Mesalazine enteric sustained-release particles and preparation method thereof

Abstract

The invention discloses a preparation method of mesalazine enteric sustained-release microparticles, mesalazine spherical microparticles with small particle size and high drug loading capacity prepared by a W / O / W multiple emulsion method are used as drug-containing pill cores, the particle size of the microparticles is 50-150 mu m, the roundness is high, the mechanical strength is high, and the drug loading capacity is high. Due to the high mechanical strength, the shape of the particles is still kept complete under the large atomization pressure in the fluidization coating process, due to the high roundness, coating liquid can be sprayed on the surfaces of the particles more evenly, the same slow-release effect is achieved, and the weight increment of the coating is smaller. The invention further discloses the mesalazine enteric-coated sustained-release particles prepared by the preparation method, the particle size is 50-200 microns, the mesalazine enteric-coated sustained-release particles are free of gravel feeling during oral administration, the problems of enteric-coated sustained release, difficulty in swallowing and the like can be effectively solved, and the medication compliance of patients is greatly improved. The mesalazine enteric-coated sustained-release particles prepared by the invention are used for preparing pharmaceutical preparations such as orally disintegrating tablets, granules, dry suspensions and the like.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to mesalazine enteric-coated sustained-release microparticles and a preparation method thereof. Background Art

[0002] Mesalazine (MSZ) is a salicylic acid derivative, a white or light pink powder, easily soluble in hot water, soluble in hydrochloric acid, slightly soluble in cold water and ethanol, with a melting point of 275-280°C, a chemical formula of C7H7NO3, a molecular weight of 153.135, and a chemical structure as shown below:

[0003]

[0004] Mesalazine has been clinically classified by the British Society of Gastroenterology Inflammatory Bowel Disease Group as an effective first-line treatment (Class A) drug for mild and moderate active UC. It inhibits the activity of prostaglandin synthase, reduces the production of prostaglandins, and exerts a strong anti-inflammatory effect. Mesalazine has broad market prospects. According to the latest report released by QYResearch, the global mesalazine market size will reach US$210 million by 2029 and continue to grow at a compound annual growth rate (CAGR) of 4.4%. However, mesalazine has a short half-life of only 0.5 to 2 hours, and it needs to be taken several times a day. And without any sustained-release enteric treatment, most of it will be absorbed by the stomach and small intestine, and only about 20% of the drug can reach the terminal ileum and colon, which makes the mesalazine content in the lesion site low and difficult to achieve therapeutic effects.

[0005] Mesalazine sustained-release tablets (trade name: Podesan) produced by Huiling Pharmaceuticals are coated with ethyl cellulose, which uses the sustained-release effect of ethyl cellulose to avoid the massive release of mesalazine in the front gastrointestinal tract. Ethyl cellulose is unstable in gastric acid, and tablets can only be swallowed and cannot be chewed. Therefore, coated tablets and capsules have medication compliance issues for the elderly, children and patients with dysphagia.

[0006] In order to improve the taste and medication compliance of mesalazine preparations, mesalazine sustained-release granules (trade name: Edisa) use coated controlled-release materials Eudragit-L and Eudragit-S to allow mesalazine to reach the distal intestine at an effective concentration through the upper digestive tract, and each granule of Edisa is a coated sustained-release dosage form, which has greater advantages than tablets. It can be more widely distributed in the intestine, expand the contact area between mesalazine and the diseased mucosa, and better play a local therapeutic role. However, the drug also needs to be swallowed when taken orally. In general, particles >200μm have a heavy sense of gravel when taken orally. Therefore, this product also has medication compliance problems for the elderly, children and patients with dysphagia.

[0007] At present, the commonly used granulation technologies are mainly fluidized bed granulation, spray drying granulation and extrusion spheronization granulation. Among them, fluidized bed granulation sprays the binder solution onto the fluidized drug powder to make them bond to each other to form particles. The particle size of the microparticles obtained by this method is usually between 200 and 700 μm, but the roundness of the particles is poor, the structure is loose, and the mechanical strength is low. The spray drying method disperses the liquid material into droplets and makes it contact with hot air to remove the solvent to form microparticles. The particle size of the obtained microparticles is related to the droplet size and the viscosity of the drug solution. This method can produce microparticles between 1 and 300 μm, but the granulation process needs to control a variety of process parameters such as particle drying speed, wind speed, temperature, spray speed, etc., and the particle size of the microparticles is difficult to control. The particle size of the microparticles obtained by the extrusion spheronization method is limited by the aperture of the sieve plate. Generally, the smaller the particle size, the worse the mechanical strength. It is only suitable for the preparation of drug-containing microcapsules between 300 and 3000 μm.

[0008] Publication No. CN112494461A discloses a mesalazine enteric-coated sustained-release pharmaceutical composition, including enteric-coated sustained-release micropellets and hollow capsules; the micropellets are composed of a core, an isolation layer, and an enteric layer; the core accounts for 50% to 60% by mass, the isolation layer accounts for 25% to 35%, and the enteric layer accounts for 10% to 15%. At the same time, a preparation method of mesalazine enteric-coated sustained-release micropellets is also disclosed, in which mesalazine and drug-carrying pill excipients are firstly prepared into a drug-carrying pill core by extrusion spheronization, and then a sustained-release layer and an enteric layer are coated on the drug-carrying pill by fluidized bed technology to obtain coated micropellets, and mesalazine enteric-coated sustained-release micropellets are prepared; the drug-containing micropellets are screened through a 18-20 mesh sieve, and the particle size of the micropellets is relatively large, and the particle size <200 μm for oral administration without gravel sensation is not achieved.

