KR100582604B1 - IBUPROFEN and DEXIBUPROFEN MICRO EMULSION COMPOSITION AND LIQUID MEDICINE and SOFT CAPSULE DRUG THEREOF - Google Patents

Abstract

The present invention relates to a microemulsion of ibuprofen and dexibuprofen including an antioxidant and a transparent liquid formulation and a transparent soft capsule formulation using the same, and more particularly to an emulsifier, a surfactant, an antioxidant, and an antioxidant synergist. A microemulsion composition of ibuprofen and dexibuprofen and a transparent liquid formulation and a transparent soft capsule formulation using the same.

The composition according to the present invention improves the stability and dissolution rate of the formulation simultaneously by microemulsifying the formulation using two or more surfactants and adding an antioxidant thereto, and additionally, an antioxidant synergist provides a higher effect. Could.

The formulations of the present invention, unlike conventional drugs, are not only stable at low pH but also do not produce precipitated material. In addition, it has a higher dissolution rate than conventional formulations and reduces the amount of excipients, making it easy to take a small dose.

Ibuprofen, dexibuprofen, clear soft capsule, microemulsion, antioxidant

Description

Ibuprofen and DEXIBUPROFEN MICRO EMULSION COMPOSITION AND LIQUID MEDICINE and SOFT CAPSULE DRUG THEREOF}             

1 is a result of dissolution of dexibuprofen microemulsion (samples A and B)

Figure 2 is the dissolution test results of dexibuprofen micro emulsion (samples C, D)

Figure 3 shows the results of dissolution of dexibuprofen microemulsion (samples A-1 to A-4)

Figure 4 is the dissolution test results of dexibuprofen micro emulsion (samples A-5, A-6)

Figure 5 Dexibuprofen micro particle size analysis results

The present invention relates to a microemulsion of ibuprofen and dexibuprofen including an antioxidant and a transparent liquid formulation and a transparent soft capsule formulation using the same, and more particularly to an emulsifier, a surfactant, an antioxidant, and an antioxidant synergist. A microemulsion composition of ibuprofen and dexibuprofen and a transparent liquid formulation and a transparent soft capsule formulation using the same.

Ibuprofen is a representative of non-Steroidal Anti-Inflammatory Drug, which has the effect of analgesic, antipyretic, anti-inflammatory, fast time to reach effective blood concentration, high bioavailability and low price. It is one of the commonly used antipyretic analgesic anti-inflammatory drugs.

Ibuprofen is a racemate and has both R-form and S-form, but dexibuprofen is a chiral compound composed of only S (+) isomer of ibuprofen, which is a bioactive anti-inflammatory drug that outperforms ibuprofen. .

Dexifuprofen is known to have an equivalent effect or more at 50% dose of ibuprofen, and has a rapid anti-inflammatory analgesic effect due to a shorter drug expression time compared to ibuprofen.

However, despite the merits of the above drugs, the market for dexibuprofen preparations is not yet widely activated. This is because both dexibuprofen and ibuprofen are poorly soluble drugs, and ibuprofen / dexibuprofen have low dissolution rate due to hydrophobic groups, and exposure to low pH for a certain period of time even if the dissolution rate is temporarily increased by using a surfactant. This is because the emulsion is destroyed and reprecipitation occurs.

Therefore, many studies have been conducted to improve the drug, but there are still many problems in terms of dissolution rate stability.

In other words, re-precipitation when eluted at a low pH, recrystallization occurs when stored for a long time, and excipients used in large amounts to solve the poor solubility excessive capsule size It is a problem of the ibuprofen and dexibuprofen formulations that have been used.

For example, Korean Patent Laid-Open Publication No. 1998-0701544 describes a method for a solvent system for solubilizing ibuprofen using partial ionization with PEG, PVP, glycerin, NaOH and water. The low dissolution rate in Fig. 2 is pointed out as a problem.

In particular, the Korean Laid-Open Patent Publication No. 1998-0701544 uses water in a soft capsule, which causes the stability of the capsule itself by interaction with the gelatin used in the capsule.

U.S. Patent No. 401,164 describes an ethanol-containing liquid formulation technique in which ibuprofen is solubilized using ethanol and PVP. However, the preparation prepared by this method causes a problem of recrystallization due to a change in ethanol content when stored for a long time. .

Korean Patent Application Publication No. 2002-0076439 discloses a transparent soft capsule cold medicine composition using a 0.1 to 36.5 wt% main ingredient including ibuprofen, a solubilizer such as PEG, and a thickener such as PVP, and a method of preparing the same. The difficulty in making ibuprofen formulations is that the dosage of the entire formulation becomes very large.

