U.S. patent application number 09/898553 was filed with the patent office on 2002-01-31 for compositions and methods for improved delivery of lipid regulating agents.
Invention is credited to Chen, Feng-Jing, Patel, Mahesh V..
Application Number | 20020012680 09/898553 |
Document ID | / |
Family ID | 22981541 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020012680 |
Kind Code |
A1 |
Patel, Mahesh V. ; et
al. |
January 31, 2002 |
Compositions and methods for improved delivery of lipid regulating
agents
Abstract
The present invention relates to triglyceride-free
pharmaceutical compositions for delivery of hydrophobic therapeutic
agents. Compositions of the present invention include a hydrophobic
therapeutic agent and a carrier, where the carrier is formed from a
combination of a hydrophilic surfactant and a hydrophobic
surfactant. Upon dilution with an aqueous solvent, the composition
forms a clear, aqueous dispersion of the surfactants containing the
therapeutic agent. The invention also provides methods of treatment
with hydrophobic therapeutic agents using these compositions.
Inventors: |
Patel, Mahesh V.; (Salt Lake
City, UT) ; Chen, Feng-Jing; (Salt Lake City,
UT) |
Correspondence
Address: |
REED & ASSOCIATES
800 MENLO AVENUE
SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
22981541 |
Appl. No.: |
09/898553 |
Filed: |
July 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09898553 |
Jul 2, 2001 |
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09258654 |
Feb 26, 1999 |
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6294192 |
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 9/4808 20130101;
Y10S 514/94 20130101; A61P 37/06 20180101; A61K 31/57 20130101;
Y10S 514/937 20130101; A61P 15/00 20180101; Y10S 514/938 20130101;
Y10S 514/941 20130101; A61K 9/4858 20130101; A61P 5/26 20180101;
Y10S 514/939 20130101; Y10S 514/975 20130101; B82Y 5/00 20130101;
Y10S 514/963 20130101; A61P 15/06 20180101; Y10S 514/962 20130101;
A61K 38/13 20130101; Y10S 514/942 20130101; A61P 5/24 20180101;
Y10S 514/943 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 009/00 |
Claims
What is claimed and desired to be secured by United States Letters
Patent is:
1. A pharmaceutical composition comprising: (a) a hydrophobic
therapeutic agent; and (b) a carrier, said carrier comprising: (i)
at least one hydrophilic surfactant; and (ii) at least one
hydrophobic surfactant, said hydrophilic and hydrophobic
surfactants being present in amounts such that upon mixing with an
aqueous solution the carrier forms a clear aqueous dispersion of
the hydrophilic and hydrophobic surfactants containing the
hydrophobic therapeutic agent, said composition being substantially
free of triglycerides.
2. The pharmaceutical composition of claim 1, wherein the
hydrophobic surfactant is present in an amount of less than about
200% by weight, relative to the amount of the hydrophilic
surfactant.
3. The pharmaceutical composition of claim 2, wherein the
hydrophobic surfactant is present in an amount of less than about
100% by weight, relative to the amount of the hydrophilic
surfactant.
4. The pharmaceutical composition of claim 3, wherein the
hydrophobic surfactant is present in an amount of less than about
60% by weight, relative to the amount of the hydrophilic
surfactant.
5. The pharmaceutical composition of claim 1, wherein the
hydrophilic surfactant comprises at least one non-ionic hydrophilic
surfactant having an HLB value greater than or equal to about
10.
6. The pharmaceutical composition of claim 1, wherein the
hydrophilic surfactant comprises at least one ionic surfactant.
7. The pharmaceutical composition of claim 5, which further
comprises at least one ionic surfactant.
8. The pharmaceutical composition of claim 5, wherein the non-ionic
surfactant is selected from the group consisting of
alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl
macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene
alkylphenols; polyethylene glycol fatty acids esters; polyethylene
glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty
acid esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglycerol fatty acid esters; polyoxyethylene glycerides;
polyoxyethylene sterols, derivatives, and analogues thereof;
polyoxyethylene vegetable oils; polyoxyethylene hydrogenated
vegetable oils; reaction mixtures of polyols and at least one
member of the group consisting of fatty acids, glycerides,
vegetable oils, hydrogenated vegetable oils, and sterols; sugar
esters, sugar ethers; sucroglycerides; and mixtures thereof.
9. The pharmaceutical composition of claim 5, wherein the non-ionic
hydrophilic surfactant is selected from the group consisting of
polyoxyethylene alkylethers; polyethylene glycol fatty acids
esters; polyethylene glycol glycerol fatty acid esters;
polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglycerol
fatty acid esters; polyoxyethylene glycerides; polyoxyethylene
vegetable oils; polyoxyethylene hydrogenated vegetable oils;
reaction mixtures of polyols and at least one member of the group
consisting of fatty acids, glycerides, vegetable oils, hydrogenated
vegetable oils, and sterols; and mixtures thereof.
10. The pharmaceutical composition of claim 9, wherein the
glyceride is a monoglyceride, diglyceride, triglyceride, or a
mixture thereof.
11. The pharmaceutical composition of claim 9, wherein the reaction
mixture comprises the transesterification products of a polyol and
at least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols.
12. The pharmaceutical composition of claim 9, wherein the polyol
is glycerol, ethylene glycol, polyethylene glycol, sorbitol,
propylene glycol, pentaerythritol or a mixture thereof.
13. The pharmaceutical composition of claim 5, wherein the
hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20
laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15
oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200
oleate, PEG400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40
stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl
trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30
glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,
PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl
laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil,
PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40
hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60
corn oil, PEG-6 caprate/caprylate glycerides, PEG-8
caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30
cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20
trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate,
polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl
ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl
ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,
polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate,
sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol
series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture
thereof.
14. The pharmaceutical composition of claim 5, wherein the
hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35
castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil,
PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10
laurate, PEG-6 caprate/caprylate glycerides, PEG-8
caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20,
polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10
oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose
monolaurate, a poloxamer, or a mixture thereof.
