JPH0912467A - Alpha2-macroglobulin inclusion complex for application to mucosa - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a complex composed of an inclusion complex of a protein of alpha2-macroglobulin group with one or more than one kind drug and capable of extremely increasing the mucosal absorption of a drug especially having high molecular weight such as a peptide. SOLUTION: This composition for applying to mucosa (preferably, gut mucosa) is composed of an inclusion complex of (A) a protein of alpha2- macroglobulin group (peferably, human alpha2-macroglobulin) with (B) one or more than one kind drug (preferably, a drug having a molecular weight of 1,000-100,000, and a peptide protein drug or a vaccine). A peptide protein drug of the component B is preferably one or more than one kind peptide selected from interferons, HGF, EGF, TGF-β, insulin, proinsulin and PDGF, or its derivative. Further, the vaccine is preferably a hepatitis virus vaccine, pertussis virus vaccine, polio virus vaccine, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition for transmucosal administration comprising an inclusion complex of an α ₂ macroglobulin family protein and a drug. More specifically, the present invention relates to a composition for transmucosal administration comprising an inclusion complex of a human α ₂ macroglobulin family protein and a drug, which enables easy administration of a high-molecular-weight drug, which is an alternative to an injectable preparation.

[0002]

2. Description of the Related Art Conventionally, most of drugs containing peptides and other high molecular weight drugs having a molecular weight of about 1,000 or more as an active ingredient have been administered by injection preparations. . However, this method of administration requires a patient visit, is not painful and is not a form that can be easily performed. In order to solve this problem, non-injection administration methods have been studied, and attempts have been made to absorb the drug through mucous membranes such as nasal cavity, lung, gastrointestinal tract, oral cavity and vagina.

Up to now, several transmucosal preparations showing a good absorption rate for drugs having a molecular weight of about 1,000 or more have been shown in patents, papers, conference presentations, etc., but clinical safety and absorption Most of them have not been put to practical use due to their low rate, and among the few transmucosal preparations that have been put to practical use,
Very few have obtained a satisfactory absorption rate to some extent. In particular, there is no transmucosal preparation showing a satisfactory absorption rate for a drug having a molecular weight of more than 5,000. Further, among transmucosal preparations, the development of oral preparations via the intestinal mucosa is particularly desired due to the ease of administration, but it is said that oral preparations of commercially available peptide drugs have a satisfactory absorption rate. hard.

[0004] The α ₂ macroglobulin family protein is a serum protein widely distributed in the animal kingdom, and human, rat, horseshoe crab and other such proteins are well known. It is characterized by having a thioester bond and a bait region in the molecule and having the ability to include a protease or peptide by trapping. As functions of the α ₂ macroglobulin family proteins, inhibition of the activity of unnecessary proteases or peptides and scavenging are considered.

[0005] These features of alpha ₂ macroglobulin family proteins is believed to be exerted by the large change in the conformation of alpha ₂ macroglobulin family proteins. The details will be described below for humans, but the same applies to other α ₂ macroglobulin family proteins. Over 99% of human α ₂ macroglobulin in serum has a three-dimensional structure usually called SLOW type. This α ₂ macroglobulin has a site called a bait region, in which a series of sequences that are easily recognized and decomposed by almost all proteases are concentrated inside the molecule, and when the protease is present, this bait region is recognized and decomposed. . This reaction triggers the exposure of the thioester bond site, which was previously buried in the hydrophobic region inside the molecule, to the surface of the molecule. As a result, the thioester bond is nucleophilically attacked and cleaved by the water molecule. This cleavage of the thioester bond is also caused by direct attack of the thioester bond site inside the molecule by a low molecular weight compound having high nucleophilicity such as methylamine even in the absence of protase.
This dissociation of the thioester bond triggers α ₂ macroglobulin to greatly change its three-dimensional structure so as to sterically include a protease attacking the bait region or a molecule such as a peptide existing in the vicinity. . Such a structure after the action of protease or methylamine is usually called FAST type. F
AST-type α ₂ macroglobulin has a receptor recognition site buried inside the molecule in the SLOW-type that is exposed on the surface of the molecule and is recognized by cells expressing specific receptors. Generally, the cells are recognized by endocytosis. It is believed to be taken up by. By the mechanism described above, the α ₂ macroglobulin family protein includes a compound such as a protease or a peptide to inhibit the activity (inhibition of the activity of the protease or the peptide) or is recognized by a cell expressing a specific receptor. It is taken in (Skapenji). Receptors are hepatocytes, fibroblasts,
It is known that it is particularly abundantly expressed in macrophages, astrocytes, smooth muscle cells and the like.

