JP5329866B2 - Pharmaceutical composition and preventive and therapeutic agent for joint disorders - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical composition and a preventive treatment agent useful for prevention and/or treatment of deformative or inflammatory disorders of articular tissues (such as arthropathy and arthritis). <P>SOLUTION: The medical composition and the preventive treatment agent include vitamin B<SB>1</SB>s (such as fursultiamine or its salts), glycosaminoglycans (such as chondroitin sulfate or its salts) and glucuronic acids (such as glucuronic acid or its salts, amides, chain esters or lactones) and are useful for prevention or treatment of arthritis, arthropathy, deformative arthropathy and articular function disorders. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

The present invention includes vitamin B type ₁ , glycosaminoglycans (such as sodium chondroitin sulfate) and glucuronic acids (such as glucuronolactone), and prevention or treatment of joint disorders (arthropathy and arthritis causing joint pain etc.) The present invention relates to a pharmaceutical composition and a prophylactic / therapeutic agent useful for the above.

  Conventionally, joint disorders such as joint pain have been dealt with by symptomatic treatments such as cyclooxygenase (COX) inhibitors and the like, and by invasive and problematic methods for improving QOL by artificial joint replacement. COX inhibitors have serious side effects, particularly in the digestive system, and COX2 selective inhibitors aimed at overcoming them have many problems such as cardiovascular side effects. Therefore, it is necessary to prevent and ameliorate joint disorders such as joint pain without using conventional symptomatic treatments or invasive methods, and there is a need for more effective compositions for prevention and treatment of joint disorders. Yes.

In addition to joint pain and muscle pain, vitamin B type ₁ treats peripheral neuropathy such as numbness of the limbs and neuralgia, central neuropathy such as Wernicke's encephalopathy, treatment of eye strain, treatment and resolution of constipation, Used for nutrition after sickness. In arthralgia, vitamin B type ₁ is effective against relatively mild arthralgia symptoms. Glucuronic acid is a component such as heparin, chondroitin sulfate, and hyaluronic acid, and its lactone, glucuronolactone, is a component that promotes improvement of liver function and is used as a liver function improving agent. For example, glucuronic acid sodium, glucuronolactone, and glucuronic acid amide have the function of excreting "harmful substances / toxic substances" that cause "fatigue / dullness" to the outside of the body, improving liver function in hyperbilirubinemia In addition to being used as a treatment for liver diseases for symptoms such as detoxification and pregnancy intoxication, it is also included in vitamin-containing health agents (vitamin preparations) that are taken as nutritional supplements such as nutrition tonic and physical fatigue. On the other hand, chondroitin (such as sodium chondroitin sulfate) is a biopolymer that is particularly distributed in cartilage tissue, and protects the corneal surface layer, sensorineural hearing loss (acoustic trauma), chronic nephritis, neuralgia, joint pain, low back pain. It is used to prevent periarthritis (fifty shoulders) and adhesion prevention after laparotomy. In addition, a preparation containing an injection containing sodium hyaluronate is commercially available as a therapeutic agent for knee osteoarthritis in osteoarthritis of the knee, periarthritis of the shoulder, and rheumatoid arthritis.

  Numerous pharmaceuticals containing sodium chondroitin sulfate are also commercially available or proposed. For example, JP-A-9-503197 (Patent Document 1) discloses a composition for treating human or animal connective tissue, which contains glycosaminoglycans such as chondroitin and amino sugars such as glucosamine. ing. This composition has been utilized to prevent and treat joint pain with the recovery of connective tissue. Regarding the combined effect of glucosamine and chondroitin sulfate, N. Engl. J. Med. 2006; 354: 795-808 (Non-patent Document 1) effectively reduces pain in patients with knee osteoarthritis. It has been reported that it has been suggested to be effective in a subgroup of patients presenting moderate to severe knee pain. JP-A-2000-53569 (Patent Document 2) discloses L-carnitines, glycosaminoglycans (such as chondroitin sulfate), glucosamine and excipients as compositions suitable for the prevention and treatment of joint disorders. Compositions containing are disclosed.

  On the other hand, Japanese Patent Application Laid-Open No. 2004-10533 (Patent Document 3) is derived from cartilage damage, a cartilage production promoter containing glucuronic acid, a salt thereof or a glucuronic acid precursor (such as glucuronolactone) as an active ingredient. An agent for preventing or treating diseases (eg, arthritis, rheumatism, etc.), or an agent for promoting production of glucosaminoglucan and / or proteoglucan is disclosed. This document also describes that a glucosamine salt may be further contained as an active ingredient.

Japanese Patent Application Laid-Open No. 2002-14579 (Patent Document 4) and Japanese Patent Application Laid-Open No. 2004-26846 (Patent Document 5) describe a composition containing vitamin B ₁ and glucosamine (or a composition for treating or preventing joint pain). Product). This document may further contain glycosaminoglycans (such as sodium chondroitin sulfate), glucosamines in a proportion of 10 to 500 parts by weight _per 1 part by weight of vitamin B, vitamins It may contain 30 to 200 parts by weight of glycosaminoglycan with respect to 100 parts by weight of the total amount of B ₁ and glucosamine, at least selected from vitamin B ₆ and vitamin B ₁₂ It is described that one kind may be included. This document also describes that glucuronolactone, glucuronic acid and the like may be further contained. However, there is no place to touch for composition and its effects, including the glycosaminoglycans and glucuronolactone such as vitamin B ₁ class and sodium chondroitin sulfate (glucuronic acid).

JP-A-2004-256517 (Patent Document 6), fursultiamine hydrochloride, Film coated tablets containing the sodium chondroitin sulfate and vitamin _{B 12} compounds are disclosed. This document also describes that glucuronolactone, glucuronic acid amide and the like may be further contained. However, there is no description about the effect of further using glucuronolactone or the like together.
JP-T 9-503197 (Claims) JP 2000-53569 A (Claims) JP 2004-10533 A (Claims) JP 2002-145777 A (claims, paragraph [0028]) JP 2004-26846 A (claims, paragraph [0029]) JP 2004-256517 A (Claims, paragraph [0008]) N. Engl. J. Med. 2006; 354: 795-808

  An object of the present invention is to provide a pharmaceutical composition and a prophylactic / therapeutic agent or kit useful for the prevention and / or treatment of various joint tissue degeneration or inflammatory joint disorders.

  Another object of the present invention is to provide a pharmaceutical composition and a preventive / therapeutic agent or kit useful for synergistically and effectively preventing or treating joint disorders (arthropathy, arthritis, etc.) that cause joint pain and the like. is there.

