JPH0449232A - Composition of suspension or suspension and preparation therefrom - Google Patents

Abstract

PURPOSE:To provide the subject composition containing a compound having an excellent immunosuppressive action, a pharmacologically acceptable surfactant and a saccharide alcohol in a specific ratio, exhibiting a sustain release effect and used for drugs, the compound being homogeneously, finely and stably contained. CONSTITUTION:The objective suspension composition or suspension contains a known compound of the formula [R<1> is (protected) OH; R<2> is H, R<1>; R<3> is CH3, C2H5, C3H7, allyl; R<4> is OH, OCH3; R<5> is H; R<4> and R<5> together form oxo; (n) is 1 or 2; a signal shown with a continuous line and a dotted line is a single bond or double bond; but when R<4> is OH and R<5> is H, or R<4> and R<5> together form the oxo, R<2> is not the protected OH] or a pharmacologically acceptable salt thereof, a pharmacologically acceptable surfactant and a pharmacologically acceptable saccharide alcohol as essential ingredients in a wt. ratio of 1:0.01-1:(1-5). The agent is applied for intramuscular injections, oral administrations, etc.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a suspension containing a compound represented by formula (I) below, which is known to have an excellent immunosuppressive effect, or a pharmaceutically acceptable salt thereof. The present invention relates to compositions or suspensions for use in suspensions, as well as methods for producing them, and in particular, they exhibit a stable suspension state in a medium such as physiological saline, glucose injection, wood, juice, etc., and therefore are suitable for intramuscular injection or injection. Suspension compositions that can be adapted for various forms of administration, including topical and oral administration, or suspensions prepared by suspending the same in a suspending medium, as well as their manufacture. It is about the method.

[Prior Art] General formula (wherein R1 is a hydroxy group or a protected hydroxy group, R2 is hydrogen, a hydroxy group or a protected hydroxy group, R3 is a methyl group, an ethyl group, a propyl group, or an allyl group, R4 is a hydroxy group or a methoxy group, R
5 is hydrogen, or R4 and R5 together are an oxo group, n
is an integer of 1 or 2, the symbol represented by a solid line and a dotted line means a single bond or a double bond, provided that R4 is a hydroxy group and R5 is hydrogen, or R4 and R5 together mean an oxo group. If you do,
R2 is not a protected hydroxy group) or a pharmaceutically acceptable salt thereof is known as a substance having an immunosuppressive effect (JP-A-61-148181, European Patent Publication No. 03)
23042), heart, liver, kidney, bone marrow, skin,
It is expected to be used in various medical fields including organ transplants of corneas, lungs, pancreas, intestines, limbs, etc.

[Problem to be solved by the invention] Compound (I) or a pharmaceutically acceptable salt thereof [hereinafter referred to as "compound (I)"] is used as a medicine as one of the forms of its use. , a suspension can be considered.

The present invention aims to provide an excellent suspension, particularly a suspension in which particles having a fine and uniform particle size are suspended in a stable dispersion state, and a suspension composition for providing the suspension. This is the purpose.

[Structure of the Invention] The suspension composition according to the present invention contains a pharmaceutically acceptable surfactant and a sugar alcohol in addition to the active ingredient consisting of the above compound (I), and the weight ratio of these is as follows: According to the order listed above, 1: (0,01~1): (
1 to 5) are the main points.

Further, the suspension according to the present invention is characterized in that the above suspension composition is suspended in a suspension medium at the above blending weight ratio.

Furthermore, the invention provided as the above-mentioned suspension composition and a method for producing a suspension includes a solution mixture comprising the above-mentioned compound (I), a solvent capable of dissolving the compound, and the above-mentioned surfactant, or The method further includes a step of forming a solution mixture by adding water, a step of precipitating and crystallizing the compound (I) in a mixture of a pharmaceutically acceptable sugar alcohol and water, and a step of freeze-drying. In summary, the lyophilized suspension composition is prepared by adding a suspending medium, if desired, to form a suspension.

[Detailed Description of the Invention] First, each definition used in general formula (I), specific examples thereof, and preferred embodiments thereof will be explained in detail below.

The term "lower" used in the explanation of the symbols used in the above general formula (I) and the explanation below means that the number of carbon atoms is 1 to 6, unless otherwise specified.

