Patent Application: US-60896309-A

Abstract:
this invention describes a topical delivery mechanism that contains a mixture of cetylated fatty esters that act as transdermal carriers of desired therapeutic molecules . the proposed cetyl fatty ester penetrant - complex contains specific cetyl fatty esters , polar solvents , a carrier base , antioxidants and the desired pharmaceutical , cosmetic or antigenic response eliciting molecules that are efficaciously delivered by selectively varying component ratios in the complex . the invention proposes the use of transdermal delivery of medications such as those used in treatment of urinary incontinence , testosterone deficiency , arthritic and joint pain and other pains such as pain in the neck , lower back , back , knees , headaches , and other types of inflammatory pains , peripheral neuropathic pain , pain associated with repetitive strain injuries such as myofacial pain , rapid treatment of epileptic seizures , soluble antigens in the immuno - therapeutic treatment of allergies , actives in the treatment of foot cracks and elbow cracks , actives in the treatment of facial and other wrinkles in the form of anti - aging creams and gels and other topically delivered therapies .

Description:
in describing and claiming the present invention , the following terminology will be used in accordance with the definitions set out below . 1 . “ active agent ” is used herein to refer to a chemical material or compound suitable for administration to a human patient and that induces a desired beneficial effect , e . g ., exhibits a desired pharmacological activity . the term includes , for example , drugs or agents that are therapeutically effective , prophylactically effective , and cosmetically ( and cosmeceutically ) effective . also included are derivatives and analogs of those compounds or classes of compounds specifically mentioned which also induce the desired beneficial effect . 2 . “ cosmeceuticals ” are cosmetic products that are claimed , primarily by those within the cosmetic industry , to have drug - like benefits . examples of products typically labeled as cosmeceuticals include anti - aging creams and moisturizers . the “ cosmeceutical ” label applies only to products applied topically , such as creams , lotions , gels , sprays and ointments . cosmeceuticals may contain purported active ingredients such as vitamins , peptides , phytochemicals , enzymes , antioxidants , and essential oils . 3 . “ diffusion ” is the movement of molecules through a domain , by random molecular movement , from higher concentrations to lower concentration . 4 . “ diffusion coefficient ( d )” is the diffusion coefficient of the permeant measured as area / time ( cm 2 / hr or cm 2 / sec ) 5 . “ flux ( j )” is the amount of permeant crossing the skin or entering systemic circulation . this is measured as mass / area / time ( or ug / cm 2 / hr ). 6 . “ permeant ” is a molecular species moving through or moving into the tissue . 7 . “ permeation ” is the movement of the permeant through the membrane . permeation includes partitioning of the permeant into various domains ( e . g ., keratinocytes , lipids , etc .) and diffusion through the domains . 8 . “ nutraceutical ” is ( a ) a synthetically produced bioactive compound , where no structurally identical , naturally produced analog to the synthetically produced bioactive compound exists ; or ( b ) a biologically active compound derived from a living organism , where the biologically active compound is not a dietary supplement . 9 . “ transdermal ” drug delivery is meant administration of a drug to the skin surface of an individual so that the drug passes through the skin tissue and into the individual &# 39 ; s blood stream . 10 . cfe blend : this is defined as selected group of cetylated fatty acid esters combined with other molecules , which serves as the transdermal carrier of selected molecules used in the formulations for transdermal delivery of actives specific to a particular disease or diseases or cosmetic agents or other agents for non medical and non cosmetic usage . the present invention relies greatly on cetylation of the desired fatty acid esters to facilitate more efficacious permeation and thus the delivery of the desired therapeutic molecule or molecules . broadly , the inventive composition is a medicinal composition containing a pharmaceutical or cosmecutical used for the treatment of a first predetermined ailment or a symptom thereof , and a cream comprising of a mixture of cetylated fatty ester carrier molecules used for transdermal and dermal delivery . the current invention provides properties that decrease diffusion resistance and enhance drug solubility . the vehicle of interest in this invention is constituted from the combination of the polar solvent material and the polar lipid material . both demonstrate lipophilicity and together penetrate into the stratum corneum carrying the permeant . preferably , the polar solvent material in this invention is propylene glycol and the polar lipid material is a combination of cetylated fatty esters ( cfes or also known as cetyl ester waxes ). other polar solvents used instead of or in conjunction with propylene glycol include glycerol , ethylene glycol , 1 , 2 , 6 - hexane triol , 1 , 2 , 4 - butane triol , propylene glycol ether of methyl glucose or sorbitol , dimethicone copolyol , and polyethylene glycol ( preferably , peg 50 , peg 100 and peg 500 ). the polar solvent provides hygroscopic and miscible properties that allow solubility for the cetylated esters , which in turn serve to enhance penetration for the permeant . the behavior of propylene glycol and some of the above solvents as enhancers have been disclosed in u . s . pat . nos . 