A pharmaceutical preparation, its preparation method and application

Abstract

The application discloses a solid preparation containing a compound of formula I or a pharmaceutically acceptable salt thereof and a preparation method of the solid preparation. Specifically, the solid preparation preparation method of the application can effectively improve the dissolution of a poorly soluble compound, and the obtained pharmaceutical preparation has good stability and content uniformity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations. Specifically, this invention relates to a pharmaceutical preparation containing a compound of Formula I or a pharmaceutically acceptable salt thereof, as well as its preparation method and application. Background Technology

[0002] This invention relates to a compound represented by Formula I, namely (4'R,12a'S)-N-(2,4-difluorophenyl)-7'-hydroxy-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-9'-carboxamide.

[0003] (I) The compound is a highly selective drug that exerts its inhibitory effect on HIV by binding to the active site of integrase and inhibiting the key retroviral DNA integration transfer step in the HIV replication cycle.

[0004] The preparation, physical properties, and beneficial pharmacological properties of (4'R,12a'S)-N-(2,4-difluorophenyl)-7'-hydroxy-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-9'-carboxamide are described in CN202211367919.5, which is cited in its entirety as a reference.

[0005] According to Example 1 of CN202211367919.5, the prepared compound of formula I was placed in a mixed solvent system of ethanol and water and reacted with sodium hydroxide solution to form a sodium salt, namely (4'R,12a'S)-9'-((2,4-difluorobenzyl)carbamoyl)-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-7'-oxysodium. Its limited solubility in both aqueous and non-aqueous solutions indicates that formulations containing this compound are difficult to administer. This results in tablets prepared using existing techniques, i.e., direct mixing of the active pharmaceutical ingredient with various excipients such as microcrystalline cellulose followed by direct powder compression, exhibiting low dissolution rates during the dissolution process.

[0006] To increase the solubility of this compound, the active pharmaceutical ingredient is subjected to air jet milling before the mixing step in the formulation process, thereby reducing its D... 90The particle size of this compound is ≤10μm, and the pulverized particles are relatively small, making it prone to powder agglomeration. In the formulation process, a common direct compression method is used, where the compound's micronized powder is mixed simultaneously with other excipients such as fillers, binders, and disintegrants. The mixing impact force continuously increases the strength of the compound agglomerates, leading to uneven dispersion and poor product content uniformity. For this reason, tablets prepared by directly mixing the compound's micronized powder with other excipients and then compressing them exhibit uneven distribution of various powder components, resulting in poor overall powder flowability and compressibility.

[0007] In view of the above-mentioned shortcomings, there is an urgent need in the art to develop a formulation method to improve the solubility of poorly soluble drugs in order to meet the needs of the prior art. Summary of the Invention

[0008] One object of the present invention is to provide a formulation process for improving the solubility of poorly soluble drugs.

[0009] Another object of the present invention is to provide a pharmaceutical preparation containing a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0010] A first aspect of the present invention provides a pharmaceutical preparation comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, comprising the following components in parts by weight: (I) (a) 1-20 parts of a compound of formula I or a pharmaceutically acceptable salt thereof; (b) 40-70 parts of lactose monohydrate; (c) 20-50 parts of filler; (d) 0.01-5 parts of lubricant; and (e) Disintegrant 0.1-10 parts.

[0011] In another preferred embodiment, the particle size range of the compound of formula I is 50 nm ≤ D. 90 ≤10μm; preferably 100nm≤D 90 ≤10μm; more preferably 1μm≤D 90 ≤10μm.

[0012] In another preferred embodiment, the pharmaceutically acceptable salt includes inorganic and organic salts; more preferably, the pharmaceutically acceptable salt is a salt formed by the compound of Formula I with an alkali metal or alkaline earth metal, and is selected from the group consisting of sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, and aluminum salts.

[0013] In another preferred embodiment, the pharmaceutically acceptable salt is a sodium salt of a compound of formula I.

[0014] In another preferred embodiment, the sodium salt of the compound shown in formula (I) has the structure shown in formula (II). (II).

[0015] In another preferred embodiment, the formulation comprises the following components in parts by weight: (a) 1-20 parts of compound II of formula; (b) 40-70 parts of lactose monohydrate; (c) 20-50 parts of filler; (d) 0.01-5 parts of lubricant; and (e) Disintegrant 0.1-10 parts.

