Oral pharmaceutical composition of peptide amide compound and preparation method therefor

Abstract

An oral pharmaceutical composition of a peptide amide compound A for treating pain and pruritus and a preparation method therefor. The composition comprises compound A and a microcrystalline cellulose colloidal silica co-treatment substance, and further comprises a disintegrant and / or a lubricant. The composition can be prepared into an oral preparation form such as a tablet or a capsule.

Description

An oral pharmaceutical composition of a peptide amide compound and a preparation method thereof Technical Field

[0001] The present invention relates to the technical field of chemical medicines, and in particular to an oral pharmaceutical composition of a peptide amide compound (A) for treating pain and pruritus, as well as a preparation method of the pharmaceutical composition for treating pain and pruritus and a packaging combination thereof. Background Art

[0002] Pain has been identified by the World Health Organization as the fifth vital sign after respiration, pulse, blood pressure, and body temperature. The current internationally accepted definition of pain was proposed by the International Association for the Study of Pain (IASP) in 1994: an unpleasant subjective feeling and emotional experience associated with tissue damage or potential damage. Pain is divided into acute pain and chronic pain. Depending on the duration and nature of the pain, pain within 3 months is called acute pain, and pain over 3 months is called chronic pain. Acute pain is the body's normal protective response. It occurs quickly and occurs in conjunction with specific injury lesions. Generally, the pain disappears after the primary injury heals, but it may also evolve into chronic pain under various circumstances. Chronic pain generally refers to pain that persists or recurs for more than 3 months. The causes of the lesions are complex, and physical, blood, imaging and other examinations show inconsistencies. The current classification is relatively complex and can be divided into seven types, often accompanied by emotional and psychological disorders.

[0003] Pain has become the third most common health problem after cardiovascular and cerebrovascular diseases and cancer. Pain not only causes distress for patients but also often causes psychological stress and mood disorders, increasing the risk of complications. According to statistics, the number of chronic pain sufferers in my country exceeds 300 million, with the number increasing by 10 to 20 million annually, showing a rapid increase and a younger age trend. This places a heavy economic and physical burden on patients and their families. Given the diverse pathogenesis and mechanisms of action of acute and chronic pain, treatments and medications vary. According to the WHO's three-step pain treatment ladder, Category I medications are primarily nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, the latter of which has fewer adverse reactions than NSAIDs. Category II medications include weak opioids such as tramadol. Category III medications may include strong opioids, but dosage should be controlled to minimize adverse reactions and avoid addiction. For pain treatment, developed dosage forms include oral tablets, intravenous injections, and nasal sprays, offering patients multiple treatment options and improving efficacy and patient compliance.

[0004] Compound A has peptide-like properties, making it unstable at high temperatures and prone to impurities. Peptide compounds, on the other hand, suffer from poor stability when administered orally. Therefore, during formulation development, formulation stability is a key consideration. Furthermore, careful control of process parameters and the production environment is crucial to ensure consistent raw material quality and the safety and efficacy of the final product.

[0005] CN115025205A discloses a Compound A injection. While its intravenous administration is rapid, chronic pain persists and recurs, requiring long-term administration. Compared to frequent injections, oral administration is more convenient and has better compliance. Given the excellent analgesic and antipruritic efficacy of Compound A, and the persistent and difficult-to-treat nature of chronic pain, which requires a long treatment cycle, the development of an oral Compound A medication with convenient administration, rapid action, good absorption, minimal irritation, stable quality, and good safety can alleviate patients' pain and itching symptoms and provide patients with a variety of treatment options.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide an oral pharmaceutical composition of Compound A, which is prepared by combining Compound A with a filler or other inactive ingredients. The composition of the present invention has stable quality, rapid onset of action, good absorption, low irritation, good stability and good safety.

[0008] The present invention provides an oral pharmaceutical composition of Compound A for treating pain and itching, which comprises an active ingredient Compound A and pharmaceutically acceptable excipients prepared by reasonable combination.

