KR19980059325A - Pharmaceutical composition comprising an irreversible HIV protease inhibitor - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising an irreversible HIV protease inhibitor. More specifically, the present invention relates to a composition comprising an irreversible HIV protease inhibitor including an HIV-1 or HIV-2 protease and the like and one or more pharmaceutically acceptable organic solvents. bioavailability).

Description

[Name of invention]

A pharmaceutical composition comprising an irreversible HIV protease inhibitor.

Detailed description of the invention

[Purpose of invention]

The present invention relates to pharmaceutical compositions comprising an irreversible HIV protease inhibitor. More specifically, the present invention relates to a composition comprising an irreversible HIV protease inhibitor including an HIV-1 or HIV-2 protease and the like and one or more pharmaceutically acceptable organic solvents. bioavailability).

[Technical Field to which the Invention belongs and Prior Art in the Field]

In order to measure the potential usefulness of oral administration formulations in the development of new drugs, bioavailability can be observed after oral administration of the formulations. The factors affecting bioavailability are solubility in aqueous solution of the drug and gastrointestinal tract. Absorption, dose, and first pass effect through.

Solubility in aqueous solution is one of the most important of these, and when the solubility is low, a suitable salt or other derivative or an appropriate amount of a dissolution aid may be used as a way to improve the solubility.

In addition, if the bioavailability is low because the first pass effect is very large, a method of maximizing bioavailability should be selected by minimizing the first pass effect of the drug in the small intestine and liver. The first pass effect is an enzyme metabolic effect, the metabolic effect of the enzyme is dependent on the concentration of the drug to be absorbed, the higher the concentration of the drug to be absorbed, the lower the metabolic rate. In other words, by selecting a fast-acting formulation and increasing the concentration of the drug to be absorbed, the metabolic rate is lowered and as a result, the bioavailability can be maximized.

Treatments for AIDS (Acquired Immune Deficiency Syndrome) include nucleotide derivatives and non-nucleotide derivatives that inhibit reverse transcriptase, HIV protease inhibitors, TAT protein inhibitors, and other HIV neutralizing antibodies and glycoprotein formation inhibitors. In the early stages, reverse transcriptase inhibitors were actively studied, but as toxicity and resistance problems became serious, recently, a lot of interest and research are being conducted to suppress the proliferation of viruses using protease inhibitors.

Since the virus has a very simple gene structure and produces only a few proteins that are essential for survival, there are only a few proteins that can be targeted in the development of antiviral agents, of which proteases are widely used in the development of antiviral agents. The reason for this is that since the protein of the virus is mostly transcribed into polyprotein and then matured by the protease, the protease is essential for survival in the virus.

In addition, the protease of the virus has a different characteristic from the protease in the host, and because it has a specific structure to recognize, excellent specificity and selectivity, and also acts in the early stages of viral replication can be a good target for antiviral development.

Therefore, researches on protease have been conducted for the development of antiviral agents. Recently, virus inhibitors using protease inhibitors have been developed as pharmaceuticals. For example, protease inhibitors developed to inhibit the proliferation of HIV (Human Immunodeficiency virus), a virus that causes AIDS, have prominent antiviral effects, and the recently developed HIV-1 protease inhibitors (saquinavir: roche). , Ritonavir: Evote, Indinavir: Merck) show very strong inhibitory and specificity even at low concentrations.

However, protease inhibitors must have both strong antiviral activity and good oral bioavailability in order to be used as AIDS therapeutics. There are many difficulties in finding such protease inhibitors. In order to treat chronic diseases such as AIDS, the drug must be administered for a long time and good oral bioavailability can be expected in the body. However, most protease inhibitors are a combination of hydrophobic peptides, solubility is so low that it is difficult to maintain the proper concentration at the absorption site, and the metabolism by the enzyme is so large that the first-pass effect is very high in the absorption process of the drug. There is this.

Accordingly, the present inventors have found a composition containing a pharmaceutically acceptable organic solvent that maximizes the solubility at the absorption site of the protease inhibitor, maximizes the absorption rate, and minimizes the metabolism by enzymes in the small intestine and liver after absorption. The present invention has been completed.

