CN113616621A - Levodopa and carbidopa controlled release preparation and preparation method thereof - Google Patents
Levodopa and carbidopa controlled release preparation and preparation method thereof Download PDFInfo
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- CN113616621A CN113616621A CN202110956705.0A CN202110956705A CN113616621A CN 113616621 A CN113616621 A CN 113616621A CN 202110956705 A CN202110956705 A CN 202110956705A CN 113616621 A CN113616621 A CN 113616621A
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- China
- Prior art keywords
- controlled release
- oral solid
- solid formulation
- levodopa
- carbidopa
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- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 title claims abstract description 41
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 5
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
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- 238000013268 sustained release Methods 0.000 claims 1
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- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
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Images
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a controlled release oral solid formulation comprising levodopa, carbidopa and a carboxylic acid, comprising a multi-unit mini tablet comprising a controlled release portion and an immediate release coating, and a method for preparing the same. 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.
Description
Technical Field
The present invention relates to the field of pharmaceutical manufacturing, and more particularly to a controlled release oral solid formulation comprising a multi-unit mini-tablet of carbidopa and levodopa, said mini-tablet comprising a controlled release portion and an immediate release coating. The invention also relates to a preparation method of the controlled release oral solid preparation containing the multi-unit micro-tablet.
Background
Levodopa and carbidopa are among the drugs for the treatment of parkinsonism, such as parkinson's disease and related disorders.
U.S. patent nos. 7094427, 8377474, 8454998, 8557283, 9089607, 9089608, 9463246, 9533046 disclose a combination of Carbidopa (CD) and Levodopa (LD) that includes immediate release and controlled release components, and the use of carboxylic acids (tartaric acid) other than carbidopa and levodopa to treat dopamine depleted conditions in the brain tissue of a patient. This would provide a method of reducing motor fluctuations in a parkinson's disease patient.
Currently, formulations containing Carbidopa (CD), Levodopa (LD) and tartaric acid are commercially available, for example
And (4) making capsules. The formulation contains 3 different ingredients, mixed and filled in capsules. The 3 components are (a) a controlled release component comprising levodopa, carbidopa, and one or more rate controlling excipients; (b) a carboxylic acid component comprising tartaric acid and one or more rate controlling polymers; and (c) an immediate release component comprising levodopa and carbidopa, wherein the carboxylic acid component of (b) is different from the carbidopa and direct release components of levodopa and the controlled release components 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) comprise pellets or granules.
At present, a substitute preparation with simple and controllable preparation process and low cost is urgently needed.
Disclosure of Invention
The present invention provides a novel process for the preparation of a controlled release pharmaceutical composition of Carbidopa (CD) and Levodopa (LD) using a Carboxylic Acid (CA), wherein the carboxylic acid is not a controlled release component or a separate component other than 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 that is filled in a hard capsule shell.
A first aspect of the present invention provides a controlled release oral solid formulation comprising levodopa and carbidopa, said controlled release oral solid formulation comprising a multi-unit mini-tablet, said mini-tablet comprising from the inside to the outside a controlled release portion comprising a carboxylic acid and a first portion of levodopa and carbidopa, and an immediate release coating comprising a second portion of levodopa and carbidopa.
In some preferred embodiments, the immediate release coating is coated over the controlled release portion.
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.
In some preferred embodiments, the controlled release matrix comprises levodopa, carbidopa, a carboxylic acid, a first pharmaceutically acceptable auxiliary agent, and a controlled release polymer; preferably, the first pharmaceutically acceptable auxiliary agent is selected from microcrystalline cellulose (e.g. microcrystalline cellulose PH101, PH102, PH103, PH105, PH302), corn starch, mannitol and mixtures thereof; more preferably, the first pharmaceutically acceptable auxiliary agent is microcrystalline cellulose PH101 and mannitol.
