CN101057849A - Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method - Google Patents
Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method Download PDFInfo
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- CN101057849A CN101057849A CN 200710071832 CN200710071832A CN101057849A CN 101057849 A CN101057849 A CN 101057849A CN 200710071832 CN200710071832 CN 200710071832 CN 200710071832 A CN200710071832 A CN 200710071832A CN 101057849 A CN101057849 A CN 101057849A
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Abstract
The invention discloses a diabecron and glipizide -containing slow-release agent and the method for preparing the same. The glipizide micro-pill takes blank micro-pill as carrier, and combines glipizide and other medical findings with it. The diabecron-containing slow-release micro-pill comprises diabetosan pill, slow-release coating membrane material or other medical findings. The method for preparing diabecron-containing slow-release micro-pill takes extrusion rolling method or blank micro-pill loading method. The product is characterized by safety, high efficient, low toxicity and convenient usage. It can be used to treat non-insulin-dependent diabetes mellitus.
Description
Technical field:
The present invention relates to a kind of slow releasing preparation that contains metformin hydrochloride and glipizide, the invention still further relates to a kind of preparation method of this slow releasing preparation.
Background technology:
At present, the main Therapeutic Method of type ii diabetes is insulin injection and hypoglycemic medicines such as oral sulphanylureas, biguanides.Because the difficulty to control of insulin dose and use are inconvenient, domestic biguanides clinically and sulfonylurea drugs still are used as the one line medication of treatment type ii diabetes.
The blood sugar lowering mechanism of metformin hydrochloride mainly is to increase no glycolysis, suppress the glycogen heteroplasia, reduce glycogen output and increase the sensitivity of surrounding tissue to insulin, especially obesity, the higher person of plasma insulin, Secondary cases sulphanylureas lost efficacy and type i diabetes insulinize poor blood glucose control person to be applicable to type ii diabetes.Because metformin does not stimulate insulin secretion, and can improve blood lipid metabolism, loses weight, and cardiovascular is had protective effect, be fat type ii diabetes patient drug of first choice therefore.Metformin does not have influence to euglycemia, and by approach blood sugar lowering such as inhibition glucose absorption, therefore the PD to prevention impaired glucose tolerance patient also plays an important role.Metformin hydrochloride also has the shortcoming of himself, be exactly its half-life in vivo shorter, in order to keep effective blood drug level, the clinical oral administration ordinary preparation needs three times on the one, this just brings inconvenience to the patient.And directly use the biguanides medicine, cause side effect of digestive tract easily.In addition, because common biguanides medicine bioavailability under the loss of gastric juice is lower, also be unfavorable for treating diabetes.
To be it combine with sulfonylureas receptor-specific on the β cell membrane the hypoglycemic mechanism of glipizide, thereby make K
+Pathway closure causes that transmembrane potential changes Ca
2+Passage is opened, Ca in the cytosol
2+Raise, impel insulin secretion.Be mainly used in clinically through diet and the out of contior type ii diabetes patient of physical training, its β cell has certain secretory function.Glipizide is evident in efficacy to type ii diabetes, can reverse early diabetes patient microangiopathies; The pathological changes of prevention retina and glomerule; Reduce serum cholesterol and triglyceride level, prevention coronary heart disease.Glipizide is mainly used in light moderate non-insulin-dependent diabetes mellitus patient clinically, and oral every day, consumption 2.5～30mg did not wait, and the shortcoming of glipizide is to cause hypoglycemia easily, takes a lot of people for a long time in a large number and can form secondary failure.
In sum, no matter be, or contrary treatment treatment functions, effect aspect see that metformin hydrochloride and glipizide all are two kinds of diverse hypoglycemic medicines from blood sugar lowering mechanism, therefore these two kinds of medicines also all are the unitary type preparations in the past, and the two also has different separately suitable colonies respectively.Have only clinically when occurring with the patient of or sulfonylurea drugs secondary failure dissatisfied with sulfonylurea drugs control curative effect merely, the doctor just advises the two compatibility is used, to strengthen curative effect.
