Pharmaceutical composition containing atozepam and preparation method thereof

Abstract

The invention discloses an atozepam-containing pharmaceutical composition and a preparation method thereof, the pharmaceutical composition is a solid preparation, and the preparation unit of the pharmaceutical composition comprises a double-layer tablet core composed of a quick release layer and a slow release layer, and a coating layer coating the double-layer tablet core; the quick release layer is composed of 20-30% of an atozepam bulk drug and the balance of a first auxiliary material, and the dosage percentage of the atozepam bulk drug is 20-30%, and the balance is the first auxiliary material; the sustained-release layer is composed of an atozepam raw material medicine and a second auxiliary material, the dosage percentage of the atozepam raw material medicine is 25-35%, and the balance is the second auxiliary material. The pharmaceutical composition can meet the treatment requirement of rapid effect taking in the acute attack period, the duration time of the drug effect can be prolonged, the preparation method of the pharmaceutical composition combines preparation and granulation of the amorphous solid dispersion, so that the drug is highly dispersed in a carrier in an amorphous state, the solubility and dissolution rate of atozepam are remarkably improved, and the pharmaceutical composition is suitable for clinical application. The oral bioavailability and the in-vivo exposure level are improved, and the titer ratio of clinical application is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a pharmaceutical composition containing atorgipam and its preparation method. Background Technology

[0002] Currently, migraine treatment mainly includes acute treatment and preventative treatment. Acute treatment often uses nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans, but these drugs have limited efficacy, many side effects, and can easily cause drug overuse headache (MOH). Preventative treatment often relies on antihypertensive drugs, antidepressants, and antiepileptic drugs, but these drugs are poorly tolerated by patients and are not effective for some patients.

[0003] Calcitonin gene-related peptide (CGRP) is a protein widely distributed in the peripheral and central nervous systems. It is typically released around the nervous system and participates in the transmission of pain. CGRP receptor antagonists are a class of migraine treatment drugs with a novel mechanism of action. However, these drugs have short half-lives, making it difficult to maintain effective therapeutic concentrations. Once the blood drug concentration falls below the lower limit of the therapeutic window, the efficacy is insufficient to control symptoms, potentially causing headache recurrence. Therefore, patients need to take medication frequently, causing significant disruption and inconvenience to their lives and work. Currently marketed CGRP receptor antagonists, such as atorgepam, zavigepam, ubugipam, and retemigepam, mostly have half-lives in the range of 9-12 hours, classifying them as short-lived drugs with a relatively short duration of action.

[0004] Atorgepam is a CGRP antagonist that can be used simultaneously for the acute treatment and prevention of migraines, and may also be used to address menstrual headaches in women. Its molecular structure is as follows:

[0005] Atorgapasporine is readily soluble in ethanol and methanol, slightly soluble in acetone and acetonitrile, and almost insoluble in water, classifying it as a drug with low solubility and high permeability. Atorgapasporine exhibits pH-dependent solubility within its physiological pH range (pH 1.2-6.8), meaning its solubility decreases significantly with increasing pH, which affects drug release and absorption in vivo. The low solubility of atorgapasporine is primarily due to its stable crystalline state. The crystalline state exists in a low-energy Gibbs free energy state, making it difficult to transform into other crystal forms, thus contributing to its good stability—an advantage in drug development. However, this poor solubility also limits its pharmaceutical applicability and clinical efficacy, hindering the realization of its full therapeutic benefits.

[0006] Currently, there is a lack of CGRP receptor antagonist-containing drug formulations worldwide that can both treat acute migraine attacks and maintain efficacy over a long period. Therefore, developing an atorgepam drug composition that can both treat acute migraine attacks and maintain efficacy over a long period, while establishing a simple, feasible, and large-scale industrial production process, is crucial for fully realizing its drug potential, solving practical problems in clinical applications, and reducing medication costs. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a pharmaceutical composition containing atorgepam and its preparation method, which can meet the treatment needs of rapid onset of action in the acute phase and prolong the duration of drug effect. The preparation method of the pharmaceutical composition combines the preparation of amorphous solid dispersion and granulation, so that the drug is highly dispersed in the carrier in an amorphous state, which significantly improves the solubility and dissolution rate of atorgepam, thereby improving its oral bioavailability and in vivo exposure level, and improving the cost-effectiveness of clinical application.

[0008] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows: a pharmaceutical composition containing atorgepam, the pharmaceutical composition being a solid dosage form, the dosage unit comprising a double-layer tablet core composed of an immediate-release layer and a sustained-release layer, and a coating layer covering the double-layer tablet core; the immediate-release layer is composed of atorgepam active pharmaceutical ingredient and a first excipient, wherein the percentage of atorgepam active pharmaceutical ingredient in the immediate-release layer is 20-30%, and the remainder is the first excipient; the sustained-release layer is composed of atorgepam active pharmaceutical ingredient and a second excipient, wherein the percentage of atorgepam active pharmaceutical ingredient in the sustained-release layer is 25-35%, and the remainder is the second excipient.