[0009] Publication number CN105616386A discloses a delayed and extended release pellet preparation for treating intestinal diseases, wherein the main active ingredient of the preparation is mesalazine; the pellet preparation has a sustained-release pellet core and an outer functional coating layer, wherein the sustained-release pellet core contains 0.5% to 5.0% by weight of a hydrophilic adhesive matrix HPMC that enables the pellet core to have a sustained-release effect, and the functional coating layer is a separate enteric coating layer. Also disclosed is a delayed and extended release pellet preparation for treating intestinal diseases, wherein the method firstly prepares a sustained-release pellet core by extruding and spheronizing mesalazine and HPMC, and then prepares a pellet preparation by using fluidized bed technology to coat the sustained-release pellet core with a functional enteric coating layer. However, the extrusion spheronization method is difficult and complicated, and it is difficult to scale up production. Summary of the invention

[0010] In order to solve the above technical problems, the present invention provides a preparation method of mesalazine enteric-coated sustained-release microparticles, wherein a mesalazine-containing pill core is prepared by a W / O / W multiple emulsion method, and then the pill core is subjected to fluidized bed coating. The mesalazine-containing pill core prepared by the method has high roundness and high mechanical strength, and the mesalazine enteric-coated sustained-release microparticles finally prepared have good enteric-coated sustained-release effect, and the particle size is less than 200 μm, and there is no gritty feeling when taken orally, which can improve the medication compliance of patients with dysphagia.

[0011] A method for preparing mesalazine enteric-coated sustained-release microparticles comprises the following steps:

[0012] (1) preparing a mesalazine-containing pill core: dissolving the mesalazine drug in an inner aqueous phase to obtain an inner aqueous phase solution, and dissolving a carrier material in an organic phase to obtain an organic phase solution; under shear conditions, adding the inner aqueous phase solution to the organic phase solution to form a W / O colostrum, and then pouring the W / O colostrum into an outer aqueous phase solution containing an emulsifier, stirring to solidify the emulsion, filtering, washing, and drying to obtain a mesalazine-containing pill core; the organic phase is immiscible with water;

[0013] (2) preparing a sustained-release layer coating solution and an enteric layer coating solution respectively, and coating the mesalazine-containing pill cores obtained in step (1) with a sustained-release layer and an enteric layer in sequence using a fluidized bed to obtain mesalazine enteric-coated sustained-release microparticles.

[0014] In the present invention, by granulating by the W / O / W double emulsion method, spherical microparticles with controllable particle size (50-150 μm) and high mechanical strength can be prepared as pill cores containing medicine, which have good dispersibility, high roundness and high mechanical strength. The shape remains intact during the fluidized coating process, which is convenient for subsequent fluidized bed coating.

[0015] Preferably, in step (1), the carrier material is ethyl cellulose.

[0016] Ethyl cellulose is a semi-synthetic polymer material that is non-toxic, non-irritating, has good thermal stability, has good biocompatibility and biodegradability in the body, and has good film-forming properties. Ethyl cellulose is insoluble in water and has good film-forming mechanical properties. It is an ideal drug sustained-release carrier material. Using ethyl cellulose as a carrier can achieve a relatively slow release of drugs, delay the dissolution time of some water-soluble drugs, maintain appropriate blood drug concentrations in the human body, and achieve the purpose of sustained release.

[0017] Preferably, in step (1), the organic phase is one of chloroform, dichloromethane and ethyl acetate.

[0018] Preferably, in step (1), the emulsifier is one of sodium lauryl sulfate, polyvinyl alcohol and polyvinyl pyrrolidone.

[0019] Further preferably, the carrier material is ethyl cellulose, the organic phase is dichloromethane, and the emulsifier is polyvinyl alcohol.

[0020] Preferably, the mesalazine-containing pellet core prepared by a W / O / W emulsion method using ethyl cellulose, dichloromethane and polyvinyl alcohol has a higher drug loading, a higher roundness and a higher mechanical strength.

[0021] Preferably, in step (1), the weight ratio of mesalazine to carrier material is 1:1-2.

[0022] Preferably, when the weight ratio of mesalazine to the carrier material is within the above range, the organic phase solution formed by the carrier material can completely wrap the inner aqueous phase to prevent the inner aqueous phase from flowing into the outer aqueous phase, and within this range, the prepared mesalazine-containing pill core has good fluidity and a high drug loading capacity.

[0023] Preferably, in step (1), the concentration of the carrier material in the organic phase solution is 0.05 to 0.12 g / mL.

[0024] Preferably, when the concentration of the carrier material is within the above range, a dense membrane can be formed, thereby effectively blocking the diffusion of the inner aqueous phase drug and having a high drug loading capacity.

