Ethylamine pyrazine rifamycin tablet and its preparation method

Abstract

The application discloses an ethylamine pyrazine rifampicin isoniazid tablet and a preparation method thereof. The ethylamine pyrazine rifampicin isoniazid tablet is composed of an inner granulation component, a binder, an outer total mixing component and a coating component. The inner granulation component comprises isoniazid, pyrazinamide, ethylamine butanol hydrochloride, medicinal adjuvant I and porous silicon dioxide microspheres. The outer total mixing component comprises rifampicin, an antioxidant, medicinal adjuvant II and is mixed with dry granules prepared by the inner granulation component and the binder. The ethylamine pyrazine rifampicin isoniazid tablet avoids direct contact of rifampicin with isoniazid under a wet heat condition by adding rifampicin and not participating in wet granulation. On the other hand, a new adjuvant is added in the prescription to isolate active ingredients from a physical aspect, thereby significantly reducing the generation of hydrazone impurities and ensuring the stability of API content.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an ethylaminepyrazine-rifa isonico tablet and its preparation method. Background Technology

[0002] Ethylaminopyrazine-rifampicin isoniazid tablets are the first-line fixed-dose combination preparation recommended by the World Health Organization (WHO) for the intensive phase of pulmonary tuberculosis. It consists of four active ingredients: rifampicin, isoniazid, pyrazinamide, and ethambutol hydrochloride. It has advantages such as improving patient compliance, reducing drug resistance, reducing relapse, and facilitating clinical management.

[0003] Currently, the industrial production of these four-component tablets generally employs a wet granulation process involving the mixing of all ingredients, granulating, drying, and compressing the four active ingredients along with the excipients. This process has significant drawbacks:

[0004] 1) Risk of compatibility reaction: During the wet granulation process, there are moisture, heat and shear force. Rifampin is prone to condensation reaction with isoniazid to generate 3-methylrifamycin SV isoniazid polymer impurity, which leads to a decrease in the content of effective ingredients of rifampin and isoniazid and excessive levels of related substances.

[0005] 2) Existing improvement solutions are costly: To suppress the reaction, existing technologies mostly adopt methods such as double-layer chip coating, isolation coating, and dry granulation, which rely on special tablet presses, high-end excipients and complex process control. The equipment investment is large, the process is difficult, and the production cost is high, making it difficult to promote in ordinary solid dosage form workshops.

[0006] 3) Poor adaptability to large-scale production: Complex dosage forms and processes have stringent requirements for equipment, personnel and environment, resulting in poor batch-to-batch consistency, which is not conducive to large-scale stable production.

[0007] Therefore, developing a simple, low-cost process for preparing ethylamine pyrazine rifampicin fumigant tablets that requires no high-end equipment or excessive complex excipients, and only involves adding one special excipient to the conventional wet granulation process to block the generation of impurities at the source, and is suitable for large-scale production in existing workshops, is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0008] This invention provides an ethylaminepyrazine-rifa isoflavone tablet and its preparation method, thereby addressing at least one of the many deficiencies in the prior art.

[0009] In view of this, the solution of the present invention is as follows:

[0010] The first aspect of the present invention is to provide an ethylamine pyrazine rifampicin isonicotinic acid tablet, which is composed of an internal granulation component, a binder, an external total mixture component, and a coating component; the internal granulation component includes isoniazid, pyrazinamide, ethambutol hydrochloride, pharmaceutical excipient one, and porous silica microspheres; the external total mixture component includes rifampicin, an antioxidant, and pharmaceutical excipient two, which are mixed with dry granules prepared by the internal granulation component and the binder;

[0011] The ethylamine pyrazine rifampicin isoniazid tablets, by weight, comprise the following components: 7.5 parts isoniazid, 40 parts pyrazinamide, 27.5 parts ethambutol hydrochloride, 9-12 parts pharmaceutical excipient one, 2.5-3.5 parts porous silica microspheres, 15 parts rifampicin and antioxidant, 0.5-0.6 parts antioxidant, and 2.5-3.5 parts pharmaceutical excipient two.

