CN100475214C - Medicine composite contg. Moxabilli and antioxidant - Google Patents
Medicine composite contg. Moxabilli and antioxidant Download PDFInfo
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- CN100475214C CN100475214C CNB2005100901460A CN200510090146A CN100475214C CN 100475214 C CN100475214 C CN 100475214C CN B2005100901460 A CNB2005100901460 A CN B2005100901460A CN 200510090146 A CN200510090146 A CN 200510090146A CN 100475214 C CN100475214 C CN 100475214C
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Abstract
A composite medicine with high stability contains mosapride and the antioxidant, especially the free oxygen radical remover type antioxidant, for suppressing the degradation of mosapride.
Description
Technical field
The invention belongs to drug preparation technique.
Background technology
Mosapride citrate (Mosapride Citrate) is novel third generation medicine for stomach dynamic, is mainly used in treatment esophageal reflux disease.This medicine can strengthen gastrointestinal motility, but does not influence gastric acid secretion, do not have side effect such as The extrapyramidal symptoms and diarrhoea simultaneously, and toleration is good.
Along with people's improving constantly to drug quality consciousness, the untoward reaction of finding a lot of medicines is relevant with the related substance that medicine is degraded, therefore note the degraded of medicine, reduce the content of related substance, be an importance that improves drug quality, have great importance for patient's drug safety.Mosapride citrate stability is relatively poor relatively, contains amido link in the molecular structure, and hydrolysis very easily takes place in aqueous solution.In solid preparation, owing to there is not the existence of moisture, the probability of mosapride hydrolysis does not exist, and we often find have the degradation reaction product to occur by high-efficient liquid phase chromatogram technology in formulation development, and content descends, and related substance increases.Medicine mechanism of degradation complexity under the room temperature natural conditions is various, and the mechanism of degradation of mosapride is not had a lot of research, can't learn that in the prior art mosapride can degrade because of oxidation in pharmaceutical preparation.
The dosage form of mosapride citrate mainly contains tablet on the medical market at present.Application number is that 01133743.5 Chinese patent discloses a kind of pharmaceutical purpose prescription that is suitable for being equipped with the wet granule compression tablet legal system mosapride citrate of dispersible tablet, wherein except that containing the active component mosapride citrate, also contain disintegrating agent, diluent, lubricant, fluidizer, binding agent, this prescription is applicable to the preparation dispersible tablets, but can't be applied to other dosage forms.The production cost of dispersible tablet is compared obviously higher with conventional tablet, do not have tangible competitive advantage, develops a kind of cheaply, and absorbs rapidly, and the mosapride dosage form that bioavailability is high is the target that pharmaceutical manufacturer is pursued, and also meets the interests of extensive patients.
Summary of the invention
The invention provides a kind of pharmaceutical preparation that contains mosapride and antioxidant, have the high characteristics of stability, overcome mosapride poor stability in preparation, degraded easily, related substance is checked underproof phenomenon, has improved the quality of medicine.
We find its less stable in preparation in the research and development process of mosapride, often have related substance and check defective.We change the condition of pharmaceutical preparation accelerated test, for example conditions such as light, oxygen, humidity and temperature through appropriate design, through repeatedly groping property test, find that the degraded of mosapride is quickened greatly under aerobic conditions, and under oxygen free condition, mosapride stable higher.Our these result of the tests show that fully mosapride citrate can be degraded because of oxidation.This is our creationary contrived experiment and the result who constantly gropes resulting relevant mosapride citrate degradation mechanism.
According to the result of study of front, we have done further research, and in further testing, we find to add the degraded that a certain amount of antioxidant can effectively prevent mosapride under aerobic conditions.We find that by a large amount of screening tests all antioxidant all has certain inhibitory action to the degraded of mosapride, but oxygen free radical scavenger (blocker) kind antioxidant best results.Other antioxidant is preventing that as Reducing agent, collaborative antioxidant, chelating agent etc. the effect aspect the mosapride oxidative degradation is poorer slightly than blocker, but still good stablizing effect is being arranged.
