TW201114419A - Pharmaceutical composition for Parkinson's disease - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for Parkinson's disease, comprising Levodopa, Carbidopa and Entacapone, or pharmaceutically acceptable salts thereof; wherein Entacapone is not mixed with Levodopa or Carbidopa; and at least one pharmaceutically acceptable excipient. Besides, the present invention also relates to a method for preparing the above-mentioned pharmaceutical composition.

Description

201114419 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a pharmaceutical composition for treating Parkinson's disease, and a method of preparing a pharmaceutical composition as described above. [Prior Art]

In the treatment of Parkinson's disease, the most commonly used drug is a lozenge made from a combination of Levodopa and Carbidopa. Carbidopa is an aromatic L-amino acid decarboxylase inhibitor, which is effective in reducing the conversion of levodopa to dopamine' to improve levodopa and dopamine in the brain. concentration. A variety of products are currently available for this class, such as Sinemet® from Bristol-Myers Squibb or Parcopa® from Schwarz Pharma. Wu Guoliangli No. 5, 446, 194 also reveals a drug used to treat Parkinson's disease, Entacapone. This drug is a catechol_0_methyl transferase (COMT) inhibitor, which prevents levodopa from being metabolized to 3-methoxy-4-hydroxy_L_ when used in combination with levodopa. 3-methoxy-4_hydroxy-L-phenylalanine (3-〇MD), which increases the concentration of levodopa in the brain and increases the bioactivity of levodopa. This product is available from Ortan's Comtan®. Patients can control symptoms by taking levodopa 盥: group = and a sedative containing acetonide several times a day. It is a burden for patients with iron jitter symptoms. It is difficult to have heat or =0 01/01984, which proposes a pharmaceutical composition containing levodopa and maidenone, in which kabido is mixed with ergodopa and ampoules to increase the card. More than the multi-steam shell ^ left-handed sangba bio-available i 201114419 (bioavailability). Such a composition can contain three components in one suspect at the same time, thereby improving the compliance of the patient when taking the medicine. Currently, the drug is marketed as a Stalevo® (developed by Novartis and Orion). In order to meet the different dosage combinations, the initial film coats are available in a combination of Stalevo® 50, 75, 100, 125, 150 and 200, all of which have an ampicone content of 200 mg. The contents of dopa and levodopa were 12.5/50 mg, 18.75/75 mg, 25A00 mg, 31.25/125 mg, 37.5/150 mg and 50/200 mg, respectively. However, applying the disclosure of WO 01/01984 to the manufacture of the different dosage combinations described above will make the process very complicated. Because in W0 01/01984, carbidopa is not substantially mixed with levodopa and aceco, so carbidopa needs to be granulated separately; at the same time, although levodopa and aneco can be Mixing and granulating together, but because the content of acetonide in each lozenge is fixed at 200 mg, and the ratio of levodopa to niece in different dosage combinations is not the same, the mixture of the two components is It must be prepared separately according to the requirements of different dosage combinations, so that the complexity of the process will be caused when manufacturing different dosage combinations. SUMMARY OF THE INVENTION In order to solve the above problems, the inventors have developed an improved method which simplifies the process without affecting the elution rate of the active ingredient. Accordingly, one object of the present invention is to provide a pharmaceutical composition for treating Parkinson's disease comprising levodopa, carbidopa and acetonide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Excipients accepted; wherein it is not mixed with levodopa or carbidopa. Another object of the present invention is to provide a pharmaceutical composition for treating Parkinson's disease comprising at least a first unit, a second unit, and at least one pharmaceutically acceptable excipient, wherein the first The unit contains a mixture of levodopa and carbidopa, and the second unit contains amp; TS] 201114419 朋. A further object of the present invention is to provide a method of preparing a pharmaceutical composition as hereinbefore described, which comprises the steps of: (a) mixing levodopa, carbidopa and at least one first excipient a first mixture; (b) granulating the first mixture to obtain a first granule; (c) mixing ampicone and at least one second excipient to obtain a second mixture; (d) The mixture is granulated to give a second granule; (e) the first granule and the second granule are ingot. To achieve the above object, the present invention provides a pharmaceutical composition for treating Parkinson's