in the hopper of a tablet press and pressing it into a drug-containing sustained-release tablet;

[0050] (7) dissolving the anti-burst release material in a solvent to prepare an anti-burst release coating solution;

[0051] (8) In a perforated coating pan, slowly spray the anti-burst release coating solution prepared in step (7) onto the drug-containing sustained-release tablets prepared in step (6).

[0052] Preferably, the solvent in step (1) is water.

[0053] Preferably, in step (1), the weight ratio of diltiazem hydrochloride as an active ingredient to the first binder to the solvent is (40-60): 100. More preferably, the weight ratio of diltiazem hydrochloride to the first binder to the solvent is (45-55): 100. Further preferably, in step (1), the weight ratio of diltiazem hydrochloride to the first binder to the solvent is 50:100.

[0054] Preferably, the weight ratio of tolterodine tartrate as an active ingredient and the first binder to the solvent in the step (1) is (1-10): 100. More preferably, the weight ratio of tolterodine tartrate and the first binder to the solvent is (1-5): 100. Further preferably, the weight ratio of tolterodine tartrate and the first binder to the solvent is 3: 100. Preferably, the fluidized bed coating parameters in the step (2) are as follows: inlet air temperature 50-70°C, material temperature 40-50°C, atomization pressure 1-2bar, air volume 100-300cfm, humidity not more than 30%, flow rate 5-40g / min. More preferably, the fluidized bed coating parameters in the step (2) are as follows: inlet air temperature 60°C, material temperature 45°C, atomization pressure 1.6bar, air volume 200cfm, humidity not more than 20%, flow rate 10-30g / min.

[0055] Preferably, the organic solvent in step (3) is ethanol.

[0056] Preferably, the weight ratio of the sustained-release material and plasticizer to the organic solvent in step (3) is (1-10): 100. More preferably, the weight ratio of the sustained-release material and plasticizer to the organic solvent in step (3) is (5-10): 100. Further preferably, the weight ratio of the sustained-release material and plasticizer to the organic solvent in step (3) is 8:100.

[0057] Preferably, the weight ratio of the sustained-release material, plasticizer and anti-adherent agent to the organic solvent in step (3) is (1-20): 100. More preferably, the weight ratio of the sustained-release material, plasticizer and anti-adherent agent to the organic solvent in step (3) is (5-15): 100. Further preferably, the weight ratio of the sustained-release material, plasticizer and anti-adherent agent to the organic solvent in step (3) is 10:100.

[0058] Preferably, the fluidized bed bag parameters in step (4) are as follows: inlet air temperature 35-40°C, material temperature 30-35°C, atomization pressure 1-2 bar, air volume 100-300 cfm, humidity not more than 40%, flow rate 5-20 g / min. More preferably, the fluidized bed bag parameters in step (4) are as follows: inlet air temperature 38°C, material temperature 32°C, atomization pressure 1.8 bar, air volume 200 cfm, humidity not more than 30%, flow rate 10-15 g / min.

[0059] Preferably, the solvent in step (7) is water.

[0060] Preferably, the weight ratio of the anti-burst release material to the solvent in step (7) is (1-10): 100. More preferably, the weight ratio of the anti-burst release material to the solvent in step (7) is (1-5): 100. Further preferably, the weight ratio of the anti-burst release material to the solvent in step (7) is 2:100.

[0061] The third aspect of the present invention is a method for preventing the sudden release of drugs after taking the above-mentioned sustained-release tablets with alcoholic beverages at the same time, the method comprising wrapping a coating layer of anti-burst release material outside the sustained-release tablet core, the anti-burst release material is composed of polysaccharides and cellulose derivatives, and the weight ratio of the polysaccharides to the cellulose derivatives is 1:1-10:1.

[0062] Preferably, the polysaccharide substance is guar gum, and the cellulose derivative is hypromellose E5.

[0063] Preferably, the weight ratio of the polysaccharide to the cellulose derivative is 1:1-9:1, for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.

[0064] Preferably, the drug burst release means that the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is greater than 40%.

[0065] Preferably, the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is less than 20%. More preferably, the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is less than 15%. Further preferably, the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is less than 10%.

