Prednisone enteric-coated formulation and preparation method therefor

Abstract

A prednisone enteric-coated formulation, a preparation method therefor, and use thereof. The prednisone enteric-coated formulation consists of 5%-35% of active prednisone micro enteric-coated formulation units such as enteric-coated microspheres, and an inactive pharmaceutical excipient, and has an average particle diameter of 100-1000 μm.

Description

Prednisone enteric-coated preparation and preparation method thereof Field of the invention:

[0001] The present application belongs to the field of pharmaceutical preparations. Specifically, the present application provides a prednisone enteric-coated microsphere preparation and a preparation method and application thereof. Background technology:

[0002] Due to its good anti-inflammatory and anti-allergic effects and few toxic side effects, the adrenal corticosteroid drug prednisone is widely used in clinical practice to treat diseases such as lupus erythematosus, rheumatoid arthritis, severe infections and allergies; the only dosage form of prednisone available in China is tablets.

[0003] Prednisone is the most widely used intermediate-acting glucocorticoid in clinical practice. Due to its powerful anti-inflammatory, anti-allergic, immunosuppressive, anti-rheumatic, and anti-tumor pharmacological effects, it has the following unmet clinical needs. First, it is used frequently and long-term in specific populations, such as children, the elderly, critically ill bedridden patients, and some patients using gastric tubes. However, these special groups generally suffer from swallowing difficulties, and the only prednisone preparations available in China are ordinary tablets. There is a lack of dosage forms suitable for these special groups in clinical application. Suitable dosage forms are urgently needed to improve the compliance, safety, and scientificity of the medication for these people with swallowing difficulties. Second, prednisone itself tastes bitter. The development of ordinary liquid preparations such as oral solutions will cause the bitter taste to persist in the mouth due to its fat solubility, which poses a huge challenge to children's medication compliance. Third, the adverse reactions of prednisone are closely related to the course of treatment, dosage, type of medication, usage, and route of administration. Gastric irritation is the most serious, which can easily cause peptic ulcers and progress rapidly. Severe cases manifest as sudden gastrointestinal bleeding and perforation, ulcerative esophagitis, vomiting and other adverse reactions.

[0004] However, the side chains of cortisone steroids are easily degraded by certain intestinal bacteria (see WEST HF. Prevention of peptic ulceration during corticosteroid therapy. Br Med J. 1959 Oct 10; 2(5153): 680 and Al-Sanea MM, Abdel-Hafez AA, Omar FA, Youssef AF. Biotransformation studies of prednisone using human intestinal bacteria Part II: Anaerobic incubation and docking studies. J Enzyme Inhib Med Chem. 2009 Dec; 24(6): 1211-9). The relapse rate of enteric-coated tablets in the treatment of arthritis is significantly higher than that of gastric-coated tablets. Changes in the total excretion of 17-hydroxycorticosteroids in urine can confirm that not all prednisolone is absorbed. In other words, if enteric-coated prednisolone preparations do not dissolve quickly after leaving the stomach, they will be inactivated by intestinal bacteria, which is a design difficulty for this type of drug.

[0005] Based on the above reasons, the present invention develops prednisone into an enteric-coated microsphere preparation, which can not only meet the convenience of taking by children, but also avoid the contact between the drug and the gastric mucosa, minimize the gastric irritation of the drug, and reduce the risk of gastric ulcer. The enteric-coated prednisone preparation of the present invention has the enteric characteristics of prednisone microspheres as the active ingredient, which can avoid irritation to the gastric mucosa. At the same time, the structural characteristics of the microsphere "solid dispersion" can enable the active ingredient to be quickly released and absorbed in the human intestine, avoiding the enteric-coated prednisone preparation (tablets or capsules) prepared by the traditional enteric-coated preparation process, which has slow release and long residence time in the intestine, causing the active ingredient to be destroyed by intestinal flora and unable to achieve the expected therapeutic effect. The preparation prepared by the present invention includes dosage forms such as dry suspension, granules, and dispersible tablets, and is used for patients with dysphagia including children, the elderly, seriously ill bedridden patients, and those without self-care ability. It can also be prepared into capsules or tablets, which are suitable for patients who can take medicine normally.

[0006] Summary of the Invention

[0007] Enteric-coated dry suspensions and enteric-coated dispersible tablets combine the characteristics of solid preparations—ease of portability, convenient transportation, and excellent stability—with the advantages of liquid preparations, increasing compliance among patients with dysphagia (such as children and the elderly). Drug encapsulation within microspheres completely masks the bitter taste, improving medication compliance in children. Liquid preparations are rapidly absorbed through the pylorus into the intestine, aligning with the circadian rhythm of glucocorticoid secretion, improving safety and efficacy, and possessing significant clinical advantages. Equivalence studies have demonstrated their equivalence to gastric-coated tablets currently on the market.