disease comprising: 25 to 300 mg of levodopa, 5 to 75 mg of carbidopa, and 25 to 300 mg of it Or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; wherein the acamera is not mixed with levodopa or carbidopa. In a preferred embodiment of the present invention, the pharmaceutical composition is an oral solid pharmaceutical composition; preferably, a tablet; more preferably, a double bond; preferably, the double layer One layer of the bond contains levodopa and carbidopa, and the other layer contains amphibi. In a preferred embodiment of the present invention, the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof; more preferably, the binder is microcrystalline cellulose, Hydroxypropyl methylcellulose (HPMC), povidone, crospovidone, starch, or a combination thereof; the aforementioned diluent is microcrystalline cellulose, hydroxypropyl fluorenyl fiber a saccharide, a saccharide, a mannitol, a starch, or a combination thereof; the disintegrating agent is microcrystalline cellulose, hydroxypropyl fluorenyl cellulose, crosslinked polyfluorenone, starch, or a combination thereof; The agent is microcrystalline cellulose. In a preferred embodiment of the invention, the oral solid pharmaceutical composition further comprises a film coat. 5·. 201114419 The present invention also provides a pharmaceutical composition for treating Parkinson's disease, comprising at least a first unit, a second unit, and at least one pharmaceutically acceptable excipient, wherein the first unit comprises a left-handed a mixture of dopa and carbidopa, the second unit comprises acetonide; preferably, the levodopa content is 25 to 300 mg, and the content of carbidopa is 5 to 75 mg. The content of can be 25 to 300 mg. In a preferred embodiment of the present invention, the pharmaceutical composition is an oral solid pharmaceutical composition; preferably, a tablet; more preferably, a double bond; preferably, the double layer One layer of the bond contains levodopa and carbidopa, and the other layer contains amphibi. In a preferred embodiment of the present invention, the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof; more preferably, the binder is microcrystalline cellulose or hydroxypropyl fluorenyl fiber. Or povidone, crospovidone, starch, or a combination thereof; the diluent is microcrystalline cellulose, hydroxypropyl decyl cellulose, saccharide, mannitol, starch, or a combination thereof; The powder is microcrystalline cellulose, propyl fluorenyl cellulose, cross-linked poly- _, powder, or a combination thereof. The present invention also provides a method of preparing a pharmaceutical composition as hereinbefore described, which comprises the steps of: (a) mixing levodopa, carbidopa and at least one first excipient to give a first mixture; (b) granulating the first mixture to obtain a first granule; (c) mixing ampicone and at least one second excipient to obtain a second mixture; (d) the second mixture Granulating to obtain a second particle; (e) subjecting the first particle to the second particle. In a preferred embodiment of the present invention, the foregoing step (e) compresses the first particles and the second particles into a double-layer tablet; preferably, the layer of the double-layer tablet contains levodopa and a card. Doba, another layer contains Anke. In a preferred embodiment of the present invention, the excipient is a compound, a diluent, a disintegrating agent, or a combination thereof; more preferably, the binding agent is a microcrystalline cellulose or a hydroxypropyl group. a thiol cellulose, povidone, crospovidone, starch, or a combination thereof; the diluent is microcrystalline cellulose, hydroxypropyl methylcellulose, saccharide, mannitol, starch, or a combination thereof The disintegrating agent is microcrystalline cellulose, hydroxypropyl decyl cellulose, crospovidone, starch, or a combination thereof. Preferably, the excipient is microcrystalline cellulose. In a preferred embodiment of the invention, the granulation is wet granulation. In a preferred embodiment of the present invention, further comprising the step of: pulverizing the second mixture after the step (b); preferably, the pulverized second mixture has a particle size of at most 250 μπι; Preferably, the particle size is at most 150 μπι. In a preferred embodiment of the present invention, the method further comprises the steps of: sieving the pulverized second mixture; preferably, the pulverized second mixture is passed through a 60 to 100 mesh sieve; The best is through a 100 mesh mesh screen. In a preferred embodiment of the invention, further step (e) is followed by the step of coating the tablet after tableting with a film coat. In summary, the present invention provides a pharmaceutical composition for treating Parkinson's disease, comprising levodopa, carbidopa and acetonide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Excipients