EP0084052A1 - Systeme d'administration de medicaments mi-cellulaires - Google Patents

Systeme d'administration de medicaments mi-cellulaires

Info

Publication number
EP0084052A1
EP0084052A1 EP19820902559 EP82902559A EP0084052A1 EP 0084052 A1 EP0084052 A1 EP 0084052A1 EP 19820902559 EP19820902559 EP 19820902559 EP 82902559 A EP82902559 A EP 82902559A EP 0084052 A1 EP0084052 A1 EP 0084052A1
Authority
EP
European Patent Office
Prior art keywords
acid
accordance
xenobiotic
delivery composition
bile
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19820902559
Other languages
German (de)
English (en)
Inventor
David W. Yesair
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arthur D Little Inc
Original Assignee
Arthur D Little Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arthur D Little Inc filed Critical Arthur D Little Inc
Publication of EP0084052A1 publication Critical patent/EP0084052A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • This invention relates to the delivery and release of xenobiotics within a mammalian 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 hos t which predetermines and controls the pharmacodynamics of the xenobiotic as delivered and released.
  • xenobiotics include, but are not necessarily limited to. drugs, diagnostic agents, blood substitutes endogenous biological compounds, hormones, immunoiogical adjuvants and the like.
  • a certain degree of specificity must be attained, and specificity requires that the xenobiotic reach its target selectively and controllably.
  • the absence of specificity associated with the use of many xenobiotics can thus deprive them of an appreciable part, if not essentially all, of cheir potential effectiveness in attaining the results desired from their use.
  • a chemotherapeutic drug which cannot be retained by blood plasma for a time sufficient for an appreciable amount of the drug to reach the target tissue or an orally administered drug which is destined for the blood stream but which cannot pass through the gastrointestinal tract lacks the degree of specificity which could make it highly effective.
  • a xenobiotic may exhibit essentially none or only a limited degree of the pharmacodynamics desired to realize its full potential.
  • pharmacodynamics may be listed plasma kinetics, tissue distribution, degree of tcxicity, levels of therapeutic drugs i n vivo, solubility of xenobiotics normally incompatible with other pharmaceutical formulations, and metabolic activation of the xenobiotics.
  • implant devices located, normally through a surgical procedure, in or near the organ to which the drug is to be delivered.
  • 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 polyvinyl alcohol), water-swellable (e.g., hydrogels or gelatin), hydrolytic polymers (e.g., polyiactic acids, polyglycolic acids or poIy- ⁇ -amino acids), or nonhydrolytic polymers (e.g., organopolysiioxane rubber).
  • 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.
  • the drug implant method requires the attention of skilled surgeons and support staff in order to effectively and safely utilize the device.
  • primary consi deration for administration of xenobiotics has been directed to the more facile oral delivery techniques and carriers for accomplishing such techniques.
  • oils refers to the high molecular weight glycerol esters of fatty acids principally of vegetable origin.
  • the absorption of both regular and micronized griseofulvin are somewhat enhanced if co-admin istered with meals high in fat or triglyceride content or in an oil and water emulsion.
  • Testosterone undecanoate dissolved 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.
  • the pathway of absorption of orally administered ethynyl estradioI-3-cyclopentyl ether was influenced by the vehicle of administration.
  • Triglycerides are by far the most important lipids in the diet and the chemical composition of the natural triglycerides vary considerably in their fatty acid composition and in their positional conformation. For example, the content of palmitate, oleate, and linoleate varies among the common seed oils; corn (13, 29 and 54% , respectively), peanut (6, 61 and 22%), respectively), and palm (48, 38 and 9%, respectively).
  • the digestion of triglycerides requires the enzyme, pancreatic lipase, and bile salts. This enzyme demonstrated a preferential hydrolysis of the 1 and 3 positions of the triglyceride to give the final products a 2- monoglyceride and fatty acids. Enzymatic hydrolysis of these triglycerides is incomplete and slow.
  • mice conjugated bile salts in the intestine form complexes termed "micelles" with fatty acids and monoglycerides.
  • Micelles as used in the prior art and herein are defined as lipid particles of 40-100 ⁇ 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.
  • a micelle delivery system could provide a novel carrier capable of delivering xenobiotics to very specific regions of the body.
  • Another object is to provide xenobiotic delivery compositions of the character described which are compatible with a wide variety of xenobiotics including hydrophobic, hydrophilic or a combination of hydrophobic and hydrophilic compounds and which are nontoxic and biocompatibie with the host system.
  • a further object of this invention is to provide xenobiotic delivery compositions 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 pharmacodynamics of the xenobiotic delivered and released within the host system.
