Pharmaceutical composition, preparation containing the same, kit, and method of manufacturing and use thereof

Abstract

This invention discloses a pharmaceutical composition, a formulation containing the same, a kit, and a method for manufacturing and using the same. The pharmaceutical composition comprises an active pharmaceutical ingredient and a hot-melt adhesive; the mass percentage of the active pharmaceutical ingredient is 0.3% to 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% to 30%. The pharmaceutical composition, and the formulations and kits containing the same, can rapidly release the active pharmaceutical ingredient to accelerate the onset of action, improve the stability of the active pharmaceutical ingredient, further improve patient swallowability, and enhance patient compliance during actual administration.

Description

Detailed Description of the Invention

[0001] This application claims the priority of Chinese Patent Application No. 2023108219336 with a filing date of July 5, 2023, and Chinese Patent Application No. 2024101572389 with a filing date of February 2, 2024. This application incorporates the full text of the above-mentioned Chinese patent applications by reference.

[0002] [Technical Field] The present invention relates to pharmaceutical compositions, formulations containing the same, kits, and methods for their manufacture and use. [Background Art] In certain disease areas such as movement disorders, heart disease, hypertension, asthma, pain, bleeding, bacterial or fungal infections, allergies, influenza, COVID-19, male erectile dysfunction, gastroesophageal reflux disease, etc., in order to rapidly relieve and improve the symptoms of the disease, the drug needs to exert its effect promptly after administration.

[0003] In the case of oral formulations, since there is no problem of release, solution formulations usually exert their effects relatively quickly after administration. However, in the case of active pharmaceutical ingredients that are sensitive to moisture and have low solubility, solid dosage forms are more advantageous.

[0004] Among oral solid formulations, granules, dispersible tablets, effervescent tablets, orally disintegrating tablets, and orally dissolving films can achieve the characteristic of rapid release of the active drug ingredient. In the case of children, the elderly, and patients with difficulty in swallowing, the above-mentioned formulations are more advantageous for swallowing and improve medication adherence, but they bring problems of taste and stability.

[0005] Particularly in the field of Parkinson's disease, the clinical needs of patients for the rapid onset of drug effects and ease of swallowing are as follows. Parkinson's disease (PD), also known as paralytic tremor, is one of the most common neurodegenerative diseases, primarily beginning between the ages of 50 and 65. Epidemiological studies indicate that there are over 10 million people with Parkinson's disease worldwide, with approximately 3 million in China. In China, the number of new infections exceeds 100,000 annually, and in recent years, the age of onset has tended to become younger. Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease.

[0006] Parkinson's disease is a progressive disorder caused by the loss of dopamine-producing cells in the brain. Currently, because the pathogenesis is unknown, there are no drugs that can cure the disease or stop its progression, and all medications are used only to suppress symptoms. In people with Parkinson's disease, dopamine production in the brain is reduced. Dopamine is an endogenous substance present in the brain and spinal cord that helps brain nerve cells properly control motor functions. When dopamine levels in the brain decrease, symptoms of Parkinson's disease appear, such as tremors, muscle rigidity, bradykinesia, or freeze episodes (OFF seizures) such as difficulty walking.

[0007] Dysphagia (difficulty swallowing) is common in Parkinson's disease patients. According to one epidemiological study, 11% to 81% of Parkinson's disease patients experience dysphagia, and the incidence of lung infections due to dysphagia reaches as high as 91.7% in regional statistics (Fatemeh Rajati et al. The global prevalence of oropharyngeal dysphagia in different populations: a systematic review and meta-analysis. Journal of Translational Medicine. 2022, 20:175. https: / / doi.org / 10.1186 / s12967-022-03380-0). Dysphagia is a common symptom in Parkinson's disease patients, causing many inconveniences in their daily lives, such as eating and taking medication, and seriously impacting their quality of life, being particularly severe when they are "off" (unresponsive).

[0008] As Parkinson's disease progresses and levodopa levels decline, patients may experience freezing episodes (OFF seizures) characterized by sudden onset and short duration, making it difficult for them to move forward effectively. Some patients may remain motionless for several seconds to tens of minutes after standing up. Freezing gait is a major cause of physical injury and disability in Parkinson's disease patients and also increases the financial burden on their families. If a freezing episode occurs while a patient is driving or crossing the road, it can lead to a serious car accident. Studies have shown that freezing gait occurs in 7% of patients in the early stages of idiopathic Parkinson's disease (Li Yan, Wang Lijuan, Zhang Yuhu. Research progress on freezing of gait[J]. Journal of Clinical Neurology. 2016, 29(2): 149-151.). Approximately 50% of patients with a history of Parkinson's disease of more than 10 years have experienced freezing gait. As the disease progresses, the frequency and duration of seizures increase.

[0009] In summary, improving patients' swallowing difficulties, enhancing medication compliance, and designing a drug delivery system with a rapid onset of action are effective solutions for alleviating freezing episodes in Parkinson's disease. Patients can rapidly increase their levodopa blood levels by taking the medication themselves when signs of a freezing episode appear or in the early stages of a freezing episode, thus avoiding the risks of sudden motor impairment and minimizing the impact on their daily lives.

[0010] Currently available products include APOKYN, KYNMOBI, and INBRIJA. Of these, APOKYN is an apomorphine hydrochloride injection that is extremely inconvenient to use as it is administered subcutaneously 3 to 5 times a day. After product improvements, the injection was changed to a sublingual film formulation (US 10420763 B2), i.e., KYNMOBI. Sublingual administration significantly improved medication compliance, but the incidence of side effects such as nausea remains high. INBRIJA is the first inhaled levodopa product developed using Acorda's proprietary ARCUS platform (US8404276B2), which delivers a dry levodopa powder formulation to the patient's lungs in the precise dose, avoiding oral swallowing difficulties. However, using INBRIJA requires the administration of two capsules per treatment. One capsule must be inserted into the inhaler before use, the capsule shell must be removed after administration, and the second capsule inserted and administered again. This administration step is very cumbersome for patients in the OFF state of Parkinson's disease. At the same time, this product has a high incidence of side effects such as cough, nausea, and upper respiratory tract infections (>5%), and is not suitable for patients with lung diseases such as asthma or chronic obstructive pulmonary disease (COPD).

[0011] Carbidopa is an aromatic amino acid decarboxylase inhibitor and is typically used in combination with levodopa (an aromatic amino acid and dopamine precursor drug). Carbidopa enhances levodopa's half-life and bioavailability by inhibiting peripheral decarboxylation, thereby promoting the transport of more levodopa to the brain. Carbidopa is readily broken down by external factors, producing degradation products such as DHPA (dihydroxyphenylacetone) and hydrazine, and because hydrazine is a genotoxic substance, its content in formulations is strictly controlled. Commercially available combination formulations containing levodopa and carbidopa often have high hydrazine content during storage and use, posing a significant safety risk to patients.

[0012] Voriconazole is a broad-spectrum triazole antifungal agent indicated for the treatment of invasive aspergillosis, and serious infections caused by Candida, actinomycetes, and Fusarium species, making it one of the most important drugs for treating invasive fungal diseases. Authoritative Chinese guidelines, such as the "Recommendations on the Diagnosis and Treatment of Invasive Fungal Diseases in Pediatric Hematological Disorders and Malignancies," recommend voriconazole for the treatment and prevention of invasive aspergillosis in children.

[0013] Currently, oral voriconazole formulations available domestically and internationally include tablets, dried suspensions, and capsules. Of these, the dried suspension has the advantage of being easy to administer and is suitable for children, the elderly, and other patients with swallowing difficulties. However, the voriconazole dried suspension (trade name VFEND®), an active pharmaceutical ingredient developed by Pfizer in the United States, lacks stability, has a complicated administration procedure, and may affect patient adherence to medication. The storage conditions for this drug are 2-8°C, and the entire contents of one bottle must be prepared as a dried suspension before use, but the suspension can only be stored for 14 days. Because the suspension must be administered using an oral syringe, it may cause drug phobia in pediatric patients.

[0014] Therefore, it is urgent to address the challenge of providing a drug formulation that is easy to take, releases the active ingredient quickly, and is highly stable. Developing voriconazole-containing formulations that are stable, easy to use, and improve patient compliance is essential.

[0015] [Overview of the prefecture] To solve the problems described above in the prior art, the present invention provides a pharmaceutical composition, a formulation containing the same, a kit, and a method for producing and using the same. The pharmaceutical composition, its formulation, and kit enable rapid release of the active pharmaceutical ingredient, have good drug stability, improve patient swallowing, require no prior preparation before administration, are more convenient to use, and offer significant advantages in terms of medication compliance.

[0016] To achieve the above objective, the present invention employs the following technical solutions. The first aspect of the present invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, wherein, The mass percentage of the aforementioned active pharmaceutical ingredient is 0.3% to 63%. The aforementioned hot melt adhesive is Class A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407, Alternatively, a Class B hot melt adhesive: polyethylene glycol 6000 is selected.