Examples of suitable protecting groups for the "protected hydroxy group" include the following.

1-(lower alkylthio) (lower) alkyl groups, such as lower alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc., more preferably C as a thing
3-c4 alkylthiomethyl groups, most preferably methylthiomethyl groups; tri(lower)alkylsilyls such as trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, e.g. methyl-diphenyl Tri-substituted silyl groups such as lower alkyl-diarylsilyl such as silyl, ethyl-diphenylsilyl, propyl-diphenylsilyl, tertiary-butyl-diphenylsilyl, more preferably tri(C+ to C4) alkylsilyl groups and 01 ~C4 alkyldiphenylsilyl groups, most preferably tertiary-butyl-dimethylsilyl and tertiary-butyl-diphenylsilyl groups; aliphatic acyl groups derived from carboxylic acids, sulfonic acids and carbamic acids, aromatic acyl groups and an acyl group such as an aliphatic acyl group substituted with an aromatic group; etc. The above-mentioned acyl group will be explained in more detail with specific examples as follows.

Examples of aliphatic acyl groups include formyl, acetyl,
Lower alkanoyl which may have one or more suitable substituents such as carboxy, such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc. groups, such as lower alkyl, such as cyclopropyloxyacetyl, cyclobutyloxyprobionyl, cyclohebutyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc. cyclo(lower)alkoxy(lower)alkanoyl group, camphorsulfonyl group, which may have one or more suitable substituents, such as carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl , carboxy(lower)alkylcarbamoyl groups such as carboxyhexylcarbamoyl, or for example trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylmethoxycarbonylethylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl a tri(lower)alkylsilyl(lower)alkoxycarbonyl group such as a protected carboxy(lower)alkylcarbamoyl group such as a (lower)alkylcarbamoyl group, etc. or a suitable substituent such as a protected carboxy group. Examples include lower alkylcarbamoyl groups having one or more.

Aromatic acyl groups include, for example, aroyl groups which may have one or more suitable substituents such as nitro, such as benzoyl, toluoyl, xyloyl, naphthoyl, nitofbenzoyl, dinitrobenzoyl, nitronaphthoyl, etc. Benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
Examples include arenesulfonyl groups which may have one or more suitable substituents such as halogen.

Examples of the aliphatic acyl group substituted with an aromatic group include phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-
Phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-
Examples include alkanoyl groups which may have one or more suitable substituents such as lower alkoxy and tri-(lower) alkyl, such as 2-propoxy-2-phenylacetyl.

Among the above acyl groups, more preferred acyl groups include:
C1-C4 alkanoyl group which may have carboxy, (C+-C4) alkyl group in cycloalkyl moiety
Cyclo(C5~c6)alkyloxy(c+~
C4) alkanoyl group, camphorsulfonyl group, carboxy(C+-C4) alkylcarbamoyl group, tri(
C+~C4) alkylsilyl (CI-C4) alkoxycarbonyl (C+~C4) alkylcarbamoyl group, benzoyl group which may have one or two nitro groups, benzenesulfonyl group having halogen, ClNC4
Phenyl (C+-C4) alkanoyl groups having alkoxy and tri-(C+-C4) alkyl groups are mentioned, among which the most preferred are acetyl, carboxypropionyl, menthyl oxyneacetyl, camphorsulfonyl, benzoyl, Nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2
-trifluoromethyl-2-methoxy-2-phenylacetyl and the like.

As the pharmaceutically acceptable salt of compound (I), non-toxic, conventional pharmaceutically acceptable salts are used, such as alkali metal salts such as sodium salts and potassium salts, alkali metal salts such as calcium salts and magnesium salts. Examples include salts with inorganic or organic bases such as earth metal salts, ammonium salts, and amine salts such as triethylamine salts and N-benzyl-N-methylamine salts.

In compound (1), one or more pairs of stereoisomers such as optical isomers and geometric isomers due to conformers or asymmetric carbon atoms and double bonds may exist, and such conformers or Isomers are also included within the scope of this invention.

