CN104042587A - Neogambogic acid osmotic pump type sustained-release preparation and preparation method thereof - Google Patents
Neogambogic acid osmotic pump type sustained-release preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a neogambogic acid osmotic pump type sustained-release preparation and a preparation method thereof. The sustained-release preparation comprises a neogambogic acid osmotic pump type sustained-release tablet, which is a monolithic osmotic pump type sustained-release table, wherein the neogambogic acid osmotic pump type sustained-release tablet comprises a tablet core and a sustained-release semipermeable coating film, and the weight of the sustained-release semipermeable coating film is 2-5 percent that of the tablet core; the tablet core comprises the following components in percentage by weight: 2-10 percent of neogambogic acid, 25-35 percent of osmotic active substances, 10-25 percent of co-solvent, 10-25 percent of a suspending agent and the balance of filler and/or lubricate; the semipermeable film coating liquid of the sustained-release semipermeable coating film is prepared from the following components according to the weight and volume ratio: 2-5 percent (mg/ml) of a coating material, 0.5-5 percent (mg/ml) of plasticizer and 3-15 percent (mg/ml) of pore-foaming agent. The neogambogic acid osmotic pump type sustained-release preparation has the characteristic of zero-grade drug release, is high in drug release efficiency and simple in preparation process, and is suitable for industrial production.
Description
Technical field
The present invention relates to neogambogic acid osmotic pump type controlled release preparation and preparation method thereof.
Background technology
Neogambogic acid (Gambogenic acid, GNA) be isolated a kind of compound having compared with high anti-tumor activity from Chinese medicine gamboge, it belongs to weakly acidic slightly solubility material, its anticancer spectrum is wide, toxicity is lower, to Non-small cell lung carcinoma cell A549, KB cell CNE-1, HePG2 cell and the propagation of S180 cell strain is all had to obvious inhibitory action.Its promotion and application are clinically limited but biological half-life is short because the poor dissolubility of neogambogic acid water solublity is low, blood vessel irritation is large, in body.
Osmotic pump type controlled release preparation is using osmotic pressure as release power, a kind of preparation technique taking zero level release dynamics as feature, after taking, moisture enters label from clothing film (semipermeable membrane), make the very high osmotic pressure of formation in sheet, thereby the saturated aqueous solution of medicine in sheet is disengaged by the drug release hole on sheet surface.Keep osmotic pressure constant, can keep moisture to enter the constant airspeed of label, and then make the constant rate of macromolecular material imbibition, maintain lasting constant osmotic pressure, reach rate of releasing drug constant.The development of osmotic pump type controlled release preparation is carried out mainly for two class medicines, it comprises water soluble drug and insoluble drug: for most of water soluble drugs (dissolubility is 5-30g/ml), it relatively easily makes primary osmotic pump (EOP).But for insoluble drug, because its dissolubility (C
s) lower, in the microenvironment of label, be difficult to form higher concentration and osmotic pressure and maintain effective drug release rate, or maintain lasting constant osmotic pressure and need a large amount of osmotic pressure promoter (having exceeded the heavy scope of normal sheet), therefore, insoluble drug can not be made single chamber primary osmotic pump (EOP) (single chamber primary osmotic pump claims again single chamber mono-layer osmotic pump) conventionally as water soluble drug, and to take double layer osmotic pump (or being called push-pull type osmotic pumps) preparation technique, make medicine and medicated layer macromolecule be propelled floor height molecule with suspension form and release drug release hole, reach the object of constant speed release medicine.Therefore, insoluble drug is not only difficult to be prepared into single chamber primary osmotic pump controlled release preparation, and its suitability for industrialized production more becomes a great problem in this field.In recent years, although rarely have bibliographical information that part insoluble drug is prepared into single chamber primary osmotic pump type controlled release tablet, but it is low that such single chamber primary osmotic pump type controlled release tablet still exists such as discharging drug efficiency, discharges not exclusively, cannot realize the defects such as suitability for industrialized production.So far, there is not yet bibliographical information insoluble drug neogambogic acid is prepared into single chamber primary osmotic pump controlled release preparation.
Summary of the invention
The technical problem to be solved in the present invention is, a kind of neogambogic acid osmotic pump type controlled release preparation is provided, and this controlled release preparation is single chamber primary osmotic pump type controlled release tablet, and it not only has zero-order release feature, and it is higher to have release efficiency concurrently, is applicable to the feature of suitability for industrialized production.
The present invention solves the problems of the technologies described above by following technical solution;
A kind of neogambogic acid osmotic pump type controlled release preparation provided by the invention, described controlled release preparation comprises neogambogic acid osmotic pump type controlled release tablets, described neogambogic acid osmotic pump type controlled release tablets is single chamber primary osmotic pump type controlled release tablet.
Further improve as the present invention, described neogambogic acid osmotic pump type controlled release tablets comprises label and be wrapped in the controlled release semi-transparent coating membrane of label periphery with drug release hole, and the semi-transparent coating membrane weight of described controlled release is about the 2%-5% of label weight;
Described drug release hole is to pass through laser or machine drilling setting in position, one or both sides, tablet surface, and described drug release hole diameter is about 0.6-0.8mm.
Further improve as the present invention, the semi-transparent coating membrane weight of described controlled release is about 3% of label weight.
Further improve as the present invention, described label comprises the following component of percent meter by weight:
The semi permeability film coating liquid of the semi-transparent coating membrane of described controlled release comprises the following component of volume ratio by weight:
Coating material 2%-5%;
Plasticizer 0.5%-5%;
Porogen 3%-15%.
