JPS63196524A - Carcinostatic action adjuster of transmucosal absorption type - Google Patents

Abstract

PURPOSE:To obtain the titled adjuster comprising a growth factor, a peptide corresponding part of the constituent component of the growth factor, a growth factor derivative or a salt thereof as an active ingredient and containing at least an absorption promoter. CONSTITUTION:A carcinostatic action adjuster of transmucosal absorption type comprising a growth factor (e.g. epidermal growth factor group, insulin group or blood platelet derived growth factor group), a peptide (fragment) having a partial structure of part of the growth factor, a growth factor derivative or a salt thereof as an active ingredient and containing at least an absorption promoter (e.g. 1-dodecylazacycloheptan-2-one, calcium thioglycolate, etc.). The mucosa means rectal mucosa, nasal mucosa, mucosa of oral cavity, vaginal mucosa, cornea, etc. The active ingredient is surely taken in body without causing pain of patient like injection and blood concentration is relatively long maintained. The adjuster is effective even to old men and children.

Description

DETAILED DESCRIPTION OF THE INVENTION [Background of the Invention] Technical Field The present invention relates to a transmucosally absorbable anticancer action regulator. More specifically, the present invention uses a growth factor, a peptide corresponding to a part of its constituent components, a derivative thereof, or a salt thereof (hereinafter sometimes referred to as "growth factor etc.") as an active ingredient, and the above-mentioned The present invention relates to a transmucosally absorbable anticancer action regulator that contains at least an absorption enhancer as an ingredient.

Prior Art A large number of studies have been conducted on compounds having anticancer effects, and several dozen types of compounds have already been put into practical use as anticancer agents.

Here, the term "compound with anticancer effect" refers to a compound that can be used mainly for the treatment of cancer, such as a drug used as an anticancer agent or an anti-malignant tumor agent,
A compound that has anticancer or anti-malignant tumor activity.

However, among these compounds, those with strong anticancer effects usually have strong side effects, and those with weak side effects usually have weak anticancer effects.

Therefore, research has been conducted on compounds that suppress the side effects of these compounds and enhance the inherent anticancer activity of the compounds, that is, anticancer activity regulators.

On the other hand, methods are also being used to improve treatment results regarding radiation therapy as part of cancer treatment.

Such methods include, for example, irradiation with accelerated heavy ion particles and methods using pi mesons to improve the physical dose distribution.

However, these methods require not only expensive accelerators and auxiliary facilities, but also many skilled engineers and doctors. Furthermore, radiation therapy
There are also associated drawbacks, such as greater damage to normal tissue.

Therefore, in order to solve these problems, it is necessary to provide anticancer drugs with strong anticancer effects and fewer side effects, as well as drugs that regulate anticancer effects, and to develop effective methods for applying chemotherapy and other cancer treatments. desired.

The present inventors were also conducting such research and discovered that growth factors, etc., can enhance the anticancer effect of drugs that have an anticancer effect, while reducing their side effects.
(hereinafter referred to as the "prior invention"; see Japanese Patent Application No. 61-278190).
.

However, although a clinically appropriate dosage form is desired, the essence of the invention lies in the use of growth factors, etc. as an anticancer action regulator; There has not been sufficient consideration as to what kind of dosage form is preferable other than injection. Therefore, it has been desired to investigate the dosage form.

[Summary of the invention]

Summary The present invention proposes a preferred embodiment of the dosage form of the drug according to the prior invention, as a result of studies to meet the above-mentioned needs. The present invention is based on the confirmation that when the active ingredient of the anticancer action regulator according to the prior invention is combined with an absorption enhancer, absorption from various mucous membranes is dramatically increased.

Therefore, the transmucosally absorbable anticancer action regulator of the present invention includes growth factors, peptides corresponding to some of their constituent components,
These derivatives or salts thereof are used as active ingredients, and the above ingredients include at least an absorption enhancer.

In addition, the transmucosally absorbable anticancer action regulator as used in the present invention is
In addition to those that have independent dosage forms as anticancer agents and moderators,
This also includes cases where the formulation is formulated with a compound having an anticancer effect.