4 , 973 , 468 , 4 , 006 , 218 , 3 , 551 , 154 and 3 , 472 , 931 . upon application of vehicle containing the permeant to the skin , the volatiles evaporate while the cfe complex allows for near - saturation concentration of the permeant on the skin without precipitating . the polar solvent and cfe complex act in conjunction to allow for rapid absorption and avoid formation of a waxy film that would slow permeant migration . the primary delivery effect of the cfe complex is that of a penetrant agent and to move other permeants through the permeation barrier of the stratum corneum to the site desired for utilization of the drug . this invention describes the use of cetylated fatty esters . in other patents and in routine uses , cetyl ester waxes are used primarily in formulations as stiffening agents due to the semi - solid characteristics of these molecules at temperatures below 40 ° c . while this property is useful in the formulations described for this invention , the stiffening characteristic is not part of the embodiment . a principal embodiment of this invention is to use the properties of both the cetyl and fatty acid components to act in conjunction as a penetrant agent ( cpe ). the ester composition of the proposed invention is varied depending on the properties of the active ingredients in the formulation and the desired delivery effects ( i . e ., systemic delivery , skin delivery , or tissue delivery ). the cetyl component is present with all molecules in the combination of esters used . the cetyl component facilitates entry into and through the matrix . however , the alkyl fatty acid component is variable depending on the delivery considerations or effects . 1 . this component may be of simple alkyl chain length from 8 to 35 carbons , the composition of which may be saturated , mono - to polyunsaturated , or may contain functional groups such as methoxy -, amino - or ring structures . 2 . this component may also be branched depending on the desired delivery effects . 3 . finally , different cetylated ester molecules may be used together to provide the desired delivery effects , influencing solubility and the solvent vehicle characteristics . an example would be the combination of cetyl 13 - methyl myristate , cetyl linolenate and cetyl isolaurate together to provide increased water solubility and permeation potential for more hydrophilic drugs . 4 . in some embodiments where hydrophilic properties of the drug specify , a cetylated amino ester ( such as cetyl arginine and / or cetyl ornithine ) is included in the mix of cetylated ester molecules . specifically , different cetylated ester molecules are used depending on the physico - chemical properties of the permeant ; however , the combinations are all designed either to increase permeant flux for permeants where systemic or tissue delivery is desired or to retard flux in order to maintain the permeant longer within the epidermis and dermis if the skin is the target site of delivery . it is noted that the cfes utilized in this invention have structural similarities to the ceramides ( namely , a sphingoid base and a fatty acid , which are linked by an amide bond between the carboxyl group of the fatty acid and the amino group of the base ) present in the stratum corneum matrix of human skin , but that the functional groups present on the fatty acid components in the cfe complex are included in the vehicle for the penetration properties desired for the invention . the variations in the fatty acid component of the cfe complexes serve a dual role . first is the introduction of alignment flaws in the orientation of the molecules in the complex . many fatty acids are straight - chain compounds . the hydrocarbon chains form compact orientations with hydrophilic portions compacting closely together in a lattice - like matrix . the use of cetylated forms with only saturated straight chain fatty acids results in the least disruption in alignment and least flux enhancement . unsaturation of the fatty chain into a cis structure results in a bending of the chain that would cause disruption of the intercellular lipid packing of the stratum corneum . introduction of a cetylated form with a single cis - unsaturation , such as a cetyl oleic ester , or a cis - unpolysaturated component , such as a cetyl linolenic ester , introduces the potential for more alignment flaws and greater flux enhancement . the variety of fatty acids introduce disruptions in the alignments and compactness of the complex and , in turn , similar disruptions in the lipid bilayers of keratinocyte and fluidization within the lipid matrix of the stratum corneum . the second role is to introduce functional groups that have heightened affinities for the permeants of interest ( i . e ., functional groups with polar affinities for more ionic permeants or with more lipophilic affinities for more non - polar permeants ). the structural composition of the cfe complexes is conducive for the delivery of both lipophilic and hydrophilic permeants . 