Delayed release pharmaceutical composition and its preparation method and use

Abstract

The present invention discloses a delayed-release pharmaceutical composition, and its preparation and use. The pharmaceutical composition of the present invention comprises a tablet core, which comprises a drug-containing layer and a push layer laminated on the drug-containing layer, the drug-containing layer containing a pharmaceutically active ingredient, which is levodopa or a derivative thereof, or a mixture of levodopa or a derivative thereof and a dopa decarboxylase inhibitor, and which accounts for 5 to 72.5% by weight of the drug-containing layer. The pharmaceutical composition is in the form of a capsule-shaped tablet, which can achieve a delayed release of the pharmaceutically active ingredient over 1 to 3 hours, with peak concentration reaching within 6 to 10 hours, and is therefore suitable for alleviating morning stiffness in patients with Parkinson's disease, with good prospects for use.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022115525632, filed on December 5, 2022. This application cites the above Chinese patent application in its entirety.

[0002] The present invention relates to the field of biopharmaceuticals, in particular to a delayed release pharmaceutical composition and its preparation method and use. [Background technology]

[0003] Parkinson's disease is a progressive neurodegenerative disorder caused by the loss of dopamine-producing cells in the brain. Dopamine, a substance naturally found in the brain and spinal cord, helps neurons in the brain properly control motor function. As dopamine levels in the brain decrease, symptoms of Parkinson's disease (PD), such as muscle stiffness, slowness of movement, and difficulty maintaining balance, appear. Dopamine cannot cross the blood-brain barrier (BBB), which is why oral formulations of dopamine are ineffective. Levodopa is a dopamine precursor that crosses the BBB and is converted into dopamine in brain tissue. Levodopa therapy is the "gold standard" for Parkinson's disease treatment, and most Parkinson's disease patients must undergo levodopa treatment once they reach a certain stage of the disease. However, most levodopa is decarboxylated into dopamine before reaching the brain. Therefore, levodopa is often used in combination with a decarboxylase inhibitor such as carbidopa or benserazide to prevent peripheral dopamine formation, increase brain dopamine content, and reduce the side effects caused by peripheral decarboxylation of levodopa.

[0004] The following Non-Patent Documents 1 to 20 disclose Parkinson's disease, the symptom of morning stiffness in Parkinson's disease, and the shortcomings of existing treatments.

[0005] As disclosed in Non-Patent Documents 5-11, as Parkinson's disease progresses, patients experience severe morning stiffness (morning akinesia) early in the morning, which is caused by insufficient nocturnal dopamine storage. Morning stiffness is the most common and earliest motor complication in PD patients, occurring in approximately 60% of PD patients receiving dopamine therapy, particularly in patients with mid- to late-stage Parkinson's disease, i.e., Hoehn-Yahr grades 2.5 to 3. The occurrence of morning stiffness severely impacts PD patients' daily activities, such as getting up, getting dressed, using the toilet, doing laundry, and taking medication. Symptoms of morning stiffness are also associated with postprandial abdominal bloating, abdominal discomfort, early satiety, nausea, vomiting, weight loss, and malnutrition, as well as gastrointestinal dysfunction manifested as dry mouth, drooling, dysphagia, esophageal motility disorders, gastroesophageal reflux disease, gastroparesis, constipation, and bowel problems. These symptoms significantly impact the quality of life of PD patients.

[0006] As reported in Non-Patent Document 12, gastroparesis can delay the delivery of levodopa to the duodenum, resulting in the clinical phenomenon of delayed onset of action (ON) after levodopa administration. Therefore, it is speculated that insufficient levodopa blood concentrations at night can lead to reduced and insufficient dopamine function, resulting in morning stiffness and other related symptoms such as gastroparesis. Gastroparesis can delay the absorption and onset of action of levodopa taken in the morning, creating a vicious cycle. As shown in Non-Patent Document 13, other Parkinson's disease medications, such as dopamine agonists (pramipexole, rotigotine, ropinirole), anticholinergics (amantadine), monoamine oxidase inhibitors (selegiline, rasagiline, safinamide), and COMT inhibitors (tolcapone, entacapone), can all cause gastrointestinal dysfunction.

[0007] The current treatment for morning stiffness is to provide patients with a rapid and effective peak levodopa blood concentration in the early morning to relieve morning stiffness. However, due to pharmacodynamic and pharmacokinetic reasons such as gastric emptying time, levodopa being absorbed only in the upper gastrointestinal tract, and competition with amino acids for crossing the blood-brain barrier, existing conventional levodopa formulations cannot effectively solve the problem of treating morning stiffness in Parkinson's disease due to their short half-life, irregular gastrointestinal absorption, and competitive crossing of the blood-brain barrier.

[0008] As described in Non-Patent Documents 14 and 15, a subcutaneous apomorphine formulation (APOKYN®) 2004 was released in the United States and is used for the emergency and intermittent treatment of OFF attacks in Parkinson's disease patients. While it has some effect on morning stiffness, morning stiffness impairs the patient's motor function, making self-administration difficult. Since it takes 30 to 60 minutes for the drug to take effect after administration, it significantly impacts patient self-care. Furthermore, a common side effect of subcutaneous injection is the development of nodules, which often become infected and require antibiotic treatment or surgical debridement. Furthermore, apomorphine can induce vomiting, necessitating the addition of an antiemetic before administration.

[0009] As shown in Non-Patent Document 16 below, apomorphine sublingual film (KYNMOBI®) was just released in the United States in May 2020 and is used for the emergency and intermittent treatment of OFF attacks in patients with Parkinson's disease. The incidence of side effects, such as nausea, oropharyngeal soft tissue edema, pain, and paralysis, is high.

[0010] As shown in Non-Patent Documents 17-18, the rotigotine transdermal patch (NEUPRO®) was launched in the United States in 2007 and in China in 2018. As a dopamine receptor agonist, the rotigotine transdermal patch has been shown to be effective in relieving morning stiffness and improving sleep. However, its use is limited due to side effects such as nausea, vomiting, drowsiness, and skin allergies.

[0011] As noted in Non-Patent Documents 19-20, the levodopa inhaler (INBRIJA®) was launched in the United States in 2018 and is approved by the FDA as an emergency treatment for OFF attacks. However, it requires a special device for oral inhalation, is difficult to self-administer, has low bioavailability, and according to the instructions, its Cmax is only 50% of that of oral immediate-release formulations. The incidence of respiratory adverse reactions is high at 35%. It also carries the risk of inducing bronchospasm, making it contraindicated for patients with asthma, chronic obstructive pulmonary disease (COPD), or chronic lung disease.

[0012] Theoretically, to reduce morning stiffness, patients need a high concentration of levodopa before waking up. Currently, if patients take conventional levodopa preparations (e.g., Madopar®, Sinim®) the night before, not only will effective blood drug concentrations not be maintained until they wake up in the morning, but the high concentration of levodopa produced by rapid release will have a certain stimulating effect, which may affect the patient's sleep.

[0013] While administering levodopa before bedtime can affect sleep onset, administering a specific concentration of levodopa after sleep onset can reduce muscle tension and stiffness, potentially improving sleep quality. Therefore, a delayed-release, controlled-release formulation is needed to achieve effective blood concentrations of levodopa when patients wake up in the morning, reduce morning stiffness, and improve nighttime stiffness, thereby improving patient sleep quality. As shown in Reference 21, continuous duodenal infusion of levodopa (DUODOPA / DUOPA) has a significant therapeutic effect on morning stiffness. However, continuous infusion of levodopa hydrogel for 2 to 4 months significantly reduced the total score and subscores of the PDSS-2 (PD-Sleep-Scale-Version-2) for sleep disturbance, nocturnal motor symptoms, and nocturnal PD symptoms, as well as the Epworth-Sleeping-Scale (ESS) score for daytime sleepiness. Furthermore, this treatment is invasive, requires surgery to deliver continuous perfusion directly to the upper small intestine via a tube, is expensive, and is relatively unsuitable for a limited range of patients. Currently, the drug is only administered over 16 hours during the day, not overnight.

[0014] Therefore, the most ideal treatment option for patients remains a non-invasive therapy.Therefore, there is an urgent need to develop a non-invasive delayed-release product that provides effective levodopa blood drug concentrations in the morning to reduce morning stiffness symptoms, so that PD patients are in an "ON" state rather than an "OFF" state when they wake up in the morning. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] J Jankovic. Parkinson's disease: clinical features and diagnosis. Journal of Neurology,Neurosurgery&Psychiatry,2008;79:368-376. [Non-patent document 2] NB Mercuri. Limitations of current Parkinson's disease therapy. Ann Neurol 2003;53:S3-S15. [Non-patent document 3] K Ray Chaudhuri DSc.Non-motor symptoms of Parkinson's disease:dopaminergic pathophysiology and treatment.The Lancet Neurology 2009;8:464-474. [Non-patent document 4] NB Mercuri.2005 The 'magic' of L-dopa:why is it the gold standard Parkinson's disease therapy?Trends in pharmacological sciences,2005;26:341-344. [Non-Patent Document 5] Nicola T, Simone S, Pasquale N, et al.Morning akinesia in Parkinson's disease-challenges and solutions.Journal of Parkinsonism and Restless Legs Syndrome.2016;6:57-63. [Non-patent document 6] Rizos A, Martinez-Martin P, Odin P, et al. Characterizing motor and non-motor aspects of early-morning off periods in Parkinson's disease: an international multicenter study. Parkinsonism Relat Disord. 2014;20(11):1231-1235. [Non-Patent Document 7] Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson's disease on the quality of life. Mov Disord.2005;20(2):224-230. [Non-patent document 8] Factor SA, McAlarney T, Sanchez-Ramos JR, Weiner WJ. Sleep disorders and sleep effect in Parkinson's disease. Mov Disord. 1990;5(4):280-285. [Non-Patent Document 9] Garcia-Borreguero D, Larrosa O, Bravo M.Parkinson's disease and sleep.Sleep Med Rev.2003;7(2):115-129. [Non-Patent Document 10] Pfeiffer RF.Gastrointestinal,urological,and sexual dysfunction in Parkinson's disease.Mov Disord.2010;25:94-97. [Non-Patent Document 11] Heetun ZS, Quigley EMM. Gastroparesis and Parkinson's disease: a systematic review. Parkinsonism Relat Disord. 2012;18(5):433-440. [Non-Patent Document 12] Kurlan R, Rothfield KP, Woodward WR, et al. Erratic gastric emptying of levodopa may cause “random” fluctuations of parkinsonian mobility. Neurology. 1988;38(3):419-421. [Non-Patent Document 13] Jost WH.Gastrointestinal motility problems in patients with Parkinson's disease.Effects of antiparkinsonian treatment and guidelines for management.Drugs Aging.1997;10:249-258. [Non-Patent Document 14] APOKYN Package Insert. [Non-Patent Document 15] Stuart I, Mark L, William O, et al.Apomorphine Subcutaneous Injection for the Management of Morning Akinesia in Parkinson's Disease.Mov Disord 2016:doi:10.1002 / mdc3.12350. [Non-Patent Document 16] NEUPRO Package Insert. [Non-Patent Document 17] Claudia T, Bryan K, et al.Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease:A Double-Blind,Randomized,Placebo-Controlled Study (RECOVER).Mov Disord,2011;26(1):90-99. [Non-Patent Document 18] INBRIJA Package Insert. [Non-Patent Document 19] Robert A. Hauser, et al.Orally inhaled levodopa(CVT-301) for early morning OFF periods in Parkinson's disease.Parkinsonism and Related Disorders,https: / / doi.org / 10.1016 / j.parkreldis.2019.03.026. [Non-Patent Document 20] Zibetti M, Rizzone M, Merola A, et al.Sleep improvement with levodopa-carbidopa intestinal gel infusion in Parkinson disease.Acta Neurol Scand 2013:127:e28-e32 DOI:10.1111 / ane.12075. Summary of the Invention [Problem to be solved by the invention]

[0016] The technical problem to be solved by the present invention is to provide a delayed-release pharmaceutical composition and its preparation and use to overcome the drawbacks of existing levodopa-containing sustained-release preparations, which are unable to achieve effective delayed and sustained release after the delayed release, and therefore unable to maintain effective blood levodopa concentrations in the morning and alleviate morning stiffness and other associated symptoms. The pharmaceutical composition of the present invention achieves a delayed release of the active pharmaceutical ingredient for 1 to 3 hours and can reach a peak concentration in 6 to 10 hours, preferably a delayed release of the active pharmaceutical ingredient for 2 hours and can reach a peak concentration in 6 to 8 hours, thereby alleviating the occurrence of morning stiffness and other associated symptoms. [Means for solving the problem]

[0017] The present invention solves the above technical problems by the following technical solutions.