Effects The present invention relates to the dosage form of the earlier invention, and relates to a transmucosally absorbable anticancer action regulator. As described above, since the dosage form of the present invention is a transmucosal absorption type, it can be administered without causing pain to the patient unlike injections. In addition, the incorporation of the active ingredient into the body (into the blood) is also ensured (see Examples below). Moreover, because of the above-mentioned dosage form, the blood concentration of the active ingredient can be maintained for a relatively long time compared to injections.

In addition, the dosage form of the present invention is suitable for patients with lesions, etc. in the upper gastrointestinal tract,
It can be a useful route of administration when it is difficult to administer drugs orally. Furthermore, it is not only possible for patients to administer at home, but is also useful for elderly and child patients. Since there is no need to be particularly careful about taste and odor as with oral administration, it is easy to think that it is easy to administer to children who tend to refuse these things. Furthermore, since there is a high possibility that the blood concentration can be maintained continuously, it may be possible to administer the drug before going to bed and let it work while sleeping.

[Detailed description of the invention]

Anticancer action regulator active ingredient The transmucosally absorbable anticancer action regulator of the present invention is as defined above. The active ingredients are the above-mentioned growth factors and the like.

Here, "growth factor" refers to in vivo or 1nv
1tro refers to substances that promote the growth of animal cells, but are not nutritional substances, and is a concept that includes conventional hormones and their carriers, which also fall under the category of growth factors.

Growth factors include the epidermal growth factor family, the insulin family, and the platelet-derived growth factor family, all of which can be used as active ingredients in the drug of the present invention. Among these, the epidermal growth factor family is representative. those of the insulin family, such as epidermal growth factor (EGF) and transforming growth factors (TGF), and those of the insulin family, such as insulin and insulin-like growth factors (ICF-1, ICF-1).
11) and members of the platelet-derived cell growth factor family, such as fibroblast growth factor (FGF).

The active ingredient as used in the present invention is not only the above-mentioned naturally occurring growth factors themselves, but also the growth factors that differ from the above-mentioned factors in terms of arbitrary substitutions, amino acid additions, or deletions of amino acids constituting these growth factors. It also includes substances having the same or similar physiological and pharmacological activities as the factors, so-called fragments and derivatives. In addition,
Here, the amino acid that can be arbitrarily substituted as a derivative may be any amino acid as long as it has the activity of a growth factor. or highly fat-soluble)].

Further, the growth factor derivatives also include fragment derivatives. A fragment may be a portion that has at least binding activity with a growth factor receptor (i.e., a portion that has a partial structure of the growth factor. For example, a fragment with one amino acid from the C-terminus or N-terminus). Those missing one or two or more, or the C-terminus or N
It includes those formed by cleavage from the terminal or any arbitrary part and consists of two or more amino acids.

In addition, among the above factors and their derivatives mentioned above, derivatives that have not lost their terminal amino and carboxyl groups through chemical modification have free amino and carboxyl groups, so they cannot be used as salts with acids or with bases. It can also be salt. In that case, pharmaceutically acceptable organic or inorganic acids and bases can generally be used, such as hydrochloric acid, sulfuric acid, acetic acid, malonic acid, succinic acid, sodium hydroxide, amines, etc. can be mentioned.

Derivatives also include those subjected to various chemical modifications. Such derivatives are obtained, for example, by chemical modifications known per se, such as alkylation, oxidation, reduction, deglaciation, or combinations thereof.

Therefore, the active ingredients (growth factors, etc.) of the drug of the present invention include not only the growth factors themselves, but also peptides (fragments) having partial structures thereof, derivatives thereof, and salts thereof. be.

In addition, these growth factors etc. are used in living organisms (specifically, blood,
Growth factors and their derivatives can be extracted from saliva, urine, lachrymal fluid, breast milk, various tissues and organs, etc., or prepared by various methods [Cell Growth Factor J, edited by the Japanese Society of Tissue Culture.
(Refer to the literature included in Asakura Shoten, 1984)), chemical synthesis, or genetic engineering synthesis techniques. The growth factors etc. prepared in this way are preferably of high purity.