People find successively in this compatibility use, have also solved many problems.First problem is that two kinds of unitary agent compatibilities are taken hell to pay, and missing phenomenon often has generation.In order to address this problem, abroad some producer lumps together above-mentioned two kinds of compositions and has made compound preparation.At present U.S. FDA ratified in 2002 Bristol-Myers Squibb company about compound metformin hydrochloride/glipizide conventional tablet.This has just made things convenient for taking of patient widely.Second problem is except the advantage of taking that has made things convenient for the patient, people have found that also compound preparation also has the following advantages: the one, find can improve curative effect by the complementation between the mechanism of drug action, and promptly between two kinds of medicines, exist certain synergism; The 2nd, therefore the consumption of each one-component can reduce, thereby the toxic and side effects of medicine is also reduced greatly; Three are to use the compound preparation of fixed mixing ratio, help improving patient's compliance, and this point is particularly important for the treatment of long-term chronic disease.So, obviously also just enlarge the applicable object that two kinds of compatibility of drugss are used, changed the passivity of original use.The 3rd problem is desirable not enough in the uniformity of the intravital blood drug level maintenance of people, drug release after existing compound metformin hydrochloride, glipizide conventional tablet are taken, and influenced the stationarity of blood sugar lowering process.So, domestic someone has again released the slow release formulation design of this class compound medicine, it is particular content from these designs, the present present situation of some design can't play the effect of medicament slow release, and the design that also has then is exactly directly two kinds of medicines and slow-release material to be mixed to make.It takes the back, and to want to reach ideal especially degree in the uniformity of the intravital blood drug level of people, release also be very not too easy.
Summary of the invention:
The object of the present invention is to provide a kind of slow releasing preparation that contains metformin hydrochloride and glipizide, this slow releasing preparation 24h is in vivo kept effective blood drug level, discharges evenly.Another goal of the invention of the present invention also is to provide a kind of preparation method of this slow releasing preparation.
Concrete technical scheme of the present invention is: its dosage form of this slow releasing preparation is a micropill, often release micropill by diabecron sustained-release micropill and glipizide, ratio by the active component of the medicine in two kinds of micropills is 1: the weight ratio of 50-100 is mixed and made into, and the dosage form kind is tablet or capsule.
It is to be carrier with blank micropill that glipizide is often released micropill, loads glipizide and other pharmaceutically acceptable auxiliaries and makes.Hydrochloric metformin slow-release micro-pill is made by containing metformin medicine plain ball, sustained release coating filmogen or also containing other pharmaceutically acceptable auxiliaries, and the plain ball of hydrochloric metformin medicine wherein adopts extrudes spheronization or the preparation of blank micropill Loading Method.
Among the present invention hydrochloric metformin slow-release micro-pill and glipizide often release micropill be by the medicinal component of following percentage by weight and in addition the diluent water of technology amount be prepared from.
(1) glipizide is often released micropill
Glipizide 3-5% dispersant 15-20% binding agent 1--15% celphere 70--85
Consisting of of celphere wherein:
Filler 70-100% binding agent 0---15% lubricant 0---15%
(2) hydrochloric metformin slow-release micro-pill
A contains the plain ball of two hydrochloric acid first biguanide medicines
The plain ball of hydrochloric metformin medicine can adopt a or two kinds of method preparations of b:
A, extrude spheronization
Metformin hydrochloride 50-70% filler 20---30% binding agent 3-10%
B, blank micropill Loading Method
Metformin hydrochloride 60-75% dispersant 2-20% binding agent 1---5%
Celphere 20--30%
B sustained release coating liquid layer
Slow release filmogen 60-90% lubricant 10---40% activating agent 0-1%
The preparation ratio that contains plain ball of two hydrochloric acid first biguanide medicines and sustained release coating layer is 1: 0.5---1.0;
Above-mentioned slow release filmogen is optional takes from least a in the ether derivant, acrylic polymer, vinyl macromolecule of cellulose esters derivant, cellulose ether derivative, cellulose esters; Above-mentioned filler is selected from starch and derivant, saccharide, dextrin, cellulose and derivant thereof, the vinyl macromolecule at least a; Above-mentioned binding agent is at least a in polyvidone and the hypromellose.
The preparation technology of medicine of the present invention
(1) preparation of celphere
Reconcile the baffle plate of centrifugal granulator and the position and the angle of spray gun, make material present maximum covering of the fan in centrifugal barrel, the binding agent of spray gun ejection just in time is sprayed on this covering of the fan.Adjusting makes whiff pressure 0.3Mpa, air blast flux 100～150Lmin
-1, main frame centrifugal speed 448～705rmin
-1, initial 3～5min whitewashing flow is 7～9mlmin
-1, regulating the whitewashing flow then is 5～7mlmin
-1, this process continues 3～5min, and final stage is for supplying the powder stage, and lubricant, filler are for powder speed 5～10gmin
-1, the whitewashing flow is constant, and this time in stage is longer, looks parent nucleus and grows up to the back shutdown of suitable size.Finish the back and open discharging opening, take out finished product, room temperature is dried, and takes out sieve classification promptly.
