CA2358463A1 - Polymeric delivery agents and delivery agent compounds - Google Patents

Polymeric delivery agents and delivery agent compounds Download PDF

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Publication number
CA2358463A1
CA2358463A1 CA002358463A CA2358463A CA2358463A1 CA 2358463 A1 CA2358463 A1 CA 2358463A1 CA 002358463 A CA002358463 A CA 002358463A CA 2358463 A CA2358463 A CA 2358463A CA 2358463 A1 CA2358463 A1 CA 2358463A1
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Canada
Prior art keywords
nhc
delivery agent
nhch2
polymeric delivery
bond
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Abandoned
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CA002358463A
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French (fr)
Inventor
Richard D. Conticello
Raphael M. Ottenbrite
Sam J. Milstein
John E. Smart
Eugene N. Barantsevitch
Nai Fang Wang
Jun Liao
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Virginia Commonwealth University
Emisphere Technologies Inc
Original Assignee
Virginia Commonwealth University
Richard D. Conticello
Raphael M. Ottenbrite
Emisphere Technologies, Inc.
Sam J. Milstein
John E. Smart
Eugene N. Barantsevitch
Nai Fang Wang
Jun Liao
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Application filed by Virginia Commonwealth University, Richard D. Conticello, Raphael M. Ottenbrite, Emisphere Technologies, Inc., Sam J. Milstein, John E. Smart, Eugene N. Barantsevitch, Nai Fang Wang, Jun Liao filed Critical Virginia Commonwealth University
Publication of CA2358463A1 publication Critical patent/CA2358463A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • 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
    • A61K38/27—Growth hormone [GH] (Somatotropin)
    • 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
    • A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Abstract

Polymeric delivery agents, delivery agent compounds and compositions comprising them which are useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.

Description

WO 00/40203 PCTlUS00/00476 POLYMERIC DELZ'JE~2Y AGENTS AND DELIVERY AGENT COMPOUDIDS
FIEhD OF TFiE INVENTION
The present irwention relates to compositions for delivering active agents, and particularly biologically ox chemically active e.gents. The compositions comprise a polymeric delivery agent or delivery agent compound which facilitates the deZ.ivery of the active agent to a target.
These polymeric del,ivexy agents and delivery agent compounds are well suited to form non-covalent mixtures with active agents for administration to animals. Methods for the 1~ preparation and for the administration of such compositions are also disclosed.
BACKGROUND OF THE 3:NVEI~ITTON
Conventional means for de1_ivering active agents are often severely limited b~~ biological, chemical, and physical baxriers. Typical3.y, these barriers axe imposed by the environment through which delivery occurs, the environment of the target for del~_vex-y, or the target Itself. Biologically or chemically active agents are particularly vulnerable to such barriers.
In the delivez:y to animals of pharmacological and therapeutic agents, barriers are imposed by the body. Physical _q_ barriers such as the skin and various organ membranes axe relatively impermeable to certain active agents but must be traversed before rE:aching a target, such as the circulatory system. Chemical barriers include, but are: not limited to, pH
variations in the gastrointestinal (GI) tract and degrading enzymes.
Oral delivery of many biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers.
't0 Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic Z5 substances. These agents may be rendered ineffective or may be destroyed in the GI tract by acid hydrolysis, enzymes, or the like, or may simply not be absorbed_ Many delivery agents are fairly hydrophobic, whereas many active agents axe hydrophilic. The differential aqueous 20 solubility between the delivery agent and the active agent can be problematic in designing commercially acceptable dosage formulations which exhibit biological activity in vi~cro. Thus, the ability to alter the solubility of a delivery agent would allow one to tailor the deli~crery agent to meet the needs of the 25 cargo in order to optimize its bioavailability_ The pH within .the gastrointestinal tract typically ranges from about 1 to about 8, while many delivery agents remain soluble over a rangy of only 2-2.5 pH units. During oral delivery, a signifz~ant amount of such a delivery agent could 30 precipitate out xn the stomach due to the local acidity. The -z-WO 00/40203 PCT/iJS00/00476 precipitated delivE:ry agent would then be unavailable for delivery of active agent to a point further along the Gz tract.
Increasing the span of pH solubility of the delivery agent would allow more effective delivery at lower concentrations of delivery agent.
Delivery agents generally tend to self-aggregate into micellular-like stz-uctures. The competita.on between self association and ase;ociation with the active agent typically results in at least. a portion of the delivery agent being '(O unavailable for effective delivery o~ the Fictive agent. Thus, a corresponding portion of the active agent that was administered may not be effectively delivered to the target.
inhibiting self aggregation of the delivery agent would increase the availability of delivery agent for delivery of the 'f5 active agent.
Various delivery agents for oral administration of active agents have been developed in recent years. These delivery agents include protei.noids, modified vegetable proteins, acylated or sulfonated amino acids, acylated or sulfonated 20 amino acid ketones, and acylated or sul~onated amino acid aldehydes. See, U.S. Patent Nos. 5,401,516; 5,443,841;
5,451,42.0; 5,541,1.55; 5,629,020; 5,643,957; 5,693,338;
5,709,861; 5,714,167; 5,766,633; 5,773,647; 5,792,851;
5,820,887.; 5,863,944; 5,866,536; and RE35,862_ These delivery 25 agents promote systemic absorption of active agents in the gastrointestinal tract. The interaction between the delivery agent and the active agent, as well as the interaction between the delivery agent and the cell membrane, may be important for absorption. See, U'.S. Patent No. 5,714,167.

WO 00/40203 PCTlUS00100476 There is a need for delivery agents whose solubility can be modified for a particular need, thereby changing the concentration of soluble delivery agent which is available for delivery of an active agent.
Therefore, there is a need for alternate and improved delivery agents.
SUMMARY OF TA'E INVFNTTON
The present invention provides polymeric delivery agents which are useful in. the delivery of active agents. The polymeric delivery agent comprises a polymer conjugated to a modified amino acid ox derivative thereof via a linkage group selected from the group consisting of -i~THC (O) NH-, -C (O) NH-, -NHC (O) -, -OOC-, -COO-, -NHC (O) O-, -OC (O)NH- , -CHzNH-, -NHCH2-, -cH~c (o) o-, -oc (o ~ zr~zcH2-, -c~~rr~cocHZo-, -oc~z2c (o> rrHCH2-, _ NHC (O) CHzO-, -OCH2C (O) NH-, --NH-, -O-, and carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid_ The modified amino acids may be acylated or sulfonated amino acids, ketones or aldehydes of acylated or sulfonated amino acids, salts thereof, or polyamino acids or polypeptides of any of the foregoix~g.
The polymer may be a.ny polymer including, but not limited to, alternating copolymers, block copolymers and random copolymers, which are safe for use in mammals. Preferred polymers include, but are not iim~.ted to, polyethylene;
polyacrylates; polynethacrylates; poly(oxyethylene);
poly(propylen.e); polypropylene glycol; polyethylene glycol (PEG) and derivativ,~s thereof, such as PEG-malefic anhydride copolymers; and derivatives and combinations thereof_ The molecular weight of the polymer typically ranges from about 100 to about 200,000 daltons. The molecular weight of the polymer preferably ranges from about 200 to about 10,000 daltons. In one embodiment, thE: molecular weight of the polymer ranges ~xom about 200 to about 600 daltons and more preferably ranges from about 300 to about 550 daltons.
According to one embodiment, the polymeric delivery agent comprises units ha'v'ing the formula R~s RZ
-~CH- C~-l ox salts thereof wr:ere R1 is a modified amino acid whzch is °( 5 bonded to the polytr~er v~.a a linkage group selected from the group consisting of -NHC(O)NH-, -C(O}NH-, -NHC(O)-, -OOC-, -coo-, -rrHC (o) o-, -c~c (o) NH-, -cH~H-, -r~zcz~-, -CH~rrHC (o> o-, -OC ( O ) ~IHCH2 - , -CHiNHCOCHZO - , -OCHzC ( O ) NHCHx - , -NHC ( O ) CHZO- , -OCH2C (O)NH-, -NH-, -0-, and carbon-carbon bond; RZ is H or -CH3;
and Rl° is H or -COON. Preferably, Rl is -R'-~2' r~rhere R3 is -NHC (O} NH-, -C (O) NH-, -NHC (O} -, -OOC-, -COO-, -NHC (O} O-, -OC (O) NH- , -CF~zI~TH- , -NHCFia- , -CHzNHC (O} O- , -OC (O) IsHCHz-, -CHzNHCOCH20-, -OCHZC (O) NHCH2-, -N'HC (0} CHZO-, -OCI~C (O) NH-, -NH-, -o-, ox carbon, carbon bond; and R' has the formula R~o where R5, R6, R', Re, anal R9 axe independently a bond to R', or H, Cl, Br, F, -C>H, -CH3, -OCH3, or - (CHz)~CH3;
Rl° is a bond to R3 or -COON, or -C (0) NH-RI1-Rlz Rli is a .substituted or u~zsubstituted, linear or branched alkyJ.ene raving a chain length of from about 1 to about 11 or -Ri' -R1' ~_ ;
R~'Z is a bond to R3 or is -COOH, -NHz, -OH, -C (O) -Rise -COO-Rls, -NHRls, -ORls, C1, or Br;
RI3 is a substituted or uxxsubstituted phenylene;
RIB is a ~:ubstituted or unsubstituted, linear or branched alkylene having a chain length of from about l to about 5;
R~5 is a bond to R3; anal m is trore. about 1 to about 4.
Preferably, R' is selected from the group consisting oz l~
/ N

OH O
O
off ~NH
OH
(r-coos) i N \
OH O /

II
H
/ II N
OH O I / COOH
L"J3 (II-COOH) _7_ H
N

OH O
zzz OMe., / N
n ON O
rv OH O
N
~H
o v ~o off o 'N
H
vz _g_ OMe O
'N
vzi OMe O
~N
H
VTIT
O
~NH
' CH3 zx J
OH
'w J
gz and salts thereof.

Preferably, R' is -OCH3 or -OH. According to a preferred embodiment , R~° i s -~ NH-R11-Rlz arid R''I is - ( CHz ) ~ - , - ( CHz ) y- . -(C6H5) - (CHz) 3-, - (C6H:5) -CHz-, or - (CHz) $°NH-C (O) -CHZ- .
Another embodiment is a polymeric delivery agent having units of the formula Ris-Rz4-CH CH -R1'
2 2 or salts thereof where R1' is defined as R1 above; R1' is -OH, -OCH3, or -Rlg; RI8 is defined as R1 above; and Rz' is a polymer having units of - (CHzCHzO) -, - (CH (CH3) CH20) -, or a combination thereof. R'4 typic~.lly contains from about 3 to about 200 polymeric units. Rz4 may be a random copolymer or a block copolymer . R'8 may be the same or dif f erent than R16 .
A preferred embodiment of the polymeric delivery agent has units of the formula Rz6- (CHZCI~ZO) n- CHzCHz-Rz' RZa or salts thereof where R16, Rl', and Rze are defined as above; Rz' is H or -CH,; and rz is from about 3 to about 200. Preferably, R1' and Rls are -OOC-R'. According to a preferred embodiment, R°' is -OCHz. .According to another preferred embodiment, Rib is NHC (O) -R° or -NHC (O; O-R' and n ranges from about 4 to about 15 .
Yet another embodiment is a polymeric delivery agent having units of the formula
3 PCT/US00/00476 RZ°- (CH2CH2O) a- (CA2CHCH20) d- (CHaCHzp) b-CH2CHz-Rzi 0- (CHZCA20) ~-CHZCH2Rzz or salts thereof wk~ere Ra°, RZl, and Rz2 independently are H or are defined as RI above; a, b, and c independently axe integers from about 1 to about 50; and d ranges from about 2 to about _ Preferably, R2'', R~z, and RZZ independently are -COO-R° .
Preferably, d is about 6.
10 Examples of polymeric delivex-y agents and units for the polymeric delivery agents include, but are not limited to, w-~CHz-CH~CH2-CH~-x CO CO2Na Conjugate I
wherein x is 0.02 to 0.5, preferably O.OS (Conjugate Z is a random polymer);
C~ C~x O COzNa o~
Conjugate 2 wherein x is 0.02 to 0.5, preferably 0.06 (Conjugate 1 is a random polymer);
-~-- CH-Cl~--C.H2--CH~
Na I H

