KR101763145B1 - Oral preparation having micelles that encapsulate nonsteroidal antiinflammatory drugs - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising 10 to 50% by weight of a non-steroidal anti-inflammatory agent; Oxy-C _{2 - 4} alkylene glycol Solvent 3 to 30% by weight; 3 to 30% by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)]; And 2 to 30% by weight of a polyoxyethylene surfactant. The present invention relates to an oral agent containing micelles encapsulating a non-steroidal anti-inflammatory agent, which comprises solubilizing the drug stably in an aqueous solution to increase the dissolution rate and shorten the dissolution time It has an effect of improving the absorption rate and absorption rate of the drug in the body, so that it can be effectively used as a nonsteroidal antiinflammatory agent-containing oral agent.

Description

[0002] Oral preparations containing micelles that encapsulate nonsteroidal antiinflammatory drugs

The present invention relates to an oral preparation containing micelles encapsulated with a non-steroidal anti-inflammatory agent.

Ibuprofen and naproxen are non-steroidal antiinflammatory drugs that selectively inhibit cyclooxygenase-1 and 2, thereby blocking the synthesis of prostaglandins and exhibiting anti-inflammatory, antipyretic and analgesic effects , Infectious diseases, trauma, postoperative edema or inflammation, rheumatic diseases and the like.

Dexibupropene is an S (+) isomer with the active ingredient as the chiral compound of ibuprofen. Dexibupropene has the advantage of less side effects such as gastrointestinal toxicity, hepatotoxicity and renal toxicity compared to ibuprofen containing 50:50 of R (-) and S (+) forms, have. Dexibupropene is a white crystalline powder with a peculiar smell and has a property of melting at around 50 ° C.

Propionate-based drugs such as ibuprofen and naproxen are well soluble in ethanol but do not dissolve well in water. Therefore, oral administration results in a low dissolution rate and a low dissolution rate, resulting in delayed absorption of the drug and low bioavailability.

In addition, ibuprofen and dexibupropene do not dissolve completely in gastric juice, but dissolve in intestinal juice, resulting in the problem that it takes from one hour to two hours or more until the appearance of the pharmacological effect. Furthermore, in the case of naproxene, the dissolution rate is not constant at a pH of 7.4, which is a dissolution condition, and there is a disadvantage that the dissolution rate between the preparations is significant.

Therefore, various studies have been conducted to develop a stable formulation in which ibuprofen, dexibupropene or naproxen are solubilized and the dissolution rate in aqueous solution is increased. As a representative example, various techniques have been developed, such as solubilization using an oil or an auxiliary solvent such as ethanol, or a method for producing a suspension solution using a surfactant and a cosolvent to solubilize the anti-inflammatory analgesic agent.

Specifically, Patent Document 1 discloses a pharmaceutical composition in which ibuprofen is solubilized using ethanol, polyethylene glycol or the like. Patent Document 2 discloses a pharmaceutical composition comprising ibuprofen, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene sorbitan fatty acid ester, and poly And a complex surfactant of oxy 40 castor oil and the like are heated and dissolved.

When ethanol is used as a solvent, there is a problem that the ethanol content of the preparation decreases with time and precipitation of the contents occurs. However, conventional techniques such as the above patent document have a problem in that when the drug is solubilized using oils such as castor oil The composition of the drug often separates into a solid state when the oil component is contacted with the oral liquid or the gastrointestinal solution, which has a problem that the bioavailability of the drug can be reduced to 30% or less, and the ethoxylated The unpleasant smell of castor oil should be tolerated.

Thus, the oral agent containing micelles containing the non-steroidal anti-inflammatory agent according to the present invention can be used to stably and solubilize the drug regardless of pH without using ethanol and oil to increase the dissolution rate and bioavailability of the drug, Can be minimized, thereby completing the present invention.

U.S. Patent No. 5,141,961 Korea Patent No. 1997-9001

It is an object of the present invention to provide an oral preparation containing micelles encapsulated with a non-steroidal anti-inflammatory agent.

Another object of the present invention is to provide a method for preparing an oral preparation containing micelles encapsulating the non-steroid anti-inflammatory agent.

