NZ222854A - Orally ingestible composition containing cholestyramine and at least one deodorising agent - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £22854 22 2854 NO DRAWlNfifl Priority Date(s): Complete Specification Filed: C^v AW&&1 Publication Date: MQ JP.fy..

P.O. Journal, No: NEW ZEALAND No.: Date: PATENTS ACT. 1953 COMPLETE SPECIFICATION CHOLESTYRAMINE COMPOSITIONS AND METHOD FOR PREPARATION THEREOF I/We. AMER & CO., a Connecticut corporation Sai .

-Gonncttielt 06836-, United States of America Jl77 fodcLtv Cajr^rileri*, ion, of4^0 Bon 1251 Gr-conwioh', hereby declare the invention for which I / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - Followed by - la - * -.2 2 8 5 CHOLESTYRAMINE COMPOSITIONS AND METHOD FOR PREPARATION THEREOF This invention relates to cholestyramine compositions and to a method for preparation of such compositions.

It is well known that various diseases are caused by high cholesterol levels in the blood plasma. Indeed, the most 5 serious and life-threatening of these may be cardiac diseases such as arterosclerosis and coronary heart disease.

Accordingly, the art has considered it highly desirable to provide compositions, particularly for oral administration, which effectively reduce the cholesterol level in the blood. 10 Cholestyramine, a hydrophilic polyacrylic quaternary ammonium anion exchange resin, which is described in U.S.

Patent No. 3,308,020 to Wolf et al, as well as in U. S.

Patents 3,769,399 to Hagerman et al; 3,846,541 to Howard; 4,172,120 to Todd et al; 4,252,790 to Higuchi; and 4,340,585 15 to Borzatta et al; is well known and accepted as very effective . I in reducing blood cholesterol levels. It is available commercially from the Mead-Johnson division of the Bristol-Myers Company in a powder product named "Questran".

The effectiveness of cholestyramine is based on its ability to complex with bile acids. More particularly, cholesterol is probably the sole precursor of bile acids which during normal digestion are secreted into the intestines. A major portion of the bile acids is adsorbed from the intestinal tract -10 a 22 28 54 o 0 and returned Co the liver via the enterohepatic circulation. Cholestyramine adsorbs and/or reacts, binds, combines and/or complexes with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This loss 5 of bile acids from the system leads to an increased oxidation of cholesterol to replace the loss, with a resulting decrease in beta or low density lipoprotein plasma levels and serum cholesterol levels.

Because of its low binding capacity for bile acids, 10 the normally recommended daily dose of cholestyramine is 8 to 16 grams. This presents a major problem since the resin has an unpleasant fishy odor, gritty texture and objectionable taste properties and patients find it extremely difficult to ingest this amount of material day after day. Attempts to 15 increase this binding capacity of cholestyramine, and thereby enable a reduction in the daily dosage, have consistently failed.

Prior attempts to mask the objectionable properties have been counter-productive. For instance, when cholestyramine is incorporated into cookies, breads, cake products such as 20 brownies, etc., the high saturated fat and/or sugar contents of such products tend to defeat the blood cholesterol-reducing purpose of cholestyramine and/or introduce calorie-increasing and other problems.

It is an object of this invention to provide cholestyramine 25 compositions in which the aforesaid objectionable properties, especially the fishy odor, are effectively nasked or eliminated, j! thereby making it palatable to users. 22 2 8 5 n IS a O II I It is a further object of this Invention to provide such improved cholestyramine compositions of relatively low calorie content and/or totally or substantially devoid of saturated fat.

It is still a further object of this invention to provide a process for preparing such cholestyramine compositions.

Another object of this invention is the provision of such improved cholestyramine compositions in diverse liquid and solid oral dosage forms.

Additional objects and advantages will be apparent from a consideration of the following description.

In accordance with certain of its aspects this invention relates to an orally ingestable composition comprising cholestyramine admixed with, per part by weight of the cholestyramine, at least one deodorizing agent selected from the group consisting of I about 0.2 to about 4.5 parts by weight of a water-soluble carbohydrate-containing aqueous syrup, and II about 0.2 to about 4.5 parts by weight of an alcoholic liquid polyol humectant.

Other aspects of this invention include methods for making such compositions and oral liquid and solid dosage forms thereof.

