Paracetamol dihydrocodeine tablet and preparation method thereof

Abstract

The invention provides paracetamol dihydrocodeine tablets and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. According to the invention, the paracetamol dihydrocodeine tablet is prepared by means of batching (pre-mixing), granulation, drying, size stabilization, total mixing and tabletting, and the disintegrating property of the tablet can be increased by adding carboxymethyl starch sodium in batches through an external method; the uniform dispersion stability of the two active ingredients, namely the acetaminophen and the dihydrocodeine tartrate, is improved in a manner of proportioning (premixing) and total mixing. After premixing, the content of dihydrocodeine tartrate in the obtained premix is 1.65-1.84% (the content value of the formula is 1.748%); 85.2%-89.6% of acetaminophen (the content value of the prescription is 87.4%); the RSD of dihydrocodeine tartrate in the premixed material is less than or equal to 3.5%, and the RSD of acetaminophen is less than or equal to 1.3%; after total mixing, the RSD of acetaminophen is less than or equal to 2.2%, and the RSD of dihydrocodeine tartrate is less than or equal to 1.4%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a kind of paracetamol and dihydrocodeine tablets and preparation method thereof. BACKGROUND

[0002] Paracetamol and dihydrocodeine is a compound analgesic, and the main component usually includes the following two active ingredients: acetaminophen and dihydrocodeine tartrate. Among them, acetaminophen has antipyretic analgesic effect, and is used for relieving mild to moderate pain (such as headache, toothache, arthralgia, etc.) and fever; dihydrocodeine tartrate is an opioid analgesic, which enhances the analgesic effect by acting on the central nervous system, and is suitable for moderate to severe pain.

[0003] Paracetamol and dihydrocodeine can be widely used for various pains: such as traumatic pain, postoperative pain, moderate cancer pain, muscle pain such as lumbago, back pain, rheumatic muscle pain, headache, toothache, dysmenorrhea, neuralgia and persistent pain caused by strain, sprain, sinusitis, etc. It can also be used for various severe cough, especially non-inflammatory dry cough and headache, fever and cough symptoms caused by cold.

[0004] At present, the main dosage form of paracetamol and dihydrocodeine is tablet, and the preparation method usually adopts equal amount mixing method, which is obtained by equal amount mixing, granulating, drying, whole granulating, total mixing, tabletting and aluminum plastic inner packaging. However, the dispersion uniformity of paracetamol and dihydrocodeine in the existing preparation process is poor, and the content of the two active ingredients: acetaminophen and dihydrocodeine tartrate in the tablet is not uniform and stable, which greatly limits the market promotion and use of paracetamol and dihydrocodeine tablets. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a preparation method of paracetamol and dihydrocodeine tablets. The preparation method provided by the present application can obtain paracetamol and dihydrocodeine tablets with excellent dispersion stability.

[0006] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical scheme: The present application provides a preparation method of paracetamol and dihydrocodeine tablets, comprising the following steps: Firstly, acetaminophen, dihydrocodeine tartrate, pregelatinized starch, lactose, low-substituted hydroxypropyl cellulose and the first portion of sodium carboxymethyl starch are mixed to obtain a premix; Secondly, the premix is mixed with an aqueous solution of hydroxypropyl methyl cellulose to obtain a soft material, and the soft material is granulated to obtain wet granules; Thirdly, the wet granules are dried to obtain dry granules; Fourthly, the dry granules are sieved to obtain granules after whole granulation; The third mixing is performed by adding the remaining sodium carboxymethyl starch into the granules after the whole granulation, and then adding magnesium stearate to perform the total mixing, so as to obtain the acetaminophen and dihydrocodeine granules; The acetaminophen and dihydrocodeine granules are compressed to obtain the acetaminophen and dihydrocodeine tablets. The mass of the first portion of sodium carboxymethyl starch is 35-45% of the total amount of sodium carboxymethyl starch in the formula. The mass concentration of the hydroxypropyl methyl cellulose aqueous solution is 1-4%.

