Alkali-free oral administration composition for intestinal delivery of corticosteroid drugs

Abstract

The invention discloses an oral administration multi-particle composition for intestinal delivery of corticosteroid drugs. The oral administration multi-particle composition comprises sustained release pellets and a delayed release component, the sustained-release pellet comprises a stabilizer-free quick-release drug-containing core, an isolating layer and an alkali-free sustained-release layer. The delayed release component comprises a cellulose capsule and an enteric film. The alkali-free ethyl cellulose sustained-release layer is used in the pharmaceutical composition, so that the degradation of active substances of the medicine can be avoided, and the use of a stabilizer is avoided. Compared with alkali-containing ethyl cellulose, the process flow can be reduced, and the production cost can be reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to pharmaceutical enteric-coated preparations and sustained-release preparations, and specifically relates to an alkali-free oral administration composition for intestinal delivery of corticosteroid drugs. Background Art

[0002] Budesonide, whose chemical formula is C 25 H 34 O6, a glucocorticoid drug, has significant local anti-inflammatory and anti-allergic effects. The drug can enhance the stability of endothelial cells, smooth muscle cells and lysosomal membranes, while inhibiting immune responses and reducing antibody synthesis. Therefore, oral budesonide enteric-coated microcapsules are clinically used for the maintenance treatment of mild to moderate segmental ileitis, i.e. Crohn's disease, involving the ileum and / or ascending colon.

[0003] IgA nephropathy is caused by the deposition of IgA1 immune complexes in the mesangium. These complexes originate from B cells located in the mucosa. These B cells are abundant in the distal ileum, which is rich in Peyer's patches. The prior art discloses an oral enteric release budesonide preparation. In this method, the active substance of the drug preferably exerts its effect in the distal ileum, can directly act on the site of disease, and inhibit the deposition of IgA1 immune complexes. This method avoids the serious side effects that may be caused by systemic administration.

[0004] Prior art CN102088962A discloses an oral budesonide preparation for sustained release in the intestine, the preparation comprising budesonide, Sulis (containing alkaline substances) and a stabilizer. The technology found that adding an acidic isolation layer between budesonide and Sulis can reduce the generation of impurities in the preparation.

[0005] The prior art adds alkaline substances to the active ingredients of the drug and then adds acids or stabilizers to other layers, which not only increases the process steps and excipient costs, but also increases the stability risk. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide an oral administration composition without adding alkali and stabilizer, thereby solving the cost and stability risks.

[0007] In order to solve the above technical problems, the specific technical solutions adopted by the present invention are as follows:

[0008] Provided is an alkali-free oral administration composition for intestinal delivery of corticosteroid drugs, characterized in that it comprises a sustained release component and a delayed release component; the sustained release component comprises a drug-containing core without a stabilizer, an isolation layer without acidic substances, and an ethyl cellulose layer without alkali.

[0009] The delayed-release component functions to protect the composition from being released substantially in the intestine after oral administration.

[0010] The sustained-release component comprises a corticosteroid drug. Suitable corticosteroid drugs include, but are not limited to, alclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, budesonide, methylprednisolone, mometasone, hydroprednisolone, triamcinolone, fluticasone, ciclesonide, fludrocortisone, and the like.

[0011] In some embodiments, the corticosteroid drug is budesonide.

[0012] In some specific embodiments, the sustained-release component accounts for 60% to 80% of the oral administration composition by weight; the delayed-release component accounts for 20% to 40% of the oral administration composition.

[0013] In some specific embodiments, by weight, the drug-containing core accounts for 50% to 90% of the sustained release component; the isolation layer accounts for 0.1% to 20% of the sustained release component; and the ethylcellulose layer accounts for 0.5% to 15% of the sustained release component.

[0014] Preferably, the drug-containing core accounts for 60%-90% of the sustained-release component; the isolation layer accounts for 0.1%-10% of the sustained-release component; and the ethylcellulose layer accounts for 1%-10% of the sustained-release component.

[0015] In some embodiments, the drug-containing core comprises an active substance and an inert matrix, or the drug-containing core comprises an active substance and an inert core.