accepted; wherein it is not mixed with levodopa or carbidopa. The pharmaceutical composition of the present invention is granulated by mixing different ratios of carbidopa and levodopa in different ratios, and the granules of the fixed content of ampipone will be granulated in different dosage combinations, so that only Different dosage combinations can be achieved by adjusting the amount of carbidopa and levodopa mixed granulation products, which greatly simplifies the complexity of the process compared to WO 01/01984. Moreover, the pharmaceutical composition of the present invention still has a similar dissolution mode as the conventional Parkinson's disease drug. [Embodiment] Except for other meanings explained below, all scientific terms] 7 201114419 are explained in the original meaning as understood by those of ordinary skill in the art to which the invention pertains. In case of dispute, the definition of this specification shall be the main one. As used herein, the term "excipient" means an active substance used as a carrier for a pharmaceutically active ingredient; it may include a binder, a diluent, a disintegrating agent, a lubricant, a compression aid, a preservative. , coating agents, flavors, colorants, sweeteners, and the like. As used herein, the term "binder" refers to a combination of ingredients in a drug to form a mechanical strength. Specific examples are microcrystalline cellulose, hydroxypropyl methylcellulose, and poly Vetoketone, crospovidone, /晏 powder or copolydimensional _ (COp〇lyVid〇ne): wherein the microcrystalline cellulose is preferably P101, P102, etc.; hydroxypropyl fluorenyl cellulose (HPMC) can be Low substituted propyl mercapto cellulose (HPMC-L) or high substituted hydroxypropyl methylcellulose (HPMC-H), preferably high substituted hydroxypropyl fluorenyl cellulose (HPMC-H), such as HPMC E5 LV, HPMC E15 LV, HPMC A15 LV, HPMCK3 Premium, etc.; Povidone is preferably K30, K15, K90. 'Palace powder is preferably corn powder or Starch 1500®; copovidone is preferably copolymerization _ VA64. As used herein, the term "diluent" refers to an agent that expands the size of a tablet to a size that is convenient for the patient to use, such as microcellulose, hydroxypropyl fluorenylcellulose, and paste. Dextrin, saccharide, mannitol or starch; wherein the microcrystalline cellulose is preferably p1〇1, pl〇2, etc.; the saccharide is preferably lactose; the starch is preferably corn starch. In this context, the term "disintegrant" refers to an agent that releases water and causes the tablet to swell and dissolve and disintegrate in the digestive tract to release the active ingredient. Microcrystalline cellulose, hydroxypropyl methylcellulose, cross-linked carboxymethyl fiber, Croscarmellose sodium, cross-linked poly-dimensional brewing I or temple powder; wherein crystalline cellulose is preferably pl〇1, P102, etc. Hydroxypropyl fluorenyl sulphate HPMC) is preferably a low-substituted propyl fluorenyl cellulose (hpmc_l); 201114419 The starch is preferably corn starch or Starch 1500®. The following examples are merely illustrative of the preferred embodiments and are not intended to limit the scope of the invention. Appropriate changes and modifications can be made by those skilled in the art without departing from the spirit of the invention. Embodiments Example 1 First, the ingredients in Table 1 below were prepared by wet granulation. Granules containing levodopa and carbidopa: 1.4 mg HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution, followed by the remaining HPMC E5 LV, carbidopa monohydrate The levodopa and mannitol were uniformly mixed to prepare a first mixture. Then, the first mixture and the 5% HPMC E5 LV solution are successively poured into a granulator for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until the moisture content is between From 1% to 3%, the first granule is obtained. Table 1 Ingredient weight (mg) Levodopa 100.00 Carbidopa monohydrate 27.00 Mannitol 88.00 HPMC E5 LV 6.40 Total 221.40 After the ingredients in Table 2 below were prepared by wet granulation with Angkor Granules: 2.55 mg HPMC E5LV was dissolved in water to prepare a 5% HPMC E5 LV solution, which was then sequentially mixed with the remaining HPMC E5 LV, microcrystalline cellulose, SDS, mannitol and acetonide. Have 201114419