[0008] To solve the above problems, on the one hand, the present application provides an enteric-coated preparation of prednisone, which contains prednisone micro-enteric-coated preparation units as an active ingredient and pharmaceutical excipients as inactive ingredients.

[0009] Furthermore, the prednisone enteric-coated micro-prednisone preparation unit is prednisone enteric-coated microspheres, which are composed of 10-40% prednisone and 60-90% hydroxypropyl methylcellulose phthalate by mass.

[0010] Furthermore, the prednisone microspheres are composed of 25-35% of prednisone and 65-75% of medicinal enteric-coated polymer materials by mass.

[0011] Furthermore, the prednisone enteric-coated microspheres consist of 30% prednisone and 70% hypromellose phthalate by mass.

[0012] Furthermore, the average volume particle size of the prednisone enteric-coated microspheres is 100-1000 μm, the encapsulation efficiency is greater than 80%, the dissolution rate in acid is less than 10% in 2 hours, and the dissolution rate in pH 6.8 buffer solution is greater than 80% in 30 minutes.

[0013] Furthermore, the enteric-coated preparation is an enteric-coated suspension, enteric-coated granules, enteric-coated capsules or enteric-coated dispersible tablets.

[0014] Furthermore, the enteric dry suspension comprises prednisone enteric microspheres as an active ingredient and pharmaceutically acceptable excipients such as a suspending agent, a flavoring agent, a filler, and an aromatic agent;

[0015] Furthermore, the suspending agent is selected from one or more of xanthan gum, sodium carboxymethyl cellulose, colloidal microcrystalline cellulose, hypromellose, gum arabic, and gum tragacanth, and the weight percentage of the suspending agent is 1.0%-10.0%;

[0016] Furthermore, the flavoring agent is selected from one or more of sucrose, aspartame, acesulfame potassium, sucralose, saccharin sodium, citric acid, and tartaric acid, and the weight percentage of the flavoring agent is 1.0%-10.0%;

[0017] Furthermore, the filler is selected from one or more of sucrose, corn starch, microcrystalline cellulose, lactose, and maltitol, and the weight percentage of the filler is 10.0%-90.0%;

[0018] Furthermore, the fragrance is selected from one or more of mint essence, peach essence, strawberry essence, orange essence, and lemon essence, and the weight percentage of the fragrance is 0.1%-5.0%.

[0019] Furthermore, the pharmaceutically acceptable excipients include the following components and weight percentages:

[0020] Furthermore, the enteric-coated preparation comprises the following components by weight:

[0021] Furthermore, the enteric-coated capsule contains prednisone enteric-coated microspheres as an active ingredient and pharmaceutically acceptable excipients and fillers.

[0022] Furthermore, the filler is selected from one or more of sucrose, corn starch, microcrystalline cellulose, lactose, and maltitol, and the weight percentage of the filler is 10.0%-90.0%.

[0023] Furthermore, the contents of the enteric-coated capsule preparation are composed of the following by weight:

[0024] The capsule shell is gastric soluble.

[0025] Furthermore, the enteric dispersible tablets contain prednisone enteric-coated microspheres as an active ingredient and pharmaceutically acceptable excipients such as fillers, disintegrants, binders, and lubricants.

[0026] Furthermore, the disintegrant is one or more of pharmaceutically acceptable cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, dry starch and low-substituted hydroxypropyl cellulose, and the weight percentage of the disintegrant is 1.0%-7.0%;

[0027] Furthermore, the binder is one or more of pharmaceutically acceptable povidone, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and starch slurry, and the weight percentage of the disintegrant is 1.0%-7.0%;

[0028] Furthermore, the lubricant is one or more of pharmaceutically acceptable magnesium stearate, talc, micro-powder silica gel, and stearic acid, and the weight percentage of the lubricant is 0.1%-1.0%.

[0029] Furthermore, the pharmaceutically acceptable excipients include the following components and weight percentages:

[0030] Furthermore, the enteric-coated preparation comprises the following components by weight:

[0031] On the other hand, the present application provides a method for preparing the above-mentioned enteric-coated dry suspension, which comprises: preparing prednisone enteric-coated microspheres; mixing 1 / 2 of the xanthan gum, lactose, aspartame, acesulfame potassium, and citric acid in a wet granulator, adding an appropriate amount of purified water to prepare a soft material, boiling and drying, and granulating; adding 1 / 2 of the xanthan gum, mint essence, and peach essence, and finally mixing evenly with the prednisone enteric-coated microspheres.

[0032] On the other hand, the present application provides a method for preparing the above-mentioned enteric-coated capsules, characterized in that the method comprises preparing prednisone enteric-coated microspheres; taking granular lactose and prednisone enteric-coated microspheres and mixing them evenly, filling them into 5# gastric-soluble capsule shells to prepare prednisone enteric-coated capsules.