It is recognized that in U. S. Patent 3,308,020 to Wolf et al, Example 7 thereof describes a therapeutic diet for treating hypercholesteremia containing Acrysol CQ, which is disclosed as an alternative to cholestyramine, arid corn oil, a water insoluble liquid fat unrelated to the aqueous syrupy carbohydrate solutions employed herein.

Similar comments apply to compositions fed of rats receiving cholestyramine in Formulation C of U. S.

Patent 3,769,399 to Hagerman et al, which contains modified corn starch and corn oil, and to Example 9 of U. S. Patent 3,383,281 to Wolf et al, referring to a therapeutic diet for treating hypercholesteremia containing corn oil and a water-insoluble styrene divinylbenzene quaternary ammonium compound.

\ It is also recognized that U. S. Patent 4,340,585 to \ \ Borzatta et al discloses a solution of cholestyramine resin in propylene glycol for oral administration to rats. Such solution is quite different from the paste, doughy and powder compositions formed in accordance with the present Invention, The water-soluble carbohydrate in the aqueous (water) syrup which suppresses the fishy odor of cholestyramine in accordance with this invention is usually and preferably a member of the sugar family. Preferred syrups Include corn (preferably high fructose) syrup, sucrose syrup, invert sugar syrup and the like. Other examples of operative water-soluble carbohydrates suitable for making such syrups include honey, molasses, glucose, maltose, dextrose, levulose, mannose and poly dextrose. The carbohydrate in corn syrup may have a fructose content of about 2 to 1007 by weight. It is preferred to employ corn syrup modified to contain carbohydrate having a high fructose content of about 80-100% by weight, most preferably about 90% as in Example 1 below, in the practice of the present invention since fructose is 170% w/w sweeter than sucrose.

The carbohydrate solids content of the syrup should be sufficient to initially produce upon admixture with the cholestyramine a pasty or doughy mass, generally being at least 50 wt.%, for example about 50 to 90 wt.% solids, 22 2 8 5* r> IS c preferably about 65 to 85 wt.%, more preferably about 75 to 80 wt.%, and still more preferably about 772. The amount of syrup effective for initially producing with the cholestyramine a pasty or dough mass, i.e., the syrup:cholestyramine weight ratio , is more or less dependent in any particular instance on the solids content of the syrup. Stated otherwise, the syrup solids concent and the syrup:cholestyramine weight ratio are interrelated and so adjusted as to initially produce a pasty or dough mass upon admixture of the syrup with the cholestyramine. Such weight ratio may generally range from about 4.5-0.2:1, preferably about 3:1 to 1:1, more preferably about 1.8:1 to 1.2:1, still more preferably about 1.5:1.

In accordance with a preferred embodiment of this invention, the composition is prepared by blending together the appropriate ratio of cholestyramine and water-soluble carbohydrate syrup. The mixture initially formed is very sticky with a pasty or dough-like consistency. Mixing is continued to produce a light, fluffy, odorless (devoid of fishy odor) powder of homogeneous appearance. If more than light, mechanical agitation is required to produce the light, fluffy powder, the mixture may be milled, for instance in a Fitzpatrick Mill to achieve this end, and/or the above-described syrup solids content and syrup:cholestyramine weight ratios suitably adjusted.

Alternatively, and often less preferably, the cholestyramine is blended with an alcoholic liquid polyol (polyhydric alcohol) humectant to similarly form an odorless (devoid of fishy and other objectionable odors) light, fluffy powder. These ■Y.?-VV^jg3£r • - - 22 2 8 5 0 humectants are well known, being generally water soluble.

Normally liquid humectants such as glycerine and propylene glycol are preferred. Normally solid humectants such as sorbitol, mannitol , xylitol and the like may be employed in liquid form 5 as aqueous solutions with solids contents in the ranges discussed above In connection with the carbohydrate syrups. Other useful humectants include low molecular weight liquid polyethylene glycol and polypropylene glycol (e.g. 400,600).

The liquid humectant .-cholestyramine weight ratio may 10 generally range from about 4.5-0.2:1, preferably about 3.0:1 to 0.4:1, more preferably about 2.0:1 to 0.5:1, and still more preferably about 0.6:1. The humectant/cholestyramine composition is prepared by mixing in the manner described above with respect to use of water-soluble carbohydrate syrup, with 15 similar initial production of a pasty mass which upon continued mixing changes to an odorless light fluffy powder.

