CN109223965B - Preparation method of bone-strengthening Longmu chewable tablets - Google Patents

Preparation method of bone-strengthening Longmu chewable tablets Download PDF

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CN109223965B
CN109223965B CN201811209721.8A CN201811209721A CN109223965B CN 109223965 B CN109223965 B CN 109223965B CN 201811209721 A CN201811209721 A CN 201811209721A CN 109223965 B CN109223965 B CN 109223965B
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parts
vitamin
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longmu
strengthening
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CN109223965A (en
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黄志军
向阳
吴保明
曾庆恢
明凯利
曾添
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Jianmin Pharmaceutical Groups Corp ltd
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Abstract

The invention discloses a preparation method of Longmu bone-strengthening chewable tablets, which improves the preparation process and optimizes the type and the dosage of auxiliary materials, thereby improving the content stability of vitamin D2, ensuring the curative effect of the medicament, reducing the difficulty of the preparation, improving the taste of the medicament and improving the medication compliance.

Description

Preparation method of bone-strengthening Longmu chewable tablets
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of a Longmu bone strengthening chewable tablet.
Background
CN1466976A discloses a medicine for preventing and treating rickets and osteoporosis and a preparation method thereof, the medicine belongs to a compound preparation of Chinese and western medicines, and the traditional Chinese medicines for strengthening the spleen and tonifying the kidney are adopted for compatibility, thereby playing the efficacies of strengthening the spleen and stomach and strengthening the muscles and bones, and being used for treating and preventing infantile rickets, osteomalacia and the like. The medicine is a unique variety of Jianmin pharmaceutical industry group member company, has a trade name of Longmu Zhuanggu granules, is collected in the part of 2015 edition of Chinese pharmacopoeia, is a national Chinese medicine protective variety, and is a Chinese running brand.
The Longmu bone-strengthening chewable tablet is an upgraded formulation of Longmu bone-strengthening particles, has the advantages of being more convenient to carry and take compared with granules, and the like, and has been proved by existing researches to be used for treating senile osteoporosis, particularly preventing aggravated edema and heart failure when being used for senile patients with kidney diseases and heart diseases, and having a good prevention effect on osteoporosis caused by adrenal cortical hormone.
However, the production process of chewable tablets is more complicated, which results in poor product stability, especially stability of vitamin D2. Meanwhile, the medicinal materials of the product have large extraction amount of the paste, so that the preparation is difficult to form and has poor taste compliance. Therefore, CN104147344A reports a method for purifying a dragon oyster extract by macroporous resin adsorption, which can reduce the dose for taking, reduce the bitter taste of the drug, and improve the taste of the granule when taken with water, but the method has a long production period and high cost, and the macroporous resin adsorption has a great influence on the extracted components, which can result in the loss of a large amount of active components. In addition, CN107929512A reports a method for preparing bone strengthening granules from Os Draconis and Concha Ostreae by ultra-high pressure extraction, which can increase the content of active ingredients in the extract, reduce impurities, and thus improve the drug effect, but the method still cannot improve the taste and compliance of the chewable tablet.
Disclosure of Invention
The invention aims to solve the defects and provides a preparation method of a Longmu bone-strengthening chewable tablet with better stability and compliance.
The preparation method of the bone strengthening Longmu chewable tablet provided by the invention comprises the following steps:
1) clathrating vitamin D2 with beta-cyclodextrin to obtain vitamin D2 clathrate;
2) decocting radix Codonopsis, radix astragali, radix Ophiopogonis, carapax et Plastrum Testudinis, Atractylodis rhizoma, rhizoma Dioscoreae, fructus Schisandrae chinensis, Os Draconis, Concha Ostreae, Poria, fructus Jujubae, Glycyrrhrizae radix, and endothelium corneum Gigeriae Galli in water, concentrating the extractive solution to relative density of 1.05-1.15, cooling, adding ethanol to ethanol content of 50-80%, standing, collecting supernatant, recovering ethanol under reduced pressure, and concentrating to obtain extract with relative density of 1.2-1.3;
