Carvedilol phosphate resin sustained-release microcapsule as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a carvedilol phosphate resin sustained-release microcapsule as well as preparation and application thereof. The carvedilol phosphate resin sustained-release microcapsule comprises carvedilol phosphate resin and a capsule material, the capsule material is one or two of ethyl cellulose and acrylic resin; the dosage is 5-15% of the weight of the carvedilol phosphate resin; the carvedilol phosphate resin is prepared from carvedilol phosphate and ion exchange resin through a static method or a dynamic method. The mass ratio of the carvedilol phosphate to the ion exchange resin is (2: 1)-(1: 4). The carvedilol phosphate resin microcapsule is prepared by taking ion exchange resin as a drug carrier, the carvedilol phosphate is successfully subjected to a slow release effect in vitro through an ion exchange and emulsified solvent volatilization method coating technology, and the in-vitro release rate of the prepared carvedilol phosphate resin microcapsule in a 0.15 mol / L CH3COONa + 1mol / L CH3COOH buffer solution in 24 hours is 30-50%. The ion exchange reaction of the carvedilol phosphate and the cationic resin accords with a primary kinetic model.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a carvedilol phosphate resin sustained-release microcapsule and a preparation method and application thereof. BACKGROUND

[0002] Carvedilol phosphate is a racemic antihypertensive adrenergic blocker which can selectively block alpha 1-receptors and non-selectively block beta-receptors, has no intrinsic sympathomimetic activity, and has a significant protective effect on myocardial damage caused by myocardial ischemia and myocardial infarction. It is clinically used for treating mild and moderate hypertension, ischemic heart disease, and symptomatic chronic congestive heart failure, and can also be used for treating cirrhosis.

[0003] The currently marketed products of carvedilol phosphate (CVD) are only capsules and ordinary tablets, and the commonly used tablet doses are 2.5 mg, 6.25 mg, 10 mg, etc., and the capsule dose is 10 mg. The initial oral dose is 6.25 mg each time, twice a day, and the dose is increased to 12.5 or 25 mg each time according to the valley concentration and blood pressure, and the total amount should not exceed 50 mg per day, and the blood pressure can be completely reduced within two weeks. Therefore, the patients with hypertension need to take medicine several times a day, which brings many inconveniences to the patients, and only a small part of patients can continuously take medicine for a long time. In addition, carvedilol phosphate needs to be taken with meals to slow down the absorption and avoid causing orthostatic hypotension. Carvedilol phosphate is almost insoluble in water, and its poor solubility leads to low bioavailability, and the average bioavailability is 25%, and it is rapidly absorbed orally, reaches the peak of blood drug in 2 hours, and has a significant first-pass effect. Therefore, it has significant clinical significance to develop a controlled-release dosage form with sustained-release effect, increased bioavailability, and improved patient compliance. SUMMARY

[0004] The present application aims to provide a carvedilol phosphate resin sustained-release microcapsule which can improve the bioavailability of carvedilol phosphate and the compliance of patients.

[0005] In one aspect of the present application, a carvedilol phosphate resin sustained-release microcapsule is provided, which comprises carvedilol phosphate resin and a capsule material.

[0006] The capsule material is one or both of ethyl cellulose and acrylic resin, and is preferably ethyl cellulose.

[0007] The amount of the capsule material is 2.5-15% by weight of the carvedilol phosphate resin, and is preferably 2.5-7.5%.

[0008] The carvedilol phosphate resin is prepared by a static method or a dynamic method from carvedilol phosphate and an ion exchange resin.

[0009] The ion exchange resin is a cation exchange resin, and the cation exchange resin is a weak acid cation exchange resin or a strong acid cation exchange resin.

[0010] The weak acid cation exchange resin is selected from a carboxylic acid type cation exchange resin, and preferably is D113 macroporous weak acid ion exchange resin.

[0011] The strong acid cation exchange resin is selected from a sulfonic acid type cation exchange resin, and preferably is 001x7 or 005x7 strong acid cation exchange resin.

[0012] The particle size of the cation exchange resin is 60-200 mesh, and preferably is 100-200 mesh.

[0013] The mass ratio of carvedilol phosphate and ion exchange resin is 2:1-1:4.

[0014] The carvedilol phosphate can also be other water-insoluble drugs, such as Prazonsin, nebivolol, Bevantolol, terazosin, Atenolol, Arotinolol, bisoprolol, sotalol, etc.

[0015] The carvedilol phosphate resin sustained-release microcapsule further contains a plasticizer, a continuous phase and an emulsifier.

[0016] The plasticizer is one or a mixture of several of polyethylene glycol, glycerol, triglyceride, diethyl phthalate and triethyl citrate, and preferably is diethyl phthalate.

[0017] The amount of the plasticizer is 8-20% of the capsule material, and preferably is 8-10%.

[0018] The continuous phase is liquid paraffin, and the emulsifier is Span 80.

[0019] The volume ratio of liquid paraffin to Span 80 is 8:1-2.

[0020] The application further provides a preparation method of the carvedilol phosphate resin sustained-release microcapsule, comprising the following steps:

[0021] (1) Pretreatment of the cation exchange resin:

[0022] The pretreated cation exchange resin is in sodium type or hydrogen type.

[0023] (2) Preparation of carvedilol phosphate resin by static method:

[0024] Carvedilol phosphate is dissolved in an ethanol-water solution, stirred until completely dissolved, then cation exchange resin is added, stirred, suction filtered, eluted, and dried to obtain carvedilol phosphate resin;

[0025] The volume concentration of the ethanol-water solution is 60-80%;

[0026] The mass ratio of carvedilol phosphate to cation exchange resin is 2:1-1:4;

[0027] The drug loading temperature is 25.0-45.0°C, and the ion exchange speed is not different at this temperature, preferably 25.0-30.0°C for drug loading.

[0028] When the cation exchange resin is a strong acid cation exchange resin, it is necessary to impregnate the strong acid drug resin, so as to effectively prevent the resin from swelling due to hydration, maintain the integrity of the film and avoid CVD burst release.

[0029] The preparation method is: adding 20-25% (w / v) PEG 4000 to the CVD resin, stirring at room temperature for 0.5-1h, suction filtering and drying for standby.