  • the pharmadocynamics thus beneficially altered and controlled are plasma kinetics, tissue distribution, toxicity, oral absorption, chemotherapeutic ability, metabolism and the like.
  • Yet another primary object of this invention is to provide a method for delivering and releasing a pharmaceutically effective amount of a xenobiotic within a mammalian host in a manner to exercise some predeterminabie control over the delivery site, thus enhancing the effectiveness of the xenobiotic.
  • a delivery vehicle incorporating a xenobiotic and being biocompatible with a mammalian host to deliver and release within the aqueous environment of the host thexenobiotic, 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 monoglycerides, thereby providing for the controlled release of the xenobiotic therefrom.
  • a method of forming a delivery composition for delivering to and releasing within the aqueous environment of a mammalian host a xenobiotic, the pharmacodynamics of which are predeterminably altered and controlled comprising the steps of forming lipid micelles of a composition comprising fatty acids and monoglycerides and incorporating the xenobiotic to be delivered within the lipid micelles.
  • a method of controllably delivering to and releasing a xenobiotic within the aqueous environment of 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 acceptable salts thereof, fatty acids and a monoglycerides.
  • a method of predetermining and controlling 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 thereof, fatty acids and monogiycerides, thereby controlling the pharmacodynamics of the xenobiotic.
  • the invention accordingly comprises the several steps and the relation of one or mere such steps with respect 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 detailed disclosure, and the scope of the invention will be indicated in the claims.
  • FIG. 1A Hydrolysis of U.S.P. corn oil using pancreatic lipase and various mole ratios of bile salts.
  • Figure 1D Distribution of estradiol in aqueous phase with respect to the hydrolysis of the lipid phase.
  • FIG 2A Hydrolysis mixture contained 14 C- oleic acid and its monoglyceride, 14 C-bile salt and 3 H- estradiol.
  • Figure 23 Mole percent composition of bile salts, fatty acid and monoglyceride.
  • 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 lymph asomes, which contained 0 to 2 mole ratios of phosphatidyl choline relative to monoglyceride and which were chroma tographed on Sepharose 4B gel columns.
  • Figure 33 The size distribution of lymphasomes described in A above.
  • Figure 3C The elution pattern of estradiol in phosphatidyl choline containing lymphasomes on Sepharose 4B gel chromatographic columns.
  • Figure 4A The time pattern of total estradiol derived radioactivity equivalents in systemic plasma, portal plasma and lymph of surgically prepared dogs that received ( 3 H or 14 C) estradiol in a lymphasome preparation.
  • Figure 43 The time pattern of identified estradiol equivalents, namely estradiol (E 2 ) and its glucuronide (E 2 G) and estrone (E 1 ) and its glucuronide (E 1 G) in dog systemic blood.
  • Figure 4C The time pattern cf identified estradiol, in dog portal blood.
  • Figure 4D The time pattern of identified estradiol, in dog lymph.
  • fatty acids is intended to mean the organic monobasic acids derived from linear or branched hydrocarbons of the formula C n H 2n + 2 where n is an integer 10 to 24 by the equivalent of oxidation of a methyl group to a carhoxylic acid including: saturated fatty acids of the formula C n H 2n-1 COOH such illustrated by myristic acid, palmitic acid, stearic acid, etc; monounsaturated fatty acids of the formula C n H 2n-1 COOH such illustrated by oleic acid, etc; diunsaturated fatty acids of the formula C n H 2n-3 , such illustrated by linolaic acid, etc; and triunsaturated fatty acids of the formula C n H 2n-5 COOH such illustrated by linolenic acid, etc.
  • monoglyceride as used herein, is meant the 2-monoesters formed from glycerine and the above defined fatty acids having the general formula (CH 2 ) 3 (-0H) 2 00CR where R is C 10 to C 24 alkyl including linear or branched and saturated or mono or polyunsaturated groups.
  • bile acids and the pharmaceutically acceptable salts thereof is intended to mean those naturally occurring bile acids, such illustrated by cholic acid, de oxycholic acid, lithocholic acid, chenodeoxycholic acid, 3- hydroxy-7ketocholanic acid, etc., their conjugates with the acids glycine and taurine, as well as the nontoxic cationic salts thereof.
  • Iipase as used herein is defined as any enzyme that changes fats into their component diglycerides, monoglycerides, fatty acids and glycerine. They are typically of natural origin, derived from the liver, pancrease and other digestive organs as well as from a wide variety of plants.
  • hydrolyzed triglyceride oil is intended to mean triglycerides, i.e., the above fatty acids forming esters with glycerine, enzymatically hydrolyzed to the above defined monoglycerides, 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 monogiycerides.
  • the lipid micelles of this invention are similar to the naturally occuring micelles but are composed of a synthetic mixture of certain bile acids or the pharmaceutically acceptable salts thereof, monoglycerides and fatty acids.