(2) glipizide is often released the preparation of micropill
Celphere is put in the centrifugal coating pelletizing machine, supplied powder with glipizide and mixture of dispersing agents, binding agent is sized mixing, and starts centrifugal coating pelletizing machine by following parameter: engine speed 150rmin
-1, air blast flux 20Lmin
-1, jet flow 15～20Lmin
-1, whiff pressure 0.5Mpa, spouting velocity 7～10mlmin
-1, for powder speed 5～10gmin
-1, to the whole laminations of powder till on the parent nucleus, 60 ℃ of oven dry are collected 18～24 orders and are contained pill core.
(3) preparation of the plain ball of metformin medicine
A, extrude spheronization
Take by weighing metformin hydrochloride, filler, with metformin hydrochloride, filler and the binding agent back mixing that sieves, be that 1.1: 1 ratio adds an amount of water in the ratio of water and microcrystalline Cellulose, make suitable soft material, make micropill through extruding spheronizator, extruding rotating speed is 50rmin
-1, round as a ball rotating speed is 1100rmin
-1, the round as a ball time is 4min, and round as a ball back is in 55 ℃ of baking ovens behind the dry 5h, and the micropill got between 18～24 orders of sieving is standby.
B, blank micropill Loading Method
Get celphere and put in the centrifugal granulator, with metformin, dispersant, filler mix the back to be crossed 120 mesh sieves and is placed on for powder indoorly, and binding agent is sized mixing, and regulates whiff pressure 0.3Mpa, air blast flux 100～150Lmin
-1, main frame centrifugal speed 448～705rmin
-1, initial 3～5min whitewashing flow is 7～9mlmin
-1, regulating the whitewashing flow then is 5～7mlmin
-1, this process continues 3～5min, and final stage supplies powder speed 5～10gmin for for the powder stage
-1, the whitewashing flow is constant, and this time in stage is longer, looks parent nucleus and grows up to the back shutdown of suitable size.Finish the back and open discharging opening, take out finished product, room temperature is dried promptly.
(4) preparation of metformin slow-release micro-pill
Get plain ball of a certain amount of metformin and coating solution, metformin is often released micropill place centrifugal chamber, start main frame, controllable register and spray gun position and angle, setting the coating temperature is 21～24 ℃, engine speed is 150rmin
-1～180rmin
-1, the spray pump rotating speed is 10rmin
-1～20rmin
-1, air blast flux is 8Lmin
-1～10Lmin
-1, jet flow is 6Lmin
-1～8Lmin
-1, bleed pressure is 0.4Mpa～0.7Mpa, whiff pressure 0.3Mpa.Start spray pump, in the coating process, constantly stir coating solution and make it even, after a certain amount of coating solution bag finishes, stop coating, and micropill is continued airpillow-dry 5～10min in the coating machine, close blower fan, take out coated micropill and get final product at 40～50 ℃ of ripening 24h.
(5) preparation of composite slow release preparation
Metformin slow-release micro-pill and glipizide are often released micropill incapsulate in proportion or tabletting, promptly get compound metformin slow releasing capsule or compound metformin slow releasing tablet.
Advantage of the present invention is that designed product has used the micropill dosage form first, this slow-release micro-pill belongs to multiple agent type, medicine is separated in a plurality of compartments, compare with the single dose dosage form, have curative effect repeatability and less adverse reaction rate preferably, its superiority also is: the one, and micropill is evenly distributed in gastrointestinal tract, and local excitation is little; The 2nd, because area is big, assimilation effect is good, is not subjected to the gastric emptying factor affecting; The 3rd, infiltration rate rule, even, the bioavailability difference between individuality is little, and repeatability is better; The 4th, be difficult for fragmentation, the spherolite size is even, and coating is made slow controlled release or location preparation easily; The 5th, to form by many pillers, error or the defective of indivedual pillers in preparation produces considerable influence to the drug release behavior of whole preparation incessantly; The 6th, the compound capsule by the micropill of different pharmaceutical is formed can increase stability of drug, improves curative effect, reduces untoward reaction; The 7th, be convenient to quality control and assay in producing, and micropill is fit to the compatibility of compound preparation.In recent years, because the exploitation and the production of new adjuvant make slow-release micro-pill show unique advantages in slow controlled release field, be acknowledged as one of comparatively ideal slow release formulation so far.