Further improve as the present invention, described osmotic pressure active substance comprises macromolecular substances and small-molecule substance:
Described macromolecular substances is to be selected from any in polyoxyethylene, polyvinylpyrrolidone, arabic gum and hypromellose; Described small-molecule substance is one or more the mixture being selected from sodium chloride, potassium chloride, lactose, glucose, sucrose, mannitol and/or sorbitol;
Described cosolvent is one or more the mixture being selected from sodium lauryl sulphate, L-arginine, sodium carbonate, sodium bicarbonate and/or sodium stearyl fumarate;
Described suspending agent is to be selected from any one in PEO-N10, arabic gum, agar, alginic acid, ammonium alginate, collodial silica magnesium, pectin and gelatin;
Described filler is one or more the mixture being selected from starch, lactose, microcrystalline Cellulose and/or amylum pregelatinisatum;
Described lubricant is one or more the mixture that is selected from magnesium stearate, Pulvis Talci, micropowder silica gel, hydrogenated vegetable oil and/or Polyethylene Glycol apoplexy due to endogenous wind;
Described semipermeable membrane coating material is one or more the mixture being selected from cellulose acetate, ethyl cellulose, acrylic resin, acetylbutyrylcellulose and/or polyvinyl alcohol;
Described plasticizer is one or more the mixture being selected from glycerol, propylene glycol, Polyethylene Glycol, diethyl phthalate, dibutyl phthalate and/or triglyceride;
Described porogen is the one being selected from PEG400, PEG1500, PEG4000 and PEG6000.
Further improve as the present invention, described osmotic pressure active substance is sodium chloride; Described cosolvent is L-arginine; Described suspending agent is PEO-N10;
The prescription of described label comprises the first Core formulation and the second Core formulation: described the first Core formulation is that every controlled release tablet comprises the component of percent meter by weight:
Sodium chloride, L-arginine and PEO-N10, its weight that accounts for respectively label is 30%, 12%, 20%;
Described the second Core formulation is that every controlled release tablet comprises component: the about 60mg of sodium chloride; The about 40mg of PEO-N10; The about 24mg of L-arginine.
Further improve as the present invention, described semipermeable membrane coating material is cellulose acetate, and described plasticizer is dibutyl phthalate, and described porogen is PEG4000;
Described coating solution comprises the first coating fluid prescription and the second coating fluid prescription:
Described the first coating fluid prescription comprises the component of calculating with concentration: the about 1.7mg/mL of dibutyl phthalate DBP; The about 20mg/mL of cellulose acetate CA; The about 1.8mg/mL of PEG4000;
Described the second coating fluid prescription comprises following component:
Taking the weight of cellulose acetate as benchmark, the weight that described dibutyl phthalate DBP accounts for cellulose acetate is about 10%; By weight with volume ratio meter, the about 2mg/mL of PEG4000 concentration.
Further improve as the present invention, described coating solution solvent for use is acetone, and described semipermeable membrane coating material is cellulose acetate;
Calculate with volume ratio by weight, described coating solution comprises 2% cellulose acetate acetone soln.
The technical problem to be solved in the present invention also has, and a kind of preparation method of neogambogic acid osmotic pump type controlled release preparation of applicable suitability for industrialized production is provided, and comprises the following steps:
1) mix after sieving respectively with the adjuvant except lubricant by the neogambogic acid of recipe quantity above-mentioned, use wetting agent soft material processed, the granulation of again sieving, in 35-45 DEG C of oven dry, then sieve after granulate, add the mix lubricant of recipe quantity, tabletting, pressure is controlled at 60-80N, obtains label;
2) will be dissolved in coating solution solvent for use by the semipermeable membrane coating material of recipe quantity and plasticizer, porogen by above-mentioned, stir; Label is put coating pan spray coating, and art for coating parameter is: spray velocity 5-6ml/min, coating kettle temperature 41-50 DEG C, coating pan rotating speed 40-50r/min; After coating, coated tablet is carried out to dry solidification;
3) use mechanical means or laser to prepare the aperture of a diameter 0.6-0.8mm in one or both sides, gained coated tablet surface, obtain neogambogic acid osmotic pump type controlled release tablets.
Further improve as the present invention, described wetting agent is alcoholic solution, and the concentration of described alcoholic solution is approximately more than 95%; Described coating solution solvent for use is acetone; Be 24 hours described hardening time.
Osmotic pressure active substance, cosolvent, suspending agent, filler, lubricant, semipermeable membrane coating material, plasticizer and porogen in the present invention, except above-mentioned cited, can also be other materials identical or approximate with the respective substance character of enumerating.Preferably, when in label, the ratio of neogambogic acid is selected 3-6% (percent meter by weight), the ratio of its adjuvant and medicine is less, conveniently carries out two-sided punching.When drug release hole diameter is about 0.6-0.8mm, its impact of release on medicine is less.Preferably, select the semi-transparent coating membrane weight of controlled release to be about the 2%-5% of label weight, it is too fast that reason is to be less than 2% drug release rate, and the rate of release that is greater than 5% medicine slows down because coating membrane thickness increases, and likely cause discharging not exclusively; Further preferably, the semi-transparent coating membrane weight of controlled release is about 3% of label weight.Preferably, it is 95% when above that wetting agent is selected concentration, and label hardness is qualified.The numerical value of the corresponding proportioning in the present invention's scope of data that the above-mentioned prescription of selection limits arbitrarily, 14 hours cumulative release results of preparation-obtained osmotic pump type controlled release preparation can reach more than 89.1%.In addition, the ratio data that in the present invention, the semi permeability film coating fluid component of the semi-transparent coating membrane of controlled release limits, it is the volume (unit: mL) with coating solution solvent for use, with the quality (unit: mg) that coating material, plasticizer and porogen were taken, set up formula: mg/mL calculates respectively.
A kind of neogambogic acid osmotic pump type controlled release preparation provided by the invention and preparation method thereof, neogambogic acid can be prepared into the form of mono-layer osmotic pump type controlled release tablet, and inside and outside release good relationship, have the advantages that significant zero level discharges, can realize effective adjustment drug release rate and make drug slow and constant release, extend the effective blood drug concentration time, and can make blood drug level more steady and effective, reduce poisonous side effect of medicine and medicining times, and can in its EDD, keep release performance stable, release is residual little, effect is lasting, stable curative effect, and it absorbs the feature that not affected by feed and internal milieu, improve patient's compliance to be applied to better the effect of clinical performance neogambogic acid anticancer therapy.In addition, label compacting adopts conventional method, without definite perforated surfaces.