[0016] In another preferred embodiment, the lactose monohydrate is selected from the group consisting of: spray-dried lactose, granulated lactose, ground lactose, sieved lactose, or combinations thereof; preferably, it is spray-dried lactose, granulated lactose, or combinations thereof.

[0017] In another preferred embodiment, the spray-dried lactose is formed from amorphous lactose and crystalline lactose.

[0018] In another preferred embodiment, the ratio of amorphous lactose to crystalline lactose in the spray-dried lactose is 10% to 15%.

[0019] In another preferred embodiment, the specific surface area of ​​the lactose monohydrate is 0.45-0.7 m². 2 / g; preferably 0.49-0.68m 2 / g.

[0020] In another preferred embodiment, the spray-dried lactose has a specific surface area of ​​0.45-0.7 m². 2 / g; preferably 0.49-0.68m 2 / g.

[0021] In another preferred embodiment, the Hausner index of the lactose monohydrate is 1.2-1.3; more preferably 1.2-1.25.

[0022] In another preferred embodiment, the spray-dried lactose has a spherical structure.

[0023] In another preferred embodiment, the pharmaceutical formulation exhibits a dissolution rate of ≥40% at 5 min, ≥87% at 30 min, and ≥95% at 60 min in a 0.1M HCl + 0.15% SDS solution medium.

[0024] In another preferred embodiment, The filler is selected from the group consisting of microcrystalline cellulose, starch, mannitol, pregelatinized starch, or combinations thereof; preferably microcrystalline cellulose; and / or The lubricant is selected from the group consisting of talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or combinations thereof; preferably calcium stearate or magnesium stearate; and / or The disintegrant is selected from the group consisting of: croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or combinations thereof; preferably croscarmellose sodium.

[0025] In another preferred embodiment, the formulation comprises the following components in parts by weight: (a) 1-10 parts of a compound of formula I or a pharmaceutically acceptable salt thereof; (b) 50-70 parts of lactose monohydrate; (c) 25-35 parts of filler; (d) 0.05-3 parts lubricant; and (e) 2-5 parts disintegrant.

[0026] In another preferred embodiment, the mass percentage of the compound of formula I or a pharmaceutically acceptable salt thereof in the formulation is 5-8%.

[0027] In another preferred embodiment, the mass percentage of the lactose monohydrate in the formulation is 56-62%.

[0028] In another preferred embodiment, the filler accounts for 27-33% of the mass of the formulation.

[0029] In another preferred embodiment, the lubricant accounts for 0.8-1.3% of the mass of the formulation.

[0030] In another preferred embodiment, the disintegrant accounts for 2.5-3.5% of the mass of the formulation.

[0031] In another preferred embodiment, the dosage form of the pharmaceutical preparation is selected from the group consisting of tablets, powders, granules, and capsules; preferably tablets.

[0032] In another preferred embodiment, the pharmaceutical preparation has good stability and content uniformity.

[0033] In a second aspect of the present invention, a method for preparing the pharmaceutical preparation described in the first aspect of the present invention is provided, comprising the steps of: (1) Mixing a compound of formula I or a pharmaceutically acceptable salt thereof with lactose monohydrate to obtain mixture 1; (2) Mix mixture 1 with the remaining excipients according to the formula ratio to obtain the total mixture; (3) The total mixture is subjected to direct powder compression to obtain tablets.

[0034] In another preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof from step (1) is pulverized to obtain D. 90 Active pharmaceutical ingredient with a particle size of ≤10μm.

[0035] In another preferred embodiment, the preparation method further includes: (4) Coating the tablets obtained in step (3) to obtain coated tablets.

[0036] In another preferred embodiment, the coating weight gain is 1.0% to 4.0%.

[0037] In another preferred embodiment, in step (3), the parameters for dry direct compression treatment of the total mixture are set as follows: 5mg tablets correspond to a 6mm diameter round punch, and 20mg tablets correspond to a 9mm diameter round punch.

[0038] In another preferred embodiment, the hardness of the prepared 5mg tablets is in the range of 30~90N, preferably 70-90N; the hardness of the 20mg tablets is in the range of 80~140N, preferably 110-140N.

[0039] In another preferred embodiment, the tablet strength is selected from the group consisting of: 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0040] In another preferred embodiment, the preparation method further includes: mixing mixture 1 with other auxiliary materials except lubricant according to the formula ratio, the mixing speed is 10-20 rpm and the mixing time is 5-10 min; to obtain mixture 2; mixing the obtained mixture 2 with lubricant, the mixing speed is 10-20 rpm and the mixing time is 3-10 min, to obtain the total mixture.