In addition, though some micropill in the past also all contains multiple drug component, work in-process all mixes whole drug components, and what the preparation of existing slow release formulation medicine was adopted also is same method.The present invention has then adopted the metformin slow release according to two kinds of medicines different rate of release in vivo, the difference design that glipizide is often released, promptly implemented the practice of a kind of " side's two-system ", can realize really that so more medicine keeps 24h to keep effective blood drug level in vivo, the release of medicine is also more even.Not only improved patient's compliance, be fit to the needs of clinical application development, but also had safety, efficient, low toxicity and take the plurality of advantages of aspect such as convenient.
The specific embodiment:
Embodiment 1
1, the plain ball of the hydrochloric metformin medicine of preparation
Take by weighing metformin hydrochloride 210g, filler microcrystalline Cellulose 80g and binding agent lactose 50g, with metformin hydrochloride, microcrystalline Cellulose and lactose sieve the back mixing, in the ratio of water and microcrystalline Cellulose is that 1.1: 1 ratio adds an amount of water, make suitable soft material, make micropill through extruding spheronizator, extruding rotating speed is 50rmin
-1, round as a ball rotating speed is 1100rmin
-1, the round as a ball time is 4min, and round as a ball back is in 55 ℃ of baking ovens behind the dry 5h, and the micropill got between 18～24 orders of sieving is standby.
2, preparation diabecron sustained-release micropill
Get the plain ball 500g of above-mentioned hydrochloric metformin, place centrifugal chamber, start main frame, controllable register and spray gun position and angle, setting the coating temperature is 23 ℃, engine speed is 150rmin
-1, the spray pump rotating speed is 15rmin
-1, air blast flux is 10Lmin
-1, jet flow is 8Lmin
-1, bleed pressure is 0.5Mpa, whiff pressure 0.3Mpa.Start spray pump, constantly stirring coating solution in the coating process makes it even, after finishing, the coating solution bag of being made of slow release filmogen Eudragit NE 30D 200g, EudragitL30D-55 20g, lubricant Pulvis Talci 68.2g, activating agent sodium lauryl sulphate 0.55g and water 262ml stops coating, micropill is continued airpillow-dry 5min in the coating machine, close blower fan, take out coated micropill at 50 ℃ of ripening 24h, get final product the diabecron sustained-release micropill.
3, preparation celphere
With the mixed of mass ratio 1: 1 (w/w) and add extruder, making and extruding rotating speed is 40rmin with 100g filler microcrystalline Cellulose and distilled water
-1With bamboo clappers dosing base in the extruder hopper, the medicine base is extruded to discharging opening sieve plate (aperture 0.9mm) by helical feed, becomes strip-shaped materials.After all picking out with container, disposable placing in the spheronizator on the cutterhead, the adjusting rotating speed is 1200rmin
-1, the machine that blows in, the round as a ball time is 3min, round as a ball back dry 3h in 50 ℃ of baking ovens took out sieve classification promptly.
4, the preparation glipizide is often released micropill
Celphere 96g is put in the centrifugal coating pelletizing machine; supply powder with glipizide 5g, filler microcrystalline Cellulose 20g and dispersant lactose 24g mixture; binding agent is 5% hypromellose aqueous solution; start centrifugal coating pelletizing machine by following parameter: engine speed 150rpm, air blast flux 20Lmin
-1, jet flow 18Lmin
-1, whiff pressure 0.5Mpa, spouting velocity 8mlmin
-1, for powder speed 7gmin
-1, to the whole laminations of powder till on the parent nucleus, 60 ℃ of oven dry are promptly collected 18～24 orders and are contained pill core.
5, the compound metformin hydrochloride slow releasing capsule of preparation.
Diabecron sustained-release micropill and glipizide are often released micropill incapsulate in proportion, promptly get compound metformin hydrochloride slow releasing capsule.
