Entacapone and didopa compound tablet and preparation method thereof
By using a dry granulation process and specific stabilizers, the problems of uniformity and stability in the production of entacapone and dopamine compound tablets were solved, achieving efficient and stable preparation of entacapone and dopamine compound tablets, simplifying the production process and improving product quality.
Patent Information
- Application Number
- CN202511132641.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-13
- Publication Date
- 2025-11-04
AI Technical Summary
The existing production process for entacapone and carbidopa compound tablets is difficult to match with a suitable production line. The carbidopa powder has poor uniformity, resulting in substandard product quality. Furthermore, wet granulation is prone to sticking and poor stability.
A dry granulation process is adopted, in which composite powder is obtained by spray drying. Combined with specific stabilizers and lubricants, the raw material ratio and process parameters are optimized to ensure the uniformity and stability of the finished product and improve its disintegration performance.
This technology enables high-quality production of entacapone and dopamine compound tablets, solves the sticking and bubbling problem in wet granulation, improves stability and dissolution, simplifies the production process, reduces costs, and extends product shelf life.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a compound tablet of entacapone and benserazide and a preparation method thereof. BACKGROUND
[0002] Compound levodopa is the most effective drug for treating Parkinson's disease, but as the disease progresses and the drug treatment time is prolonged, after 3 to 5 years of treatment with compound levodopa, most patients will have some complications such as adverse reactions of symptom fluctuation, movement disorder and muscle strength disorder, which is referred to as "Wearing off" phenomenon. Entacapone is a selective inhibitor of catechol-O-methyltransferase (COMT). Entacapone itself does not have an anti-parkinsonian effect and cannot pass through the blood-brain barrier, but when taken with levodopa and carbidopa compound preparation, entacapone can increase the bioavailability of the drug by preventing the conversion of levodopa to 3-O-methyl dopa (3-OMD), and prolong the plasma half-life without affecting the peak plasma concentration, thereby extending the action time of levodopa.
[0003] The entacapone and benserazide compound tablet contains three active ingredients of entacapone, levodopa and carbidopa, wherein carbidopa is in the form of monohydrate. The original research company of the entacapone and benserazide compound tablet is Orion Corporation in Finland, and the original research preparation prescription can be obtained through the product specification, and the prescriptions of products in different countries are the same. The original research patent and its homologous patents relate to an oral solid fixed-dose composition, which contains a pharmacologically effective amount of entacapone, levodopa and carbidopa or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient; the production process of the original research product (200mg / 100mg / 25mg specification) is wet granulation, and the granulation process is separated, entacapone is wet granulated with levodopa, carbidopa is wet granulated alone, and the granules are mixed together in a certain proportion.
[0004] The original research patent adopts a separate granulation process, which is difficult to match suitable production lines and production equipment with suitable production capacity. In addition, the carbidopa powder is very fine, and when mixed with uniform entacapone and levodopa granules, the content uniformity of carbidopa is prone to be unqualified, which cannot guarantee the product quality. In view of this, the present application aims to develop an entacapone and benserazide compound tablet generic drug and a simple and continuous preparation method by referring to the original research product. SUMMARY
[0005] In order to solve the above problems, the present application provides a kind of entacapone double dopa compound tablet and its preparation method, by the screening and design of raw materials, the dissolution of the original research product is similar, and the bioequivalence is equivalent, and the friability of entacapone double dopa compound tablet is good, not easy to stick, and the stability is excellent.
[0006] To solve the above technical problems, the technical scheme provided by the present application is: In the first aspect, the present application provides a kind of entacapone double dopa compound tablet, including the following mass fraction of raw materials: entacapone 200 parts, levodopa 90 parts~110 parts, carbidopa 22 parts~28 parts, mannitol 110 parts~130 parts, disintegrating diluent 150 parts~170 parts, disintegrant 25 parts~30 parts, stabilizer 0.5 parts~1.5 parts and lubricant 13 parts~17 parts; The stabilizer includes citric acid and succinic acid; the lubricant includes first lubricant and second lubricant.
[0007] Compared with the prior art, the entacapone double dopa compound tablet provided by the present application can adjust the pH value of the microenvironment with a specific stabilizer to stabilize the main drug, enhance its antioxidant effect, and improve the disintegration performance. The oxidation rate of levodopa and carbidopa is significantly reduced under acidic conditions (pH=3~5), the stabilizer is weakly acidic, and appropriate addition can reduce the pH value of the material, maintain the acidity of the material microenvironment, inhibit oxidative degradation, and enhance the stability. In addition, the specific stabilizer has low hygroscopicity and has no adverse effect on dry granulation, and appropriate addition can also improve the disintegration performance of the active ingredients.