[0041] In a third aspect of the invention, there is provided the use of spray-dried lactose for improving the dissolution and content uniformity of poorly soluble small molecule compounds in formulations.

[0042] In a fourth aspect of the invention, a method for improving the solubility of a compound of formula I or a pharmaceutically acceptable salt thereof is provided, the method comprising the step of: mixing a compound of formula I or a pharmaceutically acceptable salt thereof with lactose monohydrate; (I).

[0043] In another preferred embodiment, the lactose monohydrate is selected from the group consisting of: spray-dried lactose, granulated lactose, ground lactose, sieved lactose, or combinations thereof; preferably, it is spray-dried lactose, granulated lactose, or combinations thereof.

[0044] In another preferred embodiment, the pharmaceutical preparation is a solid dosage form or a liquid dosage form; preferably a solid dosage form (tablet).

[0045] In another preferred embodiment, the method further includes mixing the resulting mixture with excipients (e.g., fillers, disintegrants, lubricants).

[0046] In a fifth aspect of the invention, a dispersion is provided comprising a compound of formula I or a pharmaceutically acceptable salt thereof, lactose monohydrate, and a filler.

[0047] In a sixth aspect of the invention, the use of the dispersion for preparing a pharmaceutical formulation is provided, preferably, the pharmaceutical formulation being selected from capsules, powders, granules, or pellets.

[0048] In another preferred embodiment, the compound of formula I is a compound having the structure of formula I, or a stereoisomer, optical isomer, pharmaceutically acceptable salt or ester, hydrate, solvate, crystal form, or combination thereof.

[0049] In another preferred embodiment, the dispersion comprises 1-20 parts by mass of the compound of formula I or a pharmaceutically acceptable salt thereof; 40-70 parts by mass of the lactose monohydrate; and 20-50 parts by mass of the filler.

[0050] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0051] Figure 1 The dissolution curves of different raw material particle sizes in Example 5 are shown.

[0052] Figure 2 Dissolution curves for different formulation processes in Example 6 are shown. Detailed Implementation

[0053] Through extensive and in-depth research, the inventors have, for the first time, provided a solid formulation for inhibiting HIV viral activity and its preparation method. Specifically, the solid formulation comprises the active ingredient compound: (4'R,12a'S)-N-(2,4-difluorophenyl)-7'-hydroxy-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-9'-carboxamide or a pharmaceutically acceptable salt thereof, as well as lactose monohydrate, fillers, lubricants, and disintegrants. The solid formulation provided by this invention exhibits good dissolution and stability. Based on this, the inventors completed this invention.

[0054] the term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0055] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0056] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0057] All pharmaceutically acceptable excipients mentioned in this article are available commercially or can be prepared using methods known in the art.

[0058] Active ingredients The active ingredient in the pharmaceutical formulation of the present invention is a poorly soluble compound having the structure shown in Formula I, namely (4'R,12a'S)-N-(2,4-difluorophenyl)-7'-hydroxy-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-9'-carboxamide or a pharmaceutically acceptable salt thereof.

[0059] (I) The preparation method is described in the preparation method of compound 1 in specification CN202211367919.5, which is incorporated herein by reference in its entirety.

[0060] Furthermore, the active ingredient of the present invention may be the compound represented by Formula I, or a pharmaceutically acceptable salt (or ester), crystal form, or combination thereof; for example, the pharmaceutically acceptable salt refers to the salt formed by the compound represented by Formula I of the present invention with an alkali metal or alkaline earth metal, such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, aluminum salt; preferably, the active ingredient of the present invention is the sodium salt of the compound of Formula I.

[0061] Furthermore, the active ingredient of the present invention can be the sodium salt of the compound of formula I, namely (4'R,12a'S)-9'-((2,4-difluorobenzyl)carbamoyl)-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-7'-oxysodium, the preparation method of which includes: placing the compound of formula I in a mixed solvent system of ethanol and water, and reacting it with sodium hydroxide solution to form a salt, thereby obtaining the sodium salt shown in formula II.

[0062] (II) Prior to formulation preparation, the compound of formula I of the present invention or its pharmaceutically acceptable salt thereof is pulverized using a pulverization process conventionally used in the art, ultimately obtaining D. 90 Micronized raw materials with a particle size of ≤10 μm. Typically, the pulverization process includes air jet milling.

