KR20180106786A - Aqueous liquid formulation containing choline alfoscerate - Google Patents

Abstract

The present invention relates to an aqueous liquid formulation containing choline alfoscerate. The choline alfoscerate-containing aqueous liquid formulation according to the present invention hardly produces decomposition products of choline alfoscerate under long-term storage conditions and harsh storage conditions, and the formulation is stable in properties. In addition, since the formulation is easy to be taken, the drug compliance of patients with dysphagia in elderly patients requiring administration of choline alfoscerate can be increased.

Description

[0001] The present invention relates to an aqueous liquid formulation containing choline alfoscerate,

The present invention relates to aqueous liquid preparations containing choline alfoscerate.

L-alpha-glycerylphosphorylcholine (alpha-GPC), called choline alfoscerate, is a natural choline compound found in the brain. Choline alfoscerate is a precursor of acetylcholine, one of the neurotransmitters in the brain, which is metabolized in the body and acts as acetylcholine.

Choline alfoscerate exists naturally in all cells of the body, but its amount decreases as the aging progresses. Therefore, administration of choline alfoscerate is known to have a therapeutic effect on diseases in which symptoms of neurotransmitter depression are symptomatic.

Currently, choline alfoscerate is marketed as an agent for improving cerebrovascular disease and brain metabolism, and its main effects and effects are as follows.

1) secondary symptoms due to cerebrovascular defects and degenerative or degenerative brain metastatic psychiatric syndromes: diminished memory and confusion, ambition and spontaneity, decreased sense of direction, decreased motivation and spontaneity, decreased concentration

2) Emotional and Behavioral Changes: Emotional Anxiety, Irritability, Ambivalence

3) senile depression

However, choline alfoscerate has a characteristic of exhibiting deliquescence that easily dissolves in the surrounding environment by absorbing moisture. Thus, choline alfoscerate has been marketed in the form of soft capsules obtained by filling choline alfoscerate, dissolved in an oil-based solvent (e. G., Concentrated glycerin), into soft gelatin capsules.

However, in the case of the soft capsule preparation, there is a possibility that the choline alfoscerate is converted into the water-soluble soft gelatin capsule with the lapse of time, the soft capsule preparation has the possibility of microorganism degeneration, the characteristics of the gelatin capsule weak in moisture and heat There is a possibility of degeneration of the active ingredient, and the possibility that the active ingredient may be altered. The soft capsule formulation has a drawback that it is inconvenient to take in an elderly patient, especially a patient having cognitive dysfunction, I have a problem.

Recently, the development of choline alfoscerate-containing solid preparations has been studied to solve problems of deliquescence of choline alfoscerate and problems of soft capsule preparations. For example, Korean Patent Publication No. 10-2009-0088564 (Patent Document 1) discloses a pharmaceutical preparation containing choline alfoscerate, which comprises choline alfoscerate adsorbed on colloidal silicon dioxide, . Korean Patent Registration No. 10-1172699 (Patent Document 2) discloses a pharmaceutical preparation comprising an adsorbate obtained by adsorbing choline alfoscerate to magnesium aluminosilicate at a weight ratio of 1 to 2. Korean Patent Registration No. 10-1257919 (Patent Document 3) discloses a water-soluble polymer such as hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methacrylic acid copolymer, and polyethylene oxide, ≪ RTI ID = 0.0 > and / or < / RTI > the resulting coated particles.

However, these solid preparations must essentially perform the adsorption of the drug itself (i.e., choline alfoscerate) to an excipient (Patent Literatures 1 and 2) or to perform particle coating (Patent Literature 3). That is, since such choline alfoscerate-containing solid preparations are required to perform adsorption or particle coating separately, the manufacturing process is complicated and requires special facilities (for example, fluidized bed granulator) . Furthermore, in the case of producing a tablet using choline alfoscerate adsorbed on colloidal silicon dioxide according to Patent Document 1, the size of the obtained tablet becomes too large, and an elderly patient suffering from poor swallowing ability, There is a problem that the patients are very uncomfortable to take.

Therefore, there is still a need for the development of choline alfoscerate formulations that are free from the problem of compromise of choline alfoscerate, have a high storage stability of the preparation, and can increase patient compliance with the medication.

Korean Patent Publication No. 10-2009-0088564 Korean Patent Registration No. 10-1172699 Korea Patent No. 10-1257919

It is an object of the present invention to provide an oral aqueous liquid preparation comprising choline alfoscerate or a pharmaceutically acceptable salt thereof.