[0017] The mass percentage of the Class A hot melt adhesive in the pharmaceutical composition is 5% to 30%. The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12% to 25%. The aforementioned pharmaceutical composition is a pharmaceutical composition in the form of hot-melt granulated granules.

[0018] The second aspect of the present invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, wherein, The mass percentage of the aforementioned active pharmaceutical ingredient is 0.3% to 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% to 30%.

[0019] The conditions for the pharmaceutical compositions in the first and second categories are as follows. In the present invention, the active pharmaceutical ingredient may include, but is not limited to, one or more of the following: dopamine agonists, erectile dysfunction treatments, antiviral drugs, gastric acid secretion inhibitors, anticoagulants, antifungal drugs, antibacterial drugs, antiasthmatic drugs, antidepressants, antiepileptic drugs, antiallergic drugs, antihypertensive drugs, antipsychotic drugs, analgesics, anti-inflammatory drugs, antiemetics, and antitussives.

[0020] Preferably, the active pharmaceutical ingredient is a poorly soluble and easily decomposable drug, a poorly soluble and non-easily decomposable drug, a non-poorly soluble and easily decomposable drug, or a non-poorly soluble and non-easily decomposable drug. Here, the poorly soluble and easily decomposable drug agent may be selected from ritonavir, vonoprazan, rivaroxaban, posaconazole, cefdinir, cefixime, cefuroxime axetil, clarithromycin, linezolid, and duloxetine.

[0021] Here, the poorly soluble and non-easily decomposable drug agent may be selected from apixaban, tadalafil, dapoxetine, contezolid, olanzapine, aripiprazole, quetiapine fumarate, zolmitriptan, rizatriptan, almotriptan, naratriptan, frovatriptan, eletriptan, and verapamil.

[0022] Here, the poorly soluble and non-easily decomposable drug agent may be selected from voriconazole. Here, the non-poorly soluble and easily decomposable drug agent may be selected from carbidopa, oseltamivir phosphate, favipiravir, molnupiravir, lumidavir hydrobromide, nirmatrelvir, cefaclor, cefprozil, amoxicillin, montelukast sodium, levetiracetam, and desloratadine.

[0023] Here, the non-poorly soluble and non-easily decomposable drug agent may be selected from levodopa, sildenafil, vardenafil, tegoprazan, fluconazole, escitalopram oxalate, levosetilidine, amlodipine, ketorolac tromethamine, and diphenhydramine.

[0024] In the present invention, the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition may be 0.3% to 40%. In the present invention, the mass percentage of the hot melt adhesive in the pharmaceutical composition may be 14% to 25%.

[0025] In the present invention, the mass percentage of the Class A hot melt adhesive in the pharmaceutical composition may be 14% to 25%, and the mass percentage of the Class B hot melt adhesive in the pharmaceutical composition may be 15.0% to 21.6%.

[0026] In the present invention, the pharmaceutical composition may be a pharmaceutical composition in the form of hot melt granulated particles. In the present invention, the pharmaceutical composition may not contain a foaming system. Generally, the "foaming system" usually refers to a system containing an organic acid and sodium carbonate, where the system releases carbon dioxide when contacted with an aqueous solution.

[0027] In the present invention, the pharmaceutical composition may contain one or more of a disintegrant, a filler, a lubricant, a flow promoter, a flavoring agent, and a fragrance. In the present invention, the pharmaceutical composition may further contain a surfactant.

[0028] Here, the disintegrant may be one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and crospovidone, preferably croscarmellose sodium and / or low-substituted hydroxypropyl cellulose. The mass percentage of the disintegrant in the pharmaceutical composition may be 0% to 30%, preferably 10% to 22%.

[0029] Here, the disintegrant may be microcrystalline cellulose and / or pregelatinized starch. Here, the mass percentage of the disintegrant in the pharmaceutical composition may also be 0% to 22%.

[0030] Here, the filler may be mannitol and / or lactose, for example, mannitol. The mass percentage of the filler in the pharmaceutical composition may be 0% to 50%. In the actual manufacturing process of the product, the lactose generally exists in the form of lactose monohydrate, and those skilled in the art can adjust the amount to match the amount of the corresponding hydrate form based on the amount of filler used in the pharmaceutical composition.

[0031] Here, the filler may be sorbitol. Here, the lubricant may be one or more of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, magnesium silicate, and calcium silicate, for example, magnesium stearate. The mass percentage of the lubricant in the pharmaceutical composition may be 0% to 2%.

[0032] Here, the flow promoter may be talc and / or colloidal silica. The mass percentage of the flow promoter in the pharmaceutical composition may be 0% to 2%. Here, 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% to 5%.

[0033] Here, the flavoring agent may be citric acid. Here, the fragrance may be a fragrance, preferably a natural fragrance, such as orange fragrance and / or apple fragrance. The mass percentage of the fragrance in the pharmaceutical composition may be 0% to 3%.

[0034] Here, the surfactant may be one or more of glycerol monostearate, soy lecithin, lecithin, xanthan gum, polyoxyethylene stearate, and sodium lauryl sulfate. The mass percentage of the surfactant in the pharmaceutical composition may be 0% to 15%.

[0035] In some embodiments, the active pharmaceutical ingredients are carbidopa and levodopa, the mass percentage of carbidopa in the pharmaceutical composition is 0.5% to 15%, the mass percentage of levodopa in the pharmaceutical composition is 2% to 48%, and the mass ratio of carbidopa to levodopa is 1:1 to 1:24. In the actual manufacturing process of the product, carbidopa generally exists as a monohydrate, and those skilled in the art can adjust the amount used in the pharmaceutical composition to the corresponding hydrate form based on its usage.

[0036] In some preferred embodiments, the pharmaceutical composition comprises 0.5% to 10% by mass of carbidopa / levodopa, 2% to 40% of levodopa, 6% to 30% of a hot melt adhesive, and 0% to 30% of a disintegrant.

[0037] In some preferred embodiments, the pharmaceutical composition comprises 0.5% to 10% by mass of carbidopa / levodopa, 2% to 40% of levodopa, 6% to 30% of a Class A hot melt adhesive, and 0% to 30% of a disintegrant.

[0038] In some more preferred embodiments, the pharmaceutical composition comprises 5.7% to 8.3% by mass of carbidopa, 23% to 33% of levodopa, 15% to 25% of hot melt adhesive, 10.1% to 20.1% of low-substituted hydroxypropyl cellulose, and 23.2% to 33.2% of mannitol, or the pharmaceutical composition comprises 6.5% to 7.5% of carbidopa, 25.1% to 30.1% of levodopa, 17.5% to 22.5% of hot melt adhesive, 13.5% to 18.5% of low-substituted hydroxypropyl cellulose, and 27.0% to 32.0% of mannitol.

[0039] In one particular 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.

[0040] In one particular 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.

[0041] In one particular embodiment, the pharmaceutical composition comprises 10.6% carbidopa monohydrate, 39.3% levodopa, 13% poloxamer 407, 10% low-substituted hydroxypropyl cellulose, and 27.1% mannitol.

[0042] In one particular 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.

[0043] In one particular 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 silica, and 0.5% aspartame.

[0044] In one particular 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.

[0045] In one particular 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 silica, 4.7% sucrose, and 0.3% apple flavor.

[0046] In one particular embodiment, the pharmaceutical composition comprises 6.5% carbidopa monohydrate, 24% levodopa, 20.6% poloxamer 407, 15% lactose, and 33.9% mannitol.

[0047] In one particular 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.

[0048] In one particular embodiment, the pharmaceutical composition comprises 0.675% carbidopa monohydrate, 2.5% levodopa, 25% poloxamer 407, 22.5% croscarmellose sodium, and 49.325% mannitol.

[0049] In one particular embodiment, the pharmaceutical composition comprises 8.4% carbidopa monohydrate, 31.2% levodopa, 16.5% poloxamer 407, 11.5% croscarmellose sodium, and 32.4% mannitol.

[0050] In one particular embodiment, the pharmaceutical composition comprises 9.7% carbidopa monohydrate, 36% levodopa, 18% poloxamer 407, 12% low-substituted hydroxypropyl cellulose, and 24.3% mannitol.

[0051] In one particular embodiment, the pharmaceutical composition comprises 10.4% carbidopa monohydrate, 38.4% levodopa, 15% poloxamer 407, 18% low-substituted hydroxypropyl cellulose, and 18.2% lactose.

[0052] In one particular embodiment, the pharmaceutical composition comprises 10.4% carbidopa monohydrate, 38.4% levodopa, 16% poloxamer 407, 12% low-substituted hydroxypropyl cellulose, and 23.2% mannitol.

[0053] In one particular embodiment, the pharmaceutical composition comprises 10.4% carbidopa monohydrate, 38.4% levodopa, 23% poloxamer 407, 5% low-substituted hydroxypropyl cellulose, and 23.2% mannitol.

