A levodopa and carbidopa controlled release preparation and preparation method thereof

Abstract

The present invention provides a controlled release oral solid preparation containing levodopa, carbidopa and carboxylic acid and a preparation method thereof, wherein the controlled release oral solid preparation comprises a multi-unit mini-tablet, wherein the mini-tablet comprises a controlled release portion and an immediate release coating, wherein the controlled release portion comprises carboxylic acid and a first portion of levodopa and carbidopa, and the immediate release coating comprises a second portion of levodopa and carbidopa.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and more specifically to a controlled release oral solid preparation comprising a multi-unit mini-tablet of carbidopa and levodopa, wherein the mini-tablet comprises a controlled release portion and an immediate release coating. The present invention also relates to a method for preparing the controlled release oral solid preparation comprising the multi-unit mini-tablet. Background Art

[0002] Levodopa and carbidopa are drugs used to treat Parkinson's disease and related conditions.

[0003] U.S. Patent Nos. 7094427, 8377474, 8454998, 8557283, 9089607, 9089608, 9463246, 9533046 disclose a combination of carbidopa (CD) and levodopa (LD) comprising an immediate release component and a controlled release component, and the use of a carboxylic acid (tartaric acid) in addition to carbidopa and levodopa to treat a disease in which dopamine is depleted in the patient's brain tissue. This would provide a method for reducing motor fluctuations in patients with Parkinson's disease.

[0004] Currently, formulations containing carbidopa (CD), levodopa (LD) and tartaric acid are available on the market, e.g. Capsules. The formulation contains 3 different ingredients, mixed and filled in capsules. The 3 components are (a) a controlled release component containing levodopa, carbidopa and one or more rate-controlling excipients; (b) a carboxylic acid component containing tartaric acid and one or more rate-controlling polymers; and (c) an immediate release component containing levodopa and carbidopa, wherein the carboxylic acid component of (b) is different from the immediate release component of carbidopa and levodopa and the controlled release component of carbidopa and levodopa; the carboxylic acid component is a separate part and is coated with an enteric polymer; the immediate release component (c) and the carboxylic acid component (b) include pellets or granules.

[0005] The preparation process of the capsule is complicated, and it is necessary to prepare enteric-coated pellets containing carbidopa and levodopa, enteric-coated pellets containing tartaric acid, and encapsulate the two pellets in a gelatin capsule.

[0006] Currently, there is an urgent need for an alternative preparation with a simple, controllable and low-cost preparation process. Summary of the invention

[0007] The present invention provides a novel method for preparing a controlled release pharmaceutical composition of carbidopa (CD) and levodopa (LD) using carboxylic acid (CA), wherein the carboxylic acid is not a separate component other than a controlled release component or an immediate release component, but is contained in a controlled release matrix. The immediate release component, the controlled release component and the carboxylic acid component are composed of a single component in a multi-unit mini-tablet, and the multi-unit mini-tablet is filled in a hard capsule shell.

[0008] A first aspect of the present invention provides a controlled release oral solid preparation comprising levodopa and carbidopa, wherein the controlled release oral solid preparation comprises a multi-unit mini-tablet, wherein the mini-tablet comprises a controlled release portion and an immediate release coating from the inside out, wherein the controlled release portion comprises carboxylic acid and a first portion of levodopa and carbidopa, and the immediate release coating comprises a second portion of levodopa and carbidopa.

[0009] In some preferred embodiments, the immediate release coating is coated outside the controlled release portion.

[0010] In some preferred embodiments, the controlled release portion comprises a controlled release matrix and a delayed release coating, and the carboxylic acid is located within the controlled release matrix.

[0011] In some preferred embodiments, the controlled release matrix comprises levodopa, carbidopa, carboxylic acid, a first pharmaceutically acceptable excipient and a controlled release polymer; preferably, the first pharmaceutically acceptable excipient is selected from microcrystalline cellulose (e.g., microcrystalline cellulose PH101, PH102, PH103, PH105, PH302), corn starch, mannitol and a mixture thereof; more preferably, the first pharmaceutically acceptable excipient is microcrystalline cellulose PH101 and mannitol.