[0009] One object of the present invention is to provide an oral pharmaceutical composition of Compound A.

[0010] Another object of the present invention is to provide a method for preparing the oral pharmaceutical composition.

[0011] Another object of the present invention is to provide a packaged combination of the oral pharmaceutical composition.

[0012] In one aspect, the present invention provides an oral pharmaceutical composition comprising:

[0013] a) Compound A, wherein the compound A is as follows:

[0014] as well as

[0015] b) a filler selected from one or more of microcrystalline cellulose, colloidal silicon dioxide co-processed products, and pregelatinized starch.

[0016] In some embodiments, the content of Compound A in the pharmaceutical composition is 0.1% to 25% w / w.

[0017] In some embodiments, the content of Compound A in the pharmaceutical composition is 0.1% to 12% w / w.

[0018] In some embodiments, the content of Compound A in the pharmaceutical composition is 0.1% to 9% w / w.

[0019] In some embodiments, the composition further comprises other fillers selected from one or more of mannitol, microcrystalline cellulose, lactose, calcium hydrogen phosphate, and maltodextrin.

[0020] In some embodiments, the other fillers are selected from one or more of microcrystalline cellulose and mannitol.

[0021] In some embodiments, the pharmaceutical composition further contains one or more of a disintegrant and a lubricant.

[0022] In some embodiments, the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch.

[0023] In some embodiments, the disintegrant is selected from crospovidone.

[0024] In some embodiments, the lubricant is selected from one or more of magnesium stearate and sodium stearyl fumarate.

[0025] In some embodiments, the lubricant is selected from magnesium stearate.

[0026] In some embodiments, the content of the filler in the pharmaceutical composition is 75% to 98% w / w.

[0027] In some embodiments, the content of the filler in the pharmaceutical composition is 87% to 95% w / w.

[0028] In some embodiments, the content of disintegrant in the pharmaceutical composition is 0% to 5% w / w.

[0029] In some embodiments, the content of disintegrant in the pharmaceutical composition is 2% to 5% w / w.

[0030] In some embodiments, the content of disintegrant in the pharmaceutical composition is 2% to 3% w / w.

[0031] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of 0.1% to 5% w / w.

[0032] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of 0.1% to 2% w / w.

[0033] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of 0.25% to 2% w / w.

[0034] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of 0.25% to 1% w / w.

[0035] In certain embodiments, the pharmaceutical composition comprises Compound A, microcrystalline cellulose, and colloidal silicon dioxide co-process.

[0036] In certain embodiments, the pharmaceutical composition comprises Compound A, microcrystalline cellulose colloidal silicon dioxide co-process, and pregelatinized starch.

[0037] In a specific embodiment, the pharmaceutical composition comprises Compound A, microcrystalline cellulose colloidal silica co-processed product, and pregelatinized starch, wherein the weight ratio of microcrystalline cellulose colloidal silica co-processed product to pregelatinized starch is 1:0.7-1.2, preferably 1:0.8-1.1, and more preferably 1:0.8-1.0.

[0038] In certain embodiments, the pharmaceutical composition comprises Compound A, microcrystalline cellulose colloidal silicon dioxide co-process, a disintegrant, and a lubricant.

[0039] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 25% w / w.

[0040] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 12% w / w.

[0041] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 9% w / w.

[0042] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 8% w / w.

[0043] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 7% w / w.

[0044] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 6% w / w.

[0045] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 5% w / w.

[0046] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 4% w / w.

[0047] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 3% w / w.

[0048] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.1% to 2% w / w.

[0049] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 0.55% w / w.

[0050] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 2.22% w / w.

[0051] In a specific embodiment, the content of Compound A in the pharmaceutical composition is 8.8% w / w.

[0052] In a specific embodiment, the content of Compound A in the pharmaceutical composition is selected from: 0.1-1.5% w / w, 2-3% w / w, 8-9% w / w, 8-10% w / w, 0.1-10% w / w.

