Flupentixol melitracen pharmaceutical composition and preparation method thereof

Abstract

The invention provides a flupentixol melitracen pharmaceutical composition and a preparation method thereof, and relates to the field of pharmaceutical preparations. The flupentixol melitracen pharmaceutical composition provided by the invention does not contain hydrogenated vegetable oil, so that the influence on the dissolution performance of the composition in a long-term storage process is avoided, the dissolution performance equivalent to that of a reference preparation can be achieved even if a disintegrating agent is not used, and meanwhile, the composition is prepared by adopting a process of directly tabletting powder; and a wet granulation process is avoided, so that raw material medicines are prevented from being in contact with damp and hot in the preparation process, the stability is improved, and the clinical medication safety is ensured.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular, to a flupentixol and melitracen pharmaceutical composition and a preparation method thereof. Background Art

[0002] Flupentixol belongs to thioxanthene atypical antipsychotic drugs, which act by blocking dopamine receptors in the mesolimbic system and mesocortical system. Melitracen belongs to tricyclic (heterocyclic) antidepressant drugs, which play an antidepressant role by inhibiting the reuptake of norepinephrine and 5-hydroxytryptamine and increasing the concentration of these two neurotransmitters in the synaptic cleft. Since flupentixol may produce extrapyramidal side effects, and melitracen has anticholinergic side effects, therefore, the combined use of flupentixol and melitracen can, on the one hand, increase the concentration of neurotransmitters such as dopamine, norepinephrine and 5-hydroxytryptamine in the synaptic cleft, produce a synergistic effect, and enhance its antidepressant, antianxiety and excitatory properties; on the other hand, flupentixol can weaken the anticholinergic effect of melitracen, and melitracen can counteract the possible extrapyramidal side effects of flupentixol. Therefore, the combination of flupentixol and melitracen achieves the effects of synergy, efficacy enhancement and toxicity reduction.

[0003] H. Lundbeck A / S developed a compound tablet of flupentixol and melitracen, with the trade name Deanxit. Each tablet contains 0.585 mg of flupentixol dihydrochloride (0.5 mg in terms of flupentixol) and 11.24 mg of melitracen hydrochloride (10 mg in terms of melitracen). Due to its good efficacy, rapid onset and small side effects, it has become a commonly used drug for improving depressive and anxious moods, eliminating somatic symptoms, and treating neurosis, neurasthenia and autonomic nerve dysfunction. The reference preparation of flupentixol and melitracen tablets announced in the Generic Drug Reference Preparation Catalogue (the eighth batch) is the original imported preparation of Lundbeck. The patent information of Lundbeck shows that the formulation of its preparation consists of β-cyclodextrin, lactose monohydrate, corn starch, hydroxypropyl cellulose, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, talc, hydrogenated vegetable oil, magnesium stearate, among which β-cyclodextrin and hydrogenated vegetable oil can improve the stability of flupentixol. At the same time, the patent information also shows that its preparation uses wet granulation and tabletting to prepare flupentixol and melitracen tablets. The inventors found during the research and development process that the degradation impurities of flupentixol and melitracen showed an increasing trend under humid and hot conditions, and the stability decreased. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a flupentixol and melitracen pharmaceutical composition for the problems existing above. This composition does not contain hydrogenated vegetable oil and disintegrant, and its stability and dissolution properties are equivalent to those of the reference preparation.

[0005] Another object of the present invention is to provide a preparation method of a flupentixol and melitracen drug combination. The method adopts a direct powder compression process, avoiding the contact of the active pharmaceutical ingredients with heat and moisture during the granulation process, which is beneficial to improving the stability of the pharmaceutical composition.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A flupentixol and melitracen pharmaceutical composition, the excipients thereof include fillers and lubricants, and do not contain hydrogenated vegetable oil and disintegrants. The disintegrants include sodium carboxymethyl starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

[0008] In a preferred embodiment of the present invention, it includes 0.3 - 1 part by mass of flupentixol or a pharmaceutically acceptable salt thereof, 5 - 20 parts by mass of melitracen or a pharmaceutically acceptable salt thereof, 90 - 125 parts by mass of filler, and 0.3 - 3 parts by mass of lubricant.

