WO2023014175A1 - 도네페질 함유 지속방출형 미립구 - Google Patents
도네페질 함유 지속방출형 미립구 Download PDFInfo
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- WO2023014175A1 WO2023014175A1 PCT/KR2022/011672 KR2022011672W WO2023014175A1 WO 2023014175 A1 WO2023014175 A1 WO 2023014175A1 KR 2022011672 W KR2022011672 W KR 2022011672W WO 2023014175 A1 WO2023014175 A1 WO 2023014175A1
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- Prior art keywords
- donepezil
- microspheres
- drug loading
- dispersed phase
- drug
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- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 title claims abstract description 204
- 239000004005 microsphere Substances 0.000 title claims abstract description 134
- 229960003530 donepezil Drugs 0.000 title claims abstract description 102
- 238000013268 sustained release Methods 0.000 title claims description 12
- 239000012730 sustained-release form Substances 0.000 title claims description 12
- 238000002347 injection Methods 0.000 claims abstract description 23
- 239000007924 injection Substances 0.000 claims abstract description 23
- 229940079593 drug Drugs 0.000 claims description 138
- 239000003814 drug Substances 0.000 claims description 138
- 238000011068 loading method Methods 0.000 claims description 110
- 229920002988 biodegradable polymer Polymers 0.000 claims description 12
- 239000004621 biodegradable polymer Substances 0.000 claims description 12
- 239000007972 injectable composition Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 229920000642 polymer Polymers 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- 239000004372 Polyvinyl alcohol Substances 0.000 description 21
- 229920002451 polyvinyl alcohol Polymers 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 19
- 239000008280 blood Substances 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- 238000005538 encapsulation Methods 0.000 description 7
- 239000008215 water for injection Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 238000009775 high-speed stirring Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000007935 oral tablet Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
Definitions
- the present invention relates to sustained-release microspheres containing donepezil and an injection containing the same.
- Donepezil is a drug developed to treat dementia (particularly, Alzheimer's dementia), and an oral tablet is currently being sold. Currently marketed oral tablets containing donepezil are instructed to be taken once daily before bedtime.
- the sustained-release injection contains microspheres in which a drug is encapsulated in a biodegradable polymer.
- a microsphere-containing injection When such a microsphere-containing injection is injected into the body, the drug is gradually released from the microspheres injected into the body, so that the pharmacological effect can be continuously displayed. Therefore, when the sustained-release injection is administered once, the drug can be continuously displayed for a long time, for example, at least one week or more. If such a sustained-release injection is developed, for example, the drug effect can be maintained even if the drug is injected and administered every 1 week, 10 days, 4 weeks or 2 months, minimizing the number of invasions of the drug into the body and taking medication Adaptability can be dramatically improved.
- the present invention is to develop a donepezil-containing sustained-release injection that minimizes the range of fluctuations in blood drug concentration during administration, thereby minimizing side effects and continuously exhibiting pharmacological effects.
- microspheres are prepared therefrom, for example, by a single emulsification method, so that 40 to 40 to 40% of the total drug in the first half of the drug administration cycle is prepared.
- Sustained release microspheres can be provided that release 60%.
- the present invention relates to a sustained-release injectable composition containing two or more types of donepezil microspheres with different drug loadings, wherein the administration cycle (eg, administration every week, administration every 10 days, or administration every 4 days)
- the ratio of AUC during the first half of the dosing cycle to AUC during the first half of the dosing cycle i.e., AUC 0 to 1/2 dosing cycle / AUC 0 ⁇ dosing cycle
- the drug loading amount refers to the weight ratio of donepezil contained in the microspheres to the corresponding microspheres.
- the administration cycle may be designed to have a range of, for example, 7 days or more, preferably 7 days to 2 months.
- it can be designed with the goal of administering the injection of the present invention every 10 days or every 4 weeks.
- the average drug loading of the donepezil microspheres is preferably 35% or less, preferably 32% or less.
- a high drug loading may be advantageous. There is a problem in that it cannot be maintained at an effective concentration during the administration cycle, or the drug not encapsulated in the microspheres exists as crystals, resulting in high blood concentrations immediately after administration.