Brief description of the drawings
Fig. 1 is: the impact of different penetrating agent on drug release.
Fig. 2 is: the impact of different content NaCl on drug release.
Fig. 3 is: the impact of the L-arginine of different content on drug release.
Fig. 4 is: the impact of the polyoxyethylene of different content on drug release.
Fig. 5 is: the impact of the cellulose acetate of different content on drug release.
Fig. 6 is: the affect figure of the DBP of different content on drug release.
Fig. 7 is: the affect figure of the PEG of different molecular weight on drug release.
Fig. 8 is: the affect figure of the PEG4000 of different content on drug release.
Fig. 9 is: the affect figure of different film thicknesses on drug release.
Figure 10 is: neogambogic acid osmotic pump type controlled release tablets best prescription release graphics.
Figure 11 is: the average blood drug level figure after single oral dose medicine after neogambogic acid osmotic pump type controlled release tablets and reference plate (ordinary tablet).
Figure 12 is: 14 hours cumulative release percent-time graphs of vitro release of neogambogic acid osmotic pump tablet prepared by example 1.
Figure 13 is: 14 hours cumulative release percent-time graphs of vitro release of neogambogic acid osmotic pump tablet prepared by example 2.
Figure 14 is: 14 hours cumulative release percent-time graphs of vitro release of neogambogic acid osmotic pump tablet prepared by example 3.
Detailed description of the invention
By detailed description of the invention, neogambogic acid osmotic pump type controlled release tablets provided by the invention and preparation method thereof is done to further more detailed description below.
Test the preparation of 1 neogambogic acid osmotic pumps
The preparation technology of neogambogic acid osmotic pump tablet and influence factor
1.1 preparation technology
Label: neogambogic acid, PEO-N10, lactose, sodium chloride, L-arginine are crossed to 80 mesh sieves, take and mix by the equivalent method of progressively increasing afterwards by recipe quantity, add 95% alcoholic solution soft material processed, with 20 mesh sieves granulations, at 40 DEG C, dry 6h, adds appropriate magnesium stearate mix homogeneously.
The preparation of coating solution: the cellulose acetate that takes recipe quantity is dissolved in acetone, be mixed with certain density cellulose acetate acetone soln, add a certain amount of dibutyl phthalate DBP and PEG4000, be placed on magnetic stirring apparatus and under heating condition, do not stirring, until solution dissolves completely.
Tabletting and coating: install undershoot, regulate sheet and weigh and pressure, insert 200mg sheet slug particle and be pressed into sheet.Label is put in coating pan, carry out coating with the coating solution preparing, controlling temperature is (45 ± 5) DEG C, rotating speed is that the condition of 40r/min is carried out coating, increase weight and reach 4% to coating membrane, in 40 DEG C of dry 24h, to make a call to a hole with laser-beam drilling machine in coated tablet center and get final product, aperture is 0.8mm.
The impact of 1.2 Core formulations on drug release
1.2.1 the investigation of wetting agent and binding agent
Get neogambogic acid and the adjuvant of recipe quantity, mix, select respectively the polyvinylpyrrolidone PVP-K30 ethanol soft material processed of water, 70% ethanol, 95% ethanol and variable concentrations, crossing 24 mesh sieves granulates, 40～50 DEG C dry, 24 mesh sieve granulate, add 0.1% magnesium stearate, mix tabletting (200mg/ sheet).Observe the situation in granulation and tabletting process, and measure tablet hardness, the results are shown in Table .1.As seen from table, adopt 1% ethanol and 2% polyvinylpyrrolidone PVP-K30 ethanol to granulate, but water and 70% ethanol viscosity are inadequate, the granule fine powder amount of preparation is more, often there is loose sheet in tabletting, hardness is also defective, and 95% ethanol indices is all better, therefore selects the wetting agent of 95% ethanol as neogambogic acid osmotic pumps label.
The impact of the agent of table 1 different wetting and binding agent
1.2.2 the impact of different osmotic active substance on release
In osmotic pumps label, add osmotic pressure active substance to regulate the permeable pressure head inside and outside clothing film.Select respectively the sucrose of equivalent, sodium chloride, glucose is as osmotic pressure active substance, and other components unchanged in prescription, prepare neogambogic acid osmotic pump controlled release tablet according to above-mentioned preparation technology, measure the release of different time, draw release profiles.The cumulative release degree of medicine is shown in Fig. 1, and similarity judges in table 2.
The similarity analysis result of the different penetrating agent of table 2
"+" is similar; "-" dissmilarity. result shows, in Core formulation, select different types of osmotic pressure active substance, release to neogambogic acid osmotic pumps single chamber controlled release tablet has a significant effect, evaluate release profiles with similar factors, f2 value between any two as above shows, shown in .2, between sodium chloride and glucose, have notable difference, and sodium chloride and sucrose in water ratio are, sodium chloride release is more level and smooth, considers and selects sodium chloride as osmotic pressure active substance.
1.2.3 osmotic pressure active substance NaCl consumption is on the impact discharging
Selecting NaCl is osmotic pressure active substance, 25%, 30%, 35% in Core formulation, adds respectively NaCl by what account for tablet weight.Other components unchanged in Core formulation, prepare neogambogic acid osmotic pump controlled release tablet according to preparation technology, measure the cumulative release degree of different tablets, draw the curve of cumulative release degree to the time.Cumulative release degree is shown in Fig. 2, and similarity judges in table 3.
The similarity analysis result of table 3 different content NaCl
"+" is similar; "-" dissmilarity. result shows, in osmotic pumps label prescription, select the osmotic pressure active substance NaCl of different proportion, release to neogambogic acid osmotic pumps single chamber controlled release tablet has a significant effect, evaluate drug release curve with similar factors f2, f2 value between any two is as above shown shown in .3, wherein 25% and 35% consumption, 30% and 35% consumption has notable difference.The amount ranges of selected osmotic pressure active substance NaCl is not less than 25%, and along with the increase of osmotic pressure active substance ratio, drug release in vitro speed is also the trend of quickening.