[Technical problem to be achieved]

It is an object of the present invention to provide a pharmaceutical composition containing an irreversible HIV protease inhibitor and composed of a pharmaceutically acceptable organic solvent.

Specifically, the present invention relates to a solvent selected from (1) (a) propylene glycol, one polyethylene glycol, and a mixture of two or more polyethylene glycols, or (b) polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene ( 20) a solvent selected from sorbitan monooleate, polyoxyethyleneglycerol triricinoleate, polyethylene glycol 40 hydrated castor oil, fractionated palm oil, 2- (2-ethoxyethoxy) ethanol and polyethylene polypropylene glycol, or (c) Mixtures thereof and (2) organic solvents composed of ethanol or propylene glycol are used.

HIV protease inhibitors contained in the pharmaceutical composition of the present invention include compounds having the structure of Formula 1 below.

Wherein R ₁ is functionalized lower alkyl (C ₁ -C ₆ ), functionalized lower alkoxy (C ₁ -C ₆ ), functionalized lower alkyl amine (C ₁ -C ₆ ), lower substituted by aromatic Alkoxy, lower alkoxy substituted by cyclic alkyl, aromatic with one or two rings, or aromatic with one or two rings containing one or two nitrogen atoms. Lower alkyl herein means straight or branched chain alkyl of one to six carbon atoms and cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

R ₂ and R ₃ are each independently lower alkyl (C _{1 to} C ₆ ), aromatic, lower alkyl substituted with aromatic or lower acyl substituted with aromatic.

R ₄ is lower alkyl (C ₁ ~C _6), lower alkyl (C ₁ ~C _6), a lower alkylsulfonyl-substituted lower alkyl (C ₁ ~C _6), or a lower alkylsulfinyl group, an amino-substituted ( RS-) is substituted lower alkyl (C ₁ -C ₆ ).

The compound of Formula 1 contained in the pharmaceutical composition of the present invention is preferably a compound having the structure of Formula 2.

The compound of Formula 1 contained in the pharmaceutical composition of the present invention is preferably a compound having the structure of Formula 3 below.

Pharmaceutically acceptable organic solvents included in the pharmaceutical compositions of the present invention include (1) propylene glycol or polyoxyethylene (20) sorbitan monolaurate or mixtures of two or more polyethylene glycols or mixtures thereof and (2) ethanol It is preferably a mixture of.

The pharmaceutical composition of the present invention may comprise water from 0 w / w% to 50 w / w% of the total weight of the composition.

The pharmaceutical composition of the present invention may include at least one or more of pharmaceutically acceptable oils, sweeteners, fragrances, surfactants and antioxidants in addition to pharmaceutically acceptable organic solvents.

The pharmaceutical composition of the present invention is a propylene glycol wherein the HIV protease inhibitor contains from 0.3 w / w% to 20 w / w% of the total weight of the composition, and (1) from 10 w / w% to 90 w / w% of the total weight of the composition Or polyoxyethylene (20) sorbitan monolaurate which is 1 w / w% to 35 w / w% of the total weight of the composition or two or more polyethylene glycols that are 50 w / w% to 10 w / w% of the total weight of the composition The mixture or mixture thereof and (2) a pharmaceutically acceptable organic solvent mixed with a composition of ethanol which is 5 w / w% to 50 w / w% of the total weight of the composition.

[Configuration and Function of Invention]

The present invention relates to pharmaceutical compositions comprising an irreversible HIV protease inhibitor. More specifically, the present invention relates to a composition comprising an irreversible HIV protease inhibitor including HIV-1 and HIV-2 proteases and the like, and at least one pharmaceutically acceptable organic solvent. Can be improved.

The irreversible HIV protease inhibitor contained in the pharmaceutical composition of the present invention is represented by the following Chemical Formula 1.