[0012] In some preferred embodiments, the controlled release matrix comprises ethylcellulose, hypromellose, methylcellulose, povidone, and mixtures thereof; preferably, the controlled release matrix comprises hypromellose.

[0013] In some preferred embodiments, the delayed release coating comprises one or more of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate, talc and diethyl phthalate; preferably, the methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion are L100-55, s100, FS30D or L30D-55; More preferably, the delayed-release coating consists of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc.

[0014] In some preferred embodiments, the immediate release coating comprises levodopa, carbidopa and a second pharmaceutically acceptable excipient; preferably, the second pharmaceutically acceptable excipient is mannitol, cross-linked sodium carboxymethyl cellulose, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch and a mixture thereof; more preferably, the immediate release coating consists of levodopa, carbidopa and povidone K30.

[0015] In some preferred embodiments, the carboxylic acid is citric acid. More preferably, each unit of the controlled release oral formulation comprises 70 mg to 120 mg of citric acid.

[0016] In some preferred embodiments, the controlled release oral solid dosage form is a capsule.

[0017] In some preferred embodiments, the carboxylic acid and 75% of levodopa and carbidopa are contained in the controlled release portion, and 25% of levodopa and carbidopa are used as an immediate release coating and coated onto the controlled release portion.

[0018] In some preferred embodiments, the controlled release matrix is ​​prepared with a controlled release polymer; preferably, the controlled release polymer is hypromellose, carrageenan, ethyl cellulose, methyl cellulose or carbomer; more preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M or carrageenan Viscarin 109; more preferably, hypromellose K4M Cr is 0-16% of the weight of the controlled release matrix, or hypromellose K100M is 0-16% of the weight of the controlled release matrix or carrageenan Viscarin 109 is 0-3% of the weight of the controlled release matrix; most preferably, the controlled release polymer is hypromellose K4M Cr, which is 3-7% of the weight of the controlled release matrix.

[0019] In some preferred embodiments, the controlled release matrix further comprises a diluent, a lubricant and a binder; preferably, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol, the lubricant is magnesium stearate, and the binder is povidone.

[0020] In some preferred embodiments, the size of the controlled release matrix ranges between 2.0 mm and 5.5 mm.

[0021] The second aspect of the present invention provides a method for preparing the above-mentioned controlled release oral solid preparation, the method comprising:

[0022] a. The carboxylic acid, the diluent and the first portion of levodopa and carbidopa are sieved and mixed;

[0023] b. adding a binder solution and performing wet granulation, preferably using a high shear wet granulator for granulation;

[0024] c. Drying the obtained granules and refining them;

[0025] d. The controlled release polymer and lubricant are sieved, mixed with the dried and sized granules, and tableted to obtain a controlled release matrix;

[0026] e. preparing a delayed-release coating solution, coating the delayed-release coating on the controlled-release matrix, and aging;

[0027] f. preparing an immediate release coating solution and coating the delayed release coating core tablets; and

[0028] g. Put the coated tablets into the capsule shell.

[0029] In some preferred embodiments, the controlled release matrix contains 75% levodopa and carbidopa and the immediate release coating contains 25% levodopa and carbidopa.

[0030] In some preferred embodiments, in step a, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol.

[0031] In some preferred embodiments, in step a, sieving is performed using a 20-mesh sieve.

[0032] In some preferred embodiments, in step b, the adhesive solution is a povidone K30 solution.

[0033] In some preferred embodiments, in step c, a 0.8 mm sieve is used for granulation.

[0034] In some preferred embodiments, the lubricant is magnesium stearate.

[0035] In some preferred embodiments, the controlled release polymer is hypromellose, carrageenan, ethyl cellulose, methyl cellulose or carbomer; preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M or carrageenan Viscarin 109; more preferably, hypromellose K4M Cr is 0-16% of the weight of the controlled release matrix, or hypromellose K100M is 0-16% of the weight of the controlled release matrix or carrageenan Viscarin 109 is 0-3% of the weight of the controlled release matrix; most preferably, the controlled release polymer is hypromellose K4M Cr, which is 3-7% of the weight of the controlled release matrix.

