JPH06256219A - Pharmaceutical composition for transmucous administration - Google Patents

Abstract

PURPOSE:To obtain a pharmaceutical composition for transmucous administration, having remarkably decreased mucosa-stimulation action and applicable in combination with an anapnoic agent without deteriorating the respiration promoting action of the agent. CONSTITUTION:The pharmaceutical composition for transmucous administration contains 0.01-50wt.% of trehalose. Trehalose is a disaccharide having a molecular weight of 342.30 and composed of two D-glucose molecules bonded together through their reducing groups. There are three kinds of isomers different in the bonding types, i.e., alpha,alpha-bond, alpha,beta-bond and beta,beta-bond and the composition is compounded with one of the isomers or a mixture of the isomers.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition suitable for drug delivery by absorption from mucosal surfaces, which is a novel pharmaceutical composition containing trehalose for transmucosal administration. Regarding

More specifically, by incorporating trehalose into a pharmaceutical composition for transmucosal administration, the mucosal stimulating action is markedly reduced, and in a system in combination with an absorption enhancer, transmucosal administration does not impair the absorption promoting effect. Pharmaceutical composition.

[0003]

BACKGROUND ART In recent years, interest in drug administration methods for absorption through mucous membranes such as the nasal mucosa has increased. Nasal mucosal administration, in particular, has many advantages over other routes of administration. First of all, oral administration has the drawback that the amount of absorption is influenced by the metabolism of the drug in the gastrointestinal tract, but the nasal mucosa has a low enzymatic activity, so there is little decomposition of the drug and it is suitable for administration of bioactive peptides and the like. There are points. In addition, while oral administration undergoes first-pass metabolism in the liver, administration in nasal mucosa does not undergo first-pass metabolism because the drug directly transfers to the systemic circulation system. Moreover, the permeability of the nasal mucosa is higher than that of other mucous membranes such as the vaginal mucosa, and the absorption of the drug is efficient. Furthermore, transnasal mucosal administration is a desirable administration method from the viewpoint of replacement of injections and the like, that is, improvement of compliance.

By the way, absorption of a drug by intranasal administration is affected by the clearance rate in the nasal cavity. For example, the clearance rate in the nasal cavity under pathological conditions such as a cold is much higher than that in the normal state, and the absorption efficiency of the drug is significantly reduced. Therefore, various approaches have been attempted to date, such as increasing retention of the drug in the nasal cavity and decreasing ciliary motility that controls clearance, with the aim of increasing the absorption efficiency of the drug by intranasal administration. . Among them, the most commonly attempted is to enhance the permeability of mucosa, and a wide variety of absorption enhancers are used for that purpose. Examples include fatty acids,
Examples include the use of bile salts, many surfactants and chelating agents. (Life Sciences Series
s A Vol. 125 p87-104, Critic
al Reviews in Therapeutic
Drug Carrier Systems, 8
(4), 331-394, 1991).

The conventional drug composition for transmucosal administration has a problem of irritation, and the combined use system with an absorption enhancer has a problem of toxic side effects which are present together with the absorption enhancing effect on the drug. For example, many bile salts and other surfactants used as absorption enhancers histologically exert a wide range of destructive action on the surface layer of the mucosal epithelium and give irreparable damage (Pharmacia vol. 28 no. 61992). Also, chelating agents are known to have an effect of impairing calcium ion activity and a damaging effect on ciliated epithelium. Only Tauro sodium 24,25-dihydrofusidate (STD
HF has been found to have low histological toxicity (Pharmaceutical Reac
h, Vol. 7, No. 5, 1990), and report that it is accompanied by sensory stimulation (Pharmaceutical Rese
ach, Vol. 9, No. 1, 1992), and reduction of their toxicity and side effects has become an important issue for many absorption enhancers.

The inventors of the present invention have diligently studied the components of the composition in order to solve the above-mentioned problems in the prior art. As a result, by incorporating trehalose into a pharmaceutical composition for transmucosal administration, toxicity and side effects It was found that the effect of mucosal irritation can be remarkably reduced without significantly reducing the absorption promoting effect even when used in combination with the absorption promoting agent.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a novel pharmaceutical composition for transmucosal administration characterized by containing trehalose.

