JP2000143542A - Sparingly soluble immunosuppressant-containing o/w emulsion pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject safe pharmaceutical preparation excellent in solubility of a sparingly soluble immunosuppressant in water and capable of manifesting excellent pharmacological effects by including the sparingly soluble immunosuppressant, a phospholipid and a liquid paraffin. SOLUTION: This O/W emulsion pharmaceutical preparation (preferably an eye drop, an ear drop, etc.), is obtained by including (A) a sparingly soluble immunosuppressant (preferably a cyclosporin), (B) a phospholipid, (C) a liquid paraffin and (D) water. The amount of the ingredient B used is preferably 5-50 pts.wt. based on 1 pt.wt. of the ingredient A and the amount of the ingredient C used is preferably 0.5-5 pts.wt. based on 1 pt.wt. of the ingredient B. The O/W emulsion is prepared by dissolving the phospholipid such as egg yolk lecithin and the sparingly soluble immunosuppressant in a suitable organic solvent such as hexane under stirring, then distilling off the solvent, forming a phospholipid thin film, adding the liquid paraffin, distilled water, etc., to the formed thin film, carrying out the preemulsification, subsequently emulsifying the resultant preemulsion with an emulsifier and regulating the prepared emulsion to objective pH (preferably 5-9).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an O / W emulsion preparation containing a sparingly soluble immunosuppressant as a drug.

[0002]

2. Prior Art and Problems to be Solved by the Invention
In addition, the bioavailability of poorly soluble drugs
It is known to depend on the solubility of For example, poorly soluble
Poorly soluble drug when administered as an oral solid preparation
The rate of drug absorption and release from the drug is rate-limiting (see “
Drug Bioavailability and Bioequivalence Testing "
Hiroyasu Ogata, Masayoshi Samejima Pharmaceutical Times Co., Ltd.
line). Also, if a poorly soluble drug is instilled in the form of a suspension,
In the case of drug transfer to ocular tissue,
Dependent on the rate of dissolution of the drug from the offspring (J. Phar
m. Sci. , 64 (6), 931-936 (197
5)). Thus, poorly soluble like cyclosporin
Drugs are bioavailable due to poor solubility in water
Is known to be very bad. The above is
Tacrolimus, the same immunosuppressant as cyclosporine, and
33-epi-chloro-33-desoxy-a
The same applies to scomycin. Cyclospoli
Are a group of known to have immunosuppressive activity.
It is a non-polar oligopeptide. Major of cyclosporine
The component is cyclosporin A (C₆₂H ₁₁₁N
₁₁O₁₂) And other similar compounds (cyclosporin
The presence of BZ) is also known. Cyclosporin A is transferred to the kidney
Suppression of rejection in transplantation, rejection in bone marrow transplantation
And control of graft-versus-host disease, rejection in liver transplantation
Suppression, psoriasis vulgaris, pustular psoriasis, erythroderma psoriasis, arthropathy
Plaque psoriasis, aplastic anemia, erythroblastosis, nephrotic syndrome
It has been used as a therapeutic drug. Ophthalmology
Various diseases such as immune-mediated keratoconjunctivitis sicca (KCS or
Dry eye disease), eye symptoms of Behcet's syndrome, herpes
Keratitis, spring keratoconjunctivitis, allergic keratoconjunctivitis, chronic
Induced by keratitis, uveitis and ophthalmic surgery in general
As a therapeutic agent for inflammation or immunosuppressant during corneal transplantation
It is a very useful compound that is expected. Only
Unfortunately, the water solubility of cyclosporine is not
It is always known to be low. Therefore, Table 10-5
Cyclosporin A as described in 00414
Aqueous like commonly used injections and eye drops
Not only difficult to prepare as a formulation, but also substantial
Was considered impossible. So, cyclosporine
When used as an injection, use polyoxyethylene
Cyclosporine dissolved in castor oil and ethanol
Ejections (Sandymun® Injection, Novartis)
Pharma Co., Ltd.). But injection
The polyoxyethylene castor oil contained in
It has been reported that the drug may cause
There is a problem in terms of integrity. In addition, cyclosporin eye drops
When using as a commercially available injection solution in olive oil
Dilute oily eye drops have been used. But this
Una oily eye drops are described in JP-B-6-67850.
As if they had burning sensation, pain, redness, etc.
It is known that the feeling of use is poor. In addition,
Experimental Example 2 As shown in Comparative Example 2 in Table 2, cyclosporin was used.
Contains oily ophthalmic solution for allergic conjunctivitis
It did not show any clear inhibitory effect on Dell. .