Embodiment 2
1, preparation celphere
Adopt centrifugal granulation to prepare celphere, take by weighing microcrystalline Cellulose 500g and put in the centrifugal granulator, the pelletize condition is whiff pressure 0.3Mpa, air blast flux 125Lmin
-1, main frame centrifugal speed 550rmin
-1, initial 4min whitewashing flow is 8mlmin
-1, regulating the whitewashing flow then is 6mlmin
-1, this process continues 4min, and final stage is 20rmin for for the powder stage for powder machine rotating speed
-1, the whitewashing flow is constant, looks parent nucleus and grows up to the back shutdown of suitable size.Finish the back and open discharging opening, take out finished product, room temperature is dried, and crosses sieve classification promptly.
2, the plain ball of the hydrochloric metformin of preparation
Getting the blank micropellets 80g of 40～60 purpose microcrystalline Cellulose puts in the centrifugal granulator; metformin hydrochloride 250g, microcrystalline Cellulose 7.5g and lactose 12.5g are mixed; crossing 120 mesh sieves is placed on for powder indoor; with 5% hydroxypropyl methylcellulose aqueous solution is binding agent; adopt centrifugal granulation to prepare the plain ball of metformin hydrochloride; the pelletize condition is for regulating whiff pressure 0.3Mpa, air blast flux 150Lmin
-1, main frame centrifugal speed 500rmin
-1, initial 4min whitewashing flow is 8mlmin
-1, regulating the whitewashing flow then is 6mlmin
-1, this process continues 4min, and final stage is 7gmin for for the powder stage for powder speed
-1, the whitewashing flow is constant, looks parent nucleus and grows up to the back shutdown of suitable size.Finish the back and open discharging opening, take out finished product, room temperature is dried promptly.
3, preparation diabecron sustained-release micropill
Get the plain ball of the hydrochloric metformin of 500g, place centrifugal chamber, start main frame, controllable register and spray gun position and angle, setting the coating temperature is 23 ℃, engine speed is 150rmin
-1, the spray pump rotating speed is 15rmin
-1, air blast flux is 10Lmin
-1, jet flow is 8Lmin
-1, bleed pressure is 0.5Mpa, whiff pressure 0.3Mpa.Start spray pump, constantly stirring coating solution in the coating process makes it even, after finishing, the coating solution bag of being made of Eudragit NE 30D 200g, EudragitL30D-55 20g, Pulvis Talci 68.2g, sodium lauryl sulphate 0.55g and water 262ml stops coating, micropill is continued airpillow-dry 5～10min in the coating machine, close blower fan, take out coated micropill at 40～50 ℃ of ripening 24h, get final product the diabecron sustained-release micropill.
4, the preparation glipizide is often released micropill
Microcrystalline Cellulose parent nucleus 96g is put in the centrifugal coating pelletizing machine; supply powder with glipizide 5g, microcrystalline Cellulose 20g and lactose 24g mixture; with 5% hypromellose aqueous solution is binding agent, starts centrifugal coating pelletizing machine by following parameter: engine speed 150rpm, air blast flux 20Lmin
-1, jet flow 18Lmin
-1, whiff pressure 0.5Mpa, spouting velocity 8mlmin
-1, for powder speed 7gmin
-1To the whole laminations of powder till on the parent nucleus.60 ℃ of oven dry promptly.Collect 18～24 orders and contain pill core.
5, the compound metformin hydrochloride slow releasing capsule of preparation.
With the plain ball of diabecron sustained-release micropill and glipizide tabletting in proportion, promptly get compound diabecron sustained-release tablet.
Example 3
This example for the animal drugs of product of the present invention for zoology test, by setting up the HPLC method of measuring metformin hydrochloride concentration in the dog plasma, with the common slow releasing tablet of metformin hydrochloride is standard control, estimates that with area-method the relative bioavailability of compound metformin hydrochloride slow-release micro-pill of the present invention is 97.9%.After obeying product diabecron sustained-release micropill 250mg of the present invention to Canis familiaris L., the terminal half-life of estimation is 10.97 ± 2.36 hours, and peak time and peak concentration were respectively 5.8 ± 1.7 hours and 1114.37 ± 27.23ng/ml; Average retention time is 11.54 ± 1.49 hours, and area under curve is 1419.524 ± 246.5ng/ml.Take the common slow releasing tablet of 10mg metformin hydrochloride to Canis familiaris L., the terminal half-life of estimation is 2.09 ± 1.22 hours, and peak time and peak concentration were respectively 1.39 ± 0.52 hours and 248.4 ± 12.37ng/ml; Average retention time is 6.47 ± 0.42 hours, and area under curve is 952.369 ± 250.6ng/ml.Show that through the t analysis of experiments t1/2, mean residence time are significantly greater than the common slow releasing tablet of metformin hydrochloride (p＜0.05), peak time prolongs (p＜0.01), peak concentration significantly is lower than the common slow releasing tablet of metformin hydrochloride (p＜0.01), the two-system area under a curve does not have significant difference (p＜0.05), and the excellent results of product of the present invention has been described.