[0053] In certain embodiments, the pharmaceutical composition comprises Compound A, microcrystalline cellulose colloidal silicon dioxide co-process, pregelatinized starch, crospovidone, and magnesium stearate.

[0054] In a specific embodiment, the pharmaceutical composition includes Compound A, microcrystalline cellulose colloidal silicon dioxide co-processing material, pregelatinized starch, and magnesium stearate. In particular, pregelatinized starch can also be used as a disintegrant.

[0055] In a specific embodiment, the pharmaceutical composition comprises 0.1-10% w / w Compound A, 40-55% w / w microcrystalline cellulose colloidal silicon dioxide co-process, 40-50% w / w pregelatinized starch, 2-5% w / w crospovidone, and 0.1-0.5% w / w magnesium stearate.

[0056] In a specific embodiment, the pharmaceutical composition comprises 2.2% w / w Compound A, 50% w / w microcrystalline cellulose colloidal silicon dioxide co-process, 44.4% w / w pregelatinized starch, 3% w / w crospovidone, 0.25% w / w magnesium stearate.

[0057] In a specific embodiment, the pharmaceutical composition comprises 8.8% w / w Compound A, 43.4% w / w microcrystalline cellulose colloidal silicon dioxide co-process, 44.4% w / w pregelatinized starch, 3% w / w crospovidone, 0.25% w / w magnesium stearate.

[0058] In a specific embodiment, the pharmaceutical composition comprises 2.3% w / w Compound A, 51.6% w / w microcrystalline cellulose colloidal silicon dioxide co-process, 45.8% w / w pregelatinized starch, 0.26% w / w magnesium stearate.

[0059] In a specific embodiment, the pharmaceutical composition comprises 2.2% w / w Compound A, 50.1% w / w microcrystalline cellulose colloidal silicon dioxide co-process, 44.4% w / w pregelatinized starch, 3% w / w crospovidone, 0.25% w / w magnesium stearate.

[0060] In a specific embodiment, the pharmaceutical composition comprises 2.2% w / w Compound A, 49% w / w microcrystalline cellulose colloidal silicon dioxide co-process, 43.6% w / w pregelatinized starch, 4.9% w / w crospovidone, 0.25% w / w magnesium stearate.

[0061] In a specific embodiment, the pharmaceutical composition comprises 1.1% w / w Compound A, 53.4% ​​w / w microcrystalline cellulose colloidal silicon dioxide co-process (dry oven), 44.4% w / w pregelatinized starch (dry oven), 1% w / w magnesium stearate.

[0062] In a specific embodiment, the pharmaceutical composition comprises 11.1% w / w Compound A, 43.4% w / w microcrystalline cellulose colloidal silicon dioxide co-process (dry oven), 44.4% w / w pregelatinized starch (dry oven), 1% w / w magnesium stearate.

[0063] In a specific embodiment, the pharmaceutical composition comprises 4.4% w / w Compound A, 48% w / w microcrystalline cellulose colloidal silicon dioxide co-process (dry oven), 44.4% w / w pregelatinized starch (dry oven), 2-3% w / w crospovidone, and 0.25-1% w / w magnesium stearate.

[0064] In a specific embodiment, the pharmaceutical composition comprises 4.4% w / w Compound A, 48% w / w microcrystalline cellulose colloidal silicon dioxide co-process (LM), 44.4% w / w pregelatinized starch (LM), 2-3% w / w crospovidone, and 0.25-1% w / w magnesium stearate.

[0065] In a specific embodiment, the pharmaceutical composition comprises 4.4% w / w Compound A, 48% w / w microcrystalline cellulose colloidal silicon dioxide co-process (LM, oven dried), 44.4% w / w pregelatinized starch (LM, oven dried), 2-3% w / w crospovidone, and 0.25-1% w / w magnesium stearate.

[0066] In a specific embodiment, the pharmaceutical composition comprises 4.8% w / w Compound A, 95.2% w / w microcrystalline cellulose colloidal silicon dioxide co-process.