[0018] The present invention provides a pharmaceutical composition comprising a tablet core, the tablet core comprising a drug-containing layer and a push layer laminated on the drug-containing layer, the drug-containing layer comprising a pharmaceutically active ingredient; the content of the pharmaceutically active ingredient in the drug-containing layer is 5 to 72.5 wt %, the content being the weight percentage of the pharmaceutically active ingredient in the drug-containing layer; In the drug-containing layer, the pharmaceutically active ingredient is levodopa or a derivative thereof, or a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, when the pharmaceutically active ingredient is a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor is ≦14.5 wt.% but not 0, and the content is the weight percentage of the ingredient in the drug-containing layer; The pharmaceutical composition is in the form of a capsule-type tablet.

[0019] In the present invention, the content of the pharmaceutically active ingredient in the drug-containing layer is preferably 30 to 72.5% by weight, for example, 31.5% by weight, 50% by weight, 53% by weight, 58% by weight, 59.6% by weight, 63% by weight, or 68.1% by weight.

[0020] In the present invention, the content of levodopa or a derivative thereof in the drug-containing layer may be a conventional content for such formulations in the art, and may further be 27 to 63 wt%, for example, 27.7 wt%, 31.5 wt%, 41.7 wt%, 46.9 wt%, 50 wt%, 51.1 wt%, 53.6 wt%, 55.5 wt%, or 63 wt%, where the content is the weight percentage of the component in the drug-containing layer.

[0021] In the present invention, the levodopa derivative in the drug-containing layer may be levodopa hydrate, levodopa alkyl ester, a pharmaceutically acceptable salt of levodopa, a deuterated levodopa alkyl ester, or a pharmaceutically acceptable salt of a deuterated levodopa alkyl ester.

[0022] In the present invention, the type of the dopa decarboxylase inhibitor in the drug-containing layer may be carbidopa hydrate, a pharmaceutically acceptable salt of carbidopa, benserazide, or a pharmaceutically acceptable salt of benserazide, and preferably is, for example, carbidopa monohydrate.

[0023] In the present invention, when the pharmaceutically active ingredients in the drug-containing layer are "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor may be 3.7 to 14.5 wt%, for example, 3.75 wt%, 6.91 wt%, 7.5 wt%, 11.3 wt%, 12.7 wt%, or 14.5 wt%, and the content is the weight percentage of the component in the drug-containing layer.

[0024] In the present invention, the drug-containing layer may further comprise a pharmaceutical excipient, which may be a conventional pharmaceutical excipient used in such formulations.

[0025] In a preferred embodiment of the present invention, the pharmaceutical excipient may comprise one or more of a drug carrier, a filler, a surfactant, a lubricant, and an antioxidant, and may further comprise a "drug carrier and a lubricant," a "drug carrier, a filler and a lubricant," a "drug carrier, a filler, a surfactant and a lubricant," or a "drug carrier, a filler, a surfactant, an antioxidant and a lubricant."

[0026] Here, the type and content of the drug carrier may be the type and content of conventional drug carriers in such formulations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0027] The drug carrier may be one or more of polyvinylpyrrolidone, copolyvidone, carbomer, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyoxyethylene, and sodium alginate, and may also be a mixture of polyvinylpyrrolidone and hydroxypropylcellulose, or hydroxypropylcellulose.

[0028] When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains a drug carrier, the content of the drug carrier may be ≦40 wt%, but may not be 0, and may even be 10-40 wt%, for example, 15 wt%, 16 wt%, 29.5 wt%, 30.0 wt%, 31 wt%, or 38.5 wt%.

[0029] When the drug carrier is a mixture of polyvinylpyrrolidone and hydroxypropyl cellulose, the weight ratio of the hydroxypropyl cellulose to polyvinylpyrrolidone is preferably (1-8):1, for example, 2.1:1, 2.2:1, 3.1:1, 3.5:1 or 7.1:1.

[0030] Here, the type and content of the filler may be the conventional type and content in such preparations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0031] The filler may be one or more of lactose, starch, pregelatinized starch, dextrin, mannitol, sorbitol and microcrystalline cellulose, and may also be a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, sorbitol or mannitol.

[0032] When the drug-containing layer contains a pharmaceutical excipient and the pharmaceutical excipient contains a filler, the content of the filler may be ≦51 wt%, but may not be 0, and may be 5 to 51 wt%, for example, 5 wt%, 8.5 wt%, 10 wt%, 15 wt%, 18 wt%, 19 wt%, 19.5 wt%, 20 wt%, 32 wt%, 41.5 wt%, or 51 wt%.

[0033] Preferably, in the drug-containing layer, when the pharmaceutical excipient comprises a drug carrier and a filler, the weight ratio of the filler to the drug carrier may be (1-6):1, or even (1-2):1.

[0034] More preferably, when the drug carrier is a mixture of polyvinylpyrrolidone and hydroxypropyl cellulose, or hydroxypropyl cellulose, and the filler is sorbitol, a mixture of sorbitol and lactose, or a mixture of sorbitol and mannitol, the weight ratio of sorbitol in the filler to hydroxypropyl cellulose in the drug carrier is preferably (1-2):1, for example, 1:1, 1.95:1, or 2:1.

[0035] Here, the type and content of the surfactant may be the conventional type and content in such formulations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0036] The surfactant may be one or more of polysorbate, poloxamer, fatty acid glyceride, sodium dodecylbenzenesulfonate and sodium dodecyl sulfate, for example, poloxamer (407).

[0037] When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains a surfactant, the content of the surfactant may be ≦19 wt%, but may not be 0, and may be 5 to 19 wt%, for example, 5 wt%, 10 wt%, or 19 wt%.

[0038] Here, the type and content of the lubricant may be the conventional type and content in such formulations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0039] The lubricant is preferably one or more of stearic acid, silicon dioxide, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, more preferably magnesium stearate and / or silicon dioxide.

[0040] When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains a lubricant, the content of the lubricant may be ≦2.5 wt %, but may not be 0, and may even be 1-2.5 wt %, for example, 1 wt % or 2.5 wt %.

[0041] Here, the type and content of the antioxidant may be the conventional type and content in such formulations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0042] The antioxidant is one or more of dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C and vitamin E, for example, dibutylhydroxytoluene.

[0043] When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains an antioxidant, the content of the antioxidant may be ≦1.0 wt %, but may not be 0, and may be 0.1 to 0.5%, for example, 0.33 wt %.

[0044] In one preferred embodiment of the present invention, the drug-containing layer comprises a component from any one of the following groups: (1) the pharmaceutically active ingredient, the pharmaceutical carrier, and the lubricant; (2) the pharmaceutically active ingredient, the pharmaceutical carrier, the filler, and the lubricant, (3) the pharmaceutically active ingredient, the pharmaceutical carrier, the filler, the surfactant, and the lubricant, (4) The pharmaceutically active ingredient, the pharmaceutical carrier, the filler, the surfactant, the antioxidant, and the lubricant.

[0045] The dosage of each component is as described in the present invention.

[0046] In one preferred embodiment of the present invention, the drug-containing layer is composed of components from any one of the following groups: (1) 14.5% by weight of carbidopa monohydrate, 53.6% by weight of levodopa, 31.0% by weight of hydroxypropyl cellulose, and 1.0% by weight of magnesium stearate, (2) 12.7% by weight of carbidopa monohydrate, 46.9% by weight of levodopa, 31% by weight of hydroxypropyl cellulose, 8.5% by weight of mannitol, and 1% by weight of magnesium stearate, (3) 11.3% by weight of carbidopa monohydrate, 41.7% by weight of levodopa, 31% by weight of hydroxypropyl cellulose, 15% by weight of mannitol, and 0.5% by weight of magnesium stearate, (4) 50% by weight of levodopa, 31.0% by weight of hydroxypropyl cellulose, 18% by weight of mannitol, and 1% by weight of magnesium stearate (5) 63% by weight of levodopa, 11% by weight of hydroxypropyl cellulose, 10.0% by weight of sorbitol, 5% by weight of polyvinylpyrrolidone, 10% by weight of poloxamer, and 1% by weight of magnesium stearate (6) 31.5% by weight of levodopa, 20% by weight of hydroxypropyl cellulose, 19% by weight of sorbitol, 9.5% by weight of polyvinylpyrrolidone, 19% by weight of poloxamer, and 1% by weight of magnesium stearate (7) 31.5% by weight of levodopa, 29% by weight of hydroxypropyl cellulose, 19% by weight of sorbitol, 9.5% by weight of polyvinylpyrrolidone, 10% by weight of poloxamer, and 1% by weight of magnesium stearate (8) 63% by weight of levodopa, 10% by weight of hydroxypropyl cellulose, 19.5% by weight of sorbitol, 5% by weight of poloxamer, 0.5% by weight of silicon dioxide, and 2% by weight of magnesium stearate; (9) 31.5% by weight of levodopa, 31% by weight of lactose, 10% by weight of hydroxypropyl cellulose, 20% by weight of sorbitol, 5% by weight of poloxamer (407), 0.5% by weight of silicon dioxide, and 2% by weight of magnesium stearate; (10) 7.5% by weight of carbidopa monohydrate, 55.5% by weight of levodopa, 11% by weight of hydroxypropyl cellulose, 20% by weight of sorbitol, 5% by weight of poloxamer (407), and 1% by weight of magnesium stearate; (11) 63.0% by weight of levodopa, 14.8% by weight of hydroxypropyl cellulose, 14.8% by weight of sorbitol, 5% by weight of poloxamer (407), 0.5% by weight of silicon dioxide, and 2.0% by weight of magnesium stearate; (12) 63.0 wt% levodopa, 11.8 wt% hydroxypropyl cellulose, 17.7 wt% sorbitol, 5 wt% poloxamer (407), 0.5 wt% silicon dioxide, and 2.0 wt% magnesium stearate; (13) 7.5% by weight of carbidopa monohydrate, 55.5% by weight of levodopa, 10% by weight of hydroxypropyl cellulose, 10% by weight of poloxamer (407), 10% by weight of sorbitol, 4.5% by weight of polyvinylpyrrolidone, 2.0% by weight of magnesium stearate, and 0.5% by weight of silicon dioxide; (14) 7.5% by weight of carbidopa monohydrate, 55.5% by weight of levodopa, 15% by weight of hydroxypropyl cellulose, 15% by weight of sorbitol, 4.17% by weight of polyvinylpyrrolidone, 0.33% by weight of dibutylhydroxytoluene, 2.0% by weight of magnesium stearate, and 0.5% by weight of silicon dioxide; (15) 6.91 wt% carbidopa monohydrate, 51.1 wt% levodopa, 30 wt% hydroxypropyl cellulose, 5 wt% sorbitol, 4.19 wt% polyvinylpyrrolidone, 0.31 wt% dibutylhydroxytoluene, 0.5 wt% silicon dioxide, and 2 wt% magnesium stearate, (16) 7.5% by weight of carbidopa monohydrate, 55.5% by weight of levodopa, 10% by weight of hydroxypropyl cellulose, 10% by weight of sorbitol, 10% by weight of poloxamer (407), 4.17% by weight of polyvinylpyrrolidone, 0.33% by weight of dibutylhydroxytoluene, 2.0% by weight of magnesium stearate, and 0.5% by weight of silicon dioxide; (17) 7.5% by weight of carbidopa monohydrate, 55.5% by weight of levodopa, 15% by weight of hydroxypropyl cellulose, 15% by weight of sorbitol, 4.17% by weight of polyvinylpyrrolidone, 0.33% by weight of dibutylhydroxytoluene, 2.0% by weight of magnesium stearate, and 0.5% by weight of silicon dioxide; (18) 3.75% by weight of carbidopa monohydrate, 27.7% by weight of levodopa, 31.5% by weight of mannitol, 10% by weight of hydroxypropyl cellulose, 10% by weight of poloxamer (407), 10% by weight of sorbitol, 4.5% by weight of polyvinylpyrrolidone, 0.5% by weight of silicon dioxide, and 2% by weight of magnesium stearate; (19) 3.75% by weight of carbidopa monohydrate, 27.7% by weight of levodopa, 10% by weight of hydroxypropyl cellulose, 10% by weight of poloxamer (407), 41.5% by weight of sorbitol, 4.5% by weight of polyvinylpyrrolidone, 1.5% by weight of silicon dioxide, and 2% by weight of magnesium stearate.

[0047] In the present invention, the push layer may further comprise one or more of a swelling agent, an osmotic pressure enhancer, a lubricant, and a colorant, or may comprise a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant.

[0048] The ingredients and contents of the swelling agent, osmotic pressure enhancer, colorant, and lubricant may be of the type and content conventional in such preparations in the art, and the contents are expressed as weight percentages of the ingredients in the drug-containing layer. In the present invention, the following ingredients and contents are particularly preferred.

[0049] Here, the swelling agent may be one or more of sodium carboxymethyl starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose (e.g., sodium carboxymethylcellulose (9H4XF)), hydroxyethyl cellulose, carbomer, sodium alginate, carrageenan, and polyoxyethylene, for example, sodium carboxymethylcellulose and hydroxypropyl cellulose.

[0050] When the swelling agent is sodium carboxymethylcellulose and hydroxypropylcellulose, the weight ratio of the sodium carboxymethylcellulose to hydroxypropylcellulose is preferably (2 to 4):1, for example, 2.5:1 or 3.5:1.

