CN109125282B - Omeprazole enteric capsule and preparation method thereof - Google Patents
Omeprazole enteric capsule and preparation method thereof Download PDFInfo
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- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention discloses an omeprazole enteric capsule and a preparation method thereof, wherein the omeprazole enteric capsule is formed by filling an omeprazole enteric pellet in a gelatin capsule shell. The omeprazole enteric-coated pellet comprises an omeprazole drug-loaded pellet core, an isolating layer and an enteric-coated layer from inside to outside in sequence. The omeprazole medicine-carrying pill core is prepared by adopting an extrusion rolling method, and the isolating layer and the enteric-coated layer are prepared by adopting a fluidized bed coating method. Different from the original ground product, the omeprazole drug-loaded pill core is added with Tween 80 and low-substituted hydroxypropyl cellulose on the basis of omeprazole, anhydrous lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, hydroxypropyl cellulose and lauryl sodium sulfate. The omeprazole enteric capsule prepared by the invention not only does not change the stability and the reproducibility of the product, but also improves the in-vitro dissolution rate of the medicament, particularly improves the uniformity among individuals, ensures that the peak reaching time of the blood concentration of different healthy subjects is more consistent, and has good application value in the aspect of clinical application.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an omeprazole enteric-coated pellet, an omeprazole enteric-coated capsule prepared from the omeprazole enteric-coated pellet and a preparation method of the omeprazole enteric-coated capsule.
Background
The proton pump inhibitor is benzimidazole compound, and can be used for treating peptic ulcer, esophageal reflux disease, gastrinoma syndrome and helicobacter pylori. Hitherto, commercially available proton pump inhibitors abroad include omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, dexrabeprazole, dexlansoprazole, etc., while commercially available proton pump inhibitors at home include omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, etc., and registered dextrorabeprazole, dexlansoprazole, etc. are being reported. Omeprazole, marketed in the united states in 1988, is the first benzimidazole proton pump inhibitor on the market.
According to Thomson Newport data base, Aspirin corporation marketed in Lusenberg under the trade name of "L OSEC" on 31/3/1988, first omeprazole enteric capsule (sold under the trade name of "L OSEC", Loxek) on 20 mg.1989 for 1/30/1989, first omeprazole enteric capsule (sold under the trade name of "L OSEC" in England, sold under the trade name of 20 mg) on 1989 for 30/6/1989, omeprazole enteric capsule (sold under the trade name of 20 mg) on Spanish for 30/1990, enteric capsule (sold under the trade name of "PRI L OSEC" on Greek for 20 mg) on 1989/14/1989, enteric capsule of Aspirin is approved by FDA, omeprazole enteric capsule (sold under the trade name of 10mg, 20mg, 40mg, sold under the trade name of "PRI L OSEC", sold under the trade name of 20mg on 2008, sold under the trade name of L, sold under the trade name of 10mg dry mix of PRI.
Currently, the main dosage forms of omeprazole on the market at home are enteric-coated tablets and enteric-coated capsules. The specification of the product on the market is 10mg, 20mg and 40 mg. 15 enterprises market omeprazole enteric-coated tablets in China, more than 50 enterprises market omeprazole enteric-coated capsules in China, and the number of approved medicines is up to 114.
Omeprazole enteric capsules (specification: 10mg, 20 mg) of the alsikan pharmaceutical limited company are approved to be sold on the market, and the approved characters are respectively: h20030413 and H20030412, the omeprazole enteric capsule (specification: 20 mg) is originally developed and produced into chemical products for sale.
The omeprazole enteric capsule which is marketed in Greek 4, 30.4.1990 by Aslicon is Sigma lambda η rho ά Gamma α Sigma tau rho α Vtheta tau iota ά kappa α psi ά kappa iota α mu pi rho α zeta ό lambda η (trade name: L OSEC 20mg omeprazole), and the drug is marketed in Europe for many years and is a drug with complete and sufficient safety and effectiveness data, and the third item which conforms to the CFDA reference preparation selection principle is drawn to the fact that if the original researched drug and the internationally recognized same drug are not marketed domestically, the drug marketed in the EU, the United states and Japan and listed as the reference preparation can be selected.
On 19.7.2017, the national food and drug administration (fda) issued a catalog of imitation pharmaceutical reference formulations (seventh and eighth lots) (nos. 115 and 116 in 2017), in which omeprazole enteric capsules 10MG, 20MG and 40MG of AstraZeneca UK L approved are listed as reference formulations.
