A suppository containing acetaminophen and its preparation method and use

Abstract

The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a suppository containing acetaminophen, a preparation method thereof, and a use thereof. The acetaminophen suppository of the present invention contains the following ingredients: 100 parts of acetaminophen, 50 parts of cibeline, 300-600 parts of a matrix, 30-60 parts of a surfactant, 15-50 parts of an absorption promoter, and 10-20 parts of a regulator. Pharmacological experiments have shown that the suppository prepared by the present invention has a significant therapeutic effect of clearing away heat and detoxifying, and the proportion of auxiliary materials is optimized. The prepared suppository has a good melting time limit, a low content of related substances, a long shelf life, and can be further expanded for use.

Description

Technical Field

[0001] The invention relates to a suppository containing acetaminophen and a preparation method thereof, in particular to a suppository with acetaminophen and cibeline as main active ingredients and a preparation method thereof, belonging to the field of pharmaceutical preparations. Background Art

[0002] Acetaminophen is an organic compound with the chemical formula C8H9NO2. The chemical structure is as follows:

[0003]

[0004] Acetaminophen is a metabolite of phenacetin in the body. There are many names for acetaminophen on the market, such as Tylenol, Bilitong, Baifuning, and Paracetamol. The pharmacological action is clear. It inhibits the prostaglandin synthetase in the hypothalamic temperature regulation center and reduces the synthesis and release of prostaglandins PGE1, bradykinin, and histamine. PGE1 mainly acts on the nerve center. Its reduction will lead to a decrease in the central temperature setting point, and the surface temperature receptors will feel relatively hot, which will then cause peripheral vasodilation and sweating through neural regulation to achieve the effect of antipyretic. Its effect of inhibiting the synthesis of prostaglandins in the central nervous system is similar to that of aspirin, but the anti-inflammatory effect is weaker. It has no effect on platelets and coagulation mechanism.

[0005] Acetaminophen suppositories are mainly used for children and are common in children under 1 year old. The suppositories disclosed in the prior art are as follows:

[0006] Chinese invention patent CN110302139 A provides an acetaminophen suppository, which uses a mixed solvent system of polyethylene glycol 400 and polyethylene glycol 1500, and adds a small amount of Tween-80 and DMF to help dissolve, so that acetaminophen and essential oils can achieve a uniform dispersion effect and a long-term stability effect, which is beneficial to their transportation and storage. DMF is highly irritating to the skin.

[0007] There is no relevant report on the pharmaceutical preparation of acetaminophen and xibei pine in the existing pharmaceutical technology. Summary of the invention

[0008] In order to overcome the deficiencies of the prior art, the present invention provides a paracetamol suppository. By optimizing the matrix and excipients, the problem of the drug in the suppository flowing out and becoming ineffective due to the short residence time in the rectum during medication is solved. The content of related substances of paracetamol in the optimized process is low and the stability is high, which is suitable for further expansion of utilization.

[0009] Specifically, the technical solution of the present invention is as follows:

[0010] The present invention provides a suppository containing acetaminophen, wherein the components are calculated in parts by weight as follows:

[0011] Acetaminophen 100 parts

[0012] 50 parts of fritillary alkaloids

[0013] Matrix 300-600 copies

[0014] Surfactant 30-60 parts

[0015] Absorption enhancer 15-50 parts

[0016] 10-20 parts of conditioning agent

[0017] The preparation method of the acetaminophen suppository is:

[0018] 1) Heat the matrix to melt, cool it down to 55-65°C, add acetaminophen, continue to cool it down to 40-50°C, and set the mixture aside;

[0019] 2) Add xibei alkaloid, surfactant, absorption enhancer and regulator to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0020] Furthermore, the matrix is ​​composed of rapeseed oil and hydrogenated castor oil, and the ratio of rapeseed oil to hydrogenated castor oil is 1:2-1 calculated by weight.

[0021] Furthermore, the surfactant is selected from one or a mixture of more than one of sodium dodecyl sulfate, sodium lauryl sulfate, polyethylene glycol ester, polyethylene ether, polyoxyethylene stearate or polyoxyethylene fatty alcohol ether.