[0036] In some preferred embodiments, in step d, the controlled release polymer is sieved with a mesh size of 20 mesh.

[0037] In some preferred embodiments, in step d, the lubricant is sieved through 60 meshes.

[0038] In some preferred embodiments, in step d, tabletting is performed using a punch having a size between 2.0 mm and 5.5 mm.

[0039] In some preferred embodiments, in step e, the delayed-release coating solution comprises one or more of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate, talc, and diethyl phthalate, wherein the methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion are, for example, L100-55, s100, FS30D or L30D-55; Preferably, the delayed release coating is made of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion L30D-55, triethyl citrate and talc.

[0040] In some preferred embodiments, in step e, the concentration of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion in the delayed-release coating solution is 8-15% w / w.

[0041] In some preferred embodiments, the aging temperature in step e is 40°C.

[0042] The third aspect of the present invention provides a controlled release oral solid preparation obtained according to the above preparation method. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The accompanying drawings are used to provide a further understanding of the technical solution of the present invention and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present invention and do not constitute a limitation on the technical solution of the present invention.

[0044] Figure 1 The levodopa dissolution comparison of the homemade product 239-033 prepared in Example 3 and the reference preparation RYTARY (20002203A) is shown.

[0045] Figure 2 The comparison of carbidopa dissolution between the homemade product 239-033 prepared in Example 3 and the reference preparation RYTARY (20002203A) is shown. DETAILED DESCRIPTION

[0046] The present invention will be further described below by way of examples, which are not intended to further limit the content of the present invention. It should be understood by those skilled in the art that equivalent replacements or corresponding improvements made to the technical features of the present invention still fall within the scope of protection of the present invention.

[0047] The first aspect of the present invention provides a multi-unit mini-tablet controlled release oral solid preparation, wherein the controlled release oral solid preparation is a capsule, and the mini-tablet has a controlled release matrix, a delayed release coating and an immediate release coating from the inside to the outside, and the carboxylic acid is located in the controlled release matrix. The carboxylic acid and 75% of levodopa and carbidopa are contained in the controlled release matrix, and 25% of levodopa and carbidopa are used as an immediate release coating and coated on the mini-tablet and filled in the capsule shell. In some embodiments, the controlled release matrix comprises carboxylic acid, levodopa, carbidopa, a first pharmaceutically acceptable excipient and a controlled release coating.

[0048] In some embodiments, the first pharmaceutically acceptable auxiliary agent comprises a diluent, a lubricant and a binder. Preferably, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol. Preferably, the lubricant is magnesium stearate. Preferably, the binder is povidone.

[0049] In some embodiments, the delayed release coating comprises one or more of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate, talc and diethyl phthalate. Methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion are, for example, but not limited to L100-55, s100, FS30D and In a preferred embodiment, the delayed release coating is made of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion L30D-55, triethyl citrate and talc.

[0050] In some embodiments, the immediate release coating comprises levodopa, carbidopa and a second pharmaceutically acceptable excipient. In some embodiments, the second pharmaceutically acceptable excipient is mannitol, cross-linked sodium carboxymethylcellulose, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch and mixtures thereof. In a preferred embodiment, the immediate release coating consists of levodopa, carbidopa and povidone K30.

[0051] In some embodiments, a controlled release matrix is ​​prepared using a controlled release polymer. In some embodiments, the controlled release polymer is hypromellose, carrageenan, ethyl cellulose, methyl cellulose, sodium carboxymethyl starch, or carbomer. In a preferred embodiment, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109. Most preferably, the controlled release polymer hypromellose K4M Cr accounts for 0-16% of the weight of the controlled release matrix, or hypromellose K100M accounts for 0-16% of the weight of the controlled release matrix, or carrageenan Viscarin 109 accounts for 0-3% of the weight of the controlled release matrix.

