(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2005/0058728 A1
`(43) Pub. Date:
`Mar. 17, 2005
`Randolph et al.
`
`US 20050058728A1
`
`(54) CYTOKINE MODULATORS AND RELATED
`METHOD OF USE
`
`(76) Inventors: Russell K. Randolph, Anaheim, CA
`(US); Haeri Roh-Schmidt, Stockton,
`CA (US)
`
`Correspondence Address:
`WARNER, NORCROSS & JUDD
`IN RE: ALTICOR INC.
`INTELLECTUAL PROPERTY GROUP
`111 LYON STREET, N. W. STE 900
`GRAND RAPIDS, MI 49503-2489 (US)
`
`(21) Appl. No.:
`
`10/938,093
`
`(22) Filed:
`
`Sep. 10, 2004
`
`Related US. Application Data
`
`(60) Provisional application No. 60/502,755, ?led on Sep.
`12, 2003.
`
`Publication Classi?cation
`
`(51) Int. Cl? ................................................... .. A61K 35/78
`
`(52) US. Cl. ......................... .. 424/732; 424/765; 424/777
`
`(57)
`
`ABSTRACT
`
`A composition for modulating cytokines to regulate an
`in?ammatory or immunomodulatory response. The compo
`sition can include at least one of rosehips, blueberry, black
`berry, elderberry, cranberry, rosemary, clove, feverfeW,
`nettle root, artichoke, reishi mushroom, olive extract, green
`tea extract, grape seed extract, resveratrol, Aframomum
`melegueta, boswellia serrata extract, boswellia forte, ipri
`?avone, tocotrienols, evening primrose oil, INM-176, bor
`age oil, krill oil, at least one type of xanthophyll (e.g.,
`astaxanthin), green coffee extract and ferulic acid. Speci?
`cally, a composition of the invention can include: rosehips
`and at least one of blackberry, blueberry, elderberry, and
`optionally krill oil; or rosehips, resveratrol and at least one
`of Aframomum melegueta and astaxanthin. Based on the
`cytokine modulation and cytokine response inhibition of the
`composition, it can be used to regulate an immunomodula
`tory and/or in?ammatory response, and subsequently treat
`diseases and/or abnormal conditions associated With in?am
`matory response, for example, cardiovascular conditions,
`arthritis, osteoporosis and Alzheimer’s disease.
`
`RIMFROST EXHIBIT 1011 page 0001
`
`

`

`Patent Application Publication Mar. 17, 2005 Sheet 1 0f 2
`
`US 2005/0058728 A1
`
`RIMFROST EXHIBIT 1011 page 0002
`
`

`

`Patent Application Publication Mar. 17, 2005 Sheet 2 0f 2
`
`US 2005/0058728 A1
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`RIMFROST EXHIBIT 1011 page 0003
`
`

`

`US 2005/0058728 A1
`
`Mar. 17, 2005
`
`CYTOKINE MODULATORS AND RELATED
`METHOD OF USE
`
`melegueta. In an even further aspect, the composition can
`comprise rosehips, resveratrol and astaXanthin.
`
`[0001] This application claims bene?t of Us. Provisional
`Application 60/502,755, ?led Sep. 12, 2003, Which is hereby
`incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`[0002] The present invention relates to in?ammation
`Within the body, and more particularly, to regulating in?am
`mation to treat conditions and diseases associated thereWith.
`
`[0003] In?ammation has been linked to a variety of con
`ditions and diseases that affect the body. For example,
`in?ammation Within joints is knoWn to Worsen the symp
`toms of and structural deformities caused by arthritis and
`rheumatoid diseases, such as bursitis, tendonitis, myositis
`and osteoarthritis, as Well as bone and joint destructive
`diseases, such as osteoporosis.
`
`[0004] In?ammation also is knoWn to contribute to a
`variety of cardiovascular and metabolic disease processes,
`such as atherosclerosis, thrombosis, and insulin resistance
`associated With obesity. Atherosclerosis may increase the
`chances of stroke and myocardial infarction and insulin
`resistance may lead to diabetes.
