KR102272756B1 - Sustained drug delivery formulation for treatment of psychosis or central nervous system diseases and preparation method thereof - Google Patents

Abstract

The present invention relates to a sustained-release drug delivery formulation for the treatment of mental or central nervous system diseases and a method for preparing the same, and more particularly, to a drug delivery for the treatment of mental or central nervous system diseases, including microspheres containing biodegradable polymers and drugs It relates to formulations and methods for preparing them. The drug delivery formulation according to the present invention is a sustained-release microsphere formulation that can keep the amount of drug released into the blood constant for a long time, and improves the problem of having to administer the drug several times at regular time intervals to the conventional patient, There is an advantage that a desired release behavior can be easily and continuously obtained with a single dose. In addition, the manufacturing method of the drug delivery formulation of the present invention has the advantage of being able to reduce the manufacturing time and cost by preparing the sustained release drug delivery formulation for about 28 days or more as a simple process compared to the conventional method.

Description

Sustained-release drug delivery formulation for the treatment of mental or central nervous system diseases and a method for preparing the same {Sustained drug delivery formulation for treatment of psychosis or central nervous system diseases and preparation method thereof}

The present invention relates to a sustained-release drug delivery formulation for the treatment of mental or central nervous system diseases and a method for preparing the same, and more particularly, to a drug delivery for the treatment of mental or central nervous system diseases, including microspheres containing biodegradable polymers and drugs It relates to formulations and methods for preparing them.

Recently, the number of psychotic patients is increasing rapidly with the aging population and social stress, which are schizophrenia, schizophrenic disorder, schizoaffective disorder, bipolar disorder, non-bipolar mania, Tourette's syndrome, cyclothymic disorder, rapid Cycles, circadian rhythm, personality disorder, attention disorder with or without hyperactivity, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder caused by common drug condition, psychotic disorder related to Parkinson's disease, substance-induced sexual psychotic disorder or psychotic disorder not otherwise specified, anxiety disorders such as generalized anxiety disorder, panic disorder, post-traumatic stress disorder, impulse control disorder, phobia disorder and dissociative states.

As the number of patients with Alzheimer's disease type dementia and schizophrenia among psychosis increases, patient management is emerging as a serious social problem. Accordingly, antipsychotic drugs are rapidly being developed. Alzheimer's disease (AD) is an irreversible, progressive disorder in which brain cells (neurons) are destroyed resulting in loss of cognitive function, memory, judgment, reasoning, motor control, and pattern recognition. In the advanced stages of the disease, all memory and mental functions may be lost, and problems with memory, judgment, and thinking occur, making it impossible to work or perform daily activities. Currently, there is no cure for Alzheimer's disease, and only drugs that relieve symptoms or slow the progression of the disease exist.

Currently, the US Food and Drug Administration (FDA) has approved drugs such as donepezil, galantamine hydrobromide, and aripiprazole for the management of Alzheimer's disease. Most of these anti-dementia drugs are orally administered in the form of tablets, but it is difficult to regularly orally take the drugs to dementia patients who have lost cognitive function.

Therefore, sustained-release injections are very useful in order to improve patient convenience and compliance by reducing the frequency of drug administration, and to maintain a uniform drug release concentration for a long period of time during a single administration. Therefore, the demand for sustained-release injections of antipsychotic drugs with stable drug release for a long period of time is continuously increasing.

Conventional injection formulations such as infusion suspensions and emulsions are rapidly removed from the body after intramuscular or subcutaneous administration, so frequent injection administration was essential for the treatment of chronic diseases. Microspheres designed to solve these problems usually have a size of a micro unit, so they can be administered to humans or animals by intramuscular or subcutaneous injection. It can be manufactured to have various drug release rates, so that the drug delivery period can be controlled. Therefore, it is possible to maintain an effective therapeutic drug concentration for a long time with only one administration, thereby minimizing the total drug dosage required for treatment, and improving the patient's drug treatment compliance.

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Laid-Open Patent Publication No. 10-2018-0092497 (2018.08.20.)

An object of the present invention is to provide a sustained-release drug delivery formulation for the treatment of mental or central nervous system diseases and a method for preparing the same.

