A compound oral antipsychotic drug composition of muscarine and its preparation method

Abstract

The application discloses a kind of compound oral muscarine antipsychotic drug compositions and preparation method thereof, belong to pharmaceutical composition technical field, its technical scheme main point is a kind of compound oral muscarine antipsychotic drug compositions, the pharmaceutical composition is the composition containing two active ingredients, the composition containing two active ingredients is the combination of xanthomelin tartrate microtablet and trospium chloride microtablet, after two active ingredients are made into microtablet respectively, while guaranteeing that product can be released faster, can also increase the time of drug retention in stomach, significantly increase the penetration absorption of drug in body, reduce the fluctuation of blood drug concentration caused by the inconsistent drug release absorption behavior after each administration, so as to better play a role in body, in addition, the technical scheme in the application does not use complex production process, reduces the process development threshold, significantly increases the process reproducibility and stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical composition technology, and in particular to a compound oral muscarinic antipsychotic pharmaceutical composition and its preparation method. Background Technology

[0002] Schizophrenia, a psychiatric disorder, is a persistent and usually chronic major mental illness, and one of the more severe forms of mental illness. It is clinically common, often manifesting in young adulthood with an insidious onset. This disease alters a patient's fundamental personality, leading to a split in thought, emotion, and behavior, causing a disharmony between mental activity and the environment. It primarily affects cognitive functions, including thinking and the perception of the real world, thereby influencing behavior and emotions, placing a heavy burden on patients and their families, and putting pressure on societal medical resources and public health systems. With the advancement of medicine, our understanding of schizophrenia has deepened, and we are continuously exploring more effective treatment methods.

[0003] In the treatment of schizophrenia, traditional first-generation antipsychotics such as chlorpromazine, perphenazine, and clopidogrel are widely used, their main mechanism of action being the blocking of dopamine D2 receptors. Second-generation antipsychotics such as clozapine, risperidone, aripiprazole, paliperidone, and quetiapine are also commonly used. These drugs have a high serotonin (5-HT)2 receptor blocking effect and are known as dopamine (DA)-serotonin receptor antagonists (SDAs). In addition, the existing combination of xaprometrine and troxetine chloride is an innovative oral muscarinic antipsychotic combination, a combination of an M1 / M4 type muscarinic acetylcholine receptor agonist and a muscarinic receptor antagonist, primarily used to treat adult schizophrenia.

[0004] However, first-generation antipsychotics have significant limitations. A certain percentage of patients do not experience effective relief of positive symptoms, and they have a higher incidence of extrapyramidal and tardive dyskinesia, without improving cognitive function. While second-generation antipsychotics can treat cognitive deficits in schizophrenia patients and have fewer extrapyramidal reactions than first-generation antipsychotics, they may cause adverse reactions such as weight gain and metabolic syndrome due to abnormal glucose and lipid metabolism.

[0005] While xapromide, when used alone, can effectively alleviate the symptoms of schizophrenia, its development was discontinued due to severe adverse reactions that made it unacceptable to patients. Later, Karuna Therapeutics developed a combination of xapromide and troxochloride. Xenopromide works by activating toxic cholinergic receptors M1 and M4 in the central nervous system, while troxochloride reduces the peripheral cholinergic side effects of xapromide. This design allows xapromide and troxochloride to exert their central therapeutic effects while minimizing peripheral cholinergic side effects, creating favorable conditions for clinical application.

[0006] Xanoximeline is a poorly soluble drug with pH dependence, decreasing significantly as pH increases. Furthermore, its permeability gradually decreases with increasing physiological pH, requiring time for gastric retention to allow the drug to remain in a slightly acidic environment for a longer period, thereby increasing absorption. Traxamine chloride is a highly soluble drug, but its permeability is very poor, requiring physical methods to increase its absorption; otherwise, its therapeutic efficacy in the body will be compromised.

[0007] Existing patents CN201980064585.4, CN202080093687.1, and CN202280025152.X all describe the release of cyclophosphamide and triamcinolone acetonide compound preparations in two micro-pellet forms.

[0008] Patent CN202511174107.2 describes a compound formulation using xaprometin as the core and troxodium chloride as the outer coating, achieving rapid release of troxodium chloride. However, due to the blocking effect of the outer coating, xaprometin is difficult to release rapidly. If it is not released in time and enters the intestine, the high pH environment will further exacerbate the difficulty of release.