[0008] The present application has carried out long-term and large-scale research on entacapone double dopa compound tablet, and has strictly screened existing excipients, and has prepared entacapone double dopa compound tablet with excellent tablet core quality and excellent stability. The present application uses mannitol as a water-soluble diluent, which has good compressibility, so that the dissolution of the active ingredients is equivalent to that of the original research product.
[0009] Preferably, the entacapone double dopa compound tablet includes the following mass fraction of raw materials: entacapone 200 parts, levodopa 98 parts~102 parts, carbidopa 24 parts~26 parts, mannitol 115 parts~125 parts, disintegrating diluent 155 parts~165 parts, disintegrant 25 parts~30 parts, stabilizer 0.8 parts~1.2 parts and lubricant 14.5 parts~15.5 parts.
[0010] Preferably, the particle size of the entacapone is D90<10 μm, the particle size of the levodopa is D90<150 μm, and the particle size of the carbidopa is D90<150 μm.
[0011] Further preferably, the particle size of the entacapone is D90=9 μm~9.8 μm, the particle size of the levodopa is D90=120 μm~140 μm, and the particle size of the carbidopa is D90=120 μm~140 μm.
[0012] Preferably, the disintegrating diluent comprises microcrystalline cellulose or corn starch.
[0013] Preferably, the disintegrant comprises at least one of crospovidone, sodium carboxymethyl starch or croscarmellose sodium.
[0014] The disintegrant used in the present application has strong disintegrating property, the crospovidone (PVPP) has strong swelling property and is not affected by pH, can quickly promote tablet disintegration, and has good compatibility with the main drug. The sodium carboxymethyl starch (CMS-Na) has high water absorption and expansion rate, and fast disintegration speed, and is suitable for the rapid release of the dopa component. The croscarmellose sodium (CCMC-Na) has stable swelling capacity and good dispersibility in gastrointestinal fluid, can ensure the synchronous release of the entacapone and the dopa, improve the bioavailability, and all of them are inert excipients and do not interfere with the efficacy of the main drug.
[0015] Preferably, the mass ratio of citric acid to succinic acid in the stabilizer is 1:(3~6).
[0016] The present application further improves the stability of the tablet by limiting the amount of citric acid and succinic acid.
[0017] Preferably, the first lubricant is sodium stearyl fumarate, and the second lubricant is magnesium stearate.
[0018] Preferably, the lubricant comprises 4~6 parts of sodium stearyl fumarate and 9~11 parts of magnesium stearate. Further preferably, the lubricant comprises 5~5.5 parts of sodium stearyl fumarate and 9.5~10 parts of magnesium stearate.
[0019] The present application uses sodium stearyl fumarate and magnesium stearate as a lubricant to improve the success rate of dry granulation.
[0020] For example, the magnesium stearate needs to be sieved through a 50~70 mesh sieve before use.
[0021] Preferably, the hardness of the entacapone and dopa compound tablet is 65N~105N. Further preferably, the hardness of the entacapone and dopa compound tablet is 80N~100N.
[0022] In a second aspect, the present application provides a preparation method of the entacapone and dopa compound tablet, comprising the following steps: S100, mixing and homogenizing the disintegrating diluent and the disintegrant, and then performing spray drying to obtain a composite powder; S200: Mix entacapone, levodopa, carbidopa and mannitol, add the composite powder, stabilizer and first lubricant, and perform dry granulation, crushing and granulation to obtain entacapone bis-dopa granules. S300: Mix the entacapone bidopa granules and the second lubricant, compress into tablets, and obtain entacapone bidopa compound tablets.
[0023] Levodopa and carbidopa are unstable when exposed to moisture. Due to the mismatch of the physical properties of the active ingredients (such as poor flowability, hygroscopicity, and uneven mixing), the high sensitivity of the dry granulation process to material characteristics (such as granulation parameters and particle quality), and the limitations of excipient selection and stability, it is quite difficult to use the dry granulation and tableting process for entacapone and carbidopa compound tablets. This is also an important reason why most of the tablet formulations currently use wet granulation.