15. The pharmaceutical composition of claim 5, wherein the
hydrophilic surfactant is PEG-35 castor oil, PEG-40 hydrogenated
castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6
caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,
polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate,
PEG-24 cholesterol, a poloxamer, or a mixture thereof.
16. The pharmaceutical composition of claim 6, wherein the ionic
surfactant is selected from the group consisting of alkyl ammonium
salts; bile acids and salts, analogues, and derivatives thereof;
fatty acid derivatives of amino acids, oligopeptides, and
polypeptides; glyceride derivatives of amino acids, oligopeptides,
and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid
esters of mono-,diglycerides; succinylated monoglycerides; citric
acid esters of mono-,diglycerides; alginate salts; propylene glycol
alginate; lecithins and hydrogenated lecithins; lysolecithin and
hydrogenated lysolecithins; lysophospholipids and derivatives
thereof; phospholipids and derivatives thereof; salts of
alkylsulfates; salts of fatty acids; sodium docusate; and mixtures
thereof.
17. The pharmaceutical composition of claim 6, wherein the ionic
surfactant is selected from the group consisting of bile acids and
salts, analogues, and derivatives thereof; lecithins, lysolecithin,
phospholipids, lysophospholipids and derivatives thereof; salts of
alkylsulfates; salts of fatty acids; sodium docusate; acyl
lactylates; mono-,diacetylated tartaric acid esters of
mono-,diglycerides; succinylated monoglycerides; citric acid esters
of mono-,diglycerides; and mixtures thereof.
18. The pharmaceutical composition of claim 6, wherein the ionic
surfactant is selected from the group consisting of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholate, taurocholate, glycocholate, deoxycholate,
taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,
glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,
tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine,
N-methyl taurocholate, caproate, caprylate, caprate, laurate,
myristate, palmitate, oleate, ricinoleate, linoleate, linolenate,
stearate, lauryl sulfate, teracecyl sulfate, docusate, and salts
and mixtures thereof.
19. The pharmaceutical composition of claim 6, wherein the ionic
surfactant is selected from the group consisting of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, lysophosphatidylcholine,
PEG-phosphatidylethanolami- ne, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholate, taurocholate, glycocholate, deoxycholate,
taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate,
caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and
salts and mixtures thereof.
20. The pharmaceutical composition of claim 6, wherein the ionic
surfactant is selected from the group consisting of lecithin,
lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl
lactylate, succinylated monoglycerides, mono/diacetylated tartaric
acid esters of mono/diglycerides, citric acid esters of
mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl
sulfate, docusate, and salts and mixtures thereof.
21. The pharmaceutical composition of claim 1 wherein the
hydrophobic surfactant is a compound or mixture of compounds having
an HLB value less than about 10.
22. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is selected from the group consisting of
alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty
acid esters; acetylated glycerol fatty acid esters; lower alcohol
fatty acids esters; polyethylene glycol fatty acids esters;
polyethylene glycol glycerol fatty acid esters; polypropylene
glycol fatty acid esters; polyoxyethylene glycerides; lactic acid
derivatives of mono/diglycerides; propylene glycol diglycerides;
sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid
esters; polyoxyethylene-polyoxypropyl- ene block copolymers;
transesterified vegetable oils; sterols; sterol derivatives; sugar
esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable
oils; polyoxyethylene hydrogenated vegetable oils; reaction
mixtures of polyols and at least one member of the group consisting
of fatty acids, glycerides, vegetable oils, hydrogenated vegetable
oils, and sterols; and mixtures thereof.
23. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is selected from the group consisting of
fatty acids; lower alcohol fatty acid esters; polyethylene glycol
glycerol fatty acid esters; polypropylene glycol fatty acid esters;
polyoxyethylene glycerides; glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lactic acid derivatives of
mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene
sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block
copolymers; polyoxyethylene vegetable oils; polyoxyethylene
hydrogenated vegetable oils; reaction mixtures of polyols and at
least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols; and mixtures thereof.
24. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is selected from the group consisting of
lower alcohol fatty acids esters; polypropylene glycol fatty acid
esters; propylene glycol fatty acid esters; glycerol fatty acid
esters; acetylated glycerol fatty acid esters; lactic acid
derivatives of mono/diglycerides; sorbitan fatty acid esters;
polyoxyethylene vegetable oils; and mixtures thereof.
25. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is a glycerol fatty acid ester, an
acetylated glycerol fatty acid ester, or a mixture thereof.
26. The pharmaceutical composition of claim 25, wherein the
glycerol fatty acid ester is a monoglyceride, diglyceride, or a
mixture thereof.
27. The pharmaceutical composition of claim 26, wherein the fatty
acid of the glycerol fatty acid ester is a C.sub.6 to C.sub.20
fatty acid or a mixture thereof.
28. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is a reaction mixture of a polyol and at
least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols.
29. The pharmaceutical composition of claim 28, wherein the
reaction mixture is a transesterification product of a polyol and
at least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols.
30. The pharmaceutical composition of claim 28, wherein the polyol
is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol
or a mixture thereof.
31. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is selected from the group consisting of
myristic acid; oleic acid; lauric acid; stearic acid; palmitic
acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4
dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8
dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil;
PEG 6-20 corn oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6
peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel
oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra
esters of vegetable oil and sorbitol; pentaerythrityl di, tetra
stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl
2-4 oleate, stearate, or isostearate; polyglyceryl 4-10
pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate;
polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene
glycol mono- or diesters of a C.sub.6 to C.sub.20 fatty acid;
monoglycerides of a C.sub.6 to C.sub.20 fatty acid; acetylated
monoglycerides of C.sub.6 to C.sub.20 fatty acid; diglycerides of
C.sub.6 to C.sub.20 fatty acids; lactic acid derivatives of
monoglycerides; lactic acid derivatives of diglycerides;
cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan
tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan
monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate;
sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan
sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4
lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose
distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate;
isopropyl palmitate; ethyl linoleate; isopropyl linoleate;
poloxamers; and mixtures thereof.