[0009] While the aforementioned technical solutions can achieve rapid product release, they do not fully leverage the drug's ability to penetrate and absorb within the body. Current findings indicate that the characteristics of microgranule dosage forms pose a risk that xanoxetine may not be completely released into the intestines in an acidic environment, increasing the difficulty of drug dissolution.

[0010] The publicly available technical solutions adopt extrusion spheronization or bottom spray coating, which are complex processes with high requirements for equipment and personnel, increasing product costs and the difficulty of process reproducibility, and failing to meet the goal of process simplicity and stability. Summary of the Invention

[0011] To address the problems in the prior art, this invention provides a compound oral muscarinic antipsychotic drug composition and its preparation method. By separately preparing the two active ingredients into micro-tablets, the product can be released more quickly while also increasing the time the drug remains in the stomach, significantly increasing the drug's penetration and absorption in the body, and reducing fluctuations in blood drug concentration caused by inconsistent drug release and absorption behavior after each administration. This allows the drug to exert its effects better in the body. Furthermore, the technical solution of this invention does not employ complex production processes, lowering the process development threshold and significantly increasing process reproducibility and stability.

[0012] The first aspect of this invention is to provide a compound oral muscarinic antipsychotic pharmaceutical composition, employing the following technical solution:

[0013] A compound oral muscarinic antipsychotic drug composition, wherein the drug composition is a composition containing two active ingredients, wherein the composition containing two active ingredients is a combination of sennametrine tartrate microtablets and troxyl chloride microtablets, and the specification of the drug composition is that the content of sennametrine per unit dose is 50 mg and the content of troxyl chloride is 20 mg.

[0014] By employing the above-mentioned technical solution, xametrine tartrate and trox chloride are prepared into micro-tablets. Compared to micropellets, micro-tablets increase the time the drugs remain in the gastric environment, thereby aiding in the absorption of xametrine and avoiding the electrostatic saturation phenomenon caused by the rapid entry of trox chloride into the intestines. More importantly, the micro-tablet form does not cause differences in gastric emptying and intestinal entry behavior after each dose, significantly reducing fluctuations in blood drug concentration after each administration and leading to better treatment of the disease.

[0015] In a preferred embodiment, the raw materials used in the sennametrine tartrate microplates include: sennametrine tartrate, binder, disintegrant, excipient, lubricant, and flow aid. The amount of sennametrine tartrate used is 63.9-85.2% of the total mass of all raw materials in the sennametrine tartrate microplates, the binder accounts for 3-8% of the total mass of all raw materials, the excipient accounts for 4-25% of the total mass of all raw materials, the lubricant accounts for 0.5-2% of the total mass of all raw materials, and the flow aid accounts for 0.5-2% of the total mass of all raw materials.

[0016] In a preferred embodiment, the particle size D90 of the zenomeline tartrate is 12-20 μm.

[0017] By adopting the above technical solution, the particle size D90 of xuanomeline tartrate can be controlled within 12-20 μm, which helps to improve the drug's solubility and absorption, thereby increasing the drug's bioavailability in vivo.

[0018] In a preferred embodiment, the raw materials used in the trox ammonium chloride microplates include trox ammonium chloride, binder, disintegrant, excipient, lubricant, and flow aid. The amount of trox ammonium chloride used is 22.2-33.3% of the total mass of all raw materials in the trox ammonium chloride microplates, the binder accounts for 3-7% of the total mass of all raw materials, the excipient accounts for 55-70% of the total mass of all raw materials, the lubricant accounts for 0.5-2% of the total mass of all raw materials, and the flow aid accounts for 0.5-2% of the total mass of all raw materials.

[0019] In a preferred embodiment, the adhesive used in the zenomeprazole tartrate microsheets is one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, and pregelatinized starch;

[0020] The adhesive used in the trichloroammonium microplates is one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0021] In a preferred embodiment, the disintegrant tartaric acid microplates are made of croscarmellose sodium, and the disintegrant trox chloride microplates are made of low-substituted hydroxypropyl cellulose.

