KR102008490B1 - Controlled release pharmaceutical composition comprising choline alfoscerate or pharmaceutically acceptable salt thereof and method for manufacturing the same - Google Patents

Abstract

The present invention relates to a controlled release pharmaceutical composition comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, wherein the blood concentration of the drug persists above the baseline for at least 6 hours after oral administration.

Description

Controlled release pharmaceutical composition comprising choline alfoscerate or pharmaceutically acceptable salt etc. and method for manufacturing the same}

The present invention relates to a controlled release pharmaceutical composition comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, wherein the blood concentration of the drug persists above the baseline for at least 6 hours after oral administration.

L-α-glyceryl phosphoryl choline (GPC), also known as choline alfoscerate, is a choline nervous system precursor compound having a structure represented by the following Chemical Formula 1, and includes brain neurons and Because it has the function of normalizing the choline neurotransmitter system, it is useful as a brain function improving agent or a dementia treatment agent.

[Formula 1]

Choline alfoscerate has high hygroscopic and extremely water soluble properties, and thus it is difficult to block moisture by general granules and mixing methods. Accordingly, choline alfoscerate is currently marketed as a formulation containing liquid choline alfoscerate in soft capsules. However, in the case of commercially available soft capsule formulations, the active ingredient may transition to a water-soluble soft gelatin coating over time, and a separate soft capsule manufacturing facility is required for manufacturing, and a preservative may be used to reduce the possibility of microbial alteration of the soft capsule formulation. In many cases, gelatin capsules are weak against moisture and heat, which may cause disintegration delays during storage. In particular, older people with poor swallowing ability have disadvantages of taking them.

In addition, choline alfoscerate is well absorbed by the body with a bioavailability of 90% or more, but the oral administration time of the drug reaches the maximum concentration (Tmax) of 1.5 hours, and the intramuscular injection has a half-life of 1.5 hours. This is not a long problem. Since choline alfoscerate is mainly intended for older patients with poor swallowing ability, choline alfoscerate or its salts are released slowly in the body to maintain a constant concentration of active ingredients in the plasma and reduce the number of doses. Sustained release formulations that can increase the compliance of the administration target is required, but since choline alfoscerate is difficult to be purified into a highly hygroscopic substance, a technique for sustained release tablets of choline alfoscerate has not been developed.

Accordingly, the present inventors have provided a sustained-release formulation in the form of a matrix in which choline alfoscerate is coated with a water-insoluble or water-swellable polymer to effectively block the moisture of choline alfoscerate (Domestic Patent Application No. 10-2011- 0069969). Subsequent studies, however, show that matrix tablets with water-insoluble or water-swellable polymers have superior advantages for sustained release of hygroscopic and water-soluble choline alfoscerate, while drug release is reduced after a certain period of time after administration, resulting in liver gastrointestinal retention time. In some of these shorter cases, it has been found that the drug in the sustained release formulation may have problems with excretion without being released into the body. Therefore, there is a need to develop a novel controlled release formulation that can effectively block the infiltration of choline alfoscerate, while overcoming the problem of lower late drug release in the intestinal section of the gastrointestinal transit.

It is an object of the present invention to provide a preparation for the sustained release preparation of anti-moisture-coated choline alfoscerate, in which tablet disintegration occurs in large intestine with high pH and complete release of the drug prior to excretion and a preparation method thereof.

More specifically, one object of the present invention is to provide a controlled release pharmaceutical composition comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, the blood concentration of the drug lasting above the baseline for at least 6 hours after oral administration. It is.

It is another object of the present invention to provide a method for preparing the controlled release pharmaceutical composition.

As one embodiment for solving the above problems, the present invention relates to a controlled release pharmaceutical composition comprising choline alfoscerate or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention relates to controlled release pharmaceutical compositions comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, wherein the blood concentration of the drug persists above the baseline for at least 6 hours after oral administration.

In a more preferred embodiment, the present invention comprises choline alfoscerate or a pharmaceutically acceptable salt thereof, sustained release polymer and a pH dependent polymer, the release control of which the blood concentration of the drug persists above the baseline for at least 6 hours after oral administration. It relates to a pharmaceutical composition.

In a more preferred embodiment, the composition of the present invention is a coating portion comprising a sustained release polymer and a pH-dependent polymer is formed on the outer surface of the drug portion containing the active ingredient, the blood concentration of the drug for more than 6 hours after oral administration persists above the baseline To controlled release pharmaceutical compositions. In one embodiment, the controlled release pharmaceutical composition of the present invention

(a) a drug moiety comprising choline alfoscerate or a pharmaceutically acceptable salt thereof;

(b) a coating part formed on an outer surface of the drug part and including a sustained release polymer and a pH dependent polymer; And

(c) It may include a pharmaceutically acceptable additive on the outside of the coating.