In some preferred embodiments, the controlled release matrix comprises ethylcellulose, hypromellose, methylcellulose, povidone, and mixtures thereof; preferably, the controlled release matrix comprises hypromellose.
In some preferred embodiments, the delayed release coating comprises a methacrylic acid-ethyl acrylate copolymerAnd one or more of an aqueous dispersion thereof, triethyl citrate, talc and diethyl phthalate; preferably, the methacrylic acid-ethyl acrylate copolymer and the aqueous dispersion thereof are
L100-55、
s100、
FS30D or
L30D-55; more preferably, the delayed release coating is composed of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc.
In some preferred embodiments, the immediate release coating comprises levodopa, carbidopa, and a second pharmaceutically acceptable auxiliary agent; preferably, the second pharmaceutically acceptable auxiliary agent is mannitol, croscarmellose sodium, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch and mixtures thereof; more preferably, the immediate release coating is comprised of levodopa, carbidopa, and povidone K30.
In some preferred embodiments, the carboxylic acid is citric acid. More preferably, the controlled release oral formulation comprises 70mg to 120mg of citric acid per unit.
In some preferred embodiments, the controlled release oral solid formulation is a capsule.
In some preferred embodiments, 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 coated on the controlled release portion as an immediate release coating.
In some preferred embodiments, the controlled release matrix is prepared with a controlled release polymer; preferably, the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; more preferably, the controlled release polymer is hypromellose K4MCr, hypromellose K100M, or carrageenan Viscarin 109; more preferably, the weight of the hypromellose K4M Cr is 0-16% of the weight of the controlled release matrix, or the weight of the hypromellose K100M is 0-16% of the weight of the controlled release matrix, or the weight of the carrageenan Viscarin109 is 0-3% of the weight of the controlled release matrix; most preferably, the controlled release polymer is hypromellose K4M Cr, 3-7% by weight of the controlled release matrix.
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.
In some preferred embodiments, the size of the controlled release matrix is in the range between 2.0mm and 5.5 mm.
A second aspect of the present invention provides a method for producing the above controlled release oral solid formulation, comprising:
a. sieving and mixing the carboxylic acid, diluent, and first portion of levodopa and carbidopa;
b. adding a binder solution, and performing wet granulation, preferably by using a high-shear wet granulator;
c. drying the obtained granules, and grading;
d. sieving the controlled release polymer and lubricant, mixing with the dried and granulated granules, and tabletting to obtain controlled release matrix;
e. preparing delayed release coating liquid, coating the delayed release coating on the controlled release matrix, and aging;
f. preparing an immediate release coating solution, and coating on the delayed release coating tablet core; and
g. the coated tablet cores are loaded into capsule shells.
In some preferred embodiments, the controlled release matrix comprises 75% levodopa and carbidopa, and the immediate release coating comprises 25% levodopa and carbidopa.
In some preferred embodiments, wherein in step a, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol.
In some preferred embodiments, wherein in step a, the sieving is performed with a 20 mesh screen.
In some preferred embodiments, wherein in step b, the binder solution is povidone K30 solution.
In some preferred embodiments, wherein in step c, size stabilization is performed using a 0.8mm screen.
In some preferred embodiments, wherein the lubricant is magnesium stearate.
In some preferred embodiments, wherein the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109; more preferably, the weight of the hypromellose K4M Cr is 0-16% of the weight of the controlled release matrix, or the weight of the hypromellose K100M is 0-16% of the weight of the controlled release matrix, or the weight of the carrageenan Viscarin109 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% by weight of the controlled release matrix.
In some preferred embodiments, wherein in step d, the controlled release polymer has a mesh size of 20 mesh.
In some preferred embodiments, wherein in step d, the lubricant has a mesh size of 60 mesh.
In some preferred embodiments, wherein in step d, the tablet is compressed with a punch having a size between 2.0mm and 5.5 mm.