`
`[0005] In?ammation is also thought to contribute to the
`development of neurological disorders, for eXample, AlZhe
`imer’s disease.
`
`[0006] Indeed a large body of research noW links in?am
`mation With a Wide variety of chronic degenerative diseases.
`This research has identi?ed certain cells—macrophages—
`that produce pro-in?ammatory chemicals—cytokines—
`Which induce signaling cascades that provide an in?amma
`tory response. These cytokines play a role in in?ammatory
`reaction in response to foreign and infectious agents, trau
`matic or chronic injury, and abnormal chemical or physical
`stresses.
`
`[0007] Accordingly, treatments have been developed to
`regulate the release of in?ammatory cytokines, or the sig
`naling of in?ammatory cytokines, speci?cally the interleu
`kin-1 (IL-1) cytokine from macrophages. For example, US.
`Pat. No. 5,635,478 to Vignery discloses the use of calcitonin
`gene related peptide (CGRP) to regulate IL-l release, and
`thereby treat rheumatoid arthritis. Although highly speci?c
`CGRP is effective at regulating IL-1, its use is cost prohibi
`tive and presently it is undetermined Whether this compound
`has a toXic effect With prolonged use.
`
`SUMMARY OF THE INVENTION
`
`[0008] The aforementioned problems are overcome in the
`present invention Which provides a composition that regu
`lates interleukin cytokines and/or regulates a physiological
`response caused by interleukin cytokines. This regulation is
`effective in controlling an immune response and/or an
`in?ammatory condition. In one aspect, the composition can
`comprise rosehips and at least one of blackberry, blueberry
`and elderberry. In another aspect, the composition can
`comprise rosehips and krill oil. In yet another aspect, the
`composition can comprise rosehips, blackberry, blueberry,
`elderberry and krill oil. In a further aspect, the composition
`can comprise rosehips, resveratrol and Aframomum
`
`[0009] In a fourth aspect, the composition can comprise at
`least one ingredient chosen from rosehips, blueberry, black
`berry, elderberry, cranberry, rosemary, clove, feverfeW,
`nettle root, artichoke, reishi mushroom, olive eXtract, green
`tea eXtract (epigallocatechin gallate), grape seed eXtract,
`resveratrol, Aframomum melegueta, boswellia serrata
`eXtract, boswellia forte, ipri?avone, tocotrienols, evening
`primrose oil, INM-176, borage oil, krill oil, at least one type
`of Xanthophyll (e.g., astaXanthin), green coffee eXtract (chlo
`rogenic acid), and ferulic acid. In a more speci?c aspect, the
`composition can comprise rosehips, nettle root, olive eXtract
`and artichoke. In yet another speci?c aspect, the composi
`tion can comprise rose hips, resveratrol and astaXanthin.
`
`[0010] In a ?fth aspect, the invention can provide methods
`for controlling an immune response and/or an in?ammatory
`condition in a subject, the method comprising administering
`to the subject an effective amount of the composition of the
`invention to control the immune response and/or the in?am
`matory condition. In a speci?c aspect, the composition can
`inhibit the function of an immunomodulatory or pro-in?am
`matory cell, for eXample, a macrophage and/or a leukocyte.
`In a more speci?c aspect, the composition can inhibit the
`expression of the genes that produce interleukin cytokines,
`for eXample, by preventing the genetic transcription of those
`genes. In an even more speci?c aspect, the composition can
`inhibit the interleukin cytokine in?ammation response
`mechanism. In these aspects, the composition can reduce
`and/or eliminate pro-immunomodulatory and/or pro-in?am
`matory responses in skeletal mass, joints, muscle, tissue,
`arteries, veins, capillaries, and other organs, systems and/or
`cells.
`
`[0011] In a siXth aspect, the invention can provide a
`method of regulating and/or controlling the function of
`immune cells, such as macrophages, leukocytes and lym
`phocytes, by administering an effective amount of the com
`position to a subject.
`
`[0012] In another aspect, the invention can provide a
`method for regulating cytokine release, also referred to as
`secretion, from cells in a subject by administering to a
`subject a cytokine inhibiting amount of the composition.
