WO2018169306A1 - Aqueous liquid formulation containing choline alfoscerate - Google Patents

Abstract

The present invention relates to an aqueous liquid formulation containing choline alfoscerate. Under long-term storage conditions and harsh storage conditions, the aqueous liquid formulation containing choline alfoscerate, according to the present invention, hardly produces decomposed products of choline alfoscerate and the properties of the formulation are stable. In addition, the formulation has excellent dosing convenience, thereby enabling dosing compliance of elderly dysphagia patients requiring choline alfoscerate administration to improve.

Description

Aqueous liquid formulation containing choline alfoscerate

The present invention relates to an aqueous liquid formulation 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, and is metabolized in the body to act as acetylcholine.

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

Currently, choline alfoscerate is sold as a cerebrovascular disease and cerebral metabolism improving agent, and main effects and effects are as follows.

1) Secondary symptoms and degenerative or degenerative cerebral psychiatric syndrome caused by cerebrovascular defects: disorientation, decreased motivation and spontaneity, decreased concentration due to memory loss and confusion, motivation and spontaneity

2) Emotional and behavioral changes: emotional anxiety, irritability and apathy

3) senile pseudodepression

By the way, choline alfoscerate is characterized by exhibiting deliquescent (deliquescence) that is easily dissolved by absorbing moisture in the environment. Therefore, choline alfoscerates have been commercially available in the form of soft capsules obtained by filling choline alfoscerates dissolved in oil-based solvents (eg, concentrated glycerin) in soft gelatin capsules.

However, in the case of soft capsule formulations, there is a possibility that choline alfoscerate may migrate to the water-soluble soft gelatin coating over time, the possibility of microbial deterioration of the soft capsule formulation, and the characteristics of gelatin capsules that are weak to moisture and heat. There is a possibility of modification, and there is a possibility of alteration of the active ingredient, soft capsule formulation is very uncomfortable for elderly patients, especially those with cognitive impairment, because the capsule size is so large that the capsule capacity is poor I have a problem.

Therefore, in recent years, the development of choline alfoscerate-containing solid formulations for solving the problems of the detoxification of choline alfoscerate and the problems of soft capsule formulations has been studied. For example, Korean Patent Publication No. 10-2009-0088564 (Patent Document 1) discloses a choline alfoscerate-containing pharmaceutical preparation, which comprises choline alfoscerate adsorbed on colloidal silicon dioxide. . In addition, Korean Patent Registration No. 10-1172699 (Patent Document 2) discloses a pharmaceutical preparation comprising an adsorbate obtained by adsorbing choline alfoscerate at a weight ratio of 1 to 2 with respect to magnesium aluminate silicate. In addition, Korean Patent Registration No. 10-1257919 (Patent Document 3) is a particle coating of choline alfoscerate with water-soluble polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methacrylic acid copolymer, polyethylene oxide A pharmaceutical composition comprising the encapsulated particles obtained by this has been disclosed.

However, such solid preparations must be carried out by adsorbing the drug itself (ie, choline alfoscerate) to the excipient (Patent Documents 1 and 2) or performing particle coating (Patent Document 3). That is, since these choline alfoscerate-containing solid preparations must be separately adsorbed or coated with particles, the manufacturing process is complicated and requires special equipment (eg, fluidized bed granulators, etc.), and the production cost is increased, resulting in a production site. Difficult to apply at Furthermore, when preparing tablets using choline alfoscerate adsorbed on colloidal silicon dioxide according to Patent Document 1, the size of the tablets obtained is too large, and older patients, especially those with poor swallowing ability, have cognitive impairment. There is a problem that is very uncomfortable for patients with.

Therefore, there is still a need for the development of choline alfoscerate formulations that are free from the detoxification problem of choline alfoscerate, the storage stability of the formulation is high, and the medication compliance of the patients can be improved.

