(12) United States Patent (10) Patent No.: US 7.625,916 B2 Kawasugi (45) Date of Patent: Dec

US00762.5916B2

(12) United States Patent (10) Patent No.: US 7.625,916 B2 Kawasugi (45) Date of Patent: Dec. 1, 2009

(54) MEDICINAL COMPOSITION (56) References Cited (76) Inventor: Kaname Kawasugi, 26-10-405, U.S. PATENT DOCUMENTS Higashi-oi 5-chome, Shinagawa-ku 3,502,674. A 3/1970 Takamizawa et al. Tokyo (JP) 140-0011 4,687,777 A * 8/1987 Meguro et al...... 514,342 5,002.953 A * 3/1991 Hindley ...... 514,275 c - r 5,977.073 A * 1 1/1999 Khaled ...... 514, 19

(*) Notice: Subject to any disclaimer, the term of this 6,166,219 A * 12/2000 Yamasaki et al...... 548/309.4 patent is extended or adjusted under 35 6.251926 B1* 6/2001 Momose et al...... 514,364 U.S.C. 154(b) by 122 days. 6,660,293 B2 * 12/2003 Giordano et al...... 424/439 (21) Appl. No.: 10/572,557 FOREIGN PATENT DOCUMENTS FR 2832O64 A1 * 5, 2003 (22) PCT Filed: Sep. 17, 2003 WO O2/O51441 T 2002 (86). PCT No.: PCT/UP03/11847 OTHER PUBLICATIONS Tamai, Hiroshi. “Diabetes and Vitamin Levels', Japanese Journal of S371 (c)(1), Clinical Medicine, vol. 57, No. 10, pp. 200-203, 1999. (2), (4) Date: Mar. 17, 2006 Hashizume, Naotaka, “Vitamin B1 Deficiency”. Igaku no Ayumi, vol. 198, No. 13, pp. 949-952, 2001. (87) PCT Pub. No.: WO2005/027967 * cited by examiner PCT Pub. Date: Mar. 31, 2005 Primary Examiner Kevin Weddington (74) Attorney, Agent, or Firm Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P. (65) Prior Publication Data (57) ABSTRACT US 2007/O 10591.0 A1 May 10, 2007 A medicinal composition which comprises an insulin resis 51) Int. Cl tance-limorOV1gimproving drug and V1vitamin tamin BBorderivative Order VatiVethereof. thereof. IIn A6 IK3I/SI (2006.01) this medicinal composition, the side effects of the insulin A6 IK 3/44 (2006.01) resistance-improving drug Such as edema, heart enlargement, A6 IK 3/425 (2006.01) anemia, etc. are prevented by using vitamin B or its deriva (52) U.S. Cl...... 514/276; 514/342; 514/350; tive together. It is usable as a remedy for diabetes, a remedy 514/369; 514/866 for lifestyle related diseases, an anti-tumor agent, an anti (58) Field of Classification Search ...... 514/276, rheumatoid drug and so on. 514/342,369,350,866 See application file for complete search history. 6 Claims, No Drawings US 7.625,916 B2 1. 2 MEDICINAL COMPOSITION As mentioned above, the insulin resistance-improving drugs have problems of the side effects such as edema, heart TECHNICAL FIELD enlargement and anemia. Thus, the purpose of the invention is to provide a technique for reducing Such side effects. The present invention relates to a medicinal composition, 5 and more particularly it relates to a medicinal composition DISCLOSURE OF INVENTION which comprises an insulin resistance-improving drug as a major ingredient and in which the side-effects including In order to solve the above problems, the present inventor edema, heart enlargement and anemia caused thereby are worked assiduously to investigate the cause of the above reduced. mentioned side effect in the insulin resistance-improving 10 drugs and found that in vivo vitamin B was relatively defi BACKGROUND ART cient due to administration of an insulin resistance-improving drug. It was also found that the simultaneous administration of the insulin resistance-improving drug with Vitamin B was Insulin resistance is a pathologic condition which requires effective in prevention of the above side effect. Thus, the an excess amount of insulin over the normal amount for 15 gaining a variety of actions of insulin at the level of cells, invention was completed. organs and individuals. This pathologic condition is a state That is, the invention provides a medicinal composition meaning decrease of the insulin sensitivity in liver, skeletal which comprises an insulin resistance-improving drug and muscle and fat tissue and characteristic in type II diabetes vitamin B or its derivative. mellitus with failure of insulin secretion. Insulin resistance is much involved in formation of a pathologic condition of BEST MODE FOR CARRYING OUT THE lifestyle-related diseases Such as hypertension or hyper INVENTION lipemia in addition to diabetes mellitus and impaired glucose tolerance, and its improvement is becoming clinically more As the insulin resistance-improving drug used in the important. medicinal composition of the invention, compounds having a 25 PPARY agonist activity are exemplified. More specifically, As drugs which can possibly be used as insulin resistance PPAR-Y activation-promoting compounds of thiazolidine improving drugs inhibiting insulin resistance, compounds type such as pioglitaZone, rosiglitaZone, CS-011, and the like, which have a Y-agonist activity of peroxisome proliferator and PPAR-Yactivation-promoting compounds of non-thiazo activated receptor (PPAR)(hereinafter referred to as “PPAR-y lidine type such as TAK-559, FK-614, and the like are activation promoting compound'), which is a nuclear recep included. These compounds, if required, may be converted tor, have been known and some