[0016] An inert matrix or inert core refers to a substance in a pharmaceutical formulation that does not chemically react with the drug and does not affect the drug release characteristics.

[0017] The active substance is dispersed in an inert matrix, or coated on an inert core. Preferably, the active substance is coated on an inert core, and the inert core can be a pellet core or a tablet core, preferably a pellet core.

[0018] In some specific embodiments, the active substance is selected from one or more of alclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, budesonide, methylprednisolone, mometasone, hydroprednisolone, triamcinolone, fluticasone, ciclesonide, and fludrocortisone, preferably budesonide; the inert matrix or the inert core is selected from one or more of microcrystalline cellulose, sucrose, micropowdered silica, cross-linked polyvinylpyrrolidone, lactose, mannitol, and starch.

[0019] Methods for dispersing the active substance in an inert matrix include, but are not limited to, fluidized bed granulation, extrusion spheronization, microencapsulation, and tableting.

[0020] Among them, fluidized bed granulation is a granulation technology carried out in a fluidized bed device. The inert matrix and active substance are dispersed and mixed under the action of airflow, and the powder is aggregated into granules by spraying a binder.

[0021] Extrusion spheronization involves mixing the active substance with an inert matrix and extruding it into a strip, which is then spheronized into spherical particles by a rotating device (such as a spheronizer). This method is suitable for preparing small particles and can control the size and shape of the particles.

[0022] Microencapsulation is the process of encapsulating the active substance in tiny capsules to form microcapsules. This can be achieved through a variety of techniques such as spray drying, spray coagulation, condensation, and solvent evaporation. Microcapsules can protect the active substance, control release, and improve stability.

[0023] Tableting is a method of directly mixing the active substance with an inert matrix and then compressing it into tablets. This method is simple and quick.

[0024] The active substance is preferably coated on the inert core by spraying the coating liquid containing the active substance on the inert core, which can be obtained by granulation, extrusion spheronization, tableting, or purchased.

[0025] In some specific embodiments, the coating solution contains a binder, which accounts for 0.1% to 50% of the weight of the sustained-release component, and is selected from one or more of methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, gelatin, gum arabic, Opadry, hydroxypropyl cellulose, polyvinyl acetate, hypromellose acetate, chitosan, and sodium alginate.

[0026] The selection of these binders depends on the desired coating properties, such as solubility, release properties, mechanical strength and stability of the coating. In some specific embodiments, the isolation layer is selected from one or more of methylcellulose, polyethylene glycol, gelatin, gum arabic, Opadry, hydroxypropyl cellulose, polyvinyl alcohol, chitosan, gelatin, and polyethylene oxide. The absence of acidic substances means that citric acid monohydrate, citric acid, tartaric acid and salts thereof are not added to the isolation layer.

[0027] In some specific embodiments, the ethylcellulose in the alkali-free ethylcellulose layer is ETHOCEL.

[0028] Etosil is a non-alkaline ethyl cellulose material that is insoluble in water. It is mainly used as a tablet adhesive and film coating material, etc. It is also used as a mixed material to prepare coated sustained-release preparations and sustained-release pellets.

[0029] In some specific embodiments, the alkali-free ethylcellulose layer also includes a water-soluble material for controlling the release rate, and the water-soluble material is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, glucose, mannitol, sucrose, lactose, polyvinyl alcohol, polysorbate, sodium chloride, triethyl citrate, and sodium lauryl sulfate.

[0030] In some specific embodiments, the alkali-free ethylcellulose layer further comprises a water-insoluble material for controlling the release rate other than Etocel, wherein the water-insoluble material is selected from one or more of magnesium stearate, silicon dioxide, titanium dioxide, and talc; the water-insoluble material accounts for 0.5% to 20% by weight of the sustained-release component.

[0031] Alkali-containing ethylcellulose, such as Surelease, can provide a sustained release effect for budesonide as a sustained release material, but its alkalinity can cause the degradation of budesonide, affecting the stable storage of the preparation. Therefore, it is necessary to add a stabilizer to overcome the degradation of budesonide caused by alkali-containing ethylcellulose and increase the stability of the preparation.