[0012] Furthermore, the first pharmaceutical excipient includes a filler and a disintegrant; and / or, the second pharmaceutical excipient includes a disintegrant and a lubricant.

[0013] Preferably, the filler is corn starch, the disintegrant is sodium carboxymethyl starch, and the lubricant is magnesium stearate.

[0014] Furthermore, the antioxidant is sodium ascorbate; and / or, the binder is povidone K30.

[0015] A second aspect of the present invention is to provide a method for preparing the ethylaminepyrazine-rifaisoxanthate tablets, comprising the steps of:

[0016] 1) Pretreatment: Take isoniazid, pyrazinamide, ethambutol hydrochloride, rifampin and all excipients and sieve them separately for later use.

[0017] 2) Wet granulation: Add isoniazid, pyrazinamide, ethambutol hydrochloride, porous silica microspheres and pharmaceutical excipients to a wet granulator and mix evenly; add binder solution to form a soft mass, and sieve to form wet granules.

[0018] 3) Drying and granulation: Wet granules are dried by boiling, and dry granules are granulated after sieving.

[0019] 4) Blending: Transfer the granulated dry granules into a blender, add rifampicin, antioxidant, and pharmaceutical excipient II in sequence, and then perform blending to obtain blended granules.

[0020] 5) Tableting and Coating: The total mixed granules are compressed into tablets, and then coated to obtain ethylaminepyrazine-rifaisoxanthate tablets.

[0021] Further, in step 1), the sieve mesh size is 30-60 mesh; and / or, in steps 2) and 3), the sieve mesh size is 40 mesh.

[0022] Furthermore, in step 3), the boiling drying is carried out at 40-60°C until the moisture content is ≤3.0%.

[0023] Furthermore, the adhesive solution is povidone K30 prepared with 60% ethanol, and the amount added is 5%.

[0024] A third aspect of the present invention is to provide the use of ethylaminepyrazine-rifa isonicotinic tablets as described in the first aspect or prepared by the method described in the second aspect in the preparation of anti-tuberculosis drugs.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The ethylamine pyrazine rifampicin isoniazid tablets provided by this invention, on the one hand, avoid direct contact between rifampicin and isoniazid under humid and hot conditions by adding rifampicin externally and not participating in wet granulation; on the other hand, new excipients are added to the formulation to physically isolate the active ingredients, thereby significantly reducing the generation of hydrazone impurities and ensuring stable API content.

[0027] The preparation method provided by this invention adopts the conventional wet granulation process and common pharmaceutical excipients throughout the entire process. The process is extremely simple and the cost is extremely low: only the order of feeding is adjusted on the standard wet granulation process. There is no double-layer tableting, no isolation coating, no high-end excipients, and no special equipment. It can be directly mass-produced in existing solid dosage form workshops. Detailed Implementation

[0028] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] This invention provides an ethylamine pyrazine rifampicin isonicotinic acid tablet, which is composed of an internal granulation component, a binder, an external total mixture component, and a coating component; the internal granulation component includes isoniazid, pyrazinamide, ethambutol hydrochloride, pharmaceutical excipient one, and porous silica microspheres; the external total mixture component includes rifampicin, an antioxidant, and pharmaceutical excipient two, which are mixed with the dry granules prepared by the internal granulation component and the binder;

[0030] The ethylamine pyrazine rifampicin isoniazid tablets, by weight, comprise the following components: 7.5 parts isoniazid, 40 parts pyrazinamide, 27.5 parts ethambutol hydrochloride, 9-12 parts pharmaceutical excipient one, 2.5-3.5 parts porous silica microspheres, 15 parts rifampicin and antioxidant, 0.5-0.6 parts antioxidant, and 2.5-3.5 parts pharmaceutical excipient two.

