WO2011075912A1 - 治疗帕金森氏症的医药组合物及其制备方法 - Google Patents

治疗帕金森氏症的医药组合物及其制备方法 Download PDF

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Publication number
WO2011075912A1
WO2011075912A1 PCT/CN2009/076069 CN2009076069W WO2011075912A1 WO 2011075912 A1 WO2011075912 A1 WO 2011075912A1 CN 2009076069 W CN2009076069 W CN 2009076069W WO 2011075912 A1 WO2011075912 A1 WO 2011075912A1
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Prior art keywords
pharmaceutical composition
carbidopa
levodopa
mixture
microcrystalline cellulose
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PCT/CN2009/076069
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English (en)
French (fr)
Inventor
郝为华
王钟靓
陈蕙筠
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台湾东洋药品工业股份有限公司
因华生技制药股份有限公司
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Application filed by 台湾东洋药品工业股份有限公司, 因华生技制药股份有限公司 filed Critical 台湾东洋药品工业股份有限公司
Priority to EP09852462.2A priority Critical patent/EP2517704B1/en
Priority to PCT/CN2009/076069 priority patent/WO2011075912A1/zh
Priority to US13/518,767 priority patent/US9750702B2/en
Priority to JP2012545047A priority patent/JP5718937B2/ja
Priority to CN200980163113.0A priority patent/CN102781440B/zh
Publication of WO2011075912A1 publication Critical patent/WO2011075912A1/zh

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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
    • A61K9/2072—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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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]
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • composition for treating Parkinson's disease and preparation method thereof
  • the present invention relates to a pharmaceutical composition for treating Parkinson's disease, and a method of preparing a pharmaceutical composition as described above. Background technique
  • Carbidopa is an aromatic L-amino acid decarboxylase inhibitor, which can effectively reduce the conversion of levodopa to dopamine and increase the activity of levodopa and dopamine in the brain. concentration.
  • Sinemet® from Bristol-Myers Squibb
  • Parcopa® from Schwarz Pharma.
  • U.S. Patent No. 5,446,194 also discloses a drug for the treatment of Parkinson's disease, Entacapone (Entacapone).
  • This drug is a catechol-O-methyl transferase (COMT) inhibitor, which prevents levodopa from being metabolized to 3-methoxy when used in combination with levodopa.
  • 3-methoxy- 4-hydroxy-L-phenylalanine (3-OMD) which increases the concentration of levodopa in the brain and increases the bioavailability of levodopa .
  • Ortan's Comtan® is the drug.
  • the patient can control the symptoms by taking a lozenge containing a composition of levodopa and carbidopa several times a day and a lozenge containing an acetonide.
  • this method of taking two lozenges at a time is a burden for patients who have difficulty swallowing or have symptoms of dizziness.
  • WO 01/01984 proposes a pharmaceutical composition comprising levodopa, carbidopa and ampicone, wherein carbidopa is substantially not mixed with levodopa and anaconone to increase Kabi Dopa's bioavailability.
  • This composition can be contained in one tablet at the same time The three components can improve the patient's compliance when taking the drug.
  • the drug is marketed as a commercial stencil (Stalevo®) (developed by Novartis and Orion).
  • the initial film coats are available in a variety of dosage combinations such as Stalevo® 50, 75, 100, 125, 150 and 200, all of which have an ampicone content of 200 mg, card
  • the contents of bidopa and levodopa were 12.5/50 mg, 18.75/75 mg, 25/100 mg, 31.25/125 mg, 37.5/150 mg and 50/200 mg, respectively.
  • applying the contents disclosed in WO 01/01984 to the manufacture of the different dosage combinations described above will make the manufacturing process very complicated.
  • carbidopa is not substantially mixed with levodopa and acenapat, 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 acetonide in different dose combinations is not the same, so these two components The mixture must be prepared separately according to the requirements of the different dosage combinations, so that the complexity of the manufacturing process will be caused when manufacturing different dosage combinations. Summary of the invention
  • the inventors have developed an improved method which simplifies the production process without affecting the dissolution rate of the active ingredient.
  • a pharmaceutical composition for treating Parkinson's disease comprising levodopa, carbidopa and acetonide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical An acceptable excipient; 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 unit comprises a mixture of levodopa and carbidopa, the second unit comprising amphibi.
  • 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 ampoule It is a pharmaceutically acceptable salt of at least one pharmaceutically acceptable salt, and at least one pharmaceutically acceptable form; wherein it is not mixed with levodopa or carbidopa.
  • the pharmaceutical composition is an oral solid pharmaceutical composition; preferably, a tablet; more preferably, a bilayer tablet; One layer of the bilayer tablet contains levodopa and carbidopa, and the other layer contains amphibi.
  • the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof; more preferably, the binder is microcrystalline cellulose, hydroxypropyl Hydroxypropyl methylcellulose (HPMC), povidone, crospovidone, starch, or a combination thereof; the diluent is microcrystalline cellulose, hydroxypropyl methyl fiber a saccharide, a saccharide, a mannitol, a starch, or a combination thereof; the disintegrating agent is microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, starch, or a combination thereof; The excipient is microcrystalline cellulose.
  • HPMC hydroxypropyl Hydroxypropyl methylcellulose
  • disintegrating agent is microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, starch, or a combination thereof
  • the excipient is microcrystalline cellulose.
  • the oral solid pharmaceutical composition further comprises a film coat.
  • 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 mixture of levodopa and carbidopa, the second unit comprising ampicone; preferably, the levodopa content is 25 to 300 mg, and the carbidopa content is 5 to 75. The amount of milligrams of ampicone is 25 to 300 mg.
  • the pharmaceutical composition is an oral solid pharmaceutical composition; preferably, a tablet; more preferably, a bilayer tablet; One layer of the bilayer tablet contains levodopa and carbidopa, and the other layer contains amphibi.
  • the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof; more preferably, the binder is microcrystalline cellulose or hydroxypropyl methyl fiber. , 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 methylcellulose, crospovidone, starch, or a combination thereof.
  • the invention also provides a method of preparing a pharmaceutical composition as hereinbefore described, which comprises the following steps:
  • the step (e) is to press the first particle and the second particle into a double-layer tablet; preferably, one layer of the double-layer tablet contains levodos Ba and Carbidopa, the other layer contains Anke.