[Preceding technical literature]

[Patent Documents]

(Patent Document 1) Korean Patent Publication No. 10-2009-0088564

(Patent Document 2) Korean Patent Registration No. 10-1172699

(Patent Document 3) Korean Patent Registration 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 advantageous formulations for patients who have difficulty swallowing drugs compared to capsules or tablets. Patients in need of administration of choline alfoscerate are primarily elderly. Dementia patients, especially those who forget how to swallow food, are just biting the food in their mouths or spitting out or swallowing while they are swallowing. This is called dysphagia. Dysphagia can occur gradually as the dementia worsens, sometimes as a side effect of medication (neuro-stabilizers, antipsychotics). In the case of dysphagia, it is not easy to take bulky medicines such as tablets and capsules, oral liquid preparations can increase the convenience of taking medications for these dysphagia patients, thereby increasing the compliance.

Since choline alfoscerate is deliquescent, it is conventionally used as a method for blocking water, using a method such as packing in an aluminum bag to avoid contact with air after filling choline alfoscerate in a soft capsule, or the aforementioned patent document. Only the method of adsorbing choline alfoscerate to excipients, such as 1 and 2, was used, but no attempt was made to formulate choline alfoscerate as a liquid formulation.

The present inventors have tried to develop a formulation that can simultaneously improve the stability and dosage convenience of choline alfoscerate formulations, and the commercially available choline alfoscerate oral aqueous liquid formulation of the following composition simultaneously realizes excellent formulation stability and dosage convenience. The present invention has been completed by confirming that a preparation that exhibits bioequivalence with a soft capsule can be obtained.

The present invention provides an aqueous liquid formulation of choline alfoscerate which is excellent in the stability of choline alfoscerate and excellent storage stability of the formulation while improving the patient's convenience of medication.

In order to solve the storage stability problem of choline alfoscerate in the liquid state, the present inventors studied the composition of a stable liquid formulation under long-term storage or harsh storage conditions in the 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 adjusting agent, wherein an aqueous liquid preparation having a pH of 3.5 to 7.5 of the aqueous liquid preparation is such. It was confirmed that the stability conditions were satisfied. Although not limited thereto, the pH of the choline alfoscerate aqueous liquid formulation may preferably be 4 to 7.

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

PH regulators include, but are not limited to, organic or inorganic acids or salts 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, aqueous ammonia and ammonium carbonate.

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

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

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

On the other hand, a preservative means a substance that inhibits the growth of microorganisms in the liquid formulation of the present invention, including, for example, but not limited to paraoxybenzoic acid, benzoic acid, sorbic acid and salts thereof, all used in the art Conventional preservatives 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 liquid formulation.

In one embodiment of the present invention, paraben-based preservatives such as methyl paraben, propyl paraben or mixtures thereof may be used as the preservative.

Liquid formulations according to the invention may further comprise one or more pharmaceutically acceptable additives selected from the group consisting of sweetening, flavoring, and coloring agents.

A sweetener means an additive which is added for the purpose of improving medication compliance by imparting sweetness to the liquid formulation. Sweeteners included in the liquid formulation of the present invention are, for example, sugar, fructooligosaccharide, xylitol, maltodextrin, steviaside, aspartame, oligosaccharide, sorbitol, fructose, honey, malt, syrup , Cooked sugar, L-glutamic acid, L-glutamate, sodium saccharin, sodium saccharin, citric acid, tartaric acid, sodium tartarate, lactic acid, adipic acid, fumaric acid, sodium fumarate, potato extract (pyrozine), licorice extract (glycyrrhetenic acid), tagangka Extracts (monellin), tauumatin (thaumatin), saccharin, aspartame, acesulfame, dulcin, cyclamate sodium, glucitol, and the like. And various sweeteners known in the art can be used.

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

Flavoring agent refers to a substance that improves compliance by taking a flavour when the liquid preparation is taken, for example apple flavor, cherry flavor, orange flavor, strawberry flavor, banana flavor, grape flavor, mango flavor, peach flavor Various fruit flavors and comprehensive fruit flavors such as; Vanilla flavor; Mint flavor; One or more substances selected from the group consisting of red ginseng aroma and honey aroma can 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 total liquid formulation.

If necessary, the liquid formulation may also contain an appropriate amount of a pharmaceutically acceptable colorant.

On the other hand, in patients with dysphagia, thin liquids such as water are more likely to be heard while thick liquids may be safer. Therefore, the liquid formulation according to the present invention may have a viscosity that is suitable for patients to take and that pouch packaging is possible. To this end, the liquid formulation according to the present invention may include a viscosity modifier.