In addition, Korean Patent No. 0185294 describes a transparent liquid ibuprofen solution containing tween and polyoxy 40 hydrogenated castor oil in a ibuprofen solution containing PVP and PEG, but this patent also includes the amount of other excipients in addition to the main raw material (ibuprofen). The disadvantage is the excessive use of a very large soft capsule size. Usually, the larger the capsule, the more difficult it is for patients to take it. In addition, in the case of the Korean Patent Preparation No. 0185294, the dissolution rate decreases after a certain time, which means that ibuprofen is reprecipitated.

The present invention is proposed to solve the above problems of the prior art, it is an object of the present invention to increase the dissolution rate by using ibuprofen and dexifuprofen as a micro emulsion composition.

It is also an object of the present invention to use antioxidants and antioxidant synergists to make the compositions according to the invention stable at low pH.

It is also an object of the present invention to provide a transparent soft capsule formulation which minimizes the amount of excipients used without reprecipitation even after long term storage.

Hereinafter, the technical configuration of the present invention in more detail.

The present invention is composed of 5 to 88.5 wt% of ibuprofen or dexibuprofen, 5 to 40 wt% of emulsifier, 3 to 20 wt% of surfactant, 3 to 25 wt% of antioxidant, 0.5 to 10 wt% of antioxidant synergist It provides a micro emulsion composition of ibuprofen and dexibuprofen and a transparent soft capsule formulation using the same.

In particular, the pharmacologically active ingredients used for the microemulsion formulation compositions of the present invention are ibuprofen, dexibuprofen and especially dexibuprofen.

In addition, an amphiphilic solvent, which is an activator having one or more cationic functional groups and anionic functional groups at the same time, was used as an emulsifying agent capable of easily dispersing an emulsion.

As the material having an emulsifier, propylene glycol, polyoxy ethylene alkyl ethers (PEAE), glycerides, propylene carbonate, polyethylene glycol, transcutol, floxamer and the like can be used.

As the surfactant, any one or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester and polyoxy40 cured castor oil was selected and used. In addition to this, antioxidants were solubilized to produce more stable ibuprofen / dexibuprofen formulations. As antioxidants, unsaturated fatty acids, cetric acid, tocopherols, sodium ascorbate, sodium metabisulfite, etc. can be used. Among them, tocopherols are the most suitable.

Antioxidant synergists may also be added to the microemulsions above. Antioxidant synergists help a little in stabilizing the formulation, but do not have a large effect without the use of large doses due to the difficulty of increasing the amount of excipients. Synergists include Edefic acid, Fumaric acid and Phosphoric acid.

A more detailed description of the microemulsion of the present invention is as follows.

In the present invention, an emulsifier, a surfactant, and an antioxidant are included in the poorly soluble drug.

As an emulsifier, polyethylene glycol (PEG) having a molecular weight of 600 or less, which is an amphiphilic solvent, was used, and PEG 400 having a viscosity of 6.8 to 8.0 was used. In the present invention, the emulsifier is used about 5 to 40% by weight based on the total weight of the composition, preferably 10 to 30% by weight.

The surfactant is used in an amount of 3 to 20% by weight based on the total weight of the composition, and polyoxyethylene sorbitan fatty acid ester (tween) and polyoxy40 cured castor oil (Cremophor) are used. Preferably, both Tween80 and Cremophor are 5 to 15 Use by weight.

The antioxidant used in the present invention was used 5 to 25% by weight of tocopherol acetate, dl-α tocopherol, β-tocopherol, γ-tocopherol, etc. Among them, γ-tocopherol showed the most excellent effect, but in the present invention, For commercial economics, we chose the most easily and inexpensively available tocopherol acetate.

Accordingly, it is most preferable to include 5 to 25% by weight as tocopherol acetate, and as a synergist, Edefic acid, Fumaric acid, Phosphoric acid, etc. are used, and 0.5 to 10.00% by weight of the total weight is preferably used.

The emulsifier used in the present invention enhances the dexibuprofen solubility as the basic solvent of the present invention, and the two surfactants contribute to the increase in dissolution rate and transparency of the solution.

The meaning of 'transparency' mentioned above means that dexibuprofen itself is completely dissolved in the capsule and is faster and easier to absorb than other formulations when the drug is expressed in the body.

