KR20020071037A - Soft capsule or injection formulation containg ibuprofen by smedds - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for formulation of ibuprofen into a soft gelatin capsule or an injection using a self-micro emulsifying drug delivery system(SMEDDS) is provided. Therefore, the obtained ibuprofen soft gelatin capsule has excellent elution characteristics and the formulation increases bioavailability of a medicament. CONSTITUTION: The pharmaceutical composition contains: a surfactant such as polyoxyl caster oils; an auxiliary surfactant such as propylene glycol derivatives; oil such as caprylocaproyl macrogolglycerides; a dispersing agent such as polyvinylpyrrolidone to increase the physical stability of a medicament; a solubilizing agent for increasing the solubility of the medicament; and water as a solvent of the above composition.

Description

Soft capsules and injections of ibuprofen using solubilization method SMD eds {SOFT CAPSULE OR INJECTION FORMULATION CONTAING IBUPROFEN BY SMEDDS}

An object of the present invention is to develop a soft capsule and micro-emulsion formulation for injection through the development of ibuprofen solubilization system using SMEDDS.

Many studies have been conducted to increase the bioavailability of drugs by overcoming the poorly soluble properties of ibuprofen (solubility in water; 1.23 mg / ml), and the direction of the study includes suspensions to greatly increase the solubility of drugs. It can be divided into a simple solubilization method, a solid dispersion method using a water-soluble polymer, the study of a self-emulsifying drug delivery system that can form an emulsion or a microemulsion spontaneously. The published patents on simple solubilization techniques, including the preparation of suspensions, are as follows.

Korean Patent Publication No. 1998-0073629 discloses a transparent ibuprofen soft capsule using polyvinylpyrrolidone, polyethylene glycol having a molecular weight of 600 or less, polyoxy 40 hydrogenated fatty acid ester (twin ^® ), and polyoxy 40 hydrogenated castor oil (cremopo ^® ). The manufacturing related information has been disclosed, and Korean Patent Publication No. 97-9793 uses polyoxyethylene sorbitan fatty acid esters, among them, polysorbate 80 ^ⓡ and polyglycerol fatty acid esters, and polyglycerol condensed ricinoleic acid esters. Disclosed is a matter related to the manufacture of soft capsules containing polyvinylpyrrolidone. In Korean Patent Laid-Open Publication No. 90-13952, a patent for a suspending agent having 40 μm of ibuprofen particles as an aqueous ibuprofen composition suitable for oral administration and taste-neutral is disclosed, and Korean Patent Publication No. 95-13506 also has a bitter taste. Patents related to oral suspending agents have been disclosed, and Korean Patent Laid-Open Publication No. 1995-002745 also discloses a solubilization method of a ibuprofen liquid cold medicine using a suspending technique. In the case of foreign patents, USP 4,975,465 discloses a patent for a flavored suspension of ibuprofen suspension, while USP 4,690,826 uses polyoxyethylene-polyoxypropylene polymers having a molecular weight of 1400-2000 and 1,2-propylene glycol as main bases. A method of making a suspension by solubilizing is disclosed. USP 5071643 discloses a method for solubilizing ibuprofen using a new solvent system of glycerin, polyethylene glycol, polyvinylpyrrolidone and water, and USP 5141961 to solubilize ibuprofen using ethanol, polyethylene glycol and polyvinylpyrrolidone. Although ethanol-containing liquid compositions have been disclosed, they are expected to produce a precipitate of ibuprofen upon long-term storage. US Pat. No. 5,468,502 also discloses a system containing 25% ibuprofen, 1-10% water and 50-74% solubilizer, based on the total weight of the contents, in particular, a nonionic polyethoke having a HLB value between 8-25. Cylated surfactants, in particular polyoxyethylated sorbitan derivatives and nonionic polyalkylene glycol polymers having an HLB value between 8-25, especially liquid polyethylene glycols alone or ibuprofen having a molecular weight of 200-600 As a solubilizer, alcohol, polyhydric alcohol, fatty acid ester having 2 to 21 carbon atoms, and a nonionic polyalkylene glycol polymer solvent system, which is a mixed solution with 1-10% of ammonium acetate, are prepared into a dosage form and filled into a soft capsule. The contents in the appropriate form have been disclosed.

