CN114699407B

CN114699407B - Pharmaceutical preparation for treating duodenal ulcer and preparation process thereof

Info

Publication number: CN114699407B
Application number: CN202210418575.XA
Authority: CN
Inventors: 刘奎元; 刘金耿
Original assignee: Shandong New Time Pharmaceutical Co Ltd; First Affiliated Hospital of Zhengzhou University
Current assignee: Shandong New Time Pharmaceutical Co Ltd; First Affiliated Hospital of Zhengzhou University
Priority date: 2022-04-20
Filing date: 2022-04-20
Publication date: 2023-04-07
Anticipated expiration: 2042-04-20
Also published as: CN114699407A

Abstract

The invention belongs to the field of medicinal preparations, and particularly relates to a medicinal preparation for assisting in stopping vomit and a preparation process thereof. The omeprazole and radix ophiopogonis extract are combined to play a role in synergy, and in addition, the problem of low dissolution rate caused by difficult dissolution of omeprazole is solved by optimizing a disintegrating agent and a filling agent, and the stability of the preparation is improved.

Description

Pharmaceutical preparation for treating duodenal ulcer and preparation process thereof

Technical Field

The invention belongs to the field of medicinal preparations, relates to a medicinal preparation for assisting in stopping vomit and a preparation process thereof, and particularly relates to application of an omeprazole preparation in treating stomach diseases and assisting in treating vomit and a preparation process.

Background

Omeprazole is mainly used for duodenal ulcer and Zollinger-Ellison syndrome, and can also be used for gastric ulcer and reflux esophagitis; intravenous injection can be used for treating acute hemorrhage of peptic ulcer, is a gastric acid proton pump acting on cell surface of gastric wall, inhibits the final channel of gastric acid secretion, and has strong and lasting inhibitory effect on gastric acid secretion stimulated by various modes even basic acid secretion. Omeprazole can accelerate the healing of Duodenal Ulcer (DU) and Gastric Ulcer (GU), shortens the treatment course by 2-4 weeks, and has the advantages of rapid symptom relief, high ulcer healing rate and low recurrence rate. For zoledram which is not effective in treating histamine H2 receptor antagonist and other medicaments, omeprazole has outstanding curative effect and can replace surgical treatment in many times, so that patients are relieved from the suffering of total gastrectomy. Omeprazole treats reflux esophagitis with a healing rate of over 80% in 8 weeks, which is twice that of histamine H2 receptor antagonists.

Because omeprazole is an alkaline drug, it is unstable in acid, more impurities are generated due to acid damage, and omeprazole is also susceptible to light, heat, humidity and the like, and is further degraded. At present, the damage of gastric acid in the taking process is reduced by adding the enteric coating, but partial damage and impurity rising phenomena still exist in the long-term storage process due to the influence of auxiliary materials in the prescription, so that the side effects of the product are increased.

Chinese patent CN101732282A discloses an omeprazole enteric capsule preparation, which is composed of omeprazole, inclusion material, enteric solid dispersion carrier, disintegrating agent, excipient, etc., wherein cyclodextrin inclusion method is adopted to prepare omeprazole clathrate compound, and the clathrate compound is prepared into enteric solid dispersion and then is filled into capsule shell. Although the capsule has an advantage of rapid release in the small intestine, its acid resistance and stability are to be further improved.

The ophiopogon root mainly comprises ophiopogonin, ophiopogonone, methyl ophiopogonone, dihydro ophiopogonone and the like as active ingredients, has the effects of nourishing yin, promoting the secretion of saliva or body fluid, moistening lung and clearing heart, and is used for treating dry cough due to lung dryness, consumptive disease, cough, thirst due to body fluid consumption, vexation, insomnia, internal heat, diabetes, constipation due to intestinal dryness and the like, and at present, the combined application of omeprazole and ophiopogon root is not reported.

Disclosure of Invention

The invention overcomes the defects of the prior art, provides a pharmaceutical preparation for assisting in stopping vomit and a preparation process thereof, adopts the combined medication of omeprazole and radix ophiopogonis extract to play a role in synergy, solves the problem of low dissolution rate caused by difficult dissolution of omeprazole by optimizing a disintegrating agent and a filling agent, and improves the stability of the preparation.

