Carvedilol phosphate resin sustained-release microcapsule, preparation method therefor, and use thereof

Abstract

The present invention belongs to the technical field of pharmaceuticals, and relates to a carvedilol phosphate resin sustained-release microcapsule and preparation and use thereof. The carvedilol phosphate resin sustained-release microcapsule comprises a carvedilol phosphate resin and a capsule material. The capsule material is one or two of ethyl cellulose and acrylic resin, and the amount is 5-15% of the weight of the carvedilol phosphate resin. The carvedilol phosphate resin is prepared from carvedilol phosphate and an ion exchange resin by means of a static method or a dynamic method. The mass ratio of carvedilol phosphate to the ion exchange resin is 2:1 to 1:4. In the present invention, the ion exchange resin is used as a drug carrier to prepare the carvedilol phosphate resin microcapsule. The sustained-release effect of carvedilol phosphate is successfully achieved in vitro by means of ion exchange and emulsion solvent evaporation coating techniques. The prepared carvedilol phosphate resin microcapsule has an in vitro release rate of 30-50% in a buffer solution of 0.15 mol / L CH3COONa + 1 mol / L CH3COOH at 24 h. The ion exchange reaction between carvedilol phosphate and a cationic resin conforms to a first-order kinetic model.

Description

Carvedilol phosphate sustained-release microcapsules, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a sustained-release microcapsule of carvedilol phosphate resin, its preparation method, and its application. Background Technology

[0002] Carvedilol phosphate is a racemic antihypertensive adrenergic blocker that selectively blocks α1-receptors and non-selectively blocks β-receptors. It has no intrinsic sympathomimetic activity and provides significant protection against myocardial damage caused by myocardial hypoxia and myocardial infarction. Clinically, it is used to treat mild to moderate hypertension, ischemic heart disease, and symptomatic chronic congestive heart failure. It can also be used to treat cirrhosis.

[0003] Carvedilol phosphate (CVD) is currently available only in capsule and tablet forms. Common tablet dosages are 2.5 mg, 6.25 mg, and 10 mg, while the capsule dosage is 10 mg. The initial oral dose is 6.25 mg twice daily, which can be increased to 12.5 or 25 mg based on trough concentration and blood pressure, with a total daily dose not exceeding 50 mg. Blood pressure is usually reduced within two weeks. Therefore, hypertensive patients need to take the medication several times a day, causing considerable inconvenience, and only a small percentage of patients can maintain long-term use. Furthermore, carvedilol phosphate should be taken with meals to slow absorption and avoid orthostatic hypotension. Carvedilol phosphate is almost insoluble in water, resulting in low bioavailability (average bioavailability of 25%). It is rapidly absorbed orally, reaching peak plasma concentration in 2 hours, exhibiting a significant first-pass effect. Therefore, developing a controlled-release formulation with sustained-release properties, increased bioavailability, and improved patient compliance is of significant clinical importance. Summary of the Invention

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

[0005] In one aspect, the present invention provides a carvedilol phosphate sustained-release microcapsule, the carvedilol phosphate sustained-release microcapsule comprising carvedilol phosphate resin and a capsule material;

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

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

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

[0009] The ion exchange resin is a cation exchange resin, which is either a weakly acidic cation exchange resin or a strongly acidic cation exchange resin.

[0010] The weakly acidic cation exchange resin is selected from carboxylic acid type cation exchange resins, preferably D113 macroporous weakly acidic ion exchange resin.

[0011] The strongly acidic cation exchange resin is selected from sulfonic acid type cation exchange resins, preferably 001×7 or 005×7 strongly acidic cation exchange resins.

[0012] The cation exchange resin has a particle size of 60-200 mesh, preferably 100-200 mesh.

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

[0014] Carvedilol phosphate can also be other poorly water-soluble drugs, such as: Prazonsin, nebivolol, Bevantolol, terazosin, Atenolol, Arotinolol, bisoprolol, sotalol, etc.

[0015] The carvedilol phosphate resin sustained-release microcapsules also contain plasticizers, continuous phases, and emulsifiers.

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

[0017] The amount of plasticizer used is 8-20% of the capsule material, preferably 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 present invention also provides a method for preparing the carvedilol phosphate resin sustained-release microcapsules, comprising the following steps:

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

[0022] The cation exchange resin is pretreated to obtain sodium-form or hydrogen-form cation exchange resin;

[0023] (2) Static method for preparing carvedilol phosphate resin:

[0024] 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.

[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 to 1:4;

[0027] The drug loading temperature is 25.0-45.0℃. There is no difference in ion exchange rate at this temperature, and the drug loading temperature is preferably 25.0-30.0℃.

[0028] When the cation exchange resin is a strongly acidic cation exchange resin, it is necessary to impregnate the strongly acidic drug resin to effectively prevent resin hydration and swelling, maintain the integrity of the coating film, and avoid CVD burst release.

[0029] The preparation method is as follows: add 20-25% (w / v) PEG 4000 to CVD resin, stir at room temperature for 0.5-1h, filter and dry for later use.

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

[0031] A certain amount of capsule material was weighed and dissolved in an organic solvent, and a plasticizer was added and mixed evenly to form a dispersed phase; carvedilol phosphate resin was slowly added to the dispersed phase and stirred continuously to keep it in a suspended state.

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

[0033] While maintaining a uniformly stirred dispersion containing carvedilol phosphate resin, the continuous phase is added dropwise to the dispersion, and stirring is continued until the organic solvent has completely evaporated.