[0063] pharmaceutical preparations This invention provides a pharmaceutical formulation comprising the following components in parts by weight: (I) (a) 1-20 parts of a compound of formula I or a pharmaceutically acceptable salt thereof; (b) 40-70 parts of lactose monohydrate; (c) 20-50 parts of filler; (d) 0.01-5 parts of lubricant; and (e) Disintegrant 0.1-10 parts.

[0064] The pharmaceutical formulations of the present invention may optionally include other pharmaceutically acceptable excipients conventionally used in the art, the specific excipients used and their mass percentages being conventionally selected according to the dosage form being prepared.

[0065] Specifically, the prescription composition used in this application is shown in Table 1 below: Table 1. Composition of Solid Dosage Forms The solid dosage forms of the present invention mainly include a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, lactose monohydrate, fillers, disintegrants and lubricants, and may also include other pharmaceutically acceptable excipients depending on the dosage form.

[0066] The present invention also provides a dispersion comprising a compound of formula I or a pharmaceutically acceptable salt thereof, lactose monohydrate, and a filler. The dispersion can be mixed with a pharmaceutically acceptable carrier to prepare other pharmaceutical dosage forms.

[0067] The dispersion described herein can enhance the solubility of compound of formula I or its pharmaceutically acceptable salt, and can improve the stability and content uniformity of other dosage forms prepared subsequently.

[0068] As used in this article, the monohydrate lactose can be roughly divided into spray-dried lactose, granulated lactose, sieved lactose, and ground lactose according to its preparation process.

[0069] Spray-dried lactose is obtained by spray drying a suspension of finely ground lactose monohydrate. Due to the rapid evaporation of water, the lactose forms amorphous lactose during the spray drying process. Spray-dried lactose contains pure crystalline α-lactose monohydrate and a small amount of amorphous lactose (approximately 10-15%). Amorphous lactose improves the pressure / hardness ratio of lactose, giving spray-dried lactose better compressibility compared to crystalline α-lactose monohydrate. Unlike α,β-lactose, which undergoes brittle deformation upon compression, amorphous lactose exhibits plastic deformation. Therefore, the synergistic effect of the plastic and brittle deformation of the two types of lactose in spray-dried lactose results in better compressibility; furthermore, the near-spherical shape of spray-dried lactose also contributes to its good flowability. In addition, spray-dried lactose can promote the disintegration of tablets and improve their intrinsic dissolution properties, especially for poorly soluble drugs (such as the compounds in CN202211367919.5), which can promote the bioavailability in vivo.

[0070] The formulations or compositions of the present invention comprise, within a safe and effective range, the active ingredient of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient. "Safe and effective range" refers to an amount of the active ingredient sufficient to significantly improve the condition or have a significant improving effect without causing serious side effects. Preferably, "one dose" is one capsule or tablet.

[0071] "Pharmaceutically acceptable carriers or excipients" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and between the solid dispersions of the present invention without significantly reducing the efficacy of the solid dispersions.

[0072] Pharmaceutically acceptable examples of excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), starches, monosaccharides or polysaccharides, gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0073] There are no particular restrictions on the administration method of the pharmaceutical preparation of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, and rectal.

[0074] Solid dosage forms include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the solid dispersion is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, microcrystalline cellulose, mannitol, and silicate; (b) binders, such as hydroxypropyl methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, croscarmellose sodium, and sodium carbonate; (e) slowing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol, sodium lauryl sulfate, and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0075] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the solid dispersion in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the solid dispersion may also be formed into microcapsules with one or more of the excipients described above.

[0076] Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0077] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0078] The composition may comprise physiologically acceptable sterile aqueous or anhydrous water, dispersion, suspension, or emulsion, and sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0079] When using the pharmaceutical composition, a safe and effective amount of the composition of the present invention is administered to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–1000 mg, preferably 10–200 mg, and more preferably 20–100 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0080] The compositions of this invention can be administered alone or in combination with other therapeutic agents (e.g., formulated in the same pharmaceutical composition). The pharmaceutical compositions of this invention can also be used in combination with other known drugs for treating or improving similar symptoms. When used in combination, the original drug's administration method and dosage remain unchanged, while the pharmaceutical composition of this invention is used simultaneously or subsequently. Drug combination also includes using the pharmaceutical composition of this invention with one or more other known drugs during overlapping time periods. When the pharmaceutical composition of this invention is used in combination with one or more other drugs, the dosage of the pharmaceutical composition of this invention or the known drug may be lower than the dosage when they are used alone.