[0030] (3) Preparation of carvedilol phosphate resin sustained-release microcapsules

[0031] A certain amount of capsule material is dissolved in an organic solvent, and a plasticizer is added and uniformly mixed as a dispersed phase; carvedilol phosphate resin is slowly added to the dispersed phase, and constant stirring is performed to keep it in a suspended state;

[0032] Liquid paraffin and emulsifier are mixed and stirred uniformly as a continuous phase;

[0033] The continuous phase is added dropwise to the dispersed phase while keeping the dispersed phase containing carvedilol phosphate resin in a uniformly stirred state, and constant stirring is performed until the organic solvent is completely volatilized.

[0034] The capsule material is ethyl cellulose, and the mass volume concentration of the ethyl cellulose in the organic solvent is 1.5-2 mg / mL;

[0035] The organic solvent is one or more of acetone, ethanol, and dichloromethane, preferably acetone;

[0036] The volume ratio of liquid paraffin, emulsifier, and acetone is 8:1-2:3-4, preferably 8:1:4;

[0037] The temperature at which the constant stirring is performed until the acetone is completely volatilized is 35-55°C, preferably 45-55°C.

[0038] Finally, the phosphocarbilol resin microcapsules are washed by petroleum ether to remove the residual liquid paraffin on the surface of the microcapsules, and dried to obtain the phosphocarbilol resin sustained-release microcapsules.

[0039] The phosphocarbilol resin sustained-release microcapsules can be further prepared into a phosphocarbilol resin sustained-release suspension according to a conventional method.

[0040] The present application has the following beneficial effects: the present application uses ion exchange resin as a drug carrier to prepare phosphocarbilol resin microcapsules, and successfully makes phosphocarbilol produce sustained release in vitro through ion exchange and emulsion solvent evaporation coating technology. The prepared phosphocarbilol resin microcapsules have an in-vitro release rate of 30-50% at 24 h, achieving good sustained release effect. The ion exchange reaction between phosphocarbilol and cationic resin conforms to the first-order kinetic model, is an endothermic process, and spontaneously proceeds to the right. The analysis methods such as scanning electron microscopy (SEM), X-ray diffraction analysis (XRD), and Fourier transform infrared absorption spectrometer (FTIR) prove that the combination mode of phosphocarbilol and cationic resin is chemical combination. The in-vitro dissolution results show that the phosphocarbilol resin significantly delays release after coating, and the whole system changes from the pre-coating particle diffusion process to the membrane-controlled release and the skeleton diffusion as the main process, with the resin internal particle diffusion as the auxiliary process. Meanwhile, the resin can be coated into microcapsules to be subsequently prepared into a suspension, further improving the stability of the drug, and facilitating storage and transportation. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 Solubility of phosphocarbilol in different proportions of latent solvent (n=3);

[0042] Figure 2 Scanning electron microscopy results of strong acid resin;

[0043] A: 005x7 resin before drug loading, scale is 20.0 μm; B: strong acid drug resin prepared by 005x7 resin, scale is 20.0 μm;

[0044] Figure 3 Scanning electron microscopy results of weak acid resin;

[0045] A: D113 resin before drug loading, scale is 20.0 μm; B: weak acid drug resin prepared by D113 resin, scale is 20.0 μm;

[0046] Figure 4 X-ray spectrum of strong acid resin and other samples;

[0047] A: 005x7 resin; B: phosphocarbilol; C: physical mixture of phosphocarbilol and 005x7 resin; D: phosphocarbilol resin prepared by 005x7 resin;

[0048] Figure 5 X-ray spectra of weakly acidic resins and other samples;

[0049] A: D113 resin; B: carvedilol phosphate; C: physical mixture of carvedilol phosphate and D113 resin; D: carvedilol phosphate resin prepared with D113 resin;

[0050] Figure 6 Infrared spectra of strongly acidic resins and other samples;

[0051] A: carvedilol phosphate; B: 005x7 resin; C: physical mixture of carvedilol phosphate and 005x7 resin; D: carvedilol phosphate resin prepared with 005x7 resin;

[0052] Figure 7 Infrared spectra of weakly acidic resins and other samples;

[0053] A: carvedilol phosphate; B: D113 resin; C: physical mixture of carvedilol phosphate and D113 resin; D: carvedilol phosphate resin prepared with D113 resin;

[0054] Figure 8 Effect of PEG4000 impregnation on in vitro release behavior of strongly acidic carvedilol phosphate resin (n=3);

[0055] Figure 9 Effect of PEG4000 impregnation on in vitro release behavior of strongly acidic carvedilol phosphate resin (n=3);

[0056] Figure 10 Flow chart for coating of carvedilol phosphate resin;

[0057] Figure 11 Effect of plasticizer amount on in vitro release behavior of weakly acidic carvedilol phosphate resin sustained release microcapsules (n=3)

[0058] Figure 12 Effect of ethyl cellulose amount on in vitro release behavior of weakly acidic carvedilol phosphate resin sustained release microcapsules (n=3);

[0059] Figure 13 Effect of curing temperature on in vitro release behavior of weakly acidic carvedilol phosphate resin sustained release microcapsules (n=3);

[0060] Figure 14 Scanning electron microscope pictures of drug resin microcapsules;

[0061] A: strongly acidic carvedilol phosphate resin sustained release microcapsules, scale bar 20.0 μm; B: weakly acidic carvedilol phosphate resin sustained release microcapsules, scale bar 10.0 μm. Detailed Implementation

[0062] The present invention will now be described in detail with reference to the embodiments and accompanying drawings. The following embodiments are merely further illustrations of the present invention and do not limit the scope of application of the present invention in any way.

[0063] Example 1: Preparation of carvedilol phosphate resin

[0064] The weak acid D113 macroporous resin was crushed using a high-speed pulverizer. Both the D113 macroporous weak acid ion exchange resin and the 005×7 strong acid cation exchange resin were passed through a 100-mesh sieve. Large quantities of each ion exchange resin were weighed and placed in beakers, and a certain volume of ethanol was added to cover the resin. The mixture was stirred and soaked overnight. After standing, the supernatant was discarded. The resin was poured into a glass chromatography column, and a 0.5 mol / L HCl solution was prepared to wash the resin until the effluent was acidic. The column was then sealed, and the resin was soaked in the acidic solution for 4 hours. The glass chromatography column was washed with a large amount of distilled water until neutral. Then, a 1 mol / L NaOH solution was prepared to wash the resin until the effluent was alkaline. The column was then sealed, and the resin was soaked in the alkaline solution for 4 hours. The resin was washed with a large amount of distilled water until neutral, filtered, and dried for later use. The cation exchange resin was then converted to hydrogen or sodium form for later use.