[0032] In some embodiments, to ensure that the active ingredient can be delivered to the intestine, the delayed-release component can be further processed, such as coating it with a polymer having enteric dissolution properties, or filling it into a capsule that can delay release.

[0033] In some specific embodiments, the method for preparing an alkali-free oral composition for intestinal delivery of corticosteroid drugs also includes wrapping the delayed release component around the sustained release component, or encapsulating the sustained release component in a capsule, and then wrapping it with the delayed release component. Specifically, the sustained release component can be filled into a capsule, and after the capsule is sealed, a polymer with intestinal dissolution characteristics is coated on the outer layer of the capsule to achieve the effect of release in the intestine. Preferred capsule types include gel capsules, hypromellose capsules, and starch capsules. Alternatively, the sustained release component can also be directly filled into enteric-coated capsules sold on the market to achieve the effect of intestinal release. Another method is to fill the sustained release component wrapped by the delayed release component into a common capsule.

[0034] In some specific embodiments, the delayed release component achieves a delayed release effect by including a polymer with intestinal dissolution characteristics. Such polymers are pH-dependent, that is, they will not dissolve in the acidic environment of the stomach, but will dissolve in the alkaline environment of the intestine. In addition, these polymers may also be decomposed by specific enzymes or bacteria in the intestine. Suitable intestinal soluble polymers can be enteric cellulose esters, such as cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethylcellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate trioctyl ester, etc., or enteric acrylic copolymers, such as methyl acrylate-methacrylic acid copolymer, methyl acrylate-methacrylic acid-octyl acrylate copolymer, Eudragit L, Eudragit S, Eudragit FS, etc. The preferred delayed release material (e.g., coating composition) is a mixture based on Eudragit L100 and Eudragit S100, with a ratio range of 100:1 to 20:75; the most preferred ratio range is 60:30 to 70:20. The coating may optionally include ingredients such as anti-tack agents (eg talc, magnesium stearate), plasticizers (eg triethyl citrate) and pigments.

[0035] "Substantially released in the intestine" herein generally means that after oral administration of the pharmaceutical composition, the active substance is substantially not released before reaching the intestine, and the drug begins to release after reaching the intestine. For example, before reaching the intestine, no more than 15%, preferably no more than 10%, and most preferably no more than 5% of the drug is released from the pharmaceutical composition. Usually, drug release begins in the small intestine. Drug release may also be delayed until the pharmaceutical composition reaches a specific part of the intestine, such as the duodenum, colon, ileum, and cecum.

[0036] "Sustained release" as used herein means that when the delayed release component dissolves or decomposes, not all of the drug is released immediately, but the drug is released after a period of time. The time of drug release during this period can be controlled, and the length of time for drug release during this period depends on or is partially determined by the processing of the drug.

[0037] Appropriate in vitro dissolution tests are based on the apparatus and methods required by the Chinese Pharmacopoeia, such as in a simulated gastric environment for 2 hours, followed by intestinal environment simulated by, for example, phosphate buffer at pH 6.8 at 37°C.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The present invention uses ethyl cellulose without alkali in the pharmaceutical composition, which can reduce the degree of degradation of the active substance of the drug, thereby avoiding the use of a stabilizer. Compared with ethyl cellulose containing alkali, the present invention reduces the risk of drug stability during the production process, and can reduce the process flow and reduce production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the dissolution curve of Example 2 in a medium containing 0.05% Tween 80 at pH 1.0 to pH 6.8.

[0041] Figure 2 This is the dissolution curve of Example 3 in a medium containing 0.05% Tween 80 at pH 1.0 to pH 6.8.

[0042] Figure 3 This is the dissolution curve of Example 7 in a medium containing 0.05% Tween 80 at pH 1.0 to pH 6.8. DETAILED DESCRIPTION

[0043] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the present invention is further described below in conjunction with the embodiments. However, the present invention is not limited to the following implementation cases.