In addition, tocopherols, which are used as antioxidants, help to stabilize the formulation and prevent re-precipitation and precipitation, which enables the preparation of stable dexibuprofen microemulsions at low pH, and antioxidant synergists help and assist antioxidants. .

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1

The transparent liquid microemulsion of the present invention is prepared by first heating the polyethylene glycol (40 to 60 ° C.) and adding enough dexibuprofen to stir until it is solubilized transparently.

Add cremophor and tween 80 and stir while keeping warm. Finally, add tocopherol and stir to prepare a completely solubilized microemulsion.

The microemulsion prepared in this way is not only a simple manufacturing method but also does not cause a problem of reprecipitation or recrystallization when the transparent emulsion is formed at a temperature maintained.

In addition, it is possible to prepare transparent soft capsules by filling the soft capsules in a conventional manner by adding pharmaceutically acceptable additives such as colorants, flavoring agents, and preservatives, such as emulsions or generally used in soft capsules. It can also be applied to formulations or liquids.

Hereinafter, the dissolution rate according to the composition change of the microemulsion composition will be described using samples A, B, C, and D having the compositions shown in Tables 1 and 2 below.

Dissolution rate experiments were carried out while stirring artificial gastric juice of pH 1.2 at 50 rpm, analysis was performed using HPLC (225 nm). The standard of this experiment is in accordance with the rules described in the 2nd method (paddle method) of the Korean Pharmacopoeia General Test Methods. The measurement time was 10 to 120 minutes. This is because it is possible to know whether or not re precipitation of dexibuprofen in gastric juice occurs.

Composition of Samples A and B Usage ingredient Weight (mg)  chief ingredient  DEXIBUPROFEN 300 300  Emulsifier  PEG 400 150 150  Surfactants                                               TWEEN 80 70 70  CREMOPHOR 140 140  Antioxidant  TOCOPHEROL 105 105  Synergy  FUMARIC ACID 15 Total 765 (Sample A) 780 (Sample B)

1, the dissolution rates of Sample A and Sample B were compared. Referring to FIG. 1, the dissolution rate of Sample A increases until 60 minutes, and the increase continues after 90 minutes and 120 minutes. Also, there was no bending curve that appeared when the dissolution rate decreased. This means that the microemulsion is stable even at low pH for a long time and no reprecipitation has occurred.

Sample B adds the antioxidant synergist to the composition of Sample A. The curve pattern hardly changes and it can be seen that the dissolution rate is slightly higher than that of Sample A. Higher amounts can be expected to result in better dissolution rates, but this will increase the dosage of the formulation, so it does not seem to be necessary to add a higher amount when considering activity against dose.

Composition of Samples C and D Usage ingredient Weight (mg)  chief ingredient  DEXIBUPROFEN 300 300  Emulsifier  PEG 400 150 150  Surfactants  TWEEN 80 70 105  CREMOPHOR 140 210  Antioxidant  TOCOPHEROL Total 660 (Sample C) 765 (Sample D)

2 is a graph illustrating the dissolution rates of Sample C and Sample D. Sample C is to remove the tocopherol from Sample A, an experiment to determine the role and extent of the antioxidant tocopherol. As can be seen in Figure 2 without the use of antioxidants at low pH the emulsion can be seen that the re-precipitation phenomenon.

It can be seen that the role of the antioxidant tocopherol in the ibuprofen / dexibuprofen emulsion is very large, and even if the total weight is the same, it can be seen that the difference between with and without tocopherol.

Example 2

In the same manner as in Example 1 to prepare a dexibuprofen microemulsion having the composition shown in Table 3. Samples in Table 3 were prepared to determine the change in sample A by 30% by weight.

Sample when 30% of each item is reduced in Sample A sample DEXIBUPROFEN PEG 400 TWEEN 80 CREMOPHOR TOCOPHEROL TOTAL comparison target A-1 300 105 70 140 105 720 PEG A-2 300 150 70 98 105 723 CREMOPHOR A-3 300 150 70 140 73.5 733.5 TOCOPHEROL A-4 300 150 49 140 105 744 TWEEN

In the composition of Sample A, PEG, CREMOPHOR, TOCOPHEROL, and TWEEN are the results of the dissolution test of the emulsion, which is reduced by 30%.

As shown in FIG. 3, the sample A-1 is PEG, the sample A-2 is CREMOPHOR, the sample A-3 is TOCOPHEROL, and the sample A-4 is reduced in the amount of TWEEN to show the result. will be.

