Pharmaceutical composition, preparation containing pharmaceutical composition, suite containing pharmaceutical composition, and preparation method and application of pharmaceutical composition

Abstract

The invention discloses a pharmaceutical composition, a preparation containing the pharmaceutical composition, a kit containing the pharmaceutical composition, and a preparation method and application of the pharmaceutical composition. The pharmaceutical composition comprises the following components: an active pharmaceutical ingredient and a hot melt adhesive, wherein the mass percent of the active pharmaceutical ingredients is 0.3%-50%; the hot melt adhesive is poloxamer P188 and / or poloxamer P407; the mass percent of the hot melt adhesive in the pharmaceutical composition is 5%-30%. According to the pharmaceutical composition, the preparation containing the pharmaceutical composition and the kit containing the pharmaceutical composition, the stability of the active pharmaceutical ingredients can be improved while the active pharmaceutical ingredients are rapidly released to achieve rapid effect, swallowing of a patient can be further improved, and the medication compliance of the patient in actual taking can be improved.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, a preparation containing the same, a set, and a preparation method and application thereof. Background Art

[0002] In some disease areas, such as movement disability, heart disease, hypertension, asthma, pain, bleeding, bacterial or fungal infection, allergies, influenza, male erectile dysfunction, gastric reflux and other diseases, it is required that the drug take effect quickly after taking it in order to quickly relieve and improve the symptoms of the disease.

[0003] In oral preparations, since solutions do not have release issues, they generally take effect relatively quickly after taking them. However, for active pharmaceutical ingredients that are sensitive to moisture and have low solubility, solid preparations have more advantages.

[0004] Among oral solid preparations, granules, dispersible tablets, effervescent tablets, orodisintegrating tablets, orodissolving films and other dosage forms can achieve the characteristics of rapid release of active pharmaceutical ingredients. For children and the elderly, as well as patients with dysphagia, the above preparations can be more conducive to swallowing and improve medication compliance, but they will also bring problems with palatability and stability.

[0005] Specifically in the field of Parkinson's disease, patients' clinical needs for rapid drug onset and easier swallowing are described as follows.

[0006] Parkinson's disease (PD), also known as tremor paralysis, is one of the most common neurodegenerative diseases, which usually starts to occur between the ages of 50 and 65. Parkinson's disease has become the "second largest neurodegenerative disease" after Alzheimer's disease.

[0007] Parkinson's disease is a progressive disease caused by the loss of dopamine-producing cells in the brain. Currently, there is no drug that can cure the disease or prevent progression because the pathogenesis is unknown. All drugs are to help control symptoms. Parkinson's patients have reduced dopamine production in the brain. Dopamine is an endogenous substance present in the brain and spinal cord that helps brain nerve cells to properly control motor functions. When dopamine levels in the brain decrease, symptoms of Parkinson's disease will appear, such as freezing episodes (OFF episodes) such as tremors, muscle rigidity, slow movements, or difficulty walking.

[0008] Parkinson's disease patients generally have dysphagia. An epidemiological survey study showed that 11%-81% of Parkinson's patients have dysphagia, and lung infections caused by dysphagia are as high as 91.7% in community statistics (FatemehRajati et al. The global prevalence of oropharyngeal dysphagia in different populations: a systematic review and meta-analysis. Journal of TranslationalMedicine. 2022, 20: 175. https: / / doi.org / 10.1186 / s12967-022-03380-0). Dysphagia is a common symptom of Parkinson's disease patients, causing many inconveniences to patients' daily life such as eating and taking medicine, seriously affecting the quality of life of patients, especially in the "off" state.

[0009] As Parkinson's disease progresses, when the patient's levodopa concentration decreases, the patient will experience freezing episodes (OFF episodes), which are characterized by sudden and short-term attacks, inability to produce effective forward steps, and some patients remain motionless when they stand up, which lasts from a few seconds to tens of minutes. Freezing gait is an important cause of physical injury and disability in Parkinson's patients, and increases the economic burden on patients' families. When patients are driving or crossing the road, freezing episodes may lead to traffic accidents, resulting in serious consequences. Studies have shown (Li Yan, Wang Lijuan, Zhang Yuhu. Research progress on freezing gait [J]. Journal of Clinical Neurology. 2016, 29(2): 149-151.) that freezing gait occurs in 7% of patients with early idiopathic Parkinson's disease. About 50% of Parkinson's patients with a course of more than 10 years have experienced freezing gait. As the disease progresses, the number and duration of episodes increase.

[0010] In summary, designing a drug delivery system that improves patients' swallowing disorders, enhances medication compliance, and has a rapid onset of action is an effective solution to alleviate Parkinson's freezing attacks. Patients can take medication on their own when the signs of freezing attacks appear or in the early stages of freezing attacks, quickly increase the blood concentration of levodopa, avoid the danger of sudden motor disability, and try not to affect the patient's normal life.

[0011] The products currently on the market include APOKYN, KYNMOBI and INBRIJA. Among them, APOKYN is an injection of apomorphine hydrochloride. Compared with the frequency of use 3-5 times a day, the subcutaneous injection is extremely inconvenient. After the product upgrade, the injection was changed to a sublingual film (US 10420763 B2), namely KYNMOBI, which is administered sublingually, and the compliance of administration has been greatly improved, but it still has high adverse reactions such as nausea. INBRIJA is the first inhaled levodopa product. It uses Acorda's proprietary ARCUS platform development (US 8404276 B2) to provide patients with precise doses of levodopa dry powder preparations to avoid oral swallowing problems. However, when using INBRIJA, a dose of two capsules is required for each treatment. Before use, one capsule needs to be loaded into the inhalation device. After administration, the capsule shell is taken out, and then the second capsule is loaded and administered again; for Parkinson's patients in the OFF state, the use steps are extremely cumbersome. At the same time, this product has a high rate of adverse reactions (>5%), such as cough, nausea, upper respiratory tract infection, etc., and is not suitable for patients with lung diseases such as asthma and chronic obstructive pulmonary disease (COPD).