[0054] In one particular 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.

[0055] In one particular embodiment, the pharmaceutical composition comprises 2.5% apixaban, 25% poloxamer 188, 20% croscarmellose sodium, and 52.5% lactose monohydrate.

[0056] In one particular embodiment, the pharmaceutical composition comprises 2.5% apixaban, 18% poloxamer 407, 15% croscarmellose sodium, and 64.5% lactose monohydrate.

[0057] A third aspect of the present invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, wherein the active pharmaceutical ingredient is voriconazole and the hot-melt adhesive is Class A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407, And Class B hot melt adhesive: Selected from polyethylene glycol 6000, The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12% to 25%. The aforementioned pharmaceutical composition is a pharmaceutical composition in the form of hot-melt granulated granules.

[0058] A fourth aspect of the present invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, wherein the active pharmaceutical ingredient is voriconazole and the hot-melt adhesive is Class A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407, Alternatively, a Class B hot melt adhesive: selected from polyethylene glycol 6000, The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12% to 25%. The aforementioned pharmaceutical composition is a pharmaceutical composition in the form of hot-melt granulated granules.

[0059] The conditions for the pharmaceutical compositions in the third and fourth categories are as follows. In the present invention, the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition may be 1% to 63%, and preferably 8.3% to 63%.

[0060] In the present invention, the mass percentage of the Class A hot melt adhesive in the pharmaceutical composition may be 5% to 30%, preferably 12% to 25%, and more preferably 15.0% to 21.6%.

[0061] In the present invention, the mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is preferably 15.0% to 21.6%. In the present invention, the pharmaceutical composition may further contain one or more of the following: a disintegrant, a filler, a lubricant, a flow promoter, and a flavoring agent.

[0062] In the present invention, the pharmaceutical composition may further contain a surfactant. Here, the disintegrant may be one or more of croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and crospovidone, preferably croscarmellose sodium and / or low-substituted hydroxypropylcellulose. The mass percentage of the disintegrant in the pharmaceutical composition may be 0% to 30%, preferably 0% to 20%.

[0063] Here, the filler may be one or more of mannitol, sorbitol, and lactose, for example, mannitol. The mass percentage of the filler in the pharmaceutical composition may be 0% to 50%.

[0064] Here, the lubricant may be one or more of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, magnesium silicate, and calcium silicate, for example, magnesium stearate. The mass percentage of the lubricant in the pharmaceutical composition may be 0% to 2%.

[0065] Here, the flow promoter may be talc and / or colloidal silica. The mass percentage of the flow promoter in the pharmaceutical composition may be 0% to 2%. Here, the flavoring agent may be one or more of sucrose, maltose, stevioside, mannitol, erythrose, aspartame, citric acid, and fragrance, preferably one or more of stevioside, mannitol, erythrose, aspartame, and fragrance. The mass percentage of the flavoring agent in the pharmaceutical composition may be 0% to 5%.

[0066] Here, the surfactant may be one or more of glycerol monostearate, soy lecithin, lecithin, xanthan gum, polyoxyethylene stearate, and sodium lauryl sulfate. The mass percentage of the surfactant in the pharmaceutical composition may be 0% to 15%.

[0067] In some embodiments, the pharmaceutical composition comprises, by mass percentage, 1% to 63% of the active pharmaceutical ingredient, 5% to 30% of the Class A hot melt adhesive or 12% to 25% of the Class B hot melt adhesive, 0% to 30% of the disintegrant, 0% to 50% of the filler, 0% to 2% of the lubricant, 0% to 2% of the flow promoter, and 0% to 5% of the flavoring agent.

[0068] In some embodiments, the pharmaceutical composition comprises 1% to 63% by mass of the active pharmaceutical ingredient, 5% to 30% of the "Type A hot melt adhesive and Type B hot melt adhesive," 0% to 30% of the disintegrant, 0% to 50% of the filler, 0% to 2% of the lubricant, 0% to 2% of the flow promoter, and 0% to 5% of the flavoring agent.

[0069] In some preferred embodiments, the pharmaceutical composition comprises 8.3% to 63% by mass of voriconazole, 12% to 25% of the hot melt adhesive, 0% to 20% of the disintegrant, 0% to 50% of the filler, 0% to 2% of the lubricant, 0% to 2% of the flow enhancer, and 0% to 5% of the flavoring agent.

[0070] In some more preferred embodiments, the pharmaceutical composition comprises 33% to 55% by mass of voriconazole, 15.0% to 21.6% of the hot melt adhesive, 5% to 18% of the disintegrant, 8.5% to 36.5% of the filler, 0% to 1% of the lubricant, 0.5% to 1.5% of the flow enhancer, and 0.5% to 1.5% of the flavoring agent.

[0071] The fifth aspect of the present invention provides a pharmaceutical formulation which is a hot-melt granulated granule containing the pharmaceutical composition described above (the first to fourth aspects). Here, the particle size of the hot-melt granulated material may be less than 1000 μm.

[0072] A sixth aspect of the present invention provides an oral drug delivery kit comprising an oral drug delivery device AcuSiS® and the pharmaceutical formulation described in the fifth aspect above, wherein the pharmaceutical formulation is placed in the drug-carrying space of the oral drug delivery device AcuSiS®.

[0073] In this invention, the oral drug delivery kit does not require prior preparation before use; the lower end is immersed in water or a beverage, and the patient actively inhales it, making it suitable for patients with dysphagia, such as children and the elderly. The pharmaceutical formulation is filled into the oral drug delivery device AcuSiS®, which offers greater stability and is convenient for storage and use. This oral administration device significantly improves dysphagia in patients, particularly in the off state of Parkinson's disease patients. It requires no prior preparation before use, and the supported pharmaceutical composition has a fast dissolution rate, making it highly significant in effectively alleviating the off state of Parkinson's disease patients. When the hot-melt granulated granules are filled into the oral drug delivery device AcuSiS®, they have higher stability and reduce the degradation products DHPA and genotoxic impurities hydrazine that are generated during storage.

[0074] Preferably, the amount of the pharmaceutical preparation filled is 50 to 1000 mg. Preferably, the pharmaceutical formulation is carbidopa / levodopa granules containing 25 mg of carbidopa, 100 mg of levodopa, 66.9 mg of hot melt adhesive, 54.6 mg of low-substituted hydroxypropyl cellulose, and 113.3 mg of mannitol.

[0075] Here, the oral drug delivery device AcuSiS® is a conventionally available oral drug delivery device, and may be an oral drug delivery device protected by Chinese utility model patent CN201921652286.6. Any of the products described in any one of Examples 1 to 9 can be used in the present invention, and at the same time, similar devices that can achieve the same effect as the oral drug delivery device can also be used. Generally, it may include five components: a high-density polyethylene (HDPE) pharmaceutical AcuSiS® cap, a polypropylene (PP) pharmaceutical AcuSiS® straw, a high-density polyethylene (HDPE) pharmaceutical AcuSiS® filter housing body, a polypropylene (PP) meltblown nonwoven fabric disc, and a high-density polyethylene (HDPE) pharmaceutical AcuSiS® filter housing cap bottom sheet.

[0076] Here, the high-density polyethylene (HDPE) pharmaceutical AcuSiS® filter housing body, the polypropylene (PP) meltblown nonwoven fabric disc, and the high-density polyethylene (HDPE) pharmaceutical AcuSiS® filter housing cap bottom sheet are assembled to form the AcuSiS® filter, the polypropylene (PP) pharmaceutical AcuSiS® straw and the AcuSiS® filter are assembled to form the AcuSiS® body, the granules are filled into the AcuSiS® body for storage, and the body is sealed with the high-density polyethylene (HDPE) pharmaceutical AcuSiS® cap.

[0077] Here, each of the oral drug delivery kits may further include a sealing packaging layer for sealing the oral drug delivery device AcuSiS®.

[0078] Preferably, the sealing packaging layer is a polyester-aluminum-polyethylene composite film bag. Preferably, the sealing packaging layer further contains a desiccant, the desiccant being a bagged desiccant, and more preferably 0.25 g of a bagged desiccant.

[0079] A seventh aspect of the present invention further provides the use of a pharmaceutical composition in which the active pharmaceutical ingredients are carbidopa and levodopa, as described in the second aspect above, in the manufacture of a pharmaceutical for emergency or intermittent treatment of off-episodes of Parkinson's disease.

[0080] An eighth aspect of the present invention further provides the use of a pharmaceutical composition in which the active pharmaceutical ingredient described in the fourth aspect above is voriconazole in the manufacture of a pharmaceutical for treating or preventing an invasive fungal disease.

