U.S. patent application number 11/826833 was filed with the patent office on 2008-02-14 for conveniently implantable sustained release drug compositions.
Invention is credited to Vernon G. Wong, Louis L. Wood.
Application Number | 20080038316 11/826833 |
Document ID | / |
Family ID | 39051070 |
Filed Date | 2008-02-14 |
United States Patent
Application |
20080038316 |
Kind Code |
A1 |
Wong; Vernon G. ; et
al. |
February 14, 2008 |
Conveniently implantable sustained release drug compositions
Abstract
This invention provides for biocompatible and biodegradable
syringeable liquid, implantable solid, and injectable gel
pharmaceutical formulations useful for the treatment of systemic
and local disease states.
Inventors: |
Wong; Vernon G.; (Menlo
Park, CA) ; Wood; Louis L.; (Potomac, MD) |
Correspondence
Address: |
NIXON PEABODY, LLP
401 9TH STREET, NW
SUITE 900
WASHINGTON
DC
20004-2128
US
|
Family ID: |
39051070 |
Appl. No.: |
11/826833 |
Filed: |
July 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11236426 |
Sep 27, 2005 |
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11826833 |
Jul 18, 2007 |
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60709665 |
Aug 19, 2005 |
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60614484 |
Oct 1, 2004 |
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60831991 |
Jul 19, 2006 |
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Current U.S.
Class: |
424/426 ;
514/169 |
Current CPC
Class: |
A61P 39/06 20180101;
A61K 9/0051 20130101; A61K 31/573 20130101; A61K 31/355 20130101;
A61K 9/0024 20130101; A61K 9/0048 20130101; A61P 29/00 20180101;
A61K 38/13 20130101; A61P 27/06 20180101; A61P 37/06 20180101; A61K
31/496 20130101; A61K 9/0019 20130101; A61P 31/00 20180101; A61K
47/06 20130101; A61K 47/14 20130101 |
Class at
Publication: |
424/426 ;
514/169 |
International
Class: |
A61F 2/00 20060101
A61F002/00; A61K 31/56 20060101 A61K031/56 |
Claims
1. A pharmaceutical formulation for the sustained release of an
active agent consisting essentially of a biocompatible,
biodegradable, non-polymeric excipient and an active agent or
pharmaceutically acceptable salt thereof, wherein said formulation
is capable of being implanted by injection.
2. A pharmaceutical formulation for implantation into a patient for
the sustained release of an active agent consisting essentially of
a biocompatible, biodegradable, non-polymeric excipient and an
active agent or pharmaceutically acceptable salt thereof, wherein
said formulation exhibits an in vitro or in vivo dissolution
profile wherein about 2% to about 100% of the active agent is
released over a period ranging from about 1 day to about 105
days.
3. A pharmaceutical formulation for implantation into a patient for
the sustained release of an active agent comprising a
biocompatible, biodegradable, non-polymeric excipient and an active
agent or pharmaceutically acceptable salt thereof, wherein said
formulation exhibits an in vitro or in vivo dissolution profile
wherein about 2% to about 100% of the active agent is released over
a period ranging from about 1 day to about 365 days.
4. The pharmaceutical formulation of claim 1, wherein about 2% to
about 60% of the active agent is released over a period ranging
from about 1 day to at least about 365 days.
5. The pharmaceutical formulation of claim 1, comprising an active
agent at a concentration from about 5% to about 50% of the implant
and biodegradable, biocompatible excipient at a concentration of at
least about 5% of the implant.
6. The pharmaceutical formulation of claim 1, comprising an active
agent at a concentration from about 0.5% to about 95% of the
implant and the corresponding concentration of the excipient ranges
from about 5% to about 99.5%.
7. The pharmaceutical formulation of claim 1, wherein said
biocompatible, biodegradable excipient is selected from the group
consisting of benzyl benzoate; esters of benzoic acid with
straight, branched, or cyclic chain aliphatic alcohols having one
to twenty carbon atoms wherein one of the hydrogen atoms on the
aliphatic chain is replaced with a hydroxyl group (e.g., such
alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol,
i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol,
neo-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octonol,
n-nonanol, n-decanol, and the like); d, 1 and d1 isomers of
.alpha., .beta., .delta., .epsilon., .eta. tocopherols and similar
isomers of the tocotrienols and the esters of these tocopherols and
tocotrienols with: straight and branched chain C.sub.2 to C.sub.20
aliphatic acids, or their esters of C.sub.3 to C.sub.20 straight
chain dicarboxylic acids, including maleic, malic, fumaric,
succinic, or their esters with lactic, glycolic, benzoic,
nicotinic, pyruvic acids, succinic-PEG ester; the mono, di, and tri
esters of O-acetylcitric acid or O-propionylcitric acid or
O-butyrylcitric acid with C.sub.1 to C.sub.10 straight and branched
chain aliphatic alcohols; the mono, di, and tri esters of citric
acid with C.sub.1 to C.sub.10 straight and branched chain aliphatic
alcohols; dibenzoate esters of poly(oxyethylene) diols having low
water solubility; poly(oxypropylene)diols having low water
solubility; liquid and semisolid polycarbonate oligomers, and
dimethyl sulfone.
8. The pharmaceutical formulation of claim 1, wherein said active
agent is selected from the group consisting of analgesics,
anesthetics, narcotics, angiostatic steroids, anti-inflammatory
steroids, angiogenesis inhibitors, nonsteroidal
anti-inflammatories, anti-infective agents, anti-fungals,
anti-malarials, anti-tuberculosis agents, antivirals, alpha
androgenergic agonists, beta adrenergic blocking agents, carbonic
anhydrase inhibitors, mast cell stabilizers, miotics,
prostaglandins, antihistamines, antimicrotubule agents,
antineoplastic agents, antipoptotics, aldose reductase inhibitors,
antihypertensives, antioxidants, growth hormone antagonists,
vitrectomy agents, adenosine receptor antagonists, adenosine
deaminase inhibitor, glycosylation antagonists, anti aging
peptides, topoisemerase inhibitors, anti-metabolites, alkylating
agents, antiandrigens, anti-oestogens, oncogene activation
inhibitors, telomerase inhibitors, antibodies or portions thereof,
antisense oligonucleotides, fusion proteins, luteinizing hormone
releasing hormones agonists, gonadotropin releasing hormone
agonists, tyrosine kinase inhibitors, epidermal growth factor
inhibitors, ribonucleotide reductase inhibitors, cytotoxins, IL2
therapeutics, neurotensin antagonists, peripheral sigma ligands,
endothelin ETA/receptor antagonists, antihyperglycemics,
anti-glaucoma agents, anti-chromatin modifying enzymes, obesity
management agents, anemia therapeutics, emesis therapeutics,
neutropaenia therapeutics, tumor-induced hypercalcaemia
therapeutics, blood anticoagulants, immunosuppressive agents,
tissue repair agents, insulins, glucagon-like-peptides, botulinum
toxins, and psychotherapeutic agents.
9. A method for treating joint inflammation comprising the step of:
implanting, by injection, a pharmaceutical formulation comprising a
biodegradable, biocompatible, nonpolymeric excipient and a
steroidal or non-steroidal anti-inflammatory into a strategic
position in the inflamed joint to provide controlled and sustained
release of a therapeutically effective but nontoxic level of the
anti-inflammatory to the affected areas.
10. The method of claim 9 wherein said pharmaceutical formulation
further comprises an antioxidant.
11. The pharmaceutical formulation of claim 8, wherein the active
agent is one or more steroidal anti-inflammatory agents selected
from the group consisting of 21-acetoxypregnenolone, alclometasone,
algestone, amcinonide, beclomethasone, betamethasone, budesonide,
chloroprednisone, clobetasol, clobetasone, clocortolone,
cloprednol, corticosterone, cortisone, cortivazol, deflazacort,
desonide, desoximetasone, dexamethasone, dexamethasone 21-acetate,
dexamethasone 21-phosphate di-Na salt, diflorasone, diflucortolone,
difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,
flunisolide, fluocinolone acetonide, fluocinonide, fluocortin
butyl, fluocortolone, fluorometholone, fluperolone acetate,
fluprednidene acetate, fluprednisolone, flurandrenolide,
fluticasone propionate, formocortal, halcinonide, halobetasol
propionate, halometasone, halopredone acetate, hydrocortamate,
hydrocortisone, loteprednol etabonate, mazipredone, medrysone,
meprednisone, methylprednisolone, mometasone furoate,
paramethasone, prednicarbate, prednisolone, prednisolone
25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,
prednival, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, triamcinolone benetonide, and
triamcinolone hexacetonide.
12. The pharmaceutical formulation of claim 11, wherein the active
agent is one or more steroidal anti-inflammatory agents selected
from the group consisting of cortisone, dexamethasone,
hydrocortisone, methylprednisolone, prednisolone, prednisone, and
triamcinolone acetonide.
13. The pharmaceutical formulation of claim 12, wherein the active
agent is one or more steroidal anti-inflammatory agents selected
from the group consisting of dexamethasone and triamcinolone
acetonide.
14. The pharmaceutical formulation of claim 8, wherein the active
agent is one or more non-steroidal anti-inflammatory agents
selected from the group consisting of naproxin; diclofenac;
celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;
meloxicam; ibuprofen; ketoprofen; r-flurbiprofen; mefenamic;
nabumetone; tolmetin, and sodium salts of each of the foregoing;
ketorolac bromethamine; ketorolac tromethamine; ketorolac acid;
choline magnesium trisalicylate; rofecoxib; valdecoxib;
lumiracoxib; etoricoxib; aspirin; salicylic acid and its sodium
salt; salicylate esters of alpha, beta, gamma-tocopherols and
tocotrienols (and all their d, 1, and racemic isomers); methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters of
acetylsalicylic acid; tenoxicam; aceclofenac; nimesulide;
nepafenac; amfenac; bromfenac; flufenamate; and phenylbutazone.
15. The pharmaceutical formulation of claim 8, wherein the active
agent is one or more anti-infectives selected from the group
consisting of 2,4-diaminopyrimidines, nitrofurans, quinolones and
quinolone analogs, sulfonamides, sulfones, clofoctol, hexedine,
methenamine, methenamine anhydromethylene-citrate, methenamine
hippurate, methenamine mandelate, methenamine sulfosalicylate,
nitroxoline, taurolidine, xibomol, moxifloxacin, and
vancomycin.
16. A method of treating inflammatory conditions comprising
delivering to a patient in need thereof the pharmaceutical
formulation of claim 12.
17. The method of claim 16, wherein said pharmaceutical formulation
further comprises a quinolone or quinalone analog antibiotic.
18. The method of claim 17, wherein said pharmaceutical formulation
further comprises an antioxidant.
19. A method of treating a malady of the eye by implanting the
pharmaceutical formulation of claim 1, wherein said malady is
selected from the group consisting of allergic and infectious
conjunctivitis, uveitis of the anterior and posterior segments,
infectious endophthalmitis of the anterior segment and posterior
segment, dry-eye syndrome, post-surgical inflammation and infection
of the anterior and posterior segments, angle-closure glaucoma,
open-angle glaucoma, post-surgical glaucoma procedures,
exopthalmos, scleritis, episcleritis, Grave's disease, pseudotumor
of the orbit, lymphoma of the orbit, tumors of the orbit, orbital
cellulitis, blepharitis, intraocular tumors, retinoblastoma,
malignant melanoma, retinal fibrosis, vitreous substitute and
vitreous replacement, iris neovascularization from cataract
surgery, macular edema in central retinal vein occlusion, cellular
transplantation (as in retinal pigment cell transplantation),
cystiod macular edema, psaudophakic cystoid macular edema, diabetic
macular edema, pre-phthisical ocular hypotomy, proliferative
vitreoretinopathy, proliferative diabetic retinopathy, exudative
age-related macular degeneration, extensive exudative retinal
detachment (Coat's disease), diabetic retinal edema, diffuse
diabetic macular edema, ischemic opthalmopathy, chronic focal
immunologic and chemical corneal graft reaction, neovascular
glaucoma, pars plana vitrectomy (for proliferative diabetic
retinopathy), pars plana vitrectomy for proliferative
vitreoretinopathy, sympathetic ophthalmia, intermediate uveitis,
chronic uveitis, intraocular infection such as endophthalmitis, and
Irvine-Gass syndrome; conditions of inflammatory and immunological
in nature, sequalae of surgical complications, and acquired and
hereditary ocular conditions such as Tay-Sach's disease,
Niemann-Pick's disease, cystinosis, corneal dystrophies and
multiple myeloma.
20. The pharmaceutical formulation of claim 2, wherein said
formulation is a solid form containing from 1% to about 60% of a
limited solubility, biocompatible, biodegradable nonpolymeric
excipient.
21. The pharmaceutical formulation of claim 2, wherein said
formulation is a gel form containing from 20% to about 80% of a
limited solubility, biocompatible, biodegradable nonpolymeric
excipient.
22. The pharmaceutical formulation of claim 2, wherein said
formulation is an injectable liquid or gel form containing from 30%
to about 99.9% of a limited solubility, biocompatible,
biodegradable nonpolymeric excipient.
23. A pharmaceutical formulation for the sustained release of an
active agent consisting essentially of a biocompatible,
biodegradable, nonpolymeric excipient and an active agent or
pharmaceutically acceptable salt thereof, wherein said formulation
is capable of being implanted by injection, and wherein said
biocompatible, biodegradable excipient is selected from the group
consisting of tocopherol isomers and tocotrienol isomers and their
esters; benzyl benzoate; esters of benzoic acid with straight,
branched, or cyclic chain aliphatic alcohols having one to twenty
carbon atoms wherein one of the hydrogen atoms on the aliphatic
chain is replaced with a hydroxyl group; dibenzoate esters of
poly(oxyethylene) diols having low water solubility; dimethyl
sulfone poly(oxypropylene) diols having low water solubility; the
mono, di, and triesters of O-acetylcitric acid with C.sub.1 to
C.sub.10 straight and branched chain aliphatic alcohols; mono, di,
and triesters of citric acid with C.sub.1 to C.sub.10 straight and
branched chain aliphatic alcohols; dimethyl sulfone; omega-3 fatty
acids and their esters of C.sub.1 to C.sub.8 straight and branched
chain aliphatic alcohols; and liquid and semisolid polycarbonate
oligomers.
24. The pharmaceutical formulation of claim 7, wherein said liquid
to semisolid polycarbonate oligomers is selected from the group
consisting of those polycarbonate oligomers prepared by the
polymerization of trimethylene carbonate [poly(1,3-propanediol
carbonate)], the ester exchange polymerization of diethylene
carbonate with aliphatic diols or polyoxyalkane diols
[poly(di-1,2-propylene glycol carbonate), and
poly(tri-1,2-propylene glycol carbonate)].
25. A liquid, solid or gel formulation conveniently implantable in
a brain tumor for the sustained release of active agents,
comprising one or more of the excipients selected from group (a)
and one or more of the pharmaceutical agents selected from group
(b) or group (c), or both group (b) and group (c): (a) benzyl
benzoate; esters of benzoic acid with straight, branched, or cyclic
chain aliphatic alcohols having one to twenty carbon atoms wherein
one of the hydrogen atoms on the aliphatic chain is replaced with a
hydroxyl group (e.g., such alcohols as methanol, ethanol,
n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol,
n-pentanol, i-pentanol, neo-pentanol, n-hexanol, cyclohexanol,
n-heptanol, n-octonol, n-nonanol, n-decanol, and the like), d.1 and
d1 isomers of .alpha., .beta., .delta., .epsilon., .eta.
tocopherols and similar isomers of the tocotrienols and the esters
of these tocopherols and tocotrienols with straight and branched
chain C.sub.1 to C.sub.10 aliphatic acids, C.sub.3 to C.sub.20
straight chain dicarboxylic acids, maleic, malic, fumaric, lactic,
glycolic, benzoic, nicotinic, pyruvic acids, succinic-PEG ester,
the mono, di, and tri esters of O-acetylcitric acid or
O-propionylcitric acid or O-butyrylcitric acid with C.sub.1 to
C.sub.10 straight and branched chain aliphatic alcohols; the mono,
di, and tri esters of citric acid with C.sub.1 to C.sub.10 straight
and branched chain aliphatic alcohols, dibenzoate esters of
poly(oxyethylene) diols having low water solubility,
poly(oxypropylene)diols having low water solubility, liquid and
semisolid polycarbonate oligomers, and dimethyl sulfone, diethylene
glycol dibenzoate, triethylene glycol dibenzoate, dibenzoate esters
of poly(oxyethylene) diols of up to about 400 mwt, propylene glycol
dibenzoate, dipropylene glycol dibenzoate, tripropylene glycol
dibenzoate, dibenzoate esters of poly(oxypropylene) diols of up to
about 3000 mwt; poly(oxypropylene) diols of up to about 3000 mwt,
dimethyl sulfone, liquid to semisolid polycarbonate oligomers,
polymers and copolymers of glycolic and lactic acids, poly(lactic
acid) and poly(glycolic acid); (b) tetrahydrocortisol;
4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione;
4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
11-epicortisol; 17.alpha.-hydroxyprogesterone;
tetrahydrocortexolone; cortisone; cortisone acetate;
hydrocortisone; hydrocortisone acetate; fludrocortisones;
fludrocortisone acetate; fludrocortisone phosphate; prednisone;
prednisolone; prednisolone sodium phosphate; methylprednisolone,
methylprednisolone acetate; methylprednisolone sodium succinate;
triamcinolone; triamcinolone-16,21-diacetate; triamcinolone
acetonide; triamcinolone acetonide-21-acetate; triamcinolone
acetonide-21-disodium phosphate; triamcinolone
acetonide-21-hemisuccinate; triamcinolone benetonide; triamcinolone
hexacetonide; fluocinolone; fluocinolone acetate; fluocinolone
acetonide; dexamethasone; dexamethasone-21-acetate;
dexamethasone-21-(3,3-dimethylbutyrate); dexamethasone-21-phosphate
disodium salt; dexamethasone-21-diethylaminoacetate;
dexamethasone-21-isonicotinate; dexamethasone-21-dipropionate;
dexamethasone-21-palmitate; betamethasone;
betamethasone-21-acetate; betamethasone-21-adamantoate;
betamethasone-17-benzoate; betamethasone-17,21-dipropionate;
betamethasone-17-valerate; betamethasone-21-phosphate disodium
salt; beclomethasone; beclomethasone dipropionate; diflorasone;
diflorasone diacetate; mometasone furoate; acetazolamide; naproxen;
naproxin sodium salt; diclofenac; diclofenac sodium salt;
celecoxib; rofecoxib; valdecoxib; etoricocib; lumiracoxib;
sulindac; sulindac sodium salt; diflunisal; diflunisal sodium salt;
piroxicam; indomethacin; indomethacin sodium salt; etodolac;
etodolac sodium salt; meloxicam; ibuprofen; ibuprofen sodium salt;
ketoprofen; ketoprofen sodium salt; r-flurbiprofen; mefenamic;
mefenamic sodium salt; nabumetone; tolmetin; tolmetin sodium salt;
ketorolac bromethamine; ketorolac tromethamine; ketorolac acid;
choline magnesium trisalicylate; aspirin; salicylic acid; salicylic
acid sodium salt; salicylate esters of alpha, beta,
gamma-tocopherols (and all their d, 1, and racimic isomers);
tenoxicam; aceclofenac; nimesulide; nepafenac; amfenac; bromfenac;
flufenamate; phenylbutazone; CV 247; pegaptanib octasodium;
ranibizumab; 2-methoxyestradiol; shark cartilage extract; NX-278-L
ant-VEGF aptamer; squalamine; 2'-O-methoxyethyl) antisense C-raf
oncogene inhibitor; vitronectin and osteopontin antagonist;
combretstatin A-4 phosphate; Fab fragment alpha-V/beta-1 integrin
antagonist; alpha-v/beta-3 integrin antagonist; matrix
metalloprotienase inhibitor; matrix metalloprotienase inhibitor;
urokinase plasminogen activator fragment; vascular endothelial
growth factor antagonist; kdr tyrosine kinase inhibitor;
cytochalasin E; kallikrinin-binding protein; combretastatin analog;
pigment-epithelium derived growth factor; pigment-epithelium
derived growth factor; plasminogen kringle; rapamycin; cytokine
synthesis inhibitor/p38 mitogen-activated protein kinaseinhibitor;
vascular endothelial growth factor antagonist; vascular endothelial
growth factor antagonist; vascular endothelial growth factor
antagonist; vascular endothelial growth factor antagonist; FGF1
receptor antagonist/tyrosine kinase inhibitor (Pfizer/Sugen);
endostatin, vascular endothelial growth factor antagonist;
bradykinin B1 receptor antagonist;
bactericidal/permeability-increasing protein; protein kinase C
inhibitor; ruboxistaurinn mesylate; polysulphonic acid derivatives;
growth factor antagonists; Tunica internal endothelial cell kinase;
acetylcysteine; mannitol; antineoplaston; human
corticotropin-releasing factor; VN40101M; everolimus; GW572016;
thalidomide; temozolomide; tariquidar; doxorubicin; dalteparin;
tarceva; CC-5013; hCRF; bevacizumab; melphalan; thiotepa;
depsipeptide; erlotinib; tamoxifen; bortezomib; lenalidomide;
vorinostat; temsirolimus; modifinil; enzastuarin; motexafin
gadolinium; F-18-OMFD-PET; pemetrexed disodium; ZD6474; valproic
acid; vincristine; irinotecan; PEG-interferon alpha-2b;
procarbazine; lonafarnib; arsenic trioxide; GP9; carboplatin;
cyclophosphamide; 1311-TM-601; lapatinib; O6-benzylguanine; TP-38
toxin; cilengitide; poly-ICLC; FR901228; TransMid.TM.; talabostat;
ixabepilone; AEE788; sirolimus; alanosine; sorafenib; efaproxiral;
carmustine; .sup.131Iodine monoclonal antibody TNT-1/B;
intratumoral TransMid.TM.; topatecan; lomustine; .sup.32Phosphorus;
18F-fluorodeoxyglucose; vinblastine; BMS-247550; CC-8490; IL
13-PE38QQR; imatib mesylate; hydroxyurea; G207; radiolabeled
monoclonal antibody; 2-deoxyglucose; talampanel; retinoic acid;
gefitinib; tipifarnib; CPT-11; rituximab; efaproxiral; PS-341;
capecitabine; G-CFS; vinorelbine; DCVax.RTM.-Brain; paclitaxel;
patipilone; iressa; methotrexate; ABT-751; oxaliplatin; MS-275;
trastuzumab; pertuzumab; PS-341; 17AAG; lenalidomide; campath-1H;
somatostatin analog; resveratrol; CEP-7055; CEP-5214; PTC-299;
inhibitors of hepatocyte growth factor; statins; receptor tyrosine
kinase inhibitors; aspirin (acetylsalicylic acid), and peroxisome
proliferator-activated receptor (PPAR-alpha) activators
(fenofibrate and clofibrate); (c) Anti-neovascularization steroids
selected from the group consisting of:
21-nor-5.beta.-pregnan-3.alpha.,17.alpha.,20-triol-3-acetate;
21-nor-5.alpha.-pregnan-3.alpha.,17.alpha.,20-triol-3-phosphate;
21-nor-5.beta.-pregn-17(20)en-3.alpha.,16-diol;
21-nor-5.beta.-pregnan-3.alpha.,17.beta.,20-triol;
20-acetamide-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol-3-acetate;
3.beta.
acetamido-5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one-21-a-
cetate; 21-nor-5.alpha.-pregnan-3.alpha.,17.beta.,20-triol;
21.alpha.-methyl-5.beta.-pregnan-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-
-one-21-methyl ether;
20-azido-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
20(carbethoxymethyl)thio-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
20-(4-fluorophenyl)thio-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
16.alpha.-(2-hydroxyethyl)-17.beta.-methyl-5.beta.-androstan-3.alpha.,17.-
alpha. diol;
20-cyano-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
17.alpha.-methyl-5.beta.-androstan-3.alpha.,17.beta.-diol;
21-nor-5.beta.-pregn-17(20)en-3.alpha.-ol; 21-or
-5.beta.-pregn-17(20)en-3.alpha.-ol-3-acetate;
21-nor-5-pregn-17(20)-en-3.alpha.-ol-16-acetic acid 3-acetate;
3.beta.-azido-5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one-21-aceta-
te; and 5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one;
4-androsten-3-one-17.beta.-carboxylic acid;
17.alpha.-ethynyl-5(10)-estren-17.beta.-ol-3-one; and
17.alpha.-ethynyl-1,3,5(10)-estratrien-3,17.beta.-diol.
26. The formulation of claim 25, wherein said liquid to semisolid
polycarbonate oligomers is selected from the group consisting of
those polycarbonate oligomers prepared by the polymerization of
trimethylene carbonate [poly(1,3-propanediol carbonate)], the ester
exchange polymerization of diethylene carbonate with aliphatic
diols or polyoxyalkane diols [poly(di-1,2-propylene glycol
carbonate), and poly(tri-1,2-propylene glycol carbonate)].
27. The formulation of claim 25, wherein said statin is selected
from the group consisting of atorvastatin, fluvastatin,
rosuvastatin, pravastatin, simvastatin, lovastatin, and
cerivastatin.
28. The pharmaceutical formulation of claim 1, wherein said active
agent is an oxymethylene polymer or trimer.
29. The pharmaceutical formulation of claim 28, wherein said
oxymethylene polymer or trimer is selected from the group
consisting of Paraformaldehyde, Trioxane, Oxymethylene polymers of
acetaldehyde, Paraldehyde, and Oxymethylene polymers of
gluteraldehyde.
30. The pharmaceutical formulation of claim 8, wherein said
antioxidant is selected from the group consisting of ascorbic acids
and salts, ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl
stearate, ascorbyl-2,6-dibutyrate, d-tocopherol (.alpha., .beta.,
.gamma., .delta. isomers), d1-tocopherol (.alpha., .beta., .gamma.,
.delta. isomers), the acetate, hemisuccinate, nicotinate and
succinate-PEG ester derivatives of the above tocopherol isomers,
glutathione, .beta.-carotine, carnitine, carnitine acetate, trans
reveratrol, retinoic acid, retinyl palmitate, melatonin, timolol,
luteolin, kaempferol, thyroxine, pyrroloquinolone, retinyl
palmitate, probucol, erythorbic acid, sodium erythorbate,
.alpha.-lipoic acid, isocitrate, lutein/zeaxanthin/meso-zeaxanthin,
eugenol, isoeugenol, (-)-epicatechin, (-)-epigallocatechin gallate,
benzyl alcohol, benzyl benzoate, 2,6-di-tertbutyl-4-methoxy phenol,
butylated hydroxytoluene, butylated hydroxyanisole, quercetin,
catechin, rutin, coenzyme Q, fisetin, methyl gallate, and
superoxide dismutase.
31. The pharmaceutical formulation of claim 30, further comprising
a steroid or quinolone anti-infective.
32. The pharmaceutical formulation of claim 31, wherein said
quinolone anti-infective is selected from the group consisting of
cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin,
fleroxacin, flumequine, gatifloxacin, grepafloxacin, lomefloxacin,
miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin,
oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic
acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin,
tosufloxacin, and trovafloxacin.