The method of increasing the solubility of poorly soluble drugs by solid dispersion method using a water-soluble polymer has been published in the Republic of Korea Patent Publication No. 2000-0006503 including a study on a variety of medicines, including ibuprofen.

On the other hand, domestic published patents on the development of soft capsules using a self-emulsifying drug delivery system has not been known so far, but the contents of the invention related to ibuprofen soft capsules using the above technology as a foreign patent is disclosed in detail in WO 00/30619. The contents of are as follows.

As a self-emulsifying drug delivery system, ibuprofen contains 33-38% of polybutyylene castor oil derivatives and 30-35% of polyoxyethylene benzene castor oil derivatives. And 15-20% polyvinylpyrrolidone and 1-2% water. In the ethylene content polyoxyethylene castor oil derivatives, and having an HLB value of a trade name Peg 35HCO ^ⓡ of polyoxyethylene 35 castor oil with the trade name of Peg 40HCO ^ⓡ include polyoxyethylene 40 hydrogenated castor oil with 12 to 16, polyvinylpyrrolidone Includes PVP-K12 and PVP-K17 having a molecular weight of 2,000-11,000.

Meanwhile, in the present invention, Peg 35HCO ^ⓡ is composed of 83% of glycerin polyethylene glycol ricinolate in the hydrophobic region, 17% of polyethylene glycol and glycerin ethoxylate in the hydrophilic region, and the HLB value is 12-14. Peg 40HCO ^ⓡ is the fatty acid esters of glycol polyethylene glycol and fatty acid esters of polyethylene glycol in the region that represents the hydrophobic account for 75%, the rate is 25% Ethoxylated polyethylene glycol and a glycol in the hydrophilic portion, the HLB value, accounting for 14-16 do. Peg 35HCO ^ⓡ and Peg 40HCO ^ⓡ used in the above patent, but can be solubilized solely ibuprofen because a precipitate with the lapse of time was selectively using the polyvinylpyrrolidone in order to prevent this, the polyvinylpyrrolidone of the polymer is Since low molecular weight polyvinylpyrrolidone is used as a solubilizer and recrystallization inhibitor, it has been disclosed that PVP-K12 and PVP-K17 having a molecular weight of 2,000-11,000 were used in low molecular weight polyvinylpyrrolidone. However, the peculiar matter in the above patent is to dissolve PVP in the ibuprofen content solution, which contains 1-2% water in the minimum amount of water, and the more peculiar matter is a homogeneous solution when only the remaining excipients are mixed with ibuprofen removed. It is characterized by the fact that it cannot be prepared. In other words, ibuprofen is a very important part in the manufacture of soft capsules, and ibuprofen forms a eutectic mixture with excipients constituting the soft capsule contents solution to form a transparent and homogeneous formulation. Thus, in the patent and, optionally using Peg 35HCO ^ⓡ or Peg 40HCO ^ⓡ, to become final formulation is filled into a soft capsule because it should have an appropriate viscosity suitable for filling a soft capsule content solution, 7-15% of castor five days It was used.

In general, suspensions have high viscosity, which is inconvenient to take, difficult to dose, difficult to mix with other drugs, and have the disadvantage of causing precipitation. Currently, ibuprofen 200mg-containing products are licensed and released from 32 companies as 104 items in Korea, but 9 of the ibuprofen capsules are licensed, but all 8 items of hard capsules have been discontinued. Currently, only one kind of MK's soft capsules (Licensing-in product: American Homeproduct Co., Ltd. USA) is produced and sold by domestic soft capsule consignees. Among the NSAIDs, ibuprofen components are classified as generic drugs and can be sold without a doctor's prescription at a pharmacy. Most tablets are 200mg or 400mg tablets, but until now, patents related to ibuprofen soft capsules by domestic technology Although many have been published, the product has not been developed, and in particular, ibuprofen injections using soft capsule and microemulsion techniques by a self-emulsifying drug delivery system have not been disclosed or developed as a product.

In the present invention, by developing a solubilization technology to increase the solubility of the poorly soluble drug ibuprofen and increase the gastric dissolution rate of the drug when oral administration of ibuprofen to promote absorption of the drug to increase the bioavailability of the drug ibuprofen soft capsules and An attempt is made to develop an injectable microemulsion that can stably solubilize a drug. The main technical problem of the present invention is to develop a soft capsule of ibuprofen and a ibuprofen microemulsion formulation for injection by increasing the solubility of ibuprofen and securing a region for forming a stable microemulsion through precise phase equilibrium.