[0009] The pharmaceutical composition of this invention is a solid formulation of a dual-release formulation, which combines an immediate-release portion and a long-acting sustained-release portion in the form of an immediate-release layer and a sustained-release layer as a formulation unit. The two parts are released independently. The immediate-release layer releases the drug through rapid dissolution to meet the treatment needs of rapid onset during acute attacks. The sustained-release layer, on the other hand, maintains a stable drug concentration in the body within the therapeutic window over a longer period by regulating the release behavior, thereby achieving sustained inhibition of CGRP receptors, prolonging the duration of drug effect, reducing the frequency of administration, fundamentally improving the long-term treatment needs of migraine patients, and improving their quality of life.

[0010] The dual-release system of the pharmaceutical composition of this invention is designed by comprehensively considering key pharmaceutical parameters such as the dosage, half-life, and expected in vivo release rate of atorgepam. The release rate of the immediate-release fraction directly affects the therapeutic effect and onset time during acute attacks, while the release rate of the long-acting sustained-release fraction has a decisive impact on drug safety and the duration of efficacy.

[0011] Preferably, the weight ratio of the immediate-release layer, the sustained-release layer, and the coating layer in the formulation unit is (1-4):(4-7):(0.1-0.45).

[0012] Preferably, the first excipient includes a first carrier, a first binder, a disintegrant, a first excipient, a first lubricant, and a first flow aid, and the second excipient includes a second carrier, a second binder, a sustained-release material, a second excipient, a second lubricant, and a second flow aid.

[0013] As a further preferred embodiment, the sum of the contents of each component in the immediate-release layer is 100%, wherein: the percentage of the first carrier is 15-20%, the percentage of the first binder is 5-10%, the percentage of the disintegrant is 3-8%, the percentage of the first excipient is 30-60%, the percentage of the first lubricant is 0.5-2%, and the percentage of the first gliding agent is 0.5-2%; the sum of the contents of each component in the sustained-release layer is 100%, wherein: the percentage of the second carrier is 15-20%, the percentage of the second binder is 5-10%, the percentage of the sustained-release material is 8-15%, the percentage of the second excipient is 20-50%, the percentage of the second lubricant is 0.5-2%, and the percentage of the second gliding agent is 0.5-2%.

[0014] As a further preferred embodiment, both the first and second carriers are polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers; the first and second adhesives are selected from one or more combinations of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; the disintegrant is one or more combinations of sodium carboxymethyl starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the sustained-release material is one or more combinations of polyethylene oxide, methacrylic acid resin polymer, and hydroxypropyl methylcellulose; the first and second excipients are selected from one or more combinations of lactose, microcrystalline cellulose, and mannitol; the first and second lubricants are selected from magnesium stearate or sodium stearate fumarate; and the first and second flow aids are selected from talc or colloidal silica. The above excipients are widely available, readily accessible, and have stable performance.

[0015] Soluplus®, a novel pharmaceutical carrier, is a backbone polymer suitable for solid dispersion technology. As a hydrophilic nonionic polymer, its solubility is unaffected by changes in gastrointestinal pH. Unlike traditional solubilizers, Soluplus® has a dual function: it can act as a matrix polymer to form solid dispersions and also self-assemble into micelles in aqueous media to solubilize. This polymer also possesses surface activity, which helps maintain the supersaturated state of poorly soluble drugs in the gastrointestinal tract, thereby significantly improving their dissolution rate and apparent solubility. Especially for Biopharmaceutics Class II (low solubility, high permeability) drugs, Soluplus® exhibits excellent drug loading and solubilization properties, effectively improving the solubility and oral bioavailability of poorly soluble drugs.

[0016] Soluplus® is composed of polyethylene glycol (PEG) 6000, vinyl caprolactam, and vinyl acetate. The hydrophilic PEG 6000 forms the main chain, while the lipophilic vinyl acetate and vinyl caprolactam are randomly copolymerized as side chains, thus exhibiting both hydrophilic and lipophilic properties. It is soluble in both aqueous solutions and organic solvents such as ethanol, acetone, and methanol. This amphiphilic nature of Soluplus® is a crucial basis for its suitability as an ideal carrier for solid dispersions. The chemical structure of Soluplus® is shown below:

[0017] The first and second binders are selected from one or more combinations of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. These polymers are commonly used binders in oral solid dosage forms, exhibiting good stability, adhesion, and compressibility, and can be adapted to various process requirements, including wet granulation, by using different viscosity specifications. This invention uses an alcohol-water combined solvent system. To simultaneously ensure the effective dissolution of the binder and fully utilize its binding effect for better granulation results, the first and second binders are preferably polyvinylpyrrolidone or hydroxypropyl methylcellulose, and more preferably polyvinylpyrrolidone.

[0018] The sustained-release material is one or more combinations of polyethylene oxide, methacrylic acid polymer, and hydroxypropyl methylcellulose. These materials are all mature hydrophilic gel matrix materials with good biocompatibility, stability, and sustained-release performance, and can be available in different molecular weights or viscosity grades to meet varying release rate requirements. Polyethylene oxide (PEO) is a water-soluble polymer produced by the catalytic polymerization of ethylene oxide. It has good water solubility, excellent flowability, and can be directly compressed into tablets, making it a commonly used material for preparing matrix-type sustained-release tablets and osmotic pump systems. Hydroxypropyl methylcellulose can also form a gel layer through hydration to regulate drug release. This invention employs an external sustained-release material design, and to balance process feasibility and release performance, polyethylene oxide, with its superior flowability and compressibility, is preferred.