1 . hydrophilic compounds and ionized species require different approaches to penetration than that of uncharged lipophilic chemicals . the cetylated molecules form complexed layering in which the permeants may become incorporated noncovalently for delivery to the skin . the invention complex partitions within the stratum and allows for diffusion of the permeant to proceed at rates mediated by the properties of the drug molecules and the composition of the cetylated complex . the cetylated complex helps to reduce water loss from the stratum corneum , increasing hydration and assisting in diffusion of more ionic permeants . the cetylated complex creates permeability by disrupting the lipid organization of the stratum corneum , increasing the diffusion coefficients of the permeants . the structure of the cetylated molecules play a major role in this process . 2 . lipophilic compounds partition into and penetrate the lipid domains of the stratum corneum . the cfe complex of this proposed invention provides more efficient penetration through its affinity for the permeant , complexing as previously noted , and partitioning into the bilayer lipids , disrupting the organized packing but also dispersing within the intercellular lipids to facilitate permeant diffusion . in the first embodiment of the invention , a transdermal drug delivery carrier cream , gel , lotion , spray or patch that enhances transdermal drug delivery efficiency is proposed that utilizes a formulation comprising of a mixture of cetylated fatty esters and a polar solvent ( called cfep complex ) in a cream base and an anti - oxidant , the permeant of interest and any additional excipients ( such as fragrance , skin protectants , or colorants ). particularly preferred formulations for topical cream base cfep - complex in accordance with the first embodiment of the invention include 4 - 20 % of a penetrant in group a in a combination as listed below : a : penetrant group formula . four or more of the following in the indicated concentration ranges : cetyl arginine , 0 . 025 - 2 % cetyl 11 - cyclohexylundecanoate , 0 . 25 - 2 . 5 % cetyl decanoate , 0 . 25 - 2 % cetyl dihomo - γ - linolenate , 0 . 25 - 3 % cetyl docosapentanoate , 0 . 6 - 4 % cetyl eicosapentanoate , 0 . 6 - 4 % cetyl isolaurate , 0 . 25 - 3 % cetyl isomyristate , 0 . 25 - 3 % cetyl laurate , 0 . 05 - 1 . 6 % cetyl linolenate , 0 . 6 - 4 % cetyl 2 - methoxy - 5 - hexadecenoate , 0 . 25 - 2 . 5 % cetyl 13 - methyl myristate , 0 . 25 - 2 . 5 % cetyl myristoleate , 0 . 6 - 15 % cetyl myristate , 0 . 75 - 8 % cetyl oleate , 0 . 25 - 5 % cetyl ornithine , 0 . 025 - 2 % cetyl palmitate , 0 . 2 - 5 % cetyl palmitoleate , 0 . 3 - 2 % cetyl stearate , 0 . 05 - 1 . 6 % cetyl stearidonate , 0 . 25 - 3 % cetyl vaccenate , 0 . 25 - 3 % b : polar solvent . one or more of the following in a combined final concentration of 5 - 30 %: 1 , 2 , 4 - butane triol dimethicone copolyol ethanol ethylene glycol glycerol glyceryl monostearate 1 , 2 , 6 - hexane triol isopropanol polyethylene glycol ( preferably peg 50 , peg 100 and / or peg 500 ) propylene glycol c : cream base . depending on the permeant and the application , one of the following may be used : carbopol 940 , 0 . 2 - 5 %% cetyl stearyl alcohol 2 - 6 . 0 % cremophor 40 , 0 . 8 - 3 % disodium edta , 0 . 1 - 0 . 3 % methyl paraben 0 . 1 - 0 . 2 % propyl paraben 0 . 02 - 0 . 08 % purified water 50 - 80 % triethanolamine , ph variable concentration carbopol aqua cc , 1 - 5 % cetostearyl alcohol 2 - 6 % dimethicone , 1 - 5 % disodium edta , 0 . 1 - 0 . 3 % glycolic acid , 5 - 20 % isopropyl myristate , 1 - 5 % methyl paraben 0 . 1 - 0 . 2 % olive oil 1 - 5 % peg - 100 stearate 1 - 8 % propyl paraben 0 . 02 - 0 . 08 % purified water 25 - 40 % triethanolamine 4 - 8 % d : antioxidants . examples include , but are not limited to , one or more of the following in a final concentration of 1 - 10 %: alkyl gallates alpha lipoic acid ascorbic acid butylated hydroxyanisole butylated hydroxytoluene catechins ( such as epicatechin ( ec ) and epigallocatechin gallate ( egcg ) citric acid coq10 curcumin sodium bisulfate sodium metabisulfate thiourea tocopherol acetate oxybutynin is a muscarinic receptor antagonist used in the treatment of urinary incontinence . an active metabolite of oxybutynin , n - desethyl - oxybutynin ( des ), may play major role in secondary effects such as dry mouth . a topical application of oxybutynin was applied to the shaved skin of rabbits at concentrations of 5 mg / ml ( a ) or 0 . 5 mg / ml ( b ). the carrier formulation consisted of a penetrant group of 8 cetyl fatty esters ( 7 %, cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate ) with propylene glycol as the polar solvent ( 15 %), menthol ( 1 . 56 %), tocopherol acetate ( 1 %), in the described cream base at a ph of 6 . 0 . the application was administered once to a 40 x 60 mm area , the area covered ( secured ), and then plasma samples were taken for a 24 - hour period thereafter . the results at the indicated time points are as follows , the mean plasma level at each time point representing the average of 4 animals . the plasma levels confirmed a dose response relationship and the ability of the carrier formulation to provide effective levels of oxybutynin systemically . the penetrant group was chosen for its affinity for the relatively hydrophobic permeant and for delivery efficiencies developed for systemic applications . although intravenous injection of oxybutynin ( 5 mg ) renders a tmax of 0 . 