[0081] A ninth aspect of the present invention further provides a method for producing a pharmaceutical preparation as described in the fifth aspect above, wherein the production method is a hot-melt granulation method and includes the following steps. The hot melt adhesive is crushed to obtain a powder, mixed with the active pharmaceutical ingredient, disintegrant and filler (if disintegrant and filler are not included, they are not added), hot melt granulation is performed, and then the mixture is uniformly mixed with the remaining components of the pharmaceutical composition and sieved. Alternatively, for a pharmaceutical preparation of the pharmaceutical composition of the fourth aspect described above, the hot melt adhesive is crushed to obtain a powder, mixed with the active pharmaceutical component, disintegrant, filler, lubricant and flow promoter, hot melt granulation is performed, then uniformly mixed with the remaining components of the pharmaceutical composition, particle size adjustment is performed, and the mixture is sieved.

[0082] In the present invention, pharmaceutical formulations manufactured by the hot-melt granulation method significantly improve the compatibility of each component of the pharmaceutical composition, further promote rapid release, enhance stability, and reduce DHPA and hydrazine, which are genotoxic impurities generated during the manufacturing process.

[0083] Here, the particle size of the powder may be less than 40 mesh. Here, the temperature for hot melt granulation may be 50 to 100°C, preferably 55 to 80°C, for example, 60°C, 70°C, or 80°C.

[0084] For example, the manufacturing method includes the following steps: hot melt granulation using a twin-screw extruder, with a standard screw assembly configuration, a granulation temperature of 60-90°C, preferably 60-70°C, a screw rotation speed of 200 rpm, and a feed rotation speed of 30 rpm, and passing the resulting granules through a 20-mesh sieve to obtain product granules; or granulation using a high-shear granulator equipped with a heating jacket at a granulation temperature of 70-80°C until uniform granules are formed, and passing the hot melt granules through a 20-mesh sieve to obtain product granules; or mixing using a cone mixer at a rotation speed of 10 rpm for 10 minutes to obtain product granules.

[0085] For example, in the case of a pharmaceutical formulation of the pharmaceutical composition of the fourth aspect described above, the manufacturing method includes the following steps: a step of hot-melt granulation using a twin-screw extruder, where the granulation temperature is 55 to 90°C, preferably 60 to 80°C, the screw rotation speed is 100 to 800 rpm, and the sample speed is 5 to 80%, and the obtained granules are passed through a 14 or 16 mesh sieve to obtain product granules; or a step of granulation using a high-shear granulator equipped with a heating jacket at a granulation temperature of 70 to 80°C until uniform granules are formed, and the hot-melt granules are passed through a 14 or 16 mesh sieve to adjust the particle size to obtain product granules; or a step of mixing the granules after hot-melt granulation with the remaining components of the pharmaceutical composition using a cone mixer at a rotation speed of 10 rpm for 5 to 30 minutes to obtain product granules.

[0086] As long as it does not violate common sense in the art, the above preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention. All reagents and raw materials used in this invention are commercially available.

[0087] Positive advancement effects of the present invention: The present invention involves combining a specific amount of a specific binder with a specific amount of an active pharmaceutical ingredient and manufacturing a pharmaceutical composition using a specific hot-melt granulation process. The resulting pharmaceutical composition enables rapid release of the active pharmaceutical ingredient, ensures good raw material compatibility, and improves the stability of the active pharmaceutical ingredient. In particular, products in which the active pharmaceutical ingredients are carbidopa and levodopa are especially suitable for improving the rapid release and stability of the active pharmaceutical ingredient used in emergency or intermittent treatment during the "off" period of Parkinson's disease, and are especially suitable for improving the stability of pediatric voriconazole dry suspensions. The resulting pharmaceutical composition is delivered via a specific oral delivery device, eliminating the need for prior preparation and allowing for active inhalation by the patient, thus significantly improving swallowing in patients with dysphagia, which is advantageous for improving patient medication compliance and enhancing therapeutic effects. [Brief explanation of the drawing]

[0088] [Figure 1] This is the appearance of the oral drug delivery kit product of the present invention. 1- AcuSiS® oral drug delivery device, 2- Drug granules. [Figure 2] Figure 2a is a schematic diagram illustrating the use of the oral drug delivery kit of the present invention. Figure 2b is a schematic diagram showing the oral drug delivery kit immediately after being placed in water, and Figure 2b is a schematic diagram showing the particles inside the oral drug delivery kit being sucked in through a straw. [Figure 3] These are the drug-time curves for levodopa in the carbidopa / levodopa granule formulation and commercially available carbidopa / levodopa tablets in Example 4 of the present invention. [Figure 4] Figure 3 shows the local expansion drug time curves for levodopa in the carbidopa / levodopa granule formulation in Example 4 of the present invention and in commercially available carbidopa / levodopa. [Modes for carrying out the invention]

[0089] The present invention will be further described below with reference to embodiments, but this does not limit the present invention to the scope of the above embodiments. In the following embodiments, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or according to the product description.

[0090] Example 1 Carbidopa / levodopa granules were prepared using the following hot-melt granulation process according to the formulation in Table 1.

[0091] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Carbidopa, levodopa, and other excipients were added to a corn mixer and mixed at a rotation speed of 10 rpm for 10 minutes, after which the mixture was discharged.

[0092] The above mixed materials were placed in a high-shear granulator with a heating jacket and granulated at a granulation temperature of 70-80°C until uniform granules were formed. The hot-melt granules were passed through a 20-mesh sieve to obtain carbidopa / levodopa granules.

[0093] [Table 1]

[0094] Example 2 Carbidopa / levodopa granules were prepared using the following hot-melt granulation process according to the formulations in Table 2.

[0095] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Carbidopa, levodopa active ingredients, and excipients were added to a corn mixer and mixed at a rotation speed of 10 rpm for 10 minutes, then discharged.

[0096] Hot-melt granulation was performed using a twin-screw extruder. A standard screw assembly configuration was used, the granulation temperature was 60-70°C, the screw rotation speed was 200 rpm, and the feed rotation speed was 30 rpm. The granules obtained were passed through a 20-mesh sieve to obtain carbidopa / levodopa granules.

[0097] [Table 2]

[0098] Example 3 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 2, according to the formulation in Table 3.

[0099] [Table 3]

[0100] Example 4 According to the formulation in Table 4, 0.5% magnesium stearate and 0.5% natural orange flavor were added to the granules of Example 3, and the mixture was placed in a corn mixer and mixed at a rotation speed of 10 rpm for 10 minutes to obtain carbidopa / levodopa granules.

[0101] [Table 4]

[0102] Example 5 Carbidopa / levodopa granules were prepared using the following hot-melt granulation process according to the formulations in Table 5.

[0103] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Carbidopa, levodopa, and other excipients were added to a corn mixer and mixed at a rotation speed of 10 rpm for 10 minutes, after which the mixture was discharged.

[0104] Hot-melt granulation was performed using a twin-screw extruder. A standard screw assembly configuration was used, the granulation temperature was 70-90°C, the screw rotation speed was 200 rpm, and the feed rotation speed was 10 rpm. The granules obtained were passed through a 20-mesh sieve to obtain carbidopa / levodopa granules.

[0105] [Table 5]

[0106] Example 6 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 6.

[0107] [Table 6]

[0108] Example 7 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 7.

[0109] [Table 7]

[0110] Example 8 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 8.

[0111] [Table 8]

[0112] Example 9 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 9.

[0113] [Table 9]

[0114] Example 10 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 10.

[0115] [Table 10]

[0116] Example 11 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 11.

[0117] [Table 11]

[0118] Example 12 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 12.

[0119] [Table 12]

[0120] Example 13 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 13.

[0121] [Table 13]

[0122] Example 14 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 14.

[0123] [Table 14]

[0124] Example 15 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 5, according to the formulation in Table 15.

[0125] [Table 15]

[0126] Example 16 Apixaban granules were manufactured using the following hot-melt granulation process according to the formulation in Table 16.

[0127] Poloxamer 188 was crushed and passed through an 80-mesh sieve to obtain poloxamer 188 powder. The excipients other than apixaban were added to a corn mixer and mixed at a rotation speed of 10 rpm for 5 minutes, then discharged. Next, the API and the remaining excipients were added in a 1:2 ratio (i.e., apixaban (or substance containing apixaban):excipient) in stages and mixed, stirring the mixture at a rotation speed of 10 rpm for 5 minutes after each addition of excipient, and after the addition of the last excipient, mixing at a rotation speed of 10 rpm for 15 minutes.

[0128] Hot-melt granulation was performed using a twin-screw extruder. A standard screw assembly configuration was used, the granulation temperature was 70-80°C, the screw rotation speed was 400 rpm, and the feed rotation speed was 40 rpm. The resulting granules were passed through a 20-mesh sieve to obtain apixaban granules.

[0129] [Table 16]

[0130] Example 17 Apixaban granules were manufactured using the following hot-melt granulation process according to the formulation in Table 17.