[0019] The first and second excipients are selected from one or more combinations of lactose, microcrystalline cellulose, and mannitol. These materials are commonly used fillers in oral solid dosage forms, exhibiting good stability and compressibility. Lactose (common types include α-lactose monohydrate and anhydrous lactose) is a conventional choice for direct compression tableting; microcrystalline cellulose comes in various types, suitable for wet granulation, direct compression, and other processes, possessing good flowability and a certain degree of binding; mannitol (e.g., particle sizes of 100 SD, 200 SD, etc.) is also frequently used in direct compression processes. In this invention, the excipients are used in two parts: one part serves as a substrate (internal component) in fluidized bed granulation, and the other part serves as an external component to adjust the flowability and compressibility of the total mixture. Considering both process compatibility and material properties, the combination of microcrystalline cellulose and mannitol is preferred.

[0020] The disintegrant is one or more combinations of sodium carboxymethyl starch, calcium carboxymethyl cellulose, croscarmellose sodium, and low-substituted hydroxypropyl cellulose. These are all commonly used high-efficiency disintegrants in oral solid dosage forms. Calcium carboxymethyl cellulose is insoluble in water, but its unique chelating structure gives it strong hydrophilicity, allowing it to rapidly absorb water and swell, thus promoting the rapid disintegration of tablets into fine particles. This disintegrant also possesses good compressibility, helping to maintain the mechanical strength of the tablet. Croscarmellose sodium is another high-performance disintegrant, with high disintegration efficiency, low dosage requirement, and effective promotion of drug dispersion. In this invention, the disintegrant functions in two parts: one part is responsible for the rapid disintegration of the entire tablet, and the other part promotes further dispersion of secondary particles. Based on comprehensive disintegration performance and process applicability, the combination of croscarmellose sodium and calcium carboxymethyl cellulose is preferred; due to its higher disintegration efficiency and lower dosage, croscarmellose sodium is further preferred.

[0021] The first and second lubricants are selected from magnesium stearate or sodium stearate fumarate. Both are commonly used lubricants, whose main functions are to improve material flowability, enhance compressibility, and prevent sticking during tableting. The main difference between the two lies in their hydrophobicity and tendency to over-lubricate: sodium stearate fumarate is less hydrophobic and less likely to cause over-lubrication; while magnesium stearate has high lubrication efficiency but is more hydrophobic, requiring careful control of its dosage during the process. Considering the formulation and process characteristics of this invention, the risk of over-lubrication is low, and magnesium stearate has advantages in terms of wide availability and cost; therefore, magnesium stearate is preferred as the lubricant.

[0022] The first and second flow aids are selected from talc or colloidal silica. Both are commonly used additives that enhance material flowability by improving the surface properties of particles. Their mechanism of action lies in filling the depressions and voids on the particle surface with their extremely fine particle size and large specific surface area, reducing inter-particle friction, thereby improving overall flowability and making the morphology closer to spherical. Among them, colloidal silica (also known as micronized silica) generally has a larger specific surface area and a more significant flow aid effect. Therefore, colloidal silica is preferred as the flow aid in this invention.

[0023] A method for preparing the above-mentioned pharmaceutical composition containing atorgepam includes the following steps: S1. Preparation of the immediate-release layer mixture S1.1 Dissolve atorgepa, the first carrier, and the first binder in a solvent to obtain a first drug-containing solution; S1.2 Add a portion of the first excipient and a portion of the disintegrant to the fluidized bed, atomize and spray the first drug-containing solution into the fluidized bed and granulate it, then discharge the material to obtain the first intermediate; S1.3. The first intermediate is granulated and transferred to a hopper mixer. The remaining first excipient, the remaining disintegrant, and the first gliding agent are added and mixed evenly to obtain the second intermediate. S1.4 Add the first lubricant to the second intermediate and mix evenly to obtain the quick-release layer mixture. S2. Preparation of the slow-release layer mixture S2.1 Dissolve atorgepam, the second carrier, and the second binder in a solvent to obtain a second drug-containing solution; S2.2 Add a portion of the second excipient to the fluidized bed, atomize and spray the second drug-containing solution into the fluidized bed and granulate it, then discharge the material to obtain the third intermediate; S2.3. The third intermediate is granulated and transferred to a hopper mixer. The remaining second excipient, slow-release material and second flow aid are added and mixed evenly to obtain the fourth intermediate. S2.4 Add the second lubricant to the fourth intermediate and mix evenly to obtain the slow-release layer mixture. S3. Transfer the immediate-release layer mixture and the sustained-release layer mixture to a tablet press and compress them into a double-layer tablet core. S4. Transfer the double-layer tablet core to a coating machine and coat it with a coating solution to obtain the pharmaceutical composition containing atorgepam.