Until now, some application studies have been made and patents have been issued focusing on these functions of human α2 macroglobulin family proteins.

[0007] Kidron et al. Have shown that the combined use of a protease inhibitor improves the absorption rate of insulin in an enteral mucosal preparation comprising insulin, specific bile acids and a protease inhibitor. As one of the protease inhibitors, α2 macroglobulin is mentioned (JP-A-60-69028). Esteis et al. Have shown that the inclusion of human α2 macroglobulin in the vesicle improves the effectiveness of interferon as a vehicle for intestinal mucosal administration of interferon (JP-A-60-188328). However, in these techniques, α ₂ macroglobulin is used as a protease inhibitor, there is no description of its use as a carrier, and α ₂ macroglobulin alone is added so as to be mixed with other components. It is used, and there is no description about the inclusion complex.

[0008] In addition, Tomoda et al. Showed that a complex formed by including a conjugate of a protease with another anti-inflammatory enzyme in human α ₂ macroglobulin protease decreased its antigenicity while retaining the activity of the anti-inflammatory enzyme. It has been found that this is done (Japanese Patent Laid-Open No. 59-175885). However,
A protease is essential as one of the constituent components of this inclusion complex, and there is no description about the inclusion complex of anti-inflammatory enzyme and human α ₂ macroglobulin. Moreover, this inclusion complex is mentioned as a substance that enables injection administration in which the antigenicity of the anti-inflammatory enzyme is a particular problem, and transmucosal administration is not mentioned at all.

Inokai et al. (Biochem. Biophys. Res. Com
mun, 194 (3) 1155-1160 (1993)),
Pizzo et al. (J. Immun, 152: 1538-1545 (1
994)) found that inclusion of an antigenic epitope peptide with human α ₂ macroglobulin or simple binding thereof promotes efficient antibody production, and that α ₂ macroglobulin is useful as a carrier for vaccines. Is getting However, all of these are carried out by injection administration, which is essentially different from the present invention in which these complexes serve as carriers for permeation through mucous membranes.

Furthermore, Matsuda et al. Reported that α ₂ macroglobulin encapsulating α-galactosidase A, which is a lysosomal enzyme, was carried into lysosomes when administered to fibroblasts of patients lacking this enzyme gene. Is expressed (J. Clin. Invest. 87:
39-44 (1991)). These are inclusion complexes of α ₂ macroglobulin-enzyme and are used as carriers, but they are carriers for receptor-expressing cells and not as carriers for permeating mucosal cells.

That is, there has been no knowledge that the α ₂ macroglobulin family protein serves as a carrier that allows the drug to permeate the mucous membrane for the systemic blood flow.

[0012]

In view of the above circumstances, the inventors of the present invention have earnestly studied to develop a composition for transmucosal administration which is excellent in absorbability of high molecular weight drugs such as peptides. As a result, the composition for transmucosal administration in which a drug such as insulin or interferon is included in the α ₂ macroglobulin family protein shows transmucosal absorbability of high molecular drugs such as migration from the luminal side to the vascular side. The inventors have found that they can be significantly improved, and have completed the present invention.