Two mixtures. Next, the second mixture and the 5% HPMCE5 LV solution were successively poured into a granulator for granulation, and then the granules were passed through a 25-mesh sieve and dried in an oven at 50 ° C to obtain second granules. Until the moisture content is between 1% and 3%, Table 2 Ingredient weight (mg) Anke Peng 200.00 Microcrystalline cellulose 0.50 Mannitol 88.00 HPMC E5 LV 7.55 SDS 11.00 Total 307.05 Finally according to the ingredients in Table 3 below Preparation of a tablet: mixing the first granule comprising levodopa and carbidopa with a second granule comprising acetonide, mixing with crospovidone and magnesium stearate, and then forming a tablet . Table 3 Component weight (mg) First particle 221.40 Second particle 307.05 Cross-linked povidone 10.00 Magnesium stearate 5.00 Total amount 543.45 Dissolution test Dissolution degree is an important indicator of the bioequivalence of the drug with the same main component, if the dissolution effect Good, it means that the oral drug can be disintegrated, dissolved and released in the gastrointestinal tract at the right time, and then absorbed by the human body. The following dissolution test was carried out to monitor the dissolution of the components of levodopa, carbidopa or acetamone in the obtained tablets in 120 minutes. 201114419 (1) Dissolution test of levodopa/carbidopa: 苍照American music code USP 32, NF 27 (1791) and the US FDA website for the supply of the Diss〇lution Methods Database In the middle of the search, the carboline was obtained by carbidopa/ancoke/levodopa. The dissolution method was carried out using the USP standard Xue-type device (Basket). The rotation speed was 50 rpm, and the solvent used was 75 〇mL. 0.1N HC1 solution, but the test time was changed to 12 〇 minutes, after which it was analyzed by HPLC. In this trial, Parkinson's disease drug Stalevo®, which also contained levodopa, carbidopa, and acenapat, was used as a control drug. B (2) Anitapone's Dissolution Test: The drug dissolution method of carbidopa/anitapone/levodopa was searched according to the Dissolution Methods Database provided on the FDA website (http: //www.accessdata.fda.gov/scripts/cder/dissolution / dsp_SearchResults Dissolutions.cfm) Into the rod bit 4, where the dissolution is performed using a USP standard basket unit 125 rpm and the solvent used is 900 mL ΡΗ5·5 The dish was buffered with acid, but the test time was changed to 120 minutes, after which it was analyzed by HPLC. In this test, the original use was used as a control drug. The dissolution test was carried out as described above, and the dissolution of the components of the obtained lozenges, levodopa, carbidopa or acetonide, was monitored in 12 minutes, respectively, using the initials as a control. The results are shown in the first panel, in which the dissolution profiles of levodopa, carbidopa, and anaconone are close to the control g. 'Example 2 First, the ingredients in Table 4 below were prepared by wet granulation to obtain granules containing levodopa and carbidopa: 1.4 mg of HPMCE5LV was dissolved in water, and 11 201114419 was formulated into a 5% HPMC E5 LV solution. Then, the remaining mixture was uniformly mixed with the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol to prepare a first mixture. Then, the first mixture and the 5% HPMC E5 LV solution are successively poured into a granulator for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until the moisture content is between From 1% to 3%, the first granule is obtained. Table 4 Ingredient Weight (mg) Levodopa 100.00 Carbidopa Monohydrate 27.00 Mannitol 88.00 HPMC E5 LV 6.40 Total 221.40 After the ingredients in Table 5 below were prepared by wet granulation with Angkor Granules: microcrystalline cellulose, SDS, mannitol, PVP K30 and acetonide are uniformly mixed to prepare a second mixture, and the second mixture is poured into a pulverizer for pulverization, and then the powder is passed. 100 mesh screen. Then, the previously sieved powder is poured into a granulator, and sprayed with deionized water for granulation, and then the granulated particles are passed through a 25-mesh sieve and dried in an oven at 50 ° C until moisture content. Between 1% and 3%, the second granule is obtained. Table 5 Ingredient Weight (mg) Anke Pang 200.00 Microcrystalline Cellulose 0.50 Mannitol 88.00 PVP K30 120.00 SDS 20.00 Total 428.50 12 201114419 Finally, the lozenge was prepared according to the ingredients in Table 6 below: the above contains levodopa And the first granule of carbidopa is mixed with the second granule containing acetonide, and then mixed with crospovidone and magnesium stearate, and then tableted. Table 6 Ingredient weight (mg) First particle 221.40 granule 428.50 crospovidone 10.00 Magnesium stearate 5.00 Total amount 664.90 The dissolution test was carried out as described in Example 1, and the components of the obtained tablet were separately monitored for levodopa, The dissolution of carbidopa or acetonide in 120 minutes, using the initial as a control drug. The results are shown in the second panel, in which the rate of dissolution of levodopa and carbidopa is close to that of the control drug; and the dissolution profile of ampicone is almost identical to that of the control drug. Example 3 First, the ingredients in Table 7 below were prepared by wet granulation to obtain granules containing levodopa and carbidopa: 1.4 mg of HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution. Then, the remaining mixture was uniformly mixed with the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol to prepare a first mixture. Then, the first mixture and the 5% HPMC E5 LV solution are successively poured into a granulator for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until the moisture content is between From 1% to 3%, the first granule is obtained. 