JPH072689A - Microemulsion pharmaceutical containing hardly absorbable substance - Google Patents

Abstract

PURPOSE:To provide the subject pharmaceutical containing hardly absorbable physiologically active substance(s), low in irritancy to the mucous membrane and the skin, comprising a combination of each specific plural surfactants. CONSTITUTION:The objective pharmaceutical comprises a combination of (A) an ionic surfactant such as sodium di-2-ethylhexylsulfosuccinate, (B) a nonionic surfactant 10-20 in HLB number such as polyoxyethylene (hardened) castor oil (pref. 40-60 in the average number of moles of oxyethylene added) and (C) a second nonionic surfactant 3-7 in HLB number such as a mono- or polyglycerin fatty acid ester (pref., said fatty acid being 18C (saturated) fatty acid; 1-2 in the number of moles of the fatty acid added per mole of glycerin; 0-4 in the number of moles of glycerin added) with the component C as the essential component. In this pharmaceutical, its aqueous phase contains such physiologically active substance(s) as to be low in percutaneous/permucosal absorbability such as vasopressin.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a microemulsion preparation having improved percutaneous / transmucosal absorption of physiologically active substances which are difficult to be percutaneously / transmucosally absorbed, such as high molecular weight peptides.

[0002]

2. Description of the Related Art So far, attempts have been made to prepare microemulsions for improving the percutaneous / transmucosal absorbability of physiologically active substances.

Microemulsions using alcohols such as octanol and butanol have been proposed. However, since these alcohols have a bad odor, they are not particularly suitable for oral administration. On the other hand, when a microemulsion is prepared using a large amount of ionic surfactant, the microemulsion has a drawback that it has an irritating property on mucous membranes and skin.

In order to improve the transmucosal absorbability of insulin, calcitonin, etc., which are peptides having low transmucosal absorbability, it has been attempted to use an absorption enhancer such as bile salt in combination. It was found to cause damage and destruction of epithelial cells.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a conventional absorption enhancer such as a bile salt that damages epithelial cells without using a foul-smelling higher alcohol such as butanol or octanol. The purpose of the present invention is to prepare a microemulsion agent having low irritation to mucous membranes and skin without using. Moreover, the purpose of the preparation of such a microemulsion is to improve the absorbability of a physiologically active substance that is difficult to absorb percutaneously / transmucosally.

[0006]

The present invention has succeeded in providing a microemulsion formulation which solves the conventional problems by combining two or more specific surfactants.

The surfactant used in the present invention is selected from the surfactants of the following groups (a), (b) and (c):
The group (c) is used as an essential component, and the surfactant of any one group (a) or (b) is combined with this. The surfactants in each group are as follows.

(A) Ionic surfactant sodium di-2-ethylhexyl sulfosuccinate; sodium alkylsulfate (wherein the alkyl moiety is C ₈ -C ₂₀ , preferably C ₁₀ -C ₁₄ ). (B) HLB of 10-20 Ionic surfactant: polyoxyethylene hydrogenated or non-hardened castor oil (oxyethylene average addition mole number is 30-80, preferably 40
-60 ones), polyethylene glycol higher fatty acid esters (C ₁₆ -C ₂₀ fatty acids are saturated or unsaturated, preferably fatty acid C _18, an average addition mole number of ethylene glycol 10-40); poly polyoxyethylene alkyl ether (alkyl moiety is C ₈ -C _14, preferably C _12, oxyethylene average addition mole number 4-2
5) (c) Nonionic surfactant having HLB of 3-7: mono- or polyglycerin fatty acid ester (saturated or unsaturated C ₁₆ -C ₂₀ fatty acid, preferably C ₁₈ fatty acid, and 1 mol of glycerin Fatty acid addition mole number per 1-
2 and the number of moles of glycerin added is 0-4); sorbitan fatty acid ester (fatty acid is saturated or unsaturated C ₁₆ -C ₂₀ , preferably C ₁₆ -C ₁₈ , and the number of added moles thereof is 1-3); polyoxyethylene hydrogenated or uncured castor oil (oxyethylene average addition mole number is 3-2)
0, preferably 8-12, and more preferably 10).