[0131] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. The excipients other than apixaban were added to a corn mixer and mixed at a rotation speed of 10 rpm for 5 minutes, then discharged. Next, the API and the remaining excipients were added in a 1:2 ratio (i.e., apixaban (or substance containing apixaban):excipient) in stages, stirring the mixture at a rotation speed of 10 rpm for 5 minutes after each addition of excipient, and after the addition of the last excipient, mixing at a rotation speed of 10 rpm for 15 minutes.

[0132] Hot-melt granulation was performed using a twin-screw extruder. A standard screw assembly configuration was used, the granulation temperature was 70-80°C, the screw rotation speed was 300 rpm, and the feed rotation speed was 40 rpm. The resulting granules were passed through a 20-mesh sieve to obtain apixaban granules.

[0133] [Table 17]

[0134] Example 18 The carbidopa / levodopa granules obtained in Example 1 were filled into AcuSiS® shown in Figure 1 using the following process to obtain a carbidopa / levodopa granule formulation.

[0135] After inserting a polypropylene meltblown nonwoven fabric disc into the bottom sheet of the AcuSiS® filter housing cap of the high-density polyethylene pharmaceutical AcuSiS®, the high-density polyethylene pharmaceutical AcuSiS® filter housing was fitted with the substrate sheet to form the AcuSiS® filter. The polypropylene pharmaceutical AcuSiS® straw was then attached to the AcuSiS® filter to form the AcuSiS® body. The granules after hot-melt granulation were filled into the AcuSiS® body, and the product was sealed with the high-density polyethylene pharmaceutical AcuSiS® cap.

[0136] The above-mentioned filled AcuSiS® was sealed in a polyester / aluminum / polyethylene composite film bag, and a 0.25g desiccant packet was placed inside the bag.

[0137] As shown in Figure 2, when using the product of this embodiment, no prior preparation is necessary. Simply open the polyester / aluminum / polyethylene composite film bag, remove the cap, and place it in water, milk, or juice. When the patient inhales the medication, it instantly disperses into the liquid and is swallowed.

[0138] Example 19 The apixaban granules obtained in Example 16 were filled into AcuSiS® according to the steps of Example 18 to obtain an apixaban formulation.

[0139] Example 20 According to the formulation in Table 18, carbidopa / levodopa granules were prepared using the following hot-melt granulation process with the hot-melt adhesive poloxamer 407.

[0140] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Carbidopa, levodopa, and other excipients were added to a corn mixer and mixed at 10 rpm for 10 minutes, then drained.

[0141] Hot-melt granulation was performed using a twin-screw extruder. A standard screw assembly configuration was used, the granulation temperature was 70-90°C, the screw rotation speed was 200 rpm, and the feed rotation speed was 10 rpm. The granules obtained were passed through a 20-mesh sieve to obtain carbidopa / levodopa granules.

[0142] [Table 18]

[0143] Example 21 Carbidopa / levodopa granules were prepared using the following hot-melt granulation process according to the formulation in Table 19.

[0144] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Carbidopa, levodopa active ingredients, and excipients were added to a corn mixer and mixed at a rotation speed of 10 rpm for 10 minutes, then discharged.

[0145] Hot-melt granulation was performed using a twin-screw extruder. A standard screw assembly configuration was used, the granulation temperature was 70-80°C, the screw rotation speed was 400 rpm, and the feed rotation speed was 15 rpm. The granules obtained were passed through a 20-mesh sieve to obtain carbidopa / levodopa granules.

[0146] [Table 19]

[0147] Example 22 The carbidopa / levodopa granules obtained in Example 21 were filled into AcuSiS® as shown in Figure 1 using the following process to obtain a carbidopa / levodopa granule formulation.

[0148] After inserting a polypropylene meltblown nonwoven fabric disc into the bottom sheet of the AcuSiS® filter housing cap of the high-density polyethylene pharmaceutical AcuSiS®, the high-density polyethylene pharmaceutical AcuSiS® filter housing was fitted with the substrate sheet to form the AcuSiS® filter. The polypropylene pharmaceutical AcuSiS® straw was then attached to the AcuSiS® filter to form the AcuSiS® body. The granules after hot-melt granulation were filled into the AcuSiS® body, and the product was sealed with the high-density polyethylene pharmaceutical AcuSiS® cap.

[0149] The above-mentioned filled AcuSiS® was sealed in a polyester / aluminum / polyethylene composite film bag. Example 23 A carbidopa / levodopa granular formulation was prepared according to Example 22, and the filled AcuSiS® was sealed in a polyester / aluminum / polyethylene composite film bag, with a 0.25 g desiccant packet placed inside the bag.

[0150] Example 24 Carbidopa / levodopa granules were prepared using the hot-melt granulation process of Example 21, according to the formulation in Table 20.

[0151] [Table 20]

[0152] Example 25 Granules were produced using the hot-melt granulation process of Example 21, with the components other than sodium stearyl fumarate, according to the formulation in Table 21.

[0153] The granules and sodium stearyl sufumarate were added to a corn mixer and mixed at a rotation speed of 10 rpm for 5 minutes, then discharged to obtain carbidopa / levodopa granules.

[0154] [Table 21]

[0155] Example 26 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation in Table 22.

[0156] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 10 minutes, then discharged. The mixed material was placed in a high-shear granulator with a heated jacket and granulated at a granulation temperature of 70-80°C until uniform granules were formed. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0157] [Table 22]

[0158] Example 27 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation shown in Table 23.

[0159] Poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 30 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 70-80°C, a screw rotation speed of 200 rpm, and a sample speed of 30%. The hot melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0160] [Table 23]

[0161] Example 28 Voriconazole granules were obtained using the hot-melt granulation process of Example 27, according to the formulation in Table 24.

[0162] [Table 24]

[0163] Example 29 Following the formulation in Table 25, 0.5% magnesium stearate and 0.5% strawberry flavoring were added to the granules of Example 28, and then the mixture was placed in a corn mixer and mixed at a rotation speed of 10 rpm for 5 minutes to obtain voriconazole granules.

[0164] [Table 25]

[0165] Example 30 Voriconazole granules were obtained using the hot-melt granulation process of Example 26, according to the formulation in Table 26.

[0166] [Table 26]

[0167] Example 31 Voriconazole granules were manufactured using the following hot-melt granulation process according to formulation 27.

[0168] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 10 minutes, then discharged. The mixed material was placed in a high-shear granulator with a heated jacket and granulated at a granulation temperature of 80-90°C until uniform granules were formed. The hot-melt granules were passed through a 14-mesh sieve to obtain voriconazole granules.

[0169] [Table 27]

[0170] Example 32 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation shown in Table 28.

[0171] Poloxamer 188 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 188 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 30 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw rotation speed of 400 rpm, and a sample speed of 40%. The hot melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0172] [Table 28]

[0173] Example 33 According to the formulation in Table 29, poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder, and voriconazole granules were prepared using the hot-melt granulation process of Example 32.

[0174] [Table 29]

[0175] Example 34 According to the formulation in Table 30, poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder, and voriconazole granules were prepared using the hot-melt granulation process of Example 32.

[0176] [Table 30]

[0177] Example 35 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation shown in Table 31.

[0178] Poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 30 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 70-80°C, a screw rotation speed of 400 rpm, and a sample speed of 25%. The hot melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0179] [Table 31]

[0180] Example 36 Voriconazole granules were obtained using the hot-melt granulation process of Example 35, according to the formulation in Table 32.

[0181] [Table 32]

[0182] Example 37 Following the formulation in Table 33, 0.5% colloidal silica, 0.3% aspartame, and 0.7% orange flavoring were added to the granules of Example 35, and then the mixture was placed in a cone mixer and mixed at a rotation speed of 10 rpm for 5 minutes to obtain voriconazole granules.

[0183] [Table 33]

[0184] Example 38 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation in Table 34.

[0185] Poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 30 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw rotation speed of 400 rpm, and a sample speed of 30%. The hot melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0186] [Table 34]

[0187] Example 39 Following the formulation in Table 35, 0.5% aspartame and 0.5% orange flavoring were added to the granules of Example 38, and then the mixture was placed in a corn mixer and mixed at a rotation speed of 10 rpm for 5 minutes to obtain voriconazole granules.

[0188] [Table 35]

[0189] Example 40 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation in Table 36.

[0190] Poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 20 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw rotation speed of 800 rpm, and a sample speed of 80%. The hot melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0191] [Table 36]

[0192] Example 41 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation in Table 37.

[0193] Poloxamer 407 was pulverized and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a cone mixer and mixed at a rotation speed of 10 rpm for 20 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw rotation speed of 100 rpm, and a sample speed of 10%. The hot melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0194] [Table 37]

[0195] Example 42 Voriconazole granules were manufactured using the following hot-melt granulation process according to the formulation in Table 38.