32. The pharmaceutical composition of claim 21, wherein the
hydrophobic surfactant is selected from the group consisting of
oleic acid; lauric acid; glyceryl monocaprate; glyceryl
monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl
dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl
dioleate; acetylated monoglycerides; propylene glycol oleate;
propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6
dioleate; PEG-6 corn oil; PEG-20 corn oil; PEG-20 almond oil;
sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether;
POE-3 oleyl ether; ethyl oleate; poloxamers; and mixtures
thereof.
33. The pharmaceutical composition of claim 1, wherein the clear
aqueous dispersion has a particle size distribution having an
average particle size of less than about 100 nm.
34. The pharmaceutical composition of claim 33, wherein the clear
aqueous dispersion has a particle size distribution having an
average particle size of less than about 50 nm.
35. The pharmaceutical composition of claim 33, wherein the clear
aqueous dispersion has a particle size distribution having an
average particle size of less than about 20 nm.
36. The pharmaceutical composition of claim 1, wherein the clear
aqueous dispersion has an absorbance of less than about 0.1 at
about 400 nm when the carrier is diluted with an aqueous solution
in an aqueous solution to carrier ratio of 100:1 by weight.
37. The pharmaceutical composition of claim 36, wherein the
absorbance is less than about 0.01.
38. The pharmaceutical composition of claim 1, wherein the
hydrophobic therapeutic agent has an intrinsic water solubility of
less than about 1% by weight at 25.degree. C.
39. The pharmaceutical composition of claim 38, wherein the
intrinsic water solubility is less than about 0.1% by weight at
25.degree. C.
40. The pharmaceutical composition of claim 39, wherein the
intrinsic water solubility is less than about 0.01% by weight at
25.degree. C.
41. The pharmaceutical composition of claim 1, wherein the
therapeutic agent is a drug, a vitamin, a nutritional supplement, a
cosmeceutical, or a mixture thereof.
42. The pharmaceutical composition of claim 43, wherein the
therapeutic agent is a polyfunctional hydrophobic drug, a
lipophilic drug, a pharmaceutically acceptable salt, isomer or
derivative thereof, or a mixture thereof.
43. The pharmaceutical composition of claim 41, wherein the
therapeutic agent is selected from the group consisting of
analgesics, anti-inflammatory agents, anthelmintics,
anti-arrhythmic agents, anti-bacterial agents, anti-viral agents,
anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics,
anti-fungal agents, anti-gout agents, anti-hypertensive agents,
anti-malarials, anti-migraine agents, anti-muscarinic agents,
anti-neoplastic agents, erectile dysfunction improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-Blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine H,-receptor antagonists, keratolytics, lipid regulating
agents, anti-anginal agents, nutritional agents, opioid analgesics,
sex hormones, stimulants, muscle relaxants, anti-osteoporosis
agents, anti-obesity agents, cognition enhancers, anti-urinary
incontinence agents, nutritional oils, anti-benign prostate
hypertrophy agents, essential fatty acids, non-essential fatty
acids, and mixtures thereof.
44. The pharmaceutical composition of claim 41, wherein the
therapeutic agent is tramadol, celecoxib, etodolac, refocoxib,
oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,
flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac,
albendazole, ivermectin, amiodarone, zileuton, zafirlukast,
albuterol, montelukast, azithromycin, ciprofloxacin,
clarithromycin, dirithromycin, rifabutine, rifapentine,
trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,
efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine,
clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine,
bupropion, clomipramine, miglitol, repaglinide, glymepride,
pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide,
glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate,
lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine,
itraconazole, flucanazole, miconazole, ketoconazole, metronidazole,
griseofulvin, nitrofurantoin, spironolactone, lisinopril,
benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan,
eposartan, valsartan, candesartan, minoxidil, terzosin,
halofantrine, mefloquine, dihydroergotamine, ergotamine,
frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan,
rizatriptan, aminogluthemide, busulphan, cyclosporine,
mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel,
tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,
nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone,
metronidazole, furazolidone, paricalcitol, benzonatate, midazolam,
zolpidem, gabapentin, zopiclone, digoxin, beclomethsone,
budesonide, betamethasone, prednisolone, cisapride, cimetidine,
loperamide, famotidine, lanosprazole, rabeprazole, nizatidine,
omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine,
clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene,
calciprotiene, calcitriol, targretin, ergocalciferol,
cholecalciferol, isotreinoin, tretinoin, calcifediol, fenofibrate,
probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin,
fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide
dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D,
vitamin E, vitamin K, an essential fatty acid source, codeine,
fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol,
dihydro epiandrosterone, medroxyprogesterone, progesterone,
rimexolone, megesterol acetate, osteradiol, finasteride,
mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen,
tacrine, donepezil, raloxifene, vertoporfin, sibutramine,
pyridostigmine, a pharmaceutically acceptable salt, isomer, or
derivative thereof, or a mixture thereof.
45. The pharmaceutical composition of claim 1, wherein the
hydrophobic therapeutic agent is selected from the group consisting
of tramadol, celecoxib, etodolac, refocoxib, oxaprozin,
leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen,
tetrahydrocannabinol, capsaicin, ketorolac, albendazole,
ivermectin, amiodarone, zileuton, zafirlukast, albuterol,
montelukast, azithromycin, ciprofloxacin, clarithromycin,
dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen,
ritanovir, saquinavir, nelfinavir, efavirenz, miglitol,
repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone,
glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion,
tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B,
butenafine, terbinafine, itraconazole, flucanazole, miconazole,
ketoconazole, metronidazole, griseofulvin, nitrofurantoin,
spironolactone, halofantrine, mefloquine, dihydroergotamine,
ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan,
naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine,
mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel,
tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,
nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone,
metronidazole, furzolidone, paricalcitol, benzonatate, midazolam,
zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine,
loperamide, famotidine, lanosprazole, rabeprazole, nizatidine,
omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine,
clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene,
calciprotiene, calcitriol, targretin, ergocalciferol,
cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate,
probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin,
fluvastatin, atorvastatin, tizanidine, dantrolene, carotenes,
dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K,
essential fatty acid sources, codeine, fentanyl, methdone,
nalbuphine, pentazocine, clomiphene, danazol, dihydro
epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone,
megesterol acetate, osteradiol, finasteride, mefepristone,
amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine,
donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine,
pharmaceutically acceptable salts, isomers and derivatives thereof,
and mixtures thereof.
