Carbamazepine pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a carbamazepine pharmaceutical composition as well as a preparation method and application thereof, and belongs to the field of medicine preparation. The carbamazepine pharmaceutical composition provided by the invention comprises carbamazepine, a filler, an adhesive, a disintegrating agent and a lubricant, wherein the filling agent comprises microcrystalline cellulose, the disintegrating agent comprises low-substituted hydroxy propyl cellulose and carbamazepine, and the mass ratio of the microcrystalline cellulose to the low-substituted hydroxy propyl cellulose is 1: (2.795-2.895): (0.18-0.28). According to the carbamazepine pharmaceutical composition, the content uniformity of the medicine can be improved, the dissolution rate of a self-developed preparation is consistent with that of a reference preparation under the condition that the same specification is guaranteed, it is guaranteed that tabletting is smooth in the production process, and the carbamazepine pharmaceutical composition has actual clinical application value.

Description

Technical Field

[0001] The invention provides a carbamazepine pharmaceutical composition and a preparation method and application thereof, belonging to the field of medicine preparation. Background Art

[0002] Carbamazepine is a first-line drug or additional drug for the treatment of generalized tonic-clonic seizures and focal seizures. It can be used for children under 6 years old. The main dosage forms currently on the market include immediate-release tablets, sustained-release tablets, capsules, sustained-release capsules, etc., with a minimum specification of 0.1g. The recommended dosage for children in clinical practice is 5mg / kg per day based on body weight before 6 years old, and the dosage is increased every 5-7 days to 10mg / kg per day, and increased to 20mg / kg if necessary, generally 10-20mg / kg based on body weight, about 0.25-0.3g, not exceeding 0.4g; children aged 6-12 years old take 0.05g-0.1g on the first day, take 2 times, and increase 0.1g every other week until the effect appears; the maintenance dose is adjusted to the minimum effective dose, generally 0.4-0.8g per day.

[0003] The carbamazepine tablets currently on the market are scored tablets and unscored tablets, which can only be divided into fixed amounts (such as 1 / 2, 1 / 4, etc.), which cannot meet the needs of a large number of pediatric medication scenarios. In addition, they are prone to powder loss and breakage during division, resulting in uneven division and inaccurate dosing. Touching the tablets with bare hands can easily cause contamination, moisture, and other problems, leading to serious safety issues. Capsule dosage forms are even more difficult to divide into doses.

[0004] Patent CN115089555A discloses a carbamazepine solid tablet and a preparation method thereof. The provided carbamazepine tablet includes a carbamazepine solid dispersion, a diluent, a disintegrant and a lubricant. The carbamazepine solid dispersion includes carbamazepine and a carrier. The carbamazepine solid dispersion is prepared by hot melt extrusion technology; the carrier is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol 6000, polyvinyl alcohol, povidone K12, povidone K30, povidone K90, copovidone VA64 and Soluplus. However, the patent embodiment specification is 0.2g carbamazepine / tablet, which cannot provide a pediatric medication scenario.

[0005] Chinese patent CN114129527B discloses a microtablet and its preparation method and preparation, the components include active ingredients, fillers and / or disintegrants, the diameter is 1-5mm, and the tablet weight is 1-50mg. The active ingredient is levothyroxine sodium or oseltamivir phosphate or digoxin, and the fillers used include microcrystalline cellulose, erythritol, xylan, soybean polysaccharide, glucuronic acid, alginic acid and cassava flour, etc. The preparation process requires the active ingredient to be micronized first, then dispersed with a solvent, and then sprayed into the filler. The preparation process is complicated, and the filler ratio is not set for the active ingredient carbamazepine. Summary of the invention

[0006] In order to solve the deficiencies in the above-mentioned prior art, the present invention provides a carbamazepine pharmaceutical composition and a preparation method and application thereof. The specific technical scheme is as follows:

[0007] In a first aspect, the present invention provides a carbamazepine pharmaceutical composition, comprising carbamazepine, a filler, a binder, a disintegrant and a lubricant;

[0008] Specifically, the filler includes microcrystalline cellulose;

[0009] Specifically, the disintegrant includes low-substituted hydroxypropyl cellulose;

[0010] Specifically, the mass ratio of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose is: 1: 2.795-2.895: 0.18-0.28;

[0011] Specifically, the carbamazepine is carbamazepine or a pharmaceutically acceptable salt thereof;

[0012] Specifically, the particle size of carbamazepine is 60-75 μm;

[0013] Specifically, the composition comprises, by percentage, 18-30% carbamazepine, 50-77% microcrystalline cellulose, 2-8% binder, 2-10% low-substituted hydroxypropyl cellulose and 0.1-2% lubricant;

[0014] Specifically, the filler also includes corn starch;

[0015] Specifically, the type of microcrystalline cellulose is at least one of PH102 and UF-702.