  • the bile acids preferred in the preparation of this xenobiotic delivery vehicle are those selected from the group cholic acid, chenodioxycholic acid, dioxycholic acid and lithocholic acid. Particularly preferred are the preferred bile acids conjugated with the acids, glycine or taurine.
  • the preferred monoglycerides are those esters substituted at the 2-position of the three carbon glycerol chain, the substitution being a saturated or unsaturated linear or branched fatty acid having from 10 to 13 carbon atoms in the hydrocarbon chain (including the carboxylate group).
  • Particularly preferred are glycerol laurate, glycerol myristate, glycerol palmitate, glycerol oleate, glycerol linoleate and glycerol linolenate.
  • 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, myristic, palmitic, oleic, linoleic and linolenic acids.
  • the delivery vehicle of this invention composed of the above-disclosed bile acids and the pharmaceutically acceptable salts thereof, monoglycerides and fatty acids in ratios of 10:1:1.1:1:10 and 1:10:1, most preferably 2:2:1.
  • the acid conjugates of the bile acids of this invention are also capable of forming pharmaceutically acceptable cation salts.
  • 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 triethylamire, diethylamine, tris (hydroxymethyl)aminomethane, ethanolamine, choline, caffeine, and the like.
  • room temperature refers to about 20°C, and all temperatures and temperature ranges refer to degrees centigrade. All percents refer to weight percents and the term equivalent mole amount refers to an amount stoichio metrically equivalent to the other reactant in the reaction referred to.
  • oils per se are first enzymatically hydrolyzed, the hydrolylic 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.
  • Estradiol-17 a water insoluble drug, is soluble in triglyceride oils but will partition into an aqueous phase containing bile salts ( Figu re IC). Since bile salts are absorbed in the region of the lower ileum, estradiol administered in oil has the potential for partitioning into a bile salt-rich aqueous phase and being absorbed along with bile salts.
  • Figure 1D The partitioning characteristics of estradiol during the process of hydrolyzing triglyceride-oils is shown in Figure 1D). The partioning into the oil-phase following 1 to 3 hours represents large lipid emulsions containing triglycerides, fatty acids, monoglycerides and bile salts.
  • estradiol solubility in hydrolyzed oil preparations was preferential to that in a bile-salt rich micelle. It was found that estradiol saturation occurred between 0.004 and 0.007 mole percent relative to monoglyceride or triglyceride.
  • Lymphasome 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.
  • estradiol In preparing synthetic lipid micelles composed of saturated fatty acids, a greater molar concentration of bile salts is required.
  • estradiol has the potential of partitioning from the lymphasome into the bilesalt enriched solution ( Figure 3A).
  • estradiol administered p.o. in 20% ethanol/saline to both dogs and monkeys was rapidly and quantitatively absorbed, extensively metabolized by the intestine and liver, and rapidly excreted.
  • a significant amount of estradiol equivalents entered a slow elimination pool which had a t 1/2 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 administered intravenous dose.
  • Estradiol administered orally in 20% ethanol/sal ⁇ ne yielded more glucuronides than found for estradiol administered in the same control formulation by the intravenous route.
  • Figure 4 shows the total radiolabeled estradiol equivalents determined in plasma from the jugular and portal veins and in lymph.
  • the concentrations in plasma are initially greater than those found in lymph. Therefore a portion 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 of total radiolabeied equivalents in the lymph was initially less than that observed in portal and systemic plasma but eventually exceed them.
  • estradiol administered in a lymphasome formulation A major percentage of the estradiol administered in a lymphasome formulation, co-absorbed with the lipids and entered the systemic circulation via the thoracic lymph.
  • the cumulative area under each curve in Figure 4 is summarized in Table 2.
  • the major fraction represents the glucuronides of estradiol and estrone.
  • Both estrone and estradiol per se represents small fraction of the total equivalents.
  • the yield of glucuronides from the lymphasome-administered estradiol was less than that found for 20% ethanol/saline by either route and the yield of both estradiol and estrone was greater than that being derived from the orally administered estradiol in 20% ethanol/- saline.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Composition d'administration xénobiotique comprenant des particules mi-cellulaires lipides incorporant la substance xénobiotique. Les particules mi-cellulaires lipides comprennent un acide billiaire ou les sels pharmaceutiquement acceptables de celui-ci, un acide gras et un monoglycéride. Des procédés d'administration de la composition xénobiotique sont également décrits dans la présente invention.
EP19820902559 1981-07-23 1982-07-12 Systeme d'administration de medicaments mi-cellulaires Withdrawn EP0084052A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28623981A 1981-07-23 1981-07-23
US286239 1988-12-19

