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EP-4740962-A1 - PHARMACEUTICAL COMPOSITION, FORMULATION CONTAINING PHARMACEUTICAL COMPOSITION, KIT CONTAINING PHARMACEUTICAL COMPOSITION, PREPARATION METHOD FOR PHARMACEUTICAL COMPOSITION, AND USE OF PHARMACEUTICAL COMPOSITION

EP4740962A1EP 4740962 A1EP4740962 A1EP 4740962A1EP-4740962-A1

Abstract

A pharmaceutical composition, a formulation containing the pharmaceutical composition, a kit containing the pharmaceutical composition, a preparation method for the pharmaceutical composition, and a use of the pharmaceutical composition. 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; and the mass percentage of the hot-melt adhesive in the pharmaceutical composition is 5%-30%. According to the pharmaceutical composition, the formulation containing the pharmaceutical composition, and the kit containing the pharmaceutical composition, the active pharmaceutical ingredient can be rapidly released to achieve a fast onset of action, the stability of the active pharmaceutical ingredient is improved, the swallowing of patients can be further improved, and the patient compliance during actual medicine-taking can be further improved.

Inventors

  • FAN, MING
  • DONG, Liangchang
  • JIAO, Yan
  • ZHANG, Danyong
  • WANG, JINGYI
  • ZHAO, Wenfang
  • ZHU, Jianan
  • REN, MANMAN
  • WU, Xinyue