1.2.4 the investigation of alkaline matter L-arginine consumption to drug release
In experimentation, consider the poorly water-soluble of neogambogic acid, therefore add alkaline matter L-arginine to change the dissolubility of neogambogic acid.Other supplementary product consumptions in fixed prescription, by sheet heavy 5%, 10%, 15% in prescription, add respectively L-arginine, prepare neogambogic acid osmotic pump tablet according to preparation technology, the impact that the consumption of investigation alkaline matter L-arginine discharges neogambogic acid, draws the curve of drug accumulation release degree to the time.Drug accumulation release is shown in Fig. 3, and similarity judges in table 4.
The similarity analysis result of table 4 different content L-arginine
"+" is similar; "-" dissmilarity. experiment shows, in osmotic pumps label prescription, select the alkaline matter L-arginine of 5%, 10%, 15% different proportion, release to neogambogic acid osmotic pumps single chamber controlled release tablet has a significant impact, by release profiles, as seen along with the increase of alkaline matter L-arginine addition, drug release rate is accelerated.
1.2.5 the impact of suspending agent polyoxyethylene-N10 consumption on medicine release
This experiment selects PEO-N10 as release suspending agent, 15%, 20%, 30% in Core formulation, adds respectively polyoxyethylene by what account for tablet weight.Other components unchanged in Core formulation, prepare neogambogic acid osmotic pump controlled release tablet, measure the cumulative release degree of different time, draw the curve of cumulative release to the time.Cumulative release degree is shown in Fig. 4, and similarity judges in table 5, measures the impact of different amounts polyoxyethylene on release.
The polyoxyethylated similarity analysis result of table 5 different content
"+" is similar; "-" dissmilarity. result shows, in osmotic pumps label prescription, select the release suspending agent polyoxyethylene of different proportion, release on neogambogic acid osmotic pumps single chamber controlled release tablet has appreciable impact, along with the rate of release of the increase neogambogic acid of suspending agent polyoxyethylene ratio is accelerated.
1.2.7 the optimization of Core formulation
Comprehensive above-mentioned experiment of single factor result, chooses the amount that influential four factors of drug release is respectively to A:NaCl; B:L-arginine consumption; C:PEO-N10; D: blank.In order to ensure that neogambogic acid elementary osmotic pump controlled release tablet keeps suitable rate of release and the dynamic (dynamical) feature of zero-order release at certain hour, this experiment adopts three indexs: whether the accumulative releasing degree F1 of (1) neogambogic acid osmotic pump tablet 14h, investigate neogambogic acid and discharge completely; (2) the accumulative releasing degree F2 of 2h before neogambogic acid infiltration this film, whether investigation neogambogic acid osmotic pump controlled release tablet is prominent releases; (3) discharge dependence among equations coefficient r, investigate medicine and whether defer to zero-order release feature.The standard of 12h and front 2h medicine accumulative releasing degree is decided to be respectively to 90%, 15%, and weight coefficient is decided to be 1; The index that discharges the relative coefficient r of equation is 0.99, and weight coefficient is decided to be 5.
The computing formula of L is as follows:
The value of L=|F1-90%| × 1 × 100+|F2-15%| × 1 × 100+|r-0.99| × 5 × 100L is less, and the release effect of neogambogic acid osmotic pump controlled release tablet is better, the results are shown in Table 7 and table 8.
Table 7 factor level table
Table 8 orthogonal design and result (n=3)
Table 9 the results of analysis of variance
From table 9 variance analysis, the order that factor affects drug release is: B > C > A, optimum prescription compages is A3B2C3.From variance analysis, the consumption of cosolvent L-arginine and suspending agent has a significant impact drug release, and the best Core formulation of neogambogic acid osmotic pump tablet is: the weight that NaCl, L-arginine, PEO-N10 account for respectively label is 30%, 12%, 20%.
1.3 the impact of coating fluid prescription on drug release
1.3.1 the selection of coating solution concentration
Volume ratio is calculated by weight, prepares 1%, 2%, 3% cellulose acetate acetone soln, adds dibutyl phthalate DBP and the PEG4000 of equivalent, the label of same lot number is carried out to coating, the release of investigating medicine, drug accumulation release is shown in Fig. 5, similarity judges in table 10.
The similarity analysis result of table 10 different content cellulose acetate
"+" is similar; "-" dissmilarity. result shows that cellulose acetate acetone soln concentration is little on the rate of release impact of medicine, and f2 is between 54.3-70.5 between any two.In experimentation, consider that coating solution concentration is difficult for when lower forming coating membrane at sheet wicking surface; In the time that coating solution concentration reaches 3%, it is large that viscosity obviously becomes, and easily stops up spray gun impact spray speed when coating.In sum, finally select 2% cellulose acetate acetone soln as coating solution.
1.3.2 the impact of plasticizer consumption on drug release in coating solution
In coating solution, add appropriate plasticizer not only can improve plasticity, the moulding property of coating material, also can improve adhesion form and the engineering properties thereof of coating membrane to label.Choose the plasticizer of DBP as coating solution, the DBP that adds respectively suitable cellulose acetate weight 5%, 10%, 15% in cellulose acetate acetone soln, carries out coating to the label of same lot number, investigates the release of medicine, drug accumulation release is shown in Fig. 6, and similarity judges in table 11.
The similarity analysis result of table 11 different content DBP
"+" is similar; "-" dissmilarity, result shows, the release that in coating solution, the consumption neogambogic acid of plasticizer oozes the saturating pump controlled-releasing tablet of single chamber affects without significance.But in the time that in coating solution, plasticizer consumption is excessive, coating membrane will be too soft, while causing coating, inconvenience is controlled; In the time that the content of plasticizer is 5%, plasticization is just not too obvious, can cause the discontinuous or imperfect of coating membrane simultaneously, and therefore in coating solution, the addition of plasticizer is moderate.1.3.3 the impact of different molecular weight Polyethylene Glycol (PEG) on drug release in coating fluid prescription
In coating fluid prescription, other parameters are fixed, and add respectively PEG2000, PEG4000 and PEG6000, the label of same lot number is carried out to coating and prepare neogambogic acid elementary osmotic pump controlled release tablet.The release of investigating medicine, drug accumulation release is shown in Fig. 7, similarity judges in table 12.