  • the excipient is a binder, a diluent, a disintegrating agent, or a combination thereof; more preferably, the binder is microcrystalline cellulose or hydroxypropyl methyl fiber. , 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, hydroxypropylmethylcellulose, crospovidone, starch, or a combination thereof; preferably, the excipient is microcrystalline cellulose. In a preferred embodiment of the invention, the granulation is wet granulation.
  • the further step of the step (b) comprises: pulverizing the second mixture; preferably, the pulverized second mixture has a particle size of at most
  • the particle size is at most 150 ⁇ .
  • the further step comprises: sieving the pulverized second mixture; preferably, the pulverized second mixture is passed through 60 to 100 Mesh sieve; better, it is through a 100 mesh mesh screen.
  • the further step of the step (e) comprises the step of: coating the tablet after the tableting into a film coat.
  • 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 medicinal An acceptable excipient; wherein it is not mixed with levodopa or carbidopa.
  • the pharmaceutical composition of the present invention is a mixed granulation of carbidopa and levodopa in the same ratio of different dosage combinations, and the granules of the fixed content of acetamone will be granulated in different dosage combinations, so that only The dosage of carbidopa and levodopa mixed granulation products needs to be adjusted to achieve different dosage combinations, which greatly simplifies the complexity of the manufacturing process compared to WO 01/01984. Moreover, the pharmaceutical composition of the present invention still has a similar dissolution pattern as the conventional Parkinson's disease drug.
  • Fig. 1 shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 1 in 120 minutes, and the control drug was the initial.
  • Fig. 2 shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 2 in 120 minutes, and the control drug was the initial.
  • Fig. 3 is a view showing the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 3 within 120 minutes, and the control drug is the initial.
  • Fig. 4 is a view showing the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 4 in 120 minutes, and the control drug is the initial.
  • Fig. 5 is a view showing the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 5 in 120 minutes, and the control drug was the initial.
  • Fig. 6 is a view showing the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 6 in 120 minutes, and the control drug was the initial.
  • Fig. 7 shows the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 7 within 120 minutes, and the control drug was the initial.
  • Fig. 8 is a view showing the dissolution of levodopa, carbidopa and acetonide in the tablet prepared in Example 8 in 120 minutes, and the control drug was the initial. detailed description
  • excipient means a non-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 1" , preservatives, coatings, flavors, colorants, sweeteners, etc.
  • binder a term refers to an agent that combines the ingredients of a drug to form a mechanical strength, such as microcrystalline cellulose, hydroxypropyl methylcellulose, polydimensional Ketone, crospovidone, starch or copolyvidone: wherein the microcrystalline cellulose is preferably P101, P102, etc.; hydroxypropyl methylcellulose (HPMC) can be low substituted hydroxypropyl methyl fiber (HPMC-L) or high-substituted hydroxypropyl methylcellulose (HPMC-H), preferably high-substituted hydroxypropylmethylcellulose (HPMC-H), such as HPMC E5 LV, HPMC El 5 LV HPMC A15 LV, HPMC K3 Premium, etc.; Povidone is preferably K30, ⁇ 15, ⁇ 90, etc.; starch is preferably corn starch or Starch 1500®; copolyvidone is preferably copolyvidone VA64.
  • decient refers to an agent that expands the size of a tablet to a size that is convenient for the patient to use, such as microcrystalline cellulose, hydroxypropyl methylcellulose, Dextrm, saccharide, mannitol or starch; wherein the microcrystalline cellulose is preferably P101, P102, etc.; the saccharide is preferably lactose; the starch is preferably corn starch.
  • dismtegmnt refers to an agent that swells and dissolves in the digestive tract to release the active ingredient when exposed to water.
  • specific examples are microcrystalline cellulose, hydroxypropyl methylcellulose, Croscarmellose sodium, crospovidone or starch; wherein the microcrystalline cellulose is preferably P101, P102, etc.; Hydroxypropyl methylcellulose (HPMC) is preferably a low substituted hydroxypropyl methylcellulose (HPMC-L); the starch is preferably corn starch or Starch 1500®.
  • HPMC Hydroxypropyl methylcellulose
  • HPMC-L low substituted hydroxypropyl methylcellulose
  • starch is preferably corn starch or Starch 1500®.
  • the granules containing levodopa and carbidopa were prepared by wet granulation in the following Table 1: 1.4 mg HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution, followed by the remainder and the remainder. The HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture. Then, the first mixture and 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the first particles are obtained.
  • HPMC E5 LV 6.40 total 221.40 The ingredients in Table 2 below were then wet granulated to prepare granules containing acetonide: 2.55 mg HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution, followed by the remaining HPMC E5 LV The microcrystalline cellulose, SDS, mannitol and acenaze are uniformly mixed to prepare a second mixture. Then, the second mixture and 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the second granule is obtained.
  • a tablet was prepared according to the ingredients in Table 3: The first granule containing levodopa and carbidopa was mixed with the second granule containing acetonide, and then crospovidone and hard The magnesium oleate is mixed and then tableted.
  • Solubility is an important indicator of the bioequivalence of drugs with the same main component. If the dissolution effect is good, it means that the oral drug can be disintegrated, dissolved, released in the gastrointestinal tract at a proper time, and then absorbed by the human body.
  • Method Database retrieved the drug dissolution method of carbidopa/ancoco/levodopa (http://www.accessdata.fda.gov/scripts/cder/dissolution/ dsp-SearchResults—Dissolutions. cfm
  • the dissolution test was carried out in which the dissolution was carried out using a USP standard basket apparatus at a rotation speed of 125 rpm, and the solvent used was 900 mL of a pH 5.5 phosphate buffer solution, but the test time was changed to 120 minutes, and then used.
  • the ingredients in Table 4 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 a 5% HPMC E5 LV solution, followed by the remainder and the remainder.
  • the HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture.
  • the first mixture and 5% HPMC E5 LV solution were successively poured into a granulator for granulation, and then the granules were passed through a 25-mesh sieve. Drying in an oven at 50 ° C until the moisture content is between 1% and 3%, resulting in the first granule (
  • the ingredients in the following Table 5 were prepared by wet granulation to obtain granules containing acetonide: microcrystalline cellulose, SDS, mannitol, PVP K30 and acetonide were uniformly mixed to obtain a second
  • the mixture is poured into a pulverizer for pulverization, and then the powder is passed through a 100-mesh screen.
  • 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.