`
`[0013] In yet another aspect, the invention can provide a
`method that inhibits the response of cells to an interleukin
`cytokine by administering to a subject an effective amount
`of the composition of the invention. In a speci?c aspect, this
`administration can modulate the production of in?ammation
`biomarkers, for eXample, C reactive protein, Which is a
`biomarker produced by the liver that is indicative of eXces
`sive in?ammation in the body.
`
`[0014] In a ninth aspect, the invention can provide a
`method for treating a disease or abnormal condition caused
`by in?ammation by administering a therapeutically effective
`amount of the composition. In a speci?c aspect, the disease
`or abnormal condition includes at least one of a cardiovas
`cular disease or condition, thrombosis, a metabolic condition
`related to insulin resistance and obesity, a traumatic injury,
`arthritis, osteoporosis, and AlZheimer’s disease. In a more
`speci?c aspect, the method can include administering the
`composition to a subject having an in?ammatory condition
`to relieve or eliminate pain, tenderness, infection and/or
`
`RIMFROST EXHIBIT 1011 page 0004
`
`

`

`US 2005/0058728 A1
`
`Mar. 17, 2005
`
`discomfort following traumatic injuries, surgery or other
`events that may cause in?ammation.
`
`[0015] The present invention provides a composition and
`related methods for treating a variety of immunomodula
`tory- and in?ammation-based conditions, symptoms and
`diseases. Because the ingredients used are readily available
`and relatively inexpensive, the present invention provides a
`simple and cost-effective solution for treating a variety of
`in?ammation-caused ailments and conditions. Furthermore,
`because the ingredients are relatively stable, many can be
`mixed with other materials and provided in a multipurpose
`supplement or food product.
`[0016] These and other objects, advantages and features of
`the invention will be more readily understood and appreci
`ated by reference to the drawings and the detailed descrip
`tion of the invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0017] FIG. 1 is a sectional view of a blood vessel of a
`subject having atherosclerotic plaque development before
`being treated with the composition of the present invention
`in Example 3;
`[0018] FIG. 2 is a second sectional view of the blood
`vessel and a liver of a subject that illustrates the effects of
`interleukin cytokines in atherosclerotic plaque development
`in Example 3; and
`[0019] FIG. 3 is a third sectional view of the blood vessel
`and the liver of a subject that illustrates the effects of the
`composition on interleukin cytokines in atherosclerotic
`plaque development in Example 3.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`I. The Composition
`
`[0020]
`[0021] A composition of the invention can include one or
`more ingredients chosen from rosehips, blueberry, black
`berry, elderberry, cranberry, rosemary, clove, feverfew,
`nettle root, artichoke, reishi mushroom, olive extract, green
`tea extract (epigallocatechin gallate), grape seed extract,
`resveratrol, Aframomum melegueta, boswellia serrata
`extract, boswellia forte, ipri?avone, tocotrienols, evening
`primrose oil, INM-176, borage oil, krill oil, at least one type
`of xanthophyll (e.g., astaxanthin), green coffee extract (chlo
`rogenic acid), and ferulic acid. Speci?cally, a composition of
`the invention can include rosehips and at least one of
`blackberry, blueberry, elderberry and krill oil. Acomposition
`also can include rosehips, resveratrol and Aframomum
`melegueta. Another composition can include rosehips, res
`veratrol and astaxanthin. The composition can be adminis
`tered in any of the dosages recited herein to inhibit cytokine
`expression, production, reception, secretion and/or release,
`as well as inhibit the cytokine response, thereby reducing or
`eliminating an immunomodulatory and/or in?ammatory
`response.
`[0022] Acceptable dosages of the ingredients that may be
`effective at modulating cytokines, for example, regulating
`the production, reception, secretion and/or release of exem
`plary cytokines, such as IL-1 and/or IL-6, are presented in
`Table I below. Each dosage in Table I is an estimated
`effective daily dosage in milligrams. Furthermore, all the
`
`dosages in Table I are presented in ranges of from about the
`recited lower limit to about the upper limit. For example, the
`nettle Dosage A recites “250-2500”, which represents a
`dosage of about 250 to about 2500 milligrams of nettle per
`day.