Many attempts have been made to remedy such disadvantages of conventional preparations. JP-A-3-106812 discloses that
Cyclosporine, phospholipid, polyoxyethylene (6
0) A stable, hypoallergenic composition consisting of hydrogenated castor oil, polyethylene glycol 300 and water is disclosed. However, the composition contains POE (60) hydrogenated castor oil in the composition, so there is a problem in safety. JP-A-4-2
53907 discloses a fat emulsion comprising cyclosporine, refined soybean oil, phospholipids and / or synthetic nonionic surfactant and water. This fat emulsion is characterized by the long-lasting pharmacological action of cyclosporine, but does not describe the solubility of cyclosporin in water or release from the formulation. JP-A-6-2793
07 discloses an emulsified composition consisting of cyclosporine, several natural oils, phospholipids and water. This composition is characterized by higher safety because it does not contain polyoxyethylene castor oil, which is contained in commercially available injections. However, the solubility of cyclosporine in water and release from the formulation in this composition is not sufficient because only part of the cyclosporine is dissolved in the natural oil and the remaining cyclosporin is present in the natural oil as fine crystals. However, this is not described. JP-A-61-249918 discloses an emulsified composition comprising cyclosporin, purified egg yolk lecithin, purified soybean oil, glycerin and water. It is disclosed that this composition has excellent storage stability and has a property that the action of cyclosporine is sustained when administered to the eye. However, the solubility of cyclosporin in water and the release from the formulation in this composition are not described. JP-A-2-164830 discloses a preparation comprising cyclosporine, vegetable oil and petroleum jelly. When this formulation was administered to the eye, it was shown that the concentration of cyclosporine in ocular tissues was higher than when a formulation using mineral oil instead of vegetable oil and when castor oil was used instead of vegetable oil and petroleum jelly. I have. 6-678
50 discloses a formulation in which cyclosporin is dissolved in corn oil. The results show that the use feeling when instilled is better when the cyclosporin is dissolved in corn oil than when the preparation is dissolved in olive oil. Tokiohei 10-50
No. 0414 discloses an O / W emulsion preparation comprising higher fatty acid glycerol such as cyclosporin and castor oil and polysorbate 80 in order to improve the unpleasant feeling of use of the oil-based eye drops. This formulation did not improve the feeling of use when instilled, indicating that cyclosporine is preferentially absorbed in the lacrimal gland. However, since higher fatty acid glycerol such as castor oil and polysorbate 80 are concerned with corneal cytotoxicity, it is preferable to refrain from using them as much as possible. JP-A-9-48737 and JP-A-64-85921 disclose preparations using α-cyclodextrin or a derivative thereof, β-cyclodextrin for dissolving cyclosporin in water. Since cyclosporin is included in cyclodextrin and dissolved in water, it has been shown that it is possible to improve the uncomfortable feeling during eye drops such as oily eye drops. As described above, various formulations have been trial-produced in order to overcome the disadvantages of the conventional cyclosporin formulations, but none of them has been put to practical use.

