JPH0616556A - Formulation containing poorly soluble drug - Google Patents

Abstract

(57) [Summary] [Structure] A sparingly soluble drug-containing suspension obtained by dispersing and suspending a solid dispersion comprising a sparingly soluble drug, a water-soluble polymer and a hydrogel forming agent in water, a method for producing the suspension, and the suspension. Lyophilized product containing poorly soluble drug obtained from liquid. [Effects] The suspension containing a poorly soluble drug of the present invention has a drug concentration of 1 mg / ml or more, and drug particles of 0.1 μm
Since it is an ultrafine particle of ˜1 μm, it can be used as an injection that can be administered intravenously. It is also useful as an oral preparation having improved dissolution and bioavailability.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an ultrafine particle suspension containing an extremely sparingly soluble compound and a method for producing the same. The suspension is useful as an injection and as an oral composition with improved absorption.

[0002]

2. Description of the Related Art Benzothiepino [5,4-c] pyridazine derivatives represented by the following general formula (I) are known to be useful as selective anxiolytic agents with few side effects. (Japanese Patent Laid-Open No. 1-203838
3 gazette). Further, an oral pharmaceutical composition containing the compound and having an improved dissolution property is also known (JP-A-3-212).
No. 0). At present, a liquid preparation (injection) that can be intravenously administered is desired for acute anxiety. The compound represented by the general formula (I) was poorly soluble in various pH solutions including water, and was also poorly soluble in an organic solvent alone and / or a mixed solvent of 2 and / or 3 kinds. . Although it was soluble in polyethylene glycol 400, the solvent itself could not be used because it exhibits a pharmacological action. Therefore, it is necessary to improve the poor solubility of the compound by adding a harmless additive which itself does not exhibit a specific pharmacological action. As a method for improving the solubility of poorly soluble drugs, a method of pulverizing, a method of mixing and pulverizing,
The formation of a solid dispersion, the method of forming a soluble complex, etc. are generally known. Solubility of 0.004 by these methods
It was up to 0.2 mg / ml, which was more than 4 times the solubility of the original drug, but the particle size was too large to be suitable for injections, and the concentration or pharmacology that could be used as injections. Concentration that meets the purpose of the test (1 mg /
It has a problem that it does not reach the above (ml or more).

[0003]

[Means for Solving the Problems] The inventors of the present invention have conducted diligent research to develop an injection of general formula (I).
The present invention has been completed by finding a method for producing a suspension that is particularly suitable for intravenous administration and does not interfere with pharmacological evaluation. That is, the present invention relates to a sparingly soluble drug-containing suspension that can be used as an injection that can be administered intravenously and / or an oral preparation with improved dissolution and absorption, and a method for producing the suspension.

More specifically, the present invention provides (1) a suspension of a sparingly soluble drug, which is obtained by dispersing and suspending a solid dispersion comprising a sparingly soluble drug, a water-soluble polymer and a hydrogel-forming agent in water. ) Dissolving a poorly soluble drug in an organic solvent, distilling off the solvent of the dispersion containing the water-soluble polymer and hydrogel-forming agent little by little, and dispersing and suspending the resulting solid dispersion in water, followed by centrifugation. And a lyophilized product containing a sparingly soluble drug obtained from the suspension according to (1) above. .

As the sparingly soluble drug applicable to the present suspension, a general formula having an anxiolytic action is given.

[0006]

[Chemical 2]

(Wherein R ¹ and R ² are the same or different and are hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 alkanoyl. Amino, R ³ is hydrogen,
C _1-8 alkyl, hydroxy-C _1-4 alkyl, C _2-5
Alkanoyloxy-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl or halogen on aromatic ring, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 A bond having 1 to 3 substituents selected from alkoxy and C _2-5 alkanoylamino, aryl-C _1-4 alkyl or heteroaryl, n is 0, 1 or 2 and is a bond represented by a solid line and a dotted line. Represents a single bond or a double bond. ), But not limited thereto, other sparingly soluble drugs can also be applied.