[0066] The fourth aspect of the present invention provides an application of an anti-burst release material in the preparation of the above-mentioned sustained-release tablets, wherein the anti-burst release material is composed of a polysaccharide substance and a cellulose derivative, and the weight ratio of the polysaccharide substance to the cellulose derivative is 1:1-10:1. The anti-burst release material is wrapped around the outside of the sustained-release tablet core, and the sustained-release tablet can avoid drug burst release after being taken together with an alcoholic beverage.

[0067] Preferably, the polysaccharide substance is guar gum, and the cellulose derivative is hypromellose E5.

[0068] Preferably, the weight ratio of the polysaccharide to the cellulose derivative is 1:1-9:1, for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.

[0069] Preferably, the drug burst release means that the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is greater than 40%.

[0070] Preferably, the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is less than 20%. More preferably, the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is less than 15%. Further preferably, the drug release amount of the sustained-release tablet in a pH 1.2 hydrochloric acid solution containing 40% alcohol within 120 minutes is less than 10%.

[0071] The technical effects produced by the present invention are:

[0072] The present invention unexpectedly discovered that by using specific anti-burst release materials (e.g. guar gum and hypromellose E5 in a specific ratio), it is only necessary to prepare them into an aqueous solution and wrap them on a sustained-release tablet core comprising a multi-unit delivery system, thereby obtaining a sustained-release preparation having excellent anti-burst release effect when taken with alcoholic beverages, thereby improving the clinical safety and effectiveness of such preparations. DETAILED DESCRIPTION

[0073] Test Example 1: Investigation of the burst release behavior of diltiazem hydrochloride sustained-release tablets taken together with alcoholic beverages

[0074] 1. Test methods

[0075] 1.1. Preparation of sustained-release tablets

[0076] (1) Prescription

[0077] The prescriptions of diltiazem hydrochloride sustained-release tablets of Examples 1-4 of the present invention are shown in the following table (the drug content per unit dose is 420 mg, and the content of other excipients is in mg).

[0078]

[0079]

[0080] The prescriptions of diltiazem hydrochloride sustained-release tablets of Comparative Examples 1-4 of the present invention are shown in the following table (the drug content per unit dose is 420 mg, and the content of other auxiliary materials is in mg).

[0081]

[0082] (2) Preparation process

[0083] The preparation methods of the diltiazem hydrochloride sustained-release tablets of Examples 1-4 and Comparative Examples 2-4 are shown in the following steps 1) to 8), and the preparation method of the diltiazem hydrochloride sustained-release tablets of Comparative Example 1 is shown in the following steps 1) to 6):

[0084] 1) dissolving a prescribed amount of diltiazem hydrochloride and a first binder in water to prepare a drug-containing coating solution, wherein the weight ratio of diltiazem hydrochloride to the first binder to water is 50:100;

[0085] 2) In a fluidized bed coating machine, the drug-containing coating solution prepared in step 1) is slowly sprayed onto the blank pellet cores of the prescribed amount to prepare drug-containing immediate-release pellets. The fluidized bed coating parameters of this step are as follows: inlet air temperature 60° C., material temperature 45° C., atomization pressure 1.6 bar, air volume 200 cfm, humidity not more than 20%, and flow rate 10-30 g / min;

[0086] 3) dissolving the prescribed amount of sustained-release material and plasticizer in ethanol to prepare a sustained-release coating solution, wherein the weight ratio of the sustained-release material and plasticizer to ethanol is 8:100;

[0087] 4) In a fluidized bed coating machine, the sustained-release coating solution prepared in step 3) is slowly sprayed onto the drug-containing immediate-release pellets prepared in step 2) to prepare sustained-release coated pellets. The fluidized bed coating parameters of this step are as follows: inlet air temperature 38° C., material temperature 32° C., atomization pressure 1.8 bar, air volume 200 cfm, humidity not more than 30%, and flow rate 10-15 g / min;

[0088] 5) mixing the sustained-release coated pellets prepared in step 4) with the prescribed amount of filler, the second binder and the lubricant in a mixer;

[0089] 6) placing the mixture of step 5) in the hopper of a tablet press and pressing into drug-containing sustained-release tablets (without an anti-burst release coating layer);

[0090] 7) dissolving the anti-burst release material in water to prepare an anti-burst release coating solution, wherein the weight ratio of the anti-burst release material to water is 2:100;

[0091] 8) In a perforated coating pan, slowly spray the anti-burst release coating solution prepared in step 7) onto the drug-containing sustained-release tablets prepared in step 6) to obtain the product.

