Prednisone enteric-coated preparation and preparation method thereof

Abstract

The present invention provides a prednisone enteric-coated preparation and a preparation method and application thereof. The prednisone enteric-coated preparation is composed of 5-35% active prednisone micro-enteric-coated preparation units, such as enteric-coated microspheres and inactive pharmaceutical excipients, and its average particle size is 100-1000 μm, and the dissolution behavior complies with the regulations for enteric-coated preparations. The enteric-coated microspheres of the present invention not only avoid the stimulation of prednisone to the gastric mucosa, but also enable the active ingredients to be quickly released and absorbed in the intestine, thereby avoiding the active ingredients from being destroyed by intestinal flora. The preparation of the present invention can be in the form of suspensions, capsules and the like, suitable for patients with dysphagia or normal patients.

Description

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 Art

[0002] Due to its good anti-inflammatory and anti-allergic effects and fewer toxic side effects, the adrenal cortical hormone 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 drug 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, the above special groups generally have swallowing difficulties, and the only prednisone preparations available in China are ordinary tablets. There is a lack of suitable dosage forms for special groups in clinical applications. Suitable dosage forms are urgently needed to improve the compliance, safety, and scientificity of the above-mentioned people with swallowing difficulties. Secondly, prednisone itself tastes bitter. The development of ordinary liquid preparations such as oral solutions will cause the bitter taste to remain in the mouth due to its fat solubility, which poses a huge challenge to children's compliance with medication. Thirdly, the adverse reactions of prednisone are closely related to the course of treatment, dosage, type of medication, usage, and route of administration. In particular, gastric irritation is the most serious, which can easily cause peptic ulcers and progress rapidly. In severe cases, it manifests as sudden massive gastrointestinal bleeding and perforation, ulcerative esophagitis, vomiting and other adverse reactions.

[0004] However, the side chains of cortisone steroid drugs 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. The change in the total excretion of 17-hydroxycorticosteroids in urine can confirm that all prednisolone cannot be absorbed. That is, if the enteric-coated prednisolone preparation cannot dissolve quickly after leaving the stomach, it will be inactivated by intestinal bacteria, which is the difficulty in the design of such drugs.

[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 children taking, 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, because the enteric-coated prednisone microspheres are active ingredients, their enteric characteristics can avoid irritation to the gastric mucosa, and the structural characteristics of the microsphere "solid dispersion" can make the active ingredient quickly released and absorbed in the human intestine, avoiding the enteric-coated prednisone preparation (tablet or capsule) prepared by the traditional enteric-coated preparation process, slow release in the intestine, long residence time, causing the effective ingredient to be destroyed by the 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, which are used for patients with dysphagia including children, the elderly, severe bedridden patients, and patients with no self-care ability, and can also be prepared into capsules or tablets, which are suitable for patients who can take medicine normally. Summary of the invention

[0006] Enteric-coated dry suspensions and enteric-coated dispersible tablets have the characteristics of solid preparations, such as easy to carry, convenient transportation, good stability, etc., and the advantages of liquid preparations, which increase the compliance of patients with swallowing difficulties (such as children and the elderly). Drugs encapsulated in microspheres can completely mask the bitter taste and improve children's medication compliance; liquid preparations are quickly absorbed in the intestine through the pylorus, fitting the circadian rhythm of glucocorticoid secretion, improving the safety and effectiveness of medication, and have obvious clinical advantages. After equivalence experiments, it is equivalent to the gastric-soluble tablets currently on the market.

[0007] To solve the above problems, on the one hand, the present application provides an enteric-coated prednisone preparation, which contains prednisone enteric-coated preparation micro units as an active ingredient and pharmaceutical excipients as an inactive ingredient.

[0008] 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.

[0009] Furthermore, the prednisone microspheres are composed of 25-35% of prednisone and 65-75% of medicinal enteric-coated polymer materials by mass.

[0010] Furthermore, the prednisone enteric-coated microspheres consist of 30% prednisone and 70% hypromellose phthalate by mass.