[0004] In an attempt to increase the concentration of a sparingly soluble drug in tears immediately after instillation and to improve the bioavailability of the sparingly soluble drug, WO97 / 05882 includes, as drugs, fluorometholone or clobetasone butyrate, phospholipids,
An ophthalmic O / W emulsion formulation comprising liquid paraffin and water is disclosed. This preparation showed that the solubility of fluorometholone or clobetasone butyrate in tears was improved, and that the transferability of the drug to eye tissues was also improved. As shown in No. 1, there is no description that the O / W emulsion for eye drops containing cyclosporine significantly suppresses allergic conjunctivitis.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the problems of conventional poorly soluble immunosuppressants and their preparations, and the object of the present invention is to provide a safe and poorly soluble immunosuppressant. It is an object of the present invention to provide a novel poorly soluble immunosuppressive agent-containing preparation having excellent solubility in water. The present inventors have conducted intensive studies in order to achieve such an object. As a result, an O / W emulsion preparation containing a poorly soluble immunosuppressant, a phospholipid and liquid paraffin was found to be soluble in the water. The present invention was found to be excellent in pharmacological effect and superior in pharmacological effect to conventional oil-based preparations containing a poorly soluble immunosuppressant. In addition, the O / W emulsion preparation of the present invention does not contain polyoxyethylene castor oil unlike conventional preparations, and therefore has high safety. Further, when administered to the eye as an eye drop, unlike the oil preparation, the O / W emulsion preparation has It is expected that there is almost no irritation to the eye because the contacting part is water or phospholipid which is a main component of the cell membrane. The O / W emulsion preparation containing the poorly soluble immunosuppressive agent of the present invention can suppress rejection in renal transplantation, suppress rejection in bone marrow transplantation and suppress graft-versus-host disease, suppress rejection in liver transplantation, psoriasis vulgaris, pustules It is used as a therapeutic agent for plaque psoriasis, psoriatic erythroderma, psoriatic arthritis, aplastic anemia, erythroblastosis, nephrotic syndrome and the like. In the ophthalmic field, various diseases such as immune-mediated keratoconjunctivitis sicca (KCS or dry eye disease),
Used as a treatment for ocular symptoms of Behcet's syndrome, herpetic keratitis, spring keratoconjunctivitis, allergic keratoconjunctivitis, chronic keratitis, uveitis and inflammation induced by ophthalmic surgery in general, or as an immunosuppressant at the time of corneal transplantation. You.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The poorly soluble immunosuppressant of the present invention includes cyclosporine, tacrolimus or 33-epi-chloro-33-
desoxy-ascomincin and the like. Cyclosporins are known cyclosporins A to
Any of Z is used alone or as a mixture thereof, and cyclosporin A is particularly preferred. The concentration of the poorly soluble immunosuppressant used is not particularly limited as long as the target disease is cured, but is usually 0.001 to 0.5 w / v.
%, Preferably 0.01 to 0.2 w / v%.

[0007] The "phospholipid" used in the present invention is not particularly limited. Examples include dicetyl phosphate, sphingomyelin, synthetic phospholipids dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine or distearoyl phosphatidylcholine, and mixtures of these phospholipids. These phospholipids are, for example, Courtosomes® NC-10S
(High-purity egg yolk lecithin, Nippon Oil & Fats Co., Ltd.), purified egg yolk lecithin (Asahi Kasei Corporation), egg yolk lecithin PL-10
0H, PL-100E, PL-100LE, PC
-98N (Kewpie Corporation), powdered egg yolk lecithin (hydrogenated purified yolk lecithin) R-27, R-20,
R-5 (Asahi Kasei Corporation), PCS (soy phosphatidylcholine, Nippon Seika Co., Ltd.), PCSH (hydrogenated soy phosphatidylcholine, Nippon Seika Co., Ltd.), Coatsome (registered trademark) NC-21 (hydrogenated soy lecithin) , Nihon Yushi Co., Ltd.), egg yolk lecithin LPL-20
(Kewpie Co., Ltd.), Courtsome (registered trademark) M
C-6060 (L-α-dipalmitoylphosphatidylcholine, NOF Corporation), Coatsome (registered trademark) MA-6060 (L-α-dipalmitoylphosphatidic acid, NOF Corporation), Coatsome (registered trademark) MGLS -6060 (L-α-dipalmitoyl phosphatidyl-DL-glycerol, NOF Corporation)
And are easily available. The amount of the phospholipid used is usually 5 to 1 part by weight of the poorly soluble immunosuppressant.
The amount is from 50 to 50 parts by weight, preferably from 10 to 30 parts by weight.
When the amount of the phospholipid used is in the range of 5 to 50 parts by weight per 1 part by weight of the poorly soluble immunosuppressant, the cyclosporine is completely encapsulated in the emulsion particles, and the poorly soluble immunosuppressant in water is used. This is preferable because an emulsion having a particularly high dissolution concentration can be obtained.