`
`TABLE I
`
`Acceptable Dosages for Ingredients to Modulate Cytokines
`
`Ingredient
`
`Dosage A
`
`Dosage B
`
`250-2500
`Nettle extract
`150-1500
`Artichoke
`50-500
`Feverfew
`300-3000
`Reishi mushroom
`300-3000
`Olive extract
`150-1500
`Green tea extract
`100-1000
`Grape seed extract
`150-1500
`Aframomum melegueta extract
`350-3500
`Boswellia serrata extract
`100-1000
`Ipri?avone
`50-500
`Tocotrienols
`500-5000
`Evening primrose oil
`100-1000
`INM-176
`500-5000
`Borage Oil
`300-3000
`Krill Oil
`Green coffee extract (chlorgenic acid) 100-1000
`Ferulic acid
`100-1000
`Rosehips
`50-500
`Blackberry powder
`100-1000
`Blueberry powder
`200-2000
`Cranberry extract
`100-1000
`Rosemary extract
`100-1000
`Clove extract
`100-1000
`Resveratrol
`100-1000
`Elderberry extract
`400-4000
`
`500-1250
`300-750
`100-250
`600-1500
`600-1500
`300-750
`200-500
`300-750
`700-1750
`200-500
`100-250
`1000-2500
`200-500
`1000-2500
`600-1500
`200-500
`200-500
`500-5000
`200-500
`300-1500
`200-500
`200-500
`200-500
`200-500
`700-2500
`
`[0023] The ingredients identi?ed above in Table I are
`readily commercially available. Depending on the applica
`tion and/or the supplier, the ingredient may be an extract of
`a speci?c potency, a pure ingredient, an ingredient mixed
`with excipients, and in a variety of physical forms, e.g.,
`liquid or powder. The ingredient identi?ed is INM-176 is a
`compound of unknown composition available from Scigenic
`Company, Ltd. of Seoul, Korea.
`
`[0024] More particularly, the composition can include one
`or more than one rosehip ingredient. Examples of rosehip
`ingredients include, without limitation, dried rosehips, rose
`hip oil, and rosehip extracts. A rosehip ingredient can be
`obtained from any of the multiple species of plants that
`belong to the Rosa family, for example Rosa canina. More
`over, rosehips can include the fruit, petals and/or seeds of the
`Rosa plants.
`
`[0025] Any method can be used to prepare a rosehips
`ingredient. As an example, conventional harvesting and
`drying methods can be used to prepare dried rosehips.
`Rosehip oil can be produced with standard methods and
`processed with cellulose for tableting or powdered compo
`sitions. In addition, rosehips can be obtained commercially
`from MB North America of Torrance, Calif.
`
`[0026] A composition of the invention can contain one or
`more than one rosehips ingredient. For example, a dietary
`supplement can contain dried rosehips as well as rosehips
`extract. In addition, a composition can contain any amount
`of a rosehips component. For example, at least about 1
`percent (e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, 35,
`40, 50, 60, 70, 80, or 90 percent) of a dietary supplement can
`
`RIMFROST EXHIBIT 1011 page 0005
`
`

`

`US 2005/0058728 A1
`
`Mar. 17, 2005
`
`be a rosehips ingredient. Typically, a composition contains
`between about 500 mg and about 5000 mg of a rosehips
`ingredient.
`
`[0027] Even more particularly, the composition can
`include one or more than one blackberry ingredient.
`Examples of blackberry ingredients include, Without limi
`tation, dried blackberry, blackberry poWder, and blackberry
`extracts. Ablackberry ingredient can be obtained from any
`of the multiple species of plants that belong to the Rubus
`family, for example Rubus fruticosus.
`
`[0028] Any method can be used to prepare a blackberry
`ingredient. As an example, conventional harvesting, drying
`and poWdering methods can be used to prepare blackberry
`poWder. In addition, blackberry can be obtained commer
`cially from Van Drunen Farms Futureceuticals of Santa
`Rosa, Calif.