Omeprazole is a proton pump inhibitor, belongs to a fat-soluble weakly alkaline medicine, is easy to concentrate in an acid environment, can be specifically distributed in a secretory canaliculus of parietal cells of gastric mucosa after being taken orally, is converted into an active form of sulfenamide under the high acid environment, and is irreversibly combined with sulfydryl of H +, K + -ATP enzyme (also called proton pump) in a secretory membrane of the parietal cells through disulfide bonds to generate a compound between sulfamide and the proton pump, so that the activity of the enzyme is inhibited, and the final step of gastric acid secretion is blocked, therefore, the omeprazole has a strong and lasting inhibiting effect on gastric acid secretion caused by various reasons.
After being orally taken, the omeprazole enteric capsule is absorbed by small intestines, takes effect within 1 hour, reaches the peak value after 0.5 to 3.5 hours, lasts for more than 24 hours, can be distributed to tissues such as liver, kidney, stomach, duodenum, thyroid and the like, and easily penetrates placenta. Generally, the bioavailability of single dose is about 35%, the bioavailability of multiple dose is increased to about 60%, the binding rate of plasma protein is 95-96%, the half-life period of plasma is 0.5-1 hour, and the time of chronic liver disease patients is 3 hours. The omeprazole enteric capsule is metabolized by a liver microsomal cytochrome P450 oxidase system in vivo, about 80% of metabolites are excreted by urine, and the rest are excreted from feces after being secreted by bile.
The subject has two reasons for the difference between individuals after oral administration of omeprazole enteric capsules: the method has the advantages that the intrabatch and the interbatch differences of the omeprazole enteric capsules, namely the quality differences of different batches and/or different omeprazole enteric capsules in batches, particularly the differences exist in the aspect of in-vitro dissolution characteristics; secondly, because of the difference of the metabolism of the omeprazole enteric capsule in vivo by a liver microsomal cytochrome P450 oxidase system. As we know, the speed of enzyme metabolism in different human species is greatly different, and the half-life of omeprazole is only 0.5-1 hour, so that the Tmax and the Cmax of different subjects orally taking the omeprazole enteric capsule are greatly different, and the AUC also varies from person to person, namely varies among individuals. In general, such inter-individual variations caused by the speed and capacity of the enzyme metabolism are difficult to achieve by prescription and process adjustments.
We have surprisingly found that the Tmax, Cmax and AUC of omeprazole enteric capsules prepared by adding tween 80 and low-substituted hydroxypropylcellulose to the original ground pellets during the bioequivalence pretest of omeprazole enteric capsules are very close to each other in different subjects, both during fasting and postprandial bioequivalence tests. In contrast, in the omeprazole enteric capsule without adding tween 80 and the low-substituted hydroxypropyl cellulose, the difference of the Tmax, the Cmax and the AUC between different subjects is very large whether the subjects are fasting or postprandial, and particularly the difference of the Tmax and the Cmax under the fasting condition is larger.
Therefore, the invention starts from the formula and the process of the omeprazole enteric capsule, and increases the Tween 80 and the low-substituted hydroxypropyl cellulose on the basis of the original medicine carrying pills, so that the quality difference of the prepared omeprazole enteric capsule and the batch and/or batch products is smaller, and after different subjects take the omeprazole enteric capsule orally, the peak time of blood concentration (Tmax), the maximum blood concentration (Cmax) and the bioavailability (AUC) are basically consistent. The omeprazole enteric capsule prepared by the invention has high in-vitro release degree and good stability, more importantly, the quality of the omeprazole enteric capsule is greatly improved, the difference between individuals is reduced, and the omeprazole enteric capsule has good commercial prospect.
Disclosure of Invention
The invention aims to provide an omeprazole enteric-coated pellet.
Another object of the present invention is to provide an omeprazole enteric capsule.
The invention also aims to provide a preparation method of the omeprazole enteric capsule.
The omeprazole enteric capsule prepared by the invention not only does not change the stability and the reproducibility of the product, but also improves the in-vitro dissolution rate of the medicament, particularly improves the uniformity among individuals, ensures that the peak reaching time of the blood concentration of different healthy subjects is more consistent, and has good application value in the aspect of clinical application.
In order to achieve the above purpose, the invention provides the following technical scheme:
the omeprazole enteric-coated pellet comprises an omeprazole drug-loaded pellet core, an isolation layer and an enteric-coated layer from inside to outside in sequence, wherein the omeprazole drug-loaded pellet core comprises Tween 80 and low-substituted hydroxypropyl cellulose.
The invention provides an omeprazole enteric pellet, and further provides an omeprazole drug-loaded pellet core which also comprises omeprazole, anhydrous lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, high-substituted hydroxypropyl cellulose and sodium dodecyl sulfate.
The invention provides an omeprazole enteric pellet, and further provides the omeprazole enteric pellet, wherein the weight percentage of tween 80 and low-substituted hydroxypropyl cellulose is 1: 3-5, preferably 1:3.5, and the weight percentage of the low-substituted hydroxypropyl cellulose and omeprazole is 1: 30-70, preferably 1: 57.