[0012] Carbidopa is an aromatic amino acid decarboxylase inhibitor, usually a compound preparation composed of levodopa (an aromatic amino acid, dopamine prodrug). Carbidopa inhibits the peripheral decarboxylation of levodopa, prompting more levodopa to be transported to the brain, thereby increasing the half-life and bioavailability of levodopa. Carbidopa is easily degraded under the influence of external factors, producing degradation products such as DHPA (dihydroxyphenylacetone) and hydrazine, especially hydrazine, which is a genotoxic substance and its content in the preparation should be strictly controlled. The hydrazine content of commercially available compound preparations containing levodopa and carbidopa is often high during product storage and use, posing a greater safety hazard to patients.

[0013] How to provide a pharmaceutical preparation that is easy to take, releases active pharmaceutical ingredients quickly and has good stability is an urgent problem to be solved. Summary of the invention

[0014] In order to solve the above problems existing in the prior art, the present invention provides a pharmaceutical composition, a preparation containing the same, a set, and a preparation method and application thereof. The pharmaceutical composition, the preparation and the set can not only achieve rapid release of active pharmaceutical ingredients, but also have good drug stability, can improve patient swallowing, do not need to be prepared in advance when administering, and are more convenient to use.

[0015] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0016] The first aspect of the present invention provides a pharmaceutical composition comprising the following components: an active pharmaceutical ingredient and a hot melt adhesive; wherein:

[0017] The mass percentage of the active pharmaceutical ingredient is 0.3%-50%;

[0018] The hot melt adhesive is poloxamer P188 and / or poloxamer P407;

[0019] The mass percentage of the hot melt adhesive in the pharmaceutical composition is 5%-30%.

[0020] In the present invention, the active pharmaceutical ingredient may include but is not limited to one or more of the following: dopaminergic agents, anti-erectile dysfunction agents, antiviral agents, gastric acid secretion inhibitors, anticoagulants, antifungal agents, antibacterial agents, antiasthmatic agents, antidepressants, antiepileptic agents, antiallergic agents, antihypertensive agents, antischizophrenia agents, analgesics, anti-inflammatory agents, antiemetics and antitussives.

[0021] Preferably, the active pharmaceutical ingredient is a poorly soluble and easily degradable drug, a poorly soluble and non-easily degradable drug, a non-poorly soluble and easily degradable drug, or a non-poorly soluble and non-easily degradable drug.

[0022] The poorly soluble and easily degradable drug can be selected from the group consisting of ritonavir, vonoprazan, rivaroxaban, posaconazole, cefdinir, cefixime, cefuroxime axetil, clarithromycin, linezolid and duloxetine.

[0023] The poorly soluble and non-easily degradable drug can be selected from: apixaban, tadalafil, dapoxetine, contizolamide, olanzapine, aripiprazole, quetiapine fumarate, zolmitriptan, rizatriptan, almotriptan, naratriptan, frovatriptan, eletriptan and verapamil.

[0024] Among them, the non-poorly soluble and easily degradable drug can be selected from: carbidopa, oseltamivir phosphate, favipiravir, monolavir, deuterated remdevir hydrobromide, namatevir, cefaclor, cefprozil, amoxicillin, montelukast sodium, levetiracetam and desloratadine.

[0025] Wherein, the non-poorly soluble and non-easily degradable drug can be selected from: levodopa, sildenafil, vardenafil, tigolac, fluconazole, escitalopram oxalate, levocetirizine, amlodipine, ketorolac tromethamine and diphenhydramine.

[0026] In the present invention, the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition may be 0.3%-40%.

[0027] In the present invention, the mass percentage of the hot melt adhesive in the pharmaceutical composition may be 14%-25%.

[0028] In the present invention, the pharmaceutical composition may be a pharmaceutical composition in the form of hot-melt granules.

[0029] In the present invention, the pharmaceutical composition may not contain an effervescent system. Generally speaking, an "effervescent system" refers to a system that usually contains an organic acid and sodium carbonate, wherein the system releases carbon dioxide when in contact with an aqueous solution.

[0030] In the present invention, the pharmaceutical composition may further include one or more of the following components: a disintegrant, a filler, a lubricant, a glidant, a flavoring agent and a fragrance.

[0031] The disintegrant may be one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate and cross-linked polyvinylpyrrolidone, preferably cross-linked sodium carboxymethyl cellulose and / or low-substituted hydroxypropyl cellulose. The mass percentage of the disintegrant in the pharmaceutical composition may be 0%-30%, preferably 10%-22%.

[0032] Wherein, the filler may be mannitol and / or lactose, such as mannitol. The mass percentage of the filler in the pharmaceutical composition may be 0%-50%. In the actual product preparation process, the lactose is generally presented in the form of lactose monohydrate, and those skilled in the art know that the amount of the filler in the pharmaceutical composition is adjusted to the amount of the corresponding hydrate form.

[0033] The lubricant may be one or more of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, magnesium silicate and calcium silicate, such as magnesium stearate. The mass percentage of the lubricant in the pharmaceutical composition may be 0%-2%.

[0034] Wherein, the glidant may be talcum powder and / or colloidal silicon dioxide. The mass percentage of the glidant in the pharmaceutical composition may be 0%-2%.

[0035] The flavoring agent may be one or more of sucrose, maltose, stevioside, mannitol, erythrose and aspartame, preferably one or more of stevioside, mannitol, erythrose and aspartame. The mass percentage of the flavoring agent in the pharmaceutical composition may be 0%-5%.

[0036] The aromatic agent may be an essence, preferably a natural essence, such as orange essence and / or apple essence. The mass percentage of the aromatic agent in the pharmaceutical composition may be 0%-3%.

[0037] In certain embodiments, the active pharmaceutical ingredients are carbidopa and levodopa; the mass percentage of carbidopa in the pharmaceutical composition is 0.5%-15%; the mass percentage of levodopa in the pharmaceutical composition is 2%-48%; the mass ratio of carbidopa to levodopa is 1:1-1:24. In the actual product preparation process, the presentation form of the carbidopa is generally a monohydrate, and those skilled in the art know that the amount of the carbidopa in the pharmaceutical composition is adjusted to the amount of the corresponding hydrate form.

[0038] In some preferred embodiments, the pharmaceutical composition comprises the following components by mass percentage: 0.5%-10% carbendazim, 2%-40% levodopa, 6%-30% hot melt adhesive and 0-30% disintegrant.