Claims (5)
1, a kind of slow releasing preparation that contains metformin hydrochloride and glipizide, its dosage form of this slow releasing preparation is a micropill, often releasing micropill by diabecron sustained-release micropill and glipizide is 1 by the ratio of the active component of the medicine in two kinds of micropills: the weight ratio of 50-100 is mixed and made into, and the dosage form kind is tablet or capsule.
2, a kind of slow releasing preparation that contains metformin hydrochloride and glipizide according to claim 1 is characterized in that it is to be carrier with blank micropill that described glipizide is often released micropill, loads glipizide and other pharmaceutically acceptable auxiliaries and makes; Described hydrochloric metformin slow-release micro-pill is made by containing metformin medicine plain ball, sustained release coating filmogen or also containing other pharmaceutically acceptable auxiliaries, and the plain ball of hydrochloric metformin medicine wherein adopts extrudes spheronization or the preparation of blank micropill Loading Method.
3, a kind of slow releasing preparation that contains metformin hydrochloride and glipizide according to claim 2, it is characterized in that described diabecron sustained-release micropill and glipizide often release micropill be by the medicinal component of following percentage by weight and in addition the diluent water of technology amount be prepared from:
(1) glipizide is often released micropill
Lattice row pyrrole 3-5% dispersant 15-20% binding agent 1--15% celphere 70--85%
Consisting of of celphere wherein:
Filler 70-100% binding agent 0---15% lubricant 0---15%
(2) hydrochloric metformin slow-release micro-pill
A contains the plain ball of two hydrochloric acid first biguanide medicines
The plain ball of hydrochloric metformin medicine can adopt a or two kinds of method preparations of b:
A, extrude spheronization
Metformin hydrochloride 50-70% filler 20---30% binding agent 3-10
B, blank micropill Loading Method
Metformin hydrochloride 60-75% dispersant 2-20% binding agent 1--5% celphere 20--30%
B sustained release coating liquid layer
Slow release filmogen 60-90% lubricant 10---40% activating agent 0-1%
The configuration proportion that contains plain ball of two hydrochloric acid first biguanide medicines and sustained release coating layer is 1: 0.5---1.0; Above-mentioned slow release filmogen is optional takes from least a in the ether derivant, acrylic polymer, vinyl macromolecule of cellulose esters derivant, cellulose ether derivative, cellulose esters; Above-mentioned filler is selected from starch and derivant, saccharide, dextrin, cellulose and derivant thereof, the vinyl macromolecule at least a; Above-mentioned binding agent is at least a in polyvidone and the hypromellose.
4, a kind ofly prepare the method that contains the slow releasing preparation of metformin hydrochloride and glipizide as claimed in claim 1, it is characterized in that:
(1) preparation of celphere
Reconcile the baffle plate of centrifugal granulator and the position and the angle of spray gun, make material present maximum covering of the fan in centrifugal barrel, the binding agent of spray gun ejection or dispersant and wetting agent just in time are sprayed on this covering of the fan.Adjusting makes whiff pressure 0.3Mpa, air blast flux 100～150Lmin
-1, main frame centrifugal speed 448～705rmin
-1, initial 3～5min whitewashing flow is 7～9mlmin
-1, regulating the whitewashing flow then is 5～7mlmin
-1, this process continues 3～5min, and final stage is for supplying the powder stage, and filler is for powder speed 5～10gmin
-1, the whitewashing flow is constant, and this time in stage is longer, looks parent nucleus and grows up to the back shutdown of suitable size.Finish the back and open discharging opening, take out finished product, room temperature is dried, and takes out sieve classification promptly;
(2) glipizide is often released the preparation of micropill
Celphere is put in the centrifugal coating pelletizing machine, supplied powder with glipizide and mixture of dispersing agents, binding agent is sized mixing, and starts centrifugal coating pelletizing machine by following parameter: engine speed 150rmin
-1, air blast flux 20Lmin
-1, jet flow 15～20Lmin
-1, whiff pressure 0.5Mpa, spouting velocity 7～10mlmin
-1, for powder speed 5～10gmin