The invention provides an omeprazole enteric pellet, further, the isolating layer comprises hydroxypropyl methylcellulose and water, and the hydroxypropyl methylcellulose is coated on the surface of an omeprazole drug-loaded pellet core through a fluidized bed coating machine.
The invention provides an omeprazole enteric-coated pellet, further, an enteric-coated layer comprises Eudragit L30D-55 aqueous dispersion, polyethylene glycol 6000, sodium dodecyl sulfate and water, and hydroxypropyl methylcellulose is coated on the surface of the isolation layer through a fluidized bed coating machine.
The invention provides an omeprazole enteric-coated pellet, further, the crystal form of omeprazole is B type, the particle size distribution D90 is less than 10um, and D50 is less than 3 um.
The invention provides an omeprazole enteric pellet, and further provides an omeprazole drug-loaded pellet core which is prepared by adopting an extrusion rounding process.
The invention also provides an omeprazole enteric capsule prepared by adopting the omeprazole enteric pellet, the omeprazole enteric capsule comprises the omeprazole enteric pellet and a gelatin capsule shell, and Tween and low-substituted hydroxypropyl cellulose in each omeprazole enteric capsule are respectively not more than 1mg and 3.5 mg.
The invention also provides a preparation method of the omeprazole enteric capsule, which comprises the following steps:
(1) the preparation of the drug-loaded pill core sequentially comprises the following steps: preparing materials, preparing a granulating solution, mixing, granulating, pelleting, drying, discharging and sieving;
(2) the isolation layer coating sequentially comprises: after preparing the isolating layer coating liquid, putting the pills containing the medicine elements into a multifunctional granulating and coating machine, and setting equipment parameters: fan frequency: 10-25 Hz, inlet air temperature: not more than 70 ℃, height of the spacer ring: 20-50 mm, atomization pressure: 1.2-3.5 bar, liquid supply rotation speed: 10-200 rpm; controlling the temperature of the materials: coating the isolating layer at 35 +/-3 deg.c and stopping spraying; then drying, discharging and sieving;
(3) enteric layer coating, which comprises the following components in sequence: preparing enteric coating solution, coating, drying, discharging and sieving;
(4) filling, aluminum-plastic and outer wrapping.
The invention also provides a preparation method of the omeprazole enteric capsule, which comprises the following steps:
(1) preparation of drug-loaded pill core
Preparing materials: and taking materials from the warehouse according to the regulations. Pulverizing mannitol, and sieving with a high-efficiency pulverizer having a sieve mesh size of 1.0 mm. The operator checks the name, specification, batch number and quantity of the raw and auxiliary materials, and after the operator confirms that the raw and auxiliary materials are correct, the materials are weighed and prepared according to the prescription amount specified by the batch production instruction.
Preparing a granulating liquid: a prescribed amount of disodium hydrogen phosphate was added to a prescribed amount of purified water with stirring. After stirring well until clear and transparent, the prescribed amount of sodium dodecyl sulfate and tween 80 were added. And (3) after stirring to be uniform and no agglomeration, adding omeprazole according to the prescription amount, and stirring for not less than 15 minutes for later use.
Mixing: after the equipment is normally operated, 1 part of mannitol, lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose are taken and sequentially put into a wet mixing granulator, the technological parameters are set to be ' stirring paddle frequency is 5-20Hz ', granulating knife frequency is 1-10Hz ', and the mixture is mixed for about 600s to be granulated.
And (3) granulating: weighing the granulation liquid, and setting the technological parameters of stirring paddle frequency of 5-20Hz and granulation knife frequency of 1-10Hz for granulation. After granulation, the wet granulation is transferred to a pelleting room.
Pelleting: after the test run is normal, putting the wet particles into an extrusion rounding machine, and carrying out pelleting operation according to the parameters of 10-40 rpm of a feeding motor, 40-80 rpm of an extrusion motor and 150-800 rpm of a rounding motor. After the pelleting operation is completed, the wet pellets are transferred to a drying station.
And (3) drying: after the test run is normal, putting the collected wet pills into a multifunctional granulating and coating machine, and setting equipment parameters: fan frequency: 10-25 Hz, inlet air temperature: setting the material temperature at less than or equal to 70 ℃: drying at 40 ℃.
Discharging: when the material is dried until the moisture is less than 2.5%, the dehumidification is closed, the heating is closed, the fan is kept in an open state, and when the material temperature is less than 35 ℃, the machine is stopped for discharging.
Sieving: sieving the dried pill with 14 mesh and 20 mesh sieve respectively, collecting pill of 14 mesh to 20 mesh, weighing, wrapping with black PE bag, and placing desiccant (specification: 120 g) between two PE bags.
(2) Isolating layer coating
Preparing an isolating layer coating solution: slowly adding hydroxypropyl methylcellulose with the amount converted into the material amount into purified water under stirring, fully stirring until the material is clear and transparent, filling a material weighing label, and keeping for later use.