Liquid formulations are an advantageous formulation for patients who are less likely to swallow drugs than capsules or tablets. Patients in need of administration of choline alfoscerate are predominantly elderly. In particular, patients with dementia often forget how to swallow food, so it is often the case that the food is only bitten in the mouth or taken out during spitting or swallowing, which is called Dysphagia. Dysphagia can occur gradually as dementia worsens, and sometimes it is caused by side effects of medications (neurotransmitters, antipsychotics). In patients with dysphagia, it is not easy to take bulk medicines such as tablets or capsules, so oral liquid preparations can increase the convenience of taking medicines for patients with dysphagia, thereby increasing compliance.

Due to the deliquescence of choline alfoscerate, conventionally, as a measure for moisture interception, a method such as packing in an aluminum bag for avoiding contact with air after filling the soft capsule with choline alfoscerate is used, 1 and 2, choline alfoscerate was adsorbed to an excipient. However, there was no attempt to formulate choline alfoscerate into a liquid formulation.

The present inventors have made efforts to develop a formulation capable of simultaneously enhancing the stability and ease of use of the choline alfoscerate preparation, and as a result, it has been found that the choline alfoscerate oral aqueous liquid preparation of the following composition simultaneously achieves excellent formulation stability and ease of use, The present invention has been accomplished by confirming that a formulation exhibiting bioequivalence with a soft capsule to be obtained can be obtained.

The present invention provides a choline alfoscerate aqueous liquid preparation which is excellent in the stability of choline alfoscerate even though it is a liquid preparation, has excellent storage stability of the preparation, and has high patient convenience.

In order to solve the storage stability problem of choline alfoscerate in a liquid state, the present inventors studied the composition of a stable liquid formulation under long-term storage or harsh storage conditions in a liquid state.

As a result, an aqueous liquid preparation comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, an aqueous solvent, a pH adjusting agent, a preservative and a viscosity controlling agent, wherein the aqueous liquid formulation has a pH of 3.5 to 7.5, And the stability condition was satisfied. Preferably, the pH of the choline alfoscerate aqueous liquid preparation may be 4 to 7, although not limited thereto.

The pH of the aqueous liquid preparation can be adjusted by adding an appropriate amount of a pH adjusting agent to choline alfoscerate dissolved in an aqueous solvent.

But are not limited to, organic acids or inorganic acids or their salts selected from citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, acetic acid, tartaric acid, oxalic acid and phosphoric acid; Or at least one component selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia water and ammonium carbonate.

In the choline alfoscerate aqueous liquid preparation according to the present invention, the aqueous solvent may be contained in an amount of 80 to 99 parts by weight based on 100 parts by weight of the liquid formulation.

In one embodiment, but not limited thereto, the aqueous solvent may be, for example, water, or a mixture of water and ethanol.

In the choline alfoscerate aqueous liquid preparation according to the present invention, choline alfoscerate or a pharmaceutically acceptable salt thereof may be contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of the total amount of the liquid preparation.

On the other hand, the choline alfoscerate aqueous liquid preparation means a substance which inhibits the growth of microorganisms in the liquid preparation of the present invention, including, for example, paraoxybenzoic acid, benzoic acid, sorbic acid and salts thereof, Any conventional preservatives used in the art may be used.

The preservative may be included in an amount of 0.002 to 0.5 parts by weight based on 100 parts by weight of the total amount of the liquid preparation.

In one embodiment of the present invention, a paraben-based preservative such as methylparaben, propylparaben or a mixture thereof may be used as the preservative.

The liquid preparation according to the present invention may further comprise at least one pharmaceutically acceptable additive selected from the group consisting of sweeteners, flavoring agents, and coloring agents.

A sweetener means an additive added for the purpose of improving the adherence of medicines by imparting sweetness to liquid preparations. The sweetening agent contained in the liquid preparation of the present invention may be, for example, sugar, fructooligosaccharide, xylitol, maltodextrin, stevioside, aspartame, oligosaccharide, sorbitol, fructose, honey, malt, , Glutamic acid, L-glutamic acid, sodium saccharin, saccharin sodium, citric acid, tartaric acid, sodium tartrate, lactic acid, adipic acid, fumaric acid, sodium fumarate, potato extract (pyrozoline), glycyrrhetenic acid, But are not limited to, monellin, thaumatin, saccharin, aspartame, acesulfame, dicin, cyclamate sodium, glucitol, and the like. A variety of sweetening agents known in the art may be used.

The sweetener of the present invention may be added in an amount of 0.001 to 5 parts by weight based on 100 parts by weight of the liquid preparation of the present invention.