CH CH~)n CH2CHZOCH3 ~am.e ~ Cp2Na (CH2)k/
H O
5 wlaezeu~ k= )-11, preferably 7 or 9 n = IO to SU, preferably 33, a~ad m = S to 15, preferably 9.
Conjugate 3 is the above structure where k = 7, n = 33 and m = 8;
I-COO-CHzCHaO (CHZCHzO) SCH2CHzOH Coajugate 4 .
I-COO-CH2CHz0 (t~CHaO) 3CH~CHZOS Conjugate 5 't 5 I-COO-CHaCH~o (t~CHlO) SCH2CHzOCH3 Conjugate 6 I-COO-CHaCHzO (t~(~O),CH2CH20H Conjugate 7 II-COO-CH=CHzO (CHzCH20) SCHzCHZOH Conjugate 8 III-COO-CHxCH=O (CH2CH20? ~CHZCH20H Conjugate 9 Z-COO-CHzCH2O (CHzCH20) ~xCH2CH20H Conjugate 10 I-COO-C~CH20 (C'HzCHaO) loaCHaCHz-OOC-I Conjugate 11 PEG branched (8 artr.s) : HO- (CHaCHzO) 3- (C82CHCH20) 6- (CHaCHao) 3-H
O
~~z~o) a-$
The modified amino acid I-Coo is attached at the -OH group through an ester J.inkage at 4 of the 8 ~~arms".
Conjugate 12 I-COO-CHaC'H~O (C:HzC'33a0) 14C~2CH20CH3 Conjugate 13 Iv-COO-CHZCH20 (CHzCHzO) aCHzCH20H Conjugate 14 v-Coo-CHaCHao (CHaCHao) gCHaCHzoH Coxtjugate 15 IV-COO-CHaCH=O (CHaCH=O) 6CHaCH20H Conjugate 16 I-C~NH-C'O-0-CHzC&a(7 (CHaC~aO) s~~0~s Conjugate 3.7 I-~a~W~zO (~a~a0) s~a~z0~s Coxijugate 18 II-COO-CHaCHaO (CHzCH=O) ioCHaCHaOCH3 Conjugate 19 II-COO-CHaCH=O (CHaCHzO) sC~CHzOCH3 Conjugate 20 I-COO-CH2CH20 (CH2CH20) loC~CHZOCH3 Conjugate 21 I-CHaNH-CO-CHaO-CHaCHzO (CHzCHaO) SCHaCHaOCH3 Conjugate 22 WO 00!40203 PCT/US00/00476 I-CHaNH-CO-CH2Ct-CH2CH20 (CHZCHzO) loCH2CH2OC~3 Conjugate 23 VI-GOO-CHaCHaO ~;CH2CH20) 5CH2CHzOC~3 Conjugate 24 VI-COO-CHZCHzO ~;CH2CIi20) loC~CH=OCH~ Conjugate 25 VII-COO-CHzCFi2C) (C.HzC&a0) IoCHzCHaOC~i3 Conjugate 26 VIII-COO-C.FhCHZO (CHaCHzO) 6CF~2CHaOH Conjugate 27 III-COO-CH2CF~U (CHZCAzO) QC'.H2CHZOH Conjugate 28 IIX-COO-CIi~CH20 (C~CHaO) 6CH2CHzOH Conjugate 29 HO
O H
HO /~N \ I N p--pEG~-pMe O O
(I-COOH)-5-CHzNH-CO-CHzO-CH~C.HZO(CH=CHzO)SC~ZC~OCH3 Conjugate 30 O
0 ,~ ~.
p~p~Y
NH'~/~/\/~NH N ~ 'H
OH
xe2 rix9 Conjugate 31 PEG branched ( 8 arms ) : HO- (CHaCH20) 3- (CHZCHCHzO) 6- (CHZC8a0) 3 H
O
(~a~0) 3 x The modified amino acid I-COO is attached at the -OH group through an ester 1_~nkage at 6 of the ° "arms". Conjugate 32 I-COO-CHaCS=O- (CHaCH20) 11-CH2C&~-oOC-I Conjugate 33 ~IW.'00H) -5-~.'$~NH-~.'~~-OCHzCHz- (OCHzCHZ)43-OCHZCHa OCH3 Con3ugate 34 pEG branched (8 arms) :HO- (CFi=CH20) as- (~2~~z0) s- (Cgz~iO) 2s-H
O
(C$.aCHzO) 26-H
The modified amino acid ~-COO is attached at the -OH group through an ester linkage at 4 of the 8 "arms". Conjugate 35 The modified amino acid I-COO is attached at the -OH group through axe ester linkage at 5 of the 8 "arms". Conjugate 36 The modified amino acid I-Coo is attached at the -OH group through an ester linkage at 7 of the 8 arms". Conjugate 37 The modified amine acid I-Coo is attached at the -OH group through an ester linkage at 8 of the 8 "arms". Conjugate 38 I-COO- CHzCH20- (CHaCHzO) 45-CHzCHzOOC-I Conjugate 39 JO
I-NH-COO-CH=C8~0- (CH2CHa0) 4a-CHZCHaOC83 Conjugate 40 I-COO-CSZCHzO-- (CH2CH~0) s-CHaCHzOOC-Z Conjugate 41 XI-COO-CH2CHz0- (CH2CH20) ~-CHzCHiOH Conjugate 42 X-COO-CHzCH20- (CH2CHa0) io-CH2CH20C83 Conjugate 43 X-COO-CHZCH~O- (CH2CH20) 11-CHZCHZOH ConjugatE 44 X-COO-CHzCH20- (CH2C~0) 2o-CFizCHzO-CO-X Conjugate 45 X-COO-CHzCH20- (CH2CH20) Zo-CHaCHzOH Conjugate 46 X-COO-CHzCH20- (CHzCHzO) 11-CFI2CH2o-CO-X Conjugate 47 z~-coo-cH2c~o- (ca~c~o) s-c~cHZocsg Conjugate 48 The number of polymeric units specified in the aforementioned polymeric delivery are an average number of units. The number of units in the polymers typically may vary by up to about 10%.
Another embodiment provides a composition comprising (A.) at least one active agent; and (B) at least one of the aforementioned polymeric delivery agents. The active agent preferably is a biologically yr chemically active agent.
Methods for the preparation and administration of the composition are also provided. These compositions are useful in the delivery of active agents to selected biological systems and for increasinc or improving the bioavailability of the active agent comp~.red to administration of the active agent without the delivery agent.

The invention also includes a method of preparing a polymeric delivery agent by conjugating a modified amino acid to a polymer, via one of the aforementioned linkage groups.
The invention further includes delivery agent compounds having the foxmuLae~
H
N~CHZNH2 ~'~~ 7 C>H O
z _ cs2rrg2 OH
~NH
OH O
(I-COOH) -5-CH2NSz NHZ
/ N
(\
~H ~ / COOH

1 O (II-COON) - 5-OH O O
H
E~ N OH
/ O
v-coos and salts thereof, including but not limited to sodium salts.
These delivery agent compounds are useful for facilitating the delivery of an act.i.ve agent. Another embodiment is a composition compri:;ing one of the aforemenfiioned delivery agent compounds and an active agent.
DETAILED DESCRIPTION OF THE INVENTION
These compositions may be used to deliver various active agents through or across various biological, chemical, and physical barriers a.nd axe particularly suited for' delivering active agents that are subject to environmental degradation.
The compositions of the subject invention are particularly useful for delivering yr administering biologically. or chemically active agents to any animals, including but not limited to birds such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.
Other advantages of the present invention include the use of easy-to-prepare, inexpensive raw materials. The compositions and the methods of the present invention are cost effective, easy to pertorrn; and amenable to industrial scale up for commercial production.
The presently 3isclosed compositions deliver active agents, particularly in oral, ixztranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous, intramuscular and ocular systems as well as traversing the blood-brain barrier_ Coadministration -1$-of an active agent and a polymer-delivery agent conjugate results in an increased bioavailabzlity of the active agent compared to admini:;tration of the active agent alone.
The term "salt:s" as used in this application includes but are not limited to organic and inorganic salts, for example alkali-metal salts, such as sodium, potassium and lithium;
alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids such as lysine or arginine; and orgar.~ic amines, such as dimethylamine or pyridine. preferably, the salts are sodium salts.
I~ctive Agexa,ts Active agents suitable for use in the present invention include biologically active agents, and chemically active agents, including, but not limited to, pesticides, pharmacological agents, and therapeutic agents.
For example, biologically active agents suitable for use in the present invention include, but are not limited to, proteins, polypept~.des; peptides; hormones; polysaccharides, and particularly muco-polysaccharides and mixtures thereof;
carbohydrates; lipids; other organic eompoLU~.ds; and particularly compounds which by themselves do not pass (or which pass only a :fraction of the administered dose) through the gastro-intestinal mucosa and/or are susceptible to chemical and/or enzymatic cleavage by acids and enzymes in the gastro-intestinal tract; or any combination thereof.
Further examples include, but axe not limited to, the following, including synthetic, natural or recombinant sources thereof: growth hormones, including human growth hormones (hGH), recombinant human growth hormone (rhGH), bovine growth hormones, and porcine growth hormones; growth hormone-releasing hormones; interferons, including a, (3 and y; interleukiz~-z;
interleukin-2; insulin, including porcine, bovine, human and human recombinant, optionally having counter ions including sodium, zinc, calc:i.um and ammonium; insulin-like growth factor, including IGF-s; heparin, including unfxactionated heparin, hepari:rzoids, derma=ans, chondroitins, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight h~~parix~; calcitonin, including salmon, eel and human; ervthropoietin; atrial naturetic factor; antigens;
monoclonal antibodies; somatostatin; protease inhibitors;
adrenocorticotropin, gvnadotropin releasing hormone; oxytocin;
leutinizing-hormone-releasing-hormone; follicle stimulating 75 hormone; glucocerebrosidase; thrombopoietin; filgrastim;
prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate); vancomycin; desferroxamine (DFO); parathyroid hormone (pTH), including its fragments;
antimicrobials, including anti-fungal agents; vitamins;
analogs, fragments, mimetics or polyethylene glycol (pEG)-modified derivatives of these compounds; <>r any combination thereof .
Modified Amino Acids The modified amino acid may be an N-acylated or sulfonated amino acid, a ketox~.e or aldehyde of an acylated or sulfonated amino acid, salts thereof, and a polyamino acid or polypeptide which includes any of the foregoing.
N-acylated and sulfonated amino acid:, poly amino acids, and peptides inclLtde, but axe not limited to, amino acids wYzich have been N-acylated or sulfonated, acid poly amino acids and peptides in which at least one amino acid has been modified, by acylating or suLfonating at least oz~e free amine group with, an acylat:ing or sulfonating agent which reacts with at least one of the free amine groups pxesenr.
Preferably, thc> modified amino acids comprise one of the following structurecs:

G
OH
~NH
O
OH
z-cooH

OH O

OH
' ~NH
/ O O
H

(T - COOH ) - 5 - CxZNHz / N
OH O ,~ COOH

II-COOH

N
OH O / COOH

(TI-COON) - 5-CHZNH2 N~COOH

OH O
=zz-coos OMe. \
N~COOH
OH O
rv-cooH
OH O O
H
OH

O
v-COON
't 0 OH
OH O / I
\ .N \ O
H
OH
OMe O
\ I O
( ~ N
H
OM~a O
\ H~~~OH
I , o0 vI-coox vzz-coos vrzz --COOx ~ OH
/ 'NH
\ I' H O
C' 3 IX-COON
O
'OH
X-COON

Of~i O
~OH
xz-cooH
and salts thereof, including but not limited to sodium salts.
The modified amino acids may be in the form of salts.
Salts ir_clude but are not limited to organic and inorganic salts, for example alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids such as lysine or a.rginine; and organic amines, such as dimethylamine or p~:~ridine. Preferably, the salts are sodium salts_ An amino acid is any carbolsylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids. Poly amino acids are either peptides (which are two or more amino acids joined by a peptide bond) or are two or more amino acids linked by a bound formed by other groups which can be linked, e.g. an ester, anhydride, ox an anhydride linkage. Peptides can vary in length from dipeptides with two amino acids to pole peptides with several hundred amino acids.
One or more of th~= amino acid or peptide units may be acylated or sulfonated.
N-acylated or sulfonated amino acids are typically prepared by modifying the amino acid or an ester thereof_ Many of these compounds are prepared by acylation or sulfonation with agents having the formula X - Y - R
wherein:
R is the appro~?riate radical to yield the modification indicated in the fi;~al product, Y is C=O or X02, and X is a leaving group.
Typical leaving groups include, but are not limited to, halogens such as, for example, chlorine, bromine, and iodine.
Additionally, the corresponding anhydrides are modifying agents.
N-acylated or sulfonated amino acids can be readily prepared from amino acids by methods within the skill of those in the art based u~~on the present disclosure. For example, N-acylated or sul~on~;ted amino acids may be derived from aminobutyric acid, aminocaproic acid, and aminocaprylic acid.
Further, the ~r-acy7.ated or sulfonated amino acid above may be prepared by reacting the single amino acid with the appropriate modifying agent wh_ch reacts with a free amino moiety present in the amino acids to form amides. Protecting groups may be used to avoid unwanted side.reactions as would be J~nown to those skilled in the art.
The amino acid can be dissolved in aqueous alkaline solution of a metal hydroxide, e.g., sodium or potassium hydroxide, and heated at a temperature ranging between about 5°C and about ~0°C, preferably between about 10°C and about 40°C, for a period ranging between about Z hour anal about ~
hours, preferably about 2.5 hours. The amount of alkali employed per equivalent of NHZ groups in the amino acid generally xanges between about 1.25 and about 3 mmole, preferably between about 1.5 and about 2.2.5 mmole per equivalent of NH2. The pH of the solution generally ranges between about 8 and about 23, preferably ranging between about 20 and about 12.
Thereafter, th.~ appropriate amino modifying agent is added to the amino acid solution while stirring. The temperature of the mixture is maintained at a temperature generally ranging between about 5°C and about ~0°C, preferably between about to°C
and about 40°C, for a period ranging between about 1 and about g hours. The amount of amino modifying agent employed in relation to the quantity of amino acid is based on the moles of total free NHz in t:ze amino acid. In general, the amino modifying agent is employed in an amount ranging between about 0.5 and about 2.5 mole equ~.valents, preferably between about 0_75 and about 1.2~~ equivalents, per molar equivalent of total '15 NH2 group in the amino acid.
The reaction is quenched by adjusting the pH of the mirture with a suitable acid, e.g_, concentrated hydrochloric acid, until the pH reaches between about 2 and about 3_ The mixture separates on standing at room temperature to form a transparent upper layer and a white or ofd-white precipitate.
The upper layer is discax'ded, and the N-acylated or sulfonated amino acid is collected from the lower layer by filtration or decantation. The crude N-acylated or sulfonated amino acid is then dissolved in water at a pH ranging between about 9 and about 13, preferably between about 11 and about 13. Insoluble materials are removed by filtration and the filtrate is dried in vacuo_ The yield of N-acylated or sulfonated amino acid generally ranges between about 30 and about 60%, and usually about 45%.