-1, to the whole laminations of powder till on the parent nucleus, 60 ℃ of oven dry are collected 18～24 orders and are contained pill core;
(3) contain the preparation of the plain ball of metformin medicine
The plain ball of hydrochloric metformin medicine adopts blank micropill Loading Method; its concrete technology is: get celphere and put in the centrifugal granulator; with metformin; crossing 120 mesh sieves after dispersant, filler mix is placed on for powder indoor; binding agent is sized mixing; regulate whiff pressure 0.3Mpa, air blast flux 100～150Lmin
-1, main frame centrifugal speed 448～705rmin
-1, initial 3～5min whitewashing flow is 7～9mlmin
-1, regulating the whitewashing flow then is 5～7mlmin
-1, this process continues 3～5min, and final stage supplies powder speed 5～10gmin for for the powder stage
-1, the whitewashing flow is constant, and this time in stage is longer, looks parent nucleus and grows up to the back shutdown of suitable size.Finish the back and open discharging opening, take out finished product, room temperature is dried promptly;
(4) preparation of metformin slow-release micro-pill
Get plain ball of a certain amount of metformin and coating solution, metformin is often released micropill place centrifugal chamber, start main frame, controllable register and spray gun position and angle, setting the coating temperature is 21～24 ℃, engine speed is 150rmin
-1～180rmin
-1, the spray pump rotating speed is 10rmin
-1～20rmin
-1, air blast flux is 8Lmin
-1～10Lmin
-1, jet flow is 6Lmin
-1～8Lmin
-1, bleed pressure is 0.4Mpa～0.7Mpa, whiff pressure 0.3Mpa.Start spray pump, in the coating process, constantly stir coating solution and make it even, after a certain amount of coating solution bag finishes, stop coating, and micropill is continued airpillow-dry 5～10min in the coating machine, close blower fan, take out coated micropill and get final product at 40～50 ℃ of ripening 24h;
(5) preparation of composite slow release preparation
Metformin slow-release micro-pill and glipizide are often released micropill incapsulate in proportion or tabletting, promptly get compound metformin slow releasing capsule or compound metformin slow releasing tablet.
5, the method that contains the slow releasing preparation of metformin hydrochloride and glipizide according to claim 4, it is characterized in that: the plain ball of described hydrochloric metformin medicine adopts extrudes spheronization, concrete technology is: take by weighing metformin hydrochloride, filler, with metformin hydrochloride, filler and binding agent sieve the back mixing, in the ratio of water and microcrystalline Cellulose is that 1.1: 1 ratio adds an amount of water, make suitable soft material, make micropill through extruding spheronizator, extruding rotating speed is 50rmin
-1, round as a ball rotating speed is 1100rmin
-1, the round as a ball time is 4min, and round as a ball back is in 55 ℃ of baking ovens behind the dry 5h, and the micropill got between 18～24 orders of sieving is standby.
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| CN 200710071832 CN101057849A (en) | 2007-02-27 | 2007-02-27 | Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method |
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|---|---|---|---|
| CN 200710071832 CN101057849A (en) | 2007-02-27 | 2007-02-27 | Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method |
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| CN (1) | CN101057849A (en) |
Cited By (32)
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| CN103655570A (en) * | 2013-12-11 | 2014-03-26 | 深圳翰宇药业股份有限公司 | Sitagliptin and melbine compound sustained-release preparation and preparation method thereof |
| US8722086B2 (en) | 2007-03-07 | 2014-05-13 | Gruenenthal Gmbh | Dosage form with impeded abuse |
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| US9655853B2 (en) | 2012-02-28 | 2017-05-23 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
| US9675610B2 (en) | 2002-06-17 | 2017-06-13 | Grünenthal GmbH | Abuse-proofed dosage form |
| US9737490B2 (en) | 2013-05-29 | 2017-08-22 | Grünenthal GmbH | Tamper resistant dosage form with bimodal release profile |
| US9750701B2 (en) | 2008-01-25 | 2017-09-05 | Grünenthal GmbH | Pharmaceutical dosage form |
| US9855263B2 (en) | 2015-04-24 | 2018-01-02 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
| US9872835B2 (en) | 2014-05-26 | 2018-01-23 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