The pharmaceutical composition of the present invention is characterized in that the blood concentration of the drug is maintained above the baseline for at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours after oral administration. Therefore, the pharmaceutical composition of the present invention, unlike the conventional matrix formulation in which the amount of drug release is reduced in the second half, complete release of the drug in the large intestine with high pH.

Hereinafter, the present invention will be described in more detail.

As used herein, the term "choline alfoscerate" is also referred to as L-α-glyceryl phosphoryl choline (GPC), and refers to a compound having the structure of Formula 1 below:

[Formula 1]

In addition, choline alfoscerate is used herein to include all of choline alfoscerate or pharmaceutically acceptable salts thereof, and also to include all forms of choline alfoscerate. For example, choline alfoscerate of the present invention may be in the form of crystalline polymorphs such as amorphous choline alfoscerate or crystalline choline alfoscerate, racemates, enantiomers, isomers, hydrates, anhydrides and solvates. And, preferably, choline alfoscerate monohydrate, but is not limited thereto.

Choline alfoscerate is synthesized from D-Solketal (e.g. J. Am. Chem Soc. 70, 1394-1399, 1948), hydrolyzed from lecithin extracted from soybean (e.g. 217,765, U.S. Patent No. 5,250,719), and the like, can be prepared chemically by various organic synthesis methods known in the art.

The amount of choline alfoscerate included in the drug moiety of the present invention may be determined in consideration of the daily dose and the solubility with a solvent, in which the pharmacological effect is sufficiently exerted and does not cause side effects, and preferably about 100 mg to 1200 mg It may be included as. If the content of choline alfoscerate is less than 100 mg, the concentration of choline alfoscerate may not be sufficient to exert sufficient pharmacological effect, and if it exceeds 1200 mg, it may be difficult to control the sustained release due to high concentration of choline alfoscerate.

The drug moiety, to improve the fluidity of the drug to facilitate the coating and granulation process, and to further enhance the effect of sustained release, pharmaceutically acceptable within a range that does not impair the effect of choline alfoscerate as an active ingredient Additives such as possible glidants, sustained release polymers, glidants, or water insoluble excipients may be further included. Examples of the additives include ethyl cellulose, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, magnesium aluminomethysilicate, glyceryl Behenate, glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide, or a mixture thereof may be exemplified, but is not limited thereto.

The coating part formed on the outer surface of the drug part prevents the drug from being impregnated, and controls the release rate and the amount of release so that the drug is released slowly. It plays a role in controlling it. More specifically, the coating is characterized in that it comprises a sustained release polymer and a pH dependent polymer.

Preferably, the sustained release polymer may include one or more water-insoluble polymers, hydrophobic compounds, water swellable, hydrophilic or viscous polymers.

The water-insoluble polymer or hydrophobic compound refers to a material that is insoluble in pharmaceutically acceptable water that controls the release of the drug, and includes a water-insoluble cellulose, a water-insoluble cellulose derivative, a water-insoluble methacrylic acid copolymer, and a water-insoluble ammonometa. Acrylic acid copolymers, water-insoluble alkylacrylic acid polymers, water-insoluble methacrylic acid-ethyl acrylate copolymers, fatty acids, fatty acid esters, and the like.

More specifically, as a water-insoluble polymer, polyvinylacetate (e.g., collicoat SR30D), methacrylmethyl-ethyl acrylate copolymer (e.g. Eudragit NE30D), methyl methacrylate-ethyl acrylate-trimethylaminoethylmethacryl Acid copolymers (e.g. Eudragit RSPO), ammoniomethacrylic acid copolymers, ethylcellulose, cellulose esters, cellulose ethers, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose Triacetate, hydroxypropylmethylcellulose phthalate, glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and the like.

In addition, the water-swellable polymer refers to a polymer having a high water-absorbing capacity and a strong water holding capacity and has a property of instantaneously swelling and gelling in water, hydrophilic or viscous polymer is dissolved in pharmaceutically acceptable water to control the release of the drug It refers to a viscous polymer. Preferably, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, polyalkylene oxide, polyvinylacetate-polyvinylpyrrolidone, sodium alginate, chitosan, natural or synthetic gums (gum) type (for example, xanthan gum and locust bean gum) can be illustrated.