rf desired, am:iz~o acid esters, such as, for example benzyl, methyl, or ethyl esters of amiz~.o acid compounds, may be used to prepare the N-acylated or sulfonated amino acids of the invention_ The amino acid ester, dissolved in a suitable organic solvent such as dimethylformamide, pyridine, or tetrahydrofuran is reacted with the appropriate amino modifying agent at a temperature ranging between about 5°C and about 70°C, preferably about 25°C, for a period ranging between about 7 and about 24 hours. The amount of amino modifying agent used 90 relative to the amino acid ester is the same as described above for amino acids. This reaction may be carried out with or without a base such. as, for example, triethylamine ox diisopropylethylami.ne.
Thereafter, tr~e reaction solvent is removed under negative pressure and the e:oter functionality is removed by hydrolyzing the N-acylated or .culfonated amino acid ester with a suitable alkaline solution, e.g. 2N sodium hydroxide, at a temperature ranging between about 50°C and about 80°C, preferably about '70°C, for a period of time sufficient to hydrolyze off the ester group and fo3:m the N-acylated or sulfonated amino acid having a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, e_g. aqueous 25%
hydrochloric acid :solution, to a pH ranging between about 2 and about 2.5_ The N-acylated or sul~onated amino acid precipitates out of solution and is recovered by conventional means such as filtration or decantation. Benzyl esters may be removed by hydroge;aation in an organic solvent using a transition metal catalyst_ The N-acylated yr sulfonated amino acid may be puritied by recrystallization or by fractionation on solid column supports_ Suitable recrystalLization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation may be performed on suitable solid eolunun supports such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. When anion exchange chromatography is performed, preferably a subsequent 0-S00 mM
sodium chloride gradient is employed.
Polvmexs The polymers cf the present invention may be natural or synthetic and comprise two or more monomer:. The monomers may be the same or different, and the polymer may be linear or non-95 linear_ Polymers include but are not limited to branched or cyclic polymers. s'he polymers may be copolymers including twc or more different monomers, or homo-polymers including a single-type of monc>meric repeat. Further, polymers may be random or alternating, directed, bifunctional, polyfunctional, cross-linked, regular lattice, intermittent lattice, or amorphous.
The polymer meiy be any polymer including, but not limited to, alternating cod>olymers, block copolymers and random copolymers, which <are safe for use in mammals. Preferred polymers include, but are not limited to, polyethylene;
polyacrylates; poL;,rmethacrylates; poly(oxyethylene);
poly(propylene)s polypropylene glycol; polyethylene glycol fPEG) and derivat~.ses thereof, such as PEG-malefic anhydride copolymers; arid derivatives and combinations thereof. The molecular weight of the polymer typically ranges from about 204 to about 200,000 daltons_ The molecular weight of the polymer preferably ranges from about 200 to about 10,000 daltons_ In one embodiment, the molecular weight of the polymer ranges from about 200 to about 600 daltons and more preferably ranges from about 300 to about SSO daltons.
Polymers may be in the form of one or more salts. Salts include but are not. limited to organic and inorganic salts, for e~cample alkali-met~~l salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids such as lysine or arginine; and organic amines, such as dimethylami.ne or pyridine_ Preferably, the salts are sodium salts.
Polymeric Del._Lvery Aaent (Conju aces) One or more o:E the modified amino acids may be conjugated (covalent3y attachad) to oz~e or more of the monomeric units of the polymer via on~= of the aforementioned linkage groups.
Many of the polymeric delivery agents have solubility greater than about 200mg/mL, and have greater solubility than the corresponding modified amino acids alone. However, like most poloxamers, the solubility of PEG conjugates decreases at higher temperatures and can be characterized by the cloud point or lower critical solution temperature (LOST). The LCST is dependent on the ratio of hydrophilic/hydrophobic units in the conjugate and can be changed easily.
In general, the polymeric delivery agents of the present invention may be ~~repared as follows. For vinyl polymeric delivery agents, ~.uch as PA.A and PAA/MA polymers, the polymer and modified amino acids may each be separately dissolved zn an appropriate solvent, e.g., dimethyl formamide (DMF), to yield solutions A and B, respectively. Solution B is warmed to about 60-70°C, in the presence of a base, e.g. triethyJ.amine_ Solution B is then added to solution A and the mixture is stirred at room temperature for 24 hours. The polymeric delivery agents precipitates with the addition of dilute acid or base and is collected by centrifugation. The polymeric delivery agents ~.s then hydrolyzed, dialyzed against water, and lyophilized.
The resultant polymeric delivery agents may be analyzed by Size Exclusion Chrc>matography (SEC) in order to determine the approximate molecuJ.ar weight of the polymer and the nitrogen content of the conjugate may be used to approximate the amount of modified amino z~c~.d bound to the polymex in the polymeric delivery agent. Preferably, there is between about 5 and ~.5°s w/w bound modified amino acid in the polymeric delivery agent, and more preferably, there is between about to and 15% w/w bound modified amino acid unit in the polymeric delivery agent.
For PEG delivcary agents with ester linkages, a carboxyl-containing delivery agent reacts with PEG or PEG methyl ether in toluene at 250-16o°C in the pxesence of p-toluene sulfonic acid as a catalyst for 3-4 hours. water generated by the reaction is removed with a Dean-Stark trap. Reverse phase HQLC
is used to monitor the reaction. The reaction mixture is washed with saturated NaHC03 water soJ.ution to remove unreacted starting materials and the catalyst. The polymeric delivery agents are obtained after evaporation of toluene. The structure is further confirmed by nitrogen analysis and 1H Nt~.

PEG delivery agents with~amide, amino or urethane linkages may be prepared by reaction of an amino-containing modified amino acids with an appropriately activated polyethylene glycol in pyridine at 70-80°C far 4-5 hours and at room temperature fox about 24 hours. Pyridine is then removed by evaporation under reduced pres~ure_ The residue is thE:n dissolved in an organic solvent, e.g., methylene chloride, and the solution is washed with dilute HCl aq., N'aCl aq., and NaHC03 aq.
respectively to remove impurities. Reverse phase HPLC is used to monitor both the: reaction and the work-up process. The polymeric delivery agents is obtained after evaporation of the organic solvent. The structure is further confirmed by nitrogen analysis and 1H NMR.
In order to prepare PEG delivery agents with urea 'I5 linkages, a two step process was used. First, a urethane derivative based on the reaction of an ami.ao terminated hydrophobic compomzd and ~-nitrophenyl chloroformate is prepared_ The rea~~tion is very fast and carried out at room temperature in pyridine solution. The intermediate urethane derivative contains a good leaving group that can be eliminated on attack of nucleophilic agents. When this intermediate is reacted with an amino-terminated PEG; both 4-nitrophenol and the PEG adduct with urea lznkage were formed.

Delivery Svsteans The compositions of the present invention may include one or more active agents. zn one embodiment, the polymeric delivery agents or ~~elivery agent compounds of the present invention (collectively "delivexy agents") may be used directly as a delivery agent by simply mixing one or more delivery agent with the active agent prior to administratian. The administration mixtuxes may be prepared by mixing an aqueous solution of the delivery agent with an aqueous solution of the active ingredient, just prior to administration.
Alternatively, the delivery agent and the active agent can be admixed during the manufacturing process. The solutions may optionally contain additives such as phosphate buffer salts, citric acid, acetic acid, gelatin, and gum acacia.
Stabilizing additives may be incorporated into the delivery agex~.t solution. With some active agexi.ts, the presence of such additives F~romotes the stability and dispersibility of the agent in solution. The stabilizing additives may be employed at a concentration ranging between about 0.~. anal 50 (w/v), preferably about 0.5% (w/v). Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are gum acacia, gelatin and methyl cellulose.
The amount of active agent is an amount effective to accomplish the purpose of the particular active agent. The amount zn the composition typically is a pharmacologically or biologically effective amount. However, the amount can be less than a pharmacologically or biologically effective amount when the composition is used in a dosage unit form, such as a solid, such as a capsule, ~. tablet, or a powder, or a liquid, because the dosage unit form may contain a multiplicity of delivery agent or active agent compositions or may contain a divided pharmacologically or biologically effective amount. The total effective amounts can then be administered in cumulative units contaixiing, in total, pharmacologically or biologically or chemically active amounts of biologically or pharmacologically active agent.
The total amoL.nt of active agent to be used can be determined by those skilled in the art_ However, because the presently disclosed delivery agents provide efficient delivery, lower amounts of biologically ox chemically active agent than those used in prior dosage unit forms or delivery systems may be administered to the subject, while stil:L achieving the same blood levels and therapeutic effects.
The amount of delivery agents in the present composition is a delivery effective amount and can be determined for any particular deliver~~ agents or active agent by methods known to those skilled in the art. Tt will be this amount effective for delivery of the active agent by the chosen route of delivery.
Aosage unit forms can also include any of e~cipients;
diluents; disintegrants; lubricants; plastici2ers; colorants;
and dosing vehicles, including, but not limited to water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.
Administration of the present compositions or dosage unit forms preferably is oral, intracolonic or intraduodenal.
Particularly, the compositions of the present invention axe useful in orally administering active agents, especially those that are not ordir..arily orally deliverable.

The delivery compositions of the present invention may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as acti.nonin or epiactinonin and derivatives thereof. Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowm.a_n-Eirk inhibitor.
The compositions of the subject invention are useful for administering biologically or chemically active agents to animals. The systE:m is particularly advantageous for delivering biologically or chemically active agents which would otherwise be destroyed or rendered less effective by conditions encountered before the active agent has reached its target zone (i.e. the area in vrhich the active agent o.f the delivery composition are to be released) and within the body of the animal to which they are administered.
DESCRIPTION OF THE PREFERR$D EMBODIMENTS
The foll«wing examples illustrate the invention.
without limitati.on_ All parts are given by weight unless otherwise indicated. The number of polymeric units and molecular weights ~~f the polymers specified in the examples are an average number of units and average molecular weights. The number of units and molecular weights in the polymers typically varies by up to about i0%.
Example la: Pre,garation of 8-~T(2-hydroxy-5-a~inomethvlbeazovl) ami.rzocax~z~rlic acid ( (I-COOH) -5-CH._~NH_z,Z, hyd~en chloride salt W~ 00/40203 CA 02358463 2001-07-05 8-N(2-methoxybenzoyl) aminocaprylic acid (7.5 g, 25.6 mmol, 1 equiv.) was mixed with formaldehyde (30.7 ml, 410 mmol, 16 equiv.) and hydrochloric acid (62.6 ml, 37%, 6~4 mmol, 25 equiv.). The mixture was stirred and bubbled under ~IC1 gas at room temperature for 3 hours. Crude 8-N(2~~methoxy-5-chloromethylbenzoyl.)aminocaprylie acid (compound 1) was obtained by removal o~ formaldehyde and HCI. Pure compound 1 was obtained by rec:rystallization in acetonitrile (4.5 g, 51.4%) .
The purified E3-N(2-methoxy-S-chloromethylbenzoyl)amino caprylic acid (4.5 g, 13.2 mmol, 1 equiv.) and hexamethylenetetrarnzne (I. _ 85 g, 13 .2 mmol, 1 equiv. ) were refluxed i z~z chloro__'orm for 1 hour. The chloroform was evaporated. The rf_sidue was refluxed in a mixed solution of methyl alcohol (30 ml) arid HC1 (10 ml, 37%) for 2 hours. 8-N(2-metholcy 5-aminomethylbenzoyl)aminocaprylic acid (compound 2) was obtained by removal of the mixed solvent (3.6 g, 76.60)_ Compound .2 (3.5 g, 9.75 mmol, 1 equiv_) was dissolved in di.chloromethane (50 ml). Boron tribromide (1.84 ml, 19.5 mmol, 2O 2 equi~r_) was added to the reaction mixture at 0°C and stirred fox 2 hours. The product was filtered and. the residue was washed with dick~loromethan.e (20 ml x 2) . 8-N(2-Hydroxy 5-aminomethylbenzoyl)aminocaprylic acid, hydrochloride salt was obtained as white solid (1.8 g, 47.37°s). Properties are listed below:
H NMR (300 Mh.z, DMSO-ds) 8: 1.29 (6H, br s) 1.5 (4H,m) . .