[Formula 1]

Wherein R ₁ is functionalized lower alkyl (C ₁ -C ₆ ), functionalized lower alkoxy (C ₁ -C ₆ ), functionalized lower alkyl amine (C ₁ -C ₆ ), lower substituted by aromatic Alkoxy, lower alkoxy substituted by cyclic alkyl, aromatic with one or two rings, or aromatic with one or two rings containing one or two nitrogen atoms. Lower alkyl herein means straight or branched chain alkyl of one to six carbon atoms and cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

R ₂ and R ₃ are each independently lower alkyl (C _{1 to} C ₆ ), aromatic, lower alkyl substituted with aromatic or lower acyl substituted with aromatic.

R ₄ is lower alkyl (C ₁ ~C _6), lower alkyl (C ₁ ~C _6), a lower alkylsulfonyl-substituted lower alkyl (C ₁ ~C _6), or a lower alkylsulfinyl group, an amino-substituted ( RS-) is substituted lower alkyl (C ₁ -C ₆ ).

Preferably, R ₁ is isopropyl oxy, cyclopropyl oxy, ethyl oxy, isobutyl oxy, t-butyl oxy, 2-quinolinyl, thiophenyl or furanyl and the like, and R ₂ and R ₃ are each independently iso Propyl, isobutyl, benzyl, phenyl, ethyl, benzoyl and the like, R ₄ is methyl substituted with an amino group, (1-methyl-1-methylsulfonyl) ethyl or (1-methyl-1-methylsulfinyl) ethyl .

Of the compounds of formula 1, compounds of formula 2 and compounds of formula 3 are particularly effective for HIV-1 and HIV-2 proteases.

[Formula 2]

[Formula 3]

The compounds of Formulas 1 to 3 are nonionic and have very high metabolism by enzymes in the small intestine and liver during absorption. In particular, the drug of Formula 3 has a very low solubility of 50 µg / kg in an aqueous solution and is nonionic, so it is not possible to increase the solubility by adding an acid or a base. It was confirmed that the drug of Formula 3 was hardly absorbed when orally administered to dogs as a solid capsule formulation without any change in formulation (see Comparative Example 1 and Comparative Example 2).

Therefore, in order to maximize the rate of absorption by maximizing the solubility at the absorption site of these drugs, and to minimize the metabolism by enzymes in the small intestine and liver after absorption, drugs containing a pharmaceutically acceptable organic solvent together with the drug Pharmaceutical compositions are required.

Pharmaceutical compositions containing the HIV protease inhibitors of the present invention include the following pharmaceutically acceptable organic solvents.

(1) (i) a solvent selected from propylene glycol, one polyethylene glycol and two or more mixtures of polyethylene glycol or (b) polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monool Eight, polyoxyethyleneglycerol triricinoleate, polyethylene glycol 40 hydrated castor oil, fractionated palm oil, solvent selected from 2- (2-ethoxyethoxy) ethanol and polyethylene polypropylene glycol or (c) mixtures thereof and (2 Ethanol or propylene glycol Preferably the present invention comprises (1) propylene glycol or a mixture of polyethylene glycol 400 and polyethylene glycol 4000 (semi-solid) comprising HIV protease inhibitors (especially compounds of formula 3) Medicament, consisting of polyoxyethylene (20) sorbitan monolaurate or mixtures thereof and (2) ethanol That is acceptable by an organic solvent formulation.

The pharmaceutically acceptable organic solvent in the above is propylene glycol, polypropylene glycol, polyethylene glycol (e.g. polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 900, polyethylene glycol 540, polyethylene glycol 1000, polyethylene glycol 1450, polyethylene glycol 1540, polyethylene glycol 2000, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 4600 or polyethylene glycol 8000); Pharmaceutically acceptable alcohols such as ethanol or 2- (2-ethoxyethoxy) ethanol (Transcutol, Gattefossc, Westwood, N.J.07675) and the like; Polyoxyethylene castor oil derivatives [e.g. polyoxyethyleneglycerol tririsinoleate or polyoxyl 35 castor oil (Cremophor EL, BASF Corp.) or polyoxyethyleneglycerol oxystearate (polyethyleneglycol 40 hydrated caster oil (CremophorRH 40, BASF Corp.) or polyethyleneglycol 60 hydrated caster oil (CremophorRH 60, BASF Corp.)); Fractionated palm oil [e.g. triglycerides with mixed caprylic and capric acid (Myglyol812, Huls AG, Witten, Germany), etc.] Polyoxyethylene (20) Solbitan monolaurate, Polyoxyethylene (20) Solbitan monooleate Isopropyl palmitate, isopropyl myristate; Pharmaceutically accredited silicone fluids, etc.