[0008] The liquid paraffin used in the present invention is not particularly limited, and any viscosity and specific gravity liquid paraffin can be used. Particularly, liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable.
These liquid paraffins are light liquid paraffin Nos.
70-S, liquid paraffin no. 150-S;
No. 200-S; 260-S; 350-S
(Sanko Chemical Industry Co., Ltd.) and easily available. The amount of liquid paraffin used is generally 0.5 to 5 parts by weight, preferably 1 to 3 parts by weight, per 1 part by weight of phospholipid, and the concentration of liquid paraffin in the emulsion is 25 w / v% or less. Preferably, there is. When the amount of the liquid paraffin used is in the range of 0.5 to 5 parts by weight per 1 part by weight of the phospholipid, coloring of the emulsion due to oxidation of the phospholipid during storage is small, and the dissolution concentration of the poorly soluble immunosuppressant in water is low. It is particularly preferable because a high emulsion can be obtained. In addition, the concentration of liquid paraffin is 25 w / v.
% Or less is preferable because it is easy to administer due to low viscosity, and when used as an eye drop, an emulsion having no sticky feeling when instilled is obtained.

In preparing the emulsion of the present invention, sugars such as xylitol, mannitol, sorbitol and glucose, isotonic agents such as propylene glycol and glycerin, glycine, ε-aminocaproic acid, monoethanolamine, sodium hydroxide, hydrochloric acid PH adjusters, such as benzalkonium chloride, benzethonium chloride, invert soaps, parahydroxymethyl benzoate, parabens such as propyl parahydroxybenzoate, sorbic acid and pharmaceutically acceptable salts thereof, benzyl alcohol Preservatives, such as phenethyl alcohol or chlorobutanol,
Methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, synthetic polymers such as polyvinyl alcohol and sodium polyacrylate, proteinaceous polymers such as gelatin, thickeners such as polysaccharides such as dextran and carrageenan or gums such as xanthan gum and A thickener, a stabilizer such as EDTA or a pharmaceutically acceptable salt thereof, citric acid or a pharmaceutically acceptable salt thereof, an amino acid and a pharmaceutically acceptable salt thereof, and tocopherol and a derivative thereof. As long as the effect of the present invention is not impaired, it may be added to the poorly soluble immunosuppressant-containing O / W emulsion preparation of the present invention. The amino acids used in the present invention include histidine and its pharmaceutically acceptable salts (eg, hydrochloride), methionine,
Examples include phenylalanine and serine. Examples of the tocopherol derivative used in the present invention include tocopherol acetate, tocopherol nicotinate, and tocopherol succinate.

The emulsion of the present invention usually has a pH of 3 to 10.
PH is preferably 5 to 9 from the viewpoint of irritation, and particularly preferably 5.5 to 8.0 when used as eye drops.

