Vitamin U belladonna aluminum capsule

Abstract

The invention provides a vitamin U belladonna aluminum capsule, which is characterized in that a belladonna extract is adsorbed in pores of a mixture of a mannitol cross-polymerized barley-mountain co-treated material phemaburst # imgabs 0 # mesoporous silica # imgabs 1 #, and the mixture provides a weak acid environment for the belladonna extract. The weak acid environment can improve the stability of atropine; meanwhile, the rapid desorption of the belladonna extract can be met, so that the capsule is rapidly disintegrated; in addition, migrated moisture in a gelatin capsule shell can be locked preferentially, the stability of the vitamin UII is improved, and an acceleration test proves that the product obtained by the invention can have better dissolution behavior and stability and is obviously superior to that of an existing preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a vitamin U belladonna aluminum capsule. Background Art

[0002] Vitamin U Belladonna Aluminum Capsules are commonly used medicines for treating gastric diseases, mainly for gastric and duodenal ulcers, chronic gastritis, hyperacidity, and gastric spasm. Its main ingredients are aluminum hydroxide, vitamin UⅡ, and appropriate amounts of belladonna fluid extract. Vitamin UⅡ has the effect of purifying and healing ulcers; aluminum hydroxide has a chemical reaction of neutralizing or buffering the gastric acid already in the stomach, so that the symptoms of hyperacidity can be relieved; belladonna fluid extract has an anticholinergic effect, which can inhibit smooth muscle spasms and relieve pain. The three ingredients work in coordination.

[0003] The literature "Preliminary Study on the Process of Vitamin U Belladonna Aluminum Capsules and Its Stability Investigation" mixed pregelatinized starch with Belladonna fluid extract for 2 times and dried at 50-60℃ to obtain granules B. After mixing the prescribed amount of aluminum hydroxide and microorganism U for 5-10 minutes, add B granules, stir and mix thoroughly for 20 minutes, and sieve. Fill the capsules. The disintegration time is 11-13 minutes, the disintegration is slow, and the effect is slow.

[0004] The document "Study on Quality Control of Preparation Process of Vitamin U Belladonna Aluminum Capsules" proposed that the dispersion of belladonna extract is a key process in the production of Vitamin U Belladonna Aluminum Capsules. The belladonna extract and aluminum hydroxide are mixed in equal amounts, manually sieved through a 60-mesh sieve, and the belladonna extract is absorbed and dispersed by aluminum hydroxide before being mixed with other materials. The intermediate mixture powder is uniform, light brown, and has average fluidity. The mixing of belladonna extract and aluminum hydroxide in this process will cause the degradation of atropine in the belladonna extract.

[0005] CN 03127186.3 separately encapsulates the active ingredients in Vitamin U Belladonna Aluminum Capsule II to improve stability. The encapsulation material contains hydrophilic hydroxyl groups to improve the dissolution rate. When the inventor repeated the invention, he found that it was cumbersome and complicated, low-temperature drying, and took a long time, which was not conducive to industrial production. The invention did not provide relevant data such as dissolution.

[0006] The invention of CN 200710118276.X relates to a vitamin U belladonna aluminum composite capsule preparation, which has two capsule cavities. The chemical drug component vitamin U and aluminum hydroxide are mixed and granulated or granulated separately and then mixed, and then loaded into one capsule cavity of the composite capsule, and the dried belladonna extract is loaded into the other capsule cavity of the composite capsule, so as to separate the chemical drug from the traditional Chinese medicine, greatly improve the stability of the drug, and extend the shelf life. However, the invention requires a special capsule filling machine to be realized.

[0007] The invention of CN200410011170.6 relates to a vitamin U belladonna aluminum dispersible tablet. Mixing the raw materials together is not conducive to the stability of microorganism U. When the inventor repeated the invention, problems such as sticking occurred.

