CA2188467A1 - Modified amino acids for drug delivery - Google Patents

Modified amino acids for drug delivery

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Publication number
CA2188467A1
CA2188467A1 CA002188467A CA2188467A CA2188467A1 CA 2188467 A1 CA2188467 A1 CA 2188467A1 CA 002188467 A CA002188467 A CA 002188467A CA 2188467 A CA2188467 A CA 2188467A CA 2188467 A1 CA2188467 A1 CA 2188467A1
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CA
Canada
Prior art keywords
alkyl
acid
alkenyl
amino acid
composition according
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.)
Abandoned
Application number
CA002188467A
Other languages
French (fr)
Inventor
Andrea Leone-Bay
Nai Fang Wang
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.)
Emisphere Technologies Inc
Original Assignee
Individual
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Filing date
Publication date
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Publication of CA2188467A1 publication Critical patent/CA2188467A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/55—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C07K5/06095—Arg-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Abstract

The present invention relates to an oral delivery system, and in particular to modified amino acids or peptides for use as a delivery system of sensitive agents such as bioactive peptides. The modified amino acids or peptides can form non-covalent mixtures or microspheres with active biological agents. These mixtures or microspheres are suitable for oral administration of biologically active agents to animals. Methods for the preparation of such amino acids and peptides are also disclosed.

Description

WO 95128838 1.,~ ! 12 2188~'7 .

MODIFIED AMINO ACIDS FOR DRUG DELIVERY
The present invention relates to con"~oaiLiolIs suitable for drug delivery, and in particular to culll,uoaiLiulls in which modified amino acids orpeptides are used as carriers for Liolo~ l'y active agents including, but not limited, to bioactive peptides and the like. The modified amino acids or peptides 5 can form non-covalent mixtures or ~ ua,ulle~ ~s with biùloui~ l'y-active agents snd are suitable fûr oral adlllill;..lldLiolI to animals. Methods for the ,ul~pdldLio and for the ad,.,i.,;~,L,dLiull of such Cc,lll,uoaiLiulls are also disclosed.
Bcl~,h~Jluu~d of the Invention Conventional means for delivering biolouiually-active agents, including, but not limited to, phallllaceutical and therapeutic agents to animals often are severely limited by chemical and physical barriers imposed by the body. Oral delivery of many L,ioloui~lly active agents would be the route of choice if not for the presence of chemical and physico-chemical barriers such as15 extreme and varying pH in the gastro-intestinal (Gl) tract, exposure to powerful digestive enzymes, and i~ uelll ' " y of gastro-intestinal membranes to the active i~ul~:uk,.~L. Among the numerous pl1alll~0l0~ l agents which are not suitable for oral a.ll l ,il ,;~L, a LiOIl are biol~l; 'ly 3ctive peptides such as calcitonin and insulin. Examples of other compounds which are affected by tne physico-20 chemical barriers are pol~/sac~lla~ides and mucopolysdc..l,a,i,les, including, butnot limited to, heparin, heparinoids, all~ibiuLi~;s and other organic substrates.
These agents are rapidly destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, or the like.

~ - 17 woss/28838 r~l~ ...
2~88~67 2 Prior methods for orally a~ ,.ill9 vulnerable PllallllacolfJ~
agents have relied on co-a.l,.,il~;.tlaLi~l- of adjuvants (e,g., ~o",i"ol~ and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to increase artificially the pe~ I ~ ' Iy of the intestinal walls;
6 and on co-a~"~ .ldliUII of ~ m.c,lic inhibitors (e.g., pallur~al;~ trypsin inhibitof, di;~.u,uluu~rlrluolfJpllos~ullalt~ (DFF) and trasylol) to avoid enzymatic de-làdalioll. Liposomes have also been described as drug delivery systems for insulin and heparin. See, for instance, U.S. Patent No. 4,a39,754; Patel et al.
11976) FER~ Le1tf~rs Vol. 62, page 60; and I la~llilllulu et al. (1979) C,~dou~i"~l.
10 ,la~, Vol. 26, page 337. The broader use of the arult~ llliuned methods, however, as drug delivery systems are precluded for reasons which include: (1 ) the use of toxic amounts of adjuvants or inhibitors; (2) the lack of suitable low MW cargoes; (3) the poor stability and inadequate shelf life of the systems; (4)difficulty in manufacturing; and (5) the failure of the systems to protect the 15 activei"g,~ "l,and(6)thefailureofthesystemstopromoteaL.~.IyLiui~ofthe active agent.
More recently, Illiu~ua~ s of artificial polymers, or pluLu;.~o;ls, of mixed amino acids have been dsscribed for delivery of pl1al ~ f~uticAIc For example, U.S. Patent No. 4,925,673 describes such ll,i.;l.,"~l)u,u~, as well as 20 methods for their ,o~t:pcllaliùn and use. The proteinoid ll~iu~u~,uhf~s of the '673 patent are useful for encapsulating a number of active agents.
There is a need in the art for a simple and inexpensive delivery system which is easily prepared and which can deliver a broad range of biologically-active agents.
SumnnA~Y of the Invention ~ -Co""uo~iLiùl-sfordeliveringb;olu~ y 3ctiveagentsillCuluOlaLil~J
modified amino acids as carriers are provided.
The f~ollluo~iLiol-s comprise;
(A) at least one biulo~ 'ly active agent, and (B) (a) at least one acylated amino acid;
(b) at least one peptide comprising at least one acylated amino acid; or wo 95/28838 ~ 1 8 8 ~ 2 (c) a C~ b;llaLiù~l of (a) and (b);
wherein said acylated amino acid is acylated by (i) a C3-Cto cycloalkyl acylating agent, said agent optionally being substituted with Cl-C7 alkyl, C2-C~ alkenylr Cl-C7 alkoxy, hydroxy, phenyl, phenoxy, or-C02R, wherein R is hydrogen, C1-C4 alkyl or C2-C4 alkenyl; or (ii~ a C.~-C~0 cycloalkyl sl Ihstitl ItPrl C~-C6 alkyl acylating agent .
In an alternative ~II-Lo~l;lll~lll, these C~ JOaiLiulls are used in oral dosage unit forms. The culll,uOaiLiuils or oral dosage unit forms can be orally adlllill~Lt~ d to animals.
Des~.liu~iuo of the Drawinns Figure 1 iâ a graphic illustration of the results of oral gavage testing inratsusingcalcitoninwithcy~,lol,t,~alluyl (L)-leucine,c~.lùh~uLalloyl~ leucine and 2-methylcy.,l~ ul Ioyl-(L)-leucine carriers.
Figure 2 is a graphic illustration of the results of oral gavage testing in rats using calcitonin with cyt;lùh~:Aallo~rl (L)-arginine, cy~ pt~ alluyl-(L)-arginine, and cyclohexanoyl-(L)-phenylglycine carriers.
Figure 3 is a graphic illustration of the results of oral gavage testing in rats using calcitonin with cyclohexanoyl-(L)-arginine, cyclohexanoyl-(L)-leucine, and cyul~ al loyl-(L)-tyrosine carriers.
Figure 4 is a graphic illustration of the results of oral gavage testing in rats using calcitonin with cycl~ al~uyl-(L)-leucinercycl~h~.~alluyl-(L)-glycine and cyulopruualloyl-(L)-leucinecarriers.
Figure 5 is a graphic illustration of the results of oral gavage testing in rats using calcitonin with cycloh~ ~.alloyl-(L)-leucine carrier.
Figures 6 and 7 are graphic illustrations of the results of oral gavage testing in rats using heparin with cyclûhexanoyl-(L)-leucine carrier.
Figure 8 is a graphic illustration of the results of oral gavage testing in rats using heparin with cyulol~ allùyl-(L)-argininecarrier.