33. The pharmaceutical formulation of claim 31, wherein said
steroid is selected from the group consisting of triamcinolone,
triamcinolone acetonide, triamcinolone diacetate, triamcinolone
acetate, triamcinolone disodium phosphate, triamcinolone
hemisuccinate, triamcinolone benetonide, dexamethasone,
dexamethasone acetate, dexamethasone disodium phosphate,
dexamethasone 3,3-dimethylbutyrate, cortisone, cortisone acetate,
hydrocortisone, hydrocortisone acetate, tetrahydrocortisol,
fludrocortisones, fludrocortisone acetate, fludrocortisone
phosphate, anacortive, anacortive acetate, mometasone furoate,
fluocinolone, dexamethasone diethyl aminoacetate, dexamethasone
isonicotinate, dexamethasone palmitate, prednisone, prednisolone,
prednisolone acetate, prednisolone sodium phosphate,
methylprednisolone, methylprednisolone acetate, methylprednisolone
sodium succinate, paramethasone, etrahydrocortexolone,
betamethasone, betamethasone acetate, betamethasone disodium
phosphate, betamethasone benzoate, betamethasone valerate,
betamethasone dipropionate, betamethasone adamantoate,
beclomethasone, beclomethasone dipropionate, diflorasone, and
diflorasone diacetate.
34. The pharmaceutical formulation of claim 1, wherein said
excipient or active agent is an omega-3 fatty acid or an ester
thereof.
Description
RELATED APPLICATIONS
[0001] This application is related to and claims the benefit under
35 U.S.C. .sctn. 119(e) of U.S. Patent Application Ser. No.
60/831,991, filed Jul. 19, 2006, and is a continuation-in-part and
claims the benefit under 35 U.S.C. .sctn. 120 of U.S. patent
application Ser. No. 11/236,426, filed Sep. 27, 2005, which is
related to and claims the benefit under 35 U.S.C. .sctn. 119(e) of
U.S. Patent Applications Ser. No. 60/709,665, filed Aug. 19, 2005,
and Ser. No. 60/614,484, filed Oct. 1, 2004, each entitled
Conveniently Implantable Sustained Release Drug Compositions, by
Vernon G. Wong and Louis L. Wood. Each of the foregoing
applications is incorporated in its entirety herein.
FIELD OF THE INVENTION
[0002] This invention provides for biocompatible and biodegradable
syringeable liquid, implantable solid, and injectable gel
pharmaceutical formulations useful for the treatment of systemic
and local diseases.
BACKGROUND OF THE INVENTION
[0003] Present modes of drug delivery such as topical application,
oral delivery, and intramuscular, intravenous and subcutaneous
injection may result in high and low blood concentrations and/or
shortened half-life in the blood. In some cases, achieving
therapeutic efficacy with these standard administrations requires
large doses of medications that may result in toxic side effects.
The technologies relating to controlled drug release have been
attempted in an effort to circumvent some of the pitfalls of
conventional therapy. Their aims are to deliver medications on a
continuous and sustained manner. Additionally, local control drug
release applications are site or organ specific.
[0004] In response to these issues, reservoir delivery systems have
been explored. Non-biodegradable drug delivery systems include, for
example, Vitrasert.RTM. (Bausch & Lomb Inc.), a surgical
implant that delivers ganciclovir intraocularly; Duros.RTM. (Alza
Corp.), surgically implanted osmotic pump that delivers leuprolide
actetate to treat advanced prostate cancer; and Implanon.TM.
(Organon USA Inc.), a type of subdermal contraceptive implant.
[0005] Biodegradable implants include, for example, Lupron
Depot.RTM. (leuprolide acetate, TAP Pharm. Prods., Inc.), a
sustained-release microsphere-suspension injection of luteinizing
hormone-releasing hormone (LH-RH) analog for the treatment of
prostate cancer; and the Posurdex.RTM. dexamethasone anterior
segment drug delivery system (Allergan, Inc.) (commercial licensure
pending FDA approval).
[0006] Additionally, polyethylene glycol conjugations (pegylation)
to reduce the frequency of administration are now in use. One
example is Macugen.RTM. (pegaptanib sodium injection, (OSI)
Eyetech, Inc./Pfizer Inc.), a pegylated anti-VEGF aptamer, for use
in treating wet macular degeneration.
[0007] There remains a need for a more economical, practical, and
efficient way of producing and manufacturing drug delivery systems
that could be used locally or systemically, in solid, semi-solid,
or liquid formulations.
SUMMARY OF THE INVENTION
[0008] An object of the present invention provides for economical,
practical, and efficient drug delivery systems. According to the
present invention, this drug delivery system is produced easily,
delivered easily to the site of indication, and is both
biocompatible and biodegradable. More specifically, the
formulations of the present invention provide for novel therapies
that are easily manipulated and injected or implanted by qualified
medical practitioners. The formulations deliver therapeutic and
non-toxic levels of active agents over the desired extended time
frame, primarily at the site of implantation. The formulations are
both biocompatible and biodegradable, and disappear harmlessly
after delivering active agent to the desired site.
[0009] One embodiment of the present invention provides for a
pharmaceutical formulation for implantation into a patient for the
sustained release of an active agent comprising a biocompatible,
biodegradable excipient and an active agent or pharmaceutically
acceptable salt thereof. In an aspect of the invention, the
formulation is capable of being implanted by injection.
[0010] Another embodiment of the invention provides for a
pharmaceutical formulation for implantation into a patient for the
sustained release of an active agent comprising a biocompatible,
biodegradable excipient and an active agent or pharmaceutically
acceptable salt thereof, wherein said formulation exhibits an in
vitro dissolution profile wherein about 2% to about 100% of the
active agent is released over a period ranging from about 1 day to
at least 365 days.
[0011] Yet another embodiment provides for a pharmaceutical
formulation for implantation into a patient for the sustained
release of an active agent comprising a biocompatible,
biodegradable excipient and an active agent or pharmaceutically
acceptable salt thereof, wherein about 2% to about 60% of the
active agent is released over a period ranging from about 1 day to
about 105 days. Alternatively, about 2% to about 100% of the active
agent may be released over a period of about 25 days. Or about 2%
to about 85% of the active agent may be released over a period of
about 30 days to about 60 days. In another embodiment, about 2% to
about 60% of the active agent is released over a period ranging
from about 80 days to about 100 days.
[0012] In another aspect of the invention, the formulation
comprises an active agent at a concentration from about 5% to about
50% of the implant and includes a biodegradable, biocompatible
excipient at a concentration of at least about 5% percent of the
implant.
[0013] In another embodiment, the biocompatible, biodegradable
excipient may be chosen from tocopherol isomers and/or their
esters, tocotrienols and/or their esters, benzyl benzoate, esters
of benzoic acid with straight, branched, or cyclic chain aliphatic
alcohols having one to twenty carbon atoms wherein one of the
hydrogen atoms on the aliphatic chain is replaced with a hydroxyl
group, tocopherol isomer acetates, succinates and nicotinates,
tocotrienol isomer acetates, succinates and nicotinates, the mono,
di, and tri esters of O-acetylcitric acid or O-propionylcitric acid
or O-butyrylcitric acid with C.sub.1 to C.sub.10 straight and
branched chain aliphatic alcohols, the mono, di, and tri esters of
citric acid with C.sub.1 to C.sub.10 straight and branched chain
aliphatic alcohols, dibenzoate esters of poly(oxyethylene) diols
having low water solubility, poly(oxypropylene)diols having low
water solubility, dimethyl sulfone, liquid and semisolid
polycarbonate oligomers, or mixtures of two or more these. In an
aspect of the invention, the liquid to semisolid polycarbonate
oligomers includes those prepared by the polymerization of
trimethylene carbonate [poly(1,3-propanediol carbonate)], the ester
exchange polymerization of diethylene carbonate with aliphatic
diols or polyoxyalkane diols [poly(di-1,2-propylene glycol
carbonate), and poly(tri-1,2-propylene glycol carbonate)].
[0014] An aspect of the invention provides for a controlled and
sustained drug delivery system for the posterior segment of the
eye, comprised of a biodegradable and biocompatible liquid matrix
for direct injection. A particular aspect of the invention provides
for compositions comprising either dexamethasone or triamcinolone
acetonide and benzyl benzoate. In another aspect of this
embodiment, dexamethasone or triamcinolone acetonide is released
into the vitreous of the eye in an amount ranging from about 20
.mu.g/ml to less than about 1.0 .mu.g/ml over a period of about
sixty days to about ninety days.
[0015] Another embodiment of the present invention provides for a
biocompatible, biodegradable, syringeable liquid, implantable
solid, and injectable gel sustained release formulations of
therapeutic agents for brain tumors that may be inserted directly
into brain tumors. These formulations comprise novel biocompatible
and biodegradable syringeable liquid, implantable cohesive solids,
and injectable gel formulations conveniently placed inside brain
tumors for the sustained release of beneficial agents are obtained
by admixing one or more of the excipients of the present invention
with one or more of established and new agents for the treatment of
brain tumors, including anti-neovascularization steroids.
[0016] The active agent envisioned in an embodiment of the present
invention is one selected from one or more of the group consisting
of analgesics, anesthetics, narcotics, angiostatic steroids,
anti-inflammatory steroids, angiogenesis inhibitors, nonsteroidal
anti-inflammatories, anti-infective agents, antibiotics,
antifungals, antimalarials, antitublerculosis agents, antivirals,
alpha androgenergic agonists, beta adrenergic blocking agents,
carbonic anhydrase inhibitors, mast cell stabilizers, miotics,
prostaglandins, antihistamines, antimicrotubule agents,
antineoplastic agents, antipoptotics, aldose reductase inhibitors,
antihypertensives, antioxidants, growth hormone agonists and
antagonists, vitrectomy agents, adenosine receptor antagonists,
adenosine deaminase inhibitors, glycosylation antagonists,
anti-aging peptides, topoisemerase inhibitors, anti-metabolites,
alkylating agents, anti-andrigens, anti-oestogens, oncogene
activation inhibitors, telomerase inhibitors, antibodies or
portions thereof, antisense oligonucleotides, fusion proteins,
luteinizing hormone releasing hormones agonists, gonadotropin
releasing hormone agonists, tyrosine kinase inhibitors, epidermal
growth factor inhibitors, ribonucleotide reductase inhibitors,
cytotoxins, IL2 therapeutics, neurotensin antagonists, peripheral
sigma ligands, endothelin ETA/receptor antagonists,
antihyperglycemics, anti-glaucoma agents, anti-chromatin modifying
enzymes, insulins, glucagon-like-peptides, obesity management
agents, anemia therapeutics, emesis therapeutics, neutropaenia
therapeutics, tumor-induced hypercalcaemia therapeutics, blood
anticoagulants, immunosuppressive agents, tissue repair agents,
psychotherapeutic agents, botulinum toxins, essential fatty acids,
and nucleic acids such as siRNA and RNAi.
[0017] In another embodiment of the invention, the active agent or
excipient may be an omega-3 fatty acid or an ester thereof. Another
embodiment of the present invention provides for a formulation
comprising a nonpolymeric, biodegradable, bioabsorbable excipient
and the active agent is one or more antioxidants, either alone or
included with one or more steroids and/or quinolone
anti-infectives. Still another embodiment provides for the
transdermal delivery of active agents, for example, insulin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 presents dissolution profiles of dexamethasone (Dex)
from two formulations of Dex/poly(1,3-propanediol carbonate)I.
[0019] FIG. 2 presents dissolution profiles of Dex from two
formulations of Dex/poly(1,3-propanediol carbonate)II.
[0020] FIG. 3 represents dissolution profiles of Dex from three
formulations of Dex/poly(di-1,2 propylene glycol carbonate).
[0021] FIG. 4 depicts dissolution profiles of Dex from two
formulations of Dex/poly(tri-1,2 propylene glycol carbonate).
[0022] FIG. 5 depicts dissolution profiles of Dex released from
three formulations of Dex/benzyl benzoate.
[0023] FIG. 6 depicts dissolution profiles of Dex released from
three formulations of Dex/diethylene glycol dibenzoate.
[0024] FIG. 7 depicts dissolution profiles of triamcinolone
acetonide released from three formulations of triamcinolone
acetonide/diethylene glycol dibenzoate.
[0025] FIG. 8 depicts dissolution profiles of Dex released from
three formulations of Dex/d-tocopherol, and d1-tocopheryl
acetate.
[0026] FIG. 9 depicts a dissolution profile of Dex released from a
Dex/diethylene glycol dibenzoate formulation.
[0027] FIG. 10 depicts a dissolution profile of Dex released from a
Dex/benzyl benzoate formulation.
[0028] FIG. 11 depicts a dissolution profile of Dex released from a
Dex/tocopheryl succinate formulation.
[0029] FIG. 12 depicts a dissolution profile of Dex and
Ciprofloxacin from a 1:1 formulation of those components in benzyl
benzoate (Panel A) and a 3:1 formulation of Dex and Ciprofloxacin
in benzyl benzoate (Panel B).
[0030] FIG. 13 depicts the concentration of Dex released into the
vitreous humor from two formulation of Dex in benzyl benzoate.
[0031] FIG. 14 represents a histopathological slide of rabbit eye
tissue thirty days after a posterior segment injection of a
formulation of 25% Dex in benzyl benzoate.
[0032] FIG. 15 depicts the vitreous concentration of tramcinolone
acetonide (TA) released from a TA:benzyl benzoate composition.
[0033] FIG. 16 depicts the in vivo release of Dex released into the
aqueous humor from a Dex:d1-alpha tocopherol succinate
formulation.
[0034] FIG. 17 depicts the dissolution of Dex from a
Dex:acetone:tocopherol succinate formulation applied to solid
surfaces.
[0035] FIG. 18 shows the dissolution profile of cyclosporin from a
cyclosporin: tocopherol succinate formulation.
[0036] FIG. 19 depicts an in vivo release profile of cyclosporin
from a tocopherol succinate:cyclosporin formulation implanted the
anterior chamber of a New Zealand White (NZW) rabbit.
[0037] FIG. 20 depicts an in vivo release profile of cyclosporin
from a tocopherol succinate:cyclosporin formulation implanted the
posterior segment of a NZW rabbit eye.
[0038] FIG. 21 shows an in vivo release of cyclosporine from a
tocopherol succinate:cyclosporin formulation implanted in the
peritoneal cavity of a rat.
[0039] FIG. 22 plots in vivo blood glucose levels in mice treated
with a transdermal formulation of insulin in tocopheryl
acetate.
[0040] FIG. 23 shows in vitro release of Dex from a pellet of 1.5
mg of 50/50 wt Dex/tocopheryl succinate.
[0041] FIG. 24 presents a bar graph reflecting brain tumor volume
following either resection, or resection and subsequent treatment
with Dex.
[0042] FIG. 25 depicts the percent Dex released in vitro from a
formulation of 24% Dex and Triethyl O-Acetyl Citrate (TEAC).
[0043] FIG. 26 shows the percent Dex released in vitro from a
formulation of 20% Dex and TEAC/Tocopherol Acetate.
[0044] FIG. 27 illustrates the percent Dex released in vivo from a
formulation of 10% Dex and TEAC injected into the rabbit eye
anterior chamber (AC).
[0045] FIG. 28 presents the percent Dex released in vivo from a
formulation of 10% Dex and TEAC injected into the rabbit eye
vitreous chamber/posterior segment.
[0046] FIG. 29 depicts the kinetics of Dex released in vivo from 80
.mu.g of Dex in a formulation of 20% Dex and TEAC injected into the
rabbit eye AC.
[0047] FIG. 30 depicts the kinetics of Dex released in vivo from
900 .mu.g of Dex in a formulation of 20% Dex and TEAC injected into
the rabbit eye AC.
[0048] FIG. 31 shows the in vivo release of Ciprofloxacin from a
20% Ciprofloxacin/TEAC formulation injected into the AC of a rabbit
eye.
[0049] FIG. 32 presents the in vivo release of Cyclosporin A (CsA)
from a CsA/tocopherol formulation injected into the AC of a rabbit
eye.
[0050] FIG. 33 presents the in vivo release of Cyclosporin A (CsA)
from a CsA/TEAC formulation injected into the vitreous of a rabbit
eye.
[0051] FIG. 34 illustrates the in vivo release of active monoclonal
antibody (Mab) from three different formulations tested in the
vitreous cavity of rabbit eyes.
[0052] FIG. 35 reflects the intraocular sustained release of
rapamycin from rapamycin:TEAC formulation injected into the
vitreous cavity of rabbit eyes.
[0053] FIG. 36 shows the sustained release of ketorolac acid from a
formulation of ketorolac acid:benzyl benzoate injected into the
anterior chamber of the rabbit eye.
[0054] FIG. 37 shows the sustained release of ketorolac acid into
the vitreous from either a formulation of ketorolac acid:benzyl
benzoate or ketorolac acid:TEAC injected into the vitrous of the
rabbit eye
DETAILED DESCRIPTION OF THE INVENTION
[0055] It should be understood that this invention is not limited
to the particular methodology, protocols, and reagents, etc,
described herein and as such may vary. The terminology used herein
is for the purpose of describing particular embodiments only, and
is not intended to limit the scope of the present invention, which
is defined solely by the claims.
[0056] As used herein and in the claims, the singular forms "a,"
"an," and "the" include the plural reference unless the context
clearly indicates otherwise. Thus, for example, the reference to an
excipient is a reference to one or more such excipients, including
equivalents thereof known to those skilled in the art. Other than
in the operating examples, or where otherwise indicated, all
numbers expressing quantities of ingredients or reaction conditions
used herein should be understood as modified in all instances by
the term "about." The term "about" when used in connection with
percentages may mean .+-.1%.
[0057] All patents and other publications identified are
incorporated herein by reference for the purpose of describing and
disclosing, for example, the methodologies described in such
publications that might be used in connection with the present
invention, but are not to provide definitions of terms inconsistent
with those presented herein. These publications are provided solely
for their disclosure prior to the filing date of the present
application. Nothing in this regard should be construed as an
admission that the inventors are not entitled to antedate such
disclosure by virtue of prior invention or for any other reason.
All statements as to the date or representation as to the contents
of these documents is based on information available to the
applicants and do not constitute any admission as to the
correctness of the dates or contents of these documents.
[0058] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as those commonly understood to
one of ordinary skill in the art to which this invention
pertains.
[0059] The present invention relates to novel biocompatible,
biodegradable sustained release formulations. In various aspects of
the invention, these formulations are syringeable liquids,
mechanically cohesive solids, injectable gels, or emulsified
micells (oil in water or water in oil). A desirable feature of
these liquid, solid, and gel formulations is that they maintain a
single bolus or pellet shape at the site of their placement. That
is, they do not break up as a multitude of smaller droplets or
particles that migrate away from their intended point of placement
and/or by virtue of a resultant increase in surface area greatly
alter the intended release rate of their drug content.
[0060] The formulations of the present invention provide for novel
therapies that are easily manipulated and injected or implanted by
qualified medical practitioners. The formulations deliver
therapeutic and non-toxic levels of active agents over the desired
extended time frame, primarily at the site of implantation. The
formulations are both biocompatible and biodegradable, and
disappear harmlessly after delivering active agent to the desired
site.
[0061] The present invention relates generally, but not totally, to
the use of formulations that are of limited solubility,
biocompatible, and biodegradable (LSBB), which may also be
syringeable, for controlled and sustained release of an active
agent or a combination of active agents. Solid, gel or injectable,
controlled-sustained release systems can be fabricated by combining
LSBB and an active agent. Systems can combine more than one
biodegradable component as well as more than one active agent.
Solid forms for implantation can be produced by tableting,
injection molding or by extrusion. Gels can be produced by vortex
or mechanical mixing. Injectable formulations can be made by
pre-mixing in a syringe or mixing of the LSBB and the active agent
before or at the time of administration. Formulations may serve as
coating for stents or other implants by, for example, dipping the
stent in a liquid form of the formulation and then drying it.
[0062] In an aspect of the present invention, novel biocompatible
and biodegradable syringeable liquid, implantable cohesive solids,
and injectable gel formulations conveniently placed on or within
the human or animal body for the sustained release of active
agents, are obtained by admixing one or more excipients, such as,
for example: benzyl benzoate, esters of benzoic acid with straight,
branched, or cyclic chain aliphatic alcohols having one to twenty
carbon atoms wherein one of the hydrogen atoms on the aliphatic
chain is replaced with a hydroxyl group (e.g., such alcohols as
methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,
s-butanol, t-butanol, n-pentanol, i-pentanol, neo-pentanol,
n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol,
n-decanol, and the like), tocopherol isomer acetates, succinates
and nicotinates, tocotrienol isomer acetates, succinates and
nicotinates, the mono, di, and tri esters of O-acetylcitric acid or
O-propionylcitric acid or O-butyrylcitric acid with C.sub.1 to
C.sub.10 straight and branched chain aliphatic alcohols, the mono,
di, and tri esters of citric acid with C.sub.1 to C.sub.10 straight
and branched chain aliphatic alcohols, omega-3 fatty acids and
their esters of C.sub.1 to C.sub.8 straight and branched chain
aliphatic alcohols, dibenzoate esters of poly(oxyethylene) diols
having low water solubility, poly(oxypropylene)diols having low
water solubility, dimethyl sulfone, liquid and semisolid
polycarbonate oligomers, with a large number of established and new
active agents. In an aspect of the invention, the liquid to
semisolid polycarbonate oligomers include those prepared by the
polymerization of trimethylene carbonate [poly(1,3-propanediol
carbonate)], the ester exchange polymerization of diethylene
carbonate with aliphatic diols or polyoxyalkane diols
[poly(di-1,2-propylene glycol carbonate), and
poly(tri-1,2-propylene glycol carbonate)].
[0063] In another aspect of the invention, the solid form generally
contains about 1% to about 60% of an LSBB, the gel form generally
contains about 20% to about 80% of an LSBB, and an injectable form
(which may be a gel or liquid form) generally contains about 30% to
about 99.9% of an LSBB.
[0064] Liquid and solid LSBB formulations can be implanted, for
example, surgically, by trocar, or by needle introduction. The
formulations can be placed into body cavities such as joints by
methods well-known in the art (typically using the procedures
outlined by Cardone & Tallia, Am. Family Physician, 66 (2),
283-92 (2002); 66 (11), 2097-100 (2002); 67 (10), 2147-52 (2003);
68 (7), 1356-62 (2003); 67 (4), 745-50 (2003)); intraocular
(chambers such as the anterior chamber and posterior segment of the
eye); intratumoral injection into the prostate tumor (typically
using a procedure similar to that described by Jackson et al., 60
(5) Cancer Res., 4146-51 (2000)); intratumoral injection into
inoperable tumors (such as gliomas) in the brain (typically using a
procedure similar to that described by Emerich et al., 17 (7) Pharm
Res, 767-75 (2000)); injection or insertion into an intravertebral
disc or disc space; injection into peritoneal cavity, or
intranasal, intrathecal, subcutaneous or intramuscular injection,
injection into the epidural, subdural and/or subarachnoid space; or
the formulation may be injected or inserted directly into the
cerebral spinal fluid through the spinal canal or into the CNS
ventricular system.
[0065] Additionally, for localized active agent delivery, the
system of the present invention may be surgically implanted at or
near the site of action. This may be useful when it is used, for
example, in treating ocular conditions, primary tumors, rheumatic
and arthritic conditions, and chronic pain.
[0066] It is contemplated that these LSBB/active agent compositions
can be applied to the following, but not limited to, systems of the
human or animal body: muscular, skeletal, nervous, autonomic
nervous, vascular, lymphatic, digestive, respiratory, urinary,
female reproductive, male reproductive, endocrine or
intraparenchymal, to provide a wide variety of sustained
therapies.
[0067] Specific areas of the human or animal body to be targeted
for injection or implantation or topical applications of these
LSBB/active agents compositions include, but are not limited to:
heart, brain, spinal nerves, vertebral column, skull, neck, head,
eye, ear organs of hearing and balance, nose, throat, skin,
viscera, hair, shoulder, elbow, hand, wrist, hip, knee, ankle,
foot, teeth, gums, liver, kidney, pancreas, prostate, testicles,
ovaries, thymus, adrenal glands, pharynx, larynx, bones, bone
marrow, stomach, bowel, upper and lower intestines, bladder, lungs,
mammaries. Surgical implantation into the eye, for example, is
known in the art as described in U.S. Pat. No. 6,699,493; U.S. Pat.
No. 6,726,918; U.S. Pat. No. 6,331,313; U.S. Pat. No. 5,824,072;
U.S. Pat. No. 5,766,242; U.S. Pat. No. 5,443,505; U.S. Pat. No.
5,164,188; U.S. Pat. No. 4,997,652; and U.S. Pat. No.
4,853,224.
[0068] Solid LSBB formulations, for example, may be implanted
directly into parenchymal tissues such as the brain, spinal cord,
or any part of the CNS system, into the kidney, liver, spleen,
pancreas, lymph nodes as well as tumors. Gel LSBB systems may be
applied to surface tissues such as the skin, or as coating on
surfaces of parenchymal organs to be absorbed, or be applied
directly on the cornea, conjunctiva and on the sclera for delivery
of active agent onto the surface of and intraocularly to the eye.
Injectable LSBB formulations are less invasive and can be
delivered, for example, through a 30 gauge needle into the eye, or
through larger needles into cavities such as joints.
[0069] The system according to the present invention has particular
applicability in providing a controlled and sustained release of
active agents effective in obtaining a desired local or systemic
physiological or pharmacological effect relating at least to the
following areas: treatment of cancerous primary tumors, chronic
pain, arthritis, rheumatic conditions, hormonal deficiencies such
as diabetes and dwarfism, modification of the immune response such
as in the prevention and treatment of transplant rejection and in
cancer therapy. The system is also suitable for use in treating HIV
and HIV related opportunistic infections such as CMV,
toxoplasmosis, Pneumocystis carinii, and Mycobacterium
avium-intercellulare. The system may be used to delivery an active
agent effective in treating fungal infection of the mouth. If such
a use is desired, the system may be designed to have a shape
suitable for implanting into a tooth.
[0070] LSBB formulations are also useful for treating ocular
conditions such as glaucoma, PVR, diabetic retinopathy, uveitis,
retinal edema, vein occlusion, macular degeneration, Irvine-Gass
Syndrome and CMV retinitis, corneal diseases such as keratitis, and
corneal transplantation rejection. The formulations may also be
prepared as control-release eye drops for dry-eye or for
controlling the immune response. Regarding control of immune
responses, the formulations may contain one or more of
cyclosporine, sirolimus, or tacrolimus. Other intraocular uses
include glaucoma treatments (e.g., formulations including timolol),
antibiotic delivery, antibody delivery, and antiproliferatives
delivery (e.g., paclitaxel).
[0071] Other uses of the formulations include, for example,
mediating homograft rejection with formulations comprising
sirolimus or cyclosporine. Local cancer therapy may be delivered
to, for example, the kidney or liver, using in formulations
comprising, for example, adriamycin or small epidermal growth
factors. Prostate cancer may be treated with formulations including
fenasteride. Cardiac stents implants, central nervous system
implants (e.g., spinal implants), orthopedic implants, etc., may be
coated with formulations including growth or differentiation
factors, anti-inflammatory agents, or antibiotics.
[0072] Additionally, the pharmaceutical formulations herein provide
for methods for the management of skin wrinkles, or bladder,
prostatic and pelvic floor disorders by implanting, by injection, a
pharmaceutical formulation comprising a biodegradable,
biocompatible excipient and botulinum toxins into a strategic
position in the skin or bladder, prostate or pelvic floor region to
provide controlled and sustained release of a therapeutically
effective but non-toxic level of the botulinum toxins within the
effected areas. The pharmaceutical formulations herein also provide
methods for the management of uterine fibroids by implanting, by
injection, a pharmaceutical formulation comprising a biodegradable,
biocompatible excipient and suitable therapeutic agent, such as
pirfenidone, human interferon-alpha, GnRH antagonists, Redoxifene
and estrogen-receptor modulators, into strategic positions inside
the fibroids to provide controlled and sustained release of
therapeutically effective, but non-toxic levels, of the therapeutic
agents within the fibroids.
