KR-102963133-B1 - Microspheres containing high-dose varenicline, method for preparing the same, and pharmaceutical composition comprising the same

Abstract

The present invention relates to microspheres comprising varenicline hemipamoate and a biocompatible polymer, a method for manufacturing the same, and a pharmaceutical composition comprising the same. The microspheres containing varenicline according to the present invention encapsulate varenicline at a high concentration, exhibit a stable drug release rate over a long period, and exhibit an appropriate initial release rate, thereby enabling the maintenance of varenicline at an effective concentration in the blood for a certain period without side effects.

Inventors

• 김, 청주
• 안태군
• 김아람
• 신현호
• 박진
• 박유리
• 이기선

Assignees

• 주식회사 아울바이오

Dates

Publication Date

20260511

Application Date

20230118

Claims (17)

1. It includes varenicline hemipamoate and biocompatible polymers, Microspheres characterized by the above-mentioned biocompatible polymer being one or more selected from polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, polyamino acid, and copolymer of lactic acid and amino acid.
2. In paragraph 1, Microspheres characterized by containing the above varenicline hemipamoate in an amount of 2 to 50 weight% based on the total weight of the microspheres.
3. In paragraph 1, Microspheres characterized by containing the above varenicline hemipamoate in an amount of 10 to 30 weight% based on the total weight of the microspheres.
4. In paragraph 2, Microspheres characterized by containing the above-mentioned biocompatible polymer in an amount of 50 to 98 weight percent based on the total weight of the microspheres.
5. delete
6. In paragraph 1, The above microspheres are characterized by the release of varenicline hemipamoate continuing for 30 days or more.
7. In paragraph 1, The above microspheres are characterized by the release of varenicline hemipamoate continuing for 40 days or more.
8. In paragraph 1, Microspheres characterized by having a release amount of varenicline hemipamoate contained in the microspheres within 7 days of 25 weight% or less.
9. In paragraph 1, Microspheres characterized by having a release amount of varenicline hemipamoate contained in the above microspheres within 14 days of 60 weight% or less.
10. In paragraph 1, The above microspheres are characterized by being prepared according to an O/W (oil-in-water) type solvent evaporation or solvent extraction method comprising a biocompatible polymer, varenicline hemipamoate, and a dispersion solvent.
11. (a) a step of preparing a dispersed phase by dispersing varenicline hemipamoate and a biocompatible polymer in one or more solvents; (b) a step of adding the dispersed phase prepared above to a continuous phase and stirring to form microspheres; and (c) a step of removing the solvent; comprising, A method for manufacturing microspheres characterized in that the above-mentioned biocompatible polymer is one or more selected from polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, polyamino acid, and copolymer of lactic acid and amino acid.
12. In Paragraph 11, A method for manufacturing microspheres characterized in that the weight of varenicline hemipamoate encapsulated in microspheres obtained according to the above manufacturing method is 50% by weight or more relative to the weight of varenicline hemipamoate dissolved in step (a).
13. In Paragraph 11, A method for manufacturing microspheres characterized in that the weight of varenicline hemipamoate encapsulated in the microspheres obtained according to the above manufacturing method is 90% by weight or more relative to the weight of varenicline hemipamoate dissolved in step (a).
14. delete
15. A pharmaceutical composition for the prevention or treatment of a disease caused by impaired cholinergic receptor activity, comprising microspheres according to any one of claims 1 to 4 and 6 to 10 and a pharmaceutically acceptable carrier, Diseases caused by the aforementioned cholinergic receptor activity disorders include inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, non-tropical sprue, cystitis, vasoconstriction, anxiety disorders, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag syndrome, amyotrophic lateral sclerosis (ALS), cognitive impairment, drug/toxicity-induced cognitive impairment, disease-induced cognitive impairment, hypertension, bulimia nervosa, anorexia nervosa, obesity, cardiac arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependence and intoxication, headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, reading disorder, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy including absence seizures (vaccinational epilepsy), and attention deficit hyperactivity. A pharmaceutical composition for the prevention or treatment of diseases caused by impaired cholinergic receptor activity, characterized by ADHD or Tourette syndrome.
16. delete
17. In paragraph 15, A pharmaceutical composition characterized in that the disease caused by the above-mentioned cholinergic receptor activity disorder is nicotine dependence and addiction.