Wo 95/28838 ~ ~ 8 8 ~ ~ 7 1 ~1/

Figure 9 and 10 are graphiG illustrations of the results of ~ntraduodenal injection testing in rats using heparin with c~lul~ all4yl-(L)-leucine carrier.
Figure 11 and 12 are graphic illustrations of the results of oral 5 gavage testing in rats using low molecular weight heparin with c~Lloh~,(a. ,o yl-(L)-leucine carrier.
Figure 13 is a graphic illustrafion of the results of oral aavarde testing in rats using disodium cromoglyeate with cy~,luhl,xa,,uyl-(L)-leueine earrier.
Figure 14 is a graphie illustration of the results of oral gavâge testing in rats using interferon a2b (rhlFN) with e~l,luh~,.dl~oyl (L)-phenylglycine and cy.,lolle~a"oyl-(L)-arginine carriers.
Figure 15 is a graphic illustration of the results of oral ad", I;~lld~iOI1 testing in monkeys using interferon a2b with cyclul,~,.a"ùyl-15 phenylene and c~,,lol,exa~1u yl-arginine carriers.
Figure 16 is a graphic illustration of the results of oral gavage and intraduodenal injection testing in rats using interferon a2b and u j~lOI1~dl ~u "I (L)-phenylglycine carrier.
Figure 17 is a graphic illustration of the results of oral gavage 20 testin3 in rats using interferon a2b and cyclol,~,~d,luyl-(L)-phenylglycinecarrier.
Detailed Des~ liu11 of the Invention ~ r Modified amino acids and peptides that include at least one modified amino acid may be used as carriers to deliver b;oloy;~ l'y acfive agents 25 such as peptides, mucopoly:,dc~.l,a,ides, carbohydrates, lipids, and pesticides.
These carriers particularly are useful in rdl,il;Ld~i .g the delivery of orally sensitive ~i~loy;~.&:. y active agents. For example, hormones such as calcitonin, insulin and polysdc-il1a~ide~ such as heparin, are not conside,t,d orally ad,.,i";~L~aL,le for various reasons. Insulin, for example, is sensitive to the denaturing conditions30 of the yd:,L~ L~:,Ii"al (Gl) tract. Alsû, heparin, by virtue of its charge and hydrophilic nature, is not readily absorbed from the gut. In contrast to the modified amino acids and peptides of the present invention, unmodified free -WO 95128838 2 1 8 8 ~ 6 7 12 aminoacidsprovideinadequate~..,L~,Liù,~againstd~l iaLiul-intheGltractfor iabile bioactive agents.
The Cu~,uO:,iLiOnS of the subject invention are useful for a i",i";~L~ g i. !~ ' 'ly active agents to any animals such as birds; mammals, 5 such as primates and particularly humans; and insects.
The present invention, in several ~",i.-' "~"L~, uses readily available and ill~A,J~ hl~, starting materials, and provides a cost-effective method for preparing and isolating modified amino acids and peptides. The method is simple to perform and is amenable to industrial scale-up for 10 cu"""e" idl production.
~ ;c'__' "y 3ctive agents suitable for use with carriers disclosed herein include, but are not iimited to, peptides, and particularly small peptidello,,,~ù~es, which by ll,c;,,,_.,lv,~ pass slowly or not at all through the gastro-intestinal mucosa and/or are cllcf:pptihle to chemlcal cleavage by aclds and 15 enzymes In the 9d:~1 UillLd:,Lil ,al tract; pol~,sacclla,ldes and particularly mixtures of mucopoly~dcclldli i~ " carbohydrates; lipids; or any CullliJ;.laLiOIl thereof.
rj~xamples include, but are not limited to, human growth hormone; bovine growth hormone; growth hormone releasing hormone; i"l~, r~, uii ,, interleukin-l; insulin;
hepârin~andparticularlylowmolecularweightheparin;calcltonln;er~Llllu~uoi~Lill;
20 atrial naturetic factor; antigens; ",ol10clol-al antibodies; so,,,dLuaLdLi,,; a~ ocoi Licotropin; gonadotropin releasing hormone; oxytocin; Vd~O, vancomycin; cromylyn sodlum; iG~rt:lliUAdlllill~ (DFO); or any colllbilldLio thereof .
Ad iiLiull~lly the carrlers of the present Invention can be used to 25 deliver other active agents such as pesticldes and the like.
An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino aclds. Tile preferredamlno aclds for use in the present invention are -amino acids, and most preferably are naturally occurring ~-amino acids. Poly amino acids are either 30 peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g., an ester, anhydride or an anhydride linkage. Special mention is made of non-naturally occurring poly amino acids and particularly non-naturally occurring hetero poly amlno acids, i.e. of mixed amino acids.

~o 95/28838 2 1 8 ~ 4 6 7 A ~
Peptides are two or rnore am~no acids joined by a peptide bond.
Peptides can vary in length from di-peptides with two amino acids to polypeptides with several hundred amino acids. See, Walker, Ch~rnbers ~intnnirzll Diction~rv~ Cambridge, England: Chambers Cambridge, 1989, page 5 215. Special mentton is made of non-naturally occurring peptides and particularly non-naturally occurring peptides of mixed amino acids. The peptidesmost useful in the practico of the present invenbon include di-peptides, tri-peptides, tetra-peptides, and penta-peptidos. The pr2ferred p2ptides are di-pepffdes, and tri-peptides. Peptides can be l~omo- or hetero- peptides and can 10 include natural amino acids, synthebc amino acids, or any cO~ laLiOll thereof.
Amino acids suitable fur use in the present invention are generally of the formula o H - N (R') - (R2- C) - OH
wherein: Rl is hydrogen, C,-C4 alkyl, or C2-C4 alkenyl;
RZ jS C1-Cz4 alkyl, C2-Cz4 alkenyl, C3-Clo cycloalkyl, C3-C~o c~. ' Jr " "~I, phenyl, naphthyl, (C1-C10 alkyl) phenyl, (C2-C~o alkenyl) phenyl, (C1-C,O alkyl) naphthyl, (C2-C,O alkenyl) naphthyl, phenyl (C,-Cl0 alkyl), phenyl (CrC,0 alkenyl), naphthyl (C,-C10 alkyl), or naphthyl (C2-C,0 alkenyl);
R2 being optionally substituted with C,-C4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy, -OH, -SH, -CozR3, C3-C~o cyclOâlkyl, C3-C,0 Gj~ '~ " Iyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any c~lllL;..c,Liol) thereof, aryl, (Cl-C,O alk)aryl, ar(Cl-C1O alkyl) or any co",L;"a~ion thereof;
R2 bcing optionally interrupted by oxygen, nitrogen, sulfur, or any co"ILi,~ .l, thereof; and R3 is hydrogen, C,-C4 alkyl, or Cz-C4 alkenyl.
The preferred naturally occurring amino acids for use in the present invention as amino acids or co"",o~ "l~ of a peptide are alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, W0 95/28838 2 1 $ ~ , "~ ~ 2 histidine,isoleucine,lcucine,lysinc".,~l,iu, ,e,ornithine".~ "r~ ,proline, serine, thrconine, tryptophan, tyrosine, valine, hydroxy proline, y-carboxyglutamate, phenylglycino, or O-pl~o~,ullos~,i,,e. The profe~red amino acids are arginino, leucine, Iysine, pht."ylal~.,;.,e, tyrosine, tryptophan, valine, 5 and phenylglycine.
The preferred non-naturally occurring amino acids for use in the present invention are ,~-alanine, a-amino butyric acid, y-amino butyric acid, y-(al ,opl~ yl) butyric acid, a-amino isobutyric acid, ~-amino caproic acid, 7-amino heptanoic acid, ,~-aspartic acid, alll;llOb~ uic acid, alllillopl,t"yl acctic 10 acid, alll;.lûph~ rl butyric acid, y-glutamic acid, cysteine (ACM), ~-lysine, ~-lysine (A-Fmoc)"".:ll,;ol,;"esulfone, norleucine,norvaline,ornithine,ril-ornithine, p-nitro-phenylalanine, hydroxy proline, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid and ll,;op,~ " ,e.
The amino acids or peptides are modified by acylating at least one 15 free amine group, with an acylating agent which reacts with at least one of the free amine groups present. Suitable, but non-limiting, examples of acylating ,agents useful for modifying amino acids or peptide derivatives useful in plal;LiC;II~ the present invention include acylating agents, and particularly acid chloride acylating agents, having the formula R8 _ C--X
25 wherein R8 is (i) C3-Clo cycloalkyl, optionally substituted with C,-C7 alkyl, C2-C, alkenyl, CI-C~ alkoxy, hydroxy, phenyl, phenoxy, or-CO2R9 wherein R9 is hydrogen, C1-C4 alkyl or C2-C4 alkenyl; or (ii) C3-C10 cycloalkyl substituted CI-C~ alkyl; and 30 X is a leaving group. Preferably, R8 ;5 cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
In a reactlon in which the substrate molecule becomes cleaved, part of it (the part not CûllIa;ll ,9 the carbon) is usually called the leavinggroup. See Advanced Oraanic ChemistrY. 2d edition, Jerry March, New York: McGraw-Hill .. . . .. .. . _ .. ... _ . . ... . . . . .. . _ , . .