[0081] Preparation method This invention proposes a stepwise mixing and direct compression process for lactose, which involves first fully mixing the micronized active ingredient compound with lactose, and then mixing it with other excipients for direct compression of the powder.

[0082] Conventional manufacturing processes do not include the premixing step of lactose with the active pharmaceutical ingredient (API). Instead, the micronized API is directly mixed with all excipients and then compressed into tablets. This one-step direct mixing results in uneven distribution of various powders in the tablets, low uniformity of active ingredient content, and poor tablet stability.

[0083] The active pharmaceutical ingredient (API) refers to the compound represented by Formula I or a pharmaceutically acceptable salt thereof as the active ingredient.

[0084] Specifically, the preparation process of the present invention includes the following steps: In the process of this invention, lactose monohydrate and the active pharmaceutical ingredient are pre-mixed thoroughly to obtain a mixture. The large specific surface area of ​​lactose gives it excellent adsorption properties, which can fully adsorb micronized compounds onto the surface of the lactose and reduce the agglomeration of small-particle-size powders. In addition, the spherical structure of lactose has excellent flowability, which allows it to be more evenly distributed in the total mixed powder during the mixing process with other excipients, thereby improving the uniformity of the content of active ingredients in the formulation. The final formulation has improved compressibility, tablet dissolution, content uniformity, and stability, thus making it more industrially valuable.

[0085] Compared with the prior art, the main advantages of the present invention include: (1) The formulation process of the present invention significantly improves the flowability, compressibility and uniformity of formulation content of the total mixed powder prepared from poorly soluble compound of formula I or its pharmaceutically soluble salt.

[0086] (2) The formulation process of the present invention significantly improves the dissolution rate of poorly soluble compounds in the formulation.

[0087] (3) The formulation prepared by the present invention has good stability.

[0088] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods not specifically described in the following embodiments can be performed under conventional reaction conditions in the art or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0090] In the following embodiments, the active pharmaceutical ingredient or API used is the sodium salt form of compound of formula I, namely (4'R,12a'S)-9'-((2,4-difluorobenzyl)carbamoyl)-4'-methyl-6',8'-dioxo-6',8',12',12a'-tetrahydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine]-7'-oxysodium.

[0091] Example 1: Preparation of tablets containing API Tablets were prepared according to the prescriptions in Table 2, resulting in tablets of prescriptions 1, 2, 3, 4, and 5, respectively.

[0092] Table 2 Tablet Formulation Composition Specifically, the above tablet formulation can be obtained using the two preparation processes shown in Table 3 below: Table 3 Tablet preparation process As shown in Table 4, five tablets were prepared using process 1 in this application, and a comparative example was carried out according to process 2 in the prior art.

[0093] Table 4 Tablet Preparation Scheme Example 2: Physicochemical property analysis of fillers and flowability test of total mixed powders prepared by different schemes The lactose used in this application includes spray-dried lactose (FlowLac 100), granulated lactose (Tablettose100), and sieved lactose (Spherolac 100). Their powder test data are shown in Table 5, and the data are based on the powder test data of various types of lactose monohydrate published by the German company Metformin.

[0094] Table 5. Property data of different types of lactose monohydrate powder The compressibility of powder can be expressed by the ratio of the powder's tap density to its loose density, also known as the powder Hausner ratio formula (HR).

[0095] According to the judgment criteria, a Hausner ratio < 1.2 indicates that the powder has good flowability and does not agglomerate; a Hausner ratio in the range of 1.2 to 1.4 indicates good flowability and slight agglomeration; a Hausner ratio in the range of 1.4 to 2.0 indicates poor flowability and strong agglomeration; and a Hausner ratio > 2.0 indicates no flowability and extremely strong agglomeration.

[0096] The total mixed powders prepared by schemes 1 to 5 were taken, and their angle of repose and Hausner ratio were measured by an intelligent powder analyzer, as shown in Table 6.

[0097] Experimental results show that the spray-dried lactose proposed in this application... Step-by-step mixing Direct pressing can effectively improve the flowability of solid dosage form powder containing sodium salt of compound I.