In order to achieve the above object,

10 to 50% by weight non-steroidal anti-inflammatory agent;

Oxy-C _{2 - 4} alkylene glycol Solvent 3 to 30% by weight;

3 to 30% by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)]; And

2 to 30% by weight of a polyoxyethylene surfactant,

The non-steroidal anti-inflammatory agent may be selected from the group consisting of ibuprofen, dexibuprofen, naproxen, aspirin, celecoxib, diclofenac, diflunisal, etodolac ), Oxaprozin, piroxicam, indomethacin, ketoprofen, ketorolac, nabumetone, salsalate, sulindac, and tolmetin. The non-steroidal anti-inflammatory agent is an oral agent containing micelles encapsulated therein.

The invention also oxy-C _{2 -} to the triblock of the form of copolymers, and polyoxyethylene-based surfactants ₄ alkylene glycols, solvents, [polyethylene oxide (PEO), polyethylene oxide (PEO) - - polypropylene oxide (PPO)] Adding a non-steroidal anti-inflammatory agent, and sonicating or heating to enclose the non-steroidal anti-inflammatory agent in the micelle,

The non-steroidal anti-inflammatory agent may be selected from the group consisting of ibuprofen, dexibuprofen, naproxen, aspirin, celecoxib, diclofenac, diflunisal, etodolac ), Oxaprozin, piroxicam, indomethacin, ketoprofen, ketorolac, nabumetone, salsalate, wherein the nonsteroidal antiinflammatory agent is at least one selected from the group consisting of sulindac, tolmetin, and the like.

The oral agent containing micelles containing the nonsteroidal antiinflammatory agent according to the present invention has the effect of increasing the dissolution rate by solubilizing the drug stably in an aqueous solution and shortening the dissolution time so that the absorption rate and the absorption rate of the drug are improved when administered to the subject Therefore, it can be usefully used as a non-steroidal anti-inflammatory agent-containing oral agent.

1 is a photograph of the oral preparation of Example 1 according to the present invention filled in a hard capsule.
Fig. 2 is a photograph of the dissolution state of the oral agent of Example 1 according to the present invention as a result of elution in a pH 1.2 solution. Fig.
FIG. 3 is a photograph of the dissolution state of the oral agent of Example 1 according to the present invention as a result of elution in pH 7.2 solution. FIG.
FIG. 4 is a photograph of the dissolved state of the resultant solution of a conventional commercially available dexibuprofen oral agent in a pH 1.2 solution.
5 is a photograph of the dissolution state of the oral agent of Comparative Example 1 as a result of elution in a pH 1.2 solution.
FIG. 6 is a graph showing dissolution rates at pH 1.2 and pH 7.2 of the oral preparation of Example 1 according to the present invention. FIG.
7 is a photograph of the oral preparation of Comparative Example 14 filled with a hard capsule.
8 is a photograph of the oral preparation of Example 11 according to the present invention filled in a hard capsule.
FIG. 9 is a photograph of the dissolution state of the oral agent of Example 11 according to the present invention as a result of elution in pH 7.4 solution. FIG.
10 is a graph showing dissolution rates of oral preparations of Examples 10 and 14 and Comparative Examples 12, 17, 23, 24 and 29 in comparison with the dissolution rate of oral preparations according to the present invention.

Hereinafter, the present invention will be described in detail.

The present invention

10 to 50% by weight non-steroidal anti-inflammatory agent;

Oxy-C _{2 - 4} alkylene glycol Solvent 3 to 30% by weight;

3 to 30% by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)]; And

2 to 30% by weight of a polyoxyethylene surfactant,

The non-steroidal anti-inflammatory agent may be selected from the group consisting of ibuprofen, dexibuprofen, naproxen, aspirin, celecoxib, diclofenac, diflunisal, etodolac ), Oxaprozin, piroxicam, indomethacin, ketoprofen, ketorolac, nabumetone, salsalate, sulindac, and tolmetin. The non-steroidal anti-inflammatory agent is an oral agent containing micelles encapsulated therein.

Hereinafter, the oral preparation according to the present invention will be described in detail.

In the oral preparation according to the present invention, the non-steroidal anti-inflammatory agent is selected from the group consisting of ibuprofen, dexibuprofen, naproxen, aspirin, celecoxib, diclofenac, The compounds of the present invention may be used in combination with other drugs such as diflunisal, etodolac, oxaprozin, piroxicam, indomethacin, ketoprofen, ketorolac, nabumetone, Sulindac, tolmetin and the like are preferably used alone or in combination within a pharmaceutically acceptable range, and it is preferable to use ibuprofen, dexibupropene and naproxen alone .