1~
wo95128838 21884~7 r Book ~1977). Typical leaving ~roups include, but are not limited to, halogens such as chlorine, bromine and iodine.
Prefcrred acylating a~ents include, but are not limited to, acyl halidessuchas~t~lol~c~d~oylchloride~cyulù~uc~ld~loylchloride~c~lohc~L
5 chloridc and the like; and anhydrides, such as ct~ hc,~dlloic anhydride, cy~,lopc,,Ld,~oicanhydride,cy~;lol-c,uLd,~oicanhydride,cy~ c~,Ld,-oicanhydride, and the like. Most preferrod acylating agents are cyclollc~.allùyl chloride, cy.,lopdllL~I~oyl chloride, and c~uluhtlyldi-oyl chloride.
Preferred acylated amino acids of the present invention have the 1 0 formula O O
R4--C--N--(R6--C)--OH

wherein: R4 is li) C3-C1o cycloalkyl, optionally substituted with C1-C~ alkyl, C2-C, alkenyl, C1-C~ alkoxy, hydroxy, phenyl, phenoxy or -Co2R7, wherein R~ is hydrogen, Cl-C4 alkyl, or C2-C4 alkenyl; or (ii) C1-CO alkyl substituted with C3-C1o cycloalkyl;
R~ is hydrogen, C,-C4 alkyl, or C2-C4 alkenyl;
R6 is C1-C24 alkyl, C2-C2~ alkenyl, C3-C1o cycloalkyl, C3-C~o cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl~ phenyl, (C2-C10 slkenyl) phenyl, (C,-C10 alkyl) naphthyl, (C2-C10 alkenyl) naphthyl, phenyl (C,-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl) or naphthyl (C2-C10 alkenyl);
RG being optionally substituted with C1 -C4 alkyl, C2-C4 alkenyl, C,-C4 alkoxy, -OH, -SH, -Co2R7, C3-C10 cycloalkyl, C3-C,o cycloalkenyl, heterocycle having 3-10 ring atoms whercin the hetero atom is one or more of N, O, S or any Culllb.illdLiOll thereof, aryl, (Cl-C10 alk)aryl, ar(C1-C~O alkyl), or any 30 culll~;lldlion thereof;
R6 bein3 optionally interrupted by oxygen, nitrogen, sulfur, or any cu~llb;.ldlioll thereof; and R~ is hydrogen, Cl-C4 alkyl, or C2-C" alkenyl.

WO 9~/~8838 ~ 1 8 ~ 4 ~ 7 P~ 2 The modificd amino acids of the present invention may be prepared by reacting single amino acids, mixtures of two or more amino acids, amino acid osters, or amino acid amides, with an amine modifying agent which reacts with free amino moieties present in the amino acids to form amides. Amino acids and 5 amino acid esters are readily available from a number of c~.l....~.ci~,l sources such as Aldrich Chemical Co. (1~ ae, Wl, USA); Sigma Chemical Co, (St.
Louis, M0, USA); and Fluka Chemical Corp. (Ro.,hu,~hu,,,a, NY, USA).
The modified amino acids can be readily prepared by methods known to those skilled in the art. For example, the amino acids are dissolved 10 in an aqueous alkaline solution of a metal hydroxide, e.g., sodium or potassium h;d~uxicle and the acylating agent added. The reactlon time can range from about 1 hour and about 4 hours, preferably about 2-2.5 hours. The temperature of the mixture is ...~.:.-L~.:..ed at a temperature generally ranging between about 5C and about 70C, preferably between about 10C and about 50C. The amount of alkali employed per equivalent of NH2 groups in the arnino acids generally ranges between about 1.25 moles and about 3 moles, and is preferably between about 1.5 moles and about 2.25 moles per equivalent of NH2. The pH of the reaction solution generally ranges between about pH 8 and about pH 13, and is preferably between about pH 10 and about pH 12. The amount of amino modifying agent employed in relation to the quantity of amino acids is based on the moles of total free NH2 in the amino acids. In general, the amino modifying agent is employed in an amount ranging between about 0.5 and about 2.5 mole equivalents, preferably between about 0.75 and about 1.25 equivalents, per molar equivalent of total NH2 groups in the amino acids.
The modified amino acid formation reaction is quenched by adjustin~q the pH of the mixture with a suitable acid, e.g., col~bb..~.dl~d h~.l.ùcl,'~ ic acid, until the pH reaches between about 2 and about 3. The mixture separatcs on standing at room temperature to form a Ll a, la~ l . L upper layer and a white or off-white ,olbbi,uiLdL~. The upper layer is discarded and 30 modified amino acids are collected by ffltration or decc,,,LdLiul~. The crude modified amino acids are then mixed with water. Insoluble materials are removed by filtration and the filtrate is dried in vacuo. The yield of modified amino acids generally ranges between about 30 and about 60%, and usually wo ss/2s838 2 ~ t2 ~bout 45%. The present invention also uu~ lll,ulaL~s amino acids which have bcen modified by multiple acylation, e.g., diacylation or triacylation.
If desired, esters or amides of amino acids may be used to prepare the modified amino acids of the invention. The amino acid esters or amides, 5 dissolved in a suitable organic solvent such as dimeth~ylru~"a~h~e or pyridine, are reacted with the amino modifying agcnt at a tomperaturo ranging between sbout 5C and about 70C, preferably about 25C, for a period ranging between about 7 and about 24 hours. The amount of amino modifying agents used relative to the amino acid esters are the same as described above for amino1 0 acids.
Thereafter, the reaction solvent is removed under negative pressure -dnd optionally the ester or amide fu-,-;~io"..';Ly can be removed by hydrolyzing the modified amino acid ester with a suitable alkaline solution, e.g., 1 N sodium hydroxide, at a temperature ranging between about 50C and about 80C, pl~r~:lably about 70C, for a period of time sufficient to hydrolyze off the ester group and form the modified amino acid having a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, e.g., with an aqueous 25% hyl,u.,l,l~ric acid solution, to a pH ranging between about 2 and about 2.5. The modified amino acid pll:ui~JiLaL~ out of solution and is recovered by co" ~6~ onal means such as fi!tration or d~ca,-LdLio".
The modified amino acids may be purified by acid pl~ci~JiLdLiùl~, recr~,: " , or by rlaulionaLiull on solid column supports. rrauLiol~aLiol~ may be p~,ru~,ed on a suitable solid column supports such as silica gel, alumina, using solvent mixtures such as acetic acid/butanol/water as the mobile phase;
reversc phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange ul~lullldLuyla,ulu~ using water as the mobilephase. The modified amino acids may also be purified by extraction with a lower alcohol such as methanol, butanol, or i~uplupallùl to remove impurities such as inorganic salts.
The modified amino acids of the present invention generally are soluble in alkaline aqueous solution (pH> 9.0); partially soluble in ethanol, n-butanol and 1:1 (v/vl toluene/ethanol solution and insoluble in neutral water.

