KR19990080453A - Pharmaceutical Compositions Containing Irreversible HIV Protease Inhibitors - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating an AIDS containing an irreversible HIV protease inhibitor, specifically, the composition of the present invention contains an irreversible HIV protease inhibitor, saturated polyglycolide glycerides, a surfactant and / or ethanol, They can be mixed and prepared in a semi-solid state, and then filled into capsules, which can be used as a useful AIDS therapeutic for oral administration, which improves avoidance of taking due to bioavailability and bitter taste.

Description

Pharmaceutical Compositions Containing Irreversible HIB Protease Inhibitors

The present invention relates to pharmaceutical compositions for treating AIDS containing an irreversible HIV protease inhibitor.

More specifically, the compositions of the present invention contain irreversible HIV protease inhibitors, saturated polyglycolide glycerides, surfactants and / or ethanol, which are mixed and prepared in a semi-solid state and then filled into capsules for bioavailability. It can be used as a treatment for AIDS, which is useful for oral administration, which improves the avoidance of taking due to bioavailability and bitter taste.

In the case of general oral preparations, the bioavailability of the drug should be considered to ensure its effectiveness and safety. That is, the drug in the form of the formulation must be absorbed from the digestive tract as designed and there should be no difference in absorbency between each formulation and the lot. In order to measure the potential usefulness of oral administration formulations in the development of new drugs, the bioavailability can be observed after direct oral administration of the formulation. The factors affecting bioavailability are solubility in aqueous solution and gastrointestinal tract. Absorption, dose and first-pass effect of the drug. Solubility in aqueous solution is one of the most important factors, and if the solubility is low, a suitable salt or other derivative or an appropriate amount of a dissolving aid may be used as a way to improve the solubility.

Treatments for acquired immunodeficiency syndrome (AIDS) include nucleotide derivatives that inhibit reverse transcriptase, non-nucleotide family, HIV protease inhibitors, TAT protein inhibitors, and other anti-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, much interest and research are being conducted to suppress HIV protease, which is essential for viral infection, as an effective means of inhibiting the growth of the virus.

However, there are many difficulties in finding an inhibitor having both strong antiviral activity and excellent oral bioavailability, which are essential conditions for a useful AIDS therapeutic agent among HIV protease inhibitors. In other words, long-term administration of drugs is required for the treatment of chronic diseases such as AIDS, and the long-term administration of these drugs requires good oral and bioavailability. It is characterized by low utilization rate. One reason is that protease inhibitors are a combination of hydrophobic peptides and have very low solubility, making it difficult to maintain an appropriate concentration at the site of absorption.

After all, the design of an effective oral dosage form is of great importance for the successful development of a drug containing the protease excipient, the physicochemical properties of the drug, the drug efficacy or expected dosage of the drug, the ease and cost of the preparation process, the stability of the preparation, Considering commercial value, the appropriate method is chosen.

Accordingly, the present inventors have discovered and applied for an oral dosage composition in which a protease inhibitor has excellent solubility in pharmaceutically acceptable organic solvents and maximized solubility by appropriate combination thereof (Korean Patent Application No. 96-78663). ).

However, these drugs have a strong bitter taste, so it is difficult to take the solution as it is, and propylene glycol, which is a component in the solution formulation, has a disadvantage in that when the gelatin capsules are filled with water, the capsules are easily taken away and broken.

Accordingly, the present inventors are continuing research to develop a composition containing an irreversible HIV protease inhibitor having semi-solid physical properties that can be filled in a safe form such as a capsule, and a semi-solid in a composition consisting of an irreversible HIV protease inhibitor and a surfactant. When the mixture is mixed with a saturated polyglycolide glyceride in the state, the composition is prepared in a semi-solid state, and filling the capsule with a capsule improves the dissolution rate and maintains the concentration in plasma during oral administration for a long time. The invention has been completed.

It is an object of the present invention to provide a pharmaceutical composition containing an irreversible HIV protease inhibitor and useful for oral administration which improves the avoidance of taking due to bioavailability and bitter taste.