[0024] The method for preparing an atorgepam-containing pharmaceutical composition provided by this invention focuses on combining the preparation of amorphous solid dispersions with granulation. This method not only effectively simplifies the production process but also possesses good feasibility for large-scale industrial production. Through solid dispersion technology, drug-containing particle intermediates containing amorphous drugs are prepared, allowing the drug to be highly dispersed in amorphous form within the carrier. This significantly improves the solubility and dissolution rate of atorgepam, thereby enhancing its oral bioavailability and in vivo exposure levels. The improved solubility enables rapid release and absorption of the drug in vivo, facilitating the achievement and maintenance of effective blood drug concentrations and improving the cost-effectiveness of clinical applications.

[0025] Preferably, in steps S1.2 and S2.2, the inlet air temperature of the fluidized bed is 50-70 ℃, the atomization pressure is 0.05-0.1 MPa, the peristaltic pump speed is 5-20 rpm during atomization, and the material temperature is maintained at 33-40 ℃ during spraying and granulation. After atomization, the peristaltic pump is turned off, and drying continues until the material loss on drying (LOD) is less than 1.5%, and then the material is discharged.

[0026] Preferably, in steps S1.3 and S2.3, a sieve with a 0.6 mm aperture is used for granulation, and the granulation speed is 300-600 rpm.

[0027] Compared with the prior art, the present invention has the following advantages: (1) The pharmaceutical composition of the present invention is a solid formulation of a dual-release formulation, which combines an immediate-release portion and a long-acting sustained-release portion in the form of an immediate-release layer and a sustained-release layer as a formulation unit. The two portions are released independently. The immediate-release portion releases the drug through rapid dissolution to meet the treatment needs of rapid onset during acute attacks. The sustained-release layer, by regulating the release behavior, maintains the drug concentration in the body within the therapeutic window range for a longer period of time, thereby achieving continuous inhibition of CGRP receptors, prolonging the duration of drug effect, reducing the frequency of administration, fundamentally improving the long-term treatment needs of migraine patients, and improving their quality of life.

[0028] (2) The preparation method of the atorgepam-containing pharmaceutical composition provided by the present invention is based on the combination of the preparation of amorphous solid dispersion and granulation. This method effectively simplifies the production process and, through solid dispersion technology, enables the drug to be highly dispersed in the carrier in an amorphous state, significantly improving the solubility and dissolution rate of atorgepam, thereby improving its oral bioavailability and in vivo exposure level. The improved solubility allows the drug to be rapidly released and absorbed in vivo, which is beneficial for achieving and maintaining effective blood drug concentrations and improving the cost-effectiveness of clinical applications. Attached Figure Description

[0029] Figure 1 The dissolution curves of samples from Examples 1-3 at pH 6.8 are shown. Figure 2 The dissolution curves of samples from Examples 4-6 at pH 6.8 are shown. Figure 3 The dissolution curves of the samples from Examples 1 and 7 at pH 6.8 are shown. Figure 4 Here are the dissolution curves of the samples from Examples 1 and 8 under different media conditions (Figure 1). Figure 5 Dissolution curves of the samples from Examples 1 and 8 under different pH media conditions are shown in Figure 2. Detailed Implementation

[0030] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0031] Examples 1-3: Atorgapastoline solid dosage forms containing only an immediate-release layer were prepared using different amounts of Soluplus® as a solid dispersion carrier to investigate whether the amount of Soluplus® as a solid dispersion carrier affects the release rate of the immediate-release layer. Different amounts of Soluplus® affect the stability of atorgapastoline after it transforms into an amorphous form. If crystallization occurs, it will affect the solubility of the active ingredient, further affecting the dissolution rate of the product. Therefore, dissolution profiles were used for product characterization. The formulation design for Examples 1-3 is shown in Table 1. The designed product strength is 30 mg.

[0032] Table 1

[0033] The preparation methods of the atorgepam solid dosage forms containing only the immediate-release layer in Examples 1-3 are as follows: S1. Preparation of the immediate-release layer mixture S1.1 Dissolve atorgepan, Soluplus® and polyvinylpyrrolidone in 90% ethanol solution and stir until completely dissolved to obtain the first drug-containing solution; S1.2. Add the internally added microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose to the fluidized bed, turn on the equipment, and design the inlet air temperature of the fluidized bed to be 50-70 ℃. Adjust the inlet air volume according to the fluidization state. Atomize and spray the first drug-containing solution into the fluidized bed for granulation. The atomization pressure is 0.05-0.1 MPa, and the peristaltic pump speed is 5-20 rpm during atomization. Maintain the material temperature at 33-40 ℃ during spraying and granulation. After atomization, turn off the peristaltic pump and continue drying until the material drying weight loss is less than 1.5%. Discharge the material to obtain the first intermediate. S1.3. Using a 0.6 mm sieve, the first intermediate is granulated at a speed of 300-600 rpm and then transferred to a hopper mixer. Add the added microcrystalline cellulose, mannitol, cross-linked sodium carboxymethyl cellulose and colloidal silica, and mix evenly at a speed of 12 rpm to obtain the second intermediate. S1.4 Add magnesium stearate to the second intermediate and mix evenly to obtain the immediate-release layer mixture. S2. Transfer the immediate-release layer mixture to a tableting machine for tableting. The tablet weight is 120 mg. Use a 6.5 mm circular shallow concave die to compress the tablets to obtain plain tablets. S3. Prepare a gastric-soluble film-coating premix as a coating solution, transfer the tablets to a coating machine, and perform film coating using the coating solution. The coating weight gain is 2-4%, resulting in an atrogepan solid dosage form containing only an immediate-release layer.