[0052] In some embodiments, the carboxylic acid is citric acid.Preferably, each capsule contains 70 mg to 120 mg citric acid.

[0053] In some embodiments, the size of the microplates ranges between 2.0 mm and 5.5 mm.

[0054] The second aspect of the present invention provides a method for preparing the above-mentioned capsule, comprising:

[0055] a. The carboxylic acid, the diluent and the first portion of levodopa and carbidopa are sieved and mixed, preferably, the carboxylic acid is citric acid, most preferably, the carboxylic acid is 70 mg to 120 mg citric acid;

[0056] b. adding a binder solution and granulating; preferably, wet granulation is performed using a high shear wet granulator;

[0057] c. Drying and granulating the obtained granules;

[0058] d. The controlled release polymer and lubricant are sieved, mixed with the dried and sized granules, and tableted to obtain a core;

[0059] e. preparing a delayed-release coating solution, coating the tablet core with a delayed-release coating, and aging the tablet core;

[0060] f. preparing an immediate release coating coating solution, coating the delayed release coating coating on the core to obtain a multi-unit mini-tablet; and

[0061] g. Load the multi-unit mini-tablets into capsule shells.

[0062] Specifically, the present invention provides a method for preparing rapid-release and controlled-release capsules of carbidopa and levodopa, comprising:

[0063] The first part of carbidopa and levodopa as well as microcrystalline cellulose, mannitol and citric acid are passed through a #20 mesh screen into a high shear granulator and mixed; an aqueous solution of povidone is added thereto and granulated; the granules are dried in a fluidized bed and then dry granulated using a dry granulator equipped with a 0.8 mm screen; hypromellose is passed through a #20 mesh screen, transferred to a mixer together with the granules and mixed, and then magnesium stearate passed through a #60 mesh screen is mixed in; the mixture is tableted using a 2.0 mm round punch to obtain a controlled release matrix; methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc are used to prepare a delayed release coating solution, which is sprayed on the controlled release matrix to achieve weight gain and aged at 40°C; an immediate release coating solution is prepared by adding purified water to povidone, the second part of levodopa and carbidopa, sprayed onto the delayed release coating tablets, and filled into the capsule shell.

[0064] The third aspect of the present invention provides a controlled release oral solid preparation prepared according to the above method.

[0065] In the following examples, unless otherwise specified, the dissolution experiments were performed with reference to the U.S. FDA dissolution database dissolution method.

[0066] Example

[0067] Example 1

[0068] Table 1: Materials, models and manufacturers

[0069]

[0070] Controlled release core tablets were prepared using controlled release polymers of different viscosity grades, such as hypromellose K4M Cr (2663-4970 mpas; 2% solution), hypromellose K100M (75000-140000 mpas; 2% solution), and carrageenan (Viscarin 109, 220-350 mpas, 1.5% aqueous solution).

[0071] Different concentrations of these controlled release polymers were used: Hydroxypropyl methylcellulose K4M Cr was present in an amount ranging from 0% to 16% by weight of the controlled release matrix, HPMC K100M was present in an amount ranging from 0% to 16% by weight of the controlled release matrix, and carrageenan was present in an amount ranging from 0% to 3% by weight of the controlled release matrix.

[0072] Example 1-1: Production process using hypromellose:

[0073] Carbidopa, levodopa, microcrystalline cellulose PH101, mannitol and citric acid are passed through a #20 mesh sieve, added to a high shear granulator and mixed. The polyvidone K30 aqueous solution is added thereto and granulated. After the granules are dried in a fluidized bed, they are dried and granulated using a dry granulator equipped with a 0.8 mm screen. Hydroxypropyl methylcellulose is passed through a 20 mesh sieve, transferred to a mixer with the granules and mixed. Magnesium stearate is passed through a #60 mesh sieve, added and mixed. The mixture is tableted and filled into capsules using a 5.5 mm round punch.

