CN100455279C - Oral administered sustained release lozenge composition and its preparation method - Google Patents
Oral administered sustained release lozenge composition and its preparation method Download PDFInfo
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- CN100455279C CN100455279C CNB2004100374472A CN200410037447A CN100455279C CN 100455279 C CN100455279 C CN 100455279C CN B2004100374472 A CNB2004100374472 A CN B2004100374472A CN 200410037447 A CN200410037447 A CN 200410037447A CN 100455279 C CN100455279 C CN 100455279C
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Abstract
The present invention relates to an oral-taking release delaying lozenge composition which is characterized in that the oral-taking release delaying lozenge composition at least comprises a micrometer blood sugar lowering active component and a release delaying agent controlling the release of the active component. The present invention also provides a manufacturing method of the lozenge composition. The dissolution rate of the oral-taking release delaying lozenge is superior to the dissolution rate of the traditional blood sugar lowering preparation comprising the active component, and compared with the traditional blood sugar lowering preparation comprising the active component, the oral-taking release delaying lozenge composition has more stable and lasting absorption and better treatment effect.
Description
Technical field
The present invention is about a kind of oral delayed release (modified-release) lozenge constituent, particularly a kind of micronization blood-sugar decreasing active and the delay releasing agent of forming with hydrophilic polymer that comprises pharmacy effective dose at least, and the method for making of this oral delayed release lozenge constituent.
Background technology
Diabetes are a kind of chronic diseases, it is the hyperglycemia disease that causes by many different reasons, can cause the pathological changes or the complication of retinopathy (retinopathy), glomerule arterial sclerosis (glomerulosclerosis) and other kidney, nerve and blood vessel aspect, come the 5th of the Taiwan ten big causes of the death, from nineteen sixty per ten thousand philtrums have 0.37 people to rise to per ten thousand people in 1999 4.1 people are arranged.Diabetes mainly are divided into I type and II type, and the I type is insulin dependent diabetes mellitus (IDDM) (IDDM), is called juvenile onset diabetes in early days, under the situation of insulin injection not, are absorbed in acute ketoacidosis easily; Type ii diabetes is a non-insulin-dependent diabetes mellitus, is called maturity-onset diabetes again, because the metabolism obstacle causes, promptly due to the resistance of insulin and β cell function damaged, needs the oral hypoglycemic thing to treat.
Generally speaking, the oral hypoglycemic thing can be divided into four classes, is sulfonylurea (sulfonylurea), biguanides (biguanldes), thiazolidinedione (thiazolidinedione) and α-glucosidase inhibitor (α-glucosidaseinhibitor).Sulfonylurea is the oral hypoglycemic thing that cures mainly maturity-onset diabetes, be mainly used in non-obese type and β cell the patient of function is still arranged, acting as stimulates the pancreas excreting insulin, make the granule generation degranulation that contains insulin in the β cell, discharge the insulin in the granule, in addition, can reduce the metabolism of insulin in liver, impel the receptor number of insulin to increase.Its side effect is less, is mostly to suppress iodide ion to enter thyroid, and excessive meeting causes hypoglycemia, causes nausea, vomiting, skin itch.Taiwan hospital mostly is the sulfonylureas that uses the second filial generation at present, for example gliclazide (Gliclazide), glipizide (Glipizide) and glibenclamide (Glibenclamide) etc.; And biguanides can not stimulate insulin secretion, so cause hypoglycemic danger low than sulfonylurea, is the first-selected medication of obese type sufferer; The effect machine alternation of hosts of thiazolidinediones will be to reduce muscle and fatty tissue to the impedance of insulin and reduce endogenous glucose manufacturing; α-glucosidase inhibitor act as the α-glucosidase that suppresses on the intestinal villus limit, and suppresses the absorption of starch and disaccharidase class, reduces the rising of blood glucose value after meal, also normal and other oral hypoglycemic and usefulness.