Epidermal cell growth factor is a typical example of such growth factors. As mentioned above, epidermal growth factor has been isolated from the urine of humans and horses, as well as from the submandibular glands of rabbits, rats, and mice, and is present in salivary mammals across species. is known (Adv, Meta
b, Dls, 8.285 (1975), Japanese Patent Application Publication No. 1983
-25112, etc.]. Among these, when the drug of the present invention is applied to humans, the hEGF is preferred. For the preparation of this EGF, for example, a method of isolating it from biological components [JP-A No. 58-99418, No. 58-219124]
No. 59-204123, etc., Special Publication No. 1977-12
No. 744, No. 53-4527, No. 59-50315, No. 59-50316, No. 59-42650, etc.], chemical synthesis methods [such as Japanese Patent Application Laid-open No. 59-27858, etc.], and genetic engineering. Method of creating by
JP-A-57-122096, JP-A-58-216697, JP-A-59-42650, etc.] have been proposed.

On the other hand, EGF derivatives include those created by genetic engineering methods [human EGF (hEGF) in which the 21st amino acid residue from the N-terminus is replaced with methineon by leucine ((Leu21)-hEG
F: Japanese Unexamined Patent Publication No. 60-28994)] has been proposed. As other EGF derivatives, the C-terminus of hEGF is
hEGF-n, which lacks individual components, has also been obtained
See specification of No.-22630. In addition, here, the genetic engineering 1 knee 2'JJ sale f: h E G F J, t? by the joint researchers of the present inventors. ! i Purity (99,9
% or more), and it is preferable that the active ingredient of the drug of the present invention has such high purity. ].

Still other EGF fragments include des-(49
-53)-EGF (EGF-5), des-(48
-53)-EGF (EGF-6) (Biochemi
stry, 15.2824 (1978), Mo1. P
hariac.

1, 17.314 (1980), Vitam, 11
orm, 37.69 (1979), Cl1n, Re
s, 25.312A (1977)), EGF-(20-31) and its derivatives are considered to be the minimum unit for ECF to express its various effects [20.3
1 (Acm)Cys)EGF-(20-31)[
Proc, Natl, Acad, Sc1. , 81.1
351 (1984) and [A 1 a”) EGF −(
14-31) [Proc, Natl, Acad, S
ci, 81.1851 (1984)], a derivative obtained by treatment with cyanogen bromide.
N B r -E G F (Biochemistr
y, 15.2624 (197B) 1, etc. are also known, and such substances are also included in the category of growth factors, etc., which are the active ingredients of the drug of the present invention.i Epidermal cell growth factors are a group of growth factors. There are a number of family members, examples of which are the EGF and transforming growth factors mentioned above.
ac-Lor:TCP) as described above.

This TGF has large similarities in amino acid sequence with EGF, and is currently classified into three classes. That is, TGF.

α TGPa and TCFa. TGPa is TGPa
Alternatively, it acts synergistically with EGF to promote cell growth. TGF alone exerts this effect γ. EGF and these three TGFs belong to the same growth factor family. In particular, TCF has a high amino acid sequence similarity to EGFα, and up to 21 of the 50α residues of TGF are found at homologous positions in EGF. (Proc, Nat 1, AcadJcl
, , 81, 7303 (1984)). Also, T.G.
F binds to the EGF receptor, which competes with EGF [“Medicine History” 133.1040-1044
(1985)].

Furthermore, TGF activates the EGF receptor kinase with α Naturo, 292.259 (IHI)
], anti-EGF receptor antibody blocks the vulacrine action of TGF.

α Mel [J, Biol, Ch-am, 258.1189
5 (1984)], from these facts, EGF and TG
It is understood that F has a very similar effect. Similarly, insulin and IGFs, TGF and EG
C, which has been reported to have similar effects, such as the relationship α with F.
Adv, Matab, Dls,, 8.2OL211,
237 (1975), Endocrfnology, 1
07.1451 (1980) ) 6 In addition to insulin-like activity, IGFs also have growth factor activity. The present invention also includes homologous factors having very similar effects as these.