25 hrs , the tmax of application a was 6 hours and an effective plasma level over most of the 24 - hour observation period ( table 2 ). these features are attributed to the carrier formulation based on the penetrant group . the preferred polar solvents for penetrant groups two and three are propylene glycol with ether ethylene glycol and glycerol ( 20 %) or ethylene glycol and glyceryl monostearate ( 15 %). similar delivery characteristics are desired for topical application of testosterone . testosterone is difficult to enter through the skin due to its chemical properties . testosterone cypionate , however , is a derivative molecule with water solubility properties but it also has a high partition coefficient . our results indicated that the preferred penetrant group for this permeant is cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 7 %. the preferred polar solvent is ethanol , propylene glycol isopropanol or polyethylene glycol ( peg 50 ) at a concentration of 12 %. the desired effect is to provide skin penetration with accumulation of permeant that enters the circulation in small quantities over an extended period after application . the cfep carrying testosterone enters the skin within a few seconds and carries the testosterone into the capillaries . however , there is also a build up residual testosterone at the site of skin application , which serves as a reservoir , to be absorbed slowly over a period of time . the composition of the invention provides for the administration of permeants with anti - arthritic properties . a topical application consisting of the cetylated fatty ester complexes in concentrations of 5 % to 20 % with rubefacients ( such as methyl salicylate , menthol and for some variations capsaicin can be applied to affected areas of arthritic patients ). the permeants were at concentrations ranging from 1 - 30 %. the carrier formulation consisted of a penetrant group of 8 cetyl fatty esters ( 4 - 9 %; cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate ) with propylene glycol as the polar solvent ( 12 %), in the described cream base at a ph of 6 . 5 . one variation of carrier formulation is also an anti - inflammatory and is used topically to treat joint pain and musculoskeletal pain and other types of pains in arthritis ( kraemer w j et al . 2004 j rheumatology 31 : 767 - 74 ; kraemer w j et al . 2005 j strength and conditioning res 19 : 475 - 80 and sharan et al . 2009 , submitted for publication ), the preferred polar solvent is propylene glycol . compared with placebo base applications to a control group , the group receiving treatment to the affected area was able to obtain a statistically significant improvement in joint functionality and reduction in pain in a specified area such as neck , lower back , knees , head , and other areas with pain inflammation within 30 minutes of the application . other rubefacients found to be effective include eucalyptus oil at concentrations of 1 % to 5 %, and camphor at concentrations of 1 - 7 %. a second preferred penetrant group for this and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl myristoleate , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 9 %. a third preferred penetrant group for this and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleateplaced in a formulation at 4 - 9 %. the preferred polar solvent for penetrant groups two and three is propylene glycol with glycerol ( 15 %). the active compounds delivered with the cfep complex include targeting neuron repair and regeneration molecules like methylcobalamin , gabapentin , pre - gabalin , alpha lipoic acid , free radical neutralizing agents like alpha lipoic acid , catechins and curcumins , molecules like ketamine which is and has been used as a topical anesthetic , anti - depressants like amitriptyline , nortriptyline and other tricyclic anti - depressants that are useful delivered topically , analgesics like ketoprofen , methyl salicylate , menthol , and camphor and nsaids like diclofenac , and numerous other nsaids . neurogenic inhibitors like capsaicin can also be delivered with the cfep complex . alpha lipoic acid because of its unique solubility in both water and fat permeates well in any of the three formulations above in example 3 . ketamine [ 2 -( 2 - chlorophenyl )- 2 -( methylamino )- cyclohexanone ] is a water - soluble arylcycloalkylamine with a pka of 7 . 5 . its free base , ketamine , has lipid solubility 10 times that of thiopentone ( therefore , a cream base with elevated ph is required ). gabapentin is an anticonvulsant also with good water solubility . oral pregabalin is widely used now in the treatment of neuropathic pain and is also very compatible with our cfep complex . in our invention , which can be a topical cream , gel , spray , or a transdermal patch , we have used methylcobalamin at a concentration of 0 . 05 % to 5 % of methylcobalamin in a permeant cream base containing the penetrant group cetylated fatty esters . the preferred carrier formulation consisted of a penetrant group of cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleate ( at a concentration of 5 - 9 %, depending on the permeants ) mixed in with the cream base and polar solvent methylcobalamin in the concentration of 0 . 05 % to 5 % was easily solubilized in aqueous phase and mixed into the oil phase of the penetrant mixture to generate the desired emulsion . if capsaicin was included in the formulation , the concentration of capsaicin was 0 . 001 % to 0 . 025 %, for stability of the formulation ascorbic acid and or citric acid or other antioxidants were used in all formulations and curcuminoids were also added as they provide a cooling effectin neuropathic pain . the ph of the final formulation is also adjusted to improve penetration efficiency . the preferred polar solvent is propylene glycol and glycerol at a final concentration of 0 . 