Controlled release of biologically active compounds from multi-armed oligomers

• US 8,163,806 B2
• Filed: 09/19/2011
• Issued: 04/24/2012
• Est. Priority Date: 09/04/2007
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao S
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): AL-AWADI, DANAH J
• Application Number:
  US13/236,622
• Publication Number:
  US 20120010284A1
• Time in Patent Office: 218 Days
• Field of Search: None
• US Class Current: 514/772.3
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/552 one of the codrug's components being an antibiotic
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 39/02 Antidotes

Abstract

The present invention relates to the discovery of biodegradable multi-armed oligomers wherein the end groups of these oligomers have been functionalized with biologically active molecules. The resultant multi-armed oligomers end-functionalized with biologically active molecules have a controllable degradation profile. The hydrolytic degradation of oligomers of the present invention releases the biologically active compound as such with no change in native chemical structure.

Claims

1. An oligomer or pharmaceutically acceptable salt thereof of formula I or II:

[R¹—

O—

(Y)_b—

C(O)CH₂—

(X)_a—

OC(O)]_w—

R 

 

I

[R²—

C(O)O—

(X¹)_a—

CH₂C(O)—

(Y¹)_b—

O]_w—

R 

 

II

wherein;

R¹—

O—

is a biologically active compound residue selected from;

[6]-gingerol, 3-pentadecylcatechol, 4-salicyloylmorpholine, 5-chloro-8-quinolinol, 8-hydroxyquinoline, acacetin, albuterol, aloe-emodin, aloin, amoxicillin, apigenin, apiin, apocynin, apomorphine, aspidinol, azacyclonol, baptigenin, benzestrol, benzoresorcinol, biochanin A, butylated hydroxylanisole, butylated hydroxytoluene, carbidopa, carbuterol, cefprozil, chlorquinaldol, chrysin, coniferyl alcohol, coumestrol, coumetarol, daidzein, daphnetin, datiscetin, daunorubicin, deoxyepinephrine, diosmetin, diresorcinol, doxorubicin, ellagic acid, embelin, epirubicin, equol, eriodictyol, esculetin, esculin, ethylnorepinephrine, euginol, eupatorin, ezetimibe, fenadiazole, fisetin, flavanols, flavanones, flavones, formononetin, fraxetin, fustin, galangin, genistein, gepefrine, glycitein, gossypol, guaifenesin, harmalol, hematoxylin, homoeriodictyol, hydroxyamphetamine, hypericin, irigenin, isoproterenol, isoquercitrin, kaempferol, luteolin, mangostin, m-chlorophenol, metyrosine, morin, mycophenolic acid, myricetin, naringenin, n-methylepinephrine, nylidrin, orcinol, orobol, osalmid, oxantel, p-anol, paroxypropione, pentachlorophenol, phloretin, phloroglucinol, pinosylvine, plumbagin, p-pentyloxy-phenol, pratensein, prunetin, pyrocatechol, pyrogallol, quercetagetin, quercetin, resacetophenone, rhamnetin, rhein, rutin, sakuranetin, salicyl alcohol, salicylanilide, scopoletin, scutellarein, serotonin, thymol, vanillic acid, and vanillin;

R²—

C(═

O)O—

is a biologically active compound residue selected from;

3,5-diiodothyronine, 3,5-di-iodotyrosine, 4-hydroxy-3-methoxy-mandelic acid, 5,5′

-methylenedisalicylic acid, anacardic acid, aspirin, dopa, ethyl vanillin, homogentisic acid, homovanillic acid, p-coumaric acid, thyroxine, and tiratricol;

X is selected from;

—

OC(═

O)CH₂—

(inverse glycolic acid moiety), —

OC(═

O)CH(CH₃)—

(inverse lactic acid moiety), —

OC(═

O)CH₂OCH₂CH₂—

(inverse dioxanone acid moiety), —

OC(═

O)CH₂CH₂CH₂CH₂CH₂—

(inverse caprolactone acid moiety), —

OC(═

O)(CH₂)_y—

, or —

OC(═

O)CH₂(OCH₂CH₂)_z—

.