`
`[0029] A composition of the invention can contain one or
`more than one blackberry ingredient. For example, a dietary
`supplement can contain blackberry poWder as Well as black
`berry extract. In addition, a composition can contain any
`amount of a blackberry component. For example, at least
`about 1 percent (e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25,
`30, 35, 40, 50, 60, 70, 80, or 90 percent) of a dietary
`supplement can be a blackberry ingredient. Typically, a
`composition contains betWeen about 100 mg and about 1000
`mg of a blackberry ingredient.
`
`[0030] Further particularly, the composition can include
`one or more than one blueberry ingredient. Examples of
`blueberry ingredients include, Without limitation, dried blue
`berry, blueberry poWder, and blueberry extracts. Ablueberry
`ingredient can be obtained from any of the multiple species
`of plants that belong to the Vaccinium family, for example,
`Vaccinium corymbosum.
`
`[0031] Any method can be used to prepare a blueberry
`ingredient. As an example, conventional harvesting, drying
`and poWdering methods can be used to prepare blueberry
`poWder. In addition, blueberry can be obtained commer
`cially from Van Drunen Farms Futureceuticals of Santa
`Rosa, Calif.
`
`[0032] A composition of the invention can contain one or
`more than one blueberry ingredient. For example, a dietary
`supplement can contain blueberry poWder as Well as blue
`berry extract. In addition, a composition can contain any
`amount of a blueberry component. For example, at least
`about 1 percent (e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25,
`30, 35, 40, 50, 60, 70, 80, or 90 percent) of a dietary
`supplement can be a blueberry ingredient. Typically, a
`composition contains betWeen about 200 mg and about 2000
`mg of a blueberry ingredient.
`
`[0033] Even more particularly, the composition can
`include one or more than one elderberry ingredient.
`Examples of elderberry ingredients include, Without limita
`tion, elderberry extracts, dried elderberry and elderberry
`poWder. An elderberry ingredient an be obtained from any of
`the multiple species of plants that belong to the Sambucus
`family, for example, Sambucus canadensis.
`
`[0034] Any method can be used to prepare an elderberry
`ingredient. As an example, conventional extraction tech
`niques can be used to prepare an elderberry extract. In
`
`addition, elderberry can be obtained commercially from
`Artemis International of Fort Wayne, Ind.
`
`[0035] A composition of the invention can contain one or
`more than one elderberry ingredient. For example, a dietary
`supplement can contain elderberry poWder as Well as elder
`berry extract. In addition, a composition can contain any
`amount of an elderberry component. For example, at least
`about 1 percent (e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25,
`30, 35, 40, 50, 60, 70, 80, or 90 percent) of a dietary
`supplement can be an elderberry ingredient. Typically, a
`composition contains betWeen about 400 mg and about 4000
`mg of an elderberry ingredient.
`
`[0036] Furthermore, the composition can include Aframo
`mum melegueta. Examples of Aframomum melegueta ingre
`dients include, Without limitation, pulveriZed Aframomum
`melegueta seeds, Aframomum melegueta poWder, and Afra
`momum melegueta extracts.
`
`[0037] Any method can be used to prepare aAframomum
`melegueta ingredient. As an example, conventional harvest
`ing, drying and extracting methods can be used to prepare
`Aframomum melegueta extracts. In addition, Aframomum
`melegueta can be obtained commercially from Frontier
`Natural Products Cooperative of NorWay, IoWa.
`
`[0038] A composition of the invention can contain one or
`more than one Aframomum melegueta ingredient. For
`example, a dietary supplement can contain Aframomum
`melegueta poWder as Well asAframomum melegueta extract.
`In addition, a composition can contain any amount of a
`Aframomum melegueta component. For example, at least
`about 1 percent (e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25,
`30, 35, 40, 50, 60, 70, 80, or 90 percent) of a dietary
`supplement can be a Aframomum melegueta ingredient.
`Typically, a composition contains betWeen about 500 mg
`and about 1500 mg of aAframomum melegueta ingredient.