[0022] Furthermore, it is preferably one of sodium lauryl sulfate and sodium dodecyl sulfate.

[0023] The absorption enhancer is selected from one of deoxycholic acid, glycocholic acid, ethylenediaminetetraacetic acid, ethylene glycol ditetraacetic acid or a mixture of more than one of them.

[0024] Furthermore, it is preferably one of deoxycholic acid and glycocholic acid.

[0025] The regulator is selected from menthol, oleic acid ethanolamine, and caprylic sorbic acid.

[0026] Furthermore, preferably, the regulator is selected from menthol.

[0027] In a preferred embodiment of the present invention, the components of the acetaminophen suppository are calculated in parts by weight as follows:

[0028] Acetaminophen 100 parts

[0029] 50 parts of fritillary alkaloids

[0030] Matrix 400 copies

[0031] 45 parts of surfactant

[0032] Absorption enhancer 30 parts

[0033] 15 parts of regulator.

[0034] In a preferred embodiment of the present invention, the components of the acetaminophen suppository are calculated in parts by weight as follows:

[0035] Acetaminophen 100 parts

[0036] 50 parts of fritillary alkaloids

[0037] 200 servings of rapeseed oil

[0038] Hydrogenated castor oil base 200 parts

[0039] 45 parts of sodium lauryl sulfate

[0040] Deoxycholic acid 30 parts

[0041] Menthol 15 parts.

[0042] In a preferred embodiment of the present invention, the components of the acetaminophen suppository are calculated in parts by weight as follows:

[0043] Acetaminophen 100 parts

[0044] 50 parts of fritillary alkaloids

[0045] 200 servings of rapeseed oil

[0046] Hydrogenated castor oil base 200 parts

[0047] 45 parts of sodium lauryl sulfate

[0048] Glycocholic acid 30 parts

[0049] 15 parts of octanoic acid sorbic acid.

[0050] Furthermore, the suppository comprises the following steps:

[0051] 1) Heat the matrix to melt, cool it down to 60°C, add acetaminophen, continue to cool it down to 45°C, and set the mixture aside;

[0052] 2) Add xibei alkaloid, surfactant, absorption enhancer and regulator to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0053] The acetaminophen suppository of the present invention is used in preparing a medicine for treating paracetamol.

[0054] Compared with the prior art, the present invention has achieved remarkable technical effects:

[0055] Through pharmacological experiments, it was found that the suppository prepared by the present invention has a significantly better effect than acetaminophen or cibeline alone. Further screening of the dosage found that it can play a significant role within the dosage range of the present invention.

[0056] For the optimization of excipients, the present invention can promote the absorption of acetaminophen and play a role of sustained release and prolonged effect by selecting the type and dosage of the matrix, and optimizing its ratio. The melting time limit is good, which complies with the Chinese Pharmacopoeia 2020 edition regarding the melting time limit. Surfactants and promoters were also screened, and it was found in the accelerated test that the content of related substances was significantly reduced, solving the problem of drug deterioration during storage. For the regulator, menthol, oleic acid amine, octanoic acid sorbic acid, especially menthol, used by the inventors of this application, also have a cooling and itching effect, which can effectively relieve symptoms such as tingling caused by irritation of the rectum, and the patient applicability is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 : The rectal temperature was measured at 1h, 2h, 3h, 4h, 5h, 6h and 7h after administration. It can be seen that the drug began to take effect in the 2nd hour.

[0058] Figure 2 : From the statistics of rectal temperature measured 2 hours after drug administration, it can be seen that the positive control group and Examples 1-3 have significant differences compared with Comparative Examples 1-2 (P<0.01).

[0059] Figure 3 : It shows the results of the content of each example at 0, 1, 2, 3, and 6 months.