[0073] The technology of the present application is useful in
overcoming the difficulties reported in some cases of achieving
therapeutic efficacy, as experienced in current administrations
requiring large doses of medications that may result in toxic side
effects. An important example of this problem is the current
clinical practice of intravitreal injections of microcrystalline
triamcinolone acetonide (TA) for the treatment of intraocular
neovascular, oedematous, or inflammatory diseases. See Jonas et
al., 24 (5) Prog Retin Eye Res. 587-611 (2005), and references
therein. The therapy requires the presence of a solution of the
proper TA concentration in the vitreous chamber for periods of six
months to a year and possibly longer. The therapeutic vitreal
concentrations of TA seem to be at 1.0 .mu.g/ml or below (Matsuda
et al., 46 Invest Opthalmol Vis Sci. 1062-1068 (2005)) whereas
harmful complications (glaucoma, cataracts, cytotoxicity) can arise
when TA concentrations continuously exceed 10 .mu.g/ml over an
extended period of time. See Gillies et al., 122 (3) Arch
Opthalmol. 336-340 (2004); Jonas et al., 15 (4) Eur J Opthalmol.
462-4 (2005); Yeung et al, 44 Invest Opthalmol Vis Sci. 5293-5300
(2003). The desire to limit TA administration to one or two
injections per year (because of patient discomfort coupled with the
possibility of endophthalmitis (see Bucher et al., 123 (5) Arch
Opthalmol. 649-53 (2005)), conflicts with the ability of supplying
enough TA crystals without excursions into toxic concentrations.
The novel compositions of this invention solve this problem by
encompassing the desired amounts of TA in an injectable,
biocompatible, bioerodable medium that continuously regulates the
release of safe, therapeutic levels of intravitreal TA for periods
of six months or more.
[0074] Further regarding ocular conditions, metabolic and
inflammation conditions in the posterior segment of the eye have
been extremely difficult to treat. Such conditions as proliferative
vitreoretinopathy (PVR), uveitis, cystoid macular edema (CME),
diabetes, and macular degeneration are major causes of blindness.
Conventional methods of drug delivery, including topical,
periocular, subconjunctival or systemic administration, have had
limited success due in large part to poor drug penetration (due to
the blood-eye barrier) and toxic side effects. One efficient way of
delivering a drug to the posterior segment is to place it directly
into the vitreous cavity. Intravitreal drug injections have shown
promising results in animals and in humans, but repeated and
frequent injections have had to be performed to maintain
therapeutic levels.
[0075] For example, direct injection of corticosteroids,
particularly triamcinolone acetonide, has been effective
particularly in selected wet macular degeneration and in diabetic
retinal edemas. Because of the drugs' short half-life in the eye,
frequent injections are required. Moreover, because the drug is
being given in a bolus, uncontrolled high and then low drug
concentration levels are encountered. As a consequence, adverse
reactions such as infection, glaucoma, cataract formation, retinal
detachment and intraocular bleeding have been common adverse
occurrences. Vitrasert.RTM. (Bausch & Lomb) is a six- to
eight-month reservoir system to treat CMV retinitis with the
antiviral gancyclovir. This is a non-biodegradable system and must
be both inserted and removed surgically. Similarly, Posurdex.RTM.
(Allergan, Inc.) is a one-month biodegradable delivery system that
must be implanted surgically into the eye, and contains
dexamethasone and poly(lactic-co-glycolic acid) (PLGA) for the
treatment of posterior segment pathologies.
[0076] Hence, one embodiment of the present invention provides for
an intraocular controlled and sustained drug delivery system for
the posterior segment of the eye. It is comprised of a
biodegradable and biocompatible liquid matrix containing a
microdispersed drug or mixture of drugs, and can be injected
directly into the posterior segment with a relatively small needle.
The duration of drug delivery can be as short as a few days to many
months and up to one year or longer, and the matrix gradually and
safely dissipates over time so that there is no need to remove it.
An example embodiment comprises dexamethasone and benzyl benzoate.
In this system, intravitreal levels of dexamethasone with a 25%
formulation in 50 .mu.l delivers a mean vitreous level of
approximately 8.0 .mu.g/ml over a three-month period. In
comparison, a 25 .mu.l injection delivers a mean vitreous level of
approximately 4.0 .mu.g/ml over a sixty day period. This
composition is biocompatible, biodegradable, non-toxic, easy to
manufacture, easy to deliver, and flexible in terms of therapeutic
dose and duration of delivery.
[0077] Another aspect of the invention provides for a formulation
for limiting tissue rejection following corneal transplant. Corneal
transplant, also known as a corneal graft, or as a penetrating
keratoplasty, involves the removal of the central portion (called a
button) of the diseased cornea and replacing it with a matched
donor button of cornea. Corneal grafts are performed on patients
with damaged or scarred corneas that prevent acceptable vision.
This may be due to corneal scarring from disease or trauma.
Formulations of the present invention useful in corneal transplant
contexts may include rapamycin, cyclosporin, or a combination of
these active agents.
[0078] Further regarding cyclosporin and rapamycin, these active
agents may be used in the anterior segment and/or the posterior
segment of the eye. These are antiimmune drugs that have
antiinflammatory properties, antirejections properties,
antifibrosis activities, and antineogenesis properties. As provided
for herein, formulations of these agents either alone or in
combination may be prepared for use in the used in the anterior
segment for corneal rejection (organ rejection) or any inflammatory
conditions. Formulations may also be prepared for use in the
posterior segment or back of the eye for indications such as
macular degeneration, antineogenesis which occurs in macular
degeneration, or for cellular transplants or stem cell transplants
for repair or in maintaining the health of the retina, choroid
etc.
[0079] A wide variety of other disease states are known by those of
ordinary skill in the art, such as those described in Goodman &
Gilman, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (McGraw Hill,
2001), and REMINGTON'S PHARMACEUTICAL SCIENCES (Lippincott Williams
& Wilkins; 20th ed., 2000). Those to which the present
invention may be applied may be determined by those with ordinary
skill in the art without undue experimentation.
[0080] Suitable classes of active agents for use in the system of
the present invention include, but are not limited to the
following:
[0081] Peptides and proteins such as cyclosporin, insulins,
glucagon-like-peptides, growth hormones, insulin related growth
factor, botulinum toxins (Botox, Allergan), antibodies, and heat
shock proteins;
[0082] Anesthetics and pain killing agents such as lidocaine and
related compounds, and benzodiazepam and related compounds;
[0083] Anti-cancer agents such as 5-fluorouracil, methotrexate and
related compounds;
[0084] Anti-inflammatory agents such as 6-mannose phosphate;
[0085] Anti-fungal agents such as fluconazole and related
compounds;
[0086] Antiviral agents such as trisodium phosphomonoformate,
trifluorothymidine, acyclovir, cidofovir, ganciclovir, ddI, and
AZT;
[0087] Cell transport/mobility impending agents such as
colchicines, vincristine, cytochalasin B, and related
compounds;
[0088] Anti-glaucoma drugs such as beta-blockers: timolol,
betaxolol, and atenolol;
[0089] Immunological response modifiers such as muramyl dipeptide
and related compounds;
[0090] Steroidal compounds such as dexamethasone, prednisolone,
triamcinolone and related compounds; and
[0091] Carbonic anhydrase inhibitors such as acetazolamide,
brinzolamide, dorzolamide, and timolol maleate.
[0092] In addition to the above agents, other active agents which
are suitable for administration, especially to the eye and its
surrounding tissues, to produce a local or a systemic physiologic
or pharmacologic effect can be used in the system of the present
invention. Examples of such agents include antibiotics such as
tetracycline, chloramphenicol, ciprofloxacin, ampicillin and the
like.
[0093] Any pharmaceutically acceptable form of the active agents of
the present invention may be employed in the practice of the
present invention, e.g., the free base or a pharmaceutically
acceptable salt or ester thereof. Pharmaceutically acceptable
salts, for instance, include sulfate, lactate, acetate, stearate,
hydrochloride, tartrate, maleate, citrate, phosphate, and the
like.
[0094] The active agents may also be used in combination with
pharmaceutically acceptable carriers in additional ingredients such
as antioxidants, stabilizing agents, and diffusion enhancers. For
example, where water uptake by the active agent is undesired, the
active agent can be formulated in a hydrophobic carrier, such as a
wax or an oil, that would allow sufficient diffusion of the active
agent from the system. Such carriers are well known in the art.
[0095] In another aspect of the invention, a low solubility active
agent may be combined with a biodegradable, biocompatible excipient
of higher solubility to result in an LSBB formulation. For example,
dimethyl sulfone may be used as a binder in an LSBB formulation of
a limited solubility active agent. Hence, the use of a soluble
excipient in an LSBB formulation is within the scope of the present
invention.
[0096] In one embodiment, the active agents, e.g., proteins, may be
formulated in a glassy matrix of sugar which tends to protect the
active agent from hydrolytic degradation and extend their shelf
life and eliminate the need for cold storage. See, for example,
Franks, Long-Term Stabilization of Biologicals, 12 Bio/Technology
253-56 (1994), the contents of which are hereby incorporated by
reference.
[0097] Proteins may be formulated in a glass matrix by removing
water from a homogeneous solution thereof. The water can be removed
either by evaporation or by rapidly cold quenching the solution.
The process is commonly referred to as vitrification. As water is
removed from the solution, it becomes increasingly viscous until a
"solidified" liquid containing the proteins is obtained. The
"solidified" liquid is generically called glass.
[0098] Glasses have a number of unique physical and chemical
properties which make them ideal for active agent formulation.
Among them, the most important is that the solidified liquid
retains the molecular disorder of the original solution. This
disorder contributes to the glasses' long-term stability by
preventing crystallization and chemical reactions of the proteins
encased therein.
[0099] Sugars can also play an important part in stabilizing
protein formulations. In solution, they are known to shift the
denaturation equilibrium of proteins toward the native state. Most
sugars, particularly low molecular weight carbohydrates, are also
known to vitrify easily and to provide a glassy matrix that retards
inactivating reactions of the proteins.
[0100] For illustrative purposes, the glassy sugar matrix for use
in the system according to the present invention can be made by
compressing a lyophilized mix of a protein with sugar and a buffer,
and optionally, binders.
[0101] Examples of proteins and proteinaceous compounds which may
be formulated and employed in the delivery system according to the
present invention include those proteins which have biological
activity or which may be used to treat a disease or other
pathological condition. They include, but are not limited to
antibodies, growth hormone, Factor VIII, Factor IX and other
coagulation factors, chymotrypsin, trysinogen, alpha-interferon,
beta-galactosidase, lactate dehydrogenase, growth factors, clotting
factors, enzymes, immune response stimulators, cytokines,
lymphokines, interferons, immunoglobulins, retroviruses,
interleukins, peptides, somatostatin, somatotropin analogues,
somatomedin-C, Gonadotropic releasing hormone, follicle stimulating
hormone, luteinizing hormone, LHRH, LHRH analogues such as
leuprolide, nafarelin and geserelin, LHRH agonists and antagonists,
growth hormone releasing factor, callcitonin, colchicines,
gonadotropins such as chorionic gonadotropin, oxytocin, octreotide,
somatotropin plus and amino acid, vasopressin, adrenocorticotrophic
hormone, epidermal growth factor, prolactin, somatotropin plus a
protein, cosyntropin, lypressin, polypeptides such as thyrotropin
releasing hormone, thyroid stimulation hormone, secretin,
pancreozymin, enkephalin, glucagons, and endocrine agents secreted
internally and distributed by way of the bloodstream.
[0102] Other agents, such as .alpha..sub.1 antitrypsin, insulin,
glucagon-like-peptides, and other peptide hormones, botulinum
toxins (Botox.RTM., Allergan, Inc.), adrenal cortical stimulating
hormone, thyroid stimulating hormone, and other pituitary hormones,
interferons such as .alpha., .beta., and .delta. interferon,
erythropoietin, growth factors such as GCSFm GM-CSF, insulin-like
growth factor 1, tissue plasminogen activator, CF4, dDAVP, tumor
necrosis factor receptor, pancreatic enzymes, lactase,
interleukin-1 receptor antagonist, interleukin-2, tumor suppresser
proteins, cytotoxic proteins, viruses, viral proteins, recombinant
antibodies, portions of antibodies, and antibody fragments and the
like may be used. Analogs, derivatives, antagonists, agonists, and
pharmaceutically acceptable salts of the above may also be
used.
[0103] Other active agents encompassed in the present invention
include prodrugs. Because prodrugs are known to enhance numerous
desirable qualities of pharmaceuticals (e.g., solubility,
bioavailability, manufacturing, etc.) the pharmaceutical dosage
forms of the present invention may contain compounds in prodrug
form. Thus, the present invention is intended to cover prodrugs of
the presently claimed active agents, methods of delivering the
same, and compositions containing the same.
[0104] Analogs, such as a compound that comprises a chemically
modified form of a specific compound or class thereof, and that
maintains the pharmaceutical and/or pharmacological activities
characteristic of said compound or class, are also encompassed in
the present invention. Similarly, derivatives such as a chemically
modified compound wherein the modification is considered routine by
the ordinary skilled chemist, such as an ester or an amide of an
acid, protecting groups, such as a benzyl group for an alcohol or
thiol, and tert-butoxycarbonyl group for an amine, are also
encompassed by the present invention.
[0105] The active agents are useful for the treatment or prevention
of a variety of conditions including, but not limited to hemophilia
and other blood disorders, growth disorders, diabetes, obesity,
leukemia, hepatitis, renal failure, HIV infection, hereditary
diseases such as cerebrosidase deficiency and adenoine deaminase
deficiency, hypertension, septic shock, autoimmune disease such as
multiple sclerosis, Graves disease, systemic lupus erythematosus
and rheumatoid arthritis, shock and wasting disorders, cystic
fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel
disease, gastrointestinal and other cancers, cancerous or benign
tumors, and management of bladder, prostatic, and pelvic floor
disorders, and uterine fibroid (submucosal, subserosal, intramural,
parasitic myomas, and seedling myomas) management (using for
example but not limited to pirfenidone, human interferon-alpha,
GnRH antagonists, Redoxifene, estrogen-receptor modulators).
Additionally, the formulations of the present invention may be used
to treat intracranial aneurysms by, for example, introducing
fibrogen or plasmin.
[0106] It is further contemplated that topical formulations of
these LSBBs with active agents can be applied for the transdermal
administration of contraceptives, insulin or GLP-1, transdermal
application for alopecia treatment or delivery of aspirin or other
small molecules, smoking cessation agents, anti-obesity agents,
antivirals (herpes therapies), agents for psoriasis therapies,
agents for alopecia therapies, agents for acne therapies, agents
for erectile disfunction and antiparasitic agents, to name a
few.
[0107] The protein compounds useful in the formulations of the
present invention can be used in the form of a salt, preferably a
pharmaceutically acceptable salt. Useful salts are known to those
skilled in the art and include salts with inorganic acids, organic
acids, inorganic bases, or organic bases.
[0108] Sugars useful for preparing the glassy matrix discussed
previously include, but are not limited to, glucose, sucrose,
trehalose, lactose, maltose, raffinose, stachyose, maltodextrins,
cyclodextrins, sugar polymers such as dextrans and their
derivatives, ficoll, and starch.
[0109] Buffers useful for formulating the glassy matrix include,
but not limited to MES, HEPES, citrate, lactate, acetate, and amino
acid buffers known in the art.
[0110] The LSBB system comprising the glassy sugar matrix may be
constructed of a bioerodible polymer with low water permeability.
Such polymers include poly(glycolic acid), poly(lactic acid),
copolymers of lactic/glycolic acid, polyorthoesters,
polyanhydrides, polyphosphazones, polycaprolactone. These polymers
may be advantageous because of their slow erosion properties and
low water uptake; thus, they should not undergo undue changes
during the course of the active agent delivery.
[0111] Naturally occurring or synthetic materials that are
biologically compatible with body fluids suitable for use in the
present invention generally include polymers such as polyethylene,
polypropylene, polyethylene terephthalate, crosslinked polyester,
polycarbonate, polysulfone, poly(2-pentene),
poly(methylmethacrylate), poly(1,4-phenylene),
polytetrafluoroethylene, and poly-ethylene-vinylacetate (EVA).
[0112] In an aspect of the present invention, the excipient is also
biodegradable or bioerodible. As used herein, the terms
"bioerodible" and "biodegradable" are equivalent and are used
interchangeably. Biodegradable excipients are those which degrade
in vivo, and wherein erosion of the excipient over time is required
to achieve the agent release kinetics according to the invention.
Suitable biodegradable excipients may include but are not limited
to, for example, poly(glycolic acid), poly(lactic acid), copolymers
of lactic/glycolic acid, polyorthoesters, polyanhydrides,
polyphosphazones, polycarbonates, and polycaprolactone. The use of
polylactic polyglycolic acid is described in, for example, U.S.
Pat. No. 6,699,493. See also U.S. Pat. No. 5,869,079.
[0113] In another aspect of the invention, the excipient is
biocompatible, meaning that it does not have undue toxicity or
cause either physiologically or pharmacologically harmful effects.
In another aspect of the invention, the excipient is
biodegradable.
[0114] Examples of excipients that may be useful as biocompatible,
biodegradable and/or bioerodible excipients in the present
invention, as determined by one of ordinary skill in the art in
light of this specification, without undue experimentation,
include, but are not limited to d-.alpha.-tocopherol;
d,1-.alpha.-tocopherol; d-.beta.-tocopherol; d,1-.beta.-tocopherol;
d-.eta.-tocopherol; and d,1-.eta.-tocopherol (including acetate,
hemisuccinate, nicotinate, and succinate-PEG ester forms of each of
the foregoing, including a succinic-PEG ester such as
tocophersolan); tocotrienol isomers, and their esters; benzyl
benzoate, esters of benzoic acid with straight, branched, or cyclic
chain aliphatic alcohols having one to twenty carbon atoms wherein
one of the hydrogen atoms on the aliphatic chain is replaced with a
hydroxyl group (e.g., such alcohols as methanol, ethanol,
n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol,
n-pentanol, i-pentanol, neo-pentanol, n-hexanol, cyclohexanol,
n-heptanol, n-octonol, n-nonanol, n-decanol, and the like),
tocotrienol isomer succinates and nicotinates; the mono, di, and
tri esters of O-acetylcitric acid or O-propionylcitric acid or
O-butyrylcitric acid with C.sub.1 to C.sub.10 straight and branched
chain aliphatic alcohols, the mono, di, and tri esters of citric
acid with C.sub.1 to C.sub.10 straight and branched chain aliphatic
alcohols, dibenzoate esters of poly(oxyethylene) diols having low
water solubility, poly(oxypropylene)diols having low water
solubility, liquid and semisolid polycarbonate oligomers, and
dimethyl sulfone. The liquid to semisolid polycarbonate oligomers
may be those polycarbonate oligomers prepared by the polymerization
of trimethylene carbonate [poly(1,3-propanediol carbonate)], the
ester exchange polymerization of diethylene carbonate with
aliphatic diols or polyoxyalkane diols [poly(di-1,2-propylene
glycol carbonate), or poly(tri-1,2-propylene glycol
carbonate)].
[0115] Another example of biodegradable/biocompatible excipients
useful in the present invention are "tocols": a family of
tocopherols and tocotrienols and derivatives thereof. Tocopherols
and tocotrienols are derivatives of the simplest tocopherol,
6-hydroxy-2-methyl-2-phytylchroman. Tocopherols are also known as a
family of natural or synthetic compounds commonly called Vitamin E.
Alpha-tocopherol is the most abundant and active form of this class
of compounds. Other members of this class include .beta.-,
.gamma.-, and .delta.-tocopherols and .alpha.-tocopherol
derivatives such as tocopheryl acetate, succinate, nicotinate, and
linoleate. Useful tocotrienols include d-.delta.-tocotreinols, and
d-.beta.-, d-.gamma.-tocotrienols, and their esters.
[0116] In addition to the excipients listed above, the following
excipients having very low viscosities are valued not only by
themselves as carriers of drugs for injectable sustained release
(ISR) formulations, but also as additives to the ISR formulations
of the excipients listed above to reduce their viscosities and
thereby improve syringeability. These include: perfluorodecalin;
perfluorooctane; perfluorohexyloctane; the cyclomethicones,
especially octamethylcyclotetrasiloxane;
decamethylcyclopentasiloxane, and dodecamethylcyclohexasiloxane
polydimethylsiloxanes of viscosities below about 1000 cSt; diethyl
carbonate; and dipropylcarbonate.
[0117] It is also contemplated that these liquid and solid
LSBBs/active agent formulations can be coatings on implanted
surfaces, such as but not limited to, those on catheters, stents
(cardiac, CNS, urinary, etc.), prosthesis (artificial joints,
cosmetic reconstructions, and the like), tissue growth scaffolding
fabrics, or bones and teeth to provide a wide variety of
therapeutic properties (such as but not limited to, anti-infection,
anti-coagulation, anti-inflammation, improved adhesion, improved
tissue growth, improved biocompatibility). These surfaces can be
from a wide variety of materials, such as but not limited to,
natural rubbers, wood, ceramics, glasses, metals, polyethylene,
polypropylene, polyurethanes, polycarbonates, polyesters,
poly(vinyl acetates), poly(vinyl alcohols), poly(oxyethylenes),
poly(oxypropylenes), cellulosics, polypeptides, polyacrylates,
polymethacrylates, polycarbonates, and the like.
[0118] Active agents, or active ingredients, that may be useful in
the present invention singly or in combination, as determined by
one of ordinary skill in the art in light of this specification
without undue experimentation, include but are not limited to:
[0119] Analgesics, Anesthetics, Narcotics such as acetaminophen;
clonidine (Duraclon.RTM., Roxane Labs.) and its hydrochloride,
sulfate and phosphate salts; oxycodene (Percolone.TM., Endo Pharm.
Inc.) and its hydrochloride, sulfate, phosphate salts;
benzodiazepine; benzodiazepine antagonist, flumazenil
(Romazicon.RTM., Roche U.S. Pharm.); lidocaine; tramadol;
carbamazepine (Tegretol.RTM., Novartis Pharm.); meperidine
(Demerol.RTM., Sanofi-Synthelabo, Inc.) and its hydrochloride,
sulfate, phosphate salts; zaleplon (Sonata.RTM., Wyeth-Ayerst
Labs.); trimipramine maleate (Surmontil.RTM., Wyeth-Ayerst Labs.);
buprenorphine (Buprenex.RTM., Reckitt Benckiser Pharm.); nalbuphine
(Nubain.RTM., Endo Pharm. Inc.) and its hydrochloride, sulfate,
phosphate salts; pentazocain and hydrochloride, sulfate, phosphate
salts thereof; fentanyl and its citrate, hydrochloride, sulfate,
phosphate salts; propoxyphene or dextropropoxyphene and its
hydrochloride and napsylate salts (Darvocet.RTM., Eli Lilly &
Co.); hydromorphone (Dilaudid.RTM., Abbott Labs.) and its
hydrochloride, sulfate, and phosphate salts; methadone
(Dolophine.RTM., Roxane Labs.) and its hydrochloride, sulfate,
phosphate salts; morphine and its hydrochloride, sulfate, phosphate
salts; levorphanol (Levo-Dromoran.RTM., ICN Pharm., Inc.) and its
tartrate, hydrochloride, sulfate, and phosphate salts; hydrocodone
and its bitartrate, hydrochloride, sulfate, phosphate salts;
[0120] Angiostatic and/or Anti-inflammatory Steroids such as
anecortive acetate (Retaane.RTM., Alcon); tetrahydrocortisol;
4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione and its -21-acetate
salt; 11-epicortisol; 17.alpha.-hydroxyprogesterone;
tetrahydrocortexolone; cortisona; cortisone acetate;
hydrocortisone; hydrocortisone acetate; fludrocortisone;
fludrocortisone acetate; fludrocortisone phosphate; prednisone;
prednisolone; prednisolone sodium phosphate; methylprednisolone;
methylprednisolone acetate; methylprednisolone, sodium succinate;
triamcinolone; triamcinolone-16,21-diacetate; triamcinolone
acetonide and its -21-acetate, -21-disodium phosphate, and
-21-hemisuccinate forms; triamcinolone benetonide; triamcinolone
hexacetonide; fluocinolone and fluocinolone acetate; dexamethasone
and its 21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate
disodium salt, -21-diethylaminoacetate, -21-isonicotinate,
-21-dipropionate, and -21-palmitate forms; betamethasone and
its-21-acetate, -21-adamantoate, -17-benzoate, -17,21-dipropionate,
-17-valerate, and -21-phosphate disodium salts; beclomethasone;
beclomethasone dipropionate; diflorasone; diflorasone diacetate;
mometasone furoate; and acetazolamide (Diamox.RTM., American
Cyanamid Co.);
[0121] Nonsteroidal Anti-inflammatories such as naproxin;
diclofenac; celecoxib (Celebrex.RTM., Pfizer); sulindac;
diflunisal; piroxicam; indomethacin; etodolac; meloxicam;
ibuprofen; ketoprofen; r-flurbiprofen (Myriad Genetics, Inc.);
mefenamic; nabumetone; tolmetin, and sodium salts of each of the
foregoing; ketorolac bromethamine; ketorolac tromethamine
(Acular.RTM., Allergan, Inc.); choline magnesium trisalicylate;
rofecoxib; valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic
acid and its sodium salt; salicylate esters of alpha, beta,
gamma-tocopherols and tocotrienols (and all their d, 1, and racemic
isomers); methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
t-butyl, esters of acetylsalicylic acid; tenoxicam; aceclofenac;
nimesulide; nepafenac; amfenac; bromfenac; flufenamate; and
phenylbutazone;
[0122] Angiogenesis Inhibitors such as squalamine, squalamine
lactate (Evizon.TM., Genaear Corp.) and curcumin; Vascular
endothelial growth factor (VEGF) inhibitors including pegaptanib
(Macugen.RTM., Eyetech/Pfizer), bevacizumab (Avastin.RTM.,
Genentech, Inc.), concentrated shark cartilage extract
(Neovastat.RTM., AEterna Zentaris), PTK 787 (vatalanib, Schering
AG/Novartis), ribozyme anti-angiogenic (Angiozyme.RTM., Sirma
Therapeutics, Inc./Chiron Corp.); AZD 6474 (Zactima.RTM.,
AstraZeneca AB Ltd.), anti-angiogenesis chimeric monoclonal
antibody specific VEGF receptor 2 (IMC-1C11, ImClone Sys. Inc.),
isocoumarin 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl)
propionic acid (NM-3, Ilex Oncology Inc.), SU668 (Pfizer),
isopropoxymethyl-12-(3-hydroxypropyl) ideno[2,1-a]pyrro
[3,4-c]carbazol e-5-one (CEP-5214, Cephalon), CEP-7055 (the
N,N-dimethyl glycine ester prodrug of CEP-5214, Cephalon), and
PTC299 (PTC Therapeutics); Integrin antagonists such as
anti-.alpha..sub.v.beta..sub.3 antibody (Vitaxin.RTM., Medimmune
Inc.); RDG peptide mimetics such as S137 and S247 (Pfizer),
conformationally constrained bicyclic lactam Arg-Gly-Asp-containing
pseudopeptides such as ST1646 (Sigma Tau S.p.A.); DPC A803350
(Bristol-Myers Squibb), and o-guanidines (3D Pharmaceuticals Inc.);
matrix metalloproteinase inhibitors such as prinomastat (AG 3340,
Pfizer), (ISV-616, InSite Vision), (TIMP-3, NIH); S3304 (Shionogi);
BMS 275291 (Celltech/Bristol-Myers Squibb); SC 77964 (Pfizer);
ranibizumab (Lucentis.RTM., Genentech, Inc.); ABT 518 (Abbott
Labs.); CV 247 (Ivy Medical); NX-278-L anti-VEGF aptamer (EyeTech
Pharm.); 2'-O-mrthoxyethyl antisense C-raf oncogene inhibitor
(ISIS-13650, Isis Pharm., Inc./iCo Therapeuticals, Inc.);
vitronectin and osteopontin antagonists (3D Pharm.); combretstatin
A-4 phosphate (CA4P, OxiGene, Inc.); fab fragment
.alpha.-V/.beta.-1 integrin antagonist (Eos-200-F, Protein Design
Labs); .alpha.-v/.beta.-3 integrin antagonist (Abbott Labs.);
urokinase plasminogen activator fragment (A6, Angstrom Pharm.);
VEGF antagonist (AAV-PEDF, Chiron Corp.); kdr tyrosine kinase
inhibitor (EG-3306, Ark Therapeutics); cytochalasin E (NIH);
kallikrinin-binding protein (Med. Univ. SC); combretastatin analog
(MV-5-40, Tulane); pigment-epithelium derived growth factor (Med.