[0031] Specifically, the preparation method of the above-described ethylamine pyrazine-rifa isoflavone tablets includes the following steps:

[0032] 1) Pretreatment: Take isoniazid, pyrazinamide, ethambutol hydrochloride, rifampin and all excipients and sieve them separately for later use.

[0033] 2) Wet granulation: Add isoniazid, pyrazinamide, ethambutol hydrochloride, porous silica microspheres and pharmaceutical excipients to a wet granulator and mix evenly; add binder solution to form a soft mass, and sieve to form wet granules.

[0034] 3) Drying and granulation: Wet granules are dried by boiling, and dry granules are granulated after sieving.

[0035] 4) Blending: Transfer the granulated dry granules into a blender, add rifampicin, antioxidant, and pharmaceutical excipient II in sequence, and then perform blending to obtain blended granules.

[0036] 5) Tableting and Coating: The total mixed granules are compressed into tablets, and then coated to obtain ethylaminepyrazine-rifaisoxanthate tablets.

[0037] In this invention, rifampicin is not involved in wet granulation at all; it is added only after the granules are dried, completely avoiding contact and reaction with isoniazid under humid and hot conditions, thus significantly reducing hydrazone impurities. The addition of porous silica microspheres to the formulation further isolates rifampicin and isoniazid from a physical perspective, reducing their mutual reaction and effectively decreasing the formation of hydrazone impurities. Specifically, hydrazone impurities are ≤2.5%, and there is no significant increase in impurities after 6 months of accelerated processing, significantly superior to traditional wet granulation processes.

[0038] In a preferred embodiment, the first pharmaceutical excipient includes a filler and a disintegrant; the second pharmaceutical excipient includes a disintegrant and a lubricant. Preferably, the filler is corn starch, the disintegrant is sodium carboxymethyl starch, and the lubricant is magnesium stearate. The disintegrant promotes disintegration performance, and the lubricant ensures good tableting performance. Specifically, the disintegration time of the ethylamine pyrazine-rifa isonicotinic tablets prepared with the above excipients is ≤30 min.

[0039] In a preferred embodiment, the antioxidant is sodium ascorbate; the binder is povidone K30, preferably prepared with 50-60% ethanol to a concentration of 5%.

[0040] Example 1

[0041] The prescription for 10,000 tablets of ethylamine pyrazine, rifampicin, and isonicotinamide tablets is as follows:

[0042] ①Additional ingredients: 750g isoniazid, 4000g pyrazinamide, 2750g ethambutol hydrochloride, 1000g corn starch, 200g sodium carboxymethyl starch, and 300g porous silica microspheres;

[0043] ② Adhesive: 5% PVP K30 (50% ethanol) in appropriate amount;

[0044] ③Additional ingredients: Rifampin 1500g, Sodium ascorbate 55g, Sodium carboxymethyl starch 200g, Magnesium stearate 100g;

[0045] ④ Coating: Appropriate amount of film coating powder.

[0046] The preparation process is as follows:

[0047] 1) All raw and auxiliary materials pass through a 30-mesh sieve;

[0048] 2) Add the internal components to the wet granulator and premix for 1 min, then add the binder and continue granulation for 2 min to obtain wet granules;

[0049] 3) Dry at 55℃ until moisture content ≤ 3.0%, then granulate using a 40-mesh sieve;

[0050] 4) Add rifampin, sodium ascorbate, and sodium carboxymethyl starch and mix for 5 minutes. Finally, add magnesium stearate and continue mixing for 10 minutes.

[0051] 5) Compress the tablets and then coat them as usual to obtain the final product.