13 201114419 Table 7 Ingredient Weight (mg) Left % ζ Dopa 100.00 Carbidopa Monohydrate 27.00 Mannitol 88.00 HPMC Ε 5 LV 6.40 Total 221.40 After the ingredients in Table 8 are prepared by wet granulation Granules of Angkeng: Microcrystalline cellulose, SDS, PVPK30, mannitol and acetonide are uniformly mixed to prepare a second mixture, and the second mixture is poured into a pulverizer for pulverization, and then The powder was passed through a 100 mesh screen. Then, the previously sieved powder is poured into a granulator and sprayed with deionized water for granulation. Then, the granulated particles are passed through a 25-mesh sieve and dried in an oven at 50 ° C until moisture content. Between 1% and 3%, the second granule is obtained. Table 8 Ingredient Weight (mg) Anitapeng 200.00 Microcrystalline Cellulose 0.50 Mannitol 168.00 PYP K30 40.00 SDS 12.00 Total 420.50 Finally, the lozenge was prepared according to the ingredients in Table 9 below: firstly, the above-mentioned levodopa and The first granule of carbidopa is mixed with 5 mg of crospovidone and 1.7 mg of magnesium stearate to obtain a first mixture; the second granule comprising acetonide and 5 mg of crospovidone And mixing 3.4 mg of magnesium stearate to obtain a second mixture; the first mixture and the second mixture are then made into a double layer ingot. [s 14 201114419

The dissolution test was carried out as described in Example 1, and the obtained components, levodopa, carbidopa or acetamone, were separately monitored for use within 120 minutes & The results were as shown in the third figure. The initial dissolution rate of levodopa, carbidopa and acetonide was slightly faster than that of the control drug, but it was consistent with the control drug after 45 minutes. ′ 4 Example 4

Table 9 - Ingredient weight (mg) First particle 221.40 Dimensional granules 420.50 Crosslinked polyv. _ 10.00 Magnesium stearate 5.10 Total 657.00 Firstly, the ingredients in Table 10 below were prepared by wet granulation with levodopa and Carbidopa granules: Dissolve 1.4 mg HPMC E5 LV in water and prepare a 5/〇 HPMC E5 LV solution, followed by the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and The mannose is uniformly mixed to prepare a first mixture. Then the above-mentioned 5% HPMC E5 LV was poured into the granulator overnight to carry out the silk = the granules were placed through the 25 mesh (four) nets and the moisture content was between 1% and 3%, and the first one was obtained until Table 10_ Weight (mg) 100.00 27.00 88.00 16.40 231.40 _Ingredients__ Levodopa

Carbidopa monohydrate mannitol HPMC E5 LV Total 201114419 The ingredients in Table 11 below were prepared by wet granulation with granules containing antecone: microcrystalline cellulose, SDS, PVPK30, mannose The alcohol and the anesthesia were uniformly mixed to prepare a second mixture, and the second mixture was poured into a pulverizer for pulverization, and then the powder was passed through a 1 mesh screen. Then, the sieved powder is poured into a granulator, and deionized water is sprayed for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until moisture content. Between 1% and 3%, the second granule is obtained. Table 11 Ingredient Weight (mg) Anke Pang 200.00 Microcrystalline Cellulose 0.50 Mannitol 168.00 PVP K30 40.00 SDS 12.00 Total _420.50 Finally, the lozenge was prepared according to the ingredients in Table 12 below: First, the above contains levodopa And mixing the first granule of carbidopa with 1.7 mg of magnesium stearate to obtain a first mixture; and further comprising the second granule comprising acetonide and 5 mg of crospovidone and 3.4 mg of magnesium stearate Mixing to obtain a second mixture; the first mixture and the second mixture are then made into a double layer ingot. Table 12 Ingredient weight (mg) First particle 231.40 Second particle 420.50 crospovidone 5.00 Magnesium stearate 5.10 Total amount 662.00 16 201114419 The dissolution test was carried out as described in Example 1, and the obtained tablet was separately monitored for left-handedness. Dopa, carbidopa or amphibious in 120 minutes, using the initial as a control drug. The results are shown in the fourth panel, in which levodopa, carbidopa and acetonide are all in close proximity to the control drug. Example 5 First, the ingredients in the following Table 13 were prepared by wet granulation to obtain granules containing levodopa and carbidopa: 