Assignees

  • Shanghai WD Pharmaceutical Co., Ltd

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. A pharmaceutical composition comprising the following components: an active pharmaceutical ingredient and a hot-melt adhesive; wherein the mass percentage of the active pharmaceutical ingredient is 0.3%-63%; the hot-melt adhesive is: Class A hot-melt adhesive: Poloxamer P188 and/or Poloxamer P407; or Class B hot-melt adhesive: polyethylene glycol 6000; the mass percentage of the Class A hot-melt adhesive in the pharmaceutical composition is 5%-30%; the mass percentage of the Class B hot-melt adhesive in the pharmaceutical composition is 12%-25%; the pharmaceutical composition is a pharmaceutical composition in the form of a hot-melt granulated granule.
  2. The pharmaceutical composition according to claim 1, wherein the mass percentage of the Class A hot-melt adhesive in the pharmaceutical composition may be 14%-25%; and the mass percentage of the Class B hot-melt adhesive in the pharmaceutical composition may be 15.0%-21.6%.
  3. A pharmaceutical composition comprising 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%.
  4. The pharmaceutical composition according to any one of claims 1-3, wherein the active pharmaceutical ingredient comprises, 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, antipsychotic agents, analgesic agents, anti-inflammatory agents, antiemetic agents, and antitussive agents; 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, wherein preferably, the poorly soluble and easily degradable drug is selected from: ritonavir, vonoprazan, rivaroxaban, posaconazole, cefdinir, cefixime, cefuroxime axetil, clarithromycin, linezolid, and duloxetine; the poorly soluble and non-easily degradable drug is selected from: apixaban, tadalafil, dapoxetine, contezolid, olanzapine, aripiprazole, quetiapine fumarate, zolmitriptan, rizatriptan, almotriptan, naratriptan, frovatriptan, eletriptan, and verapamil; the non-poorly soluble and easily degradable drug is selected from: carbidopa, oseltamivir phosphate, favipiravir, molnupiravir, deuremidevir hydrobromide, nirmatrelvir, cefaclor, cefprozil, amoxicillin, montelukast sodium, levetiracetam, and desloratadine; the non-poorly soluble and non-easily degradable drug is selected from: levodopa, sildenafil, vardenafil, tegoprazan, fluconazole, escitalopram oxalate, levocetirizine, amlodipine, ketorolac tromethamine, and diphenhydramine.
  5. The pharmaceutical composition according to any one of claims 1-4, wherein 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 a hot-melt granulated granule; the pharmaceutical composition does not comprise an effervescent system; the pharmaceutical composition further comprises one or more of the following components: a disintegrant, a filler, a lubricant, a glidant, a flavoring agent, and an aromatic agent.
  6. The pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition meets one or more of the following conditions: the disintegrant is 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 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 silica; 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 a flavor, preferably a natural flavor; the mass percentage of the aromatic agent in the pharmaceutical composition is 0%-3%.
  7. The pharmaceutical composition according to claim 5 or 6, wherein the pharmaceutical composition meets one or more of the following conditions: the poorly soluble and non-easily degradable drug is also voriconazole; the pharmaceutical composition further comprises a surfactant; preferably, the surfactant is one or more of glyceryl monostearate, soy lecithin, lecithin, xanthan gum, polyoxyethylene stearate, and sodium dodecyl sulfate; preferably, the mass percentage of the surfactant in the pharmaceutical composition is 0%-15%; the disintegrant is also microcrystalline cellulose and/or pregelatinized starch; the mass percentage of the disintegrant in the pharmaceutical composition is further 0%-22%; the filler is also sorbitol; the flavoring agent is also citric acid.
  8. The pharmaceutical composition according to any one of claims 1-7, wherein the active pharmaceutical ingredient is 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 percentage by mass: 0.5%-10% carbidopa, 2%-40% levodopa, 6%-30% hot-melt adhesive, and 0-30% disintegrant; or, the pharmaceutical composition comprises the following components in percentage by mass: 0.5%-10% carbidopa, 2%-40% levodopa, 6%-30% Class A hot-melt adhesive, and 0-30% disintegrant; more preferably, the pharmaceutical composition comprises the following components in percentage by mass: 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.
  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; or Class B hot-melt adhesive: polyethylene glycol 6000; the mass percentage of the Class B hot-melt adhesive in the pharmaceutical composition is 12%-25%; the pharmaceutical composition is a pharmaceutical composition in the form of a hot-melt granulated granule.
  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 selected from: Class A hot-melt adhesive: Poloxamer P188 and/or Poloxamer P407; and Class B hot-melt adhesive: polyethylene glycol 6000; the mass percentage of the Class B hot-melt adhesive in the pharmaceutical composition is 12%-25%; the pharmaceutical composition is a pharmaceutical composition in the form of a hot-melt granulated granule.
  11. The pharmaceutical composition according to claim 9 or 10, wherein the mass percentage of the active pharmaceutical ingredient is 1%-63%; the mass percentage of the Class A hot-melt adhesive in the pharmaceutical composition is 5%-30%.
  12. The pharmaceutical composition according to any one of claims 9-11, wherein the pharmaceutical composition meets one or more of the following conditions: the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 8.3%-63%; the mass percentage of the Class A hot-melt adhesive in the pharmaceutical composition is 12%-25%, preferably 15.0%-21.6%; the mass percentage of the Class B hot-melt adhesive in the pharmaceutical composition is preferably 15.0%-21.6%; the pharmaceutical composition further comprises one or more of the following components: a disintegrant, a filler, a lubricant, a glidant, and a flavoring agent.
  13. The pharmaceutical composition according to any one of claims 9-12, wherein the pharmaceutical composition meets one or more of the following conditions: the disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and crospovidone, preferably croscarmellose sodium and/or low-substituted hydroxypropyl cellulose; the mass percentage of the disintegrant in the pharmaceutical composition is 0%-30%, preferably 0%-20%; the filler is one or more of mannitol, sorbitol, and 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 silica; 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, aspartame, citric acid, and flavor, preferably one or more of stevioside, mannitol, erythrose, aspartame, and flavor; the mass percentage of the flavoring agent in the pharmaceutical composition is 0%-5%.
  14. The pharmaceutical composition according to any one of claims 9-13, wherein the pharmaceutical composition further comprises a surfactant; preferably, the surfactant is one or more of glyceryl monostearate, soy lecithin, lecithin, xanthan gum, polyoxyethylene stearate, and sodium dodecyl sulfate; the mass percentage of the surfactant in the pharmaceutical composition is 0%-15%.
  15. The pharmaceutical composition according to any one of claims 9-14, wherein the pharmaceutical composition comprises the following components in percentage by mass: 1%-63% of the active pharmaceutical ingredient, "5%-30% of the Class A hot-melt adhesive or 12%-25% of the Class B hot-melt adhesive", 0%-30% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant, and 0%-5% of the flavoring agent; or, the pharmaceutical composition comprises the following components in percentage by mass: 1%-63% of the active pharmaceutical ingredient, 5%-30% of "the Class A hot-melt adhesive and the Class B hot-melt adhesive", 0%-30% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant, and 0%-5% of the flavoring agent; preferably, the pharmaceutical composition comprises the following components in percentage by mass: 8.3%-63% of voriconazole, 12%-25% of the hot-melt adhesive, 0%-20% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant, and 0%-5% of the flavoring agent; more preferably, the pharmaceutical composition comprises the following components in percentage by mass: 33%-55% of voriconazole, 15.0%-21.6% of the hot-melt adhesive, 5%-18% of the disintegrant, 8.5%-36.5% of the filler, 0%-1% of the lubricant, 0.5%-1.5% of the glidant, and 0.5%-1.5% of the flavoring agent.
  16. A pharmaceutical formulation, wherein the pharmaceutical formulation is a hot-melt granulated granule, and the pharmaceutical formulation comprises the pharmaceutical composition according to any one of claims 1-8.
  17. An oral administration delivery formulation kit, wherein the oral administration delivery formulation kit comprises an oral administration delivery device AcuSiS ® and the pharmaceutical formulation according to claim 16; the pharmaceutical formulation is disposed in a drug-carrying space of the oral administration delivery device AcuSiS ® ; preferably, the filling amount of the pharmaceutical composition is 50-1000 mg.
  18. A pharmaceutical formulation, wherein the pharmaceutical formulation is a hot-melt granulated granule, and the pharmaceutical formulation comprises the pharmaceutical composition according to any one of claims 9-15; preferably, the particle size of the hot-melt granulated granule is less than 1000 µm; preferably, the pharmaceutical formulation is a carbidopa-levodopa granule comprising 25 mg of carbidopa, 100 mg of levodopa, 66.9 mg of a hot-melt adhesive, 54.6 mg of low-substituted hydroxypropyl cellulose, and 113.3 mg of mannitol.
  19. An oral administration delivery formulation kit, wherein the oral administration delivery formulation kit comprises an oral administration delivery device AcuSiS ® and the pharmaceutical formulation according to claim 18; the pharmaceutical formulation is disposed in a drug-carrying space of the oral administration delivery device AcuSiS ® ; preferably, the filling amount of the pharmaceutical formulation is 50-1000 mg; preferably, the pharmaceutical formulation is a carbidopa-levodopa granule comprising 25 mg of carbidopa, 100 mg of levodopa, 66.9 mg of a hot-melt adhesive, 54.6 mg of low-substituted hydroxypropyl cellulose, and 113.3 mg of mannitol.
  20. The oral administration delivery formulation kit according to claim 17 or 19, wherein each said oral administration delivery formulation kit further comprises an encapsulation layer for sealing the oral administration delivery device AcuSiS ® ; preferably, the encapsulation layer is a polyester-aluminum-polyethylene composite film bag; preferably, a desiccant is further provided in the encapsulation layer, wherein the desiccant is a bagged desiccant, more preferably a 0.25 g bagged desiccant.

