CN116350582A - Esomeprazole sodium enteric suspension and preparation method and application thereof - Google Patents
Esomeprazole sodium enteric suspension and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an esomeprazole sodium enteric suspension and a preparation method and application thereof, belonging to the technical field of pharmaceutical preparations; the esomeprazole sodium enteric suspension adopts anion exchange resin as a carrier, the esomeprazole sodium and the anion exchange resin are combined by ions to form a drug-loaded resin compound, and then the drug-loaded resin compound is coated by enteric coating; the esomeprazole sodium enteric suspension has the advantages of good drug stability, high bioavailability, good taste, excellent enteric effect, small irritation to gastrointestinal tract and good social value and economic benefit.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an esomeprazole sodium enteric suspension, a preparation method and application thereof.
Background
At present, after in vivo conversion, drugs for inhibiting gastric acid secretion and proton pump inhibitors are combined with H/K-ATPase irreversibly by disulfide bonds, so that the H/K-ATPase is deactivated, and gastric acid secretion is inhibited. Wherein, the drug for inhibiting gastric acid secretion is irreversibly combined with H/K-ATPase, so that the curative effect is durable, and the drug can inhibit gastric acid secretion increase caused by various factors because the drug acts on the last link of gastric acid secretion, so that the acid inhibiting effect is strongest. The proton pump inhibitor is selectively combined with H/K-ATPase, and the H/K-ATPase only exists in parietal cells of the stomach, so that the PPI has specific acid inhibiting effect and high selectivity.
Esomeprazole sodium is a new generation proton pump inhibitor drug, is an S isomer developed on the basis of the primary proton pump inhibitor omeprazole, and is a first single optical isomer proton pump inhibitor drug. Esomeprazole sodium (Esomeprazole sodium, EMZ-Na) with molecular formula C 17 H 18 N 3 O 3 SNa; molecular weight 367.4; white or off-white powder; no odor; has moisture permeability; light and moisture absorption gradually change color; is soluble in water, soluble in methanol and ethanol, slightly soluble in isopropanol and acetone, and hardly soluble in dichloromethane; melting point 255.7-258.6 deg.C specific rotation of-43 deg. to-48 deg.C (1% methanol solution); alkalinity: 2% aqueous solution, pH value is 10.3-11.3. The structural formula of esomeprazole sodium is as follows:
esomeprazole sodium is mainly used for treating gastroesophageal reflux disease, peptic ulcer, reflux esophagitis and other diseases. Compared with omeprazole, the esomeprazole sodium has lower first pass effect of liver, slower clearance rate, high bioavailability and longer lasting effect, and a large number of clinical applications from the market prove that compared with other proton pump inhibitors, the esomeprazole sodium has very small individual difference and the acid inhibition capability is strongest. In addition, esomeprazole sodium is absorbed in small intestine, and the peak time of single oral administration of the esomeprazole sodium reaches the peak of blood concentration (C max ) And increases with dosage. The plasma protein binding rate of esomeprazole sodium at the therapeutic concentration was 97%.The average elimination half-life of esomeprazole sodium is about 1.25h.80% is excreted by urine and the remainder by feces, only 1% is excreted by kidney as prototype. AUC of patients with renal insufficiency was substantially identical to that of normal individuals.