In addition, the sustained-release polymers described above may be included in the coating part as well as optionally included in the drug part or outside the drug coating part.

Also preferably, the “pH dependent polymer” refers to a polymer that is dissolved or decomposed under specific pH conditions, and is an enteric cellulose derivative, an enteric methacrylic acid copolymer, an enteric amonomethacrylic acid copolymer, an enteric alkylacrylic acid copolymer, or an enteric meta. An acrylic acid-ethyl acrylate type copolymer, an enteric maleic acid type copolymer, an enteric polyvinyl derivative, etc. can be illustrated.

More specifically, as the enteric polymer, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate , Cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose, styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, acrylic acid-methacrylate methyl copolymer, Butyl acrylate-styrene-acrylic acid copolymer, methyl methacrylate-octyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid -Ethyl acrylate copolymer, vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether- Maleic anhydride copolymer, acrylonitrile-methyl methacrylate maleic anhydride copolymer, butyl styrene-maleic-maleic anhydride copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate Can be illustrated.

The content of the sustained release polymer and the pH dependent polymer included in the coating solution is preferably included in an amount of 5 to 100 parts by weight based on 100 parts by weight of choline alfoscerate. If it is less than the above content range, the choline alfoscerate may be moistened, leading to a decrease in stability. If it exceeds the above content range, the size of the preparation may increase and may cause a decrease in oral dose.

The drug coating may further include a pharmaceutically acceptable excipient, binder, plasticizer or lubricant. As the binder, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, plasmon, polyvinyl alcohol, xanthan gum, gellan and the like can be used. Preferably, hydroxypropyl methyl cellulose can be used. The plasticizer increases the plasticity of the polymer coating to increase the coating efficiency, promote the decomposition of the coating polymer, glycerol derivatives such as polyethylene glycol, glycerol and triacetin, triethyl citrate, butyryl-n-hexyl citrate And fatty acid citrate derivatives. Glidants are commonly used talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, magnesium aluminomethilicate, glyceryl behenate, glyceryl mono Stearate, glyceryl palmitostearate, colloidal silicon dioxide or mixtures thereof and the like. Preferably, it may include one or more selected from hydroxypropylmethyl cellulose, triethyl citrate and talc.

The coating liquid used to form the drug coating part may be a sustained-release polymer and a pH-dependent polymer, optionally with an excipient, a binder, a plasticizer, a lubricant, and the like in an appropriate solvent such as water, acetone, ethanol, or a mixed solvent thereof. It can be prepared by dispersing, and by coating the obtained coating solution on the choline alfoscerate drug moiety can be obtained by encapsulating drug particles.

The controlled release pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive outside the drug coating, and the additive may be appropriately selected by one of ordinary skill in the art. Pharmaceutically acceptable additives refer to carriers or diluents that do not significantly stimulate the organism and do not inhibit the biological activity and properties of the administered compound. In addition, the additives may improve the preparation, compressibility, appearance and taste of the formulation, and include, for example, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, binders, binders, suspensions. Topical Agents, Curing Agents, Antioxidants, Brighteners, Flavoring Agents, Flavoring Agents, Pigments, Coatings, Wetting Agents, Wetting Regulators, Fillers, Defoamers, Cooling Agents, Masticants, Antistatic Agents, Colorants, Dragees, Isotonic Agents, Softeners, Emulsifiers , Thickeners, blowing agents, pH adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dissolution aids, solvents, glidants and the like may be added as necessary.

Preferably, as an excipient or glidant, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, magnesium aluminometa silicate, glyceryl behenate, Glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide or mixtures thereof and the like.

The pharmaceutically acceptable additive may be included in an amount of about 0.1 to 30% by weight, preferably about 0.1 to 20% by weight relative to the total composition.

In addition, the controlled release pharmaceutical composition of the present invention may further include a sustained release polymer on the outside of the drug coating, wherein the sustained release polymer is a water-insoluble polymer, a hydrophobic compound, water swelling, hydrophilic as described above Or viscous polymers.

The composition of the present invention is not particularly limited as long as it is an oral preparation, but may be formulated in the form of tablets, capsules, granules, fine granules, or pellets, and may be used for the prevention and treatment of senile dementia, particularly for the prevention and treatment of Alzheimer's disease. have.

The particular form and dosage of administration of the formulations of the invention may be selected by the attending physician depending on the characteristics of the patient, in particular age, weight, lifestyle, level of symptoms and case. Preferably, the controlled release formulation of the present invention may be provided in a form suitable for administration once a day to maintain a constant concentration of the active ingredient in the plasma and reduce the number of administrations to be compatible with the administration subject.