[0039] In some better embodiments, the pharmaceutical composition comprises the following components in mass percentage: 5.7%-8.3% carbidopa, 23%-33% levodopa, 15%-25% hot melt adhesive, 10.1%-20.1% low-substituted hydroxypropyl cellulose and 23.2%-33.2% mannitol; or, the pharmaceutical composition comprises 6.5%-7.5% carbidopa, 25.1%-30.1% levodopa, 17.5%-22.5% hot melt adhesive, 13.5%-18.5% low-substituted hydroxypropyl cellulose and 27.0-32.0% mannitol.

[0040] In a specific embodiment, the pharmaceutical composition comprises: 7.5% carbidopa monohydrate, 27.6% levodopa, 21.6% poloxamer 407, 15.1% low-substituted hydroxypropyl cellulose and 28.2% mannitol.

[0041] In a specific embodiment, the pharmaceutical composition comprises: 7.5% carbidopa monohydrate, 27.6% levodopa, 18.5% poloxamer 407, 15.1% low-substituted hydroxypropyl cellulose and 31.3% mannitol.

[0042] In a specific embodiment, the pharmaceutical composition comprises: 10.6% carbidopa monohydrate, 39.3% levodopa, 13% poloxamer 407, 10% low-substituted hydroxypropyl cellulose and 27.1% mannitol.

[0043] In a specific embodiment, the pharmaceutical composition comprises: 10.5% carbidopa monohydrate, 39% levodopa, 12.8% poloxamer 407, 9.9% low-substituted hydroxypropyl cellulose, 26.8% mannitol, 0.5% magnesium stearate and 0.5% orange flavor.

[0044] In a specific embodiment, the pharmaceutical composition comprises: 2.7% carbidopa monohydrate, 10% levodopa, 23% poloxamer 407, 14% low-substituted hydroxypropyl cellulose, 49.3% lactose, 0.5% colloidal silicon dioxide and 0.5% aspartame.

[0045] In a specific embodiment, the pharmaceutical composition comprises: 3.2% carbidopa monohydrate, 12% levodopa, 20% poloxamer 407, 18% sodium carboxymethyl starch, 45.9% lactose, 0.6% magnesium stearate and 0.3% orange flavor.

[0046] In a specific embodiment, the pharmaceutical composition comprises: 4.4% carbidopa monohydrate, 16.4% levodopa, 6.5% poloxamer 407, 17.3% crospovidone, 49.6% mannitol, 0.8% colloidal silicon dioxide, 4.7% sucrose and 0.3% apple flavor.

[0047] In a specific embodiment, the pharmaceutical composition comprises: 6.5% carbidopa monohydrate, 24% levodopa, 20.6% poloxamer 407, 15% lactose and 33.9% mannitol.

[0048] In a specific embodiment, the pharmaceutical composition comprises: 7.5% carbidopa monohydrate, 27.6% levodopa, 29.9% poloxamer 407, 29% croscarmellose sodium, 1% magnesium stearate and 5% sucrose.

[0049] In a specific embodiment, the pharmaceutical composition comprises: 0.675% carbidopa monohydrate, 2.5% levodopa, 25% poloxamer 407, 22.5% croscarmellose sodium and 49.325% mannitol.

[0050] In a specific embodiment, the pharmaceutical composition comprises: 8.4% carbidopa monohydrate, 31.2% levodopa, 16.5% poloxamer 407, 11.5% croscarmellose sodium and 32.4% mannitol.

[0051] In a specific embodiment, the pharmaceutical composition comprises: 9.7% carbidopa monohydrate, 36% levodopa, 18% poloxamer 407, 12% low-substituted hydroxypropyl cellulose and 24.3% mannitol.

[0052] In a specific embodiment, the pharmaceutical composition comprises: 10.4% carbidopa monohydrate, 38.4% levodopa, 15% poloxamer 407, 18% low-substituted hydroxypropyl cellulose and 18.2% lactose.

[0053] In a specific embodiment, the pharmaceutical composition comprises: 10.4% carbidopa monohydrate, 38.4% levodopa, 16% poloxamer 407, 12% low-substituted hydroxypropyl cellulose and 23.2% mannitol.

[0054] In a specific embodiment, the pharmaceutical composition comprises: 10.4% carbidopa monohydrate, 38.4% levodopa, 23% poloxamer 407, 5% low-substituted hydroxypropyl cellulose and 23.2% mannitol.

[0055] In a specific embodiment, the pharmaceutical composition comprises: 7.5% carbidopa monohydrate, 27.6% levodopa, 18.5% poloxamer 407, 13% low-substituted hydroxypropyl cellulose and 33.4% mannitol.

[0056] In a specific embodiment, the pharmaceutical composition comprises: 2.5% apixaban, 25% poloxamer 188, 20% croscarmellose sodium and 52.5% lactose monohydrate.

[0057] In a specific embodiment, the pharmaceutical composition comprises: 2.5% apixaban, 18% poloxamer 407, 15% croscarmellose sodium and 64.5% lactose monohydrate.

[0058] The second aspect of the present invention provides a pharmaceutical preparation, which is a hot-melt granulated granule, and the pharmaceutical preparation comprises the pharmaceutical composition as described above.

[0059] Wherein, the particle size of the hot-melt granulation granules may be less than 1000 μm.

[0060] The third aspect of the present invention provides an oral administration delivery preparation kit, the oral administration delivery preparation kit comprising an oral administration delivery device and the drug preparation as described above; the drug preparation is provided in the oral delivery device in the space that carries the drug.

[0061] In the present invention, the oral delivery device can significantly improve the dysphagia problem of patients, especially improve the dysphagia of Parkinson's patients in the off-phase state. It does not need to be prepared in advance when used, and the drug composition carried by it has a faster dissolution rate, which is of great significance for effectively relieving the off-phase state of Parkinson's patients. The hot-melt granules are filled in the oral drug delivery device. The preparation has higher stability and can reduce the degradation product DHPA and genotoxic impurity hydrazine produced during the storage process of the preparation.

[0062] Preferably, the filling amount of the pharmaceutical preparation is 50-1000 mg.

[0063] Preferably, the pharmaceutical preparation is carbidopa granules, comprising 25 mg carbidopa, 100 mg levodopa, 66.9 mg hot melt adhesive, 54.6 mg low-substituted hydroxypropyl cellulose and 113.3 mg mannitol.