[0051] Here, the content of the swelling agent may be 25 to 89% by weight, for example, 89% by weight or 69% by weight.

[0052] wherein the osmolality enhancer may be one or more of sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, magnesium sulfate, ascorbic acid, tartaric acid, mannitol, sorbitol, xylitol, glucose, lactose and sucrose, for example, sorbitol.

[0053] Here, the content of the osmotic pressure enhancer may be 10 to 70% by weight, or may further be 10 to 30% by weight, for example, 30% by weight, and the content is the weight percentage of the component in the push layer.

[0054] wherein the lubricant may be one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, for example stearic acid.

[0055] Here, the content of the lubricant may be 0.1 to 3% by weight, for example, 0.5% by weight, and the content is the weight percentage of the component in the push layer.

[0056] wherein the colorant is one or more of iron(III) oxide, yellow iron oxide, violet iron oxide, and black iron oxide, for example, iron(III) oxide.

[0057] Here, the content of the colorant may be 0.1 to 2% by weight, for example, 0.5% by weight, and the content is the weight percentage of the component in the push layer.

[0058] In one preferred embodiment of the invention, the push layer is composed of components from the following group: (1) 49% by weight of sodium carboxymethylcellulose, 30% by weight of sorbitol, 20% by weight of hydroxypropylcellulose, 0.5% by weight of iron (III) oxide, and 0.5% by weight of magnesium stearate; (2) 69% by weight of sodium carboxymethylcellulose, 10% by weight of sorbitol, 20% by weight of hydroxypropyl cellulose, 0.5% by weight of iron (III) oxide, and 0.5% by weight of magnesium stearate.

[0059] In the present invention, the weight ratio of the drug-containing layer to the push layer may be (0.5-4):1, or may further be (2-3):1, for example, 2:1, 2.5:1, or 2.8:1.

[0060] In one preferred embodiment of the invention, the tablet core comprises ingredients from any one of the following groups: (1) the drug-containing layer: comprising the pharmaceutically active ingredient, the drug carrier, and the lubricant; the push layer: comprising the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; (2) the drug-containing layer: comprising the pharmaceutically active ingredient, the drug carrier, the filler, and the lubricant; the push layer: comprising the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; (3) the drug-containing layer: comprising the pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, and the lubricant; and the push layer: comprising the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant. (4) the drug-containing layer: comprising the pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, the antioxidant, and the lubricant; and the push layer: comprising the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant. The content of each component is the same as above.

[0061] In one preferred embodiment of the invention, the tablet core is composed of ingredients from any one of the following groups: (1) Drug-containing layer: containing 14.5% by weight of carbidopa monohydrate, 53.6% by weight of levodopa, 31.0% by weight of hydroxypropyl cellulose, and 1.0% by weight of magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (2) Drug-containing layer: containing 12.7% by weight of carbidopa monohydrate, 46.9% by weight of levodopa, 31% by weight of hydroxypropyl cellulose, 8.5% by weight of mannitol, and 1% by weight of magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (3) Drug-containing layer: containing 11.3 wt% carbidopa monohydrate, 41.7 wt% levodopa, 31 wt% hydroxypropyl cellulose, 15 wt% mannitol, and 0.5 wt% magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (4) Drug-containing layer: containing 50% by weight of levodopa, 31.0% by weight of hydroxypropyl cellulose, 18% by weight of mannitol, and 1% by weight of magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (5) Drug-containing layer: 63% by weight of levodopa, 11% by weight of hydroxypropyl cellulose, 10.0% by weight of sorbitol, 5% by weight of polyvinylpyrrolidone, 10% by weight of poloxamer, and 1% by weight of magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (6) Drug-containing layer: 31.5% by weight of levodopa, 20% by weight of hydroxypropyl cellulose, 19% by weight of sorbitol, 9.5% by weight of polyvinylpyrrolidone, 19% by weight of poloxamer, and 1% by weight of magnesium stearate; Push layer: 69% by weight sodium carboxymethylcellulose, 10% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron (III) oxide, and 0.5% by weight magnesium stearate; (7) Drug-containing layer: 31.5% by weight of levodopa, 29% by weight of hydroxypropyl cellulose, 19% by weight of sorbitol, 9.5% by weight of polyvinylpyrrolidone, 10% by weight of poloxamer, and 1% by weight of magnesium stearate; Push layer: 69% by weight sodium carboxymethylcellulose, 10% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron (III) oxide, and 0.5% by weight magnesium stearate; (8) Drug-containing layer: 31.5% by weight of levodopa, 20% by weight of hydroxypropyl cellulose, 19% by weight of sorbitol, 9.5% by weight of polyvinylpyrrolidone, 19% by weight of poloxamer, and 1% by weight of magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (9) Drug-containing layer: 31.5% by weight of levodopa, 29% by weight of hydroxypropyl cellulose, 19% by weight of sorbitol, 9.5% by weight of polyvinylpyrrolidone, 10% by weight of poloxamer, and 1% by weight of magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (10) Drug-containing layer: 63% by weight of levodopa, 10% by weight of hydroxypropyl cellulose, 19.5% by weight of sorbitol, 5% by weight of poloxamer, 0.5% by weight of silicon dioxide, and 2.0% by weight of magnesium stearate; Push layer: 69% by weight sodium carboxymethylcellulose, 10% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron (III) oxide, and 0.5% by weight magnesium stearate; (11) Drug-containing layer: 31.5% by weight of levodopa, 31% by weight of lactose, 10% by weight of hydroxypropyl cellulose, 20% by weight of sorbitol, 5% by weight of poloxamer (407), 0.5% by weight of silicon dioxide, and 2% by weight of magnesium stearate; Push layer: 69% by weight of sodium carboxymethylcellulose (9H4XF), 10% by weight of sorbitol, 20% by weight of hydroxypropyl cellulose, 0.5% by weight of iron (III) oxide, and 0.5% by weight of magnesium stearate; (12) Drug-containing layer: 7.5% by weight of carbidopa monohydrate, 55.5% by weight of levodopa, 11% by weight of hydroxypropyl cellulose, 20% by weight of sorbitol, 5% by weight of poloxamer (407), and 1% by weight of magnesium stearate; Push layer: 69% by weight of sodium carboxymethylcellulose (9H4XF), 10% by weight of sorbitol, 20% by weight of hydroxypropyl cellulose, 0.5% by weight of iron oxide, and 0.5% by weight of magnesium stearate; (13) Drug-containing layer: 63.0% by weight of levodopa, 14.8% by weight of hydroxypropyl cellulose, 14.8% by weight of sorbitol, 5% by weight of poloxamer (407), 0.5% by weight of silicon dioxide, and 2.0% by weight of magnesium stearate; Push layer: 69% by weight sodium carboxymethylcellulose, 10% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron (III) oxide, and 0.5% by weight magnesium stearate; (14) Drug-containing layer: 63.0 wt% levodopa, 11.8 wt% hydroxypropyl cellulose, 17.7 wt% sorbitol, 5 wt% poloxamer (407), 0.5 wt% silicon dioxide, and 2.0 wt% magnesium stearate; Push layer: 69% by weight sodium carboxymethylcellulose, 10% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron (III) oxide, and 0.5% by weight magnesium stearate; (15) Drug-containing layer: 7.50 wt% carbidopa monohydrate, 55.51 wt% levodopa, 10 wt% hydroxypropyl cellulose, 10 wt% poloxamer (407), 10 wt% sorbitol, 4.50 wt% polyvinylpyrrolidone, 2.0 wt% magnesium stearate, and 0.5 wt% silicon dioxide; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (16) Drug-containing layer: 7.5 wt% carbidopa monohydrate, 55.5 wt% levodopa, 15 wt% hydroxypropyl cellulose, 15 wt% sorbitol, 4.17 wt% polyvinylpyrrolidone, 0.33 wt% dibutylhydroxytoluene, 2.0 wt% magnesium stearate, and 0.5 wt% silicon dioxide; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (17) Drug-containing layer: 6.91 wt% carbidopa monohydrate, 51.1 wt% levodopa, 30 wt% hydroxypropyl cellulose, 5 wt% sorbitol, 4.19 wt% polyvinylpyrrolidone, 0.31 wt% dibutylhydroxytoluene, 0.5 wt% silicon dioxide, and 2 wt% magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (18) Drug-containing layer: 7.5 wt% carbidopa monohydrate, 55.5 wt% levodopa, 10 wt% hydroxypropyl cellulose, 10 wt% poloxamer, 10 wt% sorbitol, 4.17 wt% polyvinylpyrrolidone, 0.33 wt% dibutylhydroxytoluene, 2 wt% magnesium stearate, and 0.5 wt% silicon dioxide; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (19) Drug-containing layer: 7.5 wt% carbidopa monohydrate, 55 wt% levodopa, 15 wt% hydroxypropyl cellulose, 15 wt% sorbitol, 4.17 wt% polyvinylpyrrolidone, 0.33 wt% dibutylhydroxytoluene, 0.5 wt% silicon dioxide, and 2 wt% magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (20) Drug-containing layer: 3.75 wt% carbidopa monohydrate, 27.7 wt% levodopa, 31.5 wt% mannitol, 10 wt% hydroxypropyl cellulose, 10 wt% poloxamer (407), 10 wt% sorbitol, 4.5 wt% polyvinylpyrrolidone, 1.5 wt% silicon dioxide, and 2 wt% magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron(III) oxide, and 0.5% by weight magnesium stearate; (21) Drug-containing layer: 3.75 wt% carbidopa monohydrate, 27.7 wt% levodopa, 10 wt% hydroxypropyl cellulose, 10 wt% poloxamer (407), 41.5 wt% sorbitol, 4.5 wt% polyvinylpyrrolidone, 1.5 wt% silicon dioxide, and 2 wt% magnesium stearate; Push layer: 49% by weight sodium carboxymethylcellulose, 30% by weight sorbitol, 20% by weight hydroxypropyl cellulose, 0.5% by weight iron (III) oxide, and 0.5% by weight magnesium stearate.

[0062] In the present invention, the tablet core may be a bilayer tablet (composed of a drug-containing layer and a push layer laminated on the drug-containing layer) or a trilayer tablet (composed of a blank layer, a drug-containing layer, and a push layer laminated on the drug-containing layer), for example, a bilayer tablet.

[0063] In the present invention, the tablet core may further comprise a controlled-release membrane coating wound onto the tablet core.

[0064] Here, the release-controlling film coating may further have one or more drug release holes (the drug release holes are formed by laser punching or mechanical punching, for example, one drug release hole, two drug release holes, or three drug release holes). Preferably, the diameter of the drug release hole is 0.3 mm to 1.2 mm, for example, 1.0 mm.

[0065] The controlled-release membrane coating is a semipermeable coating, and the membrane-forming material of the semipermeable coating may be one or more of cellulose acetate, ethyl cellulose, and acrylic resin, for example, cellulose acetate. The content of the membrane-forming material may be 50 to 90% by weight, or even 60 to 90% by weight (e.g., 60%, 65%, 70%, or 90% by weight), where the content is the weight percentage of the component in the controlled-release membrane coating.

[0066] Preferably, the semipermeable coating may further comprise a pore former and a plasticizer.

[0067] wherein the pore-forming agent may be one or more of polyethylene glycol, glycerol, polyvinylpyrrolidone, copolyvidone and hydroxypropyl cellulose, such as polyvinylpyrrolidone and hydroxypropyl cellulose (hydroxypropyl cellulose HXF).

[0068] wherein the plasticizer is one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glyceryl acetate, and castor oil, such as polyethylene glycol or triethyl citrate.

[0069] Here, the semipermeable coating may comprise a mixture of cellulose acetate and copolyvidone, a mixture of "cellulose acetate, hydroxypropyl cellulose HXF and triethyl citrate", or a mixture of "cellulose acetate and triethyl citrate".

[0070] Here, the weight ratio of the release-controlling film coating to the tablet core may be a conventional weight ratio in the art, such as (2.0% to 15.0%):1 (e.g., 6.6%:1, 6.9%:1, 7.0%:1, 7.4%:1, 7.6%:1, 7.7%:1, 7.8%:1, 8.0%:1, or 8.4%:1), or may be (6.6% to 8.4%):1 or (7.4% to 7.8%):1.

[0071] In the present invention, the tablet may further include an isolation coating layer between the tablet core and the release-controlling membrane coating (the isolation coating layer is wrapped around the tablet core, and the release-controlling membrane coating is wrapped around the isolation coating layer).

[0072] Here, the film-forming material of the isolation coating layer may be hydroxypropyl cellulose EF.

[0073] Here, the weight ratio of the isolating coating layer to the tablet core may be a conventional weight ratio in the art, such as (3.0% to 5.0%):1, for example, 4.0%:1.

