CN106405028A - Application of dissolution tester in evaluation on bioequivalence of sevelamer carbonate tablets - Google Patents
Application of dissolution tester in evaluation on bioequivalence of sevelamer carbonate tablets Download PDFInfo
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Abstract
The invention discloses application of dissolution tester in the evaluation on bioequivalence of sevelamer carbonate tablets; the evaluation on bioequivalence of sevelamer carbonate tablets includes study on dynamic phosphate binding force, study on balanced phosphate binding force and the like; data of phosphate binding force is acquired by analysis through Langmuir equation; mass experiments prove that it is fully feasible to replace a water bath shaker with a dissolution tester to carry out the study on phosphate binding force of sevelamer carbonate tablets, the defects of the water bath shaker are overcome by the application of the dissolution tester, more convenient and controllable sample experimenting is achieved, and the evaluation on the bioequivalence of sevelamer carbonate tablets is more facilitated accordingly.
Description
Technical field
The invention belongs to medical research and development technology field, it is related to a kind of new opplication of digestion instrument, specifically, is applied to carbonic acid
The oxidetic research of sevelamer piece phosphorus.
Background technology
2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate is a kind of cross-linked polymer that will not be absorbed by the body, and is the activity one-tenth of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece
Point.It carries multiple amidos, is connected with polymer backbone by a carbon atom, chemical structural formula is as follows：
Wherein, a and b represents primary amine group number, and a+b=9；
C represents crosslinked group number, and c=1；
M represents the quantity of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate in extension polymer network.
2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate is water insoluble, and the mechanism of action is similar to sevelamer hydrochloride, by oral, in the effect of stomach hydrochloric acid in gastric juice
Under, generate sevelamer hydrochloride.These amidos can be combined with phosphoric acid molecules with ion exchange and hydrogen bond in enteron aisle, formed insoluble,
Do not absorbed phosphoric acid sevelamer compound, eventually through swill, excrement excretes.2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate passes through to combine
Phosphorus in enteron aisle, reduces local phosphate concentration, thus reducing the effect of internal serium inorganic phosphorus concentration, for treating end-stage renal disease
Syndrome patients' high phosphorus disease.
There is document report, to 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate, sevelamer hydrochloride and 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece, sevelamer hydrochloride piece
The oxidetic research of phosphorus, generally uses shaking bath to carry out at present.But shaking bath specification nowadays on the market,
Mode of operation differs, and is difficult to unification, thus leading to its repeatability and navigability not good.However, there is no at present with regard to digestion instrument
It is applied to the report of this purpose research.Compared with shaking bath, digestion instrument is being unified standard configuration on the market, has unified tight
The correction code of lattice and operational procedure, easily controllable at the trial and operation, there is good repeatability and operability.
Content of the invention
It is an object of the invention to provide the new application of digestion instrument, specifically there is provided digestion instrument and evaluating carbonic acid department Wella
Application in nurse piece phosphoric acid adhesion.
For realizing above-mentioned technical purpose, reach above-mentioned technique effect, the present invention is achieved through the following technical solutions：
Application in the evaluation of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence for the digestion instrument, described 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence is evaluated
Including dynamic phosphate radical adhesion research, and phosphoric acid adhesion research etc. during balance, the oxidetic data of described phosphorus is to adopt
Analyze gained with langmuir equation, calculation equation is as follows：
Wherein,
CeqRepresent the phosphate concentration in balance solution（MM）；
X represents the amount combining phosphoric acid in balance sevelamer（MM）；
M represents sevelamer usage amount（Gram）；
X/m represents the content of phosphate bonding unit weight polymer（MM/gram）；
K1 represents affinity constant；
K2 represents Langmuir force constant.
Described, described
Wherein,
A represent byWith CeqThe slope of the straight line being formed in rectangular coordinate system；
B represent byWith CeqThe intercept of the straight line being formed in rectangular coordinate system.
2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece involved in the present invention, its composition proportion（%w/w）As follows：
Active component：2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate 78.79%；
Diluent：Microcrystalline cellulose -102 13.92%；
Stabilizer：Sodium carbonate 0.10%；
Lubricant：Zinc stearate 0.19%；
Adhesive：Water 7.00%.
The invention has the beneficial effects as follows：
Experimental results demonstrate that replacing shaking bath to carry out 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphate adhesion research using digestion instrument has been
Entirely feasible, the application of digestion instrument overcomes the defect of shaking bath, realizes more convenient, more controlled sample preparation, thus more
It is easy to the evaluation of bioequivalence of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece.