The present invention will be specifically described below. The trehalose used in the novel pharmaceutical composition for transmucosal administration according to the present invention is also called micose and has a molecular weight of 342.3.
It is one of the disaccharides showing 0 and has a structure in which two molecules of D-glucose are bound to each other by their reducing groups.
In its binding mode, α, α-bond, α, β-bond,
There are three types of isomers, β and β-bonded, and naturally they exist as α and α forms. Traditionally, trehalose is
It is known as a cell dry protection substance or a cryoprotection substance. The application of this trehalose as a new preservative for foods and pharmaceuticals is under study. For example, as an immunoadjuvant to a vaccine (Adv Immunopharmacology
4 149-158 1989), or as a phase transition protective agent for dimyristoylphosphatidylcholine liposomes (Biochem Biophys Act).
a, May 24 1990, 1024 (2), p38.
0-4), and as a preservative for phosphofructokinase (Biochem Biophys Acta, Ja.
n 20 1987 923 (1), p109-1
5) and as a stabilizer for lipid membrane (Arch Bi
ochem Biophys, Feb 15 198
6, 245 (1), p134-43), and the use thereof, respectively. However, no study has been conducted so far on the effect of reducing the irritation or side effect of trehalose in the external preparation for transmucosal administration.

In the novel pharmaceutical composition for transmucosal administration according to the present invention, each of the above-mentioned three types of isomers or a mixture thereof is used and blended. The amount of trehalose blended in the composition of the present invention varies depending on the kinds of pharmacologically active substances and additives to be combined, but is 0.01% to 9% based on the total weight of the composition.
It can be appropriately determined within the range of 9.99%.

The pharmacologically active substance in the pharmaceutical composition for transmucosal administration according to the present invention is not particularly specified. Examples of the pharmacologically active substance include the following substances. Proteins and peptides such as insulin (hexamer / dimer / monomer), glucagon,
Growth hormone (somatotropin), calcitonin and its synthetic modifications, enkephalin, interferon (especially α-2 interferon for the treatment of common cold), luteinizing hormone-releasing hormone (LHRH) and analogues (nafarelin, buserelin, leuprorelin, goserelin). , Growth hormone releasing hormone (GHRH), secretin, bradykinin antagonist, growth hormone releasing factor (G
RF), thymic humoral factor (THF), thyrotropin releasing hormone (TRH), ACTH analog, insulin-like growth factor (IGF), calcitonin gene-related peptide (C
GRP), atrial natriuretic peptide, vasopressin and analogs (DDAVP, lypressin), metoclopramide, therapeutic agents for migraine (dihydroergotamine, ergomethrin, ergotamine, pizotidine), nasal vaccine (particularly AIDS vaccine), factor VIII;

Antibiotics and antibacterial agents, griseofulvin,
Cefadroxil, cefsulodin sodium, tetracycline hydrochloride, pirarubicin hydrochloride, leucomycin, gentamicin, penicillin, penicillin derivatives and erythromycin; chemotherapeutic agents such as sulfisomidine,
Sulfadimethoxine, calcium paraaminosalicylate, isoniazid, ethambutol hydrochloride, nalidixic acid, pyromidic acid, tosfloxacin tosylate; local anesthetics such as lidocaine hydrochloride, bloccaine hydrochloride, oxesazein, ethyl piperidinoacetylaminobenzoate;

Vasoconstrictors such as norphenephrine hydrochloride, phenylephrine hydrochloride, midodrine hydrochloride, methoxamine hydrochloride, dihydroergotamine mesylate; cardiotonics such as disopyramide phosphate, digitalis and digoxin; vasodilators such as nicergoline, vinpocetine, nitroglycerin, verapamil hydrochloride, isosorbide nitrate, Nifedipine, nisoldipine, nitrendipine; enzyme preparations such as lysodium chloride, urokinase; bone metabolism regulators such as vitamin B3 and active vitamin D3, PTH (parasolmon, parathyroid hormone);

Antihypertensive agents such as methyldopa; sedatives; anxiolytics; steroidal anti-inflammatory agents such as hydrocortisone, prednisone, fluticasone, prednisolone, triamcinolone, triamcinolone acetonide, dexamethasone, betamethasone, beclomethasone and beclomethasone nipropionate; Inflammatory agents such as loxoprofen sodium, ipprofen piconol, indomethacin, ufenamate, glycyrrhetinic acid, ketoprofen, suprofen, dextran sodium sulfate, piroxicam, felbinac, bufexamac, flurpiprofen, bendazac;

