CN101744725B - Optimization method for coating process parameter of sustained-release pellets - Google Patents

Abstract

The invention relates to an optimization method for a coating process parameter of sustained-release pellets, which comprises the following steps: at least one coating process parameter of the sustained-release pellets is selected and corresponding coating process value is set according to the selected coating process parameter; the sustained-release pellets are prepared according to the coating process value of the set sustained-release pellets; a coating quality characteristic parameter of the sustained-release pellets is selected and the corresponding coating quality characteristic value of the prepared sustained-release pellets is measured; a regression equation is built according to the set coating process value and the measured coating quality characteristic value; the set coating process value of the sustained-release pellets is substituted in the built regression equation to verify whether the regression equation has accuracy or not; and the ideal coating quality characteristic value of the sustained-release pellets is selected to optimize the coating process value according to the verified regression equation.

Description

The optimization method of coating process parameter of sustained-release pellets

Technical field

The present invention relates to a kind of optimization method of coating process parameter of sustained-release pellets, belong to the drug manufacture field.

Background technology

Adopting end spray fluid bed to carry out coating of pellets, to prepare sustained-release preparation be a kind of novel preparation technique that develops rapidly in the world, it is steady with blood drug level, toxic and side effects is little, take number of times few, can take together with liquid, the characteristics such as relative low price are subjected to numerous doctors and patient's welcome deeply, market prospect is very good.At the bottom of the fluid bed spray coating be by the air flow that rises rapidly with micropill in the indoor suspension fluidisation of coating, make it to be in ceaselessly flow regime, coating solution or suspension atomizing are sprayed into, namely be wrapped in the micropill surface, and the thermal air current that is passed into is dry, and coating is until increase weight to desired thickness repeatedly.In recent years, along with the development of sustained-release preparation, adopt the slow controlled release micro pill of end spray packaging technique preparation to become a widely used technology.

At present, the coating of pellets that adopts end spray technique to carry out is applicable to drug dose little mostly, the medicine good water solubility or in water dispersibility better.General technology is all take the sucrose of blank or cellulose pill core as the basis, and bag is with three layers or four layers even more clothing film, thereby reaches the speed of control drug release.Its function of different clothing films is different, generally is respectively from the inside to surface: medicine layer, sealing coat, slow release layer and protective layer.Medicine layer mainly adopts the solution of medicine or the suitable macromolecular material of suspension adding to be sprayed on the formation of micropill surface, and its Main Function is medicament-carried; Sealing coat is one deck general thin clothing layer that wraps between medicine layer and the control sustained release coating layer, avoids controlling polymer solvent dissolving some drugs molecule in the sustained release coating layer coating process, and drug molecule is embedded in the control extended release coatings film; Slow release layer then is comprised of specific slow-release material, hinders the release of medicine by different mechanisms, by the consumption of adjusting slow release layer and the release that thickness comes regulating drug; Protective layer generally is wrapped in the outermost layer of micropill, works to prevent the slow release layer wearing and tearing and improves outward appearance.

As from the foregoing, the prescription of slow-release micro-pill forms more complicated, corresponding art for coating parameter is produced the many of complexity more than general tablet or injection liquor, wherein control technological parameter many, if it is improper to control, may cause in the coating process micropill bonding, the principal agent loss is excessive or long etc. the problem of product release profiles difference, greatly affects production efficiency and product quality.Therefore, suitable technological parameter and the strict control technical process of screening is the key factor that guarantees product quality.Spray fluid bed in the general end needs the parameter of control that two kinds of fixing parameter and adjustable parameters are arranged.Preset parameter comprises the sieve plate specification, nozzle diameter, the density of filter bag and kind etc.Adjustable parameter refers to can to adjust with the condition of production in process of production, control ratio is more flexible, impact on product is also larger, and this part parameter comprises hydrojet speed, hydrojet pressure, inlet temperature, air quantity, weight of material, micropill particle size distribution, hydrojet viscosity, spouting liquid, coating time etc.Environmental factors also all may affect the production of coating of pellets product such as temperature, humidity in addition.When carrying out parameter optimization, generally fix other parameters, select one or several technological parameter as variable, and be optimized for it.

Parameter fitting by multifactor many indexs obtains regression equation, and in order to select and the production control process conditions, it is a hot research problem in the pharmaceutical manufacturing in recent years, such as patent 200710047288.0, " optimizing feruloylated dibutyrated acylglycerol thin layer chromatography developer using uniform design method ", reach the simplification purification procedures with regard to the method that has adopted multiple regression analysis, the purpose of increasing work efficiency.