Figure 1 shows the dissolution test results of the semi-solid preparations containing the HIV protease inhibitor of Formula 2 and the HIV protease inhibitor of Formula 3,

― ◆ ―: Inhibitor: Gelucire 35/10: Tween 20: Ethanol (5: 65: 20: 10);

— ■ ―: Inhibitor: gelusir 44/14: cremopoa RH 40 (5:75:20);

― ▲ ―: Inhibitor: gelusir 44/14: cremopoa RH 40 (10:75:15);

- × -: inhibitor;

Figure 2 shows the plasma concentrations after oral administration of a semi-solid formulation or solution formulation containing the HIV protease inhibitor of Formula 3 to the dog (Beagle dog) 15 mg / kg, respectively.

― ◆ ―: Semi-solid preparation of gelusir 44/14: ethanol: twin 20: inhibitor (65: 10: 20: 5);

― ■ ―: Solution preparation containing propylene glycol: ethanol: twin 20 (85: 10: 5) and inhibitor 100 mg / ml;

In order to achieve the above object, the present invention provides a pharmaceutical composition containing an HIV protease inhibitor, saturated polyglycolide glyceride, surfactant, ethanol.

Hereinafter, the present invention will be described in detail.

The present invention provides pharmaceutical compositions containing HIV protease inhibitors, saturated polyglycolide glycerides, surfactants, ethanol.

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

In Chemical Formula 1,

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 alkoxy substituted by aromatic, A lower alkoxy substituted by cyclic alkyl, an aromatic of one or two rings, or an aromatic of one or two rings containing one or two nitrogen atoms, wherein the lower alkyl is carbon By straight or branched chain alkyl of one to six atoms, cyclic alkyls include cyclopropyl, cyclobutyl cyclopentyl and cyclohexyl.

R ₂ and R ₃ are each independently selected from lower alkyl (C ₁ -C ₆ ), aromatic, lower alkyl substituted with aromatic or lower acyl substituted with aromatic, and R ₄ is lower alkyl (C ₁ -C ₆ ) , Lower alkyl substituted with an amino group (C _{1 to} C ₆ ), lower alkyl substituted with lower alkylsulfonyl (C _{1 to} C ₆ ) or lower alkyl substituted with lower alkyl sulfido (RS-) (C ₁ to C ₆ ); 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, etc. to be.

The compound of Formula 1 contained in the pharmaceutical composition of the present invention includes 5 (S)-[N- (isopropyloxy) carbonyl- (β-methanesulfonyl) valinyl] amino having a structure of Formula 2 -6-phenyl- (4 (R), 3 (S) -epoxy) hexanoyl-[(S)-(isopropyl)-(benzyl) methyl] amide compound or 5 (S) having a structure of formula -[N-isopropyloxy] carbonyl- (β-methanesulfonyl) valinyl] amino-6-phenyl- (4 (R), 3 (S) -epoxy) hexanoyl-[(S)-(iso Propyl)-(benzoyl) methyl] amide compound.

The compounds of Formulas 1 to 3 are nonionic, have low solubility, and are metabolized in large amounts by enzymes during the absorption process. In particular, the compound of Formula 3 has a very low solubility of about 50 µg / ml in an aqueous solution and is nonionic, so it is not possible to increase the solubility by adding an acid or a base. Therefore, it is hardly absorbed when administered orally as a solid capsule without any change in formulation.

In addition, the compounds of Chemical Formulas 1 to 3 have low solubility in aqueous solutions or oils, but are excellent in solubility in pharmaceutically acceptable organic solvents, so that solutions prepared by appropriate combination thereof may be prepared and used. It's so strong that it's hard to take the solution as it is.

Thus, in the present invention, the organic solvent is replaced with a saturated polyglycolide glyceride in a pharmaceutically acceptable semi-solid state. At this time, the saturated polyglycolide glycerides include at least one selected from Gelucire 35/10, Gelusir 44/14 and Gelusir 50/13.