The emulsion of the present invention can be subjected to sterilization by filtration sterilization using a membrane filter, intermittent sterilization, or the like. Further, the emulsion of the present invention can be filled in a plastic eye dropper and used as an eye drop. To preserve this for a long period of time, it may be pillow-wrapped in a laminated bag of a polyethylene film and an aluminum foil together with an oxygen scavenger (eg, Ageless (registered trademark), Mitsubishi Gas Chemical Company, Ltd.). The emulsion of the present invention can be filled in a plastic drop bottle and used as an eardrop. To preserve this for a long period of time, it may be pillow-wrapped in a laminated bag of a polyethylene film and an aluminum foil together with an oxygen scavenger (eg, Ageless (registered trademark), Mitsubishi Gas Chemical Company, Ltd.). The emulsion of the present invention can be filled into a nasal metering sprayer and used as a nasal drop. To preserve this for a long period of time, it may be pillow-wrapped in a laminated bag of a polyethylene film and an aluminum foil together with an oxygen scavenger (eg, Ageless (registered trademark), Mitsubishi Gas Chemical Company, Ltd.). After filling the emulsion of the present invention into an ampoule and sealing, an injection (intravenous injection, arterial injection, subcutaneous injection, intradermal injection, intramuscular injection, intrathecal injection, intraperitoneal injection, intraocular injection, etc.), oral liquid preparation , Can be used as an inhalant or a spray. Depending on the usage, it is used by filling it into a plastic drug bottle for an internal liquid, an electric nebulizer for an inhalant, and an atomizer for a spray.

Next, a method for producing the emulsion of the present invention will be described. Various known methods can be used.For example, after stirring and dissolving egg yolk lecithin and optionally a phospholipid such as phosphatidylethanolamine and a sparingly soluble immunosuppressant in a suitable organic solvent such as hexane and ethanol, the solvent is removed. Vacuum distillation is performed to prepare a lipid thin film. Liquid paraffin and water or an aqueous solution containing various additives such as a preservative, a buffer, a stabilizer and an isotonic agent are added thereto, and vigorously shaken and stirred to carry out preliminary emulsification. This liquid is emulsified by a commonly used emulsifying machine. HCl or Na is added to the liquid after emulsification.
The O / W emulsion containing the poorly soluble immunosuppressive agent of the present invention can be obtained by adjusting the pH to a target value by adding OH.
Further, the obtained emulsion is filtered and filled into a suitable storage container with a membrane filter, and then sterilized to obtain an emulsion preparation of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples.

EXAMPLES Example 1 Egg yolk lecithin (Coatsome (registered trademark) NC-10S,
0.35 g of phosphatidylcholine 95%, NOF Corporation, hereinafter abbreviated as EPC) and purified egg yolk lecithin (phosphatidylcholine 70%, phosphatidylethanolamine 20%, Asahi Kasei Corporation, abbreviated as PYL)
0.15 g was dissolved in a hexane / ethanol (10: 1) mixed solution. Separately, cyclosporin A (manufactured by Wako Pure Chemical Industries) 0.0
After dissolving 5 g in ethanol and mixing with the above phospholipid solution, the solvent was distilled off under reduced pressure to form a phospholipid thin film containing cyclosporin A. Liquid paraffin (No. 200-S, Sanko Chemical Co., Ltd.) is applied to this phospholipid thin film.
0.5 g, 2.2 g of glycerin and 80 ml of distilled water were added, and the mixture was vigorously shaken and stirred to perform preliminary emulsification. Distilled water was added to the pre-emulsion to make 100 ml, and then a microfreezer (M-11 manufactured by Microfluidics) was used.
0EH) under pressure of 750 kg / cm ^2.
The mixture was passed twice and emulsified. 1N NaOH is added to the liquid after emulsification.
Was added to adjust the pH to 7.4 to obtain a cyclosporin O / W emulsion of the present invention.

Comparative Example 1 The amount of liquid paraffin added in Example 1 was changed to 7.5 g,
Thereafter, a cyclosporin AO for comparison was prepared in the same manner as in Example 1.
/ W emulsion was obtained.

Comparative Example 2 Cyclosporine injection (Sandymun (registered trademark) injection,
Novartis Pharma Co., Ltd.) was diluted with olive oil of the Japanese Pharmacopoeia so that the cyclosporine content was 0.1 w / v%, to obtain a comparative cyclosporin oil-based ophthalmic solution.

