KR20210032166A - Donepezil eutectic mixture and use thereof - Google Patents

Abstract

The present invention relates to a donepezil eutectic mixture and a use thereof. A eutectic mixture of the present invention allows increased solubility and skin permeability of donepezil, and a pharmaceutical composition containing the same does not generate donepezil crystals and maintains an amorphous form, even when stored in various conditions, thereby being applicable to various formulations, while also having excellent stability and efficacy.

Description

Donepezil eutectic mixture and use thereof

The present invention relates to donepezil eutectic mixtures and uses thereof.

Alzheimer's disease is the most common degenerative brain disease that causes dementia, and is accompanied by symptoms such as personality change, nervous behavior, and depression as well as cognitive decline, and neurological disorders or physical complications appear at the end. As a drug to treat this, donepezil is used, and it is marketed as a tablet formulation containing donepezil hydrochloride.

Donepezil is an acetylcholinesterase (AChE) inhibitor and is used to treat mild and severe dementia of Alzheimer's disease. In Alzheimer's disease, where cholinergic nervous system disorders in the brain are reported, AChE inhibitors such as donepezil increase acetylcholine in the brain and activate the cholinergic nerve in the brain. The formulation of donepezil, which is currently used commercially, is in the form of a tablet (pill), and is prescribed to patients with Alzheimer's disease in an oral form.

However, in general, acetylcholinesterase inhibitors as oral drugs have severe side effects, and in particular, there are reports of problems such as liver dysfunction or digestive disorders. The cause of the above side effects is that it is generally impossible to avoid the first-pass effect to the liver, and as a result, it is easy to affect liver function, and because it is present in a high concentration in the digestive tract, side effects are likely to appear in the digestive tract. Can be lifted. In addition, in the case of oral drugs, the ratio of the maximum blood concentration reached after administration to the blood concentration after 24 hours (at the next administration) is large in terms of changes in the blood concentration of the drug after administration. There is a problem that it is not easy to maintain the therapeutic effect over a long period of time without reaching it.

In particular, most Alzheimer's patients refuse to take drugs or have difficulty swallowing or chewing drugs due to dysphagia. However, commercially available donepezil hydrochloride has difficulty in taking normal drugs due to its characteristic stimulating and sour taste. In addition, Donepezil transdermal absorption formulation uses a large amount of various permeation accelerators due to its low skin permeability, causing skin irritation problems such as skin rash, or when storing the drug in a hydrophobic matrix, solid crystals are generated to increase adhesion. There is a decrease, non-uniformity in skin permeation rate, and storage problems.

Accordingly, there is a continuous demand for the development of formulations and formulations capable of increasing drug compliance in the application of the donepezil drug.

Korean Patent Registration No. 10-1770675 Korean Patent Registration No. 10-1553207

It is an object of the present invention to provide a donepezil eutectic mixture comprising donepezil and a copolymer.

Another object of the present invention is to provide a pharmaceutical composition comprising the eutectic mixture of Donepezil.

Another object of the present invention is to provide a method for preparing the Donepezil eutectic mixture.

One aspect of the present invention for achieving the above object includes donepezil and a copolymer, and the copolymer relates to a donepezil eutectic mixture, which is a dicarboxylic acid.

Specifically, the dicarboxylic acid is azelaic acid, glutaric acid, itaconic acid, maleic acid, phthalic acid, pimelic acid, It may be one or more selected from the group consisting of sebacic acid, suberic acid, and α-ketoglutaric acid.

More specifically, the donepezil and the copolymer may be included in a weight ratio of 100:1 to 1:4, and most specifically, may be included in a weight ratio of 10:1 to 1:2.

Also, specifically, the eutectic mixture may be in a fluidized state at -70 to 250°C.