46. The pharmaceutical composition of claim 1, wherein the
therapeutic agent is selected from the group consisting of
tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide,
diclofenac, nabumetone, ibuprofen, flurbiprofen,
tetrahydrocannabinol, capsaicin, ketorolac, ivermectin, amiodarone,
zileuton, zafirlukast, albuterol, montelukast, rifabutine,
rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir,
nelfinavir, efavirenz, miglitol, repaglinide, glymepride,
pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide,
glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate,
lamotrigine, vigabatrin, terbenafine, itraconazole, flucanazole,
miconazole, ketoconazole, metronidazole, nitrofurantoin,
dihydroergotamine, ergotamine, frovatriptan, pizofetin,
zolmitriptan, pseudo-ephedrine, naratiptan, rizatriptan,
aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan,
etoposide, teniposide, paclitaxel, tacrolimus, sirolimus,
tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide,
toremifene, atovaquone, metronidazole, furzolidone, paricalcitol,
benzonatate, cisapride, cimetidine, loperamide, famotidine,
lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine,
cinnarizine, dexchlopheniramine, loratadine, clemastine,
fexofenadine, chlorpheniramine, acutretin, tazarotene,
calciprotiene, calcitriol, targretin, ergocalciferol,
cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate,
probucol, simvastatin, atorvastatin, tizanidine, dantrolene,
carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E,
vitamin K, essential fatty acid sources, danazol, dihydro
epiandrosterone, medroxyprogesterone, progesterone, rimexolone,
megesterol acetate, osteradiol, finasteride, mefepristone,
raloxifene, L-thryroxine, tamsulosin, methoxsalen, pharmaceutically
acceptable salts, isomers and derivative thereof, and mixtures
thereof.
47. The pharmaceutical composition of claim 1, wherein the
hydrophobic therapeutic agent is selected from the group consisting
of sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib,
oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole,
zileuton, zafirlukast, cisapride, fenofibrate, tizanidine,
nizatidine, fexofenadine, loratadine, famotidine, paricalcitol,
atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate,
repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus,
sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone,
rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E,
pharmaceutically acceptable salts, isomers and derivatives thereof,
and mixtures thereof.
48. The pharmaceutical composition of claim 1, wherein the
hydrophobic therapeutic agent is progesterone or cyclosporin.
49. The pharmaceutical composition of claim 1, which further
comprises a solubilizer.
50. The pharmaceutical composition of claim 49, wherein the
solubilizer is selected from the group consisting of alcohols,
polyols, amides, esters, propylene glycol ethers and mixtures
thereof.
51. The pharmaceutical composition of claim 50, wherein the alcohol
or polyol is selected from the group consisting of ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives, and mixtures thereof.
52. The pharmaceutical composition of claim 50, wherein the amide
is selected from the group consisting of 2-pyrrolidone,
2-piperidone, .epsilon.-caprolactam, N-alkylpyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
53. The pharmaceutical composition of claim 50, wherein the ester
is selected from the group consisting of ethyl propionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,
triacetin, propylene glycol monoacetate, propylene glycol
diacetate, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactone and isomers thereof, .beta.-butyrolactone and
isomers thereof, and mixtures thereof.
54. The pharmaceutical composition of claim 49, wherein the
solubilizer is selected from the group consisting of ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediol and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins,
clodextrins and derivatives thereof, ethyl propionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,
triacetin, propylene glycol diacetate, .epsilon.-caprolactone and
isomers thereof, .delta.-valerolactone and isomers thereof,
.beta.-butyrolactone and isomers thereof, 2-pyrrolidone, 2-2
piperidone, .epsilon.-caprolactam, N-methylpyrrolidone,
N-ethylpyrrolidone, N-hydroxyethyl pyrrolidone, N-octylpyrrolidone,
N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone,
glycofurol, methoxy PEG, and mixtures thereof.
55. The pharmaceutical composition of claim 49, wherein the
solubilizer is selected from the group consisting of ethanol,
isopropanol, benzyl alcohol, ethylene glycol, propylene glycol,
1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol,
transcutol, dimethyl isosorbide, polyethylene glycol,
polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose,
ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether
derivatives of cyclodextrins, ethyl propionate, tributylcitrate,
triethylcitrate, ethyl oleate, ethyl caprylate, triacetin,
.beta.-butyrolactone and isomers thereof, 2-pyrrolidone,
N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone,
N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide,
polyvinylpyrrolidone, and mixtures thereof.
56. The pharmaceutical composition of claim 49, wherein the
solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl
caprylate, dimethylacetamide, N-methylpyrrolidone,
N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene
glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl
isosorbide, or a mixture thereof.
57. The pharmaceutical composition of claim 49, wherein the
solubilizer is triacetin, ethanol, polyethylene glycol 400,
glycofurol, propylene glycol or a mixture thereof.
58. The pharmaceutical composition of claim 49, wherein the
solubilizer is present in the composition in an amount of about
400% or less by weight, based on the total weight of the
surfactants.
59. The pharmaceutical composition of claim 58, wherein the
solubilizer is present in the composition in an amount of about
200% or less by weight, based on the total weight of the
surfactants.
60. The pharmaceutical composition of claim 59, wherein the
solubilizer is present in the composition in an amount of about
100% or less by weight, based on the total weight of the
surfactants.
62. The pharmaceutical composition of claim 60, wherein the
solubilizer is present in the composition in an amount of about 50%
or less by weight, based on the total weight of the
surfactants.
62. The pharmaceutical composition of claim 61, wherein the
solubilizer is present in the composition in an amount about 25% or
less by weight, based on the total weight of the surfactants.
63. The pharmaceutical composition of claim 1, which further
comprises an antioxidant, a preservative, a chelating agent, a
viscomodulator, a tonicifier, a flavorant, a colorant, an odorant,
an opacifier, a suspending agent, a binder, or a mixture
thereof.