WO 95r28838 2 ~ 8 8 ~ 6 ~
The alkali metal salts, e.g., the sodium salt of the deritivatized amino acids are generally soluble in water at about a pH of 6-8.
Modified peptides may include one or more acylated amino acid.
Although linear modified peptides will generally include only one ac~rlated amino 5 acid, other peptide configurations such as, but not limited to, branched peptides can include more than one acylated amino acid. Peptides can be polymerized with the acylated amino acid(s) or can be acylated after poly",~ c,lion. Specialmention is made of compounds having the formula:
o CrJ~(A) wherein A is Try, Leu, Arg, Trp, or Cit; and optionally wherein if A is Try, Arg, Trp or Cit; A is acylated at 2 or nore functional groups.
Preferred compounds are those wherein A is Try: A is Tyr and is acylated at 2 functional groups; A is Leu; A is Arg; A is Arg and is acylated at20 2 funGtional groups; A is Trp; A is Trp and is acylated at 2 functional groups; A
is Cit; and A is Cit and is acylated at 2 functional groups.
Special mention is also made of compounds having the formula:
o ~(A)(B) V
wherein A is Arg or Leu and B is Arg or Leu A

Wo 9~128838 2 1 8 8 i 6 7 -- ~

wherein A is Arg or Leu; and wherein if A is Arg, A is optionally acyl ted at 2 or more functional groups;
~A

where A is Leu or phenylglycine;
O

wherein A is phenylglycine; and o ~(A) wherein A is pl,~"~ lycine.

If the amino acid is multifunctional, i.e- has more than one -OH, -NH2 or -SH group, then it may optionally be acylated at one or more functional groups to form, for example, an ester, amide, or thioester linkage.

WO 95128838 ~ 7 . ~ I/L~. 12 In one t:."Lo.~i..,ts..l, the modified amino acids or poptides may be used directly as a drug delivery carrier by simply mixing one or more modified amino acids or peptides with the active ingredient prior to ad...i..;~l,dl;~".. In an alternatiYe ~ L-d ..~ ..l, the modified amino acids may be used to form 5 ...;.,.u~,uI~e-~,co.,l . .gtheactiveagent. Themodifiedaminoacidsorpeptides of the invention are particularly useful for the oral a.l.--;-.;~l,aliùl~ of certain '; ~!c`,, "y-active agents, e,g., small peptide hormones, which, by Ll .a-..:.~lve~, do not pass or only pass slowly through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the 9a~LIuilll~ al 1 0 tract.
If the modified amino acids or peptides are to be converted into . . .;~;. u~,uI~e, ~:s such as proteinoid Il l;~- u .,ul~ ., the mixture is optionally heated to a temperature ranging between about 20 and about 50C, preferably about 40C, until the modified amino acid(s) dissolve. The final solution contains between from about 1 mg and to about 2000 mg of modified amino acids or peptides per mL of solution, p., rt . dLIy between about 1 and about 500 mg per ,mL. The concentration of active agent in the final solution varies and is dependent on the required dosage for treatment. When necessary, the exact col~ce. "~ aLio.~ can be d~ .ed by, for example, reverse phase HPLC analysis.
When the modified amino acids or peptides are used to prepare u~ e~ l:s, another useful procedure is as follows: Modified amino acids or peptides are dissolved in deionized water at a col~cellLlaLi~l~ ranging between about 75 and about 200 mg/ml, preferably about 100 mg/ml at a temperature between about 25C and about 60C, preferably about 40C. Particulate matter remaining in the solution may be removed by conventional means such as filtration.
Thereafter, the modified amino acid or peptide solution, I,,..;.,Lai,~ed at a temperature of about 40C, is mixed 1:1 (V/V) with an aqueous acid solution (also at about 40C) having an acid cu,-ce"l-aLiol~ ranging between 30 about 0.05 N and about 2 N, preferably about 1.7 N. The resulting mixture is further incubated at 40C for a period of time effective for .,.ic,u,~ e-~formation, as observed by light n,i...u~co,uy. In practicing this invention, the W0 9512W38 2 ~ ~ 8 4 6 7 P~ u ~! ~ 7 preferred order of addition is to add the modified amino acid or peptide solubion to the aqueous acid solution.
Suitable acids for ~ ;lui~,ull~lu formation includo any acid which does not (a) adversely effect the modified amino acids, or peptides e.g., initiate or propagate chemical decc.,,,,LiusiLiùn, (b) interfere with ~ u:~ullt~ ru~ dLiù~;
(c) interfere with l, ,i.,. u:.,ul ,~ i, ,cu, ,uord Lio~ of the cargo;
and (d) adversely intoract with the cargo.
Preferred acids for use in this invention inc~ude acetic acid, citric acid, hy i, u~ ic acid, pl)G:~,uhoiic acid, malic acid and maleic acid.
In practicing the invention, a ",iu,u~ 6,u stabilizing additive may be illCci,,uo~dL~d into the aqueous acid solution or into the modified amino acid 15 orproteinsolutionpriortothe.,,i..,u~uh6,~formationprocess. Withsomedrugs the presence of such additives promotes the stability and/or ~ l ' "Ly of the .,u:.,uhe,es in solubon.
The stabilizing additives may be employed at a Cul-C~ lali ranging between about 0.1 and 5 % (w/v), preferably about 0.5 % Iw/v).
20 Suitable, but non-limiting, examples of ",i..,u~ er~ stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, and polylysine. The preferred stabilizing additives are gum acacia, gelatin and methyl cellulose.
Under the above co" ~ ns, the modified amino acid molecules or peptides form hollow or solid matrix type ~ u:"~116~ wherein the cargo is 25 distributed in a carrier matrix or capsule type " ,iu. u~he~ es encapsulating liquid or solid cargo. If the modified amino acid or peptide ll~ u~ r~s are formed in the presence of a soluble material, e.g., a pl,d.~..ac~Liticai agent in the afo,e,,,~:,,liuned aqueous acid solution, this material will be encapsulated within the microspheres. In this way, one can encapsulate ,ul)dl~ cclo~ic,illy active 30 materials such as peptides, proteins, and poly~dccl~d~ides as well as chargedorganic molecules, e.g., a,,~i,,,iu,ubidl agents, which normally have poor bioavailability by the oral route. The amount of pharmaceutical agent which may be i,,~ù,uord~d by the ,.,ic,u~ul~el~ is depe,ld~"~ on a number of factors ....... _ _ _ . _ _ . . ... .... _ . .

WO g5128838 2 1 8 8 ~ ~ 7 which includo the conc~l,LldLiul~ of agent in the solution, as well as the affinity of the cargo for the carrier. The modified amino acid or peptide Illi~lu~pl-t~l~s of the invention do not alter the physiolûgical and biological ,ul Upt~l Lids of the active agent. Ful Ll le ~ , the erl~rsl ll-tion process does not 5 alter the ph~ ou; ~I pluuel Lil: . of the active agent. Any pll~..l..Ac~
agent can be il~C~I,uulclLl:d within the amino acid Illil lU:"UIlGlUs. The system is particularly advantageous fûr delivering chemical or biological agents which otherwise would be destroyed or rûndered less effective by-co,l.liLiul,s encountered within the body of the animal to which it is a.l",i";~,tt,td, before10 the ~ u~ e~u reaches its target zone (i.e., the area in which the cûntents ofthe " ,i,;, u~pl ,e~: are to be released) and ~h~ olo~ l agents which are poorlyabsorbed in the gastro-intestinal tract. The target zones can vary Jep~l~di.
upon the drug employed.
The particle size of the Illi~lu~ull~l~ plays an impûrtant role in 15 dt~ -llli.l 19 release ûf the active agent in the targeted area of the gastro-intestinal tract. The preferred IlliClU;~JllGlt:s have diameters between about <0.1 microns and about 10 microns, preferably between about 0.5 microns and about 5 microns. The ll,icru~ul~ are sufficiently small to release effectively the active agent at the targeted area within the gastro-intestinal tract such as, 20 for example, between the stomach and the jejunum. Small Illi. ,o~ e,~s can also be a.l,~,i.,isL~:,ed p,l,~"~l:r~ by being suspended in an CpplUUIidl~ carrier fluid ~e g., isotonic saline) and injected directly into the circulatory system,intramuscularly or subcutaneously. The mode of a-l",i"i .LIcLiul~ selected will vary, of course, depending upon the req~ lellL of the active agent being a.l",i";~Ll:,~d. Large amino acid nli. ,u:.pl~er~s ~>50 microns) tend to be lesseffective as oral delivery systems.
The size of the l "i~, u~ul~e, ~s formed by cu" kl. Li"g modified amino acids or peptides with water or an aqueous solution co" ~.,;., ,9 active agents can be controlled by manipulating a variety of physical or chemical pal~ Lt:l~, such- 30 as the pH, osmolarity or ionic strength of the encapsulating solution, size of the ions in solution and by the choice of acid used in the encapsulating process.
Typically, the pl~a,,,,acoloui~al c~""u~iLiùns of the present invention are prepared by mixing an aqueous solution of the carrier with an , W095128838 ~1 88~67 ~_I/L - 1~