[0064] Wherein, the oral administration delivery device It is an existing commercially available oral drug delivery device, which can be an oral drug delivery device protected in the Chinese utility model authorized patent CN201921652286.6, and any of the products in Examples 1-9 recorded therein can be used in the present invention; at the same time, similar oral drug delivery devices that can achieve the same effect can also be used. Generally speaking, it can include five components, namely, high-density polyethylene (HDPE) medicinal Cap, Polypropylene (PP) for medical use Straws, high density polyethylene (HDPE) for medical use Filter housing body, polypropylene (PP) meltblown nonwoven fabric disc and high-density polyethylene (HDPE) pharmaceutical Filter housing cap bottom piece.

[0065] Wherein, the high density polyethylene (HDPE) is medicinal Filter housing body, polypropylene (PP) meltblown nonwoven fabric disc and high-density polyethylene (HDPE) pharmaceutical The filter housing cap bottom piece is assembled to form Filter; the polypropylene (PP) medicinal Straw and After filter assembly The particles are filled and stored in the The main body is made of high-density polyethylene (HDPE) Cap seal.

[0066] Each of the oral delivery preparation sets may further include a packaging layer for sealing the oral delivery device.

[0067] Preferably, the packaging layer is a polyester / aluminum / polyethylene composite film bag.

[0068] Preferably, a desiccant is further provided in the packaging layer, and the desiccant is a bagged desiccant, more preferably a 0.25 g bagged desiccant.

[0069] The fourth aspect of the present invention also provides a use of the pharmaceutical composition as described above, wherein the active pharmaceutical ingredients are carbidopa and levodopa, in the preparation of a drug for emergency or intermittent treatment of Parkinson's disease in the off phase.

[0070] The fifth aspect of the present invention also provides a method for preparing the pharmaceutical preparation as described above, which is a hot melt granulation method, which comprises the following steps: crushing the hot melt adhesive to obtain a powder, mixing it with the active pharmaceutical ingredient, disintegrant and filler (when no disintegrant and filler are included, no addition is made), hot melt granulation, and then evenly mixing it with the remaining combination of the pharmaceutical composition, and sieving to obtain the powder.

[0071] In the present invention, the pharmaceutical preparation prepared by the hot melt granulation method can significantly improve the compatibility of the components of the pharmaceutical composition, further promote rapid release and improve stability, and reduce DHPA and genotoxic impurity hydrazine generated during the production process.

[0072] Wherein, the particle size of the powder may be less than 40 meshes.

[0073] The temperature of the hot melt granulation may be 50-100°C, preferably 55-80°C, such as 60°C, 70°C or 80°C.

[0074] For example, the preparation method comprises the following steps: hot melt granulation is performed using a twin-screw extruder, the screw combination adopts a standard configuration, the granulation temperature is 60-90°C, preferably 60-70°C, the screw speed is 200rpm, the feed speed is 30rpm, and the prepared particles are passed through a 20-mesh screen to obtain product particles; or, granulation is performed in a high shear granulator with a heating jacket, the granulation temperature is 70-80°C, until uniform particles are formed, and the hot melt particles are passed through a 20-mesh screen to obtain product particles; or, a square cone mixer is used, and mixing is performed at a speed of 10rpm for 10 minutes to obtain product particles.

[0075] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0076] The reagents and raw materials used in the present invention are commercially available.

[0077] The positive and progressive effects of the present invention are:

[0078] The present invention uses a specific amount of a specific adhesive, a specific amount of an active pharmaceutical ingredient, and a specific hot-melt granulation process to prepare a pharmaceutical composition. The obtained pharmaceutical composition can achieve rapid release of the active pharmaceutical ingredient, and can also ensure good raw material compatibility and improve the stability of the active pharmaceutical ingredient. In particular, the product whose active pharmaceutical ingredients are carbidopa and levodopa is particularly suitable for improving the rapid release and stability of the active pharmaceutical ingredient used for emergency or intermittent treatment of Parkinson's disease. The obtained pharmaceutical composition can significantly improve the swallowing of patients with dysphagia through a specific oral delivery device, thereby improving the treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1The figure shows the product appearance of the oral administration delivery preparation set of the present invention.

[0080] 1-Oral drug delivery device 2-Drug particles.

[0081] Figure 2 This is a schematic diagram of the use of the oral administration delivery preparation kit of the present invention, Figure 2 a is a schematic diagram of the oral administration delivery preparation set just inserted into water, Figure 2 b is a schematic diagram of particles being sucked through a straw in the oral administration delivery formulation set.

[0082] Figure 3 This is the drug-time curve of levodopa in the card-levodopa granule preparation of Example 4 of the present invention and the commercially available card-levodopa tablets.

[0083] Figure 4 for Figure 3 Effect Example 4 of the Invention Locally amplified drug-time curves of levodopa in the card-levodopa granule preparation and the commercially available card-levodopa tablets. DETAILED DESCRIPTION

[0084] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0085] Example 1

[0086] According to the prescription in Table 1, card left double dopa granules were prepared by the following hot melt granulation process:

[0087] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder.

[0088] Carbidopa, levodopa and other auxiliary materials were added into a square cone mixer, mixed at a speed of 10 rpm for 10 minutes, and discharged.

[0089] The mixed materials are placed in a high shear granulator with a heating jacket for granulation at a granulation temperature of 70-80°C until uniform granules are formed. The hot melt granules are passed through a 20-mesh sieve to obtain carbazodopamine granules.

[0090] Table 1. Specific component information of Example 1

[0091]

[0092]

[0093] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (6.9%) carbidopa.

[0094] Example 2

[0095] According to the prescription in Table 2, card left double dopa granules were prepared by the following hot melt granulation process:

[0096] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder.

[0097] Carbidopa, levodopa API and excipients were added into a square cone mixer, mixed at a speed of 10 rpm for 10 minutes, and discharged.

[0098] A twin-screw extruder is used for hot melt granulation. The screw combination adopts a standard configuration, the granulation temperature is 60-70°C, the screw speed is 200rpm, and the feed speed is 30rpm. The obtained granules are passed through a 20-mesh screen to obtain cardiodidopa granules.