[0009] In a preferred embodiment of the present invention, the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, sucrose, and starch; preferably, the filler is composed of microcrystalline cellulose and lactose.

[0010] In a preferred embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate, talc powder, colloidal silica, and sodium stearoyl fumarate.

[0011] In a preferred embodiment of the present invention, it includes 0.584 part by mass of flupentixol hydrochloride, 11.252 parts by mass of melitracen hydrochloride, 85 - 105 parts by mass of lactose, 5 - 20 parts by mass of microcrystalline cellulose, and 0.3 - 3 parts by mass of lubricant.

[0012] In a preferred embodiment of the present invention, the pharmaceutical composition has a coating layer, and the coating layer has a weight gain of 1% - 8% relative to the plain tablet preparation.

[0013] A preparation method of a flupentixol and melitracen pharmaceutical composition, which includes the following steps:

[0014] (1) Add flupentixol hydrochloride and lactose in two increments, continuously pass through a sieve three times, and then mix with a part of lactose to obtain mixture ①;

[0015] (2) Mix mixture ① with the remaining filler and melitracen hydrochloride, and pass through a sieve to obtain mixture ②;

[0016] (3) Mix mixture ② with magnesium stearate, and pass through a sieve to obtain mixture ③;

[0017] (4) Perform direct powder compression on mixture ③ to obtain a plain tablet.

[0018] In a preferred embodiment of the present invention, in step (1), when adding and mixing in two increments, the mass ratio of lactose to flupentixol hydrochloride in the first increment is 4-6:1 to obtain intermediate A; the mass ratio of lactose to intermediate A in the second increment is 1-3:1 to obtain intermediate B; after sieving, the mass ratio of the added lactose to intermediate B is 0.8-1.5:1.

[0019] In a preferred embodiment of the present invention, in step (4), the tablet hardness is controlled to be 3-8 kg.

[0020] In a preferred embodiment of the present invention, it further includes the following step of coating the plain tablets to obtain coated tablets, and the weight gain of the coating layer relative to the plain tablets is 1%-8%.

[0021] The beneficial effects of the present invention are as follows:

[0022] The present invention provides a flupentixol and melitracen pharmaceutical composition. This composition does not contain hydrogenated vegetable oil, avoiding the influence on the dissolution performance of the composition during long-term storage. Even without using a disintegrant, it can achieve dissolution performance equivalent to that of the reference preparation. At the same time, this composition is prepared by a direct powder compression process, avoiding the use of the wet granulation process, thereby avoiding the contact of the active pharmaceutical ingredient with heat and humidity during the preparation process, which is beneficial to improving its stability and ensuring the safety of clinical medication. Detailed implementation manners

[0023] The above content of the present invention will be further described in detail below through specific implementation manners in the form of examples. However, this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0024] Examples 1-5

[0025] This series of examples provides flupentixol and melitracen tablets with different compositions. The plain tablets include the drug active ingredients flupentixol hydrochloride and melitracen hydrochloride, and the filler is composed of lactose and microcrystalline cellulose. In addition, it also includes hydrogenated vegetable oil and magnesium stearate. The content of each component in each plain tablet is shown in Table 1.

[0026] Table 1 Composition of each plain tablet in Examples 1-5

[0027]

[0028] The preparation method of the tablets in Table 1:

[0029] Step 1: Combine lactose and flupentixol hydrochloride with a weight ratio of about 5:1, and mix them evenly to obtain Intermediate A. Then add lactose with a weight about 2 times that of Intermediate A and continue to combine. Pass the mixture through a 0.8 mm sieve continuously for 3 times. All the materials pass through the sieve. Collect the sieved materials to obtain Intermediate B. Mix the sieved materials with lactose with a weight about 1 time that of Intermediate B in a mixer, set the mixing time to 300 s and the rotation speed to 8 rpm, and mix evenly to obtain Mixture ①.