In the present invention, donepezil or a salt thereof has a chemical name of 2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxyindan-1-one, and treatment of Alzheimer's and dementia It is an acetylcholinesterase inhibitor used as a drug for

In the present invention, a'eutectic mixture' refers to a uniform melting point and a uniform mixture of fine heterogeneous crystals. Each substance constituting the eutectic mixture may have distinct physicochemical characteristics, such as molecular weight, molecular structure, logP, melting point, or endothermic amount, and may increase the solubility or dissolution of poorly soluble drugs. have. The donepezil eutectic mixture of the present invention structurally has a functional group capable of hydrogen bonding or ionic bonding, and forms a eutectic mixture through interaction with these bondable copolymers, thereby remarkably improving the solubility and skin permeability of donepezil. Can be improved.

In the present invention,'coformer' refers to a substance capable of forming a eutectic mixture of donepezil by acting, reacting, or combining with donepezil, which is a main component of a drug. Azelaic acid, glutaric acid, itaconic acid, maleic acid, phthalic acid, pimelic acid, sebacic acid, water It may be a compound such as suberic acid and α-ketoglutaric acid, but is not limited thereto, and any material capable of forming a eutectic mixture by coform with donepezil Can be included without limitation.

In one embodiment of the present invention, it was confirmed that the solubility of all of the eutectic mixtures of the present invention was remarkably excellent compared to the commercially available donepezil drug substance (Table 3), and it was confirmed that the skin permeability was also remarkably excellent (FIG. 3). It was confirmed that not only the form but also transdermal drug administration can be effectively applied.

Another aspect of the present invention relates to a pharmaceutical composition for the prevention or treatment of Alzheimer's or dementia comprising the donepezil eutectic mixture.

Donepezil is conventionally used as a drug for treating Alzheimer's and dementia and alleviating symptoms thereof, and a pharmaceutical composition comprising the eutectic mixture of donepezil of the present invention can also be applied for the prevention or treatment of Alzheimer's or dementia.

The pharmaceutical composition according to the present invention can be prepared into a pharmaceutical formulation using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In the preparation of the formulation, the pharmaceutical composition according to the present invention may additionally contain a pharmaceutically acceptable carrier within a range that does not inhibit the activity of the donepezil eutectic mixture of the present invention.

The pharmaceutically acceptable carriers are those commonly used, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils, and the like. In addition, the pharmaceutical composition of the present invention may contain diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives.

Administration of the pharmaceutical composition according to the present invention can be administered in a pharmaceutically effective amount. “Pharmaceutically effective amount” means an amount sufficient to prevent or treat a disease at a reasonable benefit/risk ratio applicable to medical treatment. The effective dosage level may be variously selected by those skilled in the art according to factors such as formulation method, patient's condition and weight, patient's sex, age, degree of disease, drug type, route and duration of administration, excretion rate, and response sensitivity. have. The effective amount may vary depending on the route of treatment, the use of excipients and the possibility of use with other agents, as will be appreciated by those of skill in the art. However, for a desirable effect, in the case of oral administration, the composition of the present invention per 1 kg of body weight per day is generally administered to an adult at 0.0001 to 100 mg/kg per day, preferably 0.001 to 100 mg/kg. However, the dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention can be administered to mammals such as mice, livestock, and humans through various routes. Specifically, the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, application or intravenous, subcutaneous, intraperitoneal injection), but oral administration is preferred. It can be administered intravaginally for the prevention and treatment of vaginitis. Solid preparations for oral administration may include powders, granules, tablets, capsules, soft capsules, pills, and the like. Liquid preparations for oral use include suspensions, solvents, emulsions, syrups, aerosols, etc.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives are included. I can. Formulations for parenteral administration include aqueous solutions, solutions, non-aqueous solutions, suspensions, emulsions, eye drops, ointments, syrups, suppositories, aerosols, and other external preparations and sterile injections, each sterilized according to a conventional method. May be used, preferably a pharmaceutical composition of cream, gel, patch, spray, ointment, warning agent, lotion, liniment, eye ointment, eye drop, pasta, or cataplasma may be prepared and used. , But is not limited thereto. Formulations for topical administration may be anhydrous or aqueous, depending on the clinical prescription. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

Specifically, the pharmaceutical composition of the present invention may be a transdermal absorption formulation. In addition, as a transdermal absorption formulation, it may be in the form of a patch or a film. In one embodiment of the present invention, it was confirmed that excellent skin permeability was shown even when applied as a transdermal absorption type formulation (FIG. 3), and it can be applied in a form that can be attached to a surface. The surface includes the skin of all parts of the body, the surface of the mouth, and the like, and is not limited to a specific part.