[0022] The amount of disintegrant in the sennamidrin tartrate microtablets is 1-5% of the total mass of all raw materials of the sennamidrin tartrate microtablets;

[0023] The amount of disintegrant in the trox chloride microplates is 2-6% of the total mass of all raw materials in the trox chloride microplates.

[0024] By adopting the above technical solutions, the inventors discovered through numerous experiments that the best disintegrant tartrate microtablet disintegrants are those made with croscarmellose sodium as the disintegrant and those made with low-substituted hydroxypropyl cellulose as the disintegrant for tromethorphan chloride microtablets. The reason for this is that the active ingredient content in croscarmellose tartrate microtablets is high, and the particles inside the microtablets are in close contact. The drug has a certain viscosity when it comes into contact with water, making it difficult for water to penetrate into the tablet core. However, when croscarmellose sodium is used, its capillary activity and hydration capacity allow it to quickly absorb water and generate a strong swelling force, "opening up" the tablet structure and rapidly destroying the tablet's integrity. This prevents the formation of a gel-like layer after the surface drug dissolves, which would hinder internal disintegrant disintegrant disintegration. Tris-chloride microplates have a low proportion of active ingredients and a high proportion of excipients. They are highly hydrophilic and do not easily form gels. When low-substituted hydroxypropyl cellulose is used, its fibrous capillary action and weak solubility can provide a mild and long-lasting disintegration effect for the tris-chloride microplates, promoting the uniform disintegration of the microplates into fine particles, which is beneficial for subsequent dissolution. If cross-linked carboxymethyl cellulose sodium is used in tris-chloride microplates with excessive disintegration power, the excessive local stress may lead to uneven disintegration, which may affect the disintegration efficiency of the tris-chloride microplates.

[0025] The swelling rate of calcium carboxymethyl cellulose is lower than that of cross-linked sodium carboxymethyl cellulose. In senna tartrate microplates containing highly active ingredients, this reduces the disintegration efficiency of the microplates. In troxodium chloride microplates, it may interact with troxodium chloride drug, and the disintegration driving force is relatively weak, which leads to a decrease in the disintegration effect of troxodium chloride microplates.

[0026] The amount of disintegrant in zenomeprazole tartrate microtablets is 1-5% of the total mass, and the amount of disintegrant in troxodium chloride microtablets is 2-6% of the total mass. This allows both types of microtablets to disintegrate well in vivo. In particular, the disintegrant effect is optimal when the amount of disintegrant in zenomeprazole tartrate microtablets is 3% and the amount of disintegrant in troxodium chloride microtablets is 4%, which facilitates the relatively consistent release of the two active ingredients and thus allows them to exert a synergistic effect in vivo.

[0027] In a preferred embodiment, the excipients used in the zenomelein tartrate microplates and tromethorphan chloride microplates are one or more of corn starch, lactose, microcrystalline cellulose, and mannitol.

[0028] In a preferred embodiment, the lubricant used in the zenomelein tartrate microplates and tromethorphan chloride microplates is one of magnesium stearate and sodium stearate fumarate.

[0029] A second aspect of the present invention is to provide a method for preparing a compound oral muscarinic antipsychotic drug composition as described above, comprising the following steps: preparing senna tartrate microtablets and troxodium chloride microtablets respectively, and then filling capsules with senna tartrate microtablets and troxodium chloride microtablets in a certain proportion.

[0030] In summary, the present invention has the following beneficial effects: the pharmaceutical composition adopts the form of sennametrine tartrate microtablets and troxyl chloride microtablets, which can solve the problem of complex preparation process of existing sennametrine and troxyl chloride combination drugs. At the same time, the combination of different disintegrants and the selection of sennametrine tartrate particle size can ensure that the release of the two active ingredients can meet the treatment needs, while increasing the degree of drug permeability and absorption, which is conducive to exerting synergistic effects in vivo and reducing adverse reactions. Attached Figure Description

[0031] Figure 1 This is the dissolution curve of tranexamic acid at pH 6.8.

[0032] Figure 2 This is the dissolution curve of fenpropathrin at pH 6.8.

[0033] Figure 3 This is a dissolution curve of trexammonium chloride under simulated in vivo conditions.

[0034] Figure 4 This is the dissolution curve of fenpropathrin under simulated in vivo conditions.