`
`[0039] A composition of the invention can include krill
`oil. Krill oil can be obtained from any member of the
`Euphausia family, for example Euphausia superba. Con
`ventional oil producing techniques can be used to obtain the
`krill oil. In addition, krill oil can be obtained commercially
`from Neptune Technologies and Bioresources of Quebec,
`Canada.
`
`[0040] A composition can contain any amount of krill oil.
`For example, at least about 1 percent (e.g., at least about 2,
`3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90
`percent) of a dietary supplement can be a krill oil. Typically,
`a composition contains betWeen about 300 mg and about
`3000 mg of a krill oil ingredient.
`
`[0041] Where the composition includes resveratrol, the
`resveratrol can be obtained from an extract of grape skin or
`other grape components. Resveratrol can be present in the
`composition in one or more different forms, for example,
`extract form and poWder form. Resveratrol can be obtained
`commercially from Charles BoWman & Co. of Holland,
`Mich.
`
`[0042] A composition can contain any amount of a res
`veratrol component. For example, at least about 1 percent
`(e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50,
`60, 70, 80, or 90 percent) of a dietary supplement can be a
`resveratrol. Typically, a composition contains betWeen about
`100 mg and about 1000 mg of a resveratrol ingredient.
`
`RIMFROST EXHIBIT 1011 page 0006
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`

`

`US 2005/0058728 A1
`
`Mar. 17, 2005
`
`[0043] Where the composition includes at least one type of
`xanthophyll, the xanthophyll can be astaxanthin. Astaxan
`thin can be obtained from natural sources or synthesized. For
`example, astaxanthin can be obtained from algae, ?ngi
`and/or crustaceans. One type of astaxanthin can be obtained
`commercially from Cyanotech Corporation of Kailua-Kona,
`Hi.
`
`[0044] A composition can contain any amount of an
`astaxanthin ingredient. For example, at least about 1 percent
`(e.g., at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50,
`60, 70, 80, or 90 percent) of a dietary supplement can be
`astaxanthin. Typically, a composition contains betWeen
`about 0.5 mg and about 50 mg of an astaxanthin ingredient.
`
`[0045] The composition can include one or more pharma
`ceutically acceptable excipients, for example, croscarmel
`lose sodium, maltodextrin, silici?ed microcrystalline cellu
`lose, silicon dioxide, stearic acid, hydroxyl propyl methyl
`cellulose (HPMC), lactose, glucose, sucrose, corn starch,
`potato starch, cellulose acetate, ethyl cellulose and the like.
`Diluents and other additives such as one or more pharma
`ceutically acceptable binding agents, ?llers, supports, thick
`ening agents, taste-improving agents, coloring agents, pre
`servatives, proteins, anti-microbials, chelating agents, inert
`gases, stabiliZers, regulators, emulsi?ers or mixtures thereof,
`can be used depending on the form of the composition
`employed.
`[0046] The ingredients of the composition can be pro
`cessed into forms having varying delivery systems. For
`example, the ingredients can be processed and included in
`capsules, tablets, gel tabs, loZenges, strips, granules, poW
`ders, concentrates, solutions, lotions, creams or suspensions.
`The ingredients can also be administered into the respiratory
`tract, eg in the treatment of asthma, anaphylactic or and
`other acute shock conditions via a spray, mist or aerosol. The
`ingredients can may be formulated, individually or in com
`bination, With other foods to provide pre-measured nutri
`tional supplements, supplemented foods, for example, single
`serving bars. In one example, the composition can include
`one ingredient administered in tablet form, and another
`compostion administered in capsule form. More generally,
`the composition can be formulated for a variety of admin
`istration routes, for example, intravenously, intramuscularly,
`subcutaneously, nasally, sublingually, intrathecally, topically
`or intradermally.
`
`[0047] The dosages of the composition may be adminis
`tered in increments determined by the disease or condition
`being treated. For example, in the treatment of arthritis, the
`composition may be administered in multiple successive
`dosages, spaced as frequently as about 6 to about 12 hours
`apart, and as long as about 2 Weeks apart. Daily dosages may
`be administered for a period to obtain symptomatic relief
`from in?ammatory tenderness, sWelling and pain. The dos
`ages may be adjusted to maintain the relief from these
`symptoms. Treatment may be a period of Weeks or months,
`or optionally, inde?nitely for chronic diseases or conditions.