  Still another object of the present invention is to provide a pharmaceutical composition and a prophylactic / therapeutic agent or kit useful for improving joint damage and expanding the range of motion of the joint.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that when vitamin B ₁ class, glycosaminoglycan class, glucuronic acid and its derivatives (such as lactone) are combined, a synergistic effect causes joint damage (joint pain). And arthritis, etc.) were found to be statistically significantly improved, and the present invention was completed.

That is, the pharmaceutical composition of the present invention comprises vitamin B ₁ (such as fursultiamine or a salt thereof), glycosaminoglycan (such as chondroitin sulfate or a salt thereof) and glucuronic acid (a glucuronic acid or a salt thereof, an amide, a chain). At least one selected from the group of esters and lactones).

The preventive / therapeutic agent of the present invention comprises vitamin B ₁ (such as fursultiamine or a salt thereof), glycosaminoglycan (such as chondroitin sulfate or a salt thereof) and glucuronic acid (a glucuronic acid or a salt thereof, an amide, a chain ester) And at least one selected from lactones) and can be used for the prevention and / or treatment of degenerative or inflammatory joint disorders. The prophylactic / therapeutic agent is useful for preventing or treating various joint disorders such as arthritis or arthropathy, osteoarthritis, joint dysfunction, and arthralgia caused by the joint disorder (for example, in arthritis or arthropathy). It can be used as a preventive or therapeutic agent for alleviating pain.

Furthermore, in the pharmaceutical composition and prophylactic / therapeutic agent of the present invention, the components may be grouped. For example, the pharmaceutical composition and prophylactic / therapeutic agent of the present invention may be separated or grouped into a preparation group containing glycosaminoglycans and a preparation group containing glucuronic acids. Vitamin B ₁ may be contained in at least one formulation group of a formulation group containing glycosaminoglycans and a formulation group containing glucuronic acid, or may be contained in another formulation group.

In the composition and prophylactic / therapeutic agent of the present invention, the vitamin B ₁ class may be thiamine, a salt thereof, a derivative thereof, or a salt thereof. Glycosaminoglycans include, for example, hyaluronic acid or a salt thereof (alkali metal salt such as sodium hyaluronate), chondroitin or chondroitin sulfate or a salt thereof (alkaline metal salt such as sodium or potassium salt, alkaline earth such as calcium salt). Metal salts, etc.), heparin, heparan sulfate or salts thereof (alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts and the like). Glucuronic acids include uronic acid (such as glucuronic acid) or its amide (such as glucuronic acid amide), its salt (such as glucuronic acid salt) or its ester (chain ester such as alkyl ester), and its lactone (glucuronic acid). Chronolactone, etc.). The amount of glycosaminoglycans, relative to vitamin _{B 1} class 1 part by weight, 0.1 to 1500 parts by weight (e.g., 0.5 to 1000 parts by weight) may be about the use of glucuronic acid amount, with respect to vitamin _{B 1} class 1 part by weight, 0.1 to 2000 parts by weight (e.g., 0.5 to 1000 parts by weight) may be about. The weight ratio of glycosaminoglycans and glucuronic acids may be about the former / the latter = 5/95 to 95/5 (for example, 65/35 to 30/70). Further compositions and prophylactic treatment agent of the present invention, other vitamins, for example, may contain at least one selected from vitamin B ₆ compound and vitamin B ₁₂ compound. For example, compositions and preventive therapeutic agent of the present invention, the vitamin B ₁ class, and vitamin B ₆ compound and / or vitamin B ₁₂ compound, and the chondroitin sulfate or a salt thereof, glucuronic acid or its amides, salts or glucurono It may contain a lactone. Furthermore, the composition and the preventive / therapeutic agent of the present invention may be substantially free of glucosamines.

Furthermore, the present invention provides (1) a pharmaceutical kit comprising two ingredients and a pharmaceutical kit comprising one ingredient among vitamin B ₁ class, glycosaminoglycans, and glucuronic acids, or (2) A pharmaceutical kit composed of three preparations each containing each component is also included.

  In the present specification, “pharmaceutical composition” and “pharmaceutical kit” are not limited to pharmaceuticals used exclusively for the prevention and / or treatment of human diseases, but are also widely used for nutritional supplements (eg supplements). It means an applicable composition or kit, and can also be referred to as a bioactive composition, a pharmacologically active composition, or a physiologically active or pharmacologically active kit. The “prophylactic and therapeutic agent” in the present specification means a preparation that can be used for the prevention and / or treatment of joint tissue (human and animal connective tissue) degeneration or inflammatory joint damage (or injury). It includes preparations for preventing and / or treating joint disorders such as arthritis or arthritis, and joint pain improving agents. Further, the “prophylactic and therapeutic agent” is sometimes simply referred to as “formulation”. Regarding “glucuronic acids”, lactone means a cyclic ester compound in which a carboxyl group and a hydroxyl group form an ester bond in the molecule, and a chain ester means an acyclic ester compound in which a carboxyl group is esterified. means.

In the present invention, since vitamin B ₁ class, glycosaminoglycans and glucuronic acid are combined, various joint tissue degeneration or inflammatory joint disorders (for example, joint disorders such as osteoarthritis and arthritis) Useful for prevention and / or treatment. It is also useful for preventing or treating joint pain. Furthermore, joint disorders (such as arthropathy and arthritis causing joint pain) can be effectively improved, and the range of motion or range of motion of the joint can be expanded.

The composition and the prophylactic / therapeutic agent of the present invention include vitamin B ₁ class, glycosaminoglycans, and glucuronic acid classes. Examples of vitamin B ₁ include thiamine or a salt thereof (for example, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl sulfate ester salt), vitamin B ₁ derivative (fursultiamine, dicetiamine, octothiamine). , Thiamine derivatives such as chicotiamine, bisibtiamine, bisbenchamine, benfotiamine, prosultiamine or salts thereof (for example, salts with inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, for example, fursultiamine hydrochloride, dicetiamine hydrochloride, etc. )) Etc. can be illustrated. These vitamins B ₁ class may be used singly or in combination. Vitamin B ₁ is often a disulfide type thiamine, such as fursultiamine, prosultiamine, octothiamine or a salt thereof, particularly fullsultiamine or a salt thereof.