[0067] In a specific embodiment, the pharmaceutical composition comprises 4.8% w / w Compound A, 95.2% w / w pregelatinized starch.

[0068] In a specific embodiment, the pharmaceutical composition comprises 4.8% w / w Compound A, 95.2% w / w microcrystalline cellulose.

[0069] In a specific embodiment, the pharmaceutical composition comprises 4.8% w / w Compound A, 95.2% w / w mannitol.

[0070] The present invention relates to a pharmaceutical preparation, which contains any one of the aforementioned pharmaceutical compositions.

[0071] In some embodiments, the amount of Compound A in a unit preparation is 0.1 mg to 10 mg.

[0072] In some embodiments, the amount of Compound A in a unit dosage form is selected from 0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, 10 mg.

[0073] In some embodiments, the unit preparation comprises the following composition: 0.5 mg of Compound A, 40-50 mg of microcrystalline cellulose colloidal silicon dioxide co-processing material, 35-45 mg of pregelatinized starch, 2.0-3.5 mg of cross-linked polyvinylpyrrolidone, and 0.15-0.3 mg of magnesium stearate.

[0074] In some embodiments, the unit preparation comprises the following composition: 2 mg of Compound A, 40-50 mg of microcrystalline cellulose colloidal silicon dioxide co-processing material, 35-45 mg of pregelatinized starch, 2.0-3.5 mg of cross-linked polyvinylpyrrolidone, and 0.15-0.3 mg of magnesium stearate.

[0075] In some embodiments, the unit preparation comprises the following composition: 8 mg of Compound A, 35-45 mg of microcrystalline cellulose colloidal silicon dioxide co-processing material, 35-45 mg of pregelatinized starch, 2.0-3.5 mg of cross-linked polyvinylpyrrolidone, and 0.15-0.3 mg of magnesium stearate.

[0076] In some embodiments, the unit preparation comprises the following composition: Compound A 0.5-10 mg, microcrystalline cellulose colloidal silicon dioxide co-processing material 35-50 mg, pregelatinized starch 35-45 mg, cross-linked polyvinylpyrrolidone 1-5 mg, and magnesium stearate 0.1-0.5 mg.

[0077] In another aspect, the present invention provides a preparation prepared from the above oral pharmaceutical composition and pharmaceutically acceptable excipients, wherein the preparation is selected from tablets or capsules.

[0078] In another aspect, the present invention provides a method for preparing the above-mentioned tablets, comprising the following steps: uniformly mixing compound A with excipients, tableting, and packaging to obtain the tablets.

[0079] In another aspect, the present invention provides a packaged combination of the above oral pharmaceutical composition, the packaged combination comprising:

[0080] a) Aluminum-plastic blister packaging,

[0081] b) desiccant,

[0082] c) Composite bags;

[0083] d) oral pharmaceutical compositions or pharmaceutical preparations of the present invention;

[0084] The blister plate of the aluminum-plastic blister package comprises a hard sheet and a medicinal aluminum foil, and the hard sheet is selected from a polyvinyl chloride solid medicinal hard sheet, a polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard sheet, and a polyvinyl chloride / polyethylene / polyvinylidene chloride solid medicinal composite hard sheet;

[0085] The desiccant is selected from a molecular sieve desiccant and a silica gel desiccant.

[0086] The composite bag is selected from polyester / aluminum / polyethylene medicinal composite bags.

[0087] The oral pharmaceutical composition provided by the present invention adopts a packaging combination suitable for the product, has good moisture-proof performance, and ensures good stability of the preparation composition and low impurity growth.

[0088] The oral pharmaceutical composition provided by the present invention can significantly improve the stability of the preparation, so that the preparation has good stability and dissolution.

[0089] Unless otherwise stated, the terms used in this application are defined as follows:

[0090] In the present invention, the "amount" refers to the ratio of the component to the final pharmaceutical composition (e.g., tablet), where w / w refers to the mass-to-mass ratio, and the unit of this application is g / g. For example, a 1% amount of Compound A means that 100 g of the pharmaceutical composition contains 1 g of Compound A.

