JPH07324032A - Preparation of anti-aids agent and anti-aids preparation - Google Patents

Abstract

PURPOSE:To provide a process for the preparation of an anti-AIDS agent easily absorbable through the digestive tracts, having improved bioavailability and suitable for oral administration and provide an anti-AIDS agent prepared by the process. CONSTITUTION:This anti-AIDS agent is produced by finely pulverizing a compound of formula (Ar is 5-isoquinolinyl or 3-pyridyl; R is methylthiomethyl or isopropyl; X is S or CH2) by a pulverizer such as a jet-mill to fine powder having particle diameter of from 0.1mum to several mum, mixing the powder with a solid acidic substance having particle diameter of 3-10mum and applying high impact, compression force or shearing force to the mixture to coat the surface of the acidic substance with the fine powder. A drug preparation having high bioavailability can be produced by using the compound of formula and the acidic substance at a weight ratio of 1:(2-5), especially 1:(2-3). The compound of formula is, e.g. N-t-butyl-3-[2-hydroxy-3-N-[2-N-(5-isoquinolyloxyacetyl)amino-3 methylthiopropanoyl]amino-4-phenylbutanoyl] pyrrolidine-4-carboxamide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an anti-AIDS drug suitable for oral administration and its preparation.

[0002]

2. Description of the Related Art The present inventors have previously found that 3-amino-2-
A specific compound containing hydroxy-4-phenylbutanoic acid in its skeletal structure is HIV (Human immunodeficiency viru).
s) It was found to be very useful as an anti-AIDS drug by extremely strongly inhibiting the activity of protease, and it was proposed as an HIV protease inhibitor (see JP-A-5-170722). Then, the above compound is suspended in a mixed solution of saline and polyethylene glycol adjusted to pH 7.2 using a phosphate buffer, and is rapidly absorbed when directly administered to the duodenum of rats. Was reported (Proceedings of the 113th Annual Meeting of the Pharmaceutical Society of Japan 30FC 15-1 (March 1993)).
However, it has been found that compounds of this kind are generally poorly soluble in water, and when orally administered, they are hardly absorbed in the digestive organs (stomach or intestine) and have low bioavailability. Therefore, when it is used as an anti-AIDS drug, especially in oral administration, a large amount of administration is required, and it is not preferable in terms of side effects or economical efficiency.

[0003]

The present invention has been made to solve the above problems. That is, an object of the present invention is to provide a method for producing an anti-AIDS drug which is easily absorbed in the digestive organs (stomach and intestine), enhances bioavailability, and is suitable for oral administration, and a preparation thereof.

[0004]

The present invention has the following general formula [I]:

[0005]

[Chemical 2]

(Wherein Ar represents a 5-isoquinolinyl group or a 3-pyridyl group, R represents a methylthiomethyl group or an isopropyl group, and X represents a sulfur atom or a methylene group). A method for producing an anti-AIDS drug, which comprises coating fine powder on the surface of a solid acidic substance, and an anti-AIDS drug containing composite particles obtained by coating fine powder of the compound on the surface of a solid acidic substance. It is a formulation.

Examples of the compound represented by the above general formula [I] include N-tert-butyl-3- [2-hydroxy-3-N-
[2-N- (5-isoquinolyloxyacetyl) amino-
3-Methylthiopropanoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, N-tert-butyl-3- [2-hydroxy-3-N-
[2-N- (5-isoquinolyloxyacetyl) amino-
3-Methylthiopropanoyl] amino-4-phenylbutanoyl] pyrrolidine-4-carboxamide, N-tert-
Butyl-3- [2-hydroxy-3-N- [2-N- (5
-Isoquinolyloxyacetyl) amino-3-methylbutanoyl] amino-4-phenylbutanoyl]-1,3
-Thiazolidine-4-carboxamide, N-tert-butyl
-3- [2-Hydroxy-3-N- [2-N- (5-isoquinolyloxyacetyl) amino-3-methylbutanoyl] amino-4-phenylbutanoyl] pyrrolidine-4
-Carboxamide, N-tert-butyl-3- [2-hydroxy-3-N- [2-N- (3-pyridyloxyacetyl) amino-3-methylpropanoyl] amino-4-phenylbutanoyl] -1 , 3-thiazolidine-4-carboxamide, N-tert-butyl-3- [2-hydroxy-
3-N- [2-N- (3-pyridyloxyacetyl) amino-3-methylthiopropanoyl] amino-4-phenylbutanoyl] pyrrolidine-4-carboxamide, N-t
ert-Butyl-3- [2-hydroxy-3-N- [2-N
-(3-Pyridyloxyacetyl) amino-3-methylbutanoyl] amino-4-phenylbutanoyl]-1,3
-Thiazolidine-4-carboxamide, N-tert-butyl
-3- [2-hydroxy-3-N- [2-N- (3-pyridyloxyacetyl) amino-3-methylbutanoyl]
Amino-4-phenylbutanoyl] pyrrolidine-4-carboxamide can be mentioned.