The similarity analysis result of table 12 different molecular weight PEG
"+" is similar; "-" dissmilarity, result shows that f2 is between the two between 51.3～68.8, and similarity is better, and the PEG of different molecular weight does not have the impact of significance on the release behavior of neogambogic acid elementary osmotic pump controlled release tablet.From medicine accumulative total release profiles, PEG molecular weight is that the medicine accumulative total release profiles of 4000 o'clock is smoother, considers and selects the porogen of PEG4000 as neogambogic acid osmotic pumps coating fluid prescription.
1.3.4 the impact of the Macrogol 4000 of variable concentrations on drug release in coating fluid prescription
In coating fluid prescription, other parameters are fixed, prepare respectively PEG4000 and account for the coating solution that coating solution concentration is 1mg/mL, 2mg/mL, 3mg/mL, according to aforementioned preparation technology, the label of same lot number is carried out to coating and prepare neogambogic acid osmotic pumps single chamber controlled release tablet, investigate the accumulative releasing degree of medicine, experimental result is shown in Fig. 8, and similarity judges in table 13.
The similarity analysis result of table 13 different content PEG4000
"+" is similar; "-" dissmilarity, result shows, and f2 is between any two between 31.96～47.0, and the content that PEG4000 accounts for coating solution has the impact of significance on the release of neogambogic acid osmotic pump tablet.In experimentation, along with the increase of porogen PEG4000 content, the rate of release of neogambogic acid osmotic pump tablet is accelerated.PEG is the high molecular polymer of long-chain, in the time being used as the prescription composition of osmotic pumps coating solution with CA simultaneously, can be crosslinked together with CA in coating process, and the mechanical strength of formed coating membrane is increased, there is good plasticity; Low-molecular-weight PEG has good water solublity in addition, therefore in neogambogic acid osmotic pump tablet drug release process, part PEG can be dissolved in stripping material, and the increase of the pore quantity on coating membrane can improve the penetrating row of coating membrane to aqueous solution, thereby can accelerate the speed of drug release.
1.3.5 the impact of film thickness on drug release
The osmotic pumps label of choosing optimization, carries out coating to label, makes respectively coating membrane with respect to label weightening finish 1%, 3%, 5%, investigates the impact that the different increment of different coating membranes thickness discharges neogambogic acid osmotic pump controlled release tablet.Experimental result is shown in Fig. 9, and similarity judges in table 14.
The similarity analysis result of the different film thicknesses of table 14
"+" is similar; "-" dissmilarity, result shows, and the coating membranes of different weightening finishes f2 is between any two between 33.6～48.8, and its release to preparation has a significant impact.The rate of release of medicine slows down because coating membrane thickness increases, and therefore coating membrane weightening finish parameter needs to control.
1.3.6 the optimization of coating fluid prescription
The factor of choosing is respectively the amount of A:DBP; B:PEG4000; C: film weightening finish; D: blank, carry out optimization of orthogonal test osmotic pump controlled release tablet coating fluid prescription, factor three is flat in table 15, and orthogonal experiments and variance analysis are in table 15 and table 16.
Table 15 orthogonal design factor level table
Table 16 orthogonal experiment and result
Table 17 the results of analysis of variance
From table 17 variance analysis, the order that factor affects drug release is: B > C > A, optimum prescription compages is A1B3C1.From variance analysis, the consumption of porogen PEG4000 has a significant impact drug release, and the best coating fluid prescription of neogambogic acid osmotic pump controlled release tablet is: DBP concentration is that 10%, PEG4000 concentration is 2mg/mL, film weightening finish 3%.
1.4 the impact of other factors on drug release
1.4.1 the prescription of neogambogic acid osmotic pumps single chamber controlled release tablet is determined
Comprehensive above-mentioned single factor and orthogonal test, finally determine that neogambogic acid osmotic pump tablet best prescription is as follows:
Core formulation:
200mg/ sheet × 500 slice
Coating fluid prescription:
Prepare neogambogic acid osmotic pump controlled release tablet according to the prescription of above-mentioned the best and preparation technology, carry out release in vitro investigation, discharge well, the results are shown in Figure 10.
1.4.2 release in vitro mechanism is investigated
The release in vitro data of the neogambogic acid osmotic pump tablet that optimum experimental is obtained are used respectively zero level, one-level and Higuchi equation model, the results are shown in Table 19.
Table 19 equation model table
| t(h) | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 14 |
| F(％) | 6.86 | 12.98 | 27.09 | 44.91 | 58.02 | 74.86 | 88.27 | 92.38 |
| -1g(1-F) | 0.0309 | 0.0604 | 0.1372 | 0.2589 | 0.3770 | 0.5996 | 0.9307 | 1.1180 |
| t 1/2(h) | 1 | 1.4142 | 2 | 2.4495 | 2.8284 | 3.1623 | 3.4641 | 3.7417 |
Adopt release and the time of different dynamic equation to neogambogic acid elementary osmotic pump controlled release tablet to carry out matching, result is as follows:
(1) Zero-order equation: at 0～14h, with F, t is carried out to linear fit, F=7.0231t+0.6318 (r=0.9946)
(2) First-order equation: at 0～14h, t is carried out to linear fit ,-1g (1-F)=0.0843t-0.1617 (r=0.9718) with-1g (1-F)
(3) Higuchi equation: at 0～14h, with F, t1/2 is carried out to linear fit, F=33.617t1/2-33.625 (r=0.9902)
Result shows that osmotic pump tablet prepared by optimum experimental is best with the correlation coefficient of zero level equation model, shows that this equation can describe the release in vitro dynamic characteristic of neogambogic acid osmotic pumps single chamber controlled release tablet preferably.
1.5 primary stabilities are investigated
1.5.1 high temperature experiment
Get a collection of homemade neogambogic acid osmotic pump controlled release tablet, put in clean vial, sealing, is stored in the baking oven of 60 DEG C 10 days, samples at the 5th day and the 10th day.Examine and determine according to requirement under inspection item, the results are shown in Table 20.Test shows that, under hot conditions, obvious variation does not occur for the release of neogambogic acid osmotic pump controlled release tablet and content, and therefore preparation is to thermally-stabilised.