[0035] Figure 5 This is a scatter plot showing the uniformity of ammonium chloride content. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to the accompanying drawings. All reagents, unless otherwise specified, are commercially available conventional reagent products.

[0037] The specifications of the compound oral muscarinic antipsychotic drug compositions obtained in the embodiments and comparative examples of this application are consistent with the specifications of the commercially available product COBENFY, which contains 50 mg of xanthamide and 20 mg of tromethorphan per unit dose.

[0038] Example 1

[0039] A method for preparing a compound oral muscarinic antipsychotic drug composition includes the following steps:

[0040] Preparation of S1, xuanomerin tartrate microplates

[0041] S1.1 The pulverized zein tartrate was used to obtain fine-particle material with a D90 of 19.56 μm;

[0042] S1.2 Add the pulverized zenomeleline tartrate, lactose (direct compression type), pregelatinized starch, cross-linked sodium carboxymethyl cellulose, and talc to a mixer and mix for 15 minutes at a speed of 15 rpm until uniformly mixed to obtain an intermediate.

[0043] S1.3 Add magnesium stearate to the intermediate and mix for 3 minutes at 12 rpm until homogeneous to obtain the total mixture.

[0044] S1.4 Transfer the total mixture to a tableting machine and perform micro-tablet compression to obtain zenomeprazole tartrate micro-tablets with a tablet weight of 15mg±2mg.

[0045] The formulation of xuannomyl tartrate microtablets is as follows:

[0046]

[0047] Preparation of S2, Trisamine Chloride Microplates

[0048] S2.1 Add trexammonium chloride, corn starch (direct compression type), mannitol, polyvinylpyrrolidone K25, low-substituted hydroxypropyl cellulose, and talc to a mixer and mix for 10 minutes at 15 rpm until homogeneous to obtain an intermediate.

[0049] S2.2 Add magnesium stearate to the intermediate and mix for 3 minutes at 15 rpm to obtain the total mixture;

[0050] S2.3 Transfer the total mixture to a tablet press for micro-tableting to obtain triammonium chloride micro-tablets with a tablet weight of 15mg±1mg;

[0051] The formulation of tromethamine chloride microtablets is as follows:

[0052]

[0053] S3. Preparation of microcapsules

[0054] Assuming 100% accuracy, 90 mg of zebuline tartrate microtablets and 60 mg of troxodium chloride microtablets are sequentially filled into gelatin capsule shells to obtain the finished product. The method for calculating the content of zebuline tartrate and troxodium chloride microtablets in the finished product is as follows:

[0055] The molecular weight of xuanomelene tartrate is 431.50, and the molecular weight of xuanomelene is 281.42. Therefore, the content of xuanomelene is 90 × 85.2% × (281.42 / 431.50) = 50 mg.

[0056] The content of tromethamine chloride = 60 × 33.3% = 19.98 mg.

[0057] Example 2

[0058] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the particle size D90 of xuanomelene tartrate microplates is 12.16 μm, while all other aspects are the same as in Example 1.

[0059] Example 3

[0060] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the amounts of disintegrant and excipients in the xametrine tartrate microtablets are different; otherwise, the method is the same as in Example 1, as detailed below:

[0061] The formulation of xuannomyl tartrate microtablets is as follows:

[0062]

[0063] Example 4

[0064] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the amounts of disintegrant and excipients used in the xametrine tartrate microtablets are different, as detailed below:

[0065] The raw material usage in xuannomilin tartrate microplates is as follows:

[0066]

[0067] Example 5

[0068] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the amounts of disintegrant and mannitol used in the troxodium chloride microtablets are different; otherwise, the method is the same as in Example 1, as detailed below:

[0069] The formulation of tromethamine chloride microtablets is as follows:

[0070]

[0071] Example 6

[0072] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the amounts of disintegrant and mannitol used in the troxodium chloride microtablets are different; otherwise, the method is the same as in Example 1, as detailed below:

[0073] The formulation of tromethamine chloride microtablets is as follows:

[0074]

[0075] Example 7

[0076] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the disintegrant used in the xuanomelein tartrate microtablets is low-substituted hydroxypropyl cellulose, while the rest is the same as in Example 1.