In general, in the case of patch preparations, the main ingredient (main drug) is uniformly distributed in the additives of the patch to exhibit a certain standard of release characteristics, but the main ingredient is precipitated as crystals over time during distribution or storage, so that the desired medicinal effect is not exhibited. Poor stability of the back is a problem. However, since the eutectic mixture of the present invention maintains the amorphous form of the drug, crystals are not formed even with changes over time and maintains the amorphous state, it is possible to maintain the initial release characteristics, so it has excellent stability, and has excellent urinating and skin permeability. It has an excellent advantage.

Another aspect of the present invention relates to a method for preventing or treating Alzheimer's or dementia, comprising administering a pharmaceutical composition comprising the donepezil eutectic mixture to a subject. In the present invention, terms such as'Donepezil eutectic mixture' are the same as described above.

The subject refers to an animal, and typically may be a mammal that can exhibit beneficial effects by treatment with the pharmaceutical composition of the present invention. Preferred examples of such subjects may include primates such as humans. In addition, such subjects may include all subjects who have symptoms of Alzheimer's or dementia, or who are at risk of having such symptoms.

Another aspect of the present invention is donepezil; And azelaic acid, glutaric acid, itaconic acid, maleic acid, phthalic acid, pimelic acid, sebacic acid, It relates to a method for producing a eutectic mixture of donepezil comprising mixing at least one copolymer selected from the group consisting of suberic acid and alpha-ketoglutaric acid. Specifically, the donepezil and the copolymer may be included in a weight ratio of 100:1 to 1:4, and more specifically, may be included in a weight ratio of 10:1 to 1:2.

Also, specifically, the eutectic mixture may be in a fluidized state at -70 to 250°C.

In an embodiment of the present invention, donepezil; And adipic acid, malic acid, malonic acid, succinic acid, tartaric acid, and vanillin. The donepezil eutectic mixture was prepared through a manufacturing method including the step of, and it was confirmed that the donepezil eutectic mixture exhibited excellent solubility and skin permeability.

Accordingly, donepezil eutectic mixture can be prepared using the above-described manufacturing method and used for the prevention and treatment of Alzheimer's or dementia.

The donepezil eutectic mixture of the present invention has significantly increased solubility and skin permeability compared to the existing donepezil, and thus can increase medication compliance. In particular, since it exhibits high skin permeability, it is possible to administer the drug through transdermal absorption, so that it may exhibit an improved therapeutic effect in Alzheimer's or dementia patients who have difficulty in taking the drug.

1 shows the results of confirming that all of Examples 1 to 9 of the present invention exhibit fluidity at room temperature through differential scanning calorimetry analysis.
Figure 2 shows the results of observing the state change according to the temperature of the eutectic mixture of Example 2.
Figure 3 shows the results of measuring the skin permeability of the eutectic mixture of Examples 1 to 9 and Comparative Example 1.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.

Example 1.Donepezil (DNP)- Preparation of azelaic acid eutectic mixture

100 mg of donepezil (purchased from: Perigo) and 100 mg of azelaic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and azelaic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-azelaic acid (1:1) was obtained.

Example 2. Preparation of donepezil-glutaric acid eutectic mixture

100 mg of donepezil and 100 mg of glutaric acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and glutaric acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-glutaric acid (1:1) was obtained.

Example 3. Preparation of donepezil-Itaconic acid eutectic mixture

100 mg of donepezil and 100 mg of itaconic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and glutaric acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-itaconic acid (1:1) was obtained.

Example 4. Preparation of donepezil-maleic acid eutectic mixture

100 mg of donepezil and 100 mg of maleic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and maleic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-maleic acid (1:1) was obtained.