At present, dosage forms and preparations suitable for patients of special crowds such as old people, children, dysphagia and the like are very limited, because of the difference of physiological functions of the patients, besides the difference of administration dosage, various conditions such as requirements on dosage forms, compliance of administration and the like are considered, and common solid preparations such as tablets, capsules and the like often have the problems of higher cost, complex process, injection pain and the like because of the limitations of difficult swallowing, inaccurate dosage division and the like, and the use of the patients such as the old and the children is often limited, so that the completion of normal treatment scheme and the exertion of drug effect are influenced. Compared with solid preparations such as tablets, capsules and the like, the oral liquid preparation has good absorption after oral administration; the medicine is convenient for patients to take in divided doses, and the dose can be adjusted according to different treatment types, different weights of patients and disease course; the liquid preparation is easier to swallow, so that the problem that the medicine is difficult to swallow is solved; besides, the defect of injection pain is avoided, and the medicine taking compliance of patients is improved. However, esomeprazole sodium has poor stability and strong bitter taste, is unacceptable for patients to take directly, and is extremely susceptible to degradation and failure in the acidic environment of the stomach. The oral liquid enteric preparation can realize that the medicine is hardly released in the stomach until the medicine is released in the intestinal canal, can avoid bitter taste generated by releasing in the oral cavity, can further avoid the degradation of the medicine in the stomach, can improve the bioavailability of the medicine, reduce the dosage of the medicine and reduce the toxic and side effects. Therefore, the esomeprazole sodium enteric suspension with good drug stability, high bioavailability, good taste, excellent enteric effect and small irritation to gastrointestinal tract is developed, and has extremely high social value and economic benefit.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides an esomeprazole sodium enteric suspension, a preparation method and application thereof; the esomeprazole sodium enteric suspension adopts anion exchange resin as a carrier, the esomeprazole sodium and the anion exchange resin are combined by ions to form a drug-loaded resin compound, and then the drug-loaded resin compound is coated by enteric coating; the esomeprazole sodium enteric suspension has the advantages of good drug stability, high bioavailability, good taste, excellent enteric effect, small irritation to gastrointestinal tract and good social value and economic benefit.
The invention firstly provides an esomeprazole sodium enteric suspension, which takes anion exchange resin as a carrier, and the esomeprazole sodium and the anion exchange resin are combined by ions to form a drug-carrying resin compound, and then the drug-carrying resin compound is coated by adopting an enteric coating.
Preferably, the anion exchange resin comprises DOULITE TM AP143/1096 resin;
the enteric coating comprises any one or more of hydroxypropyl methylcellulose acetate succinate (CAP), methacrylic acid-ethyl acrylate copolymer or hydroxypropyl methylcellulose phthalate.
Preferably, the enteric coating is a combination of any two methacrylic acid-ethyl acrylate copolymers;
the methacrylic acid-ethyl acrylate copolymer comprises Eudragit L30D-55, eudragit L100, eudragit S100, eudragit RL100 or Eudragit RS100.
Preferably, the enteric coating is a combination of Eudragit L100 and Eudragit S100; the mass ratio of Eudragit L100 to Eudragit S100 is (2-5): 1.
the invention also provides a preparation method of the esomeprazole sodium enteric suspension, which specifically comprises the following steps:
mixing esomeprazole sodium and anion exchange resin to obtain a drug-loaded resin compound, then impregnating the drug-loaded resin compound with an impregnant, stirring, drying and sieving to obtain an impregnated drug-loaded resin compound;
spraying enteric coating liquid on the surface of the impregnated drug-carrying resin compound by adopting a fluidized bed bottom spray coating technology to obtain drug-carrying resin coated microcapsules, and then mixing the obtained drug-carrying resin coated microcapsules with pharmaceutical excipients and water to obtain the esomeprazole sodium enteric suspension.
Preferably, the mass ratio of the anion exchange resin to the esomeprazole sodium is (1-3): 1;
the mass ratio of the impregnant to the anion exchange resin is 1 (0.2-0.5);
the mass ratio of the enteric coating to the impregnated drug-carrying resin composite is 1 (2-6).
Preferably, the stirring condition is that stirring is carried out for 20-40 min at 35-45 ℃;
in the fluidized bed bottom spray coating technology, corresponding parameters are as follows: the air inlet is 30-50m 3 ·h -1 The spraying speed is 0.5-1.5 mL.min -1 The air inlet temperature is 40-50 ℃.
Preferably, the pharmaceutical excipients include any one or a combination of at least two of suspending agents, humectants, sweeteners, flavoring agents, colorants, preservatives, or pH adjusters.