[0052] Example 2

[0053] The prescription for 10,000 tablets of ethylamine pyrazine, rifampicin, and isonicotinamide tablets is as follows:

[0054] ①Added ingredients: 750g isoniazid, 4000g pyrazinamide, 2750g ethambutol hydrochloride, 900g corn starch, 300g sodium carboxymethyl starch, and 320g porous silica microspheres;

[0055] ② Adhesive: 5% PVP K30 (50% ethanol) in appropriate amount;

[0056] ③Additional ingredients: Rifampin 1500g, Sodium ascorbate 55g, Sodium carboxymethyl starch 210g, Magnesium stearate 90g;

[0057] ④ Coating: Appropriate amount of film coating powder.

[0058] The preparation process is as follows:

[0059] 1) All raw and auxiliary materials pass through a 40-mesh sieve;

[0060] 2) Add the internal components to the wet granulator and premix for 1 min, then add the binder and continue granulation for 2 min to obtain wet granules;

[0061] 3) Dry at 60℃ until moisture content ≤ 3.0%, then granulate using a 40-mesh sieve;

[0062] 4) Add rifampin, sodium ascorbate, and sodium carboxymethyl starch and mix for 5 minutes. Finally, add magnesium stearate and continue mixing for 10 minutes.

[0063] 5) Compress the tablets and then coat them as usual to obtain the final product.

[0064] Comparative Example 1

[0065] The formulation and process are the same as in Example 1, except that the adhesive is replaced with a 5% PVP K30 aqueous solution.

[0066] Comparative Example 2

[0067] The prescription is the same as in Example 1, except that the porous silica microspheres are omitted.

[0068] Comparative Example 3

[0069] Rifampin, isoniazid, pyrazinamide, and ethambutol hydrochloride were added together for granulation, and the remaining excipients and processes were the same as in Example 1.

[0070] Test case

[0071] The tablets prepared in the above examples and comparative examples were tested for content and impurities, and accelerated stability of the examples was investigated. The results are shown in Tables 1 and 2.

[0072] Table 1: Test Results of Examples and Comparative Examples on Day 0

[0073] Indicator Name Internal control quality standards Example 1 Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Disintegration time limit ≤30min 18min 17min 24min 20min 22min Rifampicin content 90.0-110.0% 98.8% 98.7% 98.6% 98.4% 95.6% Isoniazid content 90.0-110.0% 99.3% 99.3% 98.4% 98.2% 96.9% Pyrazinamide content 90.0-110.0% 99.5% 99.6% 99.4% 99.3% 99.2% Ethylaminobutanol hydrochloride content 90.0-110.0% 100.0% 100.0% 99.8% 99.7% 99.8% hydrazone impurities ≤4.0% 1.85% 1.84% 2.10% 2.30% 3.95% Quinone rifampin ≤4.0% 0.30% 0.29% 0.35% 0.37% 0.63% Other single-mixed ≤1.5% 0.12% 0.12% 0.13% 0.13% 0.13% General Miscellaneous ≤10.0% 2.50% 2.49% 2.80% 3.00% 5.25%

[0074] Table 2: Stability test results of Example 1

[0075] Indicator Node 0 days Accelerate January Accelerate February Accelerate March Accelerate June Long-term 3 months Long-term June Disintegration time limit 18min 18min 19min 20min 23min 18min 20min Rifampicin content 98.8% 98.7% 98.5% 98.2% 97.3% 98.6% 98.2% Isoniazid content 99.3% 99.2% 99.0% 98.7% 97.5% 99.1% 98.5% Pyrazinamide content 99.5% 99.0% 98.5% 97.6% 96.8% 98.8% 97.9% Ethylaminobutanol hydrochloride content 100.0% 99.8% 99.6% 98.9% 98.1% 99.7% 98.5% hydrazone impurities 1.85% 1.88% 1.92% 1.96% 2.05% 1.90% 2.00% Quinone rifampin 0.30% 0.32% 0.37% 0.44% 0.52% 0.35% 0.41% Other single-mixed 0.12% 0.11% 0.10% 0.11% 0.12% 0.11% 0.12% General Miscellaneous 2.50% 2.54% 2.59% 2.63% 2.82% 2.56% 2.65%

[0076] It is not difficult to see from the above results that:

[0077] 1) Related substances: After adding the new excipients, the hydrazone impurity of this invention is ≤2.5%, which is significantly better than the traditional wet granulation process. The data of hydrazone impurity in the related substances of Comparative Example 3 is close to the limit value.

