JP2004026808A - Hemorrhoids-treating agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a hemorrhoids-treating agent having a high effectiveness, since sufficient effect is said to be not obtained by using conventional hemorrhoids-treating agents. <P>SOLUTION: This hemorrhoids-treating agent having the high effectiveness is provided by containing a basephilic fibroblastic cell-growth factor and a pharmaceutically permissible carrier. <P>COPYRIGHT: (C)2004,JPO

Description

【００２６】
【発明の効果】
塩基性線維芽細胞増殖因子を有効成分として含有することにより、有効性の高い痔疾治療剤を提供することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel therapeutic agent for hemorrhoids for treating hemorrhoids such as anal fissures, anal fissures, and anal fistulas.
[0002]
[Prior art]
Hemorrhoids are peculiar diseases or diseases that occur in the anus or rectum, and are roughly classified into hemorrhoids, anal fissures, and anal fistulas, and the symptoms are characterized by bleeding, pain, swelling, itching, and the like.
Hemorrhoids usually refer to changes in the anal venous plexus like varicose veins. Hemorrhoids are gradually formed by repeatedly congesting the anal venous plexus due to constipation, pregnancy, asthma, prolonged sitting, eating and drinking. There are internal and external hemorrhoids depending on the location of the hemorrhoids.
The anal fissure refers to, for example, a fissure wound of the anal epithelium that is rapidly formed by overgrowth. Anal fissures, hemorrhoids, cut hemorrhoids, split hemorrhoids, etc., are often symptoms of anal pain and bleeding during defecation.
An anal fistula is a condition in which the lower rectum and perianal skin are communicated in a bypass manner, and is often formed after a perianal abscess is drained. For example, bacteria invading from the anal glands form infection foci between the internal and external sphincters, inflammation spreads in various directions to form abscesses, and is drained to form fistulas. Hemorrhoids also include ulcerative diseases of the lining of the anus.
[0003]
Many treatments for acute anal fissure, which is one of the hemorrhoidal diseases, are administered with an anti-inflammatory drug, a local anesthetic, a vasoconstrictor, an astringent, or the like alone or as a combination drug. Components such as anti-inflammatory drugs, local anesthetics, vasoconstrictors, and astringents are intended to improve the symptoms of hemorrhoidal disease, are conservative, and are not strictly therapeutic. These drugs are not yet fully satisfactory in terms of efficacy, and further improvements are desired. For chronic anal fissures that have become intractable, therapeutic drugs such as nitroglycerin ointment and nifedipine ointment for surgical treatment and relaxation of the internal anal sphincter are administered. In nitroglycerin ointment, nitroglycerin is metabolized in the body and becomes NO (nitric oxide), a transmitter of non-cholinergic adrenergic inhibitory nerves, to exert an action of relaxing smooth muscle. Nifedipine, a calcium antagonist, suppresses the influx of Ca, a substance related to muscle excitation and contraction, into smooth muscle, and relaxes vascular smooth muscle. However, nitroglycerin ointment and nifedipine ointment, a calcium antagonist, usually exert a systemic effect regardless of the administration route. In such a case, there is a problem that a person having a circulatory disease may have already used it, and it is difficult to separate or control the pharmacological action. In addition, nitroglycerin has a high frequency of side effects such as headaches, and attention should be paid to its use when used.
On the other hand, surgical treatment is mainly used for anal fistula, and there is no effective remedy. That is, in the case of anal fistula, in the case of surgical treatment, the opening may be poorly cured after the operation and may become intractable, and there is no cure suitable for such a case.
[0004]
[Problems to be solved by the invention]
Under such circumstances, it is difficult to say that a conventional agent for treating hemorrhoids has achieved a sufficient effect. Therefore, an object of the present invention is to provide a highly effective therapeutic agent for hemorrhoids.
[0005]
[Means for Solving the Problems]
The present inventors have achieved various anti-inflammatory drugs, local anesthetics, vasoconstrictors, astringents, remedies for acne (bedwelling), which have not been used in the treatment of hemorrhoids, in order to achieve the above object. As a result of intensive studies on the treatment effect of hemorrhoids on skin ulcer treatment drugs, anticancer drugs, anti-athlete's foot drugs, antibacterial drugs, etc., basic fibroblast growth factor, especially trafermin, showed a better treatment effect than conventional treatments for hemorrhoids. The present inventors have found that the present invention has a highly effective and ideal therapeutic effect on hemorrhoids by shortening the healing time of the hemorrhoids, and has further studied to complete the present invention. That is, the present invention is a therapeutic agent for hemorrhoids, comprising a basic fibroblast growth factor as an active ingredient.