[0065] Carvedilol phosphate was dissolved in an ethanol-water solution and stirred until completely dissolved. Then, cation exchange resin was added, and the mixture was stirred, filtered, washed, and dried to obtain carvedilol phosphate resin.

[0066] The drug loading capacity (Qt), drug utilization rate (E), and drug loading degree (F) of the resin are calculated using the following formulas:

[0067]

[0068] V (mL) is the volume of the CVD solution; Qt (mg / mg) is the drug loading of the resin at time t; Q∞ (mg / mg) is the drug loading of the resin at equilibrium; C0 (mg / mL) is the initial concentration of CVD; Ct (mg / mL) is the concentration of CVD at time t; W R (mg) represents the mass of the resin.

[0069] (1) Investigation of the volume ratio of ethanol to water in ethanol-water solution

[0070] CVD is almost insoluble in water. Ethanol-water solution is chosen as a cosolvent for the drug. The cosolvent can cause hydrogen bonding between ethanol and water, resulting in changes in the solvent dielectric constant and polarity, thereby increasing the solubility of CVD in solution.

[0071] The excess CVD was weighed, and 5 mL of ethanol-water mixed solution with a volume ratio of 1:4, 2:3, 1:1, 3:2 and 4:1 was added, respectively, and stirred at room temperature for a period of time at the same speed. After centrifugation, the supernatant was taken, filtered through a 0.45 μm microporous filter, and the absorbance was measured at a wavelength of 285 nm by using a UV spectrophotometer. The solubility of CVD in different volume ratios of ethanol-water was investigated. The results are shown in Table 2. Figure 1

[0072] When the volume ratio of ethanol-water is 3:2, the solubility of CVD is 16.55±1.27 mg / mL, and it is basically completely dissolved. When the volume ratio of ethanol-water is 3:2-4:1, the carvedilol phosphate is completely dissolved. Considering safety and cost saving, 60% ethanol is selected as the potential solvent of CVD.

[0073] (2) Effect of resin type on drug loading

[0074] The strong acid Na + 005×7 resin and the weak acid H + D113 resin were taken as examples to investigate the effect of strong acid cation exchange resin and weak acid cation exchange resin on drug loading, respectively.

[0075] 200 mg of strong acid ion exchange resin and weak acid macroporous ion exchange resin were weighed and added to 10 mL of drug solution with a concentration of 10 mg / mL, and stirred on a shaking table at 25℃±0.5℃ and 100 rpm. The Qt(mg / mg) value was calculated by sampling and measuring at the corresponding time point.

[0076] The binding capacity of CVD to the strong acid Na + 005×7 resin is slightly stronger than that of CVD to the weak acid H + D113 resin. When the reaction reaches equilibrium, the Q t of the strong acid resin is 0.44±0.02, the Q t of the weak acid resin is 0.38±0.03, and the two drug resins basically reach equilibrium at the same time. CVD is a weak acid weak base salt, forms a strong acid weak base type complex with 005×7 resin, has strong dissociation ability, is unstable, and has slightly weak drug loading capacity; CVD forms a weak acid weak base type complex with D113 resin and a strong acid, which is not easy to dissociate, but it is difficult for weak acid to generate strong acid, and the reaction driving force is insufficient. Therefore, the weak acid cation exchange resin is preferred as the carrier of the drug resin in the present application.

[0077] (3) Effect of cation exchange resin particle size on drug loading

[0078] ​The particle size of the cation exchange resin affects the efficiency of drug loading. When the particle size of the cation exchange resin decreases, the exchange rate of CVD and the resin increases, and the time to reach equilibrium is slightly shortened. When the particle size of the cation exchange resin is 100-200 mesh, Qt is 0.42 ± 0.04; when the particle size is 60-100 mesh, Qt is 0.36 ± 0.03. During the reaction, CVD first contacts the surface of the cation exchange resin and exchanges with the active ions on the surface of the resin. As the particle size of the cation exchange resin decreases, the contact area between CVD and the resin increases, and the exchange rate increases. When the particle size is large, it is difficult for the drug to completely penetrate into the resin, resulting in a decrease in Qt. Therefore, although the drug loading speed is different at different particle sizes of 60-200 mesh, complete drug loading can be achieved. When the particle size of the resin is 100-200 mesh, the exchange rate is high and the reaction time is short, so 100-200 mesh resin is preferred for drug loading.

[0079] (4) Investigation of CVD concentration

[0080] CVD 10 mg, 50 mg, 100 mg, and 150 mg were weighed and added to 10 mL of 60% ethanol solution, respectively, and stirred until completely dissolved. The drug concentration in the solution was 1 mg / mL, 5 mg / mL, 10 mg / mL, and 15 mg / mL, respectively. 200 mg of weakly acidic ion exchange resin was added to each solution, and the solutions were stirred on a shaking table at 25.0°C ± 0.5°C and 100 rpm. Samples were taken at predetermined time points to determine the absorbance, and the effect of different initial drug concentrations (1 mg / mL, 5 mg / mL, 10 mg / mL, and 15 mg / mL) on drug loading was investigated. The results are shown in Table 1.

[0081] Under the condition of a constant amount of drug-loaded resin, as the initial concentration of the drug increases, Q∞ increases and E decreases. When the concentration of CVD increases from 1 mg / mL to 10 mg / mL, Q∞ increases rapidly and E decreases slowly. When the concentration continues to increase to 15 mg / mL, Q∞ increases slowly and E decreases rapidly, indicating that the groups on the resin have been basically exchanged by the drug ions, and the excess drug leads to an increase in drug loading and a low drug utilization rate. Therefore, the concentration of CVD is preferably 5-10 mg / mL.

[0082] Table 1 Drug loading results at different CVD concentrations (n = 3)

[0083]

[0084] (5) Effect of drug to resin ratio on drug loading

[0085] Precisely weigh CVD 50 mg completely dissolved in 5 mL of 60% ethanol solution, add 25 mg, 50 mg, 100 mg, 150 mg, 200 mg of weak acid ion exchange resin respectively, under the condition of 25.0 ℃±0.5 ℃, 100 rpm, the shaking table is stirred, the absorbance is determined at the predetermined time point, and the influence of different drug resin ratios (2:1, 1:1, 1:2, 1:3, 1:4) on drug loading is investigated.