`
`[0048] II. Method of Manufacturing the Composition
`[0049] An exemplary composition of the invention includ
`ing rosehips, blackberry poWder, blueberry poWder and
`elderberry extract can be manufactured in tablet form
`according to the folloWing processes. Other administration
`mediums, such as gel tabs, capsules, liquid and sustained
`
`release formulations, etc. can be formulated and prepared
`according to manufacturing techniques Well knoWn in the
`pharmaceutical industry.
`[0050] Rosehips, blackberry poWder, and blueberry poW
`der in the amounts recited in Dosage 1 in Table II above are
`added to silicone dioxide and placed in a polybag and
`blended until uniformly and homogeneously mixed. This
`resultant blend is placed in a Patterson Kelley
`100
`blender available from Patterson-Kelley Co., East Strouds
`burg, Pa. The folloWing ingredients in the order listed are
`then passed through a SWeco separator equipped With a
`20-mesh screen available from SWeco, Inc. of Florence, Ky.
`directly into the PK. 100 blender: dextrose, croscarmellose
`sodium, and silici?ed microcrystalline cellulose. The result
`ant composition is blended in the PK. 100 blender for 15
`minutes.
`[0051] A vegetable-based stearic acid poWder is then
`passed through the SWeco separator directly into the PK.
`100 blender. The resultant mixture is blended for an addi
`tional ?ve minutes. The resulting mixture is discharged into
`totes or super sacks, compressed, and punched into tablets
`by conventional apparatus. An acceptable range Weight for
`each individual tablet is from about 250 mg to about 500 mg.
`The amount of rosehips in each tablet is about 1200 mg, the
`amount of blackberry is about 165 mg and the amount of
`blueberry is about 330 mg. Tablets manufactured according
`to this process can be used in the in vivo testing described
`herein.
`
`[0052] A soft gel capsule of the composition can be
`manufactured to include krill oil. This capsule can be
`manufactured using conventional capsule manufacturing
`techniques. The amount of krill oil in each capsule is about
`300 mg. These capsules can be administered alone or in
`conjunction With the tablets of other ingredients of the
`composition as part of the in vivo testing described herein.
`[0053] Other compositions of the invention including
`either rosehips and blackberry poWder, or rosehips and
`blueberry poWder, can be manufactured in tablet form
`according to the tableting process described above. The
`amount of rosehips in the rosehips/blackberry tablet is about
`300 mg, and the amount of blackberry is about 80 mg. The
`amount of rosehips in the rosehips/blueberry tablet is about
`300 mg, and the amount of blueberry is about 40 mg. Tablets
`manufactured according to this process can be used in the in
`vivo testing described herein as desired.
`[0054] Another composition including rosehips, resvera
`trol and Aframomum melegueta can be manufactured in
`table form according to the tableting process described
`above, With about 300 mg rosehips, 10 mg resveratrol and 75
`mg Aframomum melegueta extract.
`[0055] Another composition of the invention including
`rosehips, resveratrol and astaxanthin can be manufactured in
`table form according to the tableting process described
`above, With about 300 mg rosehips, 10 mg resveratrol and 1
`mg astaxanthin.
`
`[0056] Yet another composition of the invention including
`olive extract, artichoke, nettle root and rosehips can be
`manufactured in tablet form according to the folloWing
`process. Olive extract, artichoke, nettle root and rosehips in
`the amounts recited in Dosage 1 in Table II above are added
`to silicone dioxide and placed in a polybag and blended until
`
`RIMFROST EXHIBIT 1011 page 0007
`
`

`

`US 2005/0058728 A1
`
`Mar. 17, 2005
`
`uniformly and homogeneously mixed. This resultant blend
`is placed in a Patterson Kelley
`100 blender available
`from Patterson-Kelley Co., East Stroudsburg, Pa. The fol
`loWing ingredients in the order listed are then passed
`through a SWeco separator equipped With a 20-mesh screen
`available from SWeco, Inc. of Florence, Ky., directly into the
`PK. 100 blender: dextrose, croscarmellose sodium, and
`silici?ed microcrystalline cellulose. The resultant composi
`tion is blended in the PK. 100 blender for 15 minutes.