  • a tablet was prepared according to the ingredients in Table 6 below: the first granule containing levodopa and carbidopa was mixed with the second granule containing acetonide, and then crospovidone and hard The magnesium oleate is mixed and then tableted.
  • Example 3 The dissolution test was carried out as described in Example 1, and the components of the obtained tablet were separately monitored for levodopa.
  • the results are shown in Figure 2, in which the rate of dissolution of levodopa and carbidopa is close to that of the control drug; and the dissolution profile of the anesthetic is almost identical to the control drug.
  • Example 3 The results are shown in Figure 2, in which the rate of dissolution of levodopa and carbidopa is close to that of the control drug; and the dissolution profile of the anesthetic is almost identical to the control drug.
  • the ingredients in Table 7 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 a 5% HPMC E5 LV solution, followed by the remainder and the remainder.
  • the HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture.
  • the first mixture and 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the first particles are obtained.
  • the ingredients in the following Table 8 were prepared by wet granulation to obtain granules containing acetonide: microcrystalline cellulose, SDS, PVP K30, mannitol and acetonide were sequentially mixed to obtain a second
  • the mixture is poured into a pulverizer for pulverization, and then the powder is passed through a 100-mesh screen.
  • 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.
  • the tablet was prepared according to the ingredients in Table 9 below: First, the first granule containing levodopa and carbidopa was mixed with 5 mg crospovidone and 1.7 mg magnesium stearate to obtain the first a mixture; the second granule comprising acetonide is further mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate to obtain a second mixture; then the first mixture and the second mixture are made Double layer ingot.
  • Example 4 The dissolution test was carried out as described in Example 1, and the dissolution of the components of levodopa, carbidopa or acetamone in the obtained tablet was monitored in 120 minutes, and the initial use was used as a control drug. The results are shown in Figure 3. Compared with the control drug, the initial dissolution rate of levodopa, carbidopa and acetonide was slightly faster, but it was consistent with the control drug after 45 minutes.
  • Example 4 The results are shown in Figure 3. Compared with the control drug, the initial dissolution rate of levodopa, carbidopa and acetonide was slightly faster, but it was consistent with the control drug after 45 minutes.
  • the ingredients in Table 10 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, followed by the remainder and the remainder.
  • the HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture.
  • the first mixture and 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the first particles are obtained.
  • a tablet was prepared according to the ingredients in Table 12 below: First, the first granule comprising levodopa and carbidopa was mixed with 1.7 mg of magnesium stearate to obtain a first mixture; The second granule of acetonide was mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate to give a second mixture; the first mixture and the second mixture were then made into a double layer ingot.
  • Example 5 The dissolution test was carried out as described in Example 1, and the dissolution of the components of levodopa, carbidopa or acetamone in the obtained tablet was monitored in 120 minutes, respectively, in which the original was used as a control drug. The results are shown in Figure 4, in which levodopa, carbidopa, and acetonide were all in close proximity to the control drug.
  • Example 5 The results are shown in Figure 4, in which levodopa, carbidopa, and acetonide were all in close proximity to the control drug.
  • the ingredients in Table 13 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 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the first particles are obtained.
  • the ingredients in Table 14 below were prepared by wet granulation to obtain granules containing acetonide: microcrystalline cellulose, SDS, PVP K30, mannitol and acetonide were sequentially mixed to obtain a second
  • the mixture is poured into a pulverizer for pulverization, and then the powder is passed through a 100-mesh screen.
  • 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.
  • a tablet was prepared according to the ingredients in Table 15 below: First, the first granule containing levodopa and carbidopa was mixed with 1.7 mg of magnesium stearate to obtain a first mixture; The second granule of acetonide is mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate to obtain a second mixture; then the first mixture and the second mixture are made into a double layer ingot, and Opadry AMB is used. A film coating process with a weight gain of 4% was carried out. Ingredient weight (mg)
  • 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 a 5% HPMC E5 LV solution, followed by the remainder and the remainder.
  • the HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture.
  • the first mixture and 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the first particles are obtained.
  • the granules were passed through a 25-mesh screen and dried in an oven at 50 ° C until the moisture content was between 1% and 3%, resulting in a second granule.
  • a tablet was prepared according to the ingredients in Table 18 below: First, the first granule comprising levodopa and carbidopa was mixed with 1.7 mg of magnesium stearate to obtain a first mixture; The second granule of acetonide was mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate to give a second mixture; the first mixture and the second mixture were then made into a double layer ingot.
  • Example 7 The dissolution test was carried out as described in Example 1, and the dissolution of the components of levodopa, carbidopa or acetamone in the obtained tablet was monitored in 120 minutes, respectively, and the initial use was used as a control. The results are shown in Fig. 6, in which the dissolution of levodopa, carbidopa or acetonide was similar to that of the control drug.
  • Example 7 The results are shown in Fig. 6, in which the dissolution of levodopa, carbidopa or acetonide was similar to that of the control drug.
  • 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 water to prepare a 5% HPMC E5 LV solution, followed by the remainder and the remainder.
  • the HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture.
  • the first mixture and 5% HPMC E5 LV solution were successively poured into a granulator for granulation, and then the granules were passed through a 25-mesh sieve. Drying in an oven at 50 ° C until the moisture content is between 1% and 3%, resulting in the first granule (
  • the ingredients in the following Table 20 were prepared by wet granulation to obtain granules containing acetonide: microcrystalline cellulose, SDS, PVP K30, mannitol and acetonide were sequentially mixed to obtain a second
  • the mixture was poured into a pulverizer for pulverization, and then the powder was passed through a sieve of 80 mesh.
  • 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.
  • a tablet was prepared according to the ingredients in Table 21 below: First, the first granule comprising levodopa and carbidopa was mixed with 1.7 mg of magnesium stearate to obtain a first mixture; The second granule of acetonide was mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate to give a second mixture; the first mixture and the second mixture were then made into a double layer ingot.
  • Example 8 The dissolution test was carried out as described in Example 1, and the dissolution of the components of levodopa, carbidopa or acetamone in the obtained tablet was monitored in 120 minutes, respectively, and the initial use was used as a control. The results are shown in Figure 7, in which the dissolution of levodopa, carbidopa or acetonide was similar to that of the control drug.
  • Example 8 The results are shown in Figure 7, in which the dissolution of levodopa, carbidopa or acetonide was similar to that of the control drug.