[0074] In the present invention, the pharmaceutical composition may further comprise an immediate-release layer containing a pharmaceutically active ingredient coated on the release-controlled film coating. The pharmaceutical composition may further comprise an immediate-release layer. The immediate-release layer preferably comprises a pharmaceutically active ingredient, a binder, and an antioxidant. The immediate-release layer preferably further comprises a pharmaceutically active ingredient, a plasticizer, an antioxidant, and a binder. The immediate-release layer preferably consists of a pharmaceutically active ingredient, an antioxidant, and a binder, or a pharmaceutically active ingredient, a plasticizer, an antioxidant, and a binder.

[0075] When the immediate release layer contains a plasticizer, the content of the plasticizer is a conventional content in the art, preferably 1-2% by weight.

[0076] If the immediate release layer comprises a plasticizer, the plasticizer may be one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glyceryl acetate, and castor oil, for example, tributyl citrate.

[0077] When the immediate release layer contains an antioxidant, the content of the antioxidant is a conventional content in the art, preferably 3-4 wt%, for example 3.38 wt% or 3.81 wt%.

[0078] If the immediate release layer includes an antioxidant, the antioxidant may be one or more of dibutylhydroxytoluene, tert-butylhydroxyanisole, dibutylphenol, vitamin C, vitamin E, and sodium sulfite, for example, dibutylhydroxytoluene.

[0079] When the immediate release layer contains a binder, the content of the binder is a conventional content in the art, preferably 10-20% by weight.

[0080] When the immediate release layer includes a binder, the binder may be one or more of polyvinylpyrrolidone, copolyvidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, for example, a mixture of hydroxypropyl cellulose and copolyvidone (the weight ratio of the two is, for example, 1:1), or hydroxypropyl cellulose.

[0081] When the immediate release layer contains a pharmaceutically active ingredient, the content of the pharmaceutically active ingredient is a conventional content in the art, preferably 70 to 90% by weight, for example, 74.7% by weight, 75.7% by weight, 86.2% by weight, or 85.3% by weight.

[0082] When the immediate-release layer comprises a pharmaceutically active ingredient, the pharmaceutically active ingredient comprises a dopa decarboxylase inhibitor. Preferably, the dopa decarboxylase inhibitor is carbidopa hydrate, a pharmaceutically acceptable salt of carbidopa, benserazide, or a pharmaceutically acceptable salt of benserazide, and preferably is carbidopa hydrate, e.g., carbidopa monohydrate.

[0083] In one preferred embodiment of the present invention, the immediate release layer is composed of ingredients from any one of the following groups: (a) 86.2% by weight of carbidopa monohydrate, 10.0% by weight of hydroxypropyl cellulose, and 3.84% by weight of dibutylhydroxytoluene; (b) 85.3% by weight of carbidopa monohydrate, 10.0% by weight of hydroxypropyl cellulose, 1.02% by weight of triethyl citrate, and 3.81% by weight of dibutylhydroxytoluene; (c) 74.7% by weight of carbidopa monohydrate, 10.0% by weight of hydroxypropyl cellulose, 10.0% by weight of copolyvidone, 2.00% by weight of triethyl citrate, and 3.38% by weight of dibutylhydroxytoluene; (d) 75.7% by weight carbidopa monohydrate, 10.0% by weight hydroxypropyl cellulose, 10.0% by weight copolyvidone, 1.00% by weight triethyl citrate, and 3.38% by weight dibutylhydroxytoluene.

[0084] In the present invention, the pharmaceutical composition may further comprise an enteric layer coated on the release-controlled coating or the immediate-release layer. The material of the enteric layer may be an acrylic resin or a cellulose derivative. The acrylic resin may be one or more of a copolymer of methacrylic acid and ethyl acrylate copolymerized in a 1:1 weight ratio, a copolymer of methacrylic acid and methyl methacrylate copolymerized in a 1:1 weight ratio, a copolymer of methacrylic acid and ethyl acrylate copolymerized in a 1:2 weight ratio, and a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate copolymerized in a 1:1:1 weight ratio. The cellulose derivative may be one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose titanate, and hydroxypropyl methylcellulose acetate succinate.

[0085] In the present invention, the shape of the capsule-shaped tablet may be a capsule shape formed by tableting in the long axis direction, or a capsule shape formed by tableting in a direction perpendicular to the long axis, for example, a capsule shape formed by tableting in the long axis direction.

[0086] In the present invention, the cross-sectional shape of the capsule-shaped tablet may be circular or non-circular, for example, circular.

[0087] When the capsule-shaped tablet has a circular cross section, the diameter of the circle may be 5 to 10 mm (e.g., 6 mm, 7 mm, or 8 mm) and the height may be 4 to 30 mm (e.g., 14.90 mm, 15.24 mm, 16.42 mm, or 16.76 mm), and further the diameter of the cross section may be 5 to 7.5 mm and the height may be 10 to 20 mm.

[0088] Here, when the cross-sectional shape of the capsule-shaped tablet is non-circular, the non-circular shape may have an axis of symmetry. The length of the major axis of the non-circular shape having an axis of symmetry may be 10 to 25 mm, and the length of the minor axis may be 5 to 25 mm. The length of the major axis of the non-circular shape having an axis of symmetry may further be 16 to 19 mm, and the length of the minor axis may further be 7 to 7.5 mm.

[0089] In one preferred embodiment of the present invention, the pharmaceutical composition is one of the following groups: (1) The drug-containing layer: contains the pharmaceutically active ingredient, the drug carrier, and the lubricant; the push layer: contains the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the cross-sectional shape of the capsule-shaped tablet is non-circular (or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis). (2) The drug-containing layer: comprises the pharmaceutically active ingredient, the drug carrier, the filler, and the lubricant; the push layer: comprises the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the cross-sectional shape of the capsule-shaped tablet is non-circular (or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis). (3) The drug-containing layer: comprises the pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, and the lubricant; the push layer: comprises the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the cross-sectional shape of the capsule-shaped tablet is non-circular (or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis). (4) The drug-containing layer: comprises the pharmaceutically active ingredient, the drug carrier, the filler, the antioxidant, and the lubricant; the push layer: comprises the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the cross-sectional shape of the capsule-shaped tablet is non-circular (or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis). (5) The drug-containing layer: comprises the pharmaceutically active ingredient, the drug carrier, the filler, and the lubricant; the push layer: comprises the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the capsule-shaped tablet has a circular cross-sectional shape (or the capsule-shaped tablet has a capsule shape formed by compressing in the long axis direction). (6) The drug-containing layer: comprises the pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, and the lubricant; the push layer: comprises the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the capsule-shaped tablet has a circular cross-sectional shape (or the capsule-shaped tablet has a capsule shape formed by compressing in the long axis direction). (7) The drug-containing layer: comprises the pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, the antioxidant, and the lubricant; the push layer: comprises the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; and the capsule-shaped tablet has a circular cross-sectional shape (or the capsule-shaped tablet has a capsule shape formed by compressing in the long axis direction).

[0090] The content of each component is the same as above.

[0091] In one preferred embodiment of the present invention, the pharmaceutical composition is of the following group (I) or (II): (I) the drug-containing layer: comprising the pharmaceutically active ingredient, the drug carrier, the filler, the antioxidant, and the lubricant, and the push layer: comprising the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant; the immediate release layer: comprising the pharmaceutically active ingredient, the binder, and the oxidizing agent; The capsule-shaped tablet has a circular cross-sectional shape (or the capsule-shaped tablet has a capsule shape formed by tableting in the long axis direction). (II) the drug-containing layer: comprising the pharmaceutically active ingredient, the drug carrier, the filler, the antioxidant, and the lubricant; and the push layer: comprising the swelling agent, the osmotic pressure enhancer, the colorant, and the lubricant. the immediate release layer: comprising the pharmaceutically active ingredient, the adhesive, the oxidizing agent, and the plasticizer; The cross-sectional shape of the capsule-shaped tablet is circular (or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in the long axis direction).

[0092] In one preferred embodiment of the present invention, the pharmaceutically active ingredient in the drug-containing layer is levodopa, and the content of levodopa is 27.7 to 63 wt %.

[0093] The dopa decarboxylase inhibitor is carbidopa or a hydrate thereof, and the content of the dopa decarboxylase inhibitor is 7.5 to 14.5% by weight.

[0094] The drug-containing layer comprises pharmaceutical excipients, which include "drug carriers, fillers and lubricants," "drug carriers, fillers, surfactants and lubricants," or "drug carriers, fillers, surfactants, antioxidants and lubricants."

[0095] The drug carrier is a "mixture of polyvinylpyrrolidone and hydroxypropyl cellulose" or hydroxypropyl cellulose, the content of the drug carrier is 10 to 40% by weight, the filler is a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, or sorbitol, the content of the filler is 8.5 to 20% by weight, and the weight ratio of sorbitol in the filler to hydroxypropyl cellulose in the drug carrier is (1 to 2:1).

[0096] The surfactant is a poloxamer, and the content of the surfactant is 5 to 19% by weight.

[0097] The lubricant is magnesium stearate and / or silicon dioxide, and the content of the lubricant is 1 to 2.5% by weight.

[0098] The antioxidant is dibutylhydroxytoluene, and the content of the antioxidant is 0.1 to 1.0% by weight.

[0099] The capsule-shaped tablet has a capsule shape formed by tableting in the major axis direction (or the cross section of the capsule-shaped tablet has a circular shape).

[0100] Preferably, the weight ratio of the release-controlling film coating to the tablet core is (7.0%-8.0%):1, and may further be (7.4%-7.8%):1.

[0101] In the present invention, the capsule-shaped tablet is preferably a controlled-release tablet, such as an osmotic pump tablet. The controlled-release tablet preferably contains 125 mg, 150 mg, 250 mg, 375 mg, or 500 mg of levodopa per tablet. In the present invention, the pharmaceutical composition is preferably taken in a supine position before going to bed and after taking the pharmaceutical composition.

[0102] In one preferred embodiment of the present invention, the drug-containing layer of the pharmaceutical composition is composed of the pharmaceutically active ingredient and the pharmaceutical excipient.

[0103] The present invention further provides a method for preparing a pharmaceutical composition, comprising the steps of:

[0104] a step of laminating and compounding the raw material particles of the drug-containing layer and the raw material particles of the push layer to form the tablet core; If the tablet core further comprises a release-controlling film coating, the tablet core is coated, the release-controlling film coating is wrapped around the tablet core, and holes are drilled in the release-controlling film coating on one side of the drug-containing layer to form drug-release holes.

[0105] When the pharmaceutical composition further comprises an immediate release layer, the immediate release layer coating is wrapped around the capsule-shaped tablet coated with the controlled-release film coating.

[0106] When the pharmaceutical composition further comprises an isolating coating layer, the isolating coating layer is first coated on the core tablet, and then a coating is coated on the isolating coating layer.

[0107] Here, the composite press may perform tableting in the major axis direction or in a direction perpendicular to the major axis direction.

[0108] The raw material particles for the drug-containing layer can be obtained by a conventional granulation method in the art, such as dry granulation, wet granulation, hot-melt granulation, or fluidized-bed granulation.

[0109] Here, the raw material particles of the push layer can be obtained by a conventional granulation method in the art, for example, dry granulation, wet granulation, or fluidized bed granulation can be used to obtain the raw material particles of the drug-containing layer.

[0110] The present invention further provides the use of the pharmaceutical composition in the preparation of a medicament for preventing or treating morning stiffness.

[0111] In said use, said morning stiffness is preferably morning stiffness caused by Parkinson's disease.

[0112] The pharmaceutical composition preferably begins to release the pharmaceutically active ingredient after a delay of 1 to 3 hours, the pharmaceutically active ingredient reaches a peak concentration in 6 to 10 hours, and the blood drug concentration is maintained at more than 50% of the peak concentration for 5 hours or more; more preferably, begins to release the pharmaceutically active ingredient after a delay of 2 hours, the pharmaceutically active ingredient reaches a peak concentration in 6 to 10 hours, and the blood drug concentration is maintained at more than 50% of the peak concentration for 7 hours or more.

[0113] The release characteristics of the pharmaceutical composition are preferably such that there is a 1-3 hour delay before the onset of release (during which period the cumulative release rate of the pharmaceutically active ingredient is ≦10%), and after the onset of release, the pharmaceutically active ingredient is released at a cumulative rate of 85% or more (including 85%) in 6-10 hours, and more preferably such that there is a 2 hour delay before the onset of release (during which period the cumulative release rate of the pharmaceutically active ingredient is ≦10%), and after the onset of release, the pharmaceutically active ingredient is released at a cumulative rate of 85% or more (including 85%).

[0114] The present invention further provides a delayed-release pharmaceutical composition, wherein the pharmaceutical composition is in the form of a controlled-release tablet.

[0115] The pharmaceutical composition comprises a pharmaceutically active ingredient, and the pharmaceutically active ingredient is levodopa or a derivative thereof, or a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, and the release (in vitro) characteristics of the composition are such that before the onset of release, the pharmaceutically active ingredient has a delay of 1 to 3 hours, and after the onset of release, the pharmaceutically active ingredient has a cumulative release rate of 85% or more (including 85%) within 6 to 10 hours, and the delay means that the cumulative release rate of the pharmaceutically active ingredient during this period is ≦10%.