[0024] The method for preparing entacapone and dopamine compound tablets provided by this invention involves first spray-drying a disintegrant diluent and a disintegrant to obtain a composite powder, which is then mixed with other raw materials. Compared to adding them separately, this method concentrates the advantages of the disintegrant diluent and the disintegrant, significantly improving the material's hygroscopicity, flowability, compressibility, and disintegration properties. The introduction of a stabilizer in conjunction with the composite powder increases the success rate of dry granulation and further enhances the quality of the entacapone and dopamine compound tablets.
[0025] Preferably, in S100, the inlet air temperature of the spray dryer is 160℃~180℃, the outlet air temperature is 60℃~80℃, the atomization pressure is 0.2MPa~0.4MPa, and the feed rate is 15mL / min~20mL / min.
[0026] For example, in S200, when mixing entacapone, levodopa, carbidopa and mannitol, the stirring speed is 10 rpm to 15 rpm and the mixing time is 12 min to 18 min.
[0027] For example, in S200, composite powder, stabilizer and first lubricant are added, mixed at 10 rpm to 15 rpm for 12 min to 18 min, passed through a 30 mesh sieve, and then dry granulated.
[0028] Preferably, in S200, during the dry granulation process, the feeding speed is 25 rpm to 50 rpm, the roller speed is 8 rpm to 12 rpm, the roller hydraulic pressure is 40 bar to 50 bar, the roller gap is 0.5 mm to 1.5 mm, the crushing speed is 80 rpm to 150 rpm, and the granulation speed is 80 rpm to 150 rpm.
[0029] In a further preferred embodiment, in S200, during the dry granulation process, the feeding speed is 35 rpm to 40 rpm, the roller speed is 9 rpm to 11 rpm, the roller hydraulic pressure is 44 bar to 46 bar, the roller gap is 0.8 mm to 1.2 mm, the crushing speed is 90 rpm to 110 rpm, and the granulation speed is 90 rpm to 110 rpm.
[0030] This invention overcomes the difficulties in preparing entacapone and dopamine compound tablets using dry granulation and tableting technology by precisely controlling the relevant parameters of dry granulation, and successfully produces entacapone and dopamine compound tablets with excellent comprehensive performance.
[0031] For example, in S200, the pulverization is carried out by sieving with a sieve aperture size of 2.0 mm.
[0032] For example, in S200, the granulation is carried out by sieving with a sieve aperture size of 1.0 mm.
[0033] Preferably, in S200, the particle size of the entacapone didopa particles is 20 mesh to 80 mesh.
[0034] In this invention, the particle size of entacapone bis-dopa granules can be determined by passing them through a 20-mesh sieve and an 80-mesh sieve, respectively. Fine powder smaller than 80 mesh is repeatedly dry-granulated until the amount of fine powder is insufficient for further granulation.
[0035] For example, in S300, mixing entacapone bis-dopa particles and a second lubricant includes the following steps: Add entacapone and dopamine granules to the mixing hopper and stir at 10-15 rpm for 8-12 minutes. Then add the second lubricant and continue stirring for 4-6 minutes.
[0036] For example, in S300, after tablet compression, the process further includes atomized film coating. The present invention allows for the selection of whether or not to perform atomized film coating as needed; the present invention does not have special requirements for the conditions of atomized film coating, and conventional operations in the art can be used.
[0037] The present invention has the following beneficial effects: This invention utilizes dry granulation and tableting technology to prepare entacapone and dopamine compound tablets. Compared to wet granulation, this method is simpler and solves the problem of tablet sticking and shattering caused by the introduction of moisture during wet granulation. It also addresses the issues of easy sticking, poor brittleness, and instability in generic entacapone and dopamine compound tablets. The dry granulation and tableting technology is simple to implement, significantly shortens the production cycle, does not involve organic solvents, has low energy consumption, is safe and environmentally friendly, and avoids high-temperature treatment steps, preventing drug degradation due to moisture and heat. It also avoids the introduction of other exogenous components, allowing for a single-stage process. The resulting product has more stable active ingredients, improving drug safety and prolonging efficacy.
[0038] This invention overcomes the difficulties in preparing entacapone and dopamine compound tablets using dry granulation and tableting technology by optimizing the prescription and precisely controlling the process parameters. It shortens the process flow, realizes continuous production, reduces production costs, and the dissolution rate, bioequivalence, accelerated testing, and long-term testing of the prepared entacapone and dopamine compound tablets are comparable to the original drug. The stability effect is even better than the original drug, and the product's shelf life is extended. Detailed Implementation
[0039] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0040] In this embodiment of the invention, mannitol 100SD was selected from Roquette Freres; microcrystalline cellulose PH101 was selected from DuPont Nutrition USA, Inc.; and croscarmellose sodium was selected from croscarmellose sodium SD711, purchased from DuPont. All other materials not specifically mentioned are commercially available products.
