CN101313892A - Glipizide calcium alginate gel rubber pellet and preparation method thereof - Google Patents
Glipizide calcium alginate gel rubber pellet and preparation method thereof Download PDFInfo
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- CN101313892A CN101313892A CNA2008100250711A CN200810025071A CN101313892A CN 101313892 A CN101313892 A CN 101313892A CN A2008100250711 A CNA2008100250711 A CN A2008100250711A CN 200810025071 A CN200810025071 A CN 200810025071A CN 101313892 A CN101313892 A CN 101313892A
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Abstract
The invention relates to a glipizide calcium alginate gel micro pill and a preparation method thereof, belonging to the medical technical field. In the method, mixture solution of glipizide and alginic acid sodium salt is prepared, wherein, the glipizide and the alginic acid sodium salt can be mixed and then put into a solvent, or the glipizide is put into a solution of the alginic acid sodium salt solution; the ratio of the alginic to the alginic acid sodium salt is between 10 to 1 and 1 to 10(w/w), and the concentration of the alginic acid sodium salt is between 0.5 and 5.0 percent; the mixture solution is added to a solution of calcium chloride in the condition of stirring, and reacts for 1 minute to 72 hours; products are filtered, taken out, washed and dried to obtain the glipizide calcium alginate gel micro pill. The preparation method adopts a calcium alginate micro pill as carrier, prepares the glipizide calcium alginate gel micro pill by dropping method in one step, has simple process and low cost. The prepared micro pill is not dissolved in artificial gastric juice, thereby reducing the stimulus to stomach; and the micro pill has high entrapment rate and drug-loading rate, releases in artificial intestinal juice slowly, improves the effect of decreasing blood sugar and has good market prospect.
Description
Technical field
The present invention relates to pharmaceutical, be specifically related to treat type ii diabetes medicine Glipizide calcium alginate gel rubber pellet and preparation method.
Background technology
Diabetes have been considered to " killer " of the third-largest harm humans health behind tumor, cardiovascular and cerebrovascular disease in the whole world.At present, the patient of the diabetes that the whole world has been made a definite diagnosis is about 1.5 hundred million, it is predicted will reach 3.0 hundred million in 2025.According to statistics, the sickness rate of diabetes is 3%～5% in the world, and the sickness rate for each person more than 50 years old is 10%.Interrelated data shows that there are more than 3,000 ten thousand diabeticss in China, annual newly-increased 150～2,000,000 patients, and wherein the type ii diabetes patient accounts for more than 90%.According to World Health Organization's recent statistics, there is diabetics 1.25 hundred million in the whole world, and average per minute just has 6 people because of suffering from diabetes death, and the death that diabetes cause has occupied the 5th of world today's cause of death.
Glipizide is a kind of second filial generation sulfonylurea anti-diabetic, and English name is Glipizide, chemistry 5-methyl by name-N-[2-[4-[[[(hexamethylene amino) carbonyl] amino] sulfonyl] phenyl] ethyl]-pyrazinecarboxamide; Molecular formula C
21H
27N
5O
4S; Molecular weight: 445.54; Be white or off-white color crystalline powder, odorless, almost tasteless; Slightly soluble in acetone, chloroform or dioxane, soluble,very slightly in ethanol, almost insoluble in water, easily molten in diluted sodium hydroxide solution; Mp 203-208 ℃, UV225nm; Chemical structural formula is as follows:
Glipizide can promote secretion of insulin, and the potassium channel of ATP-sensitivity on the film capable of inhibiting cell suppresses outward potassium flow, causes the depolarization of cell, causes calcium channel open, and calcium ion is entered in the cell by the extracellular, and insulin secretion is increased; By suppressing the activity of phosphodiesterase, the C-AMP level is increased, resolve into the effect reinforcement of free calcium in the cell in conjunction with calcium, insulin secretion increases; Can also strengthen picked-up and the utilization of peripheral tissues, liver is increased the reaction of insulin, reduce glycogen and generate glucose; Promote the transhipment of glucose in the adipose cell, increase lipogenesis; The activity of bone muscle glycogen synzyme in strengthening makes the synthetic increase of muscle glycogen; Reduce platelet aggregation and stick, blood lipid regulation helps preventing the sclerosis of atherosclerosis and blood capillary.After the glipizide medication in the body nothing obviously accumulate, lessly cause that low blood is half congealed, hypoglycemic effect is obvious.In addition, it also has the serum cholesterol of reduction and triglyceride, improves high density lipoprotein, increases the active characteristics of fibrinolysis, can also improve and reduce diabetes patient's complication in blood fat reducing.