Flavoring agent means a substance that improves the compliance of a liquid formulation by allowing the liquid formulation to feel the flavor, for example, apple, cherry, orange, strawberry, banana, grape, mango, peach And various fruit flavors and synthetic fruit flavors; Vanilla flavor; Mint flavor; Red ginseng, and honey aroma may be used. The flavoring agent may be added in an amount of 0.001 to 5 parts by weight based on 100 parts by weight of the liquid preparation.

If desired, the liquid preparation may also contain a pharmaceutically acceptable colorant in an appropriate amount.

On the other hand, in patients with dysphagia, a dilute liquid such as water can easily be heard, whereas a thick liquid can be safer. Therefore, the liquid preparation according to the present invention is suitable for patients to take and can have a viscosity capable of pouch packing. To this end, the liquid preparation according to the present invention may contain a viscosity controlling agent.

In the present invention, the viscosity regulator may be, for example, carbomer, polyethylene oxide having a molecular weight of 5,000 to 5,000,000, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, guar gum, tragacanth gum, , Polyvinylpyrrolidone, polyvinyl alcohol, vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, undifferentiated crospovidone, carboxymethylcellulose and its derivatives, alginic acid and its derivatives, silicone emulsion, Glycerol, and mixtures thereof. ≪ Desc / Clms Page number 12 >

In one embodiment of the invention, the viscosity modifying agent may be xanthan gum, glycerin or a mixture thereof.

The viscosity of the liquid preparation according to the present invention may preferably be 10 cps to 100 cps, for example, 10 cps to 80 cps, and 20 cps to 60 cps. In the case of choline alfoscerate solution, disposable stick pouch packaging is carried out in order to improve the convenience of taking the patients. In the case of a liquid having a low viscosity, when the liquid agent is filled in the nozzle for filling the liquid agent, the liquid agent may be splashed to the pouch joint portion, which may lead to poor pouch bonding. The viscosity can be measured, for example, by the following measuring instrument and conditions: Brookfield viscometer. DV-II + Pro. Spindle 18. 25 C, 75 rpm

The liquid formulation according to the present invention is excellent in the stability of choline alfoscerate and the properties of a liquid preparation even under prolonged storage conditions or severe conditions.

For example, when the liquid preparation according to the present invention is stored for 14 days under the storage condition at 60 캜, the amount of the produced flexible substance in the liquid preparation is 0.1 to 5.0 wt% based on the weight of choline alfoscerate or a pharmaceutically acceptable salt thereof %. ≪ / RTI >

Further, even under long-term storage conditions or harsh conditions, there is little change in the properties of the liquid preparation, so that the color of the liquid preparation is not changed or precipitated.

In addition, as can be seen from the following examples, the choline alfoscerate aqueous liquid preparations of the present invention having excellent formulation stability can be prepared by dissolving choline alfoscerate soft capsules or choline alfoscerate soft capsules having the same active ingredient capacity (AUC) and the highest blood concentration (C _max ) at the bioequivalence level compared to the alfoscerate tablet.

The present invention also provides the use of a choline alfoscerate aqueous liquid preparation for the treatment or prevention of the following diseases in a subject:

1) secondary symptoms due to cerebrovascular defects and degenerative or degenerative brain metastatic psychiatric syndromes: diminished memory and confusion, ambition and spontaneity, decreased sense of direction, decreased motivation and spontaneity, decreased concentration

2) Emotional and Behavioral Changes: Emotional Anxiety, Irritability, Ambivalence

3) senile depression

In the present invention, the term 'subject' refers to a warm-blooded animal such as a mammal afflicted with a specific disease, disorder or disease and includes, for example, a human, an orangutan, a chimpanzee, a mouse, a rat, a dog, a cattle, , Amount, and the like, but are not limited to these examples.

In the present invention, " treatment " includes, but is not limited to, alleviating symptoms, temporarily or permanently eliminating the cause of symptoms, or preventing or slowing the appearance of symptoms and progression of a disease, disorder or disease.

The effective amount of the active ingredient of the liquid preparation of the present invention means the amount required to effect the treatment of the disease. Accordingly, the present invention is not limited to the particular type of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, the type of formulation and the patient's age, body weight, general health status, sex and diet, Rate of administration, duration of treatment, concurrent medication, and the like. For example, the pharmaceutical composition of the present invention may be administered 1 to 3 times a day, and may be administered in the range of 200 to 1200 mg, preferably 400 mg to 1000 mg once a day on the basis of choline alfoscerate, It is not.

In one embodiment of the invention, the aqueous liquid preparation may contain 400 mg of choline alfoscerate.

For example, an aqueous liquid preparation containing 400 mg of choline alfoscerate at a single dose can be packaged in an aluminum pouch and packaged for commercialization.