[0033] On the other hand, the present application provides a method for preparing the above-mentioned enteric-coated dispersible tablets, characterized in that the method comprises preparing prednisone enteric-coated microspheres; taking lactose, microcrystalline cellulose, and povidone K30 and adding them into a wet granulator for mixing, adding an appropriate amount of purified water to prepare a soft material, boiling and drying, and then granulating; adding the cross-linked sodium carboxymethyl cellulose, cross-linked povidone and colloidal silicon dioxide and mixing evenly, and finally mixing evenly with the prednisone enteric-coated microspheres, and using a rotary tablet press to compress the tablets to prepare prednisone enteric-coated dispersible tablets.

[0034] The method for preparing micro-enteric-coated prednisone preparation units includes dissolving a pharmaceutical enteric-coated polymer material in an organic solvent, adding prednisone raw material to form an oil phase, then adding the oil phase to an aqueous phase containing an emulsifier and stirring to form emulsion droplets, which are then solidified to form microspheres. The organic solvent is selected from one or more of methyl acetate, ethyl acetate, dichloromethane, ethanol, and n-heptane; and / or the emulsifier is selected from one or more of Tween, Span, sodium lauryl sulfate, and polyvinyl alcohol.

[0035] The enteric-coated preparation of the present application is used for allergic and autoimmune inflammatory diseases. It is suitable for allergic diseases, autoimmune inflammatory diseases, acute leukemia or malignant lymphoma; the allergic diseases are connective tissue diseases, systemic lupus erythematosus, polymyositis severe, severe bronchial asthma, dermatomyositis or vasculitis, etc.

[0036] On the other hand, the present application provides the use of the above-mentioned enteric-coated preparation in the preparation of a pharmaceutical preparation for allergic diseases, autoimmune inflammatory diseases, acute leukemia or malignant lymphoma; allergic diseases are connective tissue diseases, systemic lupus erythematosus, severe polymyositis, severe bronchial asthma, dermatomyositis or vasculitis, etc.

[0037] In another aspect, the present application provides a method for treating allergic diseases, autoimmune inflammatory diseases, acute leukemia, or malignant lymphoma, characterized in that the method comprises administering the enteric-coated preparation described above to a patient; the allergic disease is a connective tissue disease, systemic lupus erythematosus, polymyositis severe, severe bronchial asthma, dermatomyositis, or vasculitis, among others. The dosage is 5-100 mg per day, preferably 10-60 mg, and the frequency of administration is 1-12 times per day, preferably 1-6 times per day.

[0038] The enteric-coated preparation of the present application is particularly suitable for patients with dysphagia, which may be caused by oropharyngeal, esophageal, psychological and other reasons; clinically known causes include but are not limited to dysphagia in children, dysphagia in the elderly, dysphagia caused by psychological reasons, dysphagia during postoperative recovery, dysphagia caused by tumors or hyperplasia, dysphagia caused by congenital defects, esophageal diseases (physical blockage or abnormal peristalsis), general muscle diseases, brain or nervous system diseases causing dysphagia, etc.

[0039] The enteric-coated prednisone preparations described herein, particularly the enteric-coated dry suspension, enteric-coated granules, and enteric-coated dispersible tablets, are well-suited for patients with dysphagia due to their favorable taste and swallowing properties. They can be used to treat allergic and autoimmune inflammatory diseases, including connective tissue diseases, systemic lupus erythematosus, polymyositis severe, severe bronchial asthma, dermatomyositis, vasculitis, and other allergic diseases, as well as acute leukemia and malignant lymphoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG1 is a scanning electron micrograph of prednisone enteric-coated microspheres of Example 1.

[0041] FIG2 is a microscopic photograph of prednisone enteric-coated microspheres prepared using hypromellose phthalate as the matrix material in Example 1.

[0042] FIG3 is a micrograph of prednisone enteric-coated microspheres prepared using Eudragit L100 matrix material in Example 2.

[0043] FIG4 shows the particle size distribution of prednisone enteric-coated microspheres in Example 1.

[0044] FIG5 is a graph showing the prednisone medication-time curve for subject 101 during the fasting test.

[0045] FIG6 is a graph showing the prednisone medication-time curve for subject 102 during the fasting test.

[0046] FIG7 is a graph showing the prednisone medication-time curve for subject 103 during the fasting test.

[0047] FIG8 is a graph showing the prednisone medication-time curve for subject 104 during a fasting test.

[0048] FIG9 is a graph showing the prednisone medication-time curve for subject 105 during the fasting test.

[0049] FIG10 is a graph showing the prednisone medication-time curve for subject 106 during a fasting test.

[0050] FIG11 is a graph showing the prednisone medication-time curve for subject 107 during the fasting test.

[0051] FIG12 is a graph showing the prednisone medication-time curve for subject 108 during the fasting test.

