Mycophenolate mofetil micro powder as well as preparation method and application thereof

Abstract

The invention discloses mycophenolate mofetil micro powder and a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations, the mycophenolate mofetil micro powder comprises mycophenolate mofetil pill cores and a coating film; the particle size of the mycophenolate mofetil pellet core is 50-250 [mu] m, and the mycophenolate mofetil pellet core is prepared from mycophenolate mofetil, a medicinal diluent and an adhesive according to the mass ratio of 1: (0-3): (0.01-0.2). The mycophenolate mofetil micro powder is small in particle size, free of gravel feeling in the oral cavity, easy to swallow, capable of being prepared into orally disintegrating tablets and the like and especially suitable for being used by people with dysphagia, the mycophenolate mofetil micro powder comprises mycophenolate mofetil pill cores and the coating film, on one hand, the coating film can shield light, improve light stability and reduce formation of Z-isomers, and on the other hand, the coating film can be used for preparing oral disintegrating tablets and the like; on the other hand, 2-morpholinyl ethanol generated by hydrolysis in the stomach can be reduced, and adverse reactions are reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and specifically relates to mycophenolate mofetil micropowder and a preparation method and application thereof. Background Art

[0002] Mycophenolate mofetil (MMF), also known as mycophenolate mofetil, is the 2-morpholinoethyl esterification product of mycophenolic acid (MPA), and its structure is shown below. Mycophenolate mofetil was developed by Roche in Switzerland and its trade name is CellCept.

[0003]

[0004] Mycophenolate mofetil is a white or off-white crystalline powder, odorless. It is easily soluble in dichloromethane; soluble in acetonitrile, ethyl acetate and 0.1 mol / L hydrochloric acid solution; slightly soluble in methanol, slightly soluble in ethanol, and insoluble in water. As the pH increases, the solubility of the API decreases significantly, showing a pH-dependent type. In acetate buffer at a pH of 4.5, the solubility is 1.31 mg / ml.

[0005] Mycophenolate mofetil is unstable to ultraviolet rays and is easily converted into the Z-isomer under ultraviolet rays. The 38th edition of the United States Pharmacopoeia and the 2015 edition of the Chinese Pharmacopoeia have set inspection items for Z-mycophenolate mofetil in capsules and tablets.

[0006] Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA). It is rapidly absorbed orally and quickly converted into active MPA. After oral administration, it is metabolized into MPA before systemic absorption, exerting a therapeutic effect. MPA is a highly effective, selective, non-competitive, and reversible inhibitor of inosine mononucleotide dehydrogenase, which can inhibit the classical synthesis pathway of guanine nucleotides. MPA is highly selective for lymphocytes. It is clinically used for the prevention of rejection reactions after renal transplantation and the treatment of refractory rejection. In addition, there are also reports of clinical studies on the application of mycophenolate mofetil in other indications, such as refractory renal disease, lupus nephritis, refractory Henoch-Schonlein purpura, polymyositis / dermatomyositis, etc.

[0007] It has been found in clinical applications that mycophenolate mofetil is prone to cause gastrointestinal adverse reactions such as abdominal pain, diarrhea, vomiting, nausea, etc., which affect the quality of life and emotional state of the recipients, reduce their compliance and tolerance, and some patients need to reduce or even stop taking the medication, resulting in a reduction in medication dosage or even discontinuation, which has a greater negative impact on medication expectations and significantly increases the risk of acute rejection reactions in recipients.

[0008] 2-Morpholinylethanol produced by degradation in the stomach may be one of the factors affecting gastrointestinal reactions. Novartis has developed enteric-coated mycophenolate sodium tablets, which replace the ester group in the molecular structure of mycophenolate mofetil with sodium salt. The purpose is to prevent immune rejection of renal transplantation while reducing the adverse reactions caused by the ester group to the digestive tract. The peak concentration of mycophenolate sodium enteric-coated tablets in recipients is higher than that of mycophenolate mofetil, and mycophenolate sodium enteric-coated tablets can only be dissolved in an environment with a pH value of ≥5. It is mainly absorbed through the small intestine and is absorbed later in the stomach than mycophenolate mofetil. The survival time of the graft is closely related to the occurrence of acute rejection and chronic rejection after transplantation, and acute rejection is closely related to the management of early immunosuppressants after transplantation. Mycophenolate sodium enteric-coated tablets have a slow peak time, which is not conducive to suppressing acute rejection.