Publications (1)

Publication Number Publication Date
EP0084052A1 true EP0084052A1 (fr) 1983-07-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP19820902559 Withdrawn EP0084052A1 (fr) 1981-07-23 1982-07-12 Systeme d'administration de medicaments mi-cellulaires

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EP (1) EP0084052A1 (fr)
WO (1) WO1983000294A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3421468A1 (de) * 1984-06-08 1985-12-19 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim Lipidnanopellets als traegersystem fuer arzneimittel zur peroralen anwendung
US4874795A (en) * 1985-04-02 1989-10-17 Yesair David W Composition for delivery of orally administered drugs and other substances
IE59067B1 (en) * 1985-04-02 1993-12-15 Yesair David W Composition for delivery of orally administered drugs and other substances
SE462894B (sv) * 1985-10-28 1990-09-17 Biogram Ab Mikrokapslar, foerfarande foer framstaellning daerav samt anvaendning
FR2633936B1 (fr) * 1988-07-05 1991-04-12 Sanofi Sa Procede d'extraction du cholesterol contenu dans une matiere grasse d'origine animale
FR2640137A1 (fr) * 1988-12-08 1990-06-15 Texinfine Sa Systemes transporteurs de principes actifs lipophiles et leur procede d'obtention
US5100662A (en) * 1989-08-23 1992-03-31 The Liposome Company, Inc. Steroidal liposomes exhibiting enhanced stability
US5221535A (en) * 1989-11-13 1993-06-22 Nova Pharmaceutical Corporation Sustained release formulations of insect repellent
IE904098A1 (en) * 1989-11-13 1991-05-22 Nova Pharm Corp Lipospheres for controlled delivery of substances
US5227165A (en) * 1989-11-13 1993-07-13 Nova Pharmaceutical Corporation Liposphere delivery systems for local anesthetics
US5188837A (en) * 1989-11-13 1993-02-23 Nova Pharmaceutical Corporation Lipsopheres for controlled delivery of substances
CA2033714A1 (fr) * 1990-01-25 1991-07-26 Alberto Ferro Preparations pharmaceutiques
US5891466A (en) * 1990-08-13 1999-04-06 Yesair; David W. Mixed Liped-Bicarbonate colloidal particles for delivering drugs or calories
ATE121618T1 (de) * 1990-08-13 1995-05-15 David W Yesair Gemischte lipid-bicarbonat-kolloidale partikel zur abgabe von arzneien und kalorien.
US5571517A (en) * 1990-08-13 1996-11-05 Yesair; David W. Mixed lipid-bicarbonate colloidal particles for delivering drugs or calories
US8003690B2 (en) 2002-12-13 2011-08-23 Jagotec Ag Topical nanoparticulate spironolactone formulation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4115313A (en) * 1974-10-08 1978-09-19 Irving Lyon Bile acid emulsions
US4217344A (en) * 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8300294A1 *

Also Published As

Publication number Publication date
WO1983000294A1 (fr) 1983-02-03

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