2 .18 (2H, t, 3 .30 (2H, q, J 6 _ 17 3.94 (2H, J Hz) _ i .3 Hz) .

q, J 6.5& Hz) 6.97 (1H, d; J 8.7 Hz) _ '7.49 (1H,d, J 6.3 .

Hz) . 8.0 (1H, s) . 8.12 (3H, br s) _ 12 _ o (IH, 22. 5 (1H, s) .

s) . Anal. for C16H25Nz04C1:Calculated: C: 55.73; H: 7_26;

N: 8.12; Cl. 10.30. Found: C: 55.59; H: 7.38; N: 8.01.;
C1: IO.l8_ Example Ib: Synthesis of N-(5-Amix~omethylsalicvloyl)-4-(4-aminophenYl) _butvr~.c acid ( (II-COOH) -5-CF~.,NH,) Salicylic acic. (50 g) was suspended in 120 g of Formalin solution (37%). Hydrogen chloride gas was bubbled through the mixture at 0°G with mechanical stirring. ZnCl:(lOg) was addea as the catalyst 5 minutes later_ The hydrogen chloride gas was slowly bubbled through the mixture for 2 hours ("h" or "hr") at o-15°C and then for another 3 h at room temperature with stirring. The reacts ion mixture was refrigerated overnight.
The precipitate foz°med was collected by filtration and dried in air_ The crude product (75 g, m.p. 115 130°C) was recrystallized from benzene to give pure product 5-chloromethylsalicy:lic acid (28_5 g, 42a), m.p. 144 - 147°C.
To a solution of acetic anhydride (1.4 g) axzd glacial acetic acid (2.7 g>, 5 chloromethylsalicylic acid (s.9 g) and one drop (using a ~~ipet) of concentrated sulfuric acid was added with stirrin~~. The reaction mixture was heated slowly to 65-70°C and held for I h. After cooling to room temperature, the reaction mixture was added gradually to 50 ml of ice water.
Two hours later, the precipitate formed was collected by filtration and dried ,z,r~ vacuo. Recrystallization from benzene gave the product O-acetyl-5-chloromethylsalicylic acid (1_7 g, 750), m.p. L19-121°C.
O-Acetyl-5-chloromethylsalicylic acid (2.9 g, 12.7 mmol) and thionyl chloride (15 g, 126 mmol) were added to 30 ml of benzene. The mixture eras reflu~ced fox 2 h with stirring.
Evaporation of ths: benzene with excess thionyl chloride gave a syrupy residue to ~nihich 30 ml of benzene was added and the solvent evaporated again.. The residue was dried in varuo overnight to remove residual SOCL~ from product O-Acetyl-5-chloromethylsalicyloyl chloride.
4-(4-Aminophenyl) butyric acid (5 g) was dissolved in 40 ml methanol_ The solution was refluxed at 80-90°C with stirring for 4 h while hydrogen chloride gas was bubbled through the solutze~n. After the xeaction mixture was cooled to zoom temperature, eahyl ether (100 ml.) was added. The mixture, which sep~~rated into two layers, was refrigerated overnight. The cr~~stalline product was collected by filtration and dried thoroughly. The filtrate was evaporated to dryness and the residue wa,> recrystallized from MeOH/benzene. The total amount of the product methyl 4-(4-aminophenyl) butyrate hydrogexz chloride obtained was 5.6 g (87.5%), m.p. 143-145°C.
Methyl 4-(4-arninophenyl) butyrate hydrogen chloride (2.6 g, 1~. _ 3 mmol) and triethylamine (2 .3 g, 22 . 6 mmol) were added to 20 ml of methylene chloride (Solution A). O-Acetyl-5-chloromethylsalicy:loyl chloride (2.8 g, 1I.3 mmol) was dissolved in 20 ml. of methylene chloride (Solution B). The solution A was addad dropwise to solution B at 0°C with stirring. The mixture was stirred at room temperature for another 2 h after the addition. The reaction mixture was then washed with 0.1 N HC1 aqueous solution twice (50 ml x 2) and saturated NaCl aqueous solution twice (50 ml x 2). The organic layer was separated and dried over an~Zydrous sodium sulfate.
The solvent was evaporated under reduced pressure to give a syrupy product [N-O-acetyl-5-chloromethylsalicyloyl))-4-4(4-aminophenyl) butyric acid methyl ester which was used in the next step without further purification.

The syrupy pro3uct obtained above was dissolved in 20 ml of chloroform (Solution C). Hexamethylenetetramine (1.58 g, 11.3 mmol) was dissolved in 20 ml of warm (about 30°C) chloroform (Solution D). Solution D was added to Solution C
and the reaction mixture was refluxed for 2 h at 60-80°C with stirring. The reaction mixture was then allowed to stand at room temperature overnight. Evaporation of the solvent gave a syrup of the complex of the previaus product with hexamethylenetetramine, which solidified after drying in vacuo for several hours.
The solid com~~lex obtained above was dissolved in 5 ml of MeOH. To this solution, 5 ml of concentrated HC1 solution was added.. The reaction mixture was stirred at 40-5o°C for 4 h. 'fhe reaction mixture was then refrigerated overn:Lght. The precipitate (NH,Cl) was filtered off. To t_he filtrate, 50m1 of MeOH was added.
The solvents were <svaporated under reduced pressure to give a syrupy product [N-(O-acetyl-5~
aminomethylsalicyl~~yl)]-4-(4~aminophenyl) butyric acid methyl, ester hydra~en.chloride which was used in the next deprotectioz~ step 3irectly without further purification.
The above syrup was dissolved in 5 m1 of MeOH. To this solution, 15 ml of 2N NaOH was added. The milk-like solution was stirred at room temperature for 4 h, while the pH was kept at 10 to 12 by adding NaOH solution. The clear solution was acidified to pl-~ S to precipitate the product, which was then collected by filtration, washed with water and ethanol and dried in air. ThE: crude product (3.0 g) was obtained with about 80°s purity checked by 1H NMR. The crude product was ref~.uxed in 30 ml of 95o alcohol for 10 min. and then filtered.

The insoluble substance was dissolved in 20 ml of water at pH
to 11. The solution was then acidified to pH 5. The precipitated produc'~ was collected by filtration and dried thoroughly; yield 2.4 g (N-(5-aminomethylsalicyloyl))-~-(4-
5 aminophenyl) butyric acid ( (IZ-COOA) -5-c~N~) (58 % for the last five steps). The m.p. was higher than 2a0°C. 1H NMR
(300MHz, DMSO-d6) ~p~>m: L.75 (2H, t) , 2 .2 (2H, t) , 2.55 (2H, t) , 3.95(2H,s), 7_05(3H,s), 7.15(lH,s), 7_5(lH,d), 7.65(lH,d), 8_18(lH,s), E.35(lH,br.s).
Example 2:Syathesis: of I-COON to XI-COOH
Compound I-COON may be prepared as follows:
A 3 L three-neck round bottom flask was fitted with an overhead mechanica'_ stirrer and a thermometer, and the Mask was cooled in an ice-bath. A solution of 8-aminocaprylic acid (100.0 g, 0.65 moles) in 2 M aqueous sodium hydroxide (1.4L) was charged into the round bottom flask_ The temperature of the solution was k~apt at about 5°C and O-acetylsal~.cyloyl chloride (198_6 g, 0.76 moles, 7..2 equiv_) was added portionwise over 7 hours. The mixture was stirred at 5°C for 12 hours to yield a yellow homogenous solution. The solution was acidif~zed with z M hydrochloric acid to pH 6.8 and was extracted with ethyl acetate (2 x 600 mL). The pH of the aqueous layer was readjusted to 6.3 and was further extracted with ethyl acetate (2 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was redissolved _40.

in a minimum volum<~ of 2,M aqueous sodium tzydroxide, and the pH
of the solution wa;~ between 9.5 and 10. The mixture was acidified with sti_=ring with 1 M hydrochloric acid to pH of about 6.2, and a s«lid was formed. The solid was filtered, washed with water (3 x 300 mL), and recrystallized from 550 methanol/watex (v/~;r) to yield Compound I-COON as an off-white solid (99.7 g, S7%). Mp 116-11.7°C. 1H NMR (300 MHz, DMSO-d~), S: 12.70 (1H, br s;, 11.95 (1H, br s) 8.81 (1H, t), 7.82 (1H, m), 7.38 (1H, m), x.84 (2H, m), 2.36 (2H, q), 2.18 (2H, t), 1.50 (4H, br m) , 1.28 (6H, m) , Anal. Calcd for C~SA21N0~: C, 64.50; H, 7.58;1 N, 5.02. Found: C. 64.26; H, 7.81; N, 4.93_ Compound III-~oOH may also be prepared by this same method using 10-amino-caprylic acid available from Tyger Scientific, Inc_ (Monmouth Junction, NJ).
Compounds VIII-COON and IX-COON may also be prepared by the same method for preparing Compound I-COOH using the appropriate starting materials.
Compound II-COO$ may be prepared as follows. Acetylsalicyloyl chloride (47.00 g, 0.24 mol, 1 equiv.) was added portionwise to a mixture o~ 4-(4-aminophenyl)butyric acid (50.OOg, 0_28 mol, 1.2 equiv.) in aqueous sodium hydroxide (?M, 300 mL)_ The reaction was stirred at 25°C for 2 hours, and the resultant solution was acidified with aqueous hydrochloric acid (1M to pH
2.1. The resultant precipitate was filtered, and was washed with aqueous hydrochloric acid (1M, 3 x 100 mL) anal water to give compound ==-COON as a pale pink solid (31.89 g, 52%). 1H
NMR (300 MH2, DMSO-d6) s~: 7.74 (1H, dd) , 7 _38 (2H, d) , 7 _21 (3H, m), 5.67 (~H, m), 6.57 (1H, m), 2.48 (2H, t), 2.07 (2H, t ) , 1. 71 (2H, m) . Anal . Calcd for C1~H1.,N0; : C, 68 _ 2 o H, 5 . 73 ;

N, 4.70. Found: C:, 68.22; H, 5.61; N, 4. G6.
Compounds VI-cOOH and VII-cOOH may be prepared by this method using the appropriate starting matexials.
compound Iy-COON many be prepared as follaw,~ . A slurry of 8-aminocaprylic acid (~S.Og, 0.471 mol) in methylene chloride (500 mL) was treated with chlorotrimethylsi.lane (102.34 g, 0.942 mol) and was heated to reflux for 2 hours. The reaction mixture was cooled to 0°C and was then treated with triethylamine (142.98 g, 1_413 mol) followed by the dropwise addition of 4-methoxy-2-acetylbenzoyl chloride (107_71 g, 0.472 mol). The reaction mixture was stirred for 0.5 hours at 0°C and then for 2 days at 25°C. Methylene chloride was removed in vacuo. NaO~T solution (2N) was added to the residue. This mixture was allowe~~ to stir for 2 hr before the mixture was acidified to pH=1 ~~rith concentrated hydrochloric acid. The resulting solid was recovered by filtration and recrystalized in methylene chloride/hexane (1/1) several times. The strueture was confirmed by 1Fi NMR. 38% Yield clean product. 8-N-(4-methoxysalicyloyl)aminocaprylic acid (59_588, 0.193 mo1)_ Compound y-cOOH may be prepared as follows.
1,8-Dzaminooctane (1.448, l0mmol) was dissolved in 5o ml of tetrahydrofuran (THF). To the solution was added dropwise succinic anhydride (l.Og, l0mmol) in 20m1 of THF at room temperature with stirring.. A precipitate formed immediately.
The reaction mixture was stirred for another 30 min. after addition. The precipitate was collected by filtration, washed thoroughly with TF:~F and dried in air. It was dissolved in 10 ml of water at pH 10. The pH was then adjusted to 1 with 1N