aqueous solution of the active ingrediont, just prior to ad~ allaLiol~.
Alternatively, the carrier and L,ioluyi~ 'y active ingredient can be admixed during the manufacturing process. The solutions may optionally contain additives such as pl~o:~,ullald buffer salts, citric acid, acetic acid, gelatin and gum acacia.In practicing the invention, stabilizing additives may be il)c~l ,uo, a Idd into the carrier solution. With some drugs, the presence of such additives promotes thc stability and d;~ "ly of the a~qent in solution.
The stabilizing additives may be employed at a CullC~Illdli ranging between about 0.1 and 5 % IW/V), preferably about 0.5 % (W/V).
Suitable, but non-limiting, oxamples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, and polylysine. The preferred ' " ,9 additives are gum acacia, gelatin and methyl cellulose.
The amount of active agent in the c~""uo:,iliùn typically is a pl,a", ~ ny ~ ly or ' !~,, "y effective amount. However, the amount can be less than a ~llalll~ ,u; lly or biOluyi~,ally effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, ~ecause the dosage unit form may contain a multiplicity of carrier/b;ùlo~ui, "y active agent c~."p~iliu,~s or may contain a divided phalll~-~c~,l.,u;~ .l'y or l~iùl~ effective amount. The total effective amounts will be ad",i";~l~,td by cumulative units cu"t~;., ,g, in total, pllal ll_rOIOu;~ y or biolouiu~l'y active amounts of ~,ùlo~ lly ~ctive agent.
The total amount of biùluyiual;~ ~ctive agent to be used can be dt~ l ,ed by those skilled in the art. However, it has surprisingly been found that with certain L,ioloyi..dlly-active agents, such as calcitonin, the use of the 25 presently disclosed carriers provides extremely efficient delivery. Therefore, lower amounts of biùlo~, "y-active agent than those used in prior dosage unit forms or delivery systems can be ad",i,~ ,dd to the subject, while still achieving the same blood levels and therapeutic effects.
The amount of carrier in the present co"l,uo.iliol~ is a delivery 30 effectivc amount and can be dtslt~ ed for any particular carrier or bi~lu~ "y-active agent by methods known to those skilled in the art.
Dosage unit forms can also include any of ~1i,Jidll~, diluents;
di;.illL~uldlll:" lubricants; pla:.liui~ ., colorants; and dosing vehicles, including, , ,, . , . ,,,,,, . ,, , , . ,,, ,, .. , . ,, . _ ,,, ,,, . _ _ _ W095JU838 218~ P~ 12 but not limited to water, 1 ,2-propane diol, ethanol, olive oil, or any c~,. ,u;.~aLion thereof.
Ad~ ,LIaLi~l~ of the present c~lllpOaiLiOIls or dosage unit forms plurlslably iS oral or by intraduodenal injection.

FXAMPLF~;
The invention will now be illustrated in the following non-limiting examples which are illustrative of the invention but are not intended to limit the scope of the invention.

PREPARATION OF N-CYCLOHFXAN0YL-(L)-TYROSINE.
(L)-Tyrosine (61.6 9., 0.34 mole) was dissolved in 190 mL of 2N sodium hydroxide. Cyl,lol~ al,oyl chloride (49.32 mL, 0.34 mole) was added dropwise to the mixture. Additional aqueous 2N sodium hydroxide was added and the 15 reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was then acidified to pH 9.5 with aqueous (4:1) hydlv~lllu~ic acid. A
c;~-iLdLe formed which was separated by vacuum filtration. The solids were dissolved in 2N sodium hydroxide and dried by Iyo~ul " ~n to furnish 33.59 of N,O-dicyclol~ d"uyl (L)-tyrosine. The product was purified by column 20 ClllUllldLUUldpll'~ on silica gel using butanol/acetic acid/water as the eluent system. The pure product was a white solid.
1. Mass Spectrum: M~ 23 m/e 314.
2. 'H NMR (300MHz,DMSO-d6): d =6.8 (d, 2H); 6.4 (d,2H); 4.4 (m, 1H~; 2.5 (ddd,2H); 2.0 (m,2H); 1.6 (m,10H); 1.2(m, 10H).
3. IR (KBr) cm-1: 3350, 2900, 2850, 1600, 1520, 1450, 1400, 1 300.
EXAMPI F 2 _ -PREPARATION OF N-CYCLOHFXANOYL-(L)-ARGININE.
(L)-Arginine (103.2 9., 0.6 mole) was dissolved in 600 mL of 2N sodium 30 hydroxide. Cyclohexanoyl chloride (87 mL, 0.6 mole) was added dropwise to the mixture. The reaction mixture was ", ,Ldi"ed at 50C for 2 hours. The mixture was then cooled to room temperature and acidified to pH 2.3 with aqueous (4:1) hy~ l,loric acid. The precipitate which formed was separated , ~ 12 wo 95/28838 ~3 8 ~ ~ ~ 7 by d~c..,.ldliul1. The solids wcre dissolvcd in 2N sodium hydtoxide and dried byIyopl I to furnish 64.1 g of crude N-c;~lul-~al,uyl-(L)-srginine. The product was purified by column ch,ur"aluu,a,ul,y on silica gel/using butanol/acetic acid/water as the eluent system. The products isolated were N-5 .y~lul~e, tl~uyl-~L~-arginineand N~a)-N~y~-.li.,y ,lûllr,~a,,uyl-~L~-arginine.N-cvclol~ uvl-~
1. Mass Spectrum: M + 1 m/c 395.
2. H NMR ~300MHz, DMSO-d6): ppm ~ = 8.75~br, 1 H~; 7.6 ~br, 5H~;
4.0 (m, 1H); 3.05 (m, 2H~; 2.15 lm, 1H~; 1.1-1.5 (br.m, 14H).
10 N~a~.N~v)-dic~/cJol~ ,o~rl-(L~-ar~inine:
1. Mass Spectrum: M + 1 m/e 285.
2. H NMR: ~300MHz, DMSO-d6): dz2.0 ~m, 3H); 1.8-1.4 ~br. m, 17H); 1.3-1.0 ~br. m, 20H~
15 EXAMPI F 3 ~
PREPARATION OF N-CYCLOHFXANOYL-(LI-CITRUI I INE.
L-Citrulline (35.2 g., 0.2 mole) was dissolved in 200 mL of 2N sodium hydroxide. Cycl~ alluyl chloride ~29 mL, 0.2 moie) was added dropwise to the mixture. The reaction mixture was nl..:.llail~e l at about 25C for 1 hour.
20 The mixture was then acidified to pH 2.6 with aqueous ~4:1 ) hydrochloric acid.
The pl~ui,uilc~l~ which formed was separated by decal,l~liol~. The solids were dissolved in 2N sodium hydroxide to pH 6.5 and dried by l~o,ul, n to furnish 44.2 g of N-cyclohexanoyl-~L)-citrulline. The product was a white solid.
1. Mass Spectrum: M + 23 m/e 308.
2. 1H NMR ~300MHz,DMSO-d6): d=4.1 ~dd, 1H); 2.9 It, 2H); 2.1 (m,2H~; 1.6-1.2 (br.m, 14H).
3. IR (KBr) cm-1: 3400, 3300, 2950, 2850, 1700, 1650, 1600, 1450, 1400 cm-1.
FXAMPLE 4 - = - ~
PFFPARATIQN OF N-CYCLOPENTAN~YL-(L)-ARGININF --(L~-Arginine (32.8 ~., 0.19 moles~ was dissolved in 188 mL of 2N sodium hydroxide. Cyclup~,lLcllloyl chloride (22.9 mL, 0.19 moles~ were added dropwise to the mixture. The reaction mixture was ~a;~L ."ed at about 25C
. _ _ _ . _ .. , .. , .: . ... _ .. :: .. , . .. _ _ _ .. ....