The dispersion medium that can be used in the present invention is an oil and fat that does not irritate the skin and mucous membranes, and it is liquid at room temperature or melts at body temperature to become liquid. Specifically, vegetable or animal edible oils (fatty acid glycerin esters) such as soybean oil, sesame oil, olive oil; saturated or unsaturated fatty acids; medium-chain fatty acids (C ₆ -C ₁₈ ) mono, di or tri. Glycerin esters can be used.

The microemulsion of the present invention can be produced by a conventionally known method.

A surfactant, which is appropriately combined with the oil component as a dispersion medium, is added and sufficiently stirred and mixed to prepare a uniform oily mixture. When the oil component is solid at room temperature, it is heated and melted, and then a surfactant is added and mixed. on the other hand,
A physiologically active substance as an active ingredient, for example, a peptide such as calcitonin or erythropoietin is dissolved in water.

The water mixture thus prepared is added with stirring to the oily mixture prepared beforehand. Further, stirring is performed to obtain a transparent liquid that becomes a microemulsion. Next, if necessary, an oil component is additionally added to adjust the content of the active ingredient.

The resulting microemulsion is very stable with dispersed droplets having a particle size of 0.4-100 nanometers (nm), preferably 1-100 nm.

Here, albumin, glycerin, glycol and other stabilizers may be added to the aqueous phase.

The physiologically active substances having low transdermal / transmucosal absorbability applicable to the present invention include peptide drugs such as vasopressin, calcitonin, erythropoietin, colony stimulating factor, interleukins, interferons, insulin and parathyroid hormone; And a poorly absorbable low molecular weight drug having a molecular weight of 1,000 or less. As the low molecular weight drug, the following drugs can be applied to the present invention.

Antibiotics: aclarubicin hydrochloride, oxytetracycline hydrochloride, cefotiam hydrochloride, carbenicillin sodium, cefmetazole sodium, etc.

Arrhythmic agents: procainamide hydrochloride, disopyramide phosphate, lidocaine hydrochloride and the like.

Cardiotonic agents: etilefrine hydrochloride, dopamine hydrochloride, etc.

Vasodilators: Trapidil, etc.

Local anesthetic: oxybuprocaine hydrochloride,
Dibucaine hydrochloride, procaine hydrochloride, etc.

Antitumor agents: pleomycin hydrochloride, cytarabine, procarbazine hydrochloride, cisplatin, vinplastin hydrochloride, neocarzinostatin, doxorubicin hydrochloride and the like.

Agents for autonomic nerves: distigmine bromide, bethanechol chloride, propantheline bromide and the like.

Antipyretic and analgesic anti-inflammatory agents: antipyrine, tiaramid hydrochloride, diclofenac sodium and the like.

Psychiatry and nerve agents: imipramine hydrochloride, clomipramine hydrochloride, thiodarin hydrochloride, flurazepam hydrochloride,
Chlorpromazine hydrochloride, repomapromazine hydrochloride, etc.

10 Narcotic analgesic / antitussive agents: oxycodone hydrochloride, etc.

11 Antispasmodic agents: cyclopentolate hydrochloride, etc.

12 Antiparkinsonian drugs: amantadine hydrochloride, promethazine hydrochloride, methixene hydrochloride, etc.

13 Other cardiovascular agents: diltiazem hydrochloride, trimetazidine hydrochloride, etc.

14 Antihypertensive agents: dihydroergotoxin mesylate, clonidine hydrochloride, etc.

15 enzyme preparations: urokinase, hyaluronidase, etc.

16 In addition, naphazoline hydrochloride, meclofenoxate hydrochloride, methylephedrine hydrochloride, homatropine hydrobromide, etc.

The mixing ratio of each component of the microemulsion of the present invention based on the volume of water is as follows.

