Pharmaceutical composition capable of delaying timed release as well as preparation method and application of pharmaceutical composition

Abstract

The invention relates to a medicine composition capable of delaying timed release as well as a preparation method and application thereof. The pharmaceutical composition comprises a tablet core, wherein the tablet core comprises a drug-containing layer and a boosting layer stacked on the drug-containing layer; the medicine-containing layer comprises a medicine active component; the active pharmaceutical ingredient is levodopa or a derivative thereof, or a mixture of the levodopa or the derivative thereof and a dopa decarboxylase inhibitor, and accounts for 5-72.5 wt% of the content of the drug-containing layer; the pharmaceutical composition is a capsule-shaped tablet, can realize 1-3 hours of delayed release of active pharmaceutical ingredients and 6-10 hours of peak concentration, can be used for reducing morning stiffness of patients with Parkinson's disease, and has a good application prospect.

Description

Delayed timed release pharmaceutical composition and preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 2022115525632, filed on December 5, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to the field of biopharmaceuticals, and in particular to a delayed timed release pharmaceutical composition, a preparation method and an application thereof. Background Art

[0003] Parkinson's disease is a progressive neurodegenerative disorder caused by the loss of dopamine-producing cells in the brain. Dopamine, a substance naturally present in the brain and spinal cord, helps nerve cells in the brain properly control motor function. As dopamine levels in the brain decrease, symptoms of Parkinson's disease (PD), such as muscle stiffness, slowed movements, and difficulty maintaining balance, emerge. Dopamine cannot cross the blood-brain barrier (BBB), which is why oral dosage forms are ineffective. Levodopa, a dopamine precursor, can cross the BBB and be converted into dopamine in brain tissue. Levodopa therapy is the "gold standard" treatment for Parkinson's disease, and almost all PD patients must receive levodopa at some stage of the disease. However, most levodopa is decarboxylated into dopamine before reaching the brain. Therefore, levodopa is often co-administered with a decarboxylase inhibitor such as carbidopa or benserazide to prevent peripheral dopamine formation, increase brain dopamine levels, and alleviate adverse reactions caused by peripheral decarboxylation of levodopa.

[0004] Parkinson's disease, the symptoms of morning stiffness in Parkinson's disease, and the inadequacy of existing treatment options are described in the following publications:

[0005] (1)J Jankovic.Parkinson's disease:clinical features and diagnosis.Journal of Neurology,Neurosurgery & Psychiatry,2008;79:368-376

[0006] (2)NB Mercuri. Limitations of current Parkinson's disease therapy. Ann Neurol 2003;53:S3–S15.

[0007] (3)K Ray Chaudhuri DSc.Non-motor symptoms of Parkinson's disease:dopaminergic pathophysiology and treatment.The Lancet Neurology 2009;8:464-474.

[0008] (4)NB Mercuri.2005The'magic'of L-dopa:why is it the gold standard Parkinson's disease therapy?Trends in pharmacological sciences,2005;26:341-344.

[0009] (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.

[0010] (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.

[0011] (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.

[0012] (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.

[0013] (9)Garcia-Borreguero D,Larrosa O,Bravo M.Parkinson’s disease and sleep.Sleep Med Rev.2003;7(2):115–129.

[0014] (10)Pfeiffer RF.Gastrointestinal,urological,and sexual dysfunction in Parkinson’s disease.Mov Disord.2010;25:94–97.

[0015] (11)Heetun ZS,Quigley EMM.Gastroparesis and Parkinson’s disease:a systematic review.Parkinsonism Relat Disord.2012;18(5):433–440.

[0016] (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.

[0017] (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.

[0018] (14)APOKYN Package Insert

[0019] (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

[0020] (16)NEUPRO Package Insert

[0021] (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.

[0022] (18)INBRIJA Package Insert

[0023] (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.

[0024] (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–e32DOI:10.1111 / ane.12075.)

[0025] As shown in references 5-11, as Parkinson's disease progresses, patients experience severe morning stiffness in the early morning due to insufficient dopamine storage at night. Morning stiffness is the most common and earliest motor complication in PD patients, occurring in approximately 60% of PD patients receiving dopamine treatment, especially those with mid-to-late stage Parkinson's disease, i.e., those with a Hoehn-Yahr grade of 2.5-3. The occurrence of morning stiffness seriously affects PD patients' daily activities, such as getting up, dressing, going to the toilet, washing, and taking medication. Morning stiffness is also associated with postprandial abdominal distension, 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, gastroparesis, constipation, and defecation disorders. These symptoms significantly affect the quality of life of PD patients.

[0026] As reported in Reference 12, gastroparesis can delay the delivery of levodopa to the duodenum, leading to the clinical phenomenon of delayed onset of action (ON) after levodopa administration. Therefore, we can infer that the lack of levodopa blood concentrations at night leads to decreased and insufficient dopaminergic function, which in turn causes morning stiffness and other related symptoms, such as gastroparesis. Gastroparesis, in turn, delays the absorption and onset of levodopa taken in the morning, creating a vicious cycle. Reference 13 shows that other Parkinson's medications, such as dopamine agonists (pramipexole, rotigotine, ropinirole), anticholinergics (amantadine), monoamine oxidase inhibitors (selegiline, rasagiline, safinamide), and COMT inhibitors (tolcapone, entacapone), can also cause gastrointestinal dysfunction.

[0027] Current treatment options for morning stiffness rely on rapidly achieving an effective levodopa blood concentration in the early morning to alleviate symptoms. However, due to pharmacodynamic and pharmacokinetic factors such as gastric emptying time, levodopa absorption limited to the upper gastrointestinal tract, and competition with amino acids across the blood-brain barrier, existing conventional levodopa formulations are inadequate for treating morning stiffness in Parkinson's disease (PD) due to their short half-life, irregular gastrointestinal absorption, and competitive blood-brain barrier crossing.

[0028] As shown in references 14-15, subcutaneous apomorphine preparations Launched in the United States in 2004, it is used for the emergency, intermittent treatment of OFF episodes in Parkinson's patients. It has some effect on morning stiffness, but because morning stiffness impairs motor function, it can be difficult for patients to self-administer the drug. The onset of action is 30-60 minutes after administration, severely impacting patients' ability to care for themselves. Furthermore, a common side effect of subcutaneous injection is the development of nodules, which often become infected, necessitating antibiotic treatment or surgical debridement. Apomorphine can cause vomiting, so an antiemetic is routinely administered before administration.

[0029] The following document 16 shows that apomorphine sublingual film It was recently launched in the US in May 2020 and is also used for the emergency, intermittent treatment of OFF episodes in Parkinson's patients. It has a high incidence of adverse reactions, including nausea, oropharyngeal soft tissue edema, pain, and paralysis.

[0030] As shown in references 17-18, rotigotine transdermal patch Launched in the US in 2007 and in China in 2018, rotigotine transdermal patches, a dopamine receptor agonist, are somewhat effective in relieving morning stiffness and improving sleep. However, adverse reactions such as nausea, vomiting, drowsiness, and skin allergies limit their use.

[0031] As shown in literature 19-20, levodopa inhalation It was launched in the United States in 2018 and approved by the FDA for emergency treatment of OFF attacks. However, because it requires the use of a special device for oral inhalation, self-administration is also difficult, and its bioavailability is low. According to the instructions, its Cmax is only 50% of that of the oral immediate-release preparation. The incidence of adverse respiratory reactions is as high as 35%, and because it has the risk of inducing bronchospasm, it is contraindicated in patients with asthma, chronic obstructive pulmonary disease (COPD) or chronic lung disease.

[0032] Theoretically, patients need a higher concentration of levodopa before getting up, which can reduce the occurrence of morning stiffness symptoms. Under existing conditions, if the patient takes a regular levodopa preparation (such as ), not only can the effective blood drug concentration not be maintained until the patient wakes up in the morning, but also the high concentration of levodopa produced by rapid release has a certain excitatory effect, which may affect the patient's sleep.

[0033] Administering levodopa before bedtime may affect sleep onset, but providing a certain concentration of levodopa after sleep can relieve muscle tension and stiffness, potentially helping to improve sleep quality. Therefore, a delayed-release controlled-release formulation is needed to ensure effective levodopa blood concentrations upon awakening, reduce morning stiffness symptoms, and improve night stiffness, thereby improving sleep quality. Although continuous levodopa duodenal infusion (DUODOPA / DUOPA), as reported in Reference 21, has shown some therapeutic effect on morning stiffness, continuous infusion of levodopa hydrogel for 2-4 months significantly reduces the PDSS-2 (PD-Sleep-Scale-version-2) total score and subscores for "sleep disturbances," "nocturnal motor symptoms," and "nocturnal PD symptoms," and also improves the ESS (Epworth Sleeping-Scale) for daytime sleepiness. Furthermore, this treatment is highly invasive, requiring surgery to pump continuous infusion directly into the upper small intestine through a tube. Furthermore, the treatment is expensive and is therefore not suitable for a wide range of patients. Currently, the drug is only used for administration during the 16 hours of the day and not at night.

[0034] Therefore, the most ideal treatment option for patients is still non-invasive therapy. Therefore, there is an urgent need to develop a non-invasive, delayed, timed-release controlled-release product that can provide PD patients with effective levodopa blood concentrations in the morning to alleviate morning stiffness, allowing patients to wake up in the "ON" state rather than the "OFF" state.

[0035] Summary of the Invention

[0036] The technical problem to be solved by the present invention is to overcome the shortcomings of existing controlled-release drugs containing levodopa, which are unable to achieve effective delayed and sustained release after delay, and thus are unable to maintain effective blood concentrations of levodopa upon waking up, alleviate morning stiffness symptoms, and other related symptoms caused thereby. To this end, a delayed timed-release pharmaceutical composition, as well as its preparation method and application, is provided. The pharmaceutical composition of the present invention can achieve a delayed release of the active pharmaceutical ingredient with a time lag of 1-3 hours, reaching peak concentration in 6-10 hours; preferably, it can also achieve a delayed release of the active pharmaceutical ingredient with a time lag of 2 hours, reaching peak concentration in 6-8 hours, thereby reducing the occurrence of morning stiffness and other related symptoms caused thereby.

[0037] The present invention solves the above technical problems through the following technical solutions.

[0038] The present invention provides a pharmaceutical composition comprising a tablet core, wherein the tablet core comprises a drug-containing layer and a booster layer stacked on the drug-containing layer; the drug-containing layer comprises a pharmaceutical active ingredient;

[0039] The content of the active pharmaceutical ingredient in the drug-containing layer is 5-72.5 wt %, where the content is the weight percentage of the active pharmaceutical ingredient in the drug-containing layer;

[0040] In the drug-containing layer, the active pharmaceutical ingredient is levodopa or its derivatives, or a mixture of levodopa or its derivatives and a dopa decarboxylase inhibitor;

[0041] When the active pharmaceutical ingredient is a mixture of "levodopa or its derivatives" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor is ≤14.5wt%, but not 0, and the content is the weight percentage of the component in the drug-containing layer;

[0042] The dosage form of the pharmaceutical composition is a capsule-shaped tablet.

[0043] In the present invention, the content of the active pharmaceutical ingredient in the drug-containing layer is preferably 30-72.5wt%, such as 31.5wt%, 50wt%, 53wt%, 58wt%, 59.6wt%, 63wt% or 68.1wt%.

[0044] In the present invention, the content of levodopa or its derivatives in the drug-containing layer can be the conventional content in such preparations in the art, and can also be 27-63wt%, for example, 27.7wt%, 31.5wt%, 41.7wt%, 46.9wt%, 50wt%, 51.1wt%, 53.6wt%, 55.5wt% or 63wt%, where the content is the weight percentage of the component in the drug-containing layer.