The composition and prophylactic / therapeutic agent of the present invention may contain other active ingredients. Active ingredients are, for example, vitamins other than vitamin B ₁ class, sleep sedative, vertiginous drugs, antipyretics, analgesics, anti-inflammatory drugs, stomachic, digestive drugs, antacids, antiemetics, antitussives, removed by phlegm Medicine, anti-asthma medicine, constipation medicine, diarrhea medicine, hyperlipidemia medicine, antianginal medicine, hypertension medicine, hypotension medicine, anti-arteriosclerosis medicine, anti-obesity medicine, heart failure medicine, myocardial infarction Drugs, antiarrhythmic drugs, diabetes drugs, peptic ulcer drugs, liver disease drugs, thyroid disease drugs, hyperuricemia drugs, rheumatism drugs, antibiotics, antidepressants, antiallergic drugs, antituberculous It may be a drug, a prostatic hypertrophy therapeutic drug, an osteoporosis therapeutic drug, an Alzheimer's disease therapeutic drug, caffeine, minerals, herbal medicine, and the like.

The vitamins may be either water-soluble vitamins or fat-soluble vitamins. Vitamins, often is at least one selected from vitamin B ₆ compound and vitamin B ₁₂ compound.

Examples of vitamin B ₆ include pyridoxines such as pyridoxine and pyridoxal or salts thereof (hydrochlorides such as pyridoxine hydrochloride, corresponding acetates, phosphates such as pyridoxal phosphate, etc.) and the like. These vitamins B ₆ compounds may be used singly or in combination.

The vitamin B ₁₂ include, for example, mecobalamin, cyanocobalamin, hydroxocobalamin, and cobalamin compound and its salts such as methylcobalamin (hydrochloride, such as hydrochloric acid hydroxocobalamin, such as acetic acid salts such as acetate hydroxocobalamin) can be exemplified. These vitamin B ₁₂ types can also be used alone or in combination of two or more.

The vitamins further include vitamin B ₂ (riboflavin such as flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, and riboflavin butyrate), vitamin C (ascorbic acid, sodium ascorbate, potassium ascorbate, ascorbine) Acid calcium), vitamin A (retinol acetate, retinol palmitate, vitamin A oil, etc.), vitamin D (ergocalciferol, cholecalciferol, etc.), vitamin E (liver oil, strong liver oil, d-α-tocopherol) Dl-α-tocopherol, d-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.), nicotinic acids (nicotinic acid, nicotinic acid) (Tinic acid amide, etc.), vitamin K, pantothenic acids (panthenol, pantothenic acid or salts thereof (calcium pantothenate), etc.), biotin, folic acid, γ-oryzanol, orotic acid, yokuinin and the like.

These vitamins can also be used alone or in combination of two or more, and may be a complex vitamin preparation. Complex vitamin preparations include, for example, vitamin B ₁ B ₆ B ₁₂ combination preparation, vitamin B ₁ B ₂ B ₆ B ₁₂ combination preparation, vitamin B ₁ B ₂ B ₆ B ₁₂ E combination preparation, vitamin B ₁ B ₂ B ₆ C A nicotinic acid / pantothenic acid compounding agent, vitamin B ₁ B ₂ B ₆ B ₁₂ nicotinic acid / pantothenic acid compounding agent, vitamin B ₁ B ₂ B ₆ B ₁₂ E, pantothenic acid compounding agent or the like may be used.

  Examples of the glycosaminoglycans include hyaluronic acid or a salt thereof (alkali metal salt such as sodium hyaluronate), chondroitin or chondroitin sulfate or a salt thereof (alkali metal salt such as sodium or potassium salt, alkali such as calcium salt). Earth metal salts), heparin, heparan sulfate or salts thereof (alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, and the like). These glycosaminoglycans can be used alone or in combination of two or more.

  Preferred glycosaminoglycans are hyaluronic acid or a salt thereof (such as sodium hyaluronate), chondroitin sulfate or a salt thereof (such as sodium chondroitin sulfate), particularly chondroitin sulfate or a salt thereof.

The amount of glycosaminoglycans, relative to vitamin _{B 1} class 1 part by weight, 0.1 to 1500 parts by weight (e.g., 0.5 to 1000 parts by weight), preferably 1 to 500 parts by weight (e.g., 2 to 200 parts by weight), more preferably 5 to 50 parts by weight (for example, 6 to 15 parts by weight). In addition, when the pharmaceutical composition and the preventive / therapeutic agent further contain other active ingredients (other vitamins, etc.), the amount of glycosaminoglycans used depends on the type of active ingredient (other vitamins, etc.). , 0.1 to 1000 parts by weight (for example, 1 to 500 parts by weight), preferably 2 to 300 parts by weight with respect to 1 part by weight of the total amount of active ingredients including vitamin B ₁ (or the total amount of vitamins) For example, it may be about 3 to 200 parts by weight), more preferably about 5 to 100 parts by weight (for example, 6 to 50 parts by weight). When the active ingredient is vitamin B ₆ class and vitamin B ₁₂ class, the amount of glycosaminoglycan used is, for example, 0.1 to 1000 parts by weight (for example, 0.1% by weight per 1 part by weight of vitamin B ₆ class). 5 to 500 parts by weight), preferably 1 to 300 parts by weight (for example, 5 to 200 parts by weight), more preferably about 10 to 100 parts by weight (for example, 20 to 60 parts by weight), vitamin B 50 to 1200000 parts by weight (for example, 100 to 1000000 parts by weight), preferably 500 to 100000 parts by weight (for example, 1000 to 50000 parts by weight), more preferably 5000 to 20000 parts by weight (for example, 1 part by weight of Class ₁₂ ) 10000 to 16000 parts by weight).

As the glucuronic acid, at least one selected from glucuronic acid and its derivatives, for example, glucuronic acid salt, glucuronic acid amide, chain ester and glucuronolactone can be used. The action of these glucuronic acids is equivalent to that of glucuronic acid. Examples of the glucuronic acid salt include metal salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, ammonium salts, and amine salts. Glucuronic acid amide can be produced by the reaction of glucuronic acid and ammonia. Examples of the chain ester include alkyl esters such as C _1-10 alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester and t-butyl ester (for example, C _1-6 alkyl ester). Can be illustrated. Examples of glucuronolactone include δ-D-glucuronolactone and γ-D-glucuronolactone. These glucuronic acids can be used alone or in combination of two or more. Preferred glucuronic acids are at least one selected from glucuronic acid, glucuronic acid amide, and glucuronolactone, for example, glucuronolactone.