[0196] Poloxamer 407 was pulverized and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole, mannitol, poloxamer 407 powder, low-substituted hydroxypropyl cellulose, and colloidal silica were added to a cone mixer and mixed at a rotation speed of 10 rpm for 30 minutes, then discharged. Hot melt granulation was performed using a twin-screw extruder at a granulation temperature of 70-80°C, a screw rotation speed of 200 rpm, and a sample speed of 20%. The hot melt granules were passed through a 16-mesh sieve, the remaining excipients were added to the sieved granules, and the mixture was placed in a cone mixer and stirred at a rotation speed of 10 rpm for 5 minutes to obtain voriconazole granules.

[0197] [Table 38]

[0198] Example 43 As shown in Figure 1, the voriconazole granules obtained in Example 28 were filled into AcuSiS® according to the following process to obtain an oral drug delivery kit containing voriconazole.

[0199] After inserting a polypropylene meltblown nonwoven fabric disc into the bottom sheet of the AcuSiS® filter housing cap of the high-density polyethylene pharmaceutical AcuSiS®, the high-density polyethylene pharmaceutical AcuSiS® filter housing was fitted with the substrate sheet to form the AcuSiS® filter, and the polypropylene pharmaceutical AcuSiS® straw was attached to the AcuSiS® filter to form the AcuSiS® body. The voriconazole granules obtained in Example 28 were filled into the AcuSiS® body, and it was sealed with the high-density polyethylene pharmaceutical AcuSiS® cap.

[0200] Example 44 The voriconazole granules obtained in Example 29 were filled into AcuSiS® according to the steps of Example 43 to obtain an oral drug delivery kit containing voriconazole. The filled AcuSiS® was sealed in a polyester / aluminum / polyethylene composite film bag, and a 0.25 g desiccant bag was placed inside the composite film bag.

[0201] As shown in Figure 2, the product of this embodiment does not need to be manufactured in advance before use. The polyester / aluminum / polyethylene composite film bag is opened directly, AcuSiS® is taken out, the cap is removed, and it is placed in water, milk, or juice. When the patient inhales it, the drug instantly disperses in the liquid and is immediately swallowed.

[0202] Example 45 Voriconazole granules were prepared using the hot-melt adhesive polyethylene glycol 6000 according to the formulation in Table 39 and the hot-melt granulation process of Example 35.

[0203]

Table 39

[0204] Example 46 According to the formulation in Table 40, voriconazole granules were produced using the hot melt granulation process of Example 35.

[0205]

Table 40

[0206] Example 47 According to the formulation in Table 41, voriconazole granules were produced using the hot melt granulation process of Example 35.

[0207]

Table 41

[0208] Example 48 According to the formulation in Table 42, voriconazole granules were produced using the hot melt granulation process of Example 35.

[0209]

Table 42

[0210] <着 Example 49 According to the formulation in Table 43, voriconazole granules were produced using the hot melt granulation process of Example 35.

[0211]

Table 43

[0212] Example 50<着 According to the formulation in Table 44, voriconazole granules were produced using the hot melt granulation process of Example 35.

[0213]

Table 44

[0214] Example 51 According to the formulation in Table 45, using the hot melt granulation process of Example 35, voriconazole granules were produced.

[0215]

Table 45

[0216] <000AB46>Example 52 According to the formulation in Table 46, adopting the hot melt adhesives polyethylene glycol 6000 and poloxamer 407, using the hot melt granulation process of Example 35, voriconazole granules were produced.

[0217]

Table 46

[0218] Comparative Examples 1 - 3 According to the formulation in Table 47, respectively adopting the hot melt adhesives glyceryl behenate 888 ATO and polyethylene glycol - 32 stearate, using the hot melt granulation process of Example 20, granules were produced.

[0219]

Table 47

[0220] Comparative Example 4 According to the formulation in Table 48, adopting the hot melt adhesive glyceryl behenate 888 ATO, using the hot melt granulation process of Example 35, voriconazole granules were produced.

[0221] <FA000972><FA000973>

Table 48

[0222] Effect Example 1: Detection in the dissolution test For the carbidopa / levodopa granules in Examples 1-3 and 24-25, the elution method used was USP method 1 (rotating basket method) at a rotation speed of 50 rpm. The elution medium was 0.1N hydrochloric acid at pH 1.0, in a volume of 750 mL. Samples were taken and detected at 5, 10, 15, 20, and 30 minutes, respectively. The elution results for Examples 1-3 and 24-25 are shown in Tables 48-50 and 55-56. Carbidopa and levodopa were rapidly released, and the elution rate at 5 minutes exceeded 90% in all cases. For the apixaban granules in Examples 16 and 17, the elution method used was USP method 2 (paddle method) at a rotation speed of 75 rpm. The elution medium was 0.05M sodium phosphate buffer containing 0.05% SLS at pH 6.8, in a volume of 900 mL. Samples were taken and detected at 5, 10, 20, 30, and 45 minutes, respectively. The dissolution results for Examples 16 and 17 are shown in Table 52, and the dissolution rate of apixaban after 5 minutes exceeded 85% in both cases.

[0223] For the carbidopa / levodopa granules of Example 20 and Comparative Examples 2-3, the USP method 1 (rotating basket method) was used for elution, with a rotation speed of 50 rpm. The elution medium was 0.1N hydrochloric acid at pH 1.0, and the volume was 750 mL. Samples were sampled and detected at 5, 10, 15, 20, and 30 minutes, respectively. The elution results are shown in Tables 53 and 54. In Example 20, carbidopa and levodopa were released rapidly, with an elution rate exceeding 90% after 5 minutes. In contrast, in Comparative Examples 2 and 3, levodopa and carbidopa were released slowly, with elution rates of 23.4%, 24.5% (Comparative Example 2), 70.0%, and 68.4% (Comparative Example 3), respectively, after 5 minutes.

[0224] [Table 49]

[0225] [Table 50]

[0226] [Table 51]

[0227] [Table 52]

[0228] [Table 53]

[0229] [Table 54]

[0230] [Table 55]

[0231] [Table 56]

[0232] Effect Example 2: Detection of raw material compatibility and formulation stability of carbidopa / levodopa granules. Compatibility tests of raw materials and excipients were performed on the carbidopa / levodopa granule formulation under conditions of 40°C / RH75%. As shown in Tables 57 and 58, among all the excipients, poloxamer 407 was found to have poor compatibility with both carbidopa and levodopa active pharmaceutical ingredients, and after formulation, there was a risk of exceeding the limits for related substances in terms of stability.

[0233] The carbidopa / levodopa granule formulations obtained in Examples 18 and 22-23 were placed under conditions of 40°C / RH75%, and samples were taken and detected after 1 month and 6 months, respectively. The test indicators were dissolution rate, related substances, and hydrazine content. The results are shown in Tables 59-61. After 6 months of accelerated sampling, there was no significant change in the dissolution rate of the carbidopa / levodopa granules, the concentration of related substances was far below the reference value, and the hydrazine content was extremely low, far below the reference value of 50 ppm. This indicates that the adoption of a hot-melt granulation process and moisture-proof packaging significantly improves the compatibility of carbidopa and levodopa with poloxamer 407, and increases the stability of the formulation.

[0234] [Table 57]

[0235] [Table 58]

[0236] [Table 59] TIFF2026524640000060.tif96170

[0237] [Table 60] TIFF2026524640000062.tif130169

[0238] [Table 61] TIFF2026524640000064.tif100170

[0239] Hydrazine is a genotoxic substance, and its content in pharmaceutical formulations must be strictly controlled. Commercially available levodopa and carbidopa combination formulations often have high hydrazine content during storage and use, posing a significant safety risk to patients. Detection revealed that samples of the commercially available carbidopa / levodopa formulations Sinemet CR and Rytary had hydrazine content of 29.6 ppm and 72.3 ppm, respectively. In contrast, carbidopa / levodopa granules manufactured using a hot-melt granulation method according to the poloxamer 407 formulation exhibited good stability and extremely low hydrazine content, never exceeding 10 ppm, with some superior products containing only 3-5 ppm, offering a significant advantage.

[0240] Effect Example 3: Phenomenon in the particle size adjustment process The particle size adjustment process phenomena of the granules obtained in Example 20 and Comparative Examples 1-3 are shown in Table 62. When the amount of hot melt adhesive used was 31% (Comparative Example 1), the granules aggregated after granulation, the surface hardened after cooling, and particle size adjustment was difficult.

[0241] [Table 62]

[0242] Effect Example 4: Bioequivalence Study An in vivo bioequivalence study was conducted in fasted, healthy adult subjects (N=12) using carbidopa / levodopa granules (25 mg / 100 mg, same process and packaging as Example 18, different batch) and carbidopa / levodopa tablets (25 mg / 100 mg, IR, Mylan, commercially available).

[0243] An open-label, parallel, randomized, two-treatment-group, two-cycle, two-sequence, single-dose, crossover Phase I clinical study investigated the mean peak time t in the human body for carbidopa / levodopa granules and carbidopa / levodopa tablets. maxThese were 40.0 minutes and 57.7 minutes, respectively, with the former being 17.7 minutes faster than the latter; expressed as a median, these represent the peak time of levodopa in the human body for carbidopa / levodopa granules and carbidopa / levodopa tablets. max The release times were 30.0 minutes and 52.5 minutes, respectively, with the former being 22.5 minutes faster than the latter (Table 63 and Figures 3-4), and this result was consistent with the trend in in vitro release (Table 64).