[0116] Preferably, the blood drug concentration of the pharmaceutically active ingredient is maintained at 50% or more of the peak concentration for 5 hours or more, and more preferably, the blood drug concentration of the pharmaceutically active ingredient is maintained at 50% or more of the peak concentration for 7 hours or more.

[0117] The release profile of the pharmaceutical composition is preferably such that the pharmaceutically active ingredient has a 2-hour delay before the onset of release, and after the onset of release, the pharmaceutical composition has a cumulative release rate of 85% or more (including 85%) within 8 hours.

[0118] Here, the pharmaceutical composition is preferably taken before going to bed and after taking the pharmaceutical composition while lying on one's back. The pharmaceutical composition is preferably the pharmaceutical composition described above. The pharmaceutical composition is preferably used for the prevention or treatment of morning stiffness. The morning stiffness is preferably morning stiffness caused by Parkinson's disease.

[0119] Here, the components of the pharmaceutical composition are the same as those described above.

[0120] The present invention further provides a method for preventing or treating morning stiffness, comprising the step of administering to a subject an effective amount of the pharmaceutical composition.

[0121] In the method, the morning stiffness is preferably morning stiffness caused by Parkinson's disease. The pharmaceutical composition is preferably taken before going to bed and after taking the composition while lying on one's back.

[0122] In the present invention, the "longitudinal direction" refers to a direction parallel to the longest axis of symmetry of the capsule-shaped tablet.

[0123] In the present invention, the term "cross section" refers to a plane parallel to the interface formed by the drug-containing layer and the push layer.

[0124] The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common knowledge in the art.

[0125] All reagents and raw materials used in the present invention are commercially available.

[0126] Positive and gradual effects of the present invention: The pharmaceutical composition of the present invention has the following excellent controlled-release effects: delayed release in vitro for 1 to 3 hours, with the cumulative release rate of the pharmaceutically active ingredient being 10% or less; sustained release for 6 to 10 hours, with the cumulative release rate of 85% or more after 6 to 10 hours; and even delayed release for 2 hours in vitro, with the cumulative release rate of the pharmaceutically active ingredient being 10% or less; sustained release for 8 to 10 hours, with the cumulative release rate of 85% or more after 8 to 10 hours.

[0127] The drug is released into the body with a 1-3 hour delay, reaching peak concentrations in 6-10 hours, and the blood drug concentration remains at more than 50% of the peak concentration for more than 5 hours, with release beginning after a 2-hour delay.

[0128] The pharmaceutical composition of the present invention allows a patient to take the medication themselves before going to bed the previous night, and allows the blood drug concentration to be maintained at or above the minimum effective concentration before waking up in the morning, so that the patient is in an "ON" state rather than an "OFF" state when waking up in the morning, thereby reducing the occurrence of morning stiffness and other associated symptoms caused thereby. [Brief explanation of the drawings]

[0129] [Figure 1] 1 shows the release curve of levodopa from the controlled-release tablet in Example 1. [Figure 2] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 1. [Figure 3] 1 shows the release curve of levodopa from the controlled-release tablet in Example 2. [Figure 4] 1 shows the release curve of levodopa from the controlled-release tablet in Example 3. [Figure 5] 1 shows the release curve of levodopa from the controlled-release tablet in Example 4. [Figure 6] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 4. [Figure 7] 1 shows the release curve of levodopa from the controlled-release tablet in Example 5. [Figure 8] 1 shows the release curve of levodopa from the controlled-release tablet in Example 6. [Figure 9] 1 shows the release curve of levodopa from the controlled-release tablet in Example 7. [Figure 10] 1 shows the release curve of levodopa from the controlled-release tablet in Example 8. [Figure 11] 1 shows the release curve of levodopa from the controlled-release tablet in Example 9. [Figure 12] 1 shows the release curve of levodopa from the controlled-release tablet in Example 10. [Figure 13] 1 shows the release curve of levodopa from the controlled-release tablet in Example 11. [Figure 14] 1 shows the release curve of levodopa from the controlled-release tablet in Example 14. [Figure 15]1 shows the release curve of levodopa from the controlled-release tablet in Example 15. [Figure 16] 1 shows the release curve of levodopa from the controlled-release tablet in Example 16. [Figure 17] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 16. [Figure 18] 1 shows the release curve of levodopa from the controlled-release tablet in Example 17. [Figure 19] 1 shows the release curve of levodopa from the controlled-release tablet in Example 18. [Figure 20] 1 shows the release curve of levodopa from the controlled-release tablet in Example 19. [Figure 21] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 19. [Figure 22] 2 shows the release curve of levodopa from the controlled-release tablet in Example 21. [Figure 23] 2 shows the release curve of carbidopa from the controlled-release tablet in Example 21. [Figure 24] 2 shows the release curve of levodopa from the controlled-release tablet in Example 22. [Figure 25] 2 shows the release curve of carbidopa from the controlled-release tablet in Example 22. [Figure 26] 1 shows the release curve of levodopa from the controlled-release tablet in Example 23. [Figure 27] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 23. [Figure 28] 1 shows the release curve of levodopa from the controlled-release tablet in Example 24. [Figure 29] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 24. [Figure 30] 1 shows the release curve of levodopa from the controlled-release tablet in Example 25. [Figure 31] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 25. [Figure 32] 1 shows the release curve of levodopa from the controlled-release tablet in Example 26. [Figure 33]1 shows the release curve of carbidopa from the controlled-release tablet in Example 26. [Figure 34] 1 shows the release curve of levodopa from the controlled-release tablet in Example 27. [Figure 35] 1 shows the release curve of carbidopa from the controlled-release tablet in Example 27. [Figure 36] 1A and 1B are diagrams showing the shape of the controlled-release tablet of the present invention, where a is a diagram showing the three-dimensional structure of the controlled-release tablet obtained by formulation 3 in Example 1, b is a right side view of the controlled-release tablet obtained by formulation 3 in Example 1, c is a diagram showing the three-dimensional structure of the controlled-release tablet of Example 11, and d is a right side view of the controlled-release tablet of Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0130] The present invention will be further described below with reference to examples, but the present invention is not limited to these examples. In the following examples, experimental methods without specific conditions are carried out according to conventional methods and conditions or selected according to the product instructions. In the following examples, "wt%" refers to the weight percentage of the component in the total weight of the layer in which the component is disposed. For example, in Formulation 1 of Example 1, carbidopa accounts for 14.5 wt%, which refers to the weight percentage of carbidopa in the total weight of the drug-containing layer formulation. Unless otherwise specified, in embodiments, the mannitol is mannitol 200SD, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF, the poloxamer is poloxamer 407 ≦80 mesh, the sorbitol is sorbitol ≦80 mesh, the polyvinylpyrrolidone is polyvinylpyrrolidone K29 / 32, and the cellulose acetate is cellulose acetate 320S.

[0131] Example 1: Screening of capsule-shaped tablets (non-circular cross section, compressed vertically to the major axis) with a standard of 37.5 mg / 150 mg (carbidopa / levodopa) and mannitol ratio The prescription is as follows:

[0132] [Table 1] TIFF2025539199000003.tif78170

[0133] Preparation method: 1. Preparation of the drug-containing layer: Carbidopa and levodopa were pre-blended with other excipients for the drug-containing layer (except for the addition of magnesium stearate), added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally added with magnesium stearate and mixed.

[0134] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0135] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with the pre-compressed drug-containing layer material, then filled with the push layer material, and compressed to obtain bilayer tablet cores, which were compressed in the direction perpendicular to the major axis.

[0136] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 5.5% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.0 mm. The specifications of the controlled-release tablets in this example were 37.5 mg / 150 mg (carbidopa / levodopa), and they were capsule-shaped biconvex tablets.

[0137] 5. Release measurement method: Take out this product and measure the release <711> Method 2 and Chinese Pharmacopoeia <0931> According to the method described above, the tablets were placed in a sinker and rotated at 75 rpm using 900 mL of 0.1 N hydrochloric acid solution as the solvent. After 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours, 2 mL of the dissolution solution after online filtration (10 mL was rinsed online before collection) was immediately sampled and designated test solutions (1), (2), (3), (4), (5), (6), (7), (8), and (9). 2 mL of 0.1 N hydrochloric acid solution at 37°C was immediately added to the dissolution cup.

[0138] Chromatography conditions: High performance liquid chromatography (USP <621> and the Chinese Pharmacopoeia <0512> ) was used, using octadecylsilane-bonded silica gel as the packing material, methanol-phosphate buffer (pH 2.1) (5:95) as the mobile phase, the flow rate was 1.0 mL / min, the detection wavelength was 280 nm, the column temperature was 35°C, and the sample chamber temperature was 6°C.

[0139] Specific results of the levodopa test are shown in Table 2 and FIG. 1, and results of the carbidopa test are shown in Table 3 and FIG.

[0140] [Table 2]

[0141] [Table 3]

[0142] Example 2: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) with a standard of 37.5 mg / 150 mg (carbidopa / levodopa) and an isolation coating The prescription is as follows:

[0143] [Table 4]

[0144] Preparation method: 1. Preparation of drug-containing layer: Same as formulation 2 in Example 1.

[0145] 2. Preparation of push layer: same as formulation 2 in Example 1.

[0146] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 320 mg of drug-containing layer material, pre-compressed, then filled with 160 mg of push layer material, and compressed to obtain bilayer tablet cores of 480 mg / tablet, which were compressed perpendicular to the major axis.

[0147] 4. Isolation Coating: Using a coating pan, the bilayer tablet cores were coated with the above isolation coating solution to a weight gain of 4.0% by weight (percentages are weight percentages relative to the tablet core).

[0148] 5. Semipermeable coating: Using a coating pan, the isolation-coated tablets were coated with the controlled-release coating solution to increase their weight by 4.0% and 6.0% by weight (percentages are based on the weight of the isolation-coated tablets). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.0 mm. The specifications of the controlled-release tablets in this embodiment were 37.5 mg / 150 mg (carbidopa / levodopa), and they were capsule-shaped biconvex tablets.

[0149] 6. Release measurement method: same as in Example 1. The specific test results for levodopa are shown in Table 5 and Figure 3.

[0150] [Table 5]

[0151] Example 3: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis), standard 37.5 mg / 150 mg (carbidopa / levodopa), CA320S + hydroxypropyl cellulose HXF The prescription is as follows:

[0152] [Table 6]

[0153] Preparation method: 1. Preparation of drug-containing layer: Same as formulation 2 in Example 1.

[0154] 2. Preparation of push layer: same as formulation 2 in Example 1.

[0155] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 320 mg of drug-containing layer material, pre-compressed, then filled with 160 mg of push layer material, and compressed to obtain bilayer tablet cores of 480 mg / tablet, which were compressed perpendicular to the major axis.

[0156] 4. Semipermeable coating: Using a coating pan, the isolation-coated tablets were coated with the controlled-release coating solution to increase their weight by 6.3% and 7.5% by weight (percentages are based on the weight percentage of the isolation-coated tablets). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.0 mm. The specifications of the controlled-release tablets in this embodiment were 37.5 mg / 150 mg (carbidopa / levodopa), and they were capsule-shaped biconvex tablets.

[0157] 5. Release measurement method: same as in Example 1. The specific test results for levodopa are shown in Table 7 and Figure 4.

[0158] [Table 7]

[0159] Example 4: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) Standard: 37.5 mg / 150 mg (carbidopa / levodopa), CA320S + triethyl citrate The prescription is as follows:

[0160] [Table 8]

[0161] Preparation method: 1. Preparation of drug-containing layer: Same as formulation 2 in Example 1.

[0162] 2. Preparation of push layer: same as formulation 2 in Example 1.

[0163] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 320 mg of drug-containing layer material, pre-compressed, then filled with 160 mg of push layer material, and compressed to obtain bilayer tablet cores of 480 mg / tablet, which were compressed perpendicular to the major axis.

[0164] 4. Seal coating: Using a coating pan, the isolation-coated tablets were coated with the controlled-release coating solution to increase their weight by 6.3% and 7.5% by weight (the percentages are based on the weight of the isolation-coated tablets). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.0 mm. The specifications of the controlled-release tablets in this embodiment were 37.5 mg / 150 mg (carbidopa / levodopa), and they were capsule-shaped biconvex tablets.

[0165] 5. Release measurement method: same as in Example 1. The specific test results for levodopa are shown in Table 9 and Figure 5, and the test results for carbidopa are shown in Table 10 and Figure 6.

[0166] [Table 9]

[0167] [Table 10]

[0168] Example 5: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) Standard: 250 mg The prescription is as follows:

[0169] [Table 11]

[0170] Preparation method: 1. Preparation of the drug-containing layer: Levodopa and other excipients for the drug-containing layer (except for the addition of magnesium stearate) were pre-mixed, added to a dry granulator and compressed into strips, then granulated through a 16-mesh stainless steel screen, and finally magnesium stearate was added and mixed for later use.

[0171] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate addition) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally added with magnesium stearate and mixed for later use.