Described above is only the general introduction of technical solution of the present invention, in order to better understand the technological means of the present invention,
And can be practiced according to the content of specification, below with presently preferred embodiments of the present invention and coordinate accompanying drawing describe in detail as after.
The specific embodiment of the present invention is shown in detail in by following examples and its accompanying drawing.
Brief description
Accompanying drawing described herein is used for providing a further understanding of the present invention, constitutes the part of the application, this
Bright schematic description and description is used for explaining the present invention, does not constitute inappropriate limitation of the present invention.In the accompanying drawings：
Fig. 1 is the chromatogram of phosphate radical solution.
Fig. 2 is in pH4（Without acid treatment）The curve map of lower 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphate adhesion.
Fig. 3 is that the water-bath 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphate of 15 minutes and 30 minutes is tied respectively under different digestion instrument rotating speeds
The curve map made a concerted effort.
Fig. 4 is the Langmuir in the lower 800 milligrams of H10-NB513-65 type 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphate adhesions of pH 7
Figure.
Fig. 5 is the Langmuir of 800 milligrams of H10-NB513-65 type 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphate adhesions under pH4
Figure.
Fig. 6 is in pH7（Without acid treatment）Lower 800 milligrams of renvela tablets and 800 milligrams of H10-NB513-65 type carbonic acid
The Langmuir figure of sevelamer piece.
Fig. 7 is in pH4（Through peracid treatment）Lower 800 milligrams of renvela tablets and 800 milligrams of H10-NB513-65 type carbonic acid
The Langmuir figure of sevelamer piece.
Specific embodiment
In order to be better understood from the essence of the present invention, below by with the contrast experiment of digestion instrument and shaking bath and result Lai
Its application in 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphoric acid adhesion research is described.
Application in the evaluation of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence for the digestion instrument, described 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence is evaluated
Including dynamic phosphate radical adhesion research, and phosphoric acid adhesion research etc. during balance, the oxidetic data of described phosphorus is to adopt
Analyze gained with langmuir equation, calculation equation is as follows：
Wherein,
CeqRepresent the phosphate concentration in balance solution（MM）；
X represents the amount combining phosphoric acid in balance sevelamer（MM）；
M represents sevelamer usage amount（Gram）；
X/m represents the content of phosphate bonding unit weight polymer（MM/gram）；
K1 represents affinity constant, and affinity constant depends on the intensity of each active force in cohesive process；
K2 represents Langmuir force constant, is known that the 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate multipotency of per unit weight from Langmuir force constant
In conjunction with how many phosphate radicals.
Knowable to balance Binding experiment, CeqCan obtain, unit be mM, m is a known coefficient, unit be gram, x
C can be deducted by initial phosphate concentrationeqAfter obtain.
Rectangular co-ordinate fasten byWith CeqConstitute straight line.Linear analysis by produce line slope（a）With
Intercept（b）.Affinity constant can be calculated by slope and intercept（k1）With Langmuir force constant（k2）, computing formula is such as
Under：
；
Wherein,
A represent byWith CeqThe slope of the straight line being formed in rectangular coordinate system；
B represent byWith CeqThe intercept of the straight line being formed in rectangular coordinate system.
2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece involved by the present embodiment, its composition proportion（%w/w）As follows：
Active component：2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate 78.79%；
Diluent：Microcrystalline cellulose -102 13.92%；
Stabilizer：Sodium carbonate 0.10%；
Lubricant：Zinc stearate 0.19%；
Adhesive：Water 7.00%.
It is used for studying the oxidetic effect of phosphorus to assess digestion instrument, we compare to shaking bath and digestion instrument
Research, comparative result such as table 1 below.
Table 1 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate tablet is in the phosphate binding constant of pH 4 and pH 7
Chromatography of ions detection method is used for detecting free phosphate radical, its typical chromatogram is as shown in Figure 1.
For shaking bath, shown in Figure 2, investigate respectively in 38.7 mM phosphoric acid solutions, 75 rpm and pH4.0
Under the conditions of（Without peracid treatment）, different time points（5,10,15,30,60,120,180,300,360,480 points
Clock）Dynamic phosphate radical adhesion.
The result of Fig. 2 shows, with shaking bath 75 rpm, 5 hours to can be only achieved water-bath balance.