[0244] [Table 63] TIFF2026524640000067.tif255166TIFF2026524640000068.tif33170

[0245] [Table 64]

[0246] Effect Example 5 Voriconazole granules obtained in Examples 35, 45, and Comparative Example 4 were subjected to detection using dissolution rate and related substances as indicators, and the results are shown in Table 65. The dissolution test method used was USP method 2 (paddle method), with a rotation speed of 50 rpm, and the dissolution medium was 0.1N hydrochloric acid at pH 1.0, in a volume of 900 mL. Samples were taken and detected at 5, 10, 20, 30, 45, and 60 minutes, respectively.

[0247] Comparing Examples 35, 45, and Comparative Example 4, when the hot-melt adhesive was glyceryl behenate 888 ATO, the dissolution rate of voriconazole granules in the first 20 minutes was significantly slower than that of granules when poloxamer 407 or polyethylene glycol 6000 was used as the adhesive. When polyethylene glycol 6000 was used as the adhesive, there was no significant difference in the dissolution rate of voriconazole granules compared to when poloxamer 407 was used. When voriconazole granules were prepared using the above three hot-melt adhesives in the same proportions, there were no significant differences in their associated substances.

[0248] [Table 65]

[0249] Detection was performed on the voriconazole granules obtained in Examples 48, 50, and 52, with the elution rate as the index, and the results are shown in Table 66. The elution method used was USP method 2 (paddle method) with a rotation speed of 50 rpm, and the elution medium was 0.1N hydrochloric acid at pH 1.0 in a volume of 900 mL. Samples were taken and detected at 5, 10, 20, 30, 45, and 60 minutes.

[0250] [Table 66]

[0251] Effect Example 6 Regarding the voriconazole granule formulation of Example 31, compatibility tests of the raw materials and excipients were conducted under 40°C / RH75% conditions. As shown in Table 67, among all the excipients, poloxamer 407 had poor compatibility with voriconazole, and after formulation, there was a risk of exceeding the limits for related substances in terms of stability.

[0252] The voriconazole-containing oral drug delivery kit obtained in Example 44 was placed under conditions of 40°C / RH75%, and samples were taken and detected after 1 month, 3 months, and 6 months, respectively. The detection indicators were the dissolution rate and related substances, and the results are shown in Table 68. The dissolution method used was USP method 2 (paddle method) at a rotation speed of 50 rpm, and the dissolution medium was 0.1N hydrochloric acid at pH 1.0 in a volume of 900 mL. Samples were taken and detected after 5, 10, 20, 30, 45, and 60 minutes. After an accelerated test of 6 months, no significant change was observed in the dissolution of voriconazole granules, and related substances were far below the limit. This indicates that the use of a hot-melt granulation process and moisture-proof packaging significantly improved the compatibility of voriconazole and poloxamer 407, and improved the stability of the granules. Compared to the original drug (voriconazole dry suspension), which needs to be stored at 2-8°C, the oral administration kit containing voriconazole used in this efficacy example can be stored for a long period under room temperature conditions, offering significant advantages in terms of stability and improved storage conditions.

[0253] [Table 67]

[0254] [Table 68]

[0255] Effect Example 7 The orally administered drug delivery kit containing voriconazole obtained in Example 44 was compared with a commercially available voriconazole dry suspension. The following is a statistical analysis of the preferences of 10 participants regarding preparation before use, method of use, storage conditions, appearance, and other overall factors for the two products.

[0256] [Table 69]

[0257] (The numbers in the table represent the number of people who prefer either the example product or the commercially available product. For example, when considering "preparation before use," 8 people prefer the oral drug delivery kit of Example 44, 0 people prefer the commercially available dry suspension, and 2 people consider both products acceptable.) Therefore, the majority of respondents preferred to choose the voriconazole-containing oral drug delivery kit of the present invention because they found it more convenient to use and store, and more attractive in appearance. Only a small number of respondents considered both products acceptable in terms of preparation, method of use, and appearance. Overall, it can be seen that the majority of people believed that the voriconazole-containing oral drug delivery kit of the present invention had more advantages than commercially available dry suspensions.

Claims

1. A pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, The mass percentage of the aforementioned active pharmaceutical ingredient is 0.3% to 63%. The aforementioned hot melt adhesive is Class A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407, Alternatively, a Class B hot melt adhesive: selected from polyethylene glycol 6000, The mass percentage of the Class A hot melt adhesive in the pharmaceutical composition is 5% to 30%. The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12% to 25%. The pharmaceutical composition is characterized by being a pharmaceutical composition in the form of hot-melt granulated granules.

2. The pharmaceutical composition according to claim 1, characterized in that the mass percentage of the Class A hot melt adhesive in the pharmaceutical composition may be 14% to 25%, and the mass percentage of the Class B hot melt adhesive in the pharmaceutical composition may be 15.0% to 21.6%.

3. A pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, The mass percentage of the aforementioned active pharmaceutical ingredient is 0.3% to 50%. The hot melt adhesive is poloxamer P188 and / or poloxamer P407. A pharmaceutical composition characterized in that the mass percentage of the hot melt adhesive in the pharmaceutical composition is 5% to 30%.

4. The active pharmaceutical ingredient includes, but is not limited to, one or more of the following: dopamine agonists, erectile dysfunction treatments, antiviral drugs, gastric acid secretion inhibitors, anticoagulants, antifungal drugs, antibacterial drugs, antiasthmatic drugs, antidepressants, antiepileptic drugs, antiallergic drugs, antihypertensive drugs, antipsychotic drugs, analgesics, anti-inflammatory drugs, antiemetics, and antitussives. Preferably, the active pharmaceutical ingredient is a poorly soluble and easily degradable drug, a poorly soluble and easily degradable drug, a non-soluble and easily degradable drug, and here preferably, The aforementioned poorly soluble and easily degradable drug agents are selected from ritonavir, vonoprazan, rivaroxaban, posaconazole, cefdinir, cefixime, cefuroxime axetil, clarithromycin, linezolid, and duloxetine. The aforementioned poorly soluble and non-degradable drug agents are selected from apixaban, tadalafil, dapoxetine, contezolid, olanzapine, aripiprazole, quetiapine fumarate, zolmitriptan, rizatriptan, almotriptan, naratriptan, flovatriptan, eletriptan, and verapamil. The aforementioned non-soluble and easily degradable drugs are selected from carbidopa, oseltamivir phosphate, favipiravir, mornupiravir, ruimidavir deuterium bromide, nilmatrellvir, cefaclor, cefprodil, amoxicillin, montelukast sodium, levetiracetam, and desloratadine. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the non-soluble and non-degradable agent is selected from levodopa, sildenafil, vardenafil, tegoprazan, fluconazole, escitalopram oxalate, levocetirizine, amlodipine, ketrolactromethamine, and diphenhydramine.

5. The mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 0.3% to 40%. The condition is that the mass percentage of the hot melt adhesive in the pharmaceutical composition is 14% to 25%. The aforementioned pharmaceutical composition is a pharmaceutical composition in the form of hot-melt granulated granules. The aforementioned pharmaceutical composition does not contain a foaming agent. The aforementioned pharmaceutical composition further comprises one or more of the following: disintegrant, filler, lubricant, flow promoter, flavoring agent, and fragrance. A pharmaceutical composition according to any one of claims 1 to 4, characterized in that it satisfies one or more of the following conditions.

6. The disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, and crospovidone, preferably croscarmellose sodium and / or low-substituted hydroxypropylcellulose. The mass percentage of the disintegrant in the pharmaceutical composition is 0% to 30%, preferably 10% to 22%. The condition that the filler is mannitol and / or lactose, The condition is that the mass percentage of the filler in the pharmaceutical composition is 0% to 50%. The condition is that the lubricant is one or more of the following: 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 further set to 0% to 2%. The condition that the flow promoter is talc and / or colloidal silica, The mass percentage of the flow promoter in the pharmaceutical composition is further set to 0% to 2%. The aforementioned 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% to 5%. The aforementioned fragrance is a fragrance, preferably a natural fragrance. The condition is that the mass percentage of the fragrance in the pharmaceutical composition is 0% to 3%. A pharmaceutical composition according to any one of claims 1 to 5, characterized in that it satisfies one or more of the following conditions.

7. The aforementioned poorly soluble and non-degradable drug is further selected from voriconazole, The pharmaceutical composition further comprises a surfactant, preferably one or more of glycerol monostearate, soy lecithin, lecithin, xanthan gum, polyoxyethylene stearate, and sodium lauryl sulfate, and preferably the mass percentage of the surfactant in the pharmaceutical composition is 0% to 15%. The disintegrant is further microcrystalline cellulose and / or pregelatinized starch, and the mass percentage of the disintegrant in the pharmaceutical composition is 0% to 22%. The filler is further specified as sorbitol. The aforementioned flavoring agent is further provided to be citric acid. The pharmaceutical composition according to claim 5 or 6, characterized in that it satisfies one or more of the following conditions.