The stability of table 20 osmotic pump tablet under hot conditions
1.5.2 strong illumination experiment
Get a collection of homemade neogambogic acid osmotic pump controlled release tablet, put in clean surface plate, in the bad border that is 45001x in illuminance, preserve 10 days, the 5th day and sampling in the 10th day.Carry out verification result in table 21 according to requiring under inspection item.Test shows that the release of neogambogic acid osmotic pump controlled release tablet and content all do not occur significantly to change, and therefore neogambogic acid osmotic pump controlled release tablet is stable to illumination.
The stability of table 21 osmotic pump tablet under high light condition
1.5.3 high humility test
Get a collection of homemade neogambogic acid osmotic pump controlled release tablet, put in clean surface plate, be stored in respectively in the container that 25 DEG C of relative humiditys are RH75% and RH92.5% 10 days, the 5th day and sampling in the 10th day.Examine and determine according to requiring under inspection item.Result is under two kinds of damp conditions, and neogambogic acid osmotic pump controlled release tablet all has obvious wettability, and the outward appearance of preparation has been transformed into pitchy by yellow, cannot carry out relevant quality arbitration.
1.5.4 accelerate experiment
Get a collection of homemade neogambogic acid osmotic pump controlled release tablet, be sealed in vial, at 40 DEG C, under the condition that relative humidity is RH75%, store 6 months, respectively the the 1st, 2,3, sampling in June, require to examine and determine according under inspection item.Result is tested through the acceleration of 6 months, and neogambogic acid osmotic pump controlled release tablet outward appearance, content and external accumulative releasing degree have no significant change.The results are shown in Table 22.
Table 22 accelerated test result
The principal element that affects osmotic pump tablet release in vitro is the prescription of label and coating solution, this experiment is selected influence factor again by optimization of orthogonal test best prescription and preparation technology on monofactorial basis, determines that best of breed prescription (every) is: NaCl60mg; PEO-N10:40mg; L-arginine 24mg; Cellulose acetate CA:20mg/mL; DBP:1.7mg/mL; PEG4000:1.8mg/mL.
Test the pharmacokinetic studies of 2 neogambogic acid osmotic pump controlled release tablets in Beagle dog body
The research of 2.1Beagle dog interior medicine dynamics
2.1.1 administration and blood sampling conceptual design
Get not 6 of the healthy adult Beagle dogs of tested other any medicines of 7d before test, 12h fasting before test but can freely drink water, according to random cross-over experiment design, is divided into 2 groups at random, carries out cross matching after 7d again.6 Beagle dogs oral neogambogic acid osmotic pump controlled release tablets (5mg/ sheet) and make each 2 of neogambogic acid ordinary tablet (it is write out a prescription with osmotic pumps label except coating not, 5mg/ sheet) by oneself respectively.0,0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,14,24h getting blood time point is respectively: osmotic pumps:; 0,0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,14,24h ordinary tablet:.Dislocation is through the EP of heparin processing pipe immediately to get blood 0.5mL from ulnar vein respectively at the appointed time, and the centrifugal 10min of 3000r/min, gets upper plasma and measure in-20 DEG C of freezing depositing to entering UHPLC-MS/MS.
2.1.2 pharmacokinetic study result of the test
Tab.23 and Tab.24 are respectively the determination of plasma concentration result of neogambogic acid ordinary tablet and neogambogic acid osmotic pump controlled release tablet, plasma concentration curve figure Figure 11 of two groups of preparations.
Table 23 single oral dose neogambogic acid oozes the blood drug level (ng/mL) of neogambogic acid after ordinary tablet
The blood drug level (ng/mL) of neogambogic acid after table 24 single oral dose neogambogic acid osmotic pumps
Be respectively 4h, 2h by the known osmotic tablets of pharmacokinetic studies of neogambogic acid osmotic pump controlled release tablet and ordinary tablet and the Tmax of ordinary tablet, Cmax is respectively 52.134ng/mL, 157.889ng/mL, the neogambogic acid infiltration controlled release tablet osmotic pumps group that shows preparation has obvious controlled-release function, and the energy long period maintains steadily, effective blood drug level, fully demonstrate the good characteristic of controlled release preparation.
2.1.3 pharmacokinetic parameter
After adopting the moving data processing software of DAS2.1.1 version medicine to two groups of preparation orals and intravenous injection, medicine drug-time curve is asked relevant pharmacokinetic parameters, the results are shown in Table 25.
Table 25 pharmacokinetic parameters
2.1.4 relative bioavailability
Taking homemade neogambogic acid ordinary tablet as reference preparation, calculate the relative bioavailability of the neogambogic acid osmotic pump controlled release tablet of preparation according to following formula.
F＝AUC0-∞(Osmot ic pump tablet)/AUCO-∞(Reference tablet)×100％
The final relative bioavailability of calculating neogambogic acid osmotic pump controlled release tablet is: F=697.364/767.951 × 100%=90.81%, results suggest neogambogic acid has higher bioavailability in Beagle dog body body, shows that this medicine has good absorption in vivo.
2.1.5 inside and outside dependency
Adopt Wagner-Nelson method to calculate in different time points medicine body and absorb percent Fa, finally the vitro Drug cumulative release degree F that absorbs percent and corresponding time point in the medicine body of different time is carried out to linear regression, investigate in neogambogic acid osmotic pump controlled-releasing lamellar body to absorb with external accumulative releasing degree whether there is certain dependency.Fa computing formula is as follows:
Result of the test is in table 26.
Table 26 neogambogic acid osmotic pump controlled release tablet inside and outside release data
With absorbing percent (Fa) in neogambogic acid osmotic pump controlled-releasing lamellar body, vitro release (F) is returned, its equation is: Fa=1.0377F+0.47715 (r=0.9896).Test shows, neogambogic acid osmotic pump controlled release tablet inside and outside dependency is good.