[0077] Example 8

[0078] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the disintegrant used in the xuanomelein tartrate microtablets is calcium carboxymethyl cellulose, while all other aspects are the same as in Example 1.

[0079] Example 9

[0080] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the disintegrant used in the tromethorphan chloride microtablets is croscarmellose sodium, while all other aspects are the same as in Example 1.

[0081] Example 10

[0082] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the disintegrant used in the troxodium chloride microtablets is calcium carboxymethyl cellulose, while all other aspects are the same as in Example 1.

[0083] Example 11

[0084] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the dosages of senna tartrate microtablets and troxetine chloride microtablets are different, as detailed below:

[0085] The formulation of xuannomyl tartrate microtablets is as follows:

[0086]

[0087] The formulation of tromethamine chloride microtablets is as follows:

[0088]

[0089] Preparation of microcapsules: 120 mg of zeinofibrate microcapsules and 90 mg of troxetine chloride microcapsules were sequentially filled into gelatin capsule shells to obtain the finished product. The content of zeinofibrate and troxetine chloride microcapsules in the finished product was calculated as follows:

[0090] The molecular weight of xuanomelene tartrate is 431.50, and the molecular weight of xuanomelene is 281.42. Therefore, the content of xuanomelene is 120 × 63.9% × (281.42 / 431.50) = 50 mg.

[0091] The content of tromethamine is approximately 20 mg (90 × 22.2%).

[0092] Comparative Example 1

[0093] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the particle size D90 of xuanomelene tartrate microtablets is 7.45 μm, while all other aspects are the same as in Example 1.

[0094] Comparative Example 2

[0095] A method for preparing a compound oral muscarinic antipsychotic drug composition differs from Example 1 in that the particle size D90 of xuanomelene tartrate microplates is 26.43 μm, while all other aspects are the same as in Example 1.

[0096] Comparison Example

[0097] The quinol-myers Squibb Co. product contains 125mg / 30mg quinolone tartrate capsules in microcapsule form, marketed under the brand name COBENFY.

[0098] Performance testing

[0099] 1. Dissolution tests were conducted on the products in the above examples, comparative examples, and control examples. Since tromethorphan chloride has high solubility in the physiological pH range, while the solubility of fenpropathrin gradually decreases with increasing pH in the physiological pH range, a phosphate buffer solution with a pH of 6.8 was selected as the dissolution medium for the study, based on the physicochemical characteristics of the raw materials.

[0100] The specific experimental conditions are as follows: Method 1 (basket method) of General Chapter 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia was adopted, with a temperature of 37℃, a rotation speed of 100 rpm, and a medium volume of 900 mL. Samples were taken into injection vials and injected into the high-performance liquid chromatograph (HPLC). Chromatograms were recorded. In addition, the main component reference standard was prepared into a reference solution, injected into the HPLC, and chromatograms were recorded. The dissolution rate or cumulative dissolution rate of the sample at each sampling point was calculated, and the similarity factor (f2) method in the non-model-dependent method was used to determine the similarity of the dissolution curves.

[0101] The formula for calculating the similarity factor (f2) in the non-model-dependent method is as follows:

[0102]

[0103] Rt represents the average dissolution amount of the control sample at time t;

[0104] Tt represents the average dissolution amount of the t-time example or comparative sample;

[0105] n is the number of sampling time points.

[0106] Sampling time points: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min.

[0107] The substances tested were triammonium chloride and zebuline tartrate. The test results are shown in Table 1 and Table 2.

[0108] Table 1. Results of dissolution of ammonium chloride.

[0109] time Example 1 Example 5 Example 6 Example 9 Example 10 Example 11 Comparison Example 0min 0% 0% 0% 0% 0% 0% 0% 5min 36% 21% 46% 52% 29% 33% 39% 10min 59% 42% 68% 76% 50% 55% 60% 15min 72% 57% 80% 87% 64% 69% 73% 30min 88% 82% 94% 98% 85% 86% 89% 45min 96% 93% 98% 99% 95% 95% 97% 60min 99% 97% 99% 99% 97% 99% 99% f2 (vs. comparative example) 85 41 58 42 53 59 NA

[0110] The dissolution curve of tromethamine chloride is as follows Figure 1 As shown, note: f2 is the dissolution curve similarity factor. f2 > 50 indicates that the dissolution curve is similar to the control example, and the closer f2 is to 100, the higher the similarity.

