Acetylcysteine coated granule capsule obtained by producing cystine through fermentation method and preparation method of acetylcysteine coated granule capsule

Abstract

The invention discloses an innovative formula of an acetylcysteine coated granule capsule obtained by producing cystine through a fermentation method and a preparation method. The formula comprises the following components: an acetylcysteine crystal raw material obtained by producing cystine through the fermentation method, a hot-melt coating material and a 2 # plant-based hollow capsule shell. According to the preparation method, an acetylcysteine crystal raw material obtained by producing cystine through a fermentation method is directly used for coating, a coating process adopts a melt coating process, and a 2 # plant-based hollow capsule shell is selected for capsule filling. The invention relates to the technical field of biological medicine health, and discloses an acetylcysteine capsule prepared by a new method, which not only solves the odor of acetylcysteine sulfydryl garlic, but also has good stability due to hygroscopicity reduction, and simultaneously meets the requirements (appeals) of vegetarians. The capsule with a suitable model is easy to swallow and convenient to carry, can be taken for a long time, and has excellent economic characteristics.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine and health technology, and in particular to a method for preparing acetylcysteine ​​coated granule capsules obtained by producing cystine through a fermentation method. Background Art

[0002] Cystine is composed of two cysteines connected by a disulfide bond. Cystine can be reduced to cysteine, and cysteine ​​can be acetylated to acetylcysteine. Most cystine on the market is produced by hydrolysis of animal hair. This invention uses a fermentation method to produce cysteine ​​to obtain acetylcysteine, which meets the needs of vegetarians or those with specific religious beliefs. General physical and chemical properties of acetylcysteine:

[0003] Chinese name: acetylcysteine

[0004] English name: Acetylcysteine

[0005] Chemical name: N-acetyl-L-cysteine

[0006] Chemical English name: N-acetyl-L-cysteine

[0007] Molecular formula: C5H9NO3S

[0008] Molecular weight: 163.20

[0009] CAS No.: 616-91-1

[0010] Structural formula:

[0011] Physical and chemical properties: This product is a white or off-white crystalline powder; has a garlic-like odor; is hygroscopic; has a melting point of 104-110°C; and is easily soluble in water or ethanol.

[0012] 1. The sulfhydryl group in the molecular structure of acetylcysteine ​​breaks the disulfide bonds between mucin molecular complexes, reduces sputum viscosity, and makes sputum easier to cough up. It is often used as an expectorant.

[0013] 2. Acetylcysteine ​​can improve cell respiration and tissue nutrition, promote corneal epithelial regeneration, and improve eye metabolism; it can be used as an eye medication.

[0014] 3. Acetylcysteine ​​has antioxidant activity and can promote the liver to synthesize glutathione antioxidant enzymes, maintain liver function, and detoxify the liver. It can be used clinically for detoxification of acetaminophen overdose and liver protection.

[0015] 4. Acetylcysteine ​​is a collagenase inhibitor. Its mechanism of action is that on the one hand it can chelate calcium ions and indirectly inhibit collagenase. On the other hand, it can reduce the disulfide bonds in the collagenase molecule through the sulfhydryl group (-SH) in its molecule, thereby making it inactive. It directly and irreversibly inhibits collagenase and reduces the decomposition of collagen in tissues. It can be used to enhance skin elasticity.

[0016] 5. Acetylcysteine ​​is a chemical precursor to glutathione, which promotes the production of glutathione, the body's most powerful antioxidant. Glutathione is one of the body's most important antioxidants, helping to protect cells from free radical damage. Acetylcysteine ​​levels determine the amount and rate of glutathione production in the body. Therefore, acetylcysteine ​​is also used for a variety of other conditions, such as chronic bronchitis, influenza, heart disease, chronic obstructive pulmonary disease, cystic fibrosis, and contrast-induced nephropathy. Studies have found that NAC levels may be low in HIV patients, and NAC is often used as a cocktail drug in HIV treatment.