After the test run is normal, putting the pills containing the medicine elements into a multifunctional granulating and coating machine, and setting equipment parameters: fan frequency: 10-25 Hz, inlet air temperature: not more than 70 ℃, height of the spacer ring: 20-50 mm, atomization pressure: 1.2-3.5 bar, liquid supply rotation speed: 10-200 rpm; controlling the temperature of the materials: coating the isolating layer at 35 + -3 deg.C, and stopping spraying after the coating liquid is sprayed.
And (3) drying: after coating, the material temperature was set to 40 ℃ and drying was carried out.
Discharging: when the moisture content of the pellet is less than 2.5%, the moisture removal is stopped, the heating is stopped, and the fan is kept on. When the temperature of the materials is less than 35 ℃, stopping the machine and discharging the materials.
Sieving: sieving the dried pellets with 14-mesh and 20-mesh sieves respectively, collecting pellets of 14-20 meshes, weighing, wrapping with black PE bag, and placing desiccant (specification: 120 g) between two PE bags.
(3) Enteric layer coating
① adding polyethylene glycol 6000 in proportion to the prescription into purified water slowly under stirring, stirring to be clear and transparent, then adding sodium dodecyl sulfate in proportion to the prescription slowly, stirring to be clear and transparent, ② weighing the water dispersion of the Eudragit L30D-55, putting into a liquid preparation barrel, stirring at low speed, ③ pouring the solution of ① into ② slowly, keeping stirring at low speed until the solution is uniform and has no agglomeration, and sieving with a 60-mesh sieve.
Coating: after the test run is normal, putting the isolation pills into a multifunctional granulating and coating machine, and setting equipment parameters: fan frequency: 10-25 Hz, inlet air temperature: not more than 70 ℃, height of the spacer ring: 20-50 mm, atomization pressure: 1.2-3.5 bar, liquid supply rotation speed: 10-200 rpm; controlling the temperature of the materials: and (4) performing enteric layer coating operation at the temperature of 33 +/-3 ℃, and stopping spraying after the enteric layer coating liquid is sprayed.
And (3) drying: after coating, the material temperature was set to 40 ℃ and drying was carried out.
Discharging: when the water content of the enteric layer pellet is less than 2.5%, the dehumidification is turned off, the heating is turned off, and the fan is kept on. When the temperature of the materials is less than 35 ℃, stopping the machine for discharging, and packaging by using a double-layer PE bag.
And adding magnesium stearate, namely calculating the using amount of the magnesium stearate according to the using amount of the magnesium stearate = × 1% of the weight of the enteric-coated pills, weighing the magnesium stearate, adding the magnesium stearate into the enteric-coated pills, respectively grasping two ends of the bag by an operator, and manually shaking the bag to mix for 10 min.
Sieving: sieving the dried enteric layer pellets with 14 mesh and 20 mesh sieves respectively, collecting pellets of 14 mesh to 20 mesh, sampling, inspecting, weighing, coating with black PE bag, and placing desiccant (specification: 120 g) between two PE bags.
(4) Filling, aluminium-plastic, wrapping
And (4) taking the qualified intermediate product and the gelatin empty capsule, calculating the filling amount according to the content of the intermediate product, and filling. And installing and adjusting the batch number of the product according to the production instruction, and performing aluminum-plastic treatment on the product with clear writing and orderly arrangement. And (3) taking the product to be packaged and the outer packaging material, and carrying out outer packaging operation, wherein the packaging specification is 1 plate per bag (composite film packaging, 1 bag of drying agent is placed in the composite film packaging), and 1 bag per box.
The invention discloses an omeprazole enteric capsule and a preparation method thereof, the omeprazole enteric pellet of the invention is respectively composed of an omeprazole drug-loaded pill core, an isolating layer and an enteric layer from inside to outside, the omeprazole drug-loaded pill core is prepared by an extrusion rounding process, and the isolating layer and the enteric layer are prepared by a fluidized bed coating method, compared with the original ground product of the omeprazole enteric capsule (production batch number: YC L K; specification: 20mg, trade name: L OSEC, manufacturer: AstraZeneca AB), the omeprazole drug-loaded pill core is added with Tween 80 and low-substituted cellulose on the basis of the original ground product of the omeprazole enteric capsule, and researches show that the omeprazole enteric capsule prepared by the invention does not change the stability and reproducibility of the product, improves the in-vitro dissolution rate of the medicament, particularly improves the uniformity among individuals, the peak reaching time of different healthy subjects tends to be more consistent, and has good application value in clinical application.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description of the present invention is provided with reference to specific embodiments.