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| US10080721B2 (en) | 2009-07-22 | 2018-09-25 | Gruenenthal Gmbh | Hot-melt extruded pharmaceutical dosage form |
| US10130591B2 (en) | 2003-08-06 | 2018-11-20 | Grünenthal GmbH | Abuse-proofed dosage form |
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| US10624862B2 (en) | 2013-07-12 | 2020-04-21 | Grünenthal GmbH | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
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| US10369109B2 (en) | 2002-06-17 | 2019-08-06 | Grünenthal GmbH | Abuse-proofed dosage form |
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| US10130591B2 (en) | 2003-08-06 | 2018-11-20 | Grünenthal GmbH | Abuse-proofed dosage form |
| US11224576B2 (en) | 2003-12-24 | 2022-01-18 | Grünenthal GmbH | Process for the production of an abuse-proofed dosage form |
| US11844865B2 (en) | 2004-07-01 | 2023-12-19 | Grünenthal GmbH | Abuse-proofed oral dosage form |
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| US8722086B2 (en) | 2007-03-07 | 2014-05-13 | Gruenenthal Gmbh | Dosage form with impeded abuse |
| US9750701B2 (en) | 2008-01-25 | 2017-09-05 | Grünenthal GmbH | Pharmaceutical dosage form |
| US9161917B2 (en) | 2008-05-09 | 2015-10-20 | Grünenthal GmbH | Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet |
| US9925146B2 (en) | 2009-07-22 | 2018-03-27 | Grünenthal GmbH | Oxidation-stabilized tamper-resistant dosage form |
| US10493033B2 (en) | 2009-07-22 | 2019-12-03 | Grünenthal GmbH | Oxidation-stabilized tamper-resistant dosage form |
| US10080721B2 (en) | 2009-07-22 | 2018-09-25 | Gruenenthal Gmbh | Hot-melt extruded pharmaceutical dosage form |
| CN102821757B (en) * | 2010-02-03 | 2016-01-20 | 格吕伦塔尔有限公司 | By extrusion mechanism for powdery medicine compositions |
| CN102821757A (en) * | 2010-02-03 | 2012-12-12 | 格吕伦塔尔有限公司 | Preparation of a powdery pharmaceutical composition by means of an extruder |
| US9636303B2 (en) | 2010-09-02 | 2017-05-02 | Gruenenthal Gmbh | Tamper resistant dosage form comprising an anionic polymer |
| US10300141B2 (en) | 2010-09-02 | 2019-05-28 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
| CN102119931B (en) * | 2011-02-21 | 2013-02-13 | 寿光富康制药有限公司 | Novel metformin hydrochloride slow-releasing tablet and preparation method thereof |
| CN102119931A (en) * | 2011-02-21 | 2011-07-13 | 寿光富康制药有限公司 | Novel metformin hydrochloride slow-releasing tablet and preparation method thereof |
| US10201502B2 (en) | 2011-07-29 | 2019-02-12 | Gruenenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
| US10864164B2 (en) | 2011-07-29 | 2020-12-15 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
| US10695297B2 (en) | 2011-07-29 | 2020-06-30 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
| CN102488660A (en) * | 2011-12-15 | 2012-06-13 | 西安天一秦昆制药有限责任公司 | Sustained-release pellet containing pirfeudone |
| US9655853B2 (en) | 2012-02-28 | 2017-05-23 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
| US10335373B2 (en) | 2012-04-18 | 2019-07-02 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
| US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
| US10154966B2 (en) | 2013-05-29 | 2018-12-18 | Grünenthal GmbH | Tamper-resistant dosage form containing one or more particles |
| US9737490B2 (en) | 2013-05-29 | 2017-08-22 | Grünenthal GmbH | Tamper resistant dosage form with bimodal release profile |
| US10624862B2 (en) | 2013-07-12 | 2020-04-21 | Grünenthal GmbH | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
| US10449547B2 (en) | 2013-11-26 | 2019-10-22 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
| CN103655570A (en) * | 2013-12-11 | 2014-03-26 | 深圳翰宇药业股份有限公司 | Sitagliptin and melbine compound sustained-release preparation and preparation method thereof |
| US9913814B2 (en) | 2014-05-12 | 2018-03-13 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
| US9872835B2 (en) | 2014-05-26 | 2018-01-23 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
| US9855263B2 (en) | 2015-04-24 | 2018-01-02 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
| US10842750B2 (en) | 2015-09-10 | 2020-11-24 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
| CN110101687A (en) * | 2019-06-19 | 2019-08-09 | 河北爱尔海泰制药有限公司 | A kind of metformin hydrochloride slow release preparation and preparation method thereof |
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