KR102091114B1 - Long-acting microspheres containing donepezil and process for preparing the same - Google Patents

Abstract

The present invention relates to a long-acting long-acting microsphere comprising donepezil, a method for manufacturing the same, and a pharmaceutical composition for parenteral containing the microsphere, by preparing donepezil as a microsphere with a biodegradable polymer, initial drug release (initial burst) ) And in-vitro release of donepezil without lag time, and it is also possible to expect the effect of reducing the frequency of administration and maintaining the effective concentration in the blood for a long time by allowing the drug to be continuously released for a long time when administered in the body. .

Description

LONG-ACTING MICROSPHERES CONTAINING DONEPEZIL AND PROCESS FOR PREPARING THE SAME

The present invention relates to a long-acting long-acting microsphere comprising donepezil, a method for manufacturing the same, and a pharmaceutical composition for parenteral containing the microsphere, by preparing donepezil as a microsphere with a biodegradable polymer, initial drug release (initial burst) ) And in-vitro release of donepezil without lag time, and it is also possible to expect the effect of reducing the frequency of administration and maintaining the effective concentration in the blood for a long time by allowing the drug to be continuously released for a long time when administered in the body. .

Dementia is a degenerative brain neurological disease associated with the brain, the central nervous system, resulting in irreversible dysfunction in the neural network by the death of slow neurons that induce degenerative diseases of the central nervous system, which eventually leads to permanent loss of the body's function. Effect.

Recently, as the number of Alzheimer's dementia patients increases along with the increase in the elderly population, management of patients has emerged as a serious social problem, and anti-dementia drugs are rapidly being developed.

Donepezil is widely used as a therapeutic agent for Alzheimer's dementia having an acetylcholinesterase inhibitory effect, and is mostly administered orally in tablet form. Looking at the current prescription pattern of the donepezil oral preparations on the market, it is usually prescribed to start by administering 5 mg once a day at bedtime and use it for 4-6 weeks, then increase it to 10 mg and administer it once a day. .

However, when the drug is taken orally to patients with dementia in this way, there is a disadvantage in that the medication adherence to what should be administered orally every day is poor, and there is a need for a long-lasting preparation.

On the other hand, oral administration of donepezil-containing oral tablets is known to cause gastrointestinal side effects such as diarrhea, nausea, loss of appetite, and muscle convulsion in some patients. In addition, since it is necessary to repeatedly take the drug once a day to bed for Alzheimer's patients, it is difficult to exhibit a continuous pharmacological effect due to the ease of taking. Accordingly, research into the development of a donepezil-containing transdermal absorbent that can reduce gastrointestinal side effects due to oral administration and improve patient compliance with medication has been attempted. However, most of the transdermal absorbents known in the prior art have low skin permeability and use a large amount of various permeation accelerators, causing skin irritation problems such as skin rash caused by the permeation accelerator. In addition, it is difficult to maintain a desired skin permeability for a long period of time (for example, 7 days or more) necessary to improve patient compliance.

Republic of Korea Patent Publication No. 2009-0101667 discloses a single layer donepezil transdermal absorber that can improve the medication compliance of dementia patients and minimize the side effects of the drug as compared to oral drugs. However, the formulation contains a low concentration of the drug for long-term dosing, and the patch containing the drug was thick, and the EVA adhesive forming the drug-containing layer despite the drug-containing layer being directly administered to the skin. There is a problem that the skin adhesion is low, there is a disadvantage that is substantially undesirable for long-term adhesion (and dosing) of 1 day or more.

To date, there have been no cases where donepezil was developed as a long-acting injection (eg, a depot injection). As an example related to the long-acting preparation of donepezil, Korean Patent No. 0904602 discloses the composition of a matrix-type sustained-release oral preparation comprising donepezil or a salt thereof and at least one enteric polymer. However, the present inventors prepared a sustained-release preparation according to the above-described configuration, and after long-term storage at 40 ° C. and 75% relative humidity, a dissolution test resulted in a significant reduction in dissolution rate, and also dissolution under food supply conditions. As a result of the test, it was confirmed that sustained release of donepezil hydrochloride was not achieved due to the collapse of the matrix tablet.