[0045] In the present invention, in the drug-containing layer, the levodopa derivative 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.

[0046] In the present invention, in the drug-containing layer, the dopa decarboxylase inhibitor may be carbidopa hydrate, a pharmaceutically acceptable salt of carbidopa, benserazide or a pharmaceutically acceptable salt of benserazide, preferably, for example, carbidopa monohydrate.

[0047] In the present invention, in the drug-containing layer, when the active pharmaceutical ingredients are "levodopa or its derivatives" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor can be 3.7-14.5wt%, for example, 3.75wt%, 6.91wt%, 7.5wt%, 11.3wt%, 12.7wt% or 14.5wt%, where the content is the weight percentage of the component in the drug-containing layer.

[0048] In the present invention, the drug-containing layer may further include pharmaceutical excipients, which may be conventional pharmaceutical excipients used in such preparations.

[0049] In a preferred embodiment of the present invention, the pharmaceutical excipients may include one or more of a drug carrier, a filler, a surfactant, a lubricant and an antioxidant, and may also include "drug carrier and lubricant", "drug carrier, filler and lubricant", "drug carrier, filler, surfactant and lubricant" or "drug carrier, filler, surfactant, antioxidant and lubricant".

[0050] The type and content of the drug carrier may be the type and content of conventional drug carriers in such preparations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0051] The drug carrier can be one or more of povidone, copovidone, carbomer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide and sodium alginate, and can also be a mixture of povidone and hydroxypropyl cellulose or hydroxypropyl cellulose.

[0052] When the drug-containing layer includes pharmaceutical excipients, and the pharmaceutical excipients include drug carriers, the content of the drug carrier may be ≤40wt%, but not 0, and may also be 10-40wt%, for example, 15wt%, 16wt%, 29.5wt%, 30.0wt%, 31wt% or 38.5wt%.

[0053] When the drug carrier is a mixture of povidone and hydroxypropyl cellulose, the weight ratio of the hydroxypropyl cellulose to the povidone is preferably (1-8):1, such as 2.1:1, 2.2:1, 3.1:1, 3.5:1 or 7.1:1.

[0054] The type and content of the filler may be conventional types and contents in such preparations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0055] The filler can be one or more of lactose, starch, pregelatinized starch, dextrin, mannitol, sorbitol and microcrystalline cellulose, and can also be a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, sorbitol or mannitol.

[0056] When the drug-containing layer includes pharmaceutical excipients, and the pharmaceutical excipients include fillers, the content of the filler may be ≤51wt%, but not 0, and may also be 5-51wt%, for example, 5wt%, 8.5wt%, 10wt%, 15wt%, 18wt%, 19wt%, 19.5wt%, 20wt%, 32wt%, 41.5wt% or 51wt%.

[0057] Preferably, in the drug-containing layer, when the pharmaceutical excipients include a drug carrier and a filler, the weight ratio of the filler to the drug carrier can be (1-6):1, or can be (1-2):1.

[0058] More preferably, when the drug carrier is a mixture of povidone 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.

[0059] The type and content of the surfactant may be conventional types and contents in such preparations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0060] The surfactant may be one or more of polysorbate, poloxamer, fatty acid glyceride, sodium dodecylbenzenesulfonate and sodium lauryl sulfate, such as poloxamer (407).

[0061] When the drug-containing layer includes pharmaceutical excipients, and the pharmaceutical excipients include surfactants, the content of the surfactant may be ≤19wt%, but not 0, and may also be 5-19wt%, for example 5wt%, 10wt% or 19wt%.

[0062] The type and content of the lubricant may be conventional types and contents in such preparations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0063] 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.

[0064] When the drug-containing layer includes pharmaceutical excipients, and the pharmaceutical excipients include lubricants, the content of the lubricant may be ≤2.5 wt%, but not 0, and may also be 1-2.5 wt%, such as 1 wt% or 2.5 wt%.

[0065] The type and content of the antioxidant may be conventional types and contents in such preparations in the art, and the content is the weight percentage of the component in the drug-containing layer.

[0066] The antioxidant may be one or more of butylated hydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C and vitamin E, such as butylated hydroxytoluene.

[0067] When the drug-containing layer includes pharmaceutical excipients, and the pharmaceutical excipients include antioxidants, the content of the antioxidant may be ≤1.0 wt %, but not 0, and may also be 0.1-0.5%, for example 0.33 wt %.

[0068] In a preferred embodiment of the present invention, the drug-containing layer comprises any one of the following components:

[0069] (1) the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier and the above-mentioned lubricant;

[0070] (2) the aforementioned active pharmaceutical ingredient, the aforementioned drug carrier, the aforementioned filler, and the aforementioned lubricant;

[0071] (3) the aforementioned active pharmaceutical ingredient, the aforementioned drug carrier, the aforementioned filler, the aforementioned surfactant, and the aforementioned lubricant;

[0072] (4) the aforementioned active pharmaceutical ingredient, the aforementioned drug carrier, the aforementioned filler, the aforementioned surfactant, the aforementioned antioxidant, and the aforementioned lubricant;

[0073] The dosage of each component is the same as that of the present invention.

[0074] In a preferred embodiment of the present invention, the drug-containing layer is composed of any one of the following components:

[0075] (1) 14.5 wt% carbidopa monohydrate, 53.6 wt% levodopa, 31.0 wt% hydroxypropylcellulose, and 1.0 wt% magnesium stearate;

[0076] (2) carbidopa monohydrate 12.7 wt%, levodopa 46.9 wt%, hydroxypropyl cellulose 31 wt%, mannitol 8.5 wt% and magnesium stearate 1 wt%;

[0077] (3) carbidopa monohydrate 11.3 wt%, levodopa 41.7 wt%, hydroxypropylcellulose 31 wt%, mannitol 15 wt% and magnesium stearate 0.5 wt%;

[0078] (4) 50 wt% levodopa, 31.0 wt% hydroxypropylcellulose, 18 wt% mannitol, and 1 wt% magnesium stearate;

[0079] (5) levodopa 63 wt%, hydroxypropylcellulose 11 wt%, sorbitol 10.0 wt%, povidone 5 wt%, poloxamer 10 wt% and magnesium stearate 1 wt%;

[0080] (6) 31.5 wt% of levodopa, 20 wt% of hydroxypropylcellulose, 19 wt% of sorbitol, 9.5 wt% of povidone, 19 wt% of poloxamer, and 1 wt% of magnesium stearate;

[0081] (7) levodopa 31.5 wt%, hydroxypropylcellulose 29 wt%, sorbitol 19 wt%, povidone 9.5 wt%, poloxamer 10 wt% and magnesium stearate 1 wt%;

[0082] (8) 63 wt% levodopa, 10 wt% hydroxypropylcellulose, 19.5 wt% sorbitol, 5 wt% poloxamer, 0.5 wt% silicon dioxide and 2 wt% magnesium stearate;

[0083] (9) levodopa 31.5 wt%, lactose 31 wt%, hydroxypropyl cellulose 10 wt%, sorbitol 20 wt%, poloxamer (407) 5 wt%, silicon dioxide 0.5 wt% and magnesium stearate 2 wt%;

[0084] (10) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 11 wt%, sorbitol 20 wt%, poloxamer (407) 5 wt% and magnesium stearate 1 wt%;

[0085] (11) 63.0 wt% of levodopa, 14.8 wt% of hydroxypropylcellulose, 14.8 wt% of sorbitol, 5 wt% of poloxamer 407, 0.5 wt% of silicon dioxide, and 2.0 wt% of magnesium stearate;

[0086] (12) 63.0 wt% of levodopa, 11.8 wt% of hydroxypropylcellulose, 17.7 wt% of sorbitol, 5 wt% of poloxamer 407, 0.5 wt% of silicon dioxide, and 2.0 wt% of magnesium stearate;

[0087] (13) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 10 wt%, poloxamer 407 10 wt%, sorbitol 10 wt%, povidone 4.5 wt%, magnesium stearate 2.0 wt% and silicon dioxide 0.5 wt%;

[0088] (14) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 15 wt%, sorbitol 15 wt%, povidone 4.17 wt%, butylated hydroxytoluene 0.33 wt%, magnesium stearate 2.0 wt% and silicon dioxide 0.5 wt%;

[0089] (15) Carbidopa monohydrate 6.91 wt%, levodopa 51.1 wt%, hydroxypropylcellulose 30 wt%, sorbitol 5 wt%, povidone 4.19 wt%, butylated hydroxytoluene 0.31 wt%, silicon dioxide 0.5 wt% and magnesium stearate 2 wt%;

[0090] (16) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 10 wt%, sorbitol 10 wt%, poloxamer (407) 10 wt%, povidone 4.17 wt%, butylated hydroxytoluene 0.33 wt%, magnesium stearate 2.0 wt% and silicon dioxide 0.5 wt%;

[0091] (17) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 15 wt%, sorbitol 15 wt%, povidone 4.17 wt%, butylated hydroxytoluene 0.33 wt%, magnesium stearate 2.0 wt% and silicon dioxide 0.5 wt%;

[0092] (18) Carbidopa monohydrate 3.75 wt%, levodopa 27.7 wt%, mannitol 31.5 wt%, hydroxypropylcellulose 10 wt%, poloxamer (407) 10 wt%, sorbitol 10 wt%, povidone 4.5 wt%, silicon dioxide 0.5 wt% and magnesium stearate 2 wt%;

[0093] (19) Carbidopa monohydrate 3.75 wt%, levodopa 27.7 wt%, hydroxypropylcellulose 10 wt%, poloxamer (407) 10 wt%, sorbitol 41.5 wt%, povidone 4.5 wt%, silicon dioxide 1.5 wt% and magnesium stearate 2 wt%.

[0094] In the present invention, the booster layer may further include one or more of a swelling agent, an osmotic pressure enhancer, a lubricant, and a colorant, and may further include a swelling agent, an osmotic pressure enhancer, a colorant, and a lubricant.

[0095] The components and contents of the expander, osmotic pressure enhancer, colorant, and lubricant may be conventional components and contents of such agents in the art, and the contents are the weight percentages of the components in the boost layer. The following components and contents are particularly preferred in the present invention:

[0096] The swelling agent may be one or more of sodium carboxymethyl starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose (such as sodium carboxymethyl cellulose (9H4XF)), hydroxyethyl cellulose, carbomer, sodium alginate, carrageenan and polyethylene oxide, such as sodium carboxymethyl cellulose and hydroxypropyl cellulose.

[0097] When the swelling agents are sodium carboxymethyl cellulose and hydroxypropyl cellulose, the mass ratio of the sodium carboxymethyl cellulose to the hydroxypropyl cellulose is preferably (2-4):1, such as 2.5:1 or 3.5:1.

[0098] The content of the expander may be 25-89 wt%, such as 89 wt% or 69 wt%.

[0099] The osmotic pressure 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, such as sorbitol.

[0100] The content of the osmotic pressure enhancer may be 10-70 wt %, or 10-30 wt %, such as 30 wt %, and the content is the weight percentage of the component in the boosting layer.

[0101] The lubricant may be one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, such as magnesium stearate.

[0102] The content of the lubricant may be 0.1-3 wt%, such as 0.5 wt%, and the content is the weight percentage of the component in the boosting layer.

[0103] The colorant may be one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black, such as iron oxide red.

[0104] The content of the colorant may be 0.1-2 wt%, such as 0.5 wt%, and the content is the weight percentage of the component in the boosting layer.