The non-steroidal anti-inflammatory agent is preferably contained in an amount of 10 to 50% by weight, more preferably 20 to 40% by weight, based on the total weight of the oral preparation. When the non-steroidal anti-inflammatory agent is contained in an amount less than 10% by weight, a problem of drug efficacy is reduced. When the non-steroidal anti-inflammatory agent is contained in an amount of more than 50% by weight,

For oral agent according to the present invention, the oxy-C _{2 - 4} alkylene glycol solvents are the (act to dissolve the non-steroidal anti-inflammatory). The oxy-C _{2 - 4} alkylene glycol solvents are diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, preferred to use a polypropylene glycol, polytetramethylene glycol and the like, and more preferable to use a polyethylene glycol It is more preferable to use PEG 200, PEG 300, PEG 400 PEG 600 or the like having a number average molecular weight of 600 or less, and polyethylene glycol 400 is most preferably used as the polyethylene glycol (PEG).

In addition, the oxy-C _{2 - 4} alkylene glycol solubilizer is more preferably contained as a preferable, and 5 to 20% by weight to be included in an amount of 3 to 30% by weight relative to the total weight of the oral. If the amount of the oxyalkylene glycol solubilizer is less than 3% by weight, the effect as a solubilizing aid is insufficient. If the solubility exceeds 30% by weight, a problem arises that the total excipient capacity increases.

In the oral preparation according to the present invention, the above-mentioned [PEO-PPO-PEO] type triblock copolymer (serves as a micelle formation). As the triblock copolymer of [PEO-PPO-PEO] type, a compound represented by the following formula (1) can be used.

[Chemical Formula 1]

HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H

(In the formula 1,

The (c ₃ H ₆ O) _b block in the triblock copolymer is 5-95 wt%

Among the triblock copolymers, (C ₂ H ₄ O) _a Both end blocks are 5-95% by weight.)

Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 124, Poloxamer 237, Poloxamer 338, Poloxamer 407, and the like can be used as the triblock copolymer residues of the [PEO-PPO-PEO] , Poloxamer 188 is preferably used.

The [PEO-PPO-PEO] type triblock copolymer is preferably contained in an amount of 3 to 30% by weight, and more preferably 5 to 20% by weight based on the total weight of the oral preparation. When the [PEO-PPO-PEO] type triblock copolymer is contained in an amount of less than 3% by weight, a non-steroidal anti-inflammatory agent is precipitated quickly. When the content exceeds 30% by weight, the particle size increases .

In the oral preparation according to the present invention, the polyoxyethylene surfactant serves to increase the solubility in an aqueous solution. As the polyoxyethylene surfactant, a compound represented by the following formula (2) may be used as the polyoxyethylene surfactant.

(2)

CH ₃ (CH ₂ ) _a (OCH ₂ CH ₂ ) _b OH

(In the formula (2)

a is an integer of 10 to 20,

and b is an integer of 10 to 60.)

(Brij 30), polyoxyl-23-lauryl ether (brij 35), polyoxyl-2-cetyl ether (brij 52), and polyoxyl-4-lauryl ether (Brij 56), polyoxyl-20-cetyl ether (brij58), polyoxyl-2-stearyl ether (brij72), polyoxyl- (Brij93), polyoxyl-10-oleyl ether (brij97), polyoxyl-20-oleyl ether (brij98) and the like can be used and polyoxyl-20-cetyl ether Do. The HLB (Hydrophile-Lipophile Balance) value of the polyoxyethylene surfactant is preferably in the range of 5 - 17, more preferably in the range of 10 - 17.

The polyoxyethylene surfactant is preferably contained in an amount of 2 to 30% by weight, more preferably 5 to 20% by weight based on the total weight of the oral preparation. If the polyoxyethylene surfactant is contained in an amount of less than 2% by weight, there is a problem that the effect of increasing solubility is not exhibited. When the polyoxyethylene surfactant is contained in an amount exceeding 30% by weight, toxicity specific to a surfactant appears.

Oral agent according to the present invention may further contain a _2- C ₄ alkylene glycol mono acids Solvent 5 to 40% by weight and inorganic bases 5 to 10% by weight. Particularly, when the non-steroidal anti-inflammatory agent according to the present invention is naproxen, it is more preferable.