As another example, Pengcheng Zhang et al. Have prepared and evaluated sustained-release microparticles of donepezil (Pengcheng Zhang, Lingli Chen, Wangwen Gu, Zhenghong Xu, Yu Gao, Yaping Li, In vitro and in vivo evaluation of donepezil -sustained release microparticles for the treatment of Alzheimer's disease, Biomaterials, 28 (2007) 1882-1888). They prepared a microsphere comprising donepezil using a copolymer of lactide and glycolide. The content of donepezil in the microsphere was 13.2%, and the drug encapsulation rate was only 66%, resulting in a lot of drug loss. In order to apply as, there is a problem that the dosage must be very large.

Accordingly, there is a need to develop a long-lasting formulation of donepezil that has stable drug release properties for a long period of time and is capable of continuously maintaining an effective concentration in blood.

Thus, the present invention is made of a microsphere with donepezil as a biodegradable polymer, and has a long-term sustained microsphere capable of continuously maintaining an effective concentration in the blood and having stable drug release properties for a long period of time, a preparation method thereof, and a parenteral containing the microspheres It is intended to provide an oral pharmaceutical composition.

In order to achieve the above object, the present invention

(a) dissolving donepezil and biodegradable polymer in dichloromethane solvent;

(b) adding the solution of donepezil and biodegradable polymer into a polyvinyl alcohol solution and stirring to form a droplet-like dispersed phase;

(c) removing the dichloromethane solvent to form microspheres; And

(D) provides a method for producing a long-lasting microspheres comprising donepezil, comprising freeze-drying the formed microspheres.

In addition, the present invention provides a long-acting type microspheres comprising donepezil obtained by the above production method.

In addition, the present invention provides a parenteral pharmaceutical composition comprising long-acting microparticles containing donepezil obtained by the above production method and a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in detail.

The active ingredient of the present invention "donepezil" has a chemical name of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl) methyl] piperidine, and the formula Have

According to one embodiment of the invention, the donepezil is present in the form of a free base.

The method for preparing long-lasting microspheres of the present invention includes (a) dissolving donepezil and biodegradable polymer in a dichloromethane solvent; (b) adding the solution of donepezil and biodegradable polymer into a polyvinyl alcohol solution and stirring to form a dispersed phase in the form of droplets; (c) removing the dichloromethane solvent to form microspheres; And (d) freeze-drying the formed microspheres.

According to one embodiment of the present invention, step (c) may be performed at a temperature of less than 39.6 ° C., which is a boiling point of a dichloromethane solvent. In addition, the step (c) may consist of a solidification step of the microspheres and a volatilization step of the solvent.

According to one embodiment of the present invention, the solidifying step of the microspheres may be performed for 1 to 3 hours at a temperature of 10 to 20 ° C, preferably 2 to 3 hours at a temperature of 20 ° C, more preferably It can be carried out for 3 hours at a temperature of 20 ℃.

According to one embodiment of the present invention, the volatilization step of the solvent may be performed for 1 to 3 hours at a temperature of 30 to 35 ° C, preferably 1 to 2 hours at a temperature of 35 ° C, more preferably It can be carried out for 1 hour at a temperature of 35 ℃.

According to an embodiment of the present invention, after filtering the microspheres formed in step (c), washing with water to remove the polyvinyl alcohol may further include after the step (c).

According to one embodiment of the present invention, in the preparation method, donepezil may be added in the form of free base, such that 15 to 50% by weight, preferably 20 to 40% by weight, based on the total weight of the microspheres, More preferably, it may be added to 20 to 30% by weight.

According to one embodiment of the present invention, the input amount of donepezil and biodegradable polymer in the above production method is in a weight ratio range of 1: 2 to 3. In the examples to be described later, donepezil was added in 1.5g, and biodegradable polymer was added in 3.5g, but the amount of these may be variable within the range of the weight ratio.