3) mixing the extract with vitamin D2 clathrate, calcium lactate, calcium gluconate, filler, sour agent, and artificial sweetener, and granulating;
4) adding magnesium stearate and essence into the granules, mixing, tabletting,
the weight parts of the raw materials are as follows:
Figure BDA0001832145470000021
preferably, the weight parts of the raw materials are as follows:
Figure BDA0001832145470000022
the filler is selected from mannitol, sorbitol, sucrose, lactose, dextrin, preferably lactose.
The sour agent is citric acid.
The artificial sweetener is selected from aspartame, stevioside, saccharin sodium, acesulfame potassium and sucralose, and is preferably sucralose.
Preferably, the granulation in step 3) is performed by spray granulation.
Further preferably, the conditions of the spray granulation are: the material temperature is 50-70 deg.C, the spraying speed is 20-50ml/min, and the atomizing pressure is 0.3-0.5 Mpa.
Because the chemical property of the vitamin D2 is very unstable, the vitamin D2 is easily degraded under the influence of temperature, humidity, pH and other chemical substances, the production process of the chewable tablet is more complicated than that of granules, the types of used auxiliary materials are more, the stability of the vitamin D2 in the chewable tablet is poorer than that of the granules, and the content detection is often unqualified in the valid period. Therefore, various means are adopted during the preparation of the chewable tablet, firstly, vitamin D2 is included, and a proper inclusion amount is determined through the stability inspection of a finished product, namely, when the dosage of beta-cyclodextrin is about 30 times of VD2, the vitamin D2 can play a good protection role on VD2, and the traditional Chinese medicine components and auxiliary materials in the chewable tablet are prevented from damaging the chewable tablet. Secondly, the amount of the sour agent is researched, and the discovery that when 10-30 parts of citric acid is added, the taste of the chewable tablet can be improved, more importantly, the acid-base environment of the chewable tablet can be adjusted, and VD2 is more stable in property under the condition. Then, the type and the using amount of the sweetening agent are optimized, and the artificially synthesized sweetening agent such as aspartame, stevioside, saccharin sodium, acesulfame potassium and the like can destroy the stability of VD2, and the VD2 has the most stable property only when sucralose is used. Finally, the type of filler is also optimized, and the lactose is found to be more favorable for VD2 stability compared with mannitol, sorbitol, sucrose, dextrin and the like.
The chewable tablet has higher requirements on the taste of the medicine due to different administration modes from granules, and the dosage of the tablet is not too high due to less auxiliary materials than granules, otherwise, the preparation is difficult to form. Therefore, the technical means is adopted, firstly, the extract after decoction and extraction is subjected to alcohol precipitation treatment, and the results show that the content of impurity components such as protein, tannin, polysaccharide, starch and the like in the extract after alcohol precipitation is reduced, the content of active components such as alkaloid, flavone, organic acid and the like is increased, and the total paste yield is only about 50% of that before alcohol precipitation, so that the forming difficulty of the tablet is reduced, the exertion of the drug effect is ensured, and in addition, the bitter taste of the tablet after alcohol precipitation is reduced, the mouthfeel is better, and the compliance is also greatly improved. Compared with the method of removing impurities by macroporous resin adsorption, the alcohol precipitation method has less influence on active ingredients and lower cost. Secondly, a method for granulating before tabletting is investigated, and compared with two methods of wet granulation and spray granulation, the results show that the spray granulation is more favorable for stabilizing the active ingredients of the traditional Chinese medicine, the granule fluidity of the spray granulation is better, and the tabletting is more favorable for tabletting and forming, and the chewable tablet prepared after the spray granulation has moderate hardness, has no granular sensation during chewing and has better taste.
Detailed Description
Example 1
1. Prescription:
Figure BDA0001832145470000041
2. the preparation method comprises the following steps:
1) the vitamin D2 inclusion compound is prepared by adopting a conventional solvent evaporation method, and the specific method comprises the following steps: dissolving beta-cyclodextrin with water, dissolving vitamin D2 with a small amount of ethanol, adding into the beta-cyclodextrin water solution, stirring until the solution is completely clear, performing rotary evaporation, and drying to obtain the vitamin D2 clathrate, wherein the vitamin D2 is embedded in the molecular cavity of the beta-cyclodextrin, so that the water solubility and the stability are improved.
2) Adding 8 times of water into thirteen medicines of codonopsis pilosula, astragalus, radix ophiopogonis, tortoise shell, bighead atractylodes rhizome, Chinese yam, schisandra chinensis, dragon bone, oyster shell, poria cocos, Chinese date, liquorice and endothelium corneum gigeriae galli, decocting for three times, wherein the amount of the water is 2 hours for the first time and 2 hours for the second time, the amount of the water is 1 hour for the third time, combining extracting solutions, concentrating until the relative density is 1.08 (measured at 75-85 ℃), cooling, adding ethanol until the alcohol content is 60%, standing, taking supernate, recovering ethanol under reduced pressure, and concentrating until the relative density is about 1.20 (measured at 75-85 ℃).
3) Mixing vitamin D2 clathrate, calcium lactate, calcium gluconate, lactose, citric acid, and sucralose, placing at the bottom of spray granulating machine, atomizing the extract, spray granulating, controlling the temperature of the material at 60 deg.C, the spraying speed at 30ml/min, and the atomizing pressure at 0.4 Mpa.
4) Adding 0.5% magnesium stearate and 0.8% orange essence into the granules, mixing, and tabletting.
Example 2
1. Effect of beta-Cyclodextrin inclusion amount on VD2 stability
The chewable tablets were prepared according to the method of example 1 with the amounts of 0.6g, 1.2g, 1.8g and 3g of beta-cyclodextrin, i.e., 10 times, 20 times, 30 times and 50 times of VD2, respectively, and after the preparation, the chewable tablets were subjected to a 6-month stability acceleration test at a relative humidity of 65% and a temperature of 30 ℃, and the VD2 content of the samples was determined by HPLC, and the results are shown in table 1 below.
TABLE 1 Effect of beta-cyclodextrin inclusion on VD2 content stability (μ g/tablet)
Amount of inclusion 0 month 1 month 2 month 3 month 4 month Month 5 6 month
10 times of 64.2 57.7 54.4 51.9 47.3 42.4 38.7
20 times of 61.9 58.3 51.7 48.2 46.1 43.7 40.5
30 times of 62.8 61.7 60.2 59.4 59.0 58.3 58.1
50 times of 64.8 63.2 62.5 61.7 61.3 60.9 60.2
From the results, when the inclusion amount is 30-50 times, the VD2 content is relatively stable in the chewable tablet, the content is only reduced by about 7% in the accelerated test of 6 months, and when the inclusion amount is less than 30 times, the VD2 content is reduced rapidly, and the stability is poor.
2. Influence of citric acid addition on VD2 stability
Chewable tablets were prepared according to the method of example 1 with the addition amounts of citric acid set to 5g, 9g, 13g, 17g, 21g, and 25g, and the results of the stability acceleration test were shown in table 2 below.
TABLE 2 Effect of citric acid addition on VD2 content stability (μ g/tablet)
Adding amount of 0 month 1 month 2 month 3 month 4 month Month 5 6 month
5g 61.5 57.8 54.7 52.6 51.1 49.7 48.9
9g 67.2 65.3 63.4 61.7 59.8 56.0 55.4
13g 64.7 64.1 62.7 61.5 60.9 60.0 59.4
17g 62.8 61.7 60.2 59.4 59.0 58.3 58.1
21g 61.1 60.3 58.9 58.0 57.1 56.9 56.2
25g 66.5 65.3 63.9 62.4 61.3 60.2 58.5
From the results, the VD2 content stability is better when the citric acid addition amount is 13-21g, and the stability of VD2 is not good when the pH value is too high or too low. And the bitter taste of the medicine can be covered by adding citric acid, and the taste of the chewable tablet is improved.
3. Effect of sweetener classes on VD2 stability
The sweeteners were aspartame, stevioside, saccharin sodium, acesulfame potassium, and sucralose, respectively, and the amounts added were all 0.6g, and chewable tablets were prepared by the method of example 1, and the results of the stability acceleration test were performed by the above method, and are shown in table 3 below.
TABLE 3 Effect of sweetener types on VD2 content stability (. mu.g/tablet)
Sweetening agent 0 month 1 month 2 month 3 month 4 month Month 5 6 month
A SiSweet of rice 63.6 60.2 55.4 51.7 48.3 45.2 42.7
Protein sugar 65.7 59.1 54.7 50.3 45.4 39.8 36.8
Stevioside 68.2 65.6 61.2 57.7 52.4 48.9 45.6
Saccharin sodium salt 62.5 58.4 56.1 53.3 51.2 49.6 48.1
Acesulfame potassium 64.4 61.7 57.3 52.2 49.8 46.0 43.3
Sucralose 62.8 61.7 60.2 59.4 59.0 58.3 58.1
From the above results, it can be seen that aspartame, stevioside, saccharin sodium and acesulfame potassium all seriously damage the stability of VD2, while VD2 has better stability when sucralose is used.