[0025] Preferably, in step (1), the volume ratio of the colostrum to the external aqueous phase solution is 1:20-50.

[0026] Mesalazine is a water-soluble drug, and its solubility increases with the increase of solvent. When the volume of the external aqueous phase solution is within the above range, the increase of mesalazine flowing out of the external aqueous phase solution can be avoided, and the prepared mesalazine-containing pill core has a higher drug loading and a smaller particle size.

[0027] Preferably, in step (1), the concentration of the emulsifier in the external aqueous phase solution is 0.05 to 1.5 w / v%.

[0028] Preferably, when the emulsifier concentration is within the above range, a thick and dense protective film is formed on the surface of the prepared mesalazine-containing pill core, which can reduce the leakage of mesalazine and has a good protective effect on the mesalazine drug.

[0029] Preferably, in step (1), the median particle size of the mesalazine-containing pill core is 50 to 150 μm.

[0030] In the present invention, the mesalazine-containing pill core prepared by the W / O / W multiple emulsion method has a small particle size and a high drug loading capacity.

[0031] Preferably, in step (2), the sustained-release layer coating solution is a mixed solution containing a sustained-release layer coating material, a first plasticizer and an anti-adhesive agent; the sustained-release layer coating material is ethyl cellulose or methacrylic acid copolymer, the first plasticizer is dibutyl phthalate, triethyl citrate and polyethylene glycol 400, and the anti-adhesive agent is glyceryl behenate.

[0032] More preferably, the sustained-release layer coating solution contains 30-35 parts of ethyl cellulose, 3-6 parts of dibutyl phthalate and 3-6 parts of glyceryl behenate by weight.

[0033] In the present invention, ethyl cellulose has a strong hydrophobic effect and is a pore-release drug, that is, there are tiny gaps between the polymer chains, and the dissolution medium can penetrate into the coating film from these gaps to dissolve the drug molecules, and then according to the osmotic pressure principle, the drug molecules are diffused from the pores into the medium to release the drug, which has an excellent sustained-release effect and is suitable for use as a coating material for a sustained-release layer.

[0034] Preferably, the sustained-release layer coating solution further contains a co-solvent Tween 80 in an amount of 1 to 2 parts.

[0035] Tween 80 has good surface active properties and can form micelle structure in water to improve the solubility of behenic acid glyceryl.

[0036] Preferably, in step (2), the enteric layer coating solution is a mixed solution containing an enteric layer coating material, a second plasticizer and an anti-adhesive agent; the enteric layer coating material is a methacrylic acid copolymer, the second plasticizer is dibutyl phthalate, triethyl citrate and polyethylene glycol 400, and the anti-adhesive agent is glyceryl behenate.

[0037] Further preferably, the enteric layer coating solution contains 60-65 parts of methacrylic acid copolymer, 6-10 parts of triethyl citrate and 6-10 parts of behenic acid glyceryl ester by weight.

[0038] In the present invention, the methacrylic acid copolymer may be a methacrylic acid and methyl methacrylate (1:1) copolymer, a methacrylic acid and methyl methacrylate (1:2) copolymer or an ethyl acrylate and methyl methacrylate (2:1) copolymer, and the methacrylic acid and methyl methacrylate (1:2) copolymer may be Eudragit S100.

[0039] In the present invention, Eudragit S100 is used as the enteric layer coating material. Eudragit S100 dissolves in a buffer solution with a pH greater than 7, and can block the release of mesalazine in the front gastrointestinal tract, thereby achieving the purpose of enteric dissolution, while not affecting the dissolution of mesalazine in the colon.

[0040] In the present invention, the solvent of the sustained-release layer coating solution and the enteric layer coating solution adopts a conventional mixed solution of ethanol and water as the solvent.

[0041] Preferably, in step (2), the weight gain of the sustained-release layer is 30% to 60% of the mesalazine-containing pill core.

[0042] Preferably, when the weight gain of the sustained-release layer is within the above range, the obtained mesalazine enteric-coated sustained-release microparticles have a better sustained-release effect.

[0043] Preferably, the weight gain of the enteric layer is 90% to 130% of the mesalazine-containing pill core.

[0044] Preferably, when the weight gain of the enteric layer is within the above range, the 2h drug release rate is less than 20%, and as the weight gain ratio of the enteric layer increases, the drug release rate of mesalazine enteric sustained-release microparticles in the gastrointestinal tract decreases, and the enteric sustained-release microparticles have good acid resistance, which can reduce the release of mesalazine in the gastrointestinal tract.

[0045] The present invention also provides mesalazine enteric-coated sustained-release microparticles obtained by the above-mentioned preparation method, which have good enteric-coated sustained-release effect. In an in vitro simulated gastrointestinal pH environment, under gastric acid pH conditions, the 2h release rate is less than 10%, and under intestinal pH conditions, the microparticles are completely released within 24h.

[0046] Preferably, the particle size of the mesalazine enteric-coated sustained-release microparticles is 50 to 200 μm.