The gelusir is a saturated polyglycolide glyceride composed of PEG-mono, PEG-di fatty acid esters, and its melting point and HLB value vary depending on the composition. 14: melting point 44 ° C., HLB 14; gelusir 35/10: melting point 35 ° C., HLB 10)

Surfactants of the pharmaceutical composition of the present invention include natural surfactants such as lecithin, glycerophospholipid, spinophospholipid, sucrose aliphatic ester, bile salts; Sorbitan aliphatic acid esters such as sorbitan monolaurate, sorbitan monooleate, and sorbitan monostearate; Polyoxyethylene sorbitan aliphatic esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate; Polyoxyethylene castor oil derivatives; Polyoxyethylene glycerol oxystearate; And poloxamers.

Preferably polyoxyethylene 20 sorbitan monolaurate (Tween 20, etc.), polyoxyethylene 20 sorbitan monooleate (Tween 80, etc.), polyoxyl 40 hydrated castor oil (Cremophore RH40, BASF, etc.), poly One or more selected from oxyl 35 castor oil (Cremophor EL, BASF, etc.) and polyoxyl 60 hydrated castor oil (Cremophor RH60, etc., BASF).

The pharmaceutical composition of the present invention may be added to vitamin E, vitamin E PEG 1000 succinate, butyrated hydroxyanisol (BHA), butyrated hydroxytoluene, in addition to the above for the chemical stability of the formulation. One or more antioxidants such as BHT).

Specifically, the pharmaceutical composition of the present invention comprises 1 w / w% to 20 w / w% of HIV protease inhibitor, 10 w / w% to 95 w / w% of saturated polyglycolide glyceride, 1 w / w% to 30 It is characterized by containing w / w% surfactant and 0w / w%-15w / w% ethanol.

The present invention also provides a capsule obtained by heating and blending the pharmaceutical composition having the composition to a semi-solid state and then filling into a soft or hard gelatin capsule.

Specifically, in the present invention, a capsule is prepared by dissolving saturated polyglycolide glyceride, ethanol, a surfactant, and a drug together at 70 ° C., and then pouring a solution in a gelatin capsule to cool the capsule, or excluding saturated ethanol. Drugs are added to the deglycerides, surfactants or mixtures thereof to physically homogeneously blend so that the drugs are simply dispersed in a carrier and filled into capsules. In the former capsule, the drug is present in an amorphous form, whereas in the latter case, the drug is in a crystalline state.

In order to investigate the bioavailability of the pharmaceutical composition of the present invention, the elution test in water and the plasma concentration maintained by oral administration to dogs were measured. As a result, the dissolution rate and the concentration of the capsules filled with the semi-solid composition of the present invention was higher than the composition containing only the drug in the dissolution test (see Fig. 1). In addition, the capsule formulation of the present invention lasted longer in plasma compared to the solution formulation upon oral administration in dogs (see FIG. 2).

The present invention will be described in more detail with reference to the following examples.

However, the following examples are merely to illustrate the invention, but the present invention is not limited thereto.

<Example 1>

HIV Protease Inhibitor Compound of Formula 3, Gelusir 44/14 (Gattefosse) and Cremophor RH40 were mixed at a weight ratio of 5:75:20 and heated in a 70 ° C. oven for about 5 minutes until the Gelusir was dissolved. After addition, the mixture was homogenized using a homogenizer (homogenizer ULTRA-TURRAX T25, IKA Labortechnik) and then filled into gelatin capsules.

<Example 2>

HIV Protease Inhibitor Compound of Formula 3, Gelusir 44/14 and Cremophor RH40 were mixed at a weight ratio of 10:75:15, heated in a 70 ° C. oven for 5 minutes until the Gelusir dissolved, and then homo The mixture was homogenized using a homogenizer (homogenizer ULTRA-TURRAX T25, IKA Labortechnik) and then filled into gelatin capsules.

<Example 3>

HIV Protease Inhibitor Compound of Formula 3, Gelusir 35/10, Tween 20, and ethanol were mixed at a weight ratio of 5: 65: 20: 10 and heated to 70 ° C. in an oven until a clear solution was obtained. The solution was filled into gelatin capsules and hardened.

<Example 4>

To a solvent mixed with propylene glycol, ethanol, and Tween 20 at a weight ratio of 85: 5: 10, an HIV protease inhibitor compound of Formula 3 was added to a concentration of 100 mg / ml, and then sonicated at 50 ° C to obtain a clear solution. And then filled into capsules.