[0007] Preferably, the formula of the acetaminophen and dihydrocodeine tablets is as follows in terms of mass fraction: Acetaminophen 500 parts; Dihydrocodeine tartrate 10 parts; Pre-gelatinized starch 10 parts; Lactose 20 parts; Low-substituted hydroxypropyl cellulose 20 parts; Hydroxypropyl methyl cellulose 2.8 parts; Sodium carboxymethyl starch 30 parts; Magnesium stearate 3 parts.

[0008] Preferably, the stirring frequency of the first mixing is 25-35 Hz, the cutting frequency is 15-25 Hz, and the mixing time is 10-20 min.

[0009] Preferably, the stirring frequency of the second mixing is 25-35 Hz, the cutting frequency is 2-4 Hz, and the mixing time is 3-8 min.

[0010] Preferably, the stirring frequency of the granulation is 20-40 Hz, the cutting frequency is 30-40 Hz, and the granulation time is 1-5 min.

[0011] Preferably, the drying temperature is 60-65°C, and the moisture content of the dried granules is 2-3 wt%. The sieving is performed through a 14-16 mesh sieve.

[0012] Preferably, the frequency of the third mixing is 7-12 Hz, and the time is 10-20 min.

[0013] Preferably, the frequency of the total mixing is 7-12 Hz, and the time is 10-20 min.

[0014] Preferably, the production speed is (5.0-11.0) ten thousand tablets / hour, the pressure of the compression is 10-30 kN, and the weight of the compressed tablets is 0.575-0.625 g.

[0015] The application provides the acetaminophen and dihydrocodeine tablets prepared by the preparation method.

[0016] The application provides a preparation method of paracetamol and dihydrocodeine tablets.

[0017] The paracetamol and dihydrocodeine tablets prepared by the method have a tablet weight of 0.575g-0.625g, a hardness of 8-11kg, an appearance, a friability of less than or equal to 0.7%, a dissolution rate of more than or equal to 83%, a disintegration time of less than or equal to 13 minutes, a tablet weight difference of less than or equal to ±4.5%, and a material balance of 98.0%-100.0% in the tabletting process. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 It is a preparation flow chart of paracetamol and dihydrocodeine tablets. Figure 2 It is a sampling point distribution in uniformity test. DETAILED DESCRIPTION

[0019] The application provides a preparation method of paracetamol and dihydrocodeine tablets, which comprises the following steps: The first mixing is performed on paracetamol, dihydrocodeine tartrate, pregelatinized starch, lactose, low-substituted hydroxypropyl cellulose and the first portion of sodium carboxymethyl starch to obtain a premix; The second mixing is performed on the premix and an aqueous solution of hydroxypropyl methyl cellulose to obtain a soft material, and the soft material is granulated to obtain wet granules; The wet granules are dried to obtain dry granules; The dry granules are sieved to obtain granules after whole granulation; The remaining sodium carboxymethyl starch is added to the granules after whole granulation for third mixing, and then magnesium stearate is added for general mixing to obtain paracetamol and dihydrocodeine granules; The paracetamol and dihydrocodeine granules are tabletted to obtain paracetamol and dihydrocodeine tablets; The mass of the first portion of sodium carboxymethyl starch is 35-45% of the total amount of sodium carboxymethyl starch in the formula; The aqueous solution of hydroxypropyl methyl cellulose has a mass concentration of 1-4%.

[0020] In the present application, the formula of the paracetamol and dihydrocodeine bitartrate tablet is preferably as follows in terms of mass fraction: Paracetamol 500 parts; Dihydrocodeine bitartrate 10 parts; Pre-gelatinized starch 10 parts; Lactose 20 parts; Low-substituted hydroxypropyl cellulose 20 parts; Hydroxypropyl methyl cellulose 2.8 parts; Sodium carboxymethyl starch 30 parts; Magnesium stearate 3 parts.