[0041] Example 1 This embodiment provides an entacapone and levodopa compound tablet (10,000 tablets), which is composed of the following raw materials in parts by weight: 2000g entacapone, 1000g levodopa, 250g carbidopa, 1220g mannitol, 1600g microcrystalline cellulose, 260g disintegrant (sodium croscarmellose), 10g stabilizer, 52g sodium stearate fumarate, and 98g magnesium stearate.
[0042] The particle size of entacapone is D90 = 9.5 μm, that of levodopa is D90 = 130 μm, and that of carbidopa is D90 = 130 μm. The stabilizer consists of citric acid and succinic acid in a mass ratio of 1:5. Magnesium stearate is passed through a 60-mesh sieve.
[0043] The preparation method of the above-mentioned entacapone and dopamine compound tablets includes the following steps: S100. Microcrystalline cellulose, disintegrant and appropriate amount of water are added to a high-speed homogenizer and mixed and homogenized. Then, spray drying is carried out (inlet air temperature is 170℃, outlet air temperature is 70℃, atomization pressure is 0.3MPa, and feed rate is 18mL / min) to obtain composite powder.
[0044] S200: Add entacapone, levodopa, carbidopa, and mannitol to the mixing hopper and mix at 12 rpm for 15 minutes. Then add the compound powder, stabilizer, and sodium stearate fumarate and mix at 12 rpm for 15 minutes. After passing through a 30-mesh sieve, put it into a dry granulator for dry granulation. The screw feed speed of the dry granulator is 40 rpm, the pressure roller speed is 10 rpm, the pressure roller oil pressure is 45 bar, the pressure roller gap is 1.0 mm, the crushing speed is 100 rpm, and the granulation speed is 100 rpm. After crushing (passing through a 2.0 mm sieve) and granulating (passing through a 1.0 mm sieve), it is sieved through a 20-mesh and an 80-mesh vibrating sieve in sequence to obtain entacapone and levodopa granules.
[0045] S300: Add entacapone bidopa granules to the mixing hopper, stir at 12 rpm for 10 minutes, add magnesium stearate and continue stirring for 5 minutes, then add to the hopper of a high-speed rotary tablet press, turn on the tablet press and press into smooth tablets to obtain entacapone bidopa compound tablets with a hardness of 90N.
[0046] Example 2 This embodiment provides an entacapone and levodopa compound tablet (10,000 tablets), which is composed of the following raw materials in parts by weight: 2000g entacapone, 1000g levodopa, 250g carbidopa, 1185g mannitol, 1600g microcrystalline cellulose, 295g disintegrant (sodium carboxymethyl starch), 10g stabilizer, 52g sodium stearate fumarate, and 98g magnesium stearate.
[0047] The particle size of entacapone is D90=9.2μm, that of levodopa is D90=135μm, and that of carbidopa is D90=135μm. The stabilizer consists of citric acid and succinic acid in a mass ratio of 1:4. Magnesium stearate is passed through a 60-mesh sieve.
[0048] The preparation method of the above-mentioned entacapone and dopamine compound tablets includes the following steps: S100. Microcrystalline cellulose, disintegrant and appropriate amount of water are added to a high-speed homogenizer and mixed and homogenized. Then, spray drying is carried out (inlet air temperature is 170℃, outlet air temperature is 70℃, atomization pressure is 0.3MPa, and feed rate is 17mL / min) to obtain composite powder.
[0049] S200: Entacapone, L-DOPA, Carbidopa, and Mannitol are added to the mixing hopper and mixed at 13 rpm for 14 minutes. Then, compound powder, stabilizer, and sodium stearate fumarate are added and mixed at 13 rpm for 14 minutes. After passing through a 30-mesh sieve, the mixture is placed into a dry granulator for dry granulation. The screw feed speed of the dry granulator is 35 rpm, the pressure roller speed is 9 rpm, the pressure roller oil pressure is 46 bar, the pressure roller gap is 0.9 mm, the crushing speed is 90 rpm, and the granulation speed is 90 rpm. After crushing (passing through a 2.0 mm sieve) and granulating (passing through a 1.0 mm sieve), the mixture is sieved through 20-mesh and 80-mesh vibrating sieves to obtain entacapone and L-DOPA granules.