64. The pharmaceutical composition of claim 1 in the form of a
preconcentrate, a diluted preconcentrate, a semi-solid dispersion,
a solid dispersion, or a sprayable solution.
65. A dosage form comprising a capsule filled with the
pharmaceutical composition of claim 1.
66. A dosage form comprising a multiparticulate carrier coated with
the pharmaceutical composition of claim 1.
67. A dosage form comprising the pharmaceutical composition of
claim 1 formulated as a solution, a cream, a lotion, an ointment, a
suppository, a spray, an aerosol, a paste or a gel.
68. The dosage form of claim 65, wherein the capsule is a hard
gelatin capsule, a soft gelatin capsule, a starch capsule or an
enteric coated capsule.
69. The pharmaceutical composition of claim 1, which further
comprises water or an aqueous buffer.
70. The pharmaceutical composition of claim 1, which further
comprises an additional amount of a hydrophobic therapeutic agent,
said additional amount not solubilized in the carrier.
71. A pharmaceutical composition comprising: (a) at least one
hydrophilic surfactant; (b) at least one hydrophobic surfactant;
and (c) a hydrophobic therapeutic agent, said pharmaceutical
composition being in the form of a clear, aqueous dispersion which
is substantially free of triglycerides.
72. The pharmaceutical composition of claim 71, wherein the
hydrophobic surfactant is present in an amount of less than about
200% by weight, relative to the amount of the hydrophilic
surfactant.
73. The pharmaceutical composition of claim 72, wherein the
hydrophobic surfactant is present in an amount of less than about
100% by weight, relative to the amount of the hydrophilic
surfactant.
74. The pharmaceutical composition of claim 73, wherein the
hydrophobic surfactant is present in an amount of less than about
60% by weight, relative to the amount of the hydrophilic
surfactant.
75. The pharmaceutical composition of claim 71, wherein the
hydrophilic surfactant comprises at least one non-ionic hydrophilic
surfactant having an HLB value greater than or equal to about
10.
76. The pharmaceutical composition of claim 71, wherein the
hydrophilic surfactant comprises at least one ionic surfactant.
77. The pharmaceutical composition of claim 75, which further
comprises at least one ionic surfactant.
78. The pharmaceutical composition of claim 75, wherein the
non-ionic surfactant is selected from the group consisting of
alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl
macrogolglycerides; polyoxyethylene alkylethers; polyoxyethylene
alkylphenols; polyethylene glycol fatty acids esters; polyethylene
glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty
acid esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglycerol fatty acid esters; polyoxyethylene glycerides;
polyoxyethylene sterols, derivatives, and analogues thereof;
polyoxyethylene vegetable oils; polyoxyethylene hydrogenated
vegetable oils; reaction mixtures of polyols and at least one
member of the group consisting of fatty acids, glycerides,
vegetable oils, hydrogenated vegetable oils, and sterols; sugar
esters, sugar ethers; sucroglycerides; and mixtures thereof.
79. The pharmaceutical composition of claim 75, wherein the
non-ionic hydrophilic surfactant is selected from the group
consisting of polyoxyethylene alkylethers; polyethylene glycol
fatty acids esters; polyethylene glycol glycerol fatty acid esters;
polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglycerol
fatty acid esters; polyoxyethylene glycerides; polyoxyethylene
vegetable oils; polyoxyethylene hydrogenated vegetable oils;
reaction mixtures of polyols and at least one member of the group
consisting of fatty acids, glycerides, vegetable oils, hydrogenated
vegetable oils, and sterols; and mixtures thereof.
80. The pharmaceutical composition of claim 79, wherein the
glyceride is a monoglyceride, diglyceride, triglyceride, or a
mixture thereof.
81. The pharmaceutical composition of claim 79, wherein the
reaction mixture comprises the transesterification products of a
polyol and at least one member of the group consisting of fatty
acids, glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols.
82. The pharmaceutical composition of claim 79, wherein the polyol
is glycerol, ethylene glycol, polyethylene glycol, sorbitol,
propylene glycol, pentaerythritol or a mixture thereof.
83. The pharmaceutical composition of claim 75, wherein the
hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20
laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15
oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200
oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40
stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl
trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30
glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,
PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl
laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil,
PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG40
hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60
corn oil, PEG-6 caprate/caprylate glycerides, PEG-8
caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30
cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20
trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate,
polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl
ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl
ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,
polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate,
sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol
series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture
thereof.
84. The pharmaceutical composition of claim 75, wherein the
hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35
castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil,
PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10
laurate, PEG-6 caprate/caprylate glycerides, PEG-8
caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20,
polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10
oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose
monolaurate, a poloxamer, or a mixture thereof.
85. The pharmaceutical composition of claim 75, wherein the
hydrophilic surfactant is PEG-35 castor oil, PEG40 hydrogenated
castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6
caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,
polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate,
PEG-24 cholesterol, a poloxamer, or a mixture thereof.
86. The pharmaceutical composition of claim 76, wherein the ionic
surfactant is selected from the group consisting of alkyl ammonium
salts; bile acids and salts, analogues, and derivatives thereof;
fatty acid derivatives of amino acids, oligopeptides, and
polypeptides; glyceride derivatives of amino acids, oligopeptides,
and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid
esters of mono-,diglycerides; succinylated monoglycerides; citric
acid esters of mono-,diglycerides; alginate salts; propylene glycol
alginate; lecithins and hydrogenated lecithins; lysolecithin and
hydrogenated lysolecithins; lysophospholipids and derivatives
thereof; phospholipids and derivatives thereof; salts of
alkylsulfates; salts of fatty acids; sodium docusate; and mixtures
thereof.
87. The pharmaceutical composition of claim 76, wherein the ionic
surfactant is selected from the group consisting of bile acids and
salts, analogues, and derivatives thereof; lecithins, lysolecithin,
phospholipids, lysophospholipids and derivatives thereof; salts of
alkylsulfates; salts of fatty acids; sodium docusate; acyl
lactylates; mono-,diacetylated tartaric acid esters of
mono-,diglycerides; succinylated monoglycerides; citric acid esters
of mono-,diglycerides; and mixtures thereof.