[0030] Step 2: Add part of lactose, microcrystalline cellulose and melitracen hydrochloride, and pass them through a 0.8 mm sieve once. Set the mixing time to 300 s and the rotation speed to 8 rpm. Stop the machine and discharge the materials after mixing. Then use a mobile granulator to screen the mixed materials. After screening, add the remaining lactose to rinse the granulator, and collect the sieved materials to obtain Mixture ②.

[0031] Step 3: Put Mixture ② into a lifting hopper mixer, set the mixing time to 900 s and the rotation speed to 8 rpm. Then put magnesium stearate into the mixer, set the mixing time to 300 s and the rotation speed to 8 rpm. Stop the machine after mixing to obtain Mixture ③.

[0032] Step 4: Press the powdery Mixture ③ into tablets, controlling the hardness to be 3 - 8 kg to obtain plain tablets.

[0033] Step 5: Put the plain tablets into a coating machine for coating, with the coating weight gain of 1 - 8% to obtain flupentixol and melitracen tablets.

[0034] Experimental Example 1

[0035] During the research process, the inventor found that microcrystalline cellulose has strong water absorption and is incompatible with flupentixol hydrochloride, which will reduce the product stability. However, when lactose and microcrystalline cellulose are jointly used as fillers and within a suitable proportion range, the tablets can maintain good stability. In this experimental example, the stability of the reference preparation with packaging and the self-made sample was studied under the combined conditions of 50 °C and 75% RH. Therefore, in the screening study of the dosage ratio of the two, the tablets of Examples 1 - 5 were investigated, that is, the influence of different dosage ratios of lactose and microcrystalline cellulose on the product stability. The results are shown in Table 2.

[0036] Table 2 Influence of different dosages of lactose and microcrystalline cellulose on the stability of tablets

[0037]

[0038]

[0039] Note: The reference preparation is flupentixol and melitracen tablets produced by H. Lundbeck A / S, batch number 2708183, the same below.

[0040] As shown in the investigation results in Table 2, when the dosage of microcrystalline cellulose is 5 - 20 mg and the dosage of lactose is 85 - 105 mg, the total amount of related substances (total impurities) generated by the preparation shown in Table 1 under the combined conditions of 50 °C and 75% RH is less, showing excellent stability.

[0041] Experimental Example 2

[0042] During the research process, the inventor found that for the preparation added with hydrogenated vegetable oil, during the stability test, especially under high temperature conditions, the dissolution performance changed significantly. The investigation on the dissolution performance of the preparation added with hydrogenated vegetable oil is shown in Tables 4 and 5.

[0043] Table 4 Dissolution Results of Flupentixol (0.1 mol / L Hydrochloric Acid Solution)

[0044]

[0045] Table 5 Dissolution Results of Melitracen (0.1 mol / L Hydrochloric Acid Solution)

[0046]

[0047] As can be seen from the results in Tables 4 and 5, after standing at 70 °C for only 1 day, the dissolution of flupentixol and melitracen in the reference preparation and the preparation of Example 4 slowed down significantly, and the dissolution behavior was significantly different from that on day 0.

[0048] Examples 6 - 8

[0049] Based on the aforementioned experimental results, through analysis and experiments, the inventor found that the factor causing the slowdown of tablet dissolution might be hydrogenated vegetable oil, and thus designed different formulation prescriptions without hydrogenated vegetable oil. Some of the prescription compositions are shown in Table 6.

[0050] Table 6 Composition of Flupentixol and Melitracen Tablets without Hydrogenated Vegetable Oil

[0051]

[0052] The preparation method of the tablets in Examples 6 - 8 is the same as that in Examples 1 - 5.

[0053] The stability and dissolution performance of the tablets without hydrogenated vegetable oil were investigated. The stability investigation conditions were the same as those in Experimental Example 1. The investigation results are shown in Tables 7 and 8 - 9.

