Domiphen lozenge and preparation process thereof

Abstract

The invention relates to domiphen buccal tablets and a preparation process thereof, and belongs to the field of pharmaceutical preparations. The domiphen lozenge comprises the following components in percentage by weight: 0.5%-2% of domiphen, 86%-87.54% of a filling agent, 8.5%-9% of an adhesive, 1.9%-2.8% of a lubricating agent, 0.5%-0.7% of a flavoring agent and 0-0.06% of a pigment. According to the present invention, the formula and the preparation process of the existing commercially available domiphen buccal tablet are optimally designed, and the dissolubility of the domiphen buccal tablet is greater than or equal to 15 min no matter the dissolving medium is water or artificial saliva; the domiphen lozenge can stably and uniformly release the dosage within the first 10 minutes, the dosage release rate is relatively stable, and the domiphen lozenge is beneficial to stably exerting the drug effect for a long time; the RSD value of the content uniformity of the tablet is less than 5%, the quality of the tablet can be stably controlled in the mass production process, and the application value is high.

Description

Technical Field

[0001] The invention relates to a domiphene lozenge and a preparation process thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Domiphene is an organic compound with the chemical formula C 22 H 40 BrNO is a white or slightly yellow crystalline powder that is soluble in water. It is mainly used as a disinfectant and preservative. It can be used for the auxiliary treatment of oral and throat infections, as well as for the disinfection of skin and traumatic infections and surgical instruments.

[0003] At present, the relevant preparations of domiphene are mainly concentrated in gels, mouthwashes, etc., such as "An anti-inflammatory and antibacterial domiphene mouthwash and its preparation method" with publication (announcement) number CN108042383A, "A gel for relieving dry mouth" with publication (announcement) number CN105748507B, etc. There are no reports on patent applications related to lozenges.

[0004] Based on this, the present invention is proposed. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a domiphene lozenge and a preparation process thereof. The specific technical scheme is as follows:

[0006] In a first aspect, the present invention provides a domiphene lozenge comprising the following components in percentage by weight:

[0007]

[0008]

[0009] The sum of the weight percentages of the above components is 100%.

[0010] In a further improvement, the filler is one or more of sucrose, lactose, and microcrystalline cellulose.

[0011] In a further improvement, the binder is one or more of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and maltodextrin.

[0012] In a further improvement, the lubricant is one or more of talc and magnesium stearate.

[0013] In a further improvement, the flavoring agent is peppermint oil.

[0014] In a further improvement, the pigment is one or more of brilliant blue pigment and sunset yellow pigment.

[0015] In a second aspect, a process for preparing a domiphene lozenge comprises the following steps:

[0016] Step 1, weighing domiphene, filler, binder, lubricant, flavoring agent, and pigment according to the prescription amount, wherein the filler is spray-dried lactose, microcrystalline cellulose PH302 and microcrystalline cellulose PH200, the binder is hydroxypropyl-β-cyclodextrin, the lubricant is talc and magnesium stearate, the flavoring agent is peppermint oil, and the pigment is brilliant blue pigment and sunset yellow pigment;

[0017] Step 2, dissolving domiphene in a wetting agent to prepare a domiphene solution, pouring the domiphene solution, spray-dried lactose, microcrystalline cellulose PH302, hydroxypropyl-β-cyclodextrin, brilliant blue pigment and sunset yellow pigment into a trough-type megasonic disperser for megasonic dispersion, and the mixing and dispersion time is 3 to 5 minutes. After the dispersion is completed, pouring the materials in the trough-type megasonic disperser into a high-efficiency wet mixing granulator and mixing for 10 to 15 minutes to prepare wet granules passing through a 14-mesh screen;

[0018] Step 3, drying the wet granules with a boiling granulation dryer, discharging after cooling, and obtaining first dry granules; dissolving peppermint oil in ethanol to prepare a peppermint oil dispersion, adding the peppermint oil dispersion to the first dry granules, stirring and mixing evenly, and then sieving the sieving granules with a 14-mesh screen, and sending the sieving granules to the boiling granulation dryer for drying again to obtain second dry granules, wherein the moisture content of the second dry granules is controlled to be 2.0±1.0%;

[0019] Step 4: pour the second dry granules into a single-arm lifting hopper mixer, add magnesium stearate, talcum powder and microcrystalline cellulose PH200 by external addition method, stir and mix for 20 to 30 minutes to obtain a total mixture; send the total mixture into a tablet press for tableting to obtain domiphene lozenges.