8. The active pharmaceutical ingredients are carbidopa and levodopa, the mass percentage of carbidopa in the pharmaceutical composition is 0.5% to 15%, preferably 2% to 15%, the mass percentage of levodopa in the pharmaceutical composition is 2% to 48%, preferably 5% to 48%, and the mass ratio of carbidopa to levodopa is 1:1 to 1:

24. Preferably, the pharmaceutical composition comprises 0.5% to 10% by mass of carbidopa, 2% to 40% of levodopa, 6% to 30% of a hot-melt adhesive and 0% to 30% of a disintegrant, or, the pharmaceutical composition comprises 0.5% to 10% by mass of carbidopa, 2% to 40% of levodopa, 6% to 30% of a Class A hot-melt adhesive and 0% to 30% of a disintegrant. Preferably, the pharmaceutical composition comprises 5.7% to 8.3% by mass of carbidopa, 23% to 33% of levodopa, 15% to 25% of hot melt adhesive, 10.1% to 20.1% of low-substituted hydroxypropyl cellulose, and 23.2% to 33.2% of mannitol, or the pharmaceutical composition comprises 6.5% to 7.5% of carbidopa, 25.1% to 30.1% of levodopa, 17.5% to 22.5% of hot melt adhesive, 13.5% to 18.5% of low-substituted hydroxypropyl cellulose, and 27.0% to 32.0% of mannitol, as described in any one of claims 1 to 7.

9. A pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, wherein the active pharmaceutical ingredient is voriconazole, and the hot-melt adhesive is Class A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407, Alternatively, a Class B hot melt adhesive: selected from polyethylene glycol 6000, The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12% to 25%. The pharmaceutical composition is characterized by being a pharmaceutical composition in the form of hot-melt granulated granules.

10. A pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive, wherein the active pharmaceutical ingredient is voriconazole, and the hot-melt adhesive is Class A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407, And Class B hot melt adhesive: Selected from polyethylene glycol 6000, The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12% to 25%. The pharmaceutical composition is characterized by being a pharmaceutical composition in the form of hot-melt granulated granules.

11. The mass percentage of the aforementioned active pharmaceutical ingredient is 1% to 63%, The pharmaceutical composition according to claim 9 or 10, characterized in that the mass percentage of the Class A hot melt adhesive in the pharmaceutical composition is 5% to 30%.

12. The mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 8.3% to 63%. The mass percentage of the Class A hot melt adhesive in the pharmaceutical composition is 12% to 25%, preferably 15.0% to 21.6%. The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is preferably 15.0% to 21.6%. The aforementioned pharmaceutical composition further comprises one or more of the following: disintegrant, filler, lubricant, flow promoter, and flavoring agent. A pharmaceutical composition according to any one of claims 9 to 11, characterized in that it satisfies one or more of the following conditions.

13. The disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and crospovidone, preferably croscarmellose sodium and / or low-substituted hydroxypropylcellulose. The mass percentage of the disintegrant in the pharmaceutical composition is 0% to 30%, preferably 0% to 20%. The filler is one or more of mannitol, sorbitol, and lactose. The condition is that the mass percentage of the filler in the pharmaceutical composition is 0% to 50%. The condition is that the lubricant is one or more of the following: 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 further set to 0% to 2%. The condition that the flow promoter is talc and / or colloidal silica, The mass percentage of the flow promoter in the pharmaceutical composition is 0% to 2%. The aforementioned flavoring is one or more of sucrose, maltose, stevioside, mannitol, erythrose, aspartame, citric acid, and flavorings, preferably one or more of stevioside, mannitol, erythrose, aspartame, and flavorings. The condition is that the mass percentage of the flavoring agent in the pharmaceutical composition is 0% to 5%. A pharmaceutical composition according to any one of claims 9 to 12, characterized in that it satisfies one or more of the following conditions.

14. The pharmaceutical composition further comprises a surfactant, preferably one or more of glycerol monostearate, soy lecithin, lecithin, xanthan gum, polyoxyethylene stearate, and sodium lauryl sulfate, and the mass percentage of the surfactant in the pharmaceutical composition is 0% to 15%, as described in any one of claims 9 to 13.

15. The pharmaceutical composition comprises, by mass percentage, 1% to 63% of the active pharmaceutical ingredient, 5% to 30% of the Class A hot melt adhesive or 12% to 25% of the Class B hot melt adhesive, 0% to 30% of the disintegrant, 0% to 50% of the filler, 0% to 2% of the lubricant, 0% to 2% of the flow promoter, and 0% to 5% of the flavoring agent. Alternatively, the pharmaceutical composition comprises 1% to 63% by mass of the active pharmaceutical ingredient, 5% to 30% of the "Type A hot melt adhesive and Type B hot melt adhesive," 0% to 30% of the disintegrant, 0% to 50% of the filler, 0% to 2% of the lubricant, 0% to 2% of the flow promoter, and 0% to 5% of the flavoring agent. Preferably, the pharmaceutical composition comprises 8.3% to 63% by mass of voriconazole, 12% to 25% of the hot melt adhesive, 0% to 20% of the disintegrant, 0% to 50% of the filler, 0% to 2% of the lubricant, 0% to 2% of the flow promoter, and 0% to 5% of the flavoring agent. Preferably, the pharmaceutical composition is characterized by comprising 33% to 55% by mass of voriconazole, 15.0% to 21.6% of the hot melt adhesive, 5% to 18% of the disintegrant, 8.5% to 36.5% of the filler, 0% to 1% of the lubricant, 0.5% to 1.5% of the flow promoter, and 0.5% to 1.5% of the flavoring agent, as described in any one of claims 9 to 14.

16. A pharmaceutical preparation characterized by comprising a hot-melt granulated granule and the pharmaceutical composition described in any one of claims 1 to 8.

17. The oral drug delivery device AcuSiS® and the pharmaceutical formulation described in claim 16, wherein the pharmaceutical formulation is placed within the drug-carrying space of the oral drug delivery device AcuSiS®. Preferably, an oral drug delivery kit characterized in that the amount of the pharmaceutical preparation filled is 50 to 1000 mg.

18. A pharmaceutical formulation comprising a hot-melt granulated granule, the pharmaceutical composition described in any one of claims 9 to 15, preferably having a particle size of less than 1000 μm, and preferably the pharmaceutical formulation being carbidopa / levodopa granules, and comprising 25 mg of carbidopa, 100 mg of levodopa, 66.9 mg of hot-melt adhesive, 54.6 mg of low-substituted hydroxypropyl cellulose, and 113.3 mg of mannitol.

19. The oral drug delivery device AcuSiS® and the pharmaceutical formulation described in claim 18, wherein the pharmaceutical formulation is placed within the drug-carrying space of the oral drug delivery device AcuSiS®. Preferably, the amount of the pharmaceutical preparation filled is 50 to 1000 mg. Preferably, the pharmaceutical formulation is carbidopa / levodopa granules, and the oral drug delivery kit is characterized by containing 25 mg of carbidopa, 100 mg of levodopa, 66.9 mg of hot melt adhesive, 54.6 mg of low-substituted hydroxypropyl cellulose, and 113.3 mg of mannitol.

20. Each of the oral drug delivery kits further comprises an sealing layer used to seal the oral drug delivery device AcuSiS®, Preferably, the sealing packaging layer is a polyester-aluminum-polyethylene composite film bag. Preferably, the sealing packaging layer further comprises a desiccant, the desiccant being a bagged desiccant, and more preferably 0.25 g of a bagged desiccant, the oral drug delivery kit according to claim 17 or 19.

21. Use of the pharmaceutical composition according to claim 8 in the manufacture of a pharmaceutical used for emergency or intermittent treatment of off-episodes of Parkinson's disease.

22. Use of the pharmaceutical composition according to any one of claims 9 to 15 in the manufacture of a pharmaceutical used for the treatment or prevention of invasive fungal diseases.

23. A method for producing a pharmaceutical preparation according to claim 16 or 18, wherein the production method is a hot melt granulation method, The hot melt adhesive is crushed to obtain a powder, mixed with the active pharmaceutical ingredient, disintegrant, and filler, hot melt granulation is performed, and then the mixture is uniformly mixed with the remaining components of the pharmaceutical composition and sieved. Alternatively, a manufacturing method characterized by comprising the steps of crushing the hot melt adhesive to obtain a powder, mixing it with the active pharmaceutical ingredient, disintegrant, filler, lubricant and flow promoter, hot melt granulation, then uniformly mixing it with the remaining components of the pharmaceutical composition, adjusting the particle size, and sieving.

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