The ratio of water to surfactant is 1: 2 to 1: 2.
00, preferably 1: 3 to 1:20.

The ratio of water to oil component is 1: 3 to 1: 500.
It is 0, preferably 1: 6-1: 5000.

The obtained drug-containing microemulsion is formulated into a percutaneous absorption preparation, a transmucosal absorption preparation, or an oral preparation by a conventional method as described below.

Percutaneous absorption preparation: A lint cloth is applied to an adhesive tape, impregnated with a microemulsion drug solution, and applied to the skin. Further, a reservoir type patch can be used instead of the lint cloth.

Transmucosal Absorber: a) Nasal administration agent: A microemulsion drug solution is filled in a spray container for nasal administration and spray-coated on the nasal mucosa.

B) Rectal suppository: A suitable heat-fusible material such as non-oil-soluble polyethylene glycol is heated and melted, and a hollow suppository outer shell is molded with a molding die for suppositories. The microemulsion drug solution is injected and filled, and the opening is sealed with a melted suppository shell material, and the drug solution is sealed. It is used by inserting it into the rectum.

A suppository is formed by using a fat-and-oil base that melts in the rectum as an oil component and adding a water component while the base is melted and stirring to form a microemulsion, which is solidified by cooling. This suppository is used by inserting it into the rectum.

Oral preparation: A gelatin hard capsule is filled with a microemulsion drug solution, and a gelatin solution is applied to the fitting portion between the body of the capsule and the cap to prevent the drug solution from leaking out, and after drying, hydroxypropylmethylcellulose phthalate (HPMC), etc. Apply the enteric substance of
It is made into an enteric preparation, dried, and then administered orally.

Gelatin soft capsules can be used instead of hard capsules.

The present invention will be described in more detail below with reference to examples and experimental examples.

[0043]

Example 1 Di-2-ethylhexyl sodium sulfosuccinate (surfactant 1) 7 g Diglyceryl monooleate (HLB = 5.5) (surfactant 2) 5 g Isotonic phosphate buffer (water component) ) 2 g calcitonin (drug) 5 mg tri fatty acid (C ₈ -C ₁₀₎ glycerol ester (oil component) to a total volume of 100 g.

About 90% of the oil component is taken as a surfactant 1
(Group a) and surfactant 2 (group c) were added and sufficiently stirred. On the other hand, calcitonin was dissolved in the water component. The calcitonin aqueous solution was added while stirring the mixed liquid of the oil component and the surfactant, and the stirring was further continued. When a transparent liquid was obtained, the remaining oil component was added while the stirring was continued to make the total amount.

A laser light scattering particle size distribution measuring device (manufactured by Otsuka Electronics, DLS700 type Ar laser output 15)
mW), a W / O type microemulsion having a particle size distribution with an average particle size of 14 nm was obtained.

Example 2 Polyoxyethylene hydrogenated castor oil (EO = 40, HLB = 12.5) (surfactant 1) 8 g Diglyceryl monooleate (HLB = 5.5) (surfactant 2) 8 g cow serum albumin isotonic phosphate buffer (water component) 1 g erythropoietin (drug) 1.25 mg tri fatty acid (C ₈ -C ₁₀₎ glycerol ester (oil component) to a total volume of 100 g.

About 90% of the oil component is taken as a surfactant 1
(Group b) and Surfactant 2 (group c) were added and thoroughly stirred. Since the surfactant 1 is in a semi-solid state at room temperature,
Stirring was performed while heating. On the other hand, erythropoietin was dissolved in the water component. Return the mixture of the oil component and the surfactant to room temperature, add the erythropoietin aqueous solution while stirring, and continue stirring, and if a clear liquid is obtained, add the remaining oil component while continuing stirring and add the total amount. did.

When this liquid was measured by a laser light scattering type particle size distribution measuring device (NICOMP 370 type Ar laser output 70 mW), the average particle size was 30 nm.
A W / O type microemulsion having a particle size distribution of was obtained.