  Glucuronic acids may be synthesized or commercially available products (for example, glucuronolactone can be obtained from Sumitomo Chemical Co., Ltd.) may be used as they are. The glucuronic acids are pulverized by a pulverizer such as a hammer mill, and have an appropriate particle size, for example, an average particle size of 5-1000 μm, preferably 10-500 μm (for example, 15-200 μm), more preferably 20-100 μm ( For example, you may adjust and use about 20-80 micrometers.

The amount of glucuronic acid used is usually 0.1 to 2000 parts by weight (eg 0.5 to 1000 parts by weight), preferably 1 to 500 parts by weight (eg 1 to 1 part by weight _per 1 part by weight of vitamin B ₁ ). 200 parts by weight), more preferably about 2 to 20 parts by weight (for example, 5 to 15 parts by weight). In addition, when the pharmaceutical composition and the preventive / therapeutic agent further contain other active ingredients (other vitamins, etc.), the amount of glucuronic acid used depends on the type of the active ingredient (other vitamins, etc.). _It can be selected from a range of about 0.01 to 10000 parts by weight (for example, 0.1 to 5000 parts by weight) with respect to 1 part by weight of the total amount of active ingredients including Class ₁ (or the total amount of vitamins). ~ 1000 parts by weight (for example, 3 to 500 parts by weight), preferably about 5 to 300 parts by weight (for example, 6 to 100 parts by weight), more preferably about 7 to 70 parts by weight (for example, 8 to 50 parts by weight). There may be. When the active ingredient is vitamin B _{6 or} vitamin B ₁₂ , the amount of glucuronic acid used is usually 1 to 500 parts by weight (eg 1 to 300 parts by weight, for example, per 1 part by weight of vitamin B ₆ ). ), Preferably 2 to 200 parts by weight (for example, 4 to 150 parts by weight), more preferably about 10 to 100 parts by weight (for example, 30 to 70 parts by weight), and vitamin B ₁₂ type 1 part by weight Is usually 50 to 1500000 parts by weight (for example, 100 to 1000000 parts by weight), preferably 1000 to 100000 parts by weight (for example, 5000 to 50000 parts by weight), and more preferably 10,000 to 20000 parts by weight (for example, 12000 to 20000 parts by weight). 18000 parts by weight).

  The weight ratio of glucuronic acid and glycosaminoglycan can be selected from the range of the former / the latter = 5/95 to 95/5 (for example, 10/90 to 90/10), and usually 15/85 to 85. / 15 is often the case. The weight ratio between glucuronic acid and glycosaminoglycan is the former / the latter = 35/65 to 75/25 (for example, 40/60 to 70/30), preferably 45/55 to 65/35 (for example, 50/50 to 60/40).

  The pharmaceutical composition of the present invention may further contain glucosamines (glucosamine or a salt thereof, such as glucosamine hydrochloride, etc.), but in many cases it is not substantially contained. The content of glucosamines may be in the range of about 0 to 100 parts by weight (preferably 0 to 50 parts by weight, particularly 0 to 20 parts by weight) with respect to 100 parts by weight of glucuronic acids.

Since the pharmaceutical composition of the present invention combines vitamin B ₁ , glycosaminoglycans and glucuronic acids, joint tissue degeneration or inflammatory joint disorders (for example, joint disorders such as osteoarthritis and arthritis) ) Can be improved synergistically with a statistically significant difference. That is, in the group administered with a combination of vitamin B ₁ and sodium chondroitin sulfate and the group administered with glucuronolactone alone, the damage suppression effect of femoral joint cartilage and tibial joint cartilage is 1% in the rabbit model system. It is not statistically significant in the significant difference test. On the other hand, when vitamin B ₁ type, chondroitin sulfate sodium and glucuronolactone are administered in combination, the effect of suppressing the injury of articular cartilage is clearly prevented and / or treated in a significant difference test with a risk rate of 1%. Is recognized and the effect is synergistic. Moreover, also in comprehensive evaluation (histopathological evaluation), the effect of the pharmaceutical composition of this invention is recognized by a big significant difference. In addition, as shown in the examples, the experimental osteoarthritis model by partial excision of the meniscus of the rabbit knee joint was used, and as a result of a histological evaluation of the articular cartilage degeneration inhibitory effect, glucuronic acids were substituted. using glucosamine Te, it is administered in combination with a vitamin B ₁ class and glycosaminoglycans, statistically significant differences in the risk rate of 5% significance test was observed.

  The composition of the present invention can be used in various preparation forms such as solid preparations (powder, fine granules or granules, pills, tablets (plain tablets or uncoated tablets), capsules, film-coated granules or granules. , Film coatings such as film-coated tablets (sugar-coated tablets), liquid preparations (solutions, elixirs, suspensions, emulsions, syrups, drinks, etc.) and semi-solid preparations (creams, jellies, ointments, Gels, poultices, etc.). Furthermore, the composition of the present invention may be an oral preparation (such as an internal preparation) or a parenteral preparation (external preparation such as a patch).

  In addition, when glycosaminoglycans and glucuronic acids (for example, glucuronolactone, etc.) are used in combination, the preparation may discolor over time and the preparation quality and stability over time may be reduced. Moreover, the usage-amount of these components is usually comparatively large. In such a case, the preparation (solid preparation etc.) is divided into a plurality of these components in order to suppress contact between glycosaminoglycans and glucuronic acids, that is, a group containing glycosaminoglycans, It is preferable to contain in the form grouped into the group containing glucuronic acids. The form of grouping is not particularly limited as long as the plurality of components are separated by intervening or separating components and direct contact is suppressed, and for example, powdery, granular (for example, granular) form, layered form It may be. The grouping can usually be performed by formulating at least one of a plurality of components with a carrier component (eg, granulation by granulation, etc.) and / or coating, and the other components are in powder form, etc. It may be a form. Usually, a formulation group (granulated powder group, for example, granule or sized powder powder group) in which glycosaminoglycans are formulated with a carrier component, and a formulation group (granulated powder group) in which glucuronic acid is formulated with a carrier component In many cases, for example, a granule or a sized powder group is formed. Also, grouped preparations are prepared by formulating both preparation groups into one dosage form. In addition, solid preparations (tablets etc.) containing glycosaminoglycans (such as sodium chondroitin sulfate) swell due to moisture absorption when stored under high humidity, resulting in cracks and deformation of the solid preparations (tablets etc.) May reduce stability. Even in such a case, when glycosaminoglycans are granulated and grouped in the form of granulated products (granule or granulated powder etc.) and mixed with ingredients containing glucuronic acid, they are formulated with high humidity. Even when stored under low temperature (for example, under low temperature and high humidity), cracking and deformation of the solid preparation can be effectively prevented.