[0047] The present invention also provides the use of the above-mentioned mesalazine enteric-coated sustained-release microparticles in the preparation of orally disintegrating tablets, granules and dry suspensions.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] (1) The present invention adopts small-diameter and high-drug-loaded mesalazine spherical microparticles prepared by a W / O / W multiple emulsion method as the core of the drug-containing pills. The microparticles have a particle size of 50 to 150 μm, high roundness, and high mechanical strength. The high mechanical strength allows the microparticles to maintain their shape intact under a large atomization pressure during the fluidized coating process. The high roundness allows the coating liquid to be sprayed more evenly on the surface of the microparticles, achieving the same sustained-release effect with less coating weight gain.

[0050] (2) The particle size of the mesalazine enteric-coated sustained-release microparticles prepared by the present invention is 50 to 200 μm, and there is no gritty feeling when taken orally, which can effectively solve the problems of enteric-coated sustained-release and dysphagia, and greatly improve the patient's medication compliance.

[0051] (3) The mesalazine enteric-coated sustained-release microparticles prepared by the present invention are used to prepare orodisintegrating tablets, granules, dry suspensions and other pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The following are scanning electron micrographs of the mesalazine-containing pill cores prepared in Example 1, wherein A to C are scanning electron micrographs at scales of 1 mm, 500 μm, and 100 μm, respectively.

[0053] Figure 2 : are scanning electron micrographs of the mesalamine-containing pill cores prepared in Examples 2 to 5, wherein A to D are scanning electron micrographs of the mesalamine-containing pill cores of Examples 2 to 5, respectively.

[0054] Figure 3 The figures are scanning electron microscope images of the mesalamine-containing pill cores prepared in Examples 8 to 10, wherein A to C are scanning electron microscope images of the mesalamine-containing pill cores of Examples 8 to 10, respectively.

[0055] Figure 4 These are scanning electron micrographs of the mesalamine-containing pill core with a sustained-release layer and the mesalamine enteric-coated sustained-release microparticles obtained in Example 13, wherein A is a scanning electron micrograph of the mesalamine-containing pill core with a sustained-release layer, and B is a scanning electron micrograph of the mesalamine enteric-coated sustained-release microparticles.

[0056] Figure 5 The figure is a statistical chart of the in vitro sustained-release effect of mesalazine-containing pellet cores with a sustained-release layer having a sustained-release layer weight gain of 30%, 40%, 50% and 60%.

[0057] Figure 6 This is a statistical chart of the in vitro acid-resistant effect of mesalazine enteric-coated sustained-release microparticles with enteric layer weight gains of 90%, 100%, 110%, 120% and 130%. DETAILED DESCRIPTION

[0058] The present invention will be further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited to the following examples.

[0059] The raw materials used in the present invention are all commercially available.

[0060] Example 1: Preparation of mesalazine-containing pellet cores by W / O / W emulsion method

[0061] 0.15 g of mesalazine raw material was weighed and dissolved in 2.0 mL of an aqueous solution containing 140 μL of hydrochloric acid to obtain an inner aqueous phase solution; 0.3 g of ethyl cellulose was weighed and dissolved in 3.0 mL of dichloromethane to obtain an organic phase solution; under a shearing condition of 18000 rpm, the inner aqueous phase solution was injected into the organic phase solution, and ice-bathed for 5 min to obtain W / O colostrum; the colostrum was then injected into 100 mL of an aqueous solution containing 1.0% polyvinyl alcohol to form W / O / W emulsion droplets; then, the emulsion droplets were gradually solidified to form spherical particles at a low speed of 800 rpm for 3 h, and after filtering, washing and drying, a mesalazine-containing pill core was prepared.

[0062] Table 1: Preparation method of Example 1

[0063]

[0064] Examples 2-7: Preparation of colostrum containing mesalazine pill cores by W / O / W emulsion method

[0065] Weigh 0.15 g of mesalazine raw material and dissolve it in 2.0 mL of an aqueous solution containing 140 μL of hydrochloric acid to obtain an inner aqueous phase solution; change the ratio of mesalazine to ethyl cellulose or the concentration of ethyl cellulose and the organic phase, the specific scheme is as shown in the following table, under the shear condition of 18000 rpm, inject the inner aqueous phase solution into the organic phase solution, and shear for 5 minutes in an ice bath to obtain W / O colostrum; the remaining preparation steps are the same as those in Example 1.

[0066] Table 2: Preparation methods of Examples 2 to 7

[0067]

[0068] Examples 8-12: Investigation of the emulsification steps for preparing mesalazine-containing pill cores by W / O / W emulsion method

[0069] 0.15 g of mesalazine raw material was weighed and dissolved in 2.0 mL of an aqueous solution containing 140 μL of hydrochloric acid to obtain an inner aqueous phase solution; 0.3 g of ethyl cellulose was weighed and dissolved in 3.0 mL of dichloromethane to obtain an organic phase solution; under a shearing condition of 18000 rpm, the inner aqueous phase solution was injected into the organic phase solution, and ice-bathed for 5 min to obtain W / O colostrum; the volume ratio of colostrum to the external aqueous phase solution or the type and concentration (w / v%) of the emulsifier in the emulsion formation step was changed, and the specific scheme was as shown in the following table, and the remaining preparation steps were the same as in Example 1.