As everyone knows, in the industrialization of sustained-release preparation, the parameter that end spray fluid bed need to be controlled is more, and is difficult to control, therefore the repeatability of the control of technical process and product quality is an industry difficult problem, exists a lot of uncertain.Present most of enterprise relies on experienced skilled industrial worker to control technical process, guarantee process stabilizing, but this sustainable development for long-term production and enterprise is pernicious.Therefore, set up a kind of process parameter control system of scientific and quantification, extremely important for the production of slow-release micro-pill.

Summary of the invention

Technical problem to be solved by this invention is that the technical process control and the product quality reproduction that overcome the slow-release micro-pill coating production exist a lot of probabilistic deficiencies.

The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of optimization method of coating process parameter of sustained-release pellets, and the method may further comprise the steps:

Step 10, select the coating process parameter of at least one slow-release micro-pill, and set corresponding coating process numerical value according to the coating process parameter of selecting;

Step 11, according to the coating process numerical value of the slow-release micro-pill of setting, prepare slow-release micro-pill;

The coating quality characterisitic parameter of step 12, selected slow-release micro-pill, and measure the corresponding coating quality intrinsic numeric of the slow-release micro-pill of preparing;

Step 13, according to the coating process numerical value of setting and the coating quality intrinsic numeric of mensuration, set up regression equation;

Step 14, with the regression equation that the coating process numerical value substitution of the slow-release micro-pill of described setting is set up, verify whether described regression equation has accuracy, if having accuracy, then execution in step 15, if do not have accuracy, then execution in step 10;

Step 15, according to the regression equation through checking, the coating quality intrinsic numeric of selected desirable slow-release micro-pill is optimized coating process numerical value.

The invention has the beneficial effects as follows: many for technological parameter in the present slow-release micro-pill coating production, unmanageable problem, various process parameters to the slow-release micro-pill coating production is optimized processing, by the processing parameter and the mass property parameter that affect product quality are carried out regression analysis, obtain corresponding regression equation, and the processing parameter after obtaining to optimize by equation, as a result requirement of different quality according to slow-release micro-pill, obtain corresponding processing parameter, improve operability and the repeatability of technique, and improve the quality based on the slow controlled release product of coating of pellets technology.

Further, described coating process parameter comprises viscosity, the coating liquid density of hydrojet speed, hydrojet pressure, inlet temperature, air quantity, weight of material, micropill particle size distribution, coating solution, pH value, spouting liquid, coating time, ambient temperature or the ambient humidity of coating solution.

Further, described coating quality characterisitic parameter comprises the release of medicine-feeding rate, the uniformity, balanced ratio, micropill flowability, particle size distribution or different time points.

Further, described slow-release micro-pill is prepared by coating equipment in sugar production line, and this coating equipment in sugar production line comprises end spray coating fluid bed.

Further, the described method of setting up regression equation is multifactor multilevel method for designing, comprises orthogonal design method, Parameters design or homogenization method for designing.

Description of drawings

Fig. 1 is the flow chart of the optimization method of coating process parameter of sustained-release pellets of the present invention.

The specific embodiment

Below in conjunction with accompanying drawing principle of the present invention and feature are described, institute gives an actual example and only is used for explaining the present invention, is not be used to limiting scope of the present invention.

Fig. 1 is the flow chart of the optimization method of coating process parameter of sustained-release pellets of the present invention.As shown in Figure 1, the method may further comprise the steps:

Step 10, select the coating process parameter of at least one slow-release micro-pill, and set corresponding coating process numerical value according to the coating process parameter of selecting;

Step 11, according to the coating process numerical value of the slow-release micro-pill of setting, prepare slow-release micro-pill;

The coating quality characterisitic parameter of step 12, selected slow-release micro-pill, and measure the corresponding coating quality intrinsic numeric of the slow-release micro-pill of preparing;

Step 13, according to the coating process numerical value of setting and the coating quality intrinsic numeric of mensuration, set up regression equation;

Step 14, with the regression equation that the coating process numerical value substitution of the slow-release micro-pill of described setting is set up, verify whether described regression equation has accuracy, if having accuracy, then execution in step 15, if do not have accuracy, then execution in step 10;

Step 15, according to the regression equation through checking, the coating quality intrinsic numeric of selected desirable slow-release micro-pill is optimized coating process numerical value.