I~C1 water solution. The precipitate was filtered off- The filtrate was lyophilized to give a solid powder, which was then extracted with ethanol- Evaporation o~ ethanol gave 8-aminooctylsuccinic monoamide hydrogen chloride 2.2g (78%), which was used for next reaction without further purification.
8-Aminooctylsuccinic monoamide hydrogen chloride (2.2g, 7.8mmo1) was dissolved in 25 ml of 1N NaOH water solution. To the solution was added O-acetylsalicyloyl chloride (1.558, 7.8mmo1) in three portions over a 2 hour period at room temperature with stirring. The mixture wa~~ stirred for another 2 hours. The pH of the reaction mixture was adjusted to 7.
The precipitate formed was filtered off. The pH of the filtrate was then adjusted to 2. The solution was kept at room temperature fox 2 hours. The precipitate was collected by filtration and dried in air. It was purified by recrystallization from ethanol/water, yield 1.5g (55%) 8-Salicyloylaminoactyl succinic monoamide compound v-COOH, m.p.
123-125 °C. Its structure was confirmed by reverse phase HPLC
(tR = 4 _ 3 min _ ) , eJ.e_mental analysis anal 1H NMR _ Elemental Analysis for CxyH28N205= Calculated: C 62.63, H 7.69, N 7.69;
Found: C 62.84, H 7.60, N' 7.60. ~H NMR (300 MHz, DMSO-d6, ppm):
12.7 (bx, J.H) . L2 .0 (br, 1H) , 8.8 (t, 1H) , 7.8 (q. ~.H) . 7.35 (h, IH) , 6 . 8 (q, 2H) , 3 .2 (m, 2H) , 2 _ 95 (m, 2H) , 2 .35 (t, 2H) , 2 .2 (t, 2H), 1.5(m,2H) and I.2(m, IOH).
Compvnds x-COON and g=-COO$ are commercially available from Aldrich (Milwaukee, WI).
Example 3. Preparation o~ Coaiuaate 1 Acryloyl chloride (~:5 ml) was added dropwise to a solution of N-hydroxysuccinimide (57_6 g) in 77 ml of triethylamine and 750 ml of chloroform at 0°C over 40 minutes. The reaction mixture was stirred for an additional 40 minutes at room temperature, and then was washed with 300 ml of ice water and 300 ml of saturated NaCl solution. The organic layer was dried over anhydrous sodium sulfate in the presence o~ 50 mg of a-butylpyrocatechol. After filtration, the filtrate was evaporated to 10o ml, to wh~.ch 350 ml of n-hexane/ethyl acetate 'IO (6:s) was added with vigorous stirring to precipitate the product. The mixture was refrigerated overnight, and the precipitate was filtered and dried .zn vacua. Recrystallizatiori from ethyl acetate/hexane (I.:J.) gage SS g of pure product N-acryloxysuccinimide, m.p. 69-70°C. An additional 12 g of the t5 product was isolated from the mother liquor. The total yield was 910.
IS g (0.89 mol) of product N-acryloxysuccinimide and °1 mg AIEN (2,2'-azobisisobutyronitrile) (0.49 mrr~ol) were dissolved in Z0o ml of benzene. Nitrogen gas was bubbled through the 20 solution for 10 minutes and the flask was sealed. The reaction mixture was placed in an oil bath at 60°C fox 24 hours. The polymer precipitate was filtered, washed with benzene, and dried in vacuo. The yield of poly(N-acryloxysuceinimide) was 15g (quantitative).
25 3.75 g (22 mmol) of product poly(N-acryloxysuccinimide) was dissolved in 55 ml of DMF (solution E)_ 0_8 g (2.6 mmol) of N-(5-aminomethylsala.cyloyl)-8-aminocaprylic acid prepared as in Example 1 were di.ssoJ.ved at 60-70°C in SS ml DMF and 0.52g of triethylamin.e (solution F)_ The warm solution F was added 30 gradually to solution E and the mixture was stirred at room WO 00140203 PCTlUS00/00476 temperature for 2g hours. The polymer conjugate of poly(N-acrylo.~cysuccinimidE~) and N-(5-aminomethylsalicyloyl)-8-aminocaprylic acid ("unhydrolyzed polymer conjugate") was precipitated with c.ilute O.1N HCl and collected by centrifugation. Then, unhydrolyzed polymer conjugate was hydrolyzed in 40 mI of 4% NaHC~, solution for 40~ hours at room temperature and dialyzed against water for 48 hours using Spectra/Por dialysis membrane (MW cut-off 7.000)(Spectrum Inc., Laguna Hills, CA). The solution was lyophilized and dried to give 2.23 g (85%) Cf conjugatE 1 (I-COOH)-5-CIizNH-PAA. No low molecular weight compounds were found with SEC analysis. Mw =
225,300, Mn = 131,300, Mw/Mn = 1_72_ The rzitrogen content in the conjugate was 1_39%, which corresponds to 14.7% of the delivery agent in the conjugate.
Example 4: P_reparat~on of Con-iuqate 2 (II-Coos)-5-CBaNH-PAA, conjugate was prepared by the method outlined in Example 3, except that N-(5-aminomethylsalicyloyl)-4-(4-aminophenyl)butyric acid from Example 2 was used in place of the product from Example 1, and after conjugation the polymer was precipitated with 2% NaHCO, solution (rather than 0.1N HC1). The yield was 80%. SEC analysis: Mw = 210,900, Mn .- 118,600, Mw/Mn = 1.79. The nitrogen content of the conjugate was o_95% ox 12% of the delivery agent in the conjugate_ Example 5: P_rebarati.on of Conjugate 3 Alternating cc-polymer of M-PEG allyl ether and malefic anhydride available from Shearwater Polymers, Inc. (Huntsville, Alabama) was used. The co-polymer has an average molecular weight of PEG chain in the co-polymer unit of about 1500 D, and a total molecular weight of 14,000 D. 2.45g of the co-polymer was dissolved in 30 ml of DMF. 464 mg of the product from Example 1 (I-COON-5-CHzNH2) was dissolved in 70 ml of DMF where 2 ml Et;N have been added, and both solutions were mixed together and stixxed at zoom temperature for 24 hours. The reaction was monitored by HPLC analysis. Then the solution was reduced in vacuo. The solid was dissolved in l.OOm1 of water and the pH of the solution was adjusted to 10.5-11Ø This solution was dialysed against water (Mw~utorf=3, 000) for a total of 72 hours . 2 . 05g (70 % ) of (I-COON) -5-CH=NH-PEG/maleic anhydride was obtained. The final product was analyzed by reverse phase HPLC, SEC and ~TMR_ Based on HPLC data, it contained no more than 1.5% of the product from Example z. SEC
data: Mw 20,100 M# 11, 200 Mw/Mn 1.79. The nitrogen content in the conjugate was 1.07% or 10.5% w/w of the delivery agent bound to the polymex.
Example 6: Poly (ethylene glycol) fPEG] -del3.very agent coa~ucates premared via esterif icatioxi reaction A number of PE~s-delivery agent conjugates of different molecular weight an~~ functionality have been prepared using linear mono- and dihydroxy terminated PEG MW=200-4,500 and branched polyfunctional PEG of molecular weight 1,770 and 10,000 available fr~~rn Shearwater Polymers, Inc. (Huntsville, WO 00!40203 PCT/US00/00476 ~.L). The examples of the structures of PEG and the delivery agents used for the esterification reaction are indicated below:
PEG linear . HO-(C8'ZCHZ-O)m-R m=4-100 , R=H , OCH3 pEG branched ( 8 arms) : HO- (CHZCH2O) ~- (CHzCHCHaO) 6- (CHZCH20) ~-H
O
(CHzCH20) 3-H
Example 6a. The reaction was carried out in a 0.5L round T5 bottom flask equipped with a condenser and a Dean-Stark trap_ 30g of PEG MW=300 (Carbowax 300) and 5 g of I-COON were dissolved in 175 mL of toluene. 0.6g of the catalyst p-toluene sulfonzc acid monohydrate was added. The solution was refluxed for 30-a0 min. and then a second portion of Z-COOH (Sg) was added. The reaction was monitored by reverse phase HPLC and was stopped when only 3-5% of non-reacting z-COO$ was found on the chromatogram. This normally takes 3-9: hours, and in this case took approximately 3 hours. The solution was cooled to room temperature and poured into 750 mL of slightly basic water (pH=7.5-8.0 adjusted with NaHC03 saturated solution) and was left for 3-4 hours in the separation funnel. Three layers formed: a top toluene layer, an intermediate water layer and a bottom layer containing the target conjugate_ The bottom layer was separated and was reduced under ~racuum. 13.2g (63%) of oily product was obtained. NMR confirmed the conjugate's structure : -.COOCH2-~ 8=4 . L3 ppm ( trip! . ) and the absence of COOH group. The content of nitrogen was 2_54% (calculated 2.5~%). The calculated molecular weight of the conjugate is -.600. The structure of the conjugate is shown below.
I-COO-CHzGHsO (C:HaCHzO) SC~CHiOH Conjugate 4 The following conjugates were prepared by the same method using the appropriate starting materials. The molecular weights of the PEG are given in parentheses. Conjugates 14 (300) , 15 (300) . 7.6 (400) , 24 (350) , 25 (550) , 26 (350) , 27 (400) , 28 (300) , 29 (400) , ~~2 (2, 000) , 33 (600) , 35 (10, 000) , 36 (10, 000) , 70 37(10,000), 38(10,()00), 39(2,000) (the product precipitated out in a separation funnel), 41(3o0)(the product precipitated out in a separation. funnel) , 42 (300) , 43 (550) , 44 (600) , 45 (1, 000) , 46(1,000), 47(600), were px'epared by this method with appropriate startizig materials .
Example 6b. The s<~me procedure as in 6a was used to prepare a conjugate based oxz Carbowax200 and the delivery agent I-C0o13.
The yield of the conjugate was 67%. Nitrogen content was 3.OI%. The calcul<~,ted molecular weight is 470 D. The structure is shown below.
I-COO-C:H;;CS20 (C~CH=O) 3CHaCHsOH Conjugate 5 Example 6c. The r~=action was carried out using the same equipment as in 6a. 5.6g of poly(ethyiene glycol) methyl ether MW=350 (Aldrich) and 3.6g of I-COOg were dissolved in 80 mL of toluene. 0.3g of catalyst p-toluene sulfonic acid monohydrate was added. The solution was refluxed for 3 hours_ The solution was then cooled to room temperature and transferred -48~

