KR20080049938A - Remedies for degenerative arthritis - Google Patents

Abstract

A therapeutic agent of degenerative arthritis comprising hyaluronan is provided to be easily mass-produced at a relatively cheap cost, to cause no toxicity and antigenicity and show very little side effects. An agent for treating degenerative arthritis comprises hyaluronan as an effective ingredient, wherein the hyaluronan has -D-glucuronic acid-beta-1,3-D-N-acetylglucosamine-beta-1,4- as one unit and is HA4 including two of the unit. The agent is an oral dosage form.

Description

REMEDIES FOR DEGENERATIVE ARTHRITIS

The present invention relates to a therapeutic agent for deformable arthrosis comprising hyaluronan as an active ingredient.

Hyaluronan is a long chain polysaccharide composed of two-saccharide repeating units of D-glucuronic acid and N-acetyl-D-glucosamine. On the other hand, oligosaccharides are also known. Hyaluronan is manufactured by extracts from biological tissues such as bronchial tubes, umbilical cords, skin, joint fluids, or fermentation methods using bacteria of the Streptococcus bacteria, which are used as pharmaceuticals and cosmetics because they do not have toxicological and immunological effects. For example, the treatment of arthritis by intraarticular injection of hyaluronan is well known. In the following description, the tetrasaccharide hyaluronan is described as HA4.

HA4 is reported to have a therapeutic and inhibitory effect on organ preservation, liver failure and gastric ulcer (see Patent Document 1). It is also known that HA4 has a stress protein expression enhancing effect and a cell death suppressing effect (see Non-Patent Document 1).

On the other hand, deformable arthrosis is a disease that causes the destruction of cartilage and the proliferative change of bone and cartilage due to the degenerative degeneration of the components of the joint in the joint disease accompanying chronic arthritis. In addition, arthritis (ileitis) occurs secondary (secondary) by this change. Initially, the stratum corneum is seen after excessive use of the joint and calms down to stability. Progression causes pain even during light exercise or at rest, and night pain is often seen. Strong bending and straightening of the joints, a popping sound during exercise, or swelling of joints due to arthritis, joint fluid may be stored.

The causes include genetic factors, such as obesity, joint instability, recurrent subluxation and dislocation, labor and sports loads, based on degenerative degeneration (age change) of joint components. It is involved in the process.

Treatment is stabilized initially by taking an anti-inflammatory drug or an analgesic drug, or by applying a poultice or tape containing an analgesic agent. In the knee, strengthening exercises of the quadriceps muscles are effective. Abdominal strength training (lying on your side and lifting your legs up) is effective in the hip. In degenerative arthrosis of the knee or hip, the use of a cane is effective because it reduces the burden on the joint. Injection of a joint protectant into the joint is also effective. Infusion therapy of steroids in joints may increase joint destruction if abused and requires attention. If the pain or deformation is strong, surgery on the knee or hip joint, such as osteotomy or artificial joints.

[Patent Document 1] WO2002 / 004471

[Non-Patent Document 1] Xu H, Ito T, Tawada A, Maeda H, Yamanokuchi H, Isahara K, Yoshida K, Uchiyama Y, Asari A. Effect of hyaluronan oligosaccharides on the expression of heat shock protein 72. J Biol Chem. 2002 10; 277 (19): 17308-14.

An object of the present invention is to provide a therapeutic agent for deformable arthrosis.

The therapeutic agent for deformable arthrosis according to the present invention, which achieves the above object, contains hyaluronan as an active ingredient.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail. In the following description, the therapeutic agents according to the invention are referred to only as medicaments.

As the hyaluronan contained in the medicament according to the present invention, at least two sugars containing at least one disaccharide unit in which the 1-position of β-D-glucuronic acid and the 3-position of β-DN-acetylglucosamine are bound In addition, as long as it is basically composed of β-D-glucuronic acid and β-DN-acetylglucosamine, a sugar obtained by combining two or more sugar units with one or more of these elements may be used, and derivatives thereof, for example The thing which has hydrolysable protecting groups, such as an acyl group, can also be used. An unsaturated sugar may be sufficient as the said sugar, and as an unsaturated sugar, the non-reducing terminal sugar, the thing in which the 4- and 5-position carbons of glucuronic acid are unsaturated is normally mentioned. Specific examples of the hyaluronan used in the present invention include those extracted from natural products such as animals, those obtained by culturing microorganisms, and those synthesized chemically or enzymatically. For example, it can be obtained from well-known extraction methods and purification methods from biological tissues such as bronchial tube, umbilical cord, skin, and joint fluid. It can also be produced by a fermentation method using bacteria of the Streptococcus genus.