[0074] Example 1-2: Production process using carrageenan:

[0075] Carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, citric acid and carrageenan were sieved through a 20 mesh screen and transferred to a high shear granulator for mixing. The polyvidone K30 aqueous solution was added thereto and granulated. After the granules were dried in a fluidized bed, they were granulated using a dry granulator equipped with a 0.8 mm screen. The granules of the dry granulation were transferred to a mixer for mixing. Magnesium stearate was sieved through a #60 mesh screen, added and mixed. The mixture was tableted with a 5.5 mm round punch and filled into capsules.

[0076] Table 2: Formulation composition of the controlled release matrix of carbidopa and levodopa capsules (percentages based on the total weight of the controlled release matrix), compressed with a 5.5 mm punch.

[0077]

[0078]

[0079] Dissolution data: The U.S. FDA dissolution database dissolution method was used to develop the prescription.

[0080] US FDA Dissolution Database Dissolution parameters: pH 7.0, 50 mM phosphate buffer, basket apparatus, 75 rpm, dissolution medium: 900 ml

[0081] Table 3: Dissolution of carbidopa and levodopa capsules (5.5 mm controlled release matrix) in pH 7.0, 50 mM phosphate buffer (basket apparatus, 75 rpm, dissolution medium: 900 ml)

[0082]

[0083] CD-carbidopa; LD-levodopa

[0084] Note: The controlled release matrix contains 75% of API and the immediate release coating contains 25% of API. Therefore, for comparison with the reference product (RLD), 25% of the actual value of the % delayed release (DR) was added to optimize the controlled release portion.

[0085] Conclusion: The F2 in batch 239-016 was more than 50. Therefore, HPMC K4M Cr was selected from this study for further optimization study.

[0086] Example 2: Development Strategy for a 2.0 mm Controlled Release Matrix in a Capsule

[0087] Example 2-1: Optimization study of controlled release matrix

[0088] The controlled release matrix was prepared by tableting with a 2.0 mm punch and using Hydroxypropyl methylcellulose K4M Cr as the controlled release polymer. Different concentrations of Hydroxypropyl methylcellulose K4M Cr were selected for study, ranging from 3% to 7% of the weight of the controlled release matrix to 90 to 120 mg of anhydrous citric acid per capsule. The specific composition details are shown in the table below.

[0089] Table 4: Formulation composition of controlled release matrix for compression of carbidopa and levodopa capsules using 2.0 mm punch

[0090]

[0091] Production process using Hydroxypropyl Methylcellulose:

[0092] Carbidopa, levodopa, microcrystalline cellulose PH101, mannitol and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. The povidone K30 aqueous solution was added thereto and granulated. After the granules were dried in a fluidized bed, they were dried and granulated using a dry granulator equipped with a 0.8 mm screen. Hydroxypropyl methylcellulose was passed through a #20 mesh screen and transferred to a mixer with the granules and mixed. Magnesium stearate was passed through a #60 mesh screen and added to the mixture of granules and hypromellose and mixed. The mixture was tableted with a 2.0 mm round punch and filled into capsules.

[0093] Dissolution data: Use the US FDA dissolution database dissolution method to develop and evaluate formulation parameters for controlled release matrices

[0094] US FDA dissolution database dissolution parameters:

[0095] pH 7.0, 50 mM phosphate buffer, basket apparatus, 75 rpm, dissolution medium: 900 mL

[0096] Table 5: Dissolution of Carbidopa and Levodopa Capsules (2.0 mm controlled release matrix) in pH 7.0, 50 mM phosphate buffer (basket apparatus, 75 rpm, dissolution medium: 900 mL)

[0097]

[0098] CD-carbidopa; LD-levodopa

[0099] Note: The controlled release matrix contains 75% of the API. The immediate release coating contains 25% of the API. Therefore, for comparison with the RLD, 25% of the actual % delayed release (DR) was added to optimize the controlled release portion.

[0100] Conclusion: The dissolution profiles of batches 239-031 and 239-033 met the requirements, with F2 values ​​greater than 50. Therefore, the dosage of HPMC K4M Cr was determined to be 5% of the weight of the controlled release matrix, and the dosage of anhydrous citric acid was determined to be 100 mg / capsule, and tablets were compressed using a 2.0 mm punch.