6 % to 15 % the patch consists of a semipermeable membrane that encloses a bilayer core . the active agent layer contains methylcobalamin and the cfep penetrant formulation ; the push layer contains osmotic agents and excipients . the active agent layer is highly absorbent containing defined quantities of the methylcobalamin in the permeant delivery matrix . an adhesive outer covering maintains patch contact with the skin . the second preferred penetrant is cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate at a concentration of 4 - 9 %. a third preferred preferred penetrant group for this and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl myristoleate , cetyl oleate , and cetyl palmitoleate ) placed in a formulation at 4 - 9 %. when pain caused by neuropathic pain was assessed post treatment with a cream containing methylcobalamin , there was a significant reduction in pain as measured by vas scale in arms , and legs . the penetrant group helps deliver the methylcobalamin to the damaged neurons and help reduces the pain . the reduction in pain was significant in both arms and legs . orally administered methylcobalamin although effective in reducing neuropathic pain takes several weeks for efficacy to set in . in an extension of the above invention in the treatment of diabetic neuropathic pain , post herpetic neuralgia , fibromyalgia , and convulsions , we use pregabalin and gabapentin in a topical cream , gel , spray , or a transdermal patch , at a concentration of 0 . 01 % to 15 % of pregabalin or gabapentin in a cream base containing the penetrant group cetylated fatty esters . the formulation can be with or without capsaicin when formulated for neuropathic pain release . the formulation also can contain methylcobalamin and pregabalin wherein the two molecules acting via different mechanisms of action may provide effective pain relief . this invention could potentially also obviate abuse and dependence on the drug found with oral treatment and also significantly reduce the adverse effects seen in the oral formulations . the preferred carrier formulation for pregabalin or gabapentin with or without capsaicin or in combination with methylcobalamin consisted of a penetrant group of cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleate at a concentration of 5 - 9 %, depending on the permeants , mixed in with the penetrant cream base and polar solvent placed in a formulation containing 0 . 01 % to 15 % pregabalin or gabapentin ; and when methyl cobalamin is also combined with pregabalin , the concentration of methylcobalamin is 0 . 05 % to 5 %. when capsaicin was also used its concentration was at 0 . 001 % to 0 . 025 %. these molecules were easily solubilized in aqueous phase and mixed in the oil phase of the penetrant mixture . for stability any antioxidant such as ascorbic acid or citric acid or others were used in all formulations and curcuminoids were also added to soothe inflammation associated with neuropathic pain . the ph of the final formulation is also adjusted to improve penetration efficiency . the preferred polar solvent is propylene glycol and glycerol at a final concentration of 0 . 6 % to 15 %. a transdermal patch may be prepared using conventional methods and the pregabalin or gabapentin with or without methylcobalamin and with or without capsaicin dissolved in the cetyl fatty ester pentrant formulation described previously . the patch would have an active agent layer with penetrant matrix , an osmotic push layer and semipermeable membrane held in place with an adhesive layer . the second preferred penetrant for the above invention is cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate , at a concentration of 4 - 9 %. a third preferred preferred penetrant group for the above invention and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl myristoleate , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 9 %. the above invention can be adapted to a topical cream , gel , lotion , spray or a patch with appropriate cfep complex to deliver the drugs and molecules . a formulation for transdermal delivery using the cefp - complex and various rubefacients as described in example 3 using a sodium stearate based gel stick in a plastic mold , similar to deodorant sticks . numerous rubefacients such as methyl salicylate , menthol , and camphor in concentrations of 1 - 30 %, individually or in combinations , and with other neurogenic inhibitors such as capsaicin in concentrations of 0 . 001 % to 0 . 025 % either singly or in combination with other rubefacients . the stick gel formulation can also contain vitamin b12 ( methylcobalamin ) in concentrations of 0 . 05 to 5 % to be used by diabetic patients suffering from neuropathic pain and patients suffering from other forms of neurological pain . similarly the stick gel formulation can also contain pregabalin with or without methylcobalamin in concentrations of 0 . 01 to 15 % to be used by diabetic patients suffering from neuropathic pain and patients suffering from other forms of neurological pain . the carrier formulation consisted of a penetrant group of 8 cetyl fatty esters ( 4 - 9 %, cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate ) with propylene glycol as the polar solvent ( 12 %), tocopherol acetate ( 1 %), in the described cream base at a ph of 6 . 