The choline alfoscerate-containing aqueous liquid preparations according to the present invention hardly produce decomposition products of choline alfoscerate under long-term storage conditions and harsh storage conditions, and the formulations are stable in properties. In addition, since it is easy to take, it is possible to increase the compliance of patients with dysphagia in elderly patients requiring administration of choline alfoscerate. In the case of patients with dementia, the choline alfoscerate aqueous liquid preparation according to the present invention, which is excellent in stability even under severe storage conditions, may be difficult to confirm and observe the storage conditions of the medicines. In particular, the bioavailability and formulation stability It is possible to provide a choline alfoscerate preparation which is excellent in portability and storage, and which is easy to take.

Fig. 1 shows the results of a PK test evaluating the bioequivalence of the test drug (Preparation Example 2) according to Experimental Example 3.

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below. The present invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Is provided to fully convey the scope of the invention to those skilled in the art, and the invention is only defined by the scope of the claims.

[ Example ]

In order to prepare the liquid preparation and to select the stable pH of the main component, after preparing the aqueous solution containing 400 mg of choline alfoscerate, the pH is adjusted to the desired pH with the pH adjuster as shown in the following table. I looked at it. In order to determine the stability of the active ingredient according to the storage condition of the liquid, the choline alfoscerate content was analyzed according to each analysis time, in addition to the acceleration condition, the temperature was kept at 60 ° C. and 80 ° C.

[Table 1]

Manufacturing example  1 to 8 Liquid  Content of ingredients and preparation method

Test Example  1. Choline Alfoscerate  Mercury Liquid  Storage stability according to pH

To evaluate the storage stability according to the pH of the choline alfoscerate aqueous solution, the liquid preparations according to Preparation Examples 1 to 8 were stored in a chamber set at an accelerated storage condition at a temperature of 40 DEG C and a relative humidity of 75% The content of serrate and the pH stability were compared together. The pH value of each preparation example was finally measured before putting the sample into the temperature-set chamber, and then it was put into the chamber. After stirring the choline alfoselate solution taken out at each time point for 10 minutes, the pH value of each solution And the content test was carried out according to the choline alfoscerate content test method. The pH measurement value of the choline alfoscerate aqueous solution and the choline alfoscerate content as a main component are shown in Table 2.

As shown in Table 2, it was confirmed that the choline alfoscerate aqueous pharmaceutical preparation of the present invention was stable in the pH stability and choline alfoscerate content of the solution for 2 weeks under the accelerated storage conditions in the pH range of 2 to 8 there was. The content test standard is 95.0 ~ 105.0%, and the content test value is included in the standard.

[Table 2]

Accelerated storage of choline Alfoscerate  Confirmation of content and pH stability

Test Example  2. Colin Alfoscerate  Mercury Liquid  Storage stability under severe storage conditions

As shown in Test Example 1, the content and pH stability of the choline alfoscerate aqueous solution were confirmed under accelerated storage conditions. As a result, excellent storage stability was confirmed in the entire pH range.

Thus, in Test Example 2, the stability of the liquid agent and the content of choline alfoscerate were compared with each other during storage for 4 weeks in a chamber set at a temperature of 60 ° C and 80 ° C to confirm the storage stability under harsh storage conditions. As a result of Test Example 1, excellent storage stability was confirmed in the entire pH range, and in Test Example 2, a sample in a pH range of 9 was added to conduct a storage stability test. The pH value of each preparation example was finally measured and then put in the chamber before putting the sample into the temperature set chamber. The choline alfoscerate aqueous solution taken out at each time point was put into a transparent beaker and visualized by visual observation, . At this time, the content test was carried out in the same manner as in Test Example 1, and the choline alfoscerate contents thereof are shown in [Table 3] and [Table 4].

As shown in Table 3 below, the change in choline alfoscerate content was confirmed according to the pH of the solution when stored at 60 ° C for 28 days. It was confirmed that choline alfoselate was stable at pH 4 ~ 8 of final solution, and choline alfoselate stability was decreased at pH 2 ~ 3 and pH 9.

As shown in Table 4, changes in the content of choline alfoscerate were confirmed according to the pH of the liquid even when stored at a temperature of 80 ° C for 28 days. At the temperature of 80 ° C, it was confirmed that the properties changed from white opaque liquid to brown after storage for 28 days, but the choline alfoscerate content was stable at the final pH 4-8 of the prepared liquid, Were similar to those at and at 60 ℃ storage conditions. However, at pH 2 ~ 3 and pH 9, the stability of choline alfoselate decreased more rapidly than that at 60 ℃ storage condition.