The use of the therapeutic agent for hemorrhoids according to the present invention may be performed by directly administering the therapeutic agent for hemorrhoids of the present invention to a hemorrhoidal disease site or treating hemorrhoids, and the effect of the hemorrhoidal surgery is insufficient, and the therapeutic agent for hemorrhoids of the present invention after surgery. Is administered directly to the site of hemorrhoid disease to treat hemorrhoids.
[0006]
That is, the present invention
(1) a therapeutic agent for hemorrhoids, comprising a basic fibroblast growth factor and a pharmaceutically acceptable carrier;
(2) The therapeutic agent for hemorrhoids according to (1), wherein the target disease is anal fissure.
(3) The therapeutic agent for hemorrhoids according to the above (1), wherein the target disease is an anal fistula,
(4) The therapeutic agent for hemorrhoids according to any one of (1) to (3), wherein the dosage form is a hydrophilic semisolid preparation.
(5) The therapeutic agent for hemorrhoidal disease according to (4), wherein the hydrophilic semisolid preparation is a gel.
(6) The therapeutic agent for hemorrhoidal disease according to the above (5), wherein hydroxypropylcellulose is contained in an amount of 1 to 15% by mass relative to the whole preparation.
(7) The therapeutic agent for hemorrhoids according to any of the above (1) to (3), wherein the dosage form is a hydrophobic semisolid preparation,
(8) The therapeutic agent for hemorrhoids according to (1) to (7), wherein the basic fibroblast growth factor is trafermin.
(9) Use of basic fibroblast growth factor as an active ingredient for treating anal fissure,
(10) Use of basic fibroblast growth factor as an active ingredient for treatment of anal fistula,
(11) The use according to the above (9) or (10), wherein the basic fibroblast growth factor is trafermin.
About.
[0007]
BEST MODE FOR CARRYING OUT THE INVENTION
The basic fibroblast growth factor used as an active ingredient of the therapeutic agent for hemorrhoids of the present invention is abbreviated as bFGF, and there is no particular limitation. Accordingly, the active ingredient of the present invention may be any compound as long as it has a function of proliferating basic fibroblasts. Preferred examples of the basic fibroblast growth factor include, for example, WO 87/01728 (Japanese Patent Laid-Open No. 63-500843), WO 89/04832 (Japanese Patent Laid-Open No. 2-504468), and WO 86/07595 (Japanese Patent Laid-open No. No. 63-500036), WO 87/03885 (Japanese Patent Publication No. 63-501953), European Patent Application No. 237966 (Japanese Patent Application Laid-Open No. 63-226287), and European Patent Application No. 281822. (JP-A-2-193), EP-A-326907 (JP-A-2-209894), EP-A-394951 (JP-A-3-61494), European Patent Published Japanese Patent Application No. 493737 (JP-A-5-124975) and the like Those placing of, and the like.
Among these bFGFs, a polypeptide having the following 154 amino acid sequence of SEQ ID NO: 1 and a polypeptide having the 153 amino acid sequence of SEQ ID NO: 2 produced by the genetic engineering technique described in WO 87/01728 are: It is particularly preferable in terms of stability and easy supply of a necessary amount of material at all times. The basic fibroblast growth factor having the amino acid sequence of SEQ ID NO: 1 is, specifically, λ prepared from human kidney mRNA as described in Examples of JP-A-63-500843. _gt 10 cDNA using the library from bovine 1.4kb basic sub fragments prepared a cDNA clone of bFGF in humans, to construct an expression vector obtained by expressing the clone.
The basic fibroblast growth factor consists of an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 in which one or several amino acids have been added, deleted or substituted, and Those that can act as blast growth factors are also included in the scope.
The basic fibroblast growth factor may be used singly or as a mixture of two or more. For example, a mixture in which the protein having the amino acid sequence of SEQ ID NO: 1 is 65% or more and the protein having the amino acid sequence of SEQ ID NO: 2 is 35% or less may be used.