of them have been employed 30 into Such derivatives as pharmaceutically acceptable salts of for type II diabetes mellitus. These compounds have a blood them. Sugar-lowering effect in addition to lipid metabolism-im Particularly preferred insulin resistance-improving drugs proving effect. are PPAR-Y activation-promoting compounds of thiazolidine As for PPAR-Y activation promoting compounds, thiazoli type, pioglitaZone and rosiglitaZone as well as their deriva dine-type compounds and non-thiazolidine-type compounds 35 tives such as addition salts. are known. The thiazolidine-type compound includes trogli On the other hand, vitamin B (thiamine) used in the taZone, pioglitaZone, rosiglitaZone, CS-011, and the like; and medicinal composition of the invention is a well-known the non-thiazolidine-type compound includes TAK-559: water-soluble vitamin, which has almost no side effect evenin FK-614, and the like. overdose and of which the cost is low. The vitamin B deriva It has been considered that these insulin resistance-improv 40 tives are also known, including, for example, fursultiamine, ing drugs primarily act on adipocytes through PPARY to benfotiamine, octotiamine, prosultiamine, bisbentiamine, accelerate differentiation of the adipocytes and inhibit an dicetiamine hydrochloride, thiamine hydrochloride, thia insulin resistance causative factor such as TNF-C. to improve minedisulfide, co-carboxylase, and the like. the insulin resistance. Details are not clear. In producing the medicinal composition of the invention, In this connection, the first launched insulin resistance 45 the above-mentioned insulin resistance-improving drug and improving drug in the world was a thiazolidine-type com vitamin B or its derivative (hereinafter, referred to as “Vita pound troglitaZone, but this was withdrawn because of occur mins B) are combined with a suitable pharmaceutically rence of serious hepatic disturbance. Subsequently, the same acceptable carrier, then mixed, and formulated into a desired thiazolidine compounds, pioglitaZone and rosiglitaZone, pharmaceutical preparation. were developed and at present these two drugs have been used 50 The amount of the insulin resistance-improving drug to be oversea as insulin resistance improving drugs; in Japan, combined for a dose unit of medicinal composition of the pioglitaZone alone has been used. invention is preferably from 5 to 300 mg, and the amount of However, there was a problem in the insulin resistance Vitamins B to be combined is preferably from 1 to 500 mg. improving drugs since they have other side-effects, i.e., There is no particular limitation in the combination ratio edema, heart enlargement, anemia, and Soon, particularly between the insulin resistance-improving drug and Vitamins edema. That is, in pioglitaZone, rosiglitaZone and troglita 55 B, and Vitamins B may be used in an amount of about 0.01 Zone, the side-effects such as edema and anemia have been to 200 parts by weight, preferably about 0.05 to 40 parts by observed in several percentage, and in pioglitaZone conges weight, for one part by weight of the insulin resistance-im tive heart failure has been recognized. This is one of the proving drug. reasons why they are not so used domestically in Japan More specifically, when pioglitazone hydrochloride which though they have a high usefulness as insulin resistance 60 is only one insulin resistance-improving drug available in improving drugs. Japan is used in the medicinal composition of the invention, a Such edema as a side-effect has been observed in all of the preferred combination is illustrated as follows. That is, piogli So far known thiazolidine-type compounds under develop taZone hydrochloride is incorporated in one unit dose of the ment; when the edema occurs as side effect, the administra pharmaceutical preparation in the amount of 15-45 mg, which tion has to be stopped in some cases, and in another case a 65 amount is a dose (oral administration) of pioglitaZone hydro diuretic is required; thus, these have big problems in using as chloride for once a day. On the other hand, when fursul drugs. tiamine is used as Vitamins B in combination, it may be US 7.625,916 B2 3 4 incorporated in the amount of 5-100 mg for one unit dose. This amount may also be adapted in a case in which fursul TABLE 2 tiamine is replaced by benfotiamine as another Vitamins B. The medicinal composition of the invention may be for Weight ratio of the heart mulated into Solid preparations such as powders, pellets, to the body weight granules, tablets, capsules, and so on, or liquid preparations Administration (%) Such as liquids and solutions. Pioglitazone HCl O.35 There is no particular limitation in carriers used in produc alone ing the medicinal composition of the invention, and a powder Pioglitazone HCl + O.31 or liquid carrier may be employed according to the objective Benfotiamine formulation. In addition, if necessary, a suitable additive used 10 in the pharmaceutical field may be added. As clearly seen from Table 1, a tendency of improvement of Though mixture preparations