88. The pharmaceutical composition of claim 76, wherein the ionic
surfactant is selected from the group consisting of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholate, taurocholate, glycocholate, deoxycholate,
taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,
glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,
tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine,
N-methyl taurocholate, caproate, caprylate, caprate, laurate,
myristate, palmitate, oleate, ricinoleate, linoleate, linolenate,
stearate, lauryl sulfate, teracecyl sulfate, docusate, and salts
and mixtures thereof.
89. The pharmaceutical composition of claim 76, wherein the ionic
surfactant is selected from the group consisting of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, lysophosphatidylcholine,
PEG-phosphatidylethanolami- ne, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholate, taurocholate, glycocholate, deoxycholate,
taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate,
caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and
salts and mixtures thereof.
90. The pharmaceutical composition of claim 76, wherein the ionic
surfactant is selected from the group consisting of lecithin,
lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl
lactylate, succinylated monoglycerides, mono/diacetylated tartaric
acid esters of mono/diglycerides, citric acid esters of
mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl
sulfate, docusate, and salts and mixtures thereof.
91. The pharmaceutical composition of claim 71 wherein the
hydrophobic surfactant is a compound or mixture of compounds having
an HLB value less than about 10.
92. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is selected from the group consisting of
alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty
acid esters; acetylated glycerol fatty acid esters; lower alcohol
fatty acids esters; polyethylene glycol fatty acids esters;
polyethylene glycol glycerol fatty acid esters; polypropylene
glycol fatty acid esters; polyoxyethylene glycerides; lactic acid
derivatives of mono/diglycerides; propylene glycol diglycerides;
sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid
esters; polyoxyethylene-polyoxypropyl- ene block copolymers;
transesterified vegetable oils; sterols; sterol derivatives; sugar
esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable
oils; polyoxyethylene hydrogenated vegetable oils; reaction
mixtures of polyols and at least one member of the group consisting
of fatty acids, glycerides, vegetable oils, hydrogenated vegetable
oils, and sterols; and mixtures thereof.
93. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is selected from the group consisting of
fatty acids; lower alcohol fatty acid esters; polyethylene glycol
glycerol fatty acid esters; polypropylene glycol fatty acid esters;
polyoxyethylene glycerides; glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lactic acid derivatives of
mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene
sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block
copolymers; polyoxyethylene vegetable oils; polyoxyethylene
hydrogenated vegetable oils; reaction mixtures of polyols and at
least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols; and mixtures thereof.
94. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is selected from the group consisting of
lower alcohol fatty acids esters; polypropylene glycol fatty acid
esters; propylene glycol fatty acid esters; glycerol fatty acid
esters; acetylated glycerol fatty acid esters; lactic acid
derivatives of mono/diglycerides; sorbitan fatty acid esters;
polyoxyethylene vegetable oils; and mixtures thereof.
95. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is a glycerol fatty acid ester, an
acetylated glycerol fatty acid ester, or a mixture thereof.
96. The pharmaceutical composition of claim 95, wherein the
glycerol fatty acid ester is a monoglyceride, diglyceride, or a
mixture thereof.
97. The pharmaceutical composition of claim 96, wherein the fatty
acid of the glycerol fatty acid ester is a C.sub.6 to C.sub.20
fatty acid or a mixture thereof.
98. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is a reaction mixture of a polyol and at
least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols.
99. The pharmaceutical composition of claim 98, wherein the
reaction mixture is a transesterification product of a polyol and
at least one member of the group consisting of fatty acids,
glycerides, vegetable oils, hydrogenated vegetable oils, and
sterols.
100. The pharmaceutical composition of claim 98, wherein the polyol
is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol
or a mixture thereof.
101. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is selected from the group consisting of
myristic acid; oleic acid; lauric acid; stearic acid; palmitic
acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4
dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8
dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil;
PEG 6-20 corn oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6
peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel
oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra
esters of vegetable oil and sorbitol; pentaerythrityl di, tetra
stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl
2-4 oleate, stearate, or isostearate; polyglyceryl 4-10
pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate;
polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene
glycol mono- or diesters of a C.sub.6 to C.sub.20 fatty acid;
monoglycerides of a C.sub.6 to C.sub.20 fatty acid; acetylated
monoglycerides of C.sub.6 to C.sub.20 fatty acid; diglycerides of
C.sub.6 to C.sub.20 fatty acids; lactic acid derivatives of
monoglycerides; lactic acid derivatives of diglycerides;
cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan
tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan
monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate;
sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan
sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4
lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose
distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate;
isopropyl palmitate; ethyl linoleate; isopropyl linoleate;
poloxamers; and mixtures thereof.
102. The pharmaceutical composition of claim 91, wherein the
hydrophobic surfactant is selected from the group consisting of
oleic acid; lauric acid; glyceryl monocaprate; glyceryl
monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl
dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl
dioleate; acetylated monoglycerides; propylene glycol oleate;
propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6
dioleate; PEG-6 corn oil; PEG-20 corn oil; PEG-20 almond oil;
sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether;
POE-3 oleyl ether; ethyl oleate; poloxamers; and mixtures
thereof.
103. The pharmaceutical composition of claim 71, wherein the clear
aqueous dispersion has a particle size distribution having an
average particle size of less than about 100 nm.
104. The pharmaceutical composition of claim 103, wherein the clear
aqueous dispersion has a particle size distribution having an
average particle size of less than about 50 nm.
105. The pharmaceutical composition of claim 103, wherein the clear
aqueous dispersion has a particle size distribution having an
average particle size of less than about 20 nm.
106. The pharmaceutical composition of claim 71, wherein the clear
aqueous dispersion has an absorbance of less than about 0.1 at 400
nm when the ratio of the weight of water to the total weight of the
hydrophilic surfactant, the hydrophobic surfactant and the
therapeutic agent is 100:1.