[0020] In a further improvement, the wetting agent is ethanol or water. The function of the wetting agent is to improve the dispersion effect; in the subsequent drying process, the wetting agent will be basically removed, so it is not included in the formula.

[0021] As a further improvement, in step 2, during the megasonic dispersion process of the trough type megasonic disperser, the megasonic frequency is 3.17 MHz.

[0022] As a further improvement, the mass ratio of the microcrystalline cellulose PH302 to the microcrystalline cellulose PH200 is 5:1, and the total mass of the microcrystalline cellulose PH302 and the microcrystalline cellulose PH200 accounts for 6% of the domiphene lozenge.

[0023] Beneficial effects of the present invention:

[0024] The invention optimizes the formula and preparation process of the existing commercially available domiphene lozenges, and the solubility of the domiphene lozenges is ≥15min regardless of whether the dissolving medium is water or artificial saliva; it means that the domiphene lozenges can stably and evenly release the drug amount within the first 10min, and the drug amount release rate is relatively stable, which is conducive to long-term and stable exertion of drug efficacy; the content uniformity RSD value of the tablets is less than 5%, which is conducive to stably controlling the quality of the tablets in the mass production process, and has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the dissolution rate curve of the domiphene lozenge in Example 1;

[0026] Figure 2 This is the dissolution rate curve of the mid-dofen lozenges in group 12;

[0027] Figure 3 This is the dissolution rate curve of the mid-miphene lozenges in group 13;

[0028] Figure 4 This is the dissolution rate curve of the mid-dofen lozenges in group 14;

[0029] Figure 5 This is the dissolution rate curve of the mid-dofen lozenges in group 15;

[0030] Figure 6 is the dissolution rate curve of the reference preparation. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0032] Example 1

[0033] Prescription 1 is as follows:

[0034]

[0035] The preparation process of the domiphene lozenge comprises the following steps:

[0036] Step 1. According to prescription 1, domiphene, filler, binder, lubricant, flavoring agent, and pigment are weighed. The filler is spray-dried lactose, microcrystalline cellulose PH302, and microcrystalline cellulose PH200. The binder is hydroxypropyl-β-cyclodextrin. The lubricant is talc and magnesium stearate. The flavoring agent is peppermint oil. The pigment is brilliant blue pigment and sunset yellow pigment.

[0037] Step 2, dissolving domiphene in water to prepare a domiphene solution, pouring the domiphene solution, spray-dried lactose, microcrystalline cellulose PH302, hydroxypropyl-β-cyclodextrin, brilliant blue pigment and sunset yellow pigment into a trough megasonic disperser for megasonic dispersion, the megasonic frequency is 3.17 MHz, the mixing and dispersing time is 3 to 5 minutes, after the dispersion is completed, pouring the materials in the trough megasonic disperser into a high-efficiency wet mixing granulator and mixing for 10 to 15 minutes to prepare wet granules passing through a 14-mesh sieve;

[0038] Step 3, drying the wet granules with a boiling granulation dryer, discharging after cooling, and obtaining first dry granules; dissolving peppermint oil in ethanol to prepare a peppermint oil dispersion, adding the peppermint oil dispersion to the first dry granules, stirring and mixing evenly, and then sieving the sieving granules with a 14-mesh screen, and sending the sieving granules to the boiling granulation dryer for drying again to obtain second dry granules, wherein the moisture content of the second dry granules is controlled to be 2.0±1.0%;

[0039] Step 4: pour the second dry granules into a single-arm lifting hopper mixer, add magnesium stearate, talcum powder and microcrystalline cellulose PH200 by external addition method, stir and mix for 20 to 30 minutes to obtain a total mixture; send the total mixture into a tablet press for tableting to obtain domiphene lozenges.