Claims (1)

1. A preparation method of Longmu bone strengthening chewable tablets is characterized by comprising the following steps:
1) clathrating vitamin D2 with beta-cyclodextrin to obtain vitamin D2 clathrate;
2) decocting radix Codonopsis, radix astragali, radix Ophiopogonis, carapax et Plastrum Testudinis, Atractylodis rhizoma, rhizoma Dioscoreae, fructus Schisandrae chinensis, Os Draconis, Concha Ostreae, Poria, fructus Jujubae, Glycyrrhrizae radix, and endothelium corneum Gigeriae Galli in water, concentrating the extractive solution to relative density of 1.05-1.15, cooling, adding ethanol to ethanol content of 50-80%, standing, collecting supernatant, recovering ethanol under reduced pressure, and concentrating to obtain extract with relative density of 1.2-1.3;
3) mixing the extract with vitamin D2 clathrate, calcium lactate, calcium gluconate, lactose, citric acid, and sucralose, and spray granulating under the conditions of: the material temperature is 50-70 ℃, the spraying speed is 20-50ml/min, and the atomizing pressure is 0.3-0.5 Mpa;
4) adding magnesium stearate and essence into the granules, mixing uniformly, tabletting,
the weight parts of the raw materials are as follows:
codonopsis pilosula 225 parts, astragalus root 112.5 parts and ophiopogon root 225 parts
67.5 parts of tortoise shell, 135 parts of bighead atractylodes rhizome and 270 parts of Chinese yam
Fructus Schisandrae 135 parts Os Draconis 67.5 parts Concha Ostreae 67.5 parts
Poria cocos 225 parts, Chinese date 112.5 parts, licorice root 67.5 parts
Endothelium corneum gigeriae galli 112.5 parts calcium lactate 333.3 parts calcium gluconate 101.2 parts
Vitamin D20.06 parts of beta-cyclodextrin 1.8 parts of lactose 700 parts
Citric acid 17 parts of sucralose 0.6 part.
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Publication number Priority date Publication date Assignee Title
CN102688307A (en) * 2012-06-14 2012-09-26 山东阿如拉药物研究开发有限公司 Chinese medicine composition Xueshan Weibao chewable tablet and preparation method thereof
CN103550630A (en) * 2013-11-08 2014-02-05 山东阿如拉药物研究开发有限公司 Medlar thirst-eliminating chewable tablet as well as preparation method and application thereof
CN104147344A (en) * 2014-07-23 2014-11-19 武汉健民药业集团股份有限公司 Preparation method of Longmu Zhuanggu granule

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CN102688307A (en) * 2012-06-14 2012-09-26 山东阿如拉药物研究开发有限公司 Chinese medicine composition Xueshan Weibao chewable tablet and preparation method thereof
CN103550630A (en) * 2013-11-08 2014-02-05 山东阿如拉药物研究开发有限公司 Medlar thirst-eliminating chewable tablet as well as preparation method and application thereof
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