were used as examples in the hemoglobin decrease (anemia) was recognized in the benfo above description, needless to say, the insulin resistance tiamine-combined group in comparison with the group to improving drug and the Vitamins B may respectively be which pioglitaZone hydrochloride alone was administered. formulated independently, and they may be used in a com 15 As shown in Table 2, a tendency of improvement in the bined preparation. heart weight gain (heart enlargement) was recognized in the Effect benfotiamine-combined group, in which the relative heart Regarding the mechanism of edema formation as a side weight ratio after administration is lower than that in the effect in the insulin resistance-improving drug, it has been group to which pioglitaZone hydrochloride alone was admin reported that there are possibilities such as increase of Na istered. reabsorption-accelerating action of insulin in renal, direct From these results, it was shown that the combined use of accelerating action to a NaHCO-co-transporter in renal, benfotiamine can inhibit the side effect caused by sole admin sthenic effect in vascular permeability by increase of the istration of pioglitaZone hydrochloride. blood VEGF level, and so on. The heart enlargement and anemia are considered due to increase of the amount of cir 25 INDUSTRIAL APPLICABILITY culating plasma caused by them. The medicinal composition of the invention, in which an It has been found by the present inventor that one of causes insulin resistance-improving drug is used in combination of the above side effects exists in increase of vitamin B with Vitamins B, is not accompanied by the side effect such demand in the living body induced by the insulin resistance as edema, heart enlargement and anemia, though the insulin improving drug. 30 Thus, the effect of the invention is to prevent and improve resistance-improving drug is contained as a major drug; in the relative deficiency of vitamin B in the living body by addition, no decrease of the drug effect is recognized. administering vitamin B along with an insulin resistance Vitamins B used together shows almost no side effect even improving drug and reduce the side effects such as edema, in overdose and is available in relatively low cost. Thus, the heart enlargement, anemia, etc. medicinal composition of the invention is Superior in Safety 35 and economical point of view as medicine. EXAMPLES Therefore, the medicinal composition of the invention can be used to decrease the blood sugar level for type II diabetes The invention will be explained in more detail by the fol mellitus. lowing examples which are not intended as a limitation The insulin resistance-improving drug contained in the thereof. 40 medicinal composition of the invention has a lipid metabo lism improving effect, anti-tumor effect and anti-rheumatoid Example 1 effect, and can be used as a remedy for diabetes mellitus, remedy for lifestyle related diseases, anti-tumor agent, anti Repeated oral administration test for 10 days using rats: rheumatoid drug, and so on. SD-Family rats (Cr:CD:IGS) of 8 weeks of age were The invention claimed is: divided into two groups; in one group, pioglitaZone hydro 45 1. A medicinal composition comprising an insulin resis chloride is orally administered at a dose of 240 mg/kg/day for tance-improving drug and vitamin B or derivative thereof in 10 days forcibly through a gastric probe, and the in the other an amount effective for inhibiting at least one side effect of group, 240 mg/kg/day of pioglitaZone hydrochloride and 100 said insulin resistance-improving drug, which side effect is mg/kg/day of benfotiamine were administered in the same selected from the group consisting of edema, heart enlarge manner. After termination of the administration, the blood 50 ment and anemia, and wherein the insulin resistance-improv was collected from the rats and the hemoglobin (Hb) value ing drug is selected from the group consisting of pioglitaZone, was determined. Then, the rats were killed, and their hearts rosiglitazone and CS-011, and salts thereof. were weighed (relative weight). Table 1 shows the result 2. The medicinal composition claimed in claim 1, wherein regarding the blood Hb, and Table 2 shows the weight ratio of the insulin resistance-improving drug is pioglitaZone. the heart to the body weight. 55 3. The medicinal composition claimed in claim 1, wherein the insulin resistance-improving drug is rosiglitaZone. TABLE 1. 4. The medicinal composition claimed in claim 1, wherein Blood Hb conc. Blood Hb conc. the insulin resistance-improving drug is CS-011. before after 5. The medicinal composition claimed in claim 1, compris administration administration 60 Administration (gd) (gd) ing 5 to 300 mg of insulin resistance-improving drug, and 1 to 500 mg of vitamin B or derivative thereof for one unit dose. Pioglitazone HCI 12.9 13.6 6. A method comprising administering the medicinal com alone Pioglitazone HCl + 12.9 14.1 position as claimed in claim 1 in an effective amount to a Benfotiamine 65 subject in need thereof.