Adopting the sustained release hypoglycemic drug is very important to reach the therapeutic effect that steadily continues concerning the disease treatment of diabetics, especially patient of diabetes must be taken medicine for a long time with disease controlling, under the situation that must take medicine, must develop and to make the patient obtain the medicine of optimal treatment as far as possible, and avoid bringing negative effect because of taking these medicines; For the medicine that postpones release type, because can the effective maintenance dose of prolong drug in blood, lasting medicine, thus the minimizing medicining times is arranged, and then make rate of release and mode more near the advantage of physiology and chronic treatment; , therefore need not use higher dosage as means, the side effect of generation or the resistance probability thereby the reduction of reaching lasting drug effect because of drug effect comparatively steadily continues yet.For example, micronization gliclazide (Gliclazide) 80 milligrams a day twice (bid) is in clinical use, and micron does not change into branchs and can't not discharge fully because of dissolution is good, so can't reach clinical effective therapeutic effect.As United States Patent (USP) the 6th, 451, No. 339 and 6,537, No. 578 grades promptly belong to the preparation that carries out at the purpose of sustained release medicament and make.
Summary of the invention
The present invention is primarily aimed at diabetics, utilizes means such as medicine stripping control, reaches the oral delayed release lozenge that meets above-mentioned purpose, and then makes medicine reach better safety and curative effect.
The object of the present invention is to provide a kind of oral delayed release (modified release) lozenge constituent, adopt micronization technology and and postpone the releasing agent combination, it is complete that the medicine stripping is discharged, and reach the purpose of lasting release.
The present invention also aims to provide a kind of method for making of oral delayed release lozenge constituent, by micronization, with postpone that releasing agent mixes, pelletize, drying and granulate etc., finally make the oral lozenge that postpones releasing effect that has.
A kind of oral delayed release lozenge constituent provided by the invention is characterized by at least and is made up of the blood-sugar decreasing active of micronization and the delay releasing agent of control active component release, and size and ratio that its micron changed particle are:
(1)≤5 micron number of particles accounts for more than 50% of toatl proportion;
(2)≤15 micron number of particles accounts for more than 90% of toatl proportion;
(3)≤25 micron number of particles accounts for more than 95% of toatl proportion; And the delay releasing agent of a control active component release.
The present invention also provides the method for making of above-mentioned oral delayed release lozenge constituent, earlier with the blood-sugar decreasing active micronization, with its mix with the delay releasing agent, pelletize, drying and granulate etc.; Add excipient at last again and make lozenge.
The oral delayed release lozenge constituent of micronization provided by the invention is through the stripping test of certain hour, the blood-sugar decreasing active of micronization with postpone releasing agent form jointly constituent than blood-sugar decreasing active not the constituent of micronization better dissolution rate is arranged, can make the product of producing have preferable absorption stability, make it use less dosage can reach preferable therapeutic effect clinically.
Wherein the blood-sugar decreasing active of micronization is selected from sulfonylurea, gliclazide (Gliclazide), glipizide (Glipizide), glibenclamide (Glibenclamide), Gree Kui Dongning County (Gliquidonem) and glimepiride (Glimepiride) and combination thereof; This delay releasing agent is selected from hydroxypropyl emthylcellulose, methylcellulose, polyvidon, hydroxypropyl cellulose, vinylacetic acid ester copolymer, polyethylene oxide and combination thereof, and this delay releasing agent accounts for 10%～60% of constituent; The weight of the blood-sugar decreasing active gliclazide (GliclazMe) of micronization is the 15%-20% of constituent.
Those skilled in the art can adjust the composition that postpones releasing agent according to selected active blood sugar-lowering substances, reach optimization so that postpone releasing effect.
Oral delayed release lozenge constituent of the present invention, it has 5%～15% micronization blood-sugar decreasing active to disengage through stripping test approximately after two hours, after four hours, have 15%～35% to disengage, after eight hours, disengage 50%～80%, and existing composition more than 85% disengages in 12 hours.
Oral delayed release lozenge constituent of the present invention is once oral every day, once takes 1 to 2 ingot, the expection but be not limited to be used for the treatment of on the purposes of diabetes.
Above-mentioned oral delayed release lozenge constituent, it forms gliclazide (Gliclazide), hydroxypropyl emthylcellulose, polyvidon, lactose, silicon dioxide, oleic acid polyalcohols sorbitol, magnesium stearate and the Pulvis Talci that comprises micronization at least.