It will be understood that with suitable adjustment of proportions, mixtures of the carbohydrate syrup type I and liquid humectant type II deodorizing agents may be similarly 20 blended with cholestyramine.

In the practice of the present invention it is often desirable to prepare an ultimate product which supplies about 2.7gms. of cholestyramine. Such a non-odorous product is readily taken orally, 3-6 times daily in order to supply the normal 25 daily prescription dosage of 8-16 gms. For example, prepackaged jportions of the above described deodorant/cholestyramlne powder containing 2.7 gms. of the cholestyramine can be readily dissolved 22 2 8 5 4 in water, skimmed milk or the like to provide a readily ingested odorless beverage. In general, orally ingestible products may be prepared containing any aliquot dosage portions of the deodorant/cholestyratnine powder of this invention, for example units or pieces of candy each containing sufficient powder to provide 2-3 grams of cholestyramine.

The deodorized compositions can also be readily provided with color and flavor to enhance their appeal to the user. For instance color material and/or flavor may be added, preferably to the deodorant, deodorizing agent or material, that is the water-soluble carbohydrate syrup or alcoholic polyol humectant, before blending with the cholestyramine.

Typical color material are those associated with citrus fruit, e.g. orange, yellow, green, etc. They are typically present in amounts of about 0.02 to 2.0 wt.% of the cholestyramine Typical flavors are those which provide mint or citrus character, e.g. peppermint, spearmint, wintergreen, clove, orange, lemon, lime, etc. They are typically present in amounts of about 0.05 to 4.0 wt.Z of the cholestyramine.

The powder or beverage made therefrom may be found by some users to be somewhat "gritty" or "chalky" to the taste and feel in the mouth. This is readily and substantially overcome by including microcrystal1ine cellulose ot a binding material (that is a gum or gum-like material) preferably with the cholestyramine prior to its mixing with the deodorizing material. Such binding materials are typically cellulose binders such as methyl cellulose hydroxyethyl cellulose, hydroxypropyl methyl cellulose, cellulose esters, sodium carboxymethy1 cellulose, etc., or polysaccharides such as the xanthamonas colloid, xanthan. The microcrystalllne 2 28 54 cellulose or binder is typically employed in amounts of about 3 to about 307, by weight of the cholestyramine, preferably about' 5 to 25%. Besides reducing grittiness or chalkiness, these additives may also reduce the tendency some users have coward constipation.

Moreover, as desired, further additives may be blended into the powder of types and in amounts well accepted in the art.

Such further additives may include artificial sweeteners such as sodium saccharin, sodium cyclamate, Aspartame, etc., as well as vitamins and minerals.

The deodorized composition of the present invention is also desirably formulated and/or shaped into unitary products such as granules, tablets, wafers, cookie shapes and the like.

In order to make such unitary solid consumable product from the above-described deodorant/cholestyramine odorless powder, water-soluble carbohydrate syrup as described above, in proportions sufficient to produce a "sheetable" dough, is blended into the powder in typical weight ratios of such carbohydrate syrup to deodorized powder of about 0.5-1.5:1, preferably about 0.8:1 to 1:1. Although any normally consumable water-soluble carbohydrate syrup may be used in making the unitary cholestyramine product, polydextrose syrup liquid is preferred because of its relatively low caloric nature and since relatively less of it is generally needed to produce the desired sheetable dough mass, for example polydextrose syrup:deodorized powder weight ratios of about 0.4:1 to 0.7;1, preferably about 0.5:1 to about 0.65:1.

Polydextrose, produced as described in U.S. 3,766,165 (1973)j and 3,876,794 (1975), is a water soluble randomly bonded condensa- j fc ! i |tion polymer of dextrose containing minor amounts of bonded sorbitol , ^ j.and citric acid. Commercially available polydextrose Type N aqueous jjsyrup (Pfizer) contains about 70% polydextrose of which 88.72 has a Ijinolecular weight (M.W.) range of about 162 to 5,000, 10Z has a M . W. j j § ■ 22 28 5 of about 5,000 to 10,000, 1.2% has a M.W. range of about 10,000 to 16,000 and 0.1% has a M.W. range of about 16,000 to 18,000.