- the donepezil microspheres preferably contain two types of theoretical drug loadings: 32-40% and 28-32%. That is, the injection of the present invention includes both donepezil-containing microspheres with a theoretical drug loading of 32 to 40% and donepezil-containing microspheres with a theoretical drug loading of 28 to 32% (here, the drug loading of the present invention is different from each other) Since two or more types of donepezil microspheres are included, the theoretical drug loading of microspheres cannot all be 32%).
- the injection of the present invention includes donepezil-containing microspheres having a theoretical drug loading of 28% or more and 32% or less and donepezil-containing microspheres having a theoretical drug loading of more than 32% and 40% or less, or a theoretical drug loading of 28% or more and 32% or less. less than donepezil-containing microspheres and donepezil-containing microspheres having a theoretical drug loading of 32% or more and 40% or less.
- the term "theoretical drug loading amount” refers to the amount of the loaded raw material donepezil and the injected raw material polymer when producing donepezil-containing microspheres, assuming that all of the injected raw material donepezil is produced in microspheres, and that all of the injected raw material donepezil is encapsulated in the microspheres. It means the loading amount of donepezil in microspheres, which can be obtained from Equation 1 below:
- Theoretical drug loading (%) [amount of donepezil added during microsphere preparation / (amount of donepezil added during microsphere preparation + amount of polymer added during microsphere preparation) ] ⁇ 100 (%)
- actual drug loading amount refers to the content of donepezil contained per 100 mg of microspheres actually prepared when the microspheres containing donepezil are prepared, and is used interchangeably with the term “drug loading amount” unless otherwise specified. and can be used
- the weight ratio of microspheres having a theoretical drug loading of 32 to 40% and microspheres having a theoretical drug loading of 28 to 32% is preferably 1:0.8 to 5.
- the donepezil microspheres include donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof and a biodegradable polymer.
- the donepezil microspheres preferably contain an average of 25 to 32 mg of donepezil or a pharmaceutically acceptable salt thereof per 100 mg of the microspheres (ie, the actual drug loading amount in the present invention is 25 to 32 mg). preferably 32%).
- the present invention relates to a method for preparing two or more types of donepezil microspheres having different drug loadings.
- the preparation may include preparing microspheres by sequentially adding the first dispersion containing donepezil and the second dispersion phase containing donepezil to the continuous phase and then stirring them.
- It may be prepared by mixing the first microsphere and the second microsphere.
- the loading amount of the first drug and the loading amount of the second drug are different from each other.
- the encapsulation rate means the ratio of the actual drug loading amount to the theoretical drug loading amount, and is calculated according to Equation 2 below:
- the encapsulation rate has a value of approximately 90% to 100%.
- the drug loading amount means a target theoretical drug loading amount or an actual drug loading amount reflecting an encapsulation rate
- the present invention by including two or more types of microspheres showing different drug loading amounts in the injection and administering the injection cycle, It can exert the effect of exhibiting uniform AUC and uniform drug concentration in blood during
- the sustained-release microsphere injection according to the present invention uses polymers having different properties or simply prepares two solutions having different drug loadings in a specific ratio with one polymer without any additional process, thereby consistently releasing the drug in the body for a target period. Therefore, it is possible to suppress side effects at a therapeutic concentration or higher and improve medication non-compliance.
- Figure 1 is the result of the 28-day drug concentration profile of Example 2 and Comparative Example in the SD rat pharmacokinetic test of Experimental Example 3.
- Example 2 is a SEM image for confirming the morphology of the donepezil-containing microspheres prepared in Example 2.