[0009] The occurrence of adverse reactions to mycophenolate mofetil may also be related to the drug dosage. The blood concentration level of MPA, especially the area under the MPA drug concentration-time curve, is significantly correlated with the incidence of infection, post-transplant rejection, gastrointestinal adverse reactions, etc. Therefore, in clinical practice, the market continuously monitors the drug concentration of mycophenolic acid, adjusts the drug dosage in a timely manner, and guides the individualized medication of patients, thereby reducing the occurrence of rejection reactions and the occurrence of adverse drug reactions.

[0010] In addition, the literature reports that the pharmacokinetics of mycophenolic acid drugs vary greatly from person to person, and the AUC of different patients can differ by 10 times. Too high blood drug concentrations can easily cause adverse reactions, while too low blood drug concentrations can easily cause insufficient immunosuppression.

[0011] At present, the only clinically available mycophenolate mofetil preparations for children are suspensions and dispersible tablets, and there are few dosage form options. In the prior art, a Chinese patent document with publication number CN108066322A discloses a mycophenolate mofetil sustained-release capsule, which consists of a pellet core and a sustained-release coating film. The pellet core includes mycophenolate mofetil, sodium deoxycholate, microcrystalline cellulose and hydroxypropyl methylcellulose; the sustained-release coating includes sodium dodecyl sulfate, talcum powder, polyvinyl alcohol, and polyoxyethylene stearate; in the invention, the sustained-release coating made of the above components has good stability, can be stored for a long time, and maintains the steady release of the drug. However, the slow peak time is not conducive to inhibiting acute rejection reactions. Summary of the invention

[0012] The invention provides a mycophenolate mofetil micropowder, which has a small particle size, has no gritty feeling in the oral cavity, is easy to swallow, can be prepared into orodisintegrating tablets, etc., and is particularly suitable for people with dysphagia. The mycophenolate mofetil micropowder comprises a mycophenolate mofetil pellet core and a coating film. The coating film can shield light, improve light stability, and reduce the formation of Z-isomers on the one hand, and can reduce 2-morpholinoethanol produced by hydrolysis in the stomach on the other hand, thereby reducing adverse reactions.

[0013] The specific technical solutions adopted are as follows:

[0014] A mycophenolate mofetil micropowder comprises a mycophenolate mofetil pellet core and a coating film; the average particle size of the mycophenolate mofetil pellet core is 50-250 μm, and the mycophenolate mofetil pellet core is composed of mycophenolate mofetil, a pharmaceutical diluent and a binder in a mass ratio of 1:0-3:0.01-0.2.

[0015] Preferably, the average particle size of the mycophenolate mofetil powder is 50 to 350 μm.

[0016] Preferably, the mycophenolate mofetil pellet core is composed of mycophenolate mofetil and a binder in a mass ratio of 1:0.02-0.15. Adding a pharmaceutical diluent will increase the weight of the tablets taken by the patient. In the drug system of the present invention, not adding a pharmaceutical diluent does not affect the quality of the mycophenolate mofetil pellet core.

[0017] The mycophenolate mofetil micropowder of the present invention has a small particle size and is a multi-unit drug delivery system. It is dispersedly distributed in the intestine, reduces the blood drug peak concentration, reduces the occurrence of gastrointestinal adverse reactions, and at the same time, can increase the contact with the intestine, promote drug absorption, and reduce individual differences.

[0018] The pharmaceutical diluents include microcrystalline cellulose, lactose, mannitol or starch.

[0019] The adhesive includes water, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone or starch slurry.

[0020] The coating film components include coating materials and auxiliary agents, wherein the coating materials are gastric soluble coating materials and / or enteric soluble coating materials, and the auxiliary agents include emulsifiers, lubricants, anti-adhesive agents, opacifiers or plasticizers.

[0021] Preferably, in the mycophenolate mofetil micropowder, the weight of the coating material in the coating film is 10-150% of the mycophenolate mofetil pellet core.

[0022] Further preferably, in the mycophenolate mofetil micropowder, the mycophenolate mofetil pellet core is composed of mycophenolate mofetil and hydroxypropyl methylcellulose in a mass ratio of 1:0.075; when the coating material is a gastric soluble acrylic resin, the weight of the coating material in the coating film is 20% of the mycophenolate mofetil pellet core, and when the coating material is an enteric soluble acrylic resin, the weight of the coating material in the coating film is 90% of the mycophenolate mofetil pellet core. Under the above preferred conditions, the mycophenolate mofetil micropowder has uniform particle size, stable quality, good roundness, and good drug dissolution performance.