[0086] Under the condition of a certain drug concentration, drug loading is carried out with the drug resin mass ratio of 2:1-1:4, and the results show that when the amount of resin added to the drug solution is small, the total amount of drug far exceeds the saturation exchange amount of resin, and with the increase of the amount of resin, sufficient resin exchange amount forms a strong driving force to promote the forward reaction, E increases, which indicates that the groups on the drug have been basically ion exchanged by the resin, and the excessive amount of resin leads to the increase of drug utilization rate and the low drug loading amount of resin. When the drug resin mass ratio is 1:2-1:4, the drug loading effect is better, and when the mass ratio is 1:2-1:3, the drug loading effect is best.

[0087] Table 2 Static method drug loading results of different drug resin ratios (n=3)

[0088]

[0089] (6) Influence of temperature on drug loading

[0090] Drug loading is carried out at 25 ℃, 30 ℃, 37 ℃, 40 ℃ and 45 ℃ respectively, and other conditions are the same, and the results show that the time required for the reaction to reach equilibrium is basically not affected by temperature, and Q∞ and E increase slightly with the increase of temperature. The increase of temperature increases the membrane diffusion rate and the diffusion rate of CVD to the internal structure of the resin, and although the ion exchange reaction is accelerated, it is not significant. In order to facilitate experimental operation, drug loading is carried out at 25.0 ℃±0.5 ℃.

[0091] Table 3 Influence of temperature on E and Q ∞

[0092]

[0093] Example 2 Preparation of carvedilol phosphate resin

[0094] Weigh 100 mg of carvedilol phosphate and dissolve it in 10 mL of 60% ethanol solution, stir until completely dissolved, then add 200 mg of pretreated D113 weak acid ion exchange resin, the particle size of the resin is 100-200 mesh, stir at 30 ℃ for 6 h, then wash the unbound drug with deionized water to obtain carvedilol phosphate weak acid resin, which is dried for use. The final resin drug loading is about 0.4 mg / mg, and the drug utilization rate is about 80%.

[0095] ​Example 3 Preparation of carvedilol phosphate resin

[0096] Carvedilol phosphate 100 mg was dissolved in 10 mL of 60% ethanol solution, stirred until completely dissolved, then 200 mg of pretreated 005 x 7 strong acid cation exchange resin was added, the resin particle size was 100-200 mesh, stirred at 30°C for 6 h, then the unbound drug was washed away with deionized water to obtain strong acid resin of carvedilol phosphate, which was dried for standby use. The final resin drug loading was about 0.42 mg / mg, and the drug utilization rate was about 75%.

[0097] Example 4 Preparation of carvedilol phosphate resin

[0098] Carvedilol phosphate 100 mg was dissolved in 10 mL of 60% ethanol-water solution, stirred until completely dissolved, then D113 weak acid cation exchange resin was added, stirred at 25°C±0.5°C for 6 h, filtered, eluted, and dried to obtain carvedilol phosphate resin.

[0099] The mass ratio of carvedilol phosphate and D113 weak acid cation exchange resin was 1:3, the resin particle size was 100-200 mesh, the initial drug concentration was 10 mg / mL, and the reaction temperature was 25.0°C±0.5°C. The final resin drug loading was about 0.39 mg / mg, and the drug utilization rate was about 84%.

[0100] Example 5 Quality evaluation of resin

[0101] (1) Resin morphology

[0102] The morphology of the blank strong acid cation resin, the blank weak acid cation resin, and the carvedilol phosphate resin after drug loading was observed by scanning electron microscopy. An appropriate amount of sample powder was placed on a copper plate (with conductive glue), gold was sprayed under vacuum conditions, and then a very narrow electron beam was used to scan the sample. Through the interaction between the electron beam and the sample, the surface morphology of the sample was observed by imaging with secondary electron signals.

[0103] The scanning electron microscopy results are shown in Figure 2 and Figure 3 . The surface of the strong acid resin was smooth and spherical, and the weak acid resin was irregular in shape after mechanical crushing. The morphology of the resin obtained after drug loading was basically consistent with that of the blank resin, and no obvious drug crystal particles were found on the surface of the resin.

[0104] (2) X-ray diffraction

[0105] Blank resin, carvedilol phosphate, physical mixture of carvedilol phosphate and resin (1:2) and carvedilol phosphate resin were analyzed by X-ray diffraction. Test conditions: room temperature; Cu target; detector: semiconductor array detector. Graphite bending monochromator, scanning speed 10° / min, mixture 5° / min. Angle test range (2θ): 5°-80°.

[0106] The X-ray spectrum results of the two resins and related samples are shown in Figure 4 and Figure 5 . In (B), there are specific crystallization peaks of carvedilol phosphate, and in (A), there are no crystallization characteristic peaks of the two blank resins. When the two resins are physically mixed with carvedilol phosphate, the characteristic peaks of carvedilol phosphate still exist, indicating that the crystal structure of carvedilol phosphate in the physical mixture has not changed. However, in (D), the characteristic crystallization peaks disappear, indicating that both resins have undergone chemical changes during the drug loading process.

[0107] The FTIR spectrum results of the two resins and related samples are shown in Figure 6 and Figure 7 . Figure 6 and 7 In (A), CVD has characteristic absorption peaks at 3485 cm -1 , v(N-H), 3064 cm -1 , aromatic ring v(=C-H), 2841 cm -1 , saturated carbon hydrogen bond v(C-H), 2405 cm -1 , ammonium salt v(N-H+), 1627 cm -1 , aromatic heterocyclic ring v(C=C), 1255 cm -1 , v(C-N), 1303 cm -1 , aryl alkyl ether v(C-O); compared with (C) and (D), in (D), the absorption band at 3405 cm -1 is wide and strong, and there is an absorption peak at 1038 cm -1 , which is speculated to be the hydroxyl v(O-H), the v(N-H) vibration peak disappears, and at the same time, the vibration peak at 2405 cm -1 disappears, indicating that CVD forms an ionic bond with the sulfonic / carboxylic acid group of the resin; in the 450-1650 cm -1 segment, the number of peaks in the (D) figure is less than that in the (C) figure, and the intensity is weakened. Therefore, it is speculated that both resins can undergo chemical changes with CVD ions, resulting in changes in the infrared spectrum.