In addition, the pharmaceutical composition of the present invention may include at least one or more pharmaceutically acceptable surfactants, oils, sweeteners, fragrances, antioxidants for chemical stability, and the like.

Pharmaceutically acceptable surfactants include pharmaceutically acceptable nonionic surfactants (polyethylene polypropylene glycol (e.g. Poloxamer127 (BASF Wyandotte Corp.)) or monovalent fatty acid esters of polyoxyethylene (20) sorbitan ( Examples: polyoxyethylene (20) sorbitan monooleate (Tween80), polyoxyethylene (20) sorbitan monostearate (Tween60), polyoxyethylene (20) sorbitan monopalmitate (Tween40), polyoxyethylene (20) sorbitan monolaurate (Tween20)), and the like, and a pharmaceutically acceptable anionic surfactant (eg, sodium lauryl sulfate, etc.).

Pharmaceutically acceptable oils are mineral or vegetable oils (e.g., saber oil, peanut oil, olive oil, fractionated palm oil [e.g. triglycerides mixed with caprylic and capric acid (Myglyol812, Huls AG, Witten, Germany) Or the like, or pharmaceutically acceptable fatty acids (eg, oleic acid, palmitic acid, etc.).

Pharmaceutically acceptable sweeteners may include fructose, aspartame, sorbitol or saccharin sodium, and the like.

Pharmaceutically acceptable fragrances include cherry, artificial banana, caramel, chocolate mint, grape, wild cherry, raspberry, strawberry, citrus, orange, pineapple, citrus lime, citrus Cream flavor, cherry vanilla flavor or cream de menthe flavor may be included.

Antioxidants for chemical stability can include ascorbic acid, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene), vitamin E, vitamin E PEG 1000 succinate and the like.

The composition of the present invention comprises an HIV protease inhibitor (preferably a compound of formula 3) comprising 0.3 w / w% to 20 w / w% of the total weight of the composition, preferably 1 w / w% to 10 w / of the total weight of the composition. It contains the pharmaceutically acceptable organic solvent contained in w% and mixed in the composition as follows.

(1) one solvent of (a) propylene glycol, one polyethylene glycol, and two or more mixtures of polyethylene glycol is contained at 10 w / w% to 90 w / w% of the total weight of the composition or (b) polyoxy Ethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, polyoxyethyleneglycerol triricinoleate, polyethylene glycol 40 hydrated castor oil, fractionated palm oil, 2- (2-ethoxyethoxy One solvent of ethanol and polyethylene polypropylene glycol contained from 1 w / w% to 35 w / w% of the total weight of the composition or (c) mixtures thereof and (2) ethanol or propylene glycol of the total weight of the composition. When contained at 5 w / w% to 50 w / w%, the composition of the present invention is a mixture of pharmaceutically acceptable organic solvents (including ethanol) from 50 w / w% to 95 w / w% of the total weight of the composition. Contained, preferably from 70 w / w% to 95 w / w% It is contained.

Meanwhile, in order for the composition according to the present invention to be a suitable oral dosage form, the bioavailability should be at least 20 w / w% to 40 w / w% or more, preferably 50 w / w% or more.

Although some drugs have good solubility in organic solvents, the bioavailability of oral administration may not be good. However, the HIV protease inhibitor, a compound of Formula 1, has solubility in pharmaceutically acceptable organic solvents in the present invention. great. When an organic solvent formulation was administered to a dog by appropriate combination of these organic solvents, it was confirmed that oral bioavailability was shown from 26 w / w% to 94 w / w% (see Examples 1 to 11).

Hereinafter, the present invention will be described in more detail by the following Comparative Examples and Examples. However, the following Comparative Examples and Examples are merely illustrative of the present invention, the scope of the present invention is not limited by the Comparative Examples and Examples.