Absorption enhancer The absorption enhancer as used in the present invention refers to a compound that can efficiently absorb the above-mentioned active ingredient into the body through the mucous membrane. Here, the mucous membrane refers to rectal mucosa, nasal mucosa, oral mucosa, vaginal mucosa, cornea, etc.

Such absorption enhancers include, for example, 1-dodecyl azacyclohebutan-2-one (U.S. Pat. No. 3,989.
816) and calcium thiogelcholate (
Ches+1ca1. Phara, Bull.

In addition to the specific compound 32(1), 26g (19$14>), (1) pyrrolidone derivatives, (2) cyclodextrins, (3) fatty acid alcohol esters, (4
) enamine derivatives, (5) salicylic acid salt conductors, (6) straight chain saturated fatty acid salts, (7) surfactants, (8) bile acid salt conductors, (9) saponins, (IO) collagen derivatives,
(11) Water-soluble chelating agents (EDTA, etc.), etc.

Although the above salicylic acid derivatives are effective as anti-inflammatory agents, other anti-inflammatory agents can also be used as absorption enhancers. A more specific explanation of these is as follows.

(1) Pyrrolidone derivative The pyrrolidone derivative used in the present invention is any compound having a pyrrolidone skeleton. Specific examples of these include 2-pyrrolidone (US Pat. No. 3,969,516), 1-methyl-2-pyrrolidone, 5-methyl-2
-pyrrolidone, 1゜5~dimethyl-2-pyrrolidone, 1
-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, etc. CB, W, Barry, +Dcrmatol
logical Formula-tions-Pcrc
utancous Absorption,”Marc
cl Dckkor Inc,, New York,
1983).

(2) Cyclodextrins The cyclodextrins used in the present invention are crown-shaped compounds in which D-glucose units are cyclically bonded through α-1,4-glucoside bonds, and generally have 6.5 or more glucose units. 7. Compounds 8 and 9 (α-1β-
1γ and δ-cyclodextrin). In addition, in the present invention, these derivatives, such as 2,6-di0
-Methyl-β-cyclodextrin, 2.3.6-)Alkylated products such as O-methyl-β-cyclodextrin can also be used (Phari+, Int,,
6.61 (1985)).

CB) m fatty acid alcohol esters The fatty acid alcohol esters used in the present invention usually have 6 to 6 carbon atoms.
20 fatty acid alcohol esters. Specific examples of these include ethyl butyrate, ethyl caproate, ethyl caprate, ethyl myristate, isopropyl myristate, octyldodecyl myristate, diethyl succinate, diethyl adipate, diisopropyl adipate, diethyl sebacate, triacetin or Examples include tributyrin (Chem.

Pharm, Bull, 29, 1708 (198
1) ).

(4) Enamine derivatives The enamine derivatives used in the present invention are a series of derivatives obtained by reacting any amino compound (including amino acids) with a β-dicarbonyl compound (for example, ethyl acetoacetate) [Chei, Phar.

Bull, 29.1988 (1981), J. Pha.
ri, Dyn, 7.143 (1984>).

Preferred specific examples of these include sodium N-(1
-methyl-2-ethoxycarbonyl-vinyl)-D-phenylalanine.

(5) Salicylic acid derivatives The salicylic acid derivatives used in the present invention are p-hydroxybenzoic acid or a series of alkyl or alkoxylated products having p-hydroxybenzoic acid as a basic skeleton, or salts thereof, and specific examples include sodium salicylate. , sodium 5-methoxysalicylate, etc. (J, Pharm, P
harmacol, 33, 334 (1981), J.
Phars+, Pharmacol,, 34.520
(1982), J. Pharm.

Set, 1.8θ5 (1982) 3.

(6) Linear saturated fatty acid salt The linear saturated fatty acid salt referred to in the present invention is typically an alkali salt of a linear saturated fatty acid having 4 to 18 carbon atoms. Specific examples include sodium caproate, sodium caprylate, sodium caprate, sodium laurate,
Examples include sodium myristate and sodium valmitate (J.