[0099] Table 2. Specific component information of Example 2

[0100] Components mg / piece wt% Carbidopa monohydrate 27.0* 7.5 Levodopa 100.0 27.6 Mannitol 113.3 31.3 Poloxamer 407 66.9 18.5 Low substituted hydroxypropyl cellulose 54.6 15.1 total 361.8 100.0

[0101] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (6.9%) carbidopa.

[0102] Example 3

[0103] According to the prescription in Table 3, carbocycline levodopa granules were prepared by the hot melt granulation process of Example 2.

[0104] Table 3. Specific component information of Example 3

[0105] Components mg / piece wt% Carbidopa monohydrate 27.0* 10.6 Levodopa 100.0 39.3 Mannitol 68.8 27.1 Poloxamer 407 33.0 13.0 Low substituted hydroxypropyl cellulose 25.4 10.0 total 254.2 100.0

[0106] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (9.8%) carbidopa.

[0107] Example 4

[0108] According to the prescription in Table 4, 0.5% magnesium stearate and 0.5% natural orange flavor were added to the granules of Example 3, and then placed in a square cone mixer and mixed at 10 rpm for 10 min to obtain carbodidopa granules.

[0109] Table 4. Specific component information of Example 4

[0110] Components mg / piece wt% Carbidopa monohydrate 27.0* 10.5 Levodopa 100.0 39.0 Mannitol 68.8 26.8 Poloxamer 407 33.0 12.8 Low substituted hydroxypropyl cellulose 25.4 9.9 Magnesium Stearate 1.28 0.5 Natural orange flavor 1.28 0.5 total 256.7 100.0

[0111] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (9.7%) carbidopa.

[0112] Example 5

[0113] According to the prescription in Table 5, the card left double dopa granules were prepared by the following hot melt granulation process:

[0114] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder.

[0115] Carbidopa, levodopa and other auxiliary materials were added into a square cone mixer, mixed at a speed of 10 rpm for 10 minutes, and discharged.

[0116] A twin-screw extruder is used for hot melt granulation. The screw combination adopts a standard configuration, the granulation temperature is 70-90°C, the screw speed is 200rpm, and the feed speed is 10rpm. The obtained granules are passed through a 20-mesh screen to obtain cardiodidopa granules.

[0117] Table 5. Specific component information of Example 5

[0118] Components mg / piece wt% Carbidopa monohydrate 27.0* 2.70 Levodopa 100.0 10.0 lactose 493.0 49.3 Poloxamer 407 230.0 23.0 Low substituted hydroxypropyl cellulose 140.0 14.0 Aspartame 5.0 0.5 Colloidal Silica 5.0 0.5 total 1000.0 100.0

[0119] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (2.5%) carbidopa.

[0120] Example 6

[0121] According to the prescription in Table 6, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0122] Table 6. Specific component information of Example 6

[0123]

[0124]

[0125] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (3.0%) carbidopa.

[0126] Example 7

[0127] According to the prescription in Table 7, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0128] Table 7. Specific component information of Example 7

[0129] Components mg / piece wt% Carbidopa monohydrate 27.0* 4.4 Levodopa 100.0 16.4 Mannitol 302.4 49.6 Poloxamer 407 39.6 6.5 sucrose 28.7 4.7 Crospovidone 105.5 17.3 Apple flavor 1.8 0.3 Colloidal Silica 4.9 0.8 total 609.9 100.0

[0130] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (4.1%) carbidopa.

[0131] Example 8

[0132] According to the prescription in Table 8, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0133] Table 8. Specific component information of Example 8

[0134] Components mg / piece wt% Carbidopa monohydrate 27.0* 6.5 Levodopa 100.0 24.0 lactose 62.5 15.0 Mannitol 141.1 33.9 Poloxamer 407 86.0 20.6 total 416.6 100.0

[0135] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (6.0%) carbidopa.

[0136] Example 9

[0137] According to the prescription in Table 9, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0138] Table 9. Specific component information of Example 9

[0139] Components mg / piece wt% Carbidopa monohydrate 27.0* 7.5 Levodopa 100.0 27.6 Poloxamer 407 108.2 29.9 sucrose 18.0 5.0 Croscarmellose Sodium 105.0 29.0 Magnesium Stearate 3.6 1.0 total 361.8 100.0

[0140] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (6.9%) carbidopa.

[0141] Example 10

[0142] According to the prescription in Table 10, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0143] Table 10. Specific component information of Example 5

[0144] Components mg / piece wt% Carbidopa monohydrate 13.5* 0.675 Levodopa 50.0 2.5 Mannitol 986.5 49.325 Poloxamer 407 500.0 25.0 Croscarmellose Sodium 450.0 22.5 total 2000.0 100.0

[0145] Note: * is the amount of carbidopa monohydrate, equivalent to 12.5 mg (0.625%) carbidopa.

[0146] Embodiment 11

[0147] According to the prescription in Table 11, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0148] Table 11. Specific component information of Example 11

[0149] Components mg / piece wt% Carbidopa monohydrate 27.0* 8.4 Levodopa 100.0 31.2 Mannitol 103.8 32.4 Poloxamer 407 52.9 16.5 Croscarmellose Sodium 36.9 11.5 total 320.6 100.0

[0150] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (7.8%) carbidopa.

[0151] Example 12

[0152] According to the prescription in Table 12, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0153] Table 12. Specific component information of Example 5

[0154] Components mg / piece wt% Carbidopa monohydrate 27.0* 9.7 Levodopa 100.0 36.0 Mannitol 67.5 24.3 Poloxamer 407 50.0 18.0 Low substituted hydroxypropyl cellulose 33.3 12.0 total 277.8 100.0

[0155] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (9.0%) carbidopa.

[0156] Embodiment 13

[0157] According to the prescription in Table 13, carbocycline levodopa granules were prepared by the hot melt granulation process of Example 5.

[0158] Table 13. Specific component information of Example 13

[0159] Components mg / piece wt% Carbidopa monohydrate 27.0* 10.4 Levodopa 100.0 38.4 lactose 47.4 18.2 Poloxamer 407 39.0 15.0 Low substituted hydroxypropyl cellulose 46.8 18.0 total 260.2 100.0

[0160] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (9.6%) carbidopa.