Example 3 Polyoxyethylene (20 mol) hydrogenated castor oil (HLB = 10.5) (surfactant 1) 4 g Polyoxyethylene (10 mol) hydrogenated castor oil (HLB = 6.5) (surfactant) Agent 2) 10 g Isotonic phosphate buffer (water component) 1 g Alpha interferon (drug) 500 μg Soybean oil (oil component) Total amount 100 g.

About 90% of the oil component is taken and the surfactant 1
(Group b) and Surfactant 2 (group c) were added and thoroughly stirred. On the other hand, interferon was dissolved in the water component. The aqueous solution of interferon was added while stirring the mixed liquid of the oil component and the surfactant, and further stirring was continued. When a transparent liquid was obtained, the rest of the oil component was added while continuing stirring to make the total amount.

When this liquid was measured by a laser light scattering type particle size distribution measuring device (Model 370 manufactured by Nicomp Corp.), a W / O type microemulsion having a particle size distribution with an average particle size of about 30 nm was obtained.

Example 4 Calcitonin (drug) 2.0 mg Isotonic phosphate buffer (water component) 1 ml POE (20) sorbitan monooleate (HLB = 15.0) (surfactant 1) 2.0 g monoolein Diglyceryl acid (HLB = 5.5) (Surfactant 2) 10.0 g Medium-chain fatty acid triglyceride (oil component) Total 100 ml Calcitonin is dissolved in a water component. Surfactant 1 (group b) and surfactant 2 (group c) are added to 80% of the oil component and stirred to dissolve. The calcitonin solution is added to the oil component in which the activator is dissolved, and the mixture is stirred. When the stirring was continued, a clear microemulsion liquid was obtained, and the oil component was added to make the total amount. When this particle size distribution was measured by a laser light scattering particle size distribution measuring device (DLS-7000 manufactured by Otsuka Electronics, Ar laser output 75 mW), the average particle size was 2.4.
An extremely fine microemulsion of nm was obtained.

Water was added to this solution and ultra-high speed centrifugation was performed to quantify calcitonin in the obtained aqueous phase.
92% of the added amount of calcitonin could be recovered (1 g was added, and the total recovered amount was 0.92 g).

Example 5 G-CSF (drug) 500 μg isotonic phosphate buffer (water component) 1 ml sodium di-2-ethylhexyl sulfosuccinate (surfactant 1) 7.0 g diglyceryl monooleate (HLB = 5) .5) (Surfactant 2) 5.0 g Medium-chain fatty acid triglyceride (oil component) 100 ml G-CSF is dissolved in a water component. Surfactant 1 (group a) and surfactant 2 (group c) are added to 80% of the oil component and stirred and dissolved. G-CSF is added to the oil component in which the activator is dissolved.
Add the lysate and stir. When the stirring was continued, a clear microemulsion liquid was obtained, and the oil component was added to make the total amount. When this particle size distribution was measured with a laser light scattering particle size distribution measuring device (Model DLS-7000 manufactured by Otsuka Electronics Co., Ltd.), an extremely fine microemulsion having an average particle size of 6.5 nm was obtained.

Water was added to this solution and ultra-high speed centrifugation was performed to quantify G-CSF in the obtained aqueous phase. As a result, 89% of the added amount of G-CSF could be recovered.

Example 6 G-CSF (drug) 500 μg isotonic phosphate buffer (water component) 1 ml polyoxyethylene (9) lauryl ether (HLB = 14.5) (surfactant 1) 10.0 g sesquiolein Acid sorbitan (HLB = 3.7) (Surfactant 2) 2.0 g Medium-chain fatty acid triglyceride (oil component) Total 100 ml G-CSF is dissolved in a water component. Surfactant 1 (group b) and surfactant 2 (group c) are stirred and dissolved in 80% of the oil component. The G-CSF solution is added to the oil component in which the activator is dissolved, and the mixture is stirred. When the stirring was continued, a clear microemulsion liquid was obtained, and the oil component was added to make the total amount. When this particle size distribution was measured with a laser light scattering particle size distribution measuring device (DLS-7000 type, manufactured by Otsuka Electronics Co., Ltd.), a microemulsion having an average particle size of 44 nm was obtained.