[0034] Atorgipam has two dissociation constants, pKa1 = 2.2 (pyridinium group) and pKa2 = 10.2 (lactam group), and its solubility decreases with increasing pH within the physiological pH range. Based on these physicochemical properties and referring to the "Guidelines for Dissolution Testing of Oral Solid Dosage Forms," ​​a phosphate buffer solution at pH 6.8 was selected as the dissolution medium to characterize the effect of the techniques disclosed in Examples 1-3 on improving drug dissolution behavior.

[0035] The experimental conditions were as follows: Method 6 (flow cell method) of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia was adopted, with a temperature of 37 ℃, a flow rate of 14 mL / min, a medium volume of 900 mL, and a closed-loop mode. Samples were taken into vials, injected into the high-performance liquid chromatograph (HPLC), and the chromatograms were recorded. In addition, the main component reference standard was prepared into a reference solution, injected into the HPLC, and the chromatograms were recorded. The dissolution rate and cumulative dissolution rate of the samples at each sampling time point were calculated.

[0036] Sampling time points: 0 min, 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min; The dissolution study results of samples from Examples 1-3 are shown in Table 2, and the dissolution curves are shown in [reference needed]. Figure 1 .

[0037] Table 2

[0038] The results showed that when the dosage of Soluplus® was 10% (formula percentage), i.e., the ratio of API to Soluplus® was 5:2, the dissolution rate did not exhibit rapid release characteristics, and the dissolution endpoint was not reached at 60 minutes. This indicates that when the dosage of Soluplus® was too low, it could not effectively maintain the amorphous state of atorgepam API, and the product may have undergone partial crystallization, leading to decreased solubility and thus a slower dissolution rate. When the dosage of Soluplus® was 15-20% (formula percentage), i.e., the ratio of API to Soluplus® was 5:3 and 5:4, the dissolution rate exhibited rapid release characteristics, and the dissolution endpoint was reached at 60 minutes, indicating complete dissolution. One of the design objectives of this invention is to improve the solubility and dissolution rate of atorgepam. The experimental results show that when the dosage of Soluplus® is 15-20% (formula percentage), rapid drug dissolution can be achieved, which is consistent with the design objectives of this invention.

[0039] Examples 4-6: Atorgapan solid dosage forms containing only a sustained-release layer were prepared using different amounts of polyethylene oxide as a sustained-release material. The study investigated whether the amount of polyethylene oxide used as a sustained-release material affected the release rate and sustained-release effect of the sustained-release layer, and further influenced the fluctuation of drug concentration in vivo. Therefore, dissolution profiles were used for product characterization. The formulation design for Examples 4-6 is shown in Table 3. The designed product specification was 60 mg.

[0040] Table 3

[0041] The preparation methods of the atorgepam solid dosage forms containing only the sustained-release layer in Examples 4-6 are as follows: S1. Preparation of the sustained-release layer mixture S1.1 Dissolve atorgepan, Soluplus® and polyvinylpyrrolidone in 90% ethanol solution to obtain a second drug-containing solution; S1.2. Add the added microcrystalline cellulose to the fluidized bed, turn on the equipment, and design the inlet air temperature of the fluidized bed to be 50-70 ℃. Adjust the inlet air volume according to the fluidization state. Atomize and spray the second drug-containing solution into the fluidized bed for granulation. The atomization pressure is 0.05-0.1 MPa, and the peristaltic pump speed is 5-20 rpm during atomization. Maintain the material temperature at 33-40 ℃ during spraying and granulation. After atomization, turn off the peristaltic pump and continue drying until the material drying loss is less than 1.5%. Discharge the material to obtain the third intermediate. S1.3. Using a 0.6 mm sieve, the third intermediate is granulated at a speed of 300-600 rpm and then transferred to a hopper mixer. Add the added microcrystalline cellulose, mannitol, polyethylene oxide and colloidal silica, mix evenly at a speed of 12 rpm to obtain the fourth intermediate. S1.4 Add magnesium stearate to the fourth intermediate and mix evenly to obtain the total mixture of the slow-release layer. S2. Transfer the total mixture of the sustained-release layer to a tableting machine for tableting. The tablet weight is 200 mg. Use an 8.0 mm circular shallow concave die to compress the tablets to obtain plain tablets. S3. Prepare a gastric-soluble film-coating premix as a coating solution, transfer the tablets to a coating machine, and perform film coating using the coating solution. The coating weight gain is 2-4%, resulting in an atrogepan solid dosage form containing only a sustained-release layer.