[0040] Example 2

[0041] Prescription 2 is as follows:

[0042]

[0043] The preparation process of the domiphene lozenge comprises the following steps:

[0044] Step 1. According to prescription 2, domiphene, a filler, a binder, a lubricant, and a flavoring agent are weighed. The filler is spray-dried lactose, microcrystalline cellulose PH302, and microcrystalline cellulose PH200. The binder is hydroxypropyl-β-cyclodextrin. The lubricant is talc and magnesium stearate. The flavoring agent is peppermint oil.

[0045] Step 2, dissolving domiphene in water to prepare a domiphene solution, pouring the domiphene solution, spray-dried lactose, microcrystalline cellulose PH302, and hydroxypropyl-β-cyclodextrin into a trough megasonic disperser for megasonic dispersion, the megasonic frequency is 3.17 MHz, and the mixing and dispersing time is 3 to 5 minutes. After the dispersion is completed, pouring the materials in the trough megasonic disperser into a high-efficiency wet mixing granulator and mixing for 10 to 15 minutes to prepare wet granules passing through a 14-mesh screen;

[0046] Step 3, drying the wet granules with a boiling granulation dryer, discharging after cooling, and obtaining first dry granules; dissolving peppermint oil in ethanol to prepare a peppermint oil dispersion, adding the peppermint oil dispersion to the first dry granules, stirring and mixing evenly, and then sieving the sieving granules with a 14-mesh screen, and sending the sieving granules to the boiling granulation dryer for drying again to obtain second dry granules, wherein the moisture content of the second dry granules is controlled to be 2.0±1.0%;

[0047] Step 4: pour the second dry granules into a single-arm lifting hopper mixer, add magnesium stearate, talcum powder and microcrystalline cellulose PH200 by external addition method, stir and mix for 20 to 30 minutes to obtain a total mixture; send the total mixture into a tablet press for tableting to obtain domiphene lozenges.

[0048] Example 3

[0049] Prescription 3 is as follows:

[0050]

[0051]

[0052] The preparation process of the domiphene lozenge comprises the following steps:

[0053] Step 1. According to prescription 1, domiphene, filler, binder, lubricant, flavoring agent, and pigment are weighed. The filler is spray-dried lactose, microcrystalline cellulose PH302, and microcrystalline cellulose PH200. The binder is hydroxypropyl-β-cyclodextrin. The lubricant is talc and magnesium stearate. The flavoring agent is peppermint oil. The pigment is brilliant blue pigment and sunset yellow pigment.

[0054] Step 2, dissolving domiphene in water to prepare a domiphene solution, pouring the domiphene solution, spray-dried lactose, microcrystalline cellulose PH302, hydroxypropyl-β-cyclodextrin, brilliant blue pigment and sunset yellow pigment into a trough megasonic disperser for megasonic dispersion, the megasonic frequency is 3.17 MHz, the mixing and dispersing time is 3 to 5 minutes, after the dispersion is completed, pouring the materials in the trough megasonic disperser into a high-efficiency wet mixing granulator and mixing for 10 to 15 minutes to prepare wet granules passing through a 14-mesh sieve;

[0055] Step 3, drying the wet granules with a boiling granulation dryer, discharging after cooling, and obtaining first dry granules; dissolving peppermint oil in ethanol to prepare a peppermint oil dispersion, adding the peppermint oil dispersion to the first dry granules, stirring and mixing evenly, and then sieving the sieving granules with a 14-mesh screen, and sending the sieving granules to the boiling granulation dryer for drying again to obtain second dry granules, wherein the moisture content of the second dry granules is controlled to be 2.0±1.0%;

[0056] Step 4: pour the second dry granules into a single-arm lifting hopper mixer, add magnesium stearate, talcum powder and microcrystalline cellulose PH200 by external addition method, stir and mix for 20 to 30 minutes to obtain a total mixture; send the total mixture into a tablet press for tableting to obtain domiphene lozenges.