WO 9sl28838 for 2 hours. The mixture was then aeidified to pH 1.5 with aqueous (4:1) hy.l,u~.lllulic aeid. The p-~c;~ dL-: whieh formed was separated by decullLdLiull.
`The solids were dissolved in 2N sodium hydroxide to pH 7.5 and dried by Iyup~ " ~ to furnish 67.4 9 of N-eyelc.~e:"L~-oyl-(L)-ar9inine. The produet 5 was a white solid. Mass Speetrum: M + 1 m/e 271.
FXAMPI F 5 -- - ~
PREPARATION OF N-CYCLOHFXANOYL-(t)-ARGlNlN_.
(t)-Arginine (14.2 9., 0.1 mole) was di$solved in 100 mL of 2N sodium 10 hydroxide. Cy~;lol,t~ uyl ehloride ~13 mL, 0.098 mole) was added dropwise to the mixture. The reaetion mixture was .".,:.,t..:.,ed at 25C for 2 hours. The mixture was then eooled to room temperature and aeidified to pH 6.6 with aqueous (4:1) I,y~,uul,lu,iu aeid. The white pl~ui~JiLdL~ whieh formed was separated by dec.lllLdLio,~. The solids were dissolved in a minimum of 2N
15 sodium hydroxide. The produet, a white solid, (11.6 9, 49%) was isolated by lowering the pH of the purified by ~. l;r;~nL;o~ with aqueous (4:1) h~.llul,lllulic 7acid to a pH of about 7-9 1. Mass Speetrum: M+ 1 m/e 2423 2. 'H NMR (300MHz, D20): ppm ~ - 4.9 (s,1H); 2.2 (m, 1H);
1.7-1.4 (m, 5H); 1.3-1.0 (m, 5H); 0.8 (s, 9H).
3. IR (KBr) em-1: 3350, 2950, 2850, 1550, 1500, 1400 em-1 Following the proeedure of Example 1 the following amino aeids 25 and peptides have been s~"Ll,e~
eyelohexanoyl-Ala, m-(eyclohexanolyamino)benzoic aeid, p-(eyelohexanoylamino)benzoic acid, 4-(ey.,lùllexdl~oyl-amino)butyric acid, 6-(cyclohexanoylamino)hexanoic acid, eyelohexanoyla"Ll"d"ilic aeid, eyelohexanoyl-Arg-Leu, eyelohexanoyl-Asp, isatoieanhydride-Asp, 30 eyelohexanoyl-Glu, eyulull~dl,oyl-Gly, cyuluhe,~dl,ùyl-Gly-Arg, cyulo~ d"uyl-lle~
cyclohexanoyl-Leu, eyelopentanoyl-Leu, eyelopropanoyl-Leu, 3-methycyclohexanoyl-Leu,2-methyuy~.lol,exd,~uyl-Leu~4-methyc~clollt:~al~oyl-Leu, cyclohexanoyl~(D)-Leu, cyclohexanoyl-(t)-Leu, eyelohexanoyl-Leu-Arg, , . .. . _ . . .

2188~ 20 cyclohexanoyl-Leu-Leul cyclvl ~ al luyl (D)-Leu-(L)-Leur c~ lol ~e~al luyl-Lcu-L
Val~cy~.lvh~alll:)yl-Lysrcy~lulll:~al~u~l Orn~c~ lullt~clllvyl-ph Phg, cvclohexvlu~allQvl-phn~ cy~.lvl~ llu~l Pi~, cyclopel~Lalluyl-phg~
C'y~,lOplupàlluyl Phg, 4-methycyclolle~anoyl-Phg, cyclohexanoyl-(D)-Phg, b cyc~lol~exa"oyl-Tio~ cyclol~,:Ac",oyl-Trp, cy~.lol~ al,oyl-Tyr-Leu, cyclo~ a Val, cy~,lO,v~ allv~rl Val, cyclohe,~c",uyl-Val-Val, cy~oh~:,vlalloyl-Leu~ and cyclohexy~,u, vpa~ luyl-Leu.
EXAMPI F 6 . ~ =
10 PREPARATION OF CAl (~ITONIN POSING SOLUTIONS:
In a test tube 400 mg of cyc.lul,~xa,,vyl-(L~-leucine was added to 2.9 ml of 15% ethanol. The solution was stirred and NaOH (1.0 N) was added to raise the pH to 7.2. Water was added to bring the total volume to 4.0 mL.
The sample had a carrier cvl~cellllalivl~ of 200 mg/mL. Calcitonin (10,ug) was 15 added to the solution. The total calcitonin COI~C~ laliO~ was 2.5 ,uglmL.
Following a similar procedure a second solution having 400 mg of ~ .lvll~Jlallvyl-(L)-leucine as the carrier and a third solution having 2-mcthylcyclol~exal ~u~ l (L)-leucine as the carrier were prepared. Each solution had a calcitonin conc~,,l,alivl~ of 2.5,~g/mL.

CALCITONIN In Vivo FXPERIMENTS IN RATS
For each sample a group of fasted rats were al ,e~LI ~ d. The rats were a.l",;.,i~ d, by oral gavage or by intraduodenal injection, one of the calcitonin/carrier dosages prepared in Example 6. The calcitonin conce,,l, alion25 in each sample was 2.5 ,ug/ml. Each rat was ~dlllill;~Lt:l~dd a dosage of four (4) mL/kg each. Blood samples were collected serially from the tail artery. Serum calcium was determined by testing with a DemandTM Calcium Kit (available from Sigma Chemical Company, St. Louis, Missouri, USA). The results of the test are illustrated in Figure 1.
EXAMPLF 8 - ~
Three samples having 400 mg/kg of cycloh~ical~vyl-(L)-arginincand 10,ug/kg of calcitonin, 400 mg/kg of .~ o~oe~lLalluyl-(L)-ar9inineand 10,Lrg/kg WO95l~8838 2 1 8 ~ ~ 7 ~2 of calcitonin, 400 mg/kg of cy~l~h~ uyl-(L)-phenylglycino and 10 ,~rg/kg of calcitonin, respectivcly were prepared. The samplos were given to fasted rats as described in Example 7. The results of the test are illustrated in Figure 2.
5 EXAMpLF g A sample having a mixture of 266 mg/kg of ~ lul,~ u;l-(L)-arginine 266 mg/kg of cyr,)ol1exr.l,uyl-(L)-leucine 266 mg/kg of cyclohexan-oyl-(L)-tyrosine and 10 ,ug/kg of calcitonin, was prepared. The sample was given to fasted rats as described in Example 7. The results of the test are illustrated in Figurc 3.
EXAMP~ F lQ
A series of samples having 400 mg/kg of cy~ l,e~ u~l-(L)-leucine and 3 ,~lg/kg of calcitonin, 400 mg/kg of .,ycluht,,~.,uyl-(L)-glycine and 3 ,ug/kg of calcitonin, 400 mg/kg of cycl~p, opanuyl-(L)-leucine and 3 IJg/kg of calcitonin, respectively were prepared. The samples were given to fasted rats as described in Example 7. The results of the test are illustrated in Figure 4.

Two samples were prepared, having 400 mg/kg of cycluht~ .,ùyl-(L)-leucineand10,ug/kgofcalcitonin,andc~yc.loh~a,loyl-~L)-leucineand3,ug/kg of calcitonin, respcctively. The samples were given to fasted rats as described in Example 7. The results of the test are illustrated in Figure 5.