Alginic acid and derivant thereof are hydrophilic colloidal state polysaccharide, be by β-(1,4) D-mannuronic acid (M) and α-(1,4) the linear macromolecular compound of L-guluronic acid (G) composition, contain carboxyl and hydroxyl freely in its molecule, can form the slightly solubility gel with the polyvalent metal ion reaction, as calcium alginate gel, owing to there is the interlaced connection of sodium alginate, alginic acid and 3 kinds of molecular structures of calcium alginate in the gel simultaneously, because adhesion is unbalanced, produce bigger space, can hold a large amount of moisture.By regulating concentration, calcium ion concentration and the water content of sodium alginate, make the slightly solubility gel of generation have swelling pH sensitivity, can be used as slow (control) release formulation carrier of oral drugs.
The disintegrate under one's belt of existing glipizide ordinary preparation, bigger to the zest of stomach, can cause nausea, untoward reaction such as vomiting, anorexia, diarrhoea, simultaneously easily by stomach acids destroy, make curative effect reduce; Though and general enteric coated preparation curative effect obviously is better than ordinary preparation, the formulation and technology relative complex is loaded down with trivial details.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of preparation process simply, significantly to reduce the release of preparation, and then reduce the Glipizide calcium alginate gel rubber pellet of side effect at gastric juice.
Another object of the present invention is to provide a kind of method for preparing above-mentioned Glipizide calcium alginate gel rubber pellet.
The present invention is achieved through the following technical solutions: 10: 1 to 1: 10 (w/w) takes by weighing glipizide and sodium alginate in proportion, and mix homogeneously adds distilled water, stirs, and abundant mixing makes the concentration of sodium alginate between 0.5%～5.0% (w/w); Or, stir, fully mixing in the glipizide adding sodium alginate distilled water solution of corresponding proportion (concentration is between 0.5%～5.0% (w/w)).Above-mentioned mixed liquor is dropwise splashed under stirring condition in the calcium chloride solution of 0.005～1mol/L (volume of calcium chloride solution should be 1 to 100 times of glipizide mixed liquor), react after 1 minute to 72 hours, the glipizide calcium gel microsphere that forms is filtered taking-up, distilled water flushing is clean, oven dry had both got glipizide calcium gel microsphere.
Reaction principle is as follows: all contain carboxyl and hydroxyl freely in the macromole of each alginic acid and derivant thereof, can form gel with multiple metal ion reaction.As sodium alginate being added in the medium of calcium ions, calcium ion will be replaced part hydrion in the sodium alginate macromole and sodium ion and be generated the calcium alginate molecule, and reaction equation is Ca
2++ HALg+NaAlg=Ca (Alg)
2+ H
++ Na
+After the glipizide mixed solution of sodium alginate splashed into calcium chloride solution, calcium alginate parcel glipizide condenses into the pearl ball and immediately in surperficial gelling, state is translucent, along with calcium ion infiltrates, gelling reaction successively takes place in pearl ball inside, and moisture is extruded, the pearl ball shrinks, and volume and weight reduces.In this process, glipizide resides in Jiao Zhuzhong because of its hydrophobic property, and finally forms glipizide calcium alginate micropill.
The invention has the beneficial effects as follows: Glipizide calcium alginate gel rubber pellet of the present invention adopts the natural macromolecular material sodium alginate as carrier material, uses the dropping preparation method one-step shaping, and technology is simple on the one hand, and production cost is low, adapts to the needs of industrialized great production.On the other hand because of the strong-hydrophobicity of glipizide, can make the gel microsphere (and general medicine is difficult to produce this effect) of higher envelop rate and drug loading, this micropill is insoluble in simulated gastric fluid, minimizing is to the stimulation of stomach, in simulated intestinal fluid, dissolve release, and than general enteric coated preparation slow release effect more than eight hours is arranged, improve therapeutic effect, have market prospect preferably.
Description of drawings
Fig. 1 is the cumulative release curve chart of the Glipizide calcium alginate gel rubber pellet of embodiment of the invention preparation.