Still further, a product commercially available as a basic fibroblast growth factor, for example, Trafermin manufactured by Kaken Pharmaceutical Co., Ltd., or a freeze-dried product of the formulation Fiblast Spray 250 or Fiblast Spray 500 may be used. .
As the therapeutic agent for hemorrhoids of the present invention, the above-mentioned basic fibroblast growth factor may be used as it is. Usually, however, the therapeutic agent for hemorrhoids of the present invention comprises a basic fibroblast growth factor and a pharmaceutically acceptable carrier ( Extender, excipient, etc.) according to a method known per se.
[0008]
The pharmaceutically acceptable carrier may be either a hydrophobic base or a hydrophilic base, and examples of the hydrophobic base include coconut oil, palm kernel oil, camellia oil, olive oil, and soybean oil which are liquid at room temperature. Sesame oil, corn oil, medium chain fatty acid triglyceride, isopropyl myristate, liquid paraffin, or semi-solid white petrolatum at normal temperature, purified lanolin, gelled hydrocarbon, or glyceryl monostearate, polyoxyethylene hydrogenated castor oil, sorbitan One or a combination of two or more surfactants such as fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, dextrin fatty acid esters, and sucrose fatty acid esters, and higher alcohols such as stearyl alcohol and cetanol. There may be one which is pharmaceutically acceptable is not limited thereto.
Examples of the hydrophilic base include one or a combination of purified water, physiological saline, glycerin, polyethylene glycol, sorbitol, 1,3-butylene glycol, propylene glycol, and ethanol, and a water-soluble polymer. Examples include certain hydroxypropylcellulose, carboxyvinyl polymer, carmellose, carmellose sodium, etc., but are not limited thereto, and may be pharmaceutically acceptable.
Among these, white petrolatum, medium-chain fatty acid triglyceride, and liquid paraffin are preferable as the hydrophobic semisolid agent.
Further, as the hydrophilic semi-solid agent, purified water, physiological saline, water for injection, the above-mentioned solution attached to the product, or a combination of polyethylene glycol and hydroxypropylcellulose as a gelling agent is preferable. A preferable gel is produced by, for example, mixing a freeze-dried product of basic fibroblast growth factor with hydroxypropylcellulose having a viscosity of about 1,000 to 4,000 cps described in the 14th revised Japanese Pharmacopoeia, purified water, Physiological saline, water for injection or a solution attached to the product is added to gel to obtain a gel. At this time, hydroxypropylcellulose is used in an amount of about 1 to 15% by mass, preferably 1 to 5% by mass based on the whole preparation. The gel can also be produced by mixing an aqueous solution of a freeze-dried product of basic fibroblast growth factor and an aqueous solution of hydroxypropylcellulose. Further, in consideration of stability, it is preferable to use a freeze-dried product of basic fibroblast growth factor after dissolving it before use.
[0009]
If desired, the therapeutic agent for hemorrhoids of the present invention may contain other active ingredients which are usually used as therapeutic agents for hemorrhoids. Such active ingredients include, for example, prednisolone acetate, corticosteroids such as hydrocortisone or betamethasone, for example, local anesthetics such as lidocaine or dibucaine, for example, indomethacin, aspirin, antipyretic analgesics such as sodium salicylate, for example, Anti-inflammatory agents such as lysozyme chloride or glycyrrhetinic acid, for example, antipruritic agents such as crotamiton, for example, wound healing agents such as allantoin, for example, liver agents, ergocalciferol, riboflavin, vitamin agents such as pyridoxine hydrochloride, tocopherol or tocopherol acetate; For example, sulfa drugs such as sulfisomidine, sulfisomidine sodium, homosulfamine or sulfadiazine, chlorhexidine hydrochloride, cetrimide, decalinium chloride or salt Fungicides such as benzalkonium chloride, for example, diphenhydramine, diphenhydramine hydrochloride, antihistamines such as chlorpheniramine maleate, but such antibiotics include, but are not limited thereto.