An object of the present invention is to maximize the therapeutic effect by suppressing excessive drug release through the drug delivery formulation and controlling drug release at a constant rate to maintain the drug concentration in the blood for about 28 days or more.

The present invention is to solve the above problems, and provides a sustained-release drug delivery formulation for the treatment of psychiatric or central nervous system diseases, comprising microspheres containing biodegradable polymer and antipsychotic agent or central nervous system disease agent.

The biodegradable polymer of the present invention is a polymer material with excellent biocompatibility because it is decomposed into water and carbon dioxide harmless to the human body through the citric acid cycle, which is a normal metabolic process in the body when administered to the body. to form an outer wall material of the microsphere, and the drug release rate is controlled according to the type and composition of the biodegradable polymer. An antipsychotic agent or a central nervous system disease agent is encapsulated in the biodegradable polymer to form spherical microspheres.

The biodegradable polymer used in the present invention is polyethylene glycol (Polyethyleneglycol, PEG), polycaprolactone (PCL), polyalkylcarbonate (Polyalkylcarbonate), polyamino acid (Polyamino acid), polyhydroxybutyric acid (Polyhydroxybutyric acid) ), Polyorthoester, Polyanhydride, Pluronic (Poly(ethylene oxide)poly(propylene oxide)poly(ethylene oxide), Pluronic), Polylactide (PLA), Poly Polyglycolide (PGA), polylactide-co-glycolide (PLGA), (polylactide-co-glycolide)-glucose (Polylactide-co-glycolide-glucose, PLGA-glucose), methoxy Including synthetic polymers such as polyethylene glycol-(polycaprolactone-co-polylactide) (MPEG-(PCL-co-PLLA)), carboxymethylcellulose, algin, alginic acid or alginate (alginic acid, alginate) ), hyaluronic acid, polypeptides or proteins, gelatin, casein, chitin derivatives, chitosan, and natural polymers such as small intestine submucosa.

The amount and rate of drug release can be controlled according to the type and combination of the biodegradable polymer. For example, the rate of decomposition of polylactide-co-glycolide (PLGA) in the human body depends on the ratio of the components of polylactide (PLA) to polyglycolide (PGA), which results in the drug release rate. Adjustable. Therefore, the drug release rate can be controlled by using such a biodegradable polymer as a matrix for controlling drug release.

In a preferred embodiment of the present invention, the biodegradable polymer is polylactide (PLA); Alternatively, it may be a mixture of polylactide (PLA) and polylactide-co-glycolide (PLGA), and in this case, the drug release behavior and drug encapsulation rate are determined according to the weight ratio of PLA and PLGA in the mixture of PLA and PLGA. can be adjusted Preferably, in the mixture of PLA and PLGA, the weight ratio of PLA and PLGA may be 3:7 to 7:3.

In addition, since the drug release rate is different depending on the molecular weight of the biodegradable polymer, it is preferable to use a biodegradable polymer having a molecular weight of 10,000 to 200,000 Da, preferably 20,000 Da to 90,000 Da.

In addition, the biodegradable polymer; And the weight ratio of the antipsychotic agent or the central nervous system disease agent is 5:5 to 9:1, preferably 6:4 to 7:3, when considering the drug loading rate and encapsulation efficiency integrally.

The particle size of the microspheres is preferably 10 μm to 100 μm, more preferably 10 μm to 60 μm, but is not limited thereto.

In addition, the encapsulation efficiency of the microspheres is preferably 40% or more, more preferably 80% or more, and most preferably 90% or more, but is not limited thereto.

In addition, the sustained release drug delivery formulation may be for injection.

In addition, when the sustained-release drug delivery formulation is injected subcutaneously at 10 mg/kg to 100 mg/kg, drug release into the blood can be sustained for 28 days or more.

The drug used in the drug delivery formulation of the present invention is not limited in type as long as it is a drug used as an antipsychotic agent or a central nervous system disease agent. Preferably, the drug of the present invention may be selected from the group consisting of donepezil, aripiprazole, galantamine and ropinirole.

The mental disorders of the present invention include schizophrenia, bipolar disorder, non-bipolar mania, Tourette's syndrome, circulatory disorder, rapid cycle, circadian rhythm, personality disorder, attention disorder, delusional disorder, psychotic disorder, psychotic disorder related to Parkinson's disease, anxiety disorder, panic disorder, post-traumatic stress disorder, impulse control disorder, phobias disorder, dissociative states and depression.