Described step 14 may further comprise the steps:

The regression equation calculation that step 140, employing obtain goes out the coating quality intrinsic numeric of corresponding slow-release micro-pill;

Step 141, make difference value=| the difference of the coating quality intrinsic numeric of the coating quality intrinsic numeric of the slow-release micro-pill that calculates-mensuration |, judge according to the size of difference value whether the regression equation of setting up has preparatory.

Described step 15 may further comprise the steps:

The coating quality intrinsic numeric of step 150, selected desirable slow-release micro-pill;

Step 151, with the coating quality intrinsic numeric substitution of the described desirable slow-release micro-pill regression equation through checking;

Step 152, calculate the coating process numerical value of corresponding slow-release micro-pill;

The process parameter value that step 153, employing calculate is produced, and detects every mass property parameter.

Described regression equation is divided into regression equation with one unknown and multiple regression equation.In setting up the process of regression equation, namely carry out in the regression analysis process, if two or more independent variables are arranged, just be called multiple regression.In fact, a kind of phenomenon usually interrelates with a plurality of factors, is jointly predicted or is estimated dependent variable by the optimum combination of a plurality of independent variables, than only predicting with an independent variable or estimating more effective, more realistic.Therefore multiple regression is larger than the Practical significance of simple regression.

At present multiple regression has been widely used among the data statistics of new drug clinical experiment and clinical treatment.The method that adopts Multiple regression statistics to analyze, optimize preparation production technique, can carry out analysis-by-synthesis to the parameter that several units are different, meaning is different, analyze different single factors and interaction factor for the influence degree of target component, thereby reach the purpose of optimal control.The instrument that can be used at present regression analysis is a lot, mostly adopts ripe computer software such as SAS, SPSS, EXCEL, Mathlab etc.

Described slow-release micro-pill is chosen buspirone hydrochloride, below take buspirone hydrochloride as specific embodiment this optimization method is described in detail.

Buspirone hydrochloride is antianxiety drugs, and is soluble in water, and suitable exploitation becomes film coated slow release preparation.The prescription of buspirone hydrochloride slow-release micro-pill is comprised of three layers of coating, is respectively medicine layer, and sealing coat and slow release layer are specifically write out a prescription composed as follows: the blank sucrose ball core of 500 grams; The medicine-feeding layer that comprises 30 gram buspirone hydrochlorides, 4 gram hydroxypropyl emthylcelluloses (Hydroxypropylmethyl cellulose is called for short HPMC), 1 gram Polyethylene Glycol, 2.5 gram Pulvis Talci and 100 ml waters; Comprise 8 gram hydroxypropyl emthylcelluloses, 0.8 gram Polyethylene Glycol and 100 ml water sealing coats; The mass ratio of Aquacoat and water is the slow release layer of 4:3; And the protective layer that comprises 8 gram hydroxypropyl emthylcelluloses, 0.8 gram Polyethylene Glycol and 100 ml waters.

For making things convenient for the industrialization of piller coating, adopt computer software SAS and Three factors-levels orthogonal experiment design that the coating process parameter of buspirone slow-release micro-pill is optimized, concrete optimization method may further comprise the steps:

Step a: select hydrojet pressure, hydrojet speed and inlet temperature as the coating process parameter of buspirone slow-release micro-pill, and set corresponding coating process numerical value according to the coating process parameter of selecting.

Consider that hydrojet pressure, hydrojet speed and inlet temperature are on three larger coating process parameters of coating result impact, therefore select these three coating process parameters and set corresponding coating process numerical value.The setting of corresponding coating process numerical value needs the accumulation of lot of experimental data.The mode of data accumulation of the present invention mainly contains two kinds: the first: for existing product on the market, can carry out by daily production the accumulation of data, along with the carrying out that produces, thereby obtain a large amount of random data, accumulate more essential information, constantly technique is optimized and improves; The second: for the product that has just gone on the market, there is not sufficient creation data, can pass through specific experimental design method, carry out the experiment of limited number of times, carry out regression analysis as the basis take some more representational data, and the calculation optimization parameter, for formal large production is laid a good foundation.

The buspirone hydrochloride of choosing in the embodiment of the invention is existing product on the market, therefore the mode of coating process numerical value accumulation adopts the mode of the first data accumulation.As shown in table 1, be coating process parameter and the corresponding coating process numerical value of buspirone hydrochloride slow-release micro-pill selection.Wherein, make X represent coating process parameter, Z represents the group number that different coating process numerical value form.