[0101] Example 2-2: Optimization study of delayed release coating layer of 2.0 mm microtablets in capsules

[0102] The controlled release matrix prepared in Example 2-1 was coated with a delayed release coating liquid containing 8-15% w / w of a methacrylic acid copolymer. The delayed release coated tablets were placed in capsules and the dissolution curve was checked.

[0103] Production process:

[0104] Carbidopa, levodopa, microcrystalline cellulose PH101, mannitol and citric acid are passed through a #20 mesh screen into a high shear granulator and mixed. A povidone K30 aqueous solution is added thereto and granulated. After the granules are dried in a fluidized bed, they are dry granulated using a dry granulator equipped with a 0.8 mm screen. Hydroxypropyl methylcellulose is passed through a #20 mesh screen, transferred to a mixer together with the granules and mixed. Magnesium stearate is passed through a #60 mesh, added and mixed. The mixture is tableted with a 2.0 mm round punch. Methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc are formulated into a delayed release coating solution, sprayed on a controlled release matrix and weighted, and after aging at 40°C, filled into capsules and the dissolution curve is tested.

[0105] Table 6: Formulation composition of delayed-release coated tablets of carbidopa and levodopa capsules compressed with a 2.0 mm punch

[0106]

[0107]

[0108] US FDA dissolution database dissolution parameters:

[0109] Acid phase: Simulated gastric fluid (without enzymes), 900 ml, basket apparatus, 75 rpm

[0110] Buffer stage: pH 7.0, 50 mM phosphate buffer, 900 mL, basket apparatus, 75 rpm

[0111] Table 7: Dissolution of delayed-release coated tablets in simulated gastric fluid and phosphate buffer solution

[0112]

[0113] CD-carbidopa; LD-levodopa

[0114] Note: The controlled release matrix contains 75% of the API. The immediate release coating contains 25% of the API. Therefore, for comparison with the RLD, the actual value of % delayed release (DR) of 25% of the released amount was added to optimize the controlled release portion.

[0115] Conclusion: The dissolution curve of batch 239-033 (12% delayed release coating tablets) meets the requirements, and the F2 value is greater than 50. Therefore, the dosage of HPMC K4M Cr is determined to be 5% of the weight of the controlled release matrix, the dosage of anhydrous citric acid is determined to be 100 mg / capsule, and the weight gain of the delayed release coating is 12% of the weight of the controlled release matrix.

[0116] Example 3: Study on rapid-release and controlled-release capsule preparations

[0117] Production process using Hydroxypropyl Methylcellulose:

[0118] The first part of carbidopa and levodopa as well as microcrystalline cellulose PH101, mannitol and citric acid are passed through a #20 mesh sieve into a high shear granulator and mixed. The aqueous solution of povidone K30 is added thereto and granulated. After the granules are dried in a fluidized bed, they are dry granulated using a dry granulator equipped with a 0.8 mm screen. Hydroxypropyl methylcellulose is passed through a 20 mesh sieve, transferred to a mixer together with the granules and mixed. Magnesium stearate is passed through a #60 mesh, added and mixed. The mixture is tableted using a 2.0 mm round punch. Methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc are used to prepare the delayed layer coating solution, sprayed on the plain tablets to achieve weight gain, and aged at 40°C. The immediate release coating solution is prepared by adding purified water to povidone K30, the second part of levodopa and carbidopa, sprayed onto the delayed release coated tablets, filled into capsules and the dissolution curve is tested. The dissolution curve is shown in Figure 1 and Figure 2 .