The central nervous system disease of the present invention is a brain tumor, cerebral infarction, hypertensive cerebral hemorrhage, cerebral contusion, cerebral arteriovenous malformation, brain abscess, encephalitis, hydrocephalus, epilepsy, concussion, cerebral palsy, dementia, Alzheimer's disease, spinal cord tumor, spinal arteriovenous malformation and spinal infarction. may include

Drug-encapsulated microspheres can be prepared by incorporating the drug into the biodegradable polymer. The microspheres may further include one or more additives such as preservatives, preservatives and excipients. The mixing process is a single axis ultrasonic atomization method [B.S. Kim, J. M. Oh, K. S. Kim et al, Biomaterials, 30, 902 (2009); B. S. Kim, J. M. Oh, H. Hyun et al, MOLECULAR PHARMACEUTICS, 6, 353 (2009)] or a method for preparing microspheres using a syringe. Through the single-axis ultrasonic spraying method, microspheres having a double structure having different compositions of the central core portion and the outer portion coated with the central core portion can be prepared, and in this case, the drug content in the microsphere is an average of 85% or more and a maximum of 99% It has the advantage of exhibiting an excellent drug encapsulation rate to reach , and suppressing the initial release amount.

In addition, the present invention comprises the steps of (a) mixing a biodegradable polymer and a solvent to prepare a polymer solution; (b) preparing a drug solution by mixing an antipsychotic agent or a central nervous system disease agent and a solvent; and (c) mixing and dispersing the drug solution in the polymer solution to prepare microspheres.

Representative manufacturing methods of microspheres for drug delivery using polymers include solvent extraction, solvent evaporation, and spray drying. Depending on the manufacturing method, the characteristics of microspheres such as particle size, drug release characteristics, and drug encapsulation rate are affected. Therefore, an appropriate manufacturing method must be selected. Briefly describing the solvent evaporation method, a drug is dispersed or dissolved in an organic solvent in which a polymer compound is dissolved, and then emulsified in a dispersion medium such as water to prepare an oil-in-water (O/W, oil-in-water) emulsion, and then The drug-containing polymer microspheres are formed by evaporating the organic solvent through the air/water interface by diffusing the organic solvent in the dispersion medium.

In particular, the production method of the sustained-release drug delivery formulation of the present invention can reduce the manufacturing time and cost of the drug delivery formulation by preparing microspheres in a simple manner using a single-axis nozzle ultrasonic sprayer.

The drug delivery formulation according to the present invention is a sustained-release microsphere formulation that can keep the amount of drug released into the blood constant for a long time, and improves the problem of having to administer the drug several times at regular time intervals to the conventional patient, There is an advantage that the desired release behavior can be easily obtained continuously for about 28 days or more with a single dose. In addition, the manufacturing method of the drug delivery formulation of the present invention has the advantage of being able to reduce the manufacturing time and cost by preparing the sustained release drug delivery formulation as a simple process compared to the conventional method.

1 shows the results showing the drug release behavior from the depot by preparing a sustained-release drug delivery formulation (using donepezil) according to the present invention and then subcutaneously injecting it into an animal.
2 is a view of microspheres prepared by varying the weight ratio of the biodegradable polymer and donepezil through an optical microscope.
3 shows microspheres (using donepezil) prepared by varying the molecular weight of PLGA and the weight ratios of PLA and PLGA, observed through an optical microscope.
4 shows the results of drug release from the depot by subcutaneously injecting a sustained-release drug delivery formulation containing microspheres prepared by varying the weight ratio of biodegradable polymer and donepezil to an animal.
5 shows the results showing the drug release behavior from the depot by varying the amount of the sustained-release drug delivery formulation injected subcutaneously into the animal.
6 shows the results showing the drug release behavior from the depot by injecting a sustained-release drug delivery formulation containing microspheres prepared with different molecular weights of PLGA under the skin of an animal.
7 is an observation of microspheres prepared by varying the weight ratio of the biodegradable polymer and aripiprazole through an optical microscope.
8 is an observation of microspheres (using aripiprazole) prepared by varying the molecular weight of PLGA and the weight ratios of PLA and PLGA through an optical microscope.
9 is an observation of microspheres prepared using biodegradable polymers and various antipsychotics or central nervous system diseases (donepezil, aripiprazole, galantamine and ropinirole) through an optical microscope.