Coating process parameter and corresponding coating process numerical value that table 1 buspirone hydrochloride slow-release micro-pill is selected

According to the Three factors-levels orthogonal experiment design, on the basis of table 1, obtain about the coating process parameter of selection and the orthogonal array of corresponding coating process numerical value, as shown in table 2, amount to 9 groups of coating process numerical value.

The coating process parameter that table 2 buspirone hydrochloride slow-release micro-pill is selected and the orthogonal array of corresponding coating process numerical value

Step b: according to the coating process numerical value of the buspirone slow-release micro-pill of setting, prepare the buspirone slow-release micro-pill.

The coating equipment in sugar production line of described preparation buspirone slow-release micro-pill is fluid bed, and the preferred fluid bed of the present embodiment is spray coating fluid bed at the bottom of the Glatt GPCG1.1 type.

The technological parameter of fluid bed is set as respectively above-mentioned 9 groups coating process numerical value, prepares 9 kinds of different buspirone slow-release micro-pill.

Step c: select the coating quality characterisitic parameter of buspirone slow-release micro-pill, and measure the corresponding coating quality intrinsic numeric of the buspirone slow-release micro-pill of preparing.

With respect to common oral solid formulation, the mass property parameter that slow-release micro-pill need to be controlled is also many.Topmost several mass property parameter has each point etc. on medicine-feeding rate, the uniformity, balanced ratio, micropill flowability, particle size distribution, the release profiles.Wherein, medicine-feeding rate and balanced ratio mainly are the indications to production efficiency, if these two indexs are excessively low, illustrate that then material loss is excessive.Each point characterizes the release conditions of micropill on the different time points on the release profiles, and this is one of of paramount importance quality control index of slow-release micro-pill, and release profiles can reappear, and then can guarantee therapeutic effect and the safety of preparation.Selected medicine-feeding rate and release rate are the coating quality characterisitic parameter of buspirone slow-release micro-pill in the present invention.Wherein, release rate is measured respectively 1 hour Cumulative release amount of buspirone slow-release micro-pill, 4 hours Cumulative release amounts and 12 hours Cumulative release amounts.

According to 9 kinds that prepare different buspirone slow-release micro-pill, the coating quality intrinsic numeric of specific this micropill is as shown in table 3 respectively.Wherein, make Y represent the coating quality characterisitic parameter, W represents the lot number of 9 kinds of different buspirone slow-release micro-pill, the first release rate is expressed as 1 hour Cumulative release amount of buspirone slow-release micro-pill, the second release rate is expressed as 4 hours Cumulative release amounts of buspirone slow-release micro-pill, and the 3rd release rate is expressed as 12 hours Cumulative release amounts of buspirone slow-release micro-pill.

The coating quality characterisitic parameter that table 3 buspirone slow-release micro-pill is selected and the coating quality intrinsic numeric of mensuration

Steps d: according to the coating process numerical value of buspirone slow-release micro-pill setting and the coating quality intrinsic numeric of mensuration, set up multiple regression equation.

The present invention carries out the multivariate statistics regression fit by SAS data statistic analysis software, can realize the regression analysis to different factor forms, such as X, X ², X ³, X-1,1gX and interaction factor x ₁x ₂, x ₂x ₃, x ₁x ₃, x ₁x ₂x ₃Deng, investigate x value corresponding to multi-form X for the impact of y value corresponding to Y, obtain accurately regression fit equation.Wherein, x represents coating process numerical value, x ₁Expression hydrojet pressure, x ₂Expression hydrojet speed, x ₃The expression inlet temperature, y represents coating quality intrinsic numeric, y ₁Represent the numerical value that the first release rate is corresponding, y ₂The numerical value that the second release rate is corresponding, y ₃The numerical value that the 3rd release rate is corresponding, y ₄The numerical value that the medicine-feeding rate is corresponding.Find through fitting result, with equation (1)

$y=f(x_1,x_2,x_3)=\mathrm{\α}+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_i{x}_i+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_i{x}_i^2+\mathrm{\ϵ}---\left(1\right)$

Degree of fitting best, wherein α represents constant term, β is variation coefficient, ε represents other random error.