Figure 1 is a surfactant Cremophor EL ^ⓡ of polyoxyl castor oil, a secondary surface active agent in a variety that is found when a Labrasol ^ⓡ, of caprylocaproyl macrogolglyceride oil is added and then producing a SMEDDS using of propyleneglycol laurate Lauroglycol FCC ^ⓡ water Phase equilibrium of the phase observed (M, microemulsion zone; E, emulsion zone; Tr, homogeneous clear solution; Tu, cloudy opaque solution; 2P, zone separated into two phases; 3P, three phases) Separated areas).

Figure 2 is a ibuprofen soft capsule prepared according to Example 2 and the B tablet (200 mg / tab, hereinafter referred to as control S) of the commercially available formulation S and I tablet (200 mg / tab, referred to as the control D) of Company D The result of comparative dissolution test according to USP USIV elution regulation at pH 7.2 (▲, control S; ●, ibuprofen soft capsule; ■, control D).

3 is a ibuprofen soft capsule prepared according to Example 2 and the B tablet of commercially available company S (200 mg / tab, hereinafter referred to as control S) and D company I tablets (200 mg / tab, hereinafter referred to as control D) Figure shows comparative dissolution test results in pH 1.2 solution (●, ibuprofen soft capsule; ▲, control S; ■, control D).

4 is a ibuprofen soft capsule prepared according to Example 2 and B tablets (200 mg / tab, control S) company S and 200 tablets of company D (200 mg / tab, control D) Figure shows comparative dissolution test results in pH 4.0 solution (●, ibuprofen soft capsule; ▲, control S; ■, control D).

FIG. 5 shows ibuprofen soft capsules prepared according to Example 2 and B tablets (200 mg / tab, hereinafter referred to as control S) of S company and commercially available I tablets (200 mg / tab, hereinafter referred to as control D) Figure shows comparative dissolution test results in pH 6.8 solution (●, ibuprofen soft capsule; ▲, control S; ■, control D).

FIG. 6 shows ibuprofen soft capsules prepared according to Example 2 and B tablets (200 mg / tab, hereinafter referred to as control S) of S company and commercially available I tablets (200 mg / tab, hereinafter referred to as control D) Figure shows comparative dissolution test results in water (●, ibuprofen soft capsule; ▲, control S; ■, control D).

Figure 7 is a figure showing the change of dissolution rate of ibuprofen according to the formulation with increasing pH (●, ibuprofen soft capsule; ▲, control S; ■, control D).

FIG. 8 is oral administration of 40 mg / kg of rats with oral administration of ibuprofen to a water dispersion of ibuprofen SMEDDS prepared according to Example 2, a water suspension of control S and a 0.5% MC (methylcellulose) water suspension solution of ibuprofen raw powder. After 10, 20, 30, 60, 120, 240, 360, 480, 720 minutes, samples were taken and analyzed by HPLC (●, ibuprofen SMEDDS; ▲, ibuprofen powder suspension; ■, ibuprofen MC suspension).

9 is a sample every 10, 20, 30, 60, 120, 240, 360, 480, 720 minutes after oral administration of ibuprofen 40mg / kg and the injection of ibuprofen microemulsion to the carotid artery in an amount of 8mg / kg It was taken and analyzed by HPLC (●, ibuprofen SMEDDS; ○, ibuprofen microemulsion).

The present invention is a novel ibuprofen solubilizing agent using a Self-Micro Emulsifying Drug Delivery System (SMEDDS) having the above-mentioned advantages, and comprises a pharmaceutical composition comprising the following components (1) to (5): as,

(1) polyoxyl castor oils as surfactants,

(2) propylene glycol laurate, which is a propylene glycol-based cosurfactant,

(3) caprylocaproyl macrogolgly-cerides, which are medium chain triglycerides as oils,

(4) PVP (polyvinylpyrrolidone) as a dispersing agent,

(5) ethyl alcohol, transcutol ^® and dissolution aids;

(6) Water and the like are contained as a dispersion medium for forming a microemulsion.