[0091] In the embodiment of the present invention, SMCC is a co-processed product of microcrystalline cellulose and colloidal silicon dioxide, which is a high-functional excipient based on microcrystalline cellulose and is prepared by blending and drying microcrystalline cellulose and colloidal silicon dioxide in water. Currently, this pharmaceutical-grade excipient product is sold on the market by multiple manufacturers. DETAILED DESCRIPTION

[0092] The following embodiments illustrate the technical problems, technical solutions and beneficial effects to be solved by the present invention. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0093] Example 1: Filler Screening

[0094] Preparation process: Compound A was uniformly mixed with different fillers in a certain mass ratio, and the mixture was dispensed into vials. The vials were placed with or without the vials under accelerated conditions (40°C ± 2°C / 75% ± 5% RH) for 28 days. The changes in related substances in the samples were observed. The results are shown in Table 1.

[0095] Table 1 Filler type screening

[0096] Results: As shown in Table 1, after Compound A was stored under accelerated conditions (40°C ± 2°C / 75% ± 5% RH) for 28 days, no significant growth of impurities was observed in the closed container (water-proof and moisture-proof). However, significant growth of impurities was observed in the open container, indicating that Compound A is sensitive to humidity.

[0097] After 28 days of storage under accelerated conditions (40°C ± 2°C / 75% ± 5% RH), the impurity growth trends for samples 1-5 were similar under both open and closed conditions. The type of filler in the formulation significantly affected the stability of the sample, with the growth of related substances in sample 5 being more pronounced.

[0098] Under closed-cell (water- and moisture-proof) conditions, the filler pregelatinized starch and Compound A showed good stability and compatibility. The stability of Compound A in the SMCC filler group was significantly better than that in the microcrystalline cellulose group.

[0099] Example 2: Preparation stability study

[0100] Based on the results of Example 1, the effects of drying different fillers and excipients on the stability of the formulation compositions were compared. The formulation formulas are shown in Tables 2 and 3.

[0101] Preparation process: sieve the excipients separately, mix compound A with the excipients evenly, and press into tablets.

[0102] Among them, SMCC (LM), pregelatinized starch (LM), SMCC and pregelatinized starch in prescriptions 9-11 were all dried and pretreated (here LM represents the low moisture content type of the auxiliary material).

[0103] Table 2 Preparation stability test prescription (1)

[0104] Table 3 Preparation stability test prescription (2)

[0105] The bare chips of the formulations of the above formulations 6-11 were subjected to a 2-month stability test under accelerated conditions (40°C ± 2°C / 75% ± 5% RH, open). The test results are shown in Tables 4 and 5 below.

[0106] Table 4 Preparation (bare chip) stability test results (1)

[0107] Table 5 Preparation (bare chip) stability test results (2)

[0108] When commercially available low-moisture excipients SMCC (LM) and pregelatinized starch (LM) were used to prepare the preparation, or the excipients were dried and pretreated, the initial moisture content of the preparation was significantly reduced, but after 2 months of accelerated growth, the moisture content and impurities increased significantly.

[0109] These results show that after two months of accelerated retention of bare die samples, the number and total amount of impurities in each formulation increased significantly. This suggests that the stability of this product can be further improved by strengthening the product packaging to isolate it from external moisture.

[0110] Based on the above formulation, the formulation samples were packaged in aluminum-plastic blisters and then sealed in polyester / aluminum / polyethylene pharmaceutical composite bags with a molecular sieve desiccant to produce packaged samples. These packaged samples were subjected to a two-month stability study under accelerated conditions (40°C ± 2°C / 75% ± 5% RH). The results are shown in Tables 6 and 7 below.