Water was added to this solution and ultra-high speed centrifugation was performed to quantify G-CSF in the obtained aqueous phase. As a result, 86% of the added amount of G-CSF could be recovered.

Example 7 Carbenicillin sodium (drug) 400 mg Distilled water (water component) 1.0 ml Polyoxyethylene (20) sorbitan monooleate (HLB = 15.0) (surfactant 1) 2.0 g sesquioleic acid Sorbitan (HLB = 3.7) (Surfactant 2) 10.0 g Medium-chain fatty acid triglyceride (oil component) Total 100 ml Carbenicillin sodium is dissolved in the water component. 80%
Amount of oil component in surfactant 1 (group b) and surfactant 2 (c
Group) and stir to dissolve. The carbenicillin sodium solution is added to the oil component in which the activator is dissolved, and the mixture is stirred. When the stirring was continued, a clear microemulsion liquid was obtained, and the oil component was added to make the total amount. When this particle size distribution was measured with a laser light scattering particle size distribution measuring device (Model DLS-7000 manufactured by Otsuka Electronics Co., Ltd.), a microemulsion having an average particle size of 9.2 nm was obtained.

Example 8 Antipyrine (drug) 200 mg Distilled water (water component) 1 ml Sodium di-2-ethylhexyl sulfosuccinate 7.0 g (surfactant 1) Diglyceryl monooleate (HLB = 5.5) (surfactant) Agent 2) 5.0 g Medium-chain fatty acid triglyceride (oil component) Total 100 ml Dissolve antipyrine in the water component. Surfactant 1 (group a) and surfactant 2 (group c) are added to 80% of the oil component and stirred and dissolved. An antipyrine solution is added to the oil component in which the activator is dissolved, and the mixture is stirred. When the stirring was continued, a clear microemulsion liquid was obtained, and the oil component was added to make the total amount.

Example 9 Propantheline bromide (drug) 100 mg Distilled water (water component) 1 ml Sodium di-2-ethylhexyl sulfosuccinate (surfactant 1) 7.0 g Diglyceryl monooleate (HLB = 5.5) (Surfactant 2) 5.0 g Medium-chain fatty acid triglyceride (oil component) 100 ml in total Dissolve propantheline bromide in the water component. Surfactant 1 (group a) and surfactant 2 (group c) are added to 80% of the oil component and stirred and dissolved. A propantheline bromide solution is added to the oil phase containing the activator and stirred. When the stirring was continued, a clear microemulsion liquid was obtained, and the oil component was added to make the total amount.

Example 10 Procainamide hydrochloride (drug) 400 mg Distilled water (water component) 1.0 ml Polyoxyethylene (9) lauryl ether (HLB = 14.5) (surfactant 1) 10.0 g Sorbitan sesquioleate (HLB = 3.7) (Surfactant 2) 2.0 g Medium-chain fatty acid triglyceride (oil component) 100 ml in total Procainamide hydrochloride is dissolved in a water component. 80% oil component in surfactant 1 (group b) and surfactant 2 (group c)
Add and stir to dissolve. A procainamide hydrochloride solution is added to the oil component in which the activator is dissolved, and the mixture is stirred. When stirring was continued, a clear microemulsion liquid was obtained, and medium-chain fatty acid triglyceride was added to make the total amount.

Example 11 Riboflavin sodium phosphate (drug) 10 mg Distilled water (water component) 1 ml Sodium di-2-ethylhexyl sulfosuccinate (surfactant 1) 7.0 g Diglyceryl monooleate (HLB = 5.5) (Surfactant 2) 5.0 g Medium-chain fatty acid triglyceride (oil component) Total 100 ml Riboflavin sodium phosphate is stirred and dissolved in a water component. For the oil component, surfactant 1 (group a) and surfactant 2 (c
Group) is added, and the mixture is stirred and dissolved, to which a solution of sodium riboflavin phosphate is added and stirred. When the stirring is continued, a pale yellow clear microemulsion liquid is obtained.