[0161] Embodiment 14

[0162] According to the prescription in Table 14, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0163] Table 14. Specific component information of Example 14

[0164] Components mg / piece wt% Carbidopa monohydrate 27.0* 10.4 Levodopa 100.0 38.4 Mannitol 60.4 23.2 Poloxamer 407 41.6 16.0 Low substituted hydroxypropyl cellulose 31.2 12.0 total 260.2 100.0

[0165] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (9.6%) carbidopa.

[0166] Embodiment 15

[0167] According to the prescription in Table 15, the carbocycline granules were prepared by the hot melt granulation process of Example 5.

[0168] Table 15. Specific component information of Example 15

[0169] Components mg / piece wt% Carbidopa monohydrate 27.0* 10.4 Levodopa 100.0 38.4 Mannitol 60.4 23.2 Poloxamer 407 59.8 23.0 Low substituted hydroxypropyl cellulose 13.0 5.00 total 260.2 100.0

[0170] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (9.6%) carbidopa.

[0171] Example 16

[0172] According to the prescription in Table 16, apixaban granules were prepared by the following hot melt granulation process:

[0173] Poloxamer 188 was crushed and passed through an 80-mesh sieve to obtain poloxamer 188 powder.

[0174] Add the excipients except apixaban to the square cone mixer, mix at a speed of 10 rpm for 5 minutes, and discharge. Then, add the API and the remaining excipients in a 1:2 ratio (i.e., apixaban (or material containing apixaban): excipients), mix at a speed of 10 rpm for 5 minutes after each addition of the excipients, and mix at a speed of 10 rpm for 15 minutes after the last addition of the excipients.

[0175] A twin-screw extruder was used for hot melt granulation. The screw combination was of standard configuration, the granulation temperature was 70-80°C, the screw speed was 400rpm, and the feed speed was 40rpm. The obtained granules were passed through a 20-mesh sieve to obtain apixaban granules.

[0176] Table 16. Specific component information of Example 16

[0177] Components mg / piece wt% Apixaban 2.5 2.5 Lactose Monohydrate 52.5 52.5 Poloxamer 188 25.0 25.0 Croscarmellose Sodium 20.0 20.0 total 100.0 100.0

[0178] Embodiment 17

[0179] According to the prescription in Table 17, apixaban granules were prepared by the following hot melt granulation process:

[0180] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder.

[0181] Add the excipients except apixaban to the square cone mixer, mix at a speed of 10 rpm for 5 minutes, and discharge. Then, add the API and the remaining excipients in a 1:2 ratio (i.e., apixaban (or material containing apixaban): excipients), mix at a speed of 10 rpm for 5 minutes after each addition of the excipients, and mix at a speed of 10 rpm for 15 minutes after the last addition of the excipients.

[0182] A twin-screw extruder was used for hot melt granulation. The screw combination was of standard configuration, the granulation temperature was 70-80°C, the screw speed was 300 rpm, and the feed speed was 40 rpm. The obtained granules were passed through a 20-mesh sieve to obtain apixaban granules.

[0183] Table 17. Specific component information of Example 17

[0184] Components mg / piece wt% Apixaban 2.5 2.5 Lactose Monohydrate 64.5 64.5 Poloxamer 407 18.0 18.0 Croscarmellose Sodium 15.0 15.0 total 100.0 100.0

[0185] Embodiment 18

[0186] The card levodopa granules obtained in Example 1 were filled into the following manner: Figure 1 shown In the case of Deka Levodopa granules:

[0187] Loading polypropylene meltblown nonwoven discs into high-density polyethylene pharmaceutical The filter housing cap bottom sheet is then filled with high-density polyethylene medicinal The filter housing and the bottom sheet are buckled together to form Filter; Polypropylene for medicinal use Straw and After filter assembly The main body; fill the hot melt granulated particles into The main body is made of high-density polyethylene Cap seal.

[0188] Use polyester / aluminum / polyethylene composite film bags to pack the above-mentioned Seal the bag and add a bag of 0.25g desiccant into the bag.

[0189] like Figure 2 As shown, when the product of this embodiment is used, there is no need to prepare it in advance. Just open the polyester / aluminum / polyethylene composite film bag, remove the cap, and place it in water, milk or juice. When the patient inhales it, the medicine is instantly dispersed in the liquid and then swallowed.

[0190] Embodiment 19

[0191] The apixaban granules obtained in Example 16 were filled into Obtain apixaban preparations.

[0192] Embodiment 20

[0193] According to the prescription in Table 18, the hot melt adhesive poloxamer 407 was used to prepare the card left double dopa granules by the following hot melt granulation process:

[0194] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder.

[0195] Carbidopa, levodopa and other auxiliary materials were added into a square cone mixer, mixed at a speed of 10 rpm for 10 minutes, and discharged.

[0196] A twin-screw extruder is used for hot melt granulation. The screw combination adopts a standard configuration, the granulation temperature is 70-90°C, the screw speed is 200rpm, and the feed speed is 10rpm. The obtained granules are passed through a 20-mesh screen to obtain cardiodidopa granules.

[0197] Comparative Examples 1-3

[0198] According to the prescription in Table 18, hot melt adhesives glyceryl behenate 888ATO and polyethylene glycol-32 stearate were used respectively to prepare granules using the hot melt granulation process in Example 20.

[0199] Table 18. Specific component information of Example 20 and Comparative Examples 1-3

[0200]

[0201] Note: * is the amount of carbidopa monohydrate, equivalent to 25 mg (6.9%) carbidopa.

[0202] Effect Example 1 Dissolution Test Detection

[0203] For the carbidopa granules of embodiment 1-3, the dissolution method adopts USP method 1 (basket method), rotation speed 50rpm, dissolution medium is 0.1N hydrochloric acid of pH1.0, volume is 750mL, and sampling is detected at 5, 10, 15, 20 and 30 minutes respectively. The dissolution results of embodiment 1-3 are shown in Table 19-21, and the release of carbidopa and levodopa is rapid, and the 5min dissolution rate is greater than 90%. For the apixaban granules of embodiment 16 and 17, the dissolution method adopts USP method 2 (paddle method), rotation speed 75rpm, dissolution medium is 0.05M sodium phosphate buffer containing 0.05% SLS of pH=6.8, volume is 900mL, and sampling is detected at 5, 10, 20, 30 and 45 minutes respectively. The dissolution results of embodiment 16 and 17 are shown in Table 22, and the dissolution rate of 5min apixaban is greater than 85%.