Specifically, the technical scheme of the invention is as follows:

the invention provides an omeprazole preparation, which comprises omeprazole, a radix ophiopogonis extract and pharmaceutically acceptable auxiliary materials.

Further, the ophiopogon root extract is one or more of ophiopogonin A, ophiopogonin B ', ophiopogonin C ', ophiopogonin D ', ophiopogonone A, ophiopogonone B, methyl ophiopogonone A, methyl ophiopogonone B and dihydro ophiopogonone A.

Preferably, the ophiopogon root extract is one or more of ophiopogonone B, ophiopogonone A, methyl ophiopogonone A and methyl ophiopogonone B.

In particular, the ophiopogon root extract is ophiopogonone B.

Furthermore, the weight ratio of the omeprazole to the ophiopogon root extract is 2.1-0.5.

Further, the pharmaceutically acceptable auxiliary materials include, but are not limited to, fillers, disintegrants, lubricants, binders.

Further, the filler is selected from one or more of dextrin, microcrystalline cellulose, pregelatinized starch, sucrose, lactose, mannitol, calcium bicarbonate, calcium sulfate and calcium carbonate; the disintegrating agent is selected from one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium alginate and poloxamer; the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, superfine silica gel powder and talcum powder; the adhesive is one or more selected from polyvidone, methylcellulose, hydroxypropyl cellulose, hypromellose, and ethyl cellulose.

Further, the components are as follows by weight ratio:

preferably, the first and second liquid crystal display elements are,

in particular, the weight ratio of calcium bicarbonate to mannitol is 1:2-5.

In particular, the weight ratio of the low-substituted hydroxypropyl cellulose to the sodium alginate is 1.

Further preferably, the components are as follows by weight ratio:

further, the omeprazole formulation further comprises an enteric coating.

Compared with the prior art, the invention has the beneficial effects that:

(1) According to the invention, the radix ophiopogonis extract is added into the formula, and the type and proportion of the radix ophiopogonis extract are optimized, so that the synergistic effect with omeprazole can be surprisingly found, and rat duodenal ulcer index, expression of GAS and MTL contents in plasma and expression of IL-1 beta and TNF-alpha levels in serum are verified through rat experiments, and the omeprazole preparation has a better curative effect on rat duodenal ulcer than common preparations sold in the market.

(2) The invention optimizes the type and proportion of the disintegrant, and particularly can improve the dissolution rate of the omeprazole in the artificial intestinal juice when the weight ratio of the low-substituted hydroxypropyl cellulose to the sodium alginate is 1.5-1.

(3) The invention preferably selects the type and proportion of the filling agent, particularly the weight ratio of calcium bicarbonate to mannitol is 1.

Drawings

FIG. 1: influence of disintegrant on dissolution rate of preparation in artificial intestinal juice

FIG. 2: effect of Filler on formulation stability

FIG. 3: index of duodenal ulcer after model building of each group of rats

FIG. 4 is a schematic view of: 7d dosing index of duodenal ulcer in each group of rats

FIG. 5: administration of 7d expression of GAS content in rat plasma

FIG. 6: administration of 7d MTL expression in plasma of rats in each group

FIG. 7 is a schematic view of: 7d serum level expression of IL-1 beta in rats

FIG. 8: expression of TNF-alpha levels in serum of 7d dosed rats

Detailed Description

In order to make the purpose and technical solution of the present invention more clear, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.

Example 1 (omeprazole enteric-coated tablets 1000 tablets)

The preparation method comprises the following steps: adopting dry granulation, respectively crushing omeprazole, dwarf lilyturf tuber extract, filling agent, disintegrating agent, lubricating agent and adhesive according to the formula ratio, sieving, mixing, tabletting, and coating enteric coating on tabletted plain tablets to obtain the compound tablet.