In the case of sample A-1, the dissolution rate was slightly decreased as a whole. Also, in the case of sample A-2 and sample A-4, the dissolution rate was similarly decreased. However, this is greater than that of Sample A-1. In addition, in the case of sample A-3, not only the dissolution rate was lowered, but also the dissolution rate was decreased after elapse of time, which indicates that re-precipitation of dexibuprofen occurred in the emulsion.

Example 3

In the same manner as in Example 1 to prepare a dexibuprofen emulsion having the composition shown in Table 4. This is to compare the change when the total weight is reduced in Sample A.

DEXIBUPROFEN PEG 400 TWEEN 80 CREMOPHOR TOCOPHEROL TOTAL A-5 300 150 40 80 60 630 A-6 300 150 30 60 45 585 A-7 300 100 40 80 60 580 A-8 300 100 30 60 45 535

The composition of Table 4 is an emulsion of lowering the values of all excipients in the composition of Sample A as a whole. In case of Samples A-7 and A-8, re-precipitation occurred over time, and thus did not elute. In the case of sample A-6, the dissolution rate which did not meet expectations was shown.

In FIG. 4, the dissolution rate test result of the sample A-5 and the sample A-6 was shown by the graph.

Example 4

In this example, the long term storage of the dexibuprofen microemulsion was confirmed whether or not recrystallization. Experimental conditions were three cases of freezing, 4 ℃, room temperature, the duration was 30 days.

As can be seen in Table 5 below, it can be seen that re-precipitation occurred in dexibuprofen emulsion when a certain amount of ratio was not filled. It can be seen that the ideal ratio of dexibuprofen microemulsion is stable in no case and does not lose its transparency. (+: Precipitate formation,-: no precipitation)

Recrystallization experiment for long term preservation of microemulsion Sample  A, B. C, D A-1 A-2 A-3. A-4 A-5 A-6 A-7 A-8 Determination (+,-) - +- - - - - - -+ + ++

Example 5

Particles of dexibuprofen microemulsion (Sample A) were analyzed. As a result, as shown in Figure 5, the particle distribution of the dexibuprofen microemulsion of the present invention is very even, it can be seen that the average particle size is about 5㎛.

The fact that the cumulative curve is not divided into pieces is evidence that all excipients are well compatible with dexibuprofen, which can be expected to prevent the separation of emulsions.

The microemulsions according to the present invention are excellent in stability even at low pH and do not form precipitates over time, and thus the increased dissolution rate makes the bioexpression excellent.

In addition, the amount of excipients was reduced to a minimum, which greatly reduced the size of the capsule, which is sufficient to reduce the patient's refusal to take it.

In particular, for higher bioavailability of dexibuprofen, it is possible to provide transparent soft capsule formulations, syrups, and clear liquids, which are evidence of complete dissolution of dexibuprofen, which simultaneously resolves the patient's discomfort, as well as pH stability and precipitation prevention. There is.

Claims (10)

Solubilized ibuprofen and dexibuprofen compositions, 5-88.5% by weight of ibuprofen or dexibuprofen, propylene glycol, emulsifier of any one or more selected from the group consisting of propylene glycol, polyoxy ethylene alkyl ethers (PEAE), glycerides, propylene carbonate, polyethylene glycol, transcutol, floxamer 5 to 40% by weight, 3 to 20% by weight of any one or more surfactants selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and polyoxy40 cured castor oil, antioxidants 3 to 25% by weight, antioxidant synergists 0.5 Microemulsion of ibuprofen and dexibuprofen, characterized in that it is composed of from 10% by weight to A transparent soft capsule formulation prepared using the microemulsion of ibuprofen and dexibuprofen of claim 1 delete delete The microemulsion of ibuprofen and dexibuprofen according to claim 1, wherein the antioxidant is at least one selected from the group consisting of unsaturated fatty acids, cetric acid, tocopherols, sodium ascorbate, sodium metabisulfite. The microemulsion of ibuprofen and dexibuprofen according to claim 1, wherein the antioxidant synergist is any one or more selected from the group consisting of edefic acid, fumaric acid and phosphoric acid. The microemulsion of ibuprofen and dexibuprofen according to claim 3, wherein the polyethylene glycol is PEG 400 having a viscosity of 6.8 to 8.0. 6. The microemulsion of ibuprofen and dexibuprofen according to claim 5, wherein the tocopherols are γ-tocopherol. A transparent capsule preparation, which is prepared using the microemulsion composition of ibuprofen and dexibuprofen of claim 1 A liquid preparation prepared by using the microemulsion of ibuprofen and dexibuprofen of claim 1

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