Anti-inflammatory enzyme preparations such as chymotrypsin and bromelain, serathiopeptidase; antihistamines such as oxatomide, diphenhydramine hydrochloride, chlorpheniramine maleate and clemastine; antiallergic agents (antitussive / expectorant asthma therapeutic agents) such as sodium cromoglycate, codeine phosphate and Isoproterenol hydrochloride, ephedrine hydrochloride, ipdilast; various hormone agents such as medroxyprogesterone acetate (MPA),
Progesterone, testosterone, estriol, tetracosactide acetate, fluoxymesterone; antidepressants such as imipramine hydrochloride, alprazolam, oxazolam, oxazepam, diazepam, cloxazolam;

Immunomodulators such as 2-cyano-3-
(1,4-Dihydro-1-phenyl- (1) -benzothiopyran) (4,3C) -pyrazol-3-yl-3
-Oxo-N-phenylpropanamide and the like; antitumor agents such as doxyfluridine, cyclophosphamide, nimustine hydrochloride, thiotepa, methotrexate, etoposide,
Bleomycin hydrochloride, pepleomycin sulfate, doxorubicin hydrochloride, mitoxantrone hydrochloride, epirubicin hydrochloride;

Anti-dementia agents such as aniracetam, citicoline, cytochrome C, idebenone, inderoxazine hydrochloride, meclofenoxate, piracetam, pyrithioxine, bifemelane hydrochloride, dihydroergotoxin mesylate, ifenprodil, nicardipine, nicergoline,
γ-amino-β-hydroxybutyric acid (GABOB),
L-dopa, acetyl-L-carnitine, dimethylsulfoxide (DMSO), amantadine hydrochloride, aspirin;

Tranquilizers such as bromperidol, tiapride hydrochloride, haloperidol, zotepine, sulpiride, etizolam, tofisopam, clotiazepam, diazepam, alprazopam; sleep-inducing agents such as triazolam, flunitrazepam, estazolam, nitrazepam, flurazepam hydrochloride, etizolam, etizolam, etizolam, and Agents such as chlorpromazine hydrochloride, triflupromazine hydrochloride, levomepromazine hydrochloride, perazine maleate, thioproperazine mesylate, propeliciazin, haloperidol, spiperone, meprobamate,
Hydroxyzine hydrochloride, oxypertin, carpipramine hydrochloride, imipramine hydrochloride, amitriptyline hydrochloride, mianserin hydrochloride, safradine hydrochloride;

Skeletal muscle relaxants such as suxamethonium chloride, chlormezanone, tolperisone hydrochloride; agents for autonomic nerves such as acetylcholine chloride, neostigmine bromide, trazoline hydrochloride; anticonvulsants such as butropium bromide, N.
-Methylscopolamine methylsulfate, timepidium bromide, oxapium iodide, trospium chloride, furopropion; anti-Parkinson's agents such as biperidene hydrochloride, trihexyphenidyl hydrochloride, bromocriptine mesylate,
Levodopa;

Antiepileptic agents such as phenytoin, phenobarbital, sodium phenobarbital, sodium valproate; ophthalmic agents such as pilocarvine hydrochloride, atropine sulfate, tropicamide, pyrenoxine; otolaryngological agents such as naphazoline nitrate, chloramphenicol, beclomethasone propionate. , Amlexanox; opiates such as opium alkaloids, morphine hydrochloride, morphine sulfate, cocaine hydrochloride, fentanyl citrate, codeine phosphate; diabetes drugs such as tolbutamide,
Chlorpropamide, glibenclamide, metformin hydrochloride.

When the pharmacologically active substance has isomers or optical isomers, these isomers and mixtures thereof can also be used. The pharmacologically active substance may be contained alone or in combination of two or more kinds. It goes without saying that the blending amount is appropriately determined according to the type of each pharmacologically active substance or the mode of application thereof.