[0204] For the carbidopa granules of Example 20 and Comparative Examples 2-3, the dissolution method adopts USP Method 1 (basket method), the rotation speed is 50 rpm, the dissolution medium is 0.1N hydrochloric acid with pH 1.0, the volume is 750 mL, and samples are taken for testing at 5, 10, 15, 20 and 30 minutes respectively. The dissolution results are shown in Tables 23 and 24. In Example 20, the release of carbidopa and levodopa is rapid, and the 5-min dissolution rate is greater than 90%, while the release of levodopa and carbidopa in Comparative Examples 2 and 3 is slow, and the 5-min dissolution rates are 23.4% and 24.5% (Comparative Example 2); 70.0% and 68.4% (Comparative Example 3), respectively.

[0205] Table 19. Dissolution test results of the card-left double dopa granules obtained in Example 1

[0206] Sampling points / min Carbidopa dissolution % Levodopa dissolution % 5 97.5 99.8 10 97.7 100.1 15 97.7 100.2 20 97.5 100.1 30 97.7 100.3

[0207] Table 20. Dissolution test results of the card-left double dopa granules obtained in Example 2

[0208] Sampling points / min Carbidopa dissolution % Levodopa dissolution % 5 99.1 98.8 10 100.0 99.9 15 99.8 99.9 20 100.0 100.0 30 100.0 100.0

[0209] Table 21. Dissolution test results of the card-left double dopa granules obtained in Example 3

[0210] Sampling points / min Carbidopa dissolution % Levodopa dissolution % 5 98.2 100.8 10 98.6 101.5 15 98.3 101.3 20 98.4 101.6 30 98.7 101.6

[0211] Table 22. Dissolution test results of the apixaban granules obtained in Example 16 and Example 17

[0212]

[0213] Table 23. Levodopa dissolution of the levodopa granules obtained in Example 20 and Comparative Examples 2-3

[0214]

[0215] Table 24. Carbidopa dissolution of carbidopa granules obtained in Example 20 and Comparative Examples 2-3

[0216]

[0217] Effect Example 2 Compatibility of raw materials and stability of preparations of carbodidopa granules

[0218] A compatibility study of raw and excipients was conducted on the formulation of carbidopa levodopa granules at 40°C / RH75%. It was found, as shown in Tables 25 and 26, that among all the excipients, poloxamer 407 had poor compatibility with both carbidopa and levodopa APIs. After preparation into the preparation, there was a risk of exceeding the stability limit for related substances.

[0219] The carbidopa granules obtained in Example 18 were placed under 40°C / RH75%, and sampled for testing at 1 month and 6 months, respectively, and the test indicators were dissolution, related substances and hydrazine content. The results are shown in Table 27. After 6 months of accelerated sampling, the dissolution of carbidopa granules did not change significantly, the related substances were far below the limit, and the hydrazine content was extremely low, far below the limit of 50 ppm. It is shown that the use of hot melt granulation technology and moisture-proof packaging can significantly improve the compatibility of carbidopa and levodopa with poloxamer 407 and increase the stability of the preparation.

[0220] Table 25. Compatibility study results of raw materials of carbodidopa granules 1

[0221]

[0222] Table 26. Compatibility study results of raw materials of carbodidopa granules 2

[0223]

[0224] Table 27. Stability test results of the carbodidopa granules of Example 18

[0225]

[0226] Hydrazine is a genotoxic substance, and its content in preparations should be strictly controlled. The hydrazine content of commercially available compound preparations containing levodopa and carbidopa is often high during product storage and use, posing a greater safety hazard to patients. Through testing, it was found that the hydrazine content of samples of the commercially available carbidopa / levodopa preparations Sinemet CR and Rytary was 29.6ppm and 72.3ppm, respectively; while the carbidopa granules using the poloxamer 407 formulation and hot-melt granulation process have good stability and an extremely low hydrazine content of only 3-5ppm, which is a significant advantage.

[0227] Effect Example 3 Granulation Process Phenomenon

[0228] The granulation process phenomena of the granules obtained in Example 20 and Comparative Examples 1-3 are shown in Table 28. When the amount of hot melt adhesive used is 31% (Comparative Example 1), the granules are in a lumpy shape after granulation, and the texture is hard after cooling, making it difficult to granulate.

[0229] Table 28. Process phenomena of Example 20 and Comparative Examples 1-3

[0230] Process phenomenon Embodiment 20 The granules after granulation are crisp and easy to re-granulate Comparative Example 1 After granulation, the pellets are lumps (excessive binder), and the texture is hard after cooling, making it difficult to granulate. Comparative Example 2 The granules after granulation are crisp and easy to re-granulate Comparative Example 3 The granules after granulation are crisp and easy to re-granulate

[0231] Effect Example 4 Bioequivalence Study

[0232] A bioequivalence study was conducted in healthy adult subjects (N=12) under fasting conditions using carbidopa granules (25 mg / 100 mg, same process and packaging as Example 18, different batches) and carbidopa tablets (25 mg / 100 mg, IR, produced by Mylan, commercially available).

[0233] An open-label, parallel, randomized, two-treatment, two-cycle, two-sequence, single-dose, crossover phase I clinical study showed that, expressed as mean, the peak time of levodopa in carbo-levodopa granules and carbo-levodopa tablets in humans was t max The peak time of levodopa in human body in carbazodopamine granules and carbazodopamine tablets was t max The former was 30.0 min and 52.5 min respectively, and the latter was 22.5 min faster (Table 29 and Figure 3-4 ); This result is consistent with the trend of in vitro release (Table 30).

[0234] Table 29. Pharmacokinetic data of carbohydidine granules and carbohydidine tablets in healthy adult subjects under fasting conditions

[0235]

[0236] Table 30. In vitro release data of carbodiol granules and carbodiol tablets

[0237]

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the following components: an active pharmaceutical ingredient and a hot melt adhesive; wherein, The mass percentage of the active pharmaceutical ingredient is 0.3%-50%; The hot melt adhesive is poloxamer P188 and / or poloxamer P407; The mass percentage of the hot melt adhesive in the pharmaceutical composition is 5%-30%.