[0011] Furthermore, the average volume particle size of the prednisone enteric-coated microspheres is 100-1000 μm, the encapsulation rate is greater than 80%, the dissolution in acid is less than 10% in 2 hours, and the dissolution in pH 6.8 buffer solution is greater than 80% in 30 minutes.

[0012] Furthermore, the enteric-coated preparation is an enteric-coated suspension, enteric-coated granules, enteric-coated capsules or enteric-coated dispersible tablets.

[0013] Further, the enteric dry suspension comprises prednisone enteric microspheres as an active ingredient and pharmaceutically acceptable excipients such as suspending agents, flavoring agents, fillers, and aromatics;

[0014] 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%;

[0015] Furthermore, the flavoring agent is selected from one or more of sucrose, aspartame, acesulfame potassium, sucralose, sodium saccharin, citric acid, and tartaric acid, and the weight percentage of the flavoring agent is 1.0%-10.0%;

[0016] 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%;

[0017] 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%.

[0018] Furthermore, the pharmaceutically acceptable excipients include the following components and their weight percentage contents:

[0019] Xanthan gum 4.0～7.0％ lactose 10.0～90.0％ Aspartame 1.0～2.0％ Acesulfame K 1.0～2.0％ Citric Acid 2.0～5.0％ Mint flavor 0.1～0.5％ Peach flavor 0.5～1.0％

[0020] Furthermore, the composition of the enteric-coated preparation by weight is:

[0021] Prednisone Enteric-coated Microspheres 15.00％ Xanthan gum 6.00％ lactose 72.40％ Aspartame 1.50％ Acesulfame K 1.00％ Citric Acid 3.00％ Mint flavor 0.30％ Peach flavor 0.80％

[0022] Furthermore, the enteric-coated capsule contains prednisone enteric-coated microspheres as an active ingredient and pharmaceutically acceptable auxiliary material fillers.

[0023] 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%.

[0024] Furthermore, the capsule contents of the enteric-coated preparation are composed of:

[0025]

[0026]

[0027] The capsule shell is gastric soluble.

[0028] Furthermore, the enteric dispersible tablets contain prednisone enteric microspheres as an active ingredient and pharmaceutically acceptable auxiliary materials such as fillers, disintegrants, binders, and lubricants.

[0029] 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%;

[0030] Furthermore, 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%;

[0031] 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%.

[0032] Furthermore, the pharmaceutically acceptable excipients include the following components and their weight percentage contents:

[0033] lactose 10.0～40.0％ Microcrystalline Cellulose 10.0～50.0％ Povidone K30 2.0～5.0％ Croscarmellose Sodium 2.0～5.0％ Crospovidone 2.0～5.0％ Colloidal Silica 0.01～0.1％

[0034] Furthermore, the composition of the enteric-coated preparation by weight is:

[0035] Prednisone Enteric-coated Microspheres 10％ lactose 35％ Microcrystalline Cellulose 46.95％ Povidone K30 2％ Croscarmellose Sodium 3％ Crospovidone 3％ Colloidal Silica 0.05％

[0036] On the other hand, the present application provides a method for preparing the above-mentioned enteric dry suspension, which comprises: preparing prednisone enteric 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 drying, and granulating; adding 1 / 2 of the xanthan gum, mint flavor, and peach flavor to mix, and finally mixing evenly with the prednisone enteric microspheres.

[0037] 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, and preparing prednisone enteric-coated capsules.

[0038] On the other hand, the present application provides a method for preparing the above-mentioned enteric dispersible tablets, characterized in that the method comprises preparing prednisone enteric 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 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 microspheres, using a rotary tablet press to tablet, and preparing prednisone enteric dispersible tablets.

[0039] The method for preparing the micro-enteric-coated prednisone preparation unit comprises: dissolving a medicinal enteric-coated polymer material in an organic solvent, adding a 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, and solidifying the emulsion droplets 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 dodecyl sulfate, and polyvinyl alcohol.