After blending of polydextrose syrup or the like carbohydrate syrup with the deodorized powder, a dough readily forms which can be formed, rolled, pressed or extruded into sheets Such sheets can then be sliced or rolled more thinly and cut into any desired shapes, such as wafers which provide a dosage amount of cholestyramine.

When wafers are formed in accordance with the present invention, for instance measuring about 1/8 - 1/4 inch in thickness and about 1.5 - 2.5 inches in average diameter, they possess sufficient cohesiveness and structural strength to be packaged and shipped for ultimate consumption.

Structural strength and cohesiveness of wafers may be 10 further Increased by the presence in the deodorized powder of the binding gums or gum-like materials discussed above as well as water dlspersible proteins such as vital wheat gluten, sodium caseinate, egg plbumin, soy isolate or the like. Typically the weight ratio of such cohesiveness-increasing additive to 15 cholestyramine is about 0.05-0.5:1.

Moreover, structural strength and cohesiveness of wafers can also be increased by coating the wafer product in i industrially recognized manners or by sandwiching the wafer as a filling between previously formed solid pieces of ingestible 20 material.

The following Examples are only illustrative of the invention and not limitative. All amounts and proportions referred to herein and in the appended claims are by weight and temperatures are in degrees F, unless Otherwise indicated.

EXAMPLE 1 Mixture A and Mixture B ar Mixture A Cholestyramine Methyl Cellulose (Dow AL51V) Xanthan Gum Mixture B 902 High Fructose Corn Syrup (77Z Liquid Orange Flavor Liquid Orange Color Mixtures A and B are combi mixer with a paddle, blended for 5 minutes, the sides are scraped down with the paddle and then blending is continued for an additional 10 minutes. The mixture is sticky and essentially dough-like in consistency at first but turns to a light and fluffy powder with no unpleasant odor.

Next 13.5 parts of polydextrose Type N liquid (Pfizer) are added and blended for 1 minute until a dough is formed. The sides are scraped down with the paddle and the ingredients are mixed until they are uniformly dispersed throughout the dough .

The dough is then rolled out to a uniform thickness of 3/16" using a rolling pin. In some preparations a small amount of starch is added should sticking occur. Wafers are then cut out using a "Hex" cutter measuring 1 15/16" (flat side to flat side). Each water weighs 11.8 grams and three wafers contain the normal daily dosage of 8.0 grams of cholestyramine. 22 2 8 5 e prepared: 8.0 parts 1.0 parts 0.7 parts solids) 12.0 parts 0.1 parts 0.07 parts ned in a Hobart A-120 vertical EXAMPLE 2 22 2 8 Mixture A and Mixture B are prepared: Mixture A Cholestyramine 8.0 grains FMC Microcrystal 1 ine Cellulose 0.5 grains (Type B CL-611) Aspartame 0.05 grams Mixture B Glycerine (99.5%) A.8 grams Liquid Lemon Lime 0.1 grams Liquid Mint Green 0.05 grams Mixture A is blended with Mixture B in a 250 ml. glass beaker with a spatula. The mixture Is paste-like at first but becomes a light and fluffy powder with no unpleasant odor as blending is continued. The deodorized light fluffy powder is added to one cup of cold tap water to produce a desirable, readily ingestible beverage containing the normal daily dosage of 8 grams of cholestyramine.

EXAMPLE 3 Mixture A and Mixture B are prepared: Mixture A Parts Cholestyramine 8.0 Xanthan Gum 0.7 Vital Wheat Gluten 1.2 Butter/Vanilla/Lemon Flavor 0.25 Mixture B Parts Invert Sugar Aqueous Syrup (77% solids) 12.0 Liquid Yellow 0.01

Claims (23)