Specific examples of the compound of the general formula (I) include:
The following compounds and their optical isomers are exemplified. 2-
(4-Chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-3 (2H)-
On 7,7-dioxide, 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,5
4-c] pyridazin-3 (2H) -one, 10-chloro-2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothieno [5,4-c] pyridazine-3
(2H) -one 7-oxide, 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7-oxide, 2- (4 -Chlorophenyl) -4,4a, 5
6-Tetrahydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7-oxide, 2
-(4-chlorophenyl) -10-fluoro-5,6-
Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one, 2- (4-chlorophenyl)
-10-Fluoro-5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one
7-oxide, 2- (4-bromophenyl) -5,6-
Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7-oxide, 2- (4-bromophenyl) -4,4a, 5,6-tetrahydro-
[1] Benzothieno [5,4-c] pyridazine-3
(2H) -one 7-oxide, 10-fluoro-2-
(4-Fluorophenyl) -5,6-dihydro- [1]
Benzothieno [5,4-c] pyridazine-3 (2H)
-One, 8-chloro-2- (4-chlorophenyl)-
5,6-Dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7-oxide, 1
0-fluoro-2- (4-fluorophenyl) -5,6
-Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7-oxide

In the above (1) and (2), the water-soluble polymer is one or more selected from hydroxypropylmethylcellulose, hydroxymethylcellulose or methylcellulose, and the hydrogel-forming agent is sodium starch glycolate and / or Alternatively, carboxymethyl starch is used. Hydroxypropylmethyl cellulose is preferred as the water-soluble polymer, and sodium starch glycolate is preferred as the hydrogel-forming agent. The organic solvent used is preferably one having a low boiling point that dissolves a poorly soluble drug and can be easily distilled off, and examples thereof include methanol, ethanol, acetone and dichloromethane.

The suspension of the present invention and the method for producing the same are
(B) Additives that act as protective colloids that prevent droplets or particles from aggregating or becoming agglomerates when the organic solvent is distilled off, and that also suppress the sedimentation of particles in water (water-soluble). Polymer) and (b) an additive that forms a gel in cold water and swells and precipitates (hydrogel forming agent), and a poorly soluble drug and an additive that belongs to both groups (a) and (b) are selected. It is characterized in that the fine particles are prepared and separated and concentrated efficiently by adding and dispersing and / or suspending them in water at a high concentration. This feature was completed by obtaining the knowledge of the following (1) to (5).

(1) As a poorly soluble drug, hydroxypropylmethyl cellulose, hydroxymethyl cellulose and / or
Alternatively, when a method in which a water-soluble polymer such as methyl cellulose is added and the solvent is distilled off, the amount of ultrafine particles of the poorly soluble drug is improved as compared with other fine grinding methods. (2) By adopting a method of distilling off the solvent while supplying as little solvent as possible at the time of the preparation described in the item (1), compared with the method of concentrating from a large amount of solvent, ultrafine particles of 1 μm or less The amount produced is dramatically increased. (3) By combining the sparingly soluble drug with the compound described in (1) and the compound capable of forming an aqueous gel, the suspension can be collected in the upper layer as a suspension concentrated to a high concentration without aggregating the ultrafine particles. (4) In the "concentration / separation using gel" described in the item (3), the particle size of the fine particles depends on the combination of the viscosity and / or concentration of the water-soluble polymer to be used and the centrifugation conditions.
The particle size distribution and / or the concentration can be adjusted. (5) In the "concentration / separation using gel" described in the item (3), in order to obtain a fine particle suspension having a high concentration, it is easily dispersed in cold water and swollen to a volume of 300 times, Sodium starch glycolate or carboxymethyl starch, which have the property of settling, are effective.