[0016] Preferably, the composition comprises, by percentage, 18-22% carbamazepine, 10-25% corn starch, 50-67% microcrystalline cellulose, 2-4% binder, 2-6% low-substituted hydroxypropyl cellulose and 0.1-1% lubricant;

[0017] Specifically, the binder is at least one of hydroxypropyl cellulose, copovidone, hydroxypropyl cellulose, hydroxyethyl cellulose, polymethacrylate, sodium alginate and pregelatinized starch;

[0018] Specifically, the lubricant is at least one of magnesium stearate, talc, calcium stearate, sodium stearate, stearic acid, adipic acid, sodium stearyl fumarate, calcium behenate, glyceryl sodium behenate and glyceryl fumarate.

[0019] In a second aspect, the present invention provides a method for preparing the above-mentioned carbamazepine pharmaceutical composition, comprising the following steps:

[0020] S1. Mix carbamazepine, corn starch, binder and low-substituted hydroxypropyl cellulose evenly;

[0021] S2, uniformly mixing the mixed material obtained in step S1 with microcrystalline fibers of equal mass;

[0022] S3, uniformly mixing the mixture obtained in step S2 with the remaining microcrystalline fibers;

[0023] S4, mixing the mixture obtained in step S3 and magnesium stearate uniformly, and tableting;

[0024] Specifically, the carbamazepine needs to pass through a 150-200 mesh sieve.

[0025] In a third aspect, the present invention provides a use of the above-mentioned carbamazepine pharmaceutical composition or the carbamazepine pharmaceutical composition prepared by the above-mentioned preparation method in the preparation of carbamazepine microtablets;

[0026] The carbamazepine micro-tablet has a tablet weight of 20-30 mg and a diameter of 2-3 mm.

[0027] In a fourth aspect, the present invention provides a carbamazepine microtablet, comprising the above-mentioned carbamazepine pharmaceutical composition or the carbamazepine pharmaceutical composition prepared by the above-mentioned preparation method;

[0028] Specifically, the carbamazepine micro-tablet has a tablet weight of 20-30 mg and a diameter of 2-3 mm.

[0029] In a fifth aspect, the present invention provides an application of microcrystalline cellulose and low-substituted hydroxypropyl cellulose in combination for improving the content uniformity and dissolution rate of carbamazepine microtablets;

[0030] Specifically, the model of the microcrystalline cellulose is at least one of PH102 and UF-702;

[0031] Specifically, the carbamazepine microtablet has a tablet weight of 20-30 mg and a diameter of 2-3 mm;

[0032] Specifically, the mass ratio of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose in the carbamazepine micro-tablets is 1:2.795-2.895:0.18-0.28.

[0033] Beneficial effects:

[0034] (1) The carbamazepine micro-tablets of the present invention have good content uniformity;

[0035] (2) The process of the present invention is simple, low-cost and suitable for commercial production. DETAILED DESCRIPTION

[0036] The present invention is described below by specific examples to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are all commercially available unless otherwise specified.

[0037] 1. Examples and Comparative Examples

[0038] Example 1

[0039] A carbamazepine micro-tablet, the raw and auxiliary materials are shown in Table 1.

[0040] Table 1 List of raw and auxiliary materials for Example 1

[0041]

[0042]

[0043] The preparation method of carbamazepine microtablets comprises the following steps:

[0044] S1. Pass carbamazepine through a 200-mesh sieve, pour the above-mentioned mass of carbamazepine, corn starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose into a hopper mixer, and mix them evenly at 10 rpm for 5 min;

[0045] S2, pouring the mixed material obtained in step S1 and an equal mass of microcrystalline cellulose into a hopper mixer, mixing at 10 rpm for 5 min;

[0046] S3, pouring the mixture obtained in step S2 and the remaining microcrystalline cellulose into a hopper mixer, mixing at 10 rpm for 5 min;

[0047] S4, pouring the mixture obtained in step S3 and magnesium stearate into a hopper mixer, mixing evenly at 10 rpm for 5 min, and tableting.