The term 'pharmaceutical composition' as used in this specification and the appended claims is defined as a composition in which each component or component itself is a pharmaceutically acceptable composition.

In the present invention, the solubilization method of ibuprofen is solubilized ibuprofen in surfactant, co-surfactant, oil, adding a dispersing agent to prevent the precipitation of the drug and increase the dispersion and solubility of the solution, and then add a dissolution aid to further improve the solubility of the drug. It is further enhanced to obtain a soft capsule composition which contains water as an aqueous phase as a dispersed phase of the mixture to obtain an injection composition as an emulsion or microemulsion.

In order to produce the soft capsule, the component (1) is 10 to the total weight of the component (1) + component (2) + component (3) + component (4) + component (5)] in the composition of the present invention. It is suitable to be present in an amount of 30%, preferably 20 to 30%, and component (2) is suitably present at 10 to 30%, preferably 15 to 30%, in the total weight of the composition of the present invention. . It is also suitable that component (3) is present at 10-25%, preferably 20-25%, based on the total weight of the composition of the present invention, and component (4) is 1.0- about the total weight of the composition of the present invention. It is suitable to be present in an amount of 5.0%, and component (5) is suitably present in an amount of 0.1 to 5.0% relative to the total weight of the composition of the present invention.

On the other hand, in order to prepare a microemulsion, the component (1) is a total of component (1) + component (2) + component (3) + component (4) + component (5) + component (6)] in the composition of the present invention. It is suitable to be present in an amount of 3 to 15%, preferably 4 to 12% by weight, and component (2) is 4 to 15%, preferably 4 to 11% of the total weight of the composition of the present invention. It is appropriate to exist. It is also suitable that component (3) is present at 5 to 15%, preferably 7 to 10%, based on the total weight of the composition of the present invention, and component (4) is 1.0 to the total weight of the composition of the present invention. It is suitable to be present in an amount of 5.0%, preferably 1.0 to 2%. Component (5) is suitably present in an amount of 0.1 to 5.0%, preferably 1.0 to 3%, based on the total weight of the composition of the present invention, and component (6) is 35 to the total weight of the composition of the present invention. It is suitable to be present in an amount of ˜60%, preferably 50 to 55%.

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

First, detailed descriptions of FIG. 1 to FIG. 12 according to experiments are as follows.

1 is a polyoxyl castor oil as a surfactant, in particular polyoxyl castor oil of the brand name Cremophor EL ^® , caproylcapryl macrogolglycerides as an auxiliary surfactant acids (caprylocapryl macroglycerides), inter alia with a particular trade name La bra brush (Labrasol ^ⓡ) of caproic ilka ruffle macrogol glyceride acids (caprylocapryl macroglycerides), propylene as five days glycol laurate (propyleneglycol laurate), among others trade name LAU glycol shown in (Lauroglycol FCC ^ⓡ) of propylene glycol monolaurate (propyleneglycol laurate), as a solubilizer ethanol (ethyl alcohol) the oil content of the microemulsion region is SMEDDS as phase diagram created by using 40-70% area It was found that it forms when SMEDDS contains more than 50% of moisture.

Subsequently, the solubility measurement of ibuprofen in various oils and surfactants was conducted and the results are shown in Table 1. Ibuprofen has a very low solubility in water of 1.23 mg / ml, but 792.4 mg / ml for Cremophor EL ^® , 841.2 mg / ml for Labrasol ^® , and Lauroglycol FCC ^® The drug solubility was 470.4 mg / ml, which showed very high drug solubility compared to water, and the solubility of the SMEDDS consisting of a mixture of a surfactant, a cosurfactant, and an oil was 764.5 mg / ml, resulting in the SMEDDS of the present invention. Was found to be a solubilization system that can dramatically increase the solubility of ibuprofen, which is very poorly soluble in water.

Table 1

Solubility of Ibuprofen

^a) Each data are represented as means ± SD (n = 3)

^b) see USP 24

Figure 3 is a diagram showing the dissolution patterns in pH 7.2 buffer according to the USP ⅩⅩ IV regulations, Figures 4 to 7 is according to the various pH and media types according to the comparative dissolution test criteria of drug efficacy equivalence test management guidelines and alternative drug designations The detailed description as a result of the dissolution pattern is as follows.