[0008] The invention of CN200510033217.3 relates to a compound vitamin U belladonna aluminum tablet for treating gastric ulcer disease, with an outer layer of aluminum hydroxide, which plays an acid-reducing role; belladonna extract plays an analgesic and spasmolytic role, and the inner core layer of vitamin U plays an anti-ulcer role and promotes the healing and regeneration of gastric mucosal wound surface ten minutes after taking the medicine. The preparation is complex and requires a special tablet press to achieve. No relevant quality inspection has been found.

[0009] CN200520028108.8 prepared vitamin U belladonna aluminum II into micro-pellets and then coated them. No relevant quality inspection was found.

[0010] The invention CN 201510195356.X involves adding an antioxidant to vitamin U, but the atropine content of the prepared vitamin U belladonna aluminum capsule II is significantly reduced in a stability study.

[0011] During the research and development of vitamin U belladonna aluminum capsules, the inventors found that the development of the preparation had the following difficulties: belladonna extract was highly viscous and difficult to disperse evenly, resulting in sticking problems during the filling process, slow disintegration, slow onset of preparation, and low content of vitamin UⅡ and atropine.

[0012] The inventors considered that the problems encountered in the production of vitamin U belladonna aluminum capsule preparations were mainly caused by belladonna extract. The inventors tried to use microcrystalline cellulose, starch, pregelatinized starch, calcium hydrogen phosphate and other materials to granulate belladonna extract, but problems such as stickiness, slow disintegration and low content still existed. At the same time, it was found that water migration in the gelatin capsule shell would also cause the decomposition of vitamin UⅡ.

[0013] The inventors have developed a vitamin U belladonna aluminum capsule and a preparation method during the research process to solve the above problems and make the product suitable for industrial production. Summary of the invention

[0014] The purpose of the present invention is to provide a vitamin U belladonna aluminum capsule and a preparation method thereof in view of the above-mentioned defects of the prior art. The vitamin U belladonna aluminum capsule prepared by the present invention has a simple preparation process, is non-sticky, disintegrates quickly, has low content of vitamin UⅡ and atropine, and is suitable for industrial production.

[0015] Specifically, the present invention is achieved through the following technical solutions:

[0016] A vitamin U belladonna aluminum capsule containing vitamin UⅡ, belladonna extract, aluminum hydroxide, mannitol cross-polymerization and maize co-processing product pharmaburst Mesoporous silica AL-1FP, magnesium stearate.

[0017] The vitamin U belladonna aluminum capsule is characterized in that belladonna extract, mannitol cross-polymerization and wheat straw co-processing product pharmaburst Mesoporous silica The mass ratio of AL-1FP is 1:(3-10):(0.2~2).

[0018] The vitamin U belladonna aluminum capsule is characterized in that each unit of the preparation contains vitamin U II, belladonna extract, aluminum hydroxide, mannitol cross-linked copolymerized wheat and mountain co-processed pharmaburst Mesoporous silica The mass ratio of AL-1FP and magnesium stearate is 5:1:14:(3-10):(0.2-2):(0.15-0.55).

[0019] The vitamin U belladonna aluminum capsule is characterized in that each unit of preparation contains the following components: vitamin U II, belladonna extract, aluminum hydroxide, mannitol cross-linked copolymer wheat and mountain co-processed product pharmaburst Mesoporous silica The mass ratio of AL-1FP and magnesium stearate is 50 mg: 10 mg: 140 mg: 30-100 mg: 2-20 mg: 1.5-5.5 mg.

[0020] The present invention also provides a method for preparing vitamin U belladonna aluminum capsules, which comprises the following steps:

[0021] a. Weigh the prescribed amount of mannitol cross-linked copolymerization and Maishan co-processed product pharmaburst Mesoporous silica AL-1FP was mixed in a wet mixer granulator to obtain mixture 1.

[0022] b. Add mixture 1 to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry them in a boiling dryer at 40°C for 20 minutes.