Example 2 (omeprazole enteric capsule 1000 granules)

The preparation method comprises the following steps: taking a proper amount of water as a wetting agent, respectively crushing and sieving omeprazole, radix ophiopogonis extract, a filling agent, a disintegrating agent, a lubricating agent and an adhesive according to the prescription amount, pouring the crushed mixture into a wet mixing granulator, stirring the mixture to obtain wet granules, coating enteric-coated granules, and filling the granules into capsules to obtain the omeprazole enteric-coated capsule.

Example 3 (omeprazole enteric-coated tablets 1000 tablets)

Example 4 (omeprazole enteric-coated tablets 1000 tablets)

Example 5 investigation of the Effect of disintegrant on dissolution of formulation

A: dry starch

B: low substituted cellulose + crospovidone (1 parts by weight

C: low-substituted cellulose + sodium alginate (1 part by weight

D: low-substituted cellulose + sodium alginate (weight ratio 1

E: commercially available omeprazole enteric-coated tablets

The formula amount of the disintegrant is 10g, other auxiliary materials, active ingredients and the preparation method are the same as those in example 1, a single-factor experiment is designed, and the influence of the disintegrant on the dissolution rate of the preparation in the artificial intestinal juice is researched.

Fig. 1 is an experimental result of the influence of the disintegrant on the dissolution rate of the preparation in the artificial intestinal juice, and researches show that calcium bicarbonate and mannitol are selected as the disintegrant, the proportion is controlled, the dissolution effect is good, the dissolution rate reaches 98%, and the release is complete and uniform within the range of 0.5-1.

Example 6 investigation of the Effect of Filler on formulation stability

A: starch

B: calcium bicarbonate + sucrose (1 part by weight

C: calcium bicarbonate + mannitol (1 part by weight

D: calcium bicarbonate + mannitol (1 part by weight

E: calcium bicarbonate + mannitol (1 part by weight

F: commercially available omeprazole enteric-coated tablets

The total amount of the filler is 200g, and other auxiliary materials, active ingredients and the preparation method are the same as those in example 1, a single-factor experiment is designed, and the influence of the filler on the stability of the preparation is researched.

The related substances are determined by high performance liquid chromatography (general rule 0512). And (4) avoiding light.

Test solution: taking appropriate amount of the product, adding mobile phase for dissolving, and diluting to obtain solution containing 0.2mg per 1 ml.

Control solution: precisely measuring a proper amount of the test solution, and quantitatively diluting with a mobile phase to obtain a solution containing about 2 mu g of the test solution per 1 ml.

System applicability solution: taking about 1mg of omeprazole and an impurity I reference substance respectively, placing the omeprazole and the impurity I reference substance into a 10ml measuring flask, adding a mobile phase for dissolution, diluting to a scale, and shaking up.

Chromatographic conditions are as follows: octyl silane bonded silica gel is used as a filling agent; 0.01mol/L disodium hydrogen phosphate solution (pH adjusted to 7.6 with phosphoric acid) -acetonitrile (75: 25) is used as a mobile phase; the detection wavelength is 280nm; the injection volume was 20. Mu.l.

System applicability requirements: the number of theoretical plates is not less than 2000 calculated according to omeprazole peak. The separation between the omeprazole peak and the impurity I peak should be greater than 2.0.

The determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times.

Limitation: if an impurity peak exists in a chromatogram of the test solution, the area of a single impurity peak is not more than 0.3 times (0.3%) of the area of a main peak of the control solution, and the sum of the areas of the impurity peaks is not more than 1.0% of the area of the main peak of the control solution.

The preparation of groups A-F was tested for a long period under the experimental conditions of commercial package, temperature 25 + -2 deg.C, relative humidity 60% + -10%, and sampling at 0 month, 3 months, 6 months, 9 months, 12 months, 24 months, 36 months during the test period, and the content of the related substances was determined as described above.

The result is shown in figure 2, the filler has a great influence on the stability of the preparation, the calcium bicarbonate + mannitol (weight part ratio is 1.

Acute toxicity, long term toxicity test

1. Acute toxicity test: after the omeprazole enteric-coated tablet in the embodiment 1 of the invention is administrated to rats by stomach irrigation according to the half lethal dose LD50, no obvious acute toxicity is found.