Preferably, the suspending agent comprises any one or a combination of at least two of xanthan gum, glycerol and sodium carboxymethyl cellulose;
the humectant comprises glycerin;
the flavoring agent comprises any one or a combination of at least two of orange essence, lemon essence or orange essence;
the preservative comprises any one or a combination of at least two of propyl paraben, methyl parahydroxybenzoate, ethyl parahydroxybenzoate and sodium benzoate;
the pH regulator comprises any one or the combination of two of anhydrous citric acid and sodium citrate.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, the anion exchange resin is used as a carrier to prepare the esomeprazole sodium drug-loaded resin compound, so that the stability of the drug can be enhanced to a certain extent, the bad taste of the drug can be covered, and the drug-loaded resin compound is subjected to enteric coating, so that the drug is prevented from being degraded in gastric acid environment, is directionally released in intestinal tracts, the bioavailability of the drug can be improved, and the dosage of patients is reduced. Finally, the enteric solution liquid suspension prepared by dispersing the coated microcapsule in the suspension medium can overcome the limitations of enteric tablets, capsules and injection which are on the market at present, for example, the solid preparation is not suitable for the old and children and dysphagia patients to take, the injection has the problems of injection pain and the like, the oral liquid preparation is convenient to take, flexible and accurate in dosage, and the enteric solution liquid suspension can be absorbed more thoroughly in the distribution area of the intestinal tract, and can greatly improve the compliance of the affected limbs.
According to the invention, the medicine carrying resin compound is prepared by adjusting the mass ratio of the anion exchange resin to the esomeprazole sodium, so that the conditions of too low medicine carrying amount, poor medicine effect or increased medicine carrying amount caused by too high relative mass of the anion exchange resin are avoided, and the conditions of too low medicine utilization rate and medicine waste caused by too low relative mass of the anion exchange resin are avoided.
Drawings
Figure 1 is an in vitro release profile of sodium esomeprazole enteric suspension.
Detailed Description
The invention will be further described with reference to the drawings and the specific embodiments, but the scope of the invention is not limited thereto.
Example 1:
(1) The preparation raw materials of the esomeprazole sodium enteric suspension are as follows:
(2) Preparation of esomeprazole sodium enteric suspension:
mixing Esomeprazole sodium with water, and adding DOULITE TM AP143/1096 resin, and the concentration of the drug in the solution is determined by sampling at regular time. When the concentration of the drug in the solution is no longer changed with time, balancing is achieved, the unbound drug on the surface of the resin is washed off by deionized water, and the resin composite carrying the drug is obtained by vacuum drying at 35 ℃.
Then the drug-loaded resin composite is added into an aqueous solution containing 15% (w/w) PEG4000 and 5% (w/w) PEG6000, stirred at 40 ℃ for 30min, and dried in vacuum at 35 ℃ to obtain the impregnated drug-loaded resin composite.
Eudragit L100 and Eudragit S100 are dissolved in a mixed solution of acetone and methanol (v/v=5:1), and PEG400 is used as a plasticizer to prepare a coating liquid with 6% (w/w) solid content; coating the impregnated drug-carrying resin compound by adopting a fluidized bed bottom spray coating technology, and controlling the air inlet quantity to be 40m 3 ·h -1 The liquid spraying rate is 1 mL/min -1 The air inlet temperature is 45 ℃, and the drug-carrying resin coated microcapsule is obtained.
And finally, uniformly mixing the drug-carrying resin coated microcapsule with the pharmaceutic adjuvant and the pure water in the step (1) to obtain the esomeprazole sodium enteric suspension.
Example 2:
(1) The preparation raw materials of the esomeprazole sodium enteric suspension are as follows:
(2) Preparation of esomeprazole sodium enteric suspension:
mixing Esomeprazole sodium with water, and adding DOULITE TM AP143/1096 resin, and the concentration of the drug in the solution is determined by sampling at regular time. When the concentration of the drug in the solution is no longer changed with time, balancing is achieved, the unbound drug on the surface of the resin is washed off by deionized water, and the resin composite carrying the drug is obtained by vacuum drying at 35 ℃.