For digestion instrument, referring to shown in Fig. 3 and Biao 2, having investigated respectively in 38.7 mM phosphoric acid solutions and pH4.0 condition
Under（Without peracid treatment）, different rotating speeds（50,75,100,125,150,200 rpm）, different time points（15, 30, 45,
60,90,120,240,360 minutes）Dynamic phosphate radical adhesion.Result such as table 2 below：
The phosphate radical adhesion mean value of table 2 different digestion instrument rotating speeds under pH4.0（mmol/g）
The data that test period in table 2 is 15 minutes and 30 minutes is formed in the 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate under different digestion instrument rotating speeds
The curve map of piece phosphate adhesion, as shown in Figure 3.
Show from the result of Fig. 3 and Biao 2, water-bath 30 minutes is the optimum balance time.
According to U.S. FDA to 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece in vitro bioequivalence research suggestion, respectively at least eight not
With under concentration（1.0,2.5,5.0,7.5,10.0,14.5,30.0,38.7 mM）Carry out potassium dihydrogen phosphate equilibrant force research
（PH4 and pH7）.Result of study is as shown in table 3：
Table 3 uses shaking bath and digestion instrument to measure the ratio of the phosphate binding constant in pH 4 and pH 7 for the 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece
Relatively
Can be seen that from the result of table 3 and Fig. 4-7 replaces shaking bath to carry out 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece phosphate radical using digestion instrument
Adhesion research is feasible, and the application of digestion instrument overcomes the defect of shaking bath, realizes more convenient, more controlled sample
Product are tested, thus the evaluation of bioequivalence of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece of being more convenient for.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (2)
1. application in the evaluation of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence for the digestion instrument, described 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence is commented
Valency includes phosphoric acid adhesion research when dynamic phosphate radical adhesion research and balance, and the oxidetic data of described phosphorus is employing
Langmuir equation analyzes gained, and calculation equation is as follows：
Wherein,
CeqRepresent balance solution in phosphate concentration, unit be mM；
X represent balance sevelamer combine phosphoric acid amount, unit be mM；
M represents sevelamer usage amount, unit be gram；
X/m represents the content of phosphate bonding unit weight polymer, and unit is mM/gram；
K1 represents affinity constant；
K2 represents Langmuir force constant.
2. application in the evaluation of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate piece bioequivalence for the digestion instrument according to claim 1, its feature exists
In：
；
Wherein,
A represent byWith CeqThe slope of the straight line being formed in rectangular coordinate system；
B represent byWith CeqThe intercept of the straight line being formed in rectangular coordinate system.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110687263A (en) * | 2019-09-27 | 2020-01-14 | 方达医药技术（苏州）有限公司 | Application of dissolution instrument in evaluating bioequivalence of sevelamer carbonate tablet |
| CN112816575A (en) * | 2020-12-29 | 2021-05-18 | 平光制药股份有限公司 | Analysis method for phosphate binding force of sevelamer carbonate |
| CN117092274A (en) * | 2023-07-14 | 2023-11-21 | 国药集团致君（深圳）坪山制药有限公司 | Method for determining sevelamer carbonate content |
Citations (2)
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| US20070098678A1 (en) * | 2003-12-31 | 2007-05-03 | Bhagat Hitesh R | Enteric coated aliphatic amine polymer bile acid sequestrants |
| CN204008621U (en) * | 2014-05-15 | 2014-12-10 | 新疆富科思生物技术发展有限公司 | A kind of high-precision intelligent dissolution rate instrument |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070098678A1 (en) * | 2003-12-31 | 2007-05-03 | Bhagat Hitesh R | Enteric coated aliphatic amine polymer bile acid sequestrants |
| CN204008621U (en) * | 2014-05-15 | 2014-12-10 | 新疆富科思生物技术发展有限公司 | A kind of high-precision intelligent dissolution rate instrument |
Non-Patent Citations (2)
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| 刘峙嵘等: "泥煤吸附镍Langmuir等温式：线性与非线性方法对比", 《功能材料》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110687263A (en) * | 2019-09-27 | 2020-01-14 | 方达医药技术（苏州）有限公司 | Application of dissolution instrument in evaluating bioequivalence of sevelamer carbonate tablet |
| CN112816575A (en) * | 2020-12-29 | 2021-05-18 | 平光制药股份有限公司 | Analysis method for phosphate binding force of sevelamer carbonate |
| CN117092274A (en) * | 2023-07-14 | 2023-11-21 | 国药集团致君（深圳）坪山制药有限公司 | Method for determining sevelamer carbonate content |
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