All of these compounds are disclosed in JP-A-5-
It is a known compound described in Japanese Patent No. 170722, which exhibits a specifically high HIV protease activity inhibition and is useful as an anti-AIDS drug. Among these, (R) -N-tert-butyl-3-[(2S, 3S) -2-
Hydroxy-3-N-[(R) -2-N- (5-isoquinolyloxyacetyl) amino-3-methylthiopropanoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide , (S) -N-tert-butyl
-3-- [(2S, 3S) -2-hydroxy-3-N-
[(S) -2-N- (5-isoquinolyloxyacetyl) amino-3-methylbutanoyl] amino-4-phenylbutanoyl] pyrrolidine-4-carboxamide, (R) -N
-tert-butyl-3-[(2S, 3S) -2-hydroxy-
3-N-[(S) -2-N- (3-Pyridyloxyacetyl) amino-3-methylbutanoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide is preferred.

As the solid acidic substance used in the present invention, organic acids such as citric acid, tartaric acid, succinic acid, maleic acid, and ascorbic acid can be used. These acidic substances are pharmacologically acceptable substances that are metabolized in vivo, and acidic organic substances that are absorbed by the digestive organs. Among these acidic organic substances, it is preferable to use, for example, an organic acid which is pharmacologically acceptable, has two or more carboxyl groups, and has a second acid dissociation constant pKa ₂ of 5 or less from the viewpoint of safety. Particularly, it is preferable to use citric acid, which is a polybasic acid having a hydroxyl group, or tartaric acid. Further, it is also possible to use an anhydride of an organic acid having two or more of the above-mentioned carboxyl groups and having a second acid dissociation constant pKa ₂ of 5 or less.

In the present invention, the surface of the solid acidic substance is coated with a fine powder of the compound represented by the general formula [I] to form composite particles (powder). For this purpose, the particle size of the solid acidic substance should be 3 to
10 μm, and the compound represented by the general formula [I]
If the particle size is smaller than this, for example, 0.1 to several μm, and these are mixed to give a high impact, or a compression force and a shearing force are applied, the composite particles (powder) can be relatively easily prepared. Can be formed. More specifically, the compound represented by the above general formula [I] is pulverized by a pulverizer such as a jet mill, and this is mixed with a solid acidic substance having a particle size of 3 to 10 μm by a hybridizer ( For example, it may be prepared by placing it in an Nara Machinery Co., Ltd.) or an Ong Mill (eg, Hosokawa Micron Co., Ltd.) and mixing and stirring.

In this case, the compound of the above-mentioned general formula [I] and the solid acidic substance are mixed in a weight ratio of 1: 2 to 1: 5, particularly 1: 2 to 1: 3. It is preferable because a preparation having high bioavailability can be obtained.

To the composite particles (powder) obtained by the above means, additives used in ordinary preparations, for example, magnesium stearate or talc as a lubricant, crystalline cellulose as a disintegrant, and a disintegration aid. It is advisable to add sodium hydrogencarbonate as a solvent or hydroxypropyl cellulose as a binder, and mix them appropriately, and to form tablets with a tableting machine or the like. The content of the compound represented by the above general formula [I] contained in a tablet to be molded is 15 tablets per tablet.
If it is 0 to 200 mg, oral administration of 3 to 4 tablets per day will suffice, and administration will be simple and preferable.

[0013]

INDUSTRIAL APPLICABILITY The production method of the present invention makes it possible to produce an anti-AIDS drug which is easily absorbed in the digestive organs (stomach and intestines), enhances bioavailability, and is suitable for oral administration. Further, by using the preparation of the present invention, the dose can be significantly reduced, and an extremely excellent anti-AIDS drug can be obtained in terms of the occurrence of side effects or the economical efficiency. That is, the oral dose required to obtain a blood concentration of the compound as an active ingredient in order to produce a desired drug effect can be significantly reduced.