5 . compared with placebo stick gel applications to a control group , the group receiving treatment to the affected area using stick gel and cfep - complex and the rubefacients were able to obtain a statistically significant improvement in joint functionality and reduction in pain in a specified area such as neck , lower back , knees , head , and other areas with pain inflammation within 30 minutes of the application . a second preferred preferred penetrant group for this and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl myristoleate , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 9 %. a third preferred penetrant group for this and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 9 %. the preferred polar solvent for penetrant groups two and three is propylene glycol with glycerol ( 15 %). the active compounds delivered with the cfep complex in a stick gel include targeting neuron repair and regeneration molecules described in example 4 above , like methylcobalamin , gabapentin , pregaballin , alpha lipoic acid , free radical neutralizing agents like alpha lipoic acid , catechins , or curcumins , molecules like ketamine which is and has been used as a topical anesthetic , anti - depressants like amitriptyline , nortriptyline and other tricyclic anti - depressants that are useful delivered topically , analgesics like ketoprofen , methyl salicylate , menthol , and camphor and nsaids like diclofenac , and numerous other nsaids . alpha lipoic acid because of its unique solubility in both water and fat permeates well in any of the three formulations above . ketamine [ 2 -( 2 - chlorophenyl )- 2 -( methylamino )- cyclohexanone ] is a water - soluble arylcycloalkylamine with a pka of 7 . 5 . its free base , ketamine , has lipid solubility 10 times that of thiopentone , therefore , a cream base with elevated ph is required . gabapentin is an anticonvulsant also with good water solubility . the preferred carrier formulation consisted of a penetrant group in the stick gel containing cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleate at a concentration of 4 - 9 %, depending on the permeants , mixed in with the permeants cream base and polar solvent at ) placed in a formulation at 5 - 9 %. the ph of the final formulation is also adjusted to improve penetration efficiency . the preferred polar solvent is propylene glycol and glycerol at a final concentration of 12 %. the second preferred penetrant in the stick gel is cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate at a concentration of 4 - 9 %. a third preferred preferred penetrant group in the stick gel for this and similar permeant drugs is cetyl decanoate , cetyl isolaurate , cetyl myristoleate , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 9 %. transdermal delivery of diazepam and other similar agents such as pregabalin for treatment of seizures due to epilepsy and other types of seizures . a formulation for transdermal delivery is a novel format for diazepam or lorazepam or clonazepam , and utilizes the lipophilic properties of each molecule . in one example diazepam is administered in 3 doses , namely 10 mg / gram , 25 mg / gram and 50 mg / gram using a 4 - 9 % cfep - complex carrier formulation consisting of cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate . the polar solvent used is propylene glycol ( 12 %) in the described cream base at a ph of 6 . 5 . a ph range of 6 - 7 is effective and tocopherol acetate is the antioxidant at 1 %. preliminary results show that a therapeutic dose can be administered using the combinations indicated above . the permeant is first finely emulsified in the cfep - complex and polar solvent prior to addition of the cream base . a single application of diazepam delivered to mouse skin in this formulation may provide pronounced activity for 5 - 8 hours . transdermal delivery is also pronounced significantly with addition of urea and a non - ionic surfactant . pregabalin in a topical format is also an excellent anti - convulsant and useful in the treatment of seizure already described in examples 4 and 5 above . a second preferred penetrant group for this and similar permeant drugs is cetyl 13 - methyl myristate , cetyl myristate , cetyl oleate , cetyl ornithine , cetyl palmitoleate and cetyl stearate , placed in a formulation at 4 - 9 %. the preferred polar solvent is propylene glycol and glycerol at a final concentration of 12 %. the second preferred polar solvent is isopropanol and propylene glycol at 12 %. this formulation may be more effective with clonazepam . a third preferred preferred penetrant group for this and similar permeant drugs is cetyl decanoate , cetyl myristate , cetyl oleate , cetyl ornithine and cetyl palmitoleate , placed in a formulation at 4 - 9 %. the preferred polar solvent is propylene glycol and glycerol at a final concentration of 12 %. this formulation may be more effective with lorazepam . a topical application consisting of restorative and protective permeants ( such as dimethicone , white curcumin , small peptides , cyclopentasiloxane ) was applied to face and neck twice per day . the permeants were at concentrations ranging from 0 . 4 - 9 %. the carrier formulation consisted of a penetrant group of 8 cetyl fatty esters ( 4 - 9 %; cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate ) with propylene glycol as the polar solvent ( 15 %) along with tocopherol acetate ( 1 %), in the described cream base at a ph of 6 . 