[0040] 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, severe polymyositis, severe bronchial asthma, dermatomyositis or vasculitis, etc.

[0041] 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.

[0042] On the other hand, 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 above-mentioned enteric-coated preparation to a patient; the allergic disease is connective tissue disease, systemic lupus erythematosus, severe polymyositis, severe bronchial asthma, dermatomyositis or vasculitis, etc. The dosage during administration is 5-100 mg per day, preferably 10-60 mg. The frequency is 1-12 times per day, preferably 1-6 times.

[0043] 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 recovery after surgery, 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.

[0044] The enteric-coated prednisone preparations in the present application, especially the enteric-coated dry suspension, enteric-coated granules, and enteric-coated dispersible tablets, are very suitable for patients with dysphagia due to their good taste characteristics and swallowing performance. They can be used to treat allergic and autoimmune inflammatory diseases. They are suitable for connective tissue diseases, systemic lupus erythematosus, severe polymyositis, severe bronchial asthma, dermatomyositis, vasculitis and other allergic diseases, acute leukemia, malignant lymphoma, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is a scanning electron micrograph of prednisone enteric-coated microspheres in Example 1.

[0046] Figure 2 This is a microscope photograph of prednisone enteric-coated microspheres prepared using hypromellose phthalate as the matrix material in Example 1.

[0047] Figure 3 This is a micrograph of prednisone enteric-coated microspheres prepared with Eudragit L100 matrix material in Example 2.

[0048] Figure 4 This is the particle size distribution of prednisone enteric-coated microspheres in Example 1.

[0049] Figure 5 This is a graph of the prednisone medication-time curve for subject 101 during the fasting trial.

[0050] Figure 6 This is a graph of the prednisone medication-time curve for subject 102 during the fasting trial.

[0051] Figure 7 This is a graph showing the medication-time curve for the fasting prednisone trial for subject 103.

[0052] Figure 8 This is a graph of the prednisone medication-time curve for subject 104 during the fasting trial.

[0053] Fig. 9 This is a graph showing the medication-time curve for the fasting prednisone trial for subject 105.

[0054] Fig.10 This is a graph showing the medication-time curve for the fasting prednisone trial for subject 106.

[0055] Fig.11 This is a graph showing the medication-time curve for the fasting prednisone trial for subject 107.

[0056] Fig.12 This is a graph of the prednisone medication-time curve for subject 108 during the fasting trial.

[0057] Fig.13 This is a graph showing the medication-time curve for the fasting prednisone trial for subject 109.

[0058] Fig.14 This is a graph of the prednisone medication-time curve for subject 110 during the fasting trial.

[0059] Fig.15 The figure is a graph showing the average fasting prednisone medication time of the subjects.

[0060] Fig.16 This is the prednisolone medication-time curve for subject 101 in the fasting trial.

[0061] Fig.17 This is a graph showing the medication-time curve for prednisolone in the fasting trial for subject 102.

[0062] Fig.18 This is the prednisolone medication-time curve for subject 103 during the fasting trial.

[0063] Fig.19 This is a graph showing the medication-time curve for prednisolone in the fasting trial for subject 104.

[0064] Fig. 20 This is a graph showing the medication-time curve for prednisolone in the fasting trial for subject 105.

[0065] Fig.21 This is the prednisolone medication-time curve for subject 106 during the fasting trial.

[0066] Fig. 22 This is the prednisolone medication-time curve for subject 107 during the fasting trial.

[0067] Fig.23 This is a graph showing the medication-time curve for prednisolone in the fasting trial for subject 108.

[0068] Fig.24 This is the prednisolone medication-time curve for subject 109 during the fasting trial.

[0069] Fig.25 This is a graph of the prednisolone medication-time curve for subject 110 during the fasting trial.