[0014]

EXAMPLES The production method of the present invention will be described below with reference to specific examples. (1) Preparation of anti-AIDS drug By the following steps, fine particles of the compound were coated on the surface of a solid acidic substance to prepare composite particles.
Unless otherwise specified, the general-purpose compounds used in each of the following steps were those approved for use in Japan Pharmacopoeia Pharmaceuticals or pharmaceuticals in accordance with their standards.

Step (1-1) Preparation of Compound Fine Powder One kind of compound represented by the above general formula [I], (R)-, which has been manufactured and purified in advance according to the method described in JP-A-5-170722. N-tert-butyl-3-[(2S, 3S) -2-
Hydroxy-3-N-[(R) -2-N- (5-isoquinolyloxyacetyl) amino-3-methylthiopropanoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide [Hereafter, "Compound (1)"
Called. ] [Compound represented by the formula (II)] crystals (average particle size 0.5 mm) were crushed by a crusher jet mill TJ-60 (manufactured by Freund Sangyo Co., Ltd.) to a crushing load of about 6 kg / cm.
^It was crushed under the condition of ² (air pressure). When the particle size of the obtained compound fine powder was measured, the average particle size was 2 μm. The particle size was measured by measuring with a microscope (the same method was used in the following steps).

[0016]

[Chemical 3]

Step (1-2) Preparation of solid acidic substance powder As a solid acidic substance, anhydrous citric acid crystals were used. The citric acid anhydride used was a Japanese Pharmacopoeia drug approved for pharmaceutical use. To prepare the anhydrous citric acid with a particle size of 10 μm or less, a hybridizer-NHS
-0 (manufactured by Nara Machinery Co., Ltd.) was pulverized for 3 minutes under the condition of 13000 rpm. A powder having an average particle size of 7 μm was obtained.

Step (1-3) Preparation of composite particles 100 parts by weight of fine powder of compound (1) obtained in step (1-1) and powder of anhydrous citric acid obtained in step (1-2) The mixture was mixed with 200 parts by weight of the body, and the mixture was stirred for 3 minutes under the condition of 13,000 rotations / minute using Hybridizer-NHS-0 (manufactured by Nara Machinery Co., Ltd.). When the obtained powder was observed under a microscope, it was found that composite particles in which the fine powder of the compound (1) was coated on the surface of the anhydrous citric acid powder were obtained. When 3 parts by weight of the composite particles were added to water and the concentration of citric acid in the obtained solution was measured, it was found that 2 parts by weight of citric acid in terms of anhydrous citric acid was contained. .

Step (1-4) Molding of composite particles into granules 450 parts by weight of the composite particles coated with the compound (1) obtained in the above step (1-3) are mixed with light anhydrous water which promotes granule formation. 2.5 parts by weight of silicic acid was added and mixed, and the mixture was sieved through a 100 mesh sieve twice. The sieved particles were formed into granules by a roller compactor-HTC-Mini (manufactured by Freund Sangyo Co., Ltd.). The formed granules of the obtained composite particles are 18
The average diameter was adjusted using a mesh sieve.

(2) Preparation of anti-AIDS drug preparation Compound prepared in advance by the process described in (1) above
From the granules molded using the composite particles coated with the fine powder of (1), anti-AIDS drug preparations and anti-AIDS gastrolytic coating tablets were produced by the following steps.

Step (1-5) Preparation of uncoated tablet for anti-AIDS drug formulation The composite particles obtained in the above step (1-4) are formed into granules, and 452.5 parts by weight of the composite particles are slipped as an additive. The agents 5 parts by weight of magnesium stearate and 2.5 parts by weight of talc, 25 parts by weight of disintegrating agent crystalline cellulose, 15 parts by weight of disintegrating aid sodium hydrogencarbonate, and 25 parts by weight of binder hydroxypropyl cellulose were added and mixed. The mixture was compression-molded with a rotary tableting machine to obtain plain tablets having a diameter of 11 mm. This plain tablet has a weight of 525 mg per tablet, that is, contains about 150 mg of the compound (1) per tablet.

Step (1-6) Anti-AIDS drug formulation (gastric dissolution coating
The coating solution having the composition shown in Table 1 was sprayed on the plain tablet prepared in the step (1-5) to obtain a gastric-soluble coating tablet.
The coating amount was 3 to 3.5% by weight based on the above-mentioned plain tablet of the anti-AIDS drug preparation, 525 mg per tablet.