Then the drug-loaded resin composite is added into an aqueous solution containing 15% (w/w) PEG4000, stirred at 35 ℃ for 30min, and dried in vacuum at 35 ℃ to obtain the impregnated drug-loaded resin composite.
Eudragit L100 and Eudragit S100 are dissolved in a mixed solution of acetone and methanol (v/v=5:1), and PEG400 is used as a plasticizer to prepare a coating liquid with 6% (w/w) solid content; coating the impregnated drug-loaded resin compound by adopting a fluidized bed bottom spray coating technology, and controlling the air inlet quantity to be 30m 3 ·h -1 The liquid spraying rate is 0.7 mL-min -1 The air inlet temperature is 42 ℃, and the drug-carrying resin coated microcapsule is obtained.
And finally, uniformly mixing the drug-carrying resin coated microcapsule with the pharmaceutic adjuvant and the pure water in the step (1) to obtain the esomeprazole sodium enteric suspension.
Example 3:
(1) The preparation raw materials of the esomeprazole sodium enteric suspension are as follows:
(2) Preparation of esomeprazole sodium enteric suspension:
mixing Esomeprazole sodium with water, and adding DOULITE TM AP143/1096 resin, and the concentration of the drug in the solution is determined by sampling at regular time. When the concentration of the drug in the solution is no longer changed with time, balancing is achieved, the unbound drug on the surface of the resin is washed off by deionized water, and the resin composite carrying the drug is obtained by vacuum drying at 35 ℃.
Then adding the drug-loaded resin composite into an aqueous solution containing 5% (w/w) PEG6000, stirring at 45 ℃ for 40min, and vacuum drying at 35 ℃ to obtain the impregnated drug-loaded resin composite.
Eudragit L100 and Eudragit S100 are dissolved in a mixed solution of acetone and methanol (v/v=5:1), and PEG400 is used as a plasticizer to prepare a coating liquid with 6% (w/w) solid content; coating the impregnated drug-carrying resin compound by adopting a fluidized bed bottom spray coating technology, and controlling the air inlet quantity to be 50m 3 ·h -1 The liquid spraying rate is 1.5 mL-min -1 The air inlet temperature is 48 ℃, and the drug-carrying resin coated microcapsule is obtained.
And finally, uniformly mixing the drug-carrying resin coated microcapsule with the pharmaceutic adjuvant and the pure water in the step (1) to obtain the esomeprazole sodium enteric suspension.
Example 4:
the enteric suspension of sodium esomeprazole was prepared as described in example 1, with the only differences between the preparation starting materials and example 1: PEG4000 was not contained and the mass of PEG6000 was 40mg, all other conditions remained unchanged.
In vitro release experiments were performed on esomeprazole sodium enteric suspension prepared in examples 1 to 4, and release measurement was performed by referring to the second method-oar method for fourth release measurement in chinese pharmacopoeia (2020 edition). Setting the temperature to 37 ℃ and the rotating speed to 100r/min. In order to reduce the error caused by medium replacement, 500mL of NaCl hydrochloric acid solution (1.0 g of NaCl and 3.5mL of hydrochloric acid are added with pure water to 500 mL) is used as an acid dissolution medium, 400mL of 0.235mol/L disodium hydrogen phosphate aqueous solution preheated to 37 ℃ is added after 2 hours of release, the pH is regulated to 7.4 by sodium hydroxide, the temperature and the rotating speed are kept unchanged, a 0.45 mu m aqueous filter membrane is sampled at a set time point, then a subsequent filtrate is taken, the main peak area of the drug is measured by adopting a high performance liquid chromatography, the cumulative drug release amount is calculated, and the result is shown in a table 1, and the in-vitro drug release curve of the esomeprazole sodium enteric suspension prepared in example 1 is shown in figure 1.
TABLE 1 cumulative release of esomeprazole sodium enteric suspension prepared in examples 1-4
Table 1 shows the cumulative release amount of the esomeprazole sodium enteric suspension prepared in examples 1 to 4, and it can be seen from the table that the self-made esomeprazole sodium enteric suspension shows a certain degree of acid resistance, wherein the esomeprazole sodium enteric suspension prepared in examples 1 and 2 releases not more than 10% in acid medium for two hours, and finally releases not less than 80%, and has good enteric properties.