We are prepared into compositions with mosapride citrate and various antioxidant with the pharmaceutic adjuvant of using always, by the method for accelerated test, have screened the antioxidant effect of various antioxidants to mosapride citrate, and The selection result is as follows:
Oxygen free radical scavenger kind antioxidant effect has ascorbyl palmitate, alpha-tocopherol, α-tocopheryl acetate, toluene di-tert-butyl phenol (BHT), the tert-butyl group preferably to hydroxyl methoxybenzene (BHA), glycine, glutathion, lecithin, hydroquinone, Oleum thymi vulgaris.
Reducing agent class effect has dithioglycollic acid preferably, the D-xylose, xylitol, sodium formaldehyde sulphoxylate, gentisic acid ethanolamine, two Semen Myristicae PHOSPHATIDYL ETHANOLAMINE, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, two English PHOSPHATIDYL ETHANOLAMINE, D-cysteine or its salt, L-cysteine or its salt, DL-cysteine or its salt, methionine or its salt, thioglycerol, THIOGLYCOL, dithioglycerol, dithiooxamide, the sulfo-sorbic acid, thioglucose, sodium thiosulfate, thiourea, allylthiourea, ascorbic acid, the ester of ascorbic acid or salt, arabo-ascorbic acid or its salt, hypophosphorous acid or its salt, Metaphosphoric acid or its salt, sulfurous acid or its salt, bisulfites, pyrosulfite, low pressure sulfate, gallic acid or its ester, polyacrylic acid or its salt, polymetaphosphate.
Collaborative antioxidant class effect has the ester of malic acid, citric acid, citric acid or salt, pyridoxine or its salt, pyridoxamine or its salt, tartaric acid or its salt, oxine or its salt, sulphuric acid Oxoquinoline, succinic acid or its salt, Gardenia Yellow preferably.
The chelating agent effect has ethylenediaminetetraacetic acid (EDTA), disodium EDTA (EDTA-2Na), calcium disodium edathamil salt (EDTA-Na preferably
2Ca), diethyl triamine five acetic acid, dimercaptopropanol, BAL, TGA or its salt, 3-mercaptopropionic acid or its salt, 2 mercaptopropionic acid or its salt, dimercaptosuccinic acid or its salt, mercapto-propionyl-glycin, thio-2 acid.
Our part experimental preparation prescription and employed antioxidant are disclosed below, but the present invention the antioxidant kind that can use be not limited to the disclosed antioxidant kind of following embodiment scope.The mosapride citrate dosage form that contains antioxidant that following embodiment provided, not only medicine stability is good, and stripping is good, and oral absorption is rapid, the bioavailability height.
The specific embodiment
Embodiment 1
Citrate mosapride pill
| Mosapride citrate | 20.0g |
| PEG4000 | 480.0g |
| Di-t-butyl cresols (BHT) | 5.0g |
Preparation technology: take by weighing mosapride citrate raw material and di-t-butyl cresols (BHT) that recipe quantity is crossed 100 mesh sieves, add and in water-bath, in the mixed liquor that contains recipe quantity PEG4000 of heating and melting, fully stir, make it mixing, pack in the drop bottle, in following system of 95 ± 2 ℃ conditions; Splash in the glass condensation column of the methyl-silicone oil that fills 4-6 ℃, take out after the molding, inhale with absorbent paper and remove adherent methyl-silicone oil, promptly.
Embodiment 2
Citrate mosapride pill
| Mosapride citrate | 10.0g |
| PEG6000 | 500.0g |
| PEG2000 | 200.0g |
| To hydroxyl tert-butyl group methoxybenzene (BHA) | 10g |
Preparation technology: with embodiment 1.
Embodiment 3
Citrate mosapride pill
| Mosapride citrate | 20.0g |
| PEG4000 | 480.0g |
| Vitamin E (alpha-tocopherol) | 20mg |
Preparation technology: with embodiment 1.