[0042] Referring to the dissolution methods and experimental conditions of Examples 1-3, phosphate buffer solution with pH 6.8 was selected as the dissolution medium for the study to characterize the improvement effect of the technical methods disclosed in Examples 4-6 on drug dissolution behavior.

[0043] Sampling time points: 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, 24 h; The dissolution study results of samples from Examples 4-6 are shown in Table 4, and the dissolution curves are shown in [the table]. Figure 2 .

[0044] Table 4

[0045] The research results show that the amount of polyethylene oxide used has a significant impact on the product release rate. The sustained-release dissolution of the product of this invention needs to meet the following standards: 35-45% dissolution rate at 4 hours, 70-80% dissolution rate at 12 hours, and >90% dissolution rate at 20 hours. Based on the dissolution data from Examples 4-6 above, only Example 5 meets the requirements, i.e., a polyethylene oxide content of 12% (formula percentage) conforms to the design purpose of this invention.

[0046] Example 7: Preparation of atorgepam tablets. The raw materials were micronized. The dissolution behavior was compared with that of Example 1 to illustrate the effect of micronization and preparation as a solid dispersion on the product's dissolution. The formulation design of Example 7 is shown in Table 5, and the specification is designed to be 30 mg.

[0047] Table 5

[0048] The preparation method of the atropine-containing tablets in Example 7 is as follows: S1.1. Pulverize atorgipam until the particle size D90 < 10 μm, and set aside for later use; S1.2. A polyvinylpyrrolidone solution is prepared using purified water and used as an adhesive solution. S1.3. Add the internally added microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and micronized atrogepan to the fluidized bed, turn on the equipment, and design the inlet air temperature of the fluidized bed to be 50-70 ℃. Adjust the inlet air volume according to the fluidization state. Atomize and spray the first drug-containing solution into the fluidized bed for granulation. The atomization pressure is 0.1-0.2 MPa, and the peristaltic pump speed is 10-20 rpm during atomization. Maintain the material temperature at 36-43 ℃ during spraying and granulation. After atomization, turn off the peristaltic pump and continue drying until the material drying loss is less than 1.5%. Discharge the material to obtain the first intermediate. S1.3. Using a 0.6 mm sieve, the first intermediate is granulated at a speed of 300-600 rpm and then transferred to a hopper mixer. Add the added microcrystalline cellulose, mannitol, cross-linked sodium carboxymethyl cellulose and colloidal silica, and mix evenly at a speed of 12 rpm to obtain the second intermediate. S1.4 Add magnesium stearate to the second intermediate and mix evenly to obtain the immediate-release layer mixture. S2. Transfer the immediate-release layer mixture to a tableting machine for tableting. The tablet weight is 120 mg. Use a 6.5 mm circular shallow concave die to compress the tablets to obtain plain tablets. S3. Prepare a gastric-soluble film-coating premix as a coating solution, transfer the tablets to a coating machine, and perform film coating using the coating solution. The coating weight gain is 2-4%, resulting in an atrogepan solid dosage form containing only an immediate-release layer.

[0049] Referring to the dissolution methods and experimental conditions of Examples 1-3, a phosphate buffer solution with pH 6.8 was selected as the dissolution medium for the study to characterize the effect of the technical method disclosed in Example 7 on improving drug dissolution behavior.

[0050] Sampling time points: 0 min, 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min; The dissolution study results of the sample in Example 7 are shown in Table 6. A comparison of the dissolution curves with those of the sample in Example 1 is shown in Table 6. Figure 3 .

[0051] Table 6

[0052] The results show that after micronization to reduce the particle size, the dissolution rate of atorgipam is significantly lower compared to that prepared as a solid dispersion. Although the particle size is very small after micronization, the change in solubility is far less significant than that brought about by amorphous materials. Therefore, simply using raw material micronization technology to reduce particle size cannot achieve the required release rate for this product.

[0053] Example 8: A pharmaceutical composition containing atorgepam, comprising a bilayer tablet core consisting of an immediate-release layer and a sustained-release layer, was prepared using the method of the present invention. This atorgepam-containing pharmaceutical composition maintains effective release throughout. The immediate-release portion rapidly releases the drug to achieve the therapeutically required blood drug concentration, while the sustained-release portion maintains effective drug release and blood drug concentration. The formulation design of the immediate-release layer portion of Example 8 is shown in Table 7, with a designed product specification of 30 mg; the formulation design of the sustained-release layer portion is shown in Table 8, with a designed product specification of 60 mg; the formulation design of the finished product portion of the atorgepam-containing pharmaceutical composition is shown in Table 9.