[0070] Fig.26 The figure is a graph showing the average fasting test prednisolone medication time of the subjects. DETAILED DESCRIPTION

[0071] The present invention is described in detail below in conjunction with specific examples. The following examples are for demonstration purposes only, and the scope of protection 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 example formulas are calculated by weight.

[0072] Example 1

[0073] According to the present invention, the preparation of prednisone enteric-coated microspheres is carried out according to the following prescription:

[0074] Prednisone enteric-coated microspheres contain as active ingredients:

[0075] Prednisone 30％ Hydroxypropyl methylcellulose phthalate 70％

[0076] The preparation method of prednisone enteric microspheres is an emulsified solvent volatilization method, in which enteric material hydroxypropyl methylcellulose phthalate is dissolved in ethyl acetate and ethanol, prednisone raw material is added to form an oil phase, and then the oil phase is added to the water phase containing polyvinyl alcohol and stirred to form emulsion droplets, and the emulsion droplets are solidified to form microspheres. In other formulas, the basic process is the same except for the ingredients and dosage.

[0077] Prednisone enteric-coated dry suspension contains:

[0078] Prednisone Enteric-coated Microspheres 15.00％ Xanthan gum 6.00％ lactose 72.40％ Aspartame 1.50％ Acesulfame K 1.00％ Citric Acid 3.00％ Mint flavor 0.30％ Peach flavor 0.80％

[0079] Preparation method: firstly, 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, dry them at an air inlet 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, finally add prednisone enteric-coated microspheres and mix them evenly, and fill them into a double-chamber oral liquid bottle to facilitate patients to take the medicine.

[0080] Prednisone enteric-coated capsules contain:

[0081] Prednisone Enteric-coated Microspheres 22％ Granular lactose 78％

[0082] Preparation method: Take granular lactose with a D90 of about 300 μm and prednisone enteric-coated microspheres, mix them evenly, and fill them into 5# gastric-soluble capsules.

[0083] The components and contents of prednisone enteric-coated microsphere dispersible tablets are as follows:

[0084] Prednisone Enteric-coated Microspheres 10％ lactose 35％ Microcrystalline Cellulose 46.95％ Povidone K30 2％ Croscarmellose Sodium 3％ Crospovidone 3％ Colloidal Silica 0.05％

[0085] The content of the component is the percentage of the total amount of the component.

[0086] 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, use a rotary tablet press to tablet, and prepare prednisone enteric-coated dispersible tablets.

[0087] Example 2

[0088] Prednisone enteric-coated microspheres contain as active ingredients:

[0089] Prednisone 30％ Eudragit L100 70％

[0090] Prednisone enteric-coated microspheres formed by the formula of prednisone and Eudragit L100 have a large amount of floccules, as shown in the microscopic photo (see Figure 3 ). This indicates that the prescription using Eudragit L100 is not feasible.

[0091] Example 3

[0092] The preparation of prednisolone enteric-coated microspheres is carried out according to the following prescription:

[0093] Prednisolone enteric-coated microspheres contain as active ingredient:

[0094] Prednisolone 30％ Hydroxypropyl methylcellulose phthalate 70％

[0095] The inactive ingredients of prednisolone enteric-coated dry suspension contain:

[0096] Prednisolone Enteric-coated Microspheres 15％ Xanthan gum 6.00％ lactose 72.40％ Aspartame 1.50％ Acesulfame K 1.00％ Citric Acid 3.00％ Mint flavor 0.30％ Peach flavor 0.80％

[0097] Preparation method: firstly 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 air inlet 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 into the mixer and mix them, and finally add prednisolone enteric microspheres and mix them evenly.

[0098] Example 4

[0099] Prednisone enteric-coated microspheres contain as active ingredients:

[0100] Prednisone 50％ Hydroxypropyl methylcellulose phthalate 50％

[0101] The inactive ingredients of prednisone enteric-coated dry suspension contain:

[0102] Prednisone Enteric-coated Microspheres 10.00％ Xanthan gum 6.00％ lactose 77.40％ Aspartame 1.50％ Acesulfame K 1.00％ Citric Acid 3.00％ Mint flavor 0.30％ Peach flavor 0.80％

[0103] Preparation method: firstly, 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, dry them at an air inlet 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, finally add prednisone enteric-coated microspheres and mix them evenly, and fill them into a double-chamber oral liquid bottle to facilitate patients to take the medicine.