Vitamin B ₁ may be contained in at least one of the group containing glycosaminoglycans and the group containing glucuronic acids, and the group (formulation group) containing glycosaminoglycans and glucuronic acids You may make it contain in the other group (formulation group) different from the group (formulation group) containing. The solid preparation containing a plurality of groups may be a powder or a granule, or may be a tablet obtained by tableting a mixture of the plurality of groups and, if necessary, a carrier component.

Further, when a plurality of active ingredients including vitamin B ₁ are discolored or colored or inactivated (decrease in content) by direct contact, the plurality of active ingredients are preferably grouped to suppress direct contact. . For example, when vitamin B ₆ and vitamin B ₁₂ coexist, the content decreases. Therefore, it is preferable to classify vitamin B ₆ and vitamin B ₁₂ into groups. In addition, when using vitamin B ₁ , vitamin B ₆ , and vitamin B ₁₂ , classify each vitamin group (group of vitamin B ₁ , group of vitamin B ₆ and group of vitamin B ₁₂ ). Alternatively, vitamin B ₁ group may be contained in vitamin B group ₆ and / or vitamin B group ₁₂ . It should be noted that vitamin B ₁ does not change color (color) or decrease in content even when combined with vitamin B ₁₂ . Therefore, vitamin B ₁ type is often contained in vitamin B ₁₂ group.

When glycosaminoglycans and glucuronic acids are used as carrier components and vitamin B ₆ and other vitamins (vitamin B ₁ and / or vitamin B ₁₂ ) are used as vitamins, vitamin B ₁ and And / or a group comprising vitamin B ₁₂ and glycosaminoglycan (for example, granulated or sized powder group), a group comprising vitamin B ₁ and / or vitamin B ₆ and glucuronic acid (for example, It is preferable to separate it into a granulated or sized powder group). Further, the solid preparation includes a solid preparation containing a plurality of separated groups (granulated powder group, etc.), for example, the plurality of groups (granulated powder group, etc.), and if necessary, mixed with a carrier component, It may be in the form of a tablet.

  In a solid preparation, at least one of an excipient, a binder and a disintegrant is usually used as a carrier component or additive in many cases. Examples of the excipient include sugar alcohols such as D-mannitol, D-sorbitol, erythritol, and xylitol, sugars such as lactose, glucose, fructose, sucrose, and powdered reduced maltose water candy, crystalline cellulose, powdered cellulose, potato starch, Corn starch, dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, aluminate metasilicate Examples thereof include magnesium, synthetic hydrotalcite, talc and kaolin. Examples of the binder include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, crystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone (povidone), vinylpyrrolidone copolymer (copolyvidone), Examples include acrylic polymer, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol alginate, sucrose, and the like. Examples of the disintegrant include carmellose, carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, low-substituted hydroxypropylcellulose (L-HPC), crospovidone, corn starch, hydroxypropyl starch, partially pregelatinized starch, Examples include alginic acid and bentonite.

  Other carrier components or additives include lubricants (stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, beeswax, white beeswax, etc. ); Antioxidants (dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid, etc.); preservatives (paraoxybenzoates, etc.); coloring agents (turmeric extract, riboflavin) , Carotene solution, tar pigment, caramel, titanium oxide, Bengala, etc.); corrigents (sweeteners such as aspartame, ascorbic acid, stevia, menthol, licorice crude extract, simple syrup, etc.); surfactants (polyoxyethylene) Castor oil, glyceryl monostearate, sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan monolaurate), polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid esters, etc.) Agents (light anhydrous silicic acid, talc, hydrous silicon dioxide, etc.); Plasticizers (triethyl citrate, polyethylene glycol, triacetin, cetanol, etc.); Sweeteners (sucrose, mannitol, D-sorbitol, xylitol, aspartame, etc.) Or synthetic sweeteners); flavoring agents (such as menthol); adsorbents, preservatives, wetting agents, antistatic agents and the like. If reduced maltose (powdered reduced maltose water candy) is used as an excipient, the hygroscopic property is low, so even if glycosaminoglycans are included, deformation and cracking of solid preparations can be prevented, and moldability is also improved. it can.

  Glucuronic acids (for example, glucuronolactone and the like) and glycosaminoglycans can function as a carrier component of a solid preparation, in particular, a disintegrant, and can also function as an excipient. In addition, glucuronic acids (for example, glucuronolactone and the like) improve the disintegration property of the solid preparation. In particular, when a glucuronic acid (for example, glucuronolactone or the like) and a glycosaminoglycan are contained in combination, the disintegration property of the solid preparation can be further improved. Therefore, the solid preparation does not need to contain a disintegrant substantially, but may contain a disintegrant (crospovidone, croscarmellose sodium, etc.) if necessary. The amount of the disintegrant used can be selected from the range of about 0 to 20% by weight with respect to the total formulation components (total amount of the active ingredient and the carrier component) excluding the coating agent. It may be about 5 to 12% by weight, more preferably about 1 to 10% by weight (for example, 3 to 6% by weight).

  In a coating preparation coated with a coating agent (for example, coated tablet), as a coating base, hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymer, macrogol Water-soluble base such as ethyl cellulose, water-insoluble base such as ethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, acrylic acid copolymer Enteric bases such as carboxyvinyl polymer, polyvinyl Se tar diethylaminoacetate, aminoalkyl methacrylate copolymer, gastric base such as polyvinyl acetate diethylamino acetate, gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerol fatty acid ester, such as magnesium stearate can be exemplified. These coating bases can be used alone or in combination of two or more. The coating layer may be formed in one layer or a plurality of layers. Preferred coating bases are hydroxypropyl methylcellulose and polyvinyl pyrrolidone polymers (povidone, copolyvidone, etc.).

  The coating agent may further contain additives such as a filler, a lubricant, a masking agent, a plasticizer, and a colorant as necessary. Additives include talc, precipitated calcium carbonate, magnesium stearate, calcium stearate, titanium oxide, macrogol 6000, copolyvidone, triacetin, triethyl citrate, glycerin, propylene glycol, riboflavin, yellow ferric oxide, ferric oxide, yellow For example, No. 5 aluminum lake. These additives can be used alone or in combination of two or more.

  As the lubricant added to the coating agent, talc is preferable from the viewpoint of the temporal stability of the appearance. The content of the additive (such as talc) is usually 1 to 30% by weight (for example, 3 to 25% by weight), preferably 5 to 20% by weight (for example, 10 to 15) in the coating agent in terms of solid content. % By weight).