1. i. 2 2 8 5 As in Example 1, Mixtures A and B are combined, blended with 13.5 parts of polydextrose liquid and the resultant deodorized dough rolled out and cut into wafers. Each wafer is dipped into the following mixture: Parts Unbleached Pastry Flour 59.9 Polydextrose Powder 30.0 Safflower Oil 8.0 Potassium Bicarbonate 1.0 Anhydrous Monocal c iunt Phosphate 1.1 Water 45.0 The dipped wafers are placed on a parchment lined baking pan and baked for 6 minutes at 400°F. Alternatively, instead of dipping into the above mixture, each wafer is dipped in a chocolate coating mixture and heated to I15°F., drained and then cooled to set the chocolate coating. Readily ingestible, tasty coated wafers are thus produced containing incremental dosage amounts of the cholestyramine as normally prescribed. This invention has been disclosed with respect to certain preferred embodiments and it will be understood that various modifications and variations thereof obvious to those skilled in this art are to be included within the spirit and purview of this application and the scope of the appended claims. -12- 22285-1 i. What we claim is: An orally ingestible composition comprising cholestyramine admixed with, per part by weight of the cholestyramine, at least one deodorizing agent consisting of: (I) 0.2 to 4.5 parts by weight of an aqueous water-soluble carbohydrate-containing syrup; or (XI) 0.2 to 4.5 parts by weight of a liquid alcoholic polyol humectant.
2. 2. The composition of claim 1, comprising type I deodorizing agent.
3. 3. The composition of claim 1 or 2, wherein said water-soluble carbohydrate-containing syrup is selected from the group consisting of corn syrup, sucrose syrup, invert sugar syrup and polydextrose syrup.
4. 4. The composition of any one of claims 1-3, wherein said syrup contains at least 50 wt.% of the water soluble carbohydrate.
5. 5. The composition of claim 1, comprising type II deodorizing agent.
6. 6. The composition of claim 1 or claira 5, wherein said liquid alcoholic polyol humectant is glycerine, propylene glycol, sorbitol syrup, mannitol syrup, xylitol syrup, liquid polyethylene glycol or liquid polypropylene glycol.
7. 7. The composition of any one of claims 1, 5 and 6, wherein said liquid alcoholic polyol humectant is glycerine or propylene glycol.
8. 8. The composition of any one of claims 1 and 5-7, wherein the weight ratio of liquid humectant : cholestyramine ranges from 4.5 : 1 to 0.2 : 1.
9. 9. The composition of any one of claims 1-8, In the form of a paste or dough.
10. 10. The composition of any one of claims 1-8, in the form of a powder.
11. 11. The composition of any one of claims 1-8, in wafer or other solid shaped form.
12. 12. An aqueous beverage containing a dosage amount of a - 13 - I 22 2bC>4 O composition as defined in any one of claims 1-8.
13. 13. The composition of any one of claims 1-8, further containing an amount of xanthan gum or microcrystalline ^ cellulose sufficient to minimize the normally gritty texture of the composition.
14. 14. The composition of any one of claims 1-8, further containing an amount, sufficient to minimize grittiness and/or improve structural strength of solid shaped products containing said composition, of a binding material selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and polysaccharides.
15. 15. The powder composition of claim 10, admixed with sufficient additional water-soluble carbohydrate syrup to produce a sheetable dough.
16. 16. The composition of claim 15, wherein said additional water-soluble carbohydrate syrup is polydextrose syrup.
17. 17. The composition of claim 16, in the form of a wafer.
18. 18. A method of making a deodorized orally ingestible composition comprising blending approximately by weight, one | part of cholestyramine with at least one deodorizing agent I consisting of j (I) 0.2 to 4.5 parts by weight of an aqueous . ' water-soluble carbohydrate-containing syrup; or (II) 0.2 to 4.5 parts by weight of a liquid alcoholic polyol humectant, and continuing said blending to { form a paste, dough or light, fluffy substantially odorless ! powder of homogeneous appearance.
19. 19. The method of claim 18, employing a type I deodorizing agent.
20. 20. The method of claim 18, employing a type II deodorizing agent.
21. 21. The method of any one of claims 18-20. followed by blending the resulting powder with sufficient^aqueous water soluble carbohydrate-containing syrup to form a (teughyjnass, and forming the doughy mass into a solid shaj£^"pqp»i^y ingestible product. i - 14 - I i i A
22. 22. The method of claim 21, wherein said syrup blended with said powder contains polydextrose as the carbohydrate.
23. 23. A method of making an orally ingestible cholestyramine-containing composition devoid of fishy odor for reducing the cholesterol level in human blood, comprising blending a cholesterol-reducing agent consisting essentially of cholestyramine, which agent is capable of forming an insoluble complex with bile acids, with, an amount of an aqueous syrup containing at least 65wt% of water-soluble sugar carbohydrate within a cholestyramine: syrup ratio ranging from 1:1 to 1:4.5 sufficient to initially form a paste or dough. By t*&7their authorised Agent*., A. J. PARK & SON.