[0111] Table 6 Preparation (combination packaging) stability test results (3)

[0112] Table 7 Stability test results of preparations (combination packaging) (4)

[0113] The results in Tables 6 and 7 show that after using combined packaging, regardless of the initial moisture level of the formulation, the desiccant can effectively control the moisture content of each prescription tablet to a lower level, and the impurity growth trend of all samples is significantly slowed, significantly improving the stability of the formulation.

[0114] Example 3: Sample quality study

[0115] The specifications of the compound A preparation are relatively small, and the content of compound A is less than 25% of the weight of a single dose. The process and uniformity of the finished preparation are studied.

[0116] The mixing uniformity of the total blended drug powder was assessed in accordance with technical guidelines such as the "Technical Guidelines for Studying the Mixing Uniformity of Solid Oral Preparations of Chemical Drugs and the Uniformity of In-Process Control Dose Units (Trial)" issued by the Center for Drug Evaluation of the China National Drug Administration. The content uniformity of the preparation was assessed in accordance with the content uniformity test method in Part IV, General Chapter 0941, of the Chinese Pharmacopoeia (2020 edition).

[0117] Preparation process: sieve the excipients separately, mix compound A with the excipients evenly, and press into tablets.

[0118] The specific prescriptions and examination results are shown in Table 8 below.

[0119] Table 8 Sample quality study

[0120] Results: As shown in Table 8, the RSD of the mixed powder was less than 5%, and the content uniformity of the finished product was A+2.2S≤15.0. Both the mixing uniformity and content uniformity met the relevant requirements. The process and sample quality were stable.

[0121] Example 4: Dissolution curve

[0122] The dissolution of the sample in pH 1.0 buffer (rotation speed 50 rpm) was investigated according to the dissolution and release method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2). See Table 9 below for details.

[0123] Table 9 Dissolution curve

[0124] Preparation process: sieve the excipients separately, mix compound A with the excipients evenly, and press into tablets.

[0125] Results: As shown in Table 9, the samples dissolved rapidly, with the dissolution amount in 15 minutes being greater than 85%.

[0126] In summary, the pharmaceutical composition of this product uses a specific filler component mixed with Compound A to prepare a sample, and the sample is then packaged with a specific packaging composition. The preparation process of the composition is simple and stable, and the product obtained has uniform content, controllable quality, and good stability.

[0127] Example 5: Pharmacokinetics

[0128] After a single oral administration of the formulation sample of Example 3 to male Beagle dogs (3 dogs for each formulation), venous blood was collected at 0, 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The pharmacokinetic parameters were calculated using the area under the curve obtained by plotting the plasma concentration of Compound A as a function of time. A parallel intravenous injection group was tested. The pharmacokinetic results of the two groups are shown in Table 8:

[0129] Table 10 Results of pharmacokinetic investigation in dogs

[0130] According to the results in Table 10, the in vivo exposure of Beagle dogs after a single oral administration of 2 mg to 8 mg of Compound A is equivalent to the in vivo exposure of a single intravenous administration of 0.1 mg of Compound A, indicating that oral administration of Compound A can achieve the same therapeutic effect as intravenous administration.

Claims

1. An oral pharmaceutical composition, characterized in that: It includes: a) Compound A, as well as b) filler, selected from one or more of microcrystalline cellulose colloidal silicon dioxide co-processed product and pregelatinized starch, preferably microcrystalline cellulose colloidal silicon dioxide co-processed product.

2. The composition according to claim 1, characterized in that The invention comprises compound A, microcrystalline cellulose, colloidal silicon dioxide co-processed product and pregelatinized starch.

3. The composition according to claim 1 or 2, characterized in that The invention also comprises other fillers, which are selected from one or more of mannitol, microcrystalline cellulose, lactose, calcium hydrogen phosphate and maltodextrin, preferably one or more of microcrystalline cellulose and mannitol.

4. The composition according to any one of claims 1 to 3, characterized in that It may further contain one or more of a disintegrant and a lubricant.