[0105] In a preferred embodiment of the present invention, the boosting layer is composed of the following components:

[0106] (1) sodium carboxymethylcellulose 49 wt%, sorbitol 30 wt%, hydroxypropyl cellulose 20 wt%, red iron oxide 0.5 wt% and magnesium stearate 0.5 wt%;

[0107] (2) Sodium carboxymethylcellulose 69 wt%, sorbitol 10 wt%, hydroxypropyl cellulose 20 wt%, red iron oxide 0.5 wt% and magnesium stearate 0.5 wt%.

[0108] In the present invention, the weight ratio of the drug-containing layer to the booster layer can be (0.5-4):1, or (2-3):1, such as 2:1, 2.5:1 or 2.8:1.

[0109] In a preferred embodiment of the present invention, the core comprises any one of the following components:

[0110] (1) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant;

[0111] (2) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant;

[0112] (3) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned surfactant, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant;

[0113] (4) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned surfactant, the above-mentioned antioxidant, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant;

[0114] The content of each component is the same as described above.

[0115] In a preferred embodiment of the present invention, the core tablet is composed of any one of the following components:

[0116] (1) Drug-containing layer: 14.5 wt% carbidopa monohydrate, 53.6 wt% levodopa, 31.0 wt% hydroxypropylcellulose, and 1.0 wt% magnesium stearate;

[0117] In the push layer: sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0118] (2) Drug-containing layer: 12.7 wt% carbidopa monohydrate, 46.9 wt% levodopa, 31 wt% hydroxypropylcellulose, 8.5 wt% mannitol, and 1 wt% magnesium stearate;

[0119] In the push layer: sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0120] (3) Drug-containing layer: 11.3 wt% carbidopa monohydrate, 41.7 wt% levodopa, 31 wt% hydroxypropylcellulose, 15 wt% mannitol, and 0.5 wt% magnesium stearate;

[0121] In the push layer: sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0122] (4) Drug-containing layer: 50 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 18 wt% mannitol, and 1 wt% magnesium stearate;

[0123] In the push layer: sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0124] (5) Drug-containing layer: 63 wt% levodopa, 11 wt% hydroxypropylcellulose, 10.0 wt% sorbitol, 5 wt% povidone, 10 wt% poloxamer, and 1 wt% magnesium stearate;

[0125] Sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0126] (6) Drug-containing layer: 31.5 wt% levodopa, 20 wt% hydroxypropyl cellulose, 19 wt% sorbitol, 9.5 wt% povidone, 19 wt% poloxamer, and 1 wt% magnesium stearate;

[0127] In the push layer: sodium carboxymethylcellulose 69wt%, sorbitol 10wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0128] (7) Drug-containing layer: 31.5 wt% levodopa, 29 wt% hydroxypropyl cellulose, 19 wt% sorbitol, 9.5 wt% povidone, 10 wt% poloxamer, and 1 wt% magnesium stearate;

[0129] Sodium carboxymethylcellulose 69wt%, sorbitol 10wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0130] (8) Drug-containing layer: 31.5 wt% levodopa, 20 wt% hydroxypropyl cellulose, 19 wt% sorbitol, 9.5 wt% povidone, 19 wt% poloxamer, and 1 wt% magnesium stearate;

[0131] In the push layer: sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0132] (9) Drug-containing layer: 31.5 wt% levodopa, 29 wt% hydroxypropyl cellulose, 19 wt% sorbitol, 9.5 wt% povidone, 10 wt% poloxamer, and 1 wt% magnesium stearate;

[0133] In the push layer: sodium carboxymethylcellulose 49wt%, sorbitol 30wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0134] (10) Drug-containing layer: 63 wt% levodopa, 10 wt% hydroxypropyl cellulose, 19.5 wt% sorbitol, 5 wt% poloxamer, 0.5 wt% silicon dioxide, and 2.0 wt% magnesium stearate;

[0135] In the push layer: sodium carboxymethylcellulose 69wt%, sorbitol 10wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0136] (11) Drug-containing layer: 31.5 wt% of levodopa, 31 wt% of lactose, 10 wt% of hydroxypropyl cellulose, 20 wt% of sorbitol, 5 wt% of poloxamer (407), 0.5 wt% of silicon dioxide and 2 wt% of magnesium stearate;

[0137] In the push layer: sodium carboxymethylcellulose (9H4XF) 69wt%, sorbitol 10wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0138] (12) Drug-containing layer: carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropyl cellulose 11 wt%, sorbitol 20 wt%, poloxamer (407) 5 wt% and magnesium stearate 1 wt%;

[0139] In the push layer: sodium carboxymethylcellulose (9H4XF) 69wt%, sorbitol 10wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0140] (13) 63.0 wt% of levodopa, 14.8 wt% of hydroxypropylcellulose, 14.8 wt% of sorbitol, 5 wt% of poloxamer 407, 0.5 wt% of silicon dioxide, and 2.0 wt% of magnesium stearate;

[0141] In the push layer: sodium carboxymethylcellulose 69wt%, sorbitol 10wt%, hydroxypropyl cellulose 20wt%, red iron oxide 0.5wt% and magnesium stearate 0.5wt%;

[0142] (14) 63.0 wt% of levodopa, 11.8 wt% of hydroxypropylcellulose, 17.7 wt% of sorbitol, 5 wt% of poloxamer 407, 0.5 wt% of silicon dioxide, and 2.0 wt% of magnesium stearate;

[0143] The push layer contains: 69 wt% sodium carboxymethyl cellulose, 10 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0144] (15) Carbidopa monohydrate 7.50 wt%, levodopa 55.51 wt%, hydroxypropylcellulose 10 wt%, poloxamer 407 10 wt%, sorbitol 10 wt%, povidone 4.50 wt%, magnesium stearate 2.0 wt% and silicon dioxide 0.5 wt%;

[0145] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0146] (16) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 15 wt%, sorbitol 15 wt%, povidone 4.17 wt%, butylated hydroxytoluene 0.33 wt%, magnesium stearate 2.0 wt% and silicon dioxide 0.5 wt%;

[0147] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0148] (17) Carbidopa monohydrate 6.91 wt%, levodopa 51.1 wt%, hydroxypropylcellulose 30 wt%, sorbitol 5 wt%, povidone 4.19 wt%, butylated hydroxytoluene 0.31 wt%, silicon dioxide 0.5 wt% and magnesium stearate 2 wt%;

[0149] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0150] (18) Carbidopa monohydrate 7.5 wt%, levodopa 55.5 wt%, hydroxypropylcellulose 10 wt%, poloxamer 10 wt%, sorbitol 10 wt%, povidone 4.17 wt%, butylated hydroxytoluene 0.33 wt%, magnesium stearate 2 wt% and silicon dioxide 0.5 wt%;

[0151] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0152] (19) Carbidopa monohydrate 7.5 wt%, levodopa 55 wt%, hydroxypropylcellulose 15 wt%, sorbitol 15 wt%, povidone 4.17 wt%, butylated hydroxytoluene 0.33 wt%, silicon dioxide 0.5 wt% and magnesium stearate 2 wt%;

[0153] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0154] (20) carbidopa monohydrate 3.75 wt%, levodopa 27.7 wt%, mannitol 31.5 wt%, hydroxypropylcellulose 10 wt%, poloxamer (407) 10 wt%, sorbitol 10 wt%, povidone 4.5 wt%, silicon dioxide 1.5 wt% and magnesium stearate 2 wt%;

[0155] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0156] (21) Carbidopa monohydrate 3.75 wt%, levodopa 27.7 wt%, hydroxypropylcellulose 10 wt%, poloxamer (407) 10 wt%, sorbitol 41.5 wt%, povidone 4.5 wt%, silicon dioxide 1.5 wt% and magnesium stearate 2 wt%;

[0157] The push-up layer contains: 49 wt% sodium carboxymethylcellulose, 30 wt% sorbitol, 20 wt% hydroxypropyl cellulose, 0.5 wt% red iron oxide and 0.5 wt% magnesium stearate.

[0158] In the present invention, the tablet core can be a double-layer tablet (consisting of a drug-containing layer and a booster layer stacked on the drug-containing layer) or a three-layer tablet (consisting of a blank layer, a drug-containing layer and a booster layer in sequence), for example, a double-layer tablet.

[0159] In the present invention, the tablet core may further include a controlled release film coating wrapped around the tablet core.

[0160] The controlled-release membrane coating may further have one or more drug-releasing holes (the drug-releasing holes are punched by laser or mechanical punching, for example, one, two or three drug-releasing holes). Preferably, the diameter of the drug-releasing holes is 0.3 mm to 1.2 mm, for example, 1.0 mm.

[0161] The controlled-release membrane coating is a semipermeable membrane coating, and the film-forming material of the semipermeable membrane coating can be one or more of cellulose acetate, ethyl cellulose, and acrylic resin, for example, cellulose acetate. The content of the film-forming material can be 50-90 wt%, or can be 60-90 wt% (for example, 60 wt%, 65 wt%, 70 wt%, or 90 wt%), where the content is the weight percentage of the component in the controlled-release membrane coating.

[0162] Preferably, the semipermeable coating may further include a pore-forming agent and a plasticizer.

[0163] The porogen may be one or more of polyethylene glycol, glycerol, povidone, copovidone and hydroxypropyl cellulose, such as copovidone and hydroxypropyl cellulose (hydroxypropyl cellulose HXF).

[0164] The plasticizer may be one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetin and castor oil, such as polyethylene glycol or triethyl citrate.

[0165] The semipermeable coating may include a mixture of cellulose acetate and copovidone, a mixture of cellulose acetate, hydroxypropyl cellulose HXF and triethyl citrate, or a mixture of cellulose acetate and triethyl citrate.

[0166] Among them, the weight ratio of the controlled release membrane coating to the tablet core can be a conventional weight ratio in the art, which can be (2.0%-15.0%):1 (for example, 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); it can also be (6.6%-8.4%):1, and can also be (7.4%-7.8%):1.

[0167] In the present invention, a separation coating layer may be further included between the tablet core and the controlled release membrane coating (the separation coating layer is wrapped on the tablet core, and the controlled release membrane coating is wrapped on the separation coating layer).

[0168] Wherein, the film-forming material of the isolation coat layer may be hydroxypropyl cellulose EF.

[0169] The weight ratio of the isolation coating layer to the core tablet may be a conventional weight ratio in the art, which may be (3.0%-5.0%):1, for example, 4.0%:1.

[0170] In the present invention, the pharmaceutical composition may further comprise a rapid-release layer containing a pharmaceutically active ingredient coated on the controlled-release membrane. The pharmaceutical composition may further comprise a rapid-release layer. The rapid-release layer preferably comprises a pharmaceutically active ingredient, a binder, and an antioxidant. The rapid-release layer further preferably comprises a pharmaceutically active ingredient, a plasticizer, an antioxidant, and a binder. The rapid-release layer further preferably comprises a pharmaceutically active ingredient, an antioxidant, and a binder, or alternatively, comprises a pharmaceutically active ingredient, a plasticizer, an antioxidant, and a binder.

[0171] When the immediate-release layer includes a plasticizer, the content of the plasticizer is conventional in the art, preferably 1-2 wt %.

[0172] When the immediate-release layer includes 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, triacetin and castor oil, such as tributyl citrate.

[0173] When the immediate-release layer includes an antioxidant, the content of the antioxidant is conventional in the art, preferably 3-4 wt%, such as 3.38 wt% or 3.81 wt%.

[0174] When the immediate-release layer includes an antioxidant, the antioxidant may be one or more of butylated hydroxytoluene, butylated hydroxyanisole, dibutylphenol, vitamin C, vitamin E and sodium sulfite, such as butylated hydroxytoluene.