Comparative Example 1

After filling the gelatin capsule with the compound of Formula 3, the dog was orally administered to the dog at 15 mg / kg, and the bioavailability was determined (see Reference Experiment 1 for Measuring Oral Bioavailability).

Comparative Example 2

After filling the compound of Formula 3 with gelatin capsules and orally administering 15 mg / kg to the fasted dog, the bioavailability was determined (see Reference Experiment 1 for Measuring Oral Bioavailability).

Comparative Example 3

After dissolving the compound of Formula 3, polyvinylpyrrolidone and lecithin in chloroform in a ratio of 1: 1, the powder was prepared by spray drying, filled into gelatin capsules and orally administered to dogs at 15 mg / kg. Utilization was determined (see Reference Example 1 Measurement of Oral Bioavailability).

Comparative Example 4

After dissolving the compound of Formula 3, Poloxamer127 and hydroxypropyl-beta-cyclodextrin in water at a ratio of 4: 1: 4, the powder was prepared by lyophilization and filled into gelatin capsules, and then administered orally at 15 mg / kg in dogs. The bioavailability was then determined (see Reference Example 1 Measurement of Oral Bioavailability).

Example 1

The compound of formula 3 was dissolved in a solvent mixed with propylene glycol and ethanol 9: 1 to make 0.3 w / w% and orally administered at 15 mg / kg in dogs. Measurement experiment 2).

Example 2

The compound of formula 3 was dissolved in water containing 6 w / w% sodium lauryl sulfate and dissolved at 1 w / w%, and then orally administered at 15 mg / kg in dogs to obtain bioavailability (Reference Example of Oral Bioavailability). Measurement experiment 2).

Example 3

Sodium lauryl sulfate was dissolved in a solvent mixed with propylene glycol and ethanol 1: 1 to 2.5 w / w%, and the compound of Formula 3 was dissolved to 20 w / w%, and then filled into gelatin capsules. Bioavailability was determined after oral administration at 15 mg / kg (see Reference Example 1 Measurement of Oral Bioavailability).

Example 4

Dissolve Poloxamer127 in a solvent mixed with propylene glycol and ethanol 1: 1 to make 5 w / w%, dissolve the compound of Formula 3 to 20 w / w%, and fill it in gelatin capsules Bioavailability was determined after oral administration at / kg (see Reference Example 1 Measurement of Oral Bioavailability).

Example 5

The compound of formula 3 was dissolved in oleic acid to make 50 w / w%, and then mixed with 10: 6 w / w% Poloxamer ^and 127 in 4: 6 water to make an emulsion. Bioavailability was determined after oral administration in kg (see Reference Example 1 Measurement of Oral Bioavailability).

Example 6

The compound of formula 3 was dissolved in oleic acid in which 6 w / w% Poloxamer127 was dissolved to make 20 w / w%, and then filled into gelatin capsules and orally administered to dogs at 15 mg / kg. Oral bioavailability measurement experiment 1).

Example 7

After dissolving the compound of Formula 3 in a solvent in which propylene glycol, ethanol, and Tween20 were mixed at 90: 5: 5 to 20 w / w%, the gel was filled in gelatin capsules and orally administered at 15 mg / kg in dogs. (Reference Example 1 Measurement of Oral Bioavailability).

Example 8

After dissolving the compound of Formula 3 in a solvent in which propylene glycol, ethanol and Tween20 were mixed at 85: 10: 5 to 15 w / w%, the gel was filled in gelatin capsules and orally administered to dogs at 15 mg / kg for bioavailability. (Reference Example 1 Measurement of Oral Bioavailability).

Example 9

The compound of formula 3 was dissolved in a solvent mixed with oleic acid and ethanol at a ratio of 10: 1 to 9 w / w%, filled in gelatin capsules, orally administered to dogs at 15 mg / kg, and then bioavailable. Example Oral Bioavailability Measurement Experiment 1).

Example 10

The compound of formula 3 was dissolved in a solvent in which polyethylene glycol 400, polyethylene glycol 4000, ethanol and Tween20 were mixed at 35: 15: 15: 30 to make 10 w / w%, and then filled into gelatin capsules at 15 mg / kg. Bioavailability was determined after oral administration (see Reference Example 1 Measurement of Oral Bioavailability).

