CN118078745A - Preparation method of metformin hydrochloride oral solution - Google Patents
Preparation method of metformin hydrochloride oral solution Download PDFInfo
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- CN118078745A CN118078745A CN202410408602.4A CN202410408602A CN118078745A CN 118078745 A CN118078745 A CN 118078745A CN 202410408602 A CN202410408602 A CN 202410408602A CN 118078745 A CN118078745 A CN 118078745A
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- metformin hydrochloride
- oral solution
- hydrochloride oral
- purified water
- inulin
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 116
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 110
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 110
- 229940100688 oral solution Drugs 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000008213 purified water Substances 0.000 claims abstract description 38
- 229920001202 Inulin Polymers 0.000 claims abstract description 35
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 claims abstract description 35
- 229940029339 inulin Drugs 0.000 claims abstract description 35
- 238000003756 stirring Methods 0.000 claims abstract description 34
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000003755 preservative agent Substances 0.000 claims abstract description 11
- 230000002335 preservative effect Effects 0.000 claims abstract description 11
- 238000005303 weighing Methods 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000011259 mixed solution Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 238000011049 filling Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 63
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 13
- 235000010234 sodium benzoate Nutrition 0.000 claims description 13
- 239000004299 sodium benzoate Substances 0.000 claims description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000007958 cherry flavor Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
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- 235000019658 bitter taste Nutrition 0.000 abstract description 9
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- 229960003105 metformin Drugs 0.000 abstract description 6
- 230000007547 defect Effects 0.000 abstract description 4
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- 210000004369 blood Anatomy 0.000 description 8
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- MQRKKLAGBPVXCD-UHFFFAOYSA-L calcium;1,1-dioxo-1,2-benzothiazol-2-id-3-one;hydrate Chemical compound O.[Ca+2].C1=CC=C2C([O-])=NS(=O)(=O)C2=C1.C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 MQRKKLAGBPVXCD-UHFFFAOYSA-L 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 229940043243 saccharin calcium Drugs 0.000 description 8
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- 241000167854 Bourreria succulenta Species 0.000 description 7
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- 229960003885 sodium benzoate Drugs 0.000 description 5
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- 241000699670 Mus sp. Species 0.000 description 4
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- 230000001603 reducing effect Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
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- 208000019505 Deglutition disease Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation method of metformin hydrochloride oral solution, belonging to the technical field of pharmaceutical preparations. The method comprises the following steps: weighing purified water accounting for 50% of the total mass of the metformin hydrochloride oral solution, heating to 40-50 ℃, sequentially adding preservative and metformin hydrochloride into the purified water, mixing and stirring until the mixture is completely dissolved, sequentially adding inulin and essence, and stirring until the mixture is completely dissolved to obtain a mixed solution; slowly dripping the pH regulator into the mixed solution, continuously stirring until the pH is 4.5-5.8, stopping adding the pH regulator, fixing the volume to 100% by using purified water, filtering and filling to obtain the metformin hydrochloride oral solution. The invention develops the metformin hydrochloride oral solution which can not only improve the defect of the bitter taste of the metformin, but also avoid the use of sweetener with potential safety risk, and has practical application value.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a preparation method of a metformin hydrochloride oral solution for treating diabetes.
Background
With the continuous improvement of living water, people with three highs increase year by year, and the prevalence of diabetes becomes more common due to the increasingly lower ages. People suffering from diabetes mellitus need to strictly control diet in daily life, various complications are prevented, and once the diabetes mellitus is diagnosed, people suffering from diabetes mellitus need to take medicine for life, so that the happiness index of the patients is seriously affected. Therefore, the hypoglycemic agent is safe and effective, and convenient to use, and can bring a lot of comfort to patient groups.