That is, the present invention is a composition for transmucosal administration, which comprises an inclusion complex of an α ₂ macroglobulin family protein and one or more drugs.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the α ₂ macroglobulin family protein can include an α ₂ macroglobulin family protein, a complex thereof, or a mutant thereof.
Specific examples include the following. Human α ₂ macroglobulin, human PZP, rat α ₁ macroglobulin, rat α ₂ macroglobulin, horseshoe crab α macroglobulin, ovomacroglobulin. Among these, human α ₂ macroglobulin is most preferred because of its low antigenicity and high inclusion ability. A mutant is a product obtained by modifying, deleting, or adding a part of the amino acid sequence of these α ₂ macroglobulin family proteins by a genetic engineering method, etc., and a modified product has a sugar chain or the like as a part thereof. It means the one added.

In the present invention, the drug preferably has a molecular weight of 1,000 because it can be efficiently clathrated.
More than 100,000 (100,000) or less, for example, peptide proteinaceous drugs and / or vaccines can be mentioned.
More preferably, a peptide is preferable because it can be efficiently included.

In the present invention, examples of the peptide proteinaceous drug include the following, but the present invention is not limited thereto. Interferons, SOD, catalase, APC, HG
F, EPO, G-CSF, GM-CSF, interleukin, ANP, somatostatin, tPA, antithrombin, blood coagulation factor IV, hirudin, endorphin,
ACTH, neurotensin, angiotensin, transferrin, endothelin, vasopressin, desmopressin, PTH, LH, LHRH, prolactin, glucagon, gastrin, secretin, oxytocin, urokinase, VIP, TGF-β, PDGF, TNF-.
α, calcitonin, insulin, proinsulin, EG
One or more peptides selected from the group consisting of F, GH, GHRH, and somatomedin C, and derivatives thereof.

In the present invention, among the above-mentioned peptide protein drugs, as the drug targeting the liver which strongly expresses the receptor for the α ₂ macroglobulin family protein, interferons and HG are particularly preferable.
One or more peptides selected from the group consisting of F, EGF, TGF-β, insulin, proinsulin, PDGF and derivatives thereof can be mentioned.

The following are specific examples of vaccines in the present invention, but the present invention is not limited to these. One or more vaccines selected from the group consisting of hepatitis virus vaccine, pertussis virus vaccine, diphtheria virus vaccine, tetanus virus vaccine, AIDS virus vaccine, influenza virus vaccine, poliovirus vaccine, rhinovirus vaccine. In the present invention, an influenza virus vaccine can be mentioned as a particularly preferable vaccine among the above vaccines. The amount of such a peptide protein drug or vaccine used is not particularly limited as long as it is an amount effective for the intended treatment.

The method for preparing the inclusion complex of the α ₂ macroglobulin family protein and the drug of the present invention includes, for example, human α
_{2 A} macroglobulin-containing solution (for example, 0.1 M phosphate buffer, pH 7.0, etc.) and a nucleophilic reagent such as 2 to 4 times the molar amount of protease or 2 to 40 times the molar amount of methylamine and 10 It is carried out by mixing a drug in an amount equal to or more than a double molar amount. The mixture has a temperature of about 4 to 40 ° C. and a pH of
This can be done by mixing in about 6-8. In this case, only one kind of drug can be included, or two or more kinds of drugs can be included as necessary. In the present invention, the inclusion of the drug in the α ₂ macroglobulin family protein means that all of the drug is encapsulated in the α ₂ macroglobulin family protein molecule, and only a part of the drug is coated, It also refers to the state where the other parts are protruding. The protease used for the preparation may be any protease as long as it forms a complex with the α ₂ macroglobulin family protein. Examples thereof include trypsin, chymotrypsin, thrombin, plasmin, elastase, subtilisin, thermolysin, papain, bromoline and the like, and examples of the nucleophilic reagent include methylamine and ethylamine.

As described above, after the drug is included in the α ₂ macrobroblin family derivative, the reaction solution as described in the prior art of Inoi et al. A powdery or freeze-dried powdery or liquid inclusion complex of the α ₂ macroglobulin family protein and one or more drugs can be obtained, and thus the composition for transmucosal administration of the present invention is obtained. can get.