EXAMPLE 1 micronization of omeprazole
50Kg of omeprazole raw material which is sieved by a sieve of 80 meshes is weighed, the omeprazole raw material is micronized in a gas-containing MQ L03 airflow pulverizer (manufactured by Weifang Elmer powder technology equipment Co., Ltd.), 46.8Kg of micronized omeprazole is obtained through a screen of 325 meshes, the yield is 93.6 percent, a small sample of the micronized omeprazole is taken and detected by a Mastersizer 2000 Marvin laser particle size analyzer (manufactured by British Marvin instruments Co., Ltd.), D50 is 2.93um, and D90 is 7.32 um.
EXAMPLE 2 preparation of omeprazole enteric capsules
(1) Preparation of omeprazole drug-carrying layer
1180g of the crushed mannitol is weighed for later use. 20g of disodium hydrogenphosphate weighed out was added to 391g of purified water with stirring. After stirring well to be clear and transparent, 2g of sodium lauryl sulfate (and 1g of Tween 80) was added. Stirring to be uniform without agglomeration, adding 200g of omeprazole, and stirring for no less than 15 minutes for later use. Weighing mannitol, lactose, microcrystalline cellulose and high-substituted hydroxypropyl cellulose (and low-substituted hydroxypropyl cellulose) according to the formula amount, sequentially putting into a wet mixing granulator, setting reasonable process parameters, and waiting for granulation. Weighing the granulation liquid, setting reasonable process parameters, and granulating. And putting the wet granules into an extrusion rounding machine, and pelleting, drying, stopping and discharging according to reasonable process parameters. And (3) respectively sieving the dried medicine-containing pills with 14-mesh and 20-mesh sieves, collecting the medicine-containing pills between 14-mesh and 20-mesh sieves, weighing, coating a black PE bag outside, and putting a drying agent between the two PE bags.
(2) Preparation of the isolating layer
And slowly adding the hydroxypropyl methylcellulose with the amount converted into the material amount into the purified water under the stirring state, and fully stirring until the material is clear and transparent for later use. Putting the pills containing the medicinal components into a multifunctional granulating and coating machine, and controlling the temperature of the materials: coating the isolating layer at 35 + -3 deg.C, and stopping spraying after the coating liquid is sprayed. After coating, the material temperature was set to 40 ℃ and drying was carried out. Stopping the machine to discharge when the moisture of the isolating layer pellet is less than 2.5%. Sieving the dried pellets with 14-mesh and 20-mesh sieves respectively, collecting pellets of 14-20 meshes, weighing, wrapping with black PE bags, and placing desiccant between the two PE bags.
(3) Preparation of enteric coatings
Slowly adding polyethylene glycol 6000 with a reduced formula amount into purified water under a stirring state, stirring until the mixture is clear and transparent, then slowly adding sodium dodecyl sulfate with a reduced formula amount, stirring until the mixture is clear and transparent, weighing 8930D-55 water dispersion of Uygur L30D-55 water dispersion, putting the water dispersion into a liquid preparation barrel, stirring at a low speed, slowly pouring a mixed solution of polyethylene glycol 6000 and sodium dodecyl sulfate into L30D-55 water dispersion of Uygur L D-55 water dispersion, keeping stirring at a low speed until the mixture is uniform and free of agglomeration, sieving with a 60-mesh sieve, putting an isolation pill into a multifunctional granulating and coating machine, controlling the material temperature to be 33 +/-3 ℃, performing enteric-coated layer coating operation, stopping spraying after the enteric-coated layer coating liquid is sprayed, setting the material temperature to be 40 ℃, drying, stopping the machine when the moisture of the enteric-coated pellets is less than 2.5%, packaging with a double-layer PE bag, weighing magnesium stearate according to the formula amount, adding the magnesium stearate into the enteric-coated pellets, mixing for 10min, respectively sieving with 14-mesh and 20-mesh sieves, collecting pellets between 14-mesh and sampling, weighing PE pellets, and putting a black drying agent in a double-layer bag.
(4) Filling capsule
And (3) taking the qualified intermediate product and the gelatin hollow capsule, calculating the filling amount according to the content of the intermediate product, filling, aluminum-plastic and externally wrapping (composite film packaging, and placing 1 pack of drying agent in the capsule), and obtaining the self-made preparation prepared by the invention.
Example 3 comparison of in vitro dissolution characteristics of omeprazole enteric capsules (T1, T2) prepared by the preparation method of the present invention and original ground product (R) of omeprazole enteric capsules
Referring to the determination method of acid resistance and dissolution rate of omeprazole enteric capsules in the second department of the 'Chinese pharmacopoeia' 2015 year edition, the acid resistance, water and phosphate buffer solution with pH6.8 are determined by high performance liquid chromatography under the condition of chromatography according to the content determination item of the omeprazole enteric capsules; because the omeprazole enteric capsule is degraded in the dissolving process in the phosphate buffer solution with the pH value of 6.0, the high performance liquid chromatography is not applicable, so the ultraviolet spectrophotometry is adopted for determination.