The suspension of the present invention is prepared by dissolving 1 part by weight of a poorly soluble drug in an organic solvent, adding 3-4 parts by weight of a water-soluble polymer and 4-9 parts by weight of a hydrogel-forming agent, and stirring the mixture with a magnetic stirrer. Was uniformly dispersed, and the solvent was distilled off while supplying the dispersion little by little to obtain a powder. The obtained powder was dispersed and suspended in water, and shaken with a shaker for 2 to 4 hours. After that, it can be obtained by centrifuging (3000 rpm × 5 minutes to 10 minutes) and collecting the upper layer. The hydrogel forming agent may be added in the process of dispersing / suspending the powder in water without adding it to the organic solvent. In this way, a highly soluble suspension containing a poorly soluble drug is obtained, which has a drug concentration of 1 mg / ml or more and an ultrafine particle having a drug particle size of 1 μm or less, preferably 0.1 μm to 1 μm. . Further, the suspension can be made into a freeze-dried product by a conventional method.

The suspension of the present invention may be used as an injection for intravenous administration of a sparingly soluble compound such as the anxiolytic drug represented by the general formula (I) by dissolving the suspension as it is or by dissolving the freeze-dried product before use. Can be used. It is also useful as an oral preparation with improved dissolution and bioavailability.
Further, formulation additives such as molding aids and lubricants can be added directly to the suspension, and tablets (including sugar-coated tablets and film-coated tablets), powders (granules, fine granules and films to them) can be added. Coated products are also included), capsules and the like for use as a medicine. The content of the compound in the pharmaceutical composition of the present invention is preferably 10 to 50% by weight.

[0014]

The present invention will be described in detail below with reference to reference examples and examples, but these do not limit the present invention. The extremely sparingly soluble compound used was 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,5].
4-c] pyridazin-3 (2H) -one 7,7-dioxide (referred to as compound A). The solubility of Compound A in water is 0.001 mg / ml.

Reference Example 1

(1) Complex formation method Compound A 1 part Various cyclodextrins 1 part Compound A 1g is mixed with various cyclodextrins (α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclodextrin, hydroxypropyl). -Β-cyclodextrin) in a molar ratio of 1:
The mixture was added so that the amount became 1, and an appropriate amount of water was added, and the mixture was kneaded in an automatic mortar and then dried in a hot air dryer (60 ° C.) for 2 hours.
The residue was ground in a mortar and passed through a 60 mesh sieve.

(2) Mixing and Grinding Method Compound A 1 part Carboxymethyl starch 1 part or 9 parts Compound A and carboxymethyl starch were mixed, and about 10 g thereof was mixed and ground for 2 hours using an automatic mortar. Compound A 1 part Starch phosphate 9 parts Compound A and starch phosphate were mixed, and about 10 g thereof was mixed and ground for 2 hours using an automatic mortar. Compound A 1 part Starch glycolate sodium 9 parts Compound A and starch glycolate sodium are mixed,
About 10 g thereof was mixed and ground for 2 hours using an automatic mortar.

(3) Solid Dispersion Method Compound A 1 part Water-soluble polymer 4 parts Compound A 1 g was dissolved in acetone 1000 ml, and then polyvinylpyrrolidone k25 or hydroxypropylmethyl cellulose 4 g was added. Polyvinylpyrrolidone k2
Since 5 solidified in the acetone solution, it was dissolved by adding 100 ml of methylene chloride. The solvent was distilled off under reduced pressure in a water bath (70 ° C.), and the obtained powder was crushed in a mortar and sieved with a 60 mesh sieve.

The powder obtained in the above (1), (2) and (3) was weighed in an amount equivalent to 10 mg in terms of compound A, 10 ml of water was added, and the mixture was shaken for 4 hours, and then measured by a two-wavelength difference absorptiometry. Then, the solubility of Compound A in water was determined and is shown in Table 1. Both formulations had 4 compared to the solubility of the drug alone.
Although a more than doubled improvement was observed, it did not reach the concentration required for the pharmacological test (1 mg / ml or more).