The mucous membrane of the present invention includes nasal cavity, oral cavity, lung,
Stomach, intestinal tract, vagina and the like can be mentioned, and among these, stomach, intestinal tract, and in particular intestinal tract can be mentioned as preferable ones. The composition for transmucosal administration of the present invention described above,
As a single composition for these mucous membranes, or as a pharmaceutically acceptable excipient, such as starch, lactose, grapes, crystalline cellulose, water, physiological saline, buffer, etc .;
It may be a pharmaceutical composition to be administered as a solid or liquid composition together with other necessary binders, antioxidants and the like. Specifically, as a preparation for transmucosal administration containing such a pharmaceutical composition, conventionally known preparations applicable to mucous membranes such as tablets, powders, granules, capsules and liquids can be used. .

In the present invention, as the administration method, a general method for administering a drug to each mucous membrane can be applied. Of these, the method of oral administration when administered to the intestinal mucosa is most preferable because of its simple administration. In the case of a solid preparation for transmucosal administration, it is desirable that the active ingredient be administered as an enteric-coated preparation such as an enteric-coated capsule preparation in order to prevent inactivation of the stomach surface under strong acidity. .

When used as a liquid preparation for transmucosal administration, there is a method in which the prepared solution of the inclusion complex is put in a spray container or a syringe and sprayed or dropped onto a mucosal site such as the nasal cavity. Furthermore, the freeze-dried powder is filled in the capsule as it is, set in a dedicated spraying device, the needle is pierced, and thereby a minute hole is opened at the top and bottom of the capsule,
Next, there is a method in which air is blown in with a rubber ball or the like and jetted to a mucous membrane site such as the nasal cavity.

It is of great medical value that the present invention can provide a preparation capable of efficiently transmucosally administering a drug, particularly a high molecular weight peptide protein drug or vaccine.

[0025]

EXAMPLES The effects of the composition for transmucosal administration of the present invention will be described below with reference to Examples. [Reference Example 1] Human α ₂ macroglobulin labeled by FITC (manufactured by Seikagaku Corporation) was used in an amount of 2 times the molar amount of bovine pancreatic trypsin (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.1M phosphate buffer (p.
H7.0) at 37 ° C., and the reaction solution was subjected to gel filtration to obtain FAST type human α ₂ macroglobulin. This was dissolved in an isotonic phosphate buffer solution having a pH of 6.95 so as to have a concentration of 1 mg / ml, and this was used as a sample solution. This sample solution was used as a reflux liquid in rats
A tu whole intestinal perfusion experiment was performed. Reflux speed is 5 ml / m
in. And sample the solution after refluxing over time,
The fluorescence intensity was measured and converted into the human α ₂ macroglobulin (α ₂ M) concentration (μg / ml) in the Serosul solution. Table 1 shows the results.

[Reference Example 2] In Reference Example 1, a sample solution of human α2 macroglobulin labeled with SLOW type FITC not reacted with protease in place of FAST type human α ₂ macroglobulin (concentration 1 mg / ml )
Was prepared and the same experiment as in Reference Example 1 was conducted. Table 1 shows the results
Shown in

[0027]

[Table 1]

FAST-type human α ₂ macroglobulin (Reference Example 1) reacted with a protease ap the rat intestine.
Penetrates from ical to basolateral. On the other hand, it was shown that SLOW-type human α ₂ macroglobulin (Reference Example 2) does not penetrate at all.