Univ. SC); pigment-epithelium derived growth factor (AdPEDF,
GenVec, Inc.); plasminogen kringle (Med. Univ. SC); rapamycin;
cytokine synthesis inhibitor/p38 mitogen-activated protein kinase
inhibitor (SB-220025, GlaxoSmithKline); vascular endothelial growth
factor antagonist (SP-(V5.2)C, Supratek); vascular endothelial
growth factor antagonist (SU10944, Sugen/Pfizer); vascular
endothelial growth factor antagonist (VEGF-R, Johnson &
Johnson/Celltech); vascular endothelial growth factor antagonist
(VEGF-TRAP, Regeneron); FGF1 receptor antagonist/tyrosine kinase
inhibitor (Pfizer/Sugen); endostatin, vascular endothelial growth
factor antagonist (EntreMed, Inc., Rockville, Md.); bradykinin B1
receptor antagonist (B-9858, Cortech, Inc.);
bactericidal/permeability-increasing protein (Neuprex.RTM., Xoma
Ltd.); protein kinase C inhibitor (Hypericin, Sigma-Aldrich, St.
Louis, Mo.); ruboxistaurinn mesylate (LY-333531, Eli Lilly &
Co.); polysulphonic acid derivatives (Fuji Photo Film); growth
factor antagonists (TBC-2653, TBC-3685, Texas Biotech. Corp.);
Tunica internal endothelial cell kinase (Amgen Inc.);
[0123] Anti-bacterials including aztreonam; cefotetan and its
disodium salt; loracarbef; cefoxitin and its sodium salt; cefazolin
and its sodium salt; cefaclor; ceftibuten and its sodium salt;
ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodium
salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil;
ceftazidime; cefotaxime and its sodium salt; cefadroxil;
ceftazidime and its sodium salt; cephalexin; cefamandole nafate;
cefepime and its hydrochloride, sulfate, and phosphate salt;
cefdinir and its sodium salt; ceftriaxone and its sodium salt;
cefixime and its sodium salt; cefpodoxime proxetil; meropenem and
its sodium salt; imipenem and its sodium salt; cilastatin and its
sodium salt; azithromycin; clarithromycin; dirithromycin;
erythromycin and hydrochloride, sulfate, or phosphate salts
ethylsuccinate, and stearate forms thereof; clindamycin;
clindamycin hydrochloride, sulfate, or phosphate salt; lincomycin
and hydrochloride, sulfate, or phosphate salt thereof; tobramycin
and its hydrochloride, sulfate, or phosphate salt; streptomycin and
its hydrochloride, sulfate, or phosphate salt; vancomycin and its
hydrochloride, sulfate, or phosphate salt; neomycin and its
hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;
colistimethate and its sodium salt; quinupristin; dalfopristin;
amoxicillin; ampicillin and its sodium salt; clavulanic acid and
its sodium or potassium salt; penicillin G; penicillin G
benzathine, or procaine salt; penicillin G sodium or potassium
salt; carbenicillin and its disodium or indanyl disodium salt;
piperacillin and its sodium salt; ticarcillin and its disodium
salt; sulbactam and its sodium salt; moxifloxacin; ciprofloxacin;
ofloxacin; levofloxacins; norfloxacin; gatifloxacin; trovafloxacin
mesylate; alatrofloxacin mesylate; trimethoprim; sulfamethoxazole;
demeclocycline and its hydrochloride, sulfate, or phosphate salt;
doxycycline and its hydrochloride, sulfate, or phosphate salt;
minocycline and its hydrochloride, sulfate, or phosphate salt;
tetracycline and its hydrochloride, sulfate, or phosphate salt;
oxytetracycline and its hydrochloride, sulfate, or phosphate salt;
chlortetracycline and its hydrochloride, sulfate, or phosphate
salt; metronidazole; rifampin; dapsone; atovaquone; rifabutin;
linezolide; polymyxin B and its hydrochloride, sulfate, or
phosphate salt; sulfacetamide and its sodium salt; minocycline; and
clarithromycin;
[0124] Anti-infective Agents such as 2,4-diaminopyrimidines (e.g.,
brodimoprim, tetroxoprim, trimethoprim); nitrofurans (e.g.,
furaltadone, furazolium chloride, nifuradene, nifuratel,
nifurfoline, nifurpirinol, nifurprazine, nifurtoinol,
nitrofurantoin); quinolones and analogs (e.g., cinoxacin,
ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin,
flumequine, gatifloxacin, grepafloxacin, lomefloxacin, miloxacin,
nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic
acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid,
rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin,
trovafloxacin); sulfonamides (e.g., acetyl sulfamethoxypyrazine,
benzylsulfamide, chloramine-b, chloramine-t, dichloramine t,
n.sup.2-formylsulfisomidine,
n.sup.4-.beta.-d-glucosylsulfanilamide, mafenide,
4'-(methylsulfamoyl) sulfanilanilide, noprylsulfamide,
phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,
succinylsulfathiazole, sulfabenzamide, sulfacetamide,
sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,
sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,
sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid,
sulfamerazine, sulfameter, sulfamethazine, sulfamethizole,
sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine,
sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide,
4-sulfanilamidosalicylic acid, n.sup.4-sulfanilylsulfanilamide,
sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran,
sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine,
sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole,
sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole);
sulfones (e.g., acedapsone, acediasulfone, acetosulfone sodium,
dapsone, diathymosulfone, glucosulfone sodium, solasulfone,
succisulfone, sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone
sodium, thiazolsulfone); and others (e.g., clofoctol, hexedine,
methenamine, methenamine anhydromethylene-citrate, methenamine
hippurate, methenamine mandelate, methenamine sulfosalicylate,
nitroxoline, taurolidine, and xibomol); moxifloxacin; and
gatifloxacin;
[0125] Antifungals such as amphotericin B; pyrimethamine;
flucytosine; caspofungin acetate; fluconazole; griseofulvin;
terbinafin and its hydrochloride, sulfate, or phosphate salt;
ketoconazole; micronazole; clotrimazole; econazole; ciclopirox;
naftifine; and itraconazole;
[0126] Antimalarials such as chloroquine and its hydrochloride,
sulfate or phosphate salt; hydroxychloroquine and its
hydrochloride, sulfate or phosphate salt; mefloquine and its
hydrochloride, sulfate, or phosphate salt; atovaquone; proguanil
and its hydrochloride, sulfate, or phosphate salt forms;
[0127] Antituberculosis Agents such as ethambutol and its
hydrochloride, sulfate, or phosphate salt forms; aminosalicylic
acid; isoniazid; pyrazinamide; ethionamide;
[0128] Antivirals such as amprenavir; interferon alfa-n3;
interferon alfa-2b; interferon alfacon-1; peginterferon alfa-2b;
interferon alfa-2a; lamivudine; zidovudine; amadine
(Symmetrel.RTM., Endo Pharm. Inc.) and its hydrochloride, sulfate,
and phosphate salts; indinavir and its hydrochloride, sulfate, or
phosphate salt; ganciclovir; ganciclovir sodium salt; famciclovir;
rimantadine and its hydrochloride, sulfate, or phosphate salt;
saquinavir mesylate; foscarnet; zalcitabine; ritonavir; ribavirin;
zanamivir; delavirdine mesylate; efavirenz; amantadine and its
hydrochloride, sulfate, or phosphate salt; palivizumab; oseltamivir
and its hydrochloride, sulfate, or phosphate salt; abacavir and its
hydrochloride, sulfate, or phosphate salt; valganciclovir and its
hydrochloride, sulfate, or phosphate salt; valacyclovir and its
hydrochloride, sulfate, or phosphate salt; didanosine; nelfinavir
mesylate; nevirapine; cidofovir; acyclovir; trifluridine;
penciclovir; zinc oxide; zinc salicylate; zinc salts of all isomers
of tocopherol hemisuccnic acid; zinc salts of straight, branched,
saturated, and unsaturated chain C.sub.2 to C.sub.20 aliphatic
carboxylic acids; zinc pyruvate; zinc lactate; zinc ester
complexes; and zinc acetoacetonate or zinc acetoacetic ester
complexes;
[0129] Anti HIV/AIDS agents including stavudine, reverset
(Pharmasset, Inc./Incyte Corp.), ACH-126443 (also known as
Elvucitabine or Beta-L-Fd4C, Achillion Pharm., Inc.), MIV-310
(Boehringer Ingelheim), Zerit.RTM. (stavudine, d4tT, Bristol-Meyers
Squibb), Ziagen.RTM. (abacavir sulfate, GlaxoSmithKline),
Viread.RTM. (tenofovir disoprixil fumerate, Gilead Sci., Inc.),
hivid (Roche), Emtriva (emtricitabine, Gilead Sci., Inc.),
delavirdine (Rescriptor.RTM., Pfizer), AG-1549 (Pfizer), DPC-083
(Bristol-Myers Squibb), NSC-675451 (Advanced Life Sciences),
IMC-125 (Tibitec), azidicarbonamide, modified tripeptide
glycyl-prolyl-glycine-amide (GPG-NH2, Tripep AB), Immunitin.TM.
(Hollis-Eden Pharm.), Cytolin.RTM. (Amerimmune Pharm. Inc.),
PEHRG214 (Virionyx Corp.), MDX-010 (Gilead Sci., Inc.), TXU-PAP
(Wayne Hughes Inst), Proleukin.RTM. (aldesleukin, Chiron Corp.),
BAY 50-4798 (Bayer), BG-777 (Virocell), Crixivan.RTM. (Indinovir
sulfate, Merck & Co., Inc.), Fuzeon.RTM. (enfuvirtide, Roche
Labs. Inc.), WF-10 (Oxo Chemie), Ad5 Gag vaccine (Merck),
APL400-003 and 047 (Wyeth), Remune.RTM. (Orchestra Therapeutics,
Inc.), MVA-BN Nef (Bavarian Nordic), GTU.RTM. MultiHIV vaccine (FIT
Biotech Oyj Plc.);
[0130] Insulins such as Novolog.RTM. (insulin aspart [rDNA origin])
and Novolin.RTM. products (Novo Nordisk Inc.); Humalog.RTM.
(insulin lispro [rDNA origin]), Humalog.RTM. 75/25 and 50/50
(mixtures of insulin lispro protamine suspension and insulin
lispro), and Humulin.RTM. products (regular human insulin [rDNA
origin], Eli Lilly & Co.); Lantus.RTM. (insulin glargine [rDNA
origin], Sanofi Aventis U.S. LLC); porcine and bovine insulins;
[0131] Glucagon-like Peptide-1 (Glp1) and analogs (for diabetes
therapy and appetite suppression, cardiac protection) (see Keiffer
et al., 20 Endocr Rev., 876-913 (1999) such as liraglutide (Novo
Nordisk Inc.); Glp1 receptor stimulators such as such as
Byetta.RTM. products (exenatide, and incretin mimetic, Amylin
Pharm., Inc./Eli Lilly & Co.) and ZP-10 (Zealand Pharma A/S);
Glp-1-albumin (ConjuChem. Inc.); and Dpp-IV inhibitors (which
inhibit enzyme attack on Glp-1) such as Galvus.RTM. (vildagliptin,
formerly LAF237, Novartis), Januvia.RTM. sitagliptin, formerly
MK-0431, Merck & Co.); saxagliptin (formerly BMS-477188,
Bristol-Myers Squibb), and GSK23A (GlaxoSmithKline);
[0132] Alpha Androgenergic Agonist such as brimonidine tartrate;
Beta Adrenergic Blocking Agents such as betaxolol and its
hydrochloride, sulfate, or phosphate salt; levobetaxolol and its
hydrochloride, sulfate, or phosphate salt; and timolol maleate;
[0133] Carbonic Anhydrase Inhibitors such as brinzolamide;
dorzolamide and its drochloride, sulfate, or phosphate salt; and
dichlorphenamid;
[0134] Mast Cell Stabilizers such as pemirolast and its potassium
salt; nedocromil and its sodium salt; cromolyn and its sodium
salt;
[0135] Miotics (Cholinesterase Inhibitors) such as demecarium
bromide;
[0136] Prostaglandins such as bimatoprost; travoprost; and
latanoprost;
[0137] Antihistamines such as olopatadine and its hydrochloride,
sulfate, or phosphate salt forms; fexofenadine and its
hydrochloride, sulfate, or phosphate salt; azelastine and its
hydrochloride, sulfate, or phosphate forms; diphenhydramine and its
hydrochloride, sulfate, or phosphate forms; and promethazine and
its hydrochloride, sulfate, or phosphate forms;
[0138] Antimicrotubule Agents such as Taxoids including paclitaxel
(Taxol.RTM., Bristol-Myers Squibb); vincristine (Oncovin.RTM., Eli
Lilly & Co.) and its hydrochloride, sulfate, or phosphate salt
forms; vinblastine (Velbe.RTM., Eli Lilly & Co.) and its
hydrochloride, sulfate, or phosphate salt; vinorelbine
(Navelbine.RTM., Fabre Pharm. Inc.); colchicines; docetaxel
(Taxotere.RTM., Sanofi-Aventis U.S. LLC); RPR-109881
(Sanofi-Aventis); LIT 976 (Sanofi-Aventis); BMS 188797 and BMS
184476 (Bristol-Myers Squibb); DJ 927 (Daiichi Pharm. Inc.);
DHA-paclitaxel (Taxoprexin.RTM., Protarga, Inc.); Epothilones
including epothiloneB such as patupilone (EPO 906,
Novartis/generic), BMS 247550 and BMS-310705 (Bristol-Myers
Squibb), epothilone D (KOS 862, Kosan Biosci. Inc.), and ZK EPO
(Schering AG);
[0139] Antineoplastic agents such as doxorubicin and its
hydrochloride, sulfate, or phosphate salt; idarubicin and its
hydrochloride, sulfate, or phosphate salt; daunorubicin and its
hydrochloride, sulfate, or phosphate salt; dactinomycin; epirubicin
and its hydrochloride, sulfate, or phosphate salt; dacarbazine;
plicamycin; mitoxantrone (Novantrone.RTM., EMD Serono Inc.) and its
hydrochloride, sulfate, or phosphate salt; valrubicin; cytarabine;
nilutamide; bicalutamide; flutamide; anastrozole; exemestane;
toremifene; femara; tamoxifen and tamoxifen citrate; temozolomide
(Temador, Schering-Plough Corp.); gemcitabine and its
hydrochloride, sulfate, or phosphate salt; topotecan and its
hydrochloride, sulfate, or phosphate salt; vincristine and its
hydrochloride, sulfate, or phosphate salt; liposomal vincristine
(Teva Pharm.); methotrexate and methotrexate sodium salt;
cyclophosphamide; estramustine sodium phosphate; leuprolide and
leuprolide acetate; goserelin and goserelin acetate; estradiol;
ethinyl estradiol; Menest.RTM. esterified estrogens (Monarch
Pharm., Inc.); Premarin.RTM. conjugated estrogens (Wyeth Pharm.
Inc.); 5-fluorouracil; bortezamib (Velcade.RTM., Millennium Pharm.,
Inc.);
[0140] Antiapoptotics such as desmethyldeprenyl (DES,
RetinaPharma);
[0141] Aldose Reductase Inhibitors such as GP-1447 (Grelan); NZ-314
(parabanic acid derivative, Nippon Zoki); SG-210 (Mitsubishi
Pharma/Senju); and SJA-7059 (Senju);
[0142] Antihypertensives such as candesartan cilexetil
(Atacand.RTM., Takeda Pharm. Co./AstraZeneca AB); losartan
(Cozaar.RTM. and Hyzaar.RTM., Merck & Co.); and lisinopril
(Zestril.RTM., AstraZeneca AB and Prinivil.RTM., Merck &
Co.);
[0143] Antioxidants such as benfotiamine (Albert Einstein Col. Of
Med./WorWag Pharma); ascorbic acid and its esters; tocopherol
isomers and their esters; and raxofelast (IRFI 016, metabolized to
IRFI 005, Biomedica Foscama);
[0144] Growth Hormone Antagonists such as octreotide
(Sandostatin.RTM., Novartis); and pegvisomant (Somavert.RTM.,
Pfizer);
[0145] Vitrectomy Agents such as hyaluronidase (Vitrase.RTM., ISTA
Pharm., Inc.);
[0146] Adenosine Receptor Antagonist such as A2B adenosine receptor
antagonist (ATL-754, Adenosine Therapeutics, LLC);
[0147] Adenosine Deaminase Inhibitor such s pentostatin
(Nipent.RTM., SuperGen Inc.);
[0148] Glycosylation Antagonists such as pyridoxamine
(Pyridorin.TM., NephroGenex Inc.);
[0149] Anti-Ageing Peptides, such as Ala-Glu-Asp-Gly (Epitalon,
Geron Corp.);
[0150] Topoisomerase Inhibitors such as doxorubicin
(Adriamycin.RTM., Pfizer; Caelyx.TM. Schering-Plough Pharm.;
Doxil.RTM., Johnson & Johnson Pharmacia/generics); daunorubicin
(DaunoXome.RTM., Gilead Sci.); etoposide (Vepesid.RTM. and
Etopophos.RTM., Bristol-Myers Squibb); idarubicin (Idamycin
PFS.RTM., Pfizer); irinotecan (Camptosar.RTM., Pfizer); topotecan
(Hycamtin.RTM., GlaxoSmithKline); epirubicin (Ellence.RTM.,
Pfizer); and raltitrexed (Tomudex.RTM., AstraZeneca);
[0151] Anti-metabolites such as methotrexate (generic) and its
sodium salt; 5-fluorouracil (Adrucil.RTM., Teva Pharm. U.S.A.);
cytarabine (Cytosar.RTM., Upjohn Co.); fludarabine (Fludara.RTM.,
Bayer HealthCare Pharm.) and its forms as salts with acids;
gemcitabine (Gemzar.RTM., Eli Lilly & Co.); capecitabine
(Xeloda.RTM., Roche Labs. Inc.); and perillyl alcohol (POH,
Endorex);
[0152] Alkylating Agents such as chlorambucil (Leukeran.RTM.,
GlaxoSmithKline); cyclophosphamide (Cytoxan.RTM., Bristol-Meyers
Squibb); methchlorethanine (generic); cisplatin (Platinol.RTM.,
Bristol-Meyers Squibb); carboplatin (Paraplatin.RTM., Bristol-Myers
Squibb); temozolominde (Temodar.RTM., Schering Corp.) and
oxaliplatin (Eloxatin.RTM. Sanofi-Synthelabo, Inc.);
[0153] Anti-androgens such as flutamide (Eulexin.RTM.,
Schering-Plough); nilutamide (Nilandron.RTM., Sanofi-Aventis);
bicalutamide (Casodex.RTM., AstraZeneca);
[0154] Anti-oestrogens such as tamoxifen (Nolvadex.RTM.,
AstraZeneca); toremofine (Fareston, Orion/Shire); fulvestrant
(Faslodex.RTM., AstraZeneca); arzoxifene (Eli Lilly & Co.);
anastrozole (Arimidex.TM., AstraZeneca); letrozole (Femerar.TM.,
Novartis); formestan (Lentaron.RTM., Novartis); exemestane
(Aromasin.RTM., Pfizer); goserelin acetate (Zoladex.RTM.,
AstraZeneca); lasoxifene (Pfizer); ERA-923 (Ligand Pharm.
Inc./Wyeth); DCP 974 (DuPont/Bristol-Myers Squibb); ZK 235253, ZK
911703, and ZK 230211 (Schering AG);
[0155] Oncogene Activation Inhibitors, including for example,
Bcr-Abl Kinase Inhibition such as imatinib mesylate (Gleevec.TM.,
Novartis); Her2 Inhibition such as trastuzumab (Herceptin.RTM.,
Genentech, Inc.); MDX 210 (Medarex, Inc.); E1A (Targeted Genetics
Corp.); ME 103 and ME 104 (Pharmexa); rhuMAb-2C4 (Omnitarg,
Genentech, Inc.); C1-1033 (Pfizer); PK1 166 (Novartis Pharma AG);
GW572016 (GlaxoSmithKline); EGFr Inhibitors such as cetuximab
(Erbitux.TM., Imclone Sys. Inc.); EGFr Tyrosine Kinase Inhibitors
such as gefitinib (Iressa.RTM., formerly ZD 1839, AstraZeneca);
erlotinib (Tarceva, Genentech, Inc./OSI Pharm., Inc.); ABX-EGF
(Abgenix/Amgen); erbB receptor inhibitor (C1-1033, Pfizer); EMD
72000 (Merck KgaA); lapatinib (GW572016, GlaxoSmithKline); EKB 569
(Wyeth); PKI 166 (Novartis); and BIBX 1382 (Boehringer Ingleheim);
Farnesyl Transferase Inhibitors such as tipifamib (Zarnestra.RTM.,
Johnson & Johnson); lonafarnib (Sarasar.TM., Schering-Plough);
BMS-214,662 (Bristol-Myers Squibb); AZ3409 (AstraZeneca); CP-609754
and CP-663427 (OSI Pharmaceuticals/Pfizer); Arglabin (NuOncology
Labs Inc.); RPR-130401 (Aventis Pharm.); A-176120 (Abbott Labs.);
BIM 46228 (Biomeasure, Inc.); LB 42708 and LB 42909 (LG Chem,
Ltd.); PD 169451 (Pfizer); and SCH226374 (Schering-Plough); Bcl-2
Inhibitors such as BCL-X (Isis Pharm., Inc.); ODN 2009 (Novartis
Pharm.); GX 011 (Gemin X Biotech. Inc.); and TAS 301 (Taiho Pharm.
Co.); Cyclin Dependent Kinase Inhibitors such as flavopiridol
(generic, Aventis Oncol.); CYC202 (R-roscovitine, Cyclacel Ltd.);
BMS 387032, BMS 239091 and BMS 250904 (Bristol-Myers Squibb); CGP
79807 (Novartis Pharm.); NP102 (Nicholas Piramal India Ltd.); and
NU 6102 (AstraZeneca); Protein Kinase C Inhibitors such as
Affinitac.TM. (Isis Pharm., Inc./Eli Lilly & Co.); midostaurin
(PKC 412, Novartis/generic); bryostatin (Aphios Corp.); KW 2401
(Kyowa Hakko Kogyo/Keryx Biopharm.); LY 317615 (Eli Lilly &
Co.); perifosine (Keryx Biopharm); and balanol (SPC 100840, Sphinx
Pharm./Eli Lilly & Co.)