[0172] 3. Tablet compression: Compressed into bilayer tablets, compressed in a mold with a size of 19 × 7.5 mm (shallow concave), first filled with 500 mg of drug-containing layer material, pre-compressed, then filled with 250 mg of push layer material, and compressed to obtain bilayer tablet cores of 750 mg / tablet, which were compressed in the direction perpendicular to the major axis.

[0173] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution to a weight gain of 6.0% and 8.7% (percentages are weight percentages relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.0 mm. The controlled-release tablets in this embodiment were capsule-shaped biconvex tablets containing 250 mg of levodopa.

[0174] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 12 and Figure 7.

[0175] [Table 12]

[0176] Example 6: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 250 mg standard The prescription is as follows:

[0177] [Table 13]

[0178] Preparation method: 1. Preparation of drug-containing layer: same as in Example 5.

[0179] 2. Preparation of push layer: same as in Example 5.

[0180] 3. Tablet compression: Compressed into bilayer tablets, compressed in a mold with a size of 16 × 7 mm (shallow concave), first filled with 396.8 mg of drug-containing layer material, pre-compressed, and then filled with 198.4 mg of push layer material, and compressed to obtain bilayer tablet cores of 595.2 mg / tablet, which were compressed in the direction perpendicular to the major axis.

[0181] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 8.0% (the percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.0 mm. The controlled-release tablets in this embodiment contained 250 mg of levodopa and were capsule-shaped biconvex tablets.

[0182] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 14 and Figure 8.

[0183] [Table 14]

[0184] Example 7: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 125 mg standard The prescription is as follows:

[0185] [Table 15]

[0186] Preparation method: 1. Preparation of drug-containing layer: same as in Example 5.

[0187] 2. Preparation of push layer: same as in Example 5.

[0188] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 396.8 mg of drug-containing layer material, pre-compressed, then filled with 198.4 mg of push layer material, and compressed to obtain bilayer tablet cores of 595.2 mg / tablet, which were compressed perpendicular to the major axis.

[0189] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 8.0% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The controlled-release tablet in this embodiment had a specification of 125 mg levodopa, was a capsule-shaped biconvex tablet, and its size was 16 x 7 mm.

[0190] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 16 and Figure 9.

[0191] [Table 16]

[0192] Example 8: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 125 mg standard The prescription is as follows:

[0193] [Table 17]

[0194] Preparation method: 1. Preparation of drug-containing layer: same as in Example 5.

[0195] 2. Preparation of push layer: same as in Example 5.

[0196] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 396.8 mg of drug-containing layer material, pre-compressed, then filled with 198.4 mg of push layer material, and compressed to obtain bilayer tablet cores of 595.2 mg / tablet, which were compressed perpendicular to the major axis.

[0197] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 8.4% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The controlled-release tablet in this embodiment had a specification of 125 mg levodopa, was a capsule-shaped biconvex tablet, and its size was 16 x 7 mm.

[0198] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 18 and Figure 10.

[0199] [Table 18]

[0200] Example 9: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 125 mg standard The prescription is as follows:

[0201] [Table 19]

[0202] Preparation method: 1. Preparation of drug-containing layer: same as in Example 5.

[0203] 2. Preparation of push layer: same as in Example 5.

[0204] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 396.8 mg of drug-containing layer material, pre-compressed, then filled with 198.4 mg of push layer material, and compressed to obtain bilayer tablet cores of 595.2 mg / tablet, which were compressed perpendicular to the major axis.

[0205] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 6.9% by weight (the percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The controlled-release tablet in this embodiment contained 125 mg of levodopa and was a capsule-shaped biconvex tablet, measuring 16 x 7 mm, compressed perpendicular to the major axis.

[0206] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 20 and Figure 11.

[0207] [Table 20]

[0208] Example 10: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 125 mg standard The prescription is as follows:

[0209] [Table 21]

[0210] Preparation method: 1. Preparation of drug-containing layer: same as in Example 5.

[0211] 2. Preparation of push layer: same as in Example 5.

[0212] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 396.8 mg of drug-containing layer material, pre-compressed, then filled with 198.4 mg of push layer material, and compressed to obtain bilayer tablet cores of 595.2 mg / tablet, which were compressed perpendicular to the major axis.

[0213] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 6.6% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 125 mg (carbidopa / levodopa), a capsule-shaped biconvex tablet, and its size was 16 x 7 mm.

[0214] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 22 and Figure 12.

[0215] [Table 22]

[0216] Example 11: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 250 mg standard The prescription is as follows:

[0217] [Table 23]

[0218] Preparation method: 1. Preparation of the drug-containing layer: Levodopa was pre-blended with other excipients for the drug-containing layer (except for the addition of magnesium stearate and silicon dioxide), added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with magnesium stearate and silicon dioxide.

[0219] 2. Preparation of push layer: same as in Example 5.

[0220] 3. Tablet compression: Compressed into bilayer tablets using a Φ6 mm round punch (deep concave) mold. First, 396.8 mg of drug-containing layer material was filled. After pre-compression, 161.3 mg of push layer material was filled. Then, bilayer tablet cores of 558.1 mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0221] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.8% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 250 mg, a capsule-shaped tablet, its cross-sectional diameter was 6 mm, and its height was 14.90 mm.

[0222] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 24 and Figure 13.

[0223] [Table 24]

[0224] Example 12: Capsule-shaped tablet (circular cross section, compressed in the long axis direction) 375 mg standard The prescription is as follows:

[0225] [Table 25]

[0226] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0227] 2. Preparation of push layer: same as in Example 11.

[0228] 3. Tablet compression: Compressed into bilayer tablets using a Φ7 mm round punch (deep concave) mold. First, 595.3 mg of drug-containing layer material was filled. After pre-compression, 242.0 mg of push layer material was filled. Then, bilayer tablet cores of 837.3 mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0229] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.0% by weight (the percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 375 mg, a capsule-shaped tablet, its cross-sectional diameter was 7 mm, and its height was 16.42 mm.

[0230] Example 13: Capsule-shaped tablet (circular cross section, compressed in the long axis direction) 500 mg standard The prescription is as follows:

[0231] [Table 26]

[0232] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0233] 2. Preparation of push layer: same as in Example 11.

[0234] 3. Tablet compression: Compressed into bilayer tablets using a Φ8mm round punch (deep concave) mold. First, 793.6mg of drug-containing layer material was filled. After pre-compression, 322.6mg of push layer material was filled. Then, bilayer tablet cores of 1116.2mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0235] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.0% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 500 mg, a capsule-shaped tablet, its cross-sectional diameter was 8 mm, and its height was 16.76 mm.

[0236] Example 14: Capsule-shaped tablet (circular cross section, compressed in the long axis direction) 125 mg (LD) standard The prescription is as follows:

[0237] [Table 27]

[0238] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0239] 2. Preparation of push layer: same as in Example 11.

[0240] 3. Tablet compression: Compressed into bilayer tablets using a Φ6 mm round punch (deep concave) mold. First, 396.8 mg of drug-containing layer material was filled. After pre-compression, 161.3 mg of push layer material was filled. Then, bilayer tablet cores of 558.1 mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0241] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.4% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 125 mg, a capsule-shaped tablet, its cross-sectional diameter was 6 mm, and its height was 15.24 mm.

[0242] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 28 and Figure 14.

[0243] [Table 28]

[0244] Example 15: Capsule-shaped tablet (circular cross section, compressed in the long axis direction) 125 mg (LD) standard The prescription is as follows:

[0245] [Table 29]

[0246] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0247] 2. Preparation of push layer: same as in Example 11.

[0248] 3. Tablet compression: Compressed into bilayer tablets using a Φ6 mm round punch (deep concave) mold. First, 396.8 mg of drug-containing layer material was filled. After pre-compression, 161.3 mg of push layer material was filled. Then, bilayer tablet cores of 558.1 mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0249] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.7% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 125 mg, a capsule-shaped tablet, its cross-sectional diameter was 6 mm, and its height was 15.24 mm.

[0250] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 30 and Figure 15.

[0251] [Table 30]

[0252] Example 16: Capsule-shaped tablet (circular cross section, compressed in the long axis direction) 31.3 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0253] [Table 31]

[0254] Preparation method: 1. Preparation of drug-containing layer: same as in Example 1.

[0255] 2. Preparation of push layer: same as in Example 1.

[0256] 3. Tablet compression: Compressed into bilayer tablets using a Φ6mm round punch (deep concave) mold. First, 450.5mg of drug-containing layer material was filled. After pre-compression, 183.1mg of push layer material was filled. Then, bilayer tablet cores of 633.6mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0257] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.6% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 250 mg, carbidopa 31.3 mg, and it was a capsule-shaped tablet with a cross-sectional diameter of 6 mm and a height of 17.27 mm.

[0258] 5. Release measurement method: same as in Example 1. Specific levodopa test results are shown in Table 32 and Figure 16, and carbidopa test results are shown in Table 33 and Figure 17.

[0259] [Table 32]

[0260] [Table 33]

[0261] Example 17: Capsule-shaped tablet (circular cross section, compressed in the long axis direction) 250 mg standard Based on Example 11, the ratio of HPC:sorbitol was 1:1 or 1:1.5, and the rest was the same as Example 11. The formulation was as follows:

[0262] [Table 34] TIFF2025539199000037.tif28170

[0263] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0264] 2. Preparation of push layer: same as in Example 11.

[0265] 3. Tablet compression: Compressed into bilayer tablets using a Φ6 mm round punch (deep concave) mold. First, 396.8 mg of drug-containing layer material was filled. After pre-compression, 161.3 mg of push layer material was filled. Then, bilayer tablet cores of 558.1 mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0266] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight increased by 7.5% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.0 mm. The specifications of the controlled-release tablet in this embodiment were levodopa 250 mg, capsule-shaped tablet, its cross-sectional diameter was 6 mm, and its height was 14.90 mm.

[0267] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 35 and Figure 18.

[0268] [Table 35]

[0269] Example 18: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.3 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0270] [Table 36]

[0271] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0272] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0273] 3. Tablet compression: Compressed into bilayer tablets using a 16 × 7 mm die. First, 450.7 mg of drug-containing layer material was filled. After pre-compression, 183.3 mg of push layer material was filled. Then, bilayer tablet cores of 634.0 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0274] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution to a weight gain of 5.96.8% (percentages are weight percentages relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.00 mm. The specifications of the controlled-release tablets in this embodiment were 31.3 mg carbidopa and 250 mg levodopa.

[0275] 5. Release measurement method: Same as in Example 1. Specific test results are shown in Table 37 and Figure 19.

[0276] [Table 37]

[0277] Example 19: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.3 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0278] [Table 38]

[0279] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for the addition of magnesium stearate and silicon dioxide) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally added with magnesium stearate and silicon dioxide and mixed.

[0280] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0281] 3. Tablet compression: Compressed into bilayer tablets using a 16 × 7 mm die. First, 450.6 mg of drug-containing layer material was filled. After pre-compression, 183.2 mg of push layer material was filled. Then, bilayer tablet cores of 633.9 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0282] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 5.9% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.00 mm. The specifications of the controlled-release tablets in this embodiment were 31.3 mg of carbidopa and 250 mg of levodopa.

[0283] 5. Release measurement method: same as in Example 1. The specific test results for levodopa are shown in Table 39 and Figure 20, and the test results for carbidopa are shown in Table 40 and Figure 21.

[0284] [Table 39]

[0285] [Table 40]

[0286] Example 20: 1. Using the formulation of Example 11, prepare capsule tablets (250 mg standard) with a circular cross section and compressed in the longitudinal direction. The prescription is as follows:

[0287] [Table 41]

[0288] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0289] 2. Preparation of push layer: same as in Example 11.

[0290] 3. Tablet compression: Compressed into bilayer tablets using a 16x7mm die. First, 396.8mg of drug-containing layer material was filled. After pre-compression, 161.3mg of push layer material was filled. Then, bilayer tablet cores of 558.1mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0291] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution to a weight gain of 7.5% and 8.9% (percentages are weight percentages relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.00 mm. The standard of the controlled-release tablet in this embodiment was 250 mg of levodopa.

[0292] 5. Release measurement method: same as in Example 1.

[0293] 2. Using the capsule tablet formulation of Example 15, which has a circular cross section and is compressed in the direction of the long axis, a capsule tablet (125 mg standard) with a non-circular cross section and compressed in the direction perpendicular to the long axis was prepared. The prescription is as follows:

[0294] [Table 42]

[0295] Preparation method: 1. Preparation of drug-containing layer: same as in Example 11.

[0296] 2. Preparation of push layer: same as in Example 11.

[0297] 3. Tablet compression: Compressed into bilayer tablets using a 16x7mm die. First, 396.8mg of drug-containing layer material was filled. After pre-compression, 161.3mg of push layer material was filled. Then, bilayer tablet cores of 558.1mg / tablet were obtained by compressing in the direction perpendicular to the major axis.

[0298] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution to a weight gain of 7.5% and 9.2% (percentages are weight percentages relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.00 mm. The standard of the controlled-release tablet in this embodiment was 125 mg of levodopa.