The specific embodiment
To describe the specific embodiment of the present invention in detail below:
Embodiment 1
Take by weighing calcium chloride 11.1g, dissolved in distilled water is settled to 500ml, and getting concentration is the calcium chloride water of 0.2mol/L.Other gets glipizide 20g and sodium alginate 2g, mix homogeneously, add the 400ml distilled water, stir, it is fully mixed, then mixed liquor speed with 200drop/min under stirring condition is splashed in the above-mentioned calcium chloride solution, react after 1 minute, 80 eye mesh screens filter gel microsphere are taken out, and distilled water flushing is clean, have both got Glipizide calcium alginate gel rubber pellet.
Take by weighing calcium chloride 4.44g, dissolved in distilled water is settled to 200ml, and getting concentration is the calcium chloride water of 0.2mol/L.Other gets glipizide 1g and sodium alginate 2g, mix homogeneously, add the 200ml distilled water, stir, it is fully mixed, then mixed liquor speed with 80drop/min under stirring condition is splashed in the above-mentioned calcium chloride solution, react after 24 hours, 80 eye mesh screens filter gel microsphere are taken out, and distilled water flushing is clean, have both got Glipizide calcium alginate gel rubber pellet.
Embodiment 3
Take by weighing calcium chloride 11.1g, dissolved in distilled water is settled to 1000ml, and getting concentration is the calcium chloride water of 0.1mol/L.Other gets sodium alginate 2g adding 100ml distilled water and gets 2% sodium alginate soln, takes by weighing glipizide 500mg and adds in the above-mentioned sodium alginate soln, stirs, and it is fully mixed; Then this mixed liquor speed with 40drop/min under stirring condition is splashed in the calcium chloride solution, react after 36 hours, 80 eye mesh screens filter gel microsphere are taken out, and distilled water flushing is clean, have both got Glipizide calcium alginate gel rubber pellet.
Take by weighing calcium chloride 1.11g, dissolved in distilled water is settled to 200ml, and getting concentration is the calcium chloride water of 0.05mol/L.Other gets glipizide 400mg and sodium alginate 4g, mix homogeneously, add the 100ml distilled water, stir, it is fully mixed, then this mixed liquor speed with 10drop/min under stirring condition is splashed in the above-mentioned calcium chloride solution, react after 72 hours, 80 eye mesh screens filter gel microsphere are taken out, and distilled water flushing is clean, have both got Glipizide calcium alginate gel rubber pellet.
The assay method of drug loading and envelop rate: the Glipizide calcium alginate gel rubber pellet that takes by weighing the above embodiment preparation of 100mg is put in the 500mL measuring bottle, adds the about 300mL of pH6.8 buffer solution, 80 ℃ of water-bath 30min, put and be chilled to room temperature, ultrasonic 30min dissolves gel microsphere fully, is diluted to scale, shake up, leave standstill,, discard filtrate just through 0.8 μ m cellulose acetate filtering with microporous membrane, get subsequent filtrate and be diluted to 5 μ g/mL, measure absorbance in 275nm wavelength place.According to the standard curve equation, ask the content of calculating the gel microsphere Chinese medicine.
Weight * 100% of drug loading (LC)=(glipizide dose in the total dose-filtrate of the glipizide of input)/micropill wherein;
The total dose of glipizide * 100% of envelop rate (EE)=(glipizide dose in the total dose-filtrate of the glipizide of input)/input.
The drug loading that records above-mentioned glipizide calcium alginate micropill is 61.3 ± 2.3%, and envelop rate is 91.2 ± 5.3%.
Sample release profiles assay method: get 6 parts of the glipizide calcium alginate micropills that prepare in the foregoing description, by 2005 editions appendix XD of pharmacopeia drug release determination method, second method, method 1, operation in accordance with the law, sampling in 2 hours in the simulated gastric fluid; Respectively sampling in 1,2,4,6,8 hour, press sample drug release determination method determination and analysis in the simulated intestinal fluid, calculate glipizide cumulative release percentage rate.With the time point is abscissa, and as vertical coordinate, the cumulative release degree was 100% in 12h hour with each time point glipizide cumulative release percentage rate, draws release profiles.Three batch samples in simulated gastric fluid 2 hours release all less than 2.1%; 8h cumulative release degree is greater than 95% in simulated intestinal fluid.Release profiles in simulated intestinal fluid is seen Fig. 1.
Sample drug release determination method: by the pertinent regulations of 2005 editions two appendix drug release determination methods of pharmacopeia, determine in simulated gastric fluid, to take a sample, in simulated intestinal fluid, press time point sampling respectively in 1,2,4,6,8 hours, calculate the cumulative release rate through 2h.Three batch samples in simulated gastric fluid 2 hours release all less than 2.1%; 8h cumulative release degree is greater than 95% in simulated intestinal fluid.