[0021] In the present application, paracetamol, dihydrocodeine bitartrate, pre-gelatinized starch, lactose, low-substituted hydroxypropyl cellulose and the first part of sodium carboxymethyl starch are mixed to obtain a premix. In the present application, the hydroxypropyl content of the low-substituted hydroxypropyl cellulose is preferably 5% to 10%. The present application preferably performs the first mixing in a wet granulator, the stirring frequency of the first mixing is preferably 25 to 35 Hz, more preferably 30 Hz; the cutting frequency is preferably 15 to 25 Hz, more preferably 20 Hz; and the mixing time is preferably 10 to 20 min, more preferably 15 min.

[0022] After obtaining the premix, the present application performs a second mixing of the premix and an aqueous solution of hydroxypropyl methyl cellulose to obtain a soft material, and granulates the soft material to obtain wet granules. In the present application, the mass concentration of the aqueous solution of hydroxypropyl methyl cellulose is 1% to 4%, preferably 2%. In the present application, the preparation method of the aqueous solution of hydroxypropyl methyl cellulose preferably comprises the following steps: Add 40wt% of boiled purified water to the total amount of the preparation, put in the hydroxypropyl methyl cellulose, stir and dissolve, then add 60wt% of purified water to the total amount of the preparation, and prepare the aqueous solution of hydroxypropyl methyl cellulose.

[0023] In the present application, the second mixing is preferably performed in a wet granulator, the stirring frequency of the second mixing is preferably 25 to 35 Hz, more preferably 30 Hz, the cutting frequency is preferably 2 to 4 Hz, more preferably 2 Hz, and the mixing time is 3 to 8 min, more preferably 5 min. In the present application, the soft material is required to be dry and wet, and the color is uniform. The soft material should be required to be held together by hand and scattered by touch.

[0024] In the present application, the granulation is preferably performed in a wet granulator, the stirring frequency of the granulation is 20 to 40 Hz, more preferably 30 Hz, the cutting frequency is preferably 30 to 40 Hz, more preferably 35 Hz; and the granulation time is preferably 1 to 5 min, more preferably 2 to 5 min.

[0025] After obtaining the wet granules, the present application dries the wet granules to obtain dry granules. In the present application, the drying is preferably performed in a hot air circulating oven. In the present application, the drying temperature is preferably 60-65°C, more preferably 62-64°C; the present application preferably performs tumbling after the drying for 1 h. In the present application, the moisture content of the dry granules is preferably 2-3 wt%.

[0026] After obtaining the dry granules, the present application sieves the dry granules to obtain the granules after sizing. In the present application, the sieving is preferably performed through a 14-16 mesh sieve, more preferably a 14 mesh sieve. In the present application, the sieving is preferably performed in a swing granulator, and the model of the swing granulator is preferably YK160.

[0027] After obtaining the granules after sizing, the present application adds the remaining sodium carboxymethyl starch to the granules after sizing for third mixing, and then adds magnesium stearate for total mixing to obtain the granules of the amphetundihydrocodeine tablets. In the present application, the mass of the remaining sodium carboxymethyl starch is 55-65% of the total amount of sodium carboxymethyl starch in the formula, more preferably 60%. In the present application, the third mixing and the total mixing are preferably performed in a three-dimensional motion mixer, and the model of the three-dimensional motion mixer is preferably JSH-600B. In the present application, the frequency of the third mixing is preferably 7-12 Hz, more preferably 9 Hz, and the time is preferably 10-20 min, more preferably 15 min. In the present application, the frequency of the total mixing is preferably 7-12 Hz, more preferably 9 Hz, and the time is preferably 10-20 min, more preferably 15 min.

[0028] In the present application, the quality monitoring standards of the amphetundihydrocodeine granules are shown in Table 1: Table 1 Quality monitoring standards of amphetundihydrocodeine granules

[0029] After obtaining the amphetundihydrocodeine granules, the present application compresses the amphetundihydrocodeine granules to obtain the amphetundihydrocodeine tablets. The present application preferably uses a full-automatic high-speed tablet press to perform the compression. In the present application, at a production speed of (5.0-11.0) ten thousand tablets / hour, the pressure of the compression is preferably 10-30 kN, more preferably 20 kN, and the weight of the compressed tablets is preferably 0.575-0.625 g.