[0048] Example 2

[0049] A carbamazepine micro-tablet, which is different from Example 1 in that the mass ratios of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose are different. The raw and auxiliary materials are shown in Table 2.

[0050] Table 2 Raw and auxiliary materials of Example 3

[0051]

[0052] The preparation method is the same as that of Example 1.

[0053] Example 3

[0054] The difference from Example 1 is that the microcrystalline cellulose used is model UF-702, and the preparation method is the same as that of Example 1.

[0055] Comparative Example 1

[0056] The difference from Example 1 is that the mass ratios of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose are different. The raw and auxiliary materials are shown in Table 3. The preparation method is the same as Example 1.

[0057] Table 3 Raw and auxiliary materials of comparative example 1

[0058]

[0059] Comparative Example 2

[0060] The difference from Example 1 is that the microcrystalline cellulose used is model PH200, and the preparation method is the same as that of Example 1.

[0061] Comparative Example 3

[0062] The difference from Example 1 is that the microcrystalline cellulose is replaced by mannitol 100SD, and the preparation method is the same as that of Example 1.

[0063] Comparative Example 4

[0064] The difference from Example 1 is that the disintegrant is replaced by sodium carboxymethyl starch, and the preparation method is the same as that of Example 1.

[0065] Comparative Example 5

[0066] The difference from Example 1 is that the particle size of carbamazepine is different. The particle size of carbamazepine is 106 μm. The specific preparation steps are as follows:

[0067] S1. Pass carbamazepine through a 150-mesh sieve, pour the above-mentioned mass of carbamazepine, corn starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose into a hopper mixer, and mix them evenly at 10 rpm for 5 min;

[0068] S2, pouring the mixed material obtained in step S1 and an equal mass of microcrystalline cellulose into a hopper mixer, mixing at 10 rpm for 5 min;

[0069] S3, pouring the mixture obtained in step S2 and the remaining microcrystalline cellulose into a hopper mixer, mixing at 10 rpm for 5 min;

[0070] S4, pouring the mixture obtained in step S3 and magnesium stearate into a hopper mixer, mixing evenly at 10 rpm for 5 min, and tableting.

[0071] 2. Dissolution Test

[0072] The dissolution of Examples 1-2, Comparative Examples 1, 3, 4, 5 and the reference preparation was tested using the paddle method at 75 rpm. The results are shown in Table 4.

[0073] The reference preparation was purchased from Novartis Pharmaceuticals, Switzerland, with a specification of 0.1 g.

[0074] Table 4 Dissolution of Examples 1-2 and Comparative Examples 1, 3, 4, 5

[0075]

[0076] When the mass ratio of microcrystalline cellulose to low-substituted hydroxypropyl cellulose is 1:2.795-2.895:0.18-0.28, the dissolution of the tablets is similar to that of the reference preparation, and the dissolution effect is good.

[0077] The difference between Example 1 and Comparative Example 1 is that the mass ratios of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose are different. The mass ratios of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose in Comparative Example 1 are not within the scope of the present application, and its dissolution effect is not similar to that of the reference preparation, and the dissolution effect is poor.

[0078] When using microcrystalline cellulose PH102 and UF-702, the dissolution of the tablets was similar to that of the reference preparation, and the dissolution effect was good.

[0079] Using low-substituted hydroxypropyl cellulose as a disintegrant, the dissolution rate of the tablets was similar to that of the reference preparation, and the dissolution effect was good.

[0080] Comparative Example 3 used other types of fillers instead of microcrystalline cellulose, and its dissolution effect was not similar to that of the reference preparation.

[0081] Comparative Example 4 used other types of disintegrants instead of low-substituted hydroxypropyl cellulose, and its dissolution effect was not similar to that of the reference preparation.

[0082] Carbamazepine is a BCSⅡ drug. The dissolution rates of Comparative Examples 3 and 4 are faster than that of the reference preparation, which will cause their Cmax to be higher than that of the reference preparation, making it difficult to achieve bioequivalence in vivo.

[0083] Comparative Example 5 uses a carbamazepine API with a large particle size, and its dissolution effect is not similar to that of the reference preparation, and the overall dissolution rate is slow, which will also make it difficult for the self-developed preparation to pass the bioequivalence test.