[0299] 5. Release measurement method: same as in Example 1.

[0300] Example 21: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.3 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0301] [Table 43]

[0302] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0303] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0304] 3. Tablet compression: Compressed into bilayer tablets using a 17.5 × 7.5 mm die. First, 489.3 mg of drug-containing layer material was filled. After pre-compression, 198.9 mg of push layer material was filled. Then, bilayer tablet cores of 688.2 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0305] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution to a weight gain of 6.5% and 8.2% (percentages are weight percentages relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.00 mm. The specifications of the controlled-release tablets in this embodiment were 31.3 mg of carbidopa and 250 mg of levodopa.

[0306] 5. Release measurement method: same as in Example 1. Specific test results for levodopa are shown in Table 44 and Figure 22, and test results for carbidopa are shown in Table 45 and Figure 23.

[0307] [Table 44]

[0308] [Table 45]

[0309] Example 22: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.3 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0310] [Table 46]

[0311] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0312] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0313] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 450.6 mg of drug-containing layer material, pre-compressed, then filled with 183.3 mg of push layer material, and compressed to obtain bilayer tablet cores of 633.9 mg / tablet, which were compressed perpendicular to the major axis.

[0314] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 8.2% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 31.3 mg of carbidopa and 250 mg of levodopa.

[0315] 5. Release measurement method: same as in Example 1. Specific test results for levodopa are shown in Table 47 and Figure 24, and test results for carbidopa are shown in Table 48 and Figure 25.

[0316] [Table 47]

[0317] [Table 48]

[0318] Example 23: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 62.5 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0319] [Table 49]

[0320] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0321] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0322] 3. Tablet compression: Compressed into bilayer tablets using a 16 × 7 mm die. First, 450.6 mg of drug-containing layer material was filled. After pre-compression, 183.2 mg of push layer material was filled. Then, bilayer tablet cores of 633.8 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0323] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 6.0% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 31.3 mg of carbidopa and 250 mg of levodopa.

[0324] 5. Immediate-release coating: Using a coating pan, the extended-release tablet cores were coated with the immediate-release coating solution to a weight gain of 39.1 mg / tablet, and the specifications of the extended-release tablets in this embodiment were carbidopa 62.5 mg and levodopa 250 mg.

[0325] 6. Release measurement method: same as in Example 1. Specific levodopa test results are shown in Table 50 and Figure 26, and carbidopa test results are shown in Table 51 and Figure 27.

[0326] [Table 50]

[0327] [Table 51]

[0328] Example 24: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 15.7 mg / 125 mg (CD / LD) standard The prescription is as follows:

[0329] [Table 52]

[0330] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other auxiliary materials for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator, compressed into a strip, and granulated through a 16-mesh stainless steel screen. Finally, magnesium stearate was added and mixed.

[0331] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0332] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 450.6 mg of drug-containing layer material, pre-compressed, then filled with 183.3 mg of push layer material, and compressed to obtain bilayer tablet cores of 633.9 mg / tablet.

[0333] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 6.1% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 15.7 mg of carbidopa and 125 mg of levodopa.

[0334] 5. Release measurement method: same as in Example 1. Specific levodopa test results are shown in Table 53 and Figure 28, and carbidopa test results are shown in Table 54 and Figure 29.

[0335] [Table 53]

[0336] [Table 54]

[0337] Example 25: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 15.6 mg / 125 mg (CD / LD) standard The prescription is as follows:

[0338] [Table 55]

[0339] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator, compressed into strips, and granulated through a 16-mesh stainless steel screen. Finally, magnesium stearate and silicon dioxide were added and mixed.

[0340] 2. Push layer preparation: The push layer excipients (except for the added magnesium stearate) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0341] 3. Tablet compression: Compressed into bilayer tablets, compressed in a 16 × 7 mm (deep concave) mold, first filled with 450.6 mg of drug-containing layer material, pre-compressed, then filled with 183.3 mg of push layer material, and compressed to obtain bilayer tablet cores of 633.9 mg / tablet, which were compressed perpendicular to the major axis.

[0342] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 5.9% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 15.7 mg of carbidopa and 125 mg of levodopa.

[0343] 5. Release measurement method: same as in Example 1. Specific levodopa test results are shown in Table 56 and Figure 30, and carbidopa test results are shown in Table 57 and Figure 31.

[0344] [Table 56]

[0345] [Table 57]

[0346] Example 26: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 62.5 mg / 250 mg (CD / LD) standard The prescription is as follows:

[0347] [Table 58]

[0348] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0349] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0350] 3. Tablet compression: Compressed into bilayer tablets using a 16 × 7 mm die. First, 450.6 mg of drug-containing layer material was filled. After pre-compression, 183.2 mg of push layer material was filled. Then, bilayer tablet cores of 633.8 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0351] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution to a weight gain of 7.7% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing holes was 1.00 mm. The specifications of the controlled-release tablets in this embodiment were 31.3 mg of carbidopa and 250 mg of levodopa.

[0352] 5. Immediate-release coating: Using a coating pan, the extended-release tablet cores were coated with the immediate-release coating solution to increase the weight to 39.1 mg / tablet, and the specifications of the extended-release tablets in this embodiment were 62.5 mg carbidopa and 250 mg levodopa.

[0353] 6. Release measurement method: same as in Example 1. Specific levodopa test results are shown in Table 59 and Figure 32, and carbidopa test results are shown in Table 60 and Figure 33.

[0354] [Table 59]

[0355] [Table 60]

[0356] Example 27: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.25 mg / 125 mg (CD / LD) standard The prescription is as follows:

[0357] [Table 61]

[0358] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0359] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0360] 3. Tablet compression: Compressed into bilayer tablets using a 13 × 6 mm die. First, 225.2 mg of drug-containing layer material was filled. After pre-compression, 91.5 mg of push layer material was filled. Then, bilayer tablet cores of 316.7 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0361] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 7.3% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 15.6 mg of carbidopa and 125 mg of levodopa.

[0362] 5. Immediate-release coating: Using a coating pan, the extended-release tablet cores were coated with the immediate-release coating solution to increase the weight to 19.7 mg per tablet, and the specifications of the extended-release tablets in this embodiment were 31.25 mg of carbidopa and 125 mg of levodopa.

[0363] 6. Release measurement method: same as in Example 1. Specific levodopa test results are shown in Table 62 and Figure 34, and carbidopa test results are shown in Table 63 and Figure 35.

[0364] [Table 62]

[0365] [Table 63]

[0366] Example 28: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.25 mg / 125 mg (CD / LD) standard The prescription is as follows:

[0367] [Table 64] TIFF2025539199000068.tif66170

[0368] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0369] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0370] 3. Tablet compression: Compressed into bilayer tablets using a 13 × 6 mm die. First, 225.2 mg of drug-containing layer material was filled. After pre-compression, 91.5 mg of push layer material was filled. Then, bilayer tablet cores of 316.7 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0371] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 7.3% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 15.6 mg of carbidopa and 125 mg of levodopa.

[0372] 5. Immediate-release coating: Using a coating pan, the extended-release tablet cores were coated with the immediate-release coating solution to increase the weight to 22.5 mg per tablet, and the specifications of the extended-release tablets in this embodiment were 31.25 mg of carbidopa and 125 mg of levodopa.

[0373] Example 29: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.25 mg / 125 mg (CD / LD) standard The prescription is as follows:

[0374] [Table 65] TIFF2025539199000070.tif11170

[0375] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0376] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0377] 3. Tablet compression: Compressed into bilayer tablets using a 13 × 6 mm die. First, 225.2 mg of drug-containing layer material was filled. After pre-compression, 91.5 mg of push layer material was filled. Then, bilayer tablet cores of 316.7 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0378] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 7.3% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 15.6 mg of carbidopa and 125 mg of levodopa.

[0379] 5. Immediate-release coating: Using a coating pan, the extended-release tablet cores were coated with the immediate-release coating solution to increase the weight to 22.2 mg per tablet, and the specifications of the extended-release tablets in this embodiment were 31.25 mg of carbidopa and 125 mg of levodopa.

[0380] Example 30: Capsule-shaped tablet (non-circular cross section, compressed perpendicular to the major axis) 31.25 mg / 125 mg (CD / LD) standard The prescription is as follows:

[0381] [Table 66] TIFF2025539199000072.tif11170

[0382] Preparation method: 1. Preparation of the drug-containing layer: Levodopa, carbidopa monohydrate, and other excipients for the drug-containing layer (except for magnesium stearate and silicon dioxide additives) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally, magnesium stearate and silicon dioxide were added and mixed.

[0383] 2. Push layer preparation: The excipients for the push layer (except for the magnesium stearate additive) were pre-blended, added to a dry granulator and compressed into strips, granulated through a 16-mesh stainless steel screen, and finally mixed with the magnesium stearate.

[0384] 3. Tablet compression: Compressed into bilayer tablets using a 13 × 6 mm die. First, 225.2 mg of drug-containing layer material was filled. After pre-compression, 91.5 mg of push layer material was filled. Then, bilayer tablet cores of 316.7 mg per tablet were obtained by compressing in a direction perpendicular to the major axis.

[0385] 4. Semipermeable coating: Using a coating pan, the bilayer tablet core was coated with the above controlled-release coating solution so that the weight gain was 7.3% (percentage is the weight percentage relative to the tablet core). Holes were drilled mechanically or by laser, and the diameter of the drug-releasing hole was 1.00 mm. The specifications of the controlled-release tablet in this embodiment were 15.6 mg of carbidopa and 125 mg of levodopa.

[0386] 5. Immediate-release coating: Using a coating pan, the extended-release tablet cores were coated with the immediate-release coating solution to increase the weight to 21.9 mg per tablet, and the specifications of the extended-release tablets in this embodiment were 31.25 mg of carbidopa and 125 mg of levodopa.

Claims

1. the dosage form is a controlled-release tablet; The pharmaceutical active ingredient is levodopa or a derivative thereof, or a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor; The release characteristics of the pharmaceutical active ingredient include a time lag of 1 to 3 hours before the start of release, and a cumulative release rate of 85% or more of the pharmaceutical active ingredient in 6 to 10 hours after the start of release; A delayed-release pharmaceutical composition, wherein when the pharmaceutically active ingredient is a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor is ≦7.5 wt % but not 0, and the content is the weight percentage of the ingredient in the drug-containing layer.

2. a tablet core comprising a drug-containing layer and a push layer laminated on the drug-containing layer, the drug-containing layer comprising a pharmaceutically active ingredient; the content of the pharmaceutically active ingredient in the drug-containing layer is 5 to 72.5 wt %, the content being the weight percentage of the pharmaceutically active ingredient in the drug-containing layer; In the drug-containing layer, the pharmaceutically active ingredient is levodopa or a derivative thereof, or a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, A pharmaceutical composition characterized in that, when the pharmaceutically active ingredient is a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor is ≦7.5 wt % but not 0, the content being the weight percentage of the ingredient in the drug-containing layer, and the dosage form of the pharmaceutical composition is a capsule-type tablet.