[0057] Comparative Example 1

[0058] Table 1

[0059]

[0060]

[0061] In this example, the prescription is as shown in Table 1, and the preparation process of the domiphene lozenge is the same as that of Example 1.

[0062] Comparative Example 2

[0063] Group 7: Compared with Example 1, the only difference between this example and Example 1 is that microcrystalline cellulose PH102 is used instead of microcrystalline cellulose PH302, and the rest remains unchanged.

[0064] Group 8: Compared with Example 1, the only difference between this example and Example 1 is that microcrystalline cellulose PH105 is used instead of microcrystalline cellulose PH200, and the rest remains unchanged.

[0065] Group 9: Compared with Example 1, the only difference between this example and Example 1 is that microcrystalline cellulose PH101 is used instead of microcrystalline cellulose PH302, and the rest remains unchanged.

[0066] Comparative Example 3

[0067] In this example, according to prescription 1, the preparation process of the domiphene lozenges comprises the following steps:

[0068] Step 1. According to prescription 1, domiphene, filler, binder, lubricant, flavoring agent, and pigment are weighed. The filler is spray-dried lactose, microcrystalline cellulose PH302, and microcrystalline cellulose PH200. The binder is hydroxypropyl-β-cyclodextrin. The lubricant is talc and magnesium stearate. The flavoring agent is peppermint oil. The pigment is brilliant blue pigment and sunset yellow pigment.

[0069] Step 2, dissolving domiphene in water to prepare a domiphene solution, pouring the domiphene solution, spray-dried lactose, microcrystalline cellulose PH302, microcrystalline cellulose PH200, hydroxypropyl-β-cyclodextrin, brilliant blue pigment and sunset yellow pigment into a trough megasonic disperser for megasonic dispersion, the megasonic frequency is 3.17 MHz, the mixing and dispersing time is 3 to 5 minutes, after the dispersion is completed, pouring the materials in the trough megasonic disperser into a high-efficiency wet mixing granulator and mixing for 10 to 15 minutes to prepare wet granules passing through a 14-mesh sieve;

[0070] Step 3, drying the wet granules with a boiling granulation dryer, discharging after cooling, and obtaining first dry granules; dissolving peppermint oil in ethanol to prepare a peppermint oil dispersion, adding the peppermint oil dispersion to the first dry granules, stirring and mixing evenly, and then sieving the sieving granules with a 14-mesh screen, and sending the sieving granules to the boiling granulation dryer for drying again to obtain second dry granules, wherein the moisture content of the second dry granules is controlled to be 2.0±1.0%;

[0071] Step 4: pour the second dry granules into a single-arm lifting hopper mixer, add magnesium stearate and talcum powder by external addition method, stir and mix for 20 to 30 minutes to obtain a total mixture; send the total mixture into a tablet press for tableting to obtain domiphene lozenges.

[0072] Comparative Example 4

[0073] Group 10: Compared with Example 1, the only difference between this example and Example 1 is that β-cyclodextrin is used instead of hydroxypropyl-β-cyclodextrin in this example, and the rest remains unchanged.

[0074] Group 11: Compared with Example 1, the only difference between this example and Example 1 is that maltodextrin is used instead of hydroxypropyl-β-cyclodextrin in this example, and the rest remains unchanged.

[0075] Comparative Example 5

[0076] Group 12: The only difference between this example and Example 1 is that in this example, a trough ultrasonic disperser is used for ultrasonic dispersion instead of the megasonic dispersion of a trough megasonic disperser, and the ultrasonic frequency is 20 kHz. The rest remains unchanged.

[0077] Group 13: The only difference between this example and Example 1 is that the megasonic frequency in this example is 3.16 MHz, and the rest remains unchanged.

[0078] Group 14: The only difference between this example and Example 1 is that the megasonic frequency in this example is 1 MHz, and the rest remains unchanged.