The preferred 4000cps of the viscosity of delay releasing agent of the present invention～100,000cps.
The method for making of oral delayed release lozenge constituent provided by the invention, it comprises at least: the blood-sugar decreasing active micron is turned to: the number of particles of (1)≤5 micron accounts for more than 50% of toatl proportion; (2)≤15 micron number of particles accounts for more than 90% of toatl proportion; (3)≤25 micron number of particles accounts for more than 95% of toatl proportion; With the blood-sugar decreasing active of micronization with postpone that releasing agent mixes, pelletize, drying and granulate; Add excipient and play ingot, with make 4 to 8 kilograms of hardness lozenge.
Can add in the manufacturing of lozenge of the present invention that pharmacy can be accepted and be difficult for aitiogenic various excipient with blood-sugar decreasing active, make lozenge as extender, diluent, lubricant, correctives, disintegrating agent, binding agent or coloring agent, sweeting agent etc., for example lactose, titanium dioxide, microcrystalline Cellulose, Sorbitol, magnesium stearate and Pulvis Talci etc.; Can before beating the ingot step, add or when the micron blood-sugar decreasing active mixes with the delay releasing agent, add.Beat about the preferred 4-8 kilogram of hardness behind the ingot.
The oral delayed release lozenge constituent of a kind of novelty provided by the invention, mainly contain the blood-sugar decreasing active of micronization and, reach the purpose of the delay releasing effect of control blood-sugar decreasing active with this with the component of hydrophilic polymers as the delay releasing agent.
Description of drawings
Fig. 1 is the stripping curve that contains the Gliclazide oral lozenge constituent of micronization blood-sugar decreasing active at pure water of the present invention;
Fig. 2 is in the oral lozenge constituent of the present invention, and the gliclazide (rhombus) that contains the micronization blood-sugar decreasing active is compared with the lozenge that contains without micron blood-sugar decreasing active gliclazide (square), its two stripping curve in pure water;
Fig. 3 A and Fig. 3 B are the plasma concentration curve of gliclazide of the present invention, and Fig. 3 B is the partial enlarged drawing of Fig. 3 A, and wherein the lozenge constituent is 30mg, n=12.
The specific embodiment
Describe the present invention in detail below in conjunction with specific embodiment, but do not limit practical range of the present invention.
Preparation contains the oral lozenge constituent of hypoglycemic drug gliclazide, and composition is as described below:
30 milligrams of the gliclazide of micronization
30 milligrams of lactose
84 milligrams of hydroxypropyl emthylcelluloses
8 milligrams of polyvidon
3.2 milligrams of oleic acid polyalcohols sorbitol
1.6 milligrams of magnesium stearate
1.6 milligrams of Pulvis Talci
Amount to 160 milligrams;
Above-mentioned constituent composition is carried out following step obtains lozenge of the present invention:
(1) gliclazide, lactose, silicon dioxide, hydroxypropyl emthylcellulose, the polyvidon with micronization mixes mutually;
(2) oleic acid polyalcohols sorbitol is dissolved in the alcohol water blend;
(3) solution of aforementioned (2) is poured in the mixed-powder of aforementioned (1), the gained wet mass is made granule again, granulate (#20mesh) again after the drying;
(4) granule with step (3) gained mixes mutually with magnesium stearate, Pulvis Talci;
(5) adopt the swinging Ingot pressing machine to play ingot, its hardness is greatly between 4～8kg.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
60 milligrams of the gliclazide of micronization
60 milligrams of lactose
3.2 milligrams of silicon dioxide
168 milligrams of hydroxypropyl emthylcelluloses
16 milligrams of polyvidon
6.4 milligrams of oleic acid polyalcohols sorbitol
3.2 milligrams of magnesium stearate
3.2 milligrams of Pulvis Talci
Amount to 320 milligrams.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
30 milligrams of the gliclazide of micronization
90 milligrams of mannitols
25.6 milligrams of methylcellulose
6.4 milligrams of polyvidon