5 . a second preferred penetrant group for this and similar permeants is cetyl decanoate , cetyl isolaurate , cetyl 2 - methoxy - 5 - hexadecenoate cetyl myristoleate , cetyl ornithine , cetyl oleate , and cetyl palmitoleate , placed in a formulation at 4 - 9 %. twenty eight female and eight male subjects were studied for 71 days ( average age of the group : 44 years ). the applications resulted in statistically significant improvements in skin firmness , skin elasticity with reductions in the number and depth of wrinkles . the carrier formulation was found to be well tolerated with no skin irritation . the formulation facilitates delivery of permeants to the skin in a manner that retains permeants in the skin to provide improvements in skin properties . the data in table 3 demonstrate that statistical improvements in facial firmness can be observed as early as 28 days of treatment applied twice each day . another feature noted in table 4 would indicate that the formulation facilitates in administering permeants to affect other skin properties in a beneficial manner . the administration of permeant agents to provide restorative and protective properties to the skin is given in another example . in this example the permeants 10 % urea and 1 % dimethicone are delivered in an acidic cream formulation with additional emoluents , preferred antioxidants and hemectants . the carrier formulation consisted of a penetrant group of 8 cetyl fatty esters ( 4 - 9 %; cetyl decanoate , cetyl laurate , cetyl myristate , cetyl myristoleate , cetyl oleate , cetyl palmitate , cetyl palmitoleate and cetyl stearate ) with propylene glycol , glyceryl monostearate , cetostearyl alcohol and glycerin at a concentration of 15 %. the preferred cream base has a ph of 3 - 4 , which demonstrates the effectiveness of the permeant groups at a low ph , as depicted below in table 5 below for permeant and penetrant treated ( p & amp ; pt ) groups . thirty - two patients with severe hyperhydrosis and cracking of the cornified skin of the feet were treated with the above formulation with applications twice a day for 8 weeks . fifteen volunteers were given a placebo cream base without the permeants or the penetration group of cetylated fatty esters . the condition of foot skin was evaluated using a xerosis severity index of 0 to 3 with 0 being normal skin and 3 being severe xerosis ( large scale plates with fissures , often characterized as deep and erythematous ). results show that even as early as week 2 , a statistically significant difference was noted between the permeant and penetrant groups versus the placebo group in regards to severity of xerosis . xerosis mean index in the study group reduced dramatically while essentially no change in mean severity index was found with the placebo group . the change in mean severity index for the permeant and penetrant treated group continued to show improvements in that group with each successive week of treatment . although the rate of change slowed after the 4 th week , a 36 . 4 % change in mean values was still noted between the 6 th and 8 th week . at each week of evaluation , the mean index values for the treated group showed statistically significant improvements compared with the placebo group , which only showed some change by week 8 ( attributed to application of the base cream to the foot ). the average score for the p & amp ; pt group went from a moderate index value of 2 . 00 to a value of 0 . 23 ( mild to almost normal ) by the end of 8 weeks . the placebo group had a mean value of 1 . 6 ( mild to moderate ) by week 8 . 1 . gale , awarded on jan . 29 , 2008 u . s . pat . no . 7 , 323 , 191 , for transdermal warfarin system describes composition of matter for application to a body surface or membrane to administer warfarin by permeation through the body surface or membrane . 2 . jordan , awarded on jan . 8 , 2008 u . s . pat . no . 7 , 316 , 820 , for transdermal delivery system and relates to the discovery of a transdermal delivery system that can deliver high molecular weight pharmaceuticals and cosmetic agents to skin cells . 3 . compounds which are generally ip receptor antagonists can be traced to cournoyer , et al . in u . s . pat . no . 7 , 312 , 230 entitled carboxylic acid derivatives as ip antagonists , awarded on dec . 25 , 2007 . 4 . a transdermal delivery system ( tds ) which may be applied as an open ( liquid , gel ) or closed ( patch ) article that rapidly crosses the skin barrier can be traced to kirby , et al . in u . s . pat . no . 7 , 267 , 829 entitled ‘ compositions for rapid and non - irritating transdermal delivery of pharmaceutically active agents ’ awarded on sep . 11 , 2007 . 5 . the art of “ preparing a two - phase water - absorbent bioadhesive composition ”, discloses a method for preparing a composition that contains both a hydrophobic phase and a hydrophilic phase , contributed by u . s . pat . no . 7 , 138 , 458 issued to cleary , et al . on nov . 21 , 2006 6 . chong , awarded on aug . 28 , 2007 u . s . pat . no . 7 , 262 , 224 for cosmetic rejuvenating and healing product , method of its manufacture and uses thereof , and describes a cosmetic composition for rejuvenating the appearance of skin . 7 . u . s . pat . no . 7 , 182 , 955 , awarded for invention of “ abuse - resistant transdermal dosage form ” describes an active agent component an abusable drug substance , an overlay backing , a porous material , and an antagonist reservoir to hart , et al . on feb . 27 , 2007 . 8 . u . s . pat . no . 6 , 946 , 144 entitled transdermal delivery system , awarded to jordan on sep . 20 , 2005 relates to the discovery of a transdermal delivery system that can deliver high molecular weight pharmaceuticals and cosmetic agents to skin cells . 9 . changaris , awarded on jul . 11 , 2006 u . s . pat . no . 