[0084] 3. Content uniformity test

[0085] The content uniformity of the self-made formulation was tested, and the results are shown in Table 5.

[0086] Table 5 Content uniformity of Examples 1, 3, and Comparative Examples 1-5

[0087] batch number Example 1 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 A+2.2S 7.6 9.7 10.1 24.1 19.2 10.7 11.3

[0088] A+2.2S<15.0 means the content uniformity is qualified.

[0089] Comparative Example 2 uses microcrystalline cellulose PH200, and its A+2.2S is 24.1, which is greater than 15, and the content uniformity is unqualified; Comparative Example 3 uses mannitol 100SD as the filler instead of microcrystalline cellulose, and its A+2.2S is 19.2, which is greater than 15, and the content uniformity is unqualified.

[0090] The present invention is described in detail above. The present invention uses specific examples to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the present invention and its core ideas. It should be pointed out that for ordinary technicians in this technical field, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A carbamazepine pharmaceutical composition, characterized in that: Includes carbamazepine, fillers, binders, disintegrants and lubricants; The filler includes microcrystalline cellulose; The disintegrant comprises low-substituted hydroxypropyl cellulose; The mass ratio of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose is: 1: 2.795-2.895: 0.18-0.

28.

2. The carbamazepine pharmaceutical composition according to claim 1, characterized in that The carbamazepine is carbamazepine or a pharmaceutically acceptable salt thereof; The particle size of the carbamazepine is 50-80 μm.

3. The carbamazepine pharmaceutical composition according to claim 2, characterized in that Calculated by percentage, the composition comprises 18-30% of carbamazepine, 50-77% of microcrystalline cellulose, 2-8% of a binder, 2-10% of a low-substituted hydroxypropyl cellulose and 0.1-2% of a lubricant.

4. The carbamazepine pharmaceutical composition according to claim 1, characterized in that The filler also includes corn starch; The type of the microcrystalline cellulose is at least one of PH102 and UF-702.

5. The carbamazepine pharmaceutical composition according to claim 4, characterized in that: In terms of percentage, the composition comprises 18-22% of carbamazepine, 10-25% of corn starch, 50-67% of microcrystalline cellulose, 2-4% of a binder, 2-6% of a low-substituted hydroxypropyl cellulose and 0.1-1% of a lubricant.

6. The carbamazepine pharmaceutical composition according to any one of claims 1 to 5, characterized in that The binder is at least one of hydroxypropyl cellulose, copovidone, hydroxypropyl cellulose, hydroxyethyl cellulose, polymethacrylate and pregelatinized starch; The lubricant is at least one of magnesium stearate, talc, calcium stearate, sodium stearate, stearic acid, adipic acid, sodium stearyl fumarate, glyceryl sodium behenate and glyceryl fumarate.

7. A method for preparing the carbamazepine pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1. Mix carbamazepine, corn starch, binder and low-substituted hydroxypropyl cellulose evenly; S2, uniformly mixing the mixed material obtained in step S1 with microcrystalline fibers of equal mass; S3, uniformly mixing the mixture obtained in step S2 with the remaining microcrystalline fibers; S4, mixing the mixture obtained in step S3 and magnesium stearate uniformly, and tableting; The carbamazepine needs to pass through a 150-200 mesh sieve.

8. Use of the carbamazepine pharmaceutical composition according to any one of claims 1 to 6 or the carbamazepine pharmaceutical composition prepared by the preparation method according to claim 7 in the preparation of carbamazepine microtablets; The carbamazepine micro-tablet has a tablet weight of 20-30 mg and a diameter of 2-3 mm.

9. A carbamazepine microtablet, characterized in that: A carbamazepine pharmaceutical composition comprising any one of claims 1 to 6 or a carbamazepine pharmaceutical composition prepared by the preparation method of claim 7; The carbamazepine micro-tablet has a tablet weight of 20-30 mg and a diameter of 2-3 mm.

10. Application of microcrystalline cellulose and low-substituted hydroxypropyl cellulose in improving the content uniformity and dissolution rate of carbamazepine microtablets; The type of microcrystalline cellulose is at least one of PH102 and UF-702; The carbamazepine microtablet has a tablet weight of 20-30 mg and a diameter of 2-3 mm; The mass ratio of carbamazepine, microcrystalline cellulose and low-substituted hydroxypropyl cellulose in the carbamazepine micro-tablet is 1:2.795-2.895:0.18-0.28.

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