  The coating amount is 1% by weight or more (for example, 1 to 50% by weight), preferably 2 to 20% by weight (for example, 3 to 18% by weight), based on an uncoated preparation (elementary granule, uncoated tablet, etc.), Preferably it is about 5 to 15 weight% (for example, 6 to 12 weight%).

Solid preparations can be produced by conventional methods. The active ingredient (vitamin B ₁ class, glycosaminoglycans and glucuronic acid) and a mixture of a carrier component may be prepared powders usually granulated active ingredient with a carrier component, forming the necessary The granules are sized to prepare granules (fine granules or granules), or the mixture containing the granules (especially, the mixture of the granulated product and the carrier component) is compressed into a bare tablet. Can be prepared. Capsules can be prepared by filling capsules with the granules.

  Granulation can be performed by a conventional method, for example, stirring granulation method, fluidized bed granulation method, extrusion granulation method, dry granulation method and the like. A preferred granulation method is a fluidized bed granulation method. In granulation, an active ingredient and a carrier component are often granulated using a solution containing a binder. For example, by spraying a solution containing a binder on a fluidized bed of the active ingredient and the carrier component. Can be granulated. The coating preparation can be obtained by spraying a coating agent containing a coating base onto an uncoated preparation (elementary granule, plain tablet, etc.) using a film coating machine.

  In the liquid preparation, an aqueous medium (purified water, ethanol-containing purified water, etc.), alcohols (ethanol, glycerin, etc.), a water-soluble polymer, etc. can be used as the carrier component. As the carrier component, purified water, ethanol-containing purified water and the like are often used. As the carrier component of the semi-solid preparation, an oily base (lipid such as vegetable oil, petrolatum, liquid paraffin, etc.), a hydrophilic base (emulsion base) and the like can be used. Examples of additives include disintegration aids, antioxidants or antioxidants, surfactants, emulsifiers, dispersants, suspension agents, solubilizers, thickeners, pH adjusters or buffers, preservatives or Preservatives (such as parabens), bactericides or antibacterial agents, antistatic agents, taste-masking agents or masking agents (such as sweeteners), cooling agents, coloring agents, flavoring agents, and fragrances.

  The liquid preparation can be prepared by dissolving or dispersing each component in a carrier component, filtering or sterilizing if necessary, and filling a predetermined container. A semi-solid preparation can also be prepared by a conventional method, for example, by mixing each component and a carrier component, sterilizing if necessary, filling a predetermined container, or applying to a substrate. Liquid preparations and semi-solid preparations may also have grouped forms in order to suppress contact between glycosaminoglycans and glucuronic acids. For example, each component may be housed or filled in a separate container or fractionated chamber.

The pharmaceutical kit of the present invention includes (1) a preparation containing two components (or a packaging form in which the preparation is contained or packaged) and one component among vitamin B1, class ₁ , glycosaminoglycans, and glucuronic acids. A kit composed of a preparation (or a packaging form that contains or packages the preparation), or (2) a three-formulation that contains each component (or a packaging form that individually contains or packages each of the three preparations) It may be a kit. In the kit (1), preparations containing a plurality of components may be grouped as described above. For example, the kit contains a first element (first packaging form) that contains or packages a preparation (dosage form) containing glycosaminoglycans, and a first container that contains or packages a preparation (dosage form) containing glucuronic acids. 2 elements (second packaging form), and vitamin B ₁ may be contained in at least one of a preparation containing glycosaminoglycans and a preparation containing glucuronic acids.

The composition and preparation or kit of the present invention can be applied to mammals (humans, dogs, cats, pigs, horses, cows, rabbits, rats, birds, etc.) and is suitable for administration to humans. The dosage of the composition and preparation of the present invention can be selected according to the degree of symptoms, age, sex, body weight, administration route, etc., and the unit dosage of vitamin B type ₁ is, for example, 1 to 300 mg (for example, 10 -250 mg), preferably 50-200 mg, more preferably about 75-150 mg. Moreover, when administering a vitamin preparation containing a plurality of vitamins, the content of vitamins can be selected from a range of about 0.01 to 80% by weight relative to the whole preparation, usually 0.1 to 50% by weight, Preferably, it may be about 1 to 30% by weight. The dosage of vitamins is about 0.01 to 500 mg, preferably about 0.1 to 300 mg (for example, 0.5 to 250 mg), more preferably about 1 to 200 mg (for example, 5 to 150 mg) per day. May be. For example, in a vitamin preparation, the unit dosage of vitamin B ₆ may be about 1 to 100 mg (for example, 5 to 50 mg, preferably 10 to 30 mg), and the unit dosage of vitamin B ₁₂ is 0 It may be about 0.001 to 2 mg (for example, 0.01 to 0.5 mg, preferably 0.03 to 0.1 mg).

  The unit dosage of glycosaminoglycans can be selected from the range of, for example, about 1 to 10000 mg, and is usually 10 to 5000 mg (for example, 50 to 3000 mg), preferably 100 to 2500 mg, more preferably 300 to 2000 mg, particularly About 500-1500 mg may be sufficient. Furthermore, the unit dosage of glucuronic acid can be selected from the range of, for example, about 1 to 15000 mg, and is usually 10 to 7000 mg (for example, 50 to 5000 mg), preferably 100 to 2500 mg, more preferably 200 to 2000 mg, particularly 500. It may be about ˜1500 mg.

  The composition and the preparation of the present invention can be administered once or divided into a plurality of times (for example, 2 to 6 times) per day.

The composition, preparation or kit of the present invention prevents the degeneration of joint tissues (human and animal connective tissues) or inflammatory joint disorders by utilizing the activities of vitamin B1, class ₁ , glycosaminoglycans and glucuronic acids. Or useful for treatment. The joint disorder may be an intrinsic disorder or an extrinsic disorder caused by trauma or drugs. Examples of joint disorders include diseases derived from cartilage damage such as arthritis (such as osteoarthritis) and arthropathy (such as osteoarthritis). Etc. are also included. Therefore, the composition of the present invention can be used as a pharmaceutical preparation effective for the prevention or treatment of joint disorders such as arthritis causing osteoarthritis and osteoarthritis. More specifically, the compositions and preparations of the present invention include, for example, joints (eg, neck (cervical vertebrae), back, arms (elbow), hips, knees, ankles, etc.), particularly joints that mainly affect articular cartilage. It is useful for the prevention or treatment of diseases (such as diseases involving hypertrophy of the affected joint and surrounding tissues), and the prevention or treatment of joint pain caused by these joint diseases. Moreover, since it is effective in preventing or treating a disease of a joint tissue, the range of motion or the range of motion of the joint can be expanded.