In some preferred embodiments, wherein in step e, the delayed release coating solution comprises methacrylic acid-ethyl acrylate copolymer and aqueous dispersion thereof, triethyl citrate, talc, and orthophthalic acidOne or more of diethyl dicarboxylate, methacrylic acid-ethyl acrylate copolymer and aqueous dispersions thereof, e.g.
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 talcum powder.
In some preferred embodiments, wherein in step e, the concentration of the methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion in the delayed release coating is 8-15% w/w.
In some preferred embodiments, wherein the aging temperature in step e is 40 ℃.
A third aspect of the present invention provides a controlled release oral solid formulation obtained according to the above production method.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.
FIG. 1 shows the dissolution contrast of levodopa for the home-made product 239-033 prepared in example 3 and the reference formulation RYTARY (20002203A).
FIG. 2 shows the carbidopa dissolution comparison of the home-made product 239-033 prepared in example 3 and the reference formulation RYTARY (20002203A).
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that equivalent substitutions for the features of the invention, or corresponding modifications, may be made without departing from the scope of the invention.
In a first aspect of the present invention, there is provided a multi-unit mini-tablet controlled release oral solid formulation, wherein the controlled release oral solid formulation is a capsule, the mini-tablets have a controlled release matrix, a delayed release coating and an immediate release coating in this order from the inside out, and a carboxylic acid is located within the controlled release matrix. Wherein carboxylic acid and 75% of levodopa and carbidopa are contained in a controlled release matrix, and 25% of levodopa and carbidopa are coated as an immediate release coating on the micro-tablets, filled in capsule shells. In some embodiments, the controlled release matrix comprises a carboxylic acid, levodopa, carbidopa, a first pharmaceutically acceptable auxiliary agent, and a controlled release coating.
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.
In some embodiments, the delayed release coating comprises one or more of methacrylic acid-ethyl acrylate copolymer and aqueous dispersions thereof, triethyl citrate, talc, and diethyl phthalate. Methacrylic acid-ethyl acrylate copolymers and aqueous dispersions thereof such as, but not limited to
L100-55、
s100、
FS30D and
L30D-55. In a preferred embodiment, the delayed release coating is formed from methacrylic acid-ethyl acrylate copolymers and aqueous dispersions thereof
L30D-55, triethyl citrate and talcum powder.
In some embodiments, the immediate release coating comprises levodopa, carbidopa, and a second pharmaceutically acceptable auxiliary agent. In some embodiments, the second pharmaceutically acceptable auxiliary agent is mannitol, croscarmellose sodium, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch, and mixtures thereof. In a preferred embodiment, the immediate release coating is comprised of levodopa, carbidopa, and povidone K30.
In some embodiments, the controlled release matrix is prepared using a controlled release polymer. In some embodiments, the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, sodium carboxymethyl starch, or carbomer. In preferred embodiments, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109. Most preferably, the controlled release polymer hypromellose K4M Cr comprises 0-16% by weight of the controlled release matrix, or hypromellose K100M comprises 0-16% by weight of the controlled release matrix, or carrageenan Viscarin109 comprises 0-3% by weight of the controlled release matrix.
In some embodiments, the carboxylic acid is citric acid. Preferably, each capsule contains 70mg to 120mg of citric acid.
In some embodiments, the mini-sheet has a size in a range between 2.0mm and 5.5 mm.
In a second aspect, the present invention provides a process for preparing the above capsule, comprising:
a. sieving and mixing a carboxylic acid, a diluent, and a first portion of levodopa and carbidopa, preferably the carboxylic acid is citric acid, most preferably the carboxylic acid is 70mg to 120mg citric acid;
b. adding the adhesive solution and granulating; preferably, a high shear wet granulator is used for wet granulation;
c. drying the obtained granules, and grading;
d. sieving the controlled release polymer and lubricant, mixing with the dried and granulated granules, and tabletting to obtain tablet core;
e. preparing delayed release coating liquid, coating the delayed release coating on the tablet core, and aging;
f. preparing immediate release coating liquid, and coating on the delayed release coating tablet core to obtain multi-unit mini tablets; and
g. the multi-unit mini-tablets are loaded into the capsule shells.
