United States Patent Furda

4,223,023 September 16, 1980

Nonabsorbable lipid binder

Abstract The use of chitosan as a food additive or as a pharmaceutical preparation to reduce the absorption of lipids is disclosed. The chitosan, as such or in the form of fatty acid complex, may be admixed with food in a minor quantity; for example, an amount of about 1 to 10 percent by weight may be incorporated in a pharmaceutical preparation or composition for oral administration in an effective amount to reduce lipid absorption.

nventors! Furda; Ivan "#ay$ata, %N& 'ppl. No.! (iled! 0 !9 0,"69 #ct$ber 12, 19"8

%urrent U&S& %'ass( %urrent Internati$na' %'ass(

14!

; )*+,+-.; -/+,*0

00.1 /2,00 "*00+0101&; 00.1 /2,0. "*00+0101&; '+13 0/1,2/ "&; 00.1 0/2,0. "& -/+,*0 )*),1.0 )*+,+-.

Fie'd $) Searc*(

+e)erences %ited ,+e)erenced -./ U&S& Patent 0$cuments /-//4)0 /.24/2+ /4-/+0. )0/)1*1 5ctober 1420 'pril 142'pril 142+ 8uly 1422 6eniston et al. 7anlerberghe et al. 7anlerberghe et al. 9unn et al.

)114+14

5ctober 142.

:ogo$hin et al.

Primary Examiner: 1rown; 8ohnnie :. Attorney, Agent or Firm: ;prung, (elfe, <orn, =ynch > 3ramer Claims

#hat is claimed is! 1. ' method of reducing lipid absorption in mammals which comprises orally administering to the mammal an amount of chitosan effective to substantially reduce the lipid absorption. *. ' method according to claim 1 in which said chitosan is in the form of a fatty acid complex. Description

n certain mammals, and notably humans, it is often desirable, and sometimes necessary, to reduce the absorption of lipids such as triglycerides, fatty and bile acids, as well as cholesterol and other sterols. ?uite often, in weight control programs, it is difficult to control the ingestion of these materials and the subsequent digestion and absorption thereof cause weight and health problems. n accordance with the invention, have discovered that if chitosan is ingested by mammals, it is capable of binding many times its weight in lipids, preventing the digestion and absorption thereof and promoting their excretion. n accordance with the invention, chitosan is formulated and utili$ed as a food additive to reduce both absorption of lipids and caloric inta@e and also as a pharmaceutical for the treatment of obesity, coronary heart disease and certain gastroAintestinal disorders. 0hitosan constitutes a @nown material and is partially or fully deacetylated chitin. 0hitin is a natural celluloseAli@e polymer which is present in fungal cell walls and exos@eletons of arthropods such as insects, crabs, shrimps or lobsters. The polymer structure of chitin consists of NAacetylA9Aglucosamine units lin@ed by .beta.A"1A)& glycosidic bonds which impart to the material characteristics similar to that of cellulose. 0hitosan is conventionally prepared by the al@aline deacetylation of chitin with concentrated sodium hydroxide at elevated temperatures. 9epending upon the conditions of the deacetylation, chitosan with various degrees of acetylation is obtained. n the most common products, the degree of deacetylation is between 20