The pharmaceutical composition of the present invention is characterized in that the blood concentration lasts more than 6 hours after oral administration, preferably 8 hours or more, more preferably 10 hours or more. Experimental measurements of the pharmacokinetics of the formulations according to the invention show that the formulations of the invention raise the concentration of the drug with a smoother drug release in the latter half compared to solid formulations that do not contain pH dependent polymers, resulting in 10 hours It was confirmed that blood levels persisted above baseline. Thus, the formulations of the present invention are expected to be more easily disintegrated in the latter, resulting in smoother drug release, in contrast to conventional matrix formulations where the amount of drug release is reduced in the latter.

As another aspect, the present invention relates to a method for preparing a controlled release pharmaceutical composition containing the choline alfoscerate or a salt thereof.

Specifically, the present invention

(a) flowing a drug moiety including choline alfoscerate or a pharmaceutically acceptable salt thereof, and spraying a coating solution including a sustained-release polymer and a pH-dependent polymer to prepare a coated drug particle; And

(b) adding and mixing a pharmaceutically acceptable additive to the encapsulated drug particles.

In the manufacturing method, the step of forming the drug coating may be carried out by coating the coating solution on the drug portion in accordance with the conventional methods in the pharmaceutical field. For example, a coating solution containing a sustained release polymer and a pH dependent polymer may be prepared on a drug part using a fluidized bed granulator, sprayed into a solution state, and then dried to remove a solvent. The sustained release polymer and the pH dependent polymer included in the coating solution are as described above. In addition, the solvent used in the coating process may be a mixture of one or more methylene chloride, ethanol, acetone, water, and the like, and may be added an additional additive to increase the stability of the dispersion.

In addition, the controlled release pharmaceutical composition prepared as described above may be formulated using a conventional formulation method, for example, a direct tableting method, a compressed granulation method, or the like, which is a conventional solid preparation method.

Since the controlled release formulation of the present invention can effectively control the release rate of choline alfoscerate or a pharmaceutically acceptable salt thereof having high hygroscopicity, the convenience of administration can be increased (once daily formulation), thereby increasing the compliance of the administration target. It may exhibit an improved treatment or prophylactic effect of the subject disease. In particular, the controlled release formulation of the present invention has a characteristic that the drug is released more smoothly in the latter part of the body since the tablet is disintegrated according to the pH in the body.

Figure 1 shows the change in blood drug concentration (ng / ml) over time (hr) of the formulation of Example 4.
Figure 2 shows the change in blood drug concentration (ng / ml) with time (hr) of Comparative Example 2 preparation.
Figure 3 shows the change in blood drug concentration (ng / ml) with time (hr) of the Comparative Example 1 formulation.

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

Example  1.Colin Alfoscerate  Preparation of Release Control Formulations

20.4 g of ammonomethacrylic acid copolymer (Euradit RSPO) as a sustained-release polymer, 39.0 g of enteric methacrylic acid copolymer (Euradit L100-55) and 0.6 g of talc as a pH-dependent polymer were added to 550 g of a mixed solvent of ethanol / water. Dispersion to prepare a coating solution. 180 g of choline alfoscerate apologized with 20 mesh, ethyl cellulose (Ethocel 7cp g, fluidizing agent) (G), 24 g, talc (lubricant) 1.5 g were placed in a fluidized bed granulator in the chamber until the particle temperature reached 40 ° C. Mixed flow. When the temperature reached 40 ° C., the coating liquid prepared above was sprayed to produce granules and encapsulated particles. At this time, the intake temperature was maintained at 22 ° C to 28 ° C, the exhaust temperature was 21 ° C to 26 ° C, and the injection pressure was 0.5bar. The content of choline alfoscerate in the obtained particles was about 73%. Magnesium stearate in a proportion of 0.6% of the total weight of the encapsulated particles was mixed and lubricated.