5. The composition according to claim 4, characterized in that The disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch, preferably cross-linked polyvinylpyrrolidone; The lubricant is selected from one or more of magnesium stearate and sodium stearyl fumarate, preferably magnesium stearate.

6. The composition according to claim 4, characterized in that The invention comprises compound A, microcrystalline cellulose colloidal silicon dioxide co-processed product, filler, disintegrant and lubricant.

7. The composition according to claim 4, characterized in that The invention comprises compound A, microcrystalline cellulose colloidal silicon dioxide co-processing material, pregelatinized starch, disintegrant and magnesium stearate.

8. The composition according to claim 4, characterized in that The invention comprises compound A, microcrystalline cellulose colloidal silicon dioxide co-processed product, pregelatinized starch, cross-linked polyvinylpyrrolidone and magnesium stearate.

9. The composition according to any one of claims 4 to 8, characterized in that The content of the disintegrant in the pharmaceutical composition is 0% to 5% w / w.

10. The composition according to claim 9, characterized in that The content of the lubricant in the pharmaceutical composition is 0.25% to 2% w / w.

11. The composition according to any one of claims 1 to 10, characterized in that The content of the filler in the pharmaceutical composition is 75% to 98% w / w, preferably 87% to 95% w / w.

12. The composition according to any one of claims 11, characterized in that The content of compound A in the pharmaceutical composition is 0.1% to 25% w / w, preferably 0.1% to 12% w / w, and more preferably 0.1% to 9% w / w.

13. A pharmaceutical preparation prepared from the oral pharmaceutical composition according to any one of claims 1 to 12.

14. The pharmaceutical preparation according to claim 13, characterized in that The amount of compound A in the unit preparation is 0.1 mg to 10 mg.

15. The pharmaceutical preparation according to claim 14, characterized in that The amount of compound A in the unit preparation is selected from 0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg or 10 mg.

16. The pharmaceutical preparation according to claim 14 or 15, characterized in that Its unit preparation The invention comprises the following ingredients: 2 mg of compound A, 40-50 mg of a co-processed microcrystalline cellulose and colloidal silicon dioxide, 35-45 mg of pregelatinized starch, 2.0-3.5 mg of cross-linked polyvinylpyrrolidone, and 0.15-0.3 mg of magnesium stearate.

17. The pharmaceutical preparation according to claim 14 or 15, characterized in that Its unit preparation The invention comprises the following ingredients: 8 mg of compound A, 35-45 mg of co-processed microcrystalline cellulose and colloidal silicon dioxide, 35-45 mg of pregelatinized starch, 2.0-3.5 mg of cross-linked polyvinylpyrrolidone and 0.15-0.3 mg of magnesium stearate.

18. The pharmaceutical preparation according to any one of claims 13 to 17, characterized in that The preparation is selected from tablets or capsules.

19. A method for preparing the pharmaceutical preparation according to any one of claims 13 to 18, characterized in that: The preparation is a tablet, and the preparation method of the tablet comprises the following steps: (1) Mixing compound A and excipients uniformly; (2) Press into tablets to obtain the product.

20. A packaged combination comprising the pharmaceutical composition according to any one of claims 1 to 12 or the pharmaceutical preparation according to any one of claims 13 to 18, characterized in that: The packaging combination includes: a) Aluminum-plastic blister packaging; b) desiccant; c) Composite bags; d) The pharmaceutical composition according to any one of claims 1 to 12 or the pharmaceutical preparation according to any one of claims 13 to 18.

21. The packaging combination according to claim 20, characterized in that: The blister plate of the aluminum-plastic blister package comprises a hard sheet and a medicinal aluminum foil, wherein the hard sheet is selected from a polyvinyl chloride solid medicinal hard sheet, a polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard sheet, and a polyvinyl chloride / polyethylene / polyvinylidene chloride solid medicinal composite hard sheet; the desiccant is selected from a molecular sieve desiccant and a silica gel desiccant; and the composite bag is selected from a polyester / aluminum / polyethylene composite bag.

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