The chromatographic conditions of the high performance liquid chromatography comprise using octyl silane bonded silica gel as a filler, using 0.01 mol/L disodium hydrogen phosphate solution (pH value is adjusted to 7.6 by phosphoric acid) -acetonitrile (75: 25) as a mobile phase, and detecting wavelength is 302 nm.
From the results in tables 8 and 9, it was found that T1 and T2 and the original ground product (R) of omeprazole enteric capsule were hardly released in hydrochloric acid solution at ph1.2 for 2 hours, but the dissolution profiles in the dissolution media at ph6.0 and ph6.8 both substantially matched with those of the original ground product.
Example 7 accelerated test stability study comparison of omeprazole enteric capsules (T1, T2) prepared by the preparation method of the present invention with original ground omeprazole enteric capsule (R)
Taking an original ground omeprazole enteric capsule R and self-made preparations T1 and T2, packaging the omeprazole enteric capsule R and the self-made preparations T1 and T2, placing the omeprazole enteric capsule in a constant-temperature and constant-humidity box with the temperature of 40 +/-2 ℃ and the humidity of RH75 +/-5%, sampling once at the end of 0 month, 1 month, 2 months, 3 months and 6 months respectively, and checking the properties, the content, the dissolution rate and related substances of the omeprazole enteric capsule.
Table 10 the results show: the omeprazole enteric capsules T1 and T2 prepared by the invention are placed in a constant temperature and humidity box with the temperature of 40 +/-2 ℃ and the humidity of RH75 +/-5 percent for 6 months, and the related substances, dissolution and content measurement of the omeprazole enteric capsules have no obvious change and are basically consistent with the original ground product (R) of the omeprazole enteric capsules.
EXAMPLE 8 comparison of pharmacokinetic studies of omeprazole enteric-coated capsules (T1, T2) prepared by the preparation method of the present invention orally administered on an empty stomach with the original ground omeprazole enteric-coated capsule (R) in humans
Healthy subjects were evaluated for pharmacokinetic characteristics and bioequivalence after oral administration of omeprazole enteric capsule test preparation T1 (specification: 20mg, lot # 20170701 ZUHAISHENZHONGYAOGEN GmbH, Inc.), test preparation T2 (specification: 20mg, lot # 20171105, ZUHAISHENZHUINGYAOGEN, Inc.), and reference preparation R (specification: 20mg, lot # YC L K, Aslicon GmbH) in an fasting state.
The test is a human body bioequivalence study designed by single dose oral administration, random open, three-cycle and three-preparation tests. The dose was 20mg, the washout period was 5 days, and 15 subjects completed the test. The blood sampling time points are 0.33h, 0.67h, 1.00h, 1.33h, 1.67h, 2.00h, 2.33h, 2.67h, 3.00h, 3.50h, 4.00h, 5.00h, 6.00h, 8.00h, 10.00h, 12.00, 16.00h and 24.00h before and after administration (total 19 blood sampling points).
15 healthy subjects were selected and randomly divided into 3 groups, 5 subjects per group, demographic information and administration sequence of the subjects are shown in Table 1. the selected subjects were fasted (at least fasted for 10 hours) after dinner for 1 day before the test, administered uniformly on the second day, and after blank blood samples were collected on the test day, 1 test preparation or reference preparation was orally administered on an empty stomach, 1.240 m L warm water was taken, drinking water was prohibited for 2 hours after administration, the upper body was kept upright for 4 hours after administration, and a low fat meal was uniformly administered after 4 hours and 10 hours after administration.
The test adopts an L C-MS/MS determination method which is verified briefly to determine the concentration of omeprazole in plasma, an internal standard (deuterated omeprazole) is added after a plasma sample naturally melts, then the sample is processed by a protein precipitation method, a supernatant is taken for sample injection analysis, an analyte and the internal standard are separated by a reversed phase chromatography, and triple four-level rod mass spectrometry is used for detection.
The test adopts a standard curve method to quantify unknown samples, wherein the concentration level of the standard curve of omeprazole is 2-1000ng/m L, and the quality control concentration levels are 2, 6, 60 and 800ng/m L.
All blood samples from the same subject were assayed in one assay batch, and the assay process was blinded to the analyst, i.e., the analyst did not know the sample to drug correspondence. The pre-test biological samples were assayed in two assay batches, the first assay batch to determine plasma samples from subjects 1-3, the second assay batch to determine plasma samples from subjects 4-6, the third assay batch to determine plasma samples from subjects 7-9, the fourth assay batch to determine plasma samples from subjects 10-12, the fifth assay batch to determine plasma samples from subjects 13-15, and the sixth assay batch to determine suspect samples. After completion of the sample measurement, one point was selected for each subject at around Cmax and elimination phase in each cycle to form an ISR analysis lot.