Example 11

The compound of formula 3 was dissolved in water dissolved in 50 w / w% hydroxypropyl-beta-cyclodextrin to make 0.75 w / w%, and then orally administered to dogs at 15 mg / kg. Oral bioavailability measurement experiment 2).

Reference Example Measurement Experiment of Oral Bioavailability

Experiment 1 (Capsule Administration)

Prior to dosing, the beagle dog (7-14 kg) was fasted for 16-20 hours, but water was allowed at will. The compound was orally administered to each subject at 15 mg / kg, and then about 10 ml of water was added thereto. After administering the drug to the subject, 200 μl of blood was collected at 0, 10, 20, 40, 60, 90, 120, 240, 300, 360, 480, 600 and 720 minutes, and the plasma was separated by centrifugation. Frozen and stored at a temperature of -20 ℃ until analysis. 150 μl of methanol and 50 μl of 10% ZnSO ₄ solution were added to 100 μl of plasma samples, followed by protein removal, followed by centrifugation of the supernatant, followed by reverse phase high performance liquid chromatography with ultraviolet absorber to quantify the compound. The area under the concentration curve (hereinafter referred to as 'AUC') of the compound was determined by the trapezoidal method (Leon Shargel et al., Applied Biopharmaceutics and Pharmacokinetics, 2ed (1985), p6-8), and the absolute bioavailability was administered intravenously. The AUC obtained after oral administration and the AUC obtained after oral administration were compared. Experiments were conducted in groups of six dogs, with the figures expressed as the mean of each group. The average bioavailability for each of the compositions of Comparative Examples and Examples is shown in Table 1 below.

2. Experiment 2 (Liquid Administration)

Prior to dosing, the beagle dog (7-14 kg) was fasted for 16-20 hours, but water was allowed at will. The compound was orally administered to each subject at 15 mg / kg, and then about 10 ml of air was added thereto. After administering the drug to the subject, 200 μl of blood was collected at 0, 10, 20, 40, 60, 90, 120, 240, 300, 360, 480, 600 and 720 minutes, and the plasma was separated by centrifugation. Frozen and stored at a temperature of -20 ℃ until analysis. 150 μl of methanol and 50 μl of 10% ZnSO ₄ solution were added to 100 μl of plasma samples, followed by protein removal, followed by centrifugation of the supernatant, followed by reverse phase high performance liquid chromatography with ultraviolet absorber to quantify the compound. The area under the concentration curve (hereinafter referred to as 'AUC') of the compound was determined by the trapezoidal method (Leon Shargel et al., Applied Biopharmaceutics and Pharmacokinetics, 2ed (1985), p6-8), and the absolute bioavailability was administered intravenously. The AUC obtained after oral administration and the AUC obtained after oral administration were compared. Experiments were conducted in groups of six dogs, with the figures expressed as the mean of each group. The average bioavailability for each of the compositions of Comparative Examples and Examples is shown in Table 1 below.

Example Bioavailability (%) Comparative Example 1 0 Comparative Example 2 0 Comparative Example 3 5 Comparative Example 4 2 Example 1 35 Example 2 35 Example 3 94 Example 4 57 Example 5 26 Example 6 56 Example 7 56 Example 8 30 Example 9 57 Example 10 50 Example 11 33

As can be seen from the above results, the solution formulation (Examples 1 to 11) did not change the formulation at all (Comparative Examples 1 and 2) or when the dissolution rate was increased as a solid formulation (Comparative Examples 3 and It can be seen that bioavailability is significantly superior to Comparative Example 4).

[Effects of the Invention]

The present invention relates to a pharmaceutical composition comprising an irreversible HIV protease inhibitor, oral administration of the pharmaceutical composition of the present invention may affect the solubility of the drug, the absorption of the drug through the gastrointestinal tract, and the first-pass effect, thereby improving the bioavailability of the drug. Can be.