[0010]
The dosage forms used in the present invention include, but are not limited to, ointments, gels, suppositories, aerosols, solutions, suspensions, emulsions, patches, cataplasms, liniments, lotions and the like. is not. Preferably, a dosage form such as a suppository, an ointment, a gel or the like that can be appropriately administered to an administration site of an affected part is good. Ointments, liquids and the like are usually applied around the anus, but if desired, can be injected into the anus and rectum by being housed in an injection container. The gel is formed by cross-linking a biodegradable synthetic polymer such as polyglycolic acid / lactic acid or polyanhydride, or a natural polymer such as polysaccharide or protein. Insoluble crosslinked gelatin gel preparations and the like can be used. As the suppository, for example, base suppositories, gelatin capsule suppositories, tablet suppositories and the like can be used.
The preparation of the present invention can also be a lyophilized preparation. The stabilizing base used in the freeze-dried preparation is not particularly limited, but preferably a gluconate is used. Examples of the gluconate include potassium gluconate, magnesium gluconate, sodium gluconate and the like. Particularly preferably, magnesium gluconate is used. Gluconate can be used alone or as a mixture of two or more kinds, and may be used in combination with other conventionally used stabilizing bases.
Furthermore, the therapeutic agent for hemorrhoids of the present invention may be a sustained release preparation further containing a sustained release agent. Examples of the sustained-release agent include gelatin, a cross-linked gelatin gel obtained by treating gelatin with a cross-linking agent such as glutaraldehyde or water-soluble carbodiimide. These are manufactured according to known means.
[0011]
The administration method is not particularly limited, but in the present invention, anal administration is preferred. Specifically, an ointment or gel is applied directly to the anus. By directly applying the therapeutic agent for hemorrhoids to the affected area, it is possible to effectively treat bleeding, pain, swelling, itch and the like in the affected area.
The therapeutic agent for hemorrhoids of the present invention can be used in combination with surgical treatment. Such surgical methods include, for example, an open surgical method (Lay open method), a sphincter-sparing surgical method (coring out method), an anal fistula ligation therapy (Seton method), and the like. The therapeutic agent for hemorrhoids of the present invention may be applied to the affected part after surgery.
[0012]
Since the dose varies depending on the type and symptoms of hemorrhoids and the like, it cannot be determined unconditionally, and should be determined by a physician by judging the situation. Usually, about 5 μg / day to about 60 μg / day in terms of the active ingredient is used. And preferably about 20 μg / day to about 40 μg / day in about 1 to 2 divided doses per day.
[0013]
【Example】
Hereinafter, although an example of the present invention is described, the following disclosure is only a preferred example of the present invention and does not limit the technical scope of the present invention at all.
[0014]
Formulation Example 1
In Examples 1 to 5 below, a trafermin spray was used. As the trafermin spray, Fiblast Spray 500 sold by Kaken Pharmaceutical Co., Ltd. was used in the usage and volume described in the instruction manual.
[0015]
Formulation Example 2
A trafermin-containing ointment was prepared by mixing 500 μg of a freeze-dried trafermin product and 10 g of petrolatum, and about 0.6 g once a day was used in Example 6.
[0016]
Formulation Example 3
Lyophilize the trafermin freeze-dried product (500 μg) of Kaken Pharmaceutical's Fiblast Spray 500 in the attached dissolution solution (5 mL) of Fiblast Spray 500, add purified water (4 mL), mix uniformly, and further revise the 14th edition Hydroxypropylcellulose (0.3 g) having a viscosity of 1,000 to 4,000 cps described in the Japanese Pharmacopoeia was added and gelled at room temperature to obtain a gel. This was divided into 14 equal portions (for 2 weeks), and about 0.6 g once a day was injected into the anal canal or applied to the affected area before going to bed.
[0017]
Example 1
Patient who underwent two anal fistula operations at another hospital. Due to poor healing, she was consulted 1 year and 10 months after the initial operation. Surgery in the other hospital had no treatment of the primary orifice, and had formed a fistula tract of the fistula extending to the scrotum and three secondary ostia (perianal skin fistula). The anal fistula was cured by the Seaton method, and the anal fistula was cured, but an intractable wound was formed at the surgical site. During the following nine months, three plastic surgery resuturing operations were performed, all of which opened wounds after thread removal. After that, the patient was treated conservatively for 6 months using Actosin ointment. Although intractable wounds shrank slightly, no significant improvement was seen. Then, when the use of Formulation Example 1 was started, it was completely cured within 3 days from the start of use.