107. The pharmaceutical composition of claim 106, wherein the
absorbance is less than about 0.01.
108. The pharmaceutical composition of claim 71, wherein the
hydrophobic therapeutic agent has an intrinsic water solubility of
less than about 1% by weight at 25.degree. C.
109. The pharmaceutical composition of claim 108, wherein the
intrinsic water solubility is less than about 0.1% by weight at
25.degree. C.
110. The pharmaceutical composition of claim 109, wherein the
intrinsic water solubility is less than about 0.01% by weight at
25.degree. C.
111. The pharmaceutical composition of claim 71, wherein the
therapeutic agent is a drug, a vitamin, a nutritional supplement, a
cosmeceutical, or a mixture thereof.
112. The pharmaceutical composition of claim 111, wherein the
therapeutic agent is a polyfunctional hydrophobic drug, a
lipophilic drug, a pharmaceutically acceptable salt, isomer or
derivative thereof, or a mixture thereof.
113. The pharmaceutical composition of claim 111, wherein the
therapeutic agent is selected from the group consisting of
analgesics, anti-inflammatory agents, anthelmintics,
anti-arrhythmic agents, anti-bacterial agents, anti-viral agents,
anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics,
anti-fungal agents, anti-gout agents, anti-hypertensive agents,
anti-malarials, anti-migraine agents, anti-muscarinic agents,
anti-neoplastic agents, erectile dysfunction improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-Blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine H,-receptor antagonists, keratolytics, lipid regulating
agents, anti-anginal agents, nutritional agents, opioid analgesics,
sex hormones, stimulants, muscle relaxants, anti-osteoporosis
agents, anti-obesity agents, cognition enhancers, anti-urinary
incontinence agents, nutritional oils, anti-benign prostate
hypertrophy agents, essential fatty acids, non-essential fatty
acids, and mixtures thereof.
114. The pharmaceutical composition of claim 111, wherein the
therapeutic agent is tramadol, celecoxib, etodolac, refocoxib,
oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,
flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac,
albendazole, ivermectin, amiodarone, zileuton, zafirlukast,
albuterol, montelukast, azithromycin, ciprofloxacin,
clarithromycin, dirithromycin, rifabutine, rifapentine,
trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,
efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine,
clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine,
bupropion, clomipramine, miglitol, repaglinide, glymepride,
pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide,
glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate,
lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine,
itraconazole, flucanazole, miconazole, ketoconazole, metronidazole,
griseofulvin, nitrofurantoin, spironolactone, lisinopril,
benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan,
eposartan, valsartan, candesartan, minoxidil, terzosin,
halofantrine, mefloquine, dihydroergotamine, ergotamine,
frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan,
rizatriptan, aminogluthemide, busulphan, cyclosporine,
mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel,
tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,
nilutanide, bicalutanide, ephedrine, toremifene, atovaquone,
metronidazole, furazolidone, paricalcitol, benzonatate, midazolam,
zolpidem, gabapentin, zopiclone, digoxin, beclomethsone,
budesonide, betamethasone, prednisolone, cisapride, cimetidine,
loperamide, famotidine, lanosprazole, rabeprazole, nizatidine,
omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine,
clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene,
calciprotiene, calcitriol, targretin, ergocalciferol,
cholecalciferol, isotreinoin, tretinoin, calcifediol, fenofibrate,
probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin,
fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide
dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D,
vitamin E, vitamin K, an essential fatty acid source, codeine,
fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol,
dihydro epiandrosterone, medroxyprogesterone, progesterone,
rimexolone, megesterol acetate, osteradiol, finasteride,
mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen,
tacrine, donepezil, raloxifene, vertoporfin, sibutramine,
pyridostigmine, a pharmaceutically acceptable salt, isomer, or
derivative thereof, or a mixture thereof.
115. The pharmaceutical composition of claim 71, wherein the
hydrophobic therapeutic agent is selected from the group consisting
of tramadol, celecoxib, etodolac, refocoxib, oxaprozin,
leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen,
tetrahydrocannabinol, capsaicin, ketorolac, albendazole,
ivermectin, amiodarone, zileuton, zafirlukast, albuterol,
montelukast, azithromycin, ciprofloxacin, clarithromycin,
dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen,
ritanovir, saquinavir, nelfinavir, efavirenz, miglitol,
repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone,
glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion,
tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B,
butenafine, terbinafine, itraconazole, flucanazole, miconazole,
ketoconazole, metronidazole, griseofulvin, nitrofurantoin,
spironolactone, halofantrine, mefloquine, dihydroergotamine,
ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan,
naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine,
mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel,
tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,
nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone,
metronidazole, furzolidone, paricalcitol, benzonatate, midazolam,
zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine,
loperamide, famotidine, lanosprazole, rabeprazole, nizatidine,
omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine,
clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene,
calciprotiene, calcitriol, targretin, ergocalciferol,
cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate,
probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin,
fluvastatin, atorvastatin, tizanidine, dantrolene, carotenes,
dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K,
essential fatty acid sources, codeine, fentanyl, methdone,
nalbuphine, pentazocine, clomiphene, danazol, dihydro
epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone,
megesterol acetate, osteradiol, finasteride, mefepristone,
amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine,
donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine,
pharmaceutically acceptable salts, isomers and derivatives thereof,
and mixtures thereof.