Embodiment 1
Core formulation (in every 200mg, account for 2% of label weight calculate by the semi-transparent coating membrane weight of controlled release, plate core weight is about 196mg, and film is heavily about 4mg)
Semi permeability film coating liquid prescription:
Cellulose acetate 15mg
Diethyl phthalate 10mg
PEG4000 30mg
Preparation technology: above-mentioned neogambogic acid and the adjuvant (other adjuvants except magnesium stearate) of pressing recipe quantity crossed respectively to 100 mesh sieves, fully mix homogeneously, use 95% alcoholic solution soft material processed, cross 24 mesh sieves and granulate, 40 DEG C of oven dry, after 24 mesh sieve granulate, add the magnesium stearate of recipe quantity to mix, tabletting, pressure is controlled at 60N, obtains label.Be dissolved in 500mL acetone by the cellulose acetate of recipe quantity and diethyl phthalate, PEG4000 above-mentioned, stir and make it to become uniform solution.Label is put in coating pan, spray velocity 5ml/min, coating pan rotating speed 40r/min, 41 DEG C of coating temperature, after coating in drying baker 40 DEG C solidify 24 hours; Then the small delivery aperture of preparing a diameter 0.8mm in coated tablet one side laser boring obtains neogambogic acid mono-layer osmotic pump controlled release tablets.The release profiles of neogambogic acid osmotic pumps in sodium dodecyl sulfate solution is shown in Figure 12.In the present embodiment, 14 hours cumulative release results are that the release profiles linear fit r of 93.0%, 2-14 hour is 0.994 (wherein, r more approaches 1, proves more to have zero-order release feature).
Embodiment 2
Core formulation (in every 200mg, account for 3% of label weight calculate by the semi-transparent coating membrane weight of controlled release, plate core weight is about 194mg, and film is heavily about 6mg)
Semi permeability film coating liquid prescription:
Acrylic resin 10mg
Propylene glycol 25mg
PEG1500 75mg
Preparation technology: neogambogic acid and adjuvant (other adjuvants except hydrogenated vegetable oil) are crossed respectively to 100 mesh sieves, fully mix homogeneously, use 95% alcoholic solution soft material processed, cross 24 sieve series grains, 35 DEG C of oven dry, cross 24 mesh sieve granulate, add the hydrogenated vegetable oil of recipe quantity to mix, tabletting, pressure is controlled at 80N, obtains label.Acrylic resin and propylene glycol, PEG1500 are dissolved in 500mL acetone, stir and make it to become uniform solution.Label is put in coating pan, spray velocity 6ml/min, coating pan rotating speed 50r/min, coating temperature 50 C, after coating in drying baker 40 DEG C solidify 24 hours.Then the small delivery aperture of preparing a diameter 0.6mm in coated tablet one side laser boring obtains neogambogic acid mono-layer osmotic pump controlled release tablets.The release profiles of neogambogic acid osmotic pumps in sodium dodecyl sulfate solution is shown in Figure 13. in the present embodiment, 14 hours cumulative release results are 89.1%, the release profiles linear fit r of 2-14 hour is 0.989 (wherein, r more approaches 1, proves more to have zero-order release feature).
Embodiment 3
Core formulation (in every 200mg, account for 5% of label weight calculate by the semi-transparent coating membrane weight of controlled release, plate core weight is about 190mg, and film is heavily about 10mg)
Semi permeability film coating liquid prescription:
Ethyl cellulose 25mg
Glycerol 2.5mg
PEG6000 15mg
Preparation technology: neogambogic acid and adjuvant (other adjuvants except micropowder silica gel) are crossed respectively to 100 mesh sieves, fully mix homogeneously, use 95% alcoholic solution soft material processed, cross 24 mesh sieves and granulate, 45 DEG C of oven dry, cross 24 mesh sieve granulate, add the micropowder silica gel of recipe quantity to mix, tabletting, pressure is controlled at 70N, obtains label.Ethyl cellulose and glycerol, PEG6000 are dissolved in 500mL acetone, stir and make it to become uniform solution.Label is put in coating pan, spray velocity 5.5ml/min, coating pan rotating speed 45r/min, temperature 45 C in coating pan, after coating in drying baker 40 DEG C solidify 24 hours.Then the small delivery aperture of preparing a diameter 0.7mm in coated tablet one side laser boring obtains neogambogic acid mono-layer osmotic pump controlled release tablets.The release profiles of neogambogic acid osmotic pumps in sodium dodecyl sulfate solution is shown in Figure 14.In the present embodiment, 14 hours cumulative release results are that the release profiles linear fit r of 90.2%, 2-14 hour is 0.999 (wherein, r more approaches 1, proves more to have zero-order release feature).
Claims (10)
1. a neogambogic acid osmotic pump type controlled release preparation, is characterized in that, described controlled release preparation comprises neogambogic acid osmotic pump type controlled release tablets, and described neogambogic acid osmotic pump type controlled release tablets is single chamber primary osmotic pump type controlled release tablet.
2. neogambogic acid osmotic pump type controlled release preparation according to claim 1, is characterized in that,
Described neogambogic acid osmotic pump type controlled release tablets comprises label and be wrapped in the controlled release semi-transparent coating membrane of label periphery with drug release hole, and the semi-transparent coating membrane weight of described controlled release is about the 2%-5% of label weight;
Described drug release hole is to pass through laser or machine drilling setting in position, one or both sides, tablet surface, and described drug release hole diameter is about 0.6-0.8mm.
3. neogambogic acid osmotic pump type controlled release preparation according to claim 2, is characterized in that, the semi-transparent coating membrane weight of described controlled release is about 3% of label weight.
4. according to the neogambogic acid osmotic pump type controlled release preparation described in claim 2 or 3, it is characterized in that, described label comprises the following component of percent meter by weight:
The semi permeability film coating liquid of the semi-transparent coating membrane of described controlled release comprises the following component of volume ratio by weight:
Coating material 2%-5%;
Plasticizer 0.5%-5%;
Porogen 3%-15%.