[0017] Due to its extensive clinical mechanistic effects, acetylcysteine ​​has been developed in numerous pharmaceutical formulations, including injections, oral preparations, eye drops, and inhalers. Oral preparations are the most widely used, as oral acetylcysteine ​​often requires long-term use for the treatment of certain conditions, such as chronic bronchitis, influenza, heart disease, chronic obstructive pulmonary disease, cystic fibrosis, contrast-induced nephropathy, and even AIDS. Capsules are easily manufactured, portable, and easy to swallow, making them the optimal oral formulation for long-term use. However, during the development and production of acetylcysteine ​​capsules, it was discovered that due to the hygroscopicity of acetylcysteine, the preparation process required strict humidity requirements, resulting in caking during storage, which affected its use. Furthermore, the garlic-like odor of the thiol group in acetylcysteine ​​caused significant discomfort to users, hindering their use.

[0018] To address this issue, Chinese patent CN118924700A, titled "Nelty-cysteine ​​fine particles and their preparation method," was filed. This patent relates to a fine granular dosage form of acetylcysteine ​​and its preparation. The final dosage form of the product is fine granules. The patent claims require that the acetylcysteine ​​be pre-crushed and powder-coated to mask the odor. However, this crushing inevitably adversely affects the chemical stability of the acetylcysteine.

[0019] Chinese patent CN113750052B discloses an acetylcysteine ​​granule and its preparation method. This patent relates to an acetylcysteine ​​granule dosage form and its preparation, with the final product being a granule. The patent claims that acetylcysteine ​​is pre-mixed and dissolved with other amino acids, spray-dried and granulated, and then coated into coated pellets to achieve stability. However, the mixing, dissolving, and spray-granulation process inevitably adversely affects the chemical stability of acetylcysteine.

[0020] Chinese patent CN110392568A, N-acetylcysteine ​​preparations and uses. This patent relates to a non-gastric-soluble coated release dosage form, intended to modify the in vivo release characteristics of N-acetylcysteine. The preparation process involves mixing micronized N-acetylcysteine ​​with a coating material to form a suspension, which is then coated onto an inert blank pill core.

[0021] To date, all patents or literature related to acetylcysteine-coated granules have involved pre-coating treatment of acetylcysteine, such as crushing and dissolving, and the coating process is solvent coating. These coating processes affect the stability of acetylcysteine ​​due to its hygroscopicity and alcohol solubility.

[0022] This patent innovatively coats the raw acetylcysteine ​​crystals directly without pulverization, solvent mixing, or other treatments that could compromise their stability, thereby maximizing the stability of acetylcysteine. The coating process utilizes hot-melt coating, and the coating material consists of palm wax, vinylpyrrolidone-vinyl acetate copolymer, oleic acid polyethylene glycol glyceride, and sucrose stearate. After coating, the granules are filled into 2# plant-based capsules. The 2# size meets the required active ingredient loading and is easy to swallow. Acetylcysteine, produced by fermentation and produced using cystine, and the plant-based capsule shells meet the needs of vegetarians or adherents of specific religious beliefs. The final dosage form of acetylcysteine ​​in this invention is a capsule. Unlike fine granules or granules, which require dilution, it is often used by special populations such as children and the elderly. The 2# capsules used in this invention are simple to administer, economical, stable, odorless, and convenient for long-term use. The finished acetylcysteine-coated granular capsules of this invention offer superior stability, safety, compliance, odor resistance, and cost-effectiveness, demonstrating significant innovation.

[0023] (1) Technical problems solved

[0024] In response to the shortcomings of the existing technology, the present invention provides a method for preparing acetylcysteine ​​coated granule capsules obtained by fermenting cystine, which successfully solves the problems of poor chemical stability, garlic-like odor of sulfhydryl groups, animal source, and economic issues of acetylcysteine ​​preparations in the existing technology.

[0025] (2) Technical solution

[0026] To achieve the above objectives, the present invention provides the following technical solution: a coated granule capsule of acetylcysteine ​​obtained by fermentation to produce cystine, comprising the following components: acetylcysteine ​​crystalline raw material obtained by fermentation to produce cystine, a hot-melt coating material, and a 2# plant-based hollow capsule shell.

[0027] A method for preparing acetylcysteine ​​coated granule capsules obtained by producing cystine by a fermentation method, characterized by comprising the following steps:

[0028] Step 1: Take the acetylcysteine ​​crystal raw material, which is white and granular in appearance.