Biguanide hypoglycemic agents are one of the most commonly used hypoglycemic agents on the market at present, wherein the most common and widely used is metformin hydrochloride, which can promote anaerobic glycolysis of sugar, increase uptake of glucose by peripheral tissues such as muscles and fat, increase insulin-mediated glucose utilization and treat non-insulin-dependent diabetes. The metformin hydrochloride is developed and produced by foreign pharmaceutical enterprises, and related dosage forms of the metformin hydrochloride which are currently marketed in China mainly comprise solid preparations such as capsules and tablets, and the solid preparations have certain limitations on medication compliance of patients or children with dysphagia and the like. The metformin hydrochloride oral solution is currently produced by foreign pharmaceutical company Sun Pharmaceut ica l I ndustr ies Ltd, and the product name of the metformin hydrochloride oral solution produced by the company isThe product is marketed in the United kingdom and Germany, but is not introduced into China at present. Because the metformin is bitter in taste, the bitter taste of the metformin is required to be modified when the oral preparation is prepared, the foreign metformin hydrochloride is mainly prepared by adding medicinal auxiliary materials of saccharin calcium, and the saccharin calcium is taken as one of sweetening agents, so that the sweetness is extremely high, and the bitter taste of the metformin can be well covered. However, saccharin calcium has proven to be a potential carcinogenic risk and is not suitable for domestic children.
Therefore, the prior art has the defect of saccharin calcium which is an auxiliary material for the traditional Chinese medicine of the metformin hydrochloride oral solution, and the adopted improvement means mainly comprises: (1) Patent CN1695602a discloses a "metformin hydrochloride oral solution and a preparation method thereof", in the invention, saccharin calcium is replaced by other sweeteners with safety performance "steviosin", so as to obtain a metformin hydrochloride oral solution with better taste; (2) Patent CN117281771a discloses a "metformin hydrochloride oral solution and its preparation method", in the invention, the sweetener mainly adopts xylitol with higher safety, then adds very low amount of saccharin calcium, and combines the use of essence, and under the condition of ensuring the reduction of the dosage of saccharin calcium, the taste and bitter taste of metformin are developed.
The sweetener is used as a medicinal auxiliary material and has the effect of improving poor mouthfeel of the medicament, but reduces the use of unnecessary auxiliary materials in the preparation process of the medicament, thereby being beneficial to improving the safety of the medicament. Therefore, development of the metformin hydrochloride oral solution which can improve the defect of the bitter taste of the metformin and avoid the use of sweeteners with potential safety risks has practical application value.
Disclosure of Invention
According to the defects of the prior art, the invention aims to solve the problems in the background art by introducing the water-soluble plant polysaccharide inulin with the blood sugar reducing effect into the metformin hydrochloride oral solution. Specifically, the technical scheme of the invention comprises the following contents:
an oral solution of metformin hydrochloride comprises the following raw materials:
100mg/ml of metformin hydrochloride, 2-5 mg/ml of preservative, 180-200 mg/ml of inulin and 4-5 mg/ml of essence.
Further, the preservative comprises sodium benzoate, sodium bicarbonate or potassium bicarbonate.
Further, the flavor comprises cherry flavor.
Preferably, the metformin hydrochloride oral solution comprises the following raw materials in parts by weight:
100mg/ml metformin hydrochloride, 2mg/ml preservative, 180mg/ml inulin and 5mg/ml essence.
Further, the pH value of the metformin hydrochloride oral solution is 4.5-5.8.
A method for preparing a metformin hydrochloride oral solution, comprising the following steps:
Weighing purified water accounting for 50% of the total mass of the metformin hydrochloride oral solution, heating to 40-50 ℃, sequentially adding preservative and metformin hydrochloride into the purified water, mixing and stirring until the mixture is completely dissolved, sequentially adding inulin and essence, and stirring until the mixture is completely dissolved to obtain a mixed solution;
Slowly dripping the pH regulator into the mixed solution, continuously stirring until the pH is 4.5-5.8, stopping adding the pH regulator, fixing the volume to 100% by using purified water, filtering and filling to obtain the metformin hydrochloride oral solution.
Further, the pH adjuster includes hydrochloric acid.
Further, the stirring rotation speed in the preparation process comprises 100-200 r/min.
Further, the use mode of the pH regulator can be as follows: the total amount of the pH regulator used for regulating the pH is added twice, the first time is used before inulin is added, and the second time is added during regulating the pH value, so that the mixed solution is more stable.
Compared with the prior art, the invention has the following beneficial effects:
(1) According to the invention, the water-soluble plant polysaccharide inulin with the function of reducing blood sugar is mixed with the metformin hydrochloride to prepare the metformin hydrochloride oral solution, and the taste of the metformin hydrochloride is modified by the inulin, so that the characteristic of the metformin hydrochloride taste is improved under the condition that a sweetener is not used, and compared with the existing technology, the method adopts the sweetener saccharin calcium with potential safety threat in extremely low dosage and adopts other sweeteners, the method avoids the use of unnecessary pharmaceutical auxiliary materials, and is beneficial to improving the safety of the metformin hydrochloride oral solution.
