MICELLULAR DRUG DELIVERY SYSTEM

Abstract: A xenobiotic delivery composition comprising lipid micellular particles incorporating the xenobiotic. The lipid micellular particles comprise a bile acid or the pharmaceutically acceptable salts thereof, a fatty acid and a monoglyceride. Methods of delivering the xenobiotic composition are also set forth in this invention.

Description: MICELLULAR DRUG DELIVERY SYSTEM This invention relates to the delivery and release of xenobiotics within a mammali n host. More particularly, it relates to a xenobiotic delivery composition on the form of lipid micelles and to a method of delivering xenobiotics to a mammalian os z which predetermines and controls the pharmacodynamics of the xenobiotic as delivered and released. In many different situations and under aj-iy varied circumstances it is desirable to introduce into a mammalian host pharmacologically active agents which are foreign to the host, these agents hereinafter being termed "xenobiotics." These xenobiotics include, but are not necessarily limited to. drugs, diagnostic agents, blood substitutes endogenous biological compounds, hormones, immunoiσgical adjuvants and the like. In the administration of any xenobiotic a certain degree of specificity must be attained, and specificity requires that the xenobiotic reach its target selectively and controllabl . The absence of specificity associated with the use of many xenobiotics can thus deprive them , of an appreciable part, if net essentially ail, of cheir potential effectiveness in attaining the results desired from their use. For example, a chemctherapeucie drug which cannot be retained by b_iood plasma fcr a time sufficient for an appre¬ ciable amount of the άcig to reach the target tissue or an orally administered drug which is ces ined fcr the blood stream but which cannot pass through the gastrointestinal BAD ORIGINAL tract lacks the degr of specificity which could make it highly effective. Thus in lacking the desired specificity, " έ. xenobiotic may exhibit essentially none or only a limited degree of the pharmacodynamics cesired to realize its full potential. Among such pharmacodynamics may be listed plasma kinetics, tissue distribution, degree of tcxicity, levels of therapeutic drugs i i v o, solubility of. xenobiotics nor¬ mally incompatible with other pharmaceutical formulations, and metabolic aetivacion of the xenobiotics. In the prior art it has been- recognised that it would be desirable to beneficially alter and control the specificity or pharmacodynamics of many of the xenobiotics found to have desirable properties. One prior art approach to controlling the specificity of drugs involves the use of .implant devices located, normally through a surgical pro¬ cedure, in or near the organ to which the drug is to be delivered. Typically, these implant devices comprise a covalent matrix material containing the drug to be delivered. These matrix materials may be water-soluble (e.g., carboxy- • methyl cellulose or pciyvinyl alcohol), water-sweiiable (e.g., hydrogel≤ or gelatin), hydrolytic polymers (e.g., pαlyiactic acids, polyglycoiic acids or pcIy-=> \ -amino acids), or nonhydrolytic polymers (e.g., organopolysiioxane rubber). __Qeneraily, although these implant devices can control the rate at which the drug they contain can be delivered through diffusion or hydrolysis, they can exercise little if any alteration of the pharmacodynamics of the drug released. In addition, the drug implant method requires rhe attention cf ° M skilled surgeons and support staff in order to effectively and safely utilize the device. As such, primary consi- ■ deration for administration of xenobiotics has been directed to the more " facile oral delivery techniques and carriers for accomplishing such techniques. One method which has been used to increase the effectiveness of orally administered substances is to in¬ crease their absorption area by reducing their particle size. Particle size has been shown to be critical for orally administered steroids spironoiactone, and griseofulvin. Ξs- cradiol, the primar;/ estrogenic hormone, has shown promising pharmacological activity when administered orally and mi- crcnized estradiol was clinically effective in a preliminary study of