Specifically, the invention provides a preparation method of an immediate-release and controlled-release capsule of carbidopa and levodopa, which comprises the following steps:
passing a first portion of carbidopa and levodopa, as well as microcrystalline cellulose, mannitol, and citric acid through a #20 mesh screen into a high shear granulator and mixing; adding the povidone aqueous solution into the mixture and granulating; drying the granules in a fluidised bed and subsequently dry-granulating with a dry granulator equipped with a 0.8mm sieve; the hypromellose was passed through a #20 mesh screen, transferred to a blender with the granules and blended, followed by the incorporation of magnesium stearate which passed through a #60 mesh screen; tabletting the mixture with a 2.0mm round punch to obtain a controlled release matrix; mixing methacrylic acid-ethyl acrylate copolymer and its water dispersion, triethyl citrate and talcum powder to delayed release coating liquid, spraying on controlled release substrate to increase weight, and aging at 40 deg.C; the coating solution of the immediate release coating is prepared by adding povidone, a second part of levodopa and carbidopa into purified water, spraying the mixture onto the coating piece of the delayed release coating, and filling the coating piece into a capsule shell.
A third aspect of the present invention provides a controlled release oral solid formulation prepared according to the above method.
In the following examples, unless otherwise specified, dissolution experiments were performed by referring to the dissolution method of the FDA dissolution database in the united states.
Examples
Example 1
Table 1: materials, types and manufacturers
Controlled release core tablets are prepared by using controlled release polymers with different viscosity grades, such as hypromellose K4M Cr (2663-.
Different concentrations of these controlled release polymers were used: the content of the hydroxypropyl methylcellulose K4M Cr is 0-16% of the weight of the controlled release matrix, the content of the HPMC K100M is 0-16% of the weight of the controlled release matrix, and the content of the carrageenan is 0-3% of the weight of the controlled release matrix.
Example 1-1: the production process using hypromellose comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen, added to a high shear granulator, and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a 20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was passed through a #60 mesh screen, added and mixed. The mixture was compressed with a 5.5mm round punch and filled into capsules.
Examples 1 to 2: the production process using carrageenan comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, citric acid and carrageenan are sieved by a 20-mesh sieve, and transferred to a high-shear granulator to be mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The dry whole granules were transferred to a mixer for mixing. Magnesium stearate was passed through a #60 mesh screen, added and mixed. The mixture was compressed with a 5.5mm round punch and filled into capsules.
Table 2: formulation of controlled release matrices for carbidopa and levodopa capsules (percentages being based on total weight of controlled release matrix), compressed using a 5.5mm punch.
Dissolution rate data: the prescription is developed by adopting a dissolution method of the American FDA dissolution database.
Us FDA dissolution database dissolution parameters: pH7.0, 50mM phosphate buffer, basket apparatus, 75 rpm, dissolution medium: 900 ml of
Table 3: dissolution of carbidopa and levodopa capsules (5.5mM controlled release matrix) in 50mM phosphate buffer, pH7.0 (basket apparatus, 75 rpm, dissolution media: 900 ml)
CD-carbidopa; LD-Levodopa
Remarking: the controlled release matrix contained 75% API and the immediate release coating contained 25% API. The controlled release fraction was therefore optimized for comparison with the reference formulation (RLD) by adding the actual% Delayed Release (DR) value of 25%.
And (4) conclusion: f2 in batch 239-. Hypromellose K4M Cr was therefore selected from this study for further optimization studies.