In the present invention, hyaluronan oligosaccharide is also included in hyaluronan, and a high molecular weight hyaluronic acid having a weight average molecular weight of about 4 million from a low molecular weight hyaluronan such as disaccharide and one derivative thereof composed of one disaccharide unit. Ronan can be used. Preferably hyaluronan of about 380-900,000 weight average molecular weight which is excellent in the point of permeability in a structure | tissue, etc. are mentioned, More preferably, hyaluronan of about 2-20 sugars is mentioned.

Among the hyaluronan, the molecular weight is low, specifically, to lower the molecular weight of hyaluronan by known methods such as enzymatic decomposition, alkali decomposition, heat treatment, and ultrasonic treatment (Biochem., 33 (1994) p6503-6507). It is preferable to prepare by the method, the method of chemically or enzymatically synthesizing (Glycoconjugate J., (1993) p435-439, WO93 / 20827). For example, as an enzyme digestion method, hyaluronan degrading enzyme (hyaluronidase (derived from a testicle), hyaluronidase (derived from Streptomyces), hyaluronidase SD, etc.), chondroitinase AC, chondroitina A method of producing hyaluronan oligosaccharides by acting an enzyme that decomposes hyaluronan, such as ACII, chondroitinase ACIII, and chondroitinase ABC, on hyaluronan (neochemistry experiment lecture "Sugar II-proteoglycan) And glycosaminoglycans, '' p244-248, issued in 1991, see Tokyo Chemical Co., Ltd.).

As the alkali decomposition method, for example, a base such as sodium hydroxide of about 1 N is added to a solution of hyaluronan, warmed for several hours to lower the molecular weight, and then neutralized by addition of an acid such as hydrochloric acid to a low molecular weight hyaluronic acid. And how to get eggs. The hyaluronan used by this invention contains the form of a salt, and can use the pharmacologically acceptable salt as needed on a preparation. For example, they may be alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, amine salts such as tri (n-butyl) amine salts, triethylamine salts, pyridine salts and amino acid salts. .

The drug of the present invention can be used without particular limitation, such as a combination of hyaluronan alone having a predetermined molecular weight or a combination of hyaluronan having various molecular weights. The drug of the present invention contains hyaluronan as an active ingredient, and by administering the effective amount to a mammal including a human, deformable arthrosis can be improved without adversely affecting the living body.

The medicament of the present invention can be administered orally or parenterally, such as hyaluronan or a salt thereof, together with a carrier, an excipient, and other additives (intraarticular, intravenous, intramuscular, subcutaneous, etc.). As a medicament for intra-system administration (injection), enteral administration, transdermal administration, etc.), it is possible to formulate in any formulation, and is administered to the patient by any administration method. In particular, the medicament according to the present invention is preferably in oral formulation.

Examples of oral preparations include solid preparations such as powdered medicines, granules, capsules, and tablets; And liquid preparations such as syrups, elixirs and emulsions. Powdered medicine can be obtained by mixing with excipients, such as lactose, starch, crystalline cellulose, calcium lactate, calcium hydrogen phosphate, magnesium aluminate silicate, and silicic anhydride, for example. In addition to the above excipients, the granules are, for example, a binder such as sugar, hydroxypropyl cellulose and polyvinylpyrrolidone, a binder such as carboxymethyl cellulose and carboxymethyl cellulose calcium, carboxymethylose and carboxy, if necessary. It can be obtained by further adding a disintegrating agent such as methyl cellulose calcium and granulating it in a wet or dry manner. A tablet can be obtained by tableting the powdered medicine or granule as it is or by adding a lubricant such as magnesium stearate or talc. The tablets or granules may be coated with an enteric base such as hydroxypropylmethylcellulose phthalate or methyl methacrylate copolymer, or may be coated with ethyl cellulose, carnauba wax, hardened oil or the like, and these may be an enteric or long-acting agent. have. The light capsule can be obtained by filling the light capsule with the powdered medicine or granule. In addition, the soft capsule can be obtained by mixing hyaluronan or its salt with glycerin, polyethylene glycol, sesame oil, olive oil, or the like, and coating it with a gelatin membrane. The syrup can be obtained by dissolving sweeteners such as white sugar, sorbitol, and gluserine and hyaluronan or salts thereof in water. In addition to sweeteners and water, essential oils, ethanol, and the like may be added to form an elixir, or gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose, or the like may be used as an emulsion or suspending agent. Moreover, a coagulant, a coloring agent, a preservative, etc. can be added to these liquid formulations as needed.

Examples of parenteral preparations include injections, rectal doses, pessaries, external skin preparations, inhalants, aerosols, eye drops, and the like. Injectables include pH adjusting agents such as hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium monohydrogen phosphate and sodium dihydrogen phosphate in hyaluronan or salts thereof; Tonicity agents, such as sodium chloride and glucose; And distilled water for injection, followed by sterile filtration, can be obtained by filling into an ampoule. Furthermore, mannitol, dextrin, cyclodextrin, gelatin and the like can be further added to vacuum freeze-drying to obtain a dissolution-type injection. Moreover, after adding emulsifiers, such as lecithin, polysorbate 80, and polyoxyethylene hardened castor oil, to hyaluronan or its salt, it can also be set as the injectable emulsion emulsified in water.