Figure 2 is a ibuprofen soft capsule prepared according to Example 2 and the B tablet (200 mg / tab, hereinafter referred to as control S) of S company and commercially available I tablets (200 mg / tab, referred to as control D) The figure shows comparative dissolution test result in pH 7.2 buffer of USPV IV regulation. As shown in the figure, all formulations showed a dissolution rate of more than 80% within 1 hour.

3 is a ibuprofen soft capsule prepared according to Example 2 and the B tablet of commercially available company S (200 mg / tab, hereinafter referred to as control S) and D company I tablets (200 mg / tab, hereinafter referred to as control D) Figure shows comparative dissolution test results in pH 1.2 solution. The dissolution rate in the pH 1.2 (artificial gas solution) buffer showed a higher dissolution rate of ibuprofen soft capsules of about 2 times higher than that of Control S and about 4 times higher than that of Control D.

4 is a ibuprofen soft capsule prepared according to Example 2 and B tablets (200 mg / tab, control S) company S and 200 tablets of company D (200 mg / tab, control D) The figure shows the comparative dissolution test results in pH 4.0 solution. The dissolution rate in pH 4.0 buffer also showed that the ibuprofen soft capsule was about 2 times higher than the control S and about 4 times higher than the control D product.

FIG. 5 shows ibuprofen soft capsules prepared according to Example 2 and B tablets (200 mg / tab, hereinafter referred to as control S) of S company and commercially available I tablets (200 mg / tab, hereinafter referred to as control D) The result of comparative dissolution test in pH 6.8 solution showed similar dissolution patterns in ibuprofen soft capsule, control S and control D in pH 6.8 buffer.

FIG. 6 shows ibuprofen soft capsules prepared according to Example 2 and B tablets (200 mg / tab, hereinafter referred to as control S) of S company and commercially available I tablets (200 mg / tab, hereinafter referred to as control D) As a result of comparative dissolution test in water, the dissolution rate of control S was the highest in water, but the dissolution rate of ibuprofen soft capsule was more than 85%. According to the evaluation, it was found that the ibuprofen soft capsule and the control S of the present invention had an equivalent dissolution pattern.

7 shows the correlation between the dissolution amount of the drug (DR _2h ) and pH at 2 hours after dissolution, and it was found that the dissolution rate of ibuprofen soft capsule was more than two times higher than that of the control S and control D tablets at pH 4 or less. have. In this experiment, the dissolution rate of ibuprofen soft capsules formulated with SMEDDS was higher at low pH below pH 4 when compared to the two formulations used as a control. It was expected to represent.

It was found that the gelatin shell acted as a rate-limiting step for drug dissolution in all test media. In other words, the ibuprofen soft capsules have a lag time of about 10 to 20 minutes before elution occurs. This is because the gelatin shell absorbs moisture and swells to seal. It can be seen that the lag time of drug dissolution is determined by the time until the burst of one part. However, there was no effect on the total dissolution of the drug until 2 hours when 85% of the drug was eluted.

Based on the results of the dissolution test, the SMEDDS of the present invention can dramatically solubilize ibuprofen, a poorly soluble drug, has superior dissolution properties than commercially available control S and control D, and is very advantageous for body absorption. Was evaluated.

8 is a rat after oral administration of a water dispersion of ibuprofen SMEDDS, a 0.5% MC water suspension of ibuprofen raw powder, and a control S water suspension to evaluate the bioavailability of the ibuprofen soft capsule prepared according to Example 2. FIG. It is a result of measuring the drug blood concentration in, and the pharmacokinetic parameters obtained as a result of analyzing the concentration of drug in the blood are shown in Table 2 below. In this experiment, rats were used as experimental animals, so the final formulation could not be administered orally to rats.In the bioavailability evaluation experiment, water dispersion of soft capsule contents and water suspension of tablets were used. Reveals.

Table 2

The highest blood concentration (C _max ) and the area under the curve (AUC) were highest in the order of ibuprofen SMEDDS, control S, and raw powder. The time to reach maximum blood concentration (T _max ) was similar to ibuprofen SMEDDS and control S. The T _max of the raw powder suspension was evaluated as the latest.

As a result, C _max and AUC of ibuprofen SMEDDS were higher than control S, which is because ibuprofen soft capsules eluted rapidly in the stomach, thus increasing the likelihood of drug absorption compared to control S.