[0079] Group 15: This example is different from Example 1 in that lactose monohydrate is used instead of spray-dried lactose, and the rest remains unchanged.

[0080] Test example

[0081] 1. Content uniformity test

[0082] According to the content uniformity test method in the Chinese Pharmacopoeia, 30 tablets of the domiphene lozenges in Examples 1 to 3 and Comparative Examples 1 to 2 were sampled and tested, and the test results are shown in Table 2:

[0083] Table 2

[0084] Content uniformity RSD value (%) Example 1 0.95 Example 2 3.01 Example 3 2.09 Group 1 7.35 Group 2 8.01 Group 3 6.77 Group 4 6.44 Group 5 7.23 Group 6 8.86 Group 7 9.12 Group 8 8.35 Group 9 6.68

[0085] It can be seen from Table 2 that only when the mass ratio of microcrystalline cellulose PH302 to microcrystalline cellulose PH200 is 5:1 and the total mass of microcrystalline cellulose PH302 and microcrystalline cellulose PH200 accounts for 6% of the domiphene lozenges, the RSD value of content uniformity is <5%; in addition, if it is also microcrystalline cellulose, but other types (such as microcrystalline cellulose PH101, PH102, PH105) are used, even under the same process conditions, the RSD value of content uniformity is still >5%.

[0086] 2. Solubility test

[0087] For Examples 1 to 3 and Groups 7 to 11, the disintegration time limit test method in the Chinese Pharmacopoeia was used. One lozenge was placed in a beaker, the dissolving medium in the beaker was water or artificial saliva at 37±1°C, and the time for the domiphene lozenge to completely disintegrate or dissolve was observed and recorded. Repeat the test for 6 lozenges and take the average value; the results are shown in Table 3:

[0088] Table 3

[0089]

[0090] As can be seen from Table 3, adding microcrystalline cellulose PH200 together with a lubricant by external addition will significantly affect its solubility in artificial saliva, but will have little effect on its solubility in water. If the binder does not use hydroxypropyl-β-cyclodextrin, but uses β-cyclodextrin or maltodextrin, even if microcrystalline cellulose PH200 is used and added together with the lubricant by external addition, the solubility will decrease. Even if the binder is hydroxypropyl-β-cyclodextrin, and microcrystalline cellulose is added together with the lubricant by external addition, if the microcrystalline cellulose is not PH200, but other types, the solubility will decrease. If the added microcrystalline cellulose model is PH200 and added together with the lubricant by external addition, and the binder is hydroxypropyl-β-cyclodextrin, even if the added microcrystalline cellulose model is other types, it will not affect the solubility of the lozenge.

[0091] 3. "Drug release continuity test"

[0092] The dissolution rate under natural wetting conditions was measured with reference to the dissolution and release determination method in the Chinese Pharmacopoeia. The dissolution medium was artificial saliva, the rotation speed was 0 r / min (without stirring), and the sampling time was 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, and 10 min. The dissolution curve was drawn and linear fitting was performed. Among them, R 2It is used to measure the goodness of fit of linear regression. The closer it is to 1, the stronger the positive correlation between variables is. This means that the domiphene lozenge can stably release the drug within the first 10 minutes, and the drug release rate is relatively stable, which is conducive to exerting the drug effect. It will not cause part of the drug effect to be wasted due to too fast release, nor will it cause insufficient drug effect within this time period due to too slow release.

[0093] Since domiphene lozenges need to be released for a long time, it is necessary to maintain its long-term stable release. Although the dissolution test of groups 12 to 15 in Example 1 and Comparative Example 5 (using artificial saliva as the dissolution medium, the paddle method speed is 75r / min, and the cumulative dissolution at 15min is greater than 90%. However, in the "Drug Release Continuity Test" test, the results of groups 12 to 15 in Example 1, Comparative Example 5 and the reference preparation (National Medicine Standard H41024687) are as follows Figures 1 to 6 shown by Figure 1-6 It can be seen that the linear fit of the domiphene lozenge in Example 1 is the best, R 2 Closest to 1.