Below, The present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.

Example 1. Donepezil ( donepezil ) containing microsphere Produce

1-1. polymer ( PLA ) with different ratios of drugs microsphere Produce

Microspheres containing donepezil were prepared using a single-axis nozzle ultrasonicator. Specifically, PLA (poly lactic acid, Mw = 30,000 Da) and donepezil were dissolved in ethyl acetate (EA, ethyl acetate) to 2.0% w/v and 1.0% w/v, respectively, to prepare a solution for preparing microspheres. did.

After mixing the PLA solution and the donepezil solution in a weight ratio of 70:30, 65:35, and 60:40, it was put into a 10 ml syringe, and pushed with a syringe pump at room temperature at a flow rate of 4 ml/min. A 0.5 wt% polyvinyl alcohol (PVA) aqueous solution stabilized in advance for 1 to 2 hours was prepared, and the drug dispersion solution was sprayed into the PVA aqueous solution at a vibration frequency of 3 W/60 Hz to prepare microspheres. Next, after evaporating the solvent by stirring at 500 rpm for 2 hours at room temperature, distilled water was added to the resulting microspheres, washed by centrifugation (1500 rpm, 1 min), and freeze-dried at -74°C for 3 to 4 days. Thus, microspheres containing donepezil were prepared.

1-2. polymer ( PLA:PLGA ) with different mixing ratios microsphere Produce

Microspheres containing donepezil were prepared by the method of Example 1-1, but PLA and poly(lactic-co-glycolic acid) (PLGA) were mixed instead of PLA, and the content of donepezil was 35 when mixing the solution. % by weight.

In order to check the drug release behavior according to the mixing ratio of PLA and PLGA, a polymer solution was prepared so that PLA:PLGA was mixed in a weight ratio of 7:3, 5:5, 3:7, and the molecular weight (Mw) of PLGA was 20,000 Da, 33,000 Da or 90,000 Da was used.

1-3. with donepezil microsphere Characterization

10 mg of the microspheres prepared in Examples 1-1 and 1-2 were suspended in distilled water, respectively, and the particle size was measured using DLS, and the surface of the microsphere was examined using an optical microscope (Carl Zeiss Microimaging GmbH, Gottingen, Germany). observed through. As a result, as shown in FIGS. 2 and 3, it was found that spherical microspheres were prepared.

The content of donepezil encapsulated in microspheres was measured using HPLC. Specifically, 2 ml of acetonenitrile (ACN) was added to 6 mg of microspheres prepared according to each condition, dissolved, and 50 ml of a mobile phase solvent (tetrahydrofuran (THF) and 14 ml of triethyleneamine (TEA) were added to 1 L of distilled water) (adjusted to pH 2.0 with phosphoric acid) was added and mixed to prepare sampling. Each sample was injected into a stationary phase column (shiseido UG120 C ₁₈ , 4.6 × 250 mm, 5 μm) by 20 μl at a flow rate of 1.2 ml/min, and the drug content of the microspheres was confirmed by measuring at 40° C. and 268 nm wavelength. .

As a result of analyzing the characteristics of the microspheres prepared in Example 1-1, the drug loading increased as the donepezil content of the mixed solution increased, and the encapsulation efficiency of the microspheres was 35% of the donepezil. It was highest in the contained microspheres (Table 1).

Encapsulation efficiency (%) = (drug content of the obtained donepezil capsule/drug content of the theoretical donepezil capsule) x 100

Experiment number sample name donepezil (mg) EA
(mL) Flow rate (mL/min) PVA
(%) particle size
(μm) drug
loading rate
(%) encapsulation
efficiency
(%) Experimental Example 1 PLA:
donepezil
(70:30) 90 10 4 0.5 46.6±21.1 27.3±0.1 90.9±0.4 Experimental Example 2 PLA:
donepezil
(65:35) 105 10 4 0.5 69.4±11.3 34.4±0.1 98.3±0.2 Experimental Example 3 PLA:
donepezil
(60:40) 120 10 4 0.5 62.1±11.4 38.6±0.3 96.6±0.8

As a result of analyzing the characteristics of the microspheres prepared in Example 1-2, there was no significant difference in the drug loading rate according to the change in the molecular weight of PLGA, and the encapsulation efficiency of the microspheres was the highest when PLGA was 20,000 Da ( Table 2).