PharIl, Sci, 71.889 (1982)
).

(7) Surfactant The surfactant used in the present invention is typically a nonionic surfactant or an anionic surfactant. Specific examples thereof are as follows.

(b) Nonionic surfactants Polyhydric alcohol type nonionic surfactants such as sugar esters, fatty acid monoglycerides, anhydrosorbitol fatty acid esters, or polyoxyethylene alkyl ethers, polyoxyethylene alkyl phenyl ethers, polyoxyethylene fatty acids Examples include polyethylene glycol type nonionic surfactants such as ester, polyoxyethylene alkylamine, and polyoxyethylene sorbitan hydrosorbitol fatty acid ester.

(B) Anionic surfactants: Alkaline soaps such as sodium soap (hard soap) and potassium soap (soft soap), calcium oleate,
Metal soaps such as calcium stearate or organic salt soaps such as triethanolamine oleate, sulfated oils such as sulfated castor oil (funnel oil), and higher alcohols such as sodium lauryl sulfate and sodium cetyl sulfate. There are sulfates such as sulfuric esters and sulfonated products such as dioctyl sodium sulfosuccinate (DSS).

(8) Bile acid derivative The bile acid derivative referred to in the present invention is typically any derivative having 5β-cholanic acid as its basic skeleton.

Specific examples of these include cholic acid, taurocholic acid,
Glycocholic acid, deoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, ursodeoxycholic acid, dehydrocholic acid,
lithocholic acid and its conjugates such as glycine, taurine, sulfate or gluconic acid [Chcm,
Pharm, Bul132 (5) 194g (198
4) ].

(9) Saponins The saponins referred to in the present invention are typically triterpenoid saponins.
s l1lukurossl GaerLn,), Akebia (Akebia qulnaLa Decne,)
or other congenerous plants, PLsla japo
nlca Decne meL Planch), Caulophyllua + robus
tum Maxim, ).

Clea + atis chinensi
s 0sbeck ), Panax ginseng (Panax
japonicum C, A, Mcyer).

Daylily (Glycyrrhiza glabra L)
, var.

grandulif'cra Regal et l1
erdcr, Glycyrrhizauralans
is Fisher) or other congenerous plants, Senega (
Polygala scncga L, ), or Polygala scncga L,
var, Latlrolia Torrcyat G
ray), Bellflower (Platycodon gran
dil'lorum A, D, C,), Itohimehagi (
Polygala tcnuiroliaWild,
), Achyranthcsf'
aurici Lcv, at Van,), Cyclamen (Cyclamcncuropacuo+),
Primulaoff'1e1n
alis), Mishima Psycho (Bupleurum)
alcaLum I, , ) or its variants (Usbe
I l 11'erae), Panax ginseng (Pan
Panax ginseng (C, A, Meyer), Panax ginseng (Panax notogtnseng)
Burkll) S American ginseng (Panax q
ulnquerolius L,) or Kizota (ll
edera rhoo+ bea Bean) (Japanese Patent Laid-open No. 57-3201
No. 2 and No. 58-57400).

The triterpenoid saponins obtained from these plants are triterpenoid saponins containing hederagenin as a genin, and for example, saponin A1, saponin B1, saponin C, saponin D11, mucrodisaponin Y, 1 mucrodisaponin Y2, or mucrodisaponin X may be used. Can be done (J, Phara+acobio-D
yn,, 8.1041 (1985), Japanese Patent Application Publication No. 1983
-57400 and 58-152817).

Dosage form The present invention relates to a dosage form of the anticancer action regulating agent, which is the prior invention, and relates to the transmucosally absorbable anticancer action regulating agent defined above.

Here, the term "anticancer effect regulator" refers to an agent for regulating the anticancer effect of a compound that has an anticancer effect (enhancing the anticancer effect and/or preventing its side effects). (Please refer to the specification of the earlier application for details).

This drug usually consists of the ingredients defined above and auxiliary ingredients required for formulation.

Among these, specific examples of auxiliary components include carriers (excipients, binders, diluents, etc.), stabilizers, preservatives, and solubilizing agents. Examples of the base include the following.