7 , 074 , 418 entitled ‘ conjugated fatty acid based emulsion and methods for preparing and using same ’, describes diene conjugated fatty acids which are also useful as a carrier and delivery vehicle of the macromolecules . 10 . “ an anti - inflammatory analgesic gel composition ”, can be traced to noda , et al . in u . s . pat . no . 4 , 393 , 076 , entitled ‘ anti - inflammatory and analgesic gel composition ’ awarded on jul . 12 , 1983 . 11 . u . s . pat . no . 4 , 808 , 414 entitled “ amide penetration enhancers for transdermal delivery of systemic agents ” awarded to peck , et al . on feb . 28 , 1989 , describes topically administering with a said systemic agent an effective amount of a membrane penetration enhancer . 12 . “ a method for the treatment of osteoarthritis ” by diehl , described for alleviating the symptoms of non - rheumatoid arthritis by administering cetyl myristoleate either orally , topically , or parenterally , was awarded u . s . pat . no . 5 , 569 , 676 on oct . 29 , 1996 . 13 . discovery that by simultaneously administering particular dosage levels by means of a transdermal delivery system , anesthesia may be induced in patients , can be traced to u . s . pat . no . 5 , 635 , 204 , entitled ‘ method for transdermal induction of anesthesia , analgesia or sedation ’ awarded to gevirtz , etal . on jun . 3 , 1997 . 14 . u . s . pat . no . 5 , 646 , 151 , entitled “ kappa agonist compounds and pharmaceutical formulations thereof ” describes , compounds , compositions and method of treating hyperalgesia comprising a compound as defined in the specification awarded to kruse , et al . on jul . 8 , 1997 . 15 . disclosed are topical compositions which provide good coverage of skin imperfections , in u . s . pat . no . 5 , 972 , 359 , entitled skin care compositions and methods of improving skin appearance awarded to sine , et al . on oct . 26 , 1999 . 16 . an invention which comprises of a cream type carrier for topical delivery of medicaments including analgesics is described in u . s . pat . no . 6 , 461 , 600 , entitled “ topical pain relief composition and carrier ”, awarded to ford on oct . 8 , 2002 . 17 . ‘ topical compositions and methods for treating pain ’ describes an invention that induces a local - anesthetic effect when topically administered to intact skin , in u . s . pat . no . 6 , 638 , 981 , awarded to williams , et al . on oct . 28 , 2003 . 18 . levin , awarded u . s . pat . no . 7 , 112 , 578 on sep . 26 , 2006 entitled methods and compositions for treatment of inflammatory disease describes compositions useful for treating inflammatory diseases including arthritis are disclosed which comprise cetyl myristoleate compounds . 19 . u . s . pat . no . 4 , 049 , 824 , awarded to diehl on sep . 20 , 1977 , entitled cetyl myristoleate , describes a method for immunizing against inflammatory rheumatoid arthritis in mammals . 20 . ‘ methods of delivery of cetyl myristoleate ’ provides delivery devices for compositions of cetyl myristoleate , including transdermal delivery devices , suppositories , enteric coatings , and microencapsulation , in u . s . pat . no . 6 , 417 , 227 , awarded to lord , et al . on jul . 9 , 2002 . 21 . u . s . pat . no . 7 , 223 , 877 , awarded to leonard on may 29 , 2007 , entitled uses of hydroquinone substituted polyunsaturated fatty acids as antioxidants , relates to the use of fatty acids as antioxidants . 22 . “ synthesis of ester linked long chain alkyl moieties ’ provides a process for preparing a mixture of cetyl myristate and cetyl palmitate , in world patent wo03018731 , awarded , on mar . 6 , 2003 to cadwallader dianne ( nz ); jhaveri parag ( in ) 23 . “ pharmaceutical carriers and compositions for transdermal drug delivery ” unfolds a skin permeation enhancing agent & amp ; a surface adhesion molecule acting in synergy , in world patent wo0211784 , also published as wo0211784 ( a3 ) on feb . 14 , 2002 , awarded to herzberg max ( il ); messika eric ( il ); ghozi michal ( il ) 24 . sunamoto jiyunzou ; iwamoto kiyoshi , awarded patent jp58049311 , entitled preparation of stable liposome , describes the prevention of destruction of liposome by covering it with an ester of polysaccharide and fatty acid . 25 . hoyt kenneth ( us ); lemley paul ( us ), awarded wo9833474 , on aug . 6 , 1998 , entitled use of oil from emu or rhea birds as trans - membrane carriers for delivery of drugs , peptides and vaccines , describes a method for transdermal transportation of proteins , peptides using oil obtained from the sebaceous glands of rhea and emu birds . 26 . “ transdermal carrier materials ”, awarded ep0038512 , on oct . 28 , 1981 to schafer werner ; schafer rolf dr ; schafer doris dr for describing use of amphoteric ionic complexes as effective carriers for active pharmaceutical or cosmetic ingredients . 27 . weisman , bernard , awarded wo119981052583 , on nov . 26 , 1998 , entitled , natural composition for treating bone or joint inflammation , describes a novel composition for treating conditions characterized by bone or joint inflammation with cetyl myristoleate 28 . skin care and cosmetic ingredients dictionary , p . 243 ( 1994 ).“ handbook of pharmaceutical excipients ,” edited by arthur h . kibbe , ph . d ., am . pharm . assoc ., 3 : 292 - 294 , 2000 . 29 . “ cardinal manifestations and presentations of diseases ,” hesslink r , armstrong d , nagendran m v , sreevatsan s , barathur r ( 2002 ) 30 . cetylated fatty acids improve knee function in patients with osteoarthritis . j rheumatol 29 : 1708 - 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