2. Long-term toxicity test: the omeprazole enteric-coated tablets in the embodiment 1 of the invention are continuously administered to rats by intragastric administration for six months according to different dosages (up to half lethal dose LD 50), general conditions of the rats such as weight gain, hematology, blood biochemistry, urine convention, electrocardiogram, system anatomy, organ coefficient and histopathology are monitored, no obvious influence is found, no toxic reaction is found, and no delayed toxic reaction is found in the recovery period.

Pharmacodynamic test of omeprazole preparation on duodenal ulcer model rat

Laboratory animal

SD rat, SPF grade, 180-220g, laboratory animal license number: SYXK (lu) 20180008, supplied by lumnan pharmaceutical group, inc, was acclimatized for 1 week under standard conditions prior to the experiment.

Mode of making mold

The molding mode adopts an acetic acid permeation method: 100% glacial acetic acid is directly acted on the serosal surface of duodenum to induce ulcer of the mucosal surface of duodenum. The specific method comprises the following steps: 60 rats are taken and fed with water, fasted for 48 hours, placed in a bell jar for ether anesthesia, fixed on the back, the abdominal hair is cut off, a 2-3 cm long incision is made along the median line from the lower part of the xiphoid process, the abdominal cavity is cut open, the anterior wall of the stomach is placed upwards on a glass slide, and the glass tube is tightly buckled on the serosa of the anterior wall of the duodenum part (avoiding blood vessels). Injecting 0.05ml of 100% glacial acetic acid into the tube, keeping for 0.5 min, sucking out the acetic acid, removing the glass tube, sucking the residual acetic acid by using filter paper, and repeatedly flushing by using the physiological saline of the fire bacteria for three times, wherein the local tissue is grayish white, such as burning. Taking out the slide, covering the wound surface with omentum majus, suturing abdominal wall, and feeding conventionally. After 5 days, the rats were sacrificed by cutting the spine, and the ulcer index was determined by examining the size and depth of the ulcer (fig. 3). A total of 57 rats were successfully modelled.

Grouping of experimental animals

The rats were randomly divided into a model group, a commercially available omeprazole enteric-coated tablet group, three dose groups of example 1 (high, medium and low), and 10 rats in each group. Blank group: 10 rats were sham operated, only abdominal open and close.

Administration to each group

Commercially available omeprazole enteric-coated tablet set: 1.8mg/kg (omeprazole)

Example 1 (high dose): 3.6mg/kg (omeprazole)

Example 1 (medium dose): 1.8mg/kg (omeprazole)

Example 1 (low dose): 0.9mg/kg (omeprazole)

The rats in each administration group were gavaged with the corresponding drugs, and the rats in the blank group and the model group were gavaged with an equal amount of physiological saline for 1 time per day for 7 days.

Duodenal ulcer index of rat

As shown in fig. 4, after 7d administration, the ulcer index of each group of rats was as follows, and the difference was highly statistically significant when P < 0.01 was compared between the commercially available omeprazole enteric tablet group and example 1 (high dose) and example 1 (medium dose), respectively. The omeprazole preparation protected by the invention can effectively improve the duodenal ulcer of a rat, and the effect is better than that of a commercially available omeprazole enteric-coated tablet. Expression of GAS, MTL content level in rat plasma

After 7 days of administration, 10 rats in each group were bled from the femoral artery, and plasma was prepared and the GAS and MTL levels in the plasma were determined using an ELISA kit according to the instructions.

FIG. 5 shows the expression of GAS content in the plasma of rats in each group, wherein the GAS belongs to gastrin and is mainly secreted by G cells with open gastric antrum and duodenal mucosa, the expression of the GAS content in rats with duodenal ulcer models is obviously reduced compared with that in normal rats, after administration for 7 days, the GAS content in the plasma of rats in the commercially available omeprazole enteric tablet groups and the groups of the invention all have obvious improvement, the GAS content in the plasma of rats in the dose group of example 1 (high, medium and low) is closer to that in the normal rats, the SPSS22.0 software is adopted to carry out statistical analysis on the obtained data, and the metering data is measured by using the SPSS22.0 software

The results show that the single-factor analysis of variance is adopted for the comparison of multiple groups, and the independent sample T test method is adopted for the analysis of the two groups, so that the P of the commercially available omeprazole enteric-coated tablet group is less than 0.01 and the difference has high statistical significance when being compared with the embodiment 1 (high dose) and the embodiment 1 (medium dose) respectively.