[0023] The present invention also provides a method for preparing the mycophenolate mofetil powder, comprising the following steps:

[0024] (1) weighing mycophenolate mofetil API, a pharmaceutical diluent, and a binder in proportion, preparing the binder into a binder aqueous solution, and using a rotating multifunctional fluidized bed side spraying technology to atomize the binder aqueous solution and spray it onto the mycophenolate mofetil API and the pharmaceutical diluent in a fluidized state to prepare mycophenolate mofetil pellet cores;

[0025] (2) preparing a coating liquid, using a rotating multifunctional fluidized bed side spraying technology to atomize the coating liquid and spray it onto the fluidized mycophenolate mofetil pellet core to prepare the mycophenolate mofetil micropowder.

[0026] The pellet cores prepared by the rotating multifunctional fluidized bed side spraying technology have a small particle size and are not easy to stick together. In addition, this technology can coat the pellet cores with small particle size without sticking together, so that the particle size of the mycophenolate mofetil micropowder prepared by the method of the present invention is significantly smaller than that of the extrusion-spheronization method. The smaller the particle size, the larger the specific surface area, the faster the dissolution in the gastrointestinal tract, and the more drug absorption is promoted.

[0027] The present invention also provides a mycophenolate mofetil preparation, comprising the mycophenolate mofetil micropowder, wherein the dosage form of the mycophenolate mofetil preparation is fine granules, suspension, orodisintegrating tablet, orodisintegrating film, capsule or tablet.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The particle size of the mycophenolate mofetil micropowder provided by the present invention is 50 to 350 μm, which is a multi-unit drug delivery system, which is dispersed in the intestinal tract, can reduce blood drug concentration, and reduce the occurrence of gastrointestinal adverse reactions. At the same time, the mycophenolate mofetil micropowder can increase contact with the intestinal tract, promote drug absorption, and reduce individual differences. There is a coating on the surface of the mycophenolate mofetil micropowder, which can block light, improve light stability, and reduce the formation of Z-isomers. The coating layer of the mycophenolate mofetil micropowder can be a gastric soluble coating material or an enteric coating material, which can reduce the concentration of 2-morpholinylethanol in the stomach and reduce gastric adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is a microscope photograph of the mycophenolate mofetil pellet core in Example 1 (magnified 60 times).

[0031] Figure 2 This is a microscope photo of the mycophenolate mofetil powder coated with Eudragit EPO in Example 2 (magnified 135 times).

[0032] Figure 3 This is the mycophenolate mofetil powder coated with Eudragit L30D-55 in Example 3, wherein A is a microscope photo, and B and C are scanning electron microscope photos.

[0033] Figure 4 The dissolution curves of mycophenolate mofetil micropowder coated with Eudragit EPO in Example 2 in different media.

[0034] Figure 5 This is the dissolution curve of mycophenolate mofetil micropowder coated with Eudragit L30D-55 in Example 3 after acid resistance in a pH 6.8 medium. DETAILED DESCRIPTION

[0035] The present invention is further illustrated below in conjunction with the examples and accompanying drawings. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0036] Example 1 Mycophenolate mofetil pellet core

[0037] Take 90g of hydroxypropyl methylcellulose (HPMC) powder, prepare 1800mL of 5% HPMC aqueous solution with distilled water, take 800g of mycophenolate mofetil API, and use the rotating multifunctional fluidized bed side spray technology. The parameters are set as follows: the speed is 600rpm, the air volume is 0.5-0.6m 3 / min, air inlet temperature 60℃, air outlet temperature 40℃, atomization 0.25Mpa, backflush frequency 5s, liquid inlet speed 1.6g / min. Samples with different liquid inlet times were collected, and the particle size and distribution were detected by dry method using a laser particle size analyzer. The particle size distribution of mycophenolate mofetil pellets prepared with different amounts of HPMC is shown in Table 1. The results show that the average particle size of the prepared mycophenolate mofetil pellets is 100-250μm when the weight gain is between 5% and 11%.

[0038] Table 1 Particle size statistics of mycophenolate mofetil pellets prepared with different HPMC dosages

[0039]

[0040] The surface morphology of mycophenolate mofetil pellets was observed under a stereo microscope. The results of mycophenolate mofetil pellets with a weight gain of 7.5% HPMC were as follows: Figure 1 As shown, it can be seen that the core of the mycophenolate mofetil pellet is spherical and the size distribution is relatively concentrated.

[0041] Example 2 Eudragit EPO coated mycophenolate mofetil powder

[0042] The mycophenolate mofetil pellets prepared in Example 1 were sieved, and 300 g of pellets with mesh sizes between 80 and 160 were selected.

[0043] The aqueous dispersion coating solution of Eudragit EPO was prepared according to the formula in Table 2.