[0034] The capsule material is ethyl cellulose, and the mass-volume concentration of ethyl cellulose in an 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 stirring continues until the acetone is completely evaporated is 35-55°C, preferably 45-55°C.

[0038] Finally, the carvedilol phosphate resin microcapsules were filtered and washed with petroleum ether to remove residual liquid paraffin from the surface of the microcapsules, and then dried to obtain carvedilol phosphate resin sustained-release microcapsules.

[0039] The carvedilol phosphate resin sustained-release microcapsules can be further prepared into a carvedilol phosphate resin sustained-release suspension using conventional methods.

[0040] The beneficial effects of this invention are as follows: This invention uses ion exchange resin as a drug carrier to prepare carvedilol phosphate resin microcapsule formulations. Through ion exchange and emulsification solvent evaporation coating technology, carvedilol phosphate is successfully released in vitro. The prepared carvedilol phosphate resin microcapsules show an in vitro release rate of 30-50% after 24 hours, achieving a good sustained-release effect. The ion exchange reaction between carvedilol phosphate and the cation exchange resin follows a first-order kinetic model; the preparation is an endothermic process and proceeds spontaneously to the right. Analytical methods such as scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) confirm that the binding mechanism of carvedilol phosphate and the cation exchange resin is chemical. In vitro dissolution results show that the release of carvedilol phosphate resin is significantly delayed after coating. The entire system changes from a pre-coating particle diffusion process to one dominated by membrane-controlled release and skeletal diffusion, with internal resin particle diffusion as a secondary process. Furthermore, the resin can be coated into microcapsules and subsequently formulated into suspensions, further improving drug stability and facilitating storage and transportation. Attached Figure Description

[0041] Figure 1 shows the solubility of carvedilol phosphate in different proportions of co-solvent (n=3);

[0042] Figure 2 shows the scanning electron microscope results of the strongly acidic resin;

[0043] A: 005×7 resin before drug loading, scale bar 20.0 μm; B: Strong acid drug resin prepared from 005×7 resin, scale bar 20.0 μm;

[0044] Figure 3 shows the scanning electron microscope results of the weakly acidic resin;

[0045] A: D113 resin before drug loading, scale bar 20.0 μm; B: Weakly acidic drug resin prepared from D113 resin, scale bar 20.0 μm;

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

[0047] A: 005×7 resin; B: carvedilol phosphate; C: physical mixture of carvedilol phosphate and 005×7 resin; D: carvedilol phosphate resin prepared with 005×7 resin;

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

[0049] A: D113 resin; B: Carvedilol phosphate; C: Physical mixture of carvedilol phosphate and D113 resin; D: Carvedilol phosphate resin prepared from D113 resin;

[0050] Figure 6 shows the infrared spectra of strong acid resin and other samples;

[0051] A: Carvedilol phosphate; B: 005×7 resin; C: Physical mixture of carvedilol phosphate and 005×7 resin; D: Carvedilol phosphate resin prepared with 005×7 resin;

[0052] Figure 7 shows the infrared spectra of weakly acidic resin 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 shows the effect of strong acid and weak acid carvedilol phosphate resin on in vitro drug release behavior (n=3);

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

[0056] Figure 10 is a flowchart of carvedilol phosphate resin coating process;

[0057] Figure 11 shows the effect of plasticizer dosage on the in vitro drug release behavior of weakly acidic carvedilol phosphate sustained-release microcapsules (n=3).

[0058] Figure 12 shows the effect of ethyl cellulose dosage on the in vitro drug release behavior of weakly acidic carvedilol phosphate sustained-release microcapsules (n=3).

[0059] Figure 13 shows the effect of curing temperature on the in vitro drug release behavior of weakly acidic carvedilol phosphate sustained-release microcapsules (n=3);

[0060] Figure 14 shows a scanning electron microscope image of the 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] 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.

[0068] (1) Investigation of the volume ratio of ethanol to water in ethanol-water solution

[0069] 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.

[0070] Excess CVD was weighed and added to 5 mL of ethanol-water mixtures with volume ratios of 1:4, 2:3, 1:1, 3:2, and 4:1, respectively. The mixtures were stirred at the same speed at room temperature for a period of time, centrifuged, and the supernatant was collected. The supernatant was filtered through a 0.45 μm microporous membrane, and the absorbance was measured at 285 nm using a UV spectrophotometer to investigate the solubility of CVD in ethanol-water mixtures with different volume ratios. The results are shown in Figure 1.

[0071] When the volume ratio of ethanol to water is 3:2, the solubility of CVD is 16.55 ± 1.27 mg / mL, indicating near-complete dissolution. When the volume ratio of ethanol to water is 3:2–4:1, carvedilol phosphate dissolves completely. Considering safety and cost-effectiveness, 60% ethanol is selected as the potential solvent for CVD as follows.

[0072] (2) Effect of resin type on drug loading

[0073] With strong acid Na + Type 005×7 resin and weakly acidic H + Taking macroporous D113 resin as an example, the effects of strong acid cation exchange resin and weak acid cation exchange resin on drug loading were investigated respectively.

[0074] Weigh 200 mg of strong acid ion exchange resin and weak acid macroporous ion exchange resin respectively and add them to 10 mL of drug solution with a concentration of 10 mg / mL. Stir on a shaker at 25℃±0.5℃ and 100 rpm. Take samples at the corresponding time points and calculate the Qt (mg / mg) value.