(1) Hydrophobic base (oleaginous base) For example, cacao butter, lauric fat, lytepsol, etc.

(2) Hydrophilic base (emulsifiable base) (a) Oil-in-water type (0/W type) base (b) Water-in-oil type (W2O type) base (3) Water-soluble base, for example, macro Galls, cellulose derivatives (methylcelluloses, carboxymethylcellulose (CMC))
), glycerogelatins, acrylic gels, lactic acid gels, and polyethylene glycol derivatives.

More specifically, the dosage form of the drug of the present invention includes, for example, a nasal mucosal absorption agent, and a halved form (intrarectal administration, intravaginal administration, etc.).

Methods for formulating into these dosage forms are known techniques, and various books, literature, patent publications, etc. can be referred to. For example, as a nasal mucosal absorbent,
No. 54931, and Japanese Patent Laid-open Nos. 56-86114 and 57-64609 for the halving.

The present invention relates to the dosage form of the anticancer action regulator, but if the compound having anticancer action can be absorbed transmucosally by itself or with an absorption enhancer such as the above, As mentioned above, it may be formulated with such compounds. Alternatively, the compound having an anticancer effect and the drug of the present invention may be formulated separately and used simultaneously or for a limited time.

Compounds Having Anticancer Effects In addition to those brought about by radiation, the anticancer actions to be modulated by the present invention include those brought about by compounds having anticancer actions.

For example, the following compounds are known as compounds having anticancer effects.

(1) Alkylating agents Examples include chloromethines, night diene mustards, ethyleneiminos, alkylsulfonic acids, nitrosoureas, and epoxides.

[Book "Cancer Chemotherapy" p10-33 (1985) Published by Nankodo]. Here, in the present invention, "-" is a concept that includes derivatives and salts thereof that share a skeleton structure with these compounds and can have specific activity, and have undergone arbitrary substitution or chemical modification. It is.

Examples of such compounds include nightfujien mustards such as Iverit, nightfujiene mustard-N
-oxide, cyclophosphamide (e.g. JP-A-58-
41892, etc.), melphalan, chlorambucil, uracil mustard, Dovan, alanine-MN, and the like. Ethyleneimines include triethylenemelamine, triethylenethiophosphoramide, carbazylquinone,
There are products such as Trenimon. Examples of nitrosoureas include carmustine and lomustine.

(2) Antimetabolites such as folate antagonists (methotrexate, aminopterin, etc.), purine antagonists (6-mercaptopurine, 8-azaguanine, etc.), pyrimidine antagonists (5-mercaptopurine, 8-azaguanine, etc.)
Fluorouracil (for example, JP-A-55-7231, JP-A-51-65774, JP-A-52-48677, JP-A-52-42)
887, Publication No. 53-31676, etc.), tegafur, carmofur, etc.) [see above, vi. Cancer Chemotherapy, pp. 33-52]. In addition, recently, NFT■ (UFT), a mixed drug of tegafur and uracil, has been introduced.
■) is also used clinically.

(3) Antibiotics, such as adriamycins (adriamycin C, D
etc.), Azaserine, DON.

Sarcomycin, Carzlnophilin, mitomycins (e.g., JP-A No. 60-67433, etc.), chromomycin A3 class, pleomycin (e.g., JP-A-60-67433, etc.)
0-67425, etc.), Pepromycin, Daunorubicin, Adriamycin (Doxorubicin) which is an anthracycline antibiotic (for example, JP-A No. 60-608)
-178818, 60-67425, etc.], Aclarubicin, etc.
See the aforementioned book "Cancer Therapy", pages 52 to 77].

(4) Hormone agents, such as sex hormones (testosterone derivatives, estradiol derivatives, etc.), pituitary/adrenal cortex hormones (coccin, prednisone, dexamethacin, etc.)
[Refer to "Cancer Chemotherapy" above, pages 77-88]
.

(5) Plant alkaloids demecolcine (Deaecolc [n), Vinblastine (Vinblastlne), Vincristine (V
incristlne), podophyllotoxin (Pod
ophyl 1otoxln) etc. [see the above-mentioned "Cancer Chemotherapy", pages 89-97].