[0023] c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes.

[0024] d. Add magnesium stearate and mix for 5 minutes.

[0025] e. Filling capsules.

[0026] Vitamin UⅡ is iodinated methylmethionine. Calculated on a dry basis, it contains C6H 14INO2S shall not be less than 99.0%. It shall comply with the drug standards recorded in the national standards (volume 13) of the local standards for chemical drugs, and the standard number is: WS-10001-(HD-1231)-2002.

[0027] Belladonna extract complies with the drug standards of Part I of the 2020 edition of the Chinese Pharmacopoeia and is an extract made from the dried whole herb of Atropabelladonna L., a plant of the Solanaceae family.

[0028] The preparation method of the belladonna extract is as follows: take 1000g of belladonna grass coarse powder, use 85% ethanol as a solvent, soak for 48 hours, slowly percolate at a speed of 1-3ml per minute, collect about 3000ml of the initial percolate, store it in another container, continue percolate, wait for the alkaloids to be completely filtered out, and use the subsequent percolate as the solvent for the next percolate. The initial percolate is decompressed and ethanol is recovered at 60°C, cooled to room temperature, chlorophyll is separated and removed, filtered, and the filtrate is steamed at 60-70°C to a thick paste, 10 times the amount of ethanol is added, stirred evenly, and allowed to stand until the precipitation is complete, the supernatant is absorbed, and the ethanol is recovered at 60°C under reduced pressure, concentrated to a thick paste, and about 3g is taken out. According to the method under the item of belladonna extract content determination in the 2020 edition of the Chinese Pharmacopoeia, the content is determined, and an appropriate amount of diluent is added to make the content meet the requirements, low-temperature drying, grinding, and passing through a No. 4 sieve to obtain.

[0029] Compared with the prior art, the present invention provides a vitamin U belladonna aluminum capsule, belladonna extract is adsorbed on mannitol cross-polymerization and co-processing product pharmaburst Mesoporous silica In the pores of the AL-1FP mixture, the mixture provides a weakly acidic environment for the belladonna extract. The weakly acidic environment can improve the stability of atropine; at the same time, it can meet the rapid decomposition of the belladonna extract and make the capsule disintegrate quickly; in addition, it can preferentially lock the water that migrates in the gelatin capsule shell and improve the stability of vitamin UⅡ. Accelerated tests have proved that the product obtained by the present invention can have better dissolution behavior and stability, which is significantly better than existing preparations. DETAILED DESCRIPTION

[0030] The beneficial effects of the present invention are further described by the following examples. These examples are for illustrative purposes only and should not be construed as limiting the present invention. Obvious improvements and modifications made to the present invention by those skilled in the art are also within the scope of protection of the present invention.

[0031] The following examples are for preparing vitamin U belladonna aluminum capsules. The operations described are conventional preparation operations.

[0032] Example 1

[0033]

[0034] Preparation process:

[0035] a. Weigh 10,000 times the single dose of mannitol cross-linked copolymerized Maishan co-processed product pharmaburst Mesoporous silica AL-1FP was mixed in a wet mixer granulator to obtain mixture 1.

[0036] b. Add mixture 1 to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry them in a boiling dryer at 40°C for 20 minutes.

[0037] c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes.

[0038] d. Add magnesium stearate and mix for 5 minutes.

[0039] e. Filling capsules.

[0040] The preparation method of belladonna extract is carried out in accordance with the Part 1 of the 2020 edition of the Chinese Pharmacopoeia and meets the requirements. The belladonna extract methods used in other embodiments and comparative examples are the same as this method.