[0156] Telomerase Inhibitors such as GRN163 (Geron Corp./Kyowa
Hakko Kogyo) and G4T 405 (Aventis);
[0157] Antibody Therapy including Herceptin.RTM. (trastuzumab
Genentech, Inc.); MDX-H210 (Medarex, Inc.); SGN-15 (Seattle
Genetics); H11 (Viventia); Therex (Antisoma); rituximan
(Rituxan.RTM., Genentech); Campath (ILEX
Oncology/Millennium/Shering); Mylotarg (Celltech/Wyeth); Zevalin
(IDEC Pharmaceuticals/Schering); tositumomab (Bexxar,
Corixa/SmithKline Beecham/Coulter); epratuzumab (Lymphocide,
Immunomedics/Amgen); Oncolym (Techniclone/Schering AG); Mab Hu1D10
antibody (Protein Design Laboratories); ABX-EGF (Abgenix);
infleximab (Remicade.RTM., Centocor) and etanercept (Enbrel,
Wyeth-Ayerst);
[0158] Antisense Oligonucleotides such as Affinitac (Isis
Pharmaceuticals/Eli Lilly & Co.); and Genasence
(Genta/Aventis);
[0159] Fusion Proteins such as denileukin diftitox (Ontak,
Ligand);
[0160] Luteineizing Hormone Releasing Hormone (LHRH) Agonists aka
Gonadotropin Releasing Hormone (GnRH) Agonists such as goserelin
(Zoladex, AstraZeneca); leuporelin (Lupron, Abbott/Takeda);
leuporelin acetate implant (Viadur, ALZA/Bayer and Atigrel/Eligard,
Atrix/Sanofi-Synthelabo); and triptorelin (Trelstar,
Pharmaceuticals);
[0161] Tyrosine Kinase Inhibitors/Epidermal Growth Factor Receptor
Inhibitors such as gefitinib (Iressa, AstraZeneca, ZD 1839);
trastuzumab (Herceptin, Genentech); erlotinib (Tarceva, OSI
Pharmaceuticals, OSI 774); cetuximab (Erbitux, Imclone Systems, IMC
225); and pertuzumab (Omnitarg, Genentech, 2C4);
[0162] Ribonucleotide Reductase Inhibitors such as gallium
maltolate (Titan);
[0163] Cytotoxins such as Irofulven (MGI 114, MGI Pharma);
[0164] IL2 Therapeutics such as Leuvectin (Vical);
[0165] Neurotensin Antagonist such as SR 48692
(Sanofi-Synthelabo);
[0166] Peripheral Sigma Ligands such as SR 31747
(Sanofi-Synthelabo);
[0167] Endothelin ETA/Receptor Antagonists such as YM-598
(Yamanouchi); and atrasentan (ABT-627, Abbott);
[0168] Antihyperglycemics such as metformin (Glucophage,
Bristol-Myers Squibb) and its hydrochloride, sulfate, phosphate
salts; and miglitol (Glyset, Pharmacia/Upjohn);
[0169] Anti-glaucoma Agents such as dorzolamide (Cosopt, Merck);
timolol; betaxolol and its hydrochloride, sulfate, phosphate salts;
atenolol; and chlorthalidone;
[0170] Anti-(Chromatin Modifying Enzymes) such as suberoylanilide
hyroxaxamic acid (Aton/Merck);
[0171] Agents for Obesity Management, such as
glucagon-like-peptides, phendimettrazine and its tartrate,
hydrochloride, sulfate, phosphate salts; methamphetamine and its
hydrochloride, sulfate, phosphate salts; and sibutramine (Meridia,
Abbott) and its hydrochloride, sulfate, phosphate salts;
[0172] Treatments for Anemia such as epoetin alpha (Epogen, Amgen);
epoetin alpha (Eprex/Procrit, Johnson & Johnson); epoetin alpha
(ESPO, Sankyo and Kirin); and darbepoetin alpha (Aranesp, Amgen);
epoetin beta (NeoRecormon, Roche); epoetin beta (Epogen, Chugai);
GA-EPO (Dynepo, TKT/Aventis); epoetin omega (Elanex/Baxter); R 744
(Roche); and thrombopoetin (Genetech/Pharmacia);
[0173] Treatments for Emesis such as promethazine (Phenergan,
Wyeth); prochlorperazine; metoclopramide (Reglan, Wyeth);
droperidol; haloperidol; dronabinol (Roxane); ondasetron (Zofran,
GlaxoSmithKline); ganisetron (Kytril, Roche); dolasetron (Anzemet,
Aventis); indisetron (NN-3389, Nisshin Flour/Kyorin); aprepitant
(MK-869, Merck); palonosetron (Roche/Helsinn/MGI Pharma);
lerisetron (FAES); nolpitantium (SR 14033, Sanofi-Synthelabo);
R1124 (Roche); VML 670 (Vernalis, Eli Lilly & Co.); and CP
122721 (Pfizer);
[0174] Neutropaenia Treatments such as filgrastim (Neupogen,
Amgen); leukine (Immunex/Schering AG); filgrastim-PEG (Neulasta,
Amgen); PT 100 (Point Therapeutics); and SB 251353
(GlaxoSmithKline);
[0175] Tumor-induced Hypercalcaemia Treatments such as Bonviva
(GlaxoSmithKline); ibandronate (Bondronat, Roche); pamidronate
(Aredia, Novartis); zolendronate (Zometa, Novartis); clodronate
(Bonefos, generic); incadronate (Bisphonal, Yamanouchi); calcitonin
(Miacalcitonon, Novartis); minodronate (YM 529/Ono 5920,
Yamanouchi/Ono); and anti-PTHrP (CAL, Chugai);
[0176] Blood Anticoagulants such as Argathroban (GlaxoSmithKline);
warfarin (Coumadin, duPont); heparin (Fragmin, Pharmacia/Upjohn);
heparin (Wyeth-Ayerst); tirofiban (Aggrastat, Merck) and its
hydrochloride, sulfate, phosphate salts; dipyridamole (Aggrenox,
Boehringer Ingelheim); anagrelide (Agrylin, Shire US) and its
hydrochloride, sulfate, phosphate salts; epoprostenol (Flolan,
GlaxoSmithKline) and its hydrochloride, sulfate, phosphate salts;
eptifibatide (Integrilin, COR Therapeutics); clopidogrel (Plavix,
Bristol-Myers Squibb) and its hydrochloride, sulfate, or phosphate
salts; cilostazol (Pletal, Pharmacia/Upjohn); abciximab (Reopro,
Eli Lilly & Co.); and ticlopidine (Ticlid, Roche);
[0177] Immunosuppressive Agents such as sirolimus (rapamycin,
Rapamune.RTM., Wyeth-Ayerst); tacrolimus (Prograf, FK506); and
cyclosporins;
[0178] Tissue Repair Agents such as Chrysalin (TRAP-508,
Orthologic-Chrysalis Biotechnology);
[0179] Anti-psoriasis Agents such as anthralin; vitamin D3;
cyclosporine; methotrexate; etretinate, salicylic acid;
isotretinoin; and corticosteroids;
[0180] Anti-acne Agents such as retinoic acid; benzoyl peroxide;
sulfur-resorcinol; azelaic acid; clendamycin; erythromycin;
isotretinoin; tetracycline; minocycline;
[0181] Anti-skin parasitic Agents such as permethrin and
thiabendazole;
[0182] Treatments for Alopecia such as minoxidil and
finasteride;
[0183] Contraceptives such as medroxyprogesterone; norgestimol;
desogestrel; levonorgestrel; norethindrone; norethindrone;
ethynodiol; and ethinyl estradiol; Treatments for Smoking Cessation
including nicotine; bupropion; and buspirone;
[0184] Treatments for Erectile Disfunction such as alprostadil; and
Sildenafil;
[0185] DNA-alkyltranferase Agonist including temozolomide;
[0186] Metalloproteinase Inhibitor such as marimastat;
[0187] Agents for management of wrinkles, bladder, prostatic and
pelvic floor disorders such as botulinum toxin;
[0188] Agents for management of uterine fibroids such as
pirfenidone, human interferin-alpha, GnRH antagonists, Redoxifene,
estrogen-receptor modulators;
[0189] Transferrin Agonist including TransMID.TM. (modified
diphtheria toxin conjugated to transferrin, Tf-CRM107, Xenova Group
Ltd.);
[0190] Interleukin-13 Receptor Agonist such as IL-13-PE38QQR
(Neopharm);
[0191] Nucleic acids such as small interfering RNAs (siRNA) or RNA
interference (RNAi), particularly, for example siRNAs that
interfere with VEGF expression;
[0192] and Psychotherapeutic Agents including Anti-anxiety drugs
such as chlordiazepoxide; diazepam; chlorazepate; flurazepam;
halazepam; prazepam; clorazepam; quarzepam; alprazolam; lorazepam;
orazepam; temazepam; and triazolam; and Anti-psychotic drugs such
as chlorpromazine; thioridazine; mesoridazine; trifluorperazine;
fluphenazine; loxapine; molindone; thiothixene; haloperidol;
pimozide; and clozapine.
[0193] Those of ordinary skill in the art will appreciate that any
of the foregoing disclosed active agents may be used in combination
or mixture in the pharmaceutical formulations of the present
invention. Such mixtures or combinations may be delivered in a
single formulation, or may be embodied as different formulations
delivered either simultaneously or a distinct time points to affect
the desired therapeutic outcome. Additionally, many of the
foregoing agents may have more than one activity or have more than
one therapeutic use, hence the particular category to which they
have been ascribed herein is not limiting in any way. Similarly,
various biodegradable, biocompatible excipients may be used in
combination or in mixtures in single or multiple formulations as
required for a particular indication. These mixtures and
combinations of active agents and excipients may be determined
without undue experimentation by those of ordinary skill in the art
in light of this disclosure.
[0194] The formulations of the present invention may be sterilized
for use by methods known to those of ordinary skill in the art.
Autoclaving and e-beam have been used in informal studies of
several embodiments and have not appeared to have significant
impact. Similarly, informal stability studies indicate acceptable
stability of several embodiments. Additionally, reproducibility
between aliquots and lots is very good, with a standard deviation
of less than five percent or better. Hence, standard pharmaceutical
manufacturing techniques are readily applied to the technologies
described herein.
[0195] An example embodiment of the present invention comprises the
active agent dexamethasone and the excipient benzyl benzoate.
Dexamethasone is a glucocorticoid and typically used in the form of
the acetate or disodium phosphate ester. Glucocorticoids are
adrenocortical steroids suppressing the inflammatory response to a
variety of agents that can be of mechanical, chemical or
immunological nature. Administration of dexamethasone can be
topical, periocular, systemic (oral) and intravitreal. Doses vary
depending on the condition treated and on the individual patient
response. In ophthalmology, dexamethasone sodium phosphate
(Decadron.RTM., Merck & Co.) as a 0.1% solution has been widely
used since its introduction in 1957. The ophthalmic dose depends on
the condition treated. For control of anterior chamber
inflammation, the- topical dose is usually 1 drop, 4 times a day
for up to a month following surgery (around 0.5 mg per day). For
control of posterior segment inflammation, periocular injections of
4 mg of dexamethasone, or daily oral administration of 0.75 mg to 9
mg of dexamethasone in divided doses are not uncommon. Intravitreal
injections of 0.4 mg of dexamethasone have been administered in
conjunction with antibiotics for the treatment of
endophthalmitis.
[0196] Regarding benzyl benzoate (CAS120-51-4, FW 212.3),
previously the oral administration of benzyl benzoate was claimed
to be efficacious in the treatment of intestinal, bronchial, and
urinary ailments, but its use has been superseded by more effective
drugs. Presently, it is topically applied as a treatment for
scabies and pediculosis. Goodman & Gilman's THE PHARMACOLOGICAL
BASIS OF THERAPEUTICS 1630 (6th ed., 1980); FDA approval, Fed Reg.
310.545(a)(25)(i). Benzyl benzoate is approved in minor amounts in
foods as a flavoring (FDA, Title 21, vol. 3, ch I, subch B, part
172(F), .sctn. 172.515), and as a component in solvents for
injectable drug formulations (e.g., Faslodex.RTM. and
Delestrogen.RTM.).
[0197] Benzyl benzoate is a relatively nontoxic liquid which when
applied topically in the eye results in no damage. Grant,
TOXICOLOGY OF THE EYE 185 (2d ed., 1974). Its oral LD.sub.50 in
humans is estimated to be 0.5 g/kg-5.0 g/kg. Gosselin et al., II
CLIN TOX OF COMMERCIAL PROD. 137 (4th ed., 1976). In vivo, benzyl
benzoate is rapidly hydrolyzed to benzoic acid and benzyl alcohol.
The benzyl alcohol is subsequently oxidized to benzoic acid, which
is then conjugated with glucuronic acid and excreted in the urine
as benzoylglucuronic acid. To a lesser extent, benzoic acid is
conjugated with glycine and excreted in the urine as hippuric acid.
HANDBOOK OF PESTCIDE TOXICOLOGY 1506 (Hayes & Laws, eds.,
1991).
[0198] Dexamethasone, when mixed with benzyl benzoate, forms a
uniform suspension. A dexamethasone/benzyl benzoate formulation of
25% is easily syringeable. When the suspension is injected slowly
into the posterior segment of the eye, for example, a uniform
spherical deposit (reservoir) is formed in the vitreous body. The
reservoir maintains its integrity and in vivo "breakage" has not
been observed opthalmoscopically. Dexamethasone is then released
slowly into the vitreous humor of the posterior segment.
Dexamethasone and benzyl benzoate are eventually metabolized to
byproducts that are excreted in the urine.
[0199] Similarly, triamcinolone acetonide (TA) in benzyl benzoate
forms a syringeable suspension that retains its integrity and in
vivo. In rabbit studies involving intraocular injection of
TA/benzyl benzoate formulations, described below, near zero-order
release of TA has been observed in vivo for more than one year.
Smaller doses result in more-rapid release profiles, such that the
TA is released over a six-month period. Both Dex and TA
formulations may be useful in treating the eye following cataract
surgery or replacement.
[0200] Further regarding cataract surgery and other treatments or
diseases of the eye, an aspect of the invention provides for a
composition comprising an active agent and the LSBB excipient
useful for the treatment of iris neovascularization from cataract
surgery, macular edema in central retinal vein occlusion, cellular
transplantation (as in retinal pigment cell transplantation),
cystoid macular edema, psaudophakic cystoid macular edema, diabetic
macular edema, pre-phthisical ocular hypotomy, proliferative
vitreoretinopathy, proliferative diabetic retinopathy, exudative
age-related macular degeneration, extensive exudative retinal
detachment (Coat's disease), diabetic retinal edema, diffuse
diabetic macular edema, ischemic opthalmopathy, chronic focal
immunologic corneal graft reaction, neovascular glaucoma, pars
plana vitrectomy (for proliferative diabetic retinopathy), pars
plana vitrectomy for proliferative vitreoretinopathy, sympathetic
ophthalmia, intermediate uveitis, chronic uveitis, intraocular
infection such as endophthalmitis, and/or Irvine-Gass syndrome.
[0201] Another embodiment of the invention provides formulations
and uses of the tocopherols and/or tocotrienols and their esters
with insulins for the transdermal delivery of the insulins in the
management of diabetes. Tocopherols and/or the tocotrienols and
their esters possess outstanding capabilities to carry therapeutic
agents, especially moderate molecular weight proteins such as the
insulins, through the skin into the body. Indeed, it is
contemplated that wide variety of other therapeutic agents (such as
steroids, NSAIDs, antibiotics, hormones, growth factors,
anti-cancer agents, etc.) may be available for effective
transdermal delivery formulations with the tocopherols and/or
tocotrienols and their esters.
[0202] The advantages to bypassing oral drug delivery that allow
the enzymatic transformations of the liver and the digestive
processes of the gut (and also engender gastric distresses) have
inspired research to find alternative methods. A prime example is
insulin therapy for diabetes. Several tutorials and reviews of the
present state of insulin therapies are: Owens, 1 Nature
Reviews/Drug Discovery 529-540 (2002); Cefalu, 113 (6A) Am J Med
25S-35S (2002); Nourparvar et al., 25 (2) Trends Pharmacol Sci,
86-91 (2004). Avoidance of daily multiple painful subcutaneous
injections has led to alternative routes such as buccal/sublingual,
rectal, intranasal, pulmonary, and transdermal. Yet no completely
acceptable alternatives to injection have been established. Most
promising are pulmonary systems (Exubera.RTM., insulin human [rDNA
origin]) Inhalation Powder, Pfizer; AERx.RTM. iDMS, liquid aerosol
insulin formulation, Novo Nordisk) and as disclosed here novel
transdermal delivery formulations involving the tocopherols and/or
tocotrienols and their esters as penetrating vehicles for
therapeutic agents.
[0203] The desirability of simple and painless transdermal delivery
of insulin and other therapeutic agents has inspired a number of
transdermal approaches (iontophoresis [electrical charge];
phonophoresis (ultrasound); photoenhancement (pulsed laser); heat;
lipid vesicles; and penetrating agents [DMSO, NMP, etc.]) over the
years with incomplete results. Transdermal delivery is considered
to be hindered by the skin's relatively impermeability to large
hydrophilic polypeptides such as insulin. The present invention,
however, provides effective levels of insulin delivered in a
sustained release fashion into the bloodstream when applied as
intimate mixtures with .alpha.-tocopheryl acetate onto the skin. In
a mouse model, effective levels of insulin were delivered in a
sustained release fashion into the bloodstream of a mouse when
applied as intimate mixtures with .alpha.-tocopheryl acetate onto
the mouse skin.
[0204] Because tocopherols have long been ingredients in sunscreen
and cosmetic formulations, there are numerous references in the
literature to the tocopherols being applied to the skin and
demonstrations of their migrating through the skin. See e.g.,
Zondlo, 21 (Suppl 3) Int'l J Toxicol, 51-116 (2002). These reports
show the ease and safety with which the tocopherols can penetrate
skin, but none disclose any use of the tocopherols as penetration
enhancers or carriers of therapeutic agents through the skin into
the body. Indeed, a recent review of 102 chemical penetration
enhancers for transdermal drug delivery did not mention the
tocopherols or tocotrienols. Karande et al., 102 (13) Proc Natl
Acad Sci USA, 4688-93 (2005).
[0205] Tocopherol formulations that allow the facile and effective
transport of therapeutic agents through the skin into the body may
employ d, 1, and d1 isomers of alpha, beta, gamma and delta
tocopherols and their esters (formates, acetates, propionates,
C.sub.4 to C.sub.20 straight and branched chain aliphatic acid
esters, maleates, malonates, fumarates, succinates, ascorbates, and
nicotinates); d, 1, and d1 isomers of alpha, beta, gamma, and delta
tocotrienols and their esters (formates, acetates, propionates,
C.sub.4 to C.sub.20 straight and branched chain aliphatic acid
esters, maleates, malonates, fumarates, succinates, ascorbates, and
nicotinates).
[0206] Another embodiment of the present invention, further related
to the tocopherols, provides to formulations of 2-acetyloxy benzoic
acid and its aliphatic esters with tocopherols and tocotrienols and
licorice extracts. In particular, this aspect provides for
injectable, ingestable or topical formulations employing the
tocopherols and/or tocotrienols and/or licorice extracts with
2-acetyloxybenzoic acid (2-ABA) and certain of its aliphatic
esters, that allow all the well-known medicinal benefits of 2-ABA
and its aliphatic esters while substantially avoiding the gastric
toxicities normally associated with the ingestion of 2-ABA
itself.
[0207] Unlike the more recently developed specific COX-2 inhibiting
nonsteroidal anti-inflammatories such as celecoxib (Celebrex.RTM.,
Pfizer), rofecoxib (Vioxx.RTM., Merck), and the like, there is the
confidence that decades of pharmaceutical experience with 2-ABA
have well defined its benefits and disadvantages. The full benefits
and problems of the specific COX-2 inhibitors are still being
discovered. In the case of the "traditional" NSAIDs such as 2-ABA,
ibuprofen, naproxen, ketoprofen, diclofenac, indimethacin, etc.,
evidence accumulates on the damage they do to the stomach and small
bowel. Although the specific COX-2 inhibitors have demonstrated
lower gastrointestinal problems than 2-ABA, serious cardiovascular
problems associated with specific COX-2 inhibitors are surfacing.
As for 2-ABA, its general analgesic anti-inflammatory benefits are
legendary; and as the chemistries of both of its COX-1 and COX-2
inhibitions are revealed the cardioprotective properties associated
with its COX-1 inhibition are in striking contrast to the
cardiovascular safety problems of the COX-2 only inhibitors. The
reason for 2-ABA's gastrointestinal toxicity has been ascribed to
its COX-1 inhibition. And indeed the lower order of
gastrointestinal problems of celecoxib, rofecoxib, and the like is
seen to be due to their COX-2 only inhibition. But, interestingly,
the normal intestinal appearances in the COX-1 knockout animals
point to more subtle reasons for 2-ABA's gastrointestinal toxicity,
in which the concomitant inhibition of both COX-1 and COX-2 enzymes
may be the problem.
[0208] Whatever the mechanisms for 2-ABA's gastrointestinal
toxicity, the well demonstrated benefits of 2-ABA in other areas of
the body are incentives to seek ways to get the molecule past the
gut without damage. Of course injection or topical applications
avoid the gut, but the major mode of current administration remains
ingestion. Three distinctly different methods of lowering the gut
irritation of ingested 2-ABA have been reported. The first, and
most successful, is the discovery in studies in rats and pigs by
Rainsford and Whitehouse reported in 1980 (10 (5) Agents &
Actions, 451-56), that the methyl, ethyl, and phenyl esters of
2-ABA elicit practically no gastric ulcerogenic activity and yet
still have nearly all the anti-inflammatory properties of 2-ABA.
Surprisingly, the investigation of oral administrations of the
esters of 2-ABA has not been pursued further. Topical applications
of 2-ABA esters for acne control, sunscreen, and placating insect
bites have been reported. See U.S. Pat. No. 4,244,948, U.S. Pat.
No. 4,454,122, U.S. Pat. No. 3,119,739. The second method of
reducing 2-ABA gastric distress recommends diets rich in
tocopherols and/or tocotrienols, resulting in about a 30% to 40%
reduction in lesion formation which is not as extensive as that
provided by 2-ABA esters. See e.g., Jaarin et al., 13 (Suppl) Asia
Pac J Clin Nutr, 5170 (2004); Nafeeza et al., 11 (4) Asia Pac J
Clin Nutr 309-13 (2002); Sugimoto et al., 45 (3) Dig Dis Sci,
599-605 (2000); Stickel et al, 66 (5) Am J Clin Nutr 1218-23
(1997). The third method of reducing gastric stress is by the
concomitant oral administration of licorice extract (glycyrrhizin)
with 2-ABA. Rainsford & Whitehouse, 21 Life Sciences 371-78
(1977); Dehpour et al., 46 J Pharm Pharmacol 148-49 (1994). This
gave 66% to 80% reduction in ulceration compared to 2-ABA alone.
Formulations combining 2-ABA or its esters, the tocopherols (or
their acetates) and/or tocotrienols (or their acetates), and
licorice extracts in combination have not been tried.
[0209] Treatment of inflammatory conditions of the eye or joints by
direct injection avoids gastric distress and the inefficient
systemic exposure of the ingestion route. Ingestion in humans of
the commonly prescribe dosages of 2-ABA (0.650-1.3 g) leads to
combined 2-ABA/2-hydroxy benzoic acid (2-HBA) levels in the plasma
of about 20-100 .mu.g/ml. Kralinger et al., 35 Ophthalmic Res 107
(2003). Studies in rabbit eyes indicate that at these plasma levels
the concentration of 2-ABA/2-HBA in the vitreous is in the range of
5-10 .mu.g/ml. The 2-ABA level is much lower than 2-HBA since
within 30 minutes in the plasma about 97% of the 2-ABA is
hydrolyzed to 2-HBA. Once remaining 2-ABA reaches the vitreous its
rate of hydrolysis in that environment is greatly reduced. There an
initial level of 4 .mu.g/ml is halved in 1.5-2 hours. the half-life
of 2-HBA is not well defined since its initial concentration is
increased by the conversion of 2-ABA to 2-HBA; but the half life is
probably twice that of 2-ABA. Valeri et al., 6 (3) Lens & Eye
Toxicity Res 465-75 (1989). This highlights another advantage of
direct injection over oral (systemic) administration: injection
avoids the substantial loss of the acetyl group in the hydrolysis
of 2-ABA before it reaches its target. It has been shown that the
major method of 2-ABA's anti-inflammatory action is its ability
deactivate the COX-1 and COC-2 enzymes by irreversibly inserting
its acetyl group into these enzymes. Roth & Majerus, 56 J Clin
Invest 624-32 (1975). The ID.sub.50 for this reaction in the eye
has been determined to be in the range of 0.9-9.0 .mu.g/ml. Higgs
et al, 6 (Suppl) Agents & Actions 167-75 (1979). Kahler et al.,
262 (3) Eur J Pharmacol 261-269 (1994).
[0210] One example of an injectable sustained release (ISR) 2-ABA
formulation in the eye is the injection of a 1.0 ml tamponade of
silicone oil containing 1.67 mg into rabbit eye vitreous chamber.
Only 2-HBA was measured in the study, which observed an initial
burst of 640 .mu.g/ml within 6 hours. 2-HBA decreased to 20
.mu.g/ml in 20 hours and 5 .mu.g/ml after 120 hours. Kralinger et
al., 21 (5) Retina 513-20 (2001). The use of the ethyl ester of
2-ABA in ISR formulations should give longer half lives (longer
sustained deliveries) than 2-ABA since the ester is more
hydrophobic. Also, the incorporation of 2-ABA esters or 2-ABA into
hydrophobic excipients such as the tocopherols (or their acetates)
or the tocotrienols (or their acetates) should lead to longer
sustained deliveries.
[0211] A study of the distribution of 2-ABA and 2-HBA in the blood
and synovial fluid (human knee) from ingested 650 mg doses of 2-ABA
showed the maximum plasma levels of 3.3 .mu.g/ml 2-ABA in 7.7
minutes and 23 .mu.g/ml 2-HBA in 10.9 minutes. Maximum synovial
fluid levels were 2.5 .mu.g/ml 2-ABA in 19.4 minutes and 14.5
.mu.g/ml 2-HBA in 21.9 minutes. Soren, 6 (1) Scand J Rheumatol
17-22 (1977). The 2-ABA was gone in the blood in 75 minutes and
gone in the synovial fluid in 2.3 to 2.4 hours. A study of
intra-articular injections of 20 .mu.g/ml 2-ABA in the 33 ml of
synovial fluid in the adult human knee also revealed that the
average half life of combined 2-ABA/2-HBA was 2.4 hours. Owen et
al., 38 Brit. J. Clin. Pharma. 347-55 (1994); Wallis et al., 28
Arthritis Rheum 441-49 (1985).
[0212] In addition to the references noted above relating to
anti-inflammation therapies involving topical applications of 2-ABA
ester formulations, there are the references referring to 2-ABA
esters (U.S. Pat. No. 3,119,739, U.S. Patent Application Pub. No.
2002-0013300) or 2-ABA (U.S. Pat. No. 4,126,681) as analgesics for
skin irritations and wound healing. Other reports, however, reveal
poor results with topically applied 2-ABA to relieve pain from
insect bites (Balit et al., 41 (6) Toxicol Clin Toxicol 801-08
(2003)) or allergic reactions (Thomsen et al., 82 Acta Derm
Venereal 30-35 (2002)). Better results were found on dermal
applications of chloroform solutions of 2-ABA (Kochar et al., 47
(4) J Assoc Physicians India 337-40 (1999)) or slurries of 2-ABA in
a commercial skin moisturizer (Balakrishnan et al., 40 (8) Int J
Dermatol 535-38 (2002)) to alleviate the pain of acute herpetic
neuralgia. It is important to note that most of these reported
formulations contained water. Thus, unless these formulations were
used immediately after their preparation it is very likely
significant hydrolysis of the 2-ABAs or their esters removed the
acetyl group to give the less potent 2-HBA derivatives. There is
the need for non-aqueous or non-alcoholic penetrating excipients in
topical 2-ABA and 2-ABA ester formulations for useful shelf
life.
[0213] Hence, in an embodiment of the invention the components used
in the formulations are selected from the following two groups:
[0214] Group I: 2-acetyloxy benzoic acid, methyl 2-acetyloxy
benzoate, ethyl 2-acetyloxy benzoate, n-propyl 2-actyloxy benzoate,
isopropyl 2-acetyloxy benzoate, n-butyl 2-acetyloxy benzoate,
isobutyl 2-acetyloxy benzoate. [0215] Group II: d, 1 and d1 isomers
of alpha, beta, gamma and delta tocopherols and their acetate
esters; d, 1 and d1 isomers of alpha, beta, gamma, and delta
cotrienols and their acetate esters; all along with licorice
extracts or deglycyrrhized licorice extracts.
[0216] Thus, one aspect of this invention involves novel mixtures
of compounds selected from group I with compounds selected from
group II to give formulations for oral administration having
essentially all the beneficial therapeutic properties of 2-ABA but
with much less to none of the gastric stress associated with 2-ABA.
These novel formulations for ingestion have the general
compositions of 350 pts/wt 2-ABA or 400 to 500 pts/wt of 2-ABA
esters mixed with 40 to 400 pts/wt tocopherols or their acetates
plus 35 to 110 pts/wt tocotrienols or their acetates plus 400 to
1400 pts/wt licorice extract or degglycerrhized licorice extract. A
convenient source containing mixture of tocopherols and
tocotrienols is either palm seed oil extract (Carotech Inc. among
many suppliers) or rice bran oil extract (Eastman Chemicals, among
many other suppliers). There is some evidence that the palm seed
source is preferred because it has a higher delta tocotrienol
content. Theriault et al., 32 (5) Clin Biochem 309-19 (1999); Yap
et al., 53 (1) J Pharm Pharmacol 67-71 (2001).
[0217] An example, but non-limiting, formulation would be: 350 mg
2-ABA (or 400 mg ethyl 2-ABA); 200 mg tocopherol/tocotrienol (palm
seed oil extract); and 125 mg licorice extract. Such a formulation
might be conveniently contained in a gel capsule with one to eight
capsules/day being ingested as needed to alleviate inflammatory
conditions throughout the human or animal body.
[0218] Another aspect of this invention involves novel sustained
release mixtures of 2-ABA or 2-ABA esters with tocopherol or
tocopherol acetate for intra-ocular or intra-articular injections
as therapies for inflammatory conditions of the eye or joints of
animals or humans. The general range of amounts of these components
in the formulations is 5 to 95 pts/wt 2-ABA esters or micronized
2-ABA and 95 pts/wt to 5 pts/wt tocopherol or its acetate. An
example, but non-limiting, formulation is 250 pts/wt ethyl 2-ABA or
micronized 2-ABA; 400 pts/wt .alpha.-d1 or d-tocopherol acetate.
This formulation is amenable to injection through 20 gauge to 30
gauge needles in 10 mg to 100 mg aliquots into the vitreous chamber
of the eye to provide sustained release of therapeutic levels of
2-ABA or its ester for periods of ten days to one year. Similarly,
10 mg to 3000 mg of these formulations may be injected into the
synovial chambers of human or animal joints to provide
anti-inflammatory therapy for periods of ten days to one year.
[0219] A further aspect of this invention involves novel
formulations of 5 pts/wt to 95 pts/wt 2-ABA or its esters with 95
pts/wt to 5 pts/wt tocopherols, tocopherol acetates and/or
tocotrienols, tocotrienol acetates for the topical applications to
penetrate the skin of humans or animals to alleviate inflammation
and pain in the skin or joints. Again, a convenient source of both
the tocopherols and tocotrienols would be palm seed oil or rice
bran oil extracts. A specific non-limiting formulation would be: 60
pts/wt ethyl 2-ABA or micronized 2-ABA; 40 pts/wt palm seed oil
extract.