[0044] Table 2 Eudragit EPO aqueous dispersion coating solution formula

[0045]

[0046] Take 600g of water in a beaker, add 6g of sodium dodecyl sulfate under stirring, stir and dissolve, then add 9g of stearic acid and homogenize with a homogenizer for 30 minutes. Add 60g of Eudragit EPO powder to the solution, homogenize with a homogenizer for 30 minutes, and stir until a transparent and clear liquid is formed. Add 30g of talcum powder to the prepared EPO solution and homogenize for 30 minutes. Use a rotating multifunctional fluidized bed side spraying technology with parameters of a rotation speed of 200rpm and an air inlet of 0.5m 3 / min, inlet air temperature 45°C, outlet air temperature 30°C, atomization 0.25Mpa, backblowing frequency 5s, and liquid feeding speed 1.0g / min to prepare mycophenolate mofetil micropowder.

[0047] By changing the dosage of the coating film according to the ratio in Table 2, it is possible to prepare a mycophenolate mofetil powder in which the weight of the coating material in the coating film is 10-60% of the mycophenolate mofetil pellet core. The mycophenolate mofetil powder obtained in this embodiment has a coating material weight of 20% of the mycophenolate mofetil pellet core in the coating film.

[0048] The particle size distribution of three batches of mycophenolate mofetil powder is shown in Table 3. The average particle size D50 is about 200 μm, and D90 is less than 350 μm. Figure 2 As shown, the coated micropowder has a smooth appearance and good roundness.

[0049] Table 3 Particle size distribution of three batches of mycophenolate mofetil powder

[0050]

[0051] Example 3 Eudragit L30D-55 coated mycophenolate mofetil powder

[0052] The mycophenolate mofetil pellets prepared in Example 1 were sieved, and 50 g of pellets with mesh sizes between 80 and 160 were selected.

[0053] The aqueous dispersion coating solution of Eudragit L30D-55 was prepared according to the formula in Table 4.

[0054] Table 4 Eudragit L30D-55 aqueous dispersion coating solution formula

[0055]

[0056] Eudragit L30D-55 is used to prepare enteric-coated mycophenolate mofetil micropowder. The coating material dissolves in an environment with a pH greater than 5.5 and does not dissolve in an environment with a pH less than 5.5, thereby ensuring that the drug is not released in the stomach but begins to be released in the small intestine.

[0057] Weigh the prescribed amount of purified water, talcum powder, and triethyl citrate, use a homogenizer to shear them for 10-15 minutes (shear speed 3.5-4.5krpm), take Eudragit L30D-55, slowly pour the auxiliary material suspension into Eudragit L30D-55, and use a magnetic stirrer to stir for 15 minutes to obtain a Eudragit solid content of 15% aqueous dispersion coating liquid. Use rotary multifunctional fluidized bed side spray technology, the parameters are material temperature 27-29 ° C, atomization pressure 0.15-0.25Mpa, air volume 19-22m 3 / h, rotation speed 200rpm, liquid feeding speed 1.8g / min, to prepare mycophenolate mofetil micropowder.

[0058] By changing the amount of the coating film according to the ratio in Table 4, it is possible to prepare a mycophenolate mofetil powder in which the weight of the coating material in the coating film is 50-150% of the mycophenolate mofetil pellet core. The mycophenolate mofetil powder obtained in this embodiment has a coating material weight of 90% of the mycophenolate mofetil pellet core. The appearance characteristics of the mycophenolate mofetil powder are similar to those of the mycophenolate mofetil powder coated with Eudragit EPO, such as Figure 3 As shown in A, its appearance is smooth and round. Figure 3 The internal structure of mycophenolate mofetil powder can be seen in the electron micrographs B and C, which have a coating shell and a drug pellet core.

[0059] Example 4

[0060] The paddle method was used to determine the dissolution of the Eudragit EPO-coated mycophenolate mofetil powder in Example 2 in media of pH = 1.0, 5.0 and 6.8. 900 mL of dissolution medium was added in parallel to the dissolution cup of the dissolution apparatus, the temperature was set to 37°C, and the rotation speed was 50 rpm. The sampling time was 5 min, 15 min, 30 min, 60 min, 120 min, 180 min, and 240 min. 5 mL was sampled each time and filtered with a 0.22 mm filter membrane. The dissolution solutions of each time period were diluted with their respective dissolution media, and the absorbance of the dissolution solutions at different time points was measured with an ultraviolet spectrophotometer at a wavelength of 304 nm to calculate the dissolution amount at each time point. The dissolution curve is shown in the figure. Figure 4 As shown, the mycophenolate mofetil powder coated with Eudragit EPO is released quickly in a medium with a pH of 1.0, released slowly in a medium with a pH of 5.0, and basically not released in a medium with a pH of 6.8, which is consistent with the dissolution characteristics of Eudragit EPO. This shows that the EPO coating film on the surface of the mycophenolate mofetil pellets is intact, and the dissolution behavior of mycophenolate mofetil is well controlled by coating.