Example 2: strategy for developing 2.0mm controlled release matrix in capsule
Example 2-1: optimization of controlled Release matrices
The controlled release matrix was prepared by tabletting with a 2.0mm punch and hypromellose k4M Cr as the controlled release polymer. Hydroxypropyl methylcellulose K4M Cr with different concentrations is selected for research, the research range is that the hydroxypropyl methylcellulose K4M Cr accounts for 3% -7% of the weight of the controlled release matrix, and the anhydrous citric acid accounts for 90-120 mg/capsule. The details of the specific compositions are given in the following table.
Table 4: formulation of controlled release matrix for capdopa and levodopa capsules pressed with 2.0mm punches
The production process using hypromellose comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a #20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was sieved through a #60 mesh sieve, added to the mixture of granules and hypromellose and mixed well. The mixture was compressed with a 2.0mm round punch and filled into capsules.
Dissolution rate data: development and evaluation of prescription parameters for controlled release matrices using the dissolution method of the U.S. FDA dissolution database
Us FDA dissolution database dissolution parameters:
pH7.0, 50mM phosphate buffer, basket apparatus, 75 rpm, dissolution medium: 900 ml of
Table 5: dissolution of carbidopa and levodopa capsules (2.0 mM controlled release matrix) in 50mM phosphate buffer, pH7.0 (basket apparatus, 75 rpm, dissolution media: 900 ml)
CD-carbidopa; LD-Levodopa
Remarking: the controlled release matrix contained 75% API. The immediate release coating contained 25% API. Therefore for comparison with RLD, the control release fraction is optimized by adding 25% of the actual release value% Delayed Release (DR).
And (4) conclusion: the dissolution curves of batch Nos. 239-. Thus, the amount of hypromellose K4M Cr was determined to be 5% by weight of the controlled release matrix and the amount of anhydrous citric acid was determined to be 100 mg/capsule, compressed using a 2.0mm punch.
Example 2-2: optimization study of 2.0mm micro-tablet delayed release coating layer in capsule
The delayed release coating was coated on the controlled release substrate prepared in example 2-1 using a delayed release coating solution containing 8-15% w/w of methacrylic acid copolymer. The delayed release coated tablets were filled into capsules and the dissolution profile was examined.
The production process comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a #20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was passed through a #60 mesh, added and mixed. The mixture was compressed using a 2.0mm round punch. Mixing methacrylic acid-ethyl acrylate copolymer and its water dispersion, triethyl citrate and talcum powder to delayed release coating solution, spraying on controlled release matrix to increase weight, aging at 40 deg.C, filling into capsule, and detecting dissolution curve.
Table 6: prescription composition of 2.0mm punch pressed carbidopa and levodopa capsule delayed release coating coated tablet
Us FDA dissolution database dissolution parameters:
an acid stage: simulated gastric fluid (without enzyme), 900 ml, basket apparatus, 75 rpm
A buffering stage: pH7.0, 50mM phosphate buffer, 900 ml, basket apparatus, 75 rpm
Table 7: dissolution of delayed release coated tablets in simulated gastric fluid and phosphate buffered saline
CD-carbidopa; LD-Levodopa
Remarking: the controlled release matrix contains 75% of the drug substance. The immediate release coating contained 25% API. The actual value of the 25% release% Delayed Release (DR) was therefore added to optimize the controlled release portion for comparison with RLD.
And (4) conclusion: the dissolution profile of batch 239-033 (12% delayed release coated tablet) was found to be satisfactory with a value of F2 greater than 50. Thus, the amount of hypromellose K4M Cr was determined to be 5% by weight of the controlled release matrix, the amount of anhydrous citric acid was determined to be 100 mg/capsule, and the delayed release coating weight gain was 12% by weight of the controlled release matrix.
Example 3: examples of research on immediate release and controlled release capsule formulations
The production process using hypromellose comprises the following steps:
a first portion of carbidopa and levodopa, as well as microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a 20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was passed through a #60 mesh, added and mixed. The mixture was compressed using a 2.0mm round punch. Mixing methacrylic acid-ethyl acrylate copolymer and its water dispersion, triethyl citrate and talcum powder to the delayed layer coating solution, spraying onto plain film to increase weight, and aging at 40 deg.C. The immediate release coating solution is prepared by adding povidone K30, a second part of levodopa and carbidopa into purified water, spraying onto delayed release coating tablet, filling into capsule, and detecting dissolution curve. The dissolution curves are shown in fig. 1 and 2.