[0175] When the quick-release layer includes a binder, the content of the binder is conventional in the art, preferably 10-20 wt %.

[0176] When the immediate-release layer includes a binder, the binder can be one or more of povidone, copovidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose, such as a mixture of hydroxypropyl cellulose and copovidone (the weight ratio of the two is, for example, 1:1) or hydroxypropyl cellulose.

[0177] When the immediate-release layer includes a pharmaceutically active ingredient, the content of the pharmaceutically active ingredient is conventional in the art, preferably 70-90 wt%, such as 74.7 wt%, 75.7 wt%, 86.2 wt% or 85.3 wt%.

[0178] When the immediate-release layer includes a pharmaceutically active ingredient, the pharmaceutically active ingredient includes 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, preferably carbidopa hydrate, such as carbidopa monohydrate.

[0179] In a preferred embodiment of the present invention, the immediate-release layer is composed of any one of the following components:

[0180] (a) 86.2 wt% carbidopa monohydrate, 10.0 wt% hydroxypropylcellulose, and 3.84 wt% butylated hydroxytoluene;

[0181] (b) carbidopa monohydrate 85.3 wt%, hydroxypropylcellulose 10.0 wt%, triethyl citrate 1.02 wt% and butylated hydroxytoluene 3.81 wt%;

[0182] (c) carbidopa monohydrate 74.7 wt%, hydroxypropylcellulose 10.0 wt%, copovidone 10.0, triethyl citrate 2.00 wt% and butylated hydroxytoluene 3.38 wt%;

[0183] (d) Carbidopa monohydrate 75.7 wt%, hydroxypropylcellulose 10.0 wt%, copovidone 10.0 wt%, triethyl citrate 1.00 wt% and butylated hydroxytoluene 3.38 wt%.

[0184] In the present invention, the pharmaceutical composition may further comprise an enteric layer coated on the controlled-release membrane or the immediate-release layer. The material of the enteric layer may be an acrylic resin or a cellulose derivative. The acrylic resin is preferably one or more of a copolymer of methacrylic acid and ethyl acrylate copolymerized in a weight ratio of 1:1, a copolymer of methacrylic acid and methyl methacrylate copolymerized in a weight ratio of 1:1, a copolymer of methacrylic acid and ethyl acrylate copolymerized in a weight ratio of 1:2, or a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate copolymerized in a weight ratio of 1:1:1. The cellulose derivative is preferably one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose titanate, and hydroxypropyl methylcellulose acetate succinate.

[0185] In the present invention, the shape of the capsule-shaped tablet can be a capsule shape formed by tabletting in the long diameter direction or a capsule shape formed by tabletting in a direction perpendicular to the long diameter, for example, a capsule shape formed by tabletting in the long diameter direction.

[0186] In the present invention, the cross-section of the capsule-shaped tablet may be circular or non-circular, for example, circular.

[0187] When the cross-section of the capsule-shaped tablet is circular, the diameter of the circle may be 5-10 mm (e.g., 6 mm, 7 mm, or 8 mm), and the height may be 4-30 mm (e.g., 14.90 mm, 15.24 mm, 16.42 mm, or 16.76 mm); or the cross-section diameter may be 5-7.5 mm and the height may be 10-20 mm.

[0188] When the cross-section of the capsule-shaped tablet is non-circular, the non-circular shape may be a non-circular shape having an axis of symmetry. The non-circular shape having an axis of symmetry may have a major axis length of 10-25 mm and a minor axis length of 5-25 mm. The non-circular shape having an axis of symmetry may also have a major axis length of 16-19 mm and a minor axis length of 7-7.5 mm.

[0189] In a preferred embodiment of the present invention, the pharmaceutical composition is any one of the following groups:

[0190] (1) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned 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 tabletting in a direction perpendicular to the long diameter);

[0191] (2) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned 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 tabletting in a direction perpendicular to the long diameter);

[0192] (3) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned surfactant, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned 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 tabletting in a direction perpendicular to the long diameter);

[0193] (4) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned antioxidant, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned 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 tabletting in a direction perpendicular to the long diameter);

[0194] (5) The drug-containing layer comprises: the aforementioned active pharmaceutical ingredient, the aforementioned drug carrier, the aforementioned filler, and the aforementioned lubricant; the booster layer comprises: the aforementioned expander, the aforementioned osmotic pressure enhancer, the aforementioned colorant, and the aforementioned lubricant; the cross-sectional shape of the capsule-shaped tablet is circular (or the shape of the capsule-shaped tablet is a capsule formed by tabletting in the long diameter direction);

[0195] (6) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned surfactant, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant; the cross-sectional shape of the capsule-shaped tablet is circular (or the shape of the capsule-shaped tablet is a capsule formed by tabletting in the long diameter direction);

[0196] (7) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned surfactant, the above-mentioned antioxidant, and the above-mentioned lubricant; the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant; the cross-section of the capsule-shaped tablet is circular (or the shape of the capsule-shaped tablet is a capsule shape formed by tabletting in the long diameter direction);

[0197] The content of each component is the same as described above.

[0198] In a preferred embodiment of the present invention, the pharmaceutical composition is the following group (I) or (II):

[0199] (I) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned antioxidant, and the above-mentioned lubricant; and the booster layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant;

[0200] The quick-release layer comprises: the active pharmaceutical ingredient, the binder and the oxidant;

[0201] The cross-section of the capsule-shaped tablet is circular (or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in the long diameter direction);

[0202] (II) The drug-containing layer comprises: the above-mentioned active pharmaceutical ingredient, the above-mentioned drug carrier, the above-mentioned filler, the above-mentioned antioxidant, and the above-mentioned lubricant; the push-assist layer comprises: the above-mentioned expander, the above-mentioned osmotic pressure enhancer, the above-mentioned colorant, and the above-mentioned lubricant;

[0203] The quick-release layer comprises: the active pharmaceutical ingredient, the binder, the oxidant and the plasticizer;

[0204] The cross-section of the capsule-shaped tablet is circular (or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in the long diameter direction).

[0205] In a preferred embodiment of the present invention, the active pharmaceutical ingredient in the drug-containing layer is levodopa; the content of levodopa is 27.7-63 wt%;

[0206] The dopa decarboxylase inhibitor is carbidopa or its hydrate; the content of the dopa decarboxylase inhibitor is 7.5-14.5 wt%;

[0207] The drug-containing layer includes pharmaceutical excipients, and the pharmaceutical excipients include "drug carriers, fillers and lubricants", "drug carriers, fillers, surfactants and lubricants" or "drug carriers, fillers, surfactants, antioxidants and lubricants";

[0208] The drug carrier is a mixture of povidone and hydroxypropyl cellulose or hydroxypropyl cellulose; the content of the drug carrier is 10-40 wt%; the filler is a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, or sorbitol; the content of the filler is 8.5-20 wt%; the weight ratio of sorbitol in the filler to hydroxypropyl cellulose in the drug carrier is (1-2):1;

[0209] The surfactant is poloxamer; the content of the surfactant is 5-19wt%;

[0210] The lubricant is magnesium stearate and / or silicon dioxide; the content of the lubricant is 1-2.5wt%;

[0211] The antioxidant is butylated hydroxytoluene; the content of the antioxidant is 0.1-1.0%;

[0212] The shape of the caplet-shaped tablet is a capsule shape formed by tabletting in the long diameter direction (or the cross-section of the caplet-shaped tablet is circular).

[0213] Preferably, the weight ratio of the controlled-release membrane coating to the tablet core is (7.0%-8.0%):1, or can be (7.4%-7.8%):1.

[0214] In the present invention, the capsule-shaped tablet is preferably a controlled-release tablet, such as an osmotic pump tablet. The levodopa content of the controlled-release tablet is preferably 125 mg / tablet, 150 mg / tablet, 250 mg / tablet, 375 mg / tablet, or 500 mg / tablet. In the present invention, the pharmaceutical composition is preferably taken before bedtime and in the supine position after taking the drug.

[0215] In a preferred embodiment of the present invention, the pharmaceutical composition and the drug-containing layer are composed of the above-mentioned active pharmaceutical ingredients and the above-mentioned pharmaceutical excipients.

[0216] The present invention also provides a method for preparing the pharmaceutical composition, which comprises the following steps:

[0217] The raw material particles of the drug-containing layer and the raw material particles of the boosting layer are stacked and pressed together to form the tablet core;

[0218] When the tablet core is also coated with a controlled release membrane, the tablet core is coated, the controlled release membrane coating is wrapped on the tablet core, and holes are punched in the controlled release membrane coating on one side of the drug-containing layer to form drug release holes.

[0219] When the pharmaceutical composition further comprises a rapid-release layer, the rapid-release layer coating is coated on the capsule-shaped tablet coated with the controlled-release membrane.

[0220] When the pharmaceutical composition further comprises a separation coating layer, the separation coating layer is first coated on the core tablet, and then the coating is coated on the separation coating layer.

[0221] The composite pressing can be performed in the direction of the long diameter or in a direction perpendicular to the long diameter.

[0222] The raw material particles of the drug-containing layer can be obtained by conventional granulation methods in the art, such as dry granulation, wet granulation, hot melt granulation or fluidized bed granulation.

[0223] The raw material particles of the boosting layer can be obtained by conventional granulation methods in the art, such as dry granulation, wet granulation or fluidized bed granulation to obtain the raw material particles of the drug-containing layer.

[0224] The present invention also provides a use of the above-mentioned pharmaceutical composition in preparing a medicine for preventing or treating morning stiffness.

[0225] In the application, the morning stiffness is preferably morning stiffness caused by Parkinson's disease.

[0226] The pharmaceutical composition preferably begins to release the active pharmaceutical ingredient after a lag of 1-3 hours, reaches a peak concentration of the active pharmaceutical ingredient in 6-10 hours, and maintains a blood concentration above 50% of the peak concentration for more than 5 hours; more preferably, begins to release the active pharmaceutical ingredient after a lag of 2 hours, reaches a peak concentration of the active pharmaceutical ingredient in 6-10 hours, and maintains a blood concentration above 50% of the peak concentration for more than 7 hours.

[0227] The release characteristics of the pharmaceutical composition are preferably as follows: there is a time lag of 1-3 hours before the start of release (during this period, the cumulative release rate of the active pharmaceutical ingredient is ≤10%); after the start of release, the active pharmaceutical ingredient has a cumulative release rate of more than 85% (including 85%) in 6-10 hours; more preferably, before the start of release, the active pharmaceutical ingredient has a delay of 2 hours (during this period, the cumulative release rate of the active pharmaceutical ingredient is ≤10%); after the start of release, the active pharmaceutical ingredient has a cumulative release rate of more than 85% (including 85%) in 8 hours.

[0228] The present invention also provides a delayed timed release pharmaceutical composition, wherein the dosage form of the pharmaceutical composition is a controlled release tablet;

[0229] The composition comprises a pharmaceutical active ingredient, wherein the pharmaceutical active ingredient is levodopa or its derivatives, or a mixture of levodopa or its derivatives and a dopa decarboxylase inhibitor; the release (in vitro) characteristics of the composition are: before the start of release, the pharmaceutical active ingredient has a time lag of 1-3 hours; after the start of release, the pharmaceutical active ingredient has a cumulative release rate of 85% or more (including 85%) within 6-10 hours; the time lag means that during this period, the cumulative release rate of the pharmaceutical active ingredient is ≤10%.

[0230] Preferably, the blood concentration of the active pharmaceutical ingredient is maintained at above 50% of the peak concentration for more than 5 hours; more preferably, the blood concentration of the active pharmaceutical ingredient is maintained at above 50% of the peak concentration for more than 7 hours.