P~FPARATION OF HFPARIN DOSING SOLUTIONS: =
Following the general procedure published by Santiago, N. in Proc.
Int. Symp. Control Rel, 8ioact. Mat., Vol. 19. pages 514-515, (1992) the heparin samples were prepared. In a test tube 900 mg of 30 cycloh~a,~oyl-(L)-leucine was added to 4.5. mL of water. Heparin (74.7 mg) was dissolved in 4.5 mL of a solution of 1.7 N citric acid and 0.5% gum arabic.
The solutions were warmed to about 40C and mixed. The sample had a carrier concentration of 100 mg/mL. The heparin concentration was 8.3 mg/mL.

9! . 1 ?
WO 9~/28838 2~8g~6i~ 2Z .
Following a similar procedure a second sample having 900 mg of cyclol1exa"uyl-(L)-leucine and heparin (150 mg) was prepared. The heparin c;once,,L,~Liul~ was 16.7 mg/mL.

HEPARIN In Vivo_XPERlMENT5 IN RATS
For each sample a group of fasted rats were c" le~Ll leLi~ed. The rats were ad"~i";~Le~ ed, by oral gavage, one of the heparin/carrier dosages preparedin Example 11. The heparin COI1Céllllaliull in the samples were 8.3 and 16.7 10 mglml respectively. Each rat was ~ ,.ed a dosage of about three (3) mL/kg each. Blood samples were collccted serially from the tail artery. Heparin activity was delelll,i"ed by utilizing the activated partial II~ bù~Jla >lill time (APTT) according to the method of Henry, J.B., Clinical Dia~nosis and Ma,~au,e,,,~,,l bv I ~hnratnrV Methods: rllilcldel~Jllia~ PA; WB Saunders (1979).
5 The results of the test are illustrated in Figure 6.

Two samples were prepared, haYing 600 mglkg of cyulol~éxal~uyl-(L)-l~ucine and 50 mglkg of heparin and 600 mglkg of c~,lol~e~al lo~ l (L)-leucine 20 and 100 mglkg of heparin, respectively. The samples were given to fasted ratsas described in Example 13. The results of the test are illustrated in Figure 7.
FxAMpLE 15 . - - -Two samples were prepared, having 100 mg/kg of CYLII~e~anU1 25 (L)-arginine and 100 mglkg of heparin and 600 mglkg of cyclol~e~a (L)-arginine and 100 mglkg of heparin, respectively. The samples were given to fasted rats as described in Example 12. The results of the test are illustrated in Figure 8.

A sample having 300 mglkg of cy-;lol,e,~a,~u~l-(L)-leucine and 25 mglkg of heparin was prepared. The sample was given to rats by intraduodcnal injection. As 2 COIll,Oal i:.on heparin, at a dose of 25 mg/kg was ad",i"i:,Lered by , ,, . . _ _ _ _ _ . . _ .

p 12 WO 95/28838 ~ ~L 8 8 ~ ~ ~ lIU~, intrsduodenal injection The results of the test are illustrated ylaul~ ~ ~l'y inFigure 9.
FxAMpl F 17 A sample having 300 mg/kg of cyclohexanoyl-lL)-leucine and 50 mg/kg of heparin was prepared. The sample was given to rats by intraduodenal injection. As a c ~,I,u~,isùn cyclohexanoyl-lL)-leucine without any heparin was aJ",:. I;~lult:d by intraduodenal injection. After 30 minutes this was followed by a dose of heparin, 50 mg/kg au~",i";~la,~d by intraduodenal injection. A second Culll~ali:,OI~, a dose of heparin alone, 50 mg/kg, was also ad",i";~ d by intraduodenal injection. The results of the test are illustrated graphically in Figure 10.
EXAMPLF 18 = - =
PF._PARATION OF LOW MOLFCUI ~R WFlGHT HEPARIN SAMPI
Samples COIllail, ,g low molecular weight heparin were prepared as described in Example 12.

LOW MOLECUI ~R WFlGHT HEPARIN In Vivo FxpERlMFNTs IN RATS
Samples cu"la;";"g low molecular weight heparin ~LMWH) and cycloh~xa,~uyl-(L)-leucine as described in Example 19 were prepared and a~ ;;.L~ltd, by oral gavage, to a group of fasted rats. Blood samples were collected serially from the tail artery. Low molecular weight heparin (LMWH) was dt:L~""i"ed in plasma samples. The plasma level was measured with an antiFactor Xa assay kit available from Cl-lullloye~ A.B. Sweden. The results ûf the test are illustrated in Figure 11.

A sample having 300 mg/kg of cyclohexanoyl-(L)-leucine and 8000 lU/kg low molecular weight heparin was prepared. The sample was given to fasted rats as described in Example 20. The results of the test are illustrated in Figure 12.
. =

wo g~l28838 2 ~ g 3 ~ ~ 7 . ~1/. ., In Vivo EV~I I IATION OF CROMOGLYCOLATE PPFPARATIONS IN RATS

Following the procedures described herein samples cullL~ the carriers of the subject invention and disodium cromoglycolate were prepared.
5 The sample, in 0.85N citric acid and 0.5% acacia, contained 400 mg/kg of cy.,lol~ c."ùyl IL)-leucine and 50 mg/kg of disodium cromoglycate (DSCG). The pH of this sample was 7.1. A second sample was prepared at a pH of 4.6. The animals were ad~ i ,L~ d the samples by oral gavage. As a cc,,,,,ù~li w,~ the DSCG was delivered in water, pH 7.2, and in:citric acid, pH 3.7. The delivery 10 was evaluated by using the procedure described by A. Yoshimi in r~ ob Dyn., 15, pages 681-686, (1992). The results of the tests ar~ illustrated in Figure 13.
In Vivo _V~I I IATION OF INTERFERON PREPARATIONS IN RATS
15 EXAMPl F ~
Following the procedures described herein samples cul I Iil l9 the ~arriers of the subject invention, in a Trizma~ hydl u~ lu, icle buffer solution (Tris-HCI) at a pH of about 7-8, and interferon a2b were prepared. The animals were ad"~i";~Lt:r~:d the drug by oral gavage. The delivery was evaluated by using an 20 ELISA assay for human interferon a.
Two samples having 800 mg/kg of cyclohexanoyl-~L)-phenylglycine in a buffered solution and 1000 ,ug/kg of interferon a2b and 800 mg/kg cyclohexanoyl-(L)-arginine in a buffered solution and 1000 /lg/kg f interferon a2b were prepared. The samples were given to fasted rats by oral 25 gavage. The results of the test are illustrated in Figure 14.

Two samples having 800 mg/kg of cyclohexanoyl-(L)-phenylglycine in a buffered solution and 1000 ,ug/kg of interferon a2b and cyclohexanoyl-30 ~L)-arginine in a buffered solution and 1000 .ug/kg of interferon a2b were prepared. The samples were orally ad~ L~l ~d to monkeys. The results of the test are illustrated in Figure 15.

, WO g~il28838 2 ~ 8 ~ ~ 6 ~ ` 1?

A sample having 400 mg/kg of c~ d"oyl-(L)-phenylglycinein a buffered solution and 500 ,ua/kg of interferon a2b was prepared. The sample was given to fasted rats by oral gavage. The sample was also given to a second group of rats by intraduodenal injecti'on. The results of the test are illustrated 5 in Figure 16.

Three samples having 400 mg/k~ of cy.,lol~ allu~l-(L)-phenylglycine in a buffered solution with 10Q0 ,ug/kg of interferon a2b, 500 10 ,ug/kg of interferon a2b and 250 ,Lrg/kg of interferon a2b were prepared. Thesamples were ~iven to fasted rats by oral gavage. The results of the test are illustrated in Figure 17.
All patents, patent ,~" ,s, literature p~l'' 1iol~5 and test 15 methods cited herein are hereby il~co".o,d~d by refcrence.
Many variations of the present invention will suggest ~ ,dl~
,to those skilled in the art in light of the above detailed disclosure. All sucho.lirica~io"s are within the full intended scope of the appended claims.