And receiving the analysis data according to the accuracy data of the standard curve of the measurement analysis batch and the quality control sample. The ISR yield is 94.4%.
The blood concentration data are revealed blindly according to a clinical administration sequence table, and the blood plasma concentration-time data of the omeprazole obtained after 15 subjects take the omeprazole test preparation and the reference preparation orally after the blindness is revealed are shown in the following table.
As can be seen from tables 19 and 20, the pharmacokinetic parameters Cmax, AUClast and AUCINF _ obs of the omeprazole enteric capsules (T1 and T2) orally taken on an empty stomach produced by the present invention in humans are relatively close to each other, which indicates that the pharmacokinetic parameters Cmax, AUClast and AUCINF _ obs of T1 and T2 are not much different between individuals.
However, we can notice that Tmax is quite different: among 15 healthy subjects, Tmax of healthy subject orally administered the original study R on an empty stomach substantially reached a peak at 1.33 to 3 hours, and only subject No. 1 reached a peak at 4.5 hours in blood concentration, indicating that the difference in peak reaching time between individuals of the original study was small. Similar to the original product R, there was also a test preparation T2. Among 15 healthy subjects, Tmax of healthy subjects orally taking self-made formulation T2 on an empty stomach substantially peaked at 1.33-2.67 hours, and only subjects No. 1 and No. 10 peaked at 3.5 and 4 hours blood levels. However, T1 is completely different from T2 and R, and the range of Tmax fluctuation of healthy subjects orally taking homemade preparation T1 on an empty stomach is very wide, from 1 hour to 6 hours. This shows that, the omeprazole enteric capsule for fasting oral administration has a self-made preparation T1, the peak time of blood concentration among individuals varies greatly, that is, the difference among individuals is large, some healthy subjects take effect within 1 hour after taking the medicine, and some healthy subjects take effect within 6 hours.
Through comparative research of T1 and T2, the fact that Tween 80 and low-substituted hydroxypropyl cellulose are added into a drug-loaded pill core of T1 is beneficial to eliminating the difference of peak reaching time of blood concentration among individuals of different healthy subjects, the onset time of the drug is more consistent, the formula of T2 is easy to industrialize, and omeprazole enteric capsules with good uniformity among individuals can be produced in batches. Through comparative studies, the consistency of the onset time of the drug is obviously inferior to the result of T2 when only Tween 80 or only low-substituted hydroxypropyl cellulose is added into the prescription of the T1 omeprazole enteric-coated pellets (according to the Tamx research methods of T1 and T2, the Tmax of only Tween 80 is 1 hour to 5 hours, and the Tmax of only low-substituted hydroxypropyl cellulose is 1 hour to 4 hours), the industrialization is not easy, and the inter-individual uniformity is inferior to that of T2.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. An omeprazole enteric pellet is characterized in that the omeprazole enteric pellet sequentially comprises an omeprazole drug-loaded pellet core, an isolation layer and an enteric layer from inside to outside, the omeprazole drug-loaded pellet core comprises Tween 80 and low-substituted hydroxypropyl cellulose, the weight percentage of the Tween 80 and the low-substituted hydroxypropyl cellulose in the omeprazole enteric pellet is 1: 3-5, the weight percentage of the low-substituted hydroxypropyl cellulose and the omeprazole is 1: 30-70, the omeprazole drug-loaded pellet core further comprises omeprazole, anhydrous lactose, microcrystalline cellulose, mannitol, sodium dihydrogen phosphate, hydroxypropyl cellulose and lauryl sodium sulfate, the omeprazole drug-loaded pellet core is prepared by adopting an extrusion rounding process, the omeprazole enteric pellet is filled into a gelatin capsule shell to prepare an omeprazole enteric capsule, the crystal form of the omeprazole is type B, the particle size distribution D90<10 μm, D50<3 μm.
2. The omeprazole enteric pellet as claimed in claim 1, wherein the weight percentage of the tween 80 and the low-substituted hydroxypropylcellulose in the omeprazole enteric pellet is 1:3.5, and the weight percentage of the low-substituted hydroxypropylcellulose and the omeprazole in the omeprazole enteric pellet is 1: 57.
3. The enteric omeprazole pellet as claimed in any of claims 1 to 2, wherein the isolating layer comprises hypromellose and water, and the hypromellose is coated on the surface of the omeprazole pellet core by a fluidized bed coating machine.
4. The enteric omeprazole pellet as claimed in claim 3, wherein the enteric layer comprises Eudragit L30D-55 aqueous dispersion, polyethylene glycol 6000, sodium dodecyl sulfate and water, and the hydroxypropyl methylcellulose is coated on the surface of the isolation layer by a fluidized bed coating machine.