According to an embodiment of the present invention, the input amount of the dichloromethane solvent in the preparation method is such that the concentration of the donepezil and the biodegradable polymer solution is 30 to 70% by weight, more specifically 40 to 60% by weight. It is a sheep. When the concentration of the donepezil and the biodegradable polymer solution is less than 40% by weight due to an excessive amount of dichloromethane, the encapsulation rate of the drug may be lowered. On the contrary, the input amount of dichloromethane is insufficient and the donepezil and the biodegradable polymer solution. When the concentration of is more than 60% by weight, there is a problem that it is difficult to form the microspheres.

According to one embodiment of the present invention, the biodegradable polymer is at least one biodegradable polymer selected from the group consisting of polylactic acid (PLA), and has an inherent viscosity (IV) of 0.1 to 1.0 dL / It is preferable that it is g, and more specifically, it is preferably 0.2 to 0.5 dL / g.

In addition, the polylactic acid may or may not include a chain terminal functional group, when included, a carboxylic acid (carboxylic acid terminated) or ester group (ester terminated) may include a chain terminal functional group, relatively high hydrophobicity It is preferable to include a carboxyl group as a chain end functional group rather than an ester group.

According to one embodiment of the present invention, the polylactic acid may be Resomer ^® R203H, Resomer ^® R202H, Resomer ^® R203S, etc. manufactured and sold by Evonik. As described in the Examples described below, Resomer ^® R202H has a lower intrinsic viscosity than Resomer ^® R203H, while Resomer ^® R203H has a chain end functional group as a carboxyl group, while Resomer ^® R203S has a chain end functional group as an ester group.

In addition, the present invention provides a long-acting type microspheres comprising donepezil obtained by the above production method. The long-acting-type microspheres are in a state in which donepezil is uniformly dispersed in the microspheres, and donepezil may be included in an amount of 15 to 50% by weight relative to the total weight of the microspheres, preferably 20 to 40% by weight, , More preferably 20 to 30% by weight. When the content of donepezil in the microparticles is less than 20% by weight, the dosage is reduced because the dose is too large, and if the content of donepezil is more than 30% by weight, the drug release becomes faster when administered in the body, resulting in 1 month (4 weeks) long term Since there is a disadvantage that it is difficult to secure persistence, it is most preferable that the content of donepezil in the long-lasting-type microspheres is 20 to 30% by weight.

According to an embodiment of the present invention, the microspheres may have a size (D ₅₀ ) of 1 to 300 μm, and more specifically 1 to 150 μm.

Donepezil long-acting microspheres according to the present invention can release donepezil in the body for more than 1 month (4 weeks).

In addition, the present invention provides a pharmaceutical composition for parenteral administration comprising a long-acting microsphere comprising the donepezil and a pharmaceutically acceptable carrier.

According to one embodiment of the present invention, the pharmaceutical composition for parenteral administration may be an injection.

The pharmaceutical composition comprising donepezil according to the present invention can be used as a therapeutic agent for Alzheimer's dementia symptoms, the dosage can be variously adjusted according to the patient's age, symptoms, dosage form, etc., and 5.0 to donepezil free base It can be administered at a dose of 23.0 mg / day, specifically 5.0 to 15.0 mg / day, and more specifically 5.0 to 10.0 mg / day.

The donepezil long-acting microspheres according to the present invention may be provided as a formulation that is administered by suspending in an injectable suspension solvent at the time of final administration. Injectable suspension solutions are water-soluble organic carriers, and may include, for example, isotonic agents, thickeners, surfactants, buffers, and the like. Usable tonicity agents can be water-soluble excipients or saccharides such as mannitol, sucrose, sorbitol, trehalose, lactose, sodium chloride, and examples of thickeners include carmellose sodium, sodium carboxymethyl cellulose, povidone, and the like. As the surfactant, polysorbate 80 and polysorbate 20 may be used as the polyoxyethylene sorbitan type, and span 80 and span 20 may be used as the sorbitan ester type. In addition, sodium hydrogen phosphate, citric acid, sodium hydroxide, sodium chloride, etc. may be used as the buffer.