The _2- C ₄ alkylene glycol mono flow agents serves to enhance the dissolution rate. In the _2- C ₄ alkylene glycol mono flow agents are: ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, ethylene glycol mono-pentyl ether, ethylene glycol monohexyl ether and ethylene glycol mono-C _{2 - 6} alkyl ethers; Diethylene glycol mono C _{2 -6} alkyl ethers such as diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monopentyl ether and diethylene glycol monohexyl ether; Triethylene glycol monoethyl ether, triethylene glycol monopropyl ether, triethylene glycol monobutyl ether, triethylene glycol mono-pentyl ether, triethylene glycol monohexyl ether and diethylene glycol mono-C _{2 - 6} alkyl ether; Propylene glycol mono C _{2 -6} alkyl ethers such as propylene glycol monoethyl ether, propylene glycol monopropyl ether, propylene glycol monobutyl ether, propylene glycol monopentyl ether and propylene glycol monohexyl ether; Dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, dipropylene glycol mono-pentyl ether, dipropylene glycol monohexyl ether and dipropylene glycol mono-C _{2 - 6} alkyl ether; Tripropylene glycol monoethyl ether, tripropylene glycol monopropyl ether, tripropylene glycol monobutyl ether, tripropylene glycol mono-pentyl ether, tripropylene glycol monohexyl ether and tripropylene glycol mono-C _{2 - 6} alkyl ether; Propylene glycol mono C _{2 - 20} alkylates such as propylene glycol monocaprylate, propylene glycol monostearate and propylene glycol monolaurate, and diethylene glycol mono C _2-6 alkyl ethers, propylene glycol Mono C _{2 - 20} alkoxylates, mono C _{2 - 20} alkylates, and the like, and more preferably diethylene glycol monoethyl ether, propylene glycol monocaprylate, propylene glycol monolaurate and the like. Diethylene glycol monoethyl ether Is preferably used.

Also, the _2- C ₄ alkylene glycol mono flow agents is more preferred to be included in an amount of preferably from 20 to 40% by weight to be included in an amount of 5 to 40% by weight relative to the total weight of the oral. The _2- C ₄ alkylene glycols and mono flow agents is a problem that the overall liquid capacity increases when contained in an increase in dissolution rate and the lack occurs, and 40% by weight excess problem effect when content of less than 5% by weight.

The inorganic base serves as a pH adjusting agent. As the inorganic base, those conventionally used in the art can be used, but potassium hydroxide (KOH), sodium hydroxide (NaOH), calcium hydroxide (Ca (OH) ₂ ) and the like are preferably used.

The inorganic base is preferably contained in an amount of 5 to 10% by weight, more preferably 3 to 6% by weight based on the total weight of the oral preparation. If the amount of the inorganic base is less than 5 wt%, the pH does not affect the improvement of the elution. If the amount of the inorganic base is more than 10 wt%, the pH becomes excessively high.

The oral preparation according to the present invention may further comprise distilled water to facilitate stirring, and it is preferable that the oral preparation contains 5 to 10% by weight. If the distilled water is contained in an amount of less than 5% by weight, it takes a long time to mix the excipient. If the distilled water is contained in an amount exceeding 10% by weight, the stability of the capsule is deteriorated.

In addition, the oral preparation according to the present invention may further comprise a tension adjusting agent for improving the stability of the micelle, wherein the tension adjusting agent is selected from the group consisting of sorbitol, mannitol, xylitol, lactose, glucose, dextrose, polyvinylpyrrolidone, Potassium chloride, carbomer, phe- lurene, etc. may be used.

In the case of additionally containing a tension adjusting agent, it is preferably contained in an amount of 1 to 20% by weight, and more preferably 7 to 12% by weight based on the total weight of the oral preparation.

If the tension adjusting agent is contained in an amount less than 1% by weight based on the total weight of the oral preparation, a sufficient tension adjustment effect can not be expected. If the tension adjusting agent is contained in an amount exceeding 20% by weight, the concentration of the final antiinflammatory analgesic decreases .

When the oral preparation is formulated, it can be prepared by using excipients such as fillers and extenders which are usually used.

 The oral preparation includes tablets, pills, powders, granules, soft capsules, hard capsules and the like, and may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc may also be used.