[0104] Example 5

[0105] The lactose in the prednisone enteric-coated microsphere dry suspension of Example 1 is replaced with mannitol, and the prednisone enteric-coated dry suspension contains:

[0106] Prednisone Enteric-coated Microspheres 15％ Xanthan gum 6.00％ Mannitol 72.40％ Aspartame 1.50％ Acesulfame K 1.00％ Citric Acid 3.00％ Mint flavor 0.30％ Peach flavor 0.80％

[0107] The preparation method comprises the following steps: firstly taking 1 / 2 of the xanthan gum, mannitol, aspartame, acesulfame potassium and citric acid and mixing them in a wet granulator, adding an appropriate amount of purified water to prepare a soft material, boiling drying the wet granules, drying them at an inlet air temperature of 50-60° C. until the moisture content is less than 3%, and then granulating the granules, transferring the granules to a mixer, then adding 1 / 2 of the xanthan gum, mint essence and peach essence to the mixer and mixing the granules, finally adding prednisone enteric-coated microspheres and mixing them evenly, and filling the mixture into a double-chamber oral liquid bottle to obtain a prednisone enteric-coated microsphere dry suspension.

[0108] Example 6

[0109] The lactose in the prednisone enteric-coated microsphere dry suspension of Example 1 is replaced with sorbitol, and the prednisone enteric-coated dry suspension contains:

[0110]

[0111]

[0112] The preparation method comprises the following steps: firstly taking 1 / 2 of the xanthan gum, sorbitol, aspartame, acesulfame potassium and citric acid and mixing them in a wet granulator, adding an appropriate amount of purified water to prepare a soft material, boiling drying the wet granules, drying them at an inlet air temperature of 50-60° C. until the moisture content is less than 3%, and then granulating the granules, transferring the granules to a mixer, then adding 1 / 2 of the xanthan gum, mint essence and peach essence to the mixer and mixing them, finally adding prednisone enteric-coated microspheres and mixing them evenly, and filling the mixture into a double-chamber oral liquid bottle to obtain a prednisone enteric-coated microsphere dry suspension.

[0113] Example 7 Performance test results of various preparations

[0114] In vitro dissolution curve:

[0115] The dissolution determination method for enteric-coated preparations in the 2020 edition of the "Chinese Pharmacopoeia" was adopted. 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 to simulate the alkaline environment of the intestine to test the dissolution and release of the product.

[0116] Table 1 In vitro dissolution data of samples of various embodiments

[0117]

[0118] The results showed that the in vitro dissolution of prednisone enteric microsphere dry suspension, prednisone enteric microsphere capsule and prednisone enteric microsphere dispersible tablets all met the dissolution requirements of enteric preparations, and the dissolution in acid was less than 10%. However, the in vitro dissolution of prednisolone enteric microspheres prepared with the same formula was greater than 10% in acid, which did not meet the dissolution requirements of enteric preparations. When the ratio of prednisone to hydroxypropyl methylcellulose phthalate in Example 4 was increased to 1:1, the in vitro dissolution could not meet the dissolution requirements of enteric preparations.

[0119] Canine pharmacokinetic studies

[0120] Prednisone enteric-coated capsules, prednisone enteric-coated dry suspension and FDA commercialized prednisone tablets 5 mg (trade name: ) was studied in beagle dogs in a three-period, self-crossover controlled experimental design. Male beagle dogs were given a single oral administration 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), 5 mg per dog, respectively. The concentration of prednisone in plasma was measured by LC-MS / MS technology over three periods.