Test Example 1 The solubility of cyclosporin A in tears was determined according to WO 97/0
5882, page 10, “Examples”, according to the drug dissolution test method, the concentration of cyclosporin A dissolved in artificial tears (PBS) was evaluated (the concentration of cyclosporin A dissolved).
HPLC determination of cyclosporin A dissolved in artificial tears
It measured using. Table 1 shows that the cyclosporin AO / W emulsion of the present invention of Example 1, the comparative cyclosporin AO / W emulsion of Comparative Example 1, and the cyclosporin A oily ophthalmic solution of Comparative Example 2 were dissolved in artificial tears. The results of the sex test are shown. The emulsion of the present invention has a very high dissolved concentration of cyclosporin A in artificial tears as compared with the comparative example, indicating that the release of cyclosporin A from emulsion particles into artificial tears is excellent. Thus, the O / W emulsion preparation containing the poorly soluble immunosuppressive agent of the present invention is excellent in the solubility of the poorly soluble immunosuppressive agent in water.

[0017]

[Table 1]

Test Example 2 Effect of Cyclosporin AO / W Emulsion Ophthalmic Solution on Guinea Pig Experimental Allergic Conjunctivitis <Test Substances and Group Composition> Cyclosporine AO / W emulsion of Example 1 Cyclosporin AO / W emulsion Comparative example 1 A group of 7 to 8 Hartley male guinea pigs (Nippon Medical and Animal Materials Research Institute) each having a body weight of about 250 g was used. Control group (only antigen challenge) Used as <Experimental method> Under ether anesthesia, 50 μl of anti-OA serum (produced by Kitayama Labes) diluted 10-fold with physiological saline was injected under the upper eyelid conjunctiva of the guinea pig and passively sensitized. Seven days later, 1 ml of 0.5% Evans blue solution containing 2.5 mg OA was intravenously administered to elicit a reaction. Thirty minutes later, the animals were killed by exsanguination, and the site of dye leakage was cut out.
The method of Ayama et al. (Katayama, S. et al. Microbiol. Immun
ol., 22, 89-101, 1978). The test substance and the comparative control substance were
10 μl each was applied to both eyes before the time. <Statistical processing> Each value was expressed as the average value ± standard error of the average amount of the leaked pigment of both eyes as the amount of the leaked pigment of one individual. In the statistical processing, an F-test is performed for each group.
ent's t-test, Aspin in case of unequal variance
A significant difference test was performed by Welch's test. <Results> The results are shown in Table-2. The emulsion of the present invention having excellent solubility of cyclosporin A in tears significantly suppressed allergic inflammation as compared with the control group. On the other hand, the cyclosporin A emulsion or the cyclosporin A oily ophthalmic solution of the comparative example showed no effect.

[0019]

[Table 2]

Formulation Example 1 Egg yolk lecithin and purified yolk lecithin were dissolved in a hexane / ethanol (10: 1) mixture. Separately, cyclosporin A was dissolved in ethanol, mixed with the above phospholipid solution, and then the solvent was distilled off to form a phospholipid thin film containing cyclosporin A. Sorbic acid, disodium EDTA and glycerin were added to water for injection and dissolved to prepare an additive aqueous solution. Additive aqueous solution and liquid paraffin (No. 26)
0-S, Sanko Chemical Industry Co., Ltd.) was added to the above phospholipid thin film containing cyclosporin A, and vigorously shaken and stirred to perform preliminary emulsification. An aqueous solution of an additive was further added to this pre-emulsion to make 100 mL, and then a microfreezer (Mi
(Crofluidics: M-110EH) and emulsified by passing 30 times under a pressure of 750 kg / cm ² . Add 1N NaOH to the liquid after emulsification
Was adjusted to 5.5 to obtain the cyclosporin AO / W emulsion of the present invention. This emulsion is used with a pore size of 0.8 μm.
Was filtered and filled into a polyethylene eye dropper with a membrane filter of No. 1, and heat sterilized by an intermittent sterilization method to obtain an eye drop of the present invention. Further, the obtained ophthalmic solution of the present invention and Ageless (registered trademark) Z (Mitsubishi Gas Chemical Co., Ltd.) were pillow-packed in a laminated bag of a polyethylene film and an aluminum foil. The prescription is shown below. Component Cyclosporin A 0.02 w / v% Coatsome (registered trademark) NC-10S 0.14 w / v
% Purified egg yolk lecithin 0.06 w / v% liquid paraffin No. 260-S 0.2% w / v% EDTA disodium 0.01% w / v% Sorbic acid 0.1% w / v% Glycerin 2.2% w / v Water for injection Amount required to make the total volume 100 ml pH 5.5