[0094] In the above examples, brilliant blue pigment was purchased from Shandong Baiqianhui Biotechnology Co., Ltd., and sunset yellow pigment was purchased from Anhui Runtai Biotechnology Co., Ltd. The microcrystalline cellulose PH302, PH200, PH101, PH102, and PH105 were all purchased from Dongguan Xidian Pharmaceutical Technology Co., Ltd. Artificial saliva was purchased from Yunke Biotechnology (Taizhou) Co., Ltd.

[0095] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A domiphene lozenge, characterized in that: The composition includes the following weight percentages: Domiphene 0.5% to 2%; Filler 86%~87.54%; Adhesive 8.5% to 9%; Lubricant 1.9% to 2.8%; Flavor corrector 0.5% to 0.7%; Pigment 0~0.06%; The sum of the weight percentages of the above components is 100%.

2. A domiphene lozenge according to claim 1, characterized in that: The filler is one or more of sucrose, lactose and microcrystalline cellulose.

3. A domiphene lozenge according to claim 1, characterized in that: The binder is one or more of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and maltodextrin.

4. A domiphene lozenge according to claim 1, characterized in that: The lubricant is one or more of talc and magnesium stearate.

5. A domiphene lozenge according to claim 1, characterized in that: The flavoring agent is peppermint oil.

6. A domiphene lozenge according to claim 1, characterized in that: The pigment is one or more of brilliant blue pigment and sunset yellow pigment.

7. A process for preparing a domiphene lozenge according to any one of claims 1 to 6, characterized in that: The following steps are involved: Step 1, weighing domiphene, filler, binder, lubricant, flavoring agent, and pigment according to the prescription amount, wherein the filler is spray-dried lactose, microcrystalline cellulose PH302 and microcrystalline cellulose PH200, the binder is hydroxypropyl-β-cyclodextrin, the lubricant is talc and magnesium stearate, the flavoring agent is peppermint oil, and the pigment is brilliant blue pigment and sunset yellow pigment; Step 2, dissolving domiphene in a wetting agent to prepare a domiphene solution, pouring the domiphene solution, spray-dried lactose, microcrystalline cellulose PH302, hydroxypropyl-β-cyclodextrin, brilliant blue pigment and sunset yellow pigment into a trough-type megasonic disperser for megasonic dispersion, and the mixing and dispersion time is 3 to 5 minutes. After the dispersion is completed, pouring the materials in the trough-type megasonic disperser into a high-efficiency wet mixing granulator and mixing for 10 to 15 minutes to prepare wet granules passing through a 14-mesh screen; Step 3, drying the wet granules with a boiling granulation dryer, discharging after cooling, and obtaining first dry granules; dissolving peppermint oil in ethanol to prepare a peppermint oil dispersion, adding the peppermint oil dispersion to the first dry granules, stirring and mixing evenly, and then sieving the sieving granules with a 14-mesh screen, and sending the sieving granules to the boiling granulation dryer for drying again to obtain second dry granules, wherein the moisture content of the second dry granules is controlled to be 2.0±1.0%; Step 4, pour the second dry granules into a single-arm lifting hopper mixer, add magnesium stearate, talcum powder and microcrystalline cellulose PH200 by external addition method, stir and mix for 20 to 30 minutes to obtain a total mixture; The total mixture is fed into a tablet press for tableting to obtain domiphene lozenges.

8. A process for preparing a domiphene lozenge according to claim 7, characterized in that: The wetting agent is ethanol or water.

9. A process for preparing a domiphene lozenge according to claim 7, characterized in that: In step 2, during the megasonic dispersion process of the trough type megasonic disperser, the megasonic frequency is 3.17 MHz.

10. The process for preparing a domiphene lozenge according to claim 7, characterized in that: The mass ratio of the microcrystalline cellulose PH302 to the microcrystalline cellulose PH200 is 5:1, and the total mass of the microcrystalline cellulose PH302 and the microcrystalline cellulose PH200 accounts for 6% in the domiphene lozenge.

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