[0030] In the present application, the quality monitoring standards of the amphetundihydrocodeine tablets are shown in Table 2: Table 2 Quality monitoring standards of amphetundihydrocodeine tablets

[0031] After obtaining the paracetamol and dihydrocodeine bitartrate tablets, the present application further preferably performs packaging, which preferably comprises an inner aluminum-plastic package and an outer package. In the present application, the aluminum-plastic inner package is formed at a temperature of 120℃ to 175℃, more preferably 140 to 160℃, and the heat sealing temperature is preferably 160℃ to 240℃, more preferably 180 to 220℃. The present application preferably divides the qualified tablets into 12 tablets per plate or 10 tablets per plate using polyvinyl chloride solid pharmaceutical hard tablets / pharmaceutical aluminum foil.

[0032] In the present application, the packaging specification of the outer package is preferably 12 tablets / plate x 1 plate / carton x 400 cartons / box, 12 tablets / plate x 2 plates / carton x 240 cartons / box, 12 tablets / plate x 3 plates / carton x 200 cartons / box, or 10 tablets / plate x 4 plates / carton x 200 cartons / box.

[0033] In the present application, the preparation flow chart of the paracetamol and dihydrocodeine bitartrate tablets is as shown in Figure 1

[0034] The present application provides the paracetamol and dihydrocodeine bitartrate tablets prepared by the above preparation method.

[0035] The paracetamol and dihydrocodeine bitartrate tablets and the preparation method thereof provided by the present application will be described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0036] In the following examples, paracetamol is purchased from Hebei Jiheng (Group) Pharmaceutical Co., Ltd., dihydrocodeine bitartrate is purchased from Qinghai Pharmaceutical Co., Ltd., pregelatinized starch is purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., lactose is purchased from Zhenjiang Kangfu Biological Engineering Co., Ltd., low-substitution hydroxypropyl cellulose is purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., hydroxypropyl methyl cellulose is purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., sodium carboxymethyl starch is purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., magnesium stearate is purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., polyvinyl chloride solid pharmaceutical hard tablets are purchased from Jiangxi Chun Guang New Material Technology Co., Ltd., and pharmaceutical aluminum foil is purchased from Jiangxi Chun Guang New Material Technology Co., Ltd.

[0037] In the following examples, the calculation method of the material balance of the total mixing is as follows: material balance = (total weight of particles after total mixing + reusable product amount + non-reusable product amount + sampling amount) / (total amount of raw materials x (1 + moisture content)) x 100%; The calculation method of the material balance during tabletting is as follows: material balance = [(total amount of tablets + reusable product amount + non-reusable product amount + sampling amount) / total amount of particles] x 100%.

[0038] Example 1 The prescription amount of the paracetamol and dihydrocodeine bitartrate tablets is as follows, taking 1000 tablets as an example: Paracetamol 500g; ​Dihydrocodeine tartrate 10 g; Pre-gelatinized starch 10 g; Lactose 20 g; Low-substituted hydroxypropyl cellulose 20 g; Hydroxypropyl methyl cellulose 2.8 g; Sodium carboxymethyl starch 30 g; Magnesium stearate 3 g.

[0039] The preparation method of the paracetamol and dihydrocodeine tartrate tablet comprises the following steps: (1) ingredient preparation: paracetamol, dihydrocodeine tartrate, pre-gelatinized starch, lactose, low-substituted hydroxypropyl cellulose, and 40% sodium carboxymethyl starch are pre-mixed in a wet granulator, the stirring frequency is 30 Hz, the cutting frequency is 20 Hz, and the mixing time is 15 min.