[0061] Example 5

[0062] The paddle method was used to determine the dissolution of mycophenolate mofetil powder coated with Eudragit L30D-55 in Example 3 in a pH 6.8 medium after being acid-resistant for 2 hours at pH = 1.0. Use 750 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, and the rotation speed is 100 rpm per minute. After 120 minutes, add 250 ml of 0.2 mol / L sodium phosphate solution to adjust the pH value of the medium to 6.8. The rotation speed remains unchanged, and the operation is continued according to the law. After 0 min, 5 min, 10 min, 15 min, 30 min, and 45 min, take the solution and filter it. Take 5 mL of the filtrate and filter it with a 0.22 mm filter membrane. After the pH 6.8 dissolution medium was diluted respectively, the absorbance of the dissolution solution at different time points at a wavelength of 304 nm was measured by ultraviolet spectrophotometer, and the dissolution amount at each time point was calculated. The dissolution curve is shown in the following figure. Figure 5 As shown, the drug is almost not released at all in an acidic medium (pH 1.0), but is rapidly released after 5 minutes in a medium of pH 6.8, and the solubility of the drug is 65.3% at 10 minutes. The results show that the enteric coating of the mycophenolate mofetil micropowder prepared in Example 3 is complete and dense, which can block the release of the drug in the stomach and achieve the purpose of drug dissolution in the intestine.

[0063] The embodiments described above provide a detailed description of the technical solutions of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements or similar substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A mycophenolate mofetil powder, characterized in that: The mycophenolate mofetil micropowder comprises a mycophenolate mofetil pellet core and a coating film; the average particle size of the mycophenolate mofetil pellet core is 50-250 μm, and the mycophenolate mofetil pellet core is composed of mycophenolate mofetil, a pharmaceutical diluent and a binder in a mass ratio of 1:0-3:0.01-0.

2.

2. The mycophenolate mofetil powder according to claim 1, characterized in that The average particle size of the mycophenolate mofetil powder is 50 to 350 μm.

3. The mycophenolate mofetil powder according to claim 1, characterized in that The mycophenolate mofetil pellet core is composed of mycophenolate mofetil and a binder in a mass ratio of 1:0.02-0.

15.

4. The mycophenolate mofetil powder according to claim 1, characterized in that The pharmaceutical diluent includes microcrystalline cellulose, lactose, mannitol or starch.

5. The mycophenolate mofetil powder according to claim 1, characterized in that: The binder includes water, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone or starch slurry.

6. The mycophenolate mofetil powder according to claim 1, characterized in that: The coating film components include coating materials and auxiliary agents, wherein the coating materials are gastric soluble coating materials and / or enteric soluble coating materials, and the auxiliary agents include emulsifiers, lubricants, anti-adhesive agents, opacifiers or plasticizers.

7. The mycophenolate mofetil powder according to claim 1, characterized in that: In the mycophenolate mofetil micropowder, the weight of the coating material in the coating film is 10-150% of the mycophenolate mofetil pellet core.

8. The mycophenolate mofetil powder according to claim 1, characterized in that: In the mycophenolate mofetil micropowder, the mycophenolate mofetil pellet core is composed of mycophenolate mofetil and hydroxypropyl methylcellulose in a mass ratio of 1:0.075; when the coating material is a gastric soluble acrylic resin, the weight of the coating material in the coating film is 20% of the mycophenolate mofetil pellet core, and when the coating material is an enteric soluble acrylic resin, the weight of the coating material in the coating film is 90% of the mycophenolate mofetil pellet core.

9. The method for preparing mycophenolate mofetil powder according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) weighing mycophenolate mofetil API, a pharmaceutical diluent, and a binder in proportion, preparing the binder into a binder aqueous solution, and using a rotating multifunctional fluidized bed side spraying technology to atomize the binder aqueous solution and spray it onto the mycophenolate mofetil API and the pharmaceutical diluent in a fluidized state to prepare mycophenolate mofetil pellet cores; (2) preparing a coating liquid, using a rotating multifunctional fluidized bed side spraying technology to atomize the coating liquid and spray it onto the fluidized mycophenolate mofetil pellet core to prepare the mycophenolate mofetil micropowder.

10. A mycophenolate mofetil preparation, characterized in that: The invention comprises the mycophenolate mofetil powder as described in any one of claims 1 to 8.

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