Fig. 1 is an in vitro drug release graph of the esomeprazole sodium enteric suspension prepared in example 1, and it can be seen from the graph that the drug release in the acidic medium is not more than 10% in the first 2 hours, and the final release amount can reach about 80%, which indicates that the suspension has uniform content and obvious enteric effect.
(2) Stability evaluation:
the stability of the esomeprazole sodium enteric suspensions prepared in examples 1 to 4 was evaluated, each group of the prepared esomeprazole sodium enteric suspensions was left at room temperature for 7 days, and the stability of each suspension was evaluated according to the relevant methods in the chinese pharmacopoeia of 2020 edition, with content, drug leakage amount, sedimentation volume ratio, redispersibility as indexes, and specific results are shown in table 2.
The specific operation method for evaluating the redispersibility comprises the following steps: taking a proper amount of suspension after standing for 3 hours under the test item of sedimentation volume ratio, centrifuging for 10 minutes at normal temperature in a high-speed refrigerated centrifuge, wherein the rotating speed condition is 500r/min, taking out, turning and shaking at the same speed, and recording the turning times when the suspension reaches a uniform dispersion system again, and evaluating the results to be good, general and poor (the uniform dispersion is good when the suspension does not exceed 12 times, the uniform dispersion is good when the suspension needs 12-60 times, the uniform dispersion is good when the suspension exceeds 60 times, the uniform dispersion is still possible when the suspension does not exceed 60 times, and the uniform dispersion is poor when the suspension cannot be uniformly dispersed).
TABLE 2 stability and drug loading of Esomeprazole sodium enteric suspension prepared in examples 1-4
| Group of | Content (%) | Drug leakage (%) | Redispersibility of | Medicine-carrying quantity (mg/mg) |
| Example 1 | 97.20 | 0.46 | Good (good) | 0.936 |
| Example 2 | 94.89 | 1.23 | Good (good) | 0.662 |
| Example 3 | 94.16 | 0.89 | Good (good) | 0.724 |
| Example 4 | 95.11 | 1.16 | Good (good) | 0.929 |
As is clear from the results in Table 2, the suspension prepared in examples 2 to 4 had slightly lower leakage and content than in example 1, but had substantially uniform stability. In addition, the esomeprazole sodium enteric suspension prepared in examples 1-4 all have good redispersibility.
(3) Drug loading of anion exchange resin:
the drug-loading resin compound prepared in the step (1) of the examples 1-4 is subjected to drug-loading measurement, and the specific operation method comprises the following steps: the original concentration of esomeprazole sodium and the drug concentration in the solution after drug loading balancing were determined as represented by the formula qt= (C 0 -C t )V/W R Calculation, C 0 (mg·mL -1 ) Is the initial concentration of the drug; c (C) t (mg·mL -1 ) Is the concentration of the drug in the solution at time t; v (mL) is the solution volume; w (W) R (mg) is the mass of the resin; q (Q) t (mg·mg -1 ) Is the drug loading of the resin at time t. The results are shown in Table 2.
As can be seen from the data in table 2: examples 2-3 have relatively lower drug loading than example 1, and example 4 has higher drug loading. This demonstrates that the drug and resin loading ratio affects the drug loading of the resin, and as the resin loading increases, the drug utilization increases, but the resin loading decreases.
In summary, the anion exchange resin is used as a carrier to prepare the esomeprazole sodium drug-loaded resin compound, so that the stability of the drug can be enhanced to a certain extent, the bad taste of the drug can be covered, and the drug-loaded resin compound is subjected to enteric coating, so that the drug is prevented from being degraded in gastric acid environment, is directionally released in intestinal tracts, the bioavailability of the drug can be improved, and the dosage of patients is reduced.