[0075] CVD and strongly acidic Na + The 005×7 type resin has a slightly stronger bonding ability than CVD and weakly acidic H2O. + The bonding of macroporous D113 resin. When the reaction reaches equilibrium, the strongly acidic resin Q... t The Q of the weakly acidic resin is 0.44 ± 0.02. t The value was 0.38 ± 0.03, and the two drug resins reached equilibrium almost simultaneously. CVD is a weak acid-weak base salt, forming a strong acid-weak base complex with 005×7 resin. This complex exhibits strong dissociation ability, instability, and slightly weaker drug loading capacity. CVD forms a weak acid-weak base complex and a strong acid with D113 resin, which is not easily dissociated, but the weak acid is difficult to generate a strong acid, resulting in insufficient reaction driving force. Therefore, this invention preferably uses a weakly acidic cation exchange resin as the carrier for the drug resin.

[0076] (3) Effect of cation exchange resin particle size on drug loading

[0077] The particle size of cation exchange resin affects drug loading efficiency. When the particle size of the cation exchange resin decreases, the exchange rate between 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 resin surface. 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, the drug cannot completely penetrate into the resin, leading to a decrease in Qt. Therefore, although the drug loading rate differs at different particle sizes within the 60–200 mesh range, complete drug loading can still be achieved. When the resin particle size is 100–200 mesh, the exchange rate is high, and the reaction time is short; therefore, resin with a particle size of 100–200 mesh is preferred for drug loading.

[0078] (4) Investigation of CVD concentration

[0079] CVD concentrations of 10 mg, 50 mg, 100 mg, and 150 mg were weighed and added to 10 mL of 60% ethanol solution, respectively. The solutions were stirred until completely dissolved, resulting in drug concentrations of 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. The solutions were stirred on a shaker at 25.0℃ ± 0.5℃ and 100 rpm. Absorbance was measured at predetermined time points to investigate the effect of different initial drug concentrations (1 mg / mL, 5 mg / mL, 10 mg / mL, and 15 mg / mL) on drug loading. The results are shown in Table 1.

[0080] Under the condition of a fixed drug-loaded resin content, Q∞ increases and E decreases with increasing initial drug concentration. When the CVD concentration increases from 1 mg / mL to 10 mg / mL, Q∞ increases rapidly and E decreases slowly; however, when the concentration continues to increase to 15 mg / mL, Q∞ increases slowly while E decreases rapidly, indicating that at this point, the groups on the resin have been largely exchanged by drug ions, resulting in drug excess, increased drug loading, and low drug utilization. Therefore, a CVD concentration of 5-10 mg / mL is preferred.

[0081] Table 1. Drug loading results at different CVD concentrations (n=3)

[0082] (5) Effect of drug resin ratio on drug loading

[0083] Accurately weigh 50 mg of CVD and completely dissolve it in 5 mL of 60% ethanol solution. Add 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg of weakly acidic ion exchange resin respectively. Stir on a shaker at 25.0℃±0.5℃ and 100 rpm. Take samples at predetermined time points to measure absorbance and investigate the effect of different drug-resin ratios (2:1, 1:1, 1:2, 1:3, 1:4) on drug loading.

[0084] Under constant drug concentration, drug loading was performed at a drug-to-resin mass ratio of 2:1 to 1:4. The results showed that when the amount of resin added to the drug solution was small, the total drug volume far exceeded the resin's saturation exchange capacity. As the amount of resin increased, the sufficient resin exchange capacity created a strong driving force to promote the reaction in the forward direction, and E increased accordingly. This indicates that the drug's functional groups had been largely exchanged by the resin ions. Excess resin led to increased drug utilization but insufficient drug loading. A drug-to-resin mass ratio of 1:2 to 1:4 resulted in good drug loading, with the optimal ratio being 1:2 to 1:3.

[0085] Table 2. Static drug loading results for different drug-resin ratios (n=3)

[0086] (6) Effect of temperature on drug loading

[0087] The drug was applied at 25℃ (298K), 30℃ (303K), 37℃ (310K), 40℃ (313K), and 45℃ (318K) under the same conditions. The results showed that the time required for the reaction to reach equilibrium was largely unaffected by temperature, while Q∞ and E increased slightly with increasing temperature. Increasing the temperature increased the membrane diffusion rate and the diffusion rate into the resin structure during CVD, and although the ion exchange reaction was accelerated, the increase was not significant. For ease of experimental operation, the drug was applied at 25.0℃ ± 0.5℃.

[0088] Table 3 Temperature versus E and Q ∞ Impact

[0089] Example 2: Preparation of carvedilol phosphate resin

[0090] 100 mg of carvedilol phosphate was dissolved in 10 mL of 60% ethanol solution and stirred until completely dissolved. Then, 200 mg of pretreated D113 weakly acidic ion exchange resin (particle size 100–200 mesh) was added. The mixture was stirred at 30 °C for 6 h, and unbound drug was washed away with deionized water to obtain carvedilol phosphate weakly acidic resin, which was then dried for later use. The final resin drug loading was approximately 0.4 mg / mg, and the drug utilization rate was approximately 80%.