Example  2. Choline Alfoscerate  Preparation of Release Control Formulations

16.2 g of ethyl cellulose (Ethocel 7cp FP) as sustained-release polymer, 24 g of enteric methacrylic acid copolymer (Euragit L100-55) and talc as pH dependent polymer 0.3g was dispersed in 450g of ethanol / water mixed solvent to prepare a coating solution. 180 g of choline alfoscerate, 24 g of ethyl cellulose (Ethocel 7cp granule, G) and 1.5 g of talc (lubricant) were placed in a fluid bed granulator and mixed in a chamber until the particle temperature reached 40 ° C. Fluidized. When the temperature reached 40 ° C., the coating liquid prepared above was sprayed to produce granules and encapsulated particles. At this time, the intake temperature was maintained at 20 ° C to 26 ° C, the exhaust temperature was 19 ° C to 25 ° C, and the injection pressure was 0.5 bar. The content of choline alfoscerate in the obtained particles was about 73%. Magnesium stearate in a proportion of 0.6% of the total weight of the encapsulated particles was mixed and lubricated.

Example  3. Choline Alfoscerate  Preparation of Release Control Formulations

18.6 g of ammoniomethacrylic acid copolymer (Euradit RSPO) as a sustained-release polymer, 28.8 g of enteric methacrylic acid copolymer (Euradit L100-55) and 0.6 g of talc as a pH-dependent polymer were added to 450 g of an ethanol / water mixed solvent. Dispersion to prepare a coating solution. 180g of choline alfoscerate (3g) and 3g of sodium stearyl fumarate (1.5 g) of talc (lubricant) and applet at 20mesh Mixed flow in the chamber until. When the temperature reached 40 ° C., the coating liquid prepared above was sprayed to produce granules and encapsulated particles. At this time, the intake temperature was maintained at 20 ° C to 30 ° C, the exhaust temperature was 20 ° C to 29 ° C, and the injection pressure was 0.5bar. The content of choline alfoscerate in the obtained particles was about 77%. 10% of ethyl cellulose (Ethocel 7cp FP, sustained-release agent) and 0.6% of sodium stearyl fumarate (Pruv) were mixed and lubricated based on the total weight of the encapsulated particles.

Example  4. Choline Alfoscerate  Preparation of Release Control Formulations

17.4 g of ammoniomethacrylic acid copolymer (eudragit RSPO) as a sustained-release polymer, 26.4 g of enteric methacrylic acid copolymer (Euragit L100-55) as a pH-dependent polymer, 0.6 g of triethyl citrate (plasticizer) and talc (Lubricant) 0.6g was dispersed in 450g of ethanol / water mixed solvent to prepare a coating solution. 180 g of choline alfoscerate, 10.5 g of magnesium alumino metasilicate (Neusilin US2, lubricant), and 1.5 g of talc (lubricant), mixed with 20 mesh apples, are mixed in a chamber until the particle temperature reaches 40? Fluidized. When the temperature reached 40 ° C., the coating liquid prepared above was sprayed to produce granules and encapsulated particles. At this time, the intake temperature was maintained at 22 ° C to 28 ° C, the exhaust temperature was 20 ° C to 28 ° C, and the injection pressure was 0.5 bar. The content of choline alfoscerate in the obtained particles was about 76%. Tablets were prepared by mixing and lubricating 9% ethyl cellulose (Ethocel 7cp FP, sustained release agent) and 0.6% magnesium stearate (lubricant) relative to the total weight of the encapsulated particles.

Comparative example  1.Commercial Capsule Formulations

Commercial choline alfoscerate soft capsule formulation (Gliatyrin®, Daewoong Pharmaceutical) was used.

Comparative example  2. Preparation of Comparative Formulation

As a sustained-release polymer, a coating solution was prepared by dispersing 90 g of ammoniomethacrylic acid copolymer (eudragit RSPO), 10.0 g of triethyl citrate (plasticizer) and 1.0 g of talc (lubricant) in 300.0 g of an ethanol / water mixed solvent. . 180 g of choline alfoscerate was placed in a fluid bed granulator and flowed in the chamber until the particle temperature reached 40 ° C. When the temperature reached 40 ° C., the coating liquid prepared above was sprayed to prepare encapsulated particles. At this time, the intake air temperature was maintained at 36 ° C, the exhaust temperature at 33 ° C, and a spray pressure of 0.5 bar. The film formation rate of the obtained particles was 32% by weight relative to the active ingredient (choline alfoscerate). 793 mg of the encapsulated particles, 70 mg of ethyl cellulose FP (Ethocel 7cp FP, sustained release agent) and 7 mg of magnesium stearate (lubricant) were mixed to prepare tablets by direct tableting.