The examples are preferred embodiments of the present invention, but the present invention is not limited to the above-described embodiments, and any obvious modifications, substitutions or variations that can be made by one skilled in the art without departing from the spirit of the present invention are within the scope of the present invention.
Claims (10)
1. The esomeprazole sodium enteric suspension is characterized in that anion exchange resin is used as a carrier, the esomeprazole sodium and the anion exchange resin are combined through ions to form a drug-carrying resin compound, and then the drug-carrying resin compound is coated by adopting an enteric coating.
2. The enteric suspension of esomeprazole sodium according to claim 1, wherein said anion exchange resin comprises DOULITE TM AP143/1096 resin;
the enteric coating comprises any one or more of hydroxypropyl methylcellulose acetate succinate, methacrylic acid-ethyl acrylate copolymer or hydroxypropyl methylcellulose phthalate.
3. The enteric suspension of esomeprazole sodium according to claim 2, characterized in that said enteric coating is a combination of any two methacrylic acid-ethyl acrylate copolymers;
the methacrylic acid-ethyl acrylate copolymer comprises Eudragit L30D-55, eudragit L100, eudragit S100, eudragit RL100 or Eudragit RS100.
4. An enteric suspension of esomeprazole sodium according to claim 3, characterized in that the enteric coating is a combination of Eudragit L100 and Eudragit S100; the mass ratio of Eudragit L100 to Eudragit S100 is (2-5): 1.
5. the method for preparing the esomeprazole sodium enteric suspension according to any one of claims 1 to 4, characterized by comprising the following steps:
mixing esomeprazole sodium and anion exchange resin to obtain a drug-loaded resin compound, then impregnating the drug-loaded resin compound with an impregnant, stirring, drying and sieving to obtain an impregnated drug-loaded resin compound;
spraying enteric coating liquid on the surface of the impregnated drug-carrying resin compound by adopting a fluidized bed bottom spray coating technology to obtain drug-carrying resin coated microcapsules, and then mixing the obtained drug-carrying resin coated microcapsules with pharmaceutical excipients and water to obtain the esomeprazole sodium enteric suspension.
6. The method for preparing an esomeprazole sodium enteric suspension according to claim 5, wherein the mass ratio of the anion exchange resin to the esomeprazole sodium is (1-3): 1;
the mass ratio of the impregnant to the anion exchange resin is 1 (0.2-0.5);
the mass ratio of the enteric coating to the impregnated drug-carrying resin composite is 1 (2-6).
7. The method for preparing enteric suspension of esomeprazole sodium according to claim 5, wherein said stirring condition is stirring at 35-45 ℃ for 20-40 min.
8. The method for preparing enteric suspension of esomeprazole sodium according to claim 5, wherein in said fluidized bed bottom spray coating technique, the corresponding parameters are: the air inlet is 30-50m 3 ·h -1 The spraying speed is 0.5-1.5 mL.min -1 The air inlet temperature is 40-50 ℃.
9. The method for preparing enteric suspension of esomeprazole sodium according to claim 5, wherein said pharmaceutical excipients comprise any one or a combination of at least two of suspending agents, humectants, sweeteners, flavoring agents, colorants, preservatives, or pH adjusters.
10. The method for preparing an esomeprazole sodium enteric suspension according to claim 9, wherein the suspending agent comprises any one or a combination of at least two of xanthan gum, glycerol and sodium carboxymethyl cellulose;
the humectant comprises glycerin;
the flavoring agent comprises any one or a combination of at least two of orange essence, lemon essence or orange essence;
the preservative comprises any one or a combination of at least two of propyl paraben, methyl parahydroxybenzoate, ethyl parahydroxybenzoate and sodium benzoate;
the pH regulator comprises any one or the combination of two of anhydrous citric acid and sodium citrate.
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| CN202310318117.3A CN116350582A (en) | 2023-03-28 | 2023-03-28 | Esomeprazole sodium enteric suspension and preparation method and application thereof |
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| CN202310318117.3A CN116350582A (en) | 2023-03-28 | 2023-03-28 | Esomeprazole sodium enteric suspension and preparation method and application thereof |
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