[0023]

Table 1 Hydroxypropyl methylcellulose 50 parts by weight Polyethylene glycol 6000 5 parts by weight Ethanol 472.5 parts by weight Methylene chloride 472.5 parts by weight

(3) Disintegration test of anti-AIDS drug preparation uncoated tablet (non-coating tablet) Anti-AIDS drug preparation uncoated tablet (non-coating tablet) prepared by the method described in (1) and (2) above. A disintegration test of [Tablet A] with distilled water was performed. As a comparative example, the step (1-3) was omitted, and 150 parts by weight of the fine powder of the compound (1) obtained in the step (1-1) and the powder of anhydrous citric acid obtained in the step (1-2) were used. A tablet prepared by granulating 100 parts by weight of the body according to step (1-4) into a non-coated tablet, that is, an uncoated tablet according to step (1-5) [tablet B]. Was prepared and a disintegration test was conducted. Table 2 shows the results of the disintegration test of [Tablet A] of the example and [Tablet B] of the comparative example. Each test was conducted 6 times, and the average value of the disintegration time was obtained. From Table 2, it can be seen that the plain tablets of the examples, that is, the tablets using the composite particles prepared in the above step (1-3), have a shorter disintegration time.

[0025]

[Table 2]

(4) Absorption kinetics of anti-AIDS drug preparation (gastric dissolving coating tablet) Anti-AIDS drug preparation (gastric dissolving coating tablet) prepared by the method described in (1) and (2) above [tablet C] was used to measure the bioavailability upon oral administration.
Further, as a comparative example, the step (1-3) is omitted and the step (1-
1) Fine powder of compound (1) obtained in 1) 150 parts by weight and process (1-
Using 300 parts by weight of the anhydrous citric acid powder obtained in 2) and granulating in accordance with step (1-4),
According to (1-5) and step (1-6), a tablet [tablet D] prepared as a gastric-dissolved coating tablet was prepared, and the bioavailability during oral administration was measured. In the bioavailability at the time of oral administration, the test anti-AIDS drug preparation was orally administered 1 hour after the feeding, and then the living body to be administered (in this example, one male beagle dog was used). A predetermined amount of blood was collected, and the concentration of compound (1) dissolved in the blood was measured and estimated. The blood concentration of the compound (1) was measured by the following method.

(A) Measurement of blood concentration of the compound in question Measurement method of blood concentration of test compound As a standard solution of an internal standard compound, the primary standard prepared by dissolving the compound (1) in methanol at a concentration of 1 mg / ml in advance. Prepare the solution. Using this primary standard solution, the concentration of the compound was
Prepare three secondary standard solutions diluted with methanol as much as 1, 10 and 100 µg / ml. Blood was collected from a living body to be administered using a blood collection tube (Benject H or Prezapack II manufactured by Terumo Co., Ltd.) in which a predetermined amount of blood was heparin-coated. Centrifuge for minutes. Separated plasma will remain -80
Store frozen at ℃.

200 μl of the obtained plasma is dispensed into a 1.5 ml centrifuge tube. The above-mentioned secondary standard solution was added to the collected plasma.
Add 10 to 20 µl, and add 390 to 380 µl of methanol to make the total volume 600 µl. The concentration as an internal standard in the 600 μl sample is calculated from the total amount of the compound contained in the added secondary standard solution. The above
A 600 μl sample is agitated with a vortex mixer for 10 seconds to homogenize it, and after cooling with ice for 10 minutes, centrifuge for 15 minutes at 4 ° C and 10,000 G. The separated supernatant was filtered through a 0.22 μm filter (Millex GV, manufactured by Millipore) and analyzed by HPLC.

As HPLC, Toso-CCP is used as the liquid delivery system.
M, AS8000 for injector, UV for detector
Shimadzu CR-7A is used for the 8010 or JASCO 820-FP and the integrator, respectively. In addition, Cosmosil C ₁₈ -AR (4.6 mm ×
250 mm, made by Nacalai Tesque) or Cosmosil C ₁₈ -MS
(4.6 mm × 250 mm, manufactured by Nacalai Tesque) and a Gu column equipped with a μBondapack C ₁₈ cartridge.
Use an ard-Pak pre-column module (Waters). For analysis, use 200 μl of the supernatant prepared by the above method as the standard injection amount.