[0231] The release characteristics of the pharmaceutical composition are preferably as follows: before the start of release, the active pharmaceutical ingredient has a time lag of 2 hours; after the start of release, the active pharmaceutical ingredient has a cumulative release rate of more than 85% (including 85%) within 8 hours.

[0232] The pharmaceutical composition is preferably taken before bedtime and in a supine position. The pharmaceutical composition is preferably the pharmaceutical composition described above. The pharmaceutical composition is preferably used to prevent or treat morning stiffness. The morning stiffness is preferably caused by Parkinson's disease.

[0233] Wherein, the components of the pharmaceutical composition are the same as described above.

[0234] The present invention also provides a method for preventing or treating morning stiffness, comprising administering an effective amount of the above-mentioned pharmaceutical composition to a subject.

[0235] 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 in a supine position after taking the medicine.

[0236] In the present invention, the "longer axis direction" refers to a direction parallel to the longest axis of symmetry of the capsule-shaped tablet.

[0237] In the present invention, the "cross section" refers to a plane parallel to the interface formed by the drug-containing layer and the pusher layer.

[0238] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0239] The reagents and raw materials used in the present invention are commercially available.

[0240] The positive progress of the present invention is that the pharmaceutical composition of the present invention has the following excellent controlled release effects: after a delay of 1-3 hours in vitro, the cumulative release rate of the active pharmaceutical ingredient is less than 10%; after a sustained release of 6-10 hours, the cumulative release rate is greater than 85% in 6-10 hours, and further after a delay of 2 hours in vitro, the cumulative release rate of the active pharmaceutical ingredient is less than 10%; after a sustained release of 8-10 hours, the cumulative release rate is greater than 85% in 8-10 hours;

[0241] The drug release is initiated after a lag of 1-3 hours in the body, with peak concentrations reached in 6-10 hours, and blood concentrations maintained above 50% of peak concentrations for more than 5 hours, especially after a lag of 2 hours.

[0242] The pharmaceutical composition of the present invention enables patients to take the medicine by themselves before going to bed the night before, and the blood drug concentration before waking up in the morning is maintained above the minimum effective concentration, so that the patient is in an "ON" state instead of an "OFF" state when waking up in the morning, reducing the occurrence of morning stiffness and other related symptoms caused by it. BRIEF DESCRIPTION OF THE DRAWINGS

[0243] FIG1 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 1.

[0244] FIG2 is a release curve of carbidopa in the controlled-release tablet in Example 1.

[0245] FIG3 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 2.

[0246] FIG4 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 3.

[0247] FIG5 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 4.

[0248] FIG6 is a release curve of carbidopa from the controlled-release tablets in Example 4.

[0249] FIG7 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 5.

[0250] FIG8 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 6.

[0251] FIG9 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 7.

[0252] FIG10 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 8.

[0253] FIG11 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 9.

[0254] FIG12 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 10.

[0255] FIG13 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 11.

[0256] FIG14 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 14.

[0257] FIG15 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 15.

[0258] FIG16 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 16.

[0259] FIG17 is a release curve of carbidopa from the controlled-release tablet in Example 16.

[0260] FIG18 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 17.

[0261] FIG19 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 18.

[0262] FIG20 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 19.

[0263] FIG21 is a release curve of carbidopa from the controlled-release tablet in Example 19.

[0264] FIG22 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 21.

[0265] FIG23 is a graph showing the release curve of carbidopa from the controlled-release tablets in Example 21.

[0266] FIG24 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 22.

[0267] FIG25 is a graph showing the release curve of carbidopa from the controlled-release tablet in Example 22.

[0268] FIG26 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 23.

[0269] FIG27 is a graph showing the release curve of carbidopa from the controlled-release tablet in Example 23.

[0270] FIG28 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 24.

[0271] FIG29 is a graph showing the release curve of carbidopa from the controlled-release tablets in Example 24.

[0272] FIG30 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 25.

[0273] FIG31 is a graph showing the release curve of carbidopa from the controlled-release tablet in Example 25.

[0274] FIG32 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 26.

[0275] FIG33 is a graph showing the release curve of carbidopa from the controlled-release tablet in Example 26.

[0276] FIG34 is a graph showing the release curve of levodopa from the controlled-release tablet in Example 27.

[0277] FIG35 is a graph showing the release curve of carbidopa from the controlled-release tablet in Example 27.

[0278] Figure 36 is a shape diagram of the controlled-release tablet of the present invention, wherein a is a three-dimensional structural diagram of the controlled-release tablet obtained by prescription three in Example 1; b is a right view of the controlled-release tablet obtained by prescription three in Example 1; c is a three-dimensional structural diagram of the controlled-release tablet in Example 11; and d is a right view of the controlled-release tablet in Example 11. DETAILED DESCRIPTION

[0279] The present invention is further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described. The experimental methods in the following examples that do not specify specific conditions shall be carried out in accordance with conventional methods and conditions, or selected in accordance with the product instructions. In the following examples, "percentage by weight" refers to the weight percentage of the weight of the component in the total weight of the layer prescription in which the component is located. For example, in the first prescription of Example 1: carbidopa accounts for 14.5wt%, which means the weight percentage of carbidopa in the total weight of the drug-containing layer prescription. Unless otherwise specified, the mannitol used in the implementation is mannitol 200SD, hydroxypropyl cellulose is hydroxypropyl cellulose EXF, poloxamer is poloxamer 407≤80 mesh, sorbitol mesh is sorbitol≤80 mesh, povidone is povidone K29 / 32, and cellulose acetate is cellulose acetate 320S.

[0280] Example 1: Capsule-shaped tablets (non-circular cross-section and compressed in the direction perpendicular to the long diameter) Specifications 37.5 mg / 150 mg (carbidopa / levodopa), screening of mannitol ratio

[0281] The prescription is as follows:

[0282] Preparation method:

[0283] 1. Preparation of drug-containing layer: Carbidopa and levodopa were pre-mixed with other excipients of the drug-containing layer (except magnesium stearate), added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate was added and mixed.

[0284] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0285] 3. Tablet Compression: Press double-layer tablets with a die size of 16*7mm (deep concave). First fill the drug-containing layer material for pre-compression, then fill the booster layer material, compact to obtain a double-layer tablet core, and press in the direction perpendicular to the long diameter.

[0286] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 5.5 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a 1.0 mm diameter release aperture. The controlled-release tablets in this example are 37.5 mg / 150 mg (carbidopa / levodopa) in a biconvex capsule shape.

[0287] 5. Release determination method: Take this product and test it according to the release determination method (USP <711> Method II and Chinese Pharmacopoeia <0931> ), place the tablet in a sinker basket, use 900 ml of 0.1 N hydrochloric acid solution as solvent, rotate at 75 rpm, and operate according to the method. At 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, immediately take 2 mL of the eluate after online filtration (10 mL of online rinse before sampling) as the test solution (1), (2), (3), (4), (5), (6), (7), (8), (9), and immediately add 2 mL of 37°C 0.1 N hydrochloric acid solution to the dissolution cup.

[0288] Chromatographic conditions: according to high performance liquid chromatography (USP <621> and Chinese Pharmacopoeia <0512> ), octadecylsilane bonded silica gel as the filler; 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.

[0289] The specific levodopa test results are shown in Table 1 and Figure 1 , and the carbidopa test results are shown in Table 2 and Figure 2 .

[0290] Table 1

[0291] Table 2

[0292] Example 2: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) specifications 37.5 mg / 150 mg (carbidopa / levodopa), with an isolation layer coating

[0293] The prescription is as follows:

[0294] Preparation method:

[0295] 1. Preparation of drug-containing layer: same as the second prescription in Example 1.

[0296] 2. Preparation of boost layer: same as recipe 2 in Example 1.

[0297] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 320.0 mg of the drug-containing layer material, pre-press, then fill with 160.0 mg of the booster layer material, and compact to obtain a double-layer core tablet weighing 480.0 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0298] 4. Seal coating: Use a coating pan to coat the double-layer tablet core with the above-mentioned seal coating solution to increase the weight by 4.0 wt% (the percentage is relative to the weight percentage of the tablet core).

[0299] 5. Semipermeable Membrane Coating: Use a pan coating pan to coat the sealer-coated tablets with the controlled-release coating solution to a weight gain of 4.0 wt% and 6.0 wt% (percentages are relative to the weight of the sealer-coated tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are biconvex capsule-shaped tablets with a dosage of 37.5 mg / 150 mg (carbidopa / levodopa).

[0300] 6. Release rate determination method: Same as Example 1. The specific test results of levodopa are shown in Table 3 and Figure 3.

[0301] Table 3

[0302] Example 3: Capsule-shaped tablets (non-circular cross-section and compressed in the direction perpendicular to the long diameter) Specifications 37.5 mg / 150 mg (carbidopa / levodopa), CA320S+hydroxypropylcellulose HXF

[0303] The prescription is as follows:

[0304] Preparation method:

[0305] 1. Preparation of drug-containing layer: same as the second prescription in Example 1.

[0306] 2. Preparation of boost layer: same as recipe 2 in Example 1.

[0307] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 320.0 mg of the drug-containing layer material, pre-press, then fill with 160.0 mg of the booster layer material, and compact to obtain a double-layer core tablet weighing 480.0 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0308] 4. Semipermeable Membrane Coating: Use a coating pan to coat the sealer-coated tablets with the controlled-release coating solution to a weight gain of 6.3 wt% and 7.5 wt% (percentages are relative to the weight of the sealer-coated tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are biconvex capsule-shaped tablets with a dosage of 37.5 mg / 150 mg (carbidopa / levodopa).

[0309] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 4 and Figure 4.

[0310] Table 4

[0311] Example 4: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) Specifications 37.5 mg / 150 mg (carbidopa / levodopa), CA320S+triethyl citrate

[0312] The prescription is as follows:

[0313] Preparation method:

[0314] 1. Preparation of drug-containing layer: same as the second prescription in Example 1.

[0315] 2. Preparation of boost layer: same as recipe 2 in Example 1.

[0316] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 320.0 mg of the drug-containing layer material, pre-press, then fill with 160.0 mg of the booster layer material, and compact to obtain a double-layer core tablet weighing 480.0 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0317] 4. Semipermeable Membrane Coating: Use a coating pan to coat the sealer-coated tablets with the controlled-release coating solution to a weight gain of 6.3 wt% and 7.5 wt% (percentages are relative to the weight of the sealer-coated tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are biconvex capsule-shaped tablets with a dosage of 37.5 mg / 150 mg (carbidopa / levodopa).

[0318] 5. Release rate determination method: Same as Example 1. Specific levodopa test results are shown in Table 5 and Figure 5 , and carbidopa test results are shown in Table 6 and Figure 6 .

[0319] Table 5

[0320] Table 6

[0321] Example 5: Capsule-shaped tablets (non-circular cross-section and compressed in the direction perpendicular to the long diameter) Specifications 250 mg

[0322] The prescription is as follows:

[0323] Preparation method:

[0324] 1. Preparation of drug-containing layer: Premix levodopa with other excipients of the drug-containing layer (except magnesium stearate), add to a dry granulator and press into a ribbon, pass through a 16-mesh stainless steel sieve to granulate, and finally add magnesium stearate and mix, and set aside.

[0325] 2. Preparation of the boost layer: pre-mix the boost layer excipients (excluding magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix them for later use.

[0326] 3. Tablet Compression: Compress double-layer tablets with a die size of 19*7.5mm (shallow concave). First fill with 500mg of the drug-containing layer material, pre-press, then fill with 250mg of the booster layer material, and compact to obtain a double-layer core tablet weighing 750mg / tablet. Compress in the direction perpendicular to the long diameter.