According to above result, final y1～y4 for the fit equation group (2) of x is:

$\left\{\begin{array}{c}{y}_1=3.99542-0.48967x_1-0.03871x_2-0.11207x_3+0.11331x_1^2+0.00124x_2^2+0.00101x_3^2\\ y_2=2.06975-0.09792x_1-0.00240x_2-0.05117x_3+0.02673x_1^2+0.00046211x_3^2\\ y_3=1.69370+0.27138x_1+0.01650x_2-0.04360x_3-0.05866x_1^2-0.00075179x_2^2+0.00040239x_3^2\\ y_4=2.23384+0.23281x_1+0.00501x_2-0.05619x_3-0.05949x_1^2-0.00013470x_2^2+0.00050250x_3^2\end{array}\right.---\left(2\right)$

Step e: in the coating process numerical value substitution equation group (2) with the buspirone slow-release micro-pill of described setting, whether checking equation group (2) has accuracy, if having accuracy, and execution in step f then, if do not have accuracy, execution in step a then.

In order to verify the fitting effect of equation group (2), 9 groups in the table 2 different x values are updated in the equation group (2), calculate the coating quality intrinsic numeric of corresponding buspirone slow-release micro-pill, be called theoretical value.Measure the coating quality intrinsic numeric of buspirone slow-release micro-pill out among the step c, be called measured value.Theoretical value and measured value are compared, and the result is as shown in table 4.As can be seen from Table 4, the deviation of theoretical value and measured value is all little, have in addition be 0, illustrate that the equation group (2) of setting up is accurately.

The theoretical value of table 4 buspirone slow-release micro-pill and measured value are relatively

Step f: according to the equation group (2) through checking, select the coating quality intrinsic numeric of desirable buspirone slow-release micro-pill and optimize coating process numerical value.

In the release situation within the specific limits of the coating quality intrinsic numeric of desirable buspirone slow-release micro-pill such as medicine, can reach higher medicine-feeding rate.In an embodiment of the present invention, the first release rate is controlled between 7.5% to 12.5%, and the second release rate is controlled between 50% to 55%, and the 3rd release rate is controlled between 87.5% to 92.5%, so that the medicine-feeding rate reaches the highest.

Namely at constraints y ₁(0.0750.125), y ₂(0.50.55), y ₃(0.8750.925) lower definite y ₄The x of optimum control ₁, x ₂, x ₃That is:

$\underset{x_1,x_2,x_3}{\mathrm{Max}}{y}_4=f(x_1,x_2,x_3)={\mathrm{\α}}_4+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{4i}{x}_i+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{4i}{x}_i^2+{\mathrm{\ϵ}}_4$

Constraints is:

$\left\{\begin{array}{c}{y}_1=f(x_1,x_2,x_3)={\mathrm{\α}}_1+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{1i}{x}_i+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{1i}{x}_i^2+{\mathrm{\ϵ}}_1\\ y_2=f(x_1,x_2,x_3)={\mathrm{\α}}_2+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{2i}{x}_i+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{2i}{x}_i^2+{\mathrm{\ϵ}}_2\\ y_3=f(x_1,x_2,x_3)={\mathrm{\α}}_3+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{3i}{x}_i+\underset{i=1}{\overset{3}{\mathrm{\Σ}}}{\mathrm{\β}}_{3i}{x}_i^2+{\mathrm{\ϵ}}_3\end{array}\right.$

Select suitable x ₁.x ₂, x ₃, so that y ₁, y ₂, y ₃Meet constraint, and under this condition, make y ₄Maximum.

As shown in table 5, the random x that selects in the scope of experiment value ₁=2.0, x ₂=15, x ₃=55 as initial value, this initial value is brought in the corresponding program of computer, the parameter after computer can obtain to optimize automatically, thus parameter is optimized, and approaching the coating that carries out new a collection of buspirone slow-release micro-pill under the condition that obtains parameter, measure release and medicine-feeding rate.

Experimental result after parameter after the optimization of table 5 buspirone slow-release micro-pill and the optimization

Can find out by above result, appliance computer software, the method for available data being analyzed and further controlled technological parameter is feasible.By changing fit equation, adjust optimal conditions, can also further carry out optimal control to other parameter such as the uniformity of medicine-feeding, the release of other times point, guarantee that the technique repeatability of every batch of product reaches best state.