[0044] It should be noted that the contents of this specification are intended for people familiar with this technology to understand and read, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantive technical significance. Any adjustments that are not creative should still fall within the scope of the technical content disclosed in the present invention without affecting the effects and purposes that can be achieved by the present invention.

[0045] All components not explicitly specified in the examples can be commercial products.

[0046] Example 1

[0047] Sustained-release budesonide pellets consist of the following components:

[0048] The drug-containing micropellets contain 252g of sucrose core, 4g of budesonide, and 18g of Opadry; the isolation layer is 8.22g of Opadry; the ethyl cellulose layer contains 4.57g of ethyl cellulose Ethocel, 2.20g of hydroxypropyl cellulose, and 1.69g of triethyl citrate.

[0049] The preparation method of sustained-release budesonide pellets is as follows:

[0050] 1. Preparation of pill core:

[0051] Weigh 18g of Opadry coating mixture (Colorcon), weigh 4.0g of budesonide and add them, mix thoroughly, add 198g of purified water, and stir vigorously to form a uniform suspension, i.e., the drug solution. Use a fluidized bed to apply drug to 252g of blank sucrose pellets to obtain drug-containing pellets.

[0052] 2. Coating isolation layer:

[0053] Weigh 8.22 g of Opadry coating mixture, add 82.2 g of purified water, stir thoroughly to disperse evenly, and obtain an isolation layer coating solution. Coat the above-mentioned drug-containing pellets in a fluidized bed to obtain pellet granules.

[0054] 3. Preparation of sustained release pellets:

[0055] Weigh 4.57g of ethylcellulose Etosil and add it to 90g of 90% ethanol. After the ethylcellulose is dissolved, weigh 2.20g of hydroxypropyl cellulose and add it to the above solution. Stir vigorously until the hydroxypropyl cellulose is dissolved and clarified. Then weigh 1.69g of triethyl citrate and add it to the above solution and stir evenly. The micropellets in step 2 are coated in a fluidized bed to obtain sustained-release micropellets.

[0056] After each coating, continue fluidized drying for 15 min and sieve the coated pellets to remove oversized or undersized particles.

[0057] Example 2

[0058] Preparation of budesonide enteric-coated pellets:

[0059] 9.0 g of Eudragit L 100 and 3.0 g of Eudragit S100 were dispersed in 175 g of 95% ethanol and stirred to dissolve; 3.0 g of talc and 2.31 g of triethyl citrate were dispersed in 95% ethanol in a beaker and stirred for 10 min to obtain an enteric coating solution. 150.0 g of the above enteric coating solution was weighed and coated on 100 g of the sustained-release pellets prepared in Example 1 on a fluidized bed to finally obtain enteric budesonide pellets.

[0060] Example 3

[0061] Preparation of enteric-coated capsules containing budesonide pellets:

[0062] 1. Capsule filling

[0063] The budesonide pellets (obtained from Example 1)) were filled into No. 0 hypromellose capsules, with each capsule being filled with 290.68 mg of pellets, equivalent to 4 mg of budesonide.

[0064] 2. Capsule coating

[0065] 77.49 g Eudragit L100 and 26.00 g Eudragit S100 were dissolved in 1359 g 95% ethanol. 20.00 g triethyl citrate (plasticizer) and 26.00 g talc (anti-sticking agent) were mixed into the coating solution.

[0066] Add 3800 capsules into the Xiaolun coating machine, adjust the coating pan speed to 15rpm, set the inlet air temperature to 34-36°C, and start atomizing spraying after the capsule surface temperature reaches 34°C, with a spraying flow rate of 8g / min.

[0067] After all the coating solution was applied to the capsules, the capsules were dried in the coating pan at 50°C for 15 min.

[0068] The capsule is suitable for treating IgA nephropathy.

[0069] Example 4

[0070] Preparation of enteric-coated capsules containing budesonide pellets:

[0071] 1. Capsule filling

[0072] The budesonide pellets (obtained from Example 1) were filled into No. 0 hypromellose capsules, with each capsule being filled with 290.68 mg of pellets, equivalent to 4 mg of budesonide.