[0327] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 6.0 wt% and 8.7 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are biconvex capsule-shaped tablets with a 250 mg levodopa dosage.

[0328] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 7 and Figure 7.

[0329] Table 7

[0330] Example 6: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 250 mg

[0331] The prescription is as follows:

[0332] Preparation method:

[0333] 1. Preparation of drug-containing layer: same as Example 5.

[0334] 2. Preparation of boost layer: same as Example 5.

[0335] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 396.8 mg of the drug-containing layer material, pre-press, and then fill with 198.4 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 595.2 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0336] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer tablet cores with the controlled-release coating solution to a weight gain of 8.0 wt% (percentages are relative to the weight of the tablet core). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are biconvex capsule-shaped tablets with a 250 mg levodopa dosage.

[0337] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 8 and Figure 8.

[0338] Table 8

[0339] Example 7: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 125 mg

[0340] The prescription is as follows:

[0341] Preparation method:

[0342] 1. Preparation of drug-containing layer: same as Example 5.

[0343] 2. Preparation of boost layer: same as Example 5.

[0344] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 396.8 mg of the drug-containing layer material, pre-press, and then fill with 198.4 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 595.2 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0345] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 8.0 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example are biconvex capsule-shaped tablets with a size of 16 x 7 mm and a 125 mg dose of levodopa.

[0346] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 9 and Figure 9.

[0347] Table 9

[0348] Example 8: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 125 mg

[0349] The prescription is as follows:

[0350] Preparation method:

[0351] 1. Preparation of drug-containing layer: same as Example 5.

[0352] 2. Preparation of boost layer: same as Example 5.

[0353] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 396.8 mg of the drug-containing layer material, pre-press, and then fill with 198.4 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 595.2 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0354] 4. Semipermeable Membrane Coating: Coat the bilayer core tablets with the controlled-release coating solution using a pan coating process to a weight gain of 8.4 wt% (percentages are relative to the weight of the core tablets). Perforations are made mechanically or laser-drilled, with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example are biconvex capsules containing 125 mg of levodopa, measuring 16 x 7 mm.

[0355] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 10 and Figure 10.

[0356] Table 10

[0357] Example 9: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 125 mg

[0358] The prescription is as follows:

[0359] Preparation method:

[0360] 1. Preparation of drug-containing layer: same as Example 5.

[0361] 2. Preparation of boost layer: same as Example 5.

[0362] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 396.8 mg of the drug-containing layer material, pre-press, and then fill with 198.4 mg of the booster layer material. Compact to obtain a double-layer tablet core weighing 595.2 mg / tablet.

[0363] 4. Semipermeable Membrane Coating: Use a pan coater to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 6.9 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a 1.00 mm diameter release aperture. The controlled-release tablets in this example are 125 mg levodopa capsule-shaped biconvex tablets measuring 16 x 7 mm, compressed perpendicular to the long axis.

[0364] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 11 and Figure 11.

[0365] Table 11

[0366] Example 10: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 125 mg

[0367] The prescription is as follows:

[0368] Preparation method:

[0369] 1. Preparation of drug-containing layer: same as Example 5.

[0370] 2. Preparation of boost layer: same as Example 5.

[0371] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 396.8 mg of the drug-containing layer material, pre-press, and then fill with 198.4 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 595.2 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0372] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer tablet cores with the controlled-release coating solution to a weight gain of 6.6 wt% (percentages are relative to the weight of the tablet core). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example are 125 mg levodopa capsule-shaped biconvex tablets measuring 16 x 7 mm.

[0373] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 12 and Figure 12.

[0374] Table 12

[0375] Example 11: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 250 mg specification

[0376] The prescription is as follows:

[0377] Preparation method:

[0378] 1. Preparation of drug-containing layer: Premix levodopa with other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide), add to a dry granulator and press into ribbons, pass through a 16-mesh stainless steel sieve to granulate, and finally add magnesium stearate and silicon dioxide and mix.

[0379] 2. Preparation of boost layer: same as Example 5.

[0380] 3. Tablet Compression: Compress double-layer tablets using a Φ6 mm round punch (deep concave). First, fill with 396.8 mg of the drug-containing layer material and pre-press. Then fill with 161.3 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 558.1 mg / tablet. Compress in the long diameter direction.

[0381] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.8 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are capsule-shaped tablets with a cross-sectional diameter of 6 mm and a height of 14.90 mm, containing 250 mg of levodopa.

[0382] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 13 and Figure 13.

[0383] Table 13

[0384] Example 12: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 375 mg specification

[0385] The prescription is as follows:

[0386] Preparation method:

[0387] 1. Preparation of drug-containing layer: same as Example 11.

[0388] 2. Preparation of boost layer: same as Example 11.

[0389] 3. Tablet Compression: Compress double-layer tablets using a Φ7 mm round punch (deep concave). First, fill with 595.3 mg of the drug-containing layer material and pre-press. Then fill with 242.0 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 837.3 mg / tablet. Compress in the long diameter direction.

[0390] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.0 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a 1.0 mm diameter for drug release. The controlled-release tablets in this example are capsule-shaped tablets containing 375 mg of levodopa, with a cross-sectional diameter of 7 mm and a height of 16.42 mm.

[0391] Example 13: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 500 mg specification

[0392] The prescription is as follows:

[0393] Preparation method:

[0394] 1. Preparation of drug-containing layer: same as Example 11.

[0395] 2. Preparation of boost layer: same as Example 11.

[0396] 3. Tablet Compression: Compress double-layer tablets using a Φ8 mm round punch (deep concave). First, fill with 793.6 mg of the drug-containing layer material and pre-press. Then fill with 322.6 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 1116.2 mg / tablet. Compress in the long diameter direction.

[0397] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.0 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example contain 500 mg of levodopa in a capsule-shaped form with a cross-sectional diameter of 8 mm and a height of 16.76 mm.

[0398] Example 14: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 125 mg (LD) specification

[0399] The prescription is as follows:

[0400] Preparation method:

[0401] 1. Preparation of drug-containing layer: same as Example 11.

[0402] 2. Preparation of boost layer: same as Example 11.

[0403] 3. Tablet Compression: Compress double-layer tablets using a Φ6 mm round punch (deep concave). First, fill with 396.8 mg of the drug-containing layer material and pre-press. Then fill with 161.3 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 558.1 mg / tablet. Compress in the long diameter direction.

[0404] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.4 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example are 125 mg levodopa capsules with a cross-sectional diameter of 6 mm and a height of 15.24 mm.

[0405] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 14 and Figure 14.

[0406] Table 14

[0407] Example 15: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 125 mg (LD)

[0408] The prescription is as follows:

[0409] Preparation method:

[0410] 1. Preparation of drug-containing layer: same as Example 11.

[0411] 2. Preparation of boost layer: same as Example 11.

[0412] 3. Tablet Compression: Compress double-layer tablets using a Φ6 mm round punch (deep concave). First, fill with 396.8 mg of the drug-containing layer material and pre-press. Then fill with 161.3 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 558.1 mg / tablet. Compress in the long diameter direction.

[0413] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.7 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example are 125 mg levodopa capsules with a cross-sectional diameter of 6 mm and a height of 15.24 mm.

[0414] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 15 and Figure 15.

[0415] Table 15

[0416] Example 16: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 31.3 mg / 250 mg (CD / LD) specifications

[0417] The prescription is as follows:

[0418] Preparation method:

[0419] 1. Preparation of drug-containing layer: same as Example 1.

[0420] 2. Preparation of boost layer: same as Example 1.

[0421] 3. Tablet Compression: Compress double-layer tablets using a Φ6 mm round punch (deep concave). First, fill with 450.5 mg of the drug-containing layer material and pre-press. Then fill with 183.1 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 633.6 mg / tablet. Compress in the long diameter direction.

[0422] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.6 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 250 mg of levodopa and 31.3 mg of carbidopa in the form of capsules with a cross-sectional diameter of 6 mm and a height of 17.27 mm.

[0423] 5. Release determination: Same as Example 1. Specific levodopa test results are shown in Table 16 and Figure 16 , and carbidopa test results are shown in Table 17 and Figure 17 .

[0424] Table 16

[0425] Table 17

[0426] Example 17: Capsule-shaped tablets (circular in cross section and compressed in the long diameter direction) 250 mg specification

[0427] Based on Example 11, the ratio of HPC to Sorbitol is 1:1 or 1:1.5, and the rest is the same as Example 11. The formula is as follows:

[0428] Preparation method:

[0429] 1. Preparation of drug-containing layer: same as Example 11.

[0430] 2. Preparation of boost layer: same as Example 11.

[0431] 3. Tablet Compression: Compress double-layer tablets using a Φ6 mm round punch (deep concave). First, fill with 396.8 mg of the drug-containing layer material and pre-press. Then fill with 161.3 mg of the booster layer material and compact to obtain a double-layer core tablet weighing 558.1 mg / tablet. Compress in the long diameter direction.

[0432] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.5 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.0 mm. The controlled-release tablets in this example are capsule-shaped tablets with a cross-sectional diameter of 6 mm and a height of 14.90 mm, containing 250 mg of levodopa.

[0433] 5. Release rate determination method: Same as Example 1. Specific test results are shown in Table 18 and Figure 18.

[0434] Table 18

[0435] Example 18: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.3 mg / 250 mg (CD / LD) specifications

[0436] The prescription is as follows:

[0437] Preparation method:

[0438] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0439] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0440] 3. Tablet Compression: Double-layer tablets were prepared using a 16*7 mm die. 450.7 mg of the drug-containing layer material was first filled and pre-compressed, followed by 183.3 mg of the booster layer material. The double-layer tablets weighed 634.0 mg / tablet and were compressed perpendicular to the long diameter.

[0441] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 5.9 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 31.3 mg of carbidopa and 250 mg of levodopa.

[0442] 5. Release rate determination method: Same as Example 1. The specific test results of levodopa are shown in Table 19 and Figure 19.

[0443] Table 19

[0444] Example 19: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.3 mg / 250 mg (CD / LD)

[0445] The prescription is as follows:

[0446] Preparation method:

[0447] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0448] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0449] 3. Tablet Compression: Double-layer tablets were prepared using a 16*7 mm die. 450.6 mg of drug-containing layer material was first filled and pre-compressed, followed by 183.2 mg of booster layer material. The double-layer tablet core was compacted to obtain a weight of 633.8 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0450] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 5.9 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 31.3 mg of carbidopa and 250 mg of levodopa.

[0451] 5. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 20 and Figure 20 , and carbidopa test results are shown in Table 21 and Figure 21 .

[0452] Table 20

[0453] Table 21

[0454] Example 20:

[0455] 1. Prepare capsule-shaped tablets (250 mg) using the formula of Example 11, wherein the cross section of the capsule-shaped tablet is circular and compressed in the long diameter direction.

[0456] The prescription is as follows:

[0457] Preparation method:

[0458] 1. Preparation of drug-containing layer: same as Example 11.

[0459] 2. Preparation of boost layer: same as Example 11.

[0460] 3. Tablet Compression: Double-layer tablets were prepared using a 16*7 mm die. 396.8 mg of the drug-containing layer material was first filled and pre-compressed, followed by 161.3 mg of the booster layer material. The double-layer tablets weighed 558.1 mg / tablet and were compressed perpendicular to the long diameter.

[0461] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.5 wt% and 8.9 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example are formulated to deliver 250 mg of levodopa.

[0462] 5. Release determination method: same as Example 1.

[0463] 2. Using the formula of Example 15, which has a circular cross section and is compressed in the long diameter direction, a capsule-shaped tablet with a non-circular cross section and compressed in the direction perpendicular to the long diameter (125 mg specification) was prepared.