When compound (I) is used in the form of a suspension for pharmaceutical purposes, there are specific requirements depending on the dosage form. For example, when considering the case of use as intramuscular injection or eye drops, the former is used to prevent clogging in the injection needle and increase in flow resistance, while the latter is used to reduce the sensation of a foreign body in the eye. It is desirable to make the compound (1) dispersed in the liquid fine and uniform, but meeting these requirements is also important for other forms of administration, albeit to a different degree. It is clear that it has.

Therefore, the inventors of the present invention investigated a technique that can disperse compound (I) as finely and uniformly as possible.

After examining various means for suspending compound (I), we found that the first means to realize fine and homogeneous suspension of compound (I) is to suspend compound (I) in a solvent (hereinafter referred to as a good solvent) that can dissolve compound (I). Add compound (I) to make a homogeneous solution,
Next, it has been found that the most promising method is to add a solvent that hardly dissolves the compound (I) (hereinafter referred to as a poor solvent) to the homogeneous solution to precipitate the compound (I).

Good solvents for compound (I) include ethanol, acetone,
Examples include low-boiling organic solvents such as acetonitrile and dioxane, while water is a typical poor solvent. In the present invention, there are no particular limitations on the good solvent, but it is desirable that it does not remain in the final form of the formulation. Therefore, we selected ethanol, which can be easily removed by evaporation, and conducted experiments in combination with water, which is a poor solvent. In addition, it was learned that the objective could not be achieved by simply precipitating and crystallizing compound (1).

This is due to two reasons: Compound (I) has a relatively large molecular weight and therefore has a slow crystallization rate, and Compound (I) takes the form of oil droplets during precipitation, so the precipitated particles tend to coalesce. It is thought that it depends on the Therefore, compound (I)
When dissolving the above-mentioned surfactant in ethanol, we created a clear solution by coexisting with a surfactant and adding water if desired, and then adding water to this solution. The agent acts as a suspending agent,
It has been found that compound (I) is finely and uniformly precipitated and crystallized.

Even in this dispersed state, it can be used as a medicine. However, it is desirable to remove organic solvents such as ethanol as much as possible. Therefore, the solvent is distilled off, such as freeze-drying, to formulate a powder, and when used, an appropriate medium such as physiological saline or glucose is used. injection solution, water,
It is desirable to reconstitute the suspension by adding juice or the like before administration.

However, when the above-mentioned dispersed state was subjected to freeze-drying to evaporate the medium, the fine powder of compound (1) remaining in the container reaggregated as the medium was removed, and the powders were mixed together during storage. It was found that the particles stuck to each other or adhered to the wall of the container, and even if the above-mentioned medium was added to redisperse the particles, a good finely suspended state could not be reproduced. Therefore, a sugar alcohol is added as an excipient or filler at any point prior to freeze-drying, and the state after freeze-drying is changed to a so-called 'sea-like' state in which Compound (I) is finely dispersed in the sugar alcohol. It has been found that if the particles are formed into an island structure, redispersibility when adding a medium to return to a finely suspended state is extremely good.

In the end, this invention discovered that a good suspension state can be provided by essentially containing the three components of compound (I), a surfactant, and a sugar alcohol. The most important point in this invention is that we were able to provide a suspension composition such as the above-mentioned freeze-dried product that reproduces the following.

The three basic components in this invention are as described above, and the compound (I), surfactant, and sugar alcohol are mixed in a mixing ratio of 1: (0,01-1): (1-5) according to the order of description.
weight).

If the amount of surfactant is too small, compound (I) tends to stick together during precipitation and crystallization, making it impossible to obtain a sufficient micronization effect. If the amount is too small, the effect as an excipient or bulking agent will be insufficient, and during storage after freeze-drying, compound (I) will stick to each other or adhere to the wall surface, resulting in a suspended state. reproducibility deteriorates. On the other hand, surfactants and sugar alcohols exhibit their respective effects in proportion to the increase in their amount, but once a certain amount is exceeded, their effects reach saturation, so upper limits as mentioned above have been set. .