[0040] (2) 2% hydroxypropyl methyl cellulose aqueous solution is added for mixing, the stirring frequency is controlled to be 30 Hz, the cutting frequency is controlled to be 2 Hz, the stirring time is 5 min, the cutting frequency is adjusted to be 35 Hz, the stirring frequency is adjusted to be 30 Hz, and the cutting is performed for 5 min to obtain wet granules.

[0041] (3) the wet granules are dried at a drying temperature of 60-65°C, and the moisture content is controlled to be 2-3% to obtain dry granules.

[0042] (4) the dry granules are sieved through a 14-16 mesh sieve to perform granulation.

[0043] (5) the remaining 60% sodium carboxymethyl starch is added to the granulated granules, the frequency is 9 Hz, the mixing time is 15 min, then magnesium stearate is added, the frequency is 9 Hz, and the total mixing is performed for 15 min to obtain paracetamol and dihydrocodeine tartrate granules.

[0044] (6) the qualified granules are taken, the production speed is set to be 500-110 thousand tablets / hour, the punch setting pressure is set to be 10.0-30.0 kN, and the tablet weight is adjusted to be 0.575-0.625 g.

[0045] Three batches are produced according to the above method, and the batches are recorded as 2305001, 2305002 and 2305003. In each batch, the batch feeding amount of paracetamol is 150.00 kg, the batch feeding amount of dihydrocodeine tartrate is 3.00 kg, the batch feeding amount of pre-gelatinized starch is 3.00 kg, the batch feeding amount of lactose is 6.00 kg, the batch feeding amount of low-substituted hydroxypropyl cellulose is 6.00 kg, the batch feeding amount of hydroxypropyl methyl cellulose is 0.84 kg, the batch feeding amount of sodium carboxymethyl starch is 9.00 kg, and the batch feeding amount of magnesium stearate is 0.90 kg.

[0046] The detection results during the production of batches 2305001, 2305002 and 2305003 are shown in Table 3: Table 3 Inspection results during the production of batches 2305001, 2305002 and 2305003

[0047] The contents of acetaminophen and dihydrocodeine in batches 2305001, 2305002 and 2305003 at the batching stage are shown in Table 4.

[0048] Table 4 Contents of acetaminophen and dihydrocodeine in batches 2305001, 2305002 and 2305003 at the batching stage The sieving results of batches 2305001, 2305002 and 2305003 are shown in Table 5.

[0049] Table 5 Sieving results of batches 2305001, 2305002 and 2305003 The contents of acetaminophen and dihydrocodeine in batches 2305001, 2305002 and 2305003 after total mixing are shown in Table 6.

[0050] Table 6 Contents of acetaminophen and dihydrocodeine in batches 2305001, 2305002 and 2305003 after total mixing The detection results of batches 2305001, 2305002 and 2305003 after tabletting are shown in Table 7.

[0051] Table 7 Detection results of batches 2305001, 2305002 and 2305003 after tabletting

[0052] Uniformity test: ①During the premixing process, samples were taken at 5 min, 10 min and 15 min, respectively, and the sampling point distribution is shown in Table 8. Figure 2 Sampling points 1-4 are 4 distribution points on the upper layer of the material in the kettle body of the granulator; sampling point 5 is a distribution point at the center position of the material in the kettle body of the granulator; and sampling points 6-9 are 4 distribution points on the lower layer of the material in the kettle body of the granulator.

[0053] The contents of dihydrocodeine tartrate and acetaminophen in batches 2305001, 2305002 and 2305003 are shown in Tables 8-10: Table 8 Tartaric acid dihydrocodeine and paracetamol content of 2305001 batch

[0054] Table 9 Tartaric acid dihydrocodeine and paracetamol content of 2305002 batch

[0055] Table 10 Tartaric acid dihydrocodeine and paracetamol content of 2305003 batch

[0056] It can be seen that the content of each point is uniform and stable after premixing for 5 min, which meets the production process requirements.

