Europäisches Patentamt *EP001466621A1* (19) European Patent Office Office européen des brevets (11) EP 1 466 621 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 38/40, A61K 38/16, 13.10.2004 Bulletin 2004/42 A61K 9/14, A61K 9/16, A61K 9/20, A61K 9/48, (21) Application number: 02793463.7 A61P 1/16, A61P 3/04, (22) Date of filing: 27.12.2002 A61P 3/06, A61P 3/10, A61P 9/12 (86) International application number: PCT/JP2002/013858 (87) International publication number: WO 2003/057245 (17.07.2003 Gazette 2003/29) (84) Designated Contracting States: • TAKEUCHI, Takashi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Tottori-shi, Tottori 680-0945 (JP) IE IT LI LU MC NL PT SE SI SK TR • ANDO, Kunio Designated Extension States: Kawasaki-shi, Kanagawa 213-0033 (JP) AL LT LV MK RO • SHIMIZU, Hirohiko Mishima-shi, Shizuoka 411-0803 (JP) (30) Priority: 28.12.2001 JP 2001400641 (74) Representative: Behnisch, Werner, Dr. et al (71) Applicant: NRL Pharma, Inc. Reinhard-Skuhra-Weise & Partner, Kawasaki-shi, Kanagawa 213-0012 (JP) Patentanwälte, Postfach 44 01 51 (72) Inventors: 80750 München (DE) • HARADA, Etsumori Tottori-shi, Tottori 680-0941 (JP) (54) COMPOSITIONS FOR IMPROVING LIPID METABOLISM (57) The present invention provides a pharmaceuti- cal composition having at least one kind to be selected from the group consisting of a lactoferrin group protein comprising lactoferrin and conalbumin, and an enzy- matically decomposed product of the lactoferrin group protein comprising peptides corresponding to lactofer- ricin and lactoferricin of conalbumin an active ingredient. The composition of the present invention can be used as an agent for improving lipid metabolism. Further, it is useful for treating hypercholesterolemia, hyper-neutral lipidemia, hyper-low density lipoprotein (LDL) choleste- rolemia, hypo-high density lipoprotein (HDL) cholester- olemia, obesity, fatty liver and cholesterol gallstone and lifestyle-related diseases such as severe obesity, hyper- lipidemia, hypertension and type II diabetes. The com- position of the present invention can improve basal met- abolic rate. EP 1 466 621 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 466 621 A1 2 Description lipoprotein (LDL) and conversely decreases the choles- terol concentration present in blood high density lipopro- TECHNICAL FIELD tein (HDL) to trigger arteriosclerosis. Accordingly, the development of drugs or processed foods which can in- [0001] The present invention relates to a pharmaceu- 5 crease blood high density lipoprotein (HDL) cholesterol tical composition comprising lactoferrin and the like. The and conversely can decrease low density lipoprotein composition of the present invention can be used as an (LDL) cholesterol is one of the most globally demanded agent for improving lipid metabolism. More specifically, developments. Since statin drugs such as provastatin, the composition of the present invention is useful for simbastatin and atorvastatin which inhibit hydroxymeth- treating hypercholesterolemia, hyper-neutral lipidemia, 10 ylglutaryl conenzyme A reductase to reduce the synthet- hyper-low density lipoprotein (LDL) cholesterolemia, ic amount of the internal cholesterol play an important hypo-high density lipoprotein (HDL) cholesterolemia, role in treating the diseases of the circulatory system, obesity, fatty liver and cholesterol gallstone, and further the treatment of obesity, that is, lipid metabolic disorder for treating lifestyle-related diseases such as severe is clearly a most urgent problem. obesity, hyperlipidemia, hypertension and type II diabe- 15 [0005] The cause of obesity is overeating. By control- tes. The composition of the present invention can im- ling the appetite and increasing the physical energy con- prove basal metabolic rate. sumption together with therapeutic exercise such as jogging, anyone may well reduce weight theoretically. BACKGROUND ART However, to eat moderately and take exercise of its own 20 volition is not so simple as in words, and even if it is [0002] Our time is an age of plentiful food. With it, possible to eat moderately, reality is not so simple. It is obesity has surfaced as an important health problem said that to change eating habits established in child- which has to be overcome. In the United State of Amer- hood is the most difficult habit among the many. The ap- ica, about 30% of elementary school children are re- petite is one of pleasures which can be easily satisfied. garded as overweight children who exceed the standard 25 Furthermore, on becoming obese, thermal energy is re- weight by 30% or more. As is clear from various epide- duced in consumption and stored as the body fat that miological surveys, the obesity of school age mostly pro- much more, and thus obesity is caught in a vicious circle ceeds after attaining manhood. With it, overweight per- of bringing about obesity. The reduction in weight by sons who exceed the standard weight by 30% or more moderation in eating brings forward a health problem as appear in succession at the aging stage of from the sec- 30 well. The