enopausal therapy and was well tolerated. A recent study has shown that micronize estradiol was readily ab¬ sorbed from the gastrointestinal tract; however, the serum concentrations of estrone rather than estradiol were mark¬ edly increased. This finding indicates that orally absorbed estradiol is rapidly metabolized. The gastrointestinal mucosa, rather than the liver may be the primary site of this extensive metabolism of orally administered estradiol. In addition to reducing particle size, the effi¬ cacy of certain drugs given craliy has been improved by administering them in oil solutions. As used throughout the specification, oils refers to the high molecular weight glycerol esters of fatty acids principally of vegetable origin. For example, the absorption of both regular and micronized griseofulvin are somewhat enhanced if co-ad in- BAD istered with meals high in fat cr triglyceride content cr in an oil and water emulsion. Testosterone undecancate --dis¬ solved in arachis (peanut) oil is more biologically active than the micro-crystal suspension in water possibly due to absorption of testosterone undecancate via the lymph rather than the portal system. Similarly, the pathway of absorption of orally administered ethynyl estradioI-3-cyclopentyi ether was influenced by the vehicle of administration. Central to the numerous investigations of the mechanism of fat absorption has been the basic question as to the chemical nature of the fats which gain entrance to the mucosai cells. Triglycerides are by far the most important iipiάs in the diet and the chemical composition cf the natural tri¬ glycerides vary considerably in their fatty acid composition and in their positional conformation. Fcr example, the content cf pal itate, oleate, and lincleate varies among the common seed oils; corn (13, 29 and 5 ' , respectively), peanut (δ, βi and 225), respectively), and palm (46, 3S and 93, respectively) . The digestion cf triglycerides requires the enzyme, pancreatic lipase, and bile salts. This enzyme demonstrated a preferential hydrolysis cf the 1 and 3 posi¬ tions of the triglyceride to give the final products a 2- onoglyceride and fatty acids. Enzymatic hydrolysis of these -triglycerides is incomplete and slow. It has been shown that conjugated bile salts in the intestine form complexes termed "micelles" with fatty acids BADORIGINAL Q2.f?I and mcncglycerides . Micelles, as used in the prior art and herein are defined as lipid particles cf C-100A in diameter " that to the naked eye appear as clear (rather than milky) solutions, i.e., while oil in water, because of their very small particle size, they appear as solutions. Thus, it appears that a micelle delivery system could provide a novel carrier capable of delivering xenobiotics to very specific regions of the body. It is therefore a primary object of this invention to provide improved xenobiotic delivery compositions in the form of lipid micelles capable of being readily absorbed within the host system. Another cbjec-t is to provide xeno¬ biotic delivery compositions of the character described which are compatible with a wide variety of xenobiotics including hydrophobic, hyάrcphiiic or a combination of hy- drcphcbic and hycrophiϋc compounds and which are nontoxic and biocompatibie with the host system. A further object of this invention is to provide xenobiotic delivery composi¬ tions which are stable over extended periods of storage as well as in their use within the host system and amenable to various techniques of oral administration. Another object of this invention is to provide -xenobiotic delivery compositions capable of predeterminably and beneficially altering and controlling the pharmacodynam¬ ics of the xenobiotic delivered and released within the host -system. Among the phar adocynamics thus beneficially altered -__.,,, : -,. ,-•-—- " -7; _ s i -i - ii - '- and controlled are plasma kinetics, tissue distribution, toxicity, oral absorption, chemothera eutic ability, metab¬ olism and the like. " t ' is another primary object of this invention to provide a method of forming xenobiotic delivery composi¬ tions, in the form of lipid micelles, capable of circulating within a mammalian host thereby to deliver the xenobiotic at a predetermined site