[0070] Table 3: Preparation methods of Examples 8 to 12

[0071]

[0072] Example 13: Preparation of Mesalazine Enteric-coated Sustained-release Microparticles

[0073] (1) Encapsulation of sustained-release layer

[0074] a. Prepare the sustained-release coating solution: its components are shown in Table 4. Take Tween 80 and add water to prepare a 33% Tween 80 solution for use. Take behenic acid glyceryl and 33% Tween 80 solution and add them to deionized water. Homogenize at 80°C with a high shear homogenizer at a speed of 5000rpm for 10 minutes to obtain a mixed solution. Stir the mixed solution on a magnetic stirrer and cool it to room temperature to obtain an anti-adhesive suspension for use. Use ethanol to dissolve ethyl cellulose to obtain an ethyl cellulose solution. Add the anti-adhesive suspension and the first plasticizer while stirring, and mix them evenly to obtain a sustained-release coating solution.

[0075] Table 4: Composition of sustained-release coating solution

[0076]

[0077] b. Sustained-release layer coating: Take the mesalazine-containing pill core prepared in Example 1, place it in a fluidized bed coating machine, and use the fluidized bed bottom spray coating technology to spray the sustained-release layer coating liquid onto its surface. The parameters of the fluidized bed coating machine are as follows: inlet air temperature 35°C, outlet air temperature 30°C, dry air flow rate 10m 3 / h, atomization pressure of 0.27Mpa, peristaltic pump liquid feeding speed of 1.2g / min, shaking bag every 10s, each time lasting 1s, shaking pressure of 0.2Mpa. When the weight gain of sustained-release layer is 50% of mesalazine-containing pill core, coating is completed, and the pill core containing mesalazine with sustained-release layer is obtained through 80-mesh sieve.

[0078] (2) Encapsulating the enteric layer

[0079] a. Prepare enteric layer coating solution: Its components are shown in Table 5. Take ethanol and water as a mixture of solvents, divide it into two parts, add behenic acid glyceryl and triethyl citrate to one part of the solvent, and homogenize it at a speed of 3000rpm for 15 minutes using a high shear homogenizer to obtain a mixed solution of the second plasticizer and the anti-adherent agent; add Eudragit S100 to the other part, stir until completely dissolved to obtain a Eudragit S100 solution. Slowly pour the mixed solution of the second plasticizer and the anti-adherent agent into the Eudragit S100 solution, stir it with a stirrer, and obtain an enteric layer coating solution.

[0080] Table 5: Composition of enteric coating solution

[0081]

[0082] b. Enteric layer coating: The mesalazine-containing pill core with a sustained-release layer in step (1) is sprayed with the enteric layer coating liquid onto its surface using a fluidized bed bottom spray coating technique. The fluidized bed coating machine parameters are set as follows: inlet air temperature 30°C, outlet air temperature 26°C, atomization pressure 0.2Mpa, and dry air flow rate 12m3 / h, the peristaltic pump feed rate was 1.2g / min. When the weight gain of the enteric layer was 120% of the mesalazine-containing pill core, the coating was completed, and the mesalazine enteric sustained-release particles were obtained through a 80-mesh sieve, with a yield of 83.2%.

[0083] Sample analysis

[0084] 1. Performance Characterization of the Mesalazine-Containing Pill Cores Obtained from Examples 1 to 12

[0085] 1. Morphological characterization

[0086] The mesalazine-containing pill core was fixed on a copper plate using conductive glue, and the gold powder was coated with conductive scanning and photographed. The particle morphology and surface were observed using a scanning electron microscope. The results are as follows: Figures 1 to 3 shown.

[0087] Figure 1 The following are scanning electron micrographs of the mesalazine-containing pill cores prepared in Example 1, wherein A to C are scanning electron micrographs at scales of 1 mm, 500 μm, and 100 μm, respectively. Figure 2 : are scanning electron micrographs of the mesalamine-containing pill cores prepared in Examples 2 to 5, wherein A to D are scanning electron micrographs of the mesalamine-containing pill cores of Examples 2 to 5, respectively. Figure 3 8 are scanning electron micrographs of the mesalamine-containing pill cores prepared in Examples 8 to 10, wherein A to C are scanning electron micrographs of the mesalamine-containing pill cores of Examples 8 to 10, respectively. Figures 1 to 3 As shown in the figure, the mesalazine-containing pellet cores prepared by the W / O / W emulsion granulation method are round in shape with tiny pores on the surface, which may be caused by the volatilization of dichloromethane during the solidification process.

[0088] 2. Particle size

[0089] Connect the laser particle size analyzer to the dry method measurement module, weigh an appropriate amount of pill cores, mix the powder sample evenly and add it to the sample pool. Set the instrument parameters: acquisition time 10s, refractive index 1.00, use "Bluewave" laser technology, repeat the measurement of the sample 3 times, the results are shown in Table 6.

[0090] 3. Carr's index (CI)

[0091] The macroscopic index for evaluating powder fluidity, the Carr index, is calculated according to the following formula:

[0092] CI(%)=(ρ2-ρ1) / ρ2×100%;

[0093] ρ1 and ρ2 represent bulk density and tap density respectively. The results are shown in Table 6.