Table 8: prescription composition of finished product
Us FDA dissolution database dissolution parameters:
an acid stage: simulated gastric fluid (without enzyme), 900 ml, basket apparatus, 75 rpm
A buffering stage: pH7.0, 50mM phosphate buffer, 900 ml, basket apparatus, 75 rpm
Table 9: dissolution of delayed release coated tablet capsules in acid and buffer solutions
CD-carbidopa; LD-Levodopa
And (4) conclusion: the dissolution profile of batch 239-033 (12% delayed release coating) was found to be satisfactory, with a value of F2 of greater than 50. Thus, the amount of hypromellose K4M Cr was determined to be 5% by weight of the controlled release matrix and the amount of anhydrous citric acid was determined to be 100 mg/capsule, compressed using a 2.0mm punch and the delayed release coating layer was coated with a weight gain of 12% by weight of the controlled release matrix.
Claims (28)
1. A controlled release oral solid formulation comprising a multi-unit mini-tablet comprising from inside to outside a controlled release portion comprising a carboxylic acid and a first portion of levodopa and carbidopa and an immediate release coating comprising a second portion of levodopa and carbidopa.
2. The controlled release oral solid formulation of claim 1, wherein the immediate release coating is coated over the controlled release portion.
3. The controlled release oral solid formulation of claim 2, wherein 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.
4. The controlled release oral solid formulation of claim 3, wherein the controlled release matrix comprises levodopa, carbidopa, a carboxylic acid, a first pharmaceutically acceptable auxiliary agent, and a controlled release polymer.
5. The controlled release oral solid formulation according to claim 4, wherein the first pharmaceutically acceptable auxiliary agent is selected from the group consisting of microcrystalline cellulose, such as microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH103, microcrystalline cellulose PH105, microcrystalline cellulose PH 302; preferably, the first pharmaceutically acceptable auxiliary agent is microcrystalline cellulose PH101 and mannitol.
6. The controlled release oral solid formulation according to claim 5, wherein the controlled release matrix comprises ethylcellulose, hypromellose, methylcellulose, povidone, and mixtures thereof; preferably, the controlled release matrix comprises hypromellose.
7. Control according to claim 3A sustained release oral solid formulation, wherein the delayed release coating comprises one or more of methacrylic acid-ethyl acrylate copolymer and aqueous dispersion thereof, triethyl citrate, talc and diethyl phthalate; preferably, the methacrylic acid-ethyl acrylate copolymer and the aqueous dispersion thereof are
L100-55、
s100、
FS30D or
L30D-55; more preferably, the delayed release coating is composed of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc.
8. The controlled release oral solid formulation of claim 2, wherein the immediate release coating comprises levodopa, carbidopa, and a second pharmaceutically acceptable auxiliary agent.
9. The controlled release oral solid formulation of claim 8, wherein the second pharmaceutically acceptable auxiliary agent is mannitol, croscarmellose sodium, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch, and mixtures thereof; preferably, the immediate release coating consists of levodopa, carbidopa, and povidone K30.
10. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is citric acid.
11. The controlled release oral solid formulation of claim 10, wherein each unit of the controlled release oral formulation comprises from 70mg to 120mg of citric acid.
12. The controlled release oral solid formulation of claim 1, wherein the controlled release oral solid formulation is a capsule.
13. The controlled release oral solid formulation of claim 12, 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 coated onto the controlled release portion as an immediate release coating.
14. The controlled release oral solid formulation of claim 13, wherein the controlled release matrix is prepared with a controlled release polymer; preferably, the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; more preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109.