Description

Microspheres containing high-dose varenicline, method for preparing the same, and pharmaceutical composition comprising the same The present invention relates to microspheres containing a high dose of varenicline, a method for manufacturing the same, and a pharmaceutical composition containing the same. Varenicline is a compound with the name 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine and has a structure represented by the following chemical formula 1. [Chemical Formula 1] Varenicline, represented by Chemical Formula 1 above, binds to neuronicotinic acetylcholine-specific receptor sites and is a useful drug for improving symptoms caused by impaired cholinergic receptor activity, and is used for inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, non-tropical sprue, cystitis, vasoconstriction, anxiety disorders, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag syndrome, amyotrophic lateral sclerosis (ALS), cognitive impairment, drug/toxicity-induced cognitive impairment, disease-induced cognitive impairment, hypertension, pathological bulimia, anorexia nervosa, obesity, cardiac arrhythmia, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependence and addiction (e.g., dependence or addiction to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids, or cocaine), headache, migraine, stroke, traumatic brain injury (TBI). It is useful for the treatment of obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, reading disorder, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy including absence epilepsy, attention deficit hyperactivity disorder (ADHD), and Tourette syndrome, and for the treatment of nicotine dependence, addiction, and withdrawal, including use in smoking cessation therapy. Currently, the smoking cessation treatment Champix® or Chantix®, which contains varenicline tartrate as its main ingredient , is sold worldwide. Champix® is an adjunctive smoking cessation drug that acts as a partial agonist for α4β2 neuronal nicotine receptors, binding to acetylcholine receptors in the brain instead of nicotine to relieve smoking cravings and withdrawal symptoms. The aforementioned Champix® is known to cause common side effects such as nausea, insomnia, constipation, abdominal distention, and vomiting. In particular, while nausea is temporary, some patients may experience difficulties continuing to take the medication, and persistent nausea may occur. Clinical trials have confirmed that these symptoms increase in a dose-dependent manner. Therefore, to address this problem, the drug is administered through dose titration. First, 0.5 mg of varenicline is taken once a day for 3 days, followed by 0.5 mg twice a day from the 4th to the 7th day. Afterwards, 1.0 mg of varenicline is taken twice a day until the 12th week to maintain an effective blood concentration and alleviate withdrawal symptoms. However, such complex dosing methods have the disadvantage of significantly reducing medication adherence. Therefore, development is underway for sustained-release formulations containing varenicline as the active ingredient that can improve medication convenience, and microparticle systems are being actively researched as such sustained-release formulations. However, in microparticle systems, high initial bursts often occur. Since these initial bursts can cause side effects, including toxic reactions, it is required to eliminate or at least minimize these initial bursts in the development of microparticle systems. On the other hand, reducing initial release through adjustments to the formulation and manufacturing process typically alters the overall release profile. Therefore, it is very difficult to achieve a drug release profile that remains constant over a long period while simultaneously reducing initial release. FIG. 1 is a photograph showing the results of observing the morphology of microspheres prepared in Example 2 and Comparative Examples 2 and 3 of the present invention using a scanning electron microscope (SEM). FIG. 2 is a graph showing the experimental results evaluating the release rate of microspheres prepared in Example 2 and Comparative Example 2 encapsulated with varenicline. Figure 3 is a graph showing the NMR analysis results of the varenicline hemipamoate crystals prepared in Example 1, and Figure 4 is a graph showing the XRD analysis results of the varenicline hemipamoate crystals prepared in Example 1, and FIG. 5 is a graph showing the results of analyzing varenicline hemipamoate crystals prepared in Example 1 using a thermogravimetric analysis (TGA/DSC). Figure 6 is a graph showing the NMR analysis results of varenicline pamoate crystals prepared in Comparative Example 1. The present invention will be described in more detail below. All technical terms used in this inv