into a separation funnel_ A mixture of 53mL of water and 7mL
of saturated solution of NaT~C03 were added. The top toluene Layer was separatec., washed with water and reduced under vacuum. '~'he ffinal product was a viscous oil, yield was 92%, and nitrogen contez:.t was 2.25%. The calculated molecular weight is 620 D. The stx'ucture is shown below:
I-COO-CH.zCHzO (C~ZC~O) 5c~c~OCS3 Conjugate 6 The following conjugates were prepared by the same method using the appropriate starting matexia7.s_ The molecular weights of the PEG methyl ether are given ~.n parentheses Conjugates 3.3 (750) , 21 (550) , 40 (l, 900) and 48 (350) .
Example 6d. The same procedure as in 6a was used to prepare a conjugate based on Carbowax400 and the del~.very agent 2-COOg_ The yield of the conjugate was 63%. Nitrogen content was 2.40.
The calculated molecular weight is 700 D. The structure is shown below_ I-COO-CHaCH,zO (CHzCHzO) ~CHzC~OH Conjugate 7 Example 6e. The same procedure as in 6a was used to prepare a conjugate based an Carbowax300 (PEG MW=300) arid delivery agent II-C008_ The yield of the conjugate was 65°s, nitrogen content-2.06. The calculated molecular weight is F00 D. The structure is shown below:
II-COO-CH2~0 ~,CHzCH20) 5CH2CHzOS Conjugate 8 Conjugates 19 and 20 were prepared by this same method except that PEG methyl ether with MW'=550 and Mw=350, respectively, was used instead of pEG MW=300.
Example 6f. The same procedure as in 6a was used to prepare a conjugate based on Carbowax400 and the delivery agent III-COOH.
The yield of the conjugate was 61°s. nitrogen content was 1_98%. The calcul.3ted molecular weight is 700. The structure is shown below.
zzi-coo-c~cgz~~ (CH.~CB20) ~CHaC$ZOH Conjugate 9 $xample 6g. The same procedure as in 6a was used to prepare a conjugate based on Carbowax600 and the delivery agent z-COON.
The yield of the conjugate was 7z%. Nitrogen content was 1.05%. The calcul~ited molecular weight is 900. The structure is shown below.
I-COO-CHZCHaO (C:H=CHzO) IICHzCHzOH Conjugate 3.0 Example 6h. IS.Og (0.0065 equiv.) of PEG MW=4600 ("Carbowax 4600NF"), 1_65g (0.0058 equiv.) I-GOON and 0.45g of p-toluene sulfonic acid monok:.ydrate were disso7.ved in 120 mL of toluene.
The reaction mixture was refluxed for 13 hours. The reaction was monitored by HPLC and was stopped when a negligible amount of non-reacting I-C.OOH remained. The solutzon was reduced under vacuum. 15.38 (92°s) of so~.i.d waxy product was recovered.
The conjugate was identified by NMR, HpLC and elemental analysis (N - 0_43 %). The calcuJ.ated molecular weight is 5,100. This conjugate has the structure below:
I-COO-G&~CHaO ('CHlCT~O) 1Q2CHaCHz-OOC-I Conjugate 11 Example 6i- 6.3g of branched 8 arms PEG2000 (actual MW=1770), 4.Og I-COON and 0_2g of p-toluene sulfonic acid monohy~drate was refluxed in 30 mL of toluene for 2.5 hours. 9.9g of a viscous oily product was obtained after toluene evaporation. Based on HPLC data, the conjugate was found to contain only a negligible amount of non-reacting original z-COON. spectrum snows the presence of an est,~r group (8=4 _ 2ppm) and conf firms the absence of carboxyl groups in the conjugate_ The yield was 85~ and the Nitrogen content was 0.620. The calculated molecular weight is 2000. The compound I-COO is attached at the PEG-OH group through an ester l:~nkage at 4 of zhe 8 °arms". The conjugate i.s denoted ~Coza,jug:~te 12" .
Examgle 7: Px~et~aration of Compound I-and its hydrogen chloride salt O-Acetylsalic~~lic acid (36g, 0.2mo1) and N-hydroxysuccinimide (23g, 0.2mo1) were dissolved in 2o0m1 of DMF. 1,3-Dicyclohe:xylcarbodiim~.de (40.5g, 0.2mo1) in 50m1 of chloroform was added dropwise to the solution at 0°C with stirring. The mixture was stirred for another 20h at room temperature. The precipitate was filtered off_ E'vaporatiori of the filtrate under reduced pressux'e gave a syrupy residue_ rt was re-dissolved fir, 200m1 of chloroform. The solution was kept in freezer for 2h. The Qrecipitate was again filtered off_ The filtrate was washed with 4% sodium bicarbonate (200m1 x 3), 10% NaCl (200m1 x 2), O.1N HCl (20om1 x 2) and 10% NaCl (200m1 x 2) water svluticns, respectively. It was dried over anhydrous sodium sulfate. Evaporation of chloroform gave a syrupy product (50g, 90°s), which solidified after being dried in vacuo overnight.
The active ester obtained above (25g, 90mmo1) in 150m1 of methylene chloride was added dropwise to a solution, of 1,8-diam~.x~ooctane (26g, 180mmo1) in 500m1 of methylene chlo~'ide over a period of 2 to 3h (one drop per second). The mixture was stirred for an additional 15h. The precipitate was collected by filtr~~tion, washed with methylene chloride arzd dried in air. It was extracted with 300r~1 of O.1N lICL water solution fox 30 min. with stirring. The insoluble substance was filtered off. The filtrate was adjusted to pH 8 to 9 with 40% sodium hydroxide. Precipitation occurred at this point.
It was kept at roon temperature for 3h. The precipitate was collected by filtration. It was dried thoroughly in air, yield lOg (42~) , m.p, 155--156°C. This compound can be further purified by recryst:allizatzon from ethanol or water. Reverse phase I-PLC: tR = 2.85 min_ 1H NMR (300 MHz, DMSO-d6) , 8 (ppm) 7. . 25 ( BTT, m) , 1.45 (4H, m) , 2 _ 1 (2H, t ) , 3 . 2 (2H, m) , 6 .45 ( 1H, h), 6_6 (1H, q), 7.1 (2H, h), 7_7 (IH, q), 6.5 (3H, br), 10.8 (ZH, br) . Elemental analysis for C~SHZ~O2N2 (+0_25H20) calculated: C 67.04, H 9.12, N 10.43; found. C 67.23, H 9.37, N
10.64_ The water content was determined by KF (.25%).
The product . from above Compovad I -CHzNHa ( 0 . 3g , 7. . lmmol ) was dissolved in lOml of warm (about 50°C) anhydrous ethanol.
Anhydrous hydrogen chloride gas was bubbled through the soluta.on for lOmin. Dry air was then passed through the solution fox lOmir... Evaporation of the so7.vent gave a solid residue, which wa~ recrystallized from EtOH/Et20 to give the hydrogen chloride salt of Compound I-CHs (0.31g, 91%), m_p.119-127.°C. Re~rerse HPLC: t~ = 2.9 min_; iH NMR (300 MHz, DMSO-d6), 8 (ppm): 1.2 (8H, m), 1.5 (4H, m), (2H, m), 3_2 2_7 (2H, m) , 6 _ 85 m) 7.35 (1H, h) , 7 . 8 (zH,7 . 9 (3H, (2H, . q) , br) , 8 . 9 ( 7.H,t ) , ( br) Elemental analysis for C15H;,502NaC1:
12 . 1H, .

calculated. C 59.90, H 8.32, N 9.32; found C b0.02, H 8.22, N
9.28.
Example 8: Prex~ar,~tion of ConiuQate 17 Monomethoxy p«lyethylene glycol 350 (2g, 5.7mmo1) was dissolved in 20m1 of methylene chloride containing 4m1 of pyridine. To this solution were added 1.2g (5_8mmo1) of nitrophenylchlorofc~rmate and 85 mg of 4-dimethylaminopyridir~e as catalyst at 0°C. The reaction mixture was stirred for 2h at 0°C and another 2h at room temperature. The reaction was monitored with revE~x'se phase H'PLC. Evaporation of methylene chloride gave the :syrupy product, which was used directly for the next step reaction without further purification.
1-N-Salicyloyl.-1,8-diaminooctane (i.5g, 5.7mmo1) prepared as above in Example: 7 was dissolved in 25m1 of 70-80°C
pyridine. The solL~tion was mixed with the p-nitrophenyl monomethoxy polyethylene glycol 350 carbonate obtained from the previous reaction. The reaction mixture was stirred at room temperature for SOh. Evaporation of pyridine under reduced pressure gave a syrupy raw product. It was dissolved in 200m1 of methylene chloride. The solution was washed with O.1N HC1 (20om1 x 3), 100 NaCl (200 ml x 2), 4~ sodium bicarbonate WO 00/40203 PCTlUS00100476 (200m1 x 3) and L0% NaC1 (200m1 x 2) water solutions. It was dried over anhydrous sodium sulfate. Reverse phase HPLC was used to monitor both the reaction and the work-up process.
Evaporation of met.hylene chloride gave the product 1.9g (53%).
The structure way confirmed by reverse phase HPLC ( tR =
5.43min.), N analysis (the calculated value is 4.32, the found value was 4.04%) and NMR. A new triplet peak for one amide proton was observed at 7.2ppm; the chemical shift of methylene proton linked to the free amino group of the starting material shifted from 2.6ppm to 3.Oppm when the amino group was converted to the urethane. The calculated molecular weight is 640.
Conjugate 34 ~aas also prepared by this method using the product as prepare<i in Example 2 and PEG MW=2,000.
t5 Example 9. Prepay<ition of Corr,~iuaate 1$
~tonomethoxy polyethylene glycol 350 (3.5g, l0mmol) was dissolved irz 20m1 of chloroform containing 1.8g (l8mmol) of triethylamine. To this solution, 2.Og of tosyl chloride (z0.5mmol) was added with stirrzng. The reaction mixture was stirred overnight a.t room temperature. The precipitate was filtered off. The filtrate was diluted with IOOml of chloroform. The sclution was then washed with O.1N FiCl (100m1 x 3), 10% NaCl (10om1 x 2), ~°s sodium bicarbonate (100m1 x 2) and lOs NaCl (100m3 x 2) water solutions_ The chloroform layer was dried over anhydrous sodium sulfate_ Evaporation of chloroform gave the tosylated monomethoxy polyethylene glycol 350, which was used fox the following reaction.

1-N-SalicyJ.oyl-1,8-diaminooctane (2.648, l0mmol), D32, was dissolved in 30m1 of 70-80°C pyridine. To this solution, the tosylated monometh,oxy polyethylene glycol 350 obtained from the previous reaction in 2oml of pyridine was added dropwise over 40 minutes with stirring. The reaction was stirred at 'TO °C
for 5h and at room temperature overnight. The precipitate was filtered off. The filtrate was evaporated under reduced pressure to dryness to give a syrup raw product, which was dissolved irz 150m1 of methylene chloride. The solution was washed with 0.1N H~~l (150m1 x 3) and 20% NaCl (lSOml x 2) water solutions. The me~~hylene chloride solution was collected and dried over anhydrous sodium sulfate. lifter evaporation of methylene chloride, an oily substance was obtained. Tt was then dissolved in 200m1 of water. The milk solution, obtained 75 became clear after extraction with diethyl ether five times E200m1 x 5). The clear water solution was then extracted with 200m1 of methylene chloride. The methylene chloride layer was collected and dried ovex anhydrous sodium sulfate_ Both the reaction and the work-up process were monitored by reverse phase HPLC. Evaporation of methylene chloride gave the product 0 _ oo~g (29 0 > . The structure was confirmed by reverse phase ~IPLC
(tR = 3.73min.l, N analysis (the calculated value zs 3.65%, the found value was 3.39%) arid NMR. The peak of two protons of amine salt was observed at 8.5ppm. Four aromatic protons of p-toluenesulfonic acid were found at 7.lppm and '7.5ppm. Two methylene protons of the methylene group linked to the free amino group of the starting maternal shifted from 2.5 ppm to 3.6ppm when the amino group was converted to the p-toluenesulfonie acid salt form. The calculated molecular weight is 768.

W~ 00/40203 CA 02358463 2001-07-05 PCT/US00/00476 Example 10: Preparation of Con~uaate 22 2-(monomethox:y polyethylene glycol 350)acetic acid (MS~1=350) (12.08, 29.4mmo1) in 50 ml of methylene chloride was added in a soluticrz of 4.Og (35mmo1) of N-hydroxysucein.imide in 8 ml of DMF and 20 ml of methylene chloride. To this solution, 7.4g (36mmo1) of bCC in 30 ml of methylene chloride was added.
'f0 The reaction mixture was stirred at room temperature for 2~h.
The precipitate was fzltered off. The filtrate was kept in the fxeezer for 2h. Again the precipitate was filtered off.
The filtrate was diluted with 10o ml of methylene chloride.
'flee solution. was washed with O.1N HC1 (200m1 x 3) , 10a NaCl ( 2 0 Oml x 2 ) , 4 o sodium bicarbonate ( 2 0 Oml x 3 ) and ~. 0 s NaCl (200m1 x 2) water ;solutions an,d dried over anhydrous sodium sulfate. Evaporation of methylene chloride gave the PEG acet;c acid active ester :i.ntermediate 8.8g (58°s) , which was used for the following reaction, without further purif~.cation_ 1-N-Salicyloy=.-~., 8--diaminoocta~.e (3 .6g, 13 .6mmo1) was dissolved in 4S m1 of 70-8o°C pyridine. To the solution was added 6.9g (13.6mmo1) of the PEG acetic acid actzve ester prepaxed above. Tree xeaction mixture was stixred under nitrogen atmosphere: for 4h at 70 °C. It was then kept at room temperature overnight. Reverse phase HPLC was used to monitored the reaction. Evaporation of pyridine gave a syrupy raw product. It wa.s dissolved zn 200 ml of methylene chloride.
The solution was v~ashed with 0 .1N ~i'Gl (200m1 x3 ) , 20% NaCl (200m1 x2), 4% sodzum bicarbonate (200m1 x 3) and ZOo NaCI
(200m1 x 2) watex solutions. The methylen:e chlorzde solution was collected and dried over anhydrous sodium sulfate.
Evaporation of met.hylene chloride gave the syrupy product (6.6g, 74a), whicr. was further purified as follows. The syrupy product was dissolved in 200 ml of distilled water. The solution was refrigerated (5-10°C) overnight_ The precipitate was then carefully filtered off until a clear filtrate was obtained. The solution was extracted with l0oml of methylene chloride twice. The methylene chloride solution was dried over anhydrous sodium sulfate. Evaporation of methylene chloride gave the product 6.3g. Trace amount o~ methylene chloride was removed from the s°~rupy product by bubbling nitrogen thx-ough the product. The ~~xzemical. structure was confirmed by reverse phase HPLC (t,~ = 4_6 min.), nitrogen analysis (the calculated value is 4.28, the, found value was 4_18) and NMR. A new triplet peak for one amide proton was observed at 7.65ppm. The chemical shift of methylene proton linked to the free amino group of the start__ng material shifted from 2.6ppm to 3.lppm when the amino group was converted to the amide. The calculated molecula~x weight is 654.
Conjugate 23 Gras also prepared by this method except that 2- (monomethoxy pol~.~ethylene glycol 550) acetic acid (M!~=550) was used instead of the ?rtW=350 material.
Conjugate 30 was alsa prepared by this method except that the starting materials were 2-(manomethoxy polyethylene glycol 350) acetic acid and the product from Example 1 (I-COOx)-5-C~
N~) (instead of 1-N~-salicyloyl-I, 8-diaminooctane) .