[0111] Table 2 Dissolution Results of Xanomeprazole

[0112] time Example 1 Example 2 Example 3 Example 4 Example 7 Example 8 Example 11 Comparative Example 1 Comparative Example 2 Comparison Example 0min 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 5min 21% 23% 33% 11% 15% 13% 16% 38% 5% 23% 10min 42% 43% 54% 28% 32% 30% 37% 61% 15% 41% 15min 56% 57% 67% 42% 45% 43% 52% 74% 25% 55% 30min 78% 78% 87% 69% 71% 68% 75% 91% 46% 76% 45min 91% 91% 97% 86% 85% 83% 89% 97% 58% 89% 60min 98% 98% 98% 95% 97% 96% 97% 98% 65% 96% f2 (vs. comparative example) 86 84 48 49 56 51 70 38 28 NA

[0113] The dissolution curve of fenofibrate is as follows: Figure 2As shown. Note: f2 is the dissolution curve similarity factor. f2 > 50 indicates that the dissolution curve is similar to the control example, and the closer f2 is to 100, the higher the similarity.

[0114] Combining the dissolution results of tromethorphan chloride and xanomeprazole in Tables 1 and 2, it can be seen that:

[0115] A comparison of Examples 1-2 and Comparative Examples 1-2 shows that when the particle size of zenomeprazole tartrate is within the range defined in this application, it can maintain a similar release rate to the commercially available original formulation, thereby meeting clinical treatment needs.

[0116] Based on the dissolution results of Examples 1, 3-4, and 7-8, the optimal amount of disintegrant in Xanomelide tablets is 3%, and the optimal type of disintegrant is croscarmellose sodium.

[0117] Based on the dissolution results of Examples 1, 5-6, and 9-10, the optimal amount of disintegrant in troxammonium chloride microplates is 4%, and the optimal type of disintegrant is low-substituted hydroxypropyl cellulose.

[0118] Combining Examples 1 and 11, when the amount of zenomeprazole tartrate used was within the range of 63.9-85.2% of the total mass of all raw materials for zenomeprazole tartrate microplates, the release met the requirements.

[0119] Combining Examples 1 and 11, when the amount of trox chloride used was within the range of 22.2%-33.3% of the total mass of all raw materials for trox chloride microplates, the release met the requirements.

[0120] 2. Simulated in vivo dissolution tests were conducted on the products of Examples 1-2 and the control example described above.

[0121] After oral administration, drugs undergo disintegration, release, and absorption in the digestive tract. Establishing a reasonable method to simulate this process is crucial for evaluating product consistency. Typically, the pH of gastric juice is 1.2-2.0 on an empty stomach and 3.5-5.5 after a meal. Due to the influence of food, postprandial gastric juice also has higher viscosity, which may affect drug release. Since xaprometrine and troxetine both have high solubility and rapid dissolution rates under strongly acidic conditions (e.g., pH 1.2), they lack good distinguishability. Therefore, we did not simulate the empty stomach condition. Instead, we examined the release differences between different products under simulated postprandial conditions to illustrate product consistency or variability.

[0122] To simulate the drug release and absorption process in the body, a flow-through cell method was designed to simulate the effect of digestive fluid flow on drug release, using simulated gastric juice and simulated intestinal juice to reflect the influence of gastric juice and intestinal juice on product release.

[0123] Preparation of simulated postprandial gastric juice: Add 10% hydroxypropyl methylcellulose to pH 4.5 buffer solution.

[0124] Preparation of simulated intestinal fluid: buffer solution with a pH of 6.8.

[0125] The specific experimental conditions are as follows: The flow-through cell method was used, the temperature was 37℃, the flow rate was 7mL / min, simulated postprandial gastric juice was used from 0min to 2h, and simulated intestinal juice was used from 2h to 3h. The samples were filtered and injected into the injection vial, and then injected into the high performance liquid chromatograph. The chromatograms were recorded. In addition, the main component reference standard was prepared into a reference solution, injected into the high performance liquid chromatograph, and the chromatograms were recorded. The dissolution rate of the sample at each sampling point was calculated. The results are shown in Tables 3 and 4.