The above only is preferred embodiment of the present invention, and is in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (5)

1. the optimization method of a coating process parameter of sustained-release pellets is characterized in that may further comprise the steps:

Step 10, select the coating process parameter of at least one slow-release micro-pill, and set corresponding coating process numerical value according to the coating process parameter of selecting;

Wherein said slow-release micro-pill is buspirone hydrochloride, as shown in table 1, be coating process parameter and the corresponding coating process numerical value of buspirone hydrochloride slow-release micro-pill selection, wherein, make X represent coating process parameter, Z represents the group number that different coating process numerical value form:

，

According to the Three factors-levels orthogonal experiment design, on the basis of table 1, obtain about the coating process parameter of selection and the orthogonal array of corresponding coating process numerical value, as shown in table 2, amount to 9 groups of coating process numerical value:

；

Step 11, according to the coating process numerical value of the slow-release micro-pill of setting, prepare slow-release micro-pill;

The coating quality characterisitic parameter of step 12, selected slow-release micro-pill, and measure the corresponding coating quality intrinsic numeric of the slow-release micro-pill of preparing; Wherein, according to 9 kinds that prepare different buspirone slow-release micro-pill, measure respectively the coating quality intrinsic numeric of this micropill, as shown in table 3, wherein, make Y represent the coating quality characterisitic parameter, W represents the lot number of 9 kinds of different buspirone slow-release micro-pill, and the first release rate is expressed as 1 hour Cumulative release amount of buspirone slow-release micro-pill, and the second release rate is expressed as 4 hours Cumulative release amounts of buspirone slow-release micro-pill, the 3rd release rate is expressed as 12 hours Cumulative release amounts of buspirone slow-release micro-pill

；

Step 13, according to the coating process numerical value of setting and the coating quality intrinsic numeric of mensuration, set up regression equation:

$\left\{\begin{array}{c}{y}_1=3.99542-0.48967x_1-0.03871x_2-0.11207x_3+0.11331x_1^2+0.00124x_2^2+0.00101x_3^2\\ y_2=2.06975-0.09792x_1-0.00240x_2-0.05117x_3+0.02673x_1^2+0.00046211x_3^2\\ y_3=1.69370+0.27138x_1+0.01650x_2-0.04360x_3-0.05866x_1^2-0.00075179x_2^2+0.00040239x_3^2\\ y=2.23384+0.23281x_1+0.00501x_2-0.05619x_3-0.05949x_1^2-0.00013470x_2^2+0.00050250x_3^2\end{array}\right.$ ，

Wherein, x represents coating process numerical value, x ₁Expression hydrojet pressure, x ₂Expression hydrojet speed, x ₃The expression inlet temperature, y represents coating quality intrinsic numeric, y ₁Represent the numerical value that the first release rate is corresponding, y ₂The numerical value that the second release rate is corresponding, y ₃The numerical value that the 3rd release rate is corresponding, y ₄The numerical value that the medicine-feeding rate is corresponding;

Step 14, with the regression equation that the coating process numerical value substitution of the slow-release micro-pill of described setting is set up, verify whether described regression equation has accuracy, if having accuracy, then execution in step 15, if do not have accuracy, then execution in step 10;

Step 15, according to the regression equation through checking, the coating quality intrinsic numeric of selected desirable slow-release micro-pill is optimized coating process numerical value.

2. the optimization method of coating process parameter of sustained-release pellets according to claim 1, it is characterized in that: described slow-release micro-pill is prepared by coating equipment in sugar production line, and this coating equipment in sugar production line comprises end spray coating fluid bed.

3. the optimization method of coating process parameter of sustained-release pellets according to claim 1, it is characterized in that: the described method of setting up regression equation is multifactor multilevel method for designing, comprises orthogonal design method, Parameters design or homogenization method for designing.

4. the optimization method of coating process parameter of sustained-release pellets according to claim 1, it is characterized in that: the described regression equation that the coating process numerical value substitution of the slow-release micro-pill set is set up, verify that the step of described regression equation accuracy may further comprise the steps:

The regression equation calculation that step 140, employing obtain goes out the coating quality intrinsic numeric of corresponding slow-release micro-pill;

Step 141, make the difference ︱ of the coating quality intrinsic numeric of the coating quality intrinsic numeric of the slow-release micro-pill that difference value=︱ calculates-mensuration, judge according to the size of difference value whether the regression equation of setting up has preparatory.

5. the optimization method of coating process parameter of sustained-release pellets according to claim 1, it is characterized in that according to described regression equation through checking, the coating quality intrinsic numeric optimization coating process numerical value of selecting desirable slow-release micro-pill may further comprise the steps:

The coating quality intrinsic numeric of step 150, selected desirable slow-release micro-pill;

Step 151, with the coating quality intrinsic numeric substitution of the described desirable slow-release micro-pill regression equation through checking;

Step 152, calculate the coating process numerical value of corresponding slow-release micro-pill;

The process parameter value that step 153, employing calculate is produced, and detects every mass property parameter.

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