(6) Porphyrin substances include hematoporphyrin mercury complex salt, protoporphyrin cobalt complex salt, etc. [Cancer Chemotherapy, mentioned above, p.97
See] (7) Other immunostimulants (Krestin (PSK)
)), picibanil, lentinan, etc.), platinum preparations (
Cisplatin ((e.g., JP-A-56-152415, etc.), carpoplatin, ibrobratin, etc.) ["Chemotherapy of Cancer 1986 J Latest Medicine 41 (3) Special Issue p509
-14 (1986) Modern Igaku-sha], other lymphokines, monokines (interferon, interleukins, etc.) [as mentioned above, "Cancer Chemotherapy" p98-10
5].

Regulation of anticancer effect When using the modulator of the present invention for the purpose of enhancing the therapeutic effect of chemotherapy by combining a compound that has an anticancer effect with the modulator of the present invention, the modulator of the present invention may be administered simultaneously with the administration of the compound that has an anticancer effect. Or administer it before or after. Examples of compounds having anticancer activity that are intended to enhance the effect of the drug of the present invention include those listed above. As mentioned above, the modulator of the present invention may be formulated together with a compound that has an anticancer effect.

When the drug of the present invention is used as a radiosensitizer for the purpose of enhancing the therapeutic effect of radiotherapy, it is administered before or after irradiation of radiation in radiotherapy, or if circumstances permit, during irradiation. Regarding the radiation therapy itself, there is no need to adopt any special methods or conditions, and general radiation therapy techniques may be applied as they are. By using the drugs of the present invention in combination, radiation therapy can be performed in a lower dose range than before.

Note that the radiation source may be a general radiation source such as an X-ray, a linear high-energy X-ray, a betatron 32 MeV electron beam, or a 60 CO gamma ray.

The use of the drug of the present invention as a thermosensitizer for the purpose of enhancing the therapeutic effect of hyperthermia also follows the same administration method as for radiotherapy. In addition, in thermotherapy using the present invention, there is no need to employ special methods, conditions, etc., and general thermotherapy techniques may be applied as they are.

The dosage of the drug of the present invention may be determined depending on the patient's age, weight, medical condition, etc., and is preferably about 10 ng to 10 mg of growth factors per day for adults. It should be noted that there is no need to set any special conditions regarding the administration method and dosage of the compound having anticancer effect whose action is to be regulated by the drug of the present invention when the drug of the present invention is used in combination with the compound having anticancer effect. , each of which may be known. That is, for 5-FU and Adriamycin, the daily injection dose is 5-1, respectively.
The amount is about 5 mg/kg body weight and about 10 to 20 tag/kg body weight. The daily oral dosage of 5-FU for adults is 100 to 300 mg.

Preferred embodiments of the invention reduce this daily dose to 1
It is in unit dosage form for administration once or several times a day.

Furthermore, the present invention can also be used in the treatment of cancer in which administration of a compound having an anticancer effect is combined with radiation irradiation, application of heat, etc.

The anticancer action regulator according to the present invention is a polypeptide (hEGF), which is one of the active ingredients of this regulator, which is subcutaneously injected at 10 mg/k into 81 groups of 5 male and female mice and rats.
g, 10a+g/kg intravenously and 1 orally.
Even when administered at 0 mg/kg (equivalent to approximately 1 million times the human blood EGF concentration), there was no change in general symptoms and there were no deaths, so it can be said that the toxicity is low.

The physiological and pharmacological activities of EGF, which is one of the active ingredients of the present invention, that have been reported to date include gastric acid secretion suppressing action (Cut, 16° 1887 (197
5), 1bid, 23,951 (1982)),
Anti-ulcer effect (GuL, 22, 927 (1981), Br
1L, J. Surg, 84, 830 (1977))
, gastrointestinal mucosal protective effect [JP-A-9686 specification]
, DNA synthesis promoting effect (GuL.