[0220] Another aspect of the present invention provides
formulations useful in treating brain tumors. The incidence of
brain tumors is continuing to increase and becomes more marked as
the population ages. Thus, for example the average incidence is
1.8/100,000 people 15-24 years of age but about 18.4/100,000 of
those 65-79 years of age. The age peak is between 55 and 73 years,
although increasing numbers of young patients with glioblastomas
have been recorded in recent years. The estimated number of people
living in the US with a diagnosis of primary brain and central
nervous system tumor is about 360,000. The annual incidence of a
primary brain tumor in the U.S. is about 18,500 people, of whom
most die within the first year after discovery. Despite surgery,
irradiation, or present chemotherapy regimens, patients survive on
average for only eleven months. The tumors, by then, become large
enough to crush vital portions of the brain.
[0221] The tumors which occur most commonly originate from
astrocytes, ependymocytes and oligodendrocytes. The prognosis of
brain tumors is poor. Malignant gliomas account for 42% of all
primary brain/CNS tumors, and of these in turn glioblastoma
multiforme (GBM) and anaplastic astrocytoma, which together account
for about 80% of all malignant gliomas, and have the poorest
prognosis. The GBM is the subject of much research because it is
the most common and potentially destructive brain tumor. While many
tumors contain a mixture of cell types, GBM is the most mixed of
brain tumors. It is this characteristic that makes it difficult to
treat. While one cell type may be responsive to a treatment and
dies, other types are waiting to take over. Additionally, often
only partial tumor resection is possible, leaving remaining and
dislodged cancer cells that can stray throughout the brain. The
histologic distribution of primary brain and CNS gliomas is:
glioblastoma 50.5%, ogliodendrogliomas 9.5%, ependymomas 4.9%, all
other gliomas 9.7%, anaplastic astrocytomas 8.2%, pilocytic
astrocytomas 4.7%, diffuse astrocytomas 1.8%, all other
astrocytomas 9.3%.
[0222] The currently available nonsurgical therapeutic options,
irradiation and systemic chemotherapy, are all associated with
adverse reactions, some of which are severe, which represent
limiting factors for an increasingly aging population afflicted
with other multiple pathologies. The main problem is the fact that
recurrence of these tumors is unavoidable even with, or despite,
the use of present day aggressive surgical, radiation, and
chemotherapy regimens.
[0223] Surgical removal of a tumor though resulting in initial
relief of pressure seldom is able to capture all of the malignancy.
It has been reported that the recurrence rate and increased growth
rate is near 100% after resectioning in GMB atients. Recently it
has been demonstrated experimentally using MRI imaging that there
is an accelerated growth in brain tumor volume following incomplete
surgical resectioning. It is very likely that tissue injury
promotes cancer growth by altering the micro-environment and
provides a more permissive field for tumor expansion and invasion.
Local outpouring of inflammatory cytokines and vascular endothelial
growth factors are likely contributors to this environment. In
addition to this acceleration of the proliferation of the remaining
malignant tissue there is often significant collateral damage to
healthy tissue, troublesome bleeding and edema.
[0224] Irradiation procedures also lead to considerable collateral
damage. In addition to initial edema there are delayed reactions
over weeks to months manifested by neuropsycho-logical disorders,
dementia, and/or atrophy of the cerebral cortex among others.
[0225] The chemical therapeutic regimens which with few exceptions
involve systemic administrations with their collateral damage to
other areas of the body, also must contend with the blood-brain
barrier to penetration of the drug to the desired site. In
principle then, primary brain tumors are categorized as tumors for
which even now there are no effective, curative therapeutic
approaches.
[0226] The novel biocompatible, biodegradable sustained release
formulations revealed in the present invention are either
syringeable liquids, mechanically cohesive solids, injectable gels,
or emulsified micells (oil in water or water in oil). A desirable
feature of these liquid, solid and gel formulations is that they
maintain a single bolus or pellet shape at the site of their
placement. That is, they do not break up as a multitude of smaller
droplets or particles that migrate away from their intended point
of placement and/or by virtue of a resultant increase in surface
area greatly alter the intended release rate of their drug
content.
[0227] The present invention relates generally, but not totally, to
the use of compounds that are syringible, of limited solubility,
biocompatible and biodegradable for controlled and sustained
release of an agent or a combination of an agents. Solid, gel, or
injectable controlled-sustained release systems can be fabricated
by combining an excipient from the list above and a beneficial
agent. Systems can combine more than one of these excipients as
well as more than one beneficial agent. Solid forms for
implantation can be produced by tableting, injection molding or by
extrusion. Gel can be produced by vortex or mechanical mixing.
Injectable formulations can be made by pre-mixing in a syringe or
mixing of the excipient and the beneficial agent at the time of
administration.
[0228] Solid form generally contains 1-60% of one or more of the
excipients, 20-80% for a gel and 50-99% for a liquid. The content
of the therapeutic agent/agents can range from 10% to 90% of the
formulation. The amount of these excipient/therapeutic agent
formulations placed in the tumor can range from about 2 to 20 .mu.l
or .mu.g per ml of tumor volume. The sustained release of the
therapeutic agent/agents into the tumor can be controlled to last
from several days to several years. In a timely fashion the total
formulation disappears from the site with little or no after
effects.
[0229] Solid, liquid or gel excipient/agent formulations can be
implanted surgically or implanted by trocar or needle introduction
directly into the brain tumor such as inoperable gliomas [typically
using a procedure similar to that described by Emerich et al., 17
(7) Pharm. Res. 776-78 (2000). For localized beneficial agent
delivery, the systems of the present invention may also be
surgically implanted in or near the site of the tumor or the cavity
left from tumor resection. An especially attractive procedure is
contemplated which involves the phacoemulsion techniques commonly
used in cataract surgery. In this contemplated procedure the
phacoemulsion device adapted for intracranial operation is inserted
into the tumor and a portion of the tumor tissue is emulsified for
facile removal by irrigation. At this time a sustained release
formulation might be administered for immediate therapy (possibly a
steroidal anti-inflammatory for example). Removal of portions of
tumor tissue allows temporary relief of pressure, and the removed
tissue can be assayed to identify cell types. Knowledge of the cell
types permits the selection of the best long term therapeutic agent
or agents for the subsequent injectable sustained release
formulations to eradicate the tumor mass.
[0230] More specifically, an embodiment of the present invention
provides for a biocompatible, biodegradable, syringeable liquid,
implantable solid, and injectible gel sustained release
formulations of therapeutic agents for brain tumors that may be
inserted directly into brain tumors. These formulations comprise
novel biocompatible and biodegradable syringeable liquid,
implantable cohesive solids and injectable gel formulations
conveniently placed inside brain tumors for the sustained release
of beneficial agents are obtained by admixing one or more of the
excipients: benzyl benzoate, esters of benzoic acid with straight,
branched, or cyclic chain aliphatic alcohols having one to twenty
carbon atoms wherein one of the hydrogen atoms on the aliphatic
chain is replaced with a hydroxyl group (e.g., such alcohols as
methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,
s-butanol, t-butanol, n-pentanol, i-pentanol, neo-pentanol,
n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol,
n-decanol, and the like), mono, di and tri esters of O-acetylcitric
acid, or O-proionylcitric acid, or O-butyrylcitric acid with
C.sub.1 to C.sub.10 straight and branched chain aliphatic alcohols,
mono, di, and tri esters of citric acid with C.sub.1 to C.sub.10
straight and branched chain aliphatic alcohols, diethylene glycol
dibenzoate, triethylene glycol dibenzoate, dibenzoate esters of
poly(oxyethylene) diols up to about 400 mwt, propylene glycol
dibenzoate, dipropylene glycol dibenzoate, tripropylene glycol
dibenzoate, dibenzoate esters of poly(oxypropylene) diols up to
about 3000 mwt, poly(oxypropylene) diols up to about 3000 mwt,
dimethyl sulfone, and the various isomers of tocopherol, tocopherol
acetate, tocopherol succinate, and tocopherol nicotinate; and the
various isomers of the tocotrienols and their acetates, succinates
and nicotinates, polymeric polycarbonate oligomers; polymers and
copolymers of glycolic and lactic acids, with a large number of
established and new agents for the treatment of brain tumors.
[0231] Such agents include tetrahydrocortisol;
4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione (Anecortave
acetate, Retaane, Alcon, Inc.);
4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
11-epicortisol; 17.alpha.-hydroxyprogesterone;
tetrahydrocortexolone; cortisone; cortisone acetate;
hydrocortisone; hydrocortisone acetate; fludrocortisones;
fludrocortisone acetate; fludrocortisone phosphate; prednisone;
prednisolone; prednisolone sodium phosphate; methylprednisolone;
methylprednisolone acetate; methylprednisolone sodium succinate;
triamcinolone; triamcinolone-16,21-diacetate; triamcinolone
acetonide; triamcinolone acetonide-21-acetate; triamcinolone
acetonide-21-disodium phosphate; triamcinolone
acetonide-21-hemisuccinate; triamcinolone benetonide; triamcinolone
hexacetonide; fluocinolone; fluocinolone acetate; fluocinolone
acetonide; dexamethasone; dexamethasone-21-acetate;
dexamethasone-21-(3,3-dimethylbutyrate); dexamethasone-21-phosphate
disodium salt; dexamethasone-21-diethylaminoacetate;
dexamethasone-21-isonicotinate; dexamethasone-21-dipropionate;
dexamethasone-21-palmitate; betamethasone;
betamethasone-21-acetate; betamethasone-21-adamantoate;
betamethasone-17-benzoate; betamethasone-17,21-dipropionate;
betamethasone-17-valerate; betamethasone-21-phosphate disodium
salt; beclomethasone; beclomethasone dipropionate; diflorasone;
diflorasone diacetate; mometasone furoate; acetazolamide (Diamox);
naproxen; naproxin sodium salt; diclofenac; diclofenac sodium salt;
celecoxib; rofecoxib; valdecoxib; etoricocib; lumiracoxib;
sulindac; sulindac sodium salt; diflunisal; diflunisal sodium salt;
piroxicam; indomethacin; indomethacin sodium salt; etodolac;
etodolac sodium salt; meloxicam; ibuprofen; ibuprofen sodium salt;
ketoprofen; ketoprofen sodium salt; r-flurbiprofen (Myriad
Genetics, Inc.); mefenamic; mefenamic sodium salt; nabumetone;
tolmetin; tolmetin sodium salt; ketorolac bromethamine; ketorolac
tromethamine (Todardol.RTM., Sytex, SA); ketorolac acid; choline
magnesium trisalicylate; aspirin; salicylic acid; salicylic acid
sodium salt; salicylate esters of alpha, beta, gamma-tocopherols
(and all their d, 1, and racimic isomers); tenoxicam; aceclofenac;
nimesulide; nepafenac; amfenac; bromfenac; flufenamate;
phenylbutazone; CV 247 (Ivy Medical Chemicals plc); pegaptanib
octasodium; ranibizumab (Lucentis.RTM., Genentech, Inc.);
2-methoxyestradiol; shark cartilage extract (Neovastat, Aeterna);
NX-278-L ant-VEGF aptamer (EyeTech); squalamine (MSI-1246,
Genaera); 2'-O-methoxyethyl) antisense C-raf oncogene inhibitor
(ISIS-13650); vitronectin and osteopontin antagonists (3-D Pharm.);
combretstatin A-4 phosphate (CA4P, Oxigene); Fab fragment
alpha-V/beta-1 integrin antagonist (Eos-200-F, Protein Design
Labs); alpha-v/beta-3 integrin antagonist (Abbott); matrix
metalloprotienase inhibitor (ISV-616, InSite Vision); matrix
metalloprotienase inhibitor (TIMP-3, NIH); urokinase plasminogen
activator fragment (A6, Angstrom Pharm.); vascular endothelial
growth factor antagonist (AAV-PEDF, Chiron); kdr tyrosine kinase
inhibitor (EG-3306, Ark Therapeutics); cytochalasin E (NIH);
kallikrinin-binding protein (Med. Univ. of So. Carolina);
combretastatin analog (MV-5-40, Tulane Univ.); pigment-epithelium
derived growth factor (Med. Univ. So. Carolina); pigment-epithelium
derived growth factor (AdPEDF, GenVec/Diacrin); plasminogen kringle
(Med. Univ. So. Carolina); rapamycin; cytokine synthesis
inhibitor/p38 mitogen-activated protein kinaseinhibitor (SB-220025,
GlaxoSmithKline); vascular endothelial growth factor antagonist
(SP-(V5.2)C, Supratek Pharm. Inc.); vascular endothelial growth
factor antagonist (SU10944, Sugen/Pfizer); vascular endothelial
growth factor antagonist (VEGF-R, Johnson & Johnson/Celltech);
vascular endothelial growth factor antagonist (VEGF-TRAP,
Regeneron); FGF1 receptor antagonist/tyrosine kinase inhibitor
(Pfizer/Sugen); endostatin, vascular endothelial growth factor
antagonist (EntreMed); bradykinin B1 receptor antagonist (B-9858,
Cortech); bactericidal/permeability-increasing protein (BPI, Xoma);
protein kinase C inhibitor (Hypericin, Kansai Med. Univ.);
ruboxistaurinn mesylate (LY-333531, Eli Lilly); polysulphonic acid
derivatives (Fuji Photo Film); growth factor antagonists (TBC-2653,
TBC-3685, Texas Biotechnology); Tunica internal endothelial cell
kinase (Amgen); acetylcysteine; mannitol; antineoplaston; human
corticotropin-releasing factor; VN40101M (Pediatric Brain Tumor
Consortium); everolimus; GW572016 (NCI); thalidomide; temozolomide;
tariquidar; doxorubicin; dalteparin; tarceva; CC-5013 (NCI); hCRF
(Xerecept, Neurobiological Technologies); bevacizumab (Avastin,
Genentech); melphalan; thiotepa; depsipeptide; erlotinib;
tamoxifen; bortezomib; lenalidomide; vorinostat; temsirolimus;
modifinil; enzastuarin; motexafin gadolinium; F-18-OMFD-PET
(Advanced Biochemical Compounds, Redeberg); pemetrexed disodium;
ZD6474 (NCI); valproic acid; vincristine; irinotecan;
PEG-interferon alpha-2b; procarbazine; lonafarnib; arsenic
trioxide; GP96 (Univ. Cal. S.F.); carboplatin; cyclophosphamide;
1311-TM-601 (Trans Molecular); lapatinib; O6-benzylguanine; TP-38
toxin (NCI); cilengitide; poly-ICLC (NCI); FR901228 (NCI);
TransMid.TM. (Xenova); talabostat; ixabepilone; AEE788 (Jonson
Comprehensive Cancer Center); sirolimus; alanosine; sorafenib;
efaproxiral; carmustine; iodine I 131 monoclonal antibody TNT-1/B
(NCI); intratumoral TransMid.TM.; topatecan; lomustine; phosphorus
32; 18F-fluorodeoxyglucose (Alberta Cancer Board); vinblastine;
BMS-247550 (NCI); CC-8490 (NCI); IL 13-PE38QQR (Neopharm); imatib
mesylate; hydroxyurea; G207 (MediGene); radiolabeled monoclonal
antibody; 2-deoxyglucose; talampanel; retinoic acid; gefitinib;
tipifarnib; CPT-11 (Kentuckiana Cancer Inst); rituximab;
efaproxiral; PS-341 (FDA Office Orphan Product Development);
capecitabine; G-CFS (NCI); vinorelbine; DCVax.RTM.-Brain (Northwest
Biotherapeutics); paclitaxel; patipilone (Norvartis); iressa;
methotrexate; ABT-751 (NCI); oxaliplatin; MS-275 (NCI);
trastuzumab; pertuzumab; PS-341 (NCI); 17AAG (NCI); lenalidomide;
campath-1H; somatostatin analog; resveratrol; CEP-7055 (Cephalon);
CEP-5214 (Cephalon); PTC-299 (PTC Therapeutics); inhibitors of
hepatocyte growth factor (L2G7 mAb, Galaxy Biotech); statins such
as atorvastatin (Lipitor.RTM., Pfizer), fluvastatin (Lescor.RTM.,
Novartis), rosuvastatin (Crestor.RTM., Astra Zeneca), prevastatin
(Provacol.RTM., Teva Pharm.), simvastatin Zocar.RTM., Merck &
Co., Inc.), lovastatin (Mevorcor.RTM., Merck) or cervastatin
(Baycol.RTM., Bayer AG) (HMG-CoA reductase inhibitors); and
Receptor tyrosine kinase inhibitors.
[0232] Such agents also include Anti-neovascularization steroids
such as
21-nor-5.beta.-pregnan-3.alpha.,17.alpha.,20-triol-3-acetate;
21-nor-5.alpha.-pregnan-3.alpha.,17.alpha.,20-triol-3-phosphate;
21-nor-5.beta.-pregn-17(20)en-3.alpha.,16-diol;
21-nor-5.beta.-pregnan-3.alpha.,17.beta.,20-triol;
20-acetamide-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol-3-acetate;
3.beta.
acetamido-5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one-21-a-
cetate; 21-nor-5.alpha.-pregnan-3.alpha.,17.beta.,20-triol;
21.alpha.-methyl-5.beta.-pregnan-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-
-one-21-methyl ether;
20-azido-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
20(carbethoxymethyl)thio-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
20-(4-fluorophenyl)thio-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
16.alpha.-(2-hydroxyethyl)-17.beta.-methyl-5.beta.-androstan-3.alpha.,17.-
alpha. diol;
20-cyano-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol;
17.alpha.-methyl-5.beta.-androstan-3.alpha.,17.beta.-diol;
21-nor-5.beta.-pregn-17(20)en-3.alpha.-ol;
21-or-5.beta.-pregn-17(20)en-3.alpha.-ol-3-acetate;
21-nor-5-pregn-17(20)-en-3.alpha.-ol-16-acetic acid 3-acetate;
3.beta.-azido-5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one-21-aceta-
te; and 5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one;
4-androsten-3-one-17.beta.-carboxylic acid;
17.alpha.-ethynyl-5(10)-estren-17.beta.-ol-3-one; and
17.alpha.-ethynyl-1,3,5(10)-estratrien-3,17.beta.-diol.
[0233] Another aspect of the present invention provides for
embodiments comprising omega-3 fatty acids. The health benefits of
dietary supplements of omega-3 fatty acids and their esters are
well known. The particularly important omega-3 fatty acids in human
nutrition are .alpha.-linolenic acid (ALA, C18H30O2, fw 278.4)
eicosapentaenioc acid (EPA, C20H30O2, fw 306.5) and docosahexaenoic
acid (DHA, C22H32O2, fw 328.5). The term omega-3 signifies that the
first double bond exists between the third and second carbon atoms
counting from the terminal methyl at the opposite end of the chain
from the carbonyl group.
[0234] The human body cannot synthesize EPA or DHA except by using
ALA as an intermediate. But the presence of EPA and DHA in almost
all tissues of the body indicates the importance of these compounds
to the body and thus the judicious injection into the body of their
therapeutic formulations will be safe, efficient and effective.
These benefits also extend to the simple esters of EPA and DHA of
the C.sub.1 to C.sub.8 straight and branched chain aliphatic
alcohols such as ethyl EPA and ethyl DHA. Recently, the FDA has
approved ethyl EPA and ethyl DHA for dietary supplements. One
important property of these ethyl esters is that they can be
fractionally distilled from their readily available but crude
source, fish oil. This purification process provides the EPA and
DHA esters free from possible heavy metal and PCB contaminants.
Thus, there remains a need for the development of these purified
esters as liquid excipient vehicles for injectable sustained drug
release in various areas of the human or animal body.
[0235] The embodiments thus provide for the novel concept of
injections of omega-3 fatty acids and their esters by themselves or
as novel and therapeutic formulations with active agents directly
into strategic areas of the human or animal bodies to provide for
the sustained release of the omega-3 compounds and therapeutic but
nontoxic levels of the active agents for periods of months to over
a year.
[0236] Yet another embodiment of the present invention relates
generally to novel injectable and topically applied formulations
containing both steroids and antioxidants. Specifically, the
inclusion of antioxidants with steroids addresses the problem that
many steroids have harmful side effects arising from their being
initiators of destructive oxidative and photo-oxidative radical
chain reactions. These novel steroid-antioxidant formulations are
designed to be injected into the eye, joints, organs, or to be
applied topically externally for the known steroid therapies of
anti-inflammation and regulation of metabolic and immune functions,
but also due to the presence of antioxidants to suppress damaging
oxidative free radical reactions initiated by the steroids in
addition to harmful oxidative chemistries normally present in
cells.
[0237] Although oxygen is required for many life sustaining
metabolic reactions it also has damaging chemistries with cellular
components. These harmful chemistries involve the very reactive
oxygen components: superoxide radicals, hydrogen peroxide, hydroxyl
radicals, and organic peroxides and hydroperoxides. Polyunsaturated
lipids are important components of cells, but they are major
substrates for oxidative attack leading to cell death. Thus, the
dependence of cells on oxygen places them a precarious position
between the prolife and toxic chemistries of oxygen. To tip the
delicate balance towards life, nature provides cells with
protective antioxidant molecules such as tocopherol, ascorbic acid,
glutathione, melatonin, carotenes, carnitine and others. The
natural level of tocopherol in the human lens is around 2.2
.mu.g/ml (Yeum et al., 19 (6) Curr. Eye Res. 502-05 (1999)), and
the ascorbate level in tears is 3.52 .mu.g/ml (Choy et al., 80 (9)
Optom. Vis. Sci. 632-36 (2003)). Unfortunately the exposure of
cells to some steroids, even though for very necessary therapeutic
reasons, has been found to tip this balance towards the toxic side.
For it has been demonstrated that these steroids, especially the
glucocorticosteroids such as triamcinolone and dexamethasone,
readily interact with oxygen and/or light to become initiators of
damaging oxidative chain reactions. Miolo et al., 78 (5)
Photochemistry & Photobiology, 425-30 (2003); Calza et al., 12
(12) J. Am. Soc. Mass. Spectrom., 1286-95 (2001). Although the
co-administration of certain antioxidants with certain steroids has
been shown to ameliorate the toxic oxidative processes initiated by
the steroids (Kosano et al., 76 (6) Exp. Eye Res., 643-48 (2001)
and references therein), presently most commercial injectable
steroid formulations do not include antioxidants. See Fact sheet
inserts for Kenalog.TM., Bristol-Myers Squibb, 2006; Depo
Medrol.TM., Pharmacia, 2003; Decadron.TM., Merck Sharp & Dohme,
1995, (contains bisulfites, hydroxybenzoate esters which might have
antioxidant effects). In formulating compositions containing
antioxidant supplements one must be very careful not to add too
high a level of antioxidants, however, because it has been
demonstrated that at high levels many of these antioxidants
actually are pro-oxidants and may increase oxidative damage. Bowry
et al., 270 J. Biol. Chem. 5756-63 (1995); Halliwell, 25 Free Rad.
Res. 439-54 (1996). Using the naturally occurring antioxidants and
mimicking their levels in the cell environment would be good
practice.
[0238] The areas of therapy of particular interest for applying the
formulations of this invention involve intraocular injections (for
the indications: cystoid macular edema, exudative age-related
macular degeneration, proliferative diabetic retinopathy, diabetic
macular edema, choroidal neovascularization, retinal vein
occlusion, uveitis); intra-articular injections (for the
indications: synovitis of osteoarthritis, rheumatoid arthritis,
bursitis, gouty arthritis, epicondylitis, nonspecific
tenosynovitis, post-traumatic osteoarthritis); and topical
applications on the body exterior. The steroid components and
excipients of these novel formulations and their therapeutic
effects are well described herein and in U.S. Patent Application
Publication No. 2006/0073182. The possible adverse effects of the
steroids used in these formulations are in many cases believed to
arise from the aforementioned damaging oxidative chemistries
initiated by these steroids in the absence of proper antioxidants.
The environment of the eye is particularly damaging for it is
exposed to both oxygen and light energy. The phenolic or
quinone-like structures of the steroid molecules readily absorb
UV-A and UV-B radiation to convert these molecules to unpaired
electron radical species. These radical species can damage cell
components (especially unsaturated lipids in cell membranes) or
they can interact with oxygen to instigate damaging peroxy chain
reactions leading to cataracts (Nishigori et al., 35 (9) Life Sci.
981-85 (1984); Boscia et al., 41 (9) Invest. Opthalmol. Vis. Sci.
2461-65 (2000)), and glaucoma (Sacca et al., 84 (3) Exp. Eye Res.
389-99 (2007)). Cataract formation and glaucoma are maladies
associated with steroid therapies in the eye. In the case of
intra-articular steroid therapies repeated injections are avoided
because they lead to cartilage and bone degeneration. Reactive
oxygen species have been identified as causative agents. Kim et
al., 49 (9) Free Radic. Biol. Med. 1483-93 (2006).
[0239] Without further elaboration, one skilled in the art having
the benefit of the preceding description can utilize the present
invention to the fullest extent. The following examples are
illustrative only and do not limit the remainder of the disclosure
in any way.
EXAMPLES
Example 1
Preparation of a Poly(1,3-propanediol carbonate) I from
1,3-propanediol at 65.degree. C. and 96 hours
[0240] To 23.6 g (0.2 mole) diethyl carbonate (b.p. 128.degree. C.)
was added 15.2 g (0.2 mole) 1,3-propanediol containing 0.05 g (1.25
mmole) of metallic Na to give two liquid phases. These reactants
were placed in an open container in a 65.degree. C. oven and were
shaken occasionally. After 12 hours, the reactants were a
homogeneous solution weighing 38.0 g. The theoretical weight for
the loss of 0.4 moles (18.4 g) of ethanol in a complete reaction
would be 20.4 g. The heating and occasional shaking were continued
to give 27.0 g at 24 hours, 23.2 g at 48 hours, 21.4 g at 72 hours,
and 17.4 g at 96 hours. The product oil was washed with 15 ml 5%
aqueous acetic acid to two phases. The top phase was the water
soluble phase. The 10.5 ml bottom phase was washed with 15 ml water
to give 7.5 ml of a poly(1,3-propylene glycol carbonate) oligomer
as a water-insoluble oil.
Example 2
Preparation of Poly(1,3-propanediol carbonate) II from
1,3-propanediol at 110-150.degree. C. and 26 hours.
[0241] A mixture of 76 g (1.0 mole) 1,3-propanediol containing 0.1
g metallic Na (2.5 mmole) and 118 g (1.0 mole) diethyl carbonate
was heated at 110.degree. C. As soon as the reactants reached
60.degree. C. they formed a homogeneous solution. After heating 8
hours, the reactants had lost 48 g (52% of theoretical amount of
ethanol). The temperature was then raised to 150.degree. C. After
10 hours, the reactants lost another 46 g. A drop of this product
completely dissolved in water. The resultant 97 g of oil was mixed
with 6 g (0.05 moles) diethyl carbonate and the resultant solution
was heated with occasional stirring at 150.degree. C.
[0242] After 8 hours, the resultant syrup was found to be partially
insoluble in water. The product was washed with 100 ml 5% aqueous
acetic acid followed by four washings with 100 ml portions of water
to give 46.1 g slightly yellow viscous oil (46.1/102=45%
yield).