  • the granules containing levodopa and carbidopa were first prepared by wet granulation in the following Table 22: 1.4 mg HPMC E5 LV was dissolved in water to prepare a 5% HPMC E5 LV solution, followed by the remainder and the remainder. The HPMC E5 LV, carbidopa monohydrate, levodopa and mannitol were uniformly mixed to prepare a first mixture. Then, the first mixture and 5% HPMC E5 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 until the moisture content was introduced. From 1% to 3%, the first particles are obtained.
  • the ingredients in Table 23 below were prepared by wet granulation to obtain granules containing acetonide: microcrystalline cellulose, SDS, mannitol, PVP K30 and acetonide were uniformly mixed to obtain a second The mixture is passed through a 100 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.
  • a tablet was prepared according to the ingredients in Table 24 below: First, the first granule comprising levodopa and carbidopa was mixed with 1.7 mg of magnesium stearate to obtain a first mixture; The second granule of acetonide was mixed with 5 mg of crospovidone and 3.4 mg of magnesium stearate to give a second mixture; the first mixture and the second mixture were then made into a double layer ingot.
  • the dissolution test was carried out as described in Example 1, and the dissolution of the components of levodopa, carbidopa or acetamone in the obtained tablet was monitored in 120 minutes, respectively, and the initial use was used as a control.
  • the results are shown in Fig. 8, in which the dissolution amount of acetonide, carbidopa or acetonide was close to that of the control drug.

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Description

治疗帕金森氏症的医药组合物及其制备方法 技术领域
本发明是关于一种用于治疗帕金森氏症的医药组合物， 以及制备如前 文所述的医药组合物的方法。 背景技术
在帕金森氏症（Parkinson's disease) 的治疗上， 最常被使用的药物为左 旋多巴 （Levodopa) 以及卡比多巴 （Carbidopa) 的组合物所制成的锭剂。 卡比多巴为芳香族 L-氨基酸类脱羧基酶 （ aromatic L-amino acid decarboxylase)抑制齐 1」， 其可有效减少左旋多巴转化为多巴胺， 提高作用于 脑部的左旋多巴及多巴胺的浓度。 此类药物目前已有多种商品可供使用， 例如 Bristol-Myers Squibb销售的 Sinemet®, 或是 Schwarz Pharma销售的 Parcopa®等等。
此外，美国专利第 5,446,194号亦揭示一种用于治疗帕金森氏症的药物， 安它可朋 （恩他卡朋， Entacapone) 。 此药物为一种儿茶酚 -0-甲基转移酶 抑制剂（catechol-O-methyl transferase (COMT) inhibitor) ， 其与左旋多巴并 用时， 可防止左旋多巴被代谢为 3-甲氧基 -4-羟基 -L-苯丙氨酸 （3-methoxy- 4-hydroxy-L-phenylalanine (3-OMD)) ， 进而提高左旋多巴在脑中的浓度， 增加左旋多巴的生体可用率。 Orion生产的 Comtan®即为这种药品。
患者可藉由每天数次服用含有左旋多巴与卡比多巴的组合物的锭剂以 及含有安它可朋的锭剂来控制症状。 然而， 这种一次需服用两种锭剂的方 式对于有吞咽困难或有抖动症状的患者而言是种负担。
WO 01/01984 即提出一种包含左旋多巴、 卡比多巴以及安它可朋的药 物组合物， 其中卡比多巴实质上不与左旋多巴及安它可朋混合， 以增加卡 比多巴的生体可用率（bioavailability) 。 这种组合物可同时于一锭剂中包含 三种成分， 因此可以改善患者服药时的顺服性。 目前， 此药物已有商品化 的始立膜衣锭（Stalevo®)上市（由 Novartis与 Orion共同合作开发而成）。
为因应不同的剂量组合需求，始立膜衣锭提供有 Stalevo® 50、 75、 100、 125、 150以及 200等多种的剂量组合， 其中所有剂量的安它可朋含量均为 200 mg, 卡比多巴与左旋多巴的含量分别为 12.5/50 mg、 18.75/75 mg、 25/100 mg、 31.25/125 mg, 37.5/150 mg以及 50/200 mg。然而，将 WO 01/01984 所揭示的内容应用于制造上述不同的剂量组合时， 将使得制作过程变得很 繁杂。 因为在 WO 01/01984中， 卡比多巴实质上不与左旋多巴及安它可朋 混合， 因此卡比多巴需另行造粒； 在此同时， 虽然左旋多巴与安它可朋可 以混合一起造粒，但是因为安它可朋于每颗锭剂中的含量均固定为 200 mg, 而不同剂量组合中的左旋多巴与安它可朋的比例又并非一致， 故这二种成 分的混合物又须根据不同剂量组合的需求分别制备， 如此在制造不同剂量 组合时将造成制作过程的复杂度。 发明内容