by effecting a predetermined beneficial alteration in the pharmacodynamics of the xenobiotic. Yet another primary object of this invention is to provide a method for delivering and releasing a pharmaceu¬ tically effective amount of a xenobiotic within a mammalian host in a manner to exercise seme predeterminabie control over the delivery site, thus enhancing the effectiveness of the xenobiotic. Other objects of- the invention will in part be obvious and will in part be apparent hereinafter. . According to one aspect of this invention there is provided a delivery vehicle incorporating a xenobiotic and being biocempatibie with a mammalian host to deliver and release within the aqueous environment of the host the xenobiotic, the pharmacodynamics of which are beneficially altered by reason of its delivery by and release from the vehicle, the delivery composition being in the form of lipid micelles comprising a mixture formed from bile acids and the pharmaceutically acceptable salts thereof, fatty acids and monogiycerides, thereby providing for the controlled release of the xenobiotic therefrom. BAD ORIGINAL C.\_?I According to another aspect of this invention there is provided a method of forming a delivery composition . " for delivering to and releasing within the aqueous environ¬ ment of a " mammalian host a xenobiotic, the pharmacodynamics of which are predetermiπabiy altered and controlled, com¬ prising the steps of forming lipid micelles of a composition comprising fatty acids and monogiycerides and incorporating the xenobiotic to be delivered within the lipid micelles. .According to yet another aspect of this invention there is provided a method of cαntroiiabiy delivering to and releasing a xenobiotic within the aqueous environment cf a mammalian host, comprising the step of introducing into the mammalian host a pharmaceutically effective amount of a xenobiotic contained within lipid micelles formed from a mixture comprising bile acids and -the pharmaceutically ac¬ ceptable salts thereof, fatty acids and a monogiycerides. According to still another aspect of this inven¬ tion there is provided a method of predetermining and con¬ trolling the pharmacodynamics under which a xenobiotic is delivered within the aqueous environment of a mammalian host, comprising the step of releasing the xenobiotic within the host from lipid micelles formed from a mixture comprising bile acids and the pharmaceutically acceptable salts there¬ of, fatty acids and monogiycerides, thereby controlling the pharmacodynamics of the xenobiotic. The invention accordingly comprises the several steDS and the relation of one or mere such steos with rescect BAD ORIGINAL to each of the others, and the composition and article possessing the features, properties, and the relation of constituents, which are exemplified in the following de¬ tailed disclosure, and the scope of the invention will be indicated in the claims. For a fuller understanding of the nature and ob¬ jects of the invention, reference should be had to the following Figures and the detailed description cf the Pre¬ ferred Embodiments. Figure 1A. Hydrolysis of U.S.?. corn oil using pancreatic iipase and various mole ratios of bile salts. Figure 13. Hydrolysis of r J.S.?. corn oil using pancreatic iipase, bile salt: triglyceride ratio of 1:1, and varying the concentration cf oil and water. Figure IC. Estradiol solubility in the aqueous phase of a triglyceride: water biphase (3:7, w/w) as a function of increasing bile salt: triglyceride ratios. Figure ID. Distribution of estradiol in aqueous phase with respect to the hydrolysis of the lipid phase. __ Figure 2A. Hydrolysis mixture contained ~ d' C- oieic acid and its monogiyceride, —C-biie salt and 3H- estradicl. BAD ORIGINAL Figure 23. Mole percent composition cf bile ' salts, fatty acid and onoglyceride. -- Figure 2C. Fatty acid composition of original oil and hydrolyzed oil prior to chromatography and in the monoglyceride fraction following chromatography. Figure 2D. Fatty acid composition in the fatty acid fraction. Figure 3A. The recovery of estradiol in ly ph- asomes, which contained 0 to 2 mole ratios of phosphatidyl choiine relative to monσgi3rceride and which were chroma- • tographed cn Sepharose 43 gel columns. Figure 