14 mg of HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution. Then, the first mixture was prepared by uniformly mixing with the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol. Subsequently, the first mixture and the 5% HPMC E5 LV solution were successively introduced into a granulator for granulation, and then the granules were passed through a 25-mesh sieve and placed at 5 Torr. Dry in a 〇 oven until the moisture content is between 'to give the first granules. Table 13 Ingredient Weight (mg) Levodopa 100.00 Carbidopa Monohydrate 27.00 Mannitol 88.00 HPMC E5 LV 16.40 Total 231.40 After the ingredients in Table 14 were prepared by wet granulation with Angkor Granules: microcrystalline cellulose, SDS, PVP K30, mannitol and acetonide are uniformly mixed to prepare a second mixture, and the second compound is poured into a pulverizer for pulverization, and then The powder passed through a 1 mesh screen. Then, the previously sieved powder is poured into a granulator, and deionized water is sprayed for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until the moisture content. Between 1〇/〇_3%, the second 17 201114419 particles are obtained. Table 14 Ingredient Weight (mg) Anke Pang 200.00 Microcrystalline Cellulose 0.50 Mannitol 168.00 PVP K30 40.00 SDS 12.00 Total _420.50 • Finally, the lozenge is prepared according to the ingredients in Table 15 below: First, the above contains levodos The first granule of bar and carbidopa is mixed with 1.7 mg of magnesium stearate to give a first mixture; the second granule comprising acetonide and 5 mg of crospovidone and 3.4 mg of stearic acid are further obtained. The magnesium was mixed to give a second mixture; the first mixture and the second mixture were then made into a double layer ingot, and a 4% weight coat coating process was carried out with Opadry AMB. Table 15 Ingredient weight (mg) First particle 231.40 Second particle 420.50 Cross-linked povidone 5.00 Magnesium stearate 5.10 Opadry AMB 26.48 Total amount 688.48 The dissolution test was carried out as described in Example 1, and the components were separately monitored for left-handed rotation. The dissolution of dopa, carbidopa or acetonide in 120 minutes, using the initial as a control. The results are shown in the fifth panel, in which the dissolution rates of levodopa, carbidopa and acetonide were almost identical to those of the control. 18 201114419 Example 6 First, the ingredients in Table 16 below were prepared by wet granulation to obtain granules containing levodopa and carbidopa: 1.4 mg HPMC E5 LV was dissolved in water to prepare 5% HPMC E5 LV. The solution was then uniformly mixed with the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol to prepare a first mixture. Then, the first mixture and the 5% HPMC E5 LV solution are successively poured into a granulator for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until the moisture content is between From 1% to 3%, the first granule is obtained. Table 16 Ingredient Weight (mg) Levodopa 100.00 Carbidopa Monohydrate 27.00 Mannitol 88.00 HPMC E5 LV 16.40 Total 231.40 After the ingredients in Table 17 below were prepared by wet granulation with Angkor Granules: microcrystalline cellulose, SDS, PVPK30, mannitol and acetonide are sequentially mixed uniformly to prepare a second mixture, and the second mixture is poured into a pulverizer for pulverization, and then the powder is passed through 60. Purpose screen. Then, the previously sieved powder is poured into a granulator, and deionized water is sprayed for granulation, and then the granules are passed through a 25-mesh sieve and placed in a 5 (TC oven for drying until moisture content). Between 1% and 3%, the second granule is obtained. 19 201114419

Table 17 Ingredient Weight (mg) Anitapeng 200.00 Microcrystalline Cellulose 0.50 Mannitol 168.00 PVP K30 40.00 SDS 12.00 Total 420.50 Finally, the lozenge is prepared according to the ingredients in Table 18 below: First, the above contains levodopa and The first granule of carbidopa is mixed with 1.7 mg of magnesium stearate to obtain a hydrazine mixture; the second granule containing acetonide is mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate. A second mixture is obtained; the first mixture and the second mixture are then formed into a double layer ingot. Table 18 Ingredient weight (mg) First particle 231.40 Second particle 420.50 crospovidone 5.00 Magnesium stearate 5.10 Total amount 662.00 The dissolution test was carried out as described in Example 1, and the composition of the obtained tablet was separately monitored for levodopa, The dissolution of carbidopa or acetonide in 120 minutes, using the initial as a control. The results are shown in Figure 6, where the amount of levodopa, carbidopa or acetonide is similar to that of the control drug. Example 7 First, the ingredients in the following Table 19 