Example 5. Preparation of donepezil-phthalic acid eutectic mixture

100 mg of donepezil and 100 mg of phthalic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and phthalic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-phthalic acid (1:1) was obtained.

Example 6. Preparation of donepezil-pimelic acid eutectic mixture

100 mg of donepezil and 100 mg of pimelic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and pimelic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-pimelic acid (1:1) was obtained.

Example 7. Donepezil- Preparation of Sebacic acid eutectic mixture

100 mg of donepezil and 100 mg of sebacic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and sebacic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-sebacic acid (1:1) was obtained.

Example 8. Preparation of donepezil-suberic acid eutectic mixture

100 mg of donepezil and 100 mg of suberic acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and suberic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-suberic acid (1:1) was obtained.

Example 9. Preparation of donepezil-alpha-ketoglutaric acid eutectic mixture

100 mg of donepezil and 100 mg of alpha ketoglutaric acid were added to an ethanol (EtOH) solvent (1 mL) and stirred at 25° C. for about 30 minutes to prepare a mixed solution in which donepezil and suberic acid were dissolved. After evaporating the solvent in a drying oven at 60° C. for 24 hours, a eutectic mixture of donepezil-alphaketoglutaric acid (1:1) was obtained.

Comparative Example 1. Donepezil raw material

Commercially available donepezil raw materials were used as Comparative Example 1.

Comparative Example 2. Donepezil hydrochloride

A commercially available raw material for donepezil hydrochloride was used as Comparative Example 2.

Experimental Example 1. Differential Scanning Calorie Analysis

The thermal behavior of the sample was confirmed using a differential scanning calorimeter (DSC auto Q2000, TA instrument, New Castle, USA). Specifically, 3 to 6 mg of all samples were accurately weighed and sealed in an aluminum pan. It was measured at a heat rate of 10° C./min and a nitrogen flow rate of 40 mL/min, and the temperature range was selected from -70° C. to 250° C. for each material.

As a result of the measurement, it was confirmed that all of Examples 1 to 9 had a glass transition temperature (Tg) below room temperature, which means that they had fluidity in a paste state or a liquid state at room temperature (Table 1 and Fig. 1).

Experimental Example 2. Confirmation of state change according to temperature

In order to check the state change according to the temperature, it was observed using a high temperature microscope capable of controlling the temperature of the sample. The model used was Axioscope (A1, Carl zeiss, Oberkochen, Germany) and was performed at 20 times magnification using a microscope camera (Axio cam MRc, Carl zeiss, Oberkochen Germany). The temperature was controlled at a heating rate of 5°C/min.

Specifically, the state change according to the temperature of the eutectic mixture of Example 2 was confirmed, respectively, at 25°C (a), 50°C (b), 70°C (c), 90°C (d), 100°C (e), and 110 It was observed at a temperature of °C (f).

As a result, as shown in FIG. 2, it was confirmed that it was already in a liquid state or a paste state having fluidity from 25° C., which is a state at 94 to 99° C., which is the melting point of donepezil, and 95 to 98° C., which is the melting point of glutaric acid. It was confirmed that there was no significant difference with the.

This means that the eutectic mixture containing donepezil and the copolymer of the present invention can obtain a liquid property that improves drug absorption even when a high temperature is applied or an organic solvent is not added. This suggests that the precipitation of crystals of the main component can be prevented.

Experimental Example 3. Solubility Test

Solubility tests were performed on the Donepezil eutectic mixtures obtained in Examples 1 to 9 and Comparative Examples. Specifically, 100 mg of a sample corresponding to 50 mg of donepezil was added to 0.5 mL of distilled water (100 mg/mL concentration) and stirred at room temperature at a speed of 50 rpm using a Rotator (CRT-350, Lab companion) for 24 hours. An additional 100 mg of sample was added to the sample which was checked every 2 hours and was already transparently dissolved. In the case of melting more than 1:1, the experiment was not conducted any more.

The solubility results were classified according to the solubility standard table of the following US Pharmacopoeia.

The results of the solubility test according to the US Pharmacopoeia solubility standard are shown in Table 3 below.