[0057] 2. Uniformity test results after total mixing Prepared according to the method of Example 1, and the batches are recorded as 2311002, 2311003 and 2311004, respectively.

[0058] The uniformity of tartaric acid dihydrocodeine and paracetamol content of 2311002, 2311003 and 2311004 batches after total mixing is shown in Table 11.

[0059] Table 11 Tartaric acid dihydrocodeine and paracetamol content after total mixing

[0060] 3. Uniformity test results after tabletting The uniformity of tartaric acid dihydrocodeine and paracetamol content of 2311002, 2311003 and 2311004 batches after tabletting is shown in Table 12 and Table 13, respectively.

[0061] Table 12 Uniformity of paracetamol content after tabletting

[0062] Table 13 Uniformity of tartaric acid dihydrocodeine content after tabletting

[0063] In summary, the preparation method provided by the present application can obtain amoxiprin dihydrocodeine tablets with excellent dispersion stability.

[0064] The above merely describes the preferred embodiments of the present application, and it should be pointed out that, for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the protection scope of the present application.

Claims

1. A process for the preparation of amoxil tablet characterized in that, The method comprises the following steps: Firstly, paracetamol, dihydrocodeine tartrate, pregelatinized starch, lactose, low-substituted hydroxypropyl cellulose and the first part of sodium carboxymethyl starch are mixed to obtain a premix; Secondly, the premix is mixed with an aqueous solution of hydroxypropyl methyl cellulose to obtain a soft material, and the soft material is granulated to obtain wet granules; Thirdly, the wet granules are dried to obtain dry granules; Fourthly, the dry granules are sieved to obtain granules after sieving; Fifthly, the remaining sodium carboxymethyl starch is added to the granules after sieving to obtain a third mixture, and then magnesium stearate is added to obtain a total mixture to obtain paracetamol dihydrocodeine granules; Sixthly, the paracetamol dihydrocodeine granules are tabletted to obtain paracetamol dihydrocodeine tablets; The mass of the first part of sodium carboxymethyl starch is 35-45% of the total amount of sodium carboxymethyl starch in the formula; The mass concentration of the aqueous solution of hydroxypropyl methyl cellulose is 1-4%.

2. The production method according to claim 1, characterized by, The formula of the paracetamol dihydrocodeine tablets is as follows in terms of mass fraction: Paracetamol 500 parts; Dihydrocodeine tartrate 10 parts; Pregelatinized starch 10 parts; Lactose 20 parts; Low-substituted hydroxypropyl cellulose 20 parts; Hydroxypropyl methyl cellulose 2.8 parts; Sodium carboxymethyl starch 30 parts; Magnesium stearate 3 parts.

3. The production method according to claim 1 or 2, characterized by, The stirring frequency of the first mixing is 25-35 Hz, the cutting frequency is 15-25 Hz, and the mixing time is 10-20 min.

4. The production method according to claim 1 or 2, characterized by, The stirring frequency of the second mixing is 25-35 Hz, the cutting frequency is 2-4 Hz, and the mixing time is 3-8 min.

5. The production method according to claim 1 or 2, characterized by, The stirring frequency of the granulation is 20-40 Hz, the cutting frequency is 30-40 Hz, and the granulation time is 1-5 min.

6. The production method according to claim 1 or 2, characterized by, The drying temperature is 60-65℃, and the moisture content of the dry granules is 2-3 wt%; The sieving is sieving through a 14-16 mesh sieve.

7. The production method according to claim 1 or 2, characterized by, The frequency of the third mixing is 7-12 Hz, and the time is 10-20 min.

8. The production method according to claim 1 or 2, characterized by, The frequency of the total mixing is 7-12 Hz, and the time is 10-20 min.

9. The production method according to claim 1 or 2, characterized by, The tableting is performed at a production speed of (5.0-11.0) ten thousand tablets / hour, a pressure of 10-30 kN, and a tablet weight of 0.575-0.625 g.

10. The paracetamol dihydrocodeine tablets prepared by the preparation method of any one of claims 1-9.

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