X¹ is selected from;

—

CH₂C(═

O)O—

(glycolic acid moiety), —

CH(CH₃)C(═

O)—

(lactic acid moiety), —

CH₂CH₂OCH₂C(═

O)O—

(dioxanone acid moiety), —

CH₂CH₂CH₂CH₂CH₂C(═

O)O—

(caprolactone acid moiety), —

(CH₂)_yC(═

O)O—

, or —

(CH₂CH₂O)_zCH₂C(═

O)O—

;

Y is selected from;

—

C(═

O)CH₂O—

(glycolic ester moiety), —

C(═

O)CH(CH₃)O—

(lactic ester moiety), —

C(═

O)CH₂OCH₂CH₂O—

(dioxanone ester moiety), —

C(═

O)CH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety), —

C(═

O)(CH₂)_mO—

, or —

C(═

O)CH₂O(CH₂CH₂O)_n—

;

Y¹ is selected from;

—

OCH₂C(═

O)—

(inverse glycolic ester moiety), —

OCH(CH₃)C(═

O)—

(inverse lactic ester moiety), —

OCH₂CH₂OCH₂C(═

O)—

(inverse dioxanone ester moiety), —

OCH₂CH₂CH₂CH₂CH₂C(═

O)—

(inverse caprolactone ester moiety), —

O(CH₂)_mC(═

O)—

, or —

O(CH₂CH₂O)_nOCH₂C(═

O)—

;

R is a di-, tri, tetra-, penta- or hexaradical derived from C_2-25 alkyl, aryl, or aryl-(C_1-6alkyl)_1-3-, wherein from 1-3 of the CH₂ groups within the alkyl chain are optionally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH₂ groups within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom;

or R is the backbone of a polymer or copolymer bearing carboxylic acid and/or hydroxyl functional groups, where the average molecular weight of the polymer or copolymer is between 500 to 5000 and wherein w is an integer from about 6 to about 50;

each a and b is independently an integer from about 1 to about 10;

each m, n, y, and z is independently an integer from about 2 to about 24; and

w is an integer from about 2 to about 6.

2. An oligomer of claim 1, wherein:

R is a di-, tri, tetra-, penta- or hexaradical derived from C_2-12alkyl, phenyl, or phenyl-(C_i-6alkyl)_1-3-, wherein from 1-3 of the CH₂ groups within the alkyl chain are optionally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH₂ groups within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom;

each a and b is independently an integer from about 1 to about 5; and

w is an integer from about 2 to about 4.

3. An oligomer of claim 1, wherein:

R—

[O ]_{w is O(CH2})₂O, O(CH₂)₃O, CH(CH₂O)₃, C(CH₂O)₄, or C(CH₂CH₃)(CH₂OH)₃.

4. An oligomer of claim 1, wherein:

each X is independently —

OC(═

O)CH₂—

, —

OC(═

O)CH(CH₃)—

, —

OC(═

O)CH₂OCH₂CH₂—

, or —

OC(═

O)CH₂CH₂CH₂CH₂CH₂—

.

each X¹ is independently —

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

or —

CH₂CH₂CH₂CH₂CH₂COO—

.

each Y is independently —

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

or —

COCH₂CH₂CH₂CH₂CH₂O—

, and

each Y¹ is independently —

OCH₂CO—

;

—

OCH(CH₃)CO—

;

—

OCH₂CH₂OCH₂CO—

;

or —

OCH₂CH₂CH₂CH₂CH₂CO—

.

5. An oligomer of claim 4, wherein:

X is independently —

OCOCH₂— and

—

OCOCH(CH₃)—

;

each X¹ is independently —

CH₂COO— and

—

CH(CH₃)COO—

;

each Y is independently —

COCH₂O— and

—

COCH(CH₃)O—

; and

,

each Y¹ is independently —

OCH₂CO— and

—

OCH(CH₃)CO—

.