[0098] Table 6. Test results of repose angle and Hausner ratio of tablets prepared by schemes 1 to 5. As can be seen from Table 6, the total powder mixture prepared by spray-drying lactose has the smallest angle of repose and Hausner ratio, indicating that the total powder mixture prepared by spray-drying lactose has the best flowability.

[0099] Based on formulation experience, larger particles generally have better flowability. However, in stepwise mixing schemes 1 and 2, a large amount of drug microparticles are first adsorbed and embedded in the grooves of spherical lactose particles, forming spherical lactose intermediates carrying the active pharmaceutical ingredient. Spray-dried lactose has a narrower particle size distribution, therefore the intermediates prepared from it have better flowability than those prepared from granular lactose.

[0100] Although Scheme 3 also involved stepwise mixing, the irregular shape of the sieved lactose used and its low drug loading resulted in a large amount of active pharmaceutical ingredient powder in the prepared intermediate particles, leading to a wide particle size distribution and poor flowability.

[0101] Option 4 did not use lactose monohydrate as a filler, but used microcrystalline cellulose alone. Due to the irregular shape of cellulose itself, its flowability is not as good as that of spherical spray-dried lactose. In addition, microcrystalline cellulose adsorbs less active ingredients than lactose. The combination of these two disadvantages resulted in the worst flowability of its intermediate powder.

[0102] In Scheme 5, due to the lack of a step of pre-mixing spray-dried lactose with the active pharmaceutical ingredient, less active pharmaceutical ingredient is adsorbed on the surface of the lactose, and the intermediate powder prepared contains a large amount of micronized active pharmaceutical ingredient, resulting in poor flowability.

[0103] Example 3: Comparison of compressibility of intermediate powders prepared by different methods The total mixed powder prepared according to schemes 1 to 5 was used to compress tablets under the same main pressure (about 10 kN) using a rotary tablet press. The circular punch of the tablet press was 9 mm in diameter, and the resulting tablets were 20 mg in size. Twenty tablets of each scheme were taken and the hardness of each tablet was measured using a tablet hardness tester. The average hardness was calculated, and the results are shown in Table 7.

[0104] Table 7. Average results of tablet hardness testing for tablets prepared according to schemes 1 to 5 Hardness test results showed that formulation 1 had the best compressibility (i.e., tablets with higher hardness were obtained using the same main pressure), and the compressed tablets had a smooth surface without any nicks. Formulation 2 had slightly worse compressibility than formulation 1; formulation 3 had relatively poor compressibility; formulation 4 used microcrystalline cellulose with good plasticity, achieving a hardness of 110N, but due to the high content of fine active pharmaceutical ingredient powder in the tablets, cracking was prone to occur, leading to poor compressibility. In formulation 5, because the micronized raw material was not premixed with lactose, relatively less raw material was adsorbed onto the lactose surface, resulting in increased agglomeration of the micronized raw material in the total powder mixture, leading to poor compressibility.

[0105] The above results indicate that the spray-dried lactose stepwise mixing and direct compression process proposed in this invention can effectively improve the compressibility of the total mixed powder of solid dosage forms containing the compound shown in Formula I.

[0106] Example 4: Content uniformity test of tablets prepared by different methods Take 10 tablets of each of the coated tablets prepared by schemes 1 to 5, and use HPLC to determine the relative content of each tablet with the labeled amount as 100, calculate the mean and standard deviation S, and the absolute value A of the difference between the labeled amount and the mean. The results are shown in Table 8.

[0107] Table 8. Results of the content uniformity test of tablets prepared in Examples 1 and 2 The results showed that the tablets prepared by Scheme 1 had the best content uniformity, followed by the tablets prepared by Scheme 2; the tablets prepared by Schemes 3 and 5 had poor content uniformity, but both were less than 15, which was within the acceptable range; the tablets prepared by Scheme 4 had a content uniformity greater than 15, which was extremely poor.

[0108] Experimental results show that the spray-drying lactose stepwise mixing direct pressure process proposed in this invention can effectively improve the uniformity of the content of the compound shown in Formula I in solid dosage forms.

[0109] Example 5: Dissolution curve testing of tablets prepared by different methods Twelve coated tablets with a hardness of approximately 100N were prepared according to Schemes 1 and 6 (raw material particle size data are shown in Table 2 of Example 1). Dissolution was conducted using 0.1M HCl + 0.15% SDS solution as the dissolution medium at 37℃ ± 0.5℃, following Method II (paddle method) of the Chinese Pharmacopoeia at 75 rpm. The dissolution curve data are shown in Table 9, and the dissolution curve graph is shown in [the original text is missing]. Figure 1 .