2. The pharmaceutical composition according to claim 1, characterized in that The active pharmaceutical ingredients include, but are not limited to, one or more of the following: dopaminergic agents, anti-erectile dysfunction agents, antiviral agents, gastric acid secretion inhibitors, anticoagulants, antifungal agents, antibacterial agents, antiasthmatic agents, antidepressants, antiepileptic agents, antiallergic agents, antihypertensive agents, antischizophrenia agents, analgesics, anti-inflammatory agents, antiemetics and antitussives; preferably, the active pharmaceutical ingredients are poorly soluble and easily degradable drugs, poorly soluble and non-easily degradable drugs, non-poorly soluble and easily degradable drugs or non-poorly soluble and non-easily degradable drugs, wherein, preferably, The poorly soluble and easily degradable drug is selected from the group consisting of: ritonavir, vonoprazan, rivaroxaban, posaconazole, cefdinir, cefixime, cefuroxime axetil, clarithromycin, linezolid and duloxetine; The poorly soluble and non-easily degradable drug is selected from the group consisting of: apixaban, tadalafil, dapoxetine, contizolamide, olanzapine, aripiprazole, quetiapine fumarate, zolmitriptan, rizatriptan, almotriptan, naratriptan, frovatriptan, eletriptan and verapamil; The non-poorly soluble and easily degradable drug is selected from the group consisting of carbidopa, oseltamivir phosphate, favipiravir, monolavir, deuterated remdevir hydrobromide, namatevir, cefaclor, cefprozil, amoxicillin, montelukast sodium, levetiracetam and desloratadine; The non-poorly soluble and non-easily degradable drug is selected from the group consisting of: levodopa, sildenafil, vardenafil, tegrassen, fluconazole, escitalopram oxalate, levocetirizine, amlodipine, ketorolac tromethamine and diphenhydramine.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition meets one or more of the following conditions: The mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 0.3%-40%; The mass percentage of the hot melt adhesive in the pharmaceutical composition is 14%-25%; The pharmaceutical composition is a pharmaceutical composition in the form of hot-melt granulated particles; The pharmaceutical composition does not contain an effervescent system; The pharmaceutical composition may further comprise one or more of the following components: a disintegrant, a filler, a lubricant, a glidant, a flavoring agent, and an aromatic agent.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition meets one or more of the following conditions: The disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate and cross-linked polyvinylpyrrolidone, preferably cross-linked sodium carboxymethyl cellulose and / or low-substituted hydroxypropyl cellulose; The mass percentage of the disintegrant in the pharmaceutical composition is 0%-30%, preferably 10%-22%; The filler is mannitol and / or lactose; The mass percentage of the filler in the pharmaceutical composition is 0%-50%; The lubricant is one or more of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, magnesium silicate and calcium silicate; The mass percentage of the lubricant in the pharmaceutical composition is 0%-2%; The glidant is talc and / or colloidal silicon dioxide; The mass percentage of the glidant in the pharmaceutical composition is 0%-2%; The flavoring agent is one or more of sucrose, maltose, stevioside, mannitol, erythrose and aspartame, preferably one or more of stevioside, mannitol, erythrose and aspartame; The mass percentage of the flavoring agent in the pharmaceutical composition is 0%-5%; The aromatic agent is an essence, preferably a natural essence; The mass percentage of the aromatic in the pharmaceutical composition is 0%-3%.

5. The pharmaceutical composition according to claim 1, characterized in that The active pharmaceutical ingredients are carbidopa and levodopa; the mass percentage of carbidopa in the pharmaceutical composition is 0.5%-15%, preferably 2%-15%; the mass percentage of levodopa in the pharmaceutical composition is 2%-48%, preferably 5%-48%; the mass ratio of carbidopa to levodopa is 1:1-1:24; Preferably, the pharmaceutical composition comprises the following components in mass percentage: 0.5%-10% carbendazim, 2%-40% levodopa, 6%-30% hot melt adhesive and 0-30% disintegrant; More preferably, the pharmaceutical composition comprises the following components in mass percentage: 5.7%-8.3% carbidopa, 23%-33% levodopa, 15%-25% hot melt adhesive, 10.1%-20.1% low-substituted hydroxypropyl cellulose and 23.2%-33.2% mannitol; or, the pharmaceutical composition comprises 6.5%-7.5% carbidopa, 25.1%-30.1% levodopa, 17.5%-22.5% hot melt adhesive, 13.5%-18.5% low-substituted hydroxypropyl cellulose and 27.0-32.0% mannitol.

6. A pharmaceutical preparation, characterized in that It is a hot-melt granulation granule, and the pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 1 to 5; preferably, the particle size of the hot-melt granule is less than 1000 μm; preferably, the pharmaceutical preparation is carbidopa granules, which contain 25 mg carbidopa, 100 mg levodopa, 66.9 mg hot-melt adhesive, 54.6 mg low-substituted hydroxypropyl cellulose and 113.3 mg mannitol.

7. An oral delivery preparation kit, characterized in that: The oral administration delivery preparation kit includes an oral administration delivery device and the pharmaceutical preparation according to claim 6; wherein the pharmaceutical preparation is provided in the oral delivery device In the space that carries the drug; Preferably, the filling amount of the pharmaceutical preparation is 50-1000 mg; Preferably, the pharmaceutical preparation is carbidopa granules, which contain 25 mg carbidopa, 100 mg levodopa, 66.9 mg hot melt adhesive, 54.6 mg low-substituted hydroxypropyl cellulose and 113.3 mg mannitol.

8. The oral delivery preparation kit according to claim 7, characterized in that: Each of the oral administration delivery preparation sets further comprises a packaging layer for sealing the oral administration delivery device. Preferably, the packaging layer is a polyester / aluminum / polyethylene composite film bag; Preferably, a desiccant is further provided in the packaging layer, and the desiccant is a bagged desiccant, more preferably a 0.25 g bagged desiccant.

9. Use of the pharmaceutical composition according to claim 5 in the preparation of a medicament for emergency or intermittent treatment of Parkinson's disease in the off phase.

10. A method for preparing the pharmaceutical preparation according to claim 6, characterized in that: The preparation method is a hot melt granulation method, which comprises the following steps: crushing the hot melt adhesive to obtain powder, mixing it with the active pharmaceutical ingredient, disintegrant and filler, hot melt granulation, and then uniformly mixing it with the remaining combination of the pharmaceutical composition and sieving to obtain the powder.

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