Long-acting microparticles containing donepezil obtained by the production method according to the present invention can effectively control the release rate of the drug, thereby continuously releasing the drug for a long time in the body, thereby reducing the frequency of administration and effective long-term concentration in the blood. The effect of maintaining it can be expected.

Therefore, when manufactured as a formulation for parenteral administration such as injection, it is possible to safely and continuously exert an effect, thereby reducing the number of doses to improve patient compliance, thereby improving the treatment or prevention of target diseases including Alzheimer's dementia. Can be represented.

1A to 1I are photographs showing SEM analysis results of measuring the morphology of Donepezil long-acting microparticles prepared according to Examples 1 to 9, respectively.
2A to 2F are graphs showing the results of a long-term release test of Donepezil long-acting microparticles prepared according to Examples 1 to 9.
Figure 2a is a graph showing the comparison of the cumulative release rate of donepezil according to the time of volatilization of dichloromethane solvent for the long-acting donepezil microparticles prepared according to Examples 1 to 3.
Figure 2b is a graph showing the comparison of the cumulative release rate of donepezil according to the volatilization temperature of the dichloromethane solvent for the long-acting donepezil microparticles prepared according to Examples 1 and 4.
Figure 2c is a graph showing the comparison of the cumulative release rate of donepezil according to the solidification temperature for the long-acting donepezil microparticles prepared according to Examples 1 and 5.
Figure 2d is a graph showing the comparison of the cumulative release rate of donepezil according to the terminal functional groups of the biodegradable polymer for the long-acting donepezil microparticles prepared according to Examples 1 and 6.
Figure 2e is a graph showing the comparison of the cumulative release rate of donepezil according to the intrinsic viscosity of the biodegradable polymer for the long-acting donepezil microparticles prepared according to Examples 1 and 7.
Figure 2f is a graph showing the comparison of the cumulative release rate of donepezil according to the input amount of dichloromethane solvent to the solution of donepezil and biodegradable polymer for the donepezil long-acting microparticles prepared according to Examples 1, 8 and 9 .
Figure 3a is a graph showing the transition in blood concentration obtained after administration of long-acting microparticles of donepezil prepared according to Examples 1 and 4 to rats.
Figure 3b is a graph showing the trend of blood concentration obtained after administration of long-acting microparticles of donepezil prepared according to Examples 1 and 7 to rats.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only to illustrate the present invention, the present invention is not limited by the following examples.

Example 1: Preparation of donepezil long-acting microspheres

As a biodegradable polymer, 3.5 g of polylactic acid (Resomer ^® R203H, IV: 0.25 to 0.35 dL / g, manufacturer: Evonik) and 1.5 g of donepezil (manufacturer: Megafine, India) as a drug, 4.9 ml of dichloromethane (boiling point) : 39.6) A biodegradable polymer solution containing donepezil was prepared by dissolving in a solvent. In addition, a polyvinyl alcohol was dissolved in water to prepare a 1.25 L aqueous polyvinyl alcohol solution (concentration: 0.25 w / v%). Subsequently, the biodegradable polymer solution containing donepezil is mixed with the polyvinyl alcohol aqueous solution and then stirred at high speed to form a dispersed phase in the form of droplets, solidified at 20 ° C for 3 hours and then dichloro with stirring at 35 ° C for 1 hour. The methane solvent was removed to form microspheres. After filtering the formed microspheres, the microspheres were washed three times with water to remove polyvinyl alcohol. Subsequently, the washed microspheres were again obtained through filtration, and then freeze-dried to obtain Donepezil (containing 27% by weight) long-acting microspheres.

Examples 2 to 9: Preparation of donepezil long-acting microspheres

Examples 2 to 9 were prepared according to the method exemplified in Example 1 by varying the composition and manufacturing method. Table 1 shows the composition and manufacturing method of Examples 2 to 9.

[Table 1] Compositions and manufacturing methods of Examples 1 to 9

Experimental Example 1: Measurement of microsphere shape

After about 10 mg of the microspheres prepared in Examples 1 to 9 were fixed to an aluminum stub and coated with platinum at a vacuum of 0.1 torr and high voltage (10 kV) for 3 minutes, SEM (equipment name: Hitachi S-4800 FE-SEM ) It was mounted on the powder and the surface of the microspheres was observed using an image analysis program.