[0092] The dosage of diltiazem hydrochloride in each batch is 1500 g, and the dosage of other auxiliary materials is converted according to the unit dosage of the prescription.

[0093] 1.2 Release test of sustained-release tablets in alcohol-containing dissolution medium

[0094] The diltiazem hydrochloride sustained-release tablets prepared in Examples 1-4 and Comparative Examples 1-4 were taken respectively, and the in vitro release of each prescription was determined by the paddle method. The rotation speed was 100 rpm, the dissolution medium was a 40% alcohol concentration, pH 1.2 hydrochloric acid solution, the dissolution medium temperature was 37°C ± 0.5°C, the dissolution medium volume was 900 mL, and samples were taken at 30 minutes, 60 minutes, 90 minutes and 120 minutes, respectively. The release (%) of diltiazem hydrochloride in the sustained-release tablets was determined at an ultraviolet detection wavelength of 270 nm.

[0095] 2. Test results

[0096] The release results of diltiazem hydrochloride in alcohol-containing dissolution medium of the sustained-release tablets of Examples 1-4 of the present invention and Comparative Examples 1-4 are shown in Tables 1 and 2 below, respectively.

[0097] Table 1 Release results of Examples 1-4 of the present invention in alcohol-containing dissolution medium (%)

[0098] Time (minutes) Example 1 Example 2 Example 3 Example 4 30 0 0 0 0 60 0 3 2 5 90 2 6 5 10 120 5 9 8 17

[0099] Table 2 Release results of comparative examples 1-4 of the present invention in alcohol-containing dissolution medium (%)

[0100]

[0101]

[0102] It can be seen from the release data of Comparative Examples 1-3 in Table 2 above that when the sustained-release tablet does not contain an anti-burst release material or contains only one type of burst release material, the release of diltiazem hydrochloride in the alcohol-containing dissolution medium within 120 minutes is as high as more than 50%. Even if the sustained-release tablet contains two anti-burst release materials at the same time, but the guar gum content is less than that of hypromellose E5 (Comparative Example 4), the release of diltiazem hydrochloride within 120 minutes still reaches 40%, indicating that the sustained-release tablets prepared in Comparative Examples 1-4 have a significant burst release of the active ingredient after being taken with an alcoholic beverage.

[0103] In comparison, the release data in Table 1 show that the sustained-release tablets of Examples 1-4 release at most 17% of the drug within 120 minutes, and Examples 1-3 even control the drug release within 120 minutes to less than 10%, proving that the sustained-release tablets contain both guar gum and hypromellose E5, two anti-burst release materials, and when the guar gum content is greater than or equal to hypromellose E5, the sustained-release tablets can effectively avoid the sudden release of diltiazem hydrochloride in the dissolution medium containing alcohol. The above test results show that combining guar gum and hypromellose E5 in an appropriate ratio can effectively avoid the sudden release phenomenon of the active ingredient when taken with alcoholic beverages, thereby improving the safety and effectiveness of patients during medication.

[0104] Test Example 2: Investigation of the burst release behavior of tolterodine tartrate sustained-release tablets taken together with alcoholic beverages

[0105] 1. Test methods

[0106] 1.1. Preparation of sustained-release tablets

[0107] (1) Prescription

[0108] The prescriptions of the tolterodine tartrate sustained-release tablets of Examples 5-7 of the present invention are shown in the following table (the drug content per unit dose is 4 mg, and the content of the remaining excipients is in mg).

[0109]

[0110]

[0111] The prescription of the tolterodine tartrate sustained-release tablets of Comparative Example 5 of the present invention is shown in the following table (the drug content per unit dose is 4 mg, and the content of the remaining excipients is in mg).