As shown in Table 3, the raw materials of donepezil of Comparative Example 1 (solubility 74.55 μg/mL) and the donepezil hydrochloride (solubility of 29.86 mg/mL) of Comparative Example 2 were not dissolved or slightly dissolved in Example 1, respectively. To 9 showed that the solubility was 50 times higher than that of Comparative Example 1.

Experimental Example 4. Measurement of skin permeability

4-1. Measurement of skin permeability according to the type of coformer

The skin permeability test was performed on the eutectic mixtures of Examples 1 to 9 and Comparative Example 1 each synthesized by different types of the copolymer. Specifically, each eutectic mixture was applied to the artificial skin in an appropriate amount on a 1x1cm release liner, attached to the skin, and then fixed to the Franz cell with a clamp. An isotonic phosphate buffer solution (pH 7.4) was added to the receptor and maintained at 32.5° C., while stirring at 300 rpm with a magnetic stirrer, samples were collected for 24 hours at intervals of 4 hours.

The obtained sample was quantified using high performance liquid chromatography and an ultraviolet absorbance spectrophotometer under the following analysis conditions. Analysis conditions are as follows.

<Analysis conditions>

Column: Phenomenex, 250*4,6.5, C18 column

Mobile phase: 0.1M PBS pH 2.7 solution: Acetonitrile: Methanol = 50: 20: 30

Temperature: 25℃

Sample injection volume: 20 μl

Ultraviolet absorption wavelength: 268nm

Analysis time: 7 minutes

As a result, as shown in FIG. 3, the skin permeability of Comparative Example 1 hardly appeared until 24 hours elapsed, whereas the eutectic mixtures of Examples 1 to 9 showed improved skin permeability compared to Comparative Example 1.

In particular, Example 2 showed ^{a skin permeability of 1,475 μg/cm 2} for 24 hours, which is about 8 times more skin permeability than Comparative Example 1 at the same time.

The above results confirm that the eutectic mixture of the present invention exhibits excellent skin permeability, and indicates that the transdermal drug administration method, which is not applicable in Comparative Example 1, can be applied to the eutectic mixture of the present invention.

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as being distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims to be described later, and all changes or modified forms derived from the meaning and scope of the claims and the concept of equivalents thereof should be construed as being included in the scope of the present invention.

Claims (10)

Including donepezil and a copolymer,
Wherein the copolymer is a dicarboxylic acid (dicarboxylic acid), donepezil eutectic mixture. The method of claim 1, wherein the dicarboxylic acid is azelaic acid, glutaric acid, itaconic acid, maleic acid, phthalic acid, and pimelic acid. acid), sebacic acid, suberic acid, and alpha-ketoglutaric acid, which is one or more selected from the group consisting of, donepezil eutectic mixture. The method of claim 1, wherein the donepezil and the copolymer are contained in a weight ratio of 100:1 to 1:4, donepezil eutectic mixture. The method of claim 2, wherein the donepezil and the copolymer are contained in a weight ratio of 10:1 to 1:2, donepezil eutectic mixture. The method according to claim 1, wherein the eutectic mixture is in a fluidized state at -70 to 250°C. A pharmaceutical composition for the prevention or treatment of Alzheimer's or dementia, comprising the eutectic mixture of any one of claims 1 to 5. The method of claim 6, wherein the pharmaceutical composition is a transdermal absorption type preparation, a pharmaceutical composition for the prevention or treatment of Alzheimer's or dementia. The pharmaceutical composition of claim 7, wherein the transdermal absorption type preparation is in the form of a patch or film, preventing or treating Alzheimer's or dementia. Donepezil; And
Azelaic acid, glutaric acid, itaconic acid, maleic acid, phthalic acid, pimelic acid, sebacic acid, water Veric acid (suberic acid) and alpha ketoglutaric acid (α-ketoglutaric acid) comprising the step of mixing one or more copolymers selected from the group consisting of, Donepezil eutectic mixture. The method of claim 9, wherein the donepezil and the copolymer are mixed in a weight ratio of 10:1 to 1:2.

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