The results of SEM analysis of the morphology of Donepezil long-acting microparticles according to each example are shown in FIG. 1.

1a to 1i, the donepezil long-acting microspheres prepared in each example have a smooth spherical shape with a size ranging from 1 to 150 μm, the viscosity of the biodegradable polymer, the amount of dichloromethane solvent, and volatilization. It can be seen that it is possible to manufacture stable microspheres even with variables according to the difference in time point and volatilization temperature.

Experimental Example 2: Measurement of donepezil content and encapsulation rate in donepezil long-acting microparticles

After about 100 mg of the microspheres prepared in Examples 1 to 9 were completely dissolved sequentially using acetonitrile and solution A, filtered with a 0.45 μm syringe filter to prepare a sample solution, and the cone was enclosed in the microspheres using HPLC. The content of pezil was measured. At this time, the column used was Luna phenyl-Hexyl, C18 5 μm, 4.6 × 250 mm, the injection amount was 20 μl, and the detection wavelength was 318 nm. The mobile phase was measured using a mixed solution of pH 2.0 tetrahydrofuran, triethylamine solution (solution A) and methanol and tetrahydrofuran solution (solution B) (solution A: solution B = 3: 1).

Table 2 shows the results of the content and encapsulation rate of donepezil in the donepezil long-acting microparticles prepared in each example.

Table 2: Donepezil content and encapsulation rate of Examples 1 to 9

In general, in many previous studies, it is known that the higher the viscosity of the polymer in the production of microspheres, the higher the drug encapsulation rate and the content. In Table 2, the intrinsic viscosity of polylactic acid is higher than in Example 7, which has a low intrinsic viscosity of polylactic acid. It can be seen that Examples 1 to 3 show results of high content of donepezil and encapsulation rate.

In addition, as a result of examining the content and encapsulation rate of donepezil according to the amount of dichloromethane in the same polylactic acid, Example 9 with a low amount of dichloromethane was higher than that of Example 8 with a high amount of dichloromethane. It turns out that it shows a rate.

In addition, it can be seen from the results of Examples 1 and 6 that the content and encapsulation rate of donepezil according to the terminal functional groups of the polylactic acid do not show a large difference.

On the other hand, when the content of donepezil in the long-acting microparticles of the present invention is less than 20% by weight, the convenience of taking is reduced because the dosage amount is too large, and when the content of donepezil is 30% by weight or more, drug release occurs when administered in the body Since it has a shortcoming that it is difficult to secure long-term persistence for 1 month (4 weeks), the present invention was carried out at 20 to 30% by weight of donepezil in the long-acting microparticles.

Experimental Example 3: In-vitro long-term release test of Donepezil long-acting microspheres

In a 240 ml high-density polyethylene bottle containing about 20 mg of microspheres prepared in Examples 1 to 9, 240 ml of a pH 7.4 HEPES solution was added and maintained on a 37.0 ° C. water bath, the supernatant was taken at regular intervals and the amount of donepezil released by HPLC Was measured.

At this time, the column used was Inertsil ODS-2, C18 5 μm, 4.5 × 150 mm, the injection amount was 20 μl, and the detection wavelength was 271 nm. The mobile phase was measured using a pH 5.0 phosphate buffer and acetonitrile solution (phosphate buffer: acetonitrile = 60:40).

The long-term release test results of the donepezil long-acting microparticles prepared in each example are shown in Table 3 and FIG. 2.

Table 3: Cumulative release rate of donepezil of Examples 1-9

Table 3 shows the cumulative release rates of long-lasting microparticles of donepezil prepared in Examples 1 to 9.

In the case of the donepezil long-acting microparticles prepared in Example 1 and Example 7, it can be seen that the release rate of the drug is increased in Example 7 having a low intrinsic viscosity of the polymer (see FIG. 2E).