[0050] S300. Add entacapone and dopamine granules to the mixing hopper, stir at 13 rpm for 10 minutes, add magnesium stearate and continue stirring for 5 minutes, then add to the hopper of a high-speed rotary tablet press, turn on the tablet press and press into smooth tablets to obtain entacapone and dopamine compound tablets with a hardness of 85N.
[0051] Example 3 This embodiment provides an entacapone and levodopa compound tablet (10,000 tablets), which is composed of the following raw materials in parts by weight: 2000g entacapone, 1020g levodopa, 240g carbidopa, 1250g mannitol, 1550g microcrystalline cellulose, 300g disintegrant (crospovidone), 8g stabilizer, 55g sodium stearate fumarate, and 95g magnesium stearate.
[0052] The particle size of entacapone is D90 = 9 μm, that of levodopa is D90 = 140 μm, and that of carbidopa is D90 = 120 μm. The stabilizer consists of citric acid and succinic acid in a mass ratio of 1:6. Magnesium stearate is passed through a 50-mesh sieve.
[0053] The preparation method of the above-mentioned entacapone and dopamine compound tablets includes the following steps: S100. Microcrystalline cellulose, disintegrant and appropriate amount of water are added to a high-speed homogenizer and mixed and homogenized. Then, spray drying is carried out (inlet air temperature is 160℃, outlet air temperature is 60℃, atomization pressure is 0.2MPa, and feed rate is 15mL / min) to obtain composite powder.
[0054] S200: Entacapone, L-DOPA, Carbidopa, and Mannitol are added to the mixing hopper and mixed at 10 rpm for 18 minutes. Then, compound powder, stabilizer, and sodium stearate fumarate are added and mixed at 10 rpm for 18 minutes. After passing through a 30-mesh sieve, the mixture is placed into a dry granulator for dry granulation. The screw feed speed of the dry granulator is 30 rpm, the pressure roller speed is 11 rpm, the pressure roller oil pressure is 44 bar, the pressure roller gap is 1.2 mm, the crushing speed is 110 rpm, and the granulation speed is 110 rpm. After crushing (passing through a 2.0 mm sieve) and granulating (passing through a 1.0 mm sieve), the mixture is sieved through 30-mesh and 70-mesh vibrating sieves to obtain entacapone and L-DOPA granules.
[0055] S300. Add entacapone and dopamine granules to the mixing hopper, stir at 10 rpm for 12 minutes, add magnesium stearate and continue stirring for 4 minutes, then add to the hopper of a high-speed rotary tablet press, turn on the tablet press and press into smooth tablets to obtain entacapone and dopamine compound tablets with a hardness of 73N.
[0056] Example 4 This embodiment provides an entacapone and levodopa compound tablet (10,000 tablets), which is composed of the following raw materials in parts by weight: 2000g entacapone, 980g levodopa, 260g carbidopa, 1150g mannitol, 1650g microcrystalline cellulose, 250g disintegrant (sodium croscarmellose), 12g stabilizer, 50g sodium stearate fumarate, and 100g magnesium stearate.
[0057] The particle size of entacapone is D90 = 9.8 μm, that of levodopa is D90 = 120 μm, and that of carbidopa is D90 = 140 μm. The stabilizer consists of citric acid and succinic acid in a mass ratio of 1:3. Magnesium stearate is passed through a 70-mesh sieve.
[0058] The preparation method of the above-mentioned entacapone and dopamine compound tablets includes the following steps: S100. Microcrystalline cellulose, disintegrant and appropriate amount of water are added to a high-speed homogenizer and mixed and homogenized. Then, spray drying is carried out (inlet air temperature is 180℃, outlet air temperature is 80℃, atomization pressure is 0.4MPa, and feed rate is 20mL / min) to obtain composite powder.
[0059] S200: Add entacapone, levodopa, carbidopa, and mannitol to the mixing hopper and mix at 15 rpm for 12 minutes. Then add the compound powder, stabilizer, and sodium stearate fumarate and mix at 15 rpm for 12 minutes. After passing through a 30-mesh sieve, put it into a dry granulator for dry granulation. The screw feed speed of the dry granulator is 45 rpm, the pressure roller speed is 12 rpm, the pressure roller oil pressure is 48 bar, the pressure roller gap is 0.7 mm, the crushing speed is 120 rpm, and the granulation speed is 120 rpm. After crushing (passing through a 2.0 mm sieve) and granulating (passing through a 1.0 mm sieve), it is sieved through a 30-mesh and a 70-mesh vibrating sieve in sequence to obtain entacapone and levodopa granules.