[0094] 4. Evaluation of drug loading rate

[0095] Grind the core of the drug-containing pellet in a mortar, take about 10 mg of the ground microspheres into an EP tube, and weigh accurately. Accurately measure 10 mL of buffer and add it, and ultrasonicate for 30 minutes. Cool to room temperature and pass through a 0.45 μm water film. At a wavelength of 302 nm, measure the absorbance value by ultraviolet spectrophotometry, and substitute it into the standard curve equation to calculate the corresponding drug concentration and drug loading rate. The results are shown in Table 6.

[0096] 5. Friability

[0097] Refer to the method in European Pharmacopoeia EP 10.0 to determine the particle friability using a fluidized bed. Take 100g (m1) of the sample to be tested, weigh it accurately, and place it in the fluidized bed. Set the air inlet temperature to 35°C and the air volume to 12m 3 / h, atomization pressure 0.25Mpa, take out the particles after fluidization for 15min, pass through a 400-mesh sieve, and weigh the mass of the remaining particles on the sieve (m2); calculate the friability according to the following formula. The results are shown in Table 7: friability = 1-m2 / m1×100%.

[0098] 6. Roundness

[0099] The ratio of the length to the short diameter of 50 pill cores was observed under a microscope and the average value was taken to evaluate the roundness of the pill cores. The closer the ratio of the length to the short diameter is to 1, the better the roundness of the pill cores. The roundness of the pill cores was calculated according to the following formula. The results are shown in Table 7.

[0100] Roundness = short diameter / long diameter of pill core.

[0101] Table 6: Powder properties of mesalazine-containing pill cores obtained in Examples 1 to 12

[0102]

[0103]

[0104] Table 7: Powder properties of mesalazine-containing pellet cores prepared in Example 1

[0105]

[0106] As shown in Table 6, the particle size of the mesalazine pill core obtained in Examples 1 to 12 is 50 to 150 μm, the drug loading is 14% to 25%, the Carr index is between 20% and 35%, and the particle size of the mesalazine pill core is small. When the organic phase is dichloromethane, the solubility in water is the smallest, and the obtained mesalazine pill core has a higher drug loading rate; when the emulsifier is polyvinyl alcohol, the emulsification effect is better, and the obtained mesalazine pill core has a higher drug loading rate. Among them, the particle size of the mesalazine pill core obtained in Example 1 is 100.60 μm, the drug loading rate is 23.48% (see Table 7), the roundness is high, and the friability is low, indicating that the obtained pill core has a higher mechanical strength and meets the requirements of fluidized bed coating as a pill core.

[0107] 2. Screening of components of sustained-release coating solution

[0108] 1. Preparation of sustained-release layer free film by casting method

[0109] Triethyl citrate (TEC), polyethylene glycol 400 (PEG400) and dibutyl phthalate (DBP) were added to the sustained-release layer coating material (here ethyl cellulose) at 15% dry weight as the first plasticizer in the sustained-release layer coating solution to investigate the effects of different first plasticizer types on the mechanical properties of the free film. At the same time, the sustained-release layer coating solution without the first plasticizer was used as a control (in the preliminary experiment, the sustained-release layer coating solution did not add the anti-adhesive agent behenic acid glyceryl). About 30 mL of the coating solution was measured and poured into a horizontally placed square box with a bottom made of polytetrafluoroethylene material and a size of 15.0 cm × 15.0 cm × 1.0 cm. It was allowed to stand at room temperature until it was semi-solid, and then allowed to stand in a 40°C oven to solidify until the polymer dried into a uniform and dense film. It was then transferred to a dryer with a relative humidity of about 92.5% to soften it by moisture absorption. The film was removed and placed back in a 40°C oven for drying, and then moved to a desiccator at a relative humidity of about 43% for storage until testing.

[0110] 2. Determination of mechanical properties of free film of sustained-release layer

[0111] Cut the free film into a rectangle of 9cm×1.5cm, measure the thickness of different parts of the free film with a thickness gauge, select a film with uniform thickness, cut it into a dumbbell shape, and the effective length of the middle test part is 20mm; place the sample in the upper and lower clamps of the universal testing machine, so that the longitudinal axis of the sample coincides with the center line of the upper and lower clamps, ensure that the clamping force is appropriate, and prevent the sample from slipping or breaking in the clamp. Stretch the film at a uniform speed of 5mm / min until the film breaks, record the force-displacement curve, and calculate the mechanical performance parameters. The tensile strength, elongation at break, and elastic modulus are all the average values ​​of 3 parallel samples;

[0112] Tensile strength σ = F / (a×b);

[0113] Elongation at break ε=(L–L0 / L0)×100%;

[0114] Elastic modulus E = k / (a×b);

[0115] Wherein: σ is tensile strength (MPa), F is breaking force i.e. maximum load (N), a is free film thickness (mm), b is free film width (mm), ε is elongation at break (%), L is free film length at break (mm), L0 is initial length of free film (mm), E is elastic modulus (MPa), k is slope of elastic deformation zone of material; the effects of different first plasticizers on mechanical properties of free film are shown in Table 8.