Example 12 Amaranth (model compound) 1 mg distilled water (water component) 1 ml sodium dodecyl sulfate (surfactant 1) 4.0 g diglyceryl monooleate (HLB = 5.5) (surfactant 2) 6 0.0 g Medium-chain fatty acid triglyceride (oil component) Total 100 ml A red dye, amaranth (*), is dissolved in water as a model compound in place of the drug. 80% of the oil component was taken, the activators 1 and 2 were added thereto, and the mixture was stirred for 60 minutes to obtain a dispersion liquid of the activator. To the liquid in which the activator was dispersed in this oil component, the water component in which amaranth was dissolved was added and stirred for 80 minutes. After standing, the supernatant was collected and centrifuged at 7,000 rpm for 40 minutes to obtain a clear liquid. The particle size distribution in this liquid was measured by a laser light scattering particle size distribution measuring device (the above-mentioned DLS-manufactured by Otsuka Electronics).
7000 type), the average particle size is 52 nm
The result was obtained. Further, water was added to this solution to make a double volume, and ultra-high speed centrifugation was carried out at 55,000 rpm for 1.5 hours to obtain a slightly red aqueous phase.

*; Amaranth 3-Hydroxy-4-[(4-sulfo-1-naphthalenyl) azo] -2,7-naph
Thalenedisulfonic acid trisodium salt Experimental Example: Absorption of microemulsion chemical solution (experimental method) Transdermal absorption experiment: 0.4 to 0.7 ml of the chemical solution prepared in the above Example was applied to a 3x4 cm lint cloth lined with a 4x5 cm polyethylene sheet. Apply evenly. The back of the rat is shaved, a lint cloth impregnated with a chemical solution is attached thereto, and the rat is wrapped with an elastic bandage. Rat blood is collected over time and the concentration of the drug in the blood is quantified.

Gastrointestinal absorption experiment: The abdomen of the rat was incised,
A silicone rubber tube is passed from the stomach wall to the duodenum, and the stomach wall, the peritoneum, and the skin at the tube penetration portion are sutured. After the rat has recovered from the surgical invasion, the drug solution prepared in the above-mentioned example is administered through a silicone rubber tube and the tube is sealed. Similarly, blood is collected over time and the blood drug concentration is quantified.

Rectal (mucosal) absorption experiment: A rat was fasted from the day before, and a rubber band was applied to the anus of the rat while the feces were almost absent in the abdomen, and a tube was inserted from the anus to prepare the above-mentioned example. Inject the required amount of drug solution.
Immediately after the injection is completed, squeeze the anus with a rubber band to prevent leakage of the drug solution. Blood is collected over time to quantify the drug concentration in blood.

Intranasal administration method The intranasal administration method is the method of Hirai et al. (INTERNATIONAL JOURNAL OF
PHARMACEUTICS, 7 (1981) 317-325). That is, the rat is anesthetized and the neck is incised along the midline to expose the trachea and esophagus. A part of the trachea is incised and a polyethylene tube is inserted into the trachea to secure the airway and ligated. Seal the nostril and oral incisor canal opening with adhesive. A part of the esophagus is incised, a feeding catheter is inserted from here, the tip is introduced into the nasal cavity, and the feeding catheter insertion part of the esophagus is ligated. The microemulsion containing the drug is infused through the feeding catheter. Blood is collected over time, and the time change of blood concentration of the drug is quantified.

(Experimental Results) The data of percutaneous, oral (gastrointestinal) and transmucosal (rectal) absorption of the microemulsion preparation of the present invention are shown in the following table.

No local irritation was observed on the skin or mucous membranes of any of the preparations.