[0108] Example 6: Taking the carvedilol phosphate resin of Example 2 as an example to investigate the in vitro release conditions of the drug

[0109] (1) Selection of release medium

[0110] A certain amount of carvedilol phosphate resin (CVD resin) prepared in Example 2 was weighed into a 50 mL volumetric flask, and a certain amount of an ionic solution was added to exchange the solution, and then the flask was stirred at 100 rpm and 37.0°C±0.5°C for 8 h, and then sampled and filtered, and then determined by UV at 285 nm.

[0111] The solubility of CVD in 0.15 mol / L CH3COONa+1 mol / L CH3COOH buffer solution was higher than that in 0.15 mol / L NaCl+1 mol / L CH3COOH, and the possible reason was that CH3COONa ionized CH3COO - Hydrolysis to CH3COOH increased the solubility of CVD in the solution. When the concentration of CH3COONa increased, the absorbance also increased, indicating that high concentration of Na + The replacement effect on CVD on the resin was good, and since the absorbance values of 0.5 mol / L CH3COONa and 1 mol / L CH3COONa were not much different, it was indicated that increasing the concentration had no obvious significance for ion exchange.

[0112] In addition, different ion species also had a certain influence on the in vitro release of CVD resin. The 24 h release amount of CVD in CH3COONa+CH3COOH buffer was 49.42±1.67%, and the 24 h release amount in CH3COOK+CH3COOH buffer was 46.92±1.78%.

[0113] CVD cannot be ion exchanged with deionized water and thus cannot be released; Na + and K + have the same valence, only the atomic weight is different, and the size order of their radii is Na + >K + , and the exchange rate of Na + is greater than that of K + , and D(Na + )>D(K + ).

[0114] Therefore, the dissolution experiment of CVD selected 0.15 mol / L CH3COONa+1 mol / L CH3COOH buffer solution as the release medium.

[0115] (2) Effect of rotation speed on in vitro release of CVD resin

[0116] The rotation speed increase the CVD in-vitro dissolution rate, the CVD total dissolution amount at 75 rpm and 100 rpm is basically the same, f2>50; the rotation speed of 50 rpm is too small to make the drug insufficiently combined with the ions in the solution, the 24 h release rate is only 35.91±2.27%. Therefore, 100 rpm is selected as the standard rotation speed of the drug resin release.

[0117] Example 7 Release of carvedilol phosphate resin

[0118] The standard release condition is 37℃±0.5℃ and the rotation speed of 100 rpm with the medium volume of 100 mL; the standard release medium is 0.15 mol / L CH3COONa+1 mol / L CH3COOH solution; the sampling is performed at 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h and the release medium is immediately supplemented; the removed sample is filtered by using a 0.45 μm filter membrane and the light absorption value is measured to calculate the drug amount released by the drug resin and the cumulative drug release amount.

[0119] The release of the weakly acidic carvedilol phosphate resin of Example 2 and the strongly acidic carvedilol phosphate resin of Example 3 is shown as Figure 8 .

[0120] The results show that the 24 h release amount of the weakly acidic CVD resin is 50.42±2.05% and the 24 h release amount of the strongly acidic CVD resin is 33.48±3.22%. The release degree of the weakly acidic drug resin is much greater than that of the strongly acidic resin. The binding force between the CVD loaded with positive charge and the strongly acidic resin is greater than that between the CVD and the weakly acidic resin, the exchange ion combination ability of the CVD in the solution is less than that of the CVD and the strongly acidic resin, the CVD is difficult to compete and exchange from the strongly acidic resin with which the CVD is tightly combined, and thus the CVD combined with the strongly acidic resin is difficult to release. The D113 weakly acidic ion exchange resin is a macroporous type, which is more suitable for the loading of the poorly soluble drug, and can obviously improve the dissolution and release of the poorly soluble drug. Therefore, in order to improve the bioavailability of the drug resin, the weakly acidic drug resin is used to prepare the microcapsule.

[0121] Example 8 Pretreatment of the strongly acidic drug resin of Example 3 before coating

[0122] When the CVD microcapsule is prepared into a sustained-release suspension, the gel type resin will swell after absorbing water, leading to the rupture of the coating film and the occurrence of the burst release phenomenon after the patient takes the medicine. Therefore, the strongly acidic resin needs to be immersed before coating, so as to effectively prevent the resin from swelling after absorbing water, maintain the integrity of the coating film and avoid the burst release of the CVD. 20% (w / v) PEG 4000 is added to the CVD resin, stirred at room temperature for 0.5 h, filtered and dried for standby.

[0123] The swelling degree of the blank resin was 1.52±0.34, and the swelling degree of the non-impregnated CVD resin was 1.37±0.29. After ion exchange of the CVD and the resin, the voids of the resin were occupied, so the swelling degree of the CVD resin was slightly smaller than that of the blank resin. After treatment with the impregnant PEG4000, the swelling degree of the CVD resin was reduced to 1.10±0.11, and no swelling basically occurred.

[0124] A certain amount of the drug resin and the drug resin after impregnation treatment (containing 10 mg of CVD) were weighed, 100 mL of 1 mol / L CH3COONa+1 mol / L CH3COOH buffer was used as the dissolution medium, and the in-vitro dissolution test was carried out at a rotation speed of 100 rpm and a temperature of 37.0℃±0.5℃. The effect of impregnation on the in-vitro release behavior of the strong acid CVD resin is shown in Figure 9 .

[0125] The CVD was slowly released from the strong acid resin over time, and the 24 h release amount of the non-impregnated drug resin was 32.14±1.89%, and the 24 h release amount of the drug resin after impregnation was 31.94±2.63%.

[0126] Screening of coating prescription (taking the CVD resin of weak acid D113 as an example)

[0127] A certain amount of the sustained-release material was added to acetone and stirred until completely dissolved. Diethyl phthalate was added dropwise to the solution to uniformly mix as a dispersed phase. The CVD resin (containing 10 mg of CVD) was slowly added, and constant stirring was performed to keep it in a suspended state. Liquid paraffin and Span 80 were mixed at a volume ratio of 8:1 and stirred uniformly to serve as a continuous phase. The continuous phase was added dropwise to the dispersed phase while keeping the dispersed phase in a uniformly stirred state. Stirring was continued at a certain temperature until the acetone was completely volatilized. Finally, the CVD resin microcapsules were washed and filtered with petroleum ether to remove the residual liquid paraffin on the surface of the microcapsules, and drying was performed to obtain the prepared CVD resin microcapsules. The process flow of the coating is shown in Figure 10 .