Claims (52)

WHAT IS CLAIMED IS:
1. A composition comprising:
(A) at least one biologically active agent, and (B) (a) at least one acylated amino acid;
(b) at least one peptide comprising at least one acylated amino acid; or (c) a combination of (a) and (b);
wherein said acylated amino acid is acylated by (i) a C3-C10 cycloalkyl acylating agent, said agent optionally being substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxy, phenyl, phenoxy, or -CO2R, wherein R is hydrogen, C1-C4 alkyl or C2-C4 alkenyl; or (ii) a C3-C10 cycloalkyl substituted C1-C6 alkyl acylating agent.
2. The composition according to claim 1, wherein said amino acid has the formula wherein: R1 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl;
R is C1-C24 alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl) phenyl, (C2-C10 alkenyl) phenyl, (C1-C10 alkyl) naphthyl, (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl), or naphthyl (C2-C10 alkenyl);
R being optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -OH, -SH, -CO2R3, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C1-C10 alk)aryl, ar(C1-C10alkyl), or any combination thereof;

R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R3 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.
3. The composition according to claim 1, wherein said acylated amino acid has the formula wherein: R4 is (i) C3-C10 cycloalkyl, optionally substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxy, phenyl, phenoxy or -CO2R7, wherein R7 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl, or (ii) C3-C10 cycloalkyl substituted C1-C6 alkyl;
R5 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl;
R6 is C1-C24 alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, C1-C10 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl) phenyl, (C2-C10 alkenyl) phenyl, (C2-C10 alkyl) naphthyl, (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl), or naphthyl (C2-C10 alkenyl);
R6 being optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -OH, -SH, -CO2R7, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more atom of N, O, S or any combination thereof, aryl, C1-C10 alk)aryl, ar(C1-C10 alkyl) or any combination thereof;
R6 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R7 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.
4. The composition according to claim 1, wherein said biologi-cally-active agent is selected from the group consisting of a peptide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination thereof.
5. The composiion according to claim 1, wherein said biologi-cally-active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, calcitonin, erythropoietin, atrialnaturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or any combination thereof.
6. The composition according to claim 4, wherein said biologi-cally-active agent is selected from the group consisting of an interferon, interleukin-II, insulin, heparin, calcitonin, oxytocin, vasopressin, cromolyn sodium, vancomycin, DFO or any combination thereof.
7. The composition according to claim 6, wherein said biologically-active agent is calcitonin.
8. The composition according to claim 1, wherein said amino acid is a naturally occurring amino acid.
9. The composition according to claim 1, wherein said amino acid is a synthetic amino acid.
10. The composition according to claim 1, wherein said amino acid is an .alpha.-amino acid.
11. The composition according to claim 1, wherein said amino acid is a non-.alpha.-amino acid.
12. The composition according to claim 2, wherein said amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, phenylglycine, proline, serine, threonine, tryptophan tyrosine, valine, hydroxyproline, .gamma.-carboxyglutamate, O-phosphoserine, .beta.-alanine, .alpha.-aminobutyric acid, .gamma.-aminobutyric acid, .alpha.-aminoisobutyric acid, 4-(4-aminophenyl)butyric acid, (aminophenyl)acetic acid, aminobenzoic acid, 4-aminohippuric acid, (amino-methyl)benzoic acid .epsilon.-aminocaproic acid,7-aminoheptanoic acid, .beta.-aspartic acid, .gamma.-glutamic acid, cysteine(ACM), .epsilon.-lysine, .epsilon.-lysine (A-Fmoc), methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, and thioproline.
13. The composition according to claim 12, wherein said amino acid is selected from the group consisting of arginine, leucine, lysine, phenylalanine,tyrosine,valine,phenylglycine,4-(4-aminophenyl)butyricacid,4-(4-aminophenyl)acetic acid and aminobenzoic acid.
14. The composition according to claim 1, wherein said peptide is selected from the group consisting of a di-peptide, a tri-peptide, a tetra-peptide, or a penta-peptide.
15. The composition according to claim 14, wherein said peptide comprises at least one naturally occurring amino acid.
16. The composition according to claim 14, wherein said peptide comprises at least one synthetic amino acid.
17. The composition according to claim 14, wherein said peptide comprises at least one .alpha.-amino acid.
18. The composition according to claim 14, wherein said peptide comprises one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, phenylglycine, proline, serine, threonine, tryptophan tyrosine, valine, hydroxy proline, .gamma.-carboxyglutamate, O-phosphoserine, .beta.-alanine, .alpha.-amino butyric acid, .gamma.-amino butyric acid, .alpha.-amino isobutyric acid, .epsilon.-amino caproic acid, 7-amino heptanoic acid, .beta.-aspartic acid, .gamma.-glutamic acid, cysteine (ACM), .epsilon.-lysine, .epsilon.-lysine (A-Fmoc), methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, and thioproline.
19. The composition according to claim 18, wherein said peptide is formed from one or more amino acids selected from the group consisting of arginine, leucine, lysine, phenylalanine, tyrosine, valine, and phenylglycine.
20. The composition according to claim 1, wherein said acylating agent has the formula wherein R8 is (i) C3-C10 cycloalkyl, optionally substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxy, phenyl, phenoxy, or -CO2R9 wherein R9 is hydrogen, C1-C4 alkyl or C2-C4 alkenyl; or (ii) a C3-C10 cycloalkyl substituted C1-C16 alkyl; and X is a leaving group.
21. The composition according to claim 20, wherein R is cyclohexyl, cyclopentyl, cyclopropyl, or cycloheptyl.
22. The composition according to claim 1, wherein component (b)(i) comprises a mixture of two or more acylated amino acids.
23. The composition according to claim 1, comprising a microsphere.
24. A dosage unit form comprising (A) a composition according to claim 1; and (B) (a) an excipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or (h) any combination thereof.
25. A dosage unit form according to claim 24 comprising a tablet, a capsule, or a liquid.
26. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said animal a composition as defined in claim 1.
27. A method for preparing a composition, said method comprising mixing:
(A) at least one biologically-active agent;
(B) (a) at least one acylated amino acid;
(b) at least one peptide comprising at least one acylated amino acid; or (c) a combination of (a) and (b);
wherein said acylated amino acid is acylated by (i) a C3-C10 cycloalkyl acylating agent, said agent optionally being substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxy, phenyl, phenoxy, or -CO2R, wherein R is hydrogen, C1-C4 alkyl or C2-C4 alkenyl; or (ii) a C3-C10 cycloalkyl substituted C1-C6 alkyl acylating agent; and (C) optionally a dosing vehicle.
28. The method according to claim 27, further comprising a stabilizing additive.
29. The method according to claim 28, wherein the stabilizing additive is selected from the group consisting of gum acacia, gelatin, polyethylene glycol or polylysine.
30. A compound having the formula wherein A is Try, Leu, Arg, Trp, or Cit.
31. A compound according to claim 30, wherein a is not Leu, A
is acylated at two or more functional groups.
32. A compound according to claim 30, wherein A is Try.
33. A compound according to claim 31, wherein A is Try.
34. A compound according to claim 30, wherein A is Leu.
35. A compound according to claim 30, wherein A is Arg.
36. A compound according to claim 31, wherein A is Arg.
37. A compound according to claim 30, wherein A is Trp.
38. A compound according to claim 31, wherein A is Trp.
39. A compound according to claim 30, wherein A is Cit.
40. A compound according to claim 31, wherein A is Cit.
41. A compound having the formula wherein A and B independently are Arg or Leu.
42. A compound according to claim 41, wherein if A, B or A and B are Arg, A, B, or A and B are acylated at two or more functional groups.
43. A compound having the formula wherein A is Arg or Leu.
44. A compound according to claim 43, wherein if A is Arg, A
is Acylated at two or more functional groups.
45. A compound according to claim 43, wherein A is Arg.
46. A compound according to claim 44, wherein A is Arg.
47. A compound according to claim 43, wherein A is Leu.
48. A compound having the formula wherein A is Leu or phenylglycine.
49. A compound according to claim 48, wherein A is Leu.
50. A compound according to claim 48, wherein A is phenylglycine.
51. A compound having the formula wherein A is phenylglycine.
52. A compound having the formula wherein a is phenylglycine.
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US5629020A (en) 1997-05-13
US5935601A (en) 1999-08-10
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