  Hereinafter, the present invention will be described in more detail based on test examples and examples, but the present invention is not limited to these examples.

Test example 1
We investigated the cartilage degeneration-inhibiting effect of oral administration of fursultiamine hydrochloride, chondroitin sulfate sodium and glucuronolactone in combination with an experimental osteoarthritis model by partial excision of the meniscus of the knee joint in rabbits. For the test, 32 male rabbits (Kbl: JW, Kitayama Labes Co., Ltd.) of 14-15 weeks old were used. The animals were divided into 4 groups of 8 per group, and the test drug was orally administered for 4 weeks in the following group structure. The test drug was suspended in pure water and was orally administered by gavage at a dose of 8 mL / kg based on the weight of each individual measured most recently.

[Composition of study drug group]
Using glucuronolactone (test substance A), sodium chondroitin sulfate (test substance B), and fursultiamine hydrochloride (test substance C), the test drug group (test substance A alone) administration group, test drug 2 groups (test substance B + C) administration group, 3 groups of test drug 3 (test substance A + B + C) administration group, and a control group of vehicle (pure water) administration were added for a total of 4 groups. Details are as follows.

[Dose basis]
The doses of chondroitin sulfate sodium and fursultiamine hydrochloride were set with reference to the following document 1 (report of the same test by Kobayashi et al.). The dose of glucuronolactone was determined in a preliminary study conducted prior to this study (the effect of oral administration of glucuronolactone etc. on experimental osteoarthritis by partial excision of the rabbit meniscus). From the test results of the combination of dose (200 mg / kg / day and 1000 mg / kg / day), chondroitin sulfate sodium (800 mg / kg / day) and fursultiamine hydrochloride (109.16 mg / kg / day), cartilage degeneration suppression The dose of 1000 mg / kg / day in which the effect was observed was selected.

[Production of osteoarthritis model]
A rabbit meniscus partial excision osteoarthritis model was prepared with reference to the following literature 2 (the method of Hirota et al.) And the literature 3 (the method of Nochi et al.). Under combined anesthesia with ketamine hydrochloride and xylazine, the rabbit's lateral collateral ligament and the tendon at the beginning of the popliteal muscle were cut, and the approximately central part of the lateral meniscus was resected 1.5-2.0 mm.

[Extraction and fixation of knee joint]
After collecting the joint fluid, the femoral condyle and the tibial condyle at the left knee joint were removed, and the excised tissue was fixed with 10% neutral buffered formalin solution containing 0.5% cetylpyridinium chloride.

[Measurement of injury area]
The expression range (injury area) of the articular cartilage lesion of the femur and tibia was traced, and the injury area was calculated using image processing software. In addition, in order to avoid subjectivity entering at the time of measurement, blinding was performed.

[Preparation of pathological tissue specimen]
According to the following literature 3 (the method of Noji et al.), Pathological tissue specimens of femur and tibial articular cartilage were prepared.

  After decalcification with 10% EDTA solution (pH 7.4), paraffin sections were prepared at the sites of articular cartilage injury of the femur and tibia, and safranin O staining (safranin O, fast green and iron hematoxylin multiple staining) was performed. Evaluation of articular cartilage lesions (histopathological examination) is based on the evaluation criteria based on the evaluation criteria of Reference 4 [Colombo et al.] And Reference 5 [Kikuchi et al.] Below. Scored and evaluated. All measurements were performed in a blinded manner to eliminate the possibility of subjectivity being mixed.

[Statistical processing]
Regarding the total score of the evaluation items in the injury area and histopathological examination, an average value and a standard error were calculated in each group. A significant difference test was performed between the control group and each test drug administration group.

  The injury area was tested for equidispersity by the Bartlett method, one-way analysis of variance was further performed in the case of equal variance, and the mean values were compared by the Dunnett method if significant. In the case of unequal variance, the Kruskal-Wallis H test was performed, and when significant, the average rank was compared by Dunnett's method. The significance level was set at 5% for the Bartlett method, one-way analysis of variance and Kruskal-Wallis H test. In the Dunnett method, the risk rate was 5% and 1%. Mann-Whitney U test was performed on the total score of the evaluation items in the histopathological examination. Significance levels were 5% and 1%.

Reference 1: Kobayashi T, Notoya K, Nakamura A, Akimoto K. Fursultiamine, a vitamin B1 derivative, enhances chondroprotective effects of glucosamine hydrochloride and chondroitin sulfate in rabbit experimental osteoarthritis. Inflamm Res 2005; 54: 249-55
Reference 2: Tomoaki Hamada, Haruyo Nagahama, Katsuharu Iwadate, Satoshi Nakamura Title “Pharmacologic studies of sodium hyaluronate (ME3710) in experimental osteoarthritis (OA) and fixed joint contracture (PS) models in rabbits” "Pharmacology and treatment"1995; 23: 833-41.
Reference 3: Hiromi Noji, Naomi Yagi, Yasuhiro Oda, Katsuharu Iwadate, Koichi Tamoto, Satoshi Sekikawa Title "Bioequivalence study of novel sodium hyaluronate preparations that can be stored at room temperature""Pharmacology and treatment"2005; 33 : 303-12
Reference 4: Colombo C, Butler M, O'Byrne E, Hickman L, Swartzendruber D, Selwyn M, Steinetz B. A new model of osteoarthritis in rabbits. I. Development of knee joint pathology following lateral meniscectomy and section of the fibular collateral and sesamoid ligaments. Arthritis Rheum 1983; 26: 875-86
Reference 5: Kikuchi T, Yamada H, Shinmei M. Effect of high molecular weight hyaluronanon articular cartilage degeneration in a rabbit model of osteoarthritis. Osteoarthritis and Cartilage 1995; 4: 99-110.

  The results are shown in FIGS. 1 to 4 are graphs showing the effect on the articular cartilage injury area, FIG. 1 is a graph showing the relationship between the femoral articular cartilage injury area (concave) and the test drug, and FIG. FIG. 3 is a graph showing the relationship between the tibial articular cartilage injury area (recessed portion) and the test drug, and FIG. 4 is a tibial articular cartilage injury area (white crude portion). It is a graph which shows the relationship between a test drug. FIG. 5 is a graph showing the results of the articular cartilage injury inhibitory action expressed as a total score of evaluation items in histopathological examination.