3.2 milligrams of sodium lauryl sulphates
1.6 milligrams of magnesium stearate
1.6 milligrams of Pulvis Talci
Amount to 160 milligrams.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
60 milligrams of the gliclazide of micronization
180 milligrams of mannitols
3.2 milligrams of silicon dioxide
51.2 milligrams of methylcellulose
12.8 milligrams of polyvidon
6.4 milligrams of sodium lauryl sulphates
3.2 milligrams of magnesium stearate
3.2 milligrams of Pulvis Talci
Amount to 320 milligrams.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
30 milligrams of the gliclazide of micronization
60 milligrams of microcrystalline Cellulose
30 milligrams of lactose
24 milligrams of hydroxypropyl emthylcelluloses
4.8 milligrams of polyvidon
6.4 milligrams of oleic acid polyalcohols sorbitol
1.6 milligrams of magnesium stearate
1.6 milligrams of Pulvis Talci
Amount to 160 milligrams.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
60 milligrams of the gliclazide of micronization
120 milligrams of microcrystalline Cellulose
60 milligrams of lactose
3.2 milligrams of silicon dioxide
48 milligrams of hydroxypropyl emthylcelluloses
9.6 milligrams of polyvidon
12.8 milligrams of oleic acid polyalcohols sorbitol
3.2 milligrams of magnesium stearate
3.2 milligrams of Pulvis Talci
Amount to 320 milligrams.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
30 milligrams of the gliclazide of micronization
90 milligrams of lactose
24 milligrams of hydroxypropyl emthylcelluloses
8 milligrams of polyvidon
3.2 milligrams of oleic acid polyalcohols sorbitol
1.6 milligrams of magnesium stearate
1.6 milligrams of Pulvis Talci
Amount to 160 milligrams.
Contain the oral lozenge constituent of hypoglycemic drug gliclazide, composition is as described below:
60 milligrams of the gliclazide of micronization
180 milligrams of lactose
3.2 milligrams of silicon dioxide
48 milligrams of hydroxypropyl emthylcelluloses
16 milligrams of polyvidon
6.4 milligrams of oleic acid polyalcohols sorbitol
3.2 milligrams of magnesium stearate
3.2 milligrams of Pulvis Talci
Amount to 320 milligrams.
The in vitro tests of oral lozenge constituent of the present invention-stripping test
With the gliclazide of the micronization active component as oral lozenge, making embodiment 1 made lozenge is in the USP first type medicine basket device of 100rpm at rotating speed, carries out the stripping test in 37 ℃ of following pure water of 900 milliliters.
Gained result such as table one and shown in Figure 1.
Table one
| Time (hour) | Dissolution rate (%) |
| 0.5 | 2.0 |
| 1.0 | 4.0 |
| 1.5 | 6.2 |
| 2.0 | 9.5 |
| 2.5 | 12.9 |
| 3.0 | 16.6 |
| 3.5 | 21.2 |
| 4.0 | 25.8 |
| 4.5 | 30.6 |
| 5.0 | 35.6 |
| 5.5 | 40.8 |
| 6.0 | 46.2 |
| 6.5 | 51.5 |
| 7.0 | 56.6 |
| 7.5 | 61.4 |
| 8.0 | 66.5 |
| 8.5 | 71.5 |
| 9.0 | 76.0 |
| 9.5 | 80.6 |
| 10.0 | 85.2 |
| 10.5 | 89.3 |
| 11.0 | 93.0 |
| 11.5 | 96.5 |
| 12.0 | 100.1 |
As from the foregoing, there is 5～15% gliclazide disengage after two hours approximately in stripping test, after four hours, have 15～35% gliclazide to disengage approximately, after eight hours, have 50～80% gliclazide to disengage approximately and in 12 hours existing about 85% gliclazide disengage.
Oral lozenge constituent of the present invention (experimental group) and the next oral ingot of blood-sugar decreasing active through micronization
The in vitro tests that agent constituent (matched group) is compared-stripping test
Respectively with micronization (embodiment 1) with without the gliclazide of micronization as the active component of oral lozenge and make lozenge, at rotating speed is the USP first type medicine basket device of 100rpm, carry out the stripping test in 37 ℃ of following pure water of 900 milliliters, the gained result as shown in Figure 2.Rhombus (◆) is represented the made lozenge of active component micronization, and square (■) represents active component without the made lozenge of micronization, the result show lozenge of the present invention can be under the stripping of long period test than having preferable dissolution rate without the made lozenge of the gliclazide of micronization, and can't reach release fully without the dosage form of micronization.