In the pharmaceutical composition for transmucosal administration according to the present invention, if necessary, an absorption promoter, a bactericide, a preservative, an emulsifier, a solubilizer, which is usually used as an additive for nasal or external preparations, Stabilizers, ultraviolet absorbers, antioxidants and the like can be added. The blending ratio is usually 0.001% to 20% with respect to the total amount of the composition. The absorption enhancer is not particularly specified, but the absorption enhancers which are usually used are exemplified below. Chelating agents such as ethylenediaminetetraacetic acid, ethyleneglycolbis (2-aminoethylether) tetraacetic acid, citric acid, salicylates, alginates, N-acyl derivatives of collagen and enamines (N-aminoacyl derivatives of β-diketones);

Fatty acids such as coconut oil mono- and di-glyceride extracts having a chain length of 8 and 10 carbon atoms, monoolein or unsaturated fatty acids; bile salts such as 3α, 12α-dihydroxy-5β-cholanate and deoxychol. Sodium acid salt, sodium glycodeoxycholate, sodium taurodeoxycholate, 3α, 7α, 12α-trihydroxy-5β-cholanate, sodium colanate,
Glycocholanate, sodium taurocholanate;

Other surfactants such as saponins (glycosides), surfactins (peptide lipids), nonionic surfactants such as polyoxyethylene-9-lauryl ether (BL-9) and zwitterionic surfactants such as (3- [3-colamidopropyl-dimethylammonio 1-propanesulfonate); fusidic acid and its derivatives such as sodium tauro 24,25-dihydrofusidate (STDHF) and sodium glyco24,25-dihydrofusidate ( SGDHF);

Lysophosphatides such as lysophosphatidylcholine and especially L-α-lysophosphatidylcholine; cyclic peptide antibiotics such as bacitracin and bacitracin A; preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chloroptanol, chlorocresol, Benzalkonium chloride, chlorhexidine, organic mercury compounds;

In addition, ascorbic acid, basic amino acids and salts thereof, glycyrrhetinic acid and glycyrrhizin, O
-Acylcarnitine derivatives such as octanoylcarnitine, lauroylcarnitine, phosphatidylcarnitines and derivatives, valmitoylcarnitine, and malonates such as diethyleneoxymethylenemalonate; azacycloalkane derivatives such as 1- (2- (decylthio) ethylazacyclopentane 2- On (hereinafter, HPE
Abbreviated as -101) or 1-n-dodecylazacycloheptane; linear alkane sulfonate; carbon number 15
A macrocyclic carbonyl compound consisting of, for example, cyclopentadecanone, cyclopentadecanolide, ethylene brassylate.

These absorption enhancers are used in one kind or in combination with one or more kinds. When the absorption enhancer is mixed, the amount of trehalose added should be within a range that does not impair the absorption promoting effect of these absorption enhancers. Yes, it is usually compounded and formulated in the range of 0.01% to 50% with respect to the total amount of the composition. The amount of trehalose used with respect to various absorption enhancers is usually preferably 1 to 30% by weight. The preferred blending ratio differs depending on the type of absorption promoter and pharmacologically active substance to be combined. When a bactericide and a preservative are added to the composition, examples thereof include paraoxybenzoic acid ester, benzoic acid, sodium benzoate, propylene glycol, benzethonium chloride, sorbic acid,
Sodium sorbate and the like can be mentioned. In addition, when an emulsifier or a solubilizer is added for the purpose of dispersing or emulsifying various additives or pharmacologically active substances, a nonionic surfactant with less mucosal irritation, such as polyoxyethylene monostearate or polyoxy Ethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil (H
CO-60 and the like), crotamiton and the like, dipotassium glycyrrhizinate, and cyclodextrin with low stimulative properties such as 2-hydroxypropyl-β-cyclodextrin are used. Examples of stabilizers to be added include gelatin and albumin. Examples of UV absorbers to be blended are known P-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, furan derivatives, pyrone derivatives, camphor derivatives, nucleic acid derivatives, allantoin. Examples include derivatives, nicotine derivatives, shikonin, vitamin B ₆ derivatives and the like.
Examples of antioxidants include, for example, sodium ascorbate, tocopherol, and ester derivatives thereof, nordihydroguaseletinoic acid, dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroquinone gallate, 1-oxo-3-. Methyl-4-isopropylbenzene and the like can be mentioned.

In the present invention, the drug form of the drug composition for transmucosal administration containing trehalose as an essential component is not limited to any particular form. For example, ointment, cream, gel cream, lotion, aerosol, liquid,
Various preparation forms such as suppositories can be adopted, and various pharmaceutical preparations for transmucosal administration such as eye drops, nasal drops, oral preparations, rectal preparations and outer skin preparations can be used.

Below, the stimulation-reducing effect of trehalose and
The in-vivo test and the result which were conducted in order to examine the action effect of trehalose which protects the nasal mucosa from the destructive action without inhibiting the enhancing action of the absorption enhancer are shown.