[Example 1-1] Human α ₂ macroglobulin (manufactured by Seikagaku Corporation) in the presence of a 2-fold molar amount of bovine pancreatic trypsin (manufactured by Wako Pure Chemical Industries, Ltd.) and a 20-fold molar amount of insulin and 0.1M. After incubation in a phosphate buffer (pH 7.0) (hereinafter abbreviated as PBS) at 37 ° C., the reaction solution was subjected to gel filtration to obtain a human α ₂ macroglobulin-insulin inclusion complex. Dissolve this in PBS and add 2 insulin
Male rats (Wistar strain, body weight: 180 to 200 g) fasted for 16 hours to 0 IU / kg were forcibly orally administered with a sonde. Blood was collected from the jugular vein after a certain period of time, and the glucose concentration in the serum was measured by glucose B-test.
Using a kit (Wako Pure Chemical Industries, Ltd.), the glucose oxidase method was used to determine the blood glucose level (%; initial value). The results are shown in FIG. [Example 1-2] Human α ₂ macroglobulin (manufactured by Seikagaku Corporation) in the presence of a 20-fold molar amount of methylamine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) in a 20-fold molar amount of insulin and PBS at 37 ° C. Incubate, gel the reaction,
Human α ₂ macroglobulin-insulin inclusion complex was obtained. Dissolve this in PBS and insulin amount 20 IU / k
male rats (Wist
ar system, body weight: 180-200 g) was forcibly orally administered by a sonde. Blood was collected from the jugular vein after a fixed time, and the glucose concentration in the serum was measured by the glucose oxidase method using a glucose B-test kit (Wako Pure Chemical Industries, Ltd.). The results are shown in FIG.

[Comparative Example 1-1] Human α ₂ macroglobulin (manufactured by Seikagaku Corporation) was incubated with double molar amount of bovine pancreatic trypsin (manufactured by Wako Pure Chemical Industries, Ltd.) in PBS at 37 ° C to prepare a reaction solution. Gel filtered to give FAST human α ₂
Macroglobulin was obtained. A 20-fold molar amount of insulin was mixed with this to obtain a FAST type human α ₂ macroglobulin-insulin mixture. This mixture was dissolved in PBS and fasted for 16 hours so that the amount of insulin was 20 IU / kg. Male rats (Wistar strain, body weight: 180-2)
(00g) was forcibly orally administered by a sonde. Blood was collected from the jugular vein after a fixed time, and the glucose concentration in the serum was measured by the glucose oxidase method using a glucose B-test kit (Wako Pure Chemical Industries, Ltd.). The results are shown in FIG.

[Comparative Example 1-2] Human α ₂ macroglobulin-insulin mixture was obtained by mixing human α ₂ macroglobulin (manufactured by Seikagaku Corporation) with a 20-fold molar amount of insulin. This mixture is dissolved in PBS and the amount of insulin is 20I.
A male rat (Wistar strain, body weight: 180 to 200 g), which had been fasted for 16 hours, was forcibly orally administered with a sonde so that the dose became U / kg. Blood was collected from the jugular vein after a certain period of time, and the glucose concentration in the serum was measured by glucose B-test.
It measured by the glucose oxidase method using the kit (Wako Pure Chemical Industries Ltd.). The results are shown in FIG.

From FIG. 1, a mixture of FAST type human α ₂ macroglobulin (α ₂ M) and insulin (Comparative Example 1-
It can be seen that in 1), no hypoglycemic effect was observed. On the other hand, the mixture of SLOW-type human α ₂ macroglobulin and insulin (Comparative Example 1-2) only showed a slight hypoglycemic effect of about several percent.