5. An omeprazole enteric capsule prepared from the omeprazole enteric pellet according to claims 1-4, wherein the omeprazole enteric capsule comprises the omeprazole enteric pellet and a gelatin capsule shell, and the Tween and the low-substituted hydroxypropylcellulose in each omeprazole enteric capsule respectively do not exceed 1mg and 3.5 mg.
6. A process for preparing omeprazole enteric capsules according to claim 5, comprising the steps of:
(1) the preparation of the drug-loaded pill core sequentially comprises the following steps: preparing materials, preparing a granulating solution, mixing, granulating, pelleting, drying, discharging and sieving;
(2) the isolation layer coating sequentially comprises: after preparing the isolating layer coating liquid, putting the pills containing the medicine elements into a multifunctional granulating and coating machine, and setting equipment parameters: fan frequency: 10-25 Hz, inlet air temperature: not more than 70 ℃, height of the spacer ring: 20-50 mm, atomization pressure: 1.2-3.5 bar, liquid supply rotation speed: 10-200 rpm; controlling the temperature of the materials: coating the isolating layer at 35 +/-3 deg.c and stopping spraying; then drying, discharging and sieving;
(3) enteric layer coating, which comprises the following components in sequence: preparing enteric coating solution, coating, drying, discharging and sieving;
(4) filling, aluminum-plastic and outer wrapping.
7. A preparation method of omeprazole enteric capsules according to claim 5, wherein the preparation method of the drug-loaded pellet core is as follows:
preparing materials: taking materials from a warehouse according to the specification, crushing mannitol, wherein the size of a screen mesh of a high-efficiency crusher is 1.0mm, checking the name, specification, batch number and quantity of raw and auxiliary materials by an operator, and weighing and preparing the materials according to the prescription amount specified by a batch production instruction after the operator confirms that the materials are correct;
preparing a granulating liquid: adding the disodium hydrogen phosphate of the prescription amount into the purified water of the prescription amount under the stirring state, fully stirring until the mixture is clear and transparent, adding the sodium dodecyl sulfate and the Tween 80 of the prescription amount, stirring until the mixture is uniform and has no agglomeration, adding the omeprazole of the prescription amount, and stirring for no less than 15 minutes for later use;
mixing: after the equipment is normally operated in a test mode, 1 part of mannitol, lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose are respectively taken and sequentially put into a wet mixing granulator, the technological parameters are set to be ' stirring paddle frequency is 5-20Hz ', granulating knife frequency is 1-10Hz ', mixing is carried out for about 600s, and granulation is carried out;
and (3) granulating: weighing the granulation liquid, setting the technological parameters of stirring paddle frequency of 5-20Hz and granulation knife frequency of 1-10Hz for granulation, and transferring the wet granules to a pelleting room after the granulation is finished;
pelleting: after the test run is normal, putting the wet particles into an extrusion rounding machine, and carrying out pelleting operation according to the parameters of 10-40 rpm of a feeding motor, 40-80 rpm of an extrusion motor and 150-800 rpm of a rounding motor. After the pelleting operation is finished, transferring the wet pellets to a drying station;
and (3) drying: after the test run is normal, putting the collected wet pills into a multifunctional granulating and coating machine, and setting equipment parameters: fan frequency: 10-25 Hz, inlet air temperature: setting the material temperature at less than or equal to 70 ℃: drying at 40 ℃;
discharging: when the material is dried until the moisture content is less than 2.5%, closing the dehumidification, closing the heating, keeping the fan in an open state, and stopping the machine to discharge when the material temperature is less than 35 ℃;
sieving: and (3) respectively sieving the dried medicine-containing pills with 14-mesh and 20-mesh sieves, collecting the medicine-containing pills between 14-mesh and 20-mesh sieves, weighing, coating a black PE bag outside, and putting a drying agent between the two PE bags.
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| CN112999188A (en) * | 2019-12-19 | 2021-06-22 | 康普药业股份有限公司 | Omeprazole enteric-coated pellet and preparation method thereof |
| CN110882227A (en) * | 2019-12-26 | 2020-03-17 | 沈阳达善医药科技有限公司 | High-efficiency enteric coating composition and preparation method thereof |
| CN111150719A (en) * | 2019-12-30 | 2020-05-15 | 寿光富康制药有限公司 | Preparation method of omeprazole enteric capsule |
| CN111481525B (en) * | 2020-04-21 | 2021-04-02 | 一力制药(罗定)有限公司 | Omeprazole enteric-coated pellet and production process thereof |
| CN112957340B (en) * | 2021-02-09 | 2022-03-04 | 桂林华信制药有限公司 | Omeprazole enteric capsule and preparation method thereof |
| CN113855647B (en) * | 2021-10-29 | 2023-08-18 | 海南海灵化学制药有限公司 | Omeprazole microsphere shell core enteric capsule and preparation process thereof |
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