[0041] Preparation method: Take 1000g of coarse powder of belladonna grass, use 85% ethanol as solvent, soak for 48 hours, slowly percolate at a speed of 1-3ml per minute, collect about 3000ml of the initial percolate, store in another container, continue percolate, wait for the alkaloids to be completely percolated, and use the subsequent percolate as solvent for the next percolate. Recover ethanol from the initial percolate at 60℃ under reduced pressure, cool to room temperature, separate and remove chlorophyll, filter, steam the filtrate at 60-70℃ to a thick paste, add 10 times the amount of ethanol, stir evenly, let stand, wait for complete precipitation, absorb the supernatant, recover ethanol at 60℃ under reduced pressure, concentrate to a thick paste, take out about 3g, determine the content according to the method under [Content determination], add an appropriate amount of diluent to make the content meet the requirements, dry at low temperature, grind finely, and pass through a No. 4 sieve to obtain the product.

[0042] Example 2

[0043]

[0044] Preparation process: Same as Example 1.

[0045] Example 3

[0046]

[0047]

[0048] Preparation process: Same as Example 1.

[0049] Comparative Example 1

[0050]

[0051] Preparation process:

[0052] a. Weigh 10,000 times the single dose of mannitol cross-linked copolymerized Maishan co-processed product pharmaburst

[0053] b. cross-polymerization and copolymerization of mannitol and Maishan co-processed product pharmaburst Add to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry in a boiling dryer at 40°C for 20 minutes.

[0054] c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes.

[0055] d. Add magnesium stearate and mix for 5 minutes.

[0056] e. Filling capsules.

[0057] Comparative Example 2

[0058]

[0059] Preparation process:

[0060] a. Weigh 10,000 times the single dose of mesoporous silica AL-1FP.

[0061] b. Add mixture 1 to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry them in a boiling dryer at 40°C for 20 minutes.

[0062] c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes.

[0063] d. Add magnesium stearate and mix for 5 minutes.

[0064] e. Filling capsules.

[0065] Comparative Example 3

[0066]

[0067] Preparation process:

[0068] a. Weigh 10,000 times the single dose of the prescription, put the belladonna extract, aluminum hydroxide and vitamin UⅡ into a wet mixing granulator, stir and shear at high speed, pass through a 20-mesh sieve to granulate, and dry in a boiling dryer at 40°C for 20 minutes.

[0069] b. Add magnesium stearate and mix for 5 minutes.

[0070] c. Filling capsules.

[0071] Comparative Example 4

[0072]

[0073] Preparation process:

[0074] a. Weigh 10,000 times the single dose of mannitol cross-linked copolymerized Maishan co-processed product pharmaburst Mesoporous silica AL-1FP was mixed in a wet mixer granulator to obtain a mixture 1;

[0075] b. Add mixture 1 to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry them in a boiling dryer at 40°C for 20 minutes.

[0076] c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes.

[0077] d. Add magnesium stearate and mix for 5 minutes.

[0078] e. Filling capsules.

[0079] Comparative Example 5

[0080]

[0081] Preparation process:

[0082] a. Weigh 10,000 times the single dose of mannitol cross-linked copolymerized Maishan co-processed product pharmaburst Mesoporous silica AL-1FP was mixed in a wet mixer granulator to obtain a mixture 1;

[0083] b. Add mixture 1 to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry them in a boiling dryer at 40°C for 20 minutes.

[0084] c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes.

[0085] d. Add magnesium stearate and mix for 5 minutes.

[0086] e. Filling capsules.

[0087] Verification Example

[0088] 1. The filling volume difference and sticking behavior were investigated during the filling process, see Table 1.

[0089] Table 1

[0090] Group Difference in filling volume Investigation of filling process Example 1 -3.5％～2.7％ Non-stick punch Example 2 -3.8％～3.2％ Non-stick punch Example 3 -4.1％～4.2％ Non-stick punch Comparative Example 1 -4.5％～5.5％ Non-stick punch Comparative Example 2 -4.7％～5.7％ Non-stick punch Comparative Example 3 -12.7％～12.1％ Sticky punch Comparative Example 4 -9.8％～9.0％ Sticky punch Comparative Example 5 -10.7％～12.1％ Non-stick punch

[0091] It can be seen from the table that the difference in loading amount of Examples 1 to 3 obtained by the present invention meets the requirements, and there is no sticking to the punch rod; in contrast to Example 3 and Example 4, the difference in loading amount is large, and the punch rod is sticky; in contrast to Example 5, the punch rod is not sticky during production, but the difference in loading amount is large, indicating that mesoporous silica Too much AL-1FP will affect the loading difference.