[0060] Figure 4 : It shows the results of the melting time limit of each embodiment at 0, 1, 2, 3, and 6 months. DETAILED DESCRIPTION

[0061] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0062] Example 1: A suppository containing acetaminophen, the dosage and method are as follows:

[0063]

[0064] The preparation process is as follows:

[0065] 1) Heat and melt rapeseed oil and hydrogenated castor oil, cool to 60°C, add acetaminophen, continue to cool to 45°C, and set aside the mixture;

[0066] 2) Add xibei alkaloids, sodium lauryl sulfate, deoxycholic acid and menthol to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0067] Example 2: A suppository containing acetaminophen, the dosage and method are as follows:

[0068]

[0069] The preparation process is as follows:

[0070] 1) Heat and melt rapeseed oil and hydrogenated castor oil, cool to 55°C, add acetaminophen, continue to cool to 40°C, and set aside the mixture;

[0071] 2) Add xibei alkaloids, sodium lauryl sulfate, deoxycholic acid and menthol to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0072] Example 3: A suppository containing acetaminophen, the dosage and method are as follows:

[0073]

[0074] The preparation process is as follows:

[0075] 1) Heat and melt rapeseed oil and hydrogenated castor oil, cool to 65°C, add acetaminophen, continue to cool to 50°C, and set aside the mixture;

[0076] 2) Add xibei alkaloids, sodium lauryl sulfate, deoxycholic acid and menthol to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0077] Example 4: A suppository containing acetaminophen, the dosage and method are as follows:

[0078]

[0079] The preparation process is as follows:

[0080] 1) Heat and melt rapeseed oil and hydrogenated castor oil, cool to 60°C, add acetaminophen, continue to cool to 45°C, and set aside the mixture;

[0081] 2) Add xibei alkaloids, sodium lauryl sulfate, deoxycholic acid and menthol to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0082] Example 5: A suppository containing acetaminophen, the dosage and method are as follows:

[0083]

[0084] The preparation process is as follows:

[0085] 1) Heat and melt rapeseed oil and hydrogenated castor oil, cool to 60°C, add acetaminophen, continue to cool to 45°C, and set aside the mixture;

[0086] 2) Add xibei alkaloid, sodium lauryl sulfate, glycocholic acid and octanoic acid sorbic acid to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

[0087] Comparative Example 1: A suppository containing acetaminophen, the dosage and method are as follows:

[0088]

[0089] The preparation process is the same as that of Example 1.

[0090] Comparative Example 2: A suppository containing acetaminophen, the dosage and method are as follows:

[0091]

[0092] The preparation process is the same as that of Example 1.

[0093] Comparative Example 3: A suppository containing acetaminophen, the dosage and method are as follows:

[0094]

[0095] The preparation process is the same as that of Example 1.

[0096] Comparative Example 4: A suppository containing acetaminophen, the dosage and method are as follows:

[0097]

[0098] The preparation process is the same as that of Example 1.

[0099] Comparative Example 5: A suppository containing acetaminophen, the dosage and method are as follows:

[0100]

[0101] The preparation process is the same as that of Example 1.

[0102] Comparative Example 6: A suppository containing acetaminophen, the dosage and method are as follows:

[0103]

[0104] The preparation process is the same as that of Example 1.

[0105] Comparative Example 7: A suppository containing acetaminophen, the dosage and method are as follows:

[0106]

[0107] The preparation process is the same as that of Example 1.

[0108] Comparative Example 8: A suppository containing acetaminophen, the dosage and method are as follows:

[0109]

[0110] The preparation process is the same as that of Example 1.

[0111] Verification Example 1: Pharmacological Experiment

[0112] In order to investigate whether the suppository for rectal administration provided by the present invention achieves the purpose of the invention, a pharmacodynamic test of the antipyretic effect of Qingkailing suppository on the endotoxin-induced New Zealand rabbit fever model was carried out.

[0113] 1.1 Experimental drugs

[0114] The suppositories prepared in Examples 1-3 and Comparative Examples 1-2 were prepared in-house. The dosage was calculated based on the dosage of humans and New Zealand rabbits, with a human body weight of 70 kg; commercially available acetaminophen suppositories (positive control group); and blank suppositories (not containing any therapeutically active drug).

[0115] 1.2 Experimental animals and groups

[0116] New Zealand rabbits (weight: 1.55~2.65kg). Animal grouping: The animals were divided into groups according to body temperature balance during the experiment, with 8 rabbits in each group.