[0128] EC is insoluble in water but soluble in various organic solvents, so it is often used as a coating material to form a water-insoluble film. The higher the viscosity of EC, the firmer the film formed, so that the release speed of the drug can be adjusted, the bad odor can be covered up, and the stability of the preparation can be increased. In the present application, EC is selected as the sustained-release coating material, and the molecular weight is 448.47.

[0129] The ratio of liquid paraffin:acetone:span 80 affects the properties of the coating material, and different ratios result in different properties and release. By preparing a ternary phase diagram of liquid paraffin / acetone / span 80, it was determined that the volume ratio of liquid paraffin / acetone / span 80 was 8:4:1. Under this condition, the acetone gradually volatilized upon heating, the liquid paraffin extracted the acetone from the emulsion, and the EC solidified to form a film around the CVD resin. The system was observed to change from turbidity (emulsion) to clarity.

[0130] The effects of other conditions on the sustained-release effect of the microcapsules were investigated as follows:

[0131] A certain amount of ethyl cellulose was added to acetone and stirred until completely dissolved. Diethyl phthalate was added dropwise to the solution and mixed uniformly as the dispersed phase. CVD resin (containing 10 mg of CVD) was slowly added, and constant stirring was maintained to keep it in a suspended state. Liquid paraffin and span 80 were mixed in a volume ratio of 8:1 and stirred uniformly as the continuous phase. The volume ratio of liquid paraffin:acetone:span 80 was 8:4:1. The continuous phase was added dropwise to the dispersed phase while maintaining the uniform state of the dispersed phase under constant stirring. The stirring was continued at a certain temperature until the acetone completely volatilized. Finally, the CVD resin microcapsules were washed and filtered with petroleum ether to remove the residual liquid paraffin on the surface of the microcapsules, and then dried to obtain the prepared CVD resin microcapsules.

[0132] (1) Selection of the amount of diethyl phthalate

[0133] Ethyl cellulose was fixed at 7.5% of the CVD resin, and the CVD resin was coated according to the above method. The amount of plasticizer was 0%, 10%, and 20% of the ethyl cellulose, respectively. The effects of different plasticizers on drug release were investigated, and the results are shown in Figure 11

[0134] The results show that the release rate of CVD decreases with the increase of the amount of diethyl phthalate. When no plasticizer is used, the release rate of the CVD resin microcapsules is faster. Plasticizers can enhance the flexibility of the coating and increase the tensile strength of the microcapsules, ensuring the integrity of the coating film. Too much diethyl phthalate will result in too high viscosity of the coating system, reducing the release amount of CVD and leading to a decrease in drug utilization.

[0135] The results show that when the amount of plasticizer is 10% of the ethyl cellulose, the 24h release amount of the CVD resin microcapsules is 42.53±3.57%. Based on the above results, the amount of plasticizer used to prepare the CVD resin microcapsules is 8-10% of the mass of the coating material.

[0136] (2) Selection of the amount of ethyl cellulose

[0137] ​The insufficient amount of ethyl cellulose causes the coating film to be loose, and the drug release rate is similar to that of the uncoated CVD resin; the excess amount of ethyl cellulose causes the formed coating film to be too thick, the CVD is difficult to penetrate into the release medium from the coating film, the drug release rate of the microcapsule is greatly reduced, the drug utilization rate is too low; and the excess amount of coating will cause the drug microcapsule to precipitate during washing and greatly increase the viscosity of the microcapsule, causing the microcapsule to stick together, thereby affecting the final coating effect.

[0138] According to the method of the present embodiment, 10% diethyl phthalate, ethyl cellulose is selected as 2.5%, 7.5%, 15% of the CVD resin, and the effect of different amounts of ethyl cellulose on release is investigated, and the results are shown in Figure 12 .

[0139] The results show that the 24h release amount of the CVD resin microcapsule coated with 7.5% ethyl cellulose is 43.58±3.03%. When the amount of ethyl cellulose is 2.5-7.5% of the CVD resin, the 24h drug release amount is between 40-50%, therefore, the amount of ethyl cellulose is selected to be 2.5-7.5% of the CVD resin, preferably 7.5%.

[0140] (3) Curing temperature selection

[0141] According to the above method, the amount of ethyl cellulose is fixed at 7.5% of the CVD resin, and the amount of plasticizer is 10% of the ethyl cellulose, and the effect of different curing temperatures on release is investigated, and the results are shown in Figure 13 .

[0142] The results of the effect of curing temperature on the in vitro release of CVD microcapsules are shown in Figure 13 , the release rate of CVD increases with the increase of curing temperature. The acetone is difficult to volatilize at lower temperature, and the acetone cannot completely volatilize within the same curing time, which causes the coating film of the microcapsule to be relatively tight, and the CVD is difficult to release from the coating film. In addition, at lower temperature, the viscosity of the microcapsule is larger, and the resin microcapsule is prone to stick together, which affects the release of the drug; when the temperature is higher, the acetone volatilizes quickly, and the entire coating system has not yet reached a uniform and stable state, and the microcapsule has been partially formed, which causes the final microcapsule coating film to be loose, uneven, and have uncoated holes.

[0143] The results show that the 24h release amount of the CVD resin microcapsule prepared at a curing temperature of 45°C is 43.15±2.12%, and within the curing temperature of 45-55°C, the 24h release amount of the CVD resin microcapsule can be between 40-50%. In summary, 45-55°C is selected as the curing temperature.

[0144] In summary, the emulsified solvent evaporation method is used to coat the medicine resin: ethyl cellulose is finally determined as the capsule material, the amount is 2.5-7.5% of the CVD resin; the amount of plasticizer diethyl phthalate is 8-10% of the ethyl cellulose; the coating is carried out at 45-55℃ for 0.5-1h, and finally the medicine resin sustained-release microcapsule with obvious sustained-release effect is prepared. The drug release behavior of the medicine resin sustained-release microcapsule is mainly controlled by the membrane and the diffusion of the skeleton, and the ion exchange control is auxiliary, the drug release amount is 30-50% at 24h, preferably 40-50%, and a better sustained-release effect is achieved.