In addition, in the present invention, this oral delayed release lozenge constituent in blood level and the relation between the time as shown in Figure 3, its selection meets the health volunteer of test requirements document, take the hypoglycemic drug of micronization processing procedure of the present invention manufacturing, the mode of taking is regularly to take once every day and take continuously six, and design blood sampling point detects blood drug level; As shown in Figure 3, the dosage that hypoglycemic drug discharges in blood continues along with the prolongation of time to discharge, so can reach the effect that the control blood-sugar decreasing active postpones release.
Be incorporated as reference material in this file of quoting, each data all can be used as this description and discloses institute's part, and those skilled in the art can do from specific embodiments of the invention not depart from the improvement of application of the present invention and principle.That is, more than described the preferred embodiments of the present invention, so it is not that those skilled in the art can not depart from the improvement and the variation of category of the present invention and spirit to embodiment disclosed herein in order to qualification the present invention.
Claims (5)
1, a kind of oral delayed release lozenge constituent, it comprises at least:
Account for the blood-sugar decreasing active gliclazide of 15% to 20% micronization of lozenge constituent, the size of its micron change and ratio be,
(1)≤5 micron number of particles accounts for more than 50% of toatl proportion;
(2)≤15 micron number of particles accounts for more than 90% of toatl proportion;
(3)≤25 micron number of particles accounts for more than 95% of toatl proportion; And the delay releasing agent of control active component release, wherein, this delay releasing agent is selected from hydroxypropyl emthylcellulose, methylcellulose, polyvidon, hydroxypropyl cellulose, vinylacetic acid ester copolymer, polyethylene oxide and combination thereof.
2, oral delayed release lozenge constituent as claimed in claim 1, wherein this delay releasing agent accounts for 10% to 60% of lozenge constituent.
3, oral delayed release lozenge constituent as claimed in claim 1 or 2, it forms gliclazide, hydroxypropyl emthylcellulose, polyvidon, lactose, silicon dioxide, oleic acid polyalcohols sorbitol, magnesium stearate and the Pulvis Talci that comprises micronization at least.
4, oral delayed release lozenge constituent as claimed in claim 1 or 2, wherein the viscosity of this delay releasing agent is 4000cps-100,000cps.
5, a kind of method for making of oral delayed release lozenge constituent wherein comprises at least: with blood-sugar decreasing active gliclazide micronization, the size of its micron change and ratio be,
(1)≤5 micron number of particles accounts for more than 50% of toatl proportion;
(2)≤15 micron number of particles accounts for more than 90% of toatl proportion;
(3)≤25 micron number of particles accounts for more than 95% of toatl proportion;
With this blood-sugar decreasing active gliclazide of micronization with postpone that releasing agent is mixed, pelletize, drying and granulate; Add excipient and play ingot, make the lozenge of 4 to 8 kilograms of hardness; The blood-sugar decreasing active gliclazide of wherein said micronization accounts for 15% to 20% of described oral delayed release lozenge constituent, and described delay releasing agent is selected from hydroxypropyl emthylcellulose, methylcellulose, polyvidon, hydroxypropyl cellulose, vinylacetic acid ester copolymer, polyethylene oxide and combination thereof.
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| CN1437483A (en) * | 1999-12-28 | 2003-08-20 | 味之素株式会社 | Oral preparations for diabetes |
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Patent Citations (4)
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|---|---|---|---|---|
| US6555139B2 (en) * | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| CN1437483A (en) * | 1999-12-28 | 2003-08-20 | 味之素株式会社 | Oral preparations for diabetes |
| CN1395560A (en) * | 2000-01-14 | 2003-02-05 | 布里斯托尔-迈尔斯斯奎布公司 | Glyburide composition |
| CN1391890A (en) * | 2002-08-05 | 2003-01-22 | 成都恒瑞制药有限公司 | Oral melbine hydrocloride slow-releasing prepn and its preparing method |
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