When a test compound having high luminescence is analyzed, a method of observing the luminescence of the test compound is used for detection.
JASCO 820-FP is used as the detector, and Cosmocil C ₁₈ -MS is used as the analytical column. For the mobile phase gradient, keep the acetonitrile concentration at 30% for 3 minutes after starting the analysis (injecting the analytical sample), and set the linear gradient so that the acetonitrile concentration reaches 42% in 12 minutes. During this period, outflow (peak) of the test compound and the internal standard compound is observed. After that, increase the concentration of acetonitrile to 100% in 2 minutes, and keep the concentration of acetonitrile at 100% for 4 minutes to wash the column. For subsequent analysis of other samples, the acetonitrile concentration should be 30% in 1 minute.
Equilibrate the column for an additional 8 minutes.

On the other hand, when light absorption of the test compound is used for detection, UV8010 is used for the detector and Cosmocil C ₁₈ -AR is used for the analytical column. The mobile phase is a water-acetonitrile linear gradient, the flow rate is 1 ml / min, and the absorbance at a wavelength of 230 nm is monitored. Mobile phase gradient starts analysis (injects analytical sample)
Keep the acetonitrile concentration at 45% for the next 3 minutes and set the linear gradient to reach the acetonitrile concentration of 50% in 4 minutes. During this period, outflow (peak) of the test compound and the internal standard compound is observed. After that, keep the acetonitrile concentration at 50% for 8 minutes, then increase it to 90% in 2 minutes, and then add the acetonitrile concentration 90% for another 3 minutes.
Wash the column by keeping it at%. For subsequent analysis of other samples, reduce the acetonitrile concentration to 45% in 2 minutes and equilibrate the column for an additional 8 minutes.

The concentration of the test compound is determined based on a calibration curve for the test compound prepared in advance. When the test compound is the same as the internal standard compound, multiple levels of known concentrations to be added as the internal standard are used, and the plasma of the test compound is determined by linear regression using a plot of the measured peak intensity against the internal standard concentration. Determine the medium concentration. Also,
If necessary, it is determined based on the peak intensity (integrated intensity) shown in the measured HPLC spectrum, using the peak intensity of the internal standard compound of a known concentration simultaneously measured as an index. That is, when the test compound is different from the above internal standard compound [Compound (1)], sensitivity correction is performed using the peak intensity of the internal standard compound (known concentration).

After the oral administration of the test anti-AIDS drug preparation by the above method, the compound (1) in the blood of the living body to be administered is administered.
Was measured over time. Measured compound
(1) FIG. 1 shows an example of changes over time in plasma concentration. In addition,
The dose of the compound (1) administered was about 15 mg / kg.
Comparing the results of the anti-AIDS drug preparation of the example (stomach-coated tablet) [tablet C] and the anti-AIDS drug preparation of the comparative example [tablet D], in the tablet of the example [tablet C] It can be seen that a higher plasma concentration was obtained immediately after (15 minutes). Further, it can be seen that the plasma concentration gradually decreases 1 hour after administration, but it rapidly decreases thereafter. In addition,
The above 1 hour can be compared with the time required for the ingested food to pass through the digestive organs corresponding to the stomach and duodenum in the beagle dog, which is about 1.5 hours. On the other hand, in the tablet [Tablet D] of the comparative example, the plasma concentration gradually increases, and becomes highest at the time point 1 to 1.5 hours after administration. After that, it is found that the plasma concentration shows a gradual decrease.

From the results shown in FIG. 1, the secretion of gastric juice was promoted along with the diet, the gastric dissolution coating of tablet C was dissolved and disintegrated in the stomach immediately after administration, and was absorbed from the digestive system within 15 minutes. It can be inferred when it begins to be done. Furthermore, it can be presumed that absorption continues while passing through the gastrointestinal organs corresponding to the stomach and duodenum, and thereafter the absorption rate rapidly decreases and the plasma concentration rapidly decreases because it is metabolized or excreted in the body. On the other hand, in tablet D, the compound gradually accumulates in the blood due to the slow disintegration in the stomach and / or the slow absorption rate in the digestive organs. It can be estimated that In addition, since the amount absorbed in the initial stage is small and the concentration remaining in the stomach is relatively high, absorption continues even after 1.5 hours after administration, resulting in a decrease due to metabolism or excretion in the body. It can be estimated to make up for it. The phenomenon in which the plasma concentration of tablet D is kept relatively higher than that of tablet C 2 hours after administration can be understood from the above estimation.