In addition, in the case of the donepezil long-acting microparticles prepared in Examples 1 and 8 and 9, it can be seen that the release rate of the drug increases in Example 8, which has a low polymer concentration according to the amount of dichloromethane (see FIG. 2f). ).

In addition, in the case of the donepezil long-acting microparticles prepared in Examples 1 and 6, the release rate of the drug varies depending on the end functional group of the polymer, Example 6 using a polymer having an ester group, which is a relatively high hydrophobic end functional group. It can be seen that the release rate of the drug is delayed (see FIG. 2D).

On the other hand, Example 1 in which the solvent was volatilized at a temperature below the boiling point (39.6 ° C) of the dichloromethane solvent in the manufacturing process, and Example 4 in which the solvent was volatilized at a temperature above the boiling point was generated on the microsphere surface according to the volatilization temperature of the dichloromethane solvent. Because the thickness and density of the shell (shell) and the drug migration rate are affected, the drug release rate is different (see FIG. 2B).

In addition, in the case of the donepezil long-acting microparticles prepared in Examples 1 and 2 and 3, even if the volatilization temperature is the same in the manufacturing process, the thickness and density of the shell and the drug movement generated on the surface of the microspheres depending on the volatilization time Because it affects, the drug release rate shows different results (see FIG. 2A).

In addition, in the case of the donepezil long-acting microparticles prepared in Examples 1 and 5, the drug release rate according to the diffusion rate of the dichloromethane solvent due to the temperature difference during the solidification step in the manufacturing process may be evaluated. It is known that the solubility in water according to the temperature of the dichloromethane solvent is increased at a temperature lower than 25 ° C based on 25 ° C and at a temperature higher than 25 ° C as the temperature increases. Since the diffusion rate of the dichloromethane solvent in the initial droplet formation initial droplet state affects the thickness and density of the shell formed on the microsphere surface and the movement of the drug, the drug release rate shows different results (see FIG. 2C).

Therefore, through the present invention, as well as viscosity and terminal functional group properties of the biodegradable polymer, in-vitro long-term release of the donepezil long-acting microspheres at a constant rate (zero order release) by controlling the volatilization time and temperature of the dichloromethane solvent in the manufacturing process ).

Experimental Example 4: Dichloromethane residual amount test in Donepezil long-acting microparticles

Approximately 100 mg of Donepezil long-acting microspheres was dissolved in a GC vial and dissolved in 10 mL of an internal standard solution, and then the residual amount of dichloromethane in the microspheres was measured using GC. At this time, the column used was filled with G25 series, the inner diameter was 25 m × 0.32 mm, the film thickness was 0.5 μm, the injection amount was 1 μl, and the temperature was measured using a flame ionization detector at 250 ° C.

Table 4 below shows the results of measuring the residual amount of dichloromethane in the donepezil long-acting microparticles prepared in each example.

[Table 4] Test of residual amount of dichloromethane in Donepezil long-acting microparticles of Examples 1 to 9

Table 4 shows the results of the residual amount of dichloromethane in the donepezil long-acting microparticles prepared according to the present invention. In Examples 1 to 9 (except for Example 4) prepared at a temperature below the boiling point of the dichloromethane solution, the residual amount of dichloromethane is 600 ppm or less, which can be confirmed to sufficiently remove dichloromethane during the manufacturing process.

Experimental Example 5: pharmacokinetic evaluation

Pharmacokinetic evaluation of donepezil long-acting microspheres prepared according to the present invention was performed, and the donepezil long-acting microspheres were diluted in suspension solution to intramuscular injection (IM) into rats, and about 0.5 mL of blood sample at a defined time. After collection and pretreatment, the concentration of donepezil was analyzed using LC / MS / MS. The analysis results are shown in FIG. 3.

As shown in Figure 3a, in the case of Example 1 prepared by volatilizing the dichloromethane solvent below the boiling point of the dichloromethane solvent during the manufacturing process, it can be seen that the blood concentration during administration in the body is stably maintained for 4 weeks. On the other hand, in the case of Example 4 prepared by volatilizing the dichloromethane solvent above the boiling point of the dichloromethane solvent during the manufacturing process, it can be confirmed that the blood concentration is not stably maintained when administered in the body. The above results are confirmed to be due to the volatilization timing and temperature of the dichloromethane solvent affecting the thickness and density of the shell and the drug distribution generated on the surface of the microspheres.