On the other hand, in the administration of human α ₂ macroglobulin and insulin inclusion complex (Example 1-1: protease treatment, Example 1-2: methylamine treatment),
A hypoglycemic effect of up to about 50% is observed, indicating the usefulness of the composition of the present invention. [Example 2] Human α ₂ macroglobulin (manufactured by Seikagaku Corporation) in the presence of a 2-fold molar amount of bovine pancreatic trypsin (manufactured by Wako Pure Chemical Industries, Ltd.) and a 20-fold molar amount of ¹²⁵ I interferon and P
After incubation in BS at 37 ° C., the reaction solution was subjected to gel filtration to obtain a human α ² macroglobulin-interferon inclusion complex. This inclusion complex was made into an enteric-coated capsule formulation so as to have 1 million IU, 2 million IU, and 5 million IU in terms of interferon (complex dose: 1, 2, 5 mg), and orally administered to rats (n = 5). Immediately before administration and 0.5, 1, 2, 3, 10, 30 minutes after administration, 500 μl of blood was collected from the portal vein, and ¹²⁵ I of the collected blood was collected.
Radioactivity was measured using a gamma counter. The ¹²⁵ I radioactivity (DPM) in portal blood of each administration group is shown in FIG. (N
The average value of 5 is shown. [Comparative Example 2-1] Human α ₂ macroglobulin (manufactured by Seikagaku Corporation) was incubated with double molar amount of bovine pancreatic trypsin (manufactured by Wako Pure Chemical Industries, Ltd.) in PBS at 37 ° C, and the reaction solution was gelled. After filtration, FAST type human α ₂ macroglobulin was obtained. The FAST-type human alpha ₂ macroglobulin and 20 times the molar amount of ¹²⁵ I interferon mixed FAST human alpha ₂ macroglobulin - give the interferon mixture. This mixture was made into enteric capsule preparations so that the interferon equivalent was 1 million IU, 2 million IU, and 5 million IU (complex dose: 1, 2, 5 mg), and was orally administered to rats (n = 5). . Immediately before administration and 0.5, 1, 2, 3, 10, 30 minutes after administration, 500 μl of blood was collected from the portal vein, and ¹²⁵ I radioactivity of the collected blood was measured using a γ counter. The ¹²⁵ I radioactivity (DPM) in portal blood of each administration group is shown in FIG. (N = 5
The average value of ) Comparative Example 2-2] Human alpha ₂ macroglobulin (Seikagaku Corp.) was mixed with 2-fold molar amount of ¹²⁵ I interferon human alpha ₂ macroglobulin - give the interferon mixture. This mixture was converted into interferon 10
An enteric-coated capsule preparation was prepared so that the amount would be 0,000 IU, 2 million IU, and 5 million IU (complex dose: 1, 2, 5 mg) and was orally administered to rats (n = 5). 5 from the portal vein immediately before administration and 0.5, 1, 2, 3, 10, 30 minutes after administration
Blood was collected in an amount of 00 μl, and ¹²⁵ I radioactivity of the collected blood was measured using a γ counter. In portal blood of each administration group
¹²⁵ I radioactivity (DPM) is shown in FIG. (Indicated by the average value of n = 5.) From FIG. 2, when administered as a simple mixture with interferon (Comparative Example 2-1: FAST type, 2-2: SL)
(OW type) shows almost no radioactivity in the portal blood, whereas when administered as the inclusion complex of the present invention (Example 2), the radioactivity in portal blood permeated at a high rate. Is shown to appear.

[Example 3] Human α ₂ macroglobulin 1
mg in the presence of twice the molar amount of bovine pancreatic trypsin, influenza inactivated vaccine (A / PR / 8 (H1N1))
After incubation with 1 mg of PBS at 37 ° C., the reaction solution was subjected to gel filtration to obtain a human α ₂ macroglobulin-influenza inactivated vaccine inclusion complex. This was used as an enteric-coated capsule formulation (0.1 μg vaccine / capsule) and orally administered to rats. Four weeks after the immunization, 2 μl of an influenza virus (A / PR / 8 (H1N1)) solution
Was intranasally administered for challenge infection, and the virus titer (EID ₅₀ : 10 ⁿ ) in the nasal wash solution was measured 3 days later. Table 2 shows the results. (Indicated as an average value of n = 5.) [Comparative Example 3] 1 mg of human α ₂ macroglobulin was incubated with double molar amount of bovine pancreatic trypsin in PBS at 37 ° C, and the reaction solution was subjected to gel filtration to obtain FAST type. Human α ₂ macroglobulin was obtained. This FAST type human α
1 mg of ₂ macroglobulin and 1 mg of influenza inactivated vaccine (A / PR / 8 (H1N1)) were mixed, and the obtained human α ₂ macroglobulin-influenza inactivated vaccine mixture was used as an enteric capsule formulation (0.1 μm).
g vaccine / capsule), orally administered to rats. Four weeks after this immunization, influenza virus (A / PR /
8 (H1N1)) solution (2 μl) was intranasally administered for challenge infection, and virus titer (EID ₅₀ :) in the nasal wash solution after 3 days of challenge infection
10 ⁿ ) was measured. Table 2 shows the results. (Indicated by the average value of n = 5.)