[0464] The prescription is as follows:

[0465] Preparation method:

[0466] 1. Preparation of drug-containing layer: same as Example 11.

[0467] 2. Preparation of boost layer: same as Example 11.

[0468] 3. Tablet Compression: Double-layer tablets were prepared using a 16*7 mm die. 396.8 mg of the drug-containing layer material was first filled and pre-compressed, followed by 161.3 mg of the booster layer material. The double-layer tablets weighed 558.1 mg / tablet and were compressed perpendicular to the long diameter.

[0469] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.5 wt% and 9.2 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 125 mg of levodopa.

[0470] 5. Release determination method: same as Example 1.

[0471] Example 21: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.3 mg / 250 mg (CD / LD) specifications

[0472] The prescription is as follows:

[0473] Preparation method:

[0474] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0475] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0476] 3. Tablet Compression: Double-layer tablets were prepared using a die size of 17.5 x 7.5 mm. 489.3 mg of the drug-containing layer material was first filled and pre-compressed, followed by 198.9 mg of the booster layer material. The double-layer tablet core was compacted to obtain a weight of 688.2 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0477] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 6.5 wt% and 8.2 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to perforate the tablets, with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 31.3 mg of carbidopa and 250 mg of levodopa.

[0478] 5. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 22 and Figure 22 , and carbidopa test results are shown in Table 23 and Figure 23 .

[0479] Table 22

[0480] Table 23

[0481] Example 22: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.3 mg / 250 mg (CD / LD)

[0482] The prescription is as follows:

[0483] Preparation method:

[0484] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0485] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0486] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 450.6 mg of the drug-containing layer material, pre-press, and then fill with 183.3 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 633.9 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0487] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 8.2 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 31.3 mg of carbidopa and 250 mg of levodopa.

[0488] 5. Release rate determination method: Same as Example 1. Specific levodopa test results are shown in Table 24 and Figure 24 , and carbidopa test results are shown in Table 25 and Figure 25 .

[0489] Table 24

[0490] Table 25

[0491] Example 23: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 62.5 mg / 250 mg (CD / LD) specifications

[0492] The prescription is as follows:

[0493] Preparation method:

[0494] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0495] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0496] 3. Tablet Compression: Double-layer tablets were prepared using a 16*7 mm die. 450.6 mg of the drug-containing layer material was first filled and pre-compressed, followed by 183.2 mg of the booster layer material. The double-layer tablet core was compacted to obtain a weight of 633.8 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0497] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer tablet cores with the controlled-release coating solution to a weight gain of 6.0 wt% (percentages are relative to the weight of the tablet core). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 31.3 mg of carbidopa and 250 mg of levodopa.

[0498] 5. Rapid-release coating: The controlled-release tablet cores were coated with the rapid-release coating solution using a coating pan to a weight gain of 39.1 mg / tablet. The specifications of the controlled-release tablets in this example are 62.5 mg of carbidopa and 250 mg of levodopa.

[0499] 6. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 26 and Figure 26 , and carbidopa test results are shown in Table 27 and Figure 27 .

[0500] Table 26

[0501] Table 27

[0502] Example 24: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 15.7 mg / 125 mg (CD / LD) specifications

[0503] The prescription is as follows:

[0504] Preparation method:

[0505] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0506] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0507] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 450.6 mg of the drug-containing layer material, pre-press, and then fill with 183.3 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 633.9 mg / tablet.

[0508] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 6.1 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 15.7 mg of carbidopa and 125 mg of levodopa.

[0509] 5. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 28 and Figure 28 , and carbidopa test results are shown in Table 29 and Figure 29 .

[0510] Table 28

[0511] Table 29

[0512] Example 25: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 15.6 mg / 125 mg (CD / LD) specifications

[0513] The prescription is as follows:

[0514] Preparation method:

[0515] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0516] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0517] 3. Tablet Compression: Compress double-layer tablets using a 16*7 mm (deep concave) die. First, fill with 450.6 mg of the drug-containing layer material, pre-press, and then fill with 183.3 mg of the booster layer material. Compact to obtain a double-layer core tablet weighing 633.9 mg / tablet. Compress in a direction perpendicular to the long diameter.

[0518] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 5.9 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 15.7 mg of carbidopa and 125 mg of levodopa.

[0519] 5. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 30 and Figure 30 , and carbidopa test results are shown in Table 31 and Figure 31 .

[0520] Table 30

[0521] Table 31

[0522] Example 26: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 62.5 mg / 250 mg (CD / LD) specifications

[0523] The prescription is as follows:

[0524] Preparation method:

[0525] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0526] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0527] 3. Tablet Compression: Double-layer tablets were prepared using a 16*7 mm die. 450.6 mg of the drug-containing layer material was first filled and pre-compressed, followed by 183.2 mg of the booster layer material. The double-layer tablet core was compacted to obtain a weight of 633.8 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0528] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.7 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 31.3 mg of carbidopa and 250 mg of levodopa.

[0529] 5. Rapid-release coating: The controlled-release tablet cores were coated with the rapid-release coating solution using a coating pan to a weight gain of 39.1 mg / tablet. The specifications of the controlled-release tablets in this example are 62.5 mg of carbidopa and 250 mg of levodopa.

[0530] 6. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 32 and Figure 32 , and carbidopa test results are shown in Table 33 and Figure 33 .

[0531] Table 32

[0532] Table 33

[0533] Example 27: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.25 mg / 125 mg (CD / LD) specifications

[0534] The prescription is as follows:

[0535] Preparation method:

[0536] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0537] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0538] 3. Tablet Compression: Double-layer tablets were prepared using a 13*6 mm die. The tablets were pre-pressed with 225.2 mg of the drug-containing layer material and then filled with 91.5 mg of the booster layer material. The tablets were compacted to obtain a double-layer core weighing 316.7 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0539] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.3 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 15.6 mg of carbidopa and 125 mg of levodopa.

[0540] 5. Rapid-release coating: The controlled-release tablet cores were coated with the rapid-release coating solution using a coating pan to a weight gain of 19.7 mg / tablet. The specifications of the controlled-release tablets in this example were 31.25 mg of carbidopa and 125 mg of levodopa.

[0541] 6. Release determination method: Same as Example 1. Specific levodopa test results are shown in Table 34 and Figure 34 , and carbidopa test results are shown in Table 35 and Figure 35 .

[0542] Table 34

[0543] Table 35

[0544] Example 28: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.25 mg / 125 mg (CD / LD)

[0545] The prescription is as follows:

[0546] Preparation method:

[0547] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0548] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0549] 3. Tablet Compression: Double-layer tablets were prepared using a 13*6 mm die. The tablets were pre-pressed with 225.2 mg of the drug-containing layer material and then filled with 91.5 mg of the booster layer material. The tablets were compacted to obtain a double-layer core weighing 316.7 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0550] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.3 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 15.6 mg of carbidopa and 125 mg of levodopa.

[0551] 5. Rapid-release coating: The controlled-release tablet cores were coated with the rapid-release coating solution using a coating pan to a weight gain of 22.5 mg / tablet. The specifications of the controlled-release tablets in this example are 31.25 mg of carbidopa and 125 mg of levodopa.

[0552] Example 29: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.25 mg / 125 mg (CD / LD) specifications

[0553] The prescription is as follows:

[0554] Preparation method:

[0555] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0556] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0557] 3. Tablet Compression: Double-layer tablets were prepared using a 13*6 mm die. The tablets were pre-pressed with 225.2 mg of the drug-containing layer material and then filled with 91.5 mg of the booster layer material. The tablets were compacted to obtain a double-layer core weighing 316.7 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0558] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.3 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 15.6 mg of carbidopa and 125 mg of levodopa.

[0559] 5. Rapid-release coating: The controlled-release tablet cores were coated with the rapid-release coating solution using a coating pan to a weight gain of 22.2 mg / tablet. The specifications of the controlled-release tablets in this example are 31.25 mg of carbidopa and 125 mg of levodopa.

[0560] Example 30: Capsule-shaped tablets (non-circular cross-section and compressed perpendicular to the long diameter) 31.25 mg / 125 mg (CD / LD) specifications

[0561] The prescription is as follows:

[0562] Preparation method:

[0563] 1. Preparation of drug-containing layer: Levodopa, carbidopa monohydrate and other excipients of the drug-containing layer (except magnesium stearate and silicon dioxide) were pre-mixed, added to a dry granulator and pressed into ribbons, which were granulated through a 16-mesh stainless steel screen, and finally magnesium stearate and silicon dioxide were added and mixed.

[0564] 2. Preparation of the boost layer: pre-mix the boost layer excipients (except magnesium stearate), add them into a dry granulator and press them into ribbons, pass them through a 16-mesh stainless steel screen to granulate them, and finally add magnesium stearate and mix.

[0565] 3. Tablet Compression: Double-layer tablets were prepared using a 13*6 mm die. The tablets were pre-pressed with 225.2 mg of the drug-containing layer material and then filled with 91.5 mg of the booster layer material. The tablets were compacted to obtain a double-layer core weighing 316.7 mg / tablet. The tablets were compressed perpendicular to the long diameter.

[0566] 4. Semipermeable Membrane Coating: Use a pan coating pan to coat the bilayer core tablets with the controlled-release coating solution to a weight gain of 7.3 wt% (percentages are relative to the weight of the core tablets). Use mechanical or laser drilling to create holes with a drug release aperture diameter of 1.00 mm. The controlled-release tablets in this example contain 15.6 mg of carbidopa and 125 mg of levodopa.

[0567] 5. Rapid-release coating: The controlled-release tablet cores were coated with the rapid-release coating solution using a coating pan to a weight gain of 21.9 mg / tablet. The specifications of the controlled-release tablets in this example are 31.25 mg of carbidopa and 125 mg of levodopa.

Claims

1. A delayed time-release pharmaceutical composition, characterized in that: The dosage form of the pharmaceutical composition is a controlled-release tablet; The pharmaceutical composition comprises a pharmaceutically active ingredient, wherein the pharmaceutically active ingredient is levodopa or its derivatives, or a mixture of "levodopa or its derivatives" and a dopa decarboxylase inhibitor; The release characteristics of the composition are as follows: before the start of release, the active pharmaceutical ingredient has a time lag of 1-3 hours; after the start of release, the active pharmaceutical ingredient has a cumulative release rate of more than 85% in 6-10 hours.

2. A pharmaceutical composition, characterized in that The tablet comprises a core, wherein the core comprises a drug-containing layer and a boosting layer stacked on the drug-containing layer; the drug-containing layer comprises active pharmaceutical ingredients; The content of the active pharmaceutical ingredient in the drug-containing layer is 5-72.5 wt %, where the content is the weight percentage of the active pharmaceutical ingredient in the drug-containing layer; In the drug-containing layer, the active pharmaceutical ingredient is levodopa or its derivatives, or a mixture of "levodopa or its derivatives" and a dopa decarboxylase inhibitor; When the active pharmaceutical ingredient is a mixture of "levodopa or its derivatives" and a dopa decarboxylase inhibitor, the content of the dopa decarboxylase inhibitor is ≤14.5wt%, but not 0, and the content is the weight percentage of the component in the drug-containing layer; The dosage form of the pharmaceutical composition is a capsule-shaped tablet.