Specifically, the non-steroidal anti-inflammatory agent dissolves well in ethanol, but when ethanol is used, the ethanol volatilizes as time passes and the content decreases, so that precipitation may occur. In addition, when an oil such as castor oil is used, the solubility of the drug is increased, but the dissolution is delayed.

In the case of ibuprofen or dexibupropene, it does not dissolve at all in gastric juice (pH 1 to 2), it dissolves in intestinal juice (pH 7 to 8), and takes more than 1 hour to 2 hours until the time of administration of the drug. There is a problem that the dissolution rate is not constant depending on the form of the preparation.

However, the oral preparation of the present invention does not contain ethanol and oil, and solubilizes the drug stably in an aqueous solution irrespective of the pH to show a dissolution rate of 80% or more after 45 minutes from the start of dissolution, thereby increasing the dissolution rate and shortening the dissolution time It has an effect of improving the absorption rate and absorption rate of the drug in the body when administered to a subject, so that it can be usefully used as a nonsteroidal anti-inflammatory drug-containing oral agent.

The invention also oxy-C _{2 - 4} alkylene glycol Solvent 3 to 30% by weight; 3 to 20% by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)]; Adding 10 to 50% by weight of a non-steroidal anti-inflammatory agent to 3 to 30% by weight of a polyoxyethylene surfactant, and subjecting the micelle to a non-steroidal anti-inflammatory agent by ultrasonic treatment or heating,

The non-steroidal anti-inflammatory agent may be selected from the group consisting of ibuprofen, dexibuprofen, naproxen, aspirin, celecoxib, diclofenac, diflunisal, etodolac ), Oxaprozin, piroxicam, indomethacin, ketoprofen, ketorolac, nabumetone, salsalate, wherein the nonsteroidal antiinflammatory agent is at least one selected from the group consisting of sulindac, tolmetin, and the like.

Hereinafter, the manufacturing method according to the present invention will be described in detail.

The non-steroidal anti-inflammatory agents, oxy-C _{2 - 4} alkylene glycols, solvents, [polyethylene oxide (PEO) - polypropylene oxide (PPO) - (ethylene oxide) (PEO)] form the triblock copolymers of polyoxyethylene-based surfactants, The inorganic salts and distilled water are as described above.

The ultrasonic treatment or heating is not particularly limited so long as it can dissolve the components of the non-steroidal anti-inflammatory agent without changing it, but heating is preferred, and heating to 40 to 70 캜 is more preferable.

Specifically, the non-steroidal anti-inflammatory agent dissolves well in ethanol, but when ethanol is used, the ethanol volatilizes as time passes and the content decreases, so that precipitation may occur. In addition, when an oil such as castor oil is used, the solubility of the drug is increased, but the dissolution is delayed.

In the case of ibuprofen or dexibupropene, it does not dissolve at all in gastric juice (pH 1 to 2), it dissolves in intestinal juice (pH 7 to 8), and takes more than 1 hour to 2 hours until the time of administration of the drug. There is a problem that the dissolution rate is not constant.

However, the method for producing an oral preparation of the present invention is not limited to ethanol and oil, but may be a solution of an oxy C _2-4 alkylene glycol solubilizer such as polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO) Type block copolymers and polyoxyethylene surfactants are mixed to prepare an oral preparation, the drug is stably solubilized in an aqueous solution regardless of pH to increase the dissolution rate and shorten the dissolution time, The water absorption rate and the absorption rate of the water-soluble polymer can be improved, and the production time can be shortened and storage can be facilitated.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

The following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Example  1 to 7> Dexibupropene  Oral preparation containing active ingredient

Examples 1 to 7 of oral preparations containing dexibupropene were prepared with the respective components and contents shown in Table 1 below. Dexibuprofen (Source: ㈜ Hanseo cam), oxy-C _{2 - 4} alkylene glycols, solubilizers (polyethylene glycol 400, origin: BASF) was added and after melting at 60 ℃, triblock copolymers (poloxamer 188, Source: BASF) and a polyoxy surfactant (polyoxyl-20-cetyl ether, source: Sigma Aldrich) were added, stirred to allow mixing, and filled in a hard capsule.

< Comparative Example  1> Conventional Dexibupropene  Oral agent

A commercially available product (trade name: deckbiphen, manufactured by Cheil Pharmaceutical Co., Ltd.) was used.