[0035]

[Table 2]

From Table 2, the virus titer in the nasal wash is α
_{2 About} 100 times lower when administered as the inclusion complex of the present invention (Example 3) than when administered as a simple mixture of ₂ macroglobulin and influenza vaccine (Comparative Example 3) I understand.

[Brief description of the drawings]

FIG. 1 shows the blood glucose lowering rate (blood glucose level (%; relative to initial value)) when human α ₂ macroglobulin (α ₂ M) -insulin is orally administered. In FIG. 1, each symbol is ◯: Example 1
-1, ×: Example 1-2, □: Comparative Example 1-1, ⋄: Comparative Example 1-2.

FIG. 2 Human α ₂ macroglobulin (α ₂ M) ^-125 I
¹²⁵ I radioactivity (DPM) in portal blood after oral administration of interferon is shown. In FIG. 2, each symbol is ◯: Example 2, □: Comparative example 2-1 and ◇: Comparative example 2-2. .

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 38/23 A61K 37/26 38/11 37/28 38/27 37/30 38/04 37 / 32 38/43 37/34 38/44 37/36 38/46 37/43 38/55 37/465 38/21 37/50 39/00 37/54 47/42 37/64 37/66 H (72) Inventor Takao Fujii 4-32 Asahigaoka, Hino-shi, Tokyo Inside Teijin Limited, Tokyo Research Center

Claims (11)

[Claims] 1. A composition for transmucosal administration, which comprises an inclusion complex of an α ₂ macroglobulin family protein and one or more drugs. 2. The composition for transmucosal administration according to claim 1, wherein the mucous membrane is the intestine. 3. The drug has a molecular weight of 1,000 to 100,
The composition for transmucosal administration according to claim 1, wherein the composition is 000. 4. The composition for transmucosal administration according to claim 1, wherein the drug is a peptide / protein drug. 5. The composition for transmucosal administration according to claim 1, wherein the drug is a vaccine. 6. The peptide protein drug is an interferon, SOD, catalase, APC, HGF, EP.
O, G-CSF, GM-CSF, interleukin, A
NP, somatostatin, tPA, antithrombin, blood coagulation factor IV, hirudin, endorphin, ACT
H, neurotensin, angiotensin, transferrin, endothelin, vasopressin, desmopressin, PTH, LH, LHRH, prolactin, glucagon, gastrin, secretin, oxytocin, urokinase, VIP, TGF-β, PDGF, TNF-α, calcitonin, insulin, pro Insulin, EGF, G
The composition for transmucosal administration according to claim 4, which is one or more peptides selected from the group consisting of H, GHRH, and somatomedin C, and derivatives thereof. 7. The method according to claim 4, wherein the peptide proteinaceous drug is at least one peptite selected from the group consisting of interferons, HGF, EGF, TGF-β, insulin, proinsulin and PDGF, and derivatives thereof. A composition for mucosal administration. 8. The vaccine is a hepatitis virus vaccine, a pertussis virus vaccine, a diphtheria virus vaccine,
1 selected from the group consisting of tetanus virus vaccine, AIDS virus vaccine, influenza virus vaccine, poliovirus vaccine, rhinovirus vaccine
The composition for transmucosal administration according to claim 5, which is a vaccine of one or more species. 9. The α ₂ macroglobulin family protein is human α ₂ macroglobulin.
A composition for transmucosal administration according to the item. 10. The composition for transmucosal administration according to any one of claims 1 to 9, which is in the form of an oral preparation. 11. The inclusion complex is obtained by reacting an α ₂ macroglobulin family protein with one or more drugs in the presence of an appropriate proteolytic enzyme or nucleophile. The composition for transmucosal administration according to any one of 1.