Surfactants and sugar alcohols can be used freely as long as they are pharmaceutically acceptable. Typical examples include castor oil-based surfactants from the viewpoint of long-term storage. Surfactants, especially HCO (polyoxyethylene hydrogenated castor oil) type surfactants are preferred, and the most preferred are HCO-60, HCO-30, HCO
-40 is recommended. Other than the above, polysorbate 80
Polyoxyethylene sorbitan fatty acid ester derivatives such as, glycerin fatty acid ester derivatives such as glycerin monocabrilate, polyethylene glycol fatty acid ester conductors such as polyoxyethylene 40 monostearate, etc. can be used. Also, as a sugar alcohol,
Inositol, xylitol, or hexitols such as mannitol, sorbitol, dulcitol, etc. are used.

Next, a method for producing the suspension composition of the present invention will be explained.

In producing the suspension composition, it is necessary to take the following three steps, and each of these steps can include various modifications.

First step: Bringing compound (I) into a solution state. Second step: Precipitating compound (I) from the above solution state and dispersing compound (1) in the form of fine crystals in a medium whose volume has been increased by sugar alcohol. Step 3: Freeze-dry the fine crystal dispersed state to produce a suspension composition, and if necessary, add a suspending medium to form a suspension. Each step will be described in detail below. do.

First, in the first step, when compound (I) is brought into a solution state, compound (1) is mixed with the good solvent and the surfactant. The procedure for mixing the above three is not particularly limited, but usually a good solvent is added to compound (I) and then a surfactant is added. Alternatively, a method of mixing a good solvent and a surfactant and then mixing with compound (1), or even a method of mixing compound (1) and a surfactant and then mixing with a good solvent. good. In addition, in this step, from the viewpoint of ease of handling the surfactant, it is possible to use the surfactant by dissolving it in water. In this case, the amount of water added is such that compound (1) is It should be kept within the limit that does not precipitate. Therefore, the solution state obtained in the first step is compound (I) - good solvent -
This means that either a ternary surfactant system or a quaternary surfactant system in which water is added may be used.

Next, the second step is to precipitate and crystallize compound (1) from the solution state and finely disperse the crystals in sugar alcohol. , and the addition of sugar alcohols are essential. Addition form of water and sugar alcohol (JIL
There are no restrictions on whether the additives are used alone or in a mixture, and in the former case, the order of addition, etc.). Furthermore, the above water and sugar alcohol can be added in two or more portions, and the point is that compound (I) is precipitated in the form of fine oil droplets by the addition of water, which then becomes fine crystals. This step also includes adjusting the total amount by adding water and/or sugar alcohol until a predetermined amount is reached during the process up to or at any time thereafter.

The average particle size of the fine crystals obtained in this step is at most 150 μl, and depending on the processing conditions in each step, it is preferably 60 μm or less, more preferably 30 μm or less.
μm1 More preferably 20 μm or less, most preferably 1
It is possible to adjust the thickness to 0 μm or less.

Therefore, particularly preferable conditions will be explained.

The surfactant, which is an essential component, is 0.0% relative to compound (I).
01-1 (weight ratio), more preferably 0.05-0.
5 (weight ratio), and the sugar alcohol is also recommended to be 1 to 5 (weight ratio), more preferably 2 to 3 (weight ratio). In the second step, water is preferably added slowly to precipitate compound (I) at a rate of about 1 to 5 ml per minute relative to the amount of solution obtained in the first step, which is 300 w1. More preferably 2 to 4 meters per minute
It is recommended that it be 1.

Next, in the second step, the precipitation/crystallization process of compound (I) is preferably carried out under stirring conditions from the viewpoint of preventing oil droplets from coagulating. It is sometimes recommended to set the speed to 50 to 200 rpm, more preferably 80 to 120 rpm. Furthermore, the processing environment in the second step is 30 to 40°C.
It is recommended that

The third step, freeze-drying, may be carried out according to a conventional method, and the method of freeze-drying does not limit the present invention.

The suspension composition obtained through the above first to third steps is:
Compound (I) is finely dispersed in sugar alcohol, and a stable suspension can be obtained by adding physiological saline, glucose injection, water, juice, etc.

The content of compound (I) in the suspension is not particularly limited, but is 2.5 to 40 B/ml for intramuscular injection, 0.5 to 10 mg/ml for eye drops, and 0.5 to 10 mg/ml for syrup. It is preferable to set it as 0.5-20 mg/ml.