- Example 1 Preparation of polymer microspheres with a weight ratio of 36% and 30% theoretical drug loading of 1:1 (total theoretical drug loading is 33%)
- the organic solvent was volatilized at a temperature of 47° C. for 3 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- Example 2 Preparation of polymer microspheres with a weight ratio of 40% and 30% theoretical drug loading of 1:4 (total theoretical drug loading 32%)
- the organic solvent was volatilized at a temperature of 47° C. for 3 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- Example 3 Preparation of polymeric microspheres with a theoretical drug loading of 38% and a theoretical drug loading of 28% in a weight ratio of 1:2 (total theoretical drug loading of 31.3%)
- the organic solvent was volatilized at a temperature of 47° C. for 3 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- Example 4 Preparation of polymeric microspheres composed of 32% theoretical drug loading and 28% weight ratio of 1:1 (total theoretical drug loading 30%)
- the organic solvent was volatilized at a temperature of 47° C. for 3 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- Comparative Example 1 Preparation of polymeric microspheres in which 40% of the theoretical drug loading amount is a single weight ratio
- the organic solvent was volatilized at a temperature of 47° C. for 2 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- Comparative Example 2 Preparation of polymeric microspheres in which 30% of the theoretical drug loading amount is a single weight ratio
- the organic solvent was volatilized at a temperature of 47° C. for 3 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- Comparative Example 3 Preparation of polymeric microspheres composed of 40% theoretical drug loading and 30% weight ratio of 1:1 (total theoretical drug loading 35%)
- the organic solvent was volatilized at a temperature of 47° C. for 3 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, wet-filtered using a sieve net, and freeze-dried to finally obtain microspheres containing donepezil.
- microspheres were fixed to an aluminum stub using carbon tape, coated with platinum for 3 minutes under a vacuum of 0.1 torr and high voltage (10 kV), and then SEM (equipment name: SEC-SNE 4500M Plus A, Korea) It was mounted on powder, and the microsphere surface morphology was observed using an image analysis program (mini-SEM).
- Example 2 is a SEM picture of the microspheres prepared in Example 1.
- Example 1 Percentage of theoretical drug loading Average theoretical drug loading (%) Drug Enclosure Rate (%) Actual drug loading (%)
- Example 1 36%:30% 1:1 33.0 92.9 30.65
- the encapsulation rate is calculated according to the following equation:
- the "ratio of theoretical drug loading” represents the ratio of the total weight of microspheres having a relatively high theoretical drug loading to the total weight of microspheres having a relatively small theoretical drug loading.
- the drug encapsulation rates of Examples 1 to 4 and Comparative Examples 1 to 3 were all about 90% or more.
- This experiment is to confirm the effect of reducing the variability of blood drug concentration according to the content ratio of microspheres with different drug loading amounts.
- microspheres prepared in Examples 1 to 4 and Comparative Examples 1 to 3 were injected subcutaneously into the cervical region of SD rats, and the concentration of donepezil in blood was measured.
- AUC Absolute under Curve
- AUC is a parameter related to the amount of a drug absorbed from the digestive tract or absorbed from tissues upon administration by injection and reaching the circulatory bloodstream in the body.
- Comparative Example 1 since an excessively large amount of drug reaches the bloodstream during the first half of the administration cycle during injection administration, it is difficult to reach an effective blood concentration after the first half of the administration cycle.
- Comparative Example 2 when administered by injection, a relatively small amount of drug reaches the bloodstream during the first half of the administration cycle, and therefore, an effective blood concentration may not be reached during the first half of the administration cycle.
- Examples 1 to 4 including two types of microspheres with different drug loadings 336 hours (336 hours, half of the initial half of the administration cycle) for AUC up to 672 hours (28 days), which is the target administration cycle. 14 days) ranged from 0.4 to 0.6. That is, it exhibits a uniform AUC and uniform drug release during the target administration cycle. Therefore, when the microspheres of Examples 1 to 4 are administered by injection, the effective blood concentration can be continuously reached throughout the administration cycle, and an abnormally low blood drug concentration or an abnormally high blood drug concentration is exhibited at the beginning of the administration, resulting in a curative effect. It is possible to prevent the occurrence of a phenomenon in which the effect is not observed or the treatment effect is biased, and the medication compliance can be improved.
- microspheres with relatively high theoretical drug loadings have a relatively high theoretical drug loading of 40%
- the microspheres with relatively low theoretical drug loadings have a larger total weight.
- the total weight ratio of microspheres having a theoretical drug loading of 40% and microspheres having a theoretical drug loading of 30% is 1:4
- the average actual drug loading of the microspheres is relatively small, 30%
- the AUC ratio is 0.52, which is a desirable result.
- the theoretical drug loading of microspheres with relatively high theoretical drug loading is 40%
- the effect when the average actual drug loading of microspheres exceeds 32% and it can be seen that the effect appears preferably when the average actual drug loading of the microspheres is 32% or less. Therefore, in the present invention, when the content of microspheres having a relatively high drug loading amount is relatively high among two types of microspheres having different drug loading amounts, it can be said that it is preferable that the average actual drug loading amount of the microspheres is 32% or less.