[0052] FIG13 is a graph showing the prednisone medication-time curve for subject 109 during the fasting test.

[0053] FIG14 is a graph showing the prednisone medication-time curve for subject 110 during a fasting test.

[0054] FIG15 is a graph showing the average fasting prednisone medication time of the subjects.

[0055] FIG16 is a graph showing the prednisolone medication-time curve for subject 101 in a fasting test.

[0056] FIG17 is a graph showing the prednisolone medication-time curve for subject 102 in the fasting test.

[0057] FIG18 is a graph showing the prednisolone medication-time curve for subject 103 during the fasting test.

[0058] FIG19 is a graph showing the prednisolone medication-time curve for subject 104 during the fasting test.

[0059] FIG20 is a graph showing the prednisolone medication-time curve for subject 105 in a fasting test.

[0060] FIG21 is a graph showing the prednisolone medication-time curve for subject 106 during the fasting test.

[0061] FIG22 is a graph showing the prednisolone medication-time curve for subject 107 during the fasting test.

[0062] FIG23 is a graph showing the prednisolone medication-time curve for subject 108 during the fasting test.

[0063] FIG24 is a graph showing the prednisolone medication-time curve for subject 109 during the fasting test.

[0064] FIG25 is a graph showing the prednisolone medication-time curve for subject 110 during the fasting test.

[0065] FIG26 is a graph showing the average fasting prednisolone medication time of the subjects. DETAILED DESCRIPTION

[0066] The present invention is described in detail below with reference to specific examples. The following examples are for illustrative purposes only. The scope of the present invention is defined by the claims and is not limited to the following examples. Unless otherwise specified, the percentages or ratios in the following examples are calculated by weight.

[0067] Example 1

[0068] According to the present invention, the preparation of prednisone enteric-coated microspheres is carried out according to the following prescription:

[0069] Prednisone enteric-coated microspheres contain as active ingredients:

[0070] Prednisone enteric-coated microspheres are prepared using an emulsification and solvent evaporation method. Hydroxypropyl methylcellulose phthalate, an enteric material, is dissolved in ethyl acetate and ethanol. The prednisone raw material is then added to form an oil phase. This oil phase is then added to an aqueous phase containing polyvinyl alcohol and stirred to form emulsion droplets, which solidify to form microspheres. The basic process is the same for all other formulations, except for the ingredients and dosages.

[0071] Prednisone enteric-coated dry suspension contains:

[0072] Preparation method: first, take 1 / 2 of the xanthan gum, lactose, aspartame, acesulfame potassium, and citric acid and mix them in a wet granulator, add an appropriate amount of purified water to prepare a soft material, boil and dry the wet granules at an inlet air temperature of 50-60°C until the moisture content is less than 3%, then granulate them and transfer them to a mixer, then add 1 / 2 of the xanthan gum, mint essence, and peach essence to the mixer and mix them, finally add prednisone enteric-coated microspheres and mix evenly, and then fill them into a double-chamber oral liquid bottle for convenient medication for patients.

[0073] Prednisone enteric-coated capsules contain:

[0074] Preparation method: Take lactose granules with a D90 of about 300 μm and prednisone enteric-coated microspheres and mix them evenly, and fill them into 5# gastric-coated capsules.

[0075] The components and contents of prednisone enteric-coated microsphere dispersible tablets are as follows:

[0076] The content of the component is the percentage of the total amount of the component

[0077] Preparation method: prepare prednisone enteric-coated microspheres; take lactose, microcrystalline cellulose, and povidone K30 and add them into a wet granulator for mixing, add an appropriate amount of purified water to prepare a soft material, boil and dry, then granulate, add the cross-linked sodium carboxymethyl cellulose, cross-linked povidone and colloidal silicon dioxide and mix evenly, finally mix evenly with the prednisone enteric-coated microspheres, and use a rotary tablet press to compress the tablets to prepare prednisone enteric-coated dispersible tablets.

[0078] Example 2

[0079] Prednisone enteric-coated microspheres contain as active ingredients:

[0080] Prednisone enteric-coated microspheres formed from a formulation of prednisone and Eudragit L100 contained a large amount of flocculent matter, as shown in a microscopic photograph (see Figure 3). This indicates that the formulation using Eudragit L100 is not feasible.

[0081] Example 3

[0082] Prednisolone enteric-coated microspheres are prepared according to the following prescription:

[0083] Prednisolone enteric-coated microspheres contain as active ingredient:

[0084] The inactive ingredients of prednisolone enteric-coated dry suspension contain:

[0085] Preparation method: first, take 1 / 2 of the xanthan gum, lactose, aspartame, acesulfame potassium, and citric acid and mix them in a wet granulator, add an appropriate amount of purified water to prepare a soft material, boil and dry the wet granules at an inlet air temperature of 50-60°C until the moisture content is less than 3%, then granulate them, transfer them to a mixer, then add 1 / 2 of the xanthan gum, mint essence, and peach essence to the mixer and mix them, and finally add prednisolone enteric-coated microspheres and mix them evenly.