9 is a sample taken every 10, 20, 30, 60, 120, 240, 360, 480, 720 minutes after oral administration of ibuprofen 40mg / kg and injection of ibuprofen microemulsion to the carotid artery in an amount of 8mg / kg HPLC Table 3 shows the pharmacokinetic parameters of ibuprofen and oral soft capsules when the experimental results were applied to the non-compartment model. In the case of injections, the plasma drug concentration curve was biphasic. The half-life (T _1/2 ) in the final phase was 181.93 minutes, and the AUC and MRT were 2155.88 µg · min / ml and 118.74 minutes, respectively. On the other hand, the bioavailability (F) when administered orally was found to be an excellent formulation showing a bioavailability corresponding to about 85% of the injection when calculated by the following equation.

Table 3

Hereinafter, the production examples of the soft-calcel agent and the injectable microemulsion are described.

[Production of Ibuprofen SMEDDS]

(weight%)

Manufacturing method

Place the ibuprofen in Lauroglycol FCC ^ⓡ was fully wetted, into the Cremophor EL ^ⓡ, or Cremophor ELP ^ⓡ thereby put the Labrasol ^ⓡ and PVP was dissolved by stirring at 30 ℃ ~40 ℃. After complete dissolution, Ethanol or Transcutol ^ⓡ was added, filtered with a 1.0 μm filter, and filled into a gelatin shell to prepare ibuprofen soft capsule.

Meanwhile, the soft capsule shell prescription used the most commonly used prescription. The contents of the prescription are as follows.

[Preparation of Ibuprofen Microemulsion]

(weight%)

Manufacturing method

Place the ibuprofen in Lauroglycol FCC ^ⓡ was fully wetted, into the Cremophor EL ^ⓡ, Cremophor ELP ^ⓡ is dissolved by stirring at 30 ℃ ~40 ℃ put Labrasol ^ⓡ and PVP. After complete dissolution the input or Ethanol and Transcutol ^ⓡ to prepare a microemulsion, and then filtered through a filter 1.0㎛ adding it to water.

The present invention relates to the preparation of novel ibuprofen soft capsules and injectable microemulsions using a self-microemulsifying drug delivery system (SMEDDS), a solubilization technique for poorly soluble drugs. Ibuprofen is a drug widely used in the treatment of pain, inflammation, such as rheumatoid arthritis, osteoarthritis, ankylosing myelitis or because it is very poorly soluble in water (1.23mg / ml dissolved in water) to improve bioavailability. There is a lot of research to increase the number of. The ibuprofen solubilization technology using the SMEDDS technique of the present invention has the advantage that the solubility can be increased by several hundred times compared to the solubility in water, and excellent dissolution characteristics by formulating ibuprofen SMEDDS prepared on the basis of such a solubilization technique into a soft capsule. Ibuprofen soft capsules could be prepared, and the developed formulations were evaluated to have high bioavailability of the drug compared to commercially available formulations as a control. In addition, since the microemulsion could be spontaneously formed when the SMEDDS was dispersed in the aqueous phase, a microemulsion for injection of ibuprofen was also prepared through the solubilization technique of the present invention.

In addition, WO 00/30619 already discloses a soft capsule of ibuprofen using a self-emulsifying system, but the patent discloses an agent that forms an emulsion when dispersed in water as a solubilizing system using two surfactants and oils. The present invention is a typical three-phase SMEDDS composition consisting of a surfactant, a cosurfactant, and an oil, which is a system capable of spontaneously forming a microemulsion when applied to an aqueous phase, so that ibuprofen can be more finely dispersed when eluted in the gastrointestinal tract. While ibuprofen, the main component of the WO patent, forms a eutectic mixture with the bases of the soft capsule solution, it is possible to formulate a transparent soft capsule, whereas the present invention forms a homogeneous and transparent mixed solution with or without ibuprofen. By various It can be said to be an advanced formulation that can be applied to drugs. In addition, while the WO patent uses 7-15% of castor oil to show an appropriate viscosity when filling a soft capsule, the present composition has an advantage of having a viscosity suitable for filling in the capsule by itself. . In addition, polyvinylpyrrolidone is used to increase the physical stability of the soft capsule solution, but in the present invention, a small amount of polyvinylpyrrolidone having a molecular weight of 50,000-1,000,000 used as a thickener is used. It is characterized by the fact that it can increase the physical stability.