and 40 percent. 'lthough chitosan is usually obtained by chemical deacetylation of chitin, it may also be obtained by the fermentation of certain foods. have found that the chitosan is capable of binding various fatty acids to form the corresponding complex salts. believe that the binding is induced by the number of free amino groups in the chitosan which forms an ionic bond causing a binding effect considerably stronger than that obtained in conventional absorption or adsorption. The chitosanAfatty acid complexes can be prepared by neutrali$ation of chitosan with various amounts of fatty acids, preferably edible fatty acids, such as oleic, linoleic, palmitic, stearic or linolenic acid. These complexes can be prepared by neutrali$ation of the chitosan with various amounts of these fatty acids, including stoichiometric amounts, less than stoichiometric amounts, or greater than stoichiometric amounts than those required for the neutrali$ation of the chitosan. The chitosanAfatty acid complex, after ingestion by a mammal, will bind additional lipids, most probably due to its strong hydrophobic characteristic. ;uch lipids include natural triglycerides, fatty and bile acids, and cholesterol and other sterols, and a great portion of these bound lipids will be excreted rather than absorbed and utili$ed by the mammal. This is believed due to the following factors! 0hitosanBs inherent insolubility, nonabsorbability, and undigestibility; The strong ionic binding of fatty and bile acids which prevent their release for absorption and utili$ation; The inability of the hydrochloric acid in the stomach to hydroly$e the chitosanAfatty acid complexes "complex does not wet&; The tendency of the complexes to grow in si$e as they travel through the gastroA intestinal tract and gradually absorb and bind additional lipids; The ability of the chitosanAfatty acid complex to bind dietary triglycerides which are hydroly$ed by lipase and released as fatty acids or other volatile fatty acids "acetic, formic, butyric& formed by microbial degradation in vivo and The ability of the chitosan to bind to its matrix and promote the excretion of cholesterol and sterols which will be solubili$ed in the lipophilic phase. n accordance with one embodiment of the invention, the chitosan, as such or in the form of its fatty acid complex, is admixed with a food substance to form a composition consisting of the food substance containing a minor quantity, as for example, between 1 and 10 percent by weight, of the added chitosan, as such or as a fatty acid complex. This food composition, containing the minor quantity of the added chitosan, has a lower effective caloric value than the corresponding amount of food without the chitosan, as the chitosan in the composition has the ability of binding and preventing the absorption of a large amount of lipids. The food composition, when ingested, will thus reduce the fat inta@e of the mammal, promoting the binding and excretion of fatty materials such as cholesterols, sterols, triglycerides, and the li@e. The chitosan, as such, is not capable of binding neutral oil, but once complexed with a fatty acid, the complex is capable of absorbing neutral oil. Therefore, it is often desirable to use the chitosan at least partially in the form of its fatty acid complex.

The chitosan itself, i.e., not in the form of fatty acid complex, may, for example, be utili$ed as a low calorie filler in connection with various foods, such as breads, ca@es, coo@ies, and the li@e. n the form of the fatty acid complex, as for example, with linoleic acid, palmitic acid, stearic acid, or linolenic acid, the same may be used as a fat extender added, for example, to margarine, spreads and dips, salad dressing, or the li@e. The characteristics of the chitosan, with respect to its nonAdigestibility, its biodegradability, and its bland taste ma@e the same excellent as a food additive and, due to its ability to bind the lipids, may be considered as having a negative caloric value, i.e., lowering calorie effect of the foods to which it is added. 0hitosan, in accordance with a further embodiment of my invention, finds application as a pharmaceutical for the treatment of gall bladder disease, in which the absorption and utili$ation of lipids is not desirable; in the treatment of obesity; and in gastroA intestinal disorders or coronary disease where bile acids, cholesterol and other sterol lowering is desirable. 's a pharmaceutical preparation, the chitosan and,or the chitosanAfatty acid complex, may be admixed to form a pharmaceutical composition with any inert pharmaceutical carrier. 0hitosan may be incorporated in a pharmaceutical preparation in the form of a suspension or dispersion, for example, an aqueous suspension or dispersion containing chitosan, water, and, if desirable, an edible acid such as linoleic acid. 9osage units effective for the treatment of obesity, gall bladder and gastroAintestinal disorders, and the li@e may vary between units containing / to 1* grams of the chitosanAAchitosan fattyAacid complex, preferably ) to 2 grams of the chitosanAA chitosanAfatty acid complex. The pharmaceutical should be orally administered, preferably in the unit dosage form and preferably before meals. The following examples are given by way of illustration and not limitation. CD'%6=C; Cxample 1 EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE :ye 1read ngredients Frams EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE ;our rye culture )-0 ;alt 1)1 1lend these ingredients together at slow speed %olasses "dar@& 120 for about +A. minutes. %alt "nondiastatic& 11* 0araway seeds *. #ater /+/0 0hitosan "100 mesh& /+0ream of rye flour *040 Geast "variable& /)0 9issolve yeast in water. 'dd flour to above flour #ater 400 mixture and mix slightly. 'dd shortening and develop (lour, strong first clear -*20 dough at slow speed. ;hortening 1)* EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 9ough temperature! .0.degree.A.*.degree. (. (ermentation time! 1 hour with sour culture, )0 minutes with fermented sour rye