[0110] Table 9. Experimental results of dissolution curves of tablets prepared by different methods. Based on the dissolution results of the tablets in 0.1M HCl + 0.15% SDS medium, it can be seen that the tablets prepared by Scheme 1 are produced by air jet milling of raw materials with controlled particle size D. 90 ≤10μm, dissolution reaches a plateau faster and is more complete. The tablets prepared by scheme 6 dissolve more slowly, and still have not completely dissolved after 120 minutes.

[0111] Example 6: Dissolution curve testing of tablets prepared by different methods Twelve tablets of each type with a hardness of approximately 100 N, prepared according to schemes 1 to 5, were used. Dissolution was conducted at 37°C using 0.1M HCl + 0.15% SDS solution as the dissolution medium, following the Chinese Pharmacopoeia Dissolution Test Method II (paddle method) at 75 rpm. Dissolution data are shown in Table 10, and dissolution curves are shown in [the table / chart]. Figure 2 .

[0112] Table 10. Experimental results of dissolution curves of tablets prepared by different methods. Based on the dissolution of tablets in 0.1M HCl + 0.15% SDS medium, tablets prepared by schemes 1 and 2 dissolve faster and reach a plateau more completely. In formulations using sieved lactose and those without lactose monohydrate, the decreased adsorption capacity leads to agglomeration of a large amount of active pharmaceutical ingredient (API) powder, resulting in slower dissolution rates for schemes 3 and 4. In scheme 5, due to insufficient single-stage mixing, the spray-dried lactose did not fully combine with the API powder, causing API powder agglomeration, and the dissolution rate was also slower compared to tablets prepared using the stepwise mixing method with spray-dried lactose.

[0113] Experimental results show that the spray-drying lactose stepwise mixing and direct pressing process proposed in this invention can effectively improve the dissolution rate of solid tablets containing the compound shown in Formula I.

[0114] Example 7: Influencing Factor Experiment The products prepared by schemes 1 to 5 were subjected to influencing factor tests. The high temperature test involved placing the test sample in a suitable clean container at 60°C for 10 days, and taking samples on the 5th and 10th days. The high humidity test involved placing the test sample in a constant humidity sealed container at 25°C and a relative humidity of 92.5% ± 5% for 10 days, and taking samples on the 5th and 10th days. The strong light irradiation test involved placing the test sample open under an illuminance of 5000 Lx for 10 days, and taking samples on the 5th and 10th days. The dissolution rate and content of the products prepared by schemes 1 to 5 were then measured at 45 min. The experimental results are shown in Table 11.

[0115] Table 11 Results of the Experiment on Influencing Factors The results showed that the dissolution rate and content of the tablets prepared by schemes 1 to 5 did not change significantly, and the stability of each scheme was similar with no significant difference. This indicates that the tablets prepared by the process and formula designed in this invention have good stability.

[0116] discuss In this invention, spray-dried lactose is first uniformly mixed with micronized raw materials to form an intermediate in which the micronized raw materials are uniformly dispersed in the spray-dried lactose. This intermediate is a porous aggregate that can adsorb and retain the micronized raw material in the pores, effectively reducing the possibility of agglomeration of the micronized raw material and giving the intermediate powder good flowability. The spray-dried lactose in the intermediate can dissolve rapidly in the dissolution medium, which is beneficial to tablet disintegration, dissolution, or the formation of water channels. Subsequently, the lactose dissolves and forms hydrogen bonds with water on the drug surface through van der Waals forces, thereby reducing the hydrophobicity of the drug and allowing the compound to be completely wetted in the medium environment and fully contact the medium, thus effectively improving the solubility of the compound.

[0117] The specific surface area of ​​lactose monohydrate affects its adsorption capacity for micronized raw materials; the larger the specific surface area, the stronger the adsorption. The specific surface area data of the lactose monohydrate used in this invention are shown in Table 5. The porosity and relatively high specific surface area of ​​granulated lactose and spray-dried lactose enable them to fully adsorb active ingredients onto the lactose surface, reducing the aggregation of active ingredients. This allows for rapid water penetration and full, rapid contact with the active ingredients, thereby increasing the dissolution rate of the active ingredients.