In conclusion, it is believed that the contents of the present invention are mostly composed of novel compositions different from the above patents, and have advanced in terms of formulation.

Claims (4)

As a pharmaceutical composition for formulating ibuprofen into a soft capsule using a solubilization technique using a self-emulsifying drug delivery system (SMEDDS) or by dispersing it in an aqueous phase to form an emulsion or a microemulsion to be formulated as an injection. (1) surfactants, (2) auxiliary surfactants, (3) oil, (4) dispersants to enhance the physical stability of the drug, (5) contain a solubilizer to increase the solubility of the drug, or in addition thereto (6) A pharmaceutical composition containing water as a dispersion medium of the mixed composition of (1) to (5). The method of claim 1, (1) using a polyoxyl castor oil (polyoxyl castor oil) acids, in particular the trade name Klee Morpher (Cremophor EL or Cremophor ELP ^{ⓡ ⓡ)} of polyoxyl 35 castor oil (polyoxyl 35 castor oil) as a surface active agent, (2) the use of propylene glycol (propylene glycol), propylene glycol monolaurate (propylene glycol laurate) as a derivative, in particular, trade name glycol monolaurate (Lauroglycol FCC ^ⓡ or Lauroglycol 90 ^ⓡ) flow with the aid surfactant, (3) Caprylocaproyl macrogolglycerides, in particular, medium chain triglyceride (Labrasol ^ⓡ ) is used as the oil, (4) PVP (polyvinylpyrrolidone), especially PVP K30 or PVP K90 having a molecular weight of 50,000 or more is used as a dispersant, (5) Ethyl alcohol or transcutol as dissolution aid^Ⓡ) Pharmaceutical compositions containing (6) A pharmaceutical composition containing water as an aqueous phase to prepare the composition obtained in (5) as a microemulsion. The method according to claim 1 or 2, (1) Component (1) is 10-30% with respect to the total weight of [component (1) + component (2) + component (3) + component (4) + component (5)] of the composition of this invention, Preferably Preferably in an amount of 20-30%, (2) Component (2) is 10 to 30% of the total weight of [component (1) + component (2) + component (3) + component (4) + component (5)] of the composition of the present invention, preferably Is present in 15-30%, (3) Component (3) is 10-25% with respect to the total weight of [component (1) + component (2) + component (3) + component (4) + component (5)] of the composition of this invention, Preferably Preferably 20 to 25%, (4) Component (4) is present at 1.0 to 5.0% relative to the total weight of [Component (1) + Component (2) + Component (3) + Component (4) + Component (5)) of the composition of the present invention. , (5) Component (5) is present at 0.1 to 5.0% relative to the total weight of [Component (1) + Component (2) + Component (3) + Component (4) + Component (5)) of the composition of the present invention. Ibuprofen soft capsule formulation. The method according to claim 1 or 2, (1) Component (1) is 3 to the total weight of [component (1) + component (2) + component (3) + component (4) + component (5) + component (6)]] of the composition of the present invention. -15%, preferably in an amount of 4-12%, (2) Component (2) is 4 to the total weight of [component (1) + component (2) + component (3) + component (4) + component (5) + component (6)]] of the composition of the present invention. Present in an amount of ˜15%, preferably 4-11%, (3) Component (3) is based on the total weight of [Component (1) + Component (2) + Component (3) + Component (4) + Component (5) + Component (6))] of the composition of the present invention. -15%, preferably in an amount of 7-10%, (4) Component (4) is 1.0 based on the total weight of [Component (1) + Component (2) + Component (3) + Component (4) + Component (5) + Component (6))] of the composition of the present invention. Present in an amount of ˜5.0%, preferably 1.0-2%, (5) Component (5) is 0.1 based on the total weight of [Component (1) + Component (2) + Component (3) + Component (4) + Component (5) + Component (6))] of the composition of the present invention. -5.0%, preferably in an amount of 1.0-3%, (6) Component (6) is based on the total weight of [Component (1) + Component (2) + Component (3) + Component (4) + Component (5) + Component (6))] of the composition of the present invention. An ibuprofen-containing injectable composition present in an amount of -60%, preferably 50-55%.