3. (1) The content of the pharmaceutically active ingredient in the drug-containing layer is 30 to 72.5 wt %, for example, 31.5 wt %, 50 wt %, 53 wt %, 58 wt %, 59.6 wt %, 63 wt %, or 68.1 wt %; (2) The content of the levodopa or a derivative thereof in the drug-containing layer is 27.7 to 63% by weight, for example, 27.7%, 31.5%, 41.7%, 46.9%, 50%, 51.1%, 53.6%, 55.5%, or 63% by weight. (3) In the drug-containing layer, the levodopa derivative is levodopa hydrate, levodopa alkyl ester, a pharmaceutically acceptable salt of levodopa, a deuterated levodopa alkyl ester, or a pharmaceutically acceptable salt of a deuterated levodopa alkyl ester; (4) In the drug-containing layer, the dopa decarboxylase inhibitor is carbidopa hydrate, a pharmaceutically acceptable salt of carbidopa, benserazide, or a pharmaceutically acceptable salt of benserazide, preferably carbidopa hydrate, for example, carbidopa monohydrate; (5) The content of the dopa decarboxylase inhibitor in the drug-containing layer is 3.7 to 7.5 wt %, for example, 3.75 wt %, 6.91 wt %, or 7.5 wt %; (6) The drug-containing layer further comprises a pharmaceutical excipient, and the pharmaceutical excipient comprises one or more of a drug carrier, a filler, a surfactant, a lubricant, and an antioxidant, and may further comprise "a drug carrier and a lubricant," "a drug carrier, a filler, and a lubricant," "a drug carrier, a filler, a surfactant, and a lubricant," or "a drug carrier, a filler, a surfactant, an antioxidant, and a lubricant," (7) The cross-sectional shape of the capsule-shaped tablet is circular or non-circular; (8) The shape of the capsule-shaped tablet is a capsule shape formed by tableting in the long axis direction or a capsule shape formed by tableting in a direction perpendicular to the long axis direction; The pharmaceutical composition according to claim 2, characterized in that it satisfies one or more of the following:

4. (1) The drug carrier is one or more of polyvinylpyrrolidone, copolyvidone, carbomer, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyoxyethylene, and sodium alginate, and may further be a mixture of polyvinylpyrrolidone and hydroxypropylcellulose, or hydroxypropylcellulose; (2) When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains a drug carrier, the content of the drug carrier is ≦40 wt %, but may be 10-40 wt %, not 0, for example, 15 wt %, 16 wt %, 29.5 wt %, 30.0 wt %, 31 wt %, or 38.5 wt %; (3) The filler is one or more of lactose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, and microcrystalline cellulose, for example, a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, sorbitol, or mannitol; (4) When the drug-containing layer contains a pharmaceutical excipient and the pharmaceutical excipient contains a filler, the content of the filler is ≦51 wt%, but may be 5-51 wt%, not 0, for example, 5 wt%, 8.5 wt%, 10 wt%, 15 wt%, 18 wt%, 19 wt%, 19.5 wt%, 20 wt%, 32 wt%, 41.5 wt%, or 51 wt%; (5) The surfactant is one or more of polysorbate, poloxamer, fatty acid glyceride, sodium dodecylbenzenesulfonate, and sodium dodecyl sulfate, for example, poloxamer; (6) When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains a surfactant, the content of the surfactant is ≦19 wt %, but is not 0, and may be 5 to 19 wt %, for example, 5 wt %, 10 wt %, or 19 wt %; (7) The lubricant is one or more of stearic acid, silicon dioxide, magnesium stearate, calcium stearate, polyethylene glycol, and sodium stearyl fumarate, e.g., magnesium stearate and / or silicon dioxide; (8) When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains a lubricant, the content of the lubricant is ≦2.5 wt %, but is not 0, and may be 1-2.5 wt %, for example, 1 wt % or 2.5 wt %; (9) The antioxidant is one or more of dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C, and vitamin E, for example, dibutylhydroxytoluene; (10) When the drug-containing layer contains a pharmaceutical excipient, and the pharmaceutical excipient contains an antioxidant, the content of the antioxidant is ≦1.0 wt %, but is not 0, and may be 0.1 to 0.5 wt %, for example, 0.33 wt %; (11) When the cross-sectional shape of the capsule-shaped tablet is circular, the diameter of the circle is 5 to 10 mm, and the height is 4 to 30 mm; the cross-sectional diameter may be 5 to 7.5 mm, and the height may be 10 to 20 mm; (12) When the cross-sectional shape of the capsule-shaped tablet is non-circular, the non-circular shape has an axis of symmetry, and the length of the major axis of the non-circular shape having the axis of symmetry may be 10 to 25 mm, and the length of the minor axis may be 5 to 25 mm; the length of the major axis of the non-circular shape having the axis of symmetry may be 16 to 19 mm, and the length of the minor axis may be 7 to 7.5 mm; The pharmaceutical composition according to claim 3, characterized in that it satisfies one or more of the following:

5. When the pharmaceutical excipient comprises a drug carrier and a filler, the weight ratio of the filler to the drug carrier is (1-6):1, and may be (1-2):1; Preferably, The pharmaceutical composition according to claim 4, wherein when the drug carrier is a mixture of polyvinylpyrrolidone and hydroxypropyl cellulose, or hydroxypropyl cellulose, and the filler is sorbitol, a mixture of sorbitol and lactose, or a mixture of sorbitol and mannitol, the weight ratio of sorbitol in the filler to hydroxypropyl cellulose in the drug carrier is (1-2):1, for example, 1:1, 1.95:1, or 2:

1.

6. The drug-containing layer comprises: (1) Pharmaceutically active ingredients, drug carriers and lubricants, (2) a pharmaceutically active ingredient, a drug carrier, the filler, and the lubricant; (3) a pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, and the lubricant; (4) a pharmaceutically active ingredient, the drug carrier, the filler, the surfactant, the antioxidant, and the lubricant; and The pharmaceutically active ingredient is as defined in any one of claims 1 to 5, The pharmaceutical composition according to claim 1, wherein the drug carrier, the lubricant, the filler, the surfactant and the antioxidant are all as defined in any one of claims 2 to 5.

7. In the drug-containing layer, the pharmaceutically active ingredient is levodopa or a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, and the content of levodopa is 27.7 to 63 wt %; When the pharmaceutically active ingredient is a mixture of "levodopa or a derivative thereof" and a dopa decarboxylase inhibitor, the dopa decarboxylase inhibitor is carbidopa or a hydrate thereof, and the content of the dopa decarboxylase inhibitor is ≦7.5 wt % but not 0, the drug-containing layer comprises a pharmaceutical excipient, and the pharmaceutical excipient comprises "a drug carrier, a filler, and a lubricant," "a drug carrier, a filler, a surfactant, and a lubricant," or "a drug carrier, a filler, a surfactant, an antioxidant, and a lubricant," The drug carrier is a mixture of polyvinylpyrrolidone and hydroxypropyl cellulose, or hydroxypropyl cellulose, and the content of the drug carrier is 10 to 40 wt %; the filler is a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, or sorbitol, and the content of the filler is 8.5 to 20 wt. %; the weight ratio of sorbitol in the filler to hydroxypropyl cellulose in the drug carrier is (1-2):1; the surfactant is a poloxamer, and the content of the surfactant is 5 to 19% by weight; The lubricant is magnesium stearate and / or silicon dioxide, and the content of the lubricant is 1 to 2.5 wt %; The antioxidant is dibutylhydroxytoluene, and the content of the antioxidant is 0.1 to 1.0%; The pharmaceutical composition according to claim 1, wherein the capsule-shaped tablet has a circular cross-sectional shape.

8. 2. The pharmaceutical composition of claim 1, wherein the push layer comprises one or more of a swelling agent, an osmolality enhancing agent, a lubricant, and a colorant, preferably a swelling agent, an osmolality enhancing agent, a colorant, and a lubricant.

9. (1) the leavening agent is one or more of sodium carboxymethyl starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, carbomer, carrageenan, polyoxyethylene, and sodium alginate, e.g., sodium carboxymethylcellulose and hydroxypropyl cellulose; (2) The content of the swelling agent is 25 to 89% by weight, for example, 89% by weight or 69% by weight; (3) The osmolality enhancer is one or more of sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, magnesium sulfate, ascorbic acid, tartaric acid, mannitol, sorbitol, xylitol, glucose, lactose, and sucrose, e.g., sorbitol; (4) The content of the osmotic pressure enhancer is 10 to 70% by weight, and may be 10 to 30% by weight; (5) The lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol, and sodium stearyl fumarate, e.g., magnesium stearate; (6) The content of the lubricant is 0.1 to 3% by weight, for example, 0.5% by weight; (7) The colorant is one or more of iron (III) oxide, yellow iron oxide, violet iron oxide, and black iron oxide, for example, iron (III) oxide; (8) The content of the colorant is 0.1 to 2% by weight, for example, 0.5% by weight; The pharmaceutical composition according to claim 8, characterized in that it satisfies one or more of the following:

10. The tablet core comprises: (1) The drug-containing layer: a pharmaceutically active ingredient, a drug carrier, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; (2) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; (3) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, a surfactant, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; (4) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, a surfactant, an antioxidant, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; and In the drug-containing layer, the pharmaceutically active ingredient is as defined in any one of claims 1 to 5, and the drug carrier, the lubricant, the filler, the surfactant, and the antioxidant are all as defined in any one of claims 2 to 5, The pharmaceutical composition of claim 1, wherein in the push layer, the swelling agent, the osmotic pressure enhancer, the lubricant, and the colorant are all as defined in claim 8 or 9.

11. (1) The drug-containing layer: a pharmaceutically active ingredient, a drug carrier, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is non-circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis. (2) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is non-circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis. (3) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, a surfactant, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is non-circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis. (4) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, an antioxidant, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is non-circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in a direction perpendicular to the major axis. (5) The drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in the long axis direction. (6) the drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, a surfactant, and the lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in the long axis direction. (7) The drug-containing layer: a pharmaceutically active ingredient, a drug carrier, a filler, a surfactant, an antioxidant, and a lubricant; the push layer: a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant; The cross-sectional shape of the capsule-shaped tablet is circular, or the shape of the capsule-shaped tablet is a capsule shape formed by tableting in the long axis direction. and In the drug-containing layer, the pharmaceutically active ingredient is as defined in any one of claims 1 to 5, and the drug carrier, the lubricant, the filler, the surfactant, and the antioxidant are all as defined in any one of claims 2 to 5, The pharmaceutical composition of claim 1, wherein in the push layer, the swelling agent, the osmotic pressure enhancer, the lubricant, and the colorant are all as defined in claim 8 or 9.

12. The tablet core further comprises a release-controlling film coating surrounding the tablet core; the controlled-release membrane coating is a semipermeable membrane, and the membrane-forming material of the semipermeable membrane is one or more of cellulose acetate, ethyl cellulose, and acrylic resin, e.g., cellulose acetate; The content of the film-forming material is 50 to 90 wt %, and may be 60 to 90 wt %, for example, 60 wt %, 65 wt %, 70 wt %, or 90 wt %, The semipermeable membrane may further comprise a pore-forming agent and a plasticizer; The pore-forming agent may be one or more of polyethylene glycol, glycerol, polyvinylpyrrolidone, copolyvidone, and hydroxypropyl cellulose, such as copolyvidone and hydroxypropyl cellulose; the plasticizer is one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glyceryl acetate, and castor oil, for example, polyethylene glycol or triethyl citrate; 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the release-controlling film coating to the tablet core is (2.0% to 15.0%):1, further (6.6% to 8.4%):1, or further (7.4% to 7.8%):

1.

13. further comprising an isolating coating layer between the tablet core and the release-controlling membrane coating; The film-forming material of the isolation coating layer may be hydroxypropyl cellulose EF; The pharmaceutical composition according to claim 12, wherein the weight ratio of the isolating coating layer to the tablet core may be (3.0%-5.0%):1, for example, 4.0%:

1.

14. The pharmaceutical composition further comprises an immediate release layer, the immediate release layer comprising a pharmaceutically active ingredient, a binder, and an antioxidant, and optionally comprising a pharmaceutically active ingredient, a plasticizer, an antioxidant, and a binder; When the immediate release layer contains a plasticizer, the content of the plasticizer is preferably 1 to 2% by weight; If the immediate release layer comprises a plasticizer, the plasticizer is preferably one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glyceryl acetate, and castor oil, e.g., tributyl citrate; When the immediate release layer contains an antioxidant, the content of the antioxidant is preferably 3 to 4 wt %, for example, 3.38 wt % or 3.81 wt %; If the immediate release layer includes an antioxidant, the antioxidant is preferably one or more of dibutylhydroxytoluene, tert-butylhydroxyanisole, dibutylphenol, vitamin C, vitamin E, and sodium sulfite, e.g., dibutylhydroxytoluene; When the immediate release layer contains a binder, the content of the binder is preferably 10 to 20% by weight, When the immediate release layer comprises a binder, the binder is preferably one or more of polyvinylpyrrolidone, copolyvidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, such as a mixture of hydroxypropyl cellulose and copolyvidone, or hydroxypropyl cellulose; When the immediate release layer comprises a pharmaceutically active ingredient, the pharmaceutically active ingredient is preferably 70 to 90% by weight, for example, 74.7%, 75.7%, 86.2% or 85.3% by weight; 2. The pharmaceutical composition according to claim 1, wherein when the immediate release layer comprises a pharmaceutically active ingredient, the pharmaceutically active ingredient preferably comprises a dopa decarboxylase inhibitor, and the dopa decarboxylase inhibitor is preferably carbidopa hydrate, a pharmaceutically acceptable salt of carbidopa, benserazide or a pharmaceutically acceptable salt of benserazide, more preferably carbidopa hydrate, for example carbidopa monohydrate.

15. forming a tablet core by layering and compounding raw material particles of the drug-containing layer and raw material particles of the push layer; If the tablet core further comprises a release-controlling film coating, the tablet core is coated, the release-controlling film coating is wrapped around the tablet core, and holes are drilled in the release-controlling film coating on one side of the drug-containing layer to form drug-release holes; If the pharmaceutical composition further comprises an immediate-release layer, wrapping the immediate-release layer coating on the capsule-shaped tablet coated with the controlled-release film coating; The method for preparing a pharmaceutical composition according to any one of claims 1 to 14, wherein the composite press preferably performs tableting in the long axis direction or in the direction perpendicular to the long axis direction.

16. Use of a pharmaceutical composition according to any one of claims 1 to 12 in the preparation of a medicament for the prevention or treatment of morning stiffness, comprising: The morning stiffness is preferably morning stiffness caused by Parkinson's disease; Alternatively, a method for preventing or treating morning stiffness, comprising the step of administering to a subject an effective amount of the pharmaceutical composition according to any one of claims 1 to 12, The use or method, wherein said morning stiffness is preferably morning stiffness caused by Parkinson's disease.

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