Example Zl: Pre~tratioa of Coniuc~ate 31 S.Og(18.9mmol,) of 1.-N-salicyloyl-I,8-dzaminooctane (Compound z-C~NrH2) prepared as in Example 7 was dissolved in 200mL of 90-100°C :pyridine, and then cooled to room temperature. The resulting suspension of N~salicyloyl-1,8-diaminooctane was added by pipet to 5.73g(28.4mmo1) of ~-nitrophenyl chloroformate dissolved in 200mL of pyridixZe and stzrred fax 15 mirxutes. The solvent was removed by evaporation leaving a red ozl with precipitate. The oil was dissolved in 100mL of dichLoromethane and the precipitate was filtered off.
The dichloromethane solution was washed with O.I N HC1 (IOOmL,three times?, 5o sodium bicarbonate solution ('75mL, three times), dried over sodium sulfate and evaporated to yield 4.3g of an orange-brown solid at 53s yield of N-(4-oxycarbonyl-nitrobenzene)-N-Sa:licyloyl-I,8-diaminooctane.
The above product was then reacted with metho~~ypoly (oxyeth;rlene/oxypropylene) -2-propylamine HTJ-506 manufactured by Huntsman (~iouston, TX) (hereafter referred to as methoxyPEG=,ooo-I'T~'~z) ~ ~--95J (4.54mmol) of the above product was dissolved ix~ 2t~mL of acetonitrile and a precipitate (appro~c. 220mg) wa:; filtered off . The solution was added to 4 _ 90g (4 _ 55mmol) mEahoxyPEGl,ooo-~2 dissolved irx 20mT~ of aceto~.itrile_ The reaction was monitored with HPLC and completed after 3.5 hours at room temperature. The solvent was removed by evaporation and 6.4g of a yellow-orange oil was found. ~'he oil was dissolved in 40mL of dichloromethane_ This solution was washed twice with 50mL of O.IN HC1 (to remove unreacted methoxyPEG~,ooo-~z> ~ once with IO%NaCI solutzon, and continuously washed with 50mL portions of S% sodium bicarbonate solution until ~k-nitrophenyl was removed (as detected by reverse phase HPLC). xhe solution was dried over sodium sulfate and evaporated to yield 3.5g of a yellow-orange solid_ This solid was tr,en dissolved in 50mL of distilled water and washed with 30mL c~f diethyl ether. The water layer was collected and the final pxoduct was extracted from water with dichloromethane, dried over sodium sulfate and evaporated to yield 3.Ig of a yellow-orange wax at 57% yield of Conjugate 31.
It has been, named N-PEG-N'-(N-salicy7.oy1)~heptylamine urea.
The purity and structure was confirmed bar reverse phase HPLC, elemental. analysis (calculated value of N is 3.02%, found -3.09%) arid NMR. Two new multiplet peaks at S=5.57 ppm and 5.79 ppm of equal intensity which are characteristic far substituted areas were observed, and the peak o~ methylene proton next to amino group of starting material at 2_6 ppm disappeared. The ca3lculated MW is 1400.
Example 12: Recomb~.nan.t Human Growth Hormone (rhGH) Oral/Intracolc>ni.a Delivery Oral gavage (F'O) arzd/or intracolanic (IC) dosing solutions of delivery agent compound and rhGH in water, phosphate buffer (PB) or 5% aqueous ethanol were prepared. Typically, a solution of the cor..jugate was prepared by mixing in water and stirred. The final dosing solutions were prepared by mixing the conjugate solution with an xhGH stock solution (typically z5 mg rhGH/ml) and diluting to the desired volume (usual:Lx 3.0 ml). The compounds and rhGH dose amounts are listed below in Table 1.
_59_ Male Sprague-~Dawley rats weighing between 200-2508 were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. A
dosing group of f~.ve rats was administered one of the dosing solutions. for oval gavage (PO), an llcm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, wh~.ch was then wiped dry. The catheter was placed down. the esophagus leaving 1 cm of tubing past the 90 rat's incisors_ Solution was administered by pressing the syringe plunger. For intracolonic (IC) dosing, a 7.5 cm Rusch catheter tube (Ere:zch 8 or 6) was adapted to a syringe with an Eppendorf pipette ;yip. The syringe was filled w~.th the 0.5 ml dosing solution by drawing the solution through the catheter tube. The cathete~~ tube was wiped dry. K-Y jelly was applied to the tip, avoidixzg contact with, the eye of the tube, and the tube was inserted into the colon through the anus until the tube was no Iox~ger visible. The solution was injected by pressing the syringe plunger, and the tube was removed.
blood samples were collected serially from the tail artery, typically ~a time = 0, 15, 30, 45, 60 and 90 minutes for oral and 0, 10, 20, 30, 60 and 90 for IC dosing. Serum rFiGH
concentrations werE quantified by an rHGH immunoassay test kit (Kit # K1.F~015 fron. Genzyme Corporation Inc_, Cambridge, MA).
Prev~.ous studies indicated baseline ~ralues of about zero.
The results of PO administration are presented in Table Z
below wherein rhGH was administered with (a) delivery agent I
alone, (b) Conjugate 1, and (c) Conjugate 3. The experiments were performed at L/10 the delivery agent concentration versus that of the conjugate. Thus, at a dose of 200 mg/kg conjugate.

the actual amount of delivery agent dosed was 20 mg/kg_ Wi~,h such a concentration of delivery agent complexed with polymer there was evidencE: of systemic delivery.
Table 1: oral Admin~.stration of xhGH
Rat. GrouQ Base Mix115Min30 Min45 Min60 Mi_n90 lice 1 7625 (a) 0 84.73 1_3.19 0 IO_565 0 2 -2 (a) 0 79.98 22.69 0 5_49 0 3 -3 (a) 0 48.72 1_82 0 7_905 0 4 -4 (a) 0 45.34 46_52 35_53 34_885 2.715 S -5 (a? 0 0 58.44 0 3_922 0
6 7626 (a) 0 64_2 18,99 4_29 10.13 0
7 -2 (a) 0 43.14 23.44 18.35 15.93 1_47
8 -3 (b) 0 6.26 0 0 4_92 0
9 -4 (b) 0 30.7. 0 0 10_025 0 -5 (b) 0 26_15 0 0 9.985 0 II 7627 (b) 0 5_35 0 0 4.28 0 _1 12 -2 (b) 0 14.99 0 0 3_39 0 23 -3 (b) 0 1.3 0 0 6 _ 075 0 .74 14 -4 (b) 0 16_05 0 0 21_495 0 -5 (c) 0 14.42 0_1 0 11.26 0 1.6 7628 (c) 0 7.87 0 0 15.19 0 _1 17 ~2 (C) 0 14.31 0 0 17_545 0 I8 -3 (c) 0 0 3.57 0 4_745 0 19 -4 (c) 0 28.76 s3.~.2 0 2.7s 0 -s (c) o s.os o 0 0.235 0 Dose volume for IC administration was lml/kg. rhGH dose was Z mg/kg. For zC dosing, tkZe five samples from each time -6'i -WO 00/40203 PCTIUS00i00476 period were pooled and the maximum concentration for each group (Cmax) are reported beLo~w in Table 2.
Table 2. :Zutracolox~ic Delivery of rhGH in Rats CorijugateI~osiz~g cor~j rhGH Meaa Feak agate solution Dose Dose Serum medium (mg/kg) (mg/kg) [xhGH]

(rzg/ml) SD

1 pB 2 5 1 1 -t- 2 3 Ps 25 1 14 34 4 p$ 25 I 6 + 16 4 -''~ aq 25 1 182 ~ J.s EtoH

4 5% aq. 62 I 172 -~ 29 EtOFi 6 S% aq- 25 1 168 t 54 Etox 7 5a aq. 25 1 205 95 ~tOH

8 5% aq_ 25 1 101 32 EtOIi vrater 7. 2 0 1 3 0 -f 2
10 PB 2 5 ~. 0 - 5 1.

12 5% act. 2g 1 0 ~toH

13 5b aq. 25 1 63 43 :EtOFT

14 Sv aq 25 1 75 ~ 3S

:aoA

17 5'~ aq- 25 1 136 t 37 i'stOH

18 5'> aq. 25 I 140 51 FtOH

22 5-"s aq_ 25 2 164 53 IaOII

24 pB 25 1 0 Example 13 - Parathyroid Hormone Delivery (PTH 1-34) WO OOf40203 PCTlUS00100476 Oral/IntracoLonic Del.iverv Oral gavage (PO) and/or intracolonic (TC) dosing s<~lutions of delivery agent compound and human parathyroid hormone residues 1-3~k (PTF3:) in water and varous aqueous solutions as indicated in the Table 3 below (PEG 300 and PEG 350 is available fxom Aldrich, (Milwaukee, 'WI). Kollidon 17PF is polyvinyl-pyrrolidone available from Aldrich. PG is propylene glycol)_ Typically, a solution of the conjugate was prepared in the appropriate medium and stirred_ The final dosing solutions were prepared by mixing the conjugate solution with a PTH stock solution (typically 5 mg PTH/ml) and diluting to the desired volume (usually 3_0 ml). The final compound, P'hH and volume dose amount:, and the dosing medium used are listed below in Table 3.
Male Sprague-I~awley rats weighing between 200-2508 were fasted far 24 hour~> and administered ketamine (44 mg/kg) and chlorpromazine (l.:S mg/l~g) 15 minutes prior to dosing.
dosing group of fine rats was administered one of the dosing solutions. For oral gavage (PO), an llcm Rusch 8 French catheter was adapted to a I ml syringe with a pipette tip_ The syringe was filled with dosing solution by drawing the solution through the catheter, which, was then wiped dry. The catheter was placed down the esophagus leaving 1. cm of tubing past the rat's incisors. Sclution was administered by pressing the syringe plunger. For intracolonic (zC) dosing, a 7.5 cm Rusch catheter tube (French 8 or 6) was adapted to a syringe with an Epgendorf pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter tube_ The cathetex tube was wiped dry. K-X jelly was applied to the tip, avoiding contact with the eye of the tube, and the tube WO 00!40203 PCT/US00/00476 was inserted .into the colon through the anus until. the tube was n,o longer visible. The solution was injected by pressing the syringe plunger, and the tube was removed.
B~.ood samples were collected serially from the tail artery, typically at time = 0, z5, 30, 45, 60 and 90 minutes for oral and 0, 10, 20, 30, 60 and 90 minutes fox IC dosing.
Serum PTH concentrations were quantified by a PTH
radioimmunoassay kit (Kit # RZK 6101 from Peninsula Laboratories, Inc., San Carlos, CA). Prev~.ous studies indicated baseline values of about zero. Results from the f~.ve rats in each group were averaged for each time point_ The maximum and the arEea under the curve (AUC) are reported below in Table 3.

'able 3. Oral/Intracolonic Delive~y of PTH in Rats Conju Method dosing volume ConjugatePTH Mean Peak RUC
-gate of medium dose Dose Dose Serum [PTH~
Admini- (i.n (ml/kg)(mg/kg) (ug/kg)(pg/m~,) strationwater) t SB

4 pp zo% ntoFFy 100 200 g6 86 1285 4 pp ~o# praGaoo1 100 200 39 t 27 1694 4 p0 15% 1 100 200 44 ~ 44 784 Koll:~aon 4 pp io% PF:G3oo1 150 200 122 t 60 3520 4 p0 s% Faox 1 150 200 36 t 32 1184 4 QO is% 1 154 200 126 Z23 3684 Kolhdon 17i>P

p0 10% PF:G300y 300 200 410~ 290 9315 4 p0 s% stoFZ 1 300 200 94 27 2627 4 pp is& 1 300 200 298 t 265 6276 Kollidon 17E~F

4 pp 10% PE;G30oy 300 200 87 24 4165 4 PO 30~ 8F;G30o1 300 200 106 43 4572 14 IC s% ~~~ox 0.5 100 25 501 34 16335 22 p0 s% civric1 100 200 855 t 511 27&09 acid tP$_3.8s) 22 PO ~t"r 1 100 200 34 * 13 x.286 tpFi=7 . 75 ) 22 PO 5% NaaCO31 100 200 225 -1- 1067:4 tpxlo.za 171 14 PO 5% F,t:oFF~. 250 200 320 * 114 10933 16 p0 s% stOx 1 250 200 265 47 9965 32 PO 'aaL<r 1 100 200 246 119 4426 22 PO 7.sfi ~, 100 200 3508 +' 249861 PEC35o 267 22 PO ls% ~ 1 100 200 2755 ~ 537 242849 22 PO lsf~ 1 100 200 3173 * 250 243838 Kollidon 17PF' 22 PO ~tEr 1 100 200 3577 113 280258 22 PO 5% cit:riay. 100 200 946 .'T. 27117 acf 3 701 (pi~I-2 . 78 ) 22 PO 5'~ ~;~3 X 100 200 899 t 730 20245 tpFi=~Ø
04 ) 22 PO water 1 100 200 1678 ~- 43639 (pFi=7 763 . 82 ) 22 PO water y 100 200 118 112 5696 22 PO zs% pEU3soi 100 200 113 + 55 5201 22 PO 15% :.aG 1 100 200 273 t 235 8193 22 PO lsg 1 100 200 126 -!~ 4993 Kollidoa 117 17P:' 24 PO s~ Faox 1 100 200 48 ~ 32 2290 -25 p0 s% s=ox 1 100 200 287 134 10486 30 p0 s% F:tos y 100 200 0 0 VV~ 00/40203 CA 02358463 2001-07-05 Conju Method dosing Volume ConjugatePTH Mean teak AUC

-gate of medium dose Dose Dose Serum (PTH~

Admini-(iz~ (ml/kg)(~1k8) (~tJ/k9')(pg/ml) stratxonwat~~x) t SE

49 p0 5~ FtoH 1 100 200 73 t 73 2785 9 pp 5~ xtox 1 100 ~ 200 1467 77 106705 .