22.927 (1981), J. Physiol.
325.35 (1982)), corneal repair action [JP-A-59-65020], calcium release promoting action (Endocrinology, 107).

270 (1980)), wound healing promoting effect (Pla
st.

Rcconstr, Surg, [i4.76B(
(1979), J. Surg, Res.

Japan, 164 (1982)], anti-inflammatory effect (Unexamined Japanese Patent Publication No. 1983
-115784) and analgesic effect (Japanese Unexamined Patent Publication No. 115784).
Experimental Examples Experimental Example 1 In order to examine the transmucosal absorption effect of the active ingredient of the drug of the present invention, the following solutions and skewers were prepared.

(1) Nasal mucosal administration liquid This is hEGF (100 μg 10.1 ml/kg) 1
00 μg dissolved in 0.1 ml of solution A.

Here, solution A refers to a solution in which 10 mg of 1% carboxymethyl cellulose sodium salt and 9.7 mg of 50 mM sodium caprate were dissolved in 1 ml of Tris-HCl buffer (containing 0.01% polysorbate 80).

Note that this solution was also prepared using various gel bases such as polyacrylic gel, lactic acid gel, cellulose derivative gel, etc. instead of 1% carboxymethyl cellulose.

(2) Rectal administration solution This is prepared by adding 0.05ml of solution A to 0.05ml of the above nasal mucosa administration solution.
45 ml was added to make a 0.5 ml solution.

(3) Rectal skewer 100 μg of hEGF was dissolved in 0.5 g of glyceride base (Litepsol H-15) at 40°C.
Mix to contain 0 mM sodium caprate;
Then, it was formed into a half shape according to a conventional method. In addition, other subdivided bases include polyethylene glycol base, mono-,
G, triglyceride bases were possible.

Experimental Example 2 Transmucosal Absorption Experiment Using the solutions in 1 and 2 above and the skewer in 3, the active ingredient (h E G
The absorption status of F) was investigated.

1) Experimental animals SD male and female rats (180-200 g) were used.

2) Experimental method After fasting rats for 16 hours, they were anesthetized with bendoparbital and fixed in the anterior position on a constant temperature water bed at 37°C.

After administering the drug, close the anus with surgical adhesive and insert the carotid artery into the 6
Blood was collected at intervals of 0 minutes, and the blood concentration of EGF was measured by an enzyme antibody method (EIA method).

3) Experimental Results and Analysis of Results The results of the above experiments are shown in Table 1, and the values in the table indicate the activity of EGF (ng/ml).

N, D, indicates undetectable.

This aqueous solution is a control.

As is clear from the experimental results, the formulation of the present invention improves EG
When F was administered to rats, when the solvent was an aqueous solution (control), it was not absorbed at all, whereas when solution A was used, E was absorbed.
GF was well absorbed into the body as described above, and the blood concentration of EGF could be detected.

Therefore, when EGF is administered by these administration routes, it is possible to obtain the same anticancer effect regulating effect as when it is administered by injection.

Experimental Example 3 Next, mouse-derived EGF (mEGF) is a derivative of hEGF in which the 21st methionine (Met) in the amino acid sequence is replaced with leucine (Leu).
”] hGEF, and hEGF which is the amino acid sequence of hEGF in which two amino acids are missing from the C-terminus.
An experiment similar to the above was conducted using -II. The results obtained are shown in Table 2.

The formulation of each administration solution was as described above.

The results of this experiment showed that similar effects were obtained with derivatives and fragments of EGF, so it was thought that the present dosage form could be applied to these derivatives as well.

On the other hand, similar experiments were conducted using the above formulations for hTGF', insulin, and FGF, and the same absorption effect as EGF was obtained.

Claims (1)

[Claims] 1. A growth factor, a peptide corresponding to a part of its constituent components, a derivative thereof, or a salt thereof as an active ingredient;
A transmucosally absorbable anticancer action regulator, characterized in that the above-mentioned components include at least an absorption enhancer. 2. The anticancer action regulator according to claim 1, wherein the mucous membrane is nasal mucosa. 3. The anticancer action regulator according to claim 1, wherein the mucous membrane is rectal mucosa.