为解决上述问题， 发明人开发出一种改良方法， 在不影响有效成分的 溶离率的条件下， 使制作过程简化。
因此， 本发明目的之一是提供一种用于治疗帕金森氏症的医药组合物， 其包含左旋多巴、 卡比多巴及安它可朋或其医药可接受盐， 以及至少一种 医药上可接受的赋形剂； 其中安它可朋非与左旋多巴或卡比多巴混合。
本发明的另一目的是提供一种用于治疗帕金森氏症的医药组合物， 其至 少包含一第一单元、 一第二单元， 以及至少一种医药上可接受的赋形剂， 其 中该第一单元包含左旋多巴以及卡比多巴的混合物， 该第二单元包含安它可 朋。
本发明的又一目的是提供一种制备如前文所述的医药组合物的方法， 其包含下列歩骤： (a) 将左旋多巴、 卡比多巴及至少一种第一赋形剂混合， 得出第一混
(b) 将第一混合物粒化， 得出第一颗粒；
(c) 将安它可朋及至少一种第二赋形剂混合， 得出第二混合物； (d) 将第二混合物粒化， 得出第二颗粒；
(e) 将第一颗粒与第二颗粒进行压锭。
为达上述目的， 本发明提供一种用于治疗帕金森氏症的医药组合物， 其包含： 25至 300毫克的左旋多巴、 5至 75毫克的卡比多巴及 25至 300 毫克的安它可朋， 或其医药可接受盐， 以及至少一种医药上可接受的赋形 齐 1」； 其中安它可朋非与左旋多巴或卡比多巴混合。
在本发明的较佳实施态样中， 所述医药组合物是一口服固体医药组合 物； 较佳者， 是一锭剂； 更佳者， 是一双层锭剂； 最佳者， 所述双层锭剂 的一层包含左旋多巴及卡比多巴， 另一层包含安它可朋。
在本发明的较佳实施态样中， 所述赋形剂为结合剂、 稀释剂、 崩散剂、 或其组合； 更佳者， 所述结合剂为微晶纤维素（microcrystalline cellulose) 、 羟丙基甲基纤维素 （hydroxypropyl methylcellulose , HPMC ) 、 聚维酮 (povidone) 、 交联聚维酮 （ crospovidone ) 、 淀粉、 或其组合； 所述稀释 剂为微晶纤维素、 羟丙基甲基纤维素、 糖类、 甘露糖醇、 淀粉、 或其组合; 所述崩散剂为微晶纤维素、 羟丙基甲基纤维素、 交联聚维酮、 淀粉、 或其 组合； 最佳者， 所述赋形剂为微晶纤维素。
在本发明的较佳实施态样中， 所述口服固体医药组合物进一歩包含一 膜衣。
本发明并提供一种用于治疗帕金森氏症的医药组合物， 其至少包含一 第一单元、 一第二单元， 以及至少一种医药上可接受的赋形剂， 其中该第 一单元包含左旋多巴以及卡比多巴的混合物， 该第二单元包含安它可朋； 较佳者， 所述左旋多巴的含量为 25至 300毫克、卡比多巴的含量为 5至 75 毫克， 安它可朋的含量为 25至 300毫克。
在本发明的较佳实施态样中， 所述医药组合物是一口服固体医药组合 物； 较佳者， 是一锭剂； 更佳者， 是一双层锭剂； 最佳者， 所述双层锭剂 的一层包含左旋多巴及卡比多巴， 另一层包含安它可朋。
在本发明的较佳实施态样中， 所述赋形剂为结合剂、 稀释剂、 崩散剂、 或其组合； 更佳者， 所述结合剂为微晶纤维素、 羟丙基甲基纤维素、 聚维 酮、 交联聚维酮、 淀粉、 或其组合； 所述稀释剂为微晶纤维素、 羟丙基甲 基纤维素、 糖类、 甘露糖醇、 淀粉、 或其组合； 所述崩散剂为微晶纤维素、 羟丙基甲基纤维素、 交联聚维酮、 淀粉、 或其组合。
本发明亦提供一种制备如前文所述的医药组合物的方法， 其包含下列 歩骤：
(a) 将左旋多巴、 卡比多巴及至少一种第一赋形剂混合， 得出第一混
(b) 将第一混合物粒化， 得出第一颗粒；
(c) 将安它可朋及至少一种第二赋形剂混合， 得出第二混合物；
(d) 将第二混合物粒化， 得出第二颗粒；
(e) 将第一颗粒与第二颗粒进行压锭。
在本发明的较佳实施态样中， 所述歩骤 (e)是将第一颗粒与第二颗粒压 制成双层锭剂； 较佳者， 所述双层锭剂的一层包含左旋多巴及卡比多巴， 另一层包含安它可朋。
在本发明的较佳实施态样中， 所述赋形剂为结合剂、 稀释剂、 崩散剂、 或其组合； 更佳者， 所述结合剂为微晶纤维素、 羟丙基甲基纤维素、 聚维 酮、 交联聚维酮、 淀粉、 或其组合； 所述稀释剂为微晶纤维素、 羟丙基甲 基纤维素、 糖类、 甘露糖醇、 淀粉、 或其组合； 所述崩散剂为微晶纤维素、 羟丙基甲基纤维素、 交联聚维酮、 淀粉、 或其组合； 最佳者， 所述赋形剂 为微晶纤维素。 在本发明的较佳实施态样中， 所述粒化为湿式造粒。
在本发明的较佳实施态样中， 进一歩在歩骤 (b)之后包含下列歩骤： 将 第二混合物进行粉碎； 较佳者， 所述经粉碎后的第二混合物的粒径最大为
250 μπΐ; 更佳者， 该粒径最大为 150 μπι。
在本发明的较佳实施态样中， 进一歩包含下列歩骤： 将所述经粉碎后 的第二混合物过筛； 较佳者， 所述经粉碎后的第二混合物是通过 60至 100 目的网筛； 更佳者， 是通过 100目的网筛。
在本发明的较佳实施态样中， 进一歩在歩骤 (e)之后包含下列歩骤： 将 压锭后的锭剂包覆一膜衣。
综上所述， 本发明提供一种用于治疗帕金森氏症的医药组合物， 其包 含左旋多巴、 卡比多巴及安它可朋或其医药可接受盐， 以及至少一种医药 上可接受的赋形剂； 其中安它可朋非与左旋多巴或卡比多巴混合。
本发明的药物组合物是将不同剂量组合中成相同比例值的卡比多巴及 左旋多巴混合造粒， 而将于不同剂量组合中为固定含量的安它可朋另行造 粒， 如此仅需调整卡比多巴及左旋多巴混合造粒产物的用量， 即可达成不同 的剂量组合， 相对于 WO 01/01984所言， 大大简化了制作过程的繁杂度。 而且， 本发明的药物组合物与习知的帕金森氏症药物始立仍具有类似的溶 离模式。 附图说明
图 1为实施例 1所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。
图 2为实施例 2所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。
图 3为实施例 3所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。 图 4为实施例 4所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。
图 5为实施例 5所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。
图 6为实施例 6所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。
图 7为实施例 7所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。
图 8为实施例 8所制得的锭剂中左旋多巴、卡比多巴及安它可朋在 120 分钟内的溶离情形， 对照药物为始立。 具体实施方式
除了在下文中作其它意义解释的以外， 所有科学术语如发明所属领域 的普通技术人员的理解而作其原始意义解释。 如有争议， 应以本说明书的 定义为主。
在本文中， "赋形剂（excipient) "—词是指一种非活性物质， 用作药 物活性成分的载体； 其可包括结合剂、 稀释剂、 崩散剂、 润滑剂、 压缩助 齐 1」、 防腐剂、 包覆剂、 风味剂、 着色剂、 甜味剂等。