[0117] 1.3 Test methods

[0118] Escherichia coli endotoxin 200ng / kg was injected into the ear vein of New Zealand rabbits. The rectal temperature was measured 1.0h after the injection. The New Zealand rabbits with a temperature increase of about 0.8℃~1.7℃ were selected, and the animals were evenly divided into groups according to the temperature increase. 1.5~2 hours after the injection of endotoxin, each drug group was given the corresponding drug according to the corresponding method and dose (the drug administration period of each experimental group of New Zealand rabbits was evenly distributed), and the model control group was given the corresponding negative control. The rectal temperature was measured once at 1h, 2h, 3h, 4h, 5h, 6h, and 7h after the drug administration, and the results were reported in terms of body temperature value and body temperature difference. The same Omron electronic thermometer was used for each animal's temperature measurement several times before and after.

[0119] 1.4 Statistical analysis

[0120] Graphad Prism 9.0 software was used for data processing. The data were expressed as mean ± standard deviation ( ) indicates that the data of each group were tested for normal distribution and homogeneity of variance, which met the requirements of Pearson's test, and one-way analysis of variance was used for comparison between groups. P < 0.05 was considered statistically significant.

[0121] 1.5. Result analysis.

[0122] Figure 1 : The rectal temperature was measured at 1h, 2h, 3h, 4h, 5h, 6h and 7h after administration. It can be seen that the drug began to take effect in the 2nd hour.

[0123] Figure 2 : From the statistics of the rectal temperature of the drug 2 hours after administration, it can be seen that there are significant differences between the positive control group and Examples 1-3 and Comparative Examples 1-2 (P<0.01).

[0124] Verification Example 2: Basic Parameter Experiment

[0125] 2.1

Appearance

[0126] Check whether the surface of the suppository is intact and smooth and whether there is any oil leakage.

[0127] 2.2 [Assay]

[0128] Take 10 pills of this product, accurately weigh, cut into small pieces, mix, accurately weigh an appropriate amount (equivalent to about 0.25g of acetaminophen), place in a 250ml volumetric flask, add 80ml of 0.01mol / L sodium hydroxide solution at about 60℃, shake for 10 minutes, let cool, dilute to scale with 0.01mnol / L sodium hydroxide solution, cool in a cold water bath for 1 hour, filter, and after the filtrate reaches room temperature, accurately measure 10ml of the filtrate, place in a 100ml volumetric flask, dilute to scale with 0.01mol / L sodium hydroxide solution, shake well, accurately measure 5ml, place in a 50ml volumetric flask, dilute to scale with 0.01mol / L sodium hydroxide solution, shake well. According to the ultraviolet visible spectrophotometry method (General Rule 0401), the absorbance is measured at a wavelength of 257nm, according to the absorption coefficient of C8H9NO2 ( ) is calculated as 715, and we get the result.

[0129] 2.3 [Melt-change time limit]

[0130] According to the melting time limit inspection method in Part IV of the 2020 edition of the Chinese Pharmacopoeia, all three suppositories with a fat matrix should be completely melted, softened or have no hard core when touched within 30 minutes. If one suppository does not meet the requirements, another three suppositories should be retested, and all should meet the requirements.

[0131] 1. [Content of related substances]

[0132] Take an appropriate amount of this product (equivalent to 100 mg of acetaminophen), add 10 ml of hot water, grind and dissolve, cool in an ice bath, filter, evaporate the filtrate in a water bath, and dry the residue under reduced pressure.

[0133] Para-aminophenol is freshly prepared for clinical use. Take an appropriate amount of fine powder of this product (equivalent to approximately 0.2g of paracetamol), weigh it accurately, put it in a 10ml volumetric flask, add an appropriate amount of solvent [methanol-water (4:6)], shake to dissolve the paracetamol, dilute to the scale with solvent, shake well, filter, and take the filtrate as the test solution; take an appropriate amount of para-aminophenol reference substance and paracetamol reference substance, weigh them accurately, add the above solvent to make a mixed solution containing approximately 20μg of each in 1ml, as the reference solution. Determine according to the chromatographic conditions under the item of para-aminophenol and related substances in paracetamol. If there is a chromatographic peak in the chromatogram of the test solution that is consistent with the retention time of para-aminophenol in the reference solution, calculate the peak area according to the external standard method, and the para-aminophenol content shall not exceed 0.1% of the labeled amount of paracetamol.