[0020]

[Table 1] Table 1 Solubility of preparations prepared by various solubilization methods in water ───────────────────────────────── ──── Preparation method Additive mixture ratio ¹⁾ Solubility (mg / ml) ───────────────────────────────── ──── Complex formation method α-CyD ²⁾ 1/1 0.004 〃 β-CyD 1/1 0.004 〃 γ-CyD 1/1 0.004 〃 Dimethyl-β-CyD 1/1 0. 004 Hydroxypropyl-β-CyD 1/1 0.006 Mixing and grinding method Carboxymethyl starch 1/1 0.007 〃 Carboxymethyl starch 1/9 0.2 〃 Starch starch 1/9 0.05 〃 Glycolic acid starch Sodium 1/9 0.2 Solid dispersion method Polyvinylpyrrolidone 1/4 0.004 〃 Hydroxypropyl methylcellulose 1/4 0.070 ───────────────────────────────────── 1) Mixing ratio The composition ratio of the drug and the additive is shown, and the molar ratio is shown in the case of the complex formation method, and the weight ratio is shown in the case of the mixing and pulverizing method and the solid dispersion method. 2) Cyclodextrin is abbreviated as CyD.

Example 1

Compound A 1 part Hydroxypropyl methylcellulose 3 parts Starch glycolate sodium 6 parts After dissolving 1 g of Compound A in 1000 ml of acetone, 3 g of hydroxypropylmethylcellulose and 6 g of sodium starch glycolate are added, and the solvent is distilled off under the following conditions:
A method of concentrating and distilling 250 ml of a solvent four times and (a) a method of distilling while supplying a small amount were compared. The upper layer suspension concentration obtained by the method (a) was 1.8 mg / ml, whereas it was 14 mg / ml by the method (a), and the amount of the fine particles produced was the same as when the solvent was distilled off. It turned out that Next, the centrifugation conditions are set to 200
The comparison was made under the conditions of 0 rpm × 5 minutes and 3000 rpm × 5 minutes. The particle size distribution of the upper layer suspension after centrifuging the preparations obtained by the above methods (a) and (b) under the conditions of 2000 rpm × 5 minutes and 3000 rpm × 5 minutes is shown in FIG.
It was shown to. In the figure, the broken line and the solid line indicate the centrifugation conditions of 2000 rpm × 5 minutes and 3000 rpm, respectively.
The particle size distribution when it is set to x 5 minutes is shown. Even if the preparation obtained under the condition (a) is 10 mg if the centrifugation condition is relaxed.
Although an upper layer suspension concentration of about / ml was obtained, many particles of 1 μm or more were present, and when this suspension was intravenously administered to a rat, the animal died immediately. When the formulations (a) and (a) were centrifuged under the conditions of 3000 rpm × 5 minutes, the average particle size was 0.4 μm, and most of the particles were distributed at 1 μm or less. This fact has revealed that it is essential to collect ultrafine particles under the condition of 3000 rpm × 5 minutes or more in order to obtain a suspension that can be injected intravenously.

[0023]

[Figure 1]

Example 2

Compound A 1 part Hydroxypropyl methylcellulose 1-5 parts Sodium starch glycolate 8-4 parts The weight ratio of compound A is fixed to 1 part, and the weight ratio of hydroxypropylmethylcellulose is 1, 1.5, 2, 3 It was changed to 4 or 5 parts. 2-10 mg / in terms of compound A
After suspending in water at a concentration of ml for 2 hours and then centrifuging (3
000 rpm × 5 minutes). Regarding the concentration of Compound A in the upper layer suspension, a certain amount of liquid was sampled, acetonitrile was added, ultrasonic irradiation was carried out to dissolve Compound A, and the concentration of Compound A was calculated by the two-wavelength difference absorptiometry. At this time, the concentration of the upper layer suspension was measured and the results are shown in FIG. In the figure,-○-
○-,-△-△-,-□-□-,-●-●-and-▲
-▲-are the above-mentioned formulations in terms of Compound A, 2, 4,
The upper suspension concentration obtained when suspended in water at a concentration of 6, 8 and 10 mg / ml is shown. When the concentration when suspended in water was increased, the concentration of the upper layer suspension obtained was proportionally increased. When the weight ratio of hydroxypropylmethylcellulose was 3 to 4 parts, the concentration of the upper layer suspension was the highest, and conversely, it decreased at 5 parts. This fact indicates that in order to efficiently separate and concentrate ultrafine particles, the mutual quantitative ratio of hydroxypropylmethylcellulose that suppresses the precipitation of fine particles and sodium starch glycolate that controls the volume of the upper concentration layer by swelling and sedimentation Indicates that is important.