  1 to 4, each value represents mean ± standard error (n = 8), and Dunnett's multiple comparison shows a significant difference compared to the control group (*: p <0). .05, **: p <0.01). Moreover, in FIG. 5, each value shows the average +/- standard error (n = 8), and has shown the significant difference compared with the control group in the Mann-Whitney U test (*: p <0.05). .

  From the results of Test Example 1 above, in the experimental osteoarthritis model, the joint cartilage injury-inhibiting action by the combination of glucuronolactone, fursultiamine hydrochloride and chondroitin sulfate sodium is glucuronolactone alone or fursultiamine hydrochloride. And chondroitin sulfate sodium combination were excellent and the action was synergistic.

Formulation Example 1
To a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.), 218.32 g of fursultiamine hydrochloride, 1600 g of sodium chondroitin sulfate, 419.56 g of powdered reduced maltose water candy, and a 0.04 wt% cyanocobalamin solution were added. After spraying 300 g, 600 g of an 8 wt% hydroxypropylcellulose aqueous solution was sprayed and granulated, followed by pulverization (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain a T group sized powder. Next, 40 g of pyridoxine hydrochloride and glucuronolactone (commercially available product was pulverized to an average particle size of about 35 μm and a particle size range of 23.8 to 52.6 μm) in a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.) Product, the same applies hereinafter) 2000 g and 142 g of powdered reduced maltose water candy, sprayed with 850 g of an aqueous solution of 8% by weight hydroxypropylcellulose, granulated and then pulverized (Power Mill, Showa Chemical Machinery Co., Ltd.) Grain powder was obtained. Crospovidone (162 g) and magnesium stearate (21.6 g) were added to and mixed with 2057.4 g of Group T sized powder and 2025 g of Group B sized powder, and the resulting mixed powder was milled using a rotary tableting machine with a diameter of 9.5 mm. The tablets were made with an R-face punch having a locality radius of 8 mm to obtain plain tablets (weight 395 mg per tablet, thickness 5.5 mm).

  Using a coating solution in which 3500 g of the above undissolved tablets were dissolved and suspended in 360 g of hydroxypropylmethylcellulose (TC-5MW), 45 g of talc, 45 g of titanium oxide, and 0.938 g of yellow iron sesquioxide in 4050 g of purified water, 500 type, Paulek) was coated at 10% by weight based on the weight of the uncoated tablet to obtain film-coated tablets.

Formulation Example 2
T group sized powder was obtained in the same manner as in Formulation Example 1. Next, 40 g of pyridoxine hydrochloride and 2000 g of glucuronolactone were added to a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.), and 316 g of powdered reduced maltose water candy was sprayed, and 925 g of an 8 wt% hydroxypropylcellulose aqueous solution was sprayed. After granulation, it was pulverized (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain Group B sized powder. 21.6 g of magnesium stearate was added to and mixed with 2057.4 g of Group T sized powder and 2187 g of Group B sized powder, and mixed and mixed to obtain uncoated tablets and film-coated tablets.

Formulation Example 3
Add croscarmellose sodium 162g and magnesium stearate 21.6g to T group sized powder 2057.4g and B group sized powder 2025g obtained in the same manner as in Formulation Example 1, and mix the resulting powder. An uncoated tablet and a film-coated tablet were obtained in the same manner as in Formulation Example 1, except that tableting was performed with a rotary tableting machine.

  For the solid preparations (film-coated tablets) obtained in Preparation Examples 1 to 3, the disintegration property after initial storage and after storage for 6 months at 40 ° C. is determined immediately by the disintegration test method (general test method Japanese Pharmacopoeia 15th revision). The test was conducted according to the sex tablets.

  As a result, formulation example 1 using crospovidone as the disintegrant had an initial disintegration time of 29.7 minutes and 30.7 minutes after 6 months at 40 ° C., and formulation example using croscarmellose sodium as the disintegrant. In No. 3, the disintegration time was 34.2 minutes at the beginning, and 32.8 minutes after 6 months at 40 ° C. Further, even in Formulation Example 2 containing no disintegrant, it was 31.0 minutes at the initial stage and 31.6 minutes after 6 months at 40 ° C., showing high disintegration properties.

FIG. 1 is a graph showing the relationship between the femoral joint cartilage injury area (concave portion) and the test drug in the test example. FIG. 2 is a graph showing the relationship between the femoral joint cartilage injury area (white roughened portion) and the test drug in the test example. FIG. 3 is a graph showing the relationship between the tibial articular cartilage injury area (concave portion) and the test drug in the test example. FIG. 4 is a graph showing the relationship between the tibial articular cartilage injury area (white crude part) and the test drug in the test example. FIG. 5 is a graph showing the results of the articular cartilage injury inhibitory action in the test examples expressed by the total score of the evaluation items in the histopathological examination.

Claims (10)

Vitamin B ₁ class, prophylactic therapeutic agent for a joint disorder containing glycosaminoglycans and glucuronic acids. The prophylactic / therapeutic agent according to claim 1, comprising at least one selected from fursultiamine or a salt thereof, chondroitin sulfate or a salt thereof, glucuronic acid or a salt thereof, an amide thereof, a chain ester thereof and a lactone thereof. Prophylactic treatment agent according to claim 1 or 2, wherein the agent for prevention and treatment of deformation or inflammatory joint disorders. The prophylactic / therapeutic agent according to any one of claims 1 to 3, which is a prophylactic / therapeutic agent for arthritis or arthropathy. The prophylactic / therapeutic agent according to any one of claims 1 to 4 , which is a prophylactic / therapeutic agent for osteoarthritis. The prophylactic / therapeutic agent according to any one of claims 1 to 5 , which is a prophylactic / therapeutic agent for joint dysfunction. The prophylactic / therapeutic agent according to any one of claims 1 to 6 , which is a prophylactic / therapeutic agent for joint pain. The prophylactic / therapeutic agent according to any one of claims 1 to 7 , which relieves pain in arthritis or arthropathy. Formulation group including glycosaminoglycans, are separated into a product group containing glucuronic acid, vitamin B ₁ class is at least one product group of product group containing product group and glucuronic acids containing glycosaminoglycans Or the preventive-therapeutic agent in any one of Claims 1-8 contained in the other formulation group. Among vitamin B type ₁ , glycosaminoglycans, and glucuronic acids, (1) a formulation containing two components and a formulation containing one component, or (2) three formulations each containing each component A pharmaceutical kit for preventing and / or treating joint disorders .

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