在本文中， "结合剂（bmder) "—词是指将药物中各成分结合在一起， 形成一定机械强度的用剂， 具体实例如微晶纤维素、 羟丙基甲基纤维素、 聚维酮、 交联聚维酮、 淀粉或共聚维酮 （copolyvidone) ： 其中微晶纤维素 较佳为 P101、 P102等； 羟丙基甲基纤维素 （HPMC) 可为低取代羟丙基甲 基纤维素（HPMC-L)或高取代羟丙基甲基纤维素（HPMC-H) ， 较佳为高 取代羟丙基甲基纤维素 （HPMC-H) ， 如 HPMC E5 LV、 HPMC El 5 LV HPMC A15 LV、 HPMC K3 Premium等； 聚维酮较佳为 K30、 Κ15、 Κ90等； 淀粉较佳为玉米淀粉或 Starch 1500®； 共聚维酮较佳为共聚维酮 VA64。 在本文中， "稀释剂（d uent) "—词是指一种将锭剂的尺寸扩充到方 便患者使用的尺寸的用剂， 具体实例如微晶纤维素、 羟丙基甲基纤维素、 糊精 （dextrm) ， 糖类、 甘露糖醇或淀粉； 其中微晶纤维素较佳为 P101、 P102等； 糖类较佳为乳糖； 淀粉较佳为玉米淀粉。
在本文中， "崩散剂（dismtegmnt) "—词是指一种遇水时使药锭膨胀 溶解并在消化道中崩散而释出活性成分的用剂。 具体实例如微晶纤维素、 羟丙基甲基纤维素、 交联羧甲基纤维素钠 （Croscarmellose sodium) 、 交联 聚维酮或淀粉； 其中微晶纤维素较佳为 P101、 P102等； 羟丙基甲基纤维素 (HPMC)较佳为低取代羟丙基甲基纤维素（HPMC-L) ； 淀粉较佳为玉米 淀粉或 Starch 1500®。 下列实施例仅为最佳实施态样的例示， 非意图限制本发明的范围。 所 属领域的技术人员可藉由本发明的揭露， 在不背离本发明的精神的范围内 做出适度的变更和修正。 实施例
实施例 1
首先将下表 1 中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒。
表 1
成分 重量 (mg)
左旋多巴 100.00 卡比多巴单水合物 27.00 甘露糖醇 88.00
HPMC E5 LV 6.40 总量 221.40 之后将下表 2 中的成分以湿式造粒法制得含有安它可朋的颗粒： 将 2.55 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序 与剩余的 HPMC E5 LV、微晶纤维素、 SDS、甘露糖醇及安它可朋混合均匀， 制得第二混合物。接着先后将所述第二混合物及 5% HPMC E5 LV溶液倒入 造粒机中进行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘 干， 直至水分含量介于 1%〜3%， 得出第二颗粒。
表 2
Figure imgf000010_0001
最后依照下表 3 中的成分制得锭剂： 将所述包含左旋多巴及卡比多巴 的第一颗粒与包含安它可朋的第二颗粒混合， 再与交联聚维酮及硬脂酸镁 混合， 之后打成锭剂。
表 3
Figure imgf000010_0002
溶离试验
溶离度是主成分相同的药物的生物相等性的重要指标， 若溶离效果良 好， 则代表口服药物较能适时在胃肠道中崩散、 溶离、 释出， 之后为人体 所吸收。
进行下列溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴 或安它可朋在 120分钟内的溶离情形。 (1) 左旋多巴 /卡比多巴的溶离试验：
参照美国药典 USP 32, NF 27 (1791)及美国 FDA网站上提供的 溶离方法数据库 （Dissolution Methods Database) 中检索得到卡比 多巴 /安它可朋 /左旋多巴的药物溶离方法进行溶离试验， 溶离使用 USP标准篮式装置（Basket)， 转速为 50 rpm，所用溶媒为 750 mL 的 0.1N HC1溶液， 但试验时间改为 120分钟， 之后利用 HPLC进 行分析。在此试验中， 是使用同样含有左旋多巴、卡比多巴及安它 可朋的帕金森氏症药物始立 （Stalevo®) 来作为对照药物。
(2) 安它可朋的溶离试验：
依据在 FDA 网站上提供的溶离方法数据库 (Dissolution
Methods Database)中检索得到卡比多巴 /安它可朋 /左旋多巴的药物 溶离方法 ( http://www.accessdata.fda.gov/scripts/cder/dissolution/ dsp—SearchResults— Dissolutions. cfm)进行溶离试验， 其中溶离使用 USP标准篮式装置（Basket)，转速为 125 rpm，所用溶媒为 900 mL 的 pH5.5 的磷酸缓冲溶液， 但试验时间改为 120分钟， 之后利用
HPLC进行分析。 在此试验中， 是使用始立来作为对照药物。
如前述方法进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡 比多巴或安它可朋在 120分钟内的溶离情形， 其中使用始立来作为对照物。 结果如图 1 所示， 其中左旋多巴、 卡比多巴以及安它可朋的溶出曲线与对 照药物接近。 实施例 2
首先将下表 4 中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒 (
表 4
Figure imgf000012_0002
之后将下表 5 中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、甘露糖醇、 PVP K30及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物倒入粉碎机中进行粉碎， 之后使粉末通过 100 目的筛网。 接着将所述过筛的粉末倒入造粒机中， 并喷洒去离子水， 以进 行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘干， 直至水 分含量介于 1%〜3%， 得出第二颗粒。
Figure imgf000012_0001
Figure imgf000012_0003
最后依照下表 6 中的成分制得锭剂： 将所述包含左旋多巴及卡比多巴 的第一颗粒与包含安它可朋的第二颗粒混合， 再与交联聚维酮及硬脂酸镁 混合， 之后打成锭剂。
表 6
Figure imgf000012_0004
如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 其中使用始立来作为对照 药物。 结果如图 2所示， 其中左旋多巴及卡比多巴溶出的速度与对照药品 接近； 而安它可朋的溶出曲线与对照药物几乎一致。 实施例 3
首先将下表 7 中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒。
表 7
Figure imgf000013_0001