reduction in weight by the reduction in energy ond half of 30 years old to middle age, and thus the total intake not only reduces the white fat tissue whose de- obesity population in Western countries has accounted crease is desired but also reduces the weight of paren- for a large ratio which human beings have never expe- chymal organs at the same rate. The weight reduction rienced. Although not so conspicuous as in Western in parenchymal organs lowers immunological compe- countries, the increase of overweight children due to in- 35 tence, and the body resistance to pathogenic virus and sufficient exercise and satiation has come to a serious pathogenic microorganisms is weakened to be readily problem even in our country. seized with a disease such as a cold. Thus, what is de- [0003] Needless to say, obesity is an important dan- manded in this time of day is a weight reduction method gerous factor to the onset of ischemic heart disease, es- of selectively burning the neutral fat stored in the white sential hypertension, type II diabetes or a certain type 40 fat tissue without accompanying the weight reduction of of cancer, and the age of severe obesity is becoming parenchymal organs. lower and lower to announce a sudden increase of life- [0006] As the drugs which act on the central nerves style-related diseases beforehand. Further, also fatty to cause moderation in eating, the major ones are drugs liver and cholesterol gallstone are diseases with obesity such as madindol [C. Sirtori et al., Am. J. Med. Sci. 261: and lipid metabolic disorder for a background which can- 45 341-7(1971)] which act on the feeding center to reduce not be overlooked. Obesity not only accelerates the on- the appetite or drugs such as a stimulant and an am- set of lifestyle-related diseases but also inactivate ac- phetamine compound [O.J. Kalant, "The Ampheta- tivities to psychologically making adaptability to the so- mines; Toxicity and Addiction" (Thomas, Springfield, cial life difficult. Accordingly, obesity is a large econom- 1966)] which exhibit strong dissimilation and feed glu- ical and social loss. In the countries where overweight 50 cose by decomposition of the body constituents to re- persons are suddenly increasing, the development of duce the appetite. However, madindol has a side effect methods of preventing/treating obesity while maintain- of inducing strong constipation to cause liver disorder. ing physical condition is a pressing need. Further, the amphetamine drugs are habit-forming, and [0004] Above all, drugs or processed foods which can once fallen into drug dependence, it is very difficult to inhibit the absorption of fat in the digestive tract without 55 get out of it, and thus they have not been used as anoret- side effects are essential in the prevention/treatment of ics at all. obesity. The obesity due to overeating increases the [0007] A therapeutic method of shortening the small cholesterol concentration present in blood low density intestine by excision by a surgical operation to reduce 2 3 EP 1 466 621 A1 4 the area of the small intestinal mucosa which relates to a therapeutic drug for reducing the weight of a severely digestion and absorption. However, for improvement of obese person, and it is reported that about 30% of the obesity or hyperlipidemia, excision of part of the sound dietary fat taken in is inhibited from absorption and dis- digestive tract is not the proper way. There is a possibil- charged. However, as the defects, there are frequent di- ity that the danger of a pathogenic infection by the ab- 5 arrhea, abdominal distension and gas generation, and dominal surgical operation or the influence by shorten- furthermore it is reported that hypertension and liver fail- ing of the small intestine will be surfaced as some dis- ure are induced as the systemic side effect. Orlistat ex- ease with ages. plosively came to wide use at the time of release but [0008] Western-type meals are different from meals gradually ceased to be used due to a rash of side effects of the East Asian countries including Japan which use 10 and at present, the amount of use is one third of its ze- carbohydrates as the major energy source. The ratio of nith. When orlistat is used for a long period of time in neutral fat in caloric intake among the Western foods is order to reduce weight, periodical monitoring is required estimated 35% to 43% although it slightly varies in every and orlistat is mainly being used for severely obese per- area. Ideally, the ratio of fat in energy intake is preferably sons under the supervision of a doctor. 30% or less, and furthermore it is recommended that 15 [0011] Drugs or processed foods which reduce the ar- animal fat and butterfat which mostly contain saturated ea on which pancreatic lipase acts by fusing the micelles fatty acids are not more than half of the fat to be taken of dietary fat with each other and inhibit the absorption in and the remainder is taken in as vegetable oil and fish of dietary neutral fat have not been widely put into prac- oil which largely contain unsaturated fatty acids.