15. The controlled release oral solid formulation according to claim 14, wherein hypromellose K4M Cr is 0-16% by weight of the controlled release matrix, or hypromellose K100M is 0-16% by weight of the controlled release matrix, or carrageenan Viscarin109 is 0-3% by weight of the controlled release matrix.
16. The controlled release oral solid formulation according to claim 15, wherein the controlled release polymer is hypromellose K4M Cr, in an amount of 3-7% by weight of the controlled release matrix.
17. The controlled release oral solid formulation of claim 14, wherein the controlled release matrix further comprises a diluent, a lubricant, and a binder.
18. The controlled release oral solid formulation of claim 17, wherein the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol.
19. The controlled release oral solid formulation of claim 17, wherein the lubricant is magnesium stearate.
20. The controlled release oral solid formulation according to claim 17, wherein the binder is povidone.
21. The controlled release oral solid formulation according to any one of claims 12-20, wherein the size of the controlled release matrix is in the range between 2.0mm and 5.5 mm.
22. A method of making a controlled release oral solid formulation, the controlled release oral solid formulation being a capsule comprising a plurality of unit mini-tablets, the mini-tablets comprising a controlled release portion and an immediate release coating outside the controlled release portion, the controlled release portion comprising a controlled release matrix and a delayed release coating, the controlled release matrix comprising a carboxylic acid and a first portion of levodopa and carbidopa, and the immediate release coating comprising a second portion of levodopa and carbidopa, the method comprising:
a. sieving and mixing a carboxylic acid, a diluent, and a first portion of levodopa and carbidopa, preferably the carboxylic acid is citric acid, most preferably the carboxylic acid is 70mg to 120mg citric acid;
b. adding a binder solution, and performing wet granulation, preferably by using a high-shear wet granulator;
c. drying the obtained granules, and grading;
d. sieving the controlled release polymer and lubricant, mixing with the dried and granulated granules, and tabletting to obtain controlled release matrix;
e. preparing delayed release coating liquid, coating the delayed release coating on the controlled release matrix, and aging;
f. preparing an immediate release coating solution, and coating on the delayed release coating tablet core; and
g. the coated tablet cores are loaded into capsule shells.
23. The method of claim 22, wherein the controlled release matrix comprises 75% levodopa and carbidopa and the immediate release coating comprises 25% levodopa and carbidopa.
24. The method according to claim 22, wherein in step a, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol, and is sieved with a 20 mesh sieve; in the step b, the binder solution is povidone K30 solution; in step c, the granules were sized using a 0.8mm mesh.
25. The method of claim 22, wherein the lubricant is magnesium stearate and the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; more preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109; preferably, the hydroxypropyl methylcellulose K4M Cr is 0-16% of the weight of the controlled release matrix, or the hydroxypropyl methylcellulose K100M is 0-16% of the weight of the controlled release matrix, or the carrageenan Viscarin109 is 0-3% of the weight of the controlled release matrix; more preferably, the controlled release polymer is hypromellose K4M Cr, which is 3-7% of the weight of the controlled release matrix.
26. The method according to claim 22, wherein in step d, the controlled release polymer has a mesh size of 20 mesh and the lubricant has a mesh size of 60 mesh.
27. The method of claim 22, wherein in step d, the tablet is compressed with a punch having a size between 2.0mm and 5.5 mm.
28. The method of claim 22, wherein in step e, the delayed release coating solution comprises one or more of methacrylic acid-ethyl acrylate copolymers and aqueous dispersions thereof, such as triethyl citrate, talc, and diethyl phthalate
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 talcum powder; more preferably, the concentration of the methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion in the coating solution of the delayed release coating is 8 to 15 w/w% and the aging temperature is 40 ℃.
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| WO2024120389A1 (en) * | 2022-12-05 | 2024-06-13 | 上海汉都医药科技有限公司 | Delayed timed release pharmaceutical composition, preparation method therefor, and use thereof |
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