[0118] Furthermore, the prerequisite for applying direct powder compression technology is good material mixing uniformity, and the particle size and distribution of each material are key factors affecting the mixing effect. Micronized active pharmaceutical ingredients (APIs) after air jet milling are prone to agglomeration, resulting in uneven dispersion during preparation. In contrast, lactose monohydrate has a relatively rounded morphology and good flowability, exhibiting excellent dispersibility during mixing with micronized APIs. This significantly improves the uniformity of compound dispersion in the material. Compared to conventional direct powder compression methods that directly mix API micronized powder with microcrystalline cellulose, croscarmellose sodium, and lactose monohydrate, this step ensures uniform dispersion of the intermediate mixture of lactose monohydrate and API micronized powder in the material obtained through secondary mixing with excipients such as microcrystalline cellulose. This improves the content uniformity in tablets, thereby giving tablets prepared using this invention higher stability.

[0119] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A pharmaceutical preparation comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, characterized in that, The formulation is made from the following components: （Ⅰ） (a) A compound of formula I or a pharmaceutically acceptable salt thereof, comprising 5-8% by mass; (b) Lactose monohydrate, comprising 56-62% by mass; (c) Microcrystalline cellulose, comprising 27-33% by mass; (d) Magnesium stearate, comprising 0.8-1.3% by mass; and (e) Cross-linked sodium carboxymethyl cellulose, comprising 2.5-3.5% by mass; The particle size range of the compound of Formula I or its pharmaceutically acceptable salt is 50 nm ≤ D. 90 ≤10μm; the lactose monohydrate is spray-dried lactose with a spherical structure, and the specific surface area of ​​the lactose monohydrate is 0.45-0.7m². 2 / g.

2. The pharmaceutical preparation according to claim 1, characterized in that, The pharmaceutically acceptable salts are selected from the group consisting of sodium, potassium, lithium, calcium, magnesium, or aluminum salts.

3. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The particle size range of the compound of Formula I or its pharmaceutically acceptable salt is 100 nm ≤ D. 90 ≤10μm.

4. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The specific surface area of ​​the lactose monohydrate is 0.49-0.68 m². 2 / g.

5. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The Hausner index of the lactose monohydrate is 1.2-1.

3.

6. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The Hausner index of the lactose monohydrate is 1.2-1.

25.

7. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The method for preparing the pharmaceutical preparation includes the following steps: (1) Mixing a compound of formula I or a pharmaceutically acceptable salt thereof with lactose monohydrate to obtain mixture 1; (2) Mix mixture 1 with the remaining excipients according to the formula ratio to obtain the total mixture; (3) The total mixture is subjected to direct powder compression to obtain tablets; The preparation method further includes: mixing mixture 1 with other auxiliary materials except lubricant according to the formula ratio, the mixing speed is 10-20 rpm and the mixing time is 5-10 min; to obtain mixture 2; mixing the obtained mixture 2 with lubricant, the mixing speed is 10-20 rpm and the mixing time is 3-10 min, to obtain the total mixture.

8. The pharmaceutical preparation according to claim 1, characterized in that, The formulation is made from the following components: (a) The compound of formula I or a pharmaceutically acceptable salt thereof, comprising 6.56% by mass; (b) Spray-dried lactose, comprising 59.44% by mass; (c) Microcrystalline cellulose, comprising 30% by mass; (d) Magnesium stearate, comprising 1% by mass; and (e) Cross-linked sodium carboxymethyl cellulose, comprising 3% by mass.

9. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The dosage form of the pharmaceutical preparation is selected from the following group: tablets, powders, granules, capsules.

10. The pharmaceutical preparation according to any one of claims 1-2, characterized in that, The dosage form of the pharmaceutical preparation is tablets.

11. A method for preparing a pharmaceutical formulation according to claim 1 or 2, characterized in that, Including the following steps: (1) Mixing a compound of formula I or a pharmaceutically acceptable salt thereof with lactose monohydrate to obtain mixture 1; (2) Mix mixture 1 with the remaining excipients according to the formula ratio to obtain the total mixture; (3) The total mixture is subjected to direct powder compression to obtain tablets.

12. The method as described in claim 11, characterized in that, The preparation method further includes: mixing mixture 1 with other auxiliary materials except lubricant according to the formula ratio, the mixing speed is 10-20 rpm and the mixing time is 5-10 min; to obtain mixture 2; mixing the obtained mixture 2 with lubricant, the mixing speed is 10-20 rpm and the mixing time is 3-10 min, to obtain the total mixture.

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