(2) According to the invention, inulin and metformin hydrochloride are combined, so that on one hand, the bitter taste of metformin hydrochloride is improved, and on the other hand, the metformin hydrochloride oral solution has a better hypoglycemic effect under the condition that the total administration dosage of the metformin hydrochloride oral solution is consistent with that of the oral solution only containing metformin hydrochloride.
(3) The pH of the metformin hydrochloride oral solution is between 4.5 and 5.8, and the metformin hydrochloride oral solution has good stability, widens the pH value adjusting range of the metformin hydrochloride oral solution, and reduces the probability of exceeding the final pH value range caused by excessive addition during small-range pH value adjustment.
(4) Surprisingly, when the inulin is used for modifying the bitterness of the metformin hydrochloride, the metformin hydrochloride oral solution prepared by the method has lower impurity content, especially the impurity dicyandiamide content, than the conventional metformin hydrochloride oral solution when being subjected to impurity analysis and examination, and the inulin also has the advantages of stabilizing the metformin hydrochloride and reducing the decomposition of the metformin hydrochloride.
(5) The cosolvent of the covalent crosslinking system has a certain promoting effect on improving the bitter taste and stability of the metformin hydrochloride.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below by means of embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the present invention are commercially available or may be prepared by known methods.
Example 1:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 40 ℃, sequentially adding 2g of sodium benzoate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 100r/min until the solid is completely dissolved, then adding 100g of inulin and 1g of cherry essence, keeping the rotating speed of 100r/min for continuous stirring until the whole solid is dissolved, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding the purified water again to a constant volume of 1000ml, and then filtering and encapsulating the solution with the constant volume to obtain the metformin hydrochloride oral solution.
Example 2:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 42 ℃, sequentially adding 3g of sodium bicarbonate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 120r/min until the solid is completely dissolved, then adding 120g of inulin and 2g of cherry essence, keeping stirring at the rotating speed of 120r/min until the solid is completely dissolved, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding purified water again to a volume of 1000ml, and then filtering and encapsulating the solution with a fixed volume to obtain the metformin hydrochloride oral solution.
Example 3:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 44 ℃, sequentially adding 2g of sodium bicarbonate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 140r/min until the solid is completely dissolved, then adding 140g of inulin and 3g of cherry essence, keeping the rotating speed of 140r/min, continuously stirring until the whole solution is dissolved, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding the purified water again to a constant volume of 1000ml, and then filtering and encapsulating the solution with the constant volume to obtain the metformin hydrochloride oral solution.
Example 4:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 46 ℃, sequentially adding 4g of potassium bicarbonate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 160r/min until the solid is completely dissolved, then adding 160g of inulin and 4g of cherry essence, keeping stirring at the rotating speed of 160r/min until the solid is completely dissolved, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding purified water again to a constant volume of 1000ml, and then filtering and encapsulating the solution with the constant volume to obtain the metformin hydrochloride oral solution.
Example 5:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 48 ℃, sequentially adding 2g of sodium benzoate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 180r/min until the solid is completely dissolved, then adding 180g of inulin and 5g of cherry essence, keeping stirring at a rotating speed of 180r/min until the solid is completely dissolved, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding purified water again to a volume of 1000ml, and then filtering and encapsulating the solution with a fixed volume to obtain the metformin hydrochloride oral solution.
Example 6:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 50 ℃, sequentially adding 5g of sodium benzoate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 200r/min until the solid is completely dissolved, then adding 200g of inulin and 4g of cherry essence, keeping stirring at a rotating speed of 200r/min until the solid is completely dissolved, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding purified water again to a volume of 1000ml, and then filtering and encapsulating the solution with a fixed volume to obtain the metformin hydrochloride oral solution.