Experimental Example  1. Pharmacokinetic Test

1-1. Experiment method

Twelve male beagle dogs, weighing 7-12 kg, aged 16 to 17 months, were subjected to oral pharmacokinetic testing of choline alfoscerate. In a breeding room equipped with air conditioning and maintained at a temperature of 21 ± 2 ° C and a humidity of 50 ± 10% (RH), feed 300 g of the animal feed for beagle dogs once daily within 3% of the average body weight. Pharmacokinetic tests were performed in the following experimental groups, and n = 6 or cross over n = 12 for statistical processing. Plasma samples obtained according to the time point of blood collection were quantitatively analyzed under the following LC / MS / MS conditions, and HPLC was Agilent, and detector was multiple reaction using MRM (Multiple quadruple mass spectrometer) using AB SCIEX's API 2000 (Triple quadruple mass spectrometer). Monitoring method detected choline (m / z 104.2> 60.1) and internal standard choline chloride trimethyl-d9 (m / z 113.3> 69.3) in plasma samples. Plasma samples stored at −80 ° C. for treatment of plasma samples were thawed at room temperature after vortexing, centrifuged at 3600 rpm for 5 minutes, and then subdivided by 80 ul for protein precipitation, and the supernatant was filtered and analyzed for 5 ul.

1-2. Experiment result

After oral administration of a tablet prepared according to Example 4 using a beagle dog according to the above method, the time of blood collection before (0), after administration 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5 Plasma samples collected 14 times, 6, 8, 10, and 12 were used for pharmacokinetic testing. As a result, it showed the drug dynamics as shown in Figure 1, Tmax 2.6 hr ± 1.12hr, the drug blood concentration was seen to reach the baseline concentration in about 10 hours after administration.

In addition, after oral administration of a tablet prepared according to Comparative Example 2 using a beagle dog according to the above method, the blood collection point before (0), after administration 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 Plasma samples collected 13 times, 6, 8, 10, and 12 were confirmed by pharmacokinetic test. As a result, it showed the drug dynamics as shown in Figure 2, Tmax 2hr ± 0.38, the drug blood concentration was seen to reach the baseline concentration in about 5 hours after administration.

In addition, after oral administration of Comparative Example 1 using a beagle dog according to the above method, the blood collection point was collected eight times before (0) and 0.5, 1, 1.5, 2, 3, 4, 12 after administration. One plasma sample was used for pharmacokinetic testing. As a result, it showed the drug dynamics as shown in Figure 3, the drug blood concentration was shown to reach the baseline concentration in about 4 hours after administration.

Comparing the pharmacokinetics of FIGS. 1 and 2, in a test using a beagle dog with a shorter gastrointestinal residence time than a human, a solid preparation comprising a pH-dependent polymer was used to improve the concentration of drug in the blood with a smoother drug release in the second half. Elevated effectively, as a result it was confirmed that there is a delay in maintaining the blood concentration of the drug. Thus, formulations such as Example 4 using pH dependent polymers are expected to more readily disintegrate and facilitate drug release in the latter part when the dose of drug release is reduced due to the nature of the matrix formulation when taken by humans.

Claims (12)

(a) a drug moiety comprising choline alfoscerate or a pharmaceutically acceptable salt thereof; (b) a coating part formed on an outer surface of the drug part and including a sustained release polymer and a pH dependent polymer; And (c) a pharmaceutically acceptable additive on the outside of the coating,
At this time, the sustained-release polymer is at least one member selected from the group consisting of water-insoluble cellulose and amonomethacrylic acid copolymer, pH-dependent polymer is an enteric methacrylic acid copolymer,
A controlled release pharmaceutical composition of which the blood concentration of the choline alfoscerate or a pharmaceutically acceptable salt thereof is maintained beyond the baseline for at least 6 hours after oral administration.
The controlled release pharmaceutical composition of claim 1, wherein the blood concentration of choline alfoscerate or a pharmaceutically acceptable salt thereof persists above baseline for at least 8 hours after oral administration.
The controlled release pharmaceutical composition of claim 1, wherein the blood concentration of choline alfoscerate or a pharmaceutically acceptable salt thereof persists beyond the baseline for at least 10 hours after oral administration.
delete delete delete delete The controlled release pharmaceutical composition of claim 1, wherein the drug moiety comprises 100 to 1200 mg of choline alfoscerate.
The controlled release pharmaceutical composition of claim 1, wherein the drug moiety further comprises a pharmaceutically acceptable glidant, sustained release polymer, glidant, or excipient.
The controlled release pharmaceutical composition of claim 1, wherein the coating further comprises a pharmaceutically acceptable excipient, binder, plasticizer or glidant.
The controlled release pharmaceutical composition of claim 1, further comprising a sustained release polymer on the outside of the coating portion.
The controlled release pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable additive is a pharmaceutically acceptable lubricant or excipient.

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