[0121] Table 2 Comparison of pharmacokinetic parameters in dogs

[0122]

[0123] Table 3 T-test of pharmacokinetic parameters of each embodiment and commercially available prednisone tablets

[0124]

[0125] Table 4 Bioavailability of each embodiment and commercially available prednisone tablets

[0126]

[0127]

[0128] The results showed that the two preparations C in Example 1 max, AUC and the reference preparation had no significant differences (p<0.05 proved significant differences), indicating that the pharmacokinetic behavior of the two test preparations in male beagle dogs was very similar to that of the commercial preparations, and the bioavailability of in vivo absorption was high, indicating that the in vivo absorption of the enteric-coated microspheres of the present invention was better than that of the commercial preparations; the pharmacokinetic parameter AUC in 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 preparations, 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.

[0129] Taste evaluation - dissolution in simulated saliva

[0130] 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 (e.g. no more than 3 ml of simulated saliva), measuring the effectiveness of coatings and complexes in the formulation, and indirectly evaluating whether the taste masking technology meets the standards.

[0131] The in vitro dissolution experiment method in simulated saliva is as follows: take commercially available prednisone tablets, prednisone enteric-coated microsphere dry suspension and prednisone enteric-coated dispersible tablets to make a suspension, take out 2 ml, add 3 ml of artificial saliva, start timing, and detect the prednisone content in the solution at 30s, 1min, 2min, 3min, and 5min respectively.

[0132] Table 5 Concentration of prednisone raw materials and preparations in dissolution solution (artificial saliva)

[0133]

[0134] (3) Taste evaluation - electronic tongue

[0135] The taste analysis system of Japan's INSENT company is used to evaluate the taste by detecting the changes in membrane potential caused by the electrostatic or hydrophobic interactions between various flavor substances and artificial lipid membranes.

[0136] Table 6 Test results of bitter taste sensor and conventional bitter taste sensor

[0137]

[0138] Note: * The reference liquid is taken as the odorless point. If the value is lower than 0, the sensor response value is considered low and no analysis is performed.

[0139] Conclusion: The taste evaluation results show that the prednisone microspheres of the present invention have an excellent taste-masking effect and taste significantly better than commercially available prednisone tablets.

[0140] Example 8 Bioequivalence Experiment

[0141] Study Overview: A single (empty) oral administration of 5 mg of Example 1 prednisone enteric-coated dry suspension (specification: 5 mg) was compared with an oral administration of 5 mg of a reference preparation, commercially available prednisone tablets (trade name: Specification: 5 mg; West-Ward Pharmaceuticals International Ltd), to evaluate the relative bioavailability and pharmacokinetic characteristics of the two preparations in healthy Chinese subjects, and to preliminarily evaluate the bioequivalence and intra-individual variability of the two preparations when taken orally in the fasting state.

[0142] This study is a single-center, randomized, open, single-dose, fasting, two-preparation, two-sequence, two-cycle, double-crossover bioequivalence comparative study. This fasting study plans to enroll 10 subjects (both male and female) in a double-crossover order (two dosing sequence groups, TR and RT, the subjects are randomly assigned to one of the sequence groups, and there are 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 of each cycle (a total of 18 blood collection points). In the fasting test, all subjects completed the fasting test. The results of the pharmacokinetic statistical analysis are as follows:

[0143] Table 7 Statistical results of prednisone pharmacokinetic data in fasting test

[0144]

[0145] Table 8 Statistical results of prednisolone pharmacokinetic data in fasting test

[0146]

[0147] 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 the characteristic of enteric-coated preparation.

[0148] Prednisone is rapidly degraded and converted into prednisolone in the gastrointestinal tract, so the peak time of prednisone and prednisolone in prednisone tablets is relatively fast. From the test results, prednisolone is absorbed faster, Tmax is faster than prednisone, and Cmax and AUC are significantly greater than prednisone; enteric-coated preparations have a greater impact on the Cmax of prednisolone due to the delayed peak time. It is speculated that the degradation of enteric-coated preparations in the intestine is not as fast as that in the gastrointestinal tract, so AUC is within the equivalent range, but Cmax is small and cannot reach the equivalent range, which is consistent with the delayed Tmax. However, the pharmacological effect of this drug in the body is not concentration-dependent, and AUC is equivalent, so the efficacy equivalence can be recognized.