[0126] Table 3. Results of simulated in vivo release of fenpropathrin

[0127] time min Example 1 Example 2 Comparison Example 0 0% 0% 0% 15 3% 5% 4% 30 11% 15% 13% 45 23% 26% 25% 60 34% 38% 37% 75 20% 16% 17% 90 9% 5% 7% 105 5% 3% 4% 120 3% 2% 3% 135 2% 1% 2% 150 2% 1% 2% 165 1% 1% 1% 180 1% 0% 1% f2 (vs. comparative example) 73 81 NA

[0128] The in vivo simulated release curve of fenpropathrin is as follows: Figure 3 As shown, note: f2 is the dissolution curve similarity factor. f2 > 50 indicates that the dissolution curve is similar to the control example, and the closer f2 is to 100, the higher the similarity.

[0129] Table 4 Results of Tris-Clurium Release in Vivo

[0130] Time (min) Example 1 Comparison Example 0 0% 0% 15 6% 8% 30 15% 17% 45 28% 31% 60 42% 45% 75 16% 13% 90 6% 4% 105 3% 2% 120 2% 1% 135 1% 0% 150 0% 0% 165 0% 0% 180 0% 0% f2 (vs. comparative example) 71 NA

[0131] The in vivo simulated release curve of tromethamine is as follows: Figure 4 As shown, note: f2 is the dissolution curve similarity factor. f2 > 50 indicates that the dissolution curve is similar to the control example, and the closer f2 is to 100, the higher the similarity.

[0132] As can be seen from the results in Tables 3 and 4, the products obtained in Examples 1 and 2 of this application have the same in vivo release rate as the commercially available products of the control examples. This indicates that the compositions obtained in Examples 1-2 of this application can meet the needs of clinical treatment.

[0133] 3. A sieve (2mm mesh) passability test was conducted on the products in Example 1 and the control example to simulate the ease with which microtablets and micropellets empty from the stomach in vivo. To simulate the ability of the drug to remain in the stomach, a disintegration apparatus was designed for the study. The reciprocating motion of the disintegration apparatus was used to simulate the movement of the drug in the gastric environment. The simulation experiment was conducted using a pH 4.5 buffer solution with 10% hydroxypropyl methylcellulose added.

[0134] Experimental procedure: Three capsules each from Example 1 and the control example were placed in a disintegration apparatus for the experiment. The time and phenomena observed and recorded when the capsules passed through the bottom sieve were recorded. The results are shown in Table 5.

[0135] Table 5. Passability test results for the examples and control examples

[0136]

[0137] As shown in Table 5, the disintegration time of microcapsules was significantly longer than that of micropellets, which helps to increase gastric retention time and promote the release and osmotic absorption of xamometrine and troxetine. Based on the observed phenomena, micropellets are more likely to pass through the sieve before release, reflecting that micropellets are more easily excreted into the intestine via the pylorus. Furthermore, the time and number of times each dose unit of drug passes through the sieve vary, easily causing differences in release and absorption in the body, leading to fluctuations in blood drug concentration.

[0138] 4. The content uniformity of the products in Examples 1-2 and the control example above was studied, and the results are shown in Table 6.

[0139] The product obtained in this application, trox chloride, has a small specification and a high risk of content uniformity. Therefore, trox chloride was used as a marker for the study. Ten capsules were taken from each of Example 1, Example 2, and two batches of control examples, numbered 1-10. The content uniformity was detected by high performance liquid chromatography (HPLC), and the content was calculated based on peak area and sample weight. The calculation formula is as follows:

[0140]

[0141] In the formula

[0142] A spl Peak area of ​​trexammonium chloride in the solution of the test sample (Examples 1-2, Control Example);

[0143] A std The average peak area of ​​trexamine in the reference standard (trexamine reference standard) solution;

[0144] W std The sample weight of trexammonium chloride in the reference standard (trexammonium chloride reference standard) solution, in mg;

[0145] L: The specification of trastuzumab in trastuzumab capsules, in mg;

[0146] D std The dilution factor of the reference standard (trisamine chloride reference standard) solution;

[0147] D spl The dilution factor of the test sample (Examples 1-2, Control Example) solution;

[0148] The aim is to demonstrate, through content uniformity data, that the flake form is superior to the pellet form in the production process. The uniformity scatter plot is shown below. Figure 5As shown.