< Comparative Example  2 To 9> dexibupropene  Oral preparation containing active ingredient

Comparative Examples 1 to 7 of oral preparations containing dexibupropene were prepared in the same manner as in Example 1 with the respective components and contents shown in Table 2 below.

< Example  8-14> Oral preparation containing naproxen as an active ingredient

Examples 8 to 14 of oral preparations containing naproxen were prepared with the respective components and contents described in Table 5 below. Naproxen (Source: Korea Kolmar), _2- C ₄ alkylene glycol mono acids (diethylene glycol monoethyl ether, Source: Kolmar Korea), oxy-C _{2 - 4} alkylene glycols, solubilizers (polyethylene glycol 400, origin: BASF) , Triblock copolyester (Poloxamer 188, source: BASF) and polyoxy surfactant (polyoxyl-20-cetyl ether, source: Sigma Aldrich) were added and melted at 60 ° C., : Purified water) and distilled water were added, stirred, and filled in a hard capsule.

< Comparative Example  10 to 29> Oral preparation containing naproxen as an active ingredient

Comparative Examples 10 to 29 of oral preparations containing naproxen were prepared in the same manner as in Example 8, with the respective components and contents shown in the following Tables 3-5.

< Experimental Example  1> Dexibupropene  Test for dissolution rate of oral agent of active ingredient

The dissolution rate test was carried out using the dexibupropene oral agents Examples 1 to 7 and Comparative Examples 1 to 14.

Specifically, the elution medium was phosphate buffer (pH 7.2, 900 ml) according to the USP dexibupropene test method and tested at 150 rpm according to Method 2 of the dissolution test method. One hour after the start of the elution, the eluate was collected, filtered through a 0.45 mu m filter, and the filtrate was used as a sample solution.

To analyze the dissolution rate of dexibupropene, an ultraviolet-visible spectrophotometer (UV-Vis spectrophotometer) was used. The standard of dissolution rate of dexibupropene is 80% or more after 1 hour of elution.

The results are shown in FIG. 6 and Tables 1 and 2.

1 is a photograph of the oral preparation of Example 1 according to the present invention filled in a hard capsule.

Fig. 2 is a photograph of the dissolution state of the oral agent of Example 1 according to the present invention as a result of elution in a pH 1.2 solution. Fig.

FIG. 3 is a photograph of the dissolution state of the oral agent of Example 1 according to the present invention as a result of elution in pH 7.2 solution. FIG.

FIG. 4 is a photograph of the dissolved state of the resultant solution of a conventional commercially available dexibuprofen oral agent in a pH 1.2 solution.

5 is a photograph of the dissolution state of the oral agent of Comparative Example 1 as a result of elution in a pH 1.2 solution.

FIG. 6 is a graph showing dissolution rates at pH 1.2 and pH 7.2 of the oral preparation of Example 1 according to the present invention. FIG.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Dexibupropene 300 300 300 300 300 300 300 PEG400 100 100 100 150 150 150 150 P188 200 150 100 200 150 100 50 P407 - - - - - - - P124 - - - - - - - BRIJ58 100 150 200 50 100 150 200 weight 700 700 700 700 700 700 700 Dissolution rate 85.8 86.1 86.8 87.3 86.7 86.9 85.6

Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Dexibupropene 300 300 300 300 300 300 300 300 PEG400 100 100 - - 150 100 100 250 P188 200 300 150 200 - - 250 100 P407 - - - - - - - P124 - - - - - - - BRIJ58 - - 150 100 150 200 50 50 weight 600 700 600 600 600 600 600 600 Dissolution rate 52.3 49.9 50.5 53.3 52.4 55.6 57.5 56.1

(In Tables 1 and 2 above,

PEG 400 is polyethylene glycol 400;

P188 (F68) is Poloxamer 188;

P407 (F127) is Poloxamer 407;

P124 is poloxamer 124;

BRIJ58 is a polyoxyl-20-cetyl ether.)

As shown in Figs. 1 to 5, the oral preparation of Example 1 containing dexibupropene as an active ingredient according to the present invention contains the polyoxyethylene-based surfactant prepared according to the conventional commercial product of Comparative Example 1 and the polyoxyethylene- It can be understood that the dissolution state is remarkably improved as compared with the oral agent except for the active agent.