[0086] Example 4

[0087] Prednisone enteric-coated microspheres contain as active ingredients:

[0088] The inactive ingredients of prednisone enteric-coated dry suspension include:

[0089] Preparation method: first, take 1 / 2 xanthan gum, lactose, aspartame, acesulfame potassium, and citric acid and mix them in a wet granulator, add an appropriate amount of purified water to prepare a soft material, boil and dry the wet granules at an inlet air temperature of 50-60° C. until the moisture content is less than 3%, then granulate them, transfer them to a mixer, then add 1 / 2 xanthan gum, mint essence, and peach essence to the mixer and mix them, finally add prednisone enteric-coated microspheres and mix them evenly, and then fill them into a double-chamber oral liquid bottle for convenient medication for patients.

[0090] Example 5

[0091] The lactose in the prednisone enteric-coated microsphere dry suspension of Example 1 was replaced with mannitol. The prednisone enteric-coated dry suspension contained:

[0092] The preparation method comprises the following steps: firstly, mixing 1 / 2 of the xanthan gum, mannitol, aspartame, acesulfame potassium and citric acid in a wet granulator, adding an appropriate amount of purified water to prepare a soft material, boiling-drying the wet granules at an inlet air temperature of 50-60° C. until the moisture content is less than 3%, then granulating the granules, transferring the granules to a mixer, adding 1 / 2 of the xanthan gum, mint essence and peach essence to the mixer, mixing the granules, finally adding prednisone enteric-coated microspheres and mixing evenly, and then filling the mixture into a double-chamber oral liquid bottle to obtain a prednisone enteric-coated microsphere dry suspension.

[0093] Example 6

[0094] The lactose in the prednisone enteric-coated microsphere dry suspension of Example 1 was replaced with sorbitol. The prednisone enteric-coated dry suspension contained:

[0095] The preparation method comprises the following steps: firstly, mixing 1 / 2 of the xanthan gum, sorbitol, aspartame, acesulfame potassium and citric acid in a wet granulator, adding an appropriate amount of purified water to prepare a soft material, boiling-drying the wet granules at an inlet air temperature of 50-60° C. until the moisture content is less than 3%, then granulating the granules, transferring the granules to a mixer, adding 1 / 2 of the xanthan gum, mint essence and peach essence to the mixer, mixing the granules, and finally adding prednisone enteric-coated microspheres and mixing evenly. The mixture is then filled into a double-chamber oral liquid bottle to obtain a prednisone enteric-coated microsphere dry suspension.

[0096] Example 7 Performance test results of various preparations

[0097] In vitro dissolution curve:

[0098] The dissolution determination method for enteric-coated preparations in the 2020 edition of the "Chinese Pharmacopoeia" was used. A pH 1.0 hydrochloric acid medium was first used for 2 hours, and then the dissolution medium was adjusted to a pH 6.8 phosphate buffer solution to simulate the alkaline environment of the intestine to test the dissolution and release of the product.

[0099] Table 1 In vitro dissolution data of samples from various examples

[0100] The results showed that the in vitro dissolution of prednisone enteric-coated microsphere dry suspension, prednisone enteric-coated microsphere capsules, and prednisone enteric-coated microsphere dispersible tablets all met the dissolution requirements for enteric-coated preparations, with dissolution in acid less than 10%. However, prednisolone enteric-coated microspheres prepared with the same formula showed an in vitro dissolution in acid greater than 10%, which did not meet the dissolution requirements for enteric-coated preparations. In Example 4, when the ratio of prednisone to hydropropyl methylcellulose phthalate was increased to 1:1, the in vitro dissolution did not meet the dissolution requirements for enteric-coated preparations.

[0101] Canine pharmacokinetic studies

[0102] Prednisone enteric-coated capsules, prednisone enteric-coated dry suspension and FDA commercialized prednisone tablets 5mg (trade name: ) in beagle dogs. A three-cycle, self-crossover controlled experimental design was adopted. Male beagle dogs were given a single oral dose of the test preparation prednisone enteric-coated dry suspension (microsphere type) (T1), prednisone enteric-coated capsules (T2) and the commercial reference preparation prednisone tablets (R, batch number: PX113A), each with a specification of 5 mg / dog. The plasma concentration of prednisone was measured using LC-MS / MS technology over three cycles.