FIG. 6 shows the expression of MTL content in plasma of rats in each group, wherein MTL belongs to motilin and can promote gastrointestinal motility. The MTL content expression of rats with duodenal ulcer models is obviously reduced compared with that of normal rats, the MTL content level in the plasma of the rats is obviously improved by 7 days of administration of the commercially available omeprazole enteric tablet group and each group of the embodiment of the invention, the MTL content in the plasma of the rats in the dose group of the embodiment 1 (high, medium and low) is closer to that of the normal rats, and the P of the commercially available omeprazole enteric tablet group is less than 0.01 compared with the MTL content in the dose group of the embodiment 1 (high dose) and the MTL content in the plasma of the rats in the dose group of the embodiment 1 (medium dose), and the difference has high statistical significance. The omeprazole preparation can promote the expression of the content levels of GAS and MTL in blood plasma, and has better effect compared with the omeprazole preparation sold on the market.

TNF-alpha and IL-1 beta level expression in rat serum

After 7 days of administration, 10 rats in each group were tested for serum TNF- α and IL-1 β by enzyme-linked immunosorbent assay (ELISA).

FIG. 7 shows the level expression of IL-1 beta in the serum of rats in each group, and FIG. 8 shows the level expression of TNF-alpha in the serum of rats.

In conclusion, the radix ophiopogonis extract is added into the omeprazole preparation, the synergistic effect can be generated with omeprazole, and the measurement of index of duodenal ulcer of a rat, expression of content of GAS and MTL in blood plasma and expression of level of IL-1 beta and TNF-alpha in blood serum shows that the omeprazole preparation has better curative effect on treating the duodenal ulcer of the rat than the common preparation sold in the market.

It is noted that the omeprazole preparations prepared in examples 2-4 were also subjected to pharmacodynamic tests in rat model with duodenal ulcer, and the results show that the omeprazole preparations prepared in examples 2-4 of the present invention have better effect in treating duodenal ulcer in rat than the common commercially available preparations, which indicates that the synergistic effect can be achieved by adding a certain amount of ophiopogon root extract.

Claims

1. A pharmaceutical preparation for treating duodenal ulcer is characterized in that the pharmaceutical preparation consists of the following components in percentage by weight;

10-20 parts of omeprazole

1-5 parts of dwarf lilyturf tuber extract

150-250 parts of calcium bicarbonate and mannitol

10-20 parts of low-substituted hydroxypropyl cellulose and sodium alginate

10 to 20 portions of lubricant

5-10 parts of adhesive

The radix Ophiopogonis extract is one or more of ophiopogonone A, ophiopogonone B, methyl ophiopogonone A and methyl ophiopogonone B.

2. The pharmaceutical formulation of claim 1, wherein the ophiopogon japonicus extract is ophiopogonone B.

3. The pharmaceutical formulation according to claim 1, wherein the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, aerosil, talc; the adhesive is one or more selected from polyvidone, methylcellulose, hydroxypropyl cellulose, hypromellose, and ethyl cellulose.

4. The pharmaceutical formulation according to claim 1, wherein the weight ratio of calcium bicarbonate to mannitol is 1.

5. The pharmaceutical formulation according to claim 1, wherein the weight ratio of the low-substituted hydroxypropylcellulose to sodium alginate is 1.

6. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation consists of, by weight;

omeprazole 20 parts

1.6 parts of dwarf lilyturf tuber extract

40 portions of calcium bicarbonate

160 portions of mannitol

Low substituted hydroxypropyl cellulose 5 parts

5 parts of sodium alginate

10 portions of lubricant

5 parts of adhesive.