Rectal dosing agents are added to hyaluronan or its salts for suppositories such as mono, di or triglycerides of cacao fatty acids, polyethylene glycol and the like, and then dissolved by heating. Or after mixing the salt with polyethyleneglycol, soybean oil, etc., it can coat and coat it with a gelatin film. A skin external preparation can be obtained by adding white petrolatum, beeswax, liquid paraffin, polyethylene glycol, and the like to hyaluronan or a salt thereof, and heating and kneading as necessary. The tape agent can be obtained by kneading hyaluronan or a salt thereof with an adhesive such as rosine or an alkyl acrylate ester polymer and spreading this on a nonwoven fabric or the like. The inhalant can be obtained, for example, by dissolving or dispersing hyaluronan or a salt thereof in a propellant, such as a pharmaceutically acceptable inert gas, and filling it into a pressure resistant container.

(Administration method) The administration method of the drug which uses the hyaluronan as an active ingredient of this invention is although it does not specifically limit, Intravenous administration, oral administration, and intraarticular administration are mentioned.

(Dosage) The dosage is appropriately determined depending on the target disease, the age, health condition, and weight of the patient, but in general, 0.05-50 mg / kg is administered once or more per day.

(Toxicity) The hyaluronan used in the present invention showed little or no cytotoxicity at a dose that exhibits biological activity as a medicine.

EXAMPLE

Hereinafter, although the medicine which concerns on this invention is demonstrated in detail using an Example, the technical scope of this invention is not limited to a following example.

Example 1

In this example, HA4 was administered to C57BL / 6 mice spontaneously developing deformed arthrosis, and the effects thereof were examined.

Deformed arthrosis model animal

Twenty-week-old male C57BL / 6 mice were purchased from Nippon Charles River and used to develop degenerative arthrosis. The group was composed of negative control (physiological saline) group and HA4 (100 mg / 10 ml / kg) oral administration group.

Administration of Test Substance

In this example, 10 mg / ml HA4 was adjusted. Specifically, HA4 is Tawada et al. (Tawada A, Masa T, Oonuki Y, Watanabe A, Matsuzaki Y, Asari A. Large-scale preparation, purification, and characterization of hyaluronan oligosaccharides from 4-mers to 52-mers.Glycobiology .2002; 12 (7): 421-6.), And the concentration was adjusted with physiological saline. As a control, physiological saline (reproduction) was adjusted.

In the present Example, oral saponification was administered orally once a day for 2 weeks to mice which developed deformed arthrosis using oral sonde.

Conduct of visual observation

The healing effect of deformable arthrosis was visually determined. Specifically, after applying ink to the surface of the knee cartilage (tibia and femur) for all individuals belonging to each group, wiping with gauze, and the degree of remaining in the obstacle of the ink visually 5 Step evaluation was made (Table 1). In addition, for this evaluation method, Chang DG, Iverson EP, Schinagl RM, Sonoda M, Amiel D, Coutts RD, Sah RL. Quantitation and localization of cartilage degeneration following the induction of osteoarthritis in the rabbit knee. Osteoarthritis Cartilage. 1997 Sep; 5 (5): 357-72. Reference.

Score Remaining Rate of Ink One 0 to 20% 2 20-40% 3 40 to 60% 4 60 to 80% 5 80-100%

result

Table 2 shows the results of macroscopic findings of deformable arthrosis.

The score of each individual Physiological saline group 5,5,4,5,5 Average 4.8 HA4 group 1,2,1,2,1 Average 1.4

As a result of the present Example, the HA4 administration group confirmed the therapeutic effect of deformable arthrosis. From this result, it was demonstrated that the drug containing hyaluronan as an active ingredient suppresses deformed arthrosis.

Since the drug according to the present invention contains hyaluronan as an active ingredient, there is an advantage that it can be mass-produced relatively cheaply and easily. In addition, hyaluronan is expected to be a therapeutic agent having very few side effects because it has little toxicity or antigenicity, and enhances the therapeutic action and prevention of disease originally possessed by a living body. As described above, according to the present invention, a novel drug effective for deformable arthrosis can be provided.

Claims (3)

A therapeutic agent for deformed arthrosis, characterized by using hyaluronan as an active ingredient. The method of claim 1, wherein the hyaluronan is a 4-saccharide comprising -D-glucuronic acid-β-1,3-DN-acetylglucosamine-β-1,4- as one unit and two of them. Deformed arthrosis therapeutic agent. The agent for treating osteoarthritis according to claim 1, which is an oral administration agent.