[0029] Step 2: Take a moisture-proof molten coating material, which is a hot-melt coating auxiliary material, and heat it to form a coating melt.

[0030] Step 3: In a specific fluidized bed, coating the acetylcysteine ​​raw material with the prepared hot melt coating solution to obtain acetylcysteine ​​coated particles;

[0031] Step 4: The acetylcysteine-coated particles obtained above are used as intermediates for testing;

[0032] Step 5: Take 2# plant-based hollow capsule shells, and fill the capsules with acetylcysteine ​​coated granules according to the prescribed dosage of 0.3g of active ingredient acetylcysteine ​​per granule using a capsule filling machine to obtain acetylcysteine ​​coated granule capsules;

[0033] Step 6: After inner packaging of the acetylcysteine ​​coated granules and capsules, the acetylcysteine ​​coated granules and capsules are obtained as finished products.

[0034] As a further preferred embodiment, the acetylcysteine ​​crystal raw material in step 1 is acetylcysteine ​​obtained by fermentation to produce cystine, and the particle size of the raw material is 30-45 mesh.

[0035] As a further preferred embodiment, the melt-mixable coating excipients in step 2 are composed of 75%-85% palm wax; 10%-20% vinyl pyrrolidone-vinyl acetate copolymer; 1%-5% oleic acid polyethylene glycol glyceride; and 1%-5% sucrose stearate.

[0036] As a further preference, the weight gain of the acetylcysteine ​​coating in step 3 is preferably 5% to 15%.

[0037] As a further preference, the hollow capsule shell in step 5 is preferably 2# plant-based capsule shell.

[0038] As a further preference, the inner packaging material in step 6 is preferably a PET plastic bottle.

[0039] (3) Beneficial effects

[0040] The present invention provides a method for preparing acetylcysteine ​​coated granules and capsules obtained by fermenting cystine. The method has the following beneficial effects:

[0041] The final dosage form of the acetylcysteine ​​of the present invention is a capsule, which is different from fine granules or granules and has obvious beneficial effects: no odor, good compliance; 2# capsule is easy to swallow and convenient to take; it is economical and can be taken for a long time; cystine is produced by fermentation to obtain acetylcysteine ​​and plant-based hollow capsule shells, avoiding animal sources and meeting the needs of vegetarians or people with specific religious beliefs; the preparation process is innovative in that the acetylcysteine ​​raw material is directly melt-coated, and the hot melt coating liquid does not evaporate but solidifies, saving time, energy, and materials compared to solvent coating; direct melt coating does not require crushing or other treatments that are not conducive to its stability, and the innovative coating process maintains the stability of acetylcysteine ​​to the greatest extent; after coating, the particles are filled in plant capsules, which not only ensures product stability but also eliminates the garlic-like odor of the thiol group of the active ingredient acetylcysteine. The acetylcysteine ​​coated granule capsules of the present invention are superior in stability, safety, compliance, odor, and economy, and are significantly innovative. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 is a liquid chromatogram of the acetylcysteine ​​raw material of the present invention;

[0043] Figure 2 is a liquid chromatogram of the acetylcysteine ​​coated granules of the present invention;

[0044] Figure 3 This is a liquid chromatogram of Example 1 of the present invention;

[0045] Figure 4 This is the liquid chromatogram of Example 2 of the present invention;

[0046] Figure 5 This is the liquid chromatogram of Example 3 of the present invention;

[0047] Figure 6 This is a liquid chromatogram of Example 4 of the present invention. DETAILED DESCRIPTION

[0048] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0049] Example 1

[0050] Step 1: Take the white, granular acetylcysteine ​​crystalline raw material obtained by fermentation to produce cystine, weigh the required acetylcysteine ​​raw material through a 30-45 mesh sieve according to the prescription, and set aside;

[0051] Step 2: Weigh the prepared hot melt coating premix (80% palm wax; 10% vinylpyrrolidone-vinyl acetate copolymer; 5% oleic acid polyethylene glycol glyceride; 5% sucrose stearate) according to the designed amount and heat it to form a melt coating solution.