[0091] Example 3: Preparation of carvedilol phosphate resin

[0092] 100 mg of carvedilol phosphate was dissolved in 10 mL of 60% ethanol solution and stirred until completely dissolved. Then, 200 mg of pretreated 005×7 strong acid ion exchange resin (particle size 100–200 mesh) was added. The mixture was stirred at 30 °C for 6 h, and unbound drug was washed away with deionized water to obtain carvedilol phosphate strong acid resin, which was then dried for later use. The final resin drug loading was approximately 0.42 mg / mg, and the drug utilization rate was approximately 75%.

[0093] Example 4: Preparation of carvedilol phosphate resin

[0094] 100 mg of carvedilol phosphate was dissolved in 10 mL of 60% ethanol-water solution and stirred until completely dissolved. Then, D113 weak acid ion exchange resin was added, and the mixture was stirred at 25℃±0.5℃ for 6 h, filtered, washed, and dried to obtain carvedilol phosphate resin.

[0095] The mass ratio of carvedilol phosphate to D113 weakly acidic ion exchange resin was 1:3, the resin particle size was 100-200 mesh, the initial drug concentration was 10 mg / mL, the reaction temperature was 25.0℃±0.5℃, the final resin drug loading was approximately 0.39 mg / mg, and the drug utilization rate was approximately 84%.

[0096] Example 5: Resin Quality Assessment

[0097] (1) Morphology of resin

[0098] The morphological changes of blank strong acid cation exchange resin, blank weak acid cation exchange resin, and each carvedilol phosphate resin after drug loading were observed using scanning electron microscopy. An appropriate amount of sample powder was placed on a copper plate (with conductive adhesive), sputtered with gold under vacuum, and then scanned with an extremely narrow electron beam. The surface morphology of the sample was observed by imaging the secondary electron signal through the interaction between the electron beam and the sample.

[0099] The scanning electron microscopy results are shown in Figures 2 and 3. The strong acid resin has a smooth, spherical surface, while the weak acid resin, after mechanical crushing, has an irregular shape. The morphology of the resins after drug loading is basically the same as that of the blank resin, and no obvious drug crystal particles were found on the resin surface.

[0100] (2) X-ray diffraction

[0101] X-ray diffraction was used to analyze blank resin, carvedilol phosphate, a physical mixture of carvedilol phosphate and resin (1:2), and carvedilol phosphate resin. Test conditions: room temperature; Cu target; detector: semiconductor array detector; graphite bent crystal monochromator, scan rate 10° / min, 5° / min for mixtures. Angle measurement range (2θ): 5°–80°.

[0102] The X-ray spectra of the two resins and related samples are shown in Figures 4 and 5. Carvedilol phosphate exhibits a specific crystallization peak in (B), while neither of the two blank resins in (A) shows a characteristic crystallization peak. When the two resins were physically mixed with carvedilol phosphate, the characteristic peak of carvedilol phosphate remained, indicating that the crystal structure of carvedilol phosphate remained unchanged in the physical mixture. However, the characteristic crystallization peak disappeared in (D), indicating that both resins underwent chemical changes during drug loading.

[0103] The FTIR spectra of the two resins and related samples are shown in Figures 6 and 7. In Figures 6 and 7(A), CVD exhibits a characteristic absorption peak at 3485 cm⁻¹. -1 v(NH), 3064cm -1 Aromatic ring v (=CH), 2841cm -1 For saturated carbon-hydrogen bonds v(CH), 2405 cm -1 ammonium salt v(N-H+), 1627cm -1 Aromatic heterocyclic ring v (C=C), 1255cm -1 v(CN), 1303cm -1 It is an aryl alkyl ether v(CO); Comparing (C) and (D), in (D) 3405cm -1 The absorption bandwidth is strong at 1038 cm⁻¹ -1 There is an absorption peak at 2405 cm⁻¹, which is presumably the hydroxyl group v(OH). The vibrational peak of v(NH) disappears, and the peak at 2405 cm⁻¹ also disappears. -1 The disappearance of the vibration peak at 450–1650 cm⁻¹ indicates that CVD formed ionic bonds with the sulfonic acid / carboxylic acid groups of the resin; -1 In the segment (D), the number of peaks is less and the intensity is weaker than in the segment (C). Therefore, it is speculated that both resins can undergo chemical changes with CVD ions, leading to changes in the infrared spectra.

[0104] Example 6 uses carvedilol phosphate resin from Example 2 as an example to investigate the conditions for in vitro drug release.

[0105] (1) Selection of release medium

[0106] Weigh a certain amount of carvedilol phosphate resin (CVD resin) prepared in Example 2 and add it to a 50 mL volumetric flask. After adjusting the volume with a certain amount of ion exchange solution, stir the mixture on a shaker at 100 rpm and 37.0℃±0.5℃ for 8 h. Take a sample, filter it, and perform ultraviolet measurement at 285 nm.

[0107] The solubility of CVD in a 0.15 mol / L CH3COONa + 1 mol / L CH3COOH buffer solution is higher than its solubility in a 0.15 mol / L NaCl + 1 mol / L CH3COOH buffer solution. This is likely because CH3COONa ionizes to produce CH3COO. - Hydrolysis to form CH3COOH increases the solubility of CVD in solution. As the concentration of CH3COONa increases, the absorbance also increases, indicating that high concentrations of Na+... + The CVD displacement effect on the resin was good. Since the absorbance values ​​of 0.5 mol / L CH3COONa and 1 mol / L CH3COONa were not significantly different, it indicates that increasing the concentration at this point had no significant effect on ion exchange.