Specifically, it can be seen that the oral preparation of Example 1 according to the present invention is transparent in the hard capsule (see Fig. 1), and is dissolved in the pH 1.2 and pH 7.2 solutions in a transparent state 2 and 3), it can be seen that a commercially available product of Comparative Example 1 forms a precipitate (see FIG. 4), and the oral preparation of Comparative Example 2 shows an opaque dissolution state (see FIG. 5) .

In addition, the oral preparation of Example 1 containing dexibupropene according to the present invention as an active ingredient, when eluted at a pH of 7.2 and a pH of 1.2 in the second method at 150 rpm, showed 100% It can be seen that the elution is completed (see Fig. 6).

Therefore, the oral agent containing micelles containing the non-steroidal anti-inflammatory agent according to the present invention has an effect of improving the absorption rate and absorption rate of the drug when administered to a subject by stably solubilizing the drug and increasing the dissolution rate and shortening the dissolution time Therefore, it can be usefully used as a non-steroidal anti-inflammatory agent-containing oral agent.

< Experimental Example  2> Test of dissolution rate of oral agent of naproxen active ingredient

The dissolution rate test was carried out using the naproxen active ingredient oral agents Examples 8 to 14 and Comparative Examples 10 to 29. The elution media were 0.1 mol / L phosphate buffer (pH 7.4, 900 ml) And was tested at 50 rpm according to Method 2 of the dissolution test method. After 45 minutes from the start of elution, the eluate was collected and filtered through a 0.45 μm filter, and the filtrate was used as the sample solution. Further, 250 mg of naproxen was dissolved in 900 ml of phosphate buffer, and the filtrate obtained by filtration in the same manner as the sample solution was analyzed by high performance liquid chromatography using the standard solution.

High Performance Liquid Chromatography (HPLC) was used to analyze the dissolution rate of naproxen. The standard of naproxen dissolution rate is more than 80% after 45 minutes of leaching.

Column - Capcell Pak, C18, 5 占 퐉, 4.6 mm ID. X 250mm

Column temperature - 30

Flow rate - 1.2 ml / min

Mobile phase-acetonitrile: water: acetic anhydride (50: 49: 1)

Detector - Ultraviolet Absorption Spectrophotometer (254 nm)

The experimental results are shown in FIG. 7-10 and Tables 3 to 5 below.

7 is a photograph of the oral preparation of Comparative Example 14 filled with a hard capsule.

8 is a photograph of the oral preparation of Example 11 according to the present invention filled in a hard capsule.

FIG. 9 is a photograph of the dissolution state of the oral agent of Example 11 according to the present invention as a result of elution in pH 7.4 solution. FIG.

10 is a graph showing dissolution rates of the oral preparations of Examples 10 and 14 and Comparative Examples 12, 17, 23, 24, and 29 according to the present invention.

Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 Comparative Example 18 Naproxen 250 250 250 250 250 250 250 250 250 TRANSUCUTOL - - - - - - - - - PEG400 300 310 300 300 200 300 400 300 300 P188 20 20 - - 20 20 20 10 40 P407 - - - - - - - - - P124 - - 20 50 - - - - - BRIJ58 - - - - - - - - - KOH 30 30 30 30 - - - - - Weight (mg) 600 610 600 630 470 570 670 560 590 Dissolution rate 65.8% 64.7% 76.7% 69% 41.3% 53.3% 41.1% 53.8% 51.6%

Comparative Example 19 Comparative Example 20 Comparative Example 21 Comparative Example 22 Comparative Example 23 Comparative Example 24 Comparative Example 25 Comparative Example 26 Comparative Example 27 Naproxen 250 250 250 250 250 250 250 250 250 Transcuttle 300 300 300 300 300 200 100 200 100 PEG400 - - - - - 100 200 100 200 P188 20 30 - - - 20 20 - - P407 - - - - 30 - - 30 30 P124 - - 20 30 - - - - - BRIJ58 - - - - - - - - - KOH 30 30 30 30 30 30 30 30 30 weight 600 610 600 610 610 600 600 610 610 Dissolution rate 73.4% 71.1% 67.8% 71.3% 75.6% 75.6% 74.1% 72.2% 70.2%