<Test Example 1> Dissolution test

In 10 ml of distilled water, (1) 10 mg of the HIV protease inhibitor compound of formula 3, (2) 100 mg of the formulation obtained in Example 1 (containing 5 mg drug), (3) 100 mg of the formulation obtained in Example 2 (containing 10 mg drug), (4) Each of 100 mg (containing 5 mg of drug) obtained in Example 3 was added thereto, followed by a dissolution test at 37 ° C. and 100 rpm in a Lab-Line Microprocessor water bath shaker.

0.4 ml each at 10, 20, 40, 80, 140, 220, and 1200 minutes was filtered through a 0.22 μm filtration membrane, and the concentration in the aqueous solution was measured by reverse phase high performance liquid chromatography with an ultraviolet absorber. The results are shown in FIG. .

As a result, the compositions (2), (3), and (4) of the present invention made of a capsule preparation had higher dissolution rates and concentrations than the composition (1) containing only drugs in the dissolution test.

<Test Example 2> Measurement of blood concentration during oral administration using dog

Prior to administration of the composition of the present invention, the dog (beagle dog, 7-14 kg) was fasted for about 16-20 hours except for water. Each object was filled with a capsule containing a semi-solid agent obtained in Example 3 in a capsule, and a solution formulation containing 10 mg of a HIV protease inhibitor compound having the structure of Formula 3 in 10 ml of distilled water, as used in Example 4, 15 mg / 10 ml of water was further administered after oral administration of kg.

After administering the drug to the subject, 200 μl of blood was collected at 0, 10, 20, 40, 60, 90, 120, 180, 240, 300, and 360 minutes, respectively, and 20 ° C. until the plasma was separated and analyzed by centrifugation. Frozen at a temperature of.

150 μl of methanol and 50 μl of zinc sulfate (ZnSO ₄ ) solution were added to 100 μl of plasma sample, followed by protein removal treatment, followed by centrifugation of supernatant to perform reversed phase high performance liquid chromatography with ultraviolet absorber. The compound was quantified. The concentration curve in plasma is shown in FIG. 2.

As a result, the semi-solid capsule formulation of the present invention lasted longer in plasma than the solution formulation.

As described above, the pharmaceutical composition of the present invention contains semi-solid saturated polyglycolide glycerides and surfactants, and has semi-solid physical properties. It has been improved to avoid, and to maximize the bioavailability by improving the dissolution rate and concentration, such as problems of oral administration formulations can be useful as a pharmaceutical composition for AIDS therapeutics that require long-term administration.

Claims (5)

A pharmaceutical composition comprising an HIV protease inhibitor of Formula 1, saturated polyglycolide glyceride, surfactant, ethanol. Formula 1 In Formula 1, R ₁ is substituted functionalized lower alkyl (C ₁ -C ₆ ), functionalized lower alkoxy (C ₁ -C ₆ ), functionalized lower alkyl amine (C ₁ -C ₆ ), aromatic Lower alkoxy substituted, lower alkoxy substituted by cyclic alkyl, aromatic having one or two rings, or aromatic having 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 pharmaceutical composition of claim 1, wherein the saturated polyglycolide glyceride is selected from at least one of Gelucire 35/10, Gelusir 44/14, and Gelusir 50/13. The method of claim 1, wherein the surfactant is a natural surfactant such as lecithin, glycerophospholipid, spinophospholipid, sucrose aliphatic ester, bile salts; Sorbitan fatty acid esters of sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate; Polyoxyethylene sorbitan aliphatic esters of polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate; Polyoxyethylene castor oil derivatives; Polyoxyethylene glycerol oxystearate; Pharmaceutical composition, characterized in that at least one selected from the group consisting of poloxamer. The method according to claim 1, wherein 1 w / w% to 20 w / w% HIV protease inhibitor, 10 w / w% to 95 w / w% saturated polyglycolide glyceride, 1 w / w% to 30 w / w A pharmaceutical composition comprising% surfactant, 0 w / w% to 15 w / w% ethanol. A capsule obtained by heating and admixing the pharmaceutical composition of claim 1 or 4 and then filling into a soft or hard gelatin capsule.