[0026]

[Fig. 2]

Example 3

Composition 1 Compound A 1 part Polyvinylpyrrolidone 3 parts Starch glycolate sodium 6 parts After dissolving 1 g of Compound A in 900 ml of acetone, 3 g of polyvinylpyrrolidone k25 was added and methylene chloride 100
After adding and dissolving ml, the sodium starch glycolate is suspended, while stirring with a magnetic stirrer to keep the dispersion state, while supplying a small amount of the solvent under heating (60 ° C.) and reduced pressure conditions, The solvent was distilled off.

Composition 2 Compound A 1 part Hydroxypropyl methylcellulose 3 parts Light anhydrous silicic acid 6 parts After dissolving 1 g of Compound A in 1000 ml of acetone, 3 g of hydroxypropylmethylcellulose and light anhydrous silicic acid 6
g was added and the solvent was distilled off in the same manner as in Composition 1.

Composition 3 1 part of compound A Hydroxypropylmethylcellulose 3 parts 1 g of compound A was dissolved in 1000 ml of acetone, 3 g of hydroxypropylmethylcellulose was added, and the solvent was distilled off in the same manner as in composition 1.

Composition 4 Compound A 1 part Hydroxypropyl methylcellulose 3 parts Sodium starch glycolate 6 parts At the stage of suspending the powder obtained in the composition 3 in water, sodium starch glycolate was added and suspended.

For compositions 1 to 4, 10 in terms of compound A
It was suspended in water at a concentration of mg / ml, shaken for 2 hours, and then centrifuged (3000 rpm × 5 minutes). The concentration of Compound A in the upper layer suspension was measured by a two-wavelength difference absorption spectrophotometry after adding a fixed amount of liquid, adding acetonitrile and irradiating with ultrasonic waves to dissolve Compound A, and then calculating the Compound A concentration. did. In addition, the upper layer suspension was transferred to a graduated cylinder, and the amount of the liquid was measured. The results are shown in Table 2.

[0033]

[Table 2] Table 2 Concentration and yield of upper layer suspension of the preparation of Example 3 ─────────────────────────────── ───── Composition number Concentration Liquid amount Obtained amount (mg / ml) ¹⁾ (ml) ²⁾ (mg) ³⁾ ──────────────────── ─────────────── Composition 1 0.69 1.25 0.9 Composition 2 0.55 7.50 4.1 Composition 3 4.5 9.50 42.8 Composition 4 15.1 1.75 26.4 ─────────────────────────────────── 1) Concentration is upper layer The concentration of Compound A in the suspension is shown. 2) The liquid volume ratio indicates the volume of the suspension that could be collected in the upper layer when 10 ml of water was added. 3) The amount obtained was calculated by the right formula (amount = concentration × liquid amount). In this case, since the charged amount is 100 mg, the yield value and the yield (%) are the same value.

The method of dissolving a drug together with a water-soluble polymer and distilling off the solvent is a method for preparing a solid dispersion reported as a method for solubilizing a poorly soluble drug, and the drug is generally amorphized. . However, from the powder X-ray diffraction results of the preparation, a peak derived from Compound A was clearly observed, and Compound A was not in an amorphous state but was dispersed in the polymer as fine crystals. There was found. It was also found that the solid dispersion preparation method is more effective in producing ultrafine particles than the mixed pulverization method. The amount of ultrafine particles to be obtained varies depending on the type of water-soluble polymer used, and it was shown that hydroxypropylmethylcellulose is effective for efficiently producing ultrafine particles. From the yields of composition 3 and composition 4, it was shown that the ultrafine particles dispersed in hydroxypropylmethylcellulose were efficiently separated and concentrated. When light anhydrous silicic acid, which is a gel-forming compound, is used in place of sodium starch glycolate (composition 2), the effect of the present invention cannot be obtained.