[0108] In addition, different ion types also have a certain impact on the in vitro release of CVD resin. The release rate of CVD in CH3COONa + CH3COOH buffer solution was 49.42 ± 1.67% after 24 hours, and the release rate in CH3COOK + CH3COOH buffer solution was 46.92 ± 1.78% after 24 hours.

[0109] CVD cannot exchange ions with deionized water and therefore cannot be released; Na + With K + They have the same valence, differ only in atomic weight, and their radii are in the following order: Na + >K + Na + The exchange rate is greater than K + D(Na) + )>D(K + ).

[0110] Therefore, a 0.15 mol / L CH3COONa + 1 mol / L CH3COOH buffer solution was used as the release medium in the CVD dissolution experiment.

[0111] (2) Effect of rotation speed on in vitro release of CVD resin

[0112] Increasing the rotation speed increases the in vitro dissolution rate of CVD. The total dissolution amount of CVD at 75 rpm and 100 rpm is basically the same, f2>50. The rotation speed of 50 rpm is too low, so the drug does not bind sufficiently with ions in the solution, and the release rate at 24h is only 35.91±2.27%. Therefore, 100 rpm is selected as the standard rotation speed for drug resin release.

[0113] Example 7 Release of carvedilol phosphate resin

[0114] The standard release conditions were 37℃±0.5℃, 100rpm, and 100mL of medium. A 0.15mol / L CH3COONa + 1mol / L CH3COOH solution was used as the standard release medium. Samples were taken at 0.5h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, and 24h, and the release medium was replenished immediately. The samples were filtered through a 0.45μm filter membrane and their absorbance was measured. The amount of drug released by the drug resin and the cumulative amount of drug released were calculated.

[0115] The release of the weakly acidic carvedilol phosphate resin of Example 2 and the strongly acidic carvedilol phosphate resin of Example 3 is shown in Figure 8.

[0116] The results showed that the 24-hour release rate of the weakly acidic CVD resin was 50.42 ± 2.05%, while that of the strongly acidic CVD resin was 33.48 ± 3.22%. The release rate of the weakly acidic drug resin was significantly higher than that of the strongly acidic resin. The binding force between the positively charged drug CVD and the strongly acidic resin was greater than that with the weakly acidic resin. The binding capacity of the CVD with exchange ions in the solution was less than its binding capacity with the strongly acidic resin. Therefore, the CVD bound to the strongly acidic resin was difficult to competitively exchange out, making the release of CVD bound to the strongly acidic resin more challenging. The D113 weakly acidic ion exchange resin, being macroporous, is more suitable for encapsulating poorly soluble drugs and can significantly improve the solubility and release of such drugs. Therefore, to improve the bioavailability of drug resins, this invention uses weakly acidic drug resins to prepare microcapsules.

[0117] Example 8: Pretreatment of Strongly Acidic Drugs Before Resin Coating (Example 3)

[0118] When CVD microcapsules are prepared into sustained-release suspensions, the gel-type resin absorbs water and swells, causing the coating membrane to rupture and resulting in a burst release after patient administration. Therefore, it is necessary to impregnate the microcapsules with a strongly acidic resin before coating to effectively prevent resin hydration and swelling, maintain the integrity of the coating membrane, and avoid CVD burst release. Add 20% (w / v) PEG 4000 to the CVD resin, stir at room temperature for 0.5 h, filter, and dry for later use.

[0119] The swelling degree of the blank resin was 1.52±0.34, while that of the unimpregnated CVD resin was 1.37±0.29. After ion exchange between the CVD and resin, the CVD resin occupied the resin's voids, thus slightly reducing the swelling degree compared to the blank resin. After treatment with the impregnating agent PEG4000, the swelling degree of the CVD resin decreased to 1.10±0.11, indicating that swelling had essentially not occurred.

[0120] A certain amount of drug resin and impregnated drug resin (containing 10 mg of CVD) were weighed and used as the dissolution medium in 100 mL of 1 mol / L CH3COONa + 1 mol / L CH3COOH buffer solution. An in vitro dissolution test was conducted at 100 rpm and 37.0℃ ± 0.5℃. The effect of impregnation on the in vitro release behavior of the strongly acidic CVD resin is shown in Figure 9.

[0121] CVD was slowly released from the strongly acidic resin over time. The release amount of the unimpregnated resin after 24 hours was 32.14±1.89%, while that of the impregnated resin after 24 hours was 31.94±2.63%.

[0122] Example 8: Screening of Coating Formulations (Taking weakly acidic D113 CVD Resin as an Example)

[0123] A certain amount of sustained-release material was weighed and added to acetone, stirred until completely dissolved, and then diethyl phthalate was added dropwise to the solution and mixed evenly to form the dispersed phase. CVD resin (containing 10 mg of CVD) was slowly added to the solution while continuously stirring to keep it in suspension. Liquid paraffin and Span 80 were mixed at a volume ratio of 8:1 and stirred evenly to form the continuous phase. While maintaining a uniformly stirred dispersed phase, the continuous phase was added dropwise to the dispersed phase, and stirring was continued at a certain temperature until the acetone completely evaporated. Finally, the CVD resin microcapsules were washed with petroleum ether and filtered to remove residual liquid paraffin from the surface of the microcapsules. The microcapsules were then dried to obtain the prepared CVD resin microcapsules. The coating process flow is shown in Figure 10.