[Table 1] Utilization rate: The utilization rate by subcutaneous injection (time-dependent integrated value of blood concentration) is set to 100%.

(* 1): Erythropoietin was used instead of calcitonin in Example 1.

(Evaluation of Experimental Data) For a large molecular weight peptide such as erythropoietin, the utilization rate of 2 to 3% is epoch-making. In addition, 22 to 23% of the utilization rate of calcitonin by rectal absorption and 50% of utilization rate by nasal absorption are sufficiently practical values.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 9/107 U E S 38/22 38/28 38/23 38/11 38/21 8314-4C A61K 37/26 8314-4C 37/30 8314-4C 37/34 8314-4C 37/66 H

Claims (5)

[Claims] 1. A water-in-oil type (W / O type) microemulsion containing a non-absorbable physiologically active substance in an aqueous phase, comprising:
A microemulsion preparation characterized by using one or more kinds of the following surfactants (c) and one or more kinds of surfactants (a) or one or more kinds of (b): (a) ions system surfactant di 2-ethylhexyl sodium sulfosuccinate, alkyl sodium sulphate (the alkyl moiety _{C 8 -C 20) (b)} HLB of 10-20 nonionic surfactants: polyoxyethylene hydrogenated or non-hydrogenated castor oil (Oxyethylene average addition mole number is 30-80); polyethylene glycol higher fatty acid ester (fatty acid is a saturated or unsaturated C ₁₆ -C ₂₀ fatty acid, ethylene glycol average addition mole number is 10-40); polyoxyethylene alkyl ether (alkyl moiety is a C ₈ -C _14, oxyethylene average addition mole number 4-25) (c) H Nonionic surfactant B is 3-7: mono- or a C ₁₆ -C ₂₀ fatty acid polyglycerol fatty acid ester (fatty acid saturated or unsaturated, fatty acid addition number of moles per 1 mole of glycerin is 1-2 And glycerin addition mole number is 0-4); sorbitan fatty acid ester (fatty acid is saturated or unsaturated C ₁₆ -C ₂₀ and addition mole number is 1-3); polyoxyethylene cured or uncured Castor oil (oxyethylene average addition mole number 3-2
0). 2. The microemulsion preparation according to claim 1, wherein the surfactant is a combination of the following (a), (c) or (b), (c). (A) Ionic surfactant sodium 2-diethylhexyl sulfosuccinate; sodium alkylsulfate (alkyl portion is C ₁₀ -C ₁₄ ) (b) Nonionic surfactant having HLB of 10-20: polyoxyethylene curing or Unhardened castor oil (oxyethylene average addition mole number is 40-60); polyethylene glycol higher fatty acid ester (fatty acid is a saturated or unsaturated C ₁₈ fatty acid, ethylene glycol average addition mole number is 10-40); Polyoxyethylene alkyl ether (wherein the alkyl moiety is C ₁₂ and the average number of moles of oxyethylene added is 4-25) (c) HLB is 3-7 nonionic surfactant: mono- or polyglycerin fatty acid ester (fatty acid is a C ₁₈ saturated or unsaturated fatty acids, fatty acid addition number of moles per 1 mol of glycerin Is 1-2, further addition mole number 0-4 glycerin); sorbitan fatty acid esters (fatty acid is a C ₁₆ -C ₁₈ saturated or unsaturated, the addition molar number of 1-3); polyoxyethylene Hardened or unhardened castor oil (oxyethylene average added mole number 8-12). 3. The particle size of the microemulsion is 0.
It is 4-100 nanometer, The microemulsion formulation of Claim 1 or 2 characterized by the above-mentioned. 4. The poorly absorbable bioactive substance is vasopressin,
Calcitonin, erythropoietin, colony stimulating factor,
An interleukin, an interferon, insulin, and parathyroid hormone.
The microemulsion preparation according to 2 or 3. 5. The microemulsion preparation according to claim 1, which is in the form of a transdermal drug, an oral drug or a transmucosal drug.