5. neogambogic acid osmotic pump type controlled release preparation according to claim 4, is characterized in that, described osmotic pressure active substance comprises macromolecular substances and small-molecule substance:
Described macromolecular substances is to be selected from any in polyoxyethylene, polyvinylpyrrolidone, arabic gum and hypromellose; Described small-molecule substance is one or more the mixture being selected from sodium chloride, potassium chloride, lactose, glucose, sucrose, mannitol and/or sorbitol;
Described cosolvent is one or more the mixture being selected from sodium lauryl sulphate, L-arginine, sodium carbonate, sodium bicarbonate and/or sodium stearyl fumarate;
Described suspending agent is to be selected from any one in PEO-N10, arabic gum, agar, alginic acid, ammonium alginate, collodial silica magnesium, pectin and gelatin;
Described filler is one or more the mixture being selected from starch, lactose, microcrystalline Cellulose and/or amylum pregelatinisatum;
Described lubricant is one or more the mixture that is selected from magnesium stearate, Pulvis Talci, micropowder silica gel, hydrogenated vegetable oil and/or Polyethylene Glycol apoplexy due to endogenous wind;
Described semipermeable membrane coating material is one or more the mixture being selected from cellulose acetate, ethyl cellulose, acrylic resin, acetylbutyrylcellulose and/or polyvinyl alcohol;
Described plasticizer is one or more the mixture being selected from glycerol, propylene glycol, Polyethylene Glycol, diethyl phthalate, dibutyl phthalate and/or triglyceride;
Described porogen is the one being selected from PEG400, PEG1500, PEG4000 and PEG6000.
6. neogambogic acid osmotic pump type controlled release preparation according to claim 4, is characterized in that,
Described osmotic pressure active substance is sodium chloride; Described cosolvent is L-arginine; Described suspending agent is PEO-N10;
The prescription of described label comprises the first Core formulation and the second Core formulation: described the first Core formulation is that every controlled release tablet comprises the component of percent meter by weight:
Sodium chloride, L-arginine and PEO-N10, its weight that accounts for respectively label is 30%, 12%, 20%;
Described the second Core formulation is that every controlled release tablet comprises component: the about 60mg of sodium chloride; The about 40mg of PEO-N10; The about 24mg of L-arginine.
7. neogambogic acid osmotic pump type controlled release preparation according to claim 4, is characterized in that,
Described semipermeable membrane coating material is cellulose acetate, and described plasticizer is dibutyl phthalate, and described porogen is PEG4000;
Described coating solution comprises the first coating fluid prescription and the second coating fluid prescription:
Described the first coating fluid prescription comprises the component of calculating with concentration: the about 1.7mg/mL of dibutyl phthalate DBP; The about 20mg/mL of cellulose acetate CA; The about 1.8mg/mL of PEG4000;
Described the second coating fluid prescription comprises following component:
Taking the weight of cellulose acetate as benchmark, the weight that described dibutyl phthalate DBP accounts for cellulose acetate is about 10%; By weight with volume ratio meter, the about 2mg/mL of PEG4000 concentration.
8. according to the neogambogic acid osmotic pump type controlled release preparation described in claim 4 or 7, it is characterized in that, described coating solution solvent for use is acetone, and described semipermeable membrane coating material is cellulose acetate;
Calculate with volume ratio by weight, described coating solution comprises 2% cellulose acetate acetone soln.
9. according to the preparation method of arbitrary described neogambogic acid osmotic pump type controlled release preparation of claim 1-8, it is characterized in that, comprise the following steps:
1) mix after sieving respectively with the adjuvant except lubricant by the neogambogic acid of recipe quantity above-mentioned, use wetting agent soft material processed, the granulation of again sieving, in 35-45 DEG C of oven dry, then sieve after granulate, add the mix lubricant of recipe quantity, tabletting, pressure is controlled at 60-80N, obtains label;
2) will be dissolved in coating solution solvent for use by the semipermeable membrane coating material of recipe quantity and plasticizer, porogen by above-mentioned, stir; Label is put coating pan spray coating, and art for coating parameter is: spray velocity 5-6ml/min, coating kettle temperature 41-50 DEG C, coating pan rotating speed 40-50r/min; After coating, coated tablet is carried out to dry solidification;
3) use mechanical means or laser to prepare the aperture of a diameter 0.6-0.8mm in one or both sides, gained coated tablet surface, obtain neogambogic acid osmotic pump type controlled release tablets.
10. the preparation method of neogambogic acid osmotic pump type controlled release preparation according to claim 9, is characterized in that, described wetting agent is alcoholic solution, and the concentration of described alcoholic solution is approximately more than 95%; Described coating solution solvent for use is acetone; Be 24 hours described hardening time.
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| US20050261363A1 (en) * | 2004-05-21 | 2005-11-24 | Taiwan Sunpan Biotechnology Development Co., Ltd. | Compounds isolated from gamboge resin having activity in inhibiting the growth of tumor/cancer cells and pharmaceutical compositions comprising the same |
| CN1951382A (en) * | 2006-09-30 | 2007-04-25 | 赵爱国 | Oral formulation of neogambogic acid for treating tumor |
| CN102871983A (en) * | 2012-10-31 | 2013-01-16 | 中国人民解放军第四军医大学 | Gambogic acid colon-specific controlled release tablet and preparation method thereof |
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| US20050261363A1 (en) * | 2004-05-21 | 2005-11-24 | Taiwan Sunpan Biotechnology Development Co., Ltd. | Compounds isolated from gamboge resin having activity in inhibiting the growth of tumor/cancer cells and pharmaceutical compositions comprising the same |
| CN1951382A (en) * | 2006-09-30 | 2007-04-25 | 赵爱国 | Oral formulation of neogambogic acid for treating tumor |
| CN102871983A (en) * | 2012-10-31 | 2013-01-16 | 中国人民解放军第四军医大学 | Gambogic acid colon-specific controlled release tablet and preparation method thereof |
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| CN108434113A (en) * | 2018-04-11 | 2018-08-24 | 安徽中医药大学 | Azilsartan osmotic pump type controlled release tablets and preparation method thereof |
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