[0112]

[0113] (2) Preparation process

[0114] The preparation method of the tolterodine tartrate sustained-release tablets of Examples 5-7 is shown in the following steps 1) to 8), and the preparation method of the tolterodine tartrate sustained-release tablets of Comparative Example 5 is shown in the following steps 1) to 6):

[0115] 1) dissolving a prescribed amount of tolterodine tartrate and a binder in water to prepare a drug-containing coating solution, wherein the weight ratio of tolterodine tartrate and the binder to water is 3:100;

[0116] 2) In a fluidized bed coating machine, the drug-containing coating solution prepared in step 1) is slowly sprayed onto the blank pellet cores of the prescribed amount to prepare drug-containing immediate-release pellets. The fluidized bed coating parameters of this step are as follows: inlet air temperature 60° C., material temperature 45° C., atomization pressure 1.6 bar, air volume 200 cfm, humidity not more than 20%, and flow rate 10-30 g / min;

[0117] 3) dissolving the prescribed amount of sustained-release material, plasticizer and anti-adherent agent in ethanol to prepare a sustained-release coating solution, wherein the weight ratio of the sustained-release material, plasticizer and anti-adherent agent to ethanol is 10:100;

[0118] 4) In a fluidized bed coating machine, the sustained-release coating solution prepared in step 3) is slowly sprayed onto the drug-containing immediate-release pellets prepared in step 2) to prepare sustained-release coated pellets. The fluidized bed coating parameters of this step are as follows: inlet air temperature 38° C., material temperature 32° C., atomization pressure 1.8 bar, air volume 200 cfm, humidity not more than 30%, and flow rate 10-15 g / min;

[0119] 5) mixing the sustained-release coated pellets prepared in step 4) with the prescribed amount of filler, the second binder and the lubricant in a mixer;

[0120] 6) placing the mixture of step 5) in the hopper of a tablet press and pressing into drug-containing sustained-release tablets (without an anti-burst release coating layer);

[0121] 7) dissolving the anti-burst release material in water to prepare an anti-burst release coating solution, wherein the weight ratio of the anti-burst release material to water is 2:100;

[0122] 8) In a perforated coating pan, slowly spray the anti-burst release coating solution prepared in step 7) onto the drug-containing sustained-release tablets prepared in step 6) to obtain the product.

[0123] The dosage of tolterodine tartrate in each batch is 60 g, and the dosage of other auxiliary materials is converted according to the unit dosage of the prescription.

[0124] 1.2 Release test of sustained-release tablets in alcohol-containing dissolution medium

[0125] The tolterodine tartrate sustained-release tablets prepared in Examples 5-7 and Comparative Example 5 were taken respectively, and the in vitro release of each prescription was determined by the paddle method. The rotation speed was 100 rpm, the dissolution medium was a 40% alcohol concentration, pH 1.2 hydrochloric acid solution, the dissolution medium temperature was 37°C ± 0.5°C, the dissolution medium volume was 900 mL, and samples were taken at 30 minutes, 60 minutes, 90 minutes and 120 minutes, respectively. The release (%) of tolterodine tartrate in the sustained-release tablets was determined at an ultraviolet detection wavelength of 210 nm.

[0126] 2. Test results

[0127] The release results of tolterodine tartrate of the sustained-release tablets of Examples 5-7 of the present invention and Comparative Example 5 in a dissolution medium containing alcohol are shown in Table 3 below.

[0128] Table 3 Release results of Examples 5-7 of the present invention and Comparative Example 5 in alcohol-containing dissolution medium (%)

[0129] Time (minutes) Example 5 Example 6 Example 7 Comparative Example 5 30 0 0 0 1 60 1 1 3 10 90 3 4 8 28 120 5 7 11 50

[0130] From the release data of Comparative Example 5 in Table 3 above, it can be seen that when the sustained-release tablet does not contain anti-burst release material, the release of tolterodine tartrate in the alcohol-containing dissolution medium within 120 minutes is as high as 50%, indicating that the sustained-release tablet prepared in Comparative Example 5 has a significant burst release of the active ingredient after being taken with an alcoholic beverage.