In other words, the pharmaceutical composition of the present invention is a non-ionic, very high metabolism by enzymes in the small intestine and liver during the absorption process by dissolving the HIV protease inhibitor in a mixture of pharmaceutically acceptable organic solvent in the absorption site Maximize the solubility to maximize the rate of absorption, and after absorption to minimize the metabolism by enzymes in the small intestine and liver, eventually bringing the effect of increasing the bioavailability of the drug.

Claims (8)

A pharmaceutical composition containing an irreversible HIV protease inhibitor and consisting of the following pharmaceutically acceptable organic solvents. (1) (i) a solvent selected from propylene glycol, one polyethylene glycol and two or more mixtures of polyethylene glycol or (b) polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monool Or selected from polyoxyethyleneglycerol triricinoleate, polyethyleneglycol 40 hydrated castor oil, fractionated palm oil, 2- (2-ethoxyethoxy) ethanol and polyethylene polypropylene glycol, or (c) mixtures thereof and (2 A) ethanol or propylene glycol The pharmaceutical composition of claim 1, wherein the HIV protease inhibitor is a compound having the structure of Formula 1. [Formula 1] Wherein R ₁ is functionalized lower alkyl (C ₁ -C ₆ ), functionalized lower alkoxy (C ₁ -C ₆ ), functionalized lower alkyl amine (C ₁ -C ₆ ), lower substituted by aromatic Alkoxy, lower alkoxy substituted by cyclic alkyl, aromatic with one or two rings, or aromatic with one or two rings containing one or two nitrogen atoms. Lower alkyl herein means straight or branched chain alkyl of one to six carbon atoms and cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. R ₂ and R ₃ are each independently lower alkyl (C _{1 to} C ₆ ), aromatic, lower alkyl substituted with aromatic or lower acyl substituted with aromatic. R ₄ is lower alkyl (C ₁ ~C _6), lower alkyl (C ₁ ~C _6), a lower alkylsulfonyl-substituted lower alkyl (C ₁ ~C _6), or a lower alkylsulfinyl group, an amino-substituted ( RS-) is substituted lower alkyl (C ₁ -C ₆ ). Preferably, R ₁ is isopropyl oxy, cyclopropyl oxy, ethyl oxy, isobutyl oxy, t-butyl oxy, 2-quinolinyl, thiophenyl or furanyl and the like, and R ₂ and R ₃ are each independently iso Propyl, isobutyl, benzyl, phenyl, ethyl, benzoyl and the like, R ₄ is methyl substituted with an amino group, (1-methyl-1-methylsulfonyl) ethyl or (1-methyl-1-methylsulfinyl) ethyl . The pharmaceutical composition according to claim 2, wherein the HIV protease inhibitor is a compound having the structure of Formula 2. [Formula 2] The pharmaceutical composition according to claim 2, wherein the HIV protease inhibitor is a compound having the structure of Formula 3 below. [Formula 3] The pharmaceutically acceptable organic solvent of claim 1 is (1) propylene glycol or polyoxyethylene (20) sorbitan monolaurate or a mixture of two or more polyethylene glycols or mixtures thereof and (2) ethanol Pharmaceutical composition, characterized in that. The pharmaceutical composition of claim 1, further comprising water at 0 to 50 w / w% of the total weight of the composition. The pharmaceutical composition of claim 1, further comprising at least one of a pharmaceutically acceptable oil, a sweetener, a fragrance, a surfactant, and an antioxidant in addition to the pharmaceutically acceptable organic solvent. The method according to claim 1, wherein the HIV protease inhibitor is contained from 0.3 w / w% to 20 w / w% of the total weight of the composition, characterized in that it comprises a pharmaceutically acceptable organic solvent mixed in the composition as follows Pharmaceutical compositions. (1) propylene glycol at 10 w / w% to 90 w / w% of the total weight of the composition or polyoxyethylene at 35 w / w% to 1 w / w% of the total weight of the composition (20) sorbitan monolaurate or Two or more polyethyleneglycol mixtures or mixtures thereof which are 10 w / w% to 50 w / w% of the total weight of the composition and (2) ethanol which is 50 w / w% to 5 w / w% of the total weight of the composition.