Experiment number PLGA
Molecular Weight PLA:PLGA
weight ratio donepezil (mg) EA
(mL) Flow rate (mL/min) PVA
(%) particle size
(μm) drug
loading rate
(%) Encapsulation Efficiency
(%) Experimental Example 4 PLGA 20K 3:7 105 10 4 0.5 51.4±15.3 34.4±0.2 98.2±0.7 Experimental Example 5 5:5 105 10 4 0.5 50.5±11.4 34.4±0.1 98.1±0.4 Experimental Example 6 7:3 105 10 4 0.5 49.7±13.6 34.3±0.3 98.0±0.8 Experimental Example 7 PLGA 33K 3:7 105 10 4 0.5 48.2±12.8 34.2±0.2 97.7±0.6 Experimental Example 8 5:5 105 10 4 0.5 50.2±11.4 34.1±0.1 97.3±0.3 Experimental Example 9 7:3 105 10 4 0.5 42.7±20.3 34.0±0.4 97.1±1.0 Experimental Example 10 PLGA 90K 3:7 105 10 4 0.5 47.3±18.3 34.2±0.1 97.6±0.2 Experimental Example 11 5:5 105 10 4 0.5 45.6±18.9 34.0±0.2 97.1±0.4 Experimental Example 12 7:3 105 10 4 0.5 44.3±17.5 33.6±0.2 96.1±0.6

Example 2. Containing donepezil microsphere injection preparation

After preparing an injection using the microspheres prepared in Examples 1-1 and 1-2, the drug was injected subcutaneously into mice to form a drug depot. Specifically, by calculating the amount of donepezil microspheres required through the content of the drug measured through HPLC in Examples 1-3 carried out with the donepezil injection amount of 56 mg/kg, 0.3 mL of injection solution Microspheres prepared by varying the ratio of drug to polymer to (Saline (0.5% Na-CMC + 0.1% Polysorbate 80 + 5.0% Mannitol)) Injections were prepared by spraying each microsphere. A drug depot was formed by subcutaneous injection of mice immediately after preparation.

In addition, in order to confirm the change in drug release behavior according to the content of donepezil in the injection, the injection amount was adjusted so that the theoretical amount of the drug was 25 mg/kg or 100 mg/kg, and it was injected subcutaneously in rats.

Example 3. Subcutaneous injection of donepezil into rat microsphere Emission behavior check

In Example 2, the injection site injected subcutaneously in rats was extracted on 1, 4, 7, 14, 21, and 28 days after drug injection, respectively, and drug release behavior was measured.

Specifically, acetonitrile (ACN, acetonitrile) was added to the extracted injection, followed by mixing (vortexing) for 10 minutes, and sonication for 10 minutes to prepare a mobile phase sample. Next, HPLC was performed in the same manner as in Example 1-3 to measure the remaining amount of drug in the injection, and then the drug release rate (Drug release, %) was calculated.

As a result, in the case of Experimental Examples 1 to 3, it was confirmed that the drug was continuously released until 28 days (FIG. 4).

In addition, in the case of Experimental Example 2, when the drug release behavior according to the drug content of 25 mg/kg, 56 mg/kg, or 100 mg/kg was confirmed, it was confirmed that the drug was released up to 28 days in all (FIG. 5) .

Example 4. aripiprazole contained microsphere Produce

4-1. polymer PLA with different drug-to-drug ratios microsphere Produce

Microspheres containing aripiprazole were prepared using a single-axis nozzle ultrasonicator. Specifically, PLA (Mw = 30,000 Da) and aripiprazole were dissolved in methylene chloride (MC, Methylene chloride) to 2.0% w/v and 1.0% w/v, respectively, to prepare a solution for preparing microspheres.