Formulation Example 2 In the emulsion ophthalmic solution described in Formulation Example 1, PCSH (hydrogenated soybean phosphatidylcholine, Nippon Seika Co., Ltd.) was further added as a phospholipid, and liquid paraffin was added to N.
o. 150-S (Sanko Chemical Industry Co., Ltd.) with sorbic acid in benzyl alcohol and a pH of 5.5 to 6.0.
In place of the above, an eye drop of the present invention containing cyclosporin A was obtained. The prescription is shown below. Component Cyclosporin A 0.01 w / v% Coatsome (registered trademark) NC-10S 0.19 w / v
% Purified egg yolk lecithin 0.08 w / v% PCSH 0.03 w / v% liquid paraffin No. 150-S 0.9w / v% Disodium EDTA 0.01w / v% Benzyl alcohol 0.5w / v% Glycerin 2.2w / v% Water for injection Amount required to make the total volume 100 ml pH 6.0

Formulation Example 3 In the emulsion ophthalmic solution described in Formulation Example 1, Coatsome (registered trademark) NC-21 (hydrogenated soybean lecithin, Nippon Oil & Fat Co., Ltd.) was further added as a phospholipid, and the liquid paraffin was changed to light liquid paraffin No. . By changing the sorbic acid to benzalkonium chloride and the pH from 5.5 to 8.0 in 70-S (Sanko Chemical Industry Co., Ltd.), an eye drop of the present invention containing cyclosporin A was obtained. The prescription is shown below. Component Cyclosporin A 0.2 w / v% Coatsome (registered trademark) NC-10S 0.6 w / v% Purified egg yolk lecithin 0.3 w / v% Coatsome (registered trademark) NC-21 0.1 w / v% Light Liquid paraffin No. 70-S 0.5 w / v% Disodium EDTA 0.01 w / v% Benzalkonium chloride 0.01 w / v% Glycerin 2.2 w / v% Water for injection Amount required to make the total amount 100 ml pH 8.0

Formulation Example 4 Egg yolk lecithin and purified yolk lecithin were dissolved in a hexane / ethanol (10: 1) mixture. Separately, cyclosporin A was dissolved in ethanol, mixed with the above phospholipid solution, and then the solvent was distilled off to form a phospholipid thin film containing cyclosporin A. Sorbic acid, disodium EDTA and glycerin were added to water for injection and dissolved to prepare an additive aqueous solution. Additive aqueous solution and liquid paraffin (No. 26)
0-S, Sanko Chemical Industry Co., Ltd.) was added to the above phospholipid thin film containing cyclosporin A, and vigorously shaken and stirred to perform preliminary emulsification. An aqueous solution of an additive was further added to this pre-emulsion to make 100 mL, and then a microfreezer (Mi
(Crofluidics: M-110EH) and emulsified by passing 30 times under a pressure of 750 kg / cm ² . Add 1N NaOH to the liquid after emulsification
Was adjusted to 6.0 to obtain the cyclosporin AO / W emulsion of the present invention. This emulsion is used with a pore size of 0.8 μm.
The solution was filtered and filled into a nasal metering sprayer using a membrane filter of No. 1, and heat-sterilized by an intermittent sterilization method to obtain nasal drops. The prescription is shown below. Component Cyclosporin A 0.05 w / v% Coatsome (registered trademark) NC-10S 0.35 w / v
% Purified yolk lecithin 0.15 w / v% liquid paraffin 260-S 0.5% w / v% EDTA disodium 0.01% w / v% Sorbic acid 0.15% w / v% Glycerin 2.2% w / v% Water for injection Amount required to bring the total volume to 100ml pH 6.0

Formulation Example 5 The cyclosporin AO / W emulsion of the present invention prepared in Example 4 was filtered and filled into a dropping bottle with a membrane filter having a pore size of 0.8 μm, and heat sterilized by an intermittent sterilization method to obtain an eardrop. .