之后将下表 8 中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、 PVP K30, 甘露糖醇及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物倒入粉碎机中进行粉碎， 之后使粉末通过 100 目的筛网。 接着将所述过筛的粉末倒入造粒机中， 并喷洒去离子水， 以进 行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘干， 直至水 分含量介于 1%〜3%， 得出第二颗粒。
表 8
Figure imgf000013_0002
最后依照下表 9 中的成分制得锭剂： 首先将所述包含左旋多巴及卡比 多巴的第一颗粒与 5 mg交联聚维酮及 1.7 mg硬脂酸镁混合，得出第一混合 物；再将所述包含安它可朋的第二颗粒与 5 mg交联聚维酮及 3.4 mg硬脂酸 镁混合， 得出第二混合物； 之后将第一混合物及第二混合物制成双层锭。
表 9
Figure imgf000014_0001
如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 使用始立来作为对照药物。 结果如图 3所示， 与对照药物相比， 左旋多巴、 卡比多巴及安它可朋初期 溶出速度稍快， 但 45分钟后均与对照药物一致。 实施例 4
首先将下表 10中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒。
表 10
Figure imgf000014_0002
之后将下表 11中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、 PVP K30、 甘露糖醇及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物倒入粉碎机中进行粉碎， 之后使粉末通过 100 目的筛网。 接着将所述过筛的粉末倒入造粒机中， 并喷洒去离子水， 以进 行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘干， 直至水 分含量介于 1%〜3%， 得出第二颗粒。
表 11
Figure imgf000015_0001
最后依照下表 12中的成分制得锭剂： 首先将所述包含左旋多巴及卡比 多巴的第一颗粒与 1.7 mg硬脂酸镁混合， 得出第一混合物； 再将所述包含 安它可朋的第二颗粒与 5 mg交联聚维酮及 3.4 mg硬脂酸镁混合，得出第二 混合物； 之后将第一混合物及第二混合物制成双层锭。
表 12
Figure imgf000015_0002
如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 其中使用始立来作为对照 药物。 结果如图 4所示， 其中左旋多巴、 卡比多巴及安它可朋均与对照药 物接近。 实施例 5
首先将下表 13中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒。
表 13
Figure imgf000016_0001
之后将下表 14中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、 PVP K30, 甘露糖醇及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物倒入粉碎机中进行粉碎， 之后使粉末通过 100 目的筛网。 接着将所述过筛的粉末倒入造粒机中， 并喷洒去离子水， 以进 行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘干， 直至水 分含量介于 1%〜3%， 得出第二颗粒。
表 14
Figure imgf000016_0002
最后依照下表 15中的成分制得锭剂： 首先将所述包含左旋多巴及卡比 多巴的第一颗粒与 1.7 mg硬脂酸镁混合， 得出第一混合物； 再将所述包含 安它可朋的第二颗粒与 5 mg交联聚维酮及 3.4 mg硬脂酸镁混合，得出第二 混合物； 之后将第一混合物及第二混合物制成双层锭， 并以 Opadry AMB 进行增重 4%的膜衣包覆工程。 成分 重量 (mg)
第一颗粒 231.40 第二颗粒 420.50 交联聚维酮 5.00 硬脂酸镁 5.10
Opadry AMB 26.48 总量 688.48 如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 其中使用始立来作为对照 物。 结果如图 5所示， 其中左旋多巴、 卡比多巴及安它可朋的溶出速度均 几乎与对照物一致。 实施例 6
首先将下表 16中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒。
表 16
Figure imgf000017_0001
之后将下表 17中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、 PVP K30, 甘露糖醇及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物倒入粉碎机中进行粉碎， 之后使粉末通过 60 目的筛网。 接着将所述过筛的粉末倒入造粒机中， 并喷洒去离子水， 以进
15 行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘干， 直至水 分含量介于 1%〜3%， 得出第二颗粒。
表 17
Figure imgf000018_0001
最后依照下表 18中的成分制得锭剂： 首先将所述包含左旋多巴及卡比 多巴的第一颗粒与 1.7 mg硬脂酸镁混合， 得出第一混合物； 再将所述包含 安它可朋的第二颗粒与 5 mg交联聚维酮及 3.4 mg硬脂酸镁混合，得出第二 混合物； 之后将第一混合物及第二混合物制成双层锭。
表 18
Figure imgf000018_0002
如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 使用始立来作为对照物。 结果如图 6所示， 其中左旋多巴、 卡比多巴或安它可朋的溶出量均与对照 药物接近。 实施例 7
首先将下表 19中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒 (
表 19
Figure imgf000019_0001
之后将下表 20中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、 PVP K30, 甘露糖醇及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物倒入粉碎机中进行粉碎， 之后使粉末通过 80 目的筛网。 接着将所述过筛的粉末倒入造粒机中， 并喷洒去离子水， 以进 行造粒， 之后使所造颗粒通过 25目的筛网， 置于 50°C烘箱中烘干， 直至水 分含量介于 1%〜3%， 得出第二颗粒。
表 20
Figure imgf000019_0002