[0116] Table 8: Effect of the first plasticizer type on the mechanical properties of free films

[0117]

[0118] As can be seen from Table 8, when DBP is the first plasticizer, the values ​​of ε and σ / E of the free film of the sustained-release layer are the largest, indicating that when DBP is used as the first plasticizer, the toughness of the coating film is enhanced and the coating film is not easy to crack. On the other hand, when TEC is used as the first plasticizer, the values ​​of σ and E of the free film of the sustained-release layer are between the other two first plasticizers, indicating that the free film of the sustained-release layer prepared by TEC also has certain wear resistance and rigidity. DBP can effectively insert between ethyl cellulose molecules, significantly reduce the glass transition temperature of the free film of the sustained-release layer, and thus improve the flexibility of the free film of the sustained-release layer. The results show that the mechanical properties of the free film of the sustained-release layer are better when DBP is the first plasticizer.

[0119] 3. Screening of the proportion of the first plasticizer in the sustained-release layer coating solution

[0120] Glyceryl behenate with a dry weight of 10% of the sustained-release layer coating material (here ethyl cellulose) was selected as the anti-adhesive agent in the coating solution, and DBP with a dry weight of 5%, 10%, 15%, and 20% of the sustained-release layer coating material was used as the first plasticizer in the sustained-release layer coating solution. The mechanical properties of the free films with different first plasticizer ratios were investigated, and the results are shown in Table 9.

[0121] Table 9: Effects of different DBP ratios on the mechanical properties of the sustained-release layer free film

[0122]

[0123] As shown in Table 9, increasing the amount of the first plasticizer can enhance the flexibility of the free film of the sustained-release layer and effectively reduce the possibility of cracking and incomplete fusion of the free film of the sustained-release layer. On the other hand, since the first plasticizer can weaken the interaction between ethylcellulose, increasing the amount will reduce the strength of the free film of the sustained-release layer. The results show that the value of σ / E is the largest when DBP is 10% of the dry weight of ethylcellulose.

[0124] 3. Performance Characterization of Mesalazine Enteric-coated Sustained-release Microparticles

[0125] 1. Morphological characterization

[0126] The morphological analysis of the mesalazine enteric-coated sustained-release microparticles obtained in Example 13 was performed by referring to the above-mentioned morphological characterization method for the mesalazine-containing pill core. The results are as follows: Figure 4 shown.

[0127] Figure 4 The scanning electron microscope images of the mesalazine pill core with a sustained-release layer and the mesalazine enteric-coated sustained-release microparticles prepared in Example 13, wherein A is a scanning electron microscope image of the mesalazine pill core with a sustained-release layer, and B is a scanning electron microscope image of the mesalazine enteric-coated sustained-release microparticles. As shown in the figure, the enteric-coated sustained-release microparticles obtained after being coated with the sustained-release layer and the enteric-coated layer still retain a complete shape, and the sustained-release layer and the enteric-coated layer are completely coated, indicating that the mesalazine pill core prepared by the W / O / W multiple emulsion granulation method has a small particle size, high mechanical strength, and is not easy to break during the fluidization process. The surface of the prepared enteric-coated sustained-release microparticles is smooth and flat, the dispersion between the microparticles is good, and there is less adhesion.

[0128] 2. Evaluation of sustained-release effect

[0129] The in vitro release of the drug was investigated by dialysis membrane method. A pH 7.4 phosphate buffer was used as the release medium. According to the preparation method of Example 13, mesalazine-containing pill cores with a sustained-release layer having a weight gain of 30%, 40%, 50% and 60% were prepared respectively, and about 20 mg of the above-mentioned mesalazine-containing pill cores with a sustained-release layer were taken respectively, placed in a dialysis bag, 1 mL of release medium was accurately added to the dialysis bag, and put into an ep tube containing 9 mL of release medium, and the two ends of the dialysis bag were tied tightly. At a speed of 60 rpm and a constant temperature water bath of 37 ± 0.5 ° C, 3 mL of release solution was taken at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h, and the same volume of release medium was added. At a wavelength of 330 nm, the absorbance was determined by ultraviolet spectrophotometry, and the corresponding drug concentration and cumulative release percentage were calculated by substituting into the standard curve equation.

[0130] Figure 5 The figure is a statistical diagram of the in vitro sustained-release effect of mesalazine-containing pill cores with a sustained-release layer having a weight gain of 30%, 40%, 50% and 60%. The higher the weight gain ratio of the sustained-release layer, the better the sustained-release effect.

[0131] 3. Acid resistance evaluation

[0132] According to the preparation method of Example 13, enteric-coated mesalazine sustained-release microparticles with enteric layer weight gains of 90%, 100%, 110%, 120% and 130% were prepared respectively. 20 mg of each of the above-mentioned mesalazine enteric-coated sustained-release microparticles were accurately weighed and placed in a test tube containing 10 mL of an aqueous solution (0.1 M) of HCl. The mixture was shaken in a constant temperature water bath at 37±0.5°C at a speed of 60 rpm for 2 h. The absorbance was determined by ultraviolet spectrophotometry at a wavelength of 302 nm, and the corresponding drug concentration and drug release percentage were calculated by substituting into the standard curve equation.