Formulation Example 6 The cyclosporin AO / W emulsion of the present invention prepared in Example 4 was filtered through a membrane filter having a pore size of 0.8 μm, heat-sterilized by intermittent sterilization, filled in an electric nebulizer, and inhaled. did.

Formulation Example 7 The cyclosporin AO / W emulsion of the present invention prepared in Example 4 was filtered through a membrane filter having a pore diameter of 0.8 μm, heat-sterilized by an intermittent sterilization method, and filled into an atomizer to obtain a spray.

Formulation Example 8 The cyclosporin AO / W emulsion of the present invention prepared in Example 4 was filtered and filled into an ampoule with a membrane filter having a pore size of 0.8 μm, sealed, heat-sterilized by an intermittent sterilization method to give an oral preparation. .

Formulation Example 9 Egg yolk lecithin and purified yolk lecithin were dissolved in a hexane / ethanol (10: 1) mixture. Separately, cyclosporin A was dissolved in ethanol, mixed with the above phospholipid solution, and then the solvent was distilled off to form a phospholipid thin film containing cyclosporin A. Glycerin was added to and dissolved in water for injection to prepare an additive aqueous solution. The additive aqueous solution and liquid paraffin (No. 200-S, Sanko Chemical Industry Co., Ltd.) were added to the above phospholipid thin film containing cyclosporin A, and vigorously shaken and stirred to perform preliminary emulsification. An aqueous solution of an additive was further added to this pre-emulsion to make 100 mL, and then a microfreezer (M-11 manufactured by Microfluidics) was used.
0EH) under pressure of 750 kg / cm ^2.
The mixture was passed twice and emulsified. 1N NaOH is added to the liquid after emulsification.
Was added to adjust the pH to 7.4 to obtain a cyclosporin AO / W emulsion of the present invention. This emulsion was filtered and filled into an ampule with a membrane filter having a pore size of 0.8 μm, sealed, and then heat-sterilized by an intermittent sterilization method to obtain an injection. The prescription is shown below. Component Cyclosporin A 0.1 w / v% Coatsome (registered trademark) NC-10S 1.05 w / v
% Purified egg yolk lecithin 0.45 / v% liquid paraffin No. 200-S 2.1 w / v% glycerin 2.2 w / v% Water for injection Amount required to bring the total amount to 100 ml pH 7.4

[0029]

The O / W emulsion preparation containing a poorly soluble immunosuppressive agent of the present invention is expected to have a better feeling in use, higher safety, and stronger efficacy than conventional preparations. The emulsion of the present invention is expected to be applied to treatment of various diseases for which immunosuppressants are effective.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 38/00 A61K 47/06 Z 47/06 47/24 Z 47/24 37/02 (72) Inventor Masafumi Takeuchi 1-5-3 Nihonbashi Muromachi, Chuo-ku, Tokyo Wakamoto Pharmaceutical Co., Ltd. F-term (reference) 4C076 AA17 BB11 BB24 BB25 CC07 DD34 DD63 FF16 GG46 4C084 AA03 BA18 BA47 DA11 MA22 MA58 MA59 MA66 NA02 ZA331 ZA341 ZA551 ZA811 ZA89 ZB082

Claims (3)

[Claims] An O / W emulsion preparation containing a sparingly soluble immunosuppressant, comprising the following A to D: Poorly soluble immunosuppressant B. Phospholipid C.I. Liquid paraffin water 2. The O / W emulsion preparation containing a sparingly soluble immunosuppressant according to claim 1, wherein the sparingly soluble immunosuppressant is cyclosporin. 3. The poorly soluble drug according to any one of claims 1 to 2, wherein the dosage form is any of an oral solution, an injection, an eardrop, a nasal drop, an eye drop, a spray and an inhalant. O / containing immunosuppressant
W emulsion formulation