[0073] 2. Capsule sealing

[0074] Weigh 22.8 g of Hydroxypropyl Methylcellulose and dissolve it in 120 g of 60% ethanol. Use a casing machine to evenly coat the casing liquid on the surface of 3800 capsules. After drying, add the capsules to the coating machine.

[0075] 3. Capsule coating

[0076] Weigh 40g of Opadry and dissolve it in 760g of water, and evenly apply it on the surface of the capsules in step 2, and after drying, use the coating solution in step 2 of Example 3 to coat and obtain enteric-coated capsules.

[0077] Example 5

[0078] Sustained-release budesonide pellets consist of the following components:

[0079] The drug-containing micropellets contain 252g of sucrose core, 4g of budesonide, and 18g of Opadry; the isolation layer is 8.22g of Opadry; the ethyl cellulose layer contains 2.76g of ethyl cellulose Ethocel, 1.75g ​​of polyethylene glycol, and 1.13g of triethyl citrate.

[0080] 1. Preparation of pill core:

[0081] Weigh 18g of Opadry coating mixture (Colorcon), weigh 4.0g of budesonide and add them, mix thoroughly, add 198g of purified water, and stir vigorously to form a uniform suspension, i.e., the drug solution. Use a fluidized bed to apply drug to 252g of blank sucrose pellets to obtain drug-containing pellets.

[0082] 2. Coating isolation layer:

[0083] Weigh 8.22 g of Opadry coating mixture, add 82.2 g of purified water, stir thoroughly to disperse evenly, and obtain an isolation layer coating solution. Coat the above-mentioned drug-containing pellets in a fluidized bed to obtain pellet granules.

[0084] 3. Preparation of sustained release pellets:

[0085] Weigh 2.76g of ethylcellulose Ethocel and add it to 90g of 90% ethanol. After the ethylcellulose is dissolved, weigh 1.75g ​​of polyethylene glycol and add it to the above solution. Stir vigorously until the polyethylene glycol is dissolved and clarified. Then weigh 1.13g of triethyl citrate and add it to the above solution and stir evenly. The micropellets in step 2 are coated in a fluidized bed to obtain sustained-release micropellets.

[0086] After each coating, continue fluidized drying for 15 min and sieve the coated pellets to remove oversized or undersized particles.

[0087] Example 6

[0088] Sustained-release budesonide pellets consist of the following components:

[0089] The drug-containing micropellets contain 252g of sucrose core, 4g of budesonide, and 18g of Opadry; the isolation layer is 8.22g of Opadry; the ethyl cellulose layer contains 2.76g of ethyl cellulose Ethocel, 1.75g ​​of polyvinyl pyrrolidone, and 1.13g of triethyl citrate.

[0090] The preparation method is the same as Example 1.

[0091] Example 7: Preparation of sustained-release budesonide pellets The formulation is the same as that of Example 1, except that the sucrose pellet core is replaced with a microcrystalline cellulose pellet core.

[0092] Example 8

[0093] Sustained-release budesonide pellets consist of the following components:

[0094] The drug-containing micropellets contain 252g of sucrose core, 4g of budesonide, and 18g of Opadry; the isolation layer is 8.22g of Opadry; 0.58g of citric acid monohydrate; and the ethyl cellulose layer contains 79.97g of Surelease aqueous dispersion and 10.75g of Opadry.

[0095] The preparation of the pill core is the same as in Example 1.

[0096] 2. Coating isolation layer:

[0097] Weigh 8.22 g of Opadry coating mixture, 0.58 g of citric acid monohydrate, add 82.2 g of purified water, stir thoroughly to disperse evenly, and obtain an isolation layer coating solution. The above-mentioned drug-containing pellets are coated in a fluidized bed to obtain pellet granules.

[0098] 3. Preparation of sustained release pellets:

[0099] Weigh 79.97 g of Surelease water dispersion and 10.75 g of Opadry. Add Opadry to Surelease water dispersion and stir vigorously until Opadry is dissolved. Coat the pellets in step 2 in a fluidized bed to obtain sustained-release pellets. Transfer the coated pellets to a 65°C oven for curing for 4 hours.