3. The pharmaceutical composition according to claim 2, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) In the drug-containing layer, the content of the active pharmaceutical ingredient is 30-72.5 wt%, for example, 31.5 wt%, 50 wt%, 53 wt%, 58 wt%, 59.6 wt%, 63 wt% or 68.1 wt%; (2) In the drug-containing layer, the content of levodopa or its derivative is 27.7-63 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%; (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, such as carbidopa monohydrate; (5) In the drug-containing layer, the content of the dopa decarboxylase inhibitor is 3.7-14.5 wt%, for example, 3.75 wt%, 6.91 wt%, 7.5 wt%, 11.3 wt%, 12.7 wt% or 14.5 wt%; (6) The drug-containing layer further comprises pharmaceutical excipients, which include one or more of drug carriers, fillers, surfactants, lubricants and antioxidants, and may further include "drug carriers and lubricants", "drug carriers, fillers and lubricants", "drug carriers, fillers, surfactants and lubricants" or "drug carriers, fillers, surfactants, antioxidants and lubricants"; (7) The cross-section of the capsule-shaped tablet is circular or non-circular; (8) The shape of the capsule-shaped tablet is a capsule shape formed by tabletting in the long diameter direction or a capsule shape formed by tabletting in a direction perpendicular to the long diameter direction.

4. The pharmaceutical composition according to claim 3, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) The drug carrier is one or more of povidone, copovidone, carbomer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide and sodium alginate, and may also be a mixture of povidone and hydroxypropyl cellulose or hydroxypropyl cellulose; (2) When the drug-containing layer includes a pharmaceutical excipient, and the pharmaceutical excipient includes a drug carrier, the content of the drug carrier is ≤40 wt%, but not 0, and can be 10-40 wt%, 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, such as a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, sorbitol, or mannitol; (4) When the drug-containing layer includes a pharmaceutical excipient, and the pharmaceutical excipient includes a filler, the content of the filler is ≤51 wt%, but not 0, and can be 5-51 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%; (5) The surfactant is one or more of polysorbate, poloxamer, fatty acid glyceride, sodium dodecylbenzenesulfonate and sodium lauryl sulfate, such as poloxamer; (6) When the drug-containing layer includes a pharmaceutical excipient, and the pharmaceutical excipient includes a surfactant, the content of the surfactant is ≤19 wt%, but not 0, and can also be 5-19 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, such as magnesium stearate and / or silicon dioxide; (8) When the drug-containing layer includes a pharmaceutical excipient, and the pharmaceutical excipient includes a lubricant, the content of the lubricant is ≤2.5 wt%, but 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 butylated hydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C and vitamin E, such as butylated hydroxytoluene; (10) When the drug-containing layer includes a pharmaceutical excipient, and the pharmaceutical excipient includes an antioxidant, the content of the antioxidant is ≤1.0 wt%, but not 0, and may be 0.1-0.5%, for example 0.33 wt%; (11) When the cross-section of the capsule-shaped tablet is circular, the diameter of the circle is 5-10 mm and the height is 4-30 mm; the cross-section diameter may be 5-7.5 mm and the height may be 10-20 mm; (12) When the cross-section of the capsule-shaped tablet is non-circular, the non-circular shape is a non-circular shape having an axis of symmetry, and the length of the major axis of the non-circular shape having an axis of symmetry may be 10-25 mm, and the length of the minor axis may be 5-25 mm; the length of the major axis of the non-circular shape having an axis of symmetry may also be 16-19 mm, and the length of the minor axis may also be 7-7.5 mm.

5. The pharmaceutical composition according to claim 4, wherein When the pharmaceutical excipients include a drug carrier and a filler, the weight ratio of the filler to the drug carrier is (1-6):1, or can be (1-2):1; Preferably: When the drug carrier is a mixture of povidone 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 pharmaceutical composition according to claim 1, wherein The drug-containing layer comprises any of the following components: (1) Active pharmaceutical ingredients, drug carriers and lubricants; (2) active pharmaceutical ingredients, pharmaceutical carriers, the filler and the lubricant; (3) the active pharmaceutical ingredient, the drug carrier, the filler, the surfactant, and the lubricant; (4) the active pharmaceutical ingredient, the pharmaceutical carrier, the filler, the surfactant, the antioxidant, and the lubricant; The active pharmaceutical ingredient is the same as that in any one of claims 1 to 5; The drug carrier, the lubricant, the filler, the surfactant and the antioxidant are all as described in any one of claims 2 to 5.

7. The pharmaceutical composition according to claim 1, wherein In the drug-containing layer, the active pharmaceutical ingredient is levodopa; the content of levodopa is 27.7-63 wt%; The dopa decarboxylase inhibitor is carbidopa or its hydrate; the content of the dopa decarboxylase inhibitor is 7.5-14.5 wt%; The drug-containing layer includes pharmaceutical excipients, which include "drug carrier, filler and lubricant", "drug carrier, filler, surfactant and lubricant" or "drug carrier, filler, surfactant, antioxidant and lubricant"; The drug carrier is a mixture of povidone and hydroxypropyl cellulose or hydroxypropyl cellulose; the content of the drug carrier is 10-40wt%; The filler is a mixture of sorbitol and lactose, a mixture of sorbitol and mannitol, or sorbitol; the content of the filler is 8.5-20wt%; The weight ratio of sorbitol in the filler to hydroxypropyl cellulose in the drug carrier is (1-2):1; The surfactant is poloxamer; the content of the surfactant is 5-19wt%; The lubricant is magnesium stearate and / or silicon dioxide; the content of the lubricant is 1-2.5wt%; The antioxidant is butylated hydroxytoluene; the content of the antioxidant is 0.1-1.0%; The cross section of the capsule-shaped tablet is circular.

8. The pharmaceutical composition according to claim 1, wherein The boosting layer comprises one or more of a swelling agent, an osmotic pressure enhancer, a lubricant and a colorant, preferably comprises a swelling agent, an osmotic pressure enhancer, a colorant and a lubricant.

9. The pharmaceutical composition according to claim 8, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) The swelling agent is one or more of sodium carboxymethyl starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, carrageenan, polyethylene oxide and sodium alginate, such as sodium carboxymethyl cellulose and hydroxypropyl cellulose; (2) The content of the expander is 25-89 wt%, for example 89 wt% or 69 wt%; (3) The osmotic pressure 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, such as sorbitol; (4) The content of the osmotic pressure enhancer is 10-70 wt%, and can be 10-30 wt%; (5) The lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, such as magnesium stearate; (6) The content of the lubricant is 0.1-3 wt%, for example 0.5 wt%; (7) The colorant is one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black, such as iron oxide red; (8) The content of the colorant is 0.1-2 wt%, for example 0.5 wt%.

10. The pharmaceutical composition according to claim 1, wherein The core comprises any of the following components: (1) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; (2) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; (3) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers, surfactants and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; (4) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers, surfactants, antioxidants and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; In the drug-containing layer: the active pharmaceutical ingredient is the same as that described in any one of claims 1 to 5; the drug carrier, the lubricant, the filler, the surfactant and the antioxidant are the same as those described in any one of claims 2 to 5; In the boosting layer: the expander, the osmotic pressure enhancer, the lubricant and the colorant are all the same as those described in claim 8 or 9.

11. The pharmaceutical composition according to claim 1, wherein The composition is any one of the following groups: (1) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is non-circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in a direction perpendicular to the long diameter; (2) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is non-circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in a direction perpendicular to the long diameter; (3) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers, surfactants and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is non-circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in a direction perpendicular to the long diameter; (4) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers, antioxidants and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is non-circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in a direction perpendicular to the long diameter; (5) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in the long diameter direction; (6) The drug-containing layer comprises: active pharmaceutical ingredients, drug carriers, fillers, surfactants and the aforementioned lubricants; the booster layer comprises: the aforementioned expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in the long diameter direction; (7) The drug-containing layer contains: active pharmaceutical ingredients, drug carriers, fillers, surfactants, antioxidants and lubricants; the booster layer contains: expanders, osmotic pressure enhancers, colorants and lubricants; The cross-section of the capsule-shaped tablet is circular, or the capsule-shaped tablet is in the shape of a capsule formed by tabletting in the long diameter direction; In the drug-containing layer: the active pharmaceutical ingredient is the same as that described in any one of claims 1 to 5; the drug carrier, the lubricant, the filler, the surfactant and the antioxidant are the same as those described in any one of claims 2 to 5; In the boosting layer: the expander, the osmotic pressure enhancer, the lubricant and the colorant are all the same as those described in claim 8 or 9.

12. The pharmaceutical composition according to claim 1, wherein The tablet core further includes a controlled release film coating wrapped around the tablet core; The controlled-release membrane coating is a semipermeable membrane, and the film-forming material of the semipermeable membrane is one or more of cellulose acetate, ethyl cellulose and acrylic resin, for example, cellulose acetate; The content of the film-forming material is 50-90 wt%, and may be 60-90 wt%, such as 60 wt%, 65 wt%, 70 wt% or 90 wt%; The semipermeable coating may further include a pore-forming agent and a plasticizer; The porogen may be one or more of polyethylene glycol, glycerol, povidone, copovidone and hydroxypropyl cellulose, such as copovidone and hydroxypropyl cellulose; The plasticizer may be one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin and castor oil, such as polyethylene glycol or triethyl citrate; The weight ratio of the controlled-release membrane coating to the tablet core can be (2.0%-15.0%):1; can also be (6.6%-8.4%):1; and can also be (7.4%-7.8%):

1.

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

1.

14. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition further comprises a quick-release layer; the quick-release layer comprises a pharmaceutical active ingredient, a binder and an antioxidant, and may comprise a pharmaceutical active ingredient, a plasticizer, an antioxidant and a binder; When the immediate-release layer includes a plasticizer, the content of the plasticizer is preferably 1-2 wt %; When the immediate-release layer includes 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, triacetin and castor oil, such as tributyl citrate; When the immediate-release layer includes an antioxidant, the content of the antioxidant is preferably 3-4 wt%, such as 3.38 wt% or 3.81 wt%; When the immediate-release layer includes an antioxidant, the antioxidant is preferably one or more of butylated hydroxytoluene, butylated hydroxyanisole, dibutylphenol, vitamin C, vitamin E and sodium sulfite, such as butylated hydroxytoluene; When the quick-release layer includes a binder, the content of the binder is preferably 10-20 wt%; When the immediate-release layer includes a binder, the binder is preferably one or more of povidone, copovidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose, such as a mixture of hydroxypropyl cellulose and copovidone or hydroxypropyl cellulose; When the immediate-release layer comprises a pharmaceutically active ingredient, the pharmaceutically active ingredient is preferably 70-90 wt%, such as 74.7 wt%, 75.7 wt%, 86.2 wt% or 85.3 wt%; When the immediate-release layer includes a pharmaceutically active ingredient, the pharmaceutically active ingredient preferably includes a dopa decarboxylase inhibitor; the dopa decarboxylase inhibitor is preferably carbidopa hydrate, a pharmaceutically acceptable salt of carbidopa, benserazide or a pharmaceutically acceptable salt of benserazide, more preferably a carbidopa hydrate, such as carbidopa monohydrate.

15. A method for preparing the pharmaceutical composition according to any one of claims 1 to 14, characterized in that: It includes the following steps: The raw material particles of the drug-containing layer and the raw material particles of the boosting layer are stacked and pressed together to form the tablet core; When the tablet core is also coated with a controlled-release membrane, coating is performed on the tablet core, the controlled-release membrane coating is wrapped on the tablet core, and holes are punched in the controlled-release membrane coating on one side of the drug-containing layer to form drug-releasing holes; When the pharmaceutical composition is further coated with a quick-release layer, the quick-release layer is coated on the capsule-shaped tablet coated with the controlled-release membrane; Preferably, the composite pressing can be performed in the direction of the long diameter or in a direction perpendicular to the long diameter.

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

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