6. An oligomer of claim 1, wherein —

OC(═

O)]_w—

R is;

7. An oligomer of claim 1, wherein —

(Y¹)_b—

O]_wR is;

8. An oligomer of claim 1, wherein —

(X)_a—

OC(═

O)]_w—

R is;

9. An oligomer of claim 1, wherein —

CH₂C(═

O)—

(Y¹)_b—

O]_wR) is;

10. A pharmaceutical composition, comprising at least one compound of claim 1 and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition of claim 10, wherein the composition is suitable for administration via a route selected from oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal.

12. A pharmaceutical composition of claim 10, wherein the phenolic residue of formula I or II is derived from a phenolic compound with antimicrobial properties.

13. A pharmaceutical composition of claim 10, wherein the phenolic residue in the compound of formula I was derived from a phenolic with anti-inflammatory properties.

14. A pharmaceutical composition of claim 10, wherein the phenolic residue in the compound of formula I was derived from a phenolic with pain-reducing properties.

15. A pharmaceutical composition of claim 10, wherein the phenolic residue in the compound of formula I was derived from a phenolic with antioxidant properties.

16. An oligomer of claim 1, wherein R¹—

O—

is a biologically active compound residue selected from;

daidzein, glycitein, vanillic acid, and vanillin.

17. An oligomer of claim 1, wherein R¹—

O—

is a biologically active compound residue selected from;

acacetin, albuterol, aloe emodin, aloin, p-anol, apigenin, apiin, apocynin, aspidinol, baptigenin, benzestrol, benzoresorcinol, butylated hydroxylanisole, butylated hydroxytoluene, m-chlorophenol, 5-chloro-8-quinolinol, chlorquinaldol, chrysin, coniferyl alcohol, coumestrol, coumetarol, daphnetin, datiscetin, deoxyepinephrine, diosmetin, diresorcinol, ellagic acid, embelin, Equol, eriodictyol, esculetin, esculin, ethylnorepinephrine, eupatorin, fenadiazole, fisetin, fraxetin, fustin, galangin, genistein, gepefrine, -gingerol, gossypol, guaifenesin, harmalol, hematoxylin, homoeriodictyol, hydroxyamphetamine, 8-hydroxyquinoline, hypericin, irigenin, isoproterenol, isoquercitrin, kaempferol, luteolin, mangostin, n-methylepinephrine, metyrosine, morin, mycophenolic acid, myricetin, naringenin, nylidrin, orcinol, osalmid, oxantel, paroxypropione, pentachlorophenol, 3-pentadecylcatechol, p-pentyloxy-phenol, phloretin, phloroglucinol, pinosylvine, plumbagin, pyrocatechol, pyrogallol, quercetagetin, quercetin, resacetophenone, rhamnetin, rhein, sakuranetin, salicyl alcohol, salicylanilide, 4-salicyloylmorpholine, scopoletin, scutellarein, serotonin, thymol, vanillic acid, and vanillin.

18. An oligomer of claim 1, wherein R¹—

O—

is a biologically active compound residue selected from;

Amoxicillin, Azacyclonol, and Cefprozil.

19. An oligomer of claim 1, wherein R¹—

O—

is a biologically active compound residue selected from;

flavanones, flavones, flavanols, rutin, and quercetin.

20. An oligomer of claim 1, wherein R¹—

O—

is a biologically active compound residue selected from;

glycitein, daidzein, prunetin, biochanin A, orobol, pratensein, formononetin, genistein, and glycitein.

21. An oligomer of claim 1, wherein R¹—

O—

is a biologically active compound residue selected from;

Apomorphine, Carbidopa, Carbuterol, Daunorubicin, Doxorubicin, Epirubicin, and Ezetimibe.

22. An oligomer of claim 1, wherein R²—

C(═

O)O—

is a biologically active compound residue selected from;

anacardic acid, aspirin, p-coumaric acid, 3,5-diiodothyronine, 3,5-di-iodotyrosine, dopa, ethyl vanillin, homogentisic acid, homovanillic acid, 4-hydroxy-3-methoxy-mandelic acid, 5,5′

-methylenedisalicylic acid, thyroxine, and tiratricol.