Example 7:
the preparation method of the metformin hydrochloride oral solution specifically comprises the following steps:
Weighing 500ml of purified water, heating to 50 ℃, sequentially adding 5g of sodium benzoate and 100g of metformin hydrochloride for mixing, stirring and dissolving at a rotating speed of 200r/min until the solid is completely dissolved, then adding 200g of inulin and 4g of cherry essence, and keeping stirring at a rotating speed of 200r/min until the solid is completely dissolved; weighing 5g of anionic polymer compound sodium carboxymethyl cellulose, stirring and dissolving with 20g of deionized water, adding 5g of water-soluble polyhydroxy glycerol and 5g of water-soluble polyhydroxy Arabic, mixing, heating to 35 ℃ and stirring for reacting for 4 hours to obtain a covalent cross-linking cosolvent, mixing 10g of cosolvent with a system consisting of metformin hydrochloride and inulin, slowly dropwise adding hydrochloric acid while stirring, stopping adding hydrochloric acid when the pH value of the solution is 4.5, adding purified water again to reach 1000ml, and filtering and encapsulating the solution with the fixed volume to obtain the metformin hydrochloride oral solution.
The metformin hydrochloride oral solutions of examples 1 to 7 were subjected to nasal and taste trials and the statistical data are as follows:
In the table, "×" indicates that both nasal and nasal smell are poor and "v" indicates that nasal and nasal smell are good and no bitter taste is present.
From the results, when the addition amount of inulin is 180-200 mg/ml, essence is 4-5 mg/ml and preservative is 2-5 mg/ml, the metformin hydrochloride oral solution has good taste, and when the addition amount of inulin is 180mg/ml, essence is 5mg/ml and preservative is 2mg/ml, the effect is best;
When inulin is further increased, the bitter modification effect of the metformin hydrochloride oral solution is slightly insufficient, but a certain amount of cosolvent modified by crosslinking is added, so that the metformin hydrochloride oral solution also has good mouthfeel.
The metformin hydrochloride oral solution of example 5 was adjusted to six groups of pH 4.2, 4.5, 4.8, 5.2, 5.5 and 5.8 with hydrochloric acid and sodium bicarbonate, respectively, and then co-placed at 60±2 ℃ for 10 days, and the properties, contents and related substances were examined, and the results are shown in the following table:
As can be seen from the table, after the metformin hydrochloride oral solution with the pH ranging from 4.5 to 5.8 is treated for 10 days at the high temperature of 60+/-2 ℃, the impurities are not changed obviously, and the solution is relatively stable.
Study of the effect of the order of addition of the formulations on the stability of metformin hydrochloride oral solutions:
Study object is example 5:
test example 1:
Material addition sequence: purified water, sodium benzoate, metformin hydrochloride, inulin, essence, hydrochloric acid for adjusting pH and purified water for constant volume.
Test example 2:
material addition sequence: purified water, inulin+essence, sodium benzoate+metformin hydrochloride, pH adjustment by hydrochloric acid, and constant volume of purified water.
Test example 3:
Material addition sequence: purified water, 10% of total amount of sodium benzoate, metformin hydrochloride and hydrochloric acid, inulin, essence, 90% of total amount of hydrochloric acid, pH adjustment and constant volume of purified water.
Test example 4:
material addition sequence: purified water, sodium benzoate, metformin hydrochloride and 30% of the total amount of hydrochloric acid, inulin, essence, 70% of the total amount of hydrochloric acid, pH adjustment and purified water volume fixation.
Test example 5:
Material addition sequence: purified water, 50% of total amount of sodium benzoate, metformin hydrochloride and hydrochloric acid, inulin, essence, 50% of total amount of hydrochloric acid, pH adjustment and constant volume of purified water.
Study of the effect of the order of addition of the formulations on the stability of metformin hydrochloride oral solutions:
Study object is example 7:
test example 6:
Material addition sequence: purified water, 70% +10g cosolvent of total amount of sodium benzoate, metformin hydrochloride and hydrochloric acid, inulin and essence, pH adjustment of 30% of total amount of hydrochloric acid, and constant volume of purified water.
Test example 7:
Material addition sequence: purified water, 90% +10g cosolvent of total amount of sodium benzoate, metformin hydrochloride and hydrochloric acid, inulin and essence, pH adjustment of 10% of total amount of hydrochloric acid, and constant volume of purified water.
Test examples 1 to 7 were observed for dissolution of metformin hydrochloride oral solutions, and the results are shown in the following table:
As can be seen from the data in the table, the total amount of hydrochloric acid for adjusting the pH is batched, and hydrochloric acid is added once before inulin is added, so that the dissolution of the mixed solution and the dissolution state of the final metformin hydrochloride oral solution are helped to be stable and uniform;
by adding the covalent crosslinking cosolvent, the crosslinking system is helpful for preventing the aggregation of inulin, so that the uniform and stable dispersion of the prepared metformin hydrochloride oral solution is realized.