After mixing the PLA solution and the aripiprazole solution in a weight ratio of 70:30, 65:35, and 60:40, it was put into a 10 ml syringe, and pushed with a syringe pump at room temperature at a flow rate of 4 ml/min. A 0.5 wt% polyvinyl alcohol (PVA) aqueous solution stabilized in advance for 1 to 2 hours was prepared, and the drug dispersion solution was sprayed into the PVA aqueous solution at a vibration frequency of 3 W/60 Hz to prepare microspheres. Next, after evaporating the solvent by stirring at 500 rpm for 2 hours at room temperature, distilled water was added to the resulting microspheres, washed by centrifugation (1500 rpm, 1 min), and freeze-dried at -74°C for 3 to 4 days. Thus, aripiprazole-containing microspheres were prepared.

4-2. polymer ( PLA:PLGA ) with different mixing ratios microsphere Produce

Microspheres containing aripiprazole were prepared by the method of Example 4-1, but PLA and PLGA were mixed instead of PLA, and the content of aripiprazole was 35% by weight when the solution was mixed.

In order to check the drug release behavior according to the mixing ratio of PLA and PLGA, a polymer solution was prepared so that PLA:PLGA was mixed in a weight ratio of 7:3, 5:5, 3:7, and the molecular weight (Mw) of PLGA was 20,000 Da, 33,000 Da or 90,000 Da was used.

The surfaces of the microspheres prepared in Examples 4-1 and 4-2 were observed through an optical microscope. As a result, as shown in FIGS. 7 and 8, it was found that spherical microspheres were prepared.

4-3. aripiprazole contained microsphere Characterization

HPLC was performed to measure the content of aripiprazole encapsulated in the microspheres prepared in Examples 4-1 and 4-2. Specifically, 2 ml of acetonenitrile (ACN) was added to 6 mg of microspheres prepared according to each condition, dissolved, and then 2 ml of methanol was added and mixed to prepare a mobile phase sample. Each sample was injected into a stationary phase column (shiseido UG120 C ₁₈ , 4.6 × 250 mm, 5 μm) by 20 μl at a flow rate of 1.0 ml/min, and the drug content of the microspheres was confirmed by measuring at 35° C. and 254 nm wavelength. .

As a result of analyzing the characteristics of the microspheres prepared in Example 4-1, the drug loading increased as the content of aripiprazole in the mixed solution increased. The encapsulation efficiency of microspheres was highest in microspheres containing 35% aripiprazole (Table 3).

Experiment
number sample name Aripiprazole (mg) EA
(mL) Flow rate (mL/min) PVA
(%) particle size
(μm) drug
loading rate
(%) Encapsulation Efficiency
(%) Experimental Example 13 PLA:
Aripiprazole (70:30) 90 10 4 0.5 43.0±15.8 25.6±2.2 85.2±4.3 Experimental Example 14 PLA:
Aripiprazole (65:35) 105 10 4 0.5 52.5±22.8 30.5±1.9 87.2±3.2 Experimental Example 15 PLA:
Aripiprazole (60:40) 120 10 4 0.5 50.6±17.5 34.3±2.0 85.8±2.8

As a result of analyzing the characteristics of the microspheres prepared in Example 4-2, there was no significant difference in the drug loading rate according to the change in the molecular weight of PLGA, and the microsphere encapsulation efficiency was the highest when PLGA was 33,000 Da. (Table 4).

Experiment
number PLGA
Molecular Weight PLA:PLGA
weight ratio Aripiprazole (mg) EA
(mL) Flow rate (mL/min) PVA
(%) particle size
(μm) drug
loading rate
(%) Encapsulation Efficiency
(%) Experimental Example 16 PLGA 20K 3:7 105 10 4 0.5 43.8±14.1 29.6±0.7 82.8±0.9 Experimental Example 17 5:5 105 10 4 0.5 53.0±6.4 29.9±0.4 85.4±1.3 Experimental Example 18 7:3 105 10 4 0.5 34.2±15.7 28.6±0.6 81.7±1.6 Experimental Example 19 PLGA 33K 3:7 105 10 4 0.5 35.6±13.0 29.9±0.8 85.4±2.2 Experimental Example 20 5:5 105 10 4 0.5 48.9±21.3 30.3±0.5 86.5±1.5 Experimental Example 21 7:3 105 10 4 0.5 54.7±26.7 29.6±0.7 84.4±1.9 Experimental Example 22 PLGA 90K 3:7 105 10 4 0.5 54.7±10.7 28.7±0.1 81.9±0.1 Experimental Example 23 5:5 105 10 4 0.5 49.1±8.2 29.1±0.6 83.0±1.7 Experimental Example 24 7:3 105 10 4 0.5 42.3±10.8 28.9±0.5 82.6±1.5