PTH was also administered in capsules via PO and IC
routes. Mini hard gel capsules (size 9) with a total volume 25 Lt.L and raanu~actured by Torpac Inc . ( Fairf field, N'J, USA) were used. For IC administration, 25 ~Cg PTH/capsule and 15 mg/capsule conjugate 22 was used. For PO administration, 100 ~.g PTH/capsule and 20 mg/capsule conjugate 22 was used. The powder of PTH was mixed faith the oily conjugate in a vial in the above-mentioned ratio. A clear solution resulted.
Solution was added to capsules by syringe and weighed to reach the appropriate we:Lght .
Capsules were administered as above, with the following changes. For PO dosing, a rat/hamster capsule dispenser (available from Toa~ac, znc., Fazxfield, NJ) was marked 1o cm from the dosing end_ The capsule was placed into the dispenser, which w~cs inserted into the mouth and down the esophagus until the ~.0 cm mark meets the incisor teeth. The plunger was pushed and withdrawn. The dosixxg was optionally followed by administration of about 1.0 ml water (as in PO
dosing of solutioz~N). For IC dosing, a rat/hamster pzll dispenser was marked 7.5 cm from the dosing end. The capsule was placed into the dispenser. A small amount of KY jelly was placed at the tip cf the dispenser, and the dispenser inserted into the anus up tc the 7.5 cm mark. The plunger was pressed and withdraw_ WO 00/40203 CA 02358463 2001-07-05 PCTlUS00/00476 Results were obtained as above and are shown below in Table 4.
Table 4_ Oral/Intracolonie Delivery of PT~~ in Rats ConjuMethod dosing Dose Conju- P'f~i Mean Peak AUC

-gateof medzeam gate Dose Serum IPTH) Admini- fin Dose (~g/kg)(pg/mI) sLrationwater) (mg/kg) ~ SE

22 ~p cspsu:_e1 20 100 227b 'f' 242288 capsule 22 zC etcpsu:.e1 15 25 3438 '~' 80928 capsule 14 Example 3 - HE arias Deli.very zntracolcaiia Delivery Intracalanic (zC) dosing solutions containing a conjugate and heparin sodium USP in 25% aqueous propylene glycol. were prepared_ Typically, the oily conjugate and powdered heparin (about 166-182 TU/mg) were d~.ssolved in 25% v/v aqueous propylene glycol, vortexed and placed in a soxzicator (about 37°C). The pH was adjusted to about 7 (6.5 to 8_5) with aqueous NaOH (2N). The dosing solut~.on was sonicated to produce a clear solution. The final volume was adjusted to 3.0 ml. The final conjugate dose, heparin dose and volume dose amounts are listed beJ.ow in Table 5.
MaJ.e Sprague-Dawley rats weighing between 2~5-350g were fasted for 24 hours and were anesthetized with ketamine hydrochloride (88 mg/kg) intramuscular2y immediately prior to dosing. A dosing group of five rats was administered one o~
the dosing solutions. For intracolonic (zC) dosing, a 7.5cm, 8 WO OOf40203 PCT/US00100476 fr l2usch catheter was adapted to a 1 ml syringe with a pipette tip. The dosing c~~theter was inserted into the colon through the anus until the tube was no longer visible. The dosing solution was expre:;sed slowly into the Golon.
Citrated blood samples were collected by cardiac puncture following the administration of ketamine (88 mg/kg), typically at time ~ 0.25, 0.>, 1.0 and 1.5 hours. Heparin acti~rity was determined by utilizing the activated partial thromboplastin time (APTT) according to the method of Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods, Philadelphia, PA, W.B. Sounders (1979). Previous studies indicated baseline values of about 20 sec. Results from the five rats in each group were averaged for each time point. The maximum is reported below in 'fable 5.
Table 5. Izr.tracolonic Delivery of Fieparia ConjugateMethod of volume Conjugate Heparin Mean Peak Admini- dose Dose T>ose ApTx (sec) stratiori (ml/kg) (mg/kg) (mg/kg) SD

4 IC 1 50 25 - ~ . -163 f 14~

The above mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety.
Many varz.ations of the present invention will suggest themselves to those. skilled in the art in light of the above detailed description. All such obvious variations are within the full. intended :;cope of the appended claims.

Claims (34)

WHAT IS CLAIMED IS:
1. A polymeric delivery agent comprising a polymer conjugated to a modified amino acid or derivative thereof via a linkage group selected from the group consisting of -NHC(O)NH-, -C(O)NH-, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, and carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid.
2. The polmeric delivery agent of claim 1 wherein the modified amino acids axe acylated or sulfonated amino acids, ketones or aldehydes of acylated or sulfonated amino acids, salts thereof, or polyamino acids or polypeptides of any of the foregoing.
3. The polymeric delivery agent of claim 1 wherein the polymer is selected from the group consisting of polyethylene;
polyacrylates; polymethacrylates; poly(oxyethylene);
poly(propylene); polypropylene glycol; polyethylene glycol (PEG); PEG-maleic anhydride copolymers; and derivatives and combinations thereof.
4. The polymeric delivery agent of claim 1 wherein the polymer has a molecular weight of from about 100 to about 200,000 daltons.
5. The polymeric delivery agent of claim 4 wherein the molecular weight is from 200 to about 20,000 daltons.
6. The polymeric delivery agent of claim 5 wherein the molecular weight is from about 200 to about 600 daltons.
7. The polymeric delivery agent of claim 1 wherein the the polymeric delivery agent comprises units having the formula or salts thereof where R1 is a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of -NHC(O)NH-, -C(O)NH-, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2H-, -NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, and carbon-carbon bond;
R2 is H ox -CH3; and R19 is H or -COOH.
8. The polymeric delivery agent of claim 7 wherein R1 is -R3-R4 where R3 is -NHC(O)NH-, -C(O)NH, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, -CH2NHC(O)O-,-OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-,-OCH2C(O)NH-, -NH-, -O-, or carbon-carbon bond; and R4 has the formula where R5, R6, R7, R8, and R9 are independently a bond to R3, or H, Cl, Br, F, -OH, -CH3, -OCH3, or -(CH2)m CH3;
R10 is a bond to R3 or -COOH or -C(O)NH-R11-R12;
R11 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or -R13-R14-;
R12 is a bond to R3 or is -COOH, -NH2, -OH, -C(O)-R15, -COO-R15, -NHR15, -CR15, Cl, or Br;
R13 is a substituted or unsubstituted phenylene;
R14 is a substituted or unsubstituted, linear or branched alkylene having a chain length of froth about 1 to about 5;
R15 is a bond to R3; and m is from about 1 to about 4.
9. The polmeric delivery agent of claim 8 wherein R4 is selected from the group consisting of and salts thereof.
10. The polymeric delivery agent of claim 1 wherein the polymeric delivery agent comprises units having the formula:

or salts thereof where R16 is a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of -NHC(O)NH-, -C(O)NH-, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, and carbon-carbon bond;
R17 is -OH, -OCH3, or -R18;
R18 is defined as R1~ above; and R24 is a polymer having units of -(CH2CH2O)-, -(CH(CH3)CH2O)-, or a combination thereof.
11. The polymeric delivery agent of claim 10 wherein the polymeric delivery agent comprises units having the formula:
or salts thereof where R23 is H or -CH3; and n is from about 3 to about 200.
22. The polymeric delivery agent of claim 12 wherein R16 and R18 are independently -R3-R4 where R3 is -NHC(O)NH-, -C(O)NH-, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2--NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, or carbon-carbon bond;
and R4 has the formula ~
where R5, R6, R7, R8, and R9 are independently a bond to R3, or H, Cl, Br, F, -OH, -CH3, -OCH3, or -(CH2)m CH3;
R10 is a bond to R3 or -COOH or -C(O)NH-R11-R12;
R11 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 2 to about 11 or -R13-R14-;
R12 is a bond to R3 or is -COOH, -NH2, -OH, -C(O)-R15, -COO-R15, -NHR15, -OR15, Cl, or Br;
R13 is a substituted or unsubstituted phenylene;
R14 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about S;
R15 is a bond to R3; and m is from about 2 to about 4.
13. The polymeric delivery agent of claim 12 wherein R4 is selected from the group consisting of and salts thereof.
14. The polymeric delivery agent of claim 1 wherein the polymeric delivery agent comprises units having the formula:
or salts thereof where R20, R21, and R22 independently axe H or a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of -NHC(O)NH-, -C(O)NH-, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, and carbon-carbon bond;
a, b, and c independently are integers from about 1 to about 50; and d ranges from about 2 to about 10.
15. The polymeric delivery agent of claim 14 wherein R20, R21 and R22 are independently -R3-R4 where R3 is -NHC(O)NH-, -C(O)NH-, -NHC(O)-, -OOC-, -COO-, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O)CH2O-, -OCH2C(O)NH-, -NH-, -O-, or carbon-carbon bond; and R4 has the formula where R5, R6, R7, R8, and R9 are independently a bond to R3, or H, Cl, Br, F, -OH, -CH3, -OCH3, or - (CH2)m,CH3;
R10 is a bond to R3 or -COON or -C(O)NH-R11-R12;
R11 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or -R13-R14-, R12 is a bond to R3 or is -COOH, -NH2, -OH, -C(O)-R15, -COO-R15, -NHR15, -OR15, Cl, or Br;
R13 is a substituted or unsubstituted phenylene;
R14 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5;
R15 is a bond to R3; and m is from about 1 to about 4.
16. The polymeric delivery agent of claim 15 wherein R4 is selected from the group consisting of and salts thereof.
17. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 1.
18. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 7.
19. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 10.
20. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 14.
21. The composition of claim 17. wherein the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, and a combination thereof.
22. The composition of claim 21, wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.
23. The composition of claim 22, wherein the biologically active agent is selected from the group consisting of human growth hormone, recombinant human growth hormone, bovine growth hormone, porcine growth hormone, growth hormone-releasing hormone, an interferon, .alpha.- interferon, .beta.- interferon, .gamma.-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, cyclosporin, vasopressin, cromolyn sodium, soium chromoglycate, disodium chromoglycate, vancomycin, parathyroid hormone, fragments of parathyroid hormone; desferrioxamine, antimicrobials, anti-fungal agents, vitamins; analogs, fragments, mimetics and polyethylene glycol-modified derivatives of these compounds; and any combination thereof.
24. The composition of claim 23 wherein the active agent comprises insulin, unfractionated heparin, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, parathyroid hormone, erythropoietin, human growth hormone, recombinant human growth hormone, or combinations thereof.
25. A dosage unit form comprising:
(A) the composition of claim 17; 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.
26. The dosage unit form of claim 25, comprising a tablet, a capsule, a powder, or a liquid.
27. A method fox administering a biologically-active agent to an animal in need of the agent comprising administering to said animal the composition of claim 17 via a route selected from the group consisting of orally, intracolonically, and intraduodenally.
28. A method for preparing a composition, said method comprising:
mixing:
(A) an active agent;
(B) the polymeric delivery agent of claim 1;
and (C) optionally, a dosing vehicle.
29. A compound selected from the group consisting of and salts thereof.
30. A composition comprising (a) an active agent; and (b) the compound of claim 29.
32. A dosage unit form comprising:
(A) the composition of claim 30; 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.
32. The dosage unit form of claim 31, comprising a tablet, a capsule, a powder, or a liquid.
33. A method for administering a biologically-active agent to an animal in need of the agent comprising administering to sand animal the composition of claim 30 via a route selected from the group consisting of orally, intracolonically, and intraduodenally.
34. A method for preparing a composition, said method comprising:
mixing:
(A) an active agent;
(B) the compound of claim 29; and (C) optionally, a dosing vehicle.
CA002358463A 1999-01-08 2000-01-07 Polymeric delivery agents and delivery agent compounds Abandoned CA2358463A1 (en)

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US6627228B1 (en) 2003-09-30
AU3581300A (en) 2000-07-24
WO2000040203A2 (en) 2000-07-13
BR0008590A (en) 2001-10-30
EP1146860A4 (en) 2002-07-03
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NZ512581A (en) 2002-12-20
US7727558B2 (en) 2010-06-01
EP1146860A2 (en) 2001-10-24
IL143962A0 (en) 2002-04-21
US7208483B2 (en) 2007-04-24
US20030232085A1 (en) 2003-12-18
CN1338924A (en) 2002-03-06
US20070141022A1 (en) 2007-06-21

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