[Test Method] I Evaluation of Irritation Reducing Effect of Trehalose on General Nasal Drops Rats were anesthetized with urethane, and the formulations of Examples 1 and 2 and Comparative Examples 1 and 2 below were intranasally administered at 100 mg / kg. Then, 120 minutes later, the nasal septum was removed. The morphology of the nasal mucosa surface was observed by SEM by fixing the extracted nasal septum, dehydration, critical point drying and gold deposition according to the procedure for preparing a sample for observation with a scanning electron microscope (SEM). Table 1 shows the extent of damage to the nasal mucosa
Judgment was made according to the judgment criteria shown in Table 1 and the average value of the obtained numerical values was used as the nasal mucosa irritation index of each composition (see Table 2, Examples 1 and 2 and Comparative Examples 1 and 2).

Example 1 Commercially available nasal drop A 950 mg Trehalose 50 mg

Example 2 Commercial nasal drop B 950 mg Trehalose 50 mg

Comparative Example 1 Commercial nasal drop A 1000 mg

Comparative Example 2 Commercially available nasal drop B 1000 mg

II Effect of Addition of Trehalose on Absorption Effect of Absorption Enhancer and Evaluation of Effect of Reducing Nasal Mucosal Irritation Rats were anesthetized with urethane and the composition shown in Comparative Example 4 below was intramuscularly administered at a dose of 100 mg / kg. In addition, each composition of Examples 3 to 8 and Comparative Examples 3 and 5 to 11 was intranasally administered at a dose of 100 mg / kg to evaluate both a) absorption promoting effect and b) nasal mucosal irritation. did.

A) Evaluation of absorption promoting effect: Examples 3 to 6
And 0, 5, 15, after administration of each composition of Comparative Examples 3 to 9,
Blood was sampled at 30, 60, and 120 minutes to measure the glucose concentration in serum. The absorption-promoting effect was evaluated using the efficacy of insulin (decrease in serum glucose concentration) as an index, and Comparative Example 3
Evaluation was made based on the decrease in blood glucose level of each administration group relative to the blood glucose level of (insulin non-administration group) (see FIGS. 1 to 4).

B) Evaluation of nasal mucosa irritation: In test method a), after 120 minutes of blood collection, evaluation was carried out according to the method of I (Table 2 Examples 3 to 8 and Comparative Examples 3 and 5). 11
reference).

Example 3 Insulin 8 mg Trehalose 50 mg HPE-101 2.5 mg Dipotassium glycyrrhizinate 10 mg Physiological saline solution 929.5 mg

Example 4 Insulin 8 mg Trehalose 100 mg HPE-101 2.5 mg Dipotassium glycyrrhizinate 10 mg Physiological saline solution 879.5 mg

Example 5 Insulin 8 mg Trehalose 200 mg HPE-101 2.5 mg Dipotassium glycyrrhizinate 10 mg Physiological saline 779.5 mg

Example 6 Insulin 8 mg Trehalose 50 mg Polyoxyethylene-9-lauryl ether 5 mg (hereinafter abbreviated as BL-9) Physiological saline 937 mg

Example 7 Insulin 8 mg Trehalose 100 mg BL-9 5 mg Physiological saline 887 mg

Example 8 Insulin 8 mg Trehalose 200 mg BL-9 5 mg Physiological saline 787 mg

Comparative Example 3 Saline solution 1000 mg

Comparative Example 4 Insulin 8 mg Physiological saline 992 mg

Comparative Example 5 Insulin 8 mg HPE-101 2.5 mg Dipotassium glycyrrhizinate 10 mg Physiological saline solution 979.5 mg

Comparative Example 6 Insulin 8 mg BL-9 5 mg Physiological saline 987 mg

Comparative Example 7 Insulin 8 mg Sucrose 100 mg BL-9 5 mg Physiological saline 887 mg

Comparative Example 8 Insulin 8 mg Dihydroxypropyl-β-cyclodextrin 5 mg BL-9 5 mg Physiological saline 982 mg

Comparative Example 9 Insulin 8 mg Dihydroxypropyl-β-cyclodextrin 10 mg BL-9 5 mg Physiological saline 977 mg

Comparative Example 10 Insulin 8 mg Dihydroxypropyl-β-cyclodextrin 20 mg BL-9 5 mg Physiological saline solution 967 mg

Comparative Example 11 Insulin 8 mg Dihydroxypropyl-β-cyclodextrin 40 mg BL-9 5 mg Physiological saline solution 947 mg

[Results] The results are shown in Table 2 and FIGS.