[0149] In summary, the Cmax and AUC of prednisone in this enteric-coated preparation are within the equivalent range, the AUC of metabolites is within the equivalent range, and the Tmax is significantly postponed, 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 microspheres as an active ingredient and pharmaceutical excipients as an inactive ingredient; the prednisone microspheres consist of 25-35% of prednisone and 65-75% of hypromellose phthalate by mass.

2. The enteric-coated preparation according to claim 1, wherein the prednisone enteric-coated microspheres consist of 30% prednisone and 70% hypromellose phthalate by mass.

3. The enteric-coated preparation according to claim 1 or 2, 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%.

4. The enteric-coated preparation according to claim 1, wherein the enteric-coated preparation is an enteric-coated suspension, an enteric-coated granule, an enteric-coated capsule or an enteric-coated dispersible tablet.

5. The enteric preparation according to claim 4, wherein the enteric dry suspension comprises prednisone enteric microspheres as an active ingredient and pharmaceutically acceptable suspending agents, flavoring agents, fillers, and aromatics.

6. The enteric-coated preparation according to claim 5, 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, sodium saccharin, 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 flavor, peach flavor, strawberry flavor, orange flavor, and lemon flavor, and the weight percentage of the fragrance is 0.1%-5.0%.

7. The enteric-coated preparation according to claim 6, 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%.

8. The enteric-coated preparation according to claim 7, wherein the composition of the enteric-coated preparation by weight is: prednisone microspheres 15.00%; xanthan gum 6.00%; lactose 72.40%; aspartame 1.50%; acesulfame potassium 1.00%; citric acid 3.00%; mint flavor 0.30%; peach flavor 0.80%.

9. The enteric-coated preparation according to claim 4, wherein the enteric-coated capsule comprises prednisone enteric-coated microspheres as an active ingredient and pharmaceutically acceptable excipient fillers.

10. The enteric preparation according to claim 9, wherein 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%.

11. The enteric-coated preparation according to claim 10, 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.

12. The enteric preparation according to claim 4, wherein the enteric dispersible tablet comprises prednisone enteric microspheres as an active ingredient and a pharmaceutically acceptable filler, disintegrant, binder, and lubricant.

13. The enteric preparation according to claim 12, 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%.

14. The enteric-coated preparation according to claim 13, wherein the types and weight percentages of the pharmaceutical filler, disintegrant, binder and lubricant 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%.

15. The enteric-coated preparation according to claim 14, wherein the composition of the enteric-coated preparation by weight is: prednisone enteric microspheres 10%; lactose 35%; microcrystalline cellulose 46.95%; povidone K30 2%; cross-linked carboxymethyl cellulose sodium 3%; cross-linked povidone 3%; colloidal silicon dioxide 0.05%.

16. The method for preparing the enteric-coated preparation according to any one of claims 6 to 8, characterized in that: The method 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 drying and granulating; adding 1 / 2 of the xanthan gum, mint essence and peach essence to mix, and finally mixing evenly with the prednisone enteric-coated microspheres.

17. The method for preparing the enteric-coated preparation according to any one of claims 9 to 11, 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.

18. The method for preparing the enteric-coated preparation according to any one of claims 13 to 15, 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.

19. The preparation method according to any one of claims 16 to 18, wherein the preparation method of prednisone enteric-coated microspheres comprises: Hydroxypropyl methylcellulose phthalate 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.

20. The preparation method according to claim 19, wherein the organic solvent is selected from one or more of methyl acetate, ethyl acetate, dichloromethane, ethanol, and n-heptane; and / or wherein the emulsifier is selected from one or more of Tween, Span, sodium dodecyl sulfate, and polyvinyl alcohol.

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