[0052] Step 3: In a hot melt coating device, the acetylcysteine ​​raw material is coated with a temperature-controlled compressed air atomization coating using a prepared hot melt coating liquid to obtain acetylcysteine ​​coated particles. Weighing shows that the coating weight of the acetylcysteine ​​particles increases by 6.3%.

[0053] Step 4: The acetylcysteine ​​coated granules obtained above are used as intermediates, tested, and set aside.

[0054] Step 5: Take 2# plant-based hollow capsule shells, fill them with acetylcysteine ​​coated granules into capsules according to the prescribed dosage of 0.3g of active ingredient acetylcysteine ​​per capsule in a capsule filling machine to obtain acetylcysteine ​​coated granules capsules.

[0055] Step 6: Take a PET plastic bottle, sterilize it with ultraviolet light, and use it to package the above-mentioned acetylcysteine ​​coated granules and capsules. Label it to obtain the finished product of the acetylcysteine ​​coated granules and capsules.

[0056] Example 2

[0057] Step 1: Take the white, granular acetylcysteine ​​crystalline raw material obtained by fermentation to produce cystine, weigh the required acetylcysteine ​​raw material through a 30-45 mesh sieve according to the prescription, and set aside;

[0058] Step 2: Weigh the prepared hot melt coating premix (75% palm wax; 15% vinylpyrrolidone-vinyl acetate copolymer; 5% oleic acid polyethylene glycol glyceride; 5% sucrose stearate) according to the designed amount and heat it to form a melt coating solution.

[0059] Step 3: In a hot melt coating device, the acetylcysteine ​​raw material is coated with a temperature-controlled compressed air atomization coating using a prepared hot melt coating liquid to obtain acetylcysteine ​​coated particles. Weighing shows that the coating weight of the acetylcysteine ​​particles increases by 10.1%.

[0060] Step 4: The acetylcysteine ​​coated granules obtained above are used as intermediates, tested, and set aside.

[0061] Step 5: Take 2# plant-based hollow capsule shells, fill them with acetylcysteine ​​coated granules into capsules according to the prescribed dosage of 0.3g of active ingredient acetylcysteine ​​per capsule in a capsule filling machine to obtain acetylcysteine ​​coated granules capsules.

[0062] Step 6: Take a PET plastic bottle, sterilize it with ultraviolet light, and use it to package the above-mentioned acetylcysteine ​​coated granules and capsules. Label it to obtain the finished product of the acetylcysteine ​​coated granules and capsules.

[0063] Example 3

[0064] Step 1: Take the white, granular acetylcysteine ​​crystalline raw material obtained by fermentation to produce cystine, weigh the required acetylcysteine ​​raw material through a 30-45 mesh sieve according to the prescription, and set aside;

[0065] Step 2: Weigh the prepared hot melt coating premix (84% palm wax; 10% vinylpyrrolidone-vinyl acetate copolymer; 3% oleic acid polyethylene glycol glyceride; 3% sucrose stearate) according to the designed amount and heat it to form a melt coating solution.

[0066] Step 3: In a hot melt coating device, the acetylcysteine ​​raw material is coated with a prepared hot melt coating liquid by temperature-controlled compressed air atomization to obtain acetylcysteine ​​coated particles. Weighing shows that the coating weight of the acetylcysteine ​​particles increases by 12.7%.

[0067] Step 4: The acetylcysteine ​​coated granules obtained above are used as intermediates, tested, and set aside.

[0068] Step 5: Take 2# plant-based hollow capsule shells, fill them with acetylcysteine ​​coated granules into capsules according to the prescribed dosage of 0.3g of active ingredient acetylcysteine ​​per capsule in a capsule filling machine to obtain acetylcysteine ​​coated granules capsules.

[0069] Step 6: Take a PET plastic bottle, sterilize it with ultraviolet light, and use it to package the above-mentioned acetylcysteine ​​coated granules and capsules. Label it to obtain the finished product of the acetylcysteine ​​coated granules and capsules.

[0070] Example 4 (Comparative Example)

[0071] Step 1: Take acetylcysteine ​​raw material, which is white and granular, and weigh the required acetylcysteine ​​raw material through a 30-45 mesh sieve, and set aside;

[0072] Step 2: To enhance the fluidity of the above materials and ensure that the difference in loading volume meets the requirements, the above materials are mixed with 1% micro powder silica gel flow aid to obtain the pre-filling mixed material and set aside.