Embodiment 4
Citrate mosapride pill
| Mosapride citrate | 50.0g |
| PEG2000 | 200.0g |
| PEG10000 | 100.0g |
| Cysteine | 5mg |
Preparation technology: with embodiment 1.
Embodiment 5
Citrate mosapride pill
| Mosapride citrate | 20.0g |
| PEG4000 | 480.0g |
| Sodium sulfite | 20g |
Preparation technology: with embodiment 1.
Embodiment 6
The mosapride citrate dispersible tablet
| Mosapride citrate | 20.0g |
| Crospolyvinylpyrrolidone | 80g |
| Microcrystalline Cellulose | 110g |
| Vitamin C (ascorbic acid) | 500mg |
| 5％PVP K30Ethanol solution | In right amount |
| Magnesium stearate | 3g |
Preparation technology:
Principal agent is crossed 100 mesh sieves, and other adjuvants are crossed 80 mesh sieves, takes by weighing the principal agent of recipe quantity and vitamin C, crospolyvinylpyrrolidone and the microcrystalline Cellulose of recipe quantity, and fully mixing adds 5%PVP
K30Ethanol solution is granulated, oven dry, and the micropowder silica gel of adding recipe quantity, mixing, tabletting, promptly.
Embodiment 7
The mosapride citrate sheet
Mosapride citrate 6g
Sodium carboxymethyl cellulose 10g
Lactose 100g
Starch 20g
Ascorbyl palmitate 2.0g
The 10%PVPk30 alcoholic solution is an amount of
Magnesium stearate 2g
Preparation technology:
With embodiment 6.
Embodiment 8
Mosapride citrate capsule
Mosapride citrate 20g
Lactose 20g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 18g
Progallin A 20mg
10% starch slurry is an amount of
Preparation technology:
Mosapride citrate, lactose, microcrystalline Cellulose and carboxymethyl starch sodium in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 60 ℃, 18 mesh sieve granulate, capsule charge gets final product.
Embodiment 9
The mosapride citrate sheet
Mosapride citrate 6g
Sodium carboxymethyl cellulose 10g
Lactose 100g
Starch 20g
Sodium pyrosulfite 30g
EDTA-2Na 100mg
The 10%PVPk30 aqueous solution is an amount of
Magnesium stearate 1g
Preparation technology:
With embodiment 6.
The preparation that contains mosapride that the foregoing description is prepared, after room temperature kept sample 2 years, to the determination of related substances that all preparations are degraded, the result was as follows:
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 |
| 0.65％ | 0.55％ | 0.51％ | 0.60％ | 0.81％ | 0.79％ | 0.68％ | 0.77％ | 0.63％ |
Pharmaceutical preparation prescription recited above is equipped with the contrast that does not contain antioxidant, and after the room temperature through 2 years kept sample, the related substance of mensuration was all above 2.5%.
Claims (3)
1. pharmaceutical composition that is used for the treatment of gastric dynamic dysfunction is characterized in that it contains mosapride citrate and one or more oxygen free radical scavenger or Reducing agent.
2. pharmaceutical composition as claimed in claim 1, it is characterized in that oxygen free radical scavenger comprises that ascorbyl palmitate, alpha-tocopherol, α-tocopheryl acetate, toluene di-tert-butyl phenol, the tert-butyl group are to hydroxyl methoxybenzene, glycine, glutathion, lecithin, hydroquinone, Oleum thymi vulgaris.