In the present invention, the viscosity modifier is, for example, carbomer, polyethylene oxide having a molecular weight of 5,000 to 5,000,000, hydroxypropyl methylcellulose, hydroxypropyl cellulose, xanthan gum, guar gum, tragacanth gum, lucostong gum, carrageenan , Polyvinylpyrrolidone, polyvinyl alcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, micronized crospovidone, carboxymethylcellulose and its derivatives, alginic acid and its derivatives, silicone emulsions, One or more components selected from the group consisting of glycerol and mixtures thereof.

In one embodiment of the invention, the viscosity modifier may be xanthan gum, glycerin or mixtures thereof.

The content of the viscosity modifier may vary depending on the type, and the viscosity of the liquid formulation according to the present invention may be preferably 10 cps to 100 cps, for example, 10 cps to 80 cps, 20 cps to 60 cps. In the case of choline alfoscerate liquids, disposable stick pouch packaging is carried out to improve the convenience of taking the patient. This is because, in the case of a low viscosity liquid, when the liquid is filled in the nozzle filling the liquid, the liquid may float on the pouch joint and cause a poor pouch bonding. Although not limited thereto, the viscosity can be measured, for example, with the following measuring instruments and conditions: Brookfield viscometer. DV-II + Pro. Spindle 18. 25 ℃, 75rpm

The liquid preparation according to the present invention is excellent in stability of choline alfoscerate and properties of liquid preparation even under long-term storage conditions or harsh conditions.

For example, when the liquid formulation according to the present invention is stored and stored for 14 days under 60 ° C. storage conditions, the amount of analogue produced in the liquid formulation is 0.1 to 5.0 weight based on the weight of choline alfoscerate or a pharmaceutically acceptable salt thereof. May be%.

In addition, even under long-term storage conditions or harsh conditions, the change in the properties of the liquid formulation is small, there is no change in color of the liquid formulation or precipitation phenomenon.

In addition, as can be seen in the following examples, the choline alfoscerate aqueous liquid formulation of the present invention having excellent formulation stability has a choline alfoscerate soft capsule or choline having the same active ingredient dose as choline alfoscerate in the liquid formulation. Compared to alfoscerate tablets, bioequivalent levels of blood concentration-time curve area (AUC) and peak blood concentration (C _max ) are shown.

The invention also provides the use of an aqueous choline alfoscerate liquid formulation for treating or preventing the following diseases in a subject:

1) Secondary symptoms and degenerative or degenerative cerebral psychiatric syndrome caused by cerebrovascular defects: disorientation, decreased motivation and spontaneity, decreased concentration due to memory loss and confusion, motivation and spontaneity

2) Emotional and behavioral changes: emotional anxiety, irritability and apathy

3) senile pseudodepression

In the present invention, the 'subject' refers to a warm-blooded animal such as a mammal suffering from a specific disease, disorder or disease, for example, human, orangutan, chimpanzee, mouse, rat, dog, cow, chicken, pig, goat , Amounts, and the like, but is not limited to these examples.

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

An effective amount of the active ingredient of the liquid formulation of the present invention means an amount required to achieve treatment of a disease. Thus, the type of disease, the severity of the disease, the type and amount of the active and other ingredients contained in the composition, the type of formulation and the age, weight, general health, sex and diet, sex and diet, time of administration, route of administration and composition of the patient. It can be adjusted according to various factors including the rate of secretion, the duration of treatment, and the drug used concurrently. For example, the pharmaceutical composition of the present invention may be administered 1 to 3 times a day, and may be taken in the range of 200 to 1200 mg, preferably 400 mg to 1000 mg, based on choline alfoscerate, but is not limited thereto. It doesn't happen.

In one embodiment of the invention, the aqueous liquid formulation may comprise 400 mg choline alfoscerate.

For example, an aqueous liquid formulation containing 400 mg of choline alfoscerate in a single dose may be packaged into an aluminum pouch and commercialized.

The aqueous liquid preparation containing choline alfoscerate according to the present invention has little generation of decomposition products of choline alfoscerate under long-term storage conditions and severe storage conditions, and the properties of the preparations are stable. In addition, because of its ease of taking, it is possible to increase the medication compliance of patients with dysphagia in older adults who require the administration of choline alfoscerate. In the case of dementia patients, it may be difficult to identify and comply with the storage (storage) conditions of medicines, and the choline alfoscerate aqueous liquid preparation according to the present invention, which has excellent stability even in severe storage conditions, is particularly effective in patients with dementia. It is possible to provide choline alfoscerate formulations that are excellent, easy to carry and store, and convenient to take.