[0131] In comparison, the sustained-release tablets of Examples 5-7 release a maximum of 11% of the drug within 120 minutes, confirming that the sustained-release tablets contain both guar gum and hypromellose E5, two anti-burst release materials, and when the guar gum content is greater than or equal to hypromellose E5, the sustained-release tablets can effectively avoid the sudden release of tolterodine tartrate in the dissolution medium containing alcohol. The above test results also show that combining guar gum and hypromellose E5 in an appropriate ratio can effectively avoid the sudden release phenomenon of active ingredients when taken with alcoholic beverages, thereby improving the safety and effectiveness of patients during medication.

[0132] Although specific embodiments of the present invention have been described, it will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the scope or spirit of the present invention. Therefore, the present invention is intended to cover all such changes and modifications that fall within the scope of the appended claims and their equivalents.

Claims

1. A sustained-release tablet for preventing sudden drug release after taking with alcoholic beverages, characterized in that: The sustained-release tablet comprises a sustained-release tablet core and an anti-burst release material coating layer wrapped around the sustained-release tablet core; the anti-burst release material is composed of polysaccharides and cellulose derivatives; and the weight ratio of the polysaccharides to the cellulose derivatives is 1:1-10:

1.

2. The sustained-release tablet according to claim 1, characterized in that The polysaccharide substance is selected from one or more of guar gum, xanthan gum and gum arabic.

3. The sustained-release tablet according to claim 1, characterized in that The cellulose derivative is selected from one or more of hydroxypropyl methylcellulose, ethyl cellulose and hydroxyethyl cellulose.

4. The sustained-release tablet according to claim 1, characterized in that The sustained-release tablet core comprises sustained-release coated pellets, and the sustained-release coated pellets comprise: (a) a blank pellet core, (b) a drug coating layer wrapped outside the blank pellet core, and (c) a sustained-release coating layer wrapped outside the drug coating layer.

5. The sustained-release tablet according to claim 4, characterized in that The drug coating layer comprises an active ingredient and a first binder.

6. The sustained-release tablet according to claim 5, wherein the active ingredient is selected from one or more of diltiazem hydrochloride, tolterodine tartrate, tramadol hydrochloride and oxycodone hydrochloride.

7. The sustained-release tablet according to claim 4, characterized in that The sustained-release coating layer comprises a sustained-release material, a plasticizer and optionally an anti-adherent agent.

8. The sustained-release tablet according to claim 7, characterized in that The sustained-release material is selected from one or more of ethyl cellulose, polyacrylic acid resin, and hypromellose.

9. The sustained-release tablet according to claim 1, characterized in that The sustained-release tablet core further comprises a filler, a second binder and a lubricant.

10. The method for preparing the sustained-release tablet according to any one of claims 1 to 9, characterized in that: The method comprises the following steps: (1) dissolving a prescribed amount of active ingredient and a first binder in a solvent to prepare a drug-containing coating solution; (2) slowly spraying the drug-containing coating solution prepared in step (1) onto the prescribed amount of blank pellets in a fluidized bed coating machine to prepare drug-containing immediate-release pellets; (3) dissolving a prescribed amount of sustained-release material, a plasticizer, and an optional anti-adhesive agent in an organic solvent to prepare a sustained-release coating solution; (4) slowly spraying the sustained-release coating solution prepared in step (3) onto the drug-containing immediate-release pellets prepared in step (2) in a fluidized bed coating machine to prepare sustained-release coated pellets; (5) mixing the sustained-release coated pellets prepared in step (4) with a prescribed amount of a filler, a second binder, and a lubricant in a mixer; (6) placing the mixture of step (5) in the hopper of a tablet press and pressing it into a drug-containing sustained-release tablet; (7) dissolving the anti-burst release material in a solvent to prepare an anti-burst release coating solution; (8) In a perforated coating pan, slowly spray the anti-burst release coating solution prepared in step (7) onto the drug-containing sustained-release tablets prepared in step (6).

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