[0092] 2. Investigation of disintegration time and stability, see Table 2.

[0093] Table 2

[0094] Group Disintegration time (0 days) 40℃ / 75%RH accelerated 6 months Example 1 3min 4min Example 2 3.5min 5min Example 3 4min 5min Comparative Example 1 3.5min 6min Comparative Example 2 8min 12min Comparative Example 3 20min 30min Comparative Example 4 12min —— Comparative Example 5 5min ——

[0095] Note: Comparative Example 4 was not subjected to content investigation due to sticking, and Comparative Example 5 was not subjected to subsequent accelerated test investigation due to large difference in loading amount.

[0096] It can be seen from the table that when tested on day 0, the disintegration speed of Examples 1 to 3 obtained by the present invention is significantly higher than that of Comparative Example 3. The disintegration time of the accelerated 6-month Example is less changed than that of the comparative example, and the disintegration speed is faster.

[0097] 3. Content detection and stability investigation of vitamin U belladonna aluminum capsules, see Table 3.

[0098] Hyoscyamine sulfate (atropine sulfate)

[0099] Chromatographic conditions: octadecylsilane bonded silica gel as filler; acetonitrile-0.25% sodium dodecyl sulfate 0.004% phosphoric acid solution (40:60) as mobile phase; detection wavelength is 210nm. The theoretical plate number calculated based on the hyoscyamine sulfate peak should not be less than 2000. Limit: 0.070-0.120mg (the detection method refers to the content determination of belladonna tablets in the Chinese Pharmacopoeia 2020)

[0100] Vitamin UⅡ(iodomethylmethionine)

[0101] Chromatographic conditions: mobile phase is 0.01mol / L sodium acetate solution (adjusted to pH 6.5 with acetic acid)-acetonitrile (70:30), flow rate is 1.0mL / min, detection wavelength is 360nm, column temperature is 30c, injection volume is 10uL. (Refer to the Journal of Pharmaceutical Analysis "Determination of Vitamin U Content in Vitamin U Belladonna Aluminum Capsules by Pre-column Derivatization HPLC")

[0102] Aluminum hydroxide:

[0103] Take the contents of the capsule, mix them evenly, accurately weigh an appropriate amount (equivalent to about 0.6g of aluminum hydroxide), place it in a 250ml volumetric flask, add 20ml of hydrochloric acid and water, heat to dissolve, cool to room temperature, add water to the mark, shake well, filter, accurately measure 25ml of the filtrate, add ammonia test solution to neutralize until a precipitate just precipitates, then drop dilute hydrochloric acid until the precipitate just dissolves, add 10ml of acetic acid-ammonium acetate buffer, accurately add 25ml of disodium ethylenediaminetetraacetate titrant, boil for 5min, cool to room temperature, add 5-8 drops of xylenol orange indicator solution, titrate with zinc titrant until the solution changes from yellow to red, and correct the titration result with a blank. Each 1ml of disodium ethylenediaminetetraacetate titrant is equivalent to 2.549mg of Al2O3. (Refer to "Improvement of the Determination Method of the Content of Vitamin U Belladonna Aluminum Capsule III" in China Pharmacy Magazine) Table 3 Investigation and Determination Results of Example and Comparative Example Samples

[0104]

[0105] Note: Comparative Example 4 was not investigated for content due to sticking, and Comparative Example 5 was not investigated further due to large differences in loading amounts.