Comparative Example 28 Comparative Example 29 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Naproxen 250 250 250 250 250 250 250 250 250 Transcuttle 230 230 230 200 200 150 150 150 150 PEG400 120 100 100 100 100 50 50 50 50 P188 30 30 30 30 30 50 34 - - P407 - - - - - - - 50 34 P124 - - - - - 34 50 34 50 BRIJ58 - - 20 30 40 40 40 40 40 KOH 30 42 42 42 42 42 42 42 42 D.W. 10 10 - - - 54 54 54 54 weight 670 662 672 652 662 670 670 670 670 Dissolution rate 79.2% 77.5% 86.4% 94.6% 98.5% 96% 97.5% 96.3% 98%

(In Tables 3 to 5 above,

Transcutol is diethylene glycol monoethyl ether;

PEG 400 is polyethylene glycol 400;

P188 (F68) is Poloxamer 188;

P407 (F127) is Poloxamer 407;

P124 is poloxamer 124;

BRIJ58 is a polyoxyl-20-cetyl ether.)

As shown in Tables 3 to 5 and Figs. 7 to 9, it can be seen that the oral agent containing naproxen as an active ingredient according to the present invention has a significantly improved dissolution state as compared with the oral agent of Comparative Examples 10 to 29.

Specifically, the oral agent of Example 11 according to the present invention was found to be transparent in the hard capsule (see FIG. 8), and was dissolved in the pH 7.4 solution transparently (see FIG. 9) The oral preparation of Comparative Example 14 shows an opaque dissolution state in the hard capsule (see Fig. 7).

In addition, when the oral preparations of Examples 8 to 14 containing naproxen according to the present invention as an active ingredient eluted in a pH 7.4 solution, it was found that the 95% elution was completed within 45 minutes of the elution (see FIG. 10) .

Therefore, the oral agent containing micelles containing the non-steroidal anti-inflammatory agent according to the present invention has an effect of improving the absorption rate and absorption rate of the drug when administered to a subject by stably solubilizing the drug and increasing the dissolution rate and shortening the dissolution time Therefore, it can be usefully used as a non-steroidal anti-inflammatory agent-containing oral agent.

Claims (10)

10 to 50% by weight naproxen;
3 to 30% by weight of oxy C _2-4 alkylene glycol solubilizer;
3 to 30% by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)];
2 to 30% by weight of a polyoxyethylene surfactant;
5 to 40% by weight of a C _2-4 alkylene glycol monoolefin solvent; And
An oral preparation containing niacin encapsulated micelles containing 5 to 10% by weight of inorganic bases.
delete delete The method according to claim 1,
The C _2-4 alkylene glycol mono flow agents are C _2-4 alkylene glycol mono C _2-6 alkyl ethers, di -C _2-4 alkylene glycol mono C _2-6 alkyl ether, triethylene -C _2-4 An alkylene glycol mono C _2-6 alkyl ether, and a propylene glycol mono C _2-20 alkyl ether.
The method according to claim 1,
Wherein the inorganic base is at least one selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH) and calcium hydroxide (Ca (OH) ₂ ).
The method according to claim 1,
The oxy-C _{2 - 4} alkylene glycol solvents are diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol and polytetramethylene oral, characterized in that at least one member selected from the group consisting of glycol claim .
The method according to claim 1,
The triblock copolymer residues in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -Polyethylene Oxide (PEO)] include Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 124, Poloxamer 237, 338, and Poloxamer 407. The oral preparation according to any one of claims 1 to 31,
The method according to claim 1,
The polyoxyethylene surfactant may be at least one selected from the group consisting of polyoxyl-4-lauryl ether (brij30), polyoxyl-23-lauryl ether (brij35), polyoxyl-2-cetyl ether (brij52), polyoxyl- (brij56), polyoxyl-20-cetyl ether (brij58), polyoxyl-2-stearyl ether (brij72), polyoxyl-10-stearyl ether (brij76), polyoxyl- , Polyoxyl-10-oleyl ether (brij97), and polyoxyl-20-oleyl ether (brij98).
The method according to claim 1,
Wherein the oral agent shows a dissolution rate of 80% or more after 45 minutes from the start of dissolution.
Oxy C _2-4 alkylene glycol solubilizers, triblock copolymerates in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)], polyoxyethylene surfactants, C _2-4 alkyl A method for producing an oral preparation containing naproxen-encapsulated micelles, comprising adding naproxen to a phenol solubilizer and an inorganic base, and subjecting the naproxen to ultrasonic treatment or heating to enclose the naproxen in the micelle.

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