[0100] Example 9

[0101] The recipe is the same as that of Example 8, except that the citric acid monohydrate is removed. The preparation method is the same as that of Example 8.

[0102] Table 1 below lists the impurity levels of the samples prepared in Examples 1, 8, and 9 and stored at 25°C / 60%RH for 6 months in HDPE bottles with child-resistant polypropylene caps.

[0103] Table 1 Comparison of stability among Example 1, Example 8 and Example 9

[0104]

[0105]

[0106] As shown in the table, Surelease with an acid-containing barrier layer showed the same stability effect as Atocel without an acid-containing barrier layer, and the impurity growth was relatively smaller. Surelease without an acid-containing barrier layer showed worse stability. This indicates that direct contact between Surelease and budesonide will cause budesonide degradation. Therefore, avoiding the use of Surelease can avoid the use of an acid-containing barrier layer, thereby reducing production costs and process under the condition of the same stability.

[0107] The dissolution curves of Examples 2, 3, and 7 in a medium containing 0.05% Tween 80 at pH 1.0 to pH 6.8 are shown in the attached figure. Figure 1 , Attachment Figure 2 , Attachment Figure 3 .

[0108] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. An alkali-free oral composition for intestinal delivery of corticosteroid drugs, characterized in that: The invention comprises a sustained-release component and a delayed-release component; the sustained-release component comprises a drug-containing core without a stabilizer, an isolation layer without an acidic substance, and an ethylcellulose layer without an alkali.

2. The oral administration composition according to claim 1, characterized in that In terms of weight fraction, the sustained-release component accounts for 60% to 80% of the oral administration composition; and the delayed-release component accounts for 20% to 40% of the oral administration composition.

3. The oral administration composition according to claim 2, characterized in that In terms of weight fraction, the drug-containing core accounts for 50% to 90% of the sustained-release component; the isolation layer accounts for 0.1% to 20% of the sustained-release component; and the ethyl cellulose layer accounts for 0.5% to 15% of the sustained-release component.

4. The oral administration composition according to claim 3, characterized in that: The drug-containing core accounts for 60%-90% of the sustained-release component; the isolation layer accounts for 0.1%-10% of the sustained-release component; and the ethylcellulose layer accounts for 1%-10% of the sustained-release component.

5. The oral administration composition according to claim 1, characterized in that: The drug-containing core comprises an active substance and an inert matrix, or the drug-containing core comprises an active substance and an inert core.

6. The oral administration composition according to claim 5, characterized in that: The active substance is selected from one or more of alclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, budesonide, methylprednisolone, mometasone, hydroprednisolone, triamcinolone, fluticasone, ciclesonide, and fludrocortisone; the inert matrix or the inert core is selected from one or more of microcrystalline cellulose, sucrose, micropowder silica gel, cross-linked polyvinylpyrrolidone, lactose, mannitol, and starch.

7. The oral administration composition according to claim 1, characterized in that: The isolation layer is selected from one or more of methyl cellulose, polyethylene glycol, gelatin, gum arabic, Opadry, hydroxypropyl cellulose, polyvinyl alcohol, chitosan, gelatin, and polyethylene oxide.

8. The oral administration composition according to claim 1, characterized in that: The ethyl cellulose in the alkali-free ethyl cellulose layer is ETHOCEL.

9. The oral administration composition according to any one of claims 1 or 8, characterized in that The alkali-free ethylcellulose layer also includes a water-soluble material for controlling the release rate, and the water-soluble material is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, glucose, mannitol, sucrose, lactose, polyvinyl alcohol, polysorbate, sodium chloride, triethyl citrate, and sodium lauryl sulfate.

10. The oral administration composition according to any one of claims 1 or 8, characterized in that: The alkali-free ethylcellulose layer further comprises a water-insoluble material for controlling the release rate other than ethocide, and the water-insoluble material is selected from one or more of magnesium stearate, silicon dioxide, titanium dioxide, and talc.

Images