Embodiment 5
Present embodiment is the therapeutic effect of the above embodiment product of the present invention to the type ii diabetes patient.
121 examples are not accompanied the type ii diabetes patient of renal complication, are divided into two groups of A, B at random.The A group gives the glipizide calcium alginate micropill 5-10mg that present embodiment makes, and every day 1 time, early takes before the meal; B group (matched group) gives glipizide fast-release tablet (sugared urea goes out) 10-30mg, every day 2 times, sooner or later takes before the meal.In 6 weeks of Therapy lasted, detect fasting glucose (FPG), 2 hours after the meal blood glucose (A2 hPG), cholesterol (TCH), triglyceride (TG), glutamate pyruvate transaminase (ALT) and blood urea nitrogen (BuN) 1 time per 2 weeks.The result is as follows:
The result shows that the glipizide calcium alginate micropill of embodiment of the invention preparation can significantly reduce by 2 hours after the meal blood glucose of patient, compares with matched group, and significant difference (P＜0.01) is arranged.Hepatorenal damage (P＞0.05) does not all appear in all experimenters.This shows that the present invention is control of diabetes patient's blood glucose effectively, and effect significantly is better than commercially available general fast-release tablet, and has reduced medicining times, is admitted by the patient easilier.
Every about 25 μ L of liquid among the present invention.
Below disclose the present invention with preferred embodiment, so it is not in order to restriction the present invention, and all employings are equal to replaces or technical scheme that the equivalent transformation mode is obtained, all drops within protection scope of the present invention.
Claims (3)
1, Glipizide calcium alginate gel rubber pellet is characterized in that its prescription comprises glipizide, sodium alginate and calcium chloride, and wherein the mass ratio of glipizide and sodium alginate is 10: 1-1: 10, and calcium chloride concentration is 0.005-1mol/L.
2, the method for preparing the described Glipizide calcium alginate gel rubber pellet of claim 1 is characterized in that may further comprise the steps:
(1), in proportion take by weighing glipizide and sodium alginate, add the mixed solution that distilled water gets glipizide and sodium alginate, wherein the concentration of sodium alginate is between 0.5%～5.0% (w/w);
(2), with obtain in the step (1) mixed solution under stirring condition, dropwise add in the calcium chloride solution, the volume of calcium chloride solution is 1-100 a times of mixed liquor, reacted 1 minute-72 hours, the micropill that forms is filtered taking-up, distilled water flushing is clean, oven dry had both got glipizide calcium gel microsphere.
3, the method for preparing the described Glipizide calcium alginate gel rubber pellet of claim 1 is characterized in that may further comprise the steps:
(1), the sodium alginate soln of compound concentration between 0.5%～5.0% (w/w);
(2), glipizide is added in the solution of step (1) mix homogeneously under stirring condition;
(3), the mixed solution that step (2) is obtained is dropwise gone in the calcium chloride solution under stirring condition, the volume of calcium chloride solution is 1-100 a times of glipizide mixed liquor, reacted 1 minute-72 hours, the micropill that forms is filtered taking-up, distilled water flushing is clean, oven dry had both got glipizide calcium gel microsphere.
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| CN101313892B CN101313892B (en) | 2011-10-05 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406595A (en) * | 2011-11-02 | 2012-04-11 | 沈阳药科大学 | Floating bioadhesive porous hydrogel and preparation method thereof |
| CN105412142A (en) * | 2015-11-20 | 2016-03-23 | 杭州琅达医疗科技有限公司 | Physiological hydrated alginate hydrogel for assistant heart failure treatment and preparation method thereof |
-
2008
- 2008-05-06 CN CN2008100250711A patent/CN101313892B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406595A (en) * | 2011-11-02 | 2012-04-11 | 沈阳药科大学 | Floating bioadhesive porous hydrogel and preparation method thereof |
| CN105412142A (en) * | 2015-11-20 | 2016-03-23 | 杭州琅达医疗科技有限公司 | Physiological hydrated alginate hydrogel for assistant heart failure treatment and preparation method thereof |
| CN105412142B (en) * | 2015-11-20 | 2019-03-22 | 杭州德柯医疗科技有限公司 | Physiological hydration alginate hydrogel and preparation method thereof for heart failure adjuvant therapy |
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| CN101313892B (en) | 2011-10-05 |
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