[0145] Example 9 Preparation of carvedilol phosphate weak acid resin sustained-release microcapsule

[0146] (1) The weak acid D113 macroporous resin is broken by a high-speed pulverizer and passed through a 100-mesh screen. 10g of D113 macroporous weak acid ion exchange resin is weighed into a beaker, 100mL of ethanol is added to cover the resin, and stirring and soaking are carried out overnight. After standing, the supernatant is discarded. The resin is poured into a glass chromatography column, and 0.5mol / L HCl solution is prepared to flush the resin until the effluent is acidic. The chromatography column is closed to soak the resin in the acid solution for 4h; after washing the glass chromatography column with a large amount of distilled water until it is neutral, 1mol / L NaOH solution is prepared to clean the resin until the effluent is alkaline. The chromatography column is closed to soak the resin in the alkaline solution for 4h. After washing with a large amount of distilled water until it is neutral, it is suction filtered and dried for use.

[0147] (2) 100mg of carvedilol phosphate is dissolved in 10mL of 60% ethanol solution, stirred until completely dissolved, and then 200mg of weak acid D113 macroporous ion exchange resin is added. After stirring at 30℃ for 6h, the unbound drug is washed away with deionized water to obtain carvedilol phosphate weak acid resin, which is dried for use.

[0148] (3) 20mg of ethyl cellulose is added to 10mL of acetone, stirred until completely dissolved, and 2mg of plasticizer diethyl phthalate is added to the solution to mix uniformly as the dispersed phase; the carvedilol phosphate resin is slowly added, and constant stirring is carried out to keep it in a suspended state, the mass ratio of ethyl cellulose to carvedilol phosphate resin is 7.5%; liquid paraffin and span 80 are mixed and stirred uniformly at a volume ratio of 8:1 to serve as the continuous phase, the volume ratio of liquid paraffin:acetone:span 80 is 8:4:1. The continuous phase is added dropwise to the dispersed phase while keeping the dispersed phase in a uniform state of constant stirring, and the stirring is continued at 45℃ for 12h. Finally, the carvedilol phosphate resin microcapsule is suction filtered and washed with petroleum ether to remove the residual liquid paraffin on the surface of the microcapsule, and then dried to obtain the carvedilol phosphate weak acid resin sustained-release microcapsule.

[0149] Example 10 Preparation of carvedilol phosphate strong acid resin sustained-release microcapsule

[0150] (1) 005x7 strong acid ion exchange resin was broken by high-speed crusher and passed through a 100-mesh screen. 10 g of 005x7 strong acid ion exchange resin was weighed into a beaker, 100 mL of ethanol was added to cover the resin, and it was stirred and soaked overnight. After standing, the supernatant was discarded. The resin was poured into a glass chromatographic column, and 0.5 mol / L HC1 solution was prepared to rinse the resin until the effluent was acidic. The chromatographic column was closed to soak the resin in the acid solution for 4 h. After washing the glass chromatographic column with a large amount of distilled water until it was neutral, 1 mol / L NaOH solution was prepared to clean the resin until the effluent was alkaline. The chromatographic column was closed to soak the resin in the alkaline solution for 4 h. After washing with a large amount of distilled water until it was neutral, it was suction filtered and dried for use.

[0151] (2) 100 mg of carvedilol phosphate was dissolved in 10 mL of 60% ethanol solution, stirred until completely dissolved, then 200 mg of 005x7 strong acid ion exchange resin was added, stirred at 30°C for 6 h, then the unbound drug was washed away with deionized water to obtain strong acid resin of carvedilol phosphate, which was dried for use.

[0152] (3) The obtained strong acid resin of carvedilol phosphate was added to 20% (w / v) PEG 4000, stirred at room temperature for 0.5 h, then suction filtered and dried for use.

[0153] (4) 20 mg of ethyl cellulose was added to 10 mL of acetone, stirred until completely dissolved, and 2 mg of plasticizer diethyl phthalate was added to the solution to mix uniformly as the dispersed phase; the strong acid resin of carvedilol phosphate was slowly added thereto, and it was constantly stirred to keep it in a suspended state, the mass ratio of ethyl cellulose to strong acid resin of carvedilol phosphate was 7.5%; liquid paraffin and Span 80 were mixed in a volume ratio of 8:1 and stirred uniformly as the continuous phase, the volume ratio of liquid paraffin: acetone: Span 80 was 8:4:1. The continuous phase was added dropwise to the dispersed phase while keeping the dispersed phase constantly stirred to keep it uniform, and it was continuously stirred at 45°C for 12 h. Finally, the strong acid resin of carvedilol phosphate microcapsules were suction filtered and washed with petroleum ether to remove the residual liquid paraffin on the surface of the microcapsules, and dried to obtain the strong acid resin of carvedilol phosphate sustained-release microcapsules.

[0154] Example 11 Quality evaluation of resin sustained-release microcapsules

[0155] 1. Morphology of resin sustained-release microcapsules

[0156] The morphology of the coated strong acid resin of carvedilol phosphate microcapsules was observed by scanning electron microscopy. An appropriate amount of sample powder was placed on a copper plate (with conductive glue), gold was sprayed under vacuum conditions, and an extremely narrow electron beam was used to scan the sample. Through the interaction between the electron beam and the sample, the surface morphology of the sample was observed by using secondary electron signal imaging to determine the final coating effect.

[0157] The scanning electron microscope results, as shown in Figure 2, show that both the strong acid and weak acid carvedilol phosphate resin sustained-release microcapsules are obviously encapsulated and have complete coating films, indicating that the coating effect of the self-made samples is good. Figure 14

[0158] 2. Drug loading and physical properties of the resin sustained-release microcapsules

[0159] The strong acid carvedilol phosphate resin sustained-release microcapsules of Example 10 (containing about 10 mg of carvedilol phosphate) and the weak acid carvedilol phosphate resin sustained-release microcapsules of Example 9 (containing about 10 mg of carvedilol phosphate) were weighed and placed in a 100 mL beaker, and then diluted to 100 mL with a 0.15 mol / L CH3COONa + 1 mol / L CH3COOH solution. The solution was stirred at 100 rpm and 37°C ± 0.5°C for 24 h, and then sampled and filtered with a 0.45 μm filter. The ultraviolet absorbance was measured at 285 nm, and the content of carvedilol phosphate in the coated microcapsules was calculated.

[0160] Drug content (%) = mass of drug contained in the microcapsules / total weight of the microcapsules x 100%.