[0054] Table 7

[0055] Table 8

[0056] Table 9

[0057] The preparation method of the atorgepam-containing pharmaceutical composition in Example 8 is as follows: Atorgepa, Soluplus® and polyvinylpyrrolidone were dissolved in 90% ethanol solution and stirred until completely dissolved to obtain the first drug-containing solution; S1.2. Add the internally added microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose to the fluidized bed, turn on the equipment, and design the inlet air temperature of the fluidized bed to be 50-70 ℃. Adjust the inlet air volume according to the fluidization state. Atomize and spray the first drug-containing solution into the fluidized bed for granulation. The atomization pressure is 0.05-0.1 MPa, and the peristaltic pump speed is 5-20 rpm during atomization. Maintain the material temperature at 33-40 ℃ during spraying and granulation. After atomization, turn off the peristaltic pump and continue drying until the material drying weight loss is less than 1.5%. Discharge the material to obtain the first intermediate. S1.3. Using a 0.6 mm sieve, the first intermediate is granulated at a speed of 300-600 rpm and then transferred to a hopper mixer. Add the added microcrystalline cellulose, mannitol, cross-linked sodium carboxymethyl cellulose and colloidal silica, and mix evenly at a speed of 12 rpm to obtain the second intermediate. S1.4 Add magnesium stearate to the second intermediate and mix evenly to obtain the immediate-release layer mixture. S2. Preparation of the slow-release layer mixture S2.1 Dissolve atorgepan, Soluplus® and polyvinylpyrrolidone in 90% ethanol solution to obtain a second drug-containing solution; S2.2 Add the added microcrystalline cellulose to the fluidized bed, turn on the equipment, and design the inlet air temperature of the fluidized bed to be 50-70 ℃. Adjust the inlet air volume according to the fluidization state. Atomize and spray the second drug-containing solution into the fluidized bed for granulation. The atomization pressure is 0.05-0.1 MPa, and the peristaltic pump speed is 5-20 rpm during atomization. Maintain the material temperature at 33-40 ℃ during spraying and granulation. After atomization, turn off the peristaltic pump and continue drying until the material drying loss is less than 1.5%. Discharge the material to obtain the third intermediate. S2.3. Using a 0.6 mm sieve, the third intermediate is granulated at a speed of 300-600 rpm and then transferred to a hopper mixer. Add the added microcrystalline cellulose, mannitol, polyethylene oxide and colloidal silica, mix evenly at a speed of 12 rpm to obtain the fourth intermediate. S2.4 Add magnesium stearate to the fourth intermediate and mix evenly to obtain the total mixture of the slow-release layer. S3. The immediate-release layer mixture and the sustained-release layer mixture are transferred to a tableting machine for double-layer tableting. The immediate-release layer tablet weight is 120 mg and the sustained-release layer tablet weight is 200 mg. The tablets are compressed using a 9.0 mm circular shallow concave die to obtain plain tablets. S4. Prepare a gastric-soluble film-coating premix as a coating solution, transfer the tablets to a coating machine, and perform film coating using the coating solution. The coating weight gain is 2-4%, resulting in a pharmaceutical composition containing only atorgepam.

[0058] Atorgipam has two dissociation constants, pKa1 = 2.2 (pyridinium group) and pKa2 = 10.2 (lactam group), and its solubility decreases with increasing pH within the physiological pH range. Orally administered drugs undergo a transition from a strongly acidic environment (approximately pH 1.2) to a weakly alkaline environment (approximately pH 6.8) upon entering the gastrointestinal environment, and are therefore often used to simulate drug release behavior in vivo. Based on the physicochemical properties of atorgipam and in vivo physiological conditions, and referring to the "Guidelines for Dissolution Testing of Oral Solid Dosage Forms" and the dissolution methods and experimental conditions of Examples 1-3, hydrochloric acid solution at pH 1.2 and phosphate buffer at pH 6.8 were selected as dissolution media for the study to characterize the improvement effect of the techniques disclosed in Examples 1 and 8 on drug dissolution behavior.

[0059] Sampling points for pH 1.2 medium: 0 min, 15 min, 30 min, 45 min, then switch to pH 6.8 medium; Sampling times for pH 6.8 medium: 1 h, 2 h, 4 h, 8 h, 12 h, 16 h, 20 h, 24 h; The cumulative dissolution results of the samples from Example 1 (3 tablets per sample) and Example 8 are shown in Table 10, and their dissolution curves are compared below. Figure 4 The results of the single-point dissolution study of the samples from Example 1 (3 tablets per sample) and Example 8 are shown in Table 11, and their dissolution curves are compared below. Figure 5 .

[0060] Table 10

[0061] Table 11

[0062] The results show that the combination design of immediate-release and sustained-release drugs can achieve continuous and stable release of atorgapan, which plays an important role in stabilizing the blood drug concentration and exerting the therapeutic effect for a long time.

[0063] The above research indicates that: 1) Atorgapan is a poorly soluble drug. Using a solid dispersion can maximize its solubility. The ratio of API to carrier Soluplus® has a significant impact on the changes in solubility and release rate. The optimal ratio is API:Soluplus® = 5:(3-4). 2) Traditional immediate-release drugs, while having a fast release rate, are difficult to maintain for a long time. They can have a rapid onset of action in the body, but the duration of the effect is limited, requiring frequent dosing. Sustained-release formulations, on the other hand, have a slower release rate and are not suitable for rapid onset of analgesia. Therefore, a design combining immediate-release and sustained-release formulations can well meet the design requirements. The immediate-release and sustained-release components are released independently without affecting each other, achieving both rapid onset of action and maintaining a long-term release state, ensuring that the blood drug concentration remains at an effective therapeutic level.