[0073] Step 3: Take 2# gelatin hollow capsule shells and fill them with acetylcysteine ​​capsules in a capsule filling machine according to the prescribed dosage of 0.3g of active ingredient acetylcysteine ​​per capsule to obtain acetylcysteine ​​capsules.

[0074] Step 4: Take a PET plastic bottle and package the above acetylcysteine ​​capsules to obtain a finished acetylcysteine ​​capsule for use as a control study sample.

[0075] Accelerated stability test results of four examples (40°C, CH 75%, 3M)

[0076]

[0077]

[0078] Coating implementation effect

[0079] Comparative study results on the hygroscopicity of intermediate acetylcysteine ​​coated granules

[0080]

[0081] The experimental results of the above four examples show that the finished acetylcysteine ​​capsules prepared by the preparation method of the present invention have good appearance integrity, good fluidity of the particles on the inner wall of the capsule without agglomeration, and basically no garlic odor when taken, and low impurity content. In contrast, the finished product of the capsule directly made from the raw material drug has a fragile appearance, the internal particles are agglomerated and slightly yellowish, and the impurity content is significantly higher.

[0082] Furthermore, through experimental comparison of acetylcysteine ​​raw material particles and acetylcysteine ​​coated particles, it was found that the moisture resistance of the coated particles was significantly improved and the overall stability was better.

[0083] The acetylcysteine ​​coated granule capsules prepared by the present invention have lower impurity content, good stability of effective active ingredients, and are safer and more effective, according to test data results.

[0084] Finally, the instruction manual Figure 1-6 , provide relevant supporting materials for the source of each data.

[0085] While 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 these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A coated granule capsule of acetylcysteine ​​obtained by fermentation of cystine, characterized in that: The invention comprises the following ingredients: acetylcysteine ​​crystal raw material obtained by producing cystine by fermentation, hot-melt coating material, and 2# plant-based hollow capsule shell.

2. The method for preparing acetylcysteine ​​coated granules and capsules obtained by fermentation of cystine according to claim 1, characterized in that: The following steps are involved: Step 1: Take acetylcysteine ​​crystalline raw material obtained by fermentation to produce cystine, the raw material is white, granular, and has a particle size of 30-45 mesh; Step 2: Take a hot melt coating material composed of: 75%-85% cholesterol octanoate / palm wax; 10%-20% vinyl pyrrolidone-vinyl acetate copolymer; 1%-5% oleic acid polyethylene glycol glyceride; and 1%-5% sucrose stearate, and heat the mixture to form a coating melt. Step 3: In a hot melt coating device, coating the acetylcysteine ​​crystal raw material with the prepared hot melt coating solution to obtain acetylcysteine ​​coated particles; Step 4: The acetylcysteine-coated particles obtained above are used as intermediates for testing; Step 5, taking 2# plant-based hollow capsule shells, filling acetylcysteine ​​coated granules into capsules according to the prescribed dosage of 0.3g of active ingredient acetylcysteine ​​per capsule using a capsule filling machine to obtain acetylcysteine ​​coated granules capsules; Step 6: After inner packaging of the acetylcysteine ​​coated granules and capsules, a finished acetylcysteine ​​coated granules and capsules is obtained.

3. The method for preparing acetylcysteine ​​coated granules and capsules obtained by fermentation of cystine according to claim 2, characterized in that: The coating excipient is a hot melt coating material.

4. The method for preparing acetylcysteine ​​coated granules and capsules obtained by fermentation of cystine according to claim 2, characterized in that: The hollow capsule shell is 2# plant-based hollow capsule shell.

5. The method for preparing acetylcysteine ​​coated granules and capsules obtained by fermentation of cystine according to claim 2, characterized in that: The weight gain of the acetylcysteine ​​coating in step 3 is preferably 5% to 10%.

6. The method for preparing acetylcysteine ​​coated granules and capsules obtained by fermentation of cystine according to claim 2, characterized in that: The packaging material in step 6 is preferably a PET plastic bottle.

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