33. The- size distribution of lymphasomes described in A above. Figure 3C. The eiution pattern of estradiol in phosphatidyl choiine containing lymphasomes on Sepharose 43 gel chromatographic columns. Figure 4A. The time pattern of total estradiol derived radioactivity equivalents in systemic plasma, pcrtai ~~ plasma and lymph of surgically prepared dogs that received (3κ or 1 C) estradiol in a ly phasome preparation. Figure 43. The time pattern of identified estra ¬ diol equivalents, namely estradiol (£2) and its giucuronide BAD ORIGINAL OMPI (Ξ j -) and estrone (Ξι_) and its glucuronide (EvC-) in dog systemic blood. -Figure 4C. The time pattern cf identified estra¬ diol, in dog portal blood. Figure 4D. The time pattern of identified estra¬ diol, in dog lymph. As used herein, the term "fatty acids" is intended to mean the organic monobasic acids derived from linear or branched hydrocarbons of the formula Zr. r. * -' . where n is an integer 10 to 2^ by the equivalent of oxidation cf a methyl group to a carhcxyiic acid including: saturated fatty acids of the formula C n H2* 3 ,. ] '.C30E such illustrated by yristic acid, palmitic acid, stearic acid, etc; moncunsaturated fatty acids cf the formula C n H n-i C3 0E such illustrated by oieic acid, etc; diunsaturated fatty acids cf the formula C n H __.3, such illustrated by iinoiaic acid, etc; and triunsaturated fatty acids of the formula C n H2π-5CCGH such illustrated by linoienic acid, etc. 3y the term "monoglyceride" as used herein, is meant the 2-monoesters formed from glycerine and the above defined fatty acids having the general formula (01-1 )3 (-0H) 2 00CH where H is C 10 to C2 aikyi including linear or branched and saturated or mono cr poi unsaturated groups. The term "bile acids" and the pharmaceutically acceptable salts thereof" is intended to mean those naturally BADORIGINAL occurring bile acids, such illustrated by cholic acid, de- oxycholic acid, lithocholic acid, chenodeoxychoiic acid, 3- hydroxy-7ketocholanic acid, "" etc., their conjugates with the acids giycine and taurine, as well as the ' nontoxic cationic salts thereof. The term "Iipase" as used herein is defined as any enzyme that changes fats into their component άiglycerides ' , monogiycerides, fatty acids and glycerine. They are typi¬ cally of natural origin, derived from the liver, pancrease and other digestive organs as well as from a wide variety of plants. The term "hydrolyzed triglyceride oil" is intended to mean triglycerides, i.e., the above fatty acids forming esters with glycerine, enzymatically hydrolyzed to the above defined monogiycerides, the enzyme being Iipase as above defined. The novel delivery vehicle of the present invention is structured in the form of lipid micelles incorporating a xenobiotic agent. The term "micelles" has heretofore been applied to the form of those products found in the digestive tract (principally the duodenum and jejunum) and known to be a complex of conjugated bile salts with fatty ' acids and mono¬ giycerides. The lipid micelles of this invention are similar o the naturally occuring micelles but are composed of a synthetic mixture of certain bile acids or the pharmaceu¬ tically acceptable salts thereof, monogiycerides and fatty acids. The bile acids preferred in the preparation of this xenobiotic delivery vehicle are those selected from the group chciic acid, chencdioxychclic acid, dioxvcholic acid and lithocholic acid. Particularly preferred are the preferred bile acids conjugated with the acids, glycine or taurine. While a great variety-of monogiycerides can be used in the vehicle of this invention, the preferred monogiy¬ cerides are those esters substituted at the 2-position of the three carbon giycerol chain, the substitution being a sat¬ urated or unsaturated linear or branched fatty acid having from 10 to 13 carbon atoms in the hydrocarbon chain (including the carboxyiate group). Particularly preferred are giycerol iaurate, giycerol myristate, giycerol paimitate, giycerol oieate, giycerol iincieate and giycerol iinoienate. As in the case of the monogiycerides described above, the fatty acids finding preferred applicability in this invention are those linear or branched, saturated or unsaturated fatty acids having from 10 to 18 