[0060] S300. Add entacapone and dopamine granules to the mixing hopper, stir at 15 rpm for 8 minutes, add magnesium stearate and continue stirring for 6 minutes, then add to the hopper of a high-speed rotary tablet press, turn on the tablet press and press into smooth tablets to obtain entacapone and dopamine compound tablets with a hardness of 105N.
[0061] Example 5 This embodiment provides an entacapone and dopamine compound tablet, whose raw materials and proportions are similar to those in Example 1, except that the mass ratio of citric acid and succinic acid in the stabilizer is replaced with 1:8. The remaining components and contents are the same as in Example 1 and will not be described again.
[0062] The preparation method of the above-mentioned entacapone and dopamine compound tablets is the same as that in Example 1, and will not be repeated here.
[0063] Example 6 This embodiment provides an entacapone and dopamine compound tablet, whose raw materials and proportions are similar to those in Example 1, except that microcrystalline cellulose is replaced with an equal mass of corn starch. The remaining components and contents are the same as in Example 1 and will not be repeated.
[0064] The preparation method of the above entacapone and dopamine compound tablets is similar to that of Example 1, except that in S100, microcrystalline cellulose is replaced with corn starch, which will not be described in detail here.
[0065] Example 7 This embodiment provides an entacapone / dopa compound tablet, whose raw materials and proportions are similar to those in Example 1. The only difference is that the parameters of the dry granulator are set as follows: screw feed speed of 20 rpm, pressure roller speed of 8 rpm, pressure roller hydraulic pressure of 30 bar, pressure roller gap of 0.5 mm, crushing speed of 50 rpm, and granulation speed of 50 rpm. The remaining components and contents are the same as in Example 1 and will not be repeated.
[0066] The preparation method of the above-mentioned entacapone and dopamine compound tablets is the same as that in Example 1, and will not be repeated here.
[0067] Comparative Example 1 This comparative example provides an entacapone and dopamine combination tablet, whose raw materials and proportions are similar to those in Example 1, except that it does not contain a stabilizer. The remaining components and their contents are the same as in Example 1 and will not be described again.
[0068] The preparation method of the above entacapone and dopamine compound tablets is similar to that of Example 1, except that the stabilizer is omitted in S200, which will not be described in detail here.
[0069] Comparative Example 2 This comparative example provides an entacapone and dopamine compound tablet, whose raw materials and proportions are similar to those in Example 1, except that citric acid in the stabilizer is replaced with an equal mass of succinic acid, i.e., the stabilizer consists only of succinic acid. The remaining components and contents are the same as in Example 1 and will not be described again.
[0070] The preparation method of the above-mentioned entacapone and dopamine compound tablets is the same as that in Example 1, and will not be repeated here.
[0071] Comparative Example 3 This comparative example provides an entacapone and dopamine compound tablet, whose raw materials and proportions are similar to those in Example 1, except that citric acid in the stabilizer is replaced with an equal mass of fumaric acid. The remaining components and contents are the same as in Example 1 and will not be repeated.
[0072] The preparation method of the above-mentioned entacapone and dopamine compound tablets is the same as that in Example 1, and will not be repeated here.
[0073] Comparative Example 4 This comparative example provides an entacapone and dopamine compound tablet, whose raw materials and proportions are similar to those in Example 1, except that succinic acid in the stabilizer is replaced with an equal mass of tartaric acid. The remaining components and contents are the same as in Example 1 and will not be described again.
[0074] The preparation method of the above-mentioned entacapone and dopamine compound tablets is the same as that in Example 1, and will not be repeated here.
[0075] Comparative Example 5 This comparative example provides an entacapone and dopamine compound tablet, whose raw materials and proportions are similar to those in Example 1, except that the amount of stabilizer is replaced with 20g. The remaining components and contents are the same as in Example 1 and will not be described again.
[0076] The preparation method of the above-mentioned entacapone and dopamine compound tablets is the same as that in Example 1, and will not be repeated here.
[0077] Comparative Example 6 This comparative example provides an entacapone / dopa compound tablet, whose raw materials and proportions are similar to those in Example 1, except that mannitol is replaced with an equal mass of polyethylene glycol 6000. The remaining components and contents are the same as in Example 1 and will not be repeated.