were prepared by wet granulation to obtain granules containing levodopa and carbidopa: 1.4 mg of HPMC E5 LV was dissolved in No. 20 201114419 to prepare 5% HPMC E5. The LV solution was then uniformly mixed with the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol to prepare a first mixture. Then, the first mixture and the 5% HPMC E5 LV solution are successively poured into a granulator for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until the moisture content is between From 1% to 3%, the first granule is obtained. Table 19 Ingredient Weight (mg) Levodopa 100.00 Carbidopa Monohydrate 27.00 Mannitol 88.00 HPMC E5 LV 16.40 Total 231.40 After the ingredients in Table 20 below were prepared by wet granulation with Angkor Granules: microcrystalline cellulose, SDS, PVPK30, mannitol and acetonide are sequentially mixed uniformly to prepare a second mixture, and the second mixture is poured into a pulverizer for pulverization, and then the powder is passed through 80. Purpose screen. Then, the previously sieved powder is poured into a granulator, and sprayed with deionized water for granulation, and then the granulated particles are passed through a 25-mesh sieve and dried in an oven at 50 ° C until moisture content. Between 1% and 3%, the second granule is obtained. Table 20 Ingredient Weight (mg) Anitapeng 200.00 Microcrystalline Cellulose 0.50 Mannitol 168.00 PVP K30 40.00 SDS 12.00 Total 420.50 21 201114419 Finally, the lozenge is prepared according to the ingredients in Table 21 below: firstly, the above contains levodos The first granule of bar and carbidopa is mixed with 1.7 mg of magnesium stearate to give a first mixture; the second granule comprising acetonide and 5 mg of crospovidone and 3.4 mg of stearic acid are further obtained. The magnesium is mixed to give a second mixture, after which the first mixture and the second mixture are formed into a double layer ingot. Table 21 Ingredient weight (mg) First particle 231.40 Second particle 420.50 crospovidone 5.00 Magnesium stearate 5.10 Total amount 662.00 The dissolution test was carried out as described in Example 1, and the components of the obtained bond were separately monitored for levodopa, The use of carbidopa or antarone in the dissolution of 12 minutes is used as a control. The results are shown in the seventh panel, in which the dissolution of levodopa, carbidopa or acetonide is similar to that of the control drug. Example 8 First, the ingredients in the following Table 22 were prepared by wet granulation to obtain granules containing levodopa and carbidopa: 1.4 mg of HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution. Then, the remaining mixture was uniformly mixed with the remaining HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol to prepare a first mixture. Subsequently, the first mixture and the 5% HPMC E5 LV solution were successively granulated into a granulator for granulation, and then the granules were passed through a 25-mesh sieve and placed at 5 Torr. Dry in a crucible oven until the moisture content is between 1% and 3°/〇' to obtain the first pellet. 22 201114419

Table 22 Ingredient Weight (mg) Levodopa 100.00 Carbidopa Monohydrate 27.00 Mannitol 88.00 HPMC E5 LV 16.40 Total 231.40 After the ingredients in Table 23 below were prepared by wet granulation with Angkor Granules: Microcrystalline cellulose, SDS, mannitol, PVP K30 and acetonide were uniformly mixed to prepare a second mixture, and the second mixture was passed through a 100-mesh sieve. Then, the sieved powder is poured into a granulator, and deionized water is sprayed for granulation, and then the granules are passed through a 25-mesh sieve and dried in an oven at 50 ° C until moisture content. Between 1% and 3%, the second granule is obtained. Table 23 Component Weight (mg) Anke Peng 200.00 Microcrystalline Cellulose 0.50 Mannitol 88.00 PVP K30 120.00 SDS 20.00 Total 428.50 Finally, according to the following Table 24 Ingredients for preparing a tablet: firstly mixing the first granule comprising levodopa and carbidopa with 1.7 mg of magnesium stearate to obtain a first mixture; and further comprising the aforementioned second granule comprising acecophan and 5 The mg crospovidone and 3.4 mg magnesium stearate were mixed to give a second mixture; the first mixture and the second mixture were then made into a double layer ingot. 23 201114419 Table 24 Ingredient weight (mg) First particle 231.40 Second particle 428.50 Cross-linked povidone 5.00 Magnesium stearate 5.10 Total amount 670.00 The dissolution test was carried out as described in Example 1, and the composition of the obtained tablet was separately monitored. The dissolution of Ba, Carbidopa or Angkor in 120 minutes, using the initial as a control. The results are shown in Figure 8, where the dissolution of acetonide, carbidopa or acetonide is similar to that of the control drug.