Claims

1. A pharmaceutical composition containing atorgepam, characterized in that, The pharmaceutical composition is a solid dosage form, the formulation unit of which includes a bilayer tablet core consisting of an immediate-release layer and a sustained-release layer, and a coating layer covering the bilayer tablet core; the immediate-release layer consists of atorgepam active pharmaceutical ingredient and a first excipient, wherein the amount of atorgepam active pharmaceutical ingredient in the immediate-release layer is 20-30%, and the remainder is the first excipient; the sustained-release layer consists of atorgepam active pharmaceutical ingredient and a second excipient, wherein the amount of atorgepam active pharmaceutical ingredient in the sustained-release layer is 25-35%, and the remainder is the second excipient.

2. The pharmaceutical composition containing atorgepam according to claim 1, characterized in that, The weight ratio of the immediate-release layer, sustained-release layer, and coating layer in the formulation unit is (1-4):(4-7):(0.1-0.45).

3. The pharmaceutical composition containing atorgepam according to claim 1, characterized in that, The first excipient includes a first carrier, a first binder, a disintegrant, a first excipient, a first lubricant, and a first flow aid; the second excipient includes a second carrier, a second binder, a sustained-release material, a second excipient, a second lubricant, and a second flow aid.

4. A pharmaceutical composition containing atorgepam according to claim 3, characterized in that, The sum of the contents of each component in the immediate-release layer is 100%, wherein: the percentage of the first carrier is 15-20%, the percentage of the first binder is 5-10%, the percentage of the disintegrant is 3-8%, the percentage of the first excipient is 30-60%, the percentage of the first lubricant is 0.5-2%, and the percentage of the first gliding agent is 0.5-2%; the sum of the contents of each component in the sustained-release layer is 100%, wherein: the percentage of the second carrier is 15-20%, the percentage of the second binder is 5-10%, the percentage of the sustained-release material is 8-15%, the percentage of the second excipient is 20-50%, the percentage of the second lubricant is 0.5-2%, and the percentage of the second gliding agent is 0.5-2%.

5. The pharmaceutical composition containing atorgepam according to claim 3, characterized in that, The first and second carriers are both polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. The first and second adhesives are selected from one or more combinations of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. The disintegrant is one or more combinations of sodium carboxymethyl starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose. The sustained-release material is one or more combinations of polyethylene oxide, methacrylic acid resin polymer, and hydroxypropyl methylcellulose. The first and second excipients are selected from one or more combinations of lactose, microcrystalline cellulose, and mannitol. The first and second lubricants are selected from magnesium stearate or sodium stearate fumarate. The first and second flow aids are selected from talc or colloidal silica.

6. A method for preparing a pharmaceutical composition containing atorgepam according to any one of claims 3-5, characterized in that, Includes the following steps: S1. Preparation of the immediate-release layer mixture S1.1 Dissolve atorgepa, the first carrier, and the first binder in a solvent to obtain a first drug-containing solution; S1.2 Add a portion of the first excipient and a portion of the disintegrant to the fluidized bed, atomize and spray the first drug-containing solution into the fluidized bed and granulate it, then discharge the material to obtain the first intermediate; S1.

3. The first intermediate is granulated and transferred to a hopper mixer. The remaining first excipient, the remaining disintegrant, and the first gliding agent are added and mixed evenly to obtain the second intermediate. S1.4 Add the first lubricant to the second intermediate and mix evenly to obtain the quick-release layer mixture. S2. Preparation of the slow-release layer mixture S2.1 Dissolve atorgepam, the second carrier, and the second binder in a solvent to obtain a second drug-containing solution; S2.2 Add a portion of the second excipient to the fluidized bed, atomize and spray the second drug-containing solution into the fluidized bed and granulate it, then discharge the material to obtain the third intermediate; S2.

3. The third intermediate is granulated and transferred to a hopper mixer. The remaining second excipient, slow-release material and second flow aid are added and mixed evenly to obtain the fourth intermediate. S2.4 Add the second lubricant to the fourth intermediate and mix evenly to obtain the slow-release layer mixture. S3. Transfer the immediate-release layer mixture and the sustained-release layer mixture to a tablet press and compress them into a double-layer tablet core. S4. Transfer the double-layer tablet core to a coating machine and coat it with a coating solution to obtain the pharmaceutical composition containing atorgepam.

7. The preparation method according to claim 6, characterized in that, In steps S1.2 and S2.2, the inlet air temperature of the fluidized bed is 50-70 ℃, the atomization pressure is 0.05-0.1 MPa, the peristaltic pump speed is 5-20 rpm during atomization, and the material temperature is maintained at 33-40 ℃ during spraying and granulation. After atomization, the peristaltic pump is turned off, and drying continues until the material drying weight loss is less than 1.5%, and then the material is discharged.

8. The preparation method according to claim 6, characterized in that, In steps S1.3 and S2.3, a sieve with a 0.6 mm aperture is used for granulation, and the granulation speed is 300-600 rpm.

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