[0161] The results are shown in Tables 4 and 5.

[0162] Table 4 Drug loading and physical properties of the strong acid carvedilol phosphate resin sustained-release microcapsules

[0163]

[0164] Table 5 Drug loading and physical properties of the weak acid carvedilol phosphate resin sustained-release microcapsules

[0165]

[0166] 3. In vitro release of the resin sustained-release microcapsules

[0167] The in vitro release behaviors of the two CVD resin microcapsules were similar and had good reproducibility. The three batches of samples had good reproducibility. The 24 h drug release rates of the carvedilol phosphate resin sustained-release microcapsules of Examples 9 and 10 were 45% and 36%, respectively.

[0168] Example 12 Study on the drug release mechanism of the CVD resin microcapsules

[0169] ​The drug release behavior of the two CVD resin microcapsules was fitted by the drug release model of Table 6, and the drug release behavior of the two CVD resin microcapsules is shown in Table 7 and Table 8. The release of the CVD microcapsules is best fitted by film diffusion, and the particle diffusion (Viswanathan) is worst. The release behavior of the CVD microcapsules after coating is changed from particle diffusion to film-controlled release and mainly skeleton diffusion, with the internal particle diffusion of the resin as an auxiliary. The fitting Ritger-Peppas equation obtained n = 0.807 for the strong acid CVD resin and n = 0.6601 for the weak acid CVD resin, 0.43 < n < 0.85, and both resins exhibit irregular transport mechanisms.

[0170] Table 6 Drug release mechanism model

[0171]

[0172] (M t : t sampling point drug release amount; M ∞ : drug release amount at reaction equilibrium; k: drug release rate constant; n: release parameter. For a description of the Viswanathan release model, see the content under item “3.6”. The Ritger-Peppas drug release model approximates the microcapsule as a sphere, n < 0.43: Fick diffusion; n > 0.85: two-phase transport, skeleton dissolution mechanism; 0.43 < n < 0.85: irregular transport, drug diffusion and skeleton dissolution synergy.)

[0173] Table 7 Drug release mechanism model fitting results (strong acid resin)

[0174]

[0175] Table 8 Drug release mechanism model fitting results (weak acid resin)

[0176]

Claims

1. A sustained-release microcapsule of carvedilol phosphate resin comprising carvedilol phosphate resin, a capsule material, characterized in that, The capsule material is one or both of ethyl cellulose and acrylic resin; the amount of the capsule material is 2.5-15% by weight of the carvedilol phosphate resin, preferably 2.5-7.5%, the carvedilol phosphate resin is prepared by a static method or a dynamic method from carvedilol phosphate and ion exchange resin, the mass ratio of carvedilol phosphate and ion exchange resin is 2:1-1:4; the ion exchange resin is a cation exchange resin.

2. The carvedilol phosphate resin-extended microcapsule of claim 1, wherein, The cation exchange resin is a weak acid cation exchange resin or a strong acid cation exchange resin, the weak acid cation exchange resin is selected from carboxylic acid type cation exchange resin, preferably D113 macroporous weak acid ion exchange resin; the strong acid cation exchange resin is selected from sulfonic acid type cation exchange resin, preferably 001x7 or 005x7 strong acid cation exchange resin.

3. The resinous sustained release microcapsules of carvedilol phosphate according to claim 1 or 2, characterized in that, The strong acid cation exchange resin or weak acid cation exchange resin is broken by a high-speed pulverizer, the particle size is 60-200 mesh, preferably 100-200 mesh.

4. The carvedilol phosphate resin-extended microcapsule of claim 1, wherein, The carvedilol phosphate resin sustained-release microcapsule further comprises a plasticizer, a continuous phase, and an emulsifier, the plasticizer is one or a mixture of several of polyethylene glycol, glycerol, triglyceride, diethyl phthalate, and triethyl citrate, preferably diethyl phthalate; the continuous phase is liquid paraffin, and the emulsifier is Span 80.

5. The carvedilol phosphate resin-extended microcapsule of claim 4, wherein the carvedilol phosphate resin-extended microcapsule is characterized by, The amount of the plasticizer is 8-20% by weight of the capsule material, preferably 8-10%.

6. The resinous sustained release microcapsules of carvedilol phosphate according to any one of claims 1 to 5, characterized in that, The drug loading temperature of the carvedilol phosphate resin is 25.0-45.0℃, preferably 25.0-30.0℃.

7. The process for the preparation of the resinous sustained release microcapsules of carvedilol phosphate as claimed in claim 1, wherein, The method comprises the following steps: (1) Pretreatment of the cation exchange resin: repeatedly rinse the resin with 0.5 mol / L HCl solution and 1 mol / L NaOH solution, and finally wash with a large amount of distilled water until neutral, the resin is finally in sodium form or hydrogen form; (2) Preparation of the carvedilol phosphate resin by a static method: Dissolve carvedilol phosphate in an ethanol-water solution, stir until completely dissolved, then add the cation exchange resin, stir, filter, rinse, and dry to obtain the carvedilol phosphate resin; (3) Preparation of the carvedilol phosphate resin sustained-release microcapsule: Dissolve a certain amount of the capsule material in an organic solvent, and add a plasticizer to uniformly mix as a dispersed phase; slowly add the carvedilol phosphate resin to the dispersed phase, and continuously stir to keep it in a suspended state; Mix liquid paraffin and an emulsifier and stir uniformly as a continuous phase; Keep the dispersed phase containing the carvedilol phosphate resin in a uniform state of continuous stirring, and add the continuous phase drop by drop to the dispersed phase, and continuously stir until the organic solvent is completely volatilized.

8. The production method according to claim 7, characterized by In the step (2), the volume concentration of the ethanol-water solution is 60-80%.

9. The production method according to claim 7, characterized by, In the step (3), the organic solvent is one or several of acetone, ethanol, and dichloromethane, preferably acetone; the volume ratio of liquid paraffin, emulsifier, and organic solvent is 8:1-2:3-4, preferably 8:1:4; the temperature of the continuous stirring until the acetone is completely volatilized is 35-55℃, preferably 45-55℃.

10. The resinous sustained release microcapsules of carvedilol phosphate according to any one of claims 1 to 6, characterized in that, The carvedilol phosphate resin sustained-release microcapsule is further prepared into a carvedilol phosphate resin sustained-release preparation, which is preferably a suspension.

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