24 201114419 [Simple description of the drawings] The first figure shows the dissolution of levodopa, carbidopa and acetonide in the tablets prepared in Example 1 within 120 minutes, and the control drug is the initial. The second figure shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 2 within 120 minutes, and the control drug is the initial. The third figure shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 3 within 120 minutes, and the control drug is the initial. The fourth figure shows the dissolution of levodopa, carbidopa and acetonide in the tablets prepared in Example 4 within 120 minutes, and the control drug is the starting point. The fifth figure shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 5 within 120 minutes, and the control drug is the initial. The sixth figure shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 6 within 120 minutes, and the control drug is the initial. The seventh figure shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 7 within 120 minutes, and the control drug is the initial. The eighth figure shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 8 in 120 minutes, and the control drug is the starting point. [Main component symbol description]

None 25

Claims (1)

201114419 VII. Scope of application: 1. A pharmaceutical composition for the treatment of Parkinson's disease, comprising: 25 to 300 mg of Levodopa, 5 to 75 mg of Carbidopa and 25 to 300 mg of Entacapone, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; wherein the acamera is not mixed with levodopa or carbidopa. 2. A pharmaceutical composition as described in claim 1 of the patent application, which is an oral solid pharmaceutical composition. 3. If the pharmaceutical composition described in item 2 of the patent application is applied, it is one ingot. 4. A pharmaceutical composition as claimed in claim 3, which is a two-layer tablet. 5. The pharmaceutical composition of claim 4, wherein one layer of the two-layered key agent comprises levodopa and carbidopa, and the other layer comprises amphibi. 6. The pharmaceutical composition according to claim 1, wherein the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof. 7. The pharmaceutical composition according to claim 6, wherein the φ mixture is microcrystalline cellulose, propylmethylcellulose, povidone, cross-linked poly Crospovidone, or a combination thereof. 8. The pharmaceutical composition according to claim 6, wherein the diluent is microcrystalline cellulose, hydroxypropyl decyl cellulose, saccharide, mannitol, starch, or a combination thereof. 9. The pharmaceutical composition according to claim 6, wherein the disintegrating agent is microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, starch, or a combination thereof. 10. The pharmaceutical composition according to claim 6, wherein the excipient is microcrystalline cellulose. The pharmaceutical composition according to claim 2, wherein the oral solid pharmaceutical composition further comprises a film coat. 12. A pharmaceutical composition for treating Parkinson's disease, comprising at least a first unit, a second unit, and at least one pharmaceutically acceptable excipient, wherein the first unit comprises levodopa And a mixture of carbidopa, the second unit comprising amphibi. 13. The pharmaceutical composition according to claim 12, wherein the content of levodopa is 25 to 300 mg, the content of carbidopa is 5 to 75 mg, and the content of acetonide is 25 to 300 mg. . 14. A pharmaceutical composition as claimed in claim 12, which is a tablet. 15. A pharmaceutical composition as claimed in claim 14, which is a double layer of a bonding agent. 16. The pharmaceutical composition according to claim 12, wherein the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof. 17. The pharmaceutical composition according to claim 16, wherein the binding agent is microcrystalline cellulose, hydroxypropyl decyl cellulose, povidone, crospovidone, starch, or a combination thereof. . 18. The pharmaceutical composition according to claim 16, wherein the diluent is microcrystalline cellulose, hydroxypropyl decyl cellulose, saccharide, mannitol, starch, or a combination thereof. 19. The pharmaceutical composition according to claim 16, wherein the disintegrating agent is microcrystalline cellulose, hydroxypropyl decyl cellulose, crospovidone, starch, or a combination thereof. 20. A method of preparing a pharmaceutical composition according to claim 1, comprising the steps of: (a) mixing levodopa, carbidopa and at least one first excipient a first mixture; (b) granulating the first mixture to obtain a first granule; (c) mixing ampicone and at least one second excipient to give a mixture of AL ό 27 201114419; (d) The second mixture is granulated to obtain a second granule; (e) the first granule and the second granule are ingot. 21. The method of claim 20, wherein the aforementioned step (e) compresses the first particles and the second particles into a bilayer tablet. 22. The method of claim 21, wherein one layer of the aforementioned bilayer tablet comprises levodopa and carbidopa, and the other layer comprises acetonide. 23. The method of claim 20, wherein the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof. The pharmaceutical composition according to claim 23, wherein the binding agent is microcrystalline cellulose, hydroxypropyl decyl cellulose, povidone, crospovidone, starch, or combination. 25. The pharmaceutical composition of claim 23, wherein the diluent is microcrystalline cellulose, hydroxypropyl decyl cellulose, saccharide, mannitol, starch, or a combination thereof. 26. The pharmaceutical composition according to claim 23, wherein the disintegrating agent is microcrystalline cellulose, hydroxypropyl decyl cellulose, crospovidone, starch, or a combination thereof. The method of claim 20, wherein the second excipient is microcrystalline cellulose. 28. The method of claim 20, wherein the granulation is wet granulation. 29. The method of claim 20, further comprising the step of pulverizing the second mixture after step (b). The method of claim 29, wherein the pulverized second mixture has a particle size of at most 250 μm. The method of claim 29, wherein the pulverized second mixture has a particle size of at most 150 μm. 32. The method of claim 29, further comprising the step of: lj Ο νί 28 201114419, the step of: sieving the pulverized second mixture. 33. The method of claim 20, further comprising, after step (e), the step of coating the tablet after tableting with a film coat. 29