[0103] Table 2 Comparison of pharmacokinetic parameters in dogs

[0104] Table 3 T-test of pharmacokinetic parameters of each embodiment and commercially available prednisone tablets

[0105] Table 4 Bioavailability of each embodiment and commercially available prednisone tablets

[0106] The results showed that: the two preparations C in Example 1 max There were no significant differences in AUC and AUC between the two test preparations and the reference preparation (p<0.05 indicated a significant difference), indicating that the pharmacokinetic behavior of the two test preparations in male beagle dogs was very similar to that of the commercial preparation, and the bioavailability of the enteric-coated microspheres of the present invention was higher, indicating that the in vivo absorption of the enteric-coated microspheres of the present invention was better than that of the commercial preparation; the in vivo pharmacokinetic parameter AUC of the sample dogs of Example 5 (mannitol was used in the prescription) and Example 6 (sorbitol was used in the prescription) was significantly lower than that of the commercial preparation, indicating that mannitol and sorbitol had a significant effect on the in vivo absorption of prednisone, and the prescription of the present invention did not affect the in vivo absorption of prednisone.

[0107] Taste evaluation-dissolution in simulated saliva

[0108] Quantitative taste evaluation / in vitro dissolution testing based on analytical methods is mainly based on detecting drug ingredients in aqueous media in a short period of time (for example, no more than 3 ml of simulated saliva), measuring the effectiveness of coating and complexation in the formulation, and indirectly evaluating whether the taste masking technology meets the standards.

[0109] The in vitro dissolution test method in simulated saliva is as follows: prepare a suspension of commercially available prednisone tablets, prednisone enteric-coated microsphere dry suspension, and prednisone enteric-coated dispersible tablets. Take out 2 ml of the suspension, add 3 ml of artificial saliva, start timing, and detect the prednisone content in the solution at 30 seconds, 1 minute, 2 minutes, 3 minutes, and 5 minutes, respectively.

[0110] Table 5 Concentration of prednisone raw materials and preparations in dissolution solution (artificial saliva)

[0111] (3) Taste evaluation - electronic tongue

[0112] The taste analysis system of Japan's INSENT company is used to evaluate taste by detecting changes in membrane potential caused by electrostatic or hydrophobic interactions between various flavor substances and artificial lipid membranes.

[0113] Table 6 Test results of bitter taste sensor and conventional bitter taste sensor Note: * The reference solution is considered the tasteless point. Values ​​below 0 are considered low sensor response values ​​and are not analyzed. Conclusion: The taste evaluation results show that the prednisone microspheres of the present invention have an excellent taste masking effect and are significantly better than commercially available prednisone tablets.

[0114] Example 8 Bioequivalence Experiment

[0115] Study Overview: A single (empty) oral dose of 5 mg of Example 1 prednisone enteric-coated dry suspension (specification: 5 mg) was compared with a 5 mg oral dose of a reference preparation, commercially available prednisone tablets (trade name: The study investigated the relative bioavailability and pharmacokinetic characteristics of the two formulations in healthy Chinese volunteers, and preliminarily evaluated the bioequivalence and intra-individual variability of the two formulations after oral administration in the fasting state.

[0116] This study is a single-center, randomized, open, fasting single-dose, two-preparation, two-sequence, two-cycle, double-crossover bioequivalence comparative study. This fasting study plans to enroll 10 subjects (both male and female) and administer the drug in a double-crossover order (two dosing sequence groups, TR and RT, with subjects randomly assigned to one of the sequence groups, with 5 subjects in each sequence group). Determination of PK blood collection points: Blood samples must be collected from each subject at 0h before administration (collected within -60min) and 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 12h, and 24h after administration (a total of 18 blood collection points) in each cycle. In the fasting trial, all subjects completed the fasting trial. The results of the pharmacokinetic statistical analysis are as follows:

[0117] Table 7 Statistical results of prednisone pharmacokinetic data in fasting test

[0118] Table 8 Statistical results of prednisolone pharmacokinetic data in fasting test

[0119] In terms of AUC, the two preparations are within the equivalent range; in terms of Cmax, although the enteric-coated preparation will be smaller due to delayed dissolution, this experiment shows that it is still within the equivalent range; the peak time of prednisone is delayed by the enteric-coated preparation, showing the characteristics of delayed dissolution, which is characteristic of enteric coating.

[0120] Prednisone is rapidly degraded and converted into prednisolone in the gastrointestinal tract. Therefore, the peak time of prednisone and prednisolone in prednisone tablets is relatively fast. Based on the experimental results, prednisolone is absorbed more quickly, with a faster Tmax than prednisone, and its Cmax and AUC are significantly greater than prednisone. The delayed peak time of enteric-coated preparations significantly affects the Cmax of prednisolone. It is speculated that enteric-coated preparations do not degrade as rapidly in the intestine as in the gastrointestinal tract. Therefore, the AUC is within the equivalent range, but the Cmax is lower, not reaching the equivalent range. This is consistent with the delayed Tmax. However, the pharmacological effects of this drug in vivo are not concentration-dependent. The equivalent AUCs support the conclusion of pharmacodynamic equivalence.