Mouse experiment:
10 normal mice were taken and normally bred as a normal group. Diabetic mice (criterion of diabetic mice: fasting blood glucose: 11.1 mmoL/L) were divided into experimental groups 1, 2, 3 and 4, 10 each, and administered at a dose of 0.3g/kg, and were orally administered to the stomach once daily, wherein the experimental group 1 was fed with the metformin hydrochloride oral solution prepared in example 5, the experimental group 2 was fed with the metformin hydrochloride oral solution prepared in example 7, and the experimental group 3 was fed with the metformin hydrochloride oral solution produced in pharmaceutical company Sun Pharmaceut i ca L I ndustr i es Ltd Experimental group 4 served as a positive control, fed an equal amount of purified water. Fasting blood glucose, body weight and serum insulin were measured after 14 days and the results are shown below:
The results showed that diabetic mice in experimental groups 1,2 and 3 all had significantly lower fasting blood glucose and significantly higher serum insulin and body weight than experimental group 4 (positive control), indicating that both groups of drugs were effective in controlling blood glucose. Compared with the experimental group 3, the fasting blood glucose of the experimental group 1 and the experimental group 2 is lower, the weight control is better, and the serum insulin content is higher, so that the melbine hydrochloride oral solution has better blood glucose reducing effect under the same administration dosage.
The metformin hydrochloride oral solution of example 5 and example 7 was prepared by pharmaceutical company Sun Pharmaceut i ca l I ndustr i es LtdSample detection analysis was performed and the results are shown in the following table:
as can be seen from the data in the table, inulin in the metformin hydrochloride oral solution can improve the stability of metformin hydrochloride and reduce impurity degradation;
The covalent crosslinking system can prevent aggregation or sedimentation of drug particles, and the formed stable covalent crosslinking network structure can prevent adverse reactions between drug molecules and oxygen and the like, so that the stability of the metformin hydrochloride is further improved.
The foregoing embodiments have described the technical solutions and advantageous effects of the present invention in detail, and it should be understood that the foregoing embodiments are merely specific examples of the present invention and are not intended to limit the present invention. The present invention is subject to various changes and modifications without departing from the spirit and scope thereof, and such changes and modifications fall within the scope of the invention as hereinafter claimed.
Claims (9)
1. The metformin hydrochloride oral solution is characterized by comprising the following raw materials:
100mg/ml of metformin hydrochloride, 2-5 mg/ml of preservative, 180-200 mg/ml of inulin and 4-5 mg/ml of essence.
2. The metformin hydrochloride oral solution of claim 1, wherein the preservative comprises sodium benzoate, sodium bicarbonate or potassium bicarbonate.
3. The metformin hydrochloride oral solution according to claim 1, wherein the flavor comprises cherry flavor.
4. The metformin hydrochloride oral solution according to claim 1, which is characterized by comprising the following raw materials in parts by weight:
100mg/ml metformin hydrochloride, 2mg/ml preservative, 180mg/ml inulin and 5mg/ml essence.
5. The metformin hydrochloride oral solution according to claim 1, wherein the pH of the metformin hydrochloride oral solution is 4.5-5.8.
6. A method for preparing the metformin hydrochloride oral solution according to any one of claims 1 to 5, comprising the steps of:
Weighing purified water accounting for 50% of the total mass of the metformin hydrochloride oral solution, heating to 40-50 ℃, sequentially adding preservative and metformin hydrochloride into the purified water, mixing and stirring until the mixture is completely dissolved, sequentially adding inulin and essence, and stirring until the mixture is completely dissolved to obtain a mixed solution;
Slowly dripping the pH regulator into the mixed solution, continuously stirring until the pH is 4.5-5.8, stopping adding the pH regulator, fixing the volume to 100% by using purified water, filtering and filling to obtain the metformin hydrochloride oral solution.
7. The method for preparing an oral solution of metformin hydrochloride according to claim 6, wherein the pH adjuster comprises hydrochloric acid.
8. The method for preparing the metformin hydrochloride oral solution according to claim 6, wherein the stirring rotation speed in the preparation process is 100-200 r/min.
9. Use of the metformin hydrochloride oral solution according to any one of claims 1 to 8 in the preparation of an oral solution for diabetes.
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