sponge dough To bench or scalerArounder! ;cale and round with resting periods 1- to *0 minutes %old! round or long shape 6roof! /,) proof 1a@ing! 1a@e with steam at )11.degree. (. Cxample * EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 6ound 0a@e ngredients Frams EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE (lour "ca@e& 1.*0 0hitosan "100 mesh& )-0 ;hortening "emulsified& 1-40 ;alt -2 %il@ solids, nonfat 1)* <igh fructose syrup )* 122 ;ugar *2*) #ater 1000 #hole eggs 1-40 (lavor *. EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 6reparation (lour, chitosan and shortening are mixed for *A) minutes. Then sugar, salt, nonfat mil@ solids, high fructose syrup and water are added and mixed for - minutes at same speed. (inally, eggs and flavor are added and mixed for - minutes at low speed. =arge loaves are ba@ed at /)0.degree. (. Cxample / 6reparation of chitosanAAfatty acid complex Cmulsion consisting of linoleic acid "or any fatty acid& and water is prepared by homogeni$ation or by vigorous stirring "#aring blender& of +00 ml water containing 0.1A1.0 g ben$oic acid "preservative& 1A2 g polysorbate .0 "emulsifier& and /00 ml linoleic acid containing 0.0- g 1<' "antioxidant& The good quality emulsion is usually obtained in less than one minute of stirring. 20 g of chitosan powder ".0A*00 mesh& is added to the emulsion and stirring "homogeni$ation& is continued for another one minute. The complex of chitosanAA linoleic acid is then isolated by filtration. The ratio of fatty acid to chitosan for the preparation of the complex may vary considerably, depending on specific requirements. The preferential ratio is between 0.1!1.0 and -!1.

Cxample ) EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE ;alad 9ressing with 1lue 0heese (lavor ngredients Frams EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE ;alt +./ 0ream cheese 1)4.0 <igh fructose corn styrup )* 12.+ 7inegar 1).0 9ehydrated parsley fla@es 1.- 5il /..) 0hitosan,oleic acid complex *0.- 1lue cheese flavor to taste #ater -/.0 EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 6reparation 0ream cheese is whipped in mixer. 'll liquids are mixed together. 'll dry ingredients are mixed together. The mixes are added gradually to whipped cream cheese and mixed together until homogenous paste is obtained. The product is refrigerated. Cxample EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 0hic@en Noodle ;oup %ix ngredients Frams EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE ;alt /..0 %onosodium glutamate **.0 0hitosan,oleic acid complex 10.0 0hic@en fat 2.1 9ehydrated chic@en 1/.0 5nion powder *.. ;ugar *.0 #heat flour /.0 <ydroly$ed vegetable protein 1.* Fround parsley 0.+ Fround pepper 0./ EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 6rocedure %ix all ingredients. (ill 1+ grams of the above soup mix and )1 grams of fine noodles into )Aply laminated soup pac@ets and heatAseal. :ehydration 'dd contents of a pac@et to 1 pint of boiling water. ;immer -A. minutes. Cxample + 6reparation of chitosan powder mixture for oral administration EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE ngredients Frams EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 0hitosan powder "100A*00 mesh& .0.0 =actose 10.0 ;ucrose 4.4 5range flavor "or other flavor& as desired 0.01A0.1 EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 'n intimate mixture of these ingredients is prepared in mixer or blender and it is then pac@ed into individual pac@ages containing )A- grams of powder. This dosage should be administered as a suspension in water or a flavored vehicle. %aximum daily inta@e! 1+A*0 grams

Cxample 2 6aste "cream& of chitosanAAfatty acid complex for oral administration '. 6reparation of the Cmulsion EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 0./ g 1en$oic acid 1.- g 6olysorbate .0 0.0* g ;accharin *0 ppm (9'0 Freen No. / "colorant& is dispersed in +00 ml water 0.01 g 1<' "1utylated hydroxyanisole& 0.0) g 6eppermint 5il "flavor& is dispersed in 100 ml of oleic acid EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1. 6reparation of the 0omplex The water and oleic acid solutions are then combined and emulsion is prepared by stirring in #aring 1lender for /0A+0 seconds. 20 g of finely powdered chitosan "100 mesh& is added to this emulsion, the dispersion is vigorously stirred in blender for an additional /0A+0 seconds and the formed complex is filtered off and pac@ed into appropriate containers and stored under refrigeration. The complex can then be used for oral administration. 'lthough the invention has been described in detail with reference to certain specific embodiments, various changes and modifications will become apparent to the s@illed artisan. The invention is only intended to be limited by the appended claims or their equivalents wherein have endeavored to claim all inherent novelty. 11111