[0149] Table 6. Content uniformity data for examples and control examples.

[0150] serial number Example 1 Example 2 Comparative example (batch 1) Comparative example (batch 2) 1# 98.5% 99.1% 98.1% 96.5% 2# 99.4% 99.9% 103.4% 97.6% 3# 100.1% 100.9% 97.1% 102.1% 4# 99.1% 101.1% 96.1% 105.4% 5# 99.2% 101.5% 95.2% 95.5% 6# 97.9% 99.1% 102.3% 104.8% 7# 100.6% 98.6% 104.3% 95.9% 8# 100.1% 99.3% 96.4% 96.2% 9# 101.2% 100.4% 96.1% 95.4% 10# 99.8% 99.7% 101.7% 96.3% average value 99.6% 100.0% 99.1% 98.6% RSD 0.98% 0.98% 3.50% 4.01%

[0151] Based on the data in Table 6:

[0152] The relative standard deviations (RSDs) of the products obtained in Examples 1-2 of this application are significantly smaller than the relative standard deviations of the two batches of control examples, indicating that the micro-flake products obtained in this application are superior to micro-pellets in terms of content uniformity. Furthermore, the micro-flakes are significantly less brittle than micro-pellets, making them less prone to breakage and powder loss during production and transportation, thus better ensuring the drug content within the capsules.

[0153] The embodiments described herein are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, all equivalent changes made in accordance with the structure, shape and principle of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A compound oral muscarinic antipsychotic drug composition, characterized in that: The pharmaceutical composition is a composition containing two active ingredients, which is a combination of senna tartrate microplates and troxamine chloride microplates.

2. The compound oral muscarinic antipsychotic drug composition according to claim 1, characterized in that: The raw materials used in the sennametrine tartrate microplates include: sennametrine tartrate, binder, disintegrant, excipient, lubricant and flow aid, and the amount of sennametrine tartrate used is 63.9-85.2% of the total mass of all raw materials of sennametrine tartrate microplates.

3. The compound oral muscarinic antipsychotic drug composition according to claim 2, characterized in that: The particle size D90 of the tartaric acid xuanomeline is 12-20 μm.

4. A compound oral muscarinic antipsychotic drug composition according to claim 2 or 3, characterized in that: The raw materials used in the trox chloride microplates include trox chloride, binder, disintegrant, excipient, lubricant and flow aid, and the amount of trox chloride used is 22.2-33.3% of the total mass of all raw materials of the trox chloride microplates.

5. The compound oral muscarinic antipsychotic drug composition according to claim 4, characterized in that: The adhesive used in the tartaric acid zein microsheets is one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, and pregelatinized starch. The adhesive used in the trichloroammonium microplates is one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

6. The compound oral muscarinic antipsychotic drug composition according to claim 4, characterized in that: The disintegrant tartaric acid tablets used are croscarmellose sodium, and the disintegrant trox chloride tablets used are low-substituted hydroxypropyl cellulose. The amount of disintegrant in the sennamidrin tartrate microtablets is 1-5% of the total mass of all raw materials of the sennamidrin tartrate microtablets; The amount of disintegrant in the trox chloride microplates is 2-6% of the total mass of all raw materials in the trox chloride microplates.

7. The compound oral muscarinic antipsychotic drug composition according to claim 4, characterized in that: The excipients used in the tartaric acid benzoyl tartrate microflakes and tromethorphan chloride microflakes are one or more of corn starch, lactose, microcrystalline cellulose, and mannitol.

8. The compound oral muscarinic antipsychotic drug composition according to claim 1, characterized in that: The lubricants used in the tartaric acid benzoyl tartrate microplates and tromethamine chloride microplates are both magnesium stearate and sodium stearate fumarate.

9. A method for preparing a compound oral muscarinic antipsychotic pharmaceutical composition as described in any one of claims 1-8, characterized in that: The process includes the following steps: preparing zenomeprazole tartrate microplates and troxodium chloride microplates separately, and then filling capsules with the zenomeprazole tartrate microplates and troxodium chloride microplates in a certain proportion.

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