[0124] EC is insoluble in water but soluble in many organic solvents, and therefore is often used as a coating material to form water-insoluble films. The higher the viscosity of EC, the stronger the film, which allows for adjustment of drug release rate, masking of unpleasant odors, and increased formulation stability. This invention selects EC with a molecular weight of 448.47 as the sustained-release coating material.

[0125] The ratio of liquid paraffin:acetone:Span 80 affects the properties of the coating material; different ratios result in different properties and release rates. By constructing a ternary phase diagram of liquid paraffin / acetone / Span 80, a volume ratio of 8:4:1 was determined. Under these conditions, acetone gradually evaporated upon heating, and the liquid paraffin extracted the acetone from the emulsion. EC (extractable solidified emulsion) then coated the CVD resin surface to form a film. The observed system change was from turbid (emulsion) to clear.

[0126] The effects of other conditions on the sustained-release effect of microcapsules were investigated using the following method:

[0127] A certain amount of ethyl cellulose was weighed and added to acetone, stirred until completely dissolved, and then diethyl phthalate was added dropwise to the solution and mixed evenly to form the dispersed phase. CVD resin (containing 10 mg of CVD) was slowly added to the solution while continuously stirring to keep it in suspension. Liquid paraffin and Span 80 were mixed at a volume ratio of 8:1 and stirred evenly to form the continuous phase, with a volume ratio of liquid paraffin:acetone:Span 80 of 8:4:1. While maintaining a uniformly stirred dispersed phase, the continuous phase was added dropwise to the dispersed phase, and stirring was continued at a certain temperature until the acetone completely evaporated. Finally, the CVD resin microcapsules were washed with petroleum ether and filtered to remove residual liquid paraffin from the surface of the microcapsules. The microcapsules were then dried to obtain the prepared CVD resin microcapsules.

[0128] (1) Selection of the amount of diethyl phthalate

[0129] Ethyl cellulose was fixed at 7.5% of the CVD resin, and the CVD resin was coated according to the above method. The plasticizer dosages were 0%, 10%, and 20% of ethyl cellulose, respectively. The effect of different plasticizers on drug release was investigated, and the results are shown in Figure 11.

[0130] The results showed that the CVD release rate decreased with increasing diethyl phthalate (DEP) dosage; the release rate of CVD resin microcapsules was faster when no plasticizer was used; the plasticizer enhanced the coating flexibility, increased the tensile strength of the microcapsules, and ensured the integrity of the coating film. Excessive DEP dosage led to excessive viscosity of the coating system, reducing CVD release and consequently decreasing drug utilization.

[0131] The results showed that when the plasticizer content was 10% of ethyl cellulose, the CVD resin microcapsule release rate after 24 hours was 42.53 ± 3.57%. Based on the above results, CVD resin microcapsules were prepared by using a plasticizer content of 8-10% of the coating material mass.

[0132] (2) Selection of Ethyl Cellulose Dosage

[0133] Insufficient ethyl cellulose results in a loose coating film, with a drug release rate similar to that of uncoated CVD resin. Excessive ethyl cellulose leads to an overly thick coating film, making it difficult for CVD to penetrate from the film into the release medium, significantly reducing the drug release rate of the microcapsules and resulting in low drug utilization. Furthermore, excessive coating can cause drug microcapsules to precipitate during washing and greatly increase their viscosity, leading to microcapsule adhesion and affecting the final coating effect.

[0134] Following the method of this embodiment, 10% diethyl phthalate and ethyl cellulose were selected, with amounts of 2.5%, 7.5%, and 15% of the CVD resin, respectively. The effect of different amounts of ethyl cellulose on release was investigated, and the results are shown in Figure 12.

[0135] The results showed that the CVD resin microcapsules coated with 7.5% ethyl cellulose released 43.58 ± 3.03% of the drug over 24 hours. When the ethyl cellulose content was 2.5-7.5% of the CVD resin, the drug release over 24 hours was between 40-50%. Therefore, the amount of ethyl cellulose used was selected to be 2.5-7.5% of the CVD resin, preferably 7.5%.

[0136] (3) Selection of curing temperature

[0137] Following the method described above, the amount of ethyl cellulose was fixed at 7.5% of the CVD resin and the amount of plasticizer was fixed at 10% of the ethyl cellulose. The effect of different curing temperatures on release was investigated, and the results are shown in Figure 13.

[0138] The effect of curing temperature on the in vitro release of CVD microcapsules is shown in Figure 13. The CVD release rate increases with increasing curing temperature. At lower temperatures, acetone is less volatile, and within the same curing time, acetone cannot completely evaporate, resulting in a tighter coating film on the microcapsules, making it difficult for CVD to be released from the film. In addition, at lower temperatures, the microcapsule viscosity is higher, and the resin microcapsules are prone to adhesion, affecting drug release. At higher temperatures, acetone evaporates rapidly, and the entire coating system has not yet reached a uniform and stable state. Microcapsules have already partially formed, resulting in a loose and uneven final microcapsule coating film with unencapsulated pores.

[0139] The results showed that the CVD resin microcapsules prepared at a curing temperature of 45℃ released 43.15±2.12% over 24 hours, and the release rate of the CVD resin microcapsules remained between 40% and 50% within the curing temperature range of 45-55℃. Based on the above, 45-55℃ was selected as the curing temperature.