[0018]
Example 2
Patients who have undergone anal prolapse and radical surgery for anal fistula at 6 o'clock (the procedure for anal fistula surgery is the Lay open method: a technique for opening the fistula tract to the secondary mouth). Even after a lapse of about two and a half months, there was a complaint that the site of the Lay open did not become epithelial, and that the anus became stiff and uncomfortable due to secretions. When the use of Preparation Example 1 was started, proliferation of red granulation was first observed. After that, the granulation became a little blackish, decreased in height, and epithelialization progressed from the periphery, and healed completely in one week.
[0019]
Example 3
A patient with a pelvic rectal fistula was subjected to a radical operation by the Seaton method (Seton method). One month after the completion of the seaton (three months after surgery), the wound in the anal canal was completely healed, but epithelialization of the rubber-cut area of the perianal skin was delayed. When the use of Formulation Example 1 was started, it was completely cured in 2 weeks.
[0020]
Example 4
Patients who underwent emergency drainage surgery for diagnosis of pelvic rectal abscess and sepsis. Ten days after drainage, radical surgery was performed by the Seaton method (Seton method). When the use of Formulation Example 1 was started immediately after the rubber shedding (two months after the operation), complete healing was achieved in two weeks. Usually, the treatment of the pelvic rectal fistula by the Seaton's method requires a long time (6 months or more) until complete healing, but this could be reduced to two and a half months.
[0021]
Example 5
Female patient with anal fissure at 6 o'clock without anal stenosis. The patient was treated with a conventional hemorrhoid and laxative for 2 months, but no improvement was observed. When Formulation Example 1 was injected into the anal canal once a day in 0.35 cc increments, it was completely cured in one week.
[0022]
Example 6
When a male patient with anal fissure complaining of pain and bleeding at the time of defecation was applied carefully about 0.6 g per day to the affected area, anal pain and bleeding disappeared 10 days later.
[0023]
Example 7
A patient with IILS type fistula at 5 o'clock was subjected to radical surgery by the Seaton method (Seton method). Shedding of the rubber ring in the affected area was observed thereafter (about 3 weeks after the operation), but epithelization of the cut site by the Seaton method was poor thereafter. Since epithelialization was poor even about 3 months after the operation, about 0.6 g of the gel obtained in Preparation Example 3 was applied to the affected area per day, and as a result, the gel was cured about 2 weeks later.
[0024]
Example 8
Two other female patients in their thirties with anal fissure who did not have obvious anal stenosis were treated with other drugs for one month, and no improvement was observed. When about 0.6 g of the gel of Formulation Example 3 was injected into the anal canal or applied to the affected area, the affected area was healed 2 weeks later.
[0025]
[Sequence list]

[0026]
【The invention's effect】
By containing basic fibroblast growth factor as an active ingredient, a highly effective therapeutic agent for hemorrhoids can be provided.

Claims (11)

An agent for treating hemorrhoids, comprising a basic fibroblast growth factor and a pharmaceutically acceptable carrier. The therapeutic agent for hemorrhoids according to claim 1, wherein the target disease is anal fissure. The therapeutic agent for hemorrhoids according to claim 1, wherein the target disease is an anal fistula. The therapeutic agent for hemorrhoids according to any one of claims 1 to 3, wherein the dosage form is a hydrophilic semisolid preparation. The therapeutic agent for hemorrhoidal disease according to claim 4, wherein the hydrophilic semisolid preparation is a gel. The therapeutic agent for hemorrhoidal disease according to claim 5, wherein the composition contains 1 to 15% by mass of hydroxypropyl cellulose. The therapeutic agent for hemorrhoids according to any one of claims 1 to 3, wherein the dosage form is a hydrophobic semisolid preparation. The therapeutic agent for hemorrhoids according to any one of claims 1 to 7, wherein the basic fibroblast growth factor is trafermin. Use of basic fibroblast growth factor as an active ingredient for the treatment of anal fissure. Use of basic fibroblast growth factor as an active ingredient for the treatment of fistulas. The use according to claim 9 or 10, wherein the basic fibroblast growth factor is trafermin.