In addition, in the mixed solution, 35 wt% of galantamine or ropinirole other than the drug for mental illness used in Examples was prepared in a manner similar to that of Example, and then microspheres were prepared and, as a result of evaluating the properties, each It was confirmed that the antipsychotic agent or the central nervous system disease agent was encapsulated in the biodegradable polymer (FIG. 9), but it was confirmed that the encapsulation efficiency of the microspheres was significantly lowered compared to the case of using donepezil or aripiprazole (Table 5).

Experiment
number sample name drug
(mg) EA
(mL) flow rate
(mL/min) PVA
(%) particle size
(μm) Encapsulation Efficiency
(%) Experimental Example 25 PLA:
Donepezil (70:30) 105 10 4.0 0.5 43.0±15.8 98.3±0.2 Experimental Example 26 PLA:
Aripiprazole (70:30) 105 10 4.0 0.5 52.5±22.8 87.2±3.2 Experimental Example 27 PLA:
Galantamine (70:30) 400 10 0.4 (Galatamine) 0.5 62.6±14.2 46.6±2.9 4.0 (PLA) Experimental Example 28 PLA:
Ropinirole (70:30) 400 10 0.4 (ropinirole) 0.5 59.1±18.3 44.7±3.1 4.0 (PLA)

Claims (14)

biodegradable polymers; and
Containing microspheres containing donepezil (donepezil),
The biodegradable polymer is polylactide (PLA); or a mixture of polylactide (PLA) and polylactide-co-glycolide (PLGA) in a weight ratio of 3:7 to 7:3,
Each of the polylactide (PLA) and the polylactide-co-glycolide (PLGA) has a molecular weight of 20,000 Da to 90,000 Da, and the weight ratio of the biodegradable polymer and the donepezil is 60:40 to 65:35,
The encapsulation efficiency of the microspheres, characterized in that 90% or more
A sustained-release drug delivery formulation for the treatment of central nervous system diseases.
delete delete delete delete delete According to claim 1,
The sustained-release drug delivery formulation, characterized in that the particle size of the microspheres is 10㎛ to 100㎛.
delete According to claim 1,
The sustained release drug delivery formulation is a sustained release drug delivery formulation, characterized in that for injection.
According to claim 1,
The sustained release drug delivery formulation is a sustained release drug delivery formulation, characterized in that when injected subcutaneously at 10 mg / kg to 100 mg / kg, the drug release into the blood is continued for 28 days or more.
delete According to claim 1,
The central nervous system disease is from the group consisting of brain tumor, cerebral infarction, hypertensive cerebral hemorrhage, cerebral contusion, arteriovenous malformation, brain abscess, encephalitis, hydrocephalus, epilepsy, concussion, cerebral palsy, dementia, Alzheimer's disease, spinal cord tumor, spinal arteriovenous malformation and spinal infarction. A sustained release drug delivery formulation, characterized in that at least one selected.
delete (a) mixing a biodegradable polymer and a solvent to prepare a polymer solution;
(b) preparing a drug solution by mixing donepezil and a solvent; and
(c) mixing and dispersing the drug solution in the polymer solution to prepare microspheres,
The biodegradable polymer is polylactide (PLA); or a mixture of polylactide (PLA) and polylactide-co-glycolide (PLGA) in a weight ratio of 3:7 to 7:3,
Each of the polylactide (PLA) and the polylactide-co-glycolide (PLGA) has a molecular weight of 20,000 Da to 90,000 Da, and the weight ratio of the biodegradable polymer and the donepezil is 60:40 to 65:35,
The encapsulation efficiency of the microspheres, characterized in that 90% or more
A method for manufacturing a sustained release drug delivery formulation for the treatment of central nervous system diseases

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