[Example 5] As compound (I) R+ = hydroxy group R2 = hydroxy group R3 = allyl group R4 = methoxy group R5 = hydrogen n
=2 The symbol represented by the solid line and the dotted line = a compound that is a single bond and is in a free state. This compound has particularly excellent immunosuppressive effects and is hereinafter referred to as FK506.

F K 506 (92.3g) was dissolved in ethanol (290g).
, 7g) and 10% HCO-60 aqueous solution (180g).
g) was added to make a homogeneous solution. Distilled water for injection (360 g) was gradually added to this solution while stirring, and oil droplets of FK506 were precipitated, and then a 10% aqueous mannitol solution (2250 g) was gradually added while stirring. In this process, FK
506 becomes fine crystals, and after adjusting the total amount to 4,500 g by adding distilled water for injection, it is dispensed into injection vials and freeze-dried to obtain a suspension composition in which FK506 is finely dispersed in mannitol. Ta.

The particle size distribution of FK506 particles in the composition is 1 to 40 μm
The average particle diameter was 14 μm.

Example 2 F K 506 (0.5 g) was mixed with ethanol (1.6 g
), and a 10% aqueous HCO-60 solution (1 g) was added to make a homogeneous solution. When a 10% mannitol aqueous solution (12.5 g) was gradually added to this solution while stirring, FK50
Oil droplets No. 6 began to precipitate, and when distilled water for injection (2 g) was further added, the oil droplets became fine crystals, and further distilled water for injection was added to adjust the total amount to 25 g. Thereafter, treatment was carried out in the same manner as in Example 1 to obtain a suspension composition in which FK506 was dispersed with a particle size distribution of 3 to 60 μm and an average particle size of 20 μl.

Example 3 F K 506 (0.5 g) was mixed with ethanol (1.6 g
) and further added HCO-60 (0.1 g) to make a homogeneous solution. While stirring, add distilled water for injection (2,
FK506
Oil droplets began to precipitate and eventually crystallized. Finally, distilled water for injection was added to adjust the total amount to 25 g. Thereafter, treatment was carried out in the same manner as in Example 1 to obtain a suspension composition in which FK506 was dispersed with a particle size distribution of 1 to 30 μm and an average particle size of 10 μm.

When physiological saline was added to the suspension compositions obtained in Examples 1 to 3 so that the FK506 content was 20 mg/ml, a stable fine suspension was obtained.

[Effect of the invention] Since this invention is configured as described above, the compound (1
) can be made into a suspension with uniform content, fine, stable, and sustained release effect, and can be applied to a wide range of administration methods such as intramuscular injection, eye drops, and internal administration.

The production method of the present invention is also superior to conventional pulverization methods in terms of sterilization and prevention of foreign matter contamination.

Claims (4)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (In the formula, R^1 is a hydroxy group or a protected hydroxy group, R^2 is hydrogen, a hydroxy group or a protected hydroxy group, R^3 is a methyl group, ethyl group, propyl group or allyl group, R^4 is a hydroxy group or methoxy group, R^5 is hydrogen, or R^4 and R^5 together are an oxo group, n is 1 or an integer of 2, the symbol represented by a solid line and a dotted line means a single bond or a double bond, provided that R^4 is a hydroxy group and R^5 is hydrogen, or R^4 and R^5 are both or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable surfactant, and a pharmaceutically acceptable sugar. A suspension composition or suspension containing alcohol and having a weight ratio of 1:(0.01-1):(1-5). (2) The suspension composition or suspension according to claim (1), wherein the compound (I) or a pharmaceutically acceptable salt thereof shown in claim (1) is in the form of uniform fine particles. (3) The suspension composition or suspension according to claim (2), wherein the uniform fine particles have an average particle size of 150 μm or less. (4) A solution mixture consisting of the compound (I) shown in claim (1) or a pharmaceutically acceptable salt thereof, a solvent capable of dissolving the compound (I), and a pharmaceutically acceptable surfactant. Alternatively, a step of forming a solution mixture by further adding water to this, a step of precipitating and crystallizing compound (I) or a salt thereof in a mixture of a pharmaceutically acceptable sugar alcohol and water, and a further step of freeze-drying. 2. A method for producing a suspension composition or a suspension according to claim (I), which comprises a step of adding a suspending medium to form a suspension, if desired.