[0121] In summary, the Cmax and AUC of prednisone in this enteric-coated preparation are within the equivalent range, the AUC of the metabolite is within the equivalent range, and the Tmax is significantly delayed, which is consistent with the characteristics of enteric-coated preparations.

Claims

1. A prednisone enteric-coated preparation, characterized in that: The enteric-coated preparation contains prednisone micro-enteric-coated preparation units as active ingredients and pharmaceutical excipients as inactive ingredients.

2. The enteric preparation according to claim 1, wherein the prednisone enteric micro-prednisone preparation unit is selected from prednisone enteric microspheres, micropills, microcapsules, and microtablets, and the prednisone enteric micro-prednisone preparation unit is composed of 10-40% of prednisone and 60-90% of medicinal enteric polymer materials by mass; the medicinal enteric polymer materials are selected from one or more of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and carboxymethyl ethyl cellulose.

3. The enteric-coated preparation according to claim 2, wherein the prednisone enteric-coated microspheres are composed of 25-35% of prednisone and 65-75% of pharmaceutical enteric-coated polymer materials by mass.

4. The enteric-coated preparation according to claim 3, wherein the prednisone enteric-coated microspheres are composed of 30% prednisone and 70% medicinal enteric-coated polymer materials by mass.

5. The enteric-coated preparation according to claim 3 or 4, wherein the prednisone microspheres are prepared by one or more of the following methods: solvent evaporation, extrusion spheronization, centrifugal granulation, and fluidized bed coating, and the average volume particle size of the prednisone enteric-coated microspheres is 100 to 1000 μm, the encapsulation efficiency is greater than 80%, the dissolution in acid for 2 hours is less than 10%, and the dissolution in pH 6.8 buffer for 30 minutes is greater than 80%.

6. The enteric-coated preparation according to any one of claims 1 to 5, wherein the enteric-coated preparation is an enteric-coated suspension, an enteric-coated granule, an enteric-coated capsule, an enteric-coated dispersible tablet or an enteric-coated tablet.

7. The enteric preparation according to claim 6, wherein the enteric dry suspension comprises prednisone enteric microspheres as an active ingredient and pharmaceutically acceptable suspending agents, flavoring agents, fillers, and aromatics.

8. The enteric-coated preparation according to claim 7, wherein the suspending agent is selected from one or more of xanthan gum, sodium carboxymethyl cellulose, colloidal microcrystalline cellulose, hypromellose, gum arabic, and gum tragacanth, and the weight percentage of the suspending agent is 1.0%-10.0%; And / or, the flavoring agent is selected from one or more of sucrose, aspartame, acesulfame potassium, sucralose, saccharin sodium, citric acid, and tartaric acid, and the weight percentage of the flavoring agent is 1.0%-10.0%; And / or, the filler is selected from one or more of sucrose, corn starch, microcrystalline cellulose, lactose, and maltitol, and the weight percentage of the filler is 10.0%-90.0%; And / or, the fragrance is selected from one or more of mint essence, peach essence, strawberry essence, orange essence, and lemon essence, and the weight percentage of the fragrance is 0.1%-5.0%.

9. The enteric-coated preparation according to claim 8, wherein the types and weight percentages of the pharmaceutically acceptable suspending agents, flavoring agents, fillers and aromatics are: xanthan gum 4.0-7.0%; lactose 10.0-90.0%; aspartame 1.0-2.0%; acesulfame potassium 1.0-2.0%; citric acid 2.0-5.0%; mint flavor 0.1-0.5%; peach flavor 0.5-1.0%.

10. The enteric-coated preparation according to claim 9, wherein the composition of the enteric-coated preparation by weight is: 15.00% of prednisone enteric-coated preparation microunits; 6.00% of xanthan gum; 72.40% of lactose; Aspartame 1.50%; Acesulfame potassium 1.00%; citric acid 3.00%; mint flavor 0.30%; peach flavor 0.80%.

11. The enteric-coated preparation according to claim 6, wherein the enteric-coated capsule comprises prednisone enteric-coated microspheres as an active ingredient and pharmaceutically acceptable excipient fillers.

12. The enteric preparation according to claim 11, wherein the filler is one or more selected from sucrose, corn starch, microcrystalline cellulose, lactose, and maltitol, and the weight percentage of the filler is 10.0%-90.0%.

13. The enteric-coated preparation according to claim 12, wherein the contents of the capsule of the enteric-coated preparation are composed of: 22% prednisone enteric-coated microspheres; 78% granular lactose; and the capsule shell is gastric-soluble.

14. The enteric preparation according to claim 6, wherein the enteric dispersible tablet comprises prednisone enteric microspheres as an active ingredient and a pharmaceutically acceptable filler, disintegrant, binder, and lubricant.