[0078] The preparation method of the above entacapone and dopamine compound tablets is similar to that of Example 1, except that in S200, mannitol is replaced with polyethylene glycol 6000, which will not be described in detail here.
[0079] Comparative Example 7 This comparative example provides a method for preparing entacapone and dopamine compound tablets. The raw materials and proportions of the entacapone and dopamine compound tablets are the same as in Example 1, and will not be repeated here. The preparation method is similar to that of Example 1, except that the microcrystalline cellulose and disintegrant are not spray-dried (they are directly mixed with other raw materials). Specifically, the preparation method includes the following: S100: Add entacapone, levodopa, carbidopa, and mannitol to the mixing hopper and mix at 12 rpm for 15 minutes. Then add microcrystalline cellulose, disintegrant, stabilizer, and sodium stearate fumarate and mix at 12 rpm for 15 minutes. After passing through a 30-mesh sieve, put it into a dry granulator for dry granulation. The screw feed speed of the dry granulator is 40 rpm, the pressure roller speed is 10 rpm, the pressure roller hydraulic pressure is 45 bar, the pressure roller gap is 1.0 mm, the crushing speed is 100 rpm, and the granulation speed is 100 rpm. After crushing (passing through a 2.0 mm sieve) and granulating (passing through a 1.0 mm sieve), it is sieved through a 20-mesh and an 80-mesh vibrating sieve in sequence to obtain entacapone and levodopa granules.
[0080] S200 is the same as S300 in Example 1, and will not be described again.
[0081] Verification test According to the FDA dissolution method, the dissolution of active ingredients in the entacapone and dopamine compound tablets of Examples 1-7 and Comparative Examples 1-7, as well as the original drug (purchased from Orion Corporation, batch number 2045371) was tested. The test results are shown in Tables 1-3.
[0082] Entacapone dissolution: The cumulative dissolution of each tablet was determined by the basket method at 125 rpm and 900 mL of phosphate medium at pH 5.5 using UV chromatography. Sampling points: 5 min, 10 min, 20 min, 30 min, 45 min, and 60 min.
[0083] L-DOPA and Carbidopa dissolution: Cumulative dissolution of each tablet was determined by HPLC using the basket method at 50 rpm and 750 mL of 0.1 N hydrochloric acid medium. Sampling points: 5 min, 10 min, 20 min, 30 min, 45 min, and 60 min.
[0084] Table 1. Dissolution test results of entacapone in entacapone and dopamine combination tablets (unit: %)
[0085] Table 2. Dissolution test results of levodopa in entacapone / dopa combination tablets (unit: %)
[0086] Table 3. Dissolution test results of carbidopa in entacapone / dopa combination tablets (unit: %)
[0087] According to the Chinese Pharmacopoeia 2020, Volume IV and the Technical Guidelines for the Study of Impurities in Chemical Drugs, the entacapone and dopamine compound tablets of Examples 1-7 and Comparative Examples 1-7, as well as the original drug (purchased from Orion Corporation, batch number 2045371) were subjected to stability tests. They were placed continuously for 6 months at 40℃±2℃ and RH=75%±5%. The test results are shown in Table 4.
[0088] Table 4. Stability test results of entacapone and dopamine combination tablets (unit: %)
[0089] Bioequivalence pre-experiments were conducted on the entacapone and dopamine compound tablets of Examples 1-7 and the original drug (batch number 2045371) in terms of pharmacokinetic parameters, and the test results showed that they were equivalent.
[0090] The test results above show that the composition and dosage of stabilizers have a significant impact on the dissolution and stability of tablets. Fumaric acid is highly hygroscopic, which can easily lead to material clumping and adhesion to equipment during dry granulation, and may also promote the hydrolysis of the active pharmaceutical ingredient (especially when in contact with the catechol structure of entacapone) or oxidation. Tartaric acid can accelerate tablet disintegration, increase the release rate of levodopa, and thus increase gastrointestinal side effects. Excessive stabilizers can lead to excessive local acidity in the tablets, which may irritate the gastrointestinal tract and may neutralize with the weakly alkaline carbidopa, affecting its bioavailability. Excessive stabilizers can also lower the pH value of the material's microenvironment, causing entacapone (containing catechol groups) to hydrolyze more rapidly in an acidic environment, especially during long-term storage, which can easily produce degradation impurities.