[0119] Table 8: Formula composition of finished product

[0120]

[0121]

[0122] US FDA dissolution database dissolution parameters:

[0123] Acid phase: Simulated gastric fluid (without enzymes), 900 ml, basket apparatus, 75 rpm

[0124] Buffer stage: pH 7.0, 50 mM phosphate buffer, 900 mL, basket apparatus, 75 rpm

[0125] Table 9: Dissolution of Delayed Release Coated Tablet Capsules in Acid and Buffer Solutions

[0126]

[0127] CD-carbidopa; LD-levodopa

[0128] Conclusion: The dissolution profile of batch 239-033 (12% delayed release coating) meets the requirements, and the F2 value is greater than 50. Therefore, the amount of HPMC K4M Cr is determined to be 5% of the weight of the controlled release matrix, the amount of anhydrous citric acid is determined to be 100 mg / capsule, a 2.0 mm punch is used for tableting, and the delayed release coating weight gain is 12% of the weight of the controlled release matrix.

Claims

1. A controlled release oral solid preparation, which is a capsule comprising a multi-unit mini-tablet, wherein the mini-tablet comprises a controlled release portion and an immediate release coating from the inside out, wherein the controlled release portion comprises a carboxylic acid and a first portion of levodopa and carbidopa, and the immediate release coating comprises a second portion of levodopa and carbidopa, wherein the controlled release portion comprises a controlled release matrix and a delayed release coating, and the carboxylic acid is located in the controlled release matrix, and wherein the carboxylic acid and 75% of the levodopa and carbidopa are contained in the controlled release portion, and 25% of the levodopa and carbidopa are used as the immediate release coating and are coated on the controlled release portion; and The immediate release coating is coated outside the controlled release portion; The controlled release matrix is ​​composed of 183.75 mg of levodopa, 45.94 mg of carbidopa, 100 mg of anhydrous citric acid, a first pharmaceutically acceptable excipient, and a controlled release polymer; The first pharmaceutically acceptable excipient is 30 mg of microcrystalline cellulose PH101, 55.31 mg of mannitol, 7 mg of magnesium stearate and 15 mg of povidone K30; wherein the controlled release polymer is Hydroxypropyl methylcellulose K4M Cr 23mg; The delayed release coating is composed of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion L30D-55 42.46 mg, triethyl citrate 4.25 mg and talc 8.49 mg; The immediate release coating is composed of 61.25 mg of levodopa, 15.31 mg of carbidopa and 15.31 mg of povidone K30; The size of the controlled release matrix is ​​2.0 mm; The dissolution parameters of the US FDA dissolution database were used: pH 7.0, 50 mM phosphate buffer, basket apparatus, 75 rpm, 900 ml of dissolution medium, and F2 of the reference preparation RYTARY exceeded 50.

2. The controlled release oral solid preparation according to claim 1, wherein the controlled release matrix is ​​prepared with a controlled release polymer.

3. A method for preparing the controlled release oral solid preparation according to claim 1 or 2, wherein the controlled release oral solid preparation is a capsule comprising a multi-unit mini-tablet, wherein the mini-tablet comprises a controlled release portion and an immediate release coating outside the controlled release portion, wherein the controlled release portion comprises a controlled release matrix and a delayed release coating, wherein the controlled release matrix comprises a carboxylic acid and a first portion of levodopa and carbidopa, and the immediate release coating comprises a second portion of levodopa and carbidopa, wherein the carboxylic acid is anhydrous citric acid, and the method comprises: a. The citric acid, microcrystalline cellulose PH101, mannitol and the first portion of levodopa and carbidopa are sieved and mixed; b. Add povidone K30 solution and perform wet granulation; c. Drying the obtained granules and refining them; d. The hypromellose K4M Cr and magnesium stearate were sieved, mixed with the dried and sized granules, and tableted to obtain a controlled release matrix; e. preparing a delayed-release coating solution, coating the delayed-release coating on the controlled-release matrix, and aging; f. preparing an immediate release coating solution and coating the delayed release coating tablet core; and g. The coated tablets are loaded into the capsule shell; In step b, granulation is performed using a high shear wet granulator; In step a, sieving is performed using a 20-mesh sieve; in step c, granulation is performed using a 0.8 mm sieve; and in step d, tableting is performed using a punch with a size of 2.0 mm.

4. The method according to claim 3, wherein in step e, the aging temperature is 40°C.

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