[0133] Figure 6 The present invention is a statistical diagram of the in vitro acid resistance effect of mesalazine enteric-coated sustained-release microparticles with enteric layer weight gain of 90%, 100%, 110%, 120% and 130%, wherein, under the in vitro simulated gastrointestinal pH environment, when the enteric layer weight gain is 90% to 130%, the 2h drug release rate is lower than 20%, and as the enteric layer weight gain ratio increases, the drug release rate of mesalazine enteric-coated sustained-release microparticles in the gastrointestinal tract decreases, indicating that the mesalazine enteric-coated sustained-release microparticles prepared in the present invention have good acid resistance and can reduce the release of mesalazine in the gastrointestinal tract.

[0134] 4. Evaluation of the powder properties of the mesalazine enteric-coated sustained-release microparticles prepared in Example 13

[0135] (1) Bulk density and tap density

[0136] The test methods for bulk density and tap density are as follows, and the results are shown in Table 10.

[0137] Take the mesalazine enteric sustained-release microparticles obtained in Example 13, pour into a 10mL graduated cylinder dried to constant weight, read the volume (V1) of the sample in the graduated cylinder, and accurately weigh the mass (m), and calculate the bulk density ρ1 of the sample. After the graduated cylinder is vibrated or tapped according to a certain rule, read the volume (V2) of the sample in the graduated cylinder, calculate the tap density of the sample, i.e., the tap density ρ2 of the sample. Each sample was measured 3 times in parallel to calculate the average value and standard deviation.

[0138] Bulk density ρ1=m / V1

[0139] Tap density ρ2=m / V2

[0140] (2) Carr index and particle size

[0141] The Carr index and particle size test methods of the mesalazine-containing pill cores of Examples 1 to 12 are shown in Table 10.

[0142] Table 10: Powder properties of mesalazine enteric-coated sustained-release microparticles prepared in Example 13

[0143]

[0144] As shown in Table 10, the particle size of the mesalazine enteric sustained-release microparticles prepared in Example 13 is 177.63±32.48 μm, and the Carr index is 12.00%, indicating that the particles have good fluidity, which is conducive to the subsequent preparation of orally disintegrating tablets by direct powder compression.

[0145] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing mesalazine enteric-coated sustained-release microparticles, characterized in that: The following steps are involved: (1) preparing a mesalazine-containing pill core: dissolving the mesalazine drug in an inner aqueous phase to obtain an inner aqueous phase solution, and dissolving a carrier material in an organic phase to obtain an organic phase solution; Under shear conditions, the inner aqueous phase solution is added to the organic phase solution to form W / O colostrum, and then the W / O colostrum is poured into the outer aqueous phase solution containing an emulsifier, stirred to solidify the emulsion, filtered, washed, and dried to obtain the mesalazine-containing pill core; the organic phase is immiscible with water; (2) preparing a sustained-release layer coating solution and an enteric layer coating solution respectively, and coating the mesalazine-containing pill cores obtained in step (1) with a sustained-release layer and an enteric layer in sequence using a fluidized bed to obtain mesalazine enteric-coated sustained-release microparticles.

2. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 1, characterized in that: In step (1), the carrier material is ethyl cellulose; the organic phase is one of chloroform, dichloromethane and ethyl acetate; and the emulsifier is one of sodium dodecyl sulfate, polyvinyl alcohol and polyvinyl pyrrolidone.

3. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 1, characterized in that: In step (1), the weight ratio of mesalazine to carrier material is 1:1-2; and the concentration of carrier material in the organic phase solution is 0.05-0.12 g / mL.

4. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 1, characterized in that: In step (1), the volume ratio of the colostrum to the external aqueous phase solution is 1:20-50; and the concentration of the emulsifier in the external aqueous phase solution is 0.05-1.5 w / v%.

5. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 1, characterized in that: In step (2), the sustained-release layer coating solution is a mixed solution containing a sustained-release layer coating material, a first plasticizer and an anti-adhesive agent; the sustained-release layer coating material is ethyl cellulose or methacrylic acid copolymer, the first plasticizer is dibutyl phthalate, triethyl citrate and polyethylene glycol 400, and the anti-adhesive agent is glyceryl behenate.

6. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 5, characterized in that: The sustained-release coating solution contains 30-35 parts of ethyl cellulose, 3-6 parts of dibutyl phthalate and 3-6 parts of glyceryl behenate by weight.

7. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 1, characterized in that: In step (2), the enteric layer coating solution is a mixed solution containing an enteric layer coating material, a second plasticizer and an anti-adhesive agent; the enteric layer coating material is a methacrylic acid copolymer, the second plasticizer is dibutyl phthalate, triethyl citrate and polyethylene glycol 400, and the anti-adhesive agent is glyceryl behenate.

8. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 7, characterized in that: By weight, the composition contains 60-65 parts of methacrylic acid copolymer, 6-10 parts of triethyl citrate and 6-10 parts of glyceryl behenate.

9. The method for preparing mesalazine enteric-coated sustained-release microparticles according to claim 1, characterized in that: The particle size of the mesalazine enteric-coated sustained-release microparticles is 50 to 200 μm.

10. Mesalazine enteric-coated sustained-release microparticles obtained by the preparation method according to claims 1 to 9.

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