[Table 1]

[0053]

[Table 2]

[Action] The nasal mucosal irritation index was lowered by adding 5% of trehalose to each of the commercially available nasal drops A and B (Table 2, Examples 1 and 2 and Comparative Examples 1 and 2). Contrast). When HPE-101 was used as the absorption enhancer, 5% of trehalose reduced the nasal mucosal irritation index without impairing the absorption promotion effect, but the addition of 10% or more lost the absorption promotion effect. (See FIG. 1, Examples 3 and 4). B as an absorption promoter
When L-9 was used, it was observed that the nasal mucosal irritation index tended to decrease when the amount of trehalose added was increased (see Table 2, Examples 6 to 8). Moreover, the absorption promoting effect was still maintained even when 20% was added (see FIG. 2). When sucrose 10%, which is the same disaccharide as trehalose, was added, the absorption promoting effect was not inhibited (see FIG. 3).
The stimulation index was 2.3, which was higher than that of trehalose at the same concentration, and almost no irritation reducing effect was observed (see Table 2, Example 7 and Comparative Example 7). Japanese Patent Laid-Open No. 4-
In the use of the mucosal irritation reducing agent dihydroxypropyl-β-cyclodextrin described in JP-B-235927, a reduction in irritation index was observed between the addition amounts of 1% and 2% (see Table 2, Comparative Examples 9 and 10). ), But at the same time, the absorption promoting effect was also lost (see FIG. 4). From these results, it was proved that trehalose had a nasal mucosal irritation reducing action in the pharmaceutical composition for nasal administration. Further, it has been found that it has an excellent irritation-reducing effect on the absorption enhancer, which can reduce irritation without impairing the absorption-enhancing effect. When HPE-101 is used in combination, the optimum concentration of trehalose is 5%, whereas
Optimal concentration of trehalose when used in combination with BL-9 is 10-
Since it was around 20%, the addition amount of trehalose, which has a stimulus alleviating effect without impairing the absorption promoting effect, is
It was also found to be affected depending on the type of absorption promoter used in combination.

[0055]

EFFECTS OF THE INVENTION By using the pharmaceutical composition for transmucosal administration of the present invention containing trehalose, mucosal absorption of a pharmacologically active substance is better and mucosal irritation is higher than that of conventional preparations for transmucosal administration. Since it is possible to obtain a preparation for transmucosal administration that has a very small amount, it is possible to provide a useful and highly safe drug for transmucosal administration, which is extremely useful in the pharmaceutical industry.

[Brief description of drawings]

FIG. 1 Influence of trehalose on insulin-nasal absorption promotion effect of HPE-101.

FIG. 2 Influence of trehalose on insulin nasal absorption promotion effect of BL-9

FIG. 3 Influence of disaccharide on nasal absorption promoting effect of insulin on BL-9

FIG. 4 shows the effect of dihydroxypropyl-β-cyclodextrin on the nasal absorption promoting effect of BL-9 on insulin.

[Explanation of symbols]

The reference numerals in each figure represent the measured values of the compositions prepared by the respective formulations in Examples and Comparative Examples. The example numbers and comparative example numbers of the compositions indicated by the respective symbols are shown below. FIG. 1: + Comparative Example 3 □ Comparative Example 4 ◇ Comparative Example 5 ▽ Example 3 △ Example 4 × Example 5 FIG. 2: + Comparative Example 3 □ Comparative Example 4 ▽ Comparative Example 6 × Example 6 ΔExample 7 Example 8 Fig. 3: + Comparative Example 3 □ Comparative Example 4 ▽ Comparative Example 6 △ Example 7 ◇ Comparative Example 7 Fig. 4: + Comparative Example 3 □ Comparative Example 4 ▽ Comparative Example 8 × Comparative Example 9 △ Comparative Example 1 ◇ Comparative example 1

Claims (3)

[Claims] 1. A pharmaceutical composition for transmucosal administration, which comprises trehalose. 2. The pharmaceutical composition for transmucosal administration according to claim 1, which contains an absorption enhancer together with trehalose. 3. The pharmaceutical composition for transmucosal administration according to claim 1, wherein the content of trehalose is 0.01 to 50% by weight based on the total amount of the composition.