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

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the technical field to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

EXAMPLE

To prepare a liquid formulation and select a stable pH of the main component, after preparing an aqueous liquid formulation containing choline alfoscerate 400mg, adjust the pH to the desired pH as a pH regulator as prescribed in the table below, and then stabilize the stability by changing the content of the main component according to the storage conditions of the liquid. I looked at it. In order to determine the stability of the main components according to the conditions for the storage of the liquid solution was stored in a chamber set to a temperature of 60 degrees, 80 degrees in addition to the accelerated conditions, and choline alfoscerate content analysis was carried out according to the analysis time.

TABLE 1

Production Example  According to 1 to 8 Liquid  Component content and preparation method

Test Example 1. Storage stability according to pH of choline alfoscerate aqueous solution

In order to evaluate the storage stability according to the pH of the choline alfoscerate aqueous solution, the choline alpose was stored for 2 weeks while the liquid preparation according to Preparation Examples 1 to 8 was stored in a chamber set at an accelerated storage condition of a temperature of 40 ° C. and a relative humidity of 75%. The content of serrate and the pH stability were compared together. Before the sample was put into the temperature set chamber, the pH value of each preparation was finally measured and then put into the chamber, and the choline alfoscerate liquid solution taken out at each time point was sufficiently stirred for 10 minutes, and then the pH of each solution was measured through a pH meter. The content test was analyzed according to the choline alfoscerate content test method. The pH measured value and the choline alfoscerate content of the main component of the choline alfoscerate aqueous solution were shown in [Table 2].

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

TABLE 2

Choline according to pH under accelerated storage conditions Alfoscerate  Content and pH Stability Check

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

As described in Test Example 1, as a result of confirming the content and pH stability as an accelerated storage condition of choline alfoscerate aqueous solution, it was confirmed that excellent storage stability in the entire pH range as a whole.

Thus, in Test Example 2, to confirm the storage stability in more severe storage conditions, the temperature of the liquid and the choline alfoscerate content was compared for 4 weeks in a chamber set at a temperature of 60 and 80 degrees. As a result of Test Example 1, excellent storage stability was confirmed in the entire pH range, and in Test Example 2, a storage stability test was conducted by adding a sample in the pH 9 range. Before putting the sample into the temperature set chamber, the pH value of each preparation was finally measured and then put into the chamber. The choline alfoscerate aqueous solution taken out at each time point was visually observed in a transparent beaker, recorded, and then tested for content. Proceeded. At this time, the content test was conducted in the same manner as in Test Example 1, the choline alfoscerate content is shown in [Table 3] and [Table 4].

As shown in the following [Table 3], when stored for 28 days at 60 ° C storage temperature, choline alfoscerate content change was confirmed according to the pH of the liquid formulation. It was confirmed that choline alfoscerate was stable at the final pH of the prepared solution 4-8, and choline alfoscerate stability was decreased at pH 2-3 and pH 9.

As shown in [Table 4], the choline alfoscerate content was changed depending on the pH of the liquid even when stored at a temperature of 80 degrees for 28 days. In the storage condition at 80 ° C, it was confirmed that the appearance changed from white opaque liquid to brown color after 28 days of storage, but the choline alfoscerate content was stable at the final pH of 4 ~ 8. The results were similar to those at the 60 ° C storage condition. However, at pH 2 ~ 3 and pH 9, it was confirmed that the stability of choline alfoscerate was more rapidly lowered to a content value lower than the storage condition of 60 degrees.

TABLE 3

Choline according to pH in harsh temperature conditions (60 ℃) Alfoscerate  Content and pH Stability Check

TABLE 4

Choline according to pH in harsh temperature conditions (80 ℃) Alfoscerate  Content and pH Stability Check

Therefore, when the pH of the aqueous liquid preparation mainly containing choline alfoscerate is 3 to 8, especially 4 to 7, it is possible to provide a pharmaceutical composition that is stable in choline alfoscerate and high in pH stability even when exposed to severe environment for a long time.