In addition, as shown in Figure 3b, Resomer ^® R203H (IV: 0.25 to 0.35 dl / g) Example 1 prepared using a biodegradable polymer is confirmed that the blood concentration during administration in the body is stably maintained for 4 weeks Can. On the other hand, Resomer ^® R202H (IV: 0.16 to 0.24 dl / g) using the biodegradable polymer Example 7 prepared in the same manner as in Example 1 due to the relatively low biodegradable polymer viscosity compared to Example 1 It can be seen that the fluctuation of blood concentration is large after the initial rapid increase in blood concentration.

Accordingly, it can be seen that according to the present invention, it is possible to manufacture long-lasting microparticles of various emission patterns by controlling the intrinsic viscosity of the biodegradable polymer and the time and temperature of volatilization of the dichloromethane solvent.

Preparation Example 1: Preparation of injection

Preparation of diluent: 2250 mg of sodium carmellose, 100 mg of polysorbate 20, 99 mg of sodium monohydrogen phosphate, 109 mg of citric acid, 600 mg of sodium chloride, and 54 mg of sodium hydroxide were dissolved in purified water for injection to prepare 200 mL.

When the patient is administered, 2 mL of the diluent is added to a vial filled with 1,030 to 1,080 mg of Donepezil long-acting microparticles prepared in Example 1 and suspended for injection.

Claims (21)

(a) dissolving donepezil and a biodegradable polymer having an inherent viscosity (IV) of 0.2 to 0.5 dL / g in a dichloromethane solvent;
(b) adding the solution of donepezil and biodegradable polymer into a polyvinyl alcohol solution and stirring to form a droplet-like dispersed phase;
(c) forming a microsphere by removing the dichloromethane solvent at a temperature of less than 39.6 ° C., the boiling point of the dichloromethane solvent; And
(d) A method of manufacturing a long-lasting microsphere comprising donepezil, comprising freeze-drying the formed microspheres. The method of claim 1, wherein the step (c) comprises a solidification step of the microspheres and a volatilization step of the solvent. The method of claim 2, wherein the solidifying step of the microspheres is performed for 1 to 3 hours at a temperature of 10 to 20 ° C. The method according to claim 2, wherein the step of volatilization of the solvent is performed for 1 to 3 hours at a temperature of 30 to 35 ° C. The method of claim 1, further comprising the step of filtering the microspheres formed in the step (c), and then washing with water to remove the polyvinyl alcohol. The method according to claim 1, wherein donepezil is in the form of a free base. The method of claim 1, wherein the content of donepezil is 20 to 30% by weight based on the total weight of the microspheres. The method of claim 1, wherein the input amount of donepezil and biodegradable polymer is in a weight ratio range of 1: 2 to 3. The method of claim 1, wherein the input amount of the dichloromethane solvent is an amount such that the concentration of donepezil and the biodegradable polymer solution is 40 to 60% by weight. The method according to claim 1, wherein the biodegradable polymer is polylactic acid (PLA). 11. The method according to claim 10, wherein the chain end functional group of the polylactic acid is a carboxylic acid terminated or ester terminated. 12. The method according to claim 11, wherein the chain end functional group of the polylactic acid is a carboxyl group. A long-acting-type microsphere comprising donepezil obtained by the method according to any one of claims 1 to 12. 14. The long-lasting microsphere according to claim 13, wherein the content of donepezil is 20 to 30% by weight based on the total weight of the microspheres. The long-acting type microsphere according to claim 13, wherein the size (D ₅₀ ) is 1 to 150 μm. 14. The long-acting microsphere of claim 13, wherein the release of donepezil in the body lasts at least 4 weeks. A pharmaceutical composition for parenteral use comprising long-acting microparticles comprising donepezil obtained by the method of any one of claims 1 to 12 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 17, which is an injection. delete delete delete

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