carbon atoms in the hydrocarbon chain (including the carboxylic acid group). Particularly preferred are lauric, yristic, palmitic, oie- ic, linoleic and linoienic acids. The delivery vehicle of this invention, composed of the above-disclosed bile acids and the pharmaceutically acceptable salts thereof, monogiycerides and fatty acids in ratios of 10:1:1.1:1:10 and 1:10:1, most preferably 2:2:1. It should be understood that the acid conjugates of the bile acids of this invention are also BAD ORIGINAL - ύ rLE OMPI --. -~- - * capabie of forming pharmaceutically acceptable-cation salts. These pharmaceutically acceptable cation salts, with -respect to the acid moiety as well as the cation salts of the bile acids include for example, the alkali metals, e.g., sodium, potassium, etc.; alkaline earth metals, e.g., calcium, etc; ammonia, organic salts of triethyiamir.e, diethylamine, tris- (hydroxy ethyl)aminomethane, ethanoia ine, choiine, caffei¬ ne, and the like. The term room temperature refers to about 20°C, and all temperatures and temperature ranges refer to degrees centigrad.e.__ All β ?ercen s refer to weight percents and the term eσ.uivaient mole amount refers to an amount stoichio- metricaliy equivalent to- the other reactant in the reaction referred to. A further understanding cf the invention can be had from the foiicwing non-limiting preparation and examples. PREPARATION I When xenobiotics are administered " in oils and an enchanced absorption cf the xenobiotic is observed, the oils per se are first eπzymatically hydrolyzed, the hydroiylic components are absorbed in the region of the jejunum and subsequently resynthesized into triglycerides prior to their incorporation into chylomicrons. The enzymatic hydrolysis requires pancreatic Iipase, bile salts, divalent cations and an alkaline pH. It can be demonstrated that this hydrolysis BAD ORIGINA -- --- • «_••• is very dependent upon the mole ratio of bile salts and triglycerides (Figure 1A) and the molar concentration f the triglycerides (Figure 13); '" that the rate of the enzymatic hydrolysis is slow (Figure 13 and ID); and that, under less than optimum conditions, the reaction will not go to com¬ pletion (Figure 13). Thus it is not surprising that oil per se has not been successful as a xenobiotic-delivery vehicle. PREPARATION 2 Ξstradioi-17 , a water insoluble drug, is soluble in triglyceride oils but will partition into an aqueous phase containing bile salts ( iziire IC). Since bile salts are absorbed in the region of the lower ileu , estradiol ad¬ ministered in oil has the potential -for partitioning into a bile salt-rich aquecus phase and being absorbed along with bile salts. The partitioning characteristics cf estradiol during the process of hydrclyzing triglyceri e-cils is shown in Figure ID). The partioning into the oil-phase following I to 3 hours represents large lipid emulsions containing triglycerides, fatty acids, monogiycerides and bile salts. .At 4 hours, when most of the triglycerides have been hydro¬ lyzed, the estradiol is associated with the lipid micelle. This hydrolysis mixture was chrc atographed on a pciyacry- laaide gel column (P-10). Chromatography experiments with hydrclysates made from U.S.?. corn oil show that there is no segregation of micelles with respect to fatcy acid distrib- ution. As shown in Figure 2A, [3H]-estradiol co-eluted with the lipid micelles containing hydrolyzed [--C]-triglycerides and [ l2 *C]bile salts. The analysis of the column eiuates for salts, l4 C-fatty acids and —C-monoglycerides (Figure 2C) demonstrate that the region corresponding to 3κ- estradiol contained more than 2 moles of fatty acids, less than 2 moles of bile salts and approximately 1 mole of monogiycerides. The region where bile salts were enriched did not contain significant concentrations of estradiol. Estradiol in the presence of a hydrolyzed oil phase and excess bile salts aqueous phase partition pref rentially to the lipid micelle. Aiiquots from each of these five molar concen¬ trations of estradiol were chromatograp ed on a poiyacryiam- ide " column. The elutlon profile of the estradiol and the lymphasomes were co-incident; the bile salt-rich micelle ■ region contained minimum amounts of estradiol, even to the point that the