- This experiment is an experiment to confirm whether the results of the ratio of AUC in the pharmacokinetic (PK) test for SD rats of Experimental Example 3 appear similarly in beagle dogs, which are other experimental animal species.
- microspheres prepared in Examples 1 to 4 and Comparative Examples 1 to 3 were injected intramuscularly into the thigh of a beagle dog, and the concentration of donepezil in blood was measured.
- the AUC 0 -336h /AUC 0-672h ratio is within the range of 0.4 to 0.6, which is a uniform drug as in the case of rat administration. means release.
- microsphere-containing injectable composition according to the present invention can exhibit a constant therapeutic effect during the target administration period by exhibiting a constant AUC during the administration period, and this effect appears similarly when administered to other species.
- the injectable composition according to the present invention can be usefully used as a treatment for dementia.
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Abstract
Description
이론 약물 로딩량의 비율 | 평균 이론 약물 로딩량(%) | 약물 봉입률(%) | 실제 약물 로딩량(%) | |
실시예 1 | 36%:30% = 1:1 | 33.0 | 92.9 | 30.65 |
실시예 2 | 40%:30% = 1:4 | 32.0 | 94.2 | 30.16 |
실시예 3 | 38%:28% = 1:2 | 31.3 | 94.8 | 29.71 |
실시예 4 | 32%:28% = 1:1 | 30.0 | 95.6 | 28.68 |
비교예 1 | 40% 단독 | 40.0 | 94.4 | 37.74 |
비교예 2 | 30% 단독 | 30.0 | 89.6 | 26.88 |
비교예 3 | 40%:30% = 1:1 | 35.0 | 91.6 | 32.07 |
AUC0 -336h (hr*ng/mL) | AUC0 -672h (hr*ng/mL) | AUC0 -336h/AUC0 -672h 비(ratio) | |
실시예 1 | 5120.4 | 9288.6 | 0.55 |
실시예 2 | 6055.7 | 11639.2 | 0.52 |
실시예 3 | 5871.3 | 9997.4 | 0.59 |
실시예 4 | 4056.0 | 9209.1 | 0.44 |
비교예 1 | 17433.3 | 20335.6 | 0.86 |
비교예 2 | 3705.5 | 11651.9 | 0.32 |
비교예 3 | 13297.3 | 17602.1 | 0.76 |
AUC0 -336h (hr*ng/mL) | AUC0 -672h (hr*ng/mL) | AUC0 -336h/AUC0 -672h 비(ratio) | |
실시예 2 | 1167.9 | 2038.9 | 0.57 |
실시예 3 | 1205.6 | 2168.0 | 0.56 |
실시예 4 | 795.8 | 1629.7 | 0.49 |
Claims (10)
- 약물 로딩량이 서로 상이한 2종류 이상의 도네페질 미립구를 포함하는 지속 방출형 주사제 조성물로서,투여 주기 동안의 AUC에 대한 투여 주기의 초기 절반 동안의 AUC의 비가 0.4 ~ 0.6 인 주사제 조성물.(여기에서, 상기 약물 로딩량은 각 미립구 중에 포함되어 있는 도네페질의 해당 미립구에 대한 중량비를 의미한다)
- 제1항에 있어서, 상기 투여 주기는 1주 내지 2개월인 것을 특징으로 하는 주사제 조성물.
- 제1항에 있어서. 상기 투여 주기는 10일 내지 28일인 것을 특징으로 하는 주사제 조성물.
- 제1항에 있어서, 상기 도네페질 미립구는 이론 약물 로딩량이 32~40%인 것과 28~32%인 것의 2종류를 포함하는 것을 특징으로 하는 주사제 조성물.
- 제1항에서 상기 도네페질 미립구는 평균 약물 로딩량이 32% 이하인 것을 특징으로 하는 주사제 조성물.
- 제4항에 있어서, 이론 약물 로딩량이 32~40%인 미립구와 이론 약물 로딩량이 28~32%인 미립구의 중량비는 1 : 0.8 ~ 5인 것을 특징으로 하는 주사제 조성물.