15. The enteric preparation according to claim 14, wherein the disintegrant is one or more of pharmaceutically acceptable cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, dry starch and low-substituted hydroxypropyl cellulose, and the weight percentage of the disintegrant is 1.0%-7.0%; And / or, the binder is one or more of pharmaceutically acceptable povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and starch slurry, and the weight percentage of the disintegrant is 1.0%-7.0%; And / or, the lubricant is one or more of pharmaceutically acceptable magnesium stearate, talc, micro-powder silica gel, and stearic acid, and the weight percentage of the lubricant is 0.1%-1.0%.

16. The enteric-coated preparation according to claim 15, wherein the types and weight percentages of the pharmaceutical fillers, disintegrants, binders and lubricants are: lactose 10.0-40.0%; microcrystalline cellulose 10.0-50.0%; povidone K30 2.0-5.0%; cross-linked sodium carboxymethyl cellulose 2.0-5.0%; cross-linked povidone 2.0-5.0%; colloidal silicon dioxide 0.01-0.1%.

17. The enteric-coated preparation according to claim 16, wherein the composition of the enteric-coated preparation by weight is: 10% prednisone enteric microspheres; 35% lactose; 46.95% microcrystalline cellulose; 2% povidone K30; 3% cross-linked carboxymethyl cellulose sodium; 3% cross-linked povidone; and 0.05% colloidal silicon dioxide.

18. The method for preparing the enteric-coated preparation according to any one of claims 7 to 10, characterized in that: The method comprises: preparing prednisone enteric-coated microspheres; mixing 1 / 2 xanthan gum, lactose, aspartame, acesulfame potassium and citric acid in a wet granulator, adding an appropriate amount of purified water to prepare a soft material, boiling drying and granulating; adding 1 / 2 xanthan gum, mint essence and peach essence to mix, and finally mixing evenly with the prednisone enteric-coated microspheres.

19. The method for preparing the enteric-coated preparation according to any one of claims 11 to 13, characterized in that: The method comprises the steps of preparing prednisone enteric-coated microspheres; uniformly mixing granular lactose and prednisone enteric-coated microspheres, and filling the mixture into a 5# gastric-coated capsule shell to prepare prednisone enteric-coated microsphere capsules.

20. The method for preparing the enteric-coated preparation according to any one of claims 14 to 19, characterized in that: The method comprises the steps of preparing prednisone enteric-coated microspheres; adding lactose, microcrystalline cellulose and povidone K30 into a wet granulator for mixing, adding an appropriate amount of purified water to prepare a soft material, boiling drying, and then granulating; adding the cross-linked sodium carboxymethyl cellulose, cross-linked povidone and colloidal silicon dioxide for uniform mixing, and finally mixing the cross-linked prednisone enteric-coated microspheres for uniform mixing, and using a rotary tablet press to compress the tablets to prepare prednisone enteric-coated dispersible tablets.

21. The preparation method according to any one of claims 18 to 20, wherein the preparation method of prednisone enteric-coated microspheres comprises: The medicinal enteric polymer material is dissolved in an organic solvent, and a prednisone raw material is added to form an oil phase. The oil phase is then added to an aqueous phase containing an emulsifier and stirred to form emulsion droplets, and the emulsion droplets are solidified to form microspheres.

22. The method for preparing prednisone enteric-coated microspheres according to claim 21, wherein the organic solvent is selected from one or more of methyl acetate, ethyl acetate, dichloromethane, ethanol, and n-heptane; and / or the emulsifier is selected from one or more of Tween, Span, sodium dodecyl sulfate, and polyvinyl alcohol.

23. The enteric-coated preparation according to any one of claims 1 to 17, which is used for allergic diseases, autoimmune inflammatory diseases, acute leukemia or malignant lymphoma; the allergic disease is connective tissue disease, systemic lupus erythematosus, polymyositis severe, severe bronchial asthma, dermatomyositis or vasculitis.

24. The enteric-coated preparation according to any one of claims 1 to 17 and 23, which is used for patients with dysphagia.

25. Use of the enteric-coated preparation according to any one of claims 1 to 17 in the preparation of a pharmaceutical preparation for allergic diseases, autoimmune inflammatory diseases, acute leukemia or malignant lymphoma; the allergic disease is connective tissue disease, systemic lupus erythematosus, polymyositis severe, severe bronchial asthma, dermatomyositis or vasculitis.

26. Use of the enteric-coated preparation according to any one of claims 1 to 17 in the preparation of a pharmaceutical preparation for patients with dysphagia.

27. A method for treating allergic diseases, autoimmune inflammatory diseases, acute leukemia or malignant lymphoma, characterized in that: The method comprises administering the enteric-coated preparation according to any one of claims 1 to 17 to a patient; the allergic disease is connective tissue disease, systemic lupus erythematosus, severe polymyositis, severe bronchial asthma, dermatomyositis or vasculitis.

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