i7mphasomes were saturated with estradiol. This shows that estradiol solubility in hydrolyzed oil pre¬ parations was preferential to that in a bile-salt rich micelle. It was found that estradiol saturation occurred between 0.C04 and 0.007 mole percent relative to monogly¬ ceride or triglyceride. The fatty acid distribution of the fatty acids in both the monoglyceride fraction (Figure 23) and the fatty acid fraction • (Figure 2C) were comparable throughout the column eiuates. The monoglyceride fraction (Figure 23), in OMPI comparison to the fatty acid fraction (Figure 2C), was enriched in linoieic acid (18:2) but it is not further enriched in the region corresponding to the elution of estradiol. PREPAHATIOK 3 In these Preparations several sources of hydro¬ lyzed triglyceride oils (Table 1) are evaluated. The mole % composition varied somewhat,. but the optimum lipid micelle coeiuting with estradiol contained approximately 2 moles of fatty acid, 2 moles of bile salts, and 1 cie of mono¬ giycerides (lymphasomes). The fattjr acid distribution in the fatty acid and monoglyceride fractions are reflected in the original composition of the triglyceride-oils. Each source of oil for the ly pha≤ome preparations was replicated at least twice for the bioavaiiabiiity of estradiol in dogs. There was nothing to distinguish any oil as being better than the others. The findings fcr ail lymphasc e preparations have been, pooled. ΞXAMPLΞ 1 __ Lymphaso e preparations, i.e., containing a molar ratio of bile salt:fatty acid monoglyceride of 2:2:1, are saturated with estradiol at a molar concentration between 0.004 and 0.007 relative to monoglyceride. In preparing BADORIGINAL * —-' synthetic lipid micelles composed of saturated fatty acids, a greater molar concentration of bile salts is required.__When excess bile salts are present, estradiol has the potential of partitionin " from the lymphasome into the bilesalt enriched solution (Figure 3A). Since this situation of having excess bile salts along with lymphasome formulations of estradiol exist in the intestinal region of the duodenum and jejunum, the effect of phosphatidylcholine on this equilibrium was evaluated. The addition of phosphatidylcholine (A) changes the size dimension of the lymphasome formulation (Figure 33 and C), and results in a modest increased recovery of estra¬ diol (Figure 3A). The amount of added phosphatidylcholine that coeluted with the large lymphasomes containing estra¬ diol is shown in Figure 3C. The optimum recovery of 3* estradiol (Figure.3A) occurs when approximately half of the 0.5 moles of PC co- eluted with estradiol (Figure 3C; 0.5 elution pattern). A greater association of ?C results in even larger lymphasomes without significant increases in recovery cf estradiol. EXAMPLE 2 It has been demonstrated that estradiol adminis¬ tered p.o. in 20* ethanol/saline to both dogs and monkeys was rapidly and-quantitatively absorbed, extensively metabolized by the in.tes ' tine and liver, and rapidly excreted. A sig- nificant amount of estradiol equivalents entered a slow eii ination peel which had a tι 2 of 15 to 18 hr. The size of this slow pool being derived from an oral dose was ^ comparable to that being derived from a simultaneously ad¬ ministered intravenous dose. Estradiol administered orally in 20* ethanoi/salϊne yielded more glucuronides than found for estradiol administered in the same control formulation by the intravenous route. A comparable study was carried out in dogs in which 5Q s of estradiol orally in a lymphasome formulation and 50 ^<v intravenously in a 20* ethanol/saline solution was simultaneously administered. The results are shown in Figure and Tables 2 and 3- The comparison among the various formulations are summarized in Table 3- Figure 4 shows the total ra iolabeied estradiol equivalents determined in plasma from the jugular and portal veins and in lymph. The concentrations in plasma are ini¬ tially greater than those found in lymph. Therefore a por ion of estradiol in the lymphasome formulation was absorbed rapidly and entered in systemic circulation via the portal vein. This conclusion is supported from the pattern of estradiol and estrone in systemic blood (Figure 43) and the early appearance (peak) of metabolites in