[0078] 2) Content: The API content of all four ingredients is between 95.0% and 105.0% of the labeled amount;

[0079] 3) Disintegration time: ≤30min; Example 1 is superior to Comparative Examples 1-3. The disintegration time of the ethanol solution granulation process is better than that of the aqueous solution granulation process, and the addition of novel excipients further optimizes the disintegration performance.

[0080] 4) Stability: After 6 months of accelerated testing, there was no significant increase in impurities, and the content remained stable.

[0081] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. An ethylaminepyrazine-rifa isonico tablet, characterized in that, It is composed of an internal granulation component, a binder, an external total mixture component, and a coating component; the internal granulation component includes isoniazid, pyrazinamide, ethambutol hydrochloride, pharmaceutical excipient one, and porous silica microspheres; the external total mixture component includes rifampin, antioxidant, and pharmaceutical excipient two, which are mixed with the dry granules prepared by the internal granulation component and the binder. The ethylamine pyrazine rifampicin isoniazid tablets, by weight, comprise the following components: 7.5 parts isoniazid, 40 parts pyrazinamide, 27.5 parts ethambutol hydrochloride, 9-12 parts pharmaceutical excipient one, 2.5-3.5 parts porous silica microspheres, 15 parts rifampicin and antioxidant, 0.5-0.6 parts antioxidant, and 2.5-3.5 parts pharmaceutical excipient two.

2. The ethylaminepyrazine-rifa isonico tablets according to claim 1, characterized in that, The first pharmaceutical excipient includes a filler and a disintegrant; and / or, the second pharmaceutical excipient includes a disintegrant and a lubricant.

3. The ethylamine pyrazine-rifa isonico tablets according to claim 2, characterized in that, The filler is corn starch, the disintegrant is sodium carboxymethyl starch, and the lubricant is magnesium stearate.

4. The ethylamine pyrazine-rifa isonico tablets according to claim 1, characterized in that, The antioxidant is sodium ascorbate; and / or the binder is povidone K30.

5. The method for preparing ethylaminepyrazine-rifaisoxanone tablets according to any one of claims 1-4, characterized in that, step include: 1) Pretreatment: Isoniazid, pyrazinamide, ethambutol hydrochloride, rifampin and all excipients were sieved separately and set aside; 2) Wet granulation: Add isoniazid, pyrazinamide, ethambutol hydrochloride, porous silica microspheres and pharmaceutical excipients to a wet granulator and mix evenly; add binder solution to form a soft mass, and sieve to form wet granules; 3) Drying and granulation: Wet granules are dried by boiling, and dried granules are sieved and then granulated; 4) Blending: Transfer the granulated dry granules into a blender, add rifampin, antioxidant, and pharmaceutical excipient II in sequence, and perform formal blending to obtain blended granules; 5) Tableting and Coating: The total mixed granules are compressed into tablets, and then coated to obtain ethylaminepyrazine-rifaisoxanthate tablets.

6. The preparation method according to claim 5, characterized in that, In step 1), the sieve mesh size is 30-60 mesh; and / or, in steps 2) and 3), the sieve mesh size is 40 mesh.

7. The preparation method according to claim 5, characterized in that, In step 3), the boiling drying is carried out at 40-60°C until the moisture content is ≤3.0%.

8. The preparation method according to claim 5, characterized in that, The adhesive solution is polyvinyl ketone K30 prepared with ethanol.

9. The use of ethylaminepyrazine-rifa-isoycin tablets according to any one of claims 1-4, or ethylaminepyrazine-rifa-isoycin tablets prepared by the preparation method according to any one of claims 5-8, in the preparation of anti-tuberculosis drugs.