Description

The present application claims the right of priorities to Chinese Patent Application No. 2023108219336 filed on July 5, 2023 and Chinese Patent Application No. 2024101572389 filed on February 2, 2024. The contents of the above Chinese patent applications are incorporated herein by reference in their entireties. TECHNICAL FIELD The present disclosure relates to a pharmaceutical composition, a formulation containing the pharmaceutical composition, a kit containing the pharmaceutical composition, a preparation method for the pharmaceutical composition, and a use of the pharmaceutical composition. BACKGROUND In certain disease areas, such as motor dysfunction, heart disease, hypertension, asthma, pain, bleeding, bacterial or fungal infections, allergies, influenza, COVID-19, male erectile dysfunction, and gastric reflux, it is required that drugs take effect rapidly after administration to achieve prompt relief and improvement of disease symptoms. In oral formulations, since solution formulations do not have release issues, they generally take effect relatively quickly after administration. However, solid formulations offer greater advantages for active pharmaceutical ingredients that are moisture-sensitive or have low solubility. In oral solid formulations, dosage forms such as granules, dispersible tablets, effervescent tablets, orally disintegrating tablets, and oral dissolving films can achieve the characteristic of rapid release of active pharmaceutical ingredients. For pediatric and elderly populations, as well as patients with dysphagia, the aforementioned formulations can facilitate swallowing and improve medication adherence, but they also introduce issues related to palatability and stability. Specifically in the field of Parkinson's disease, the clinical needs for rapid drug onset and ease of swallowing are described as follows. Parkinson's disease (PD), also known as paralysis agitans, is one of the most common neurodegenerative diseases, typically onset between the ages of 50 and 65. Epidemiology indicates that there are over 10 million Parkinson's disease patients worldwide, with nearly 3 million in China. In China, more than 100,000 new cases are reported annually, and in recent years, there has been a trend toward younger onset. Parkinson's disease has become the "second most common neurodegenerative disease" after Alzheimer's disease. Parkinson's disease is a progressive disease caused by the loss of dopamine-producing cells in the brain. Currently, due to the unclear pathogenesis, there are no drugs that can cure the disease or halt its progression; all drugs aim to help control symptoms. In patients with Parkinson's disease, dopamine production in the brain is reduced. Dopamine is an endogenous substance present in the brain and spinal cord, which helps brain nerve cells properly control motor functions. When dopamine levels in the brain decrease, symptoms of Parkinson's disease will occur, such as tremors, muscle stiffness, bradykinesia, or freezing episodes (OFF episodes) like difficulty walking. Dysphagia is common among patients with Parkinson's disease. An epidemiological study indicates that 11%-81% of Parkinson's patients experience dysphagia, with pulmonary infections caused by swallowing disorders accounting for as high as 91.7% in community 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 patients, causing numerous inconveniences in daily activities such as eating and medication administration, and severely impacting the quality of life, particularly during the "OFF" state. As Parkinson's disease progresses, when the patient's levodopa concentration decreases, the patient may experience freezing episodes (OFF episodes), characterized by sudden onset and brief duration, during which patients are unable to generate effective forward steps. In some cases, patients may experience complete immobility upon standing, lasting from several seconds to several tens of minutes. Freezing gait is a significant cause of physical injury and disability in Parkinson's patients and increases the financial burden on their families. When patients are driving or crossing the road, the occurrence of freezing episodes can even lead to traffic accidents, resulting in serious consequences. Studies have shown (Li Yan, Wang Lijuan, Zhang Yuhu. Research progress on freezing of gait[J]. Journal of Clinical Neurology. 2016, 29(2): 149-151.) that freezing gait occurs in 7% of patients with early-stage idiopathic Parkinson's disease. Approximately 50% of Parkinson's patients with a disease course exceeding 10 years have experienced freezing gait. As the disease progresses, the frequency and duration of episodes increase. In summary, designing a drug delivery system that improves dy