Example 3
Preparation of a Poly(di-1,2-propylene glycol carbonate) from
di-1,2-propylene glycol
[0243] To 590 g (0.5 moles) diethyl carbonate was added 67.0 g (0.5
moles) di-1,2-propylene glycol which had been reacted with 0.02 g
Na to form a homogeneous solution. The reactants were placed in an
open flask at 100.degree. C. After 12 hours, the solution lost 23.4
g (about 50% of the theoretical 46 g ethanol). After another 15
hours at 150.degree. C. the reactants had lost a total of 53.2 g to
give a syrup that was partially insoluble in water. The product was
washed with 100 ml 5% aqueous acetic acid followed by four washing
with 100 ml portions of water to give 25.2 g colorless viscous,
water insoluble liquid poly(di-1,2-propylene glycol carbonate)
oligomer.
Example 4
Preparation of a Poly(tri-1,2-propylene glycol carbonate) from
tri-1,2-propylene glycol
[0244] To 0.1 g Na metal was added t 96.0 g (0.5 mole)
tri-1,2-propylene glycol. After 5 minutes, the Na had reacted
leaving a light yellow oil. 59.0 g (0.5 mole) diethyl carbonate was
added to this liquid and the resultant homogeneous solution was
heated to 110.degree. C. in an open flask. After 6 hours, the
reactants lost 28.0 g (61% of theory). The yellow solution was then
heated at 125.degree. C. for 8 hours, whereupon the reactants had
lost a total of 48 g (104% of theory). Another 6.0 g (0.5 moles)
diethyl carbonate were added and the temperature was raised to
150.degree. C. After 6 hours, the viscous yellow-brown product
solution was washed with 100 ml 5% aqueous acetic acid followed by
4 washings with 100 ml portions of water to give 48 g of a viscous
orange, water insoluble liquid oligomer.
Example 5
The Assay Procedure for Measuring the Release Profiles of
Dexamethasone or Triamcinolone Acetonide from their Sustained
Release Formulations (SRF)
[0245] The vials for the release studies were labeled and the
weight of each vial was recorded. To each vial was added 3-4 grams
of 0.9% saline solution and the weight was recorded. Then the SRF
was injected or placed at the bottom of the vial. The weight of the
SRF was recorded. An additional amount of 0.9% saline solution was
added to a total of 10 grams of saline. The resulting vial was kept
in an incubator or water bath at 37.degree. C. Samples were taken
periodically to measure the release profile of dexamethasone or
triamcinolone acetonide using a HPLC instrument. Sampling protocol
was carried out according to the following procedure: Using a
disposable pipette, 8 grams of the saline solution containing
dexamethasone or triamcinolone acetonide was withdrawn carefully
from each vial. 8 grams of 0.9% saline solution was then added to
each vial. The vials were kept at 37.degree. C. after sampling.
[0246] The HPLC analysis was carried out using a Beckman Gold
Instrument with an autosampler. Calibrators with three different
concentrations of dexamethasone or triamcinolone acetonide in water
were prepared. Calibrators and samples were injected onto a C18
column (Rainin, 250.times.4.6 mm) containing a guard column (C18,
4.6 mm.times.1 cm) and analyzed, respectively. The column was
eluted using a mobile phase of 45% (or 50%) acetonitrile/water,
flow rate 1.0 mL/min, and 7 (or 6) minute run time at an ambient
temperature. The detector wavelength of 238 nm was used. The
dexamethasone or triamcinolone acetonide (retention times, 6-4
minutes) concentration of each sample was calculated from the
standard curve using the software of the Beckman Gold
instrument.
[0247] A wash program to clean the HPLC column was set up during
the HPLC run. After every three or four injections, a sample
containing 20 .mu.L of acetonitrile was injected onto the column,
the column was eluted with a mobile phase of 99%
acetonitrile/water, flow rate 1 mL/min, and a run time 7 minutes.
Then the column was equilibrated back to the original mobile phase
by injecting 20 .mu.L of acetonitrile, eluting with 45% (or 50%)
acetonitrile/water, flow rate 1 mL/min, and a run time 7
minutes.
[0248] The sampling times and the active ingredient (for example
dexamethasone or triamcinolone acetonide) concentrations determined
from HPLC were recorded and tabulated. The percent drug released
and the amount of drug released were each calculated from a
Microsoft Excel software program.
Example 6
Preparation of mixtures of dexamethasone in poly(1,3-propanediol
carbonate) I and their release profiles
[0249] Preparation of 10% dexamethasone in poly(1,3-propanediol
carbonate) I: One portion by weight of dexamethasone was mixed with
nine portions by weight of the poly(1,3-propanediol carbonate) I
prepared in Example 1. The resulting suspension was stirred at an
ambient temperature until a homogeneous mixture formed. The mixture
was then aliquoted and analyzed for the release profile as shown in
FIG. 1.
[0250] Preparation of 20% dexamethasone in poly(1,3-propanediol
carbonate) I: Two portions by weight of dexamethasone were mixed
with eight portions by weight of the poly(1,3-propanediol
carbonate) I prepared in Example 1. The resulting suspension was
stirred at an ambient temperature until a homogeneous mixture
formed. The mixture was then aliquoted and analyzed for the release
profile as shown in FIG. 1.
Example 7
Preparation of mixtures of dexamethasone in poly(1,3-propanediol
carbonate) II and their release profiles
[0251] Preparation of 5% dexamethasone in poly(1,3-propanediol
carbonate) II: One portion by weight of dexamethasone was mixed
with nineteen portions by weight of the poly(1,3-propanediol
carbonate) II prepared in Example 2. The resulting suspension was
stirred at an ambient temperature until a homogeneous mixture
formed. The mixture was then aliquoted and analyzed for the release
profile as shown in FIG. 2.
[0252] Preparation of 10% dexamethasone in poly(1,3-propanediol
carbonate) II: One portion by weight of dexamethasone was mixed
with nine portions by weight of the poly (1,3-propanediol
carbonate) II prepared in Example 2. The resulting suspension was
stirred at an ambient temperature until a homogeneous mixture
formed. The mixture was then aliquoted and analyzed for the release
profile as shown in FIG. 2.
Example 8
Preparation of mixtures of dexamethasone in poly(di-1,2-propylene
glycol carbonate) and their release profiles
[0253] Preparation of 5% dexamethasone in poly(di-1,2-propylene
glycol carbonate): One portion by weight of dexamethasone was mixed
with nineteen portions by weight of the poly(di-1,2-propylene
glycol carbonate) prepared in Example 3. The resulting suspension
was stirred at an ambient temperature until a homogeneous mixture
formed. The mixture was then aliquoted and analyzed for the release
profile as shown in FIG. 3.
[0254] Preparation of 10% dexamethasone in poly(di-1,2-propylene
carbonate): One portion by weight of dexamethasone was mixed with
nine portions by weight of the poly(di-1,2-propylene glycol
carbonate) prepared in Example 3. The resulting suspension was
stirred at an ambient temperature until a homogeneous mixture
formed. The mixture was then aliquoted and analyzed for the release
profile as shown in FIG. 3.
[0255] Preparation of 20% dexamethasone in poly(di-1,2-propylene
glycol carbonate): Two portions by weight of dexamethasone were
mixed with eight portions by weight of the poly(di-1,2-propylene
glycol carbonate) prepared in Example 3. The resulting suspension
was stirred at an ambient temperature until a homogeneous mixture
formed. The mixture was then aliquoted and analyzed for the release
profile as shown in FIG. 3.
Example 9
Preparation of mixtures of dexamethasone in poly(tri-1,2-propylene
glycol carbonate) and their release profiles
[0256] Preparation of 5% dexamethasone in poly(tri-1,2-propylene
glycol carbonate): One portion by weight of dexamethasone was mixed
with nineteen portions by weight of the
poly(tri-1,2-propyleneglycol carbonate) prepared in Example 4. The
resulting suspension was stirred at an ambient temperature until a
homogeneous mixture formed. The mixture was then aliquoted and
analyzed for the release profile as shown in FIG. 4.
[0257] Preparation of 10% dexamethasone in poly(tri-1,2-propylene
glycol carbonate): One portion by weight of dexamethasone was mixed
with nine portions by weight of the poly(tri-1,2-propylene glycol)
carbonate prepared in Example 4. The resulting suspension was
stirred at an ambient temperature until the formation of a
homogeneous mixture. The mixture was then aliquoted and analyzed
for release profile as shown in FIG. 4.
Example 10
Preparation of Mixtures of Dexamethasone in Benzyl Benzoate and
their Release Profiles
[0258] In preparing 20% dexamethasone in benzyl benzoate, two
portions by weight of dexamthasone was mixed with eight portions by
weight of benzyl benzoate. The resulting suspension was stirred at
an ambient temperature until a homogeneous mixture formed. The
mixture was then aliquoted and analyzed for the release profile as
shown in FIG. 5.
[0259] Formulations containing 5% and 50% dexamethasone in benzyl
benzoate were prepared under similar conditions to the 20%
formulation, with the exception of the weight ratio of
dexamethasone/benzyl benzoate. Mixtures of 5% and 50% dexamethasone
in benzyl benzoate were prepared, and the resulting mixtures were
aliquoted and small portions were analyzed for the release profiles
as shown in FIG. 5.
[0260] Dexamethasone in benzyl benzoate forms a uniform suspension.
A formulation of 25% is easily syringeable. As the suspension is
slowly injected into the eye's posterior segment, a uniform
spherical deposit (reservoir) is formed in the vitreous body.
Dexamethasone is then released slowly into the vitreous humor of
the posterior segment. Dexamethasone and benzyl benzoate are
eventually metabolized to byproducts to be excreted in the
urine.
Example 11
Preparation of Mixtures of Dexamethasone in Diethylene Glycol
Dibenzoate and their Release Profiles
[0261] Ten percent dexamethasone in diethylene glycol dibenzoate
was prepared by mixing one portion by weight of dexamethasone (Dex)
with nine portions by weight of diethylene glycol dibenzoate. The
resulting suspension was stirred at an ambient temperature until a
homogeneous mixture formed. The mixture was then aliquoted and
analyzed for the release profile as shown in FIG. 6.
[0262] Using conditions similar to that of the 10% Dex/diethylene
glycol dibenzoate preparation, with the exception of the weight
ratios, mixtures of 5% and 25% Dex/diethylene glycol dibenzoate
formulations were prepared. The resulting mixtures were aliquoted
and small portions analyzed for the release profiles as described
previously. The resulting release profiles are shown in FIG. 6.
Example 12
Preparation of Mixtures of Triamcinolone Acetonide in Diethylene
Glycol Dibenzoate and their Release Profiles
[0263] Preparations of 5%, 10% and 25% triamcinolone acetonide in
diethylene glycol dibenzoate were prepared as follows: a 0.5, 1.0,
or 2.5 portion by weight of triamcinolone acetonide was mixed with
a 9.5, 9.0 or 7.5 portion by weight, respectively, of diethylene
glycol dibenzoate. The resulting suspension was stirred at an
ambient temperature until a homogeneous mixture formed. The mixture
was then aliquoted and analyzed for the release profile as
described previously. The resulting release profiles are shown in
FIG. 7.
Example 13
Preparation of mixtures of dexamethasone in d-tocopherol or
d,1-tocopherol acetate and their release profiles
[0264] For the preparation of 10% Dex in d-tocopherol, one portion
by weight of Dex was mixed with nine portions by weight of
d-tocopherol. The resulting suspension was stirred at an ambient
temperature until a homologous mixture formed. The mixture was then
aliquoted and analyzed for release profile as shown in FIG. 8.
[0265] For the preparation of 20% Dex in d-tocopherol, two portions
by weight of Dex was mixed with eight portions by weight of
d-tocopherol. The resulting suspension was stirred at an ambient
temperature until the formation of a homologous mixture. The
mixture was then aliquoted and analyzed for release profile as
shown in FIG. 8.
[0266] For the preparation of 50% Dex in d1-tocopherol acetate,
five portions by weight of Dex were mixed with five portions by
weight of d1-tocopherol acetate. The resulting suspension was
stirred at ambient temperature until a homologous mixture formed.
The mixture was then aliquoted and analyzed for the release profile
as shown in FIG. 8.
Example 14
Manufacturing of a Solid Drug Delivery System with Dexamethasone
and Diethylene Glycol Dibenzoate and its Release Profile
[0267] Dexamethasone powder and diethylene glycol dibenzoate by
weight were mixed thoroughly by mortar and pestle. The mixture was
placed into a Parr pellet press of 2 mm diameter to form a solid
pellet at 25.degree. C. suitable for an implant. The newly formed
pellet was then weighed in a microbalance before testing for in
vitro kinetics as shown in FIG. 9.
Example 15
Manufacturing of a Solid Drug Delivery System with Dexamethasone
and Benzyl Benzoate and its Release Profile
[0268] Dexamethasone powder and benzyl benzoate by weight were
mixed thoroughly by mortar and pestle. The mixture was then placed
into a 2 mm diameter Parr pellet press to form a pellet at
25.degree. C. suitable for an implant. The formed pellet was
weighed and recorded in a microbalance before testing for in vitro
kinetics as shown in FIG. 10.
Example 16
Manufacturing of a Solid Drug Delivery System with Dexamethasone
and Tocopheryl Succinate and its Release Profile
[0269] Dexamethasone powder and tocopheryl succinate powder were
thoroughly mixed at a ratio of 50/50 by weight. The well-mixed
powder was filled into a single barrel extruder and heated for 1
hour at 65.degree. C. before extruding through a 1 mm orifice.
Micropellets of varying sizes suitable for implants were cut from
the extruded filaments for in vitro kinetic testing as shown in
FIG. 11.
Example 17
Combination Formulations
[0270] Combination with two or more drugs conveniently formulated
with an excipient such as benzyl benzoate provides for sustained
and controlled release of the active agents. The variables of
volume, concentration and percentages of the ingredients are
factors influencing duration and therapeutic concentration of the
drug(s) released. As an example, in a 20% (wt) formulation of a 1:1
dexamethasone:ciprofloxacin in benzyl benzoate, the release profile
of the two drug is similar and the duration is about twenty-eight
to thirty-five days. The release profile of the two drugs is shown
in FIG. 12 A.
[0271] Another useful composition comprises dexamethasone and
ciproloxin at a ratio of 3:1 dexamethasone:ciprofloxacin. The
duration of release of each drug is prolonged significantly, to
about sixty days for dexamethasone and longer for ciprofloxacin, as
shown in FIG. 12 B.
Example 18
Pharmacokinetics and Metabolism of Injected Formulation Comprising
Dex
[0272] To examine the in vivo release of dexamethasone in vivo, a
composition of 25% dexamethasone by weight in benzyl benzoate (DB)
was used: 25 .mu.l (low dose) contained 6 mg dexamethasone, 50
.mu.l (high dose) contained 12 mg dexamethasone. Benzyl benzoate
(BB) served as placebo.
[0273] The in vivo release of the DB composition was studied in
twenty-four rabbits. Twenty-five .mu.l of 25% DB was injected into
the posterior segment of one eye of twelve animals and the
contralateral eye received a placebo. Another twelve animals
received 50 .mu.l of the DB in one eye and 50 .mu.l of the BB
placebo in the second eye. Animals were euthanized at the
appropriate time points and vitreous humor samples were removed
surgically. Dexamethasone concentration was determined by high
pressure liquid chromatography (HPLC) as described in Example
5.
[0274] For the high dose, the concentration of released
dexamethasone was maximal during the first week after insertion,
with a mean of 5.56 .mu.g/ml from Day 7 to Day 90, declining to a
mean level of 1.85 .mu.g/ml by Day 90. With the low dose, the mean
level of dexamethasone was 2.8 .mu.g/ml from Day 7 to Day 60,
declining to a mean level of 0.8 .mu.g/ml. See FIG. 13.
Dexamethasone was not detected in any of the control eyes.
[0275] Clinically, the 24 animals receiving the placebo or low or
high doses of the DB showed no evidence of inflammation or
infection for the entire study. Animals were examined twice weekly
both by slit-lamp opthalmoscopy and fundoscopic examination. No
evidence of cataracts, vitreous, or retinal abnormality was
observed.
[0276] Regarding histopathology, three animals were injected with
25 .mu.l of the DB in one eye and 25 .mu.l of the placebo (BB) in
the contralateral eye. Another three animals were injected with 50
.mu.l DB in one eye and 50 .mu.l BB in the other eye. They were
followed clinically weekly and were sacrificed for histopathology
at 30 days for the low dose and at 90 days for the high dose. Eyes
were fixed in 10% buffered formalin and examined after H & E
staining. The anterior segment comprising the cornea, anterior
chamber, iris, ciliary body, and lens were normal. The pigment
epithelium, Bruch's membrane, and the choroids were all within
normal limits. See FIG. 14. There were no obvious differences in
the histopathology between the treated and control eyes.
[0277] To further examine the in vivo anti-inflammatory effect of
DB, 25 .mu.l of 25% DB was injected into the vitreous of one eye of
three New Zealand White (NZW) rabbits weighing 3 kg-3.5 kg.
Twenty-four hours later, 2.5 mg of bovine serum albumin (BSA) was
injected into both eyes. The animals were examined daily as well as
opthalmologically. Between 10 to 14 days, uveitis with severe
fibrinous reaction occurred in the eye unprotected by DB. In the
eyes injected with DB, little to no inflammation was detected on
examination. Histopathology, the unprotected eye showed chronic and
acute inflammatory cells in the uveal tissues as well as in the
anterior chamber and the vitreous cavity. In the protected eye,
there was minimal evidence of inflammation with few round cell
infiltration in the choroids. The cornea, iris, retina and the
choroids were histologically intact. See Table 1 below.
TABLE-US-00001 TABLE 1 Inflammation in NZW NZW Day 0 Day 14 1 OD
BSA/DB* 3+ OS BSA 0-1+ 2 OD BSA 3-4+ OS BSA/DB Trace 3 OD BSA/DB 0
OS BSA 4+ BSA: bovine serum albumin; DB: 25%
dexamethasone/benzylbenzoate OD: right eye, OS: left eye; 0-4:
severity of posterior segment inflammation, 4+ being maximum
[0278] Another three NZW rabbits were immunized intravenously (IV)
with 10 mg of BSA. Twenty-one days later, following intradermal
injection of 0.5 mg BSA/0.1 ml saline, all animals demonstrated a
strong (+4) Arthus reaction indicating the animals were
systemically immuned to the BSA. On day thirty, one eye of each
animal was injected intravitreally with 25 .mu.l of a 25% DB
composition, and 24 hours later 0.5 mg BSA/0.1 ml normal saline was
injected into both eyes. Severe uveitis developed and persisted in
the ensuing seven to ten days in the unprotected eye, while the
protected eye was judged to be normal. On day sixty, repeat skin
testing showed that the (+4) Arthus reaction remained intact, and
reinjection of 0.5 mg BSA/0.1 ml normal saline showed similar
protection as observed on day 30. These studies imply that DB has
immediate and sustained protective effect in the experimental eye.
When these animals were again challenged with 0.5 mg BSA/0.1 ml
normal saline at 90 days, uveitis developed in all eyes, but the
inflammation in the protected (DB) eye appeared to be less severe.
See Table 2 below. Protection against inflammation with 25 .mu.l of
DB lasted for sixty days. At ninety days, there may have been an
insufficient therapeutic level of Dexamethasone in the eye.
TABLE-US-00002 TABLE 2 Inflammation in protected and unprotected
NZW eyes. NZW Day 0 Day 14 Day 30 Day 60 Day 90 1 OD BSA 3-4+ 3-4+
3-4+ OS BSA/DB* 0 0 2-3+ 2 OD BSA 4+ 3-4+ 3+ OS BSA/DB Trace 0+
2-3+ 3 OD BSA 4+ 4+ 4+ OS BSA/DB 0-1+ 0 2-4+ BSA: bovine serum
albumin; DB: 25% dexamethasone/benzylbenzoate OD: right eye, OS:
left eye; 0-4: severity of posterior segment inflammation, 4+ being
maximum
[0279] Another three NZW rabbits were immunized similarly IV with
10 mg BSA. Twenty-four hours later, one eye of each animal was
injected with 50 .mu.l of 25% DB. At three months (90 days),
intradermal skin testing evoked a +4 reaction. One week later, 0.5
mg BSA/0.1 ml normal saline was injected in both eyes of each
animal. The protected eye (injected with 50 .mu.l 25% DB) showed
little to no clinical uveitis when compared to the contralateral
unprotected eye. This indicates that chronic sustained release of
Dexamethasone was able to protect the eye up to three months when
challenged locally with BSA. See Table 3 below. TABLE-US-00003
TABLE 3 Sustained protection in protected NZW eyes. NZW Day 0 Day
90 1 OD BSA/DB* 0-1+ OS BSA 4+ 2 OD BSA/DB 0+ OS BSA 3-4+ 3 OD
BSA/DB 0-1+ OS BSA 4+ BSA: bovine serum albumin; DB: 25%
dexamethasone/benzylbenzoate OD: right eye, OS: left eye; 0-4:
severity of posterior segment inflammation, 4+ being maximum
Example 19
Pharmacokinetics and Metabolism of Injected Formulation Comprising
TA
[0280] A composition of 25% TA (Triamcinolone Acetonide) by weight
in benzyl benzoate (TA/B) was used: 25 .mu.l containing 7.0 mg TA
and 50 .mu.l containing 14 mg TA. Benzyl benzoate (BB) served as
placebo.
[0281] The in vivo release of the TA was studied in twenty-seven
rabbits. Twenty-five .mu.l (25 .mu.l) of the composition was
injected into the posterior segment of one eye of twelve animals
and the contralateral eye received 25 .mu.l of BB. Another twelve
animals received 50 .mu.l of the same composition into posterior
segment of one eye and 50 .mu.l BB into the second eye. Animals
were euthanized at the appropriate time points (each time point
n=3) and vitreous humor samples were removed surgically for TA
concentration by high-pressure liquid chromatography (HPLC) as
described in Example 5. The mean vitreous concentration TA for the
50 .mu.l TA/B at twenty-four hours was 3.25 .mu.g/ml; at 1 month
2.45 .mu.g/ml; at three months 1.45 .mu.g/ml; and at six months
1.56 .mu.g/ml. The mean vitreous TA level over the 6 month period
was 2.17 .mu.g/ml. The mean vitreous concentration of TA of the 25
.mu.l TA/B animals was 1.78 .mu.g/ml at twenty-four hours; 1.31
.mu.g/ml at one week; 0.81 .mu.g/ml at one month; 0.4 .mu.g/ml at
three months; and 0.36 .mu.g/ml at six months, with a mean of 0.93
.mu.g/ml over a six month period. TA was not detected in any of the
control eyes. See FIG. 15. For the 25 .mu.l dose, near zero-order
release was been observed in vivo for 270 days (data not shown).
For the 50 .mu.l dose, near zero-order release has been observed in
vivo for 365 days (data not shown).
[0282] Clinically, the twenty-seven animals receiving the BB
placebo showed no evidence of inflammation or infection for the
entire study. Animals were examined twice weekly both by slit-lamp
opthalmoscopy and fundoscopic examination. No evidence of
cataracts, vitreous or retinal abnormality was seen.
[0283] Regarding histopathology, six animals were injected with 50
.mu.l of 25% TA/B in the right eye and 50 .mu.l of BB in the other
eye. They were followed clinically weekly and were sacrificed for
histopathology at 180 days. Eyes were fixed in 10% buffered
formalin and examined after H & E staining. The anterior
segment comprising the cornea, anterior chamber, iris, ciliary body
and lens was normal. Histopathology of the posterior segment
(including the vitreous, retina, photoreceptors cells, pigment
epithelium, Bruch's membrane and the choroids) was within normal
limits. There were no obvious differences in the histopathology
between the treated and the control eyes.
Example 20
Solid Implant Comprising Dex
[0284] The levels of dexamethasone released from a solid implant
was studied in the anterior chamber of a NZW rabbit. A mixture of
50:50 dexamethasone (Upjohn) and d1-alpha tocopherol succinate
(Sigma) was extruded through an aperture of 790 .mu.M mm at
25.degree. C. One (1) mgm of this extruded mixture was surgically
placed in the right anterior chamber of a 4 kg NZW female rabbit.
Sampling of the aqueous humor from the anterior chamber (AC) for
HPLC dexamethasone analysis was performed in accordance with the
above example. Therapeutic sustained release levels of
dexamethasone were observed. See FIG. 16. Clinically, the animal's
eye was completely quiescent and the composition was judged to be
biocompatible.
Example 21
Sustained Release of Dexamethasone/d1-Alpha Tocopherol Succinate
Coating of Stainless Steel Surface and Cardiac Stents
[0285] A mixture of 2:8:1 (wt) of dexamethasone:acetone:tocopherol
succinate coating was applied to two stainless steel tubing
surfaces and two commercial cardiac stents. Coating was achieved by
dipping and oven drying. Elution of dexamethasone for HPLC analysis
was done in a 20 ml distilled water vial and exchange of 75% of the
total volume took place per period of assay. See FIG. 17.
Tocopherol succinate has been demonstrated to be an effective
coating medium on steel surfaces for controlled drug release. The
application of this methodology could be extended to various
materials and surfaces including wood, glass, various metals,
rubber, synthetic surfaces such as teflon, plastics, polyethylene
tubings and the like.
Example 22
Formulations Comprising Cyclosporine in Tocopherol Succinate
[0286] To study the in vitro release of 25:75 d1-alpha
tocopherol:Cyclosporin A, cyclosporin was mixed with tocopherol
succinate and extruded at 25.degree. C. through an aperture of 790
.mu.M. One mg (1 mg) of the material was placed in 10 ml distilled
water vial and aliquots were sampled for dissolution as described
above. See FIG. 18. Prolonged sustained release in a linear fashion
was observed for about 272 days.
[0287] To study the in vivo release profile, 0.75 mg of the 25:75
tocopherol succinate:cyclosporin was implanted surgically in the
right anterior chamber (AC) of the 4.0 kg NZW female rabbit. The AC
was tapped at the above time-points for HPLC determination of CsA
in the aqueous humor. See FIG. 19. Additionally, 5.0 mg of 25:75
tocopherol succinate:cyclosporine was implanted surgically into the
left posterior segment (PS) of a 4 kg NZW female rabbit eye. The
vitreous humor in the PS was tapped at the above time-point for CsA
HPLC analysis. See FIG. 20.
[0288] In another in vivo release study, 30 mg (3.times.10 mg) of a
25:75 tocopherol succinate:cyclosporin formulation was extruded
through a 1 mm aperture. The segments were implanted in the
peritoneal cavity of an adult male Sprague-Dawley rat with a trocar
through a 3 mm incision after local 0.5% lidocaine infiltration.
Cardiac puncture was performed for blood CsA LCMSMS analysis. See
FIG. 21.
[0289] Implants of cyclosporin:tocopherol succinate were injected
by needle trocar in various organs in Sprague-Dawley rats to
determine cyclosporin distribution. More specifically, extruded
20:80 tocopherol succinate:cyclosporin of various weights were
implanted. After sacrifice and harvest, all tissues were dried in a
tissue concentrator for 48 hours, crushed and soaked in 1 ml of
MeOH containing 10 ng/ml CsD. Analysis were performed with Mass
Spec Liquid Chromatography. CsA was observed as indicated below in
Table 4 and Table 5. Abbreviations: ant anterior, post posterior,
hem hemisphere. TABLE-US-00004 TABLE 4 Cyclosporin distribution in
rat liver and brain. Upper lobe mg dried tissue ng/ml CsA ng/mg CsA
Liver #1 Upper Lobe, Sacrificed Day 5, 2 mg 80% CsA in tocopherol
succinate was implanted into the right third of the middle lobe*
right third 71.4. mg 2540 35.6 middle third 119.4 191 1.6 left
third 88.4 184 2.1 middle lobe right third* 83.3 2360 28.3 left
third 88 878 10 left third 49.2 2620 53.2 blood na 0 na
Observation: CsA distribution was detected in both upper and middle
lobes when implant was implanted in the middle lobe.* Liver #2
Lower Lobe, Sacrifice 24 hours, 2 mg of implant injected. right
fifth 99.3 254 2.6 right middle 59.6 144 2.4 fifth Implant* 138.8
2420 left middle 77.5 1710 22 fifth left fifth 53.5 278 5.2
Observation: Sacrifice at 24 hours showed much higher concentration
in the section of the liver containing the implant. Brain #1,
Sacrifice 24 hours, 1 mg of the formulation was implanted. left ant
hem 47.2 72.1 15.3 left post hem 79.3 180 2.3 right ant hem* 52.7
1190 22.6 right post hem 60.8 385 6.3 blood na 0 na Observation:
CsA distribution was noted in both hemispheres even though the
implant was placed in the right ant hem.* Brain #2, 1 mg
formulation implanted in right ant hem.* left ant hem 42.2 478 11.3
left post hem 68.6 127 1.9 right ant hem* 73.9 401 5.4 right post
hem 113.7 96 0.8 blood na 0.29 na Observation: Similar to brain #
1, the left ant hem showed much higher concentration. *Site of
implantation.