[0140] In summary, this invention employs an emulsification solvent evaporation method for drug resin coating: ethyl cellulose was ultimately selected as the encapsulating material, with an amount of 2.5-7.5% of the CVD resin; diethyl phthalate, a plasticizer, was used at 8-10% of the ethyl cellulose; coating was carried out at 45-55℃ for 0.5-1 h, ultimately preparing drug resin sustained-release microcapsules with significant sustained-release effects. The drug release behavior of the drug resin sustained-release microcapsules is mainly membrane-controlled release and matrix diffusion, supplemented by ion exchange controlled release. After 24 h, the drug release amount is 30-50%, preferably 40-50%, achieving a good sustained-release effect.

[0141] Example 9: Preparation of Carvedilol Phosphate Weak Acid Resin Sustained-Release Microcapsules

[0142] (1) Crush the weak acid D113 macroporous resin using a high-speed pulverizer and pass it through a 100-mesh sieve. Weigh 10g of D113 macroporous weak acid ion exchange resin and place it in a beaker. Add 100mL of ethanol to cover the resin and stir to soak overnight. Let it stand and discard the supernatant. Pour the resin into a glass chromatography column and wash the resin with 0.5mol / L HCl solution until the effluent is acidic. Seal the chromatography column and soak the resin in the acid solution for 4 hours. Wash the glass chromatography column with plenty of distilled water until neutral. Then, wash the resin with 1mol / L NaOH solution until the effluent is alkaline. Seal the chromatography column and soak the resin in the alkaline solution for 4 hours. Wash with plenty of distilled water until neutral, filter, and dry for later use.

[0143] (2) 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 weak acid D113 macroporous ion exchange resin. Stir at 30°C for 6 h, then wash away the unbound drug with deionized water to obtain carvedilol phosphate weak acid resin. Dry it for later use.

[0144] (3) Weigh 20 mg of ethyl cellulose and add it to 10 mL of acetone. Stir until completely dissolved, and add 2 mg of plasticizer diethyl phthalate to the solution and mix evenly as the dispersed phase. Slowly add carvedilol phosphate resin to the solution and stir continuously to keep it in suspension. The mass ratio of ethyl cellulose to carvedilol phosphate resin is 7.5%. Mix liquid paraffin and Span 80 at a volume ratio of 8:1 and stir evenly to form the continuous phase. The volume ratio of liquid paraffin:acetone:Span 80 is 8:4:1. While keeping the dispersed phase uniformly stirred, add the continuous phase dropwise to the dispersed phase and stir continuously at 45°C for 12 h. Finally, filter and wash the carvedilol phosphate resin microcapsules with petroleum ether to remove residual liquid paraffin on the surface of the microcapsules, and dry to obtain carvedilol phosphate weak acid resin sustained-release microcapsules.

[0145] Example 10: Preparation of Carvedilol Phosphate Strong Acid Resin Sustained-Release Microcapsules

[0146] (1) Crush the 005×7 strong acid ion exchange resin using a high-speed pulverizer and pass it through a 100-mesh sieve. Weigh 10g of the 005×7 strong acid ion exchange resin and place it in a beaker. Add 100mL of ethanol to cover the resin and stir to soak overnight. Let it stand and discard the supernatant. Pour the resin into a glass chromatography column and wash the resin with 0.5mol / L HCl solution until the effluent is acidic. Seal the chromatography column and soak the resin in the acid solution for 4 hours. Wash the glass chromatography column with a large amount of distilled water until neutral. Then, wash the resin with 1mol / L NaOH solution until the effluent is alkaline. Seal the chromatography column and soak the resin in the alkaline solution for 4 hours. Wash with a large amount of distilled water until neutral, filter, and dry for later use.

[0147] (2) 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 005×7 strong acid ion exchange resin. Stir at 30°C for 6 h, then wash away the unbound drug with deionized water to obtain carvedilol phosphate strong acid resin. Dry it for later use.

[0148] (3) Add the obtained carvedilol phosphate strong acid resin to 20% (w / v) PEG 4000, stir at room temperature for 0.5h, filter and dry for later use.

[0149] (4) Weigh 20 mg of ethyl cellulose and add it to 10 mL of acetone. Stir until completely dissolved, and add 2 mg of plasticizer diethyl phthalate to the solution and mix evenly as the dispersed phase. Slowly add carvedilol phosphate resin to the solution and stir continuously to keep it in suspension. The mass ratio of ethyl cellulose to carvedilol phosphate resin is 7.5%. Mix liquid paraffin and Span 80 at a volume ratio of 8:1 and stir evenly to form the continuous phase. The volume ratio of liquid paraffin:acetone:Span 80 is 8:4:1. While keeping the dispersed phase uniformly stirred, add the continuous phase dropwise to the dispersed phase and stir continuously at 45°C for 12 h. Finally, filter and wash the carvedilol phosphate resin microcapsules with petroleum ether to remove residual liquid paraffin on the surface of the microcapsules, and dry to obtain carvedilol phosphate strong acid resin sustained-release microcapsules.

[0150] Example 11 Quality Assessment of Resin Sustained-Release Microcapsules

[0151] 1. Morphology of resin sustained-release microcapsules

[0152] The morphology of the coated carvedilol phosphate microcapsules was observed using scanning electron microscopy. A suitable amount of sample powder was placed on a copper plate (with conductive adhesive), sputtered with gold under vacuum, and scanned with an extremely narrow electron beam. The surface morphology of the sample was observed through secondary electron signal imaging via the interaction between the electron beam and the sample to determine the final coating effect.