[0091] Compared to mannitol, polyethylene glycol (PEG) has a solubilizing effect on levodopa and carbidopa, but its solubilizing effect on entacapone is not significant (entacapone is greatly affected by the particle size of its raw materials). As a disintegrant diluent, the overall performance of tablets made from corn starch by spray drying is slightly lower than that of microcrystalline cellulose. Compared to adding disintegrant diluents and disintegrants alone, tablets made by spray drying followed by mixing in the disintegrant diluents and disintegrants can fully utilize the synergistic effect of the disintegrant diluents and disintegrants, and can significantly improve the hygroscopicity, flowability, compressibility, and disintegration properties of the material.
[0092] This invention overcomes the difficulties in preparing entacapone and dopamine compound tablets using dry granulation and tableting technology by precisely controlling process parameters. The entacapone and dopamine particles have good uniformity and excellent lubrication effect, and no sticking or punching phenomenon was found during tableting.
[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. An entacapone / dopa compound tablet, characterized in that, The raw materials include the following parts by weight: 200 parts entacapone, 90-110 parts levodopa, 22-28 parts carbidopa, 110-130 parts mannitol, 150-170 parts disintegrant diluent, 25-30 parts disintegrant, 0.5-1.5 parts stabilizer, and 13-17 parts lubricant; The stabilizer includes citric acid and succinic acid; the lubricant includes a first lubricant and a second lubricant.
2. The entacapone / dopa compound tablet as described in claim 1, characterized in that, The entacapone and levodopa compound tablets comprise the following raw materials in parts by weight: 200 parts entacapone, 98-102 parts levodopa, 24-26 parts carbidopa, 115-125 parts mannitol, 155-165 parts disintegrant diluent, 25-30 parts disintegrant, 0.8-1.2 parts stabilizer, and 14.5-15.5 parts lubricant.
3. The entacapone / dopa compound tablet as described in claim 1 or 2, characterized in that, The particle size of the entacapone is D90 < 10 μm, the particle size of the levodopa is D90 < 150 μm, and the particle size of the carbidopa is D90 < 150 μm.
4. The entacapone / dopa compound tablet as described in claim 1 or 2, characterized in that, The disintegrating diluent includes microcrystalline cellulose or corn starch; The disintegrant includes at least one of crospovidone, sodium carboxymethyl starch, or sodium crospovidone carboxymethyl cellulose. The first lubricant is sodium stearate, and the second lubricant is magnesium stearate; the lubricant comprises 4 to 6 parts of sodium stearate and 9 to 11 parts of magnesium stearate.
5. The entacapone / dopa compound tablet as described in claim 1 or 2, characterized in that, The mass ratio of citric acid to succinic acid in the stabilizer is 1:(3~6).
6. The entacapone / dopa compound tablet as described in claim 1 or 2, characterized in that, The hardness of the entacapone-dopa compound tablets is 65N~105N.
7. The method for preparing entacapone and dopamine compound tablets according to any one of claims 1 to 6, characterized in that, Includes the following steps: S100. After homogenizing the disintegrant diluent and the disintegrant, spray dry to obtain the composite powder. S200: Mix entacapone, levodopa, carbidopa and mannitol, add the composite powder, stabilizer and first lubricant, and perform dry granulation, crushing and granulation to obtain entacapone bis-dopa granules. S300: Mix the entacapone bidopa granules and the second lubricant, compress into tablets, and obtain entacapone bidopa compound tablets.
8. The preparation method of entacapone and dopamine compound tablets as described in claim 7, characterized in that, In S100, the inlet air temperature of the spray dryer is 160℃~180℃, the outlet air temperature is 60℃~80℃, the atomization pressure is 0.2MPa~0.4MPa, and the feed rate is 15mL / min~20mL / min.
9. The preparation method of entacapone and dopamine compound tablets as described in claim 7, characterized in that, In S200, during the dry granulation process, the feeding speed is 25 rpm to 50 rpm, the roller speed is 8 rpm to 12 rpm, the roller hydraulic pressure is 40 bar to 50 bar, the roller gap is 0.5 mm to 1.5 mm, the crushing speed is 80 rpm to 150 rpm, and the granulation speed is 80 rpm to 150 rpm.
10. The preparation method of entacapone and dopamine compound tablets as described in claim 7, characterized in that, In S200, the particle size of the entacapone bis-dopa particles is 20 mesh to 80 mesh.