[0290] TABLE-US-00005 TABLE 5 Cyclosporin distribution in rat
spleen and kidney. mg dried tissue ng/ml CsA ng/mg CsA Spleen,
sections right to left, 1 mg implant in section #7.* section #1
10.3 217 21.1 section # 2 16.2 72.5 4.5 section #3 12.9 17.7 1.4
section #4 24.9 62 2.5 section #5 22.5 72.9 3.2 section #6 26.8 101
3.8 section #7* 29 1800 62 Observation: Distribution appears higher
at the opposite pole of the spleen. Kidney, 075 mg implant in lower
third. blood na 0 na upper third 156.8 314 2 middle 85.5 333 3.9
lower third* 106.1 165 1.6 Observation: CsA distribution throughout
kidney. *site of implantation.
Example 23
Transdermal Delivery of Insulin
[0291] The comparison of injected versus transdermal delivery of
several formulation of insulin was studied in a mouse model. One mg
of porcine insulin was injected IP (intraperitoneal) into a mouse.
A precipitous drop in glucose level was found within one-half hour
and developed into hypoglycemia after one hour. Hypoglycemia
persisted below perceptible levels and the animals never recovered.
One mg of porcine insulin was mixed with 0.1 ml of tocopherol
acetate and injected IP, perceptible drop in glucose level was seen
up to 3 hours and the animal remained hypoglycemic and did not
recover. IP glucose infusion did not reverse the hypoglycemia. One
mg of porcine insulin mixed with 0.1 ml of tocopherol acetate was
applied topically on the skin of a shaved mouse. A slow decline of
the glucose level was seen, with the lowest level determined at 5.5
hours. A return towards pre-treatment levels was seen at 24 hour
and 48 hour. Tocopherol IP was able to slow the hypoglycemic effect
of insulin. Transdermal insulin w Topcopherol Ac produced reduction
in glucose levels with slow recovery to pre-treatment levels after
24-48 hours. Sustained release of transdermally administered
insulin was observed.
[0292] Porcine insulin (20 mg) was mixed in 199 mg/ml of tocopheryl
acetate and formed a paste (or gel) which and was applied to the
backs of shaved albino mice as follows: Mouse #1 was treated with
39.8 mg of insulin/tocopherol acetate paste, equaling 3.6 mg of
insulin; mouse #2 was treated with 75.2 mg of insulin/tocopherol
acetate paste, equaling 6.9 mg of insulin. Tail blood glucose
levels were determined by Home Diagnostics, Inc. True Track smart
system at intervals depicted in FIG. 22. A drop in glucose level
was seen as early as one-half hour after transdermal application
followed by sustained depressed levels for up to fifteen hours. By
twenty-four hours, glucose had returned to pre-treatment levels
followed by rebound ro hyperglycemic concentrations for the next
twenty-four hours. Sustained release of transdermal administered
insulin has been demonstrated.
[0293] Pharmaceutical agents that may be delivered by this platform
include insulins, GLP-1s, analgesics, anesthetics, narcotics,
angiostatic steroids, anti-inflammatory steroids, angiogenesis
inhibitors, nonsteroidal anti-inflammatories, anti-infective
agents, anti-fungals, anti-malarials, anti-tuberculosis agents,
antivirals, alpha androgenergic agonists, beta adrenergic blocking
agents, carbonic anhydrase inhibitors, mast cell stabilizers,
miotics, prostaglandins, antihistamines, antimicrotubule agents,
antineoplastic agents, antiapoptotics, aldose reductase inhibitors,
antihypertensives, antioxidants, growth hormone antagonists,
vitrectomy agents adenosine receptor antagonists, adenosine
delaminate inhibitor, glycosylation antagonists, anti-aging
peptides, topoisemerase inhibitors, anti-metabolites, alkylating
agents, antiandrigens, anti-oestogens, oncogene activation
inhibitors, telomerase inhibitors, antibodies or portions thereof,
antisense oligonucleotides, fusion proteins, luteinizing hormone
releasing hormones agonists, gonadotropin releasing hormone
agonists, tyrosine kinase inhibitors, epidermal growth factor
inhibitors, ribonucleotide reductase inhibitors, cytotoxins, IL2
therapeutics, neurotensin antagonists, peripheral sigma ligands,
endothelin ETA/receptor antagonists, antihyperglycemics,
anti-glaucoma agents, anti-chromatin modifying enzymes, obesity
management agents, anemia therapeutics, emesis therapeutics,
neutropaenia therapeutics, tumor-induced hypercalcaemia
therapeutics, blood anticoagulants, anti-proliferatives,
immunosuppressive agents, tissue repair agents, and
psychotherapeutic agents.
Example 24
Formulation Effective in Treating Brain Tumors
[0294] The following example used a partial tumor resection brain
tumor model to investigate whether tissue injury resulted in an
accelerated, proliferative index or accelerated tumor growth. It
also indicated that suppression of inflammatory cytokines and
vascular endothelial growth factors with local sustained-release
corticosteroid will alter the rate of recurrence and growth in an
experimental mouse tumor model. This experiment used a
resection/recurrent mouse glioblatoma model in ascertaining the
effects of dexamethasone on the post-surgical environment following
tumor resection.
[0295] A pellet of 1.5 mg of 50/50 wt. dexamethasone/tocopheryl
succinate was prepared in a 1.0 diameter press. The in vitro
kinetics are shown in FIG. 23.
[0296] Briefly, mice were anesthetized by intramuscular injection
of a cocktail of ketamine (22-44 mg/kg), xylazine (2.5 mg/kg), and
acepromazine (0.75 mg/kg). Ten thousand GL-26 rat glioblastoma
cells were implanted stereotactically into the right basal ganglia
of the animal using a mouse stereotactic frame (Kopf Instruments,
Tujunga, Calif.). At day 15 after tumor implantation, the animals
were scanned in a 1.5T MRI with a T-1. Contrast medium was give via
tail vein injection prior to scanning. At day 18 another imaging
was done to confirm the tumor progression. Animals with similar
tumor size were selected for the study. Animals underwent
craniotomy and tumor resection on day 19 following general
anesthesia. The tumor was resected to about 80% completion. The
extent of resection was verified by post-operative MRI imaging.
Three animals each with similar residual tumor were grouped into
resected and resected plus dexamethasone-tocopheryl succinate
delivery system. In the treated group sustained-release
dexamethasone was placed into the resection cavity. The expansion
of the residual tumor was monitored by MR imaging. The growth rate
was determined and compared to that of control and resection arms
of the study.
[0297] Animals implanted with G126 mouse glioma cell line will grow
to a mean volume of 110 mm.sup.3 at day 25. The mean survival is 28
days. In the current experiment there was a significant difference
in the volume of the recurrent tumor at day 30 between the resected
(122.5 mm.sup.3) and the resected group treated with intratumoral
sustained-release dexamethasone (18 mm.sup.3) and the control
(233.5 mm.sup.3). See FIG. 24. These data suggest that
dexamethasone delivered locally following resection appears to be
effective in altering the rate of recurrence.
Example 25
In Situ Personalized Anti-Cancer Vaccine Production
[0298] The use of aldehydes such as formaldehyde to kill or alter
the cellular or viral components of pathogens for the formation of
vaccines is well known. The Salk polio vaccine is one example. The
pathogens are exposed to a carefully measured amount of an aqueous
aldehyde solution resulting in the death of the pathogen or
chemical alteration of the cellular or viral components to destroy
pathogenisity. In many cases the resultant altered cells, viruses,
or components are recognized by the body's immune system as foreign
resulting in therapeutic antibody production. For the production of
a patient-specific anticancer vaccine (PSAV) to a tumor, because
the highly reactive aqueous aldehyde solutions are very mobile
fluids they would be difficult to confine to the target area if
injected into the body; and considerable collateral damage to
healthy tissues might occur. Thus, presently the exposure of the
target malignant cells to the aldehyde is done outside the body and
the resultant attenuated pathogen material is then injected into
the body. Excising tumor tissue for extracorporeal vaccine
production can be traumatic, and often tumors such as glioblastomas
are inoperable. Hence, there remains a need for an improved
approach to PSAV techniques.
[0299] This embodiment allows for the precision injections of
controlled amounts of novel aldehyde, especially formaldehyde,
polyoxymethylene prodrug formulations directly into tumors in the
body. The precise, controlled nature of these prodrug injections
limits cell death or augmentation to tumor tissue only, with little
or no collateral damage to healthy tissues. The subsequent release
of resultant attenuated tumor cells or augmented cell material into
the blood stream induces personalized antibody formation that
eradicates any remaining original tumor or daughter tumors that may
have metathesized to other sites in the body. This process is
classified as producing a patient-specific anticancer vaccine
(PSAV).
[0300] The novelty of this embodiment is the use of solid and
liquid oxymethylene polymers as controlled release prodrugs of the
desired aldehydes. Aldehydes have the propensity to homopolymerize
to a variety of cyclic trimers and linear oxymethylene or
substituted oxymethylene polymers of a wide spectrum of molecular
weights. In water, these trimers and polymers slowly revert back to
their aldehyde monomers. This property offers the ability to inject
with precision these aldehyde prodrugs or their injectable
formulations with excipients into tumors in the body to allow for
the controlled and/or sustained release of the desired aldehyde
into the tumor with little or no damage to healthy tissue. The
subsequent release of killed or attenuated tumor cells or cellular
material into the blood stream induces immune responses to produce
therapeutic antibodies to destroy tumor cells throughout the
body.
[0301] Some oxymethylene polymers and trimers for this embodiment
are, for example: Paraformaldehyde, Trioxane, Oxymethylene polymers
of acetaldehyde, Paraldehyde, and Oxymethylene polymers of
gluteraldehyde.
[0302] These oxymethylene polymers and trimers can be implanted by
themselves or as mixtures with excipients into the tumor mass. A
desirable, minimally invasive method is by injection through 20
gauge to 36 gauge hypodermic needles of fluid liquid
polyoxymethylene/excipient formulations. Excipients are disclosed
herein and in U.S. Pub. No. 2006/0073182. Some example excipients
useful in the present embodiment include benzyl benzoate,
tocopherol acetate, and triethyl O-acetyl citrate. An illustrative
but non-limiting example of a formulation would be triethyl
O-acetyl citrate containing 5 to 50% by weight of micronized
crystals of paraformaldehyde.
[0303] Depending upon the size of the target tumor, 1.0 .mu.l to
100 .mu.l of this formulation may be injected into the tumor
mass.
Example 26
Omega-3 Fatty Acids and their Esters for Injectable Sustained Drug
Release Formulations
[0304] As noted above, the embodiments thus provide for the novel
concept of injections of omega-3 fatty acids and their esters by
themselves or as novel and therapeutic formulations with active
agents directly into strategic areas of the human or animal bodies
to provide for the sustained release of the omega-3 compounds and
therapeutic but nontoxic levels of the active agents for periods of
months to over a year.
[0305] The process of injecting small amounts of these omega-3
fatty acid/ester alone or their formulations containing active
agents at the site of the malady is not only maximally effective
and efficient but also avoids the waste and potentially increased
danger of systemic oral administration. These novel sustained drug
release formulations of the omega-3 liquids alone or in combination
with the other excipients disclosed herein and in U.S. Pub. No.
2006/0073182 can be injected into a variety of body areas or organs
such as but not limited to the breast, brain, pancreas, liver,
prostate, lung, etc. An especially promising application is
intraocular injection into the anterior or posterior segments of
the eye. Among a number of maladies to be treated, as listed herein
and in US 2006/0073182, are those of the retina such as macular
degeneration, retinitis pigmentosa, proliferative
vitreoretinopathy, to name a few. A potentially advantageous
property of DHA, EPA, and their esters is their importance in
maintaining healthy retinal tissue and their required presence for
proper development of neonatal retinal function. See, e.g., Jeffrey
et al., 36 (9) Lipids 859-71 (2001); SanGiovanni & Chew, 24 (1)
Prog Retin Eye Res. 87-138 (2005); Bazan, 29 (5) Trends Neurosci.
263-71 (2006); King et al., 26 (17) J. Neurosci. 4672-80 (2006).
Indeed, it is quite possible these beneficial effects of DHA/EPA
and their esters in neural development might lead to their
injectable formulations being potent adjuvants for successful stem
cell implantation and development especially in the retina, brain,
spinal cord, and the like. Also these injectable formulations use
as adjuvants for successful stem cell development of pancreatic
tissue (diabetes), cardiac tissue (coronary therapy), or skin
tissue (burn therapy) to name a few await investigation.
[0306] Some more specific, but not limiting, examples contemplated
for intraocular therapies are for inflammatory maladies of the
retinal area. Injection through 25 G to 30 G needles into the
posterior segment of 10 .mu.l to 60 .mu.l liquid microspheres of
ethyl DHA/ethyl EPA alone or as mixtures containing 10% to 50% by
weight of microcrystalline dexamethasone or triamcinolone
acetonide. This provides for the maintenance of therapeutic levels
of the omega-3 fatty acids or the approximately 0.1 to 1.0 .mu.g/ml
therapeutic concentration of the steroids in the area of the retina
for periods of months to over a year. In the case of anti-VEGF
therapy similar amounts of such agents as ranibizumab or
bevacizumab could be employed in a similar manner with the omega-3
excipients. The extensive list of other beneficial agents employed
for the list of a wide variety of maladies are disclosed herein and
in U.S. Pub. No. 2006/0073182.
Example 27
Formulations Containing Steroids and Antioxidants
[0307] This embodiment relates generally to novel injectable and
topically applied formulations containing both steroids and
antioxidants. These formulations allow the application of steroids
to achieve their intended benefits (anti-inflammation, immune
modulation) without initiation of harmful oxidative chemistries.
These example formulations are composed of one or more of the
steroids listed in Group A combined with one or more of the
antioxidants listed in Group B and all dispersed or dissolved in
one or more of the delivery vehicles selected from the excipients
described herein and listed in Group C and also described in U.S.
Pat. Appl. Pub. No. 2006/0073182. TABLE-US-00006 Group A Steroids
triamcinolone dexamethasone diethyl aminoacetate triamcinolone
acetonide dexamethasone isonicotinate triamcinolone diacetate
dexamethasone palmitate triamcinolone acetate prednisone
triamcinolone disodium phosphate prednisolone triamcinolone
hemisuccinate prednisolone acetate triamcinolone benetonide
prednisolone sodium phosphate dexamethasone methylprednisolone
dexamethasone acetate methylprednisolone acetate dexamethasone
disodium methylprednisolone sodium succinate phosphate
dexamethasone paramethasone 3,3-dimethylbutyrate cortisone
etrahydrocortexolone cortisone acetate betamethasone hydrocortisone
betamethasone acetate hydrocortisone acetate betamethasone disodium
phosphate tetrahydrocortisol betamethasone benzoate fludrocortisone
betamethasone valerate fludrocortisone acetate betamethasone
dipropionate fludrocortisone phosphate betamethasone adamantoate
anacortive beclomethasone anacortive acetate beclomethasone
dipropionate mometasone furoate diflorasone fluocinolone
diflorasone diacetate
[0308] TABLE-US-00007 Group B Antioxidants ascorbic acids and salts
retinyl palmitate ascorbyl palmitate probucol ascorbyl dipalmitate
erythorbic acid ascorbyl stearate sodium erythorbate
ascorbyl-2,6-dibutyrate .alpha.-lipoic acid d-tocopherol (.alpha.,
.beta., .gamma., .delta. isomers) isocitrate dl-tocopherol
(.alpha., .beta., .gamma., .delta. isomers) lutein/zeaxanthin/meso-
zeaxanthin the acetate, hemisuccinate, nicotinate eugenol and
succinate-PEG ester derivatives of isoeugenol the above tocopherol
isomers (-)-epicatechin glutathione (-)-epigallocatechin gallate
.beta.-carotine benzyl alcohol carnitine benzyl benzoate carnitine
acetate 2,6-di-tertbutyl-4-methoxy phenol trans reveratrol
butylated hydroxytoluene retinoic acid butylated hydroxyanisole
retinyl palmitate quercetin melatonin catechin timolol rutin
luteolin coenzyme Q kaempferol fisetin thyroxine methyl gallate
pyrroloquinolone superoxide dismutase
[0309] TABLE-US-00008 Group C Exipients d-tocopherol (.alpha.,
.beta., .gamma., .delta. isomers) dimethyl sulfone (MSM)
dl-tocopherol (.alpha., .beta., .gamma., .delta. isomers) benzyl
benzoate the acetate and esters of C-3 to liquid to semisolid
poly-carbonate C-10 straight and branched oligomers, such as those
prepared by chain aliphatic acids with the the polymerization of
trimethylene above tocopherol isomers carbonate or the ester
exchange polymerization of diethylene carbonate with aliphatic
diols or polyoxyalkane diols [poly(di-1,2- propylene glycol
carbonate) or poly(tri-1,2-propylene glycol carbonate)] triethyl,
tripropyl, or tribuyl esters tri-straight and branched chain C-1 to
of O-acetyl, O-propionyl, or C-10 aliphatic alcohol esters of
O-butyryl citrate citric acid omega-3 fatty acids and their ester
propylene glycol dibenzoate with C-1 to C-10 straight and branched
chain aliphatic alcohols dipropylene glycol dibenzoate tripropylene
glycol dibenzoate
[0310] As mentioned above, to avoid harmful pro-oxidative
chemistries care should be taken not to expose the cells to too
high a level of the antioxidants. This may present a problem as
formulators develop a one-shot formulation that administers
steroids and antioxidants for months to a year or more. The
formulation must incorporate enough antioxidants to last this long
without releasing pro-oxidative concentrations. This is achieved in
this embodiment of the invention by using lipophyllic prodrug forms
of the antioxidants such as ascorbyl palmitate, tocopherol acetate,
benzyl benzoate, and the like, which slowly release the active,
more hydrophyllic form into the cellular environment upon
hydrolysis.
[0311] Examples of an injectable sustained release formulation of
this embodiment include formulations such as: TABLE-US-00009 (1)
benzyl benzoate 60 pts/wt .alpha.-tocopherol acetate 5 pts/wt
ascorbyl palmitate 5 pts/wt triamcinolone acetonate 40 pts/wt (2)
.alpha.-tocopherol acetate 60 pts/wt ascorbyl palmitate 10 pts/wt
dexamethasone 40 pts/wt
Example 28
In vitro study of Dexamethasone in Triethyl O-Acetyl Citrate
(TEAC)
[0312] To 760 mg of TEAC was added 240 mg of Dexamethasone with
ample stirring to form a homogeneous mixture. Six mg (25 .mu.l) and
12 mg (25 .mu.l) microdrops of this mixture were each incubated in
10 ml of 0.9% saline at 37.degree. C. Periodically, 8 ml portions
were withdrawn for assaying and replaced with 8 ml of fresh 0.9%
saline. The release of Dex from a formulation consisting of 24% Dex
in TEAC is depicted in FIG. 25. The release of Dex from a
formulation consisting of a 6 mg (25 .mu.l) microdrop of 20% Dex in
1:1 TEAC/Tocopherol Acetate is reflected in FIG. 26. In summary,
these results indicate that adding Tocopherol Acetate to the TEAC
excipient can extend the sustained release of therapeutic levels of
Dex up to 450 days.
Example 29
In Vivo Study of Sustained Release of Active Agents from TEAC
Formulations
[0313] A microdrop of a mixture of 10% Dex in TEAC containing 200
.mu.g of Dex was injected into the anterior chamber (AC) of the
right eye of a rabbit with a 30 G needle. Similarly, a microdrop of
the mixture containing 400 .mu.g Dexamethasone was injected into
the AC of the left eye of a rabbit. As illustrated in FIG. 27, the
duration of therapeutic levels of Dexamethasone was seen to be
twice as long in the left AC.
[0314] A 10% Dex in TEAC formulation was injected into a rabbit
vitreous chamber/posterior segment (VC/PS). As shown in FIG. 28,
sustained therapeutic intravitreal levels of Dex were maintained
over sixty days following injection of 3 mg or 6 mg microdrops of a
10% Dex in TEAC mixture into the VC/PS.
[0315] A portion of the formulation amounting to 80 .mu.g of Dex
was injected with a 30 gauge needle into the anterior chamber of a
NZW rabbit and the kinetics measured by HPLC. Therapeutic levels
were observed over a twelve-day period, as depicted in FIG. 29.
[0316] A portion of the of the formulation amounting to 900 .mu.g
of Dex was administered into the anterior chamber of a NZW rabbit
with a 30 gauge needle and kinetics were measured by HPLC.
Therapeutic levels were observed over an eighteen-day period, as
illustrated in FIG. 30.
[0317] A microdrop of a mixture of 20% Ciprofloxacin free base (FB)
in TEAC, containing 300 .mu.g of Ciprofloxacin FB, was injected
into the AC of a rabbit eye. A therapeutic level of 2.44 .mu.g/ml
was maintained for up to five days, as shown in FIG. 31.
Example 30
In Vivo Release of Cyclosporin from Formulations Placed in the
Eye
[0318] It has been reported (see, e.g., U.S. Pat. No. 5,294,604)
that periocular administrations of cyclosporin A (CsA) are used to
treat ocular diseases involving serious intraocular inflammatory
processes requiring immunosuppression for sustained periods. Such
diseases include endogenous uveitis, Behcet's Disease, corneal
transplantation, vernal keratoconjunctivitis, ligneous
keratoconjunctivitis, dry eye syndrome, anterior uveitis and
onchocerciasis. The present embodiment provides for the intraocular
injections of CsA formulations with novel excipients allowing for
the sustained release of therapeutic, non-toxic levels of CsA,
useful as therapies for such diseases. This Example reveals the
reduction to practice of the use of these novel CsA
formulations.
[0319] Three (3.0) mg of a formulation containing a 40:60 mixture
of cyclosporin A (CsA) in tocopherol acetate was injected into the
anterior chamber of a 4.0-4.5 kg NZW rabbit. Aqueous humor samples
were obtained and assayed for CsA via liquid chromatography and
mass spectrometry. A release profile is depicted in FIG. 32.
[0320] Approximately 14.0 mg of CsA (contained in a 25:75 mixture
of CsA in triethyl acetyl citrate) was injected into the vitreous
of a 4.0-4.5 kg NZW rabbit. Vitreous samples were obtained and
assayed for CsA as described above. A release profile is depicted
in FIG. 33.
Example 31
Sustained Release and Stability of Monoclonal Antibody-Containing
Formulations
[0321] Three formulations containing 0.25 mg monoclonal antibody
(Mab) against LSD were each injected into the vitreous cavity of 4
New Zealand White rabbits (ave. 4-4.5 kg). The first formulation
the Mab was suspended in PBS buffer, the second and third
containing lyophilized Mab in 25 .mu.l of either Triethyl
AcetylCitrate (TEAC) or Benzyl Benzoate (BB) respectively. Fifty
(50) .mu.l of vitreous were sampled from each animal as shown in
Table 6 following intravitreal injections, and assayed for the Mab
LSD activity in the standard microtiter ELISA method (Biostride,
Redwood City, Calif.). TABLE-US-00010 TABLE 6 Day Ave. Ab in PBS
Ave. Ab in TEAC Ave. Ab in BB 1 3.5 1.4 3 71.5 7 49.5 3.6 1.2
[0322] The data, shown in FIG. 34, suggest that the half-life of
the Mab in PBS is between three to five days: the Mab concentration
on day three was 71.5 .mu.g/ml and day seven was 49.5 .mu.g/ml. In
contrast, the Mab concentration released from the TEAC formulation
on days one and seven were 3.5 .mu.g/ml and 3.6 .mu.g/ml,
respectively. The Mab concentration released from the BB
formulation on days one and seven were 1.4 .mu.g/ml and 1.2
.mu.g/ml, respectively. Comparable data interpretation on day seven
suggests that controlled sustained release of Mab in the rabbit
vitreous cavity can be achieved with TEAC and BB. The controlled
level was 13.7.times. (49.5/3.6) more effective in TEAC than in PBS
alone, and 41.25.times. (49.5/1.2) more effective in BB than in PBS
alone. Controlled-sustained release of the Mab in TEAC and BB is
apparent in this study, and the half-life of Mab in TEAC and BB
could be well beyond seven days. The specificity of these assays
suggests strongly that the integrity of the Mab was not affected in
the formulary with TEAC and BB. In conclusion, the formulations of
the present invention provide for the sustained release of
sensitive polypeptides without denaturing their function.
Example 32
In Vivo Release of Rapamycin from TEAC Formulations
[0323] Five (5.0) mg rapamycin contained in a 10:90 rapamycin:TEAC
mixture were injected into the vitreous cavity of one eye in three
4.0-4.5 kg. NZW rabbits. Vitreous sampling was performed in each
animal, and the concentration of released Rapamycin determined by
liquid chromatography and mass spectrometry. Results are depicted
in FIG. 35, indicating that this formulation allowed the release of
Rapamycin for over five months.
Example 33
Formulations for the In Vivo Release of Ketorolac Acid
[0324] Ketorolac acid and/or other nonsteroidal anti-inflammatory
drugs (NSAIDs) are a different class of antiinflammatory drugs used
widely in medicine and in the eye. They are less potent than
corticosteroids and have fewer or less-severe side effects on the
eye (such as glaucoma, cataracts which are common complications of
corticosteroid use in the eye). Additionally, they may be used
topically or in intraocular injection with or without sustained
release parameters. There are early clinical findings indicating
that non-sustained-release use of NSAID can be helpful in chronic
macular edema. Hence, a sustained-release formulation may prove
beneficial.
[0325] Eight-hundred (800) .mu.g of ketorolac acid
(.diamond-solid.) contained in a 20:80 ketorolac acid:BB mixture
and 700 .mu.g of ketorolac acid (.DELTA.) contained in a 20:80
ketorolac acid:TEAC mixture were injected into the anterior chamber
in one eye of each of two 4.0-4.5 kg NZW rabbits. Sampling of the
aqueous humor for ketorolac determination by HPLC was performed,
and the results are shown in FIG. 36.
[0326] Five (5.0) mg (25 .mu.l) of ketorolac acid (.diamond-solid.)
contained in a 20:80 ketorolac acid:BB mixture and 5 mg (25 .mu.l)
of ketorolac acid (.box-solid.) contained in 20:80 ketorolac
acid:TEAC mixture were injected into the vitreous cavity in one eye
each of two 4.0-4.5 kg NZW rabbits. Sampling of the vitreous humor
for ketorolac acid concentration was performed, and the results of
the determination by HPLC are shown in FIG. 37.
[0327] Modifications of the above described modes for carrying out
the invention that are obvious to those of ordinary skill in the
surgical, pharmaceutical, or related arts are intended to be within
the scope of the appended claims
* * * * *