最后依照下表 21中的成分制得锭剂： 首先将所述包含左旋多巴及卡比 多巴的第一颗粒与 1.7 mg硬脂酸镁混合， 得出第一混合物； 再将所述包含 安它可朋的第二颗粒与 5 mg交联聚维酮及 3.4 mg硬脂酸镁混合，得出第二 混合物； 之后将第一混合物及第二混合物制成双层锭。
表 21
Figure imgf000019_0003
如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 使用始立来作为对照物。 结果如图 7所示， 其中左旋多巴、 卡比多巴或安它可朋的溶出量均与对照 药物接近。 实施例 8
首先将下表 22中的成分以湿式造粒法制得含有左旋多巴及卡比多巴的 颗粒： 将 1.4 mg HPMC E5 LV溶于水中， 配制成 5% HPMC E5 LV溶液， 之后依序与剩余的 HPMC E5 LV、 卡比多巴单水合物、 左旋多巴及甘露糖 醇混合均匀，制得第一混合物。接着先后将所述第一混合物及 5% HPMC E5 LV溶液倒入造粒机中进行造粒， 之后使所造颗粒通过 25 目的筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第一颗粒。
表 22
Figure imgf000020_0001
之后将下表 23中的成分以湿式造粒法制得含有安它可朋的颗粒： 将微 晶纤维素、 SDS、 甘露糖醇、 PVP K30及安它可朋依序混合均匀， 制得第二 混合物， 再将所述第二混合物通过 100目的筛网。 接着将所述过筛的粉末倒 入造粒机中， 并喷洒去离子水， 以进行造粒， 之后使所造颗粒通过 25目的 筛网， 置于 50°C烘箱中烘干， 直至水分含量介于 1%〜3%， 得出第二颗粒。
表 23
Figure imgf000020_0002
最后依照下表 24中的成分制得锭剂： 首先将所述包含左旋多巴及卡比 多巴的第一颗粒与 1.7 mg硬脂酸镁混合， 得出第一混合物； 再将所述包含 安它可朋的第二颗粒与 5 mg交联聚维酮及 3.4 mg硬脂酸镁混合，得出第二 混合物； 之后将第一混合物及第二混合物制成双层锭。
表 24
Figure imgf000021_0001
如实施例 1所述进行溶离试验， 分别监测所得锭剂当中成分左旋多巴、 卡比多巴或安它可朋在 120分钟内的溶离情形， 使用始立来作为对照物。 结果如图 8所示， 其中安它可朋、 卡比多巴或安它可朋的溶出量与对照药 物接近。

Claims

权利要求书
1. 一种用于治疗帕金森氏症的医药组合物， 其包含：
25至 300毫克的左旋多巴、 5至 75毫克的卡比多巴及 25至 300 毫克的安它可朋， 或其医药可接受盐， 以及
至少一种医药上可接受的赋形剂；
其中安它可朋非与左旋多巴或卡比多巴混合。
2. 如权利要求 1所述的医药组合物， 其是一口服固体医药组合物。
3. 如权利要求 2所述的医药组合物， 其是一锭剂。
4. 如权利要求 3所述的医药组合物， 其是一双层锭剂。
5. 如权利要求 4所述的医药组合物，其中所述双层锭剂的一层包含左 旋多巴及卡比多巴， 另一层包含安它可朋。
6. 如权利要求 1所述的医药组合物，其中所述赋形剂为结合剂、稀释 齐 1」、 崩散剂、 或其组合。
7. 如权利要求 6所述的医药组合物， 其中所述结合剂为微晶纤维素、 羟丙基甲基纤维素、 聚维酮、 交联聚维酮、 或其组合。
8. 如权利要求 6所述的医药组合物， 其中所述稀释剂为微晶纤维素、 羟丙基甲基纤维素、 糖类、 甘露糖醇、 淀粉、 或其组合。
9. 如权利要求 6所述的医药组合物， 其中所述崩散剂为微晶纤维素、 羟丙基甲基纤维素、 交联聚维酮、 淀粉、 或其组合。
10. 如权利要求 6所述的医药组合物， 其中所述赋形剂为微晶纤维素。
11. 如权利要求 2所述的医药组合物，其中所述口服固体医药组合物进 一歩包含一膜衣。
12. 一种用于治疗帕金森氏症的医药组合物， 其至少包含一第一单元、 一第二单元， 以及至少一种医药上可接受的赋形剂，其中该第一单 元包含左旋多巴以及卡比多巴的混合物， 该第二单元包含安它可 朋。
13. 如权利要求 12所述的医药组合物， 其中左旋多巴的含量为 25至 300毫克、 卡比多巴的含量为 5至 75毫克， 安它可朋的含量为 25 至 300毫克。
14. 如权利要求 12所述的医药组合物， 其是一锭剂。
15. 如权利要求 14所述的医药组合物， 其是一双层锭剂。
16. 如权利要求 12所述的医药组合物， 其中所述赋形剂为结合剂、 稀 释剂、 崩散剂、 或其组合。
17. 如权利要求 16所述的医药组合物，其中所述结合剂为微晶纤维素、 羟丙基甲基纤维素、 聚维酮、 交联聚维酮、 淀粉、 或其组合。
18. 如权利要求 16所述的医药组合物，其中所述稀释剂为微晶纤维素、 羟丙基甲基纤维素、 糖类、 甘露糖醇、 淀粉、 或其组合。
19. 如权利要求 16所述的医药组合物，其中所述崩散剂为微晶纤维素、 羟丙基甲基纤维素、 交联聚维酮、 淀粉、 或其组合。
20. 一种制备如权利要求 1 所述的医药组合物的方法， 其包含下列歩 骤：
(a) 将左旋多巴、 卡比多巴及至少一种第一赋形剂混合， 得出第一 混合物；
(b) 将第一混合物粒化， 得出第一颗粒；
(C) 将安它可朋及至少一种第二赋形剂混合， 得出第二混合物；
(d) 将第二混合物粒化， 得出第二颗粒；
(e) 将第一颗粒与第二颗粒进行压锭。
21. 如权利要求 20所述的方法， 其中所述歩骤 (e)是将第一颗粒与第二 颗粒压制成双层锭剂。
22. 如权利要求 21所述的方法， 其中所述双层锭剂的一层包含左旋多 巴及卡比多巴， 另一层包含安它可朋。
23. 如权利要求 20所述的方法， 其中所述赋形剂为结合剂、 稀释剂、 崩散剂、 或其组合。
24. 如权利要求 23所述的方法， 其中所述结合剂为微晶纤维素、 羟丙 基甲基纤维素、 聚维酮、 交联聚维酮、 淀粉、 或其组合。
25. 如权利要求 23所述的方法， 其中所述稀释剂为微晶纤维素、 羟丙 基甲基纤维素、 糖类、 甘露糖醇、 淀粉、 或其组合。
26. 如权利要求 23所述的方法， 其中所述崩散剂为微晶纤维素、 羟丙 基甲基纤维素、 交联聚维酮、 淀粉、 或其组合。
27. 如权利要求 20所述的方法， 其中第二赋形剂为微晶纤维素。
28. 如权利要求 20所述的方法， 其中所述粒化为湿式造粒。
29. 如权利要求 20所述的方法，其进一歩在歩骤b)之后包含下列歩骤： 将第二混合物进行粉碎。
30. 如权利要求 29所述的方法， 其中所述经粉碎后的第二混合物， 其 粒径最大为 250 μπι。
31. 如权利要求 29所述的方法， 其中所述经粉碎后的第二混合物， 其 粒径最大为 150 μπι。
32. 如权利要求 29所述的方法， 其进一歩包含下列歩骤： 将所述经粉 碎后的第二混合物过筛。
33. 如权利要求 20所述的方法，其进一歩在歩骤 0；)之后包含下列歩骤： 将压锭后的锭剂包覆一膜衣。
PCT/CN2009/076069 2009-12-25 2009-12-25 治疗帕金森氏症的医药组合物及其制备方法 WO2011075912A1 (zh)

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