Experimental Example 3

In order to evaluate the bioequivalence between the preparation of Example 4 and the reference drug (Geun glutinine), a healthy subject was subjected to a PK test.

In the test, a dose corresponding to 1200 mg of choline alfoscerate was administered to the reference drug and the test drug (Preparation Example 4), respectively, and the test was completed according to the 2 * 2 cross test method. Bioavailability parameters such as blood concentration-time curve area (AUC) and peak blood concentration (Cmax) obtained from drug concentration data in each plasma were statistically considered to evaluate the bioequivalence between the two preparations. The concentration of choline in plasma was analyzed using LC / MS / MS method.

The drug equivalence criteria are calculated by log-converting the blood concentration-time curve area (AUC) and the highest blood concentration (C _max ) of the reference and test drugs according to the bioequivalence test of the Pharmacologic Equivalence Standard. In the 90% confidence interval of the converted mean difference, if both items meet the log 0.8 ~ log 1.25, the drug equivalence test is considered equivalent. However, in accordance with the BioExemption Regulation, 1) the difference between the log-converted average value of the comparative evaluation items of the control and test drugs is within log 0.9 to log 1.11, and 2) all If all conditions are equal under the conditions, equality is determined.

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

Claims (14)

1. An aqueous liquid formulation comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, an aqueous solvent, a pH adjusting agent, a preservative and a viscosity adjusting agent, having a pH of 3.5 to 7.5.
2. The method of claim 1,

   Choline alfoscerate or a pharmaceutically acceptable salt thereof is included in an amount of 1 to 10 parts by weight based on 100 parts by weight of the total liquid formulation.
3. The method according to claim 1 or 2,

   An aqueous liquid formulation having a pH of 4 to 7 of the liquid formulation.
4. The method according to any one of claims 1 to 3,

   The aqueous solvent is an aqueous liquid formulation of 80 to 99 parts by weight based on 100 parts by weight of the total liquid formulation.
5. The method according to any one of claims 1 to 4,

   An aqueous solvent is an aqueous liquid formulation which is water or a mixture of water and ethanol.
6. The method according to any one of claims 1 to 5,

   pH adjusting agents include organic or inorganic acids or salts 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, aqueous ammonia and ammonium carbonate.
7. The method according to any one of claims 1 to 6,

   The preservative is an aqueous liquid formulation of 0.002 to 0.5 parts by weight based on 100 parts by weight of the total liquid formulation.
8. The method according to any one of claims 1 to 7,

   The preservative is an aqueous liquid formulation is a paraben-based preservative.
9. The method according to any one of claims 1 to 8,

   The viscosity modifier is carbomer, polyethylene oxide, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, xanthan gum, guar gum, tragacanth gum, lucostong gum, carrageenan, polyvinylpyrrolidone, polyvinyl alcohol, vinylpi At least one selected from the group consisting of a lylidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethyl cellulose sodium mixture, micronized crospovidone, carboxymethyl cellulose and its derivatives, alginic acid and its derivatives, silicone emulsions, glycerol and mixtures thereof An aqueous liquid formulation as a component.
10. The method according to any one of claims 1 to 9,

    The aqueous liquid formulation has a viscosity of 10 cps to 100 cps.
11. The method according to any one of claims 1 to 10,

    Wherein said liquid formulation further comprises one or more pharmaceutically acceptable additives selected from the group consisting of sweetening, flavoring, and coloring agents.
12. The method according to any one of claims 1 to 11,

    When the liquid formulations were stored for 14 days under 60 ° C. storage conditions, the amount of analog produced in choline alfoscerate or a pharmaceutically acceptable salt thereof was 0.1% based on the weight of choline alfoscerate or a pharmaceutically acceptable salt thereof. To 5.0% by weight of an aqueous liquid formulation.
13. The method according to any one of claims 1 to 12,

    The aqueous liquid formulations have a bioequivalent level of blood-time curve area (AUC) and peak blood concentration (Cmax) compared to choline alfoscerate soft capsules or choline alfoscerate tablets with the same choline alfoscerate dose. An aqueous liquid formulation.
14. The method according to any one of claims 1 to 13,

    The liquid formulation is an aqueous liquid formulation comprising choline alfoscerate 400mg.

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