(B) Bioavailability upon oral administration
-Calculation The test anti-AIDS drug preparation described above was orally administered to a living body (in this example, a male Beagle dog was used) to be administered, and the time course of the plasma concentration of the compound (1) was measured. Multiple dose levels were measured. For example, based on the results shown in FIG. 1, the time average plasma concentration was calculated for 6 hours after administration to calculate the bioavailability. Mean bioavailability was used using three independent results. The results are shown in Table 3.

[0036]

Table 3 Bioavailability at Oral Administration-Bioavailability- (Average) Tablet C (Tablet of Example) 20.42% Tablet D (Tablet of Comparative Example) 12.43%

The total blood volume of the living body to be administered was estimated from its body weight, and the above-mentioned bioavailability was estimated by assuming that the compound (1) was uniformly dispersed in the plasma concentration. did. In addition, the compound is used without using a solid acidic substance such as citric acid, for example, carbonylmethylcellulose.
In the case of tablets or suspensions using sucrose as a carrier, the plasma concentration of the compound after oral administration is less than 1/10 of that of tablet D, and there is a high degree of bioavailability. No estimation could be made. For reference, when the suspension was orally administered to rats, the bioavailability estimated from the results of three times was 0.2%.

(5) Solubility of anti-AIDS drug The following series of compounds (1) to (3) [compounds in which the compound names are specifically listed from the compounds represented by the above general formula [I]
(1) is the same as above, the compounds (2) and (3) are of the formula [III] and
[IV]], the solubility in distilled water was examined using a mixture of the powder and the powder of a solid acidic substance such as citric acid described below. Also, the solubility of the composite particles prepared according to the above steps (1-1) to (1-3) in distilled water was examined. The solubility test was carried out by fixing the concentration of the solid acidic substance in distilled water to 5 g / 100 ml, and measuring the weight m _{1 of the} compound contained in the sample and the weight m ₂ of the solid acidic substance of the solid acidic substance. The ratio m ₁ : m ₂ of
1: n (where n is a positive integer) was selected, and after the lapse of a predetermined time, a method of confirming the presence or absence of an undissolved residue of the compound was adopted.
Solubility was comprehensively judged based on the result of the solubility test for each compound, and the results shown in Table 4 were obtained. In addition, no significant difference was observed in the results of the mixture and the composite particles,
I didn't distinguish.

[0039]

[Chemical 4]

[0040]

[Chemical 5]

[0041]

[Table 4] Types of solid acidic substances to be mixed and solubility in distilled water Solid acidic substances to be mixed Solubility Citric acid +++ Tartaric acid ++++ Succinic acid + Maleic acid + Ascorbic acid + Note) +++: Ratio m ₁ : m ₂ = 1: 8 all compounds are dissolved in ++: ratio m _1: m ₂ = 1: 8 in many of the compounds are dissolved +: ratio m _1: m ₂ = 1: slight compound 8 are dissolved

Since the molecular weights of the solid acidic substances are different and the molecular weights of the test compounds represented by the general formula [I] are also different, the results in Table 4 are indices indicating the tendency of solubility. Should be considered. However, it is clearly seen that citric acid and tartaric acid have a marked effect compared to the others.

[Brief description of drawings]

FIG. 1 is a compound (1) plasma obtained by orally administering an anti-AIDS drug preparation (gastric-coated tablet) [tablet C] of the Example and a comparative anti-AIDS drug preparation [tablet D] to male Beagle dogs. The result of having measured the time course of medium concentration is shown.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 401/12 207 // C07D 417/12 207

Claims (3)

[Claims] 1. The following general formula [I]: (In the formula, Ar is 5-isoquinolinyl group or 3-pyridyl group, R is methylthiomethyl group or isopropyl group, X
Is a sulfur atom or a methylene group), and the fine powder is coated on the surface of a solid acidic substance to produce an anti-AIDS drug. 2. The method according to claim 1, wherein the solid acidic substance is at least one organic acid selected from the group consisting of citric acid, tartaric acid, succinic acid, maleic acid and ascorbic acid. 3. An anti-AIDS drug preparation comprising composite particles obtained by coating the surface of a solid acidic substance with the fine powder of the compound represented by the general formula [Formula I] according to claim 1.