[0134] Accelerated test conditions: The accelerated test is carried out in a constant temperature and humidity chamber with high temperature (40°C) and high humidity (relative humidity 75±5%).

[0135] Table 1 Basic parameters of examples and comparative examples

[0136]

[0137] From the experimental results of appearance, weight difference, melting time, and content of related substances of Examples 1-5 and Comparative Examples 3-8 in Table 1, it can be seen that:

[0138] The appearance, weight difference and melting time of Examples 1-4 of the present invention are all qualified, and they are also qualified after the accelerated test; the content of related substances in the suppositories of the embodiments of the present invention is low, the content of related substances in the accelerated test is basically not increased, and the stability is high.

[0139] The changes in the types and proportions of the matrix and the active ingredients in Comparative Examples 3-8 have a greater impact on the appearance (whether there is oil leakage), which is significantly different from Examples 1-4 of the present invention.

[0140] Results Analysis

[0141] Figure 3 : It shows the results of the content of each example at 0, 1, 2, 3, and 6 months. It can be seen that after the accelerated test, the comparative examples 4-8 showed different degrees of reduction, indicating that the use of different substrates or the same substrate with the same dosage has a more significant effect on the change of acetaminophen content.

[0142] Figure 4 : It shows the results of the melting time of each example at 0, 1, 2, 3, and 6 months. It can be seen that the matrix and the surfactant have a great influence on the melting time. The inventors believe that it may be caused by the decomposition of acetaminophen or cypermethrin by using different surfactants.

Claims

1. A suppository containing acetaminophen, characterized in that: The suppository is composed of the following components in parts by weight: Acetaminophen 100 parts 50 parts of fritillary alkaloids Matrix 300-600 copies Surfactant 30-60 parts Absorption enhancer 15-50 parts 10-20 parts of regulator The matrix is ​​composed of rapeseed oil and hydrogenated castor oil, and the ratio of rapeseed oil to hydrogenated castor oil is 1:2-1 by weight; the surfactant is selected from one of sodium lauryl sulfate and sodium dodecyl sulfate, the absorption promoter is selected from one of deoxycholic acid and glycocholic acid, and the regulator is selected from one of menthol and octanoic acid sorbic acid. The preparation method of the acetaminophen suppository is as follows: 1) Heat the matrix to melt, cool it down to 55-65°C, add acetaminophen, continue to cool it down to 40-50°C, and set the mixture aside; 2) Add xibei alkaloid, surfactant, absorption enhancer and regulator to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

2. The suppository according to claim 1, characterized in that The regulator is selected from menthol.

3. The suppository according to claim 1, characterized in that The suppository is composed of the following components in parts by weight: Acetaminophen 100 parts 50 parts of fritillary alkaloids Matrix 400 copies 45 parts of surfactant Absorption enhancer 30 parts 15 parts of regulator.

4. The suppository according to claim 1, characterized in that The suppository is composed of the following components in parts by weight: Acetaminophen 100 parts 50 parts of fritillary alkaloids 200 servings of rapeseed oil 200 parts hydrogenated castor oil 45 parts of sodium lauryl sulfate Deoxycholic acid 30 parts Menthol 15 parts.

5. The suppository according to claim 1, characterized in that The suppository is composed of the following components in parts by weight: Acetaminophen 100 parts 50 parts of fritillary alkaloids 200 servings of rapeseed oil 200 parts hydrogenated castor oil 45 parts of sodium lauryl sulfate Glycocholic acid 30 parts 15 parts of octanoic acid sorbic acid.

6. The suppository according to claim 1, characterized in that The preparation method of the suppository is: 1) Heat the matrix to melt, cool it down to 60°C, add acetaminophen, continue to cool it down to 45°C, and set the mixture aside; 2) Add xibei alkaloid, surfactant, absorption enhancer and regulator to the mixture of step 1), mix well, pour into a mold, cool, and demould to obtain the product.

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