- 제1항 내지 제6항 중 어느 한 항에 있어서, 상기 도네페질 미립구는 도네페질 또는 이의 약학적으로 허용되는 염, 수화물 또는 용매화물 및 생분해성 고분자를 포함하는 주사제 조성물.
- 제5항에 있어서, 상기 도네페질 미립구는, 미립구 100mg 당 도네페질 또는 이의 약학적으로 허용되는 염을 도네페질로서 평균 25 내지 32mg 포함하는 것을 특징으로 하는 주사제 조성물.
- 도네페질 함유 미립구를 제조하는 방법으로서,제1 약물 로딩량을 갖는 도네페질 함유 제1 분산상을 제조하는 단계;제2 약물 로딩량을 갖는 도네페질 함유 제2 분산상을 제조하는 단계;상기 도네페질 함유 제1 분산상 및 도네페질 함유 제2분산상을 순차적으로 연속상에 가한 후, 교반하여 미립구를 제조하는 단계를 포함하되,상기 제1 약물 로딩량 및 상기 제2 약물 로딩량은 서로 상이하여, 약물 로딩량이 서로 상이한 2종류 이상의 도네페질 미립구를 제조하는 방법.
- 도네페질 함유 미립구를 제조하는 방법으로서,제1 약물 로딩량을 갖는 도네페질 함유 제1 분산상을 제조하는 단계;상기 도네페질 함유 제1 분산상을 연속상에 가한 후, 교반하여 제1 미립구를 제조하는 단계;제2 약물 로딩량을 갖는 도네페질 함유 제2 분산상을 제조하는 단계;상기 도네페질 함유 제2분산상을 별도의 연속상에 가한 후, 교반하여 제2 미립구를 제조하는 단계; 및상기 제1 미립구와 상기 제2 미립구를 혼합하는 단계를 포함하되,상기 제1 약물 로딩량 및 상기 제2 약물 로딩량은 서로 상이하여, 약물 로딩량이 서로 상이한 2종류 이상의 도네페질 미립구를 제조하는 방법.
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EP22853550.6A EP4382095A1 (en) | 2021-08-05 | 2022-08-05 | Sustained-release microspheres comprising donepezil |
CN202280067500.XA CN118103033A (zh) | 2021-08-05 | 2022-08-05 | 包含多奈哌齐的持续释放微球 |
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KR20160070191A (ko) * | 2013-11-06 | 2016-06-17 | 스템센트알엑스 인코포레이티드 | 신규한 항-클라우딘 항체 및 사용 방법 |
KR20180088445A (ko) * | 2015-12-04 | 2018-08-03 | 애브비 스템센트알엑스 엘엘씨 | 신규한 항-클라우딘 항체 및 사용 방법 |
KR20190064526A (ko) * | 2017-11-30 | 2019-06-10 | 주식회사 지투지바이오 | 도네페질을 함유하는 서방성 주사제제 및 그 제조방법 |
KR20190078017A (ko) * | 2017-12-26 | 2019-07-04 | 동국제약 주식회사 | 도네페질을 포함하는 장기지속형 미립구 및 이의 제조방법 |
KR102212717B1 (ko) * | 2019-11-08 | 2021-02-08 | 환인제약 주식회사 | 지속 방출을 위한 마이크로스피어 및 이의 제조 방법 |
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KR20160070191A (ko) * | 2013-11-06 | 2016-06-17 | 스템센트알엑스 인코포레이티드 | 신규한 항-클라우딘 항체 및 사용 방법 |
KR20180088445A (ko) * | 2015-12-04 | 2018-08-03 | 애브비 스템센트알엑스 엘엘씨 | 신규한 항-클라우딘 항체 및 사용 방법 |
KR20190064526A (ko) * | 2017-11-30 | 2019-06-10 | 주식회사 지투지바이오 | 도네페질을 함유하는 서방성 주사제제 및 그 제조방법 |
KR20190078017A (ko) * | 2017-12-26 | 2019-07-04 | 동국제약 주식회사 | 도네페질을 포함하는 장기지속형 미립구 및 이의 제조방법 |
KR102212717B1 (ko) * | 2019-11-08 | 2021-02-08 | 환인제약 주식회사 | 지속 방출을 위한 마이크로스피어 및 이의 제조 방법 |
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CA3231101A1 (en) | 2023-02-09 |
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