all monitored compartments (Figure 43, 4C and 4D). The appearance cf total radiolabeied equivalents in the lymph was initially less than -that observed in portal and systemic plasma but eventually exceed them. A major percentage of the estradiol admin¬ istered in a lymphasome formulation, co-absorbed with the li-pids and entered the systemic circulation via the thoracic lymph. The cumulative area under each curve in Figure 4 is . summarized in Table 2. In ail compartments the major fraction represents the glucuronides of estradiol and estrone. Both estrone and estradioi per se represents small fraction of the total equivalents. These pharmacckinetic parameters for estradiol administered orally in a lymphasome formulation can be compared to similar parameters derived from estradiol administered orally or intravenously in 20* ethanoi/saiine (Table 3). In brief, the yield of glucuronides from the iymphasαme-administered estradiol was less than that found for 20* ethanoi/saiine by either route and the yield of both estradioi and estrone was greater than that being derived from the orally administered estradiol in 20* ethanol/- saline. It will be appreciated that while the. fore¬ going disclosure relates to preferred embodiments of the invention effective in xenobiotic delivery composition, it is capable of numerous modifications or alterations which may be made by those skilled in the art without departing from the spirit and scope of the invention as set forth in the appended claims. TΛI1U. 1 1 Estim ed Composition of the l.yn.p. liis me Foπnul a iona of lϊHt rc liol % Composl l on % Dial ill >u ion* 1 Bile Fatty Moiio- 16:0 10:1 1U:2 10:3 Oil Formul tions Salts Ac 1 cia Gl yceri le Pa Imitate Olelc l.lnolo j IJιιO n Coconut Oil" 50 35 15 20/ 12 5/ 2 H/„ V, Corn Oil 40 AO 20 u/ u *'» 52/ y, 1 I Olive OIL A 5 3fl 18 1 10 W 7_ 10/ ιo O Peanut Oil 32 A 8 29 ιo/ a 5 4. W 50 "l Sesame Seed ca.25 ca.57 i.U-20 l0/ 6 '' 3 '.2 (1A-37) (76 -A 5) • Soybean Oil AO AO 20 10/,. W,„ !<>/ 1.0,. 1 I TABLE 2 . • Area Unde r the Curve; i for Radioactivity Dei rived from Estradiol- -17B Admin i is ered Ora ι « y in a I.yinp hnsoinc Formulation to Dogs Portnl Blood Total Eqi ill valentβ (Plasma) 0.096 0.199 0.'J39 0.532 0.675 0.966 E2 0.001 0.002 0.003 0.005 0.010 0.037 E 2 C 0.015 0.053 0.102 0.150 0.19A 0.292 0.00 A 0.007 0.009 0.012 0.0 J 6 0.022 TABLE 2 CONTINUED Cumulative cxt , |ifi/ml x minutes E 2 « 0.018 0.063 0.1A 0.228 0.283 0.395 ?* 15 I B l 0.001 0.001 0.003 0.006 0.007 0.0 ifi 0.00A 0.01A 0.032 0.061 0.087 0.1A2 TΛIU.E 3 Comparison of Area Under the Curve for Uadtoactiylfy Derived From Intravenous and Oral Administration o f l7fι-l.stradlol to Dogs Cummulative cxt PR/ml x I 0 minutes Ratio of Route & IV P0 P0 IV/PO 1V/P0 Formula ion EtOII-Saline l.ymphasome ElOH-Sallne Lymphasome EtOII-Sallne Systemic Blood Total Equivalents 1.A02 0.923 1.316 1.52 1.06 (Plasma) E 2 0.076 0.025 0..00 3.0A 10.85 : I E 2 C 0.A80 0.3AA 0.852 1.A0 0.56 :c-> 1 o El 0.0A2 0.026 0.010 1.62 A.20 ! | E j G 0.256 0.139 0.726 1.8A l'l 0.35 PI ' Portal Blood Total Equivalents 1.286 0.966 1.371 1.33 0.9 A (Plasma ) E 2 0.053 0.037 0.018 1.A3 2.9A E 2 G 0.AA9 0.292. N.I). 1.5A — *1 0.050 0.022 0.033 2.27 1.52 OMPI

Claims: tøhat is claimed as new and intended to be covered by Letters Patent is: " 1. A xenobiotic delivery composition comprising lipid micellular particles incorporating said xenobiotic the lipid micellular particles comprising a bile acid or the pharmaceutically acceptable salts thereof; a fatty acid; and a monoglyceride. 2. The delivery composition in accordance with claim 1 wherein said lipid micellular particles are from about 40A to about 100A in diameter. _ . The delivery composition in accordance with claim 2 wherein the bile acid is selected from the group cholic acid, deoxycholic acid, lithcc oiic acid, chenσdiαxy- cήolic acid, 3-hydroxy-7- etochoianic acid; and the pharma¬ ceutically acceρta.bie salts thereof. 4. The delivery composition in accordance with claim 3 wherein said pharmaceutically acceptable salts are the acid conjugates of said bile acids. 5. The delivery composition in accordance with ciai 4 wherein said acid conjugates are glycine or taurine. 