[0106] As can be seen from the above table, when observed on day 0, there was almost no change in atropine sulfate, iodomethylmethionine, and Al2O3 in Examples 1 to 3 and Comparative Examples 1-3 obtained by the present invention, but after accelerated treatment at 40°C / 75%RH for 6 months, the contents of atropine sulfate, iodomethylmethionine, and Al2O3 in Examples 1 to 3 were slightly reduced compared to day 0, while the contents of atropine sulfate, iodomethylmethionine, and Al2O3 in Comparative Examples 1-3 were significantly reduced compared to day 0, indicating that the embodiments obtained by the present invention have good stability.

[0107] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A vitamin U belladonna aluminum capsule, characterized in that: The preparation contains vitamin UⅡ, belladonna extract, aluminum hydroxide, mannitol cross-polymerization and maize co-processing product pharmaburst Mesoporous silica AL-1FP, magnesium stearate.

2. The vitamin U belladonna aluminum capsule according to claim 1, characterized in that: Per unit preparation of belladonna extract, mannitol cross-polymerization and Maishan co-processing product pharmaburst Mesoporous silica The mass ratio of AL-1FP is 1:(3~10):(0.2~2).

3. The vitamin U belladonna aluminum capsule according to claim 1, characterized in that: Vitamin UⅡ, belladonna extract, aluminum hydroxide, mannitol cross-polymerization and Maishan co-processing product pharmaburst per unit preparation Mesoporous silica The mass ratio of AL-1FP and magnesium stearate is 5:1:14:(3-10):(0.2-2):(0.15-0.55).

4. The vitamin U belladonna aluminum capsule according to claim 1, characterized in that: Each unit of preparation contains the following ingredients: vitamin UⅡ, belladonna extract, aluminum hydroxide, mannitol cross-linked copolymer wheat mountain co-processed pharmaburst Mesoporous silica The mass ratio of AL-1FP and magnesium stearate is 50 mg: 10 mg: 140 mg: 30-100 mg: 2-20 mg: 1.5-5.5 mg.

5. The vitamin U belladonna aluminum capsule according to claim 1, characterized in that The preparation method of the vitamin U belladonna aluminum capsule comprises the following steps: a. Weigh the prescribed amount of mannitol cross-linked copolymerization and Maishan co-processed product pharmaburst Mesoporous silica AL-1FP was mixed in a wet mixer granulator to obtain a mixture 1; b. Add mixture 1 to the belladonna extract, stir and shear at high speed, pass through a 20-mesh sieve to obtain granules of belladonna extract, and dry them in a boiling dryer at 40°C for 20 minutes. c. Add dried belladonna extract granules, vitamin UⅡ and aluminum hydroxide into a mixer and mix for 20 minutes. d. Add magnesium stearate and mix for 5 minutes. e. Filling capsules.

6. The vitamin U belladonna aluminum capsule according to claim 1, characterized in that The preparation method of the belladonna extract is as follows: take 1000g of belladonna grass coarse powder, use 85% ethanol as a solvent, soak for 48 hours, slowly percolate at a speed of 1-3ml per minute, collect about 3000ml of the initial percolate, store it in another container, continue percolate, wait for the alkaloids to be completely filtered out, and use the subsequent percolate as the solvent for the next percolate. The initial percolate is decompressed and ethanol is recovered at 60°C, cooled to room temperature, chlorophyll is separated and removed, filtered, and the filtrate is steamed at 60-70°C to a thick paste, 10 times the amount of ethanol is added, stirred evenly, and allowed to stand until the precipitation is complete, the supernatant is absorbed, and the ethanol is recovered at 60°C under reduced pressure, concentrated to a thick paste, and about 3g is taken out. According to the method under the item of belladonna extract content determination in the 2020 edition of the Chinese Pharmacopoeia, the content is determined, and an appropriate amount of diluent is added to make the content meet the requirements, low-temperature drying, grinding, and passing through a No. 4 sieve to obtain.

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