[0054] Table 7 Investigation Results of the Stability of the Tablets in Example 6

[0055]

[0056] As can be seen from the results in Table 8, the preparation of Example 6 does not contain hydrogenated vegetable oil, and under the same conditions, its stability shows a slight advantage over the reference preparation.

[0057] Table 9 Dissolution results of flupentixol in Example 6 (0.1 mol / L hydrochloric acid solution)

[0058]

[0059] Table 10 Dissolution results of melitracen in Example 6 (0.1 mol / L hydrochloric acid solution)

[0060]

[0061] As can be seen from the experimental results in Tables 9 - 10, the reference preparation contains hydrogenated vegetable oil. Under the conditions of the accelerated test, there are obvious differences in the dissolution behavior, and the dissolution is significantly slowed down. The cumulative dissolution of flupentixol and melitracen at 15 min does not reach 85%. However, for the preparation of the present invention under the conditions of the accelerated test, the dissolution behavior does not change significantly, and it is all rapid dissolution.

[0062] In summary, the flupentixol and melitracen tablets of the present invention, without adding hydrogenated vegetable oil and disintegrant, have stability and dissolution properties comparable to those of the reference preparation. Moreover, under the conditions of the accelerated test, the dissolution property is significantly better than that of the reference preparation, thus showing higher stability and having better clinical application prospects.

Claims

1. A flupentixol and melitracen pharmaceutical composition, characterized in that, Its excipients include fillers and lubricants, and do not contain hydrogenated vegetable oil and disintegrants. The disintegrants include sodium carboxymethyl starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

2. The pharmaceutical composition according to claim 1, wherein It includes 0.3 - 1 part by mass of flupentixol or a pharmaceutically acceptable salt thereof, 5 - 20 parts by mass of melitracen or a pharmaceutically acceptable salt thereof, 90 - 125 parts of filler, and 0.3 - 3 parts of lubricant.

3. The pharmaceutical composition according to claim 2, wherein The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, sucrose, and starch; preferably, the filler consists of microcrystalline cellulose and lactose.

4. The pharmaceutical composition according to claim 3, characterized in that The lubricant is selected from one or more of magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, It includes 0.584 part by mass of flupentixol hydrochloride, 11.252 parts by mass of melitracen hydrochloride, 85 - 105 parts of lactose, 5 - 20 parts of microcrystalline cellulose, and 0.3 - 3 parts of lubricant.

6. The pharmaceutical composition according to claim 5, wherein The pharmaceutical composition has a coating layer, and the coating layer has a weight gain of 1% - 8% relative to the core preparation.

7. A preparation method of a flupentixol and melitracen pharmaceutical composition, characterized in that, It includes the following steps: (1) Add lactose and flupentixol hydrochloride in two portions and mix, then pass through a sieve three times continuously, and then mix with a part of lactose to obtain mixture ①; (2) Mix mixture ① with the remaining filler and melitracen hydrochloride, and pass through a sieve to obtain mixture ②; (3) Mix mixture ② with magnesium stearate to obtain mixture ③; (4) Directly compress mixture ③ into tablets to obtain core tablets.

8. The preparation method according to claim 7, characterized in that, In step (1), during the two-step addition and mixing, the mass ratio of lactose to flupentixol hydrochloride in the first addition is 4 - 6:1 to obtain intermediate A; the mass ratio of lactose to intermediate A in the second addition is 1 - 3:1 to obtain intermediate B; after sieving, the amount of lactose added has a mass ratio of 0.8 - 1.5:1 to intermediate B.

9. The preparation method according to claim 7 or 8, characterized in that In step (4), control the tablet hardness to be 3 - 8 kg.

10. The preparation method according to claim 9, characterized in that, It further includes the following step of coating the core tablets to obtain coated tablets, and the coating layer has a weight gain of 1% - 8% relative to the core tablets.

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