6. The delivery composition in accordance with claim 2 wherein said monoglyceride is a mcnoester of giy- BAD ORIGINAL 1 cerine and a fatty acid of the formula -lCOOH; C n H n-3CCCH or n H2π-5 C00H wherein n is an integer of from 9-23- 7. The delivery composition in accordance with claim 6 wherein said fatty acid is selected from the group myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and iinoienic acid. 8. The delivery composition in accordance with claim 2 wherein said fatty acid is selected from zhe group myristic acid, palmitic acid, stearic acid, cieic acid, linoleic acid and Iinoienic acid. 9- A xenobiotic delivery composition comprising lipid micellular particles incorporating said xenobiotic the lipid micellular particles comprising a bile acid or the pharmaceutically acceptable salts thereof; a fatty acid; and a Iipase hydrolyzed triglyceride oil 10. A xenobiotic delivery composition in accord¬ ance with claim 9 wherein said lipid micellular parti-cies are from about 0A to about 100A in diameter. 11. The xenobiotic delivery composition in accord¬ ance with claim 10 wherein said acid conjugates are glycine or taurine . BAD ORIGINAL 12. A xenobiotic delivery composition in ac¬ cordance with claim 11 wherein said fatty acid is sele ' cted from the group myristic acid, palmitic acid, stearic acid, - oleic acid, linoleic acid and linoienic acid. 13- A method for delivering and releasing a xenobiotic to a mammalian host requiring said xenobiotic comprising, a xenobiotic delivery composition comprising li¬ pid micellular particles incorporating said xenobiotic, the lipid micellular particles comprising a bile acid or the pharmaceutically acceptable salts thereof; a fatty acid; and a monoglyceride. 14. The method in accordance with claim 13 wherein sa-id lipid micellular particles are from about 4θi to about 100A in diameter. 15. The method in accordance with claim 13 wherein the bile acid is selected from the group cholic acid, dε- oxychoiic acid, lithochoiic acid, chenodioxychoiic acid, 3- hydroxy-7- etochoianic acid; and the pharmaceutically accept¬ able salts thereof. I β . The method in accordance with claim 15 wherein said pharmaceutically acceptable salts are the acid conjugates of said bile acids. >?" t ~ - ~ *.- ~ ', ~ r-> ITS" cv. ~~ 17. The method in accordance with claim i β wherein said acid conjugates are glycine or taurine. " 18. " The method in accordance with claim 13 wherein said monoglyceride is a monoester of glycerine and a fatty acid of the formula C n K2 n÷ ιC00H; C n H2 n -l C0GH J c n K2 11 -3 OOH; or C n U2n-5C00H wherein n is an integer of from 9-23- 19- The method in accordance with claim 11 wherein said fatty acid is selected from the group myristic acid, palmitic acid, stearic acid, oieic acid, linoleic acid, and iinoienic acid. 20. The method in accordance with claim 13 wherein said fatty acid is selected from the group myristic acid, palmitic acid, stearic acid, oieic acid, linoleic acid and Iinoienic acid. 21. A method for delivering and releasing a xenobiotic to a mammalian host requiring said xenobiotic comprising lipid micellular particles incorporating said xenobiotic, the lipid micellular particles comprising a bile acid or the pharmaceutically acceptable salts thereof; a fatty acid: and a iipase hydrolyzed triglyceride oil. 22. The method in accordance with claim 21 wherein said lipid micellular particles are from about 1C0A in diameter. O 23- The method in accordance with claim 22 wherein -said acid conjugates are glycine or taurine. 24. The method in accordance with claim 22 wherein said fatty acid is selected from the group myristic acid, palmitic acid, stearic acid, oieic acid, linoleic acid and iinoienic acid.- 25. The method in accordance with claim 22 wherein said monoglyceride is a monoester of glycerine and a fatty acid of the formula C n H2n-*-lC00H; C n H π-3COOH; or C n H2n-5C00H wherein n is an integer of from 9-23- 26. The method in accordance with claim 25 wherein said fatty acid is selected from the group myristic acid, palmitic acid, stearic acid, oieic acid, linoieic acid, and linoi-enic acid. O-vϊPI ^ * ÷^ 4 **—* , ? ~ * ~ t ~~ * -

Inventors: YESAIR DAVID W, YESAIR, DAVID, W.
Applicants: LITTLE INC A, ARTHUR D. LITTLE, INC.
Application year: 1982
Main classification: B01J13
IPC codes: A61K9