Experimental Example 1

According to the method of composition 3 of Example 3, compound A
An upper layer suspension obtained by preparing a preparation at a composition ratio of hydroxypropylmethyl cellulose / sodium starch glycolate (1: 3: 6), and suspending the preparation in water at a concentration of 10 mg / ml in terms of compound A. Was intravenously injected into mice and rats, and as a result, it was shown that a central action was exhibited at a dose of 1 mg / kg, and the drug was effectively absorbed after the administration. Separately, an upper layer liquid prepared with a composition of hydroxypropylmethylcellulose / sodium starch glycolate (1: 2) was administered, and it was confirmed that the coexisting additives did not show a pharmacological action and were harmless.

[0037]

INDUSTRIAL APPLICABILITY As described in the present specification, particularly in the Reference Examples and Examples section, benzothiepino [5,4-c] pyridazine (including a racemic mixture or optical isomers in the case of having an asymmetric atom) Further, when it contains at least two asymmetric atoms, it also includes individual diastereomers or a mixture thereof) and extremely poorly soluble drugs and various water-soluble polymers (preferably hydroxypropylmethylcellulose), Aqueous gel-forming agents (preferably sodium starch glycolate) can be combined together to efficiently produce, disperse / suspend, and separate / concentrate ultrafine particles. The suspension can be used as an injection that can be administered intravenously as well as an oral preparation with improved absorption.

[Brief description of drawings]

1 shows the particle size distribution of the formulation of Example 1. FIG.

FIG. 2 is a graph showing the upper layer suspension concentration of Example 2.

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[Procedure amendment]

[Submission date] February 19, 1993

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[Submission date] February 19, 1993

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[Figure 1]

[Fig. 2]

Claims (7)

[Claims] 1. A hardly soluble drug-containing suspension obtained by dispersing and suspending a solid dispersion comprising a poorly soluble drug, a water-soluble polymer and a hydrogel forming agent in water. 2. A poorly soluble drug is represented by the general formula: (In the formula, R ¹ and R ² are the same or different and are hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-5 alkanoylamino, R ³ is hydrogen, C _1-8 alkyl, hydroxy-C _1-4 alkyl, C _2-5 alkanoyloxy-C _1-4 alkyl, aryl, aryl-C
_1-4 alkyl, heteroaryl or a substituent selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _2-5 alkanoylamino on the aromatic ring. 1-3
Each having an aryl, aryl-C _1-4 alkyl or heteroaryl, n is 0, 1 or 2, and a bond represented by a solid line and a dotted line is a single bond or a double bond. 3. The suspension according to claim 1, which is a benzothiepino [5,4-c] pyridazine derivative represented by 3. The water-soluble polymer is one or more selected from hydroxypropylmethyl cellulose, hydroxymethyl cellulose or methyl cellulose,
Suspension according to claim 1, characterized in that the hydrogel-forming agent is sodium starch glycolate and / or carboxymethyl starch. 4. The concentration of the poorly soluble drug in the suspension is 1 m.
The suspension according to claim 1, which is g / ml or more. 5. The suspension according to claim 1, wherein the poorly soluble drug in the suspension is ultrafine particles of 1 μm or less. 6. A poorly soluble drug is dissolved in an organic solvent, the solvent of a dispersion liquid to which a water-soluble polymer and a hydrogel forming agent are added is distilled off little by little, and the resulting solid dispersion is dispersed and suspended in water, Next, a method for producing a hardly soluble drug-containing suspension, which comprises centrifuging and collecting an upper layer suspension. 7. A freeze-dried product containing a poorly soluble drug obtained from the suspension of claim 1.