[0153] The scanning electron microscope results are shown in Figure 14. Both types of carvedilol phosphate sustained-release microcapsules were clearly encapsulated and the coating was intact, indicating that the coating effect of the self-made sample was better.

[0154] 2. Drug loading and physical properties of resin sustained-release microcapsules

[0155] Weigh separately the strongly acidic carvedilol phosphate resin sustained-release microcapsules of Example 10 (containing approximately 10 mg of carvedilol phosphate) and the weakly acidic carvedilol phosphate resin sustained-release microcapsules of Example 9 (containing approximately 10 mg of carvedilol phosphate), place them in a 100 mL beaker, make up the volume to 100 mL with 0.15 mol / L CH3COONa + 1 mol / L CH3COOH solution, stir at a speed of 100 rpm under the condition of 37°C ± 0.5°C for 24 h, take samples and filter them with a 0.45 μm filter membrane, measure the ultraviolet absorbance value at 285 nm, and calculate the content of carvedilol phosphate in the coated microcapsules.

[0156] Drug content (%) = mass of drug contained in microcapsules / total weight of microcapsules × 100%.

[0157] The results are shown in Table 4 and Table 5.

[0158] Table 4 Drug loading and physical properties of strongly acidic carvedilol phosphate resin sustained-release microcapsules

[0159] Table 5 Drug loading and physical properties of weakly acidic carvedilol phosphate resin sustained-release microcapsules

[0160] 3. In vitro release of resin sustained-release microcapsules

[0161] The in vitro release behaviors of the two kinds of CVD resin microcapsules are similar and have good reproducibility. And the reproducibility of three batches of samples is good. The 24-hour drug release rates of the carvedilol phosphate resin sustained-release microcapsules of Example 9 and Example 10 are 45% and 36% respectively.

[0162] Study on the drug release mechanism of the CVD resin microcapsules of Example 12

[0163] Data fitting was carried out on its drug release behavior through the drug release models in Table 6. The drug release behaviors of the two kinds of CVD resin microcapsules are shown in Table 7 and Table 8. The release of CVD microcapsules is best fitted by film diffusion and worst by particle diffusion (Viswanathan). After coating, the release behavior of CVD microcapsules changes from particle diffusion to mainly membrane-controlled release and matrix diffusion, supplemented by particle diffusion inside the resin. Fitting the Ritger-Peppas equation gives n = 0.807 for the strongly acidic CVD resin and n = 0.6601 for the weakly acidic CVD resin. Since 0.43 < n < 0.85, both resins show an irregular transport mechanism.

[0164] Table 6 Drug release mechanism models

[0165] (M t : drug release amount at the sampling point; M ∞:Drug release amount at reaction equilibrium; k: Drug release rate constant; n: Release parameter. For the description of the Viswanathan release model, see the content under "3.6". The Ritger-Peppas drug release model approximates the microcapsules as spheres. When n < 0.43: Fick diffusion; when n > 0.85: Two-phase transport, matrix erosion mechanism; when 0.43 < n < 0.85: Irregular transport, synergistic effect of drug diffusion and matrix erosion.)

[0166] Table 7 Fitting results of drug release mechanism models (strong acid resin)

[0167] Table 8 Fitting results of drug release mechanism models (weak acid resin)

Claims

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

2. The carvedilol phosphate resin sustained-release microcapsules according to claim 1, characterized in that, 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 resins, preferably D113 macroporous weak acid ion exchange resin. The strong acid cation exchange resin is selected from sulfonic acid type cation exchange resins, preferably 001×7 or 005×7 strong acid cation exchange resins.

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

4. The carvedilol phosphate resin sustained-release microcapsules according to claim 1, characterized in that, The carvedilol phosphate resin sustained-release microcapsules further comprise a plasticizer, a continuous phase, and an emulsifier. The plasticizer is one or a mixture of several of polyethylene glycol, glycerol, triglycerides, 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 sustained-release microcapsules according to claim 4, characterized in that, The amount of plasticizer used is 8-20% of the capsule material weight, preferably 8-10%.

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

7. The method for preparing carvedilol phosphate sustained-release microcapsules according to claim 1, characterized in that, Includes the following steps: (1) Pretreatment of cation exchange resin: The resin was repeatedly rinsed with 0.5 mol / L HCl solution and 1 mol / L NaOH solution, and finally washed with a large amount of distilled water until neutral. The resin was finally in sodium form or hydrogen form. (2) Static method for preparing carvedilol phosphate resin: 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. (3) Preparation of carvedilol phosphate resin sustained-release microcapsules: A certain amount of capsule material was weighed and dissolved in an organic solvent, and a plasticizer was added and mixed evenly to form a dispersed phase; carvedilol phosphate resin was slowly added to the dispersed phase and stirred continuously to keep it in a suspended state. Liquid paraffin and emulsifier are mixed and stirred until homogeneous as a continuous phase; While maintaining a uniformly stirred dispersion containing carvedilol phosphate resin, the continuous phase is added dropwise to the dispersion, and stirring is continued until the organic solvent has completely evaporated.

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

9. The preparation method according to claim 7, characterized in that, In step (3), the organic solvent is one or more 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 at which the stirring continues until the acetone is completely evaporated is 35-55℃, preferably 45-55℃.

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

Images