`
`[0057] A vegetable-based stearic acid poWder is then
`passed through the SWeco separator directly into the PK.
`100 blender. The resultant mixture is blended for an addi
`tional ?ve minutes. The resulting mixture is discharged into
`totes or super sacks, compressed, and punched into tablets
`by conventional apparatus. An acceptable range Weight for
`each individual tablet is from about 250 mg to about 500 mg.
`
`[0058] III. Selection of Ingredients for the Composition
`
`[0059] The present invention can include an ingredient
`screening process for selecting ingredients that are optimal
`for particular health conditions, and that can be used in the
`composition as desired. For example, in the case of a
`nutritional supplement for modulating IL-1, the active ingre
`dients can be selected via a unique screening process. The
`various factors include biological, commercial, regulatory,
`and descriptive discriminators. Some preferred discrimina
`tors and their Weighted values are outlined Table 2. Prefer
`ably, the discriminators are assigned a Weight based upon
`business or consumer driven objectives. In Table 2, a Weight
`of 3 means that the discriminator carries heavy Weighting or
`importance in the selection process (“Factor 3 Discrimina
`tor”); 2 means that the discriminator carries signi?cant
`Weight, but less than a Weight factor of 3 in the selection
`process (“Factor 2 Discriminator”); and 1 carries the least
`Weight as a discriminator (“Factor 1 Discriminator”).
`
`TABLE II
`
`Discriminators for Selecting Cytokine Modulating Ingredients
`
`Discriminator
`
`Weight
`
`Performance in IL-1 screening assay (EC
`<50 ug/ml)
`Supply Availability
`Cost per kilogram of material
`RaW Material Name
`Botanical Identity/Parent Extract
`Optional and secondary material and
`suppliers
`Potential for exclusivity
`Vertical integration possibility
`Aqueous versus hydrophobic
`compatibility
`Known active ingredients/Mechanism of
`action
`Fractional bioavailability"
`Ef?cacious daily dose based upon in vitro
`EC 50 mg
`Ef?cacious daily dose based upon
`literature (mg)
`Estimated raW material cost based upon
`bioassay EC 50 and bioavailability (cost
`per month)
`Estimated raW material cost based upon
`literature e?icacy (cost per month)
`Safety/Toxicity status
`Technical/Regulatory acceptance in
`market country
`
`3
`
`3
`3
`1
`1
`2
`
`2
`2
`2
`
`2
`
`2
`2
`
`2
`
`2
`
`2
`
`3
`3
`
`TABLE II-continued
`
`Discriminators for Selecting Cytokine Modulating Ingredients
`
`Discriminator
`
`Representation in the source company’s
`products and in the general marketplace
`Intellectual property risks
`
`Weight
`
`2
`
`2
`
`*Fractional bioavailability is the percentage of the active compounds in an
`orally ingested ingredient (expressed as a fraction) that is absorbed into
`the body, and is generally available to body tissues via the circulation. For
`example, a fractional availability of 0.10 indicates that 10% of an orally
`ingested ingredient’s actives are absorbed from the intestinal tract and are
`(for some period of time) transported in the circulation.
`
`[0060] In the above example, the primary objective is to
`?nd an effective and commercially successful IL-1 modu
`lator for human use. Selection of the best candidates is
`accomplished by summing the discriminator Weights for
`each candidate and comparing total Weighted score. Thus,
`performance of an active ingredient in modulating IL-1 is
`relevant, as is the expense to obtain the particular ingredient
`and the availability of the ingredient. Other factors relevant
`to commercial success are the ingredient’s toxicity and
`safety as Well as the technical and regulatory acceptance of
`the ingredient in the market Where the composition Will be
`sold. There may be cas