3. pharmaceutical composition as claimed in claim 1 is characterized in that Reducing agent comprises dithioglycollic acid, the D-xylose, xylitol, sodium formaldehyde sulphoxylate, gentisic acid ethanolamine, two Semen Myristicae PHOSPHATIDYL ETHANOLAMINE, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, two English PHOSPHATIDYL ETHANOLAMINE, D-cysteine or its salt, L-cysteine or its salt, DL-cysteine or its salt, methionine or its salt, thioglycerol, THIOGLYCOL, dithioglycerol, dithiooxamide, the sulfo-sorbic acid, thioglucose, sodium thiosulfate, thiourea, allylthiourea, ascorbic acid, the ester of ascorbic acid or salt, arabo-ascorbic acid or its salt, hypophosphorous acid or its salt, Metaphosphoric acid or its salt, sulfurous acid or its salt, bisulfites, pyrosulfite, low pressure sulfate, gallic acid or its ester, polyacrylic acid or its salt, polymetaphosphate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100901460A CN100475214C (en) | 2005-08-11 | 2005-08-11 | Medicine composite contg. Moxabilli and antioxidant |
| HK07107403.9A HK1102918A1 (en) | 2005-08-11 | 2007-07-10 | A pharmaceutical composition comprising mosapride and antioxidant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100901460A CN100475214C (en) | 2005-08-11 | 2005-08-11 | Medicine composite contg. Moxabilli and antioxidant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1911233A CN1911233A (en) | 2007-02-14 |
| CN100475214C true CN100475214C (en) | 2009-04-08 |
Family
ID=37720397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100901460A Active CN100475214C (en) | 2005-08-11 | 2005-08-11 | Medicine composite contg. Moxabilli and antioxidant |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100475214C (en) |
| HK (1) | HK1102918A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101273973B (en) * | 2007-03-28 | 2010-04-07 | 成都康弘药业集团股份有限公司 | Pharmaceutical combination containing Mosapride citrate |
| CN101756945B (en) * | 2008-12-24 | 2012-06-27 | 鲁南制药集团股份有限公司 | Citrate mosapride pill |
| CN107260735A (en) * | 2017-07-25 | 2017-10-20 | 合肥华方医药科技有限公司 | The Dihydropyridines drugs composition that bioavilability is improved |
| CN107308158A (en) * | 2017-07-28 | 2017-11-03 | 合肥华方医药科技有限公司 | A kind of pharmaceutical composition for improving felodipine bioavilability |
| CN107308159A (en) * | 2017-07-28 | 2017-11-03 | 合肥华方医药科技有限公司 | One kind improves isradipine bioavilability pharmaceutical composition |
| CN109745293B (en) * | 2017-11-08 | 2021-09-07 | 成都康弘药业集团股份有限公司 | Pharmaceutical composition containing mosapride citrate |
| CN114315750B (en) * | 2020-09-29 | 2024-05-10 | 鲁南制药集团股份有限公司 | Mosapride-succinic acid eutectic crystal |
| CN114560822B (en) * | 2020-11-27 | 2024-05-28 | 鲁南制药集团股份有限公司 | Mosapride dicarboxylic acid crystal |
-
2005
- 2005-08-11 CN CNB2005100901460A patent/CN100475214C/en active Active
-
2007
- 2007-07-10 HK HK07107403.9A patent/HK1102918A1/en not_active IP Right Cessation
Non-Patent Citations (6)
| Title |
|---|
| 枸橼酸莫沙必利分散片溶出度的考察. 刘戟等.华西医学杂志，第19卷第3期. 2004 |
| 枸橼酸莫沙必利分散片溶出度的考察. 刘戟等.华西医学杂志，第19卷第3期. 2004 * |
| 枸橼酸莫沙必利及其制剂的HPLC测定. 邵泓.中国药学杂志，第37卷第5期. 2002 |
| 枸橼酸莫沙必利及其制剂的HPLC测定. 邵泓.中国药学杂志，第37卷第5期. 2002 * |
| 枸橼酸莫沙必利有关杂质的研究. 刘文华等.中国药科大学学报，第32卷第2期. 2001 |
| 枸橼酸莫沙必利有关杂质的研究. 刘文华等.中国药科大学学报，第32卷第2期. 2001 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1911233A (en) | 2007-02-14 |
| HK1102918A1 (en) | 2007-12-07 |
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