[Table 3]

Cholines according to pH at severe temperature conditions (60 ° C) Alfoscerate  Confirmation of content and pH stability

[Table 4]

Choline (pH) at pH under severe temperature conditions Alfoscerate  Confirmation of content and pH stability

Therefore, when the pH of the aqueous solution containing choline alfoscerate as a main component is 3 to 8, particularly 4 to 7, even when exposed to a harsh environment for a long time, choline alfoscerate is stable and the pH stability is high.

Experimental Example 3

PK tests were conducted on healthy subjects to evaluate the bioequivalence between the two preparations of Preparation Example 4 and Chong Kun Dang Glia Thymine.

The test was completed according to the 2 * 2 crossover test using a dose corresponding to 1200 mg of choline alfoscerate, respectively, of the reference drug and the test drug (Preparation Example 4). The bioequivalence between the two formulations was evaluated by statistically examining the bioavailability parameters, such as the blood concentration-time curve subscale (AUC) and peak blood concentration (Cmax), obtained from the drug concentration data in each plasma. The concentration of choline in plasma was analyzed by LC / MS / MS method.

The drug equivalence criteria were calculated by logarithmically transforming the blood concentration-time curve (AUC) and peak blood concentration (C _max ) of the reference drug and the test drug according to the bioequivalence test of the drug equivalence test standard of the pharmacist- If both items meet within the range of log 0.8 to log 1.25 in the 90% confidence interval of the mean difference value, the equivalence test of the drug is considered to be equivalent. However, if the difference between the log-transformed mean values of the comparative evaluation items of the reference drug and the test drug is within the range of log 0.9 to log 1.11, 2) when the comparative dissolution test is performed according to the drug equivalency test standard, If all of the conditions are equivalent under the condition, it is judged to be equivalent.

Figure 1 shows the mean plasma cholinergic concentration trends (n = 15, Mean + SD) of the reference drug and the test drug. The AUCt T / R ratio was 1.034 and the Tmax T / R ratio was 0.904, which was close to 1 in the test drug (Preparation Example 4). The possibility of bioequivalence was confirmed through the average AUtC and Tmax of the test drug and the reference drug.

Claims (14)

Wherein the pH is in the range of 3.5 to 7.5, comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, an aqueous solvent, a pH adjusting agent, a preservative and a viscosity controlling agent. The method according to claim 1,
Wherein the choline alfoscerate or pharmaceutically acceptable salt thereof is contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of the total amount of the liquid preparation. The method according to claim 1,
Wherein the liquid preparation has a pH of 4 to 7. [ The method according to claim 1,
Wherein the aqueous solvent is contained in an amount of 80 to 99 parts by weight based on 100 parts by weight of the total amount of the liquid preparation. The method according to claim 1,
The aqueous solvent is water, or a mixture of water and ethanol. The method according to claim 1,
The pH adjusting agent may be an organic acid or an inorganic acid or a salt thereof selected from citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, acetic acid, tartaric acid, oxalic acid and phosphoric acid; Or at least one component selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia water and ammonium carbonate. The method according to claim 1,
Wherein the preservative is contained in an amount of 0.002 to 0.5 part by weight based on 100 parts by weight of the total amount of the liquid preparation. The method according to claim 1,
Wherein the preservative is a paraben-based preservative. The method according to claim 1,
The viscosity modifier may be at least one selected from the group consisting of carbomer, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, guar gum, tragacanth, gum lucoste, carrageenan, polyvinylpyrrolidone, polyvinyl alcohol, At least one member selected from the group consisting of alginic acid and derivatives thereof, silicone emulsion, glycerol, and mixtures thereof, at least one member selected from the group consisting of at least one member selected from the group consisting of at least one member selected from the group consisting of at least one member selected from the group consisting of: Lt; / RTI > The method according to claim 1,
Wherein the liquid formulation has a viscosity of 10 cps to 100 cps. The method according to claim 1,
Wherein the liquid formulation further comprises at least one pharmaceutically acceptable additive selected from the group consisting of sweeteners, flavoring agents, and coloring agents. The method according to claim 1,
When the liquid preparation is stored for 14 days under the storage conditions at 60 캜, the amount of the produced choline alfoscerate or a pharmaceutically acceptable salt thereof is 0.1 to 0.1% by weight of choline alfoscerate or a pharmaceutically acceptable salt thereof. To 5.0% by weight. The method according to claim 1,
The choline alfoscerate in the liquid formulation exhibits a biological equivalent level of blood concentration-time curve back-off (AUC) and peak serum concentration (< RTI ID = 0.0 > Cmax). ≪ / RTI > The method according to claim 1,
Wherein the liquid formulation comprises 400 mg of choline alfoscerate.

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