116. The pharmaceutical composition of claim 71, wherein the
therapeutic agent is selected from the group consisting of
tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide,
diclofenac, nabumetone, ibuprofen, flurbiprofen,
tetrahydrocannabinol, capsaicin, ketorolac, ivermectin, amiodarone,
zileuton, zafirlukast, albuterol, montelukast, rifabutine,
rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir,
nelfinavir, efavirenz, miglitol, repaglinide, glymepride,
pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide,
glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate,
lamotrigine, vigabatrin, terbenafine, itraconazole, flucanazole,
miconazole, ketoconazole, metronidazole, nitrofurantoin,
dihydroergotamine, ergotamine, frovatriptan, pizofetin,
zolmitriptan, pseudo-ephedrine, naratiptan, rizatriptan,
aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan,
etoposide, teniposide, paclitaxel, tacrolimus, sirolimus,
tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide,
toremifene, atovaquone, metronidazole, furzolidone, paricalcitol,
benzonatate, cisapride, cimetidine, loperamide, famotidine,
lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine,
cinnarizine, dexchlopheniramine, loratadine, clemastine,
fexofenadine, chlorpheniramine, acutretin, tazarotene,
calciprotiene, calcitriol, targretin, ergocalciferol,
cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate,
probucol, simvastatin, atorvastatin, tizanidine, dantrolene,
carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E,
vitamin K, essential fatty acid sources, danazol, dihydro
epiandrosterone, medroxyprogesterone, progesterone, rimexolone,
megesterol acetate, osteradiol, finasteride, mefepristone,
raloxifene, L-thryroxine, tamsulosin, methoxsalen, pharmaceutically
acceptable salts, isomers and derivative thereof, and mixtures
thereof.
117. The pharmaceutical composition of claim 71, wherein the
hydrophobic therapeutic agent is selected from the group consisting
of sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib,
oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole,
zileuton, zafirlukast, cisapride, fenofibrate, tizanidine,
nizatidine, fexofenadine, loratadine, famotidine, paricalcitol,
atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate,
repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus,
sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone,
rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E,
pharmaceutically acceptable salts, isomers and derivatives thereof,
and mixtures thereof.
118. The pharmaceutical composition of claim 71, wherein the
hydrophobic therapeutic agent is progesterone or cyclosporin.
119. The pharmaceutical composition of claim 71, which further
comprises a solubilizer.
120. The pharmaceutical composition of claim 119, wherein the
solubilizer is selected from the group consisting of alcohols,
polyols, amides, esters, polyethylene glycol ethers and mixtures
thereof.
121. The pharmaceutical composition of claim 120, wherein the
alcohol or polyol is selected from the group consisting of ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives, and mixtures thereof.
122. The pharmaceutical composition of claim 120, wherein the amide
is selected from the group consisting of 2-pyrrolidone,
2-piperidone, .epsilon.-caprolactam, N-alkylpyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
123. The pharmaceutical composition of claim 120, wherein the ester
is selected from the group consisting of ethyl propionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,
triacetin, propylene glycol monoacetate, propylene glycol
diacetate, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactone and isomers thereof, .beta.-butyrolactone and
isomers thereof, and mixtures thereof.
124. The pharmaceutical composition of claim 119, wherein the
solubilizer is selected from the group consisting of ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediol and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins,
clodextrins and derivatives thereof, ethyl propionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,
triacetin, propylene glycol diacetate, .epsilon.-caprolactone and
isomers thereof, .delta.-valerolactone and isomers thereof,
.beta.-butyrolactone and isomers thereof, 2-pyrrolidone,
2-piperidone, .epsilon.-caprolactam, N-methylpyrrolidone,
N-ethylpyrrolidone, N-hydroxyethyl pyrrolidone, N-octylpyrrolidone,
N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone,
glycofurol, methoxy PEG, and mixtures thereof.
125. The pharmaceutical composition of claim 119, wherein the
solubilizer is selected from the group consisting of ethanol,
isopropanol, benzyl alcohol, ethylene glycol, propylene glycol,
1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol,
transcutol, dimethyl isosorbide, polyethylene glycol,
polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose,
ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether
derivatives of cyclodextrins, ethyl propionate, tributylcitrate,
triethylcitrate, ethyl oleate, ethyl caprylate, triacetin,
.beta.-butyrolactone and isomers thereof, 2-pyrrolidone,
N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone,
N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide,
polyvinylpyrrolidone, and mixtures thereof.
126. The pharmaceutical composition of claim 119, wherein the
solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl
caprylate, dimethylacetamide, N-methylpyrrolidone,
N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene
glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl
isosorbide, or a mixture thereof.
127. The pharmaceutical composition of claim 119, wherein the
solubilizer is triacetin, ethanol, polyethylene glycol 400,
glycofurol, propylene glycol or a mixture thereof.
128. The pharmaceutical composition of claim 119, wherein the
solubilizer is present in the composition in an amount of about
400% or less by weight, based on the total weight of the
surfactants.
129. The pharmaceutical composition of claim 128, wherein the
solubilizer is present in the composition in an amount of about
200% or less by weight, based on the total weight of the
surfactants.
130. The pharmaceutical composition of claim 129, wherein the
solubilizer is present in the composition in an amount of about
100% or less by weight, based on the total weight of the
surfactants.
131. The pharmaceutical composition of claim 130, wherein the
solubilizer is present in the composition in an amount of about 50%
or less by weight, based on the total weight of the
surfactants.
132. The pharmaceutical composition of claim 131, wherein the
solubilizer is present in the composition in an amount about 25% or
less by weight, based on the total weight of the surfactants.
133. The pharmaceutical composition of claim 71, which further
comprises an antioxidant, a preservative, a chelating agent, a
viscomodulator, a tonicifier, a flavorant, a colorant, an odorant,
an opacifier or a mixture thereof.
134. The pharmaceutical composition of claim 71, which further
comprises an additional amount of a hydrophobic therapeutic agent,
said additional amount not solubilized in the carrier.
135. A pharmaceutical composition comprising: (a) a carrier, said
carrier comprising: (i) at least one hydrophilic surfactant; and
(ii) at least one hydrophobic surfactant, said hydrophilic and
hydrophobic surfactants being present in amounts such that upon
mixing with an aqueous solution the carrier forms a clear aqueous
dispersion of the hydrophilic and hydrophobic surfactants; (b) a
first amount of a hydrophobic therapeutic agent, said first amount
being solubilized in the carrier; and (c) a second amount of a
hydrophobic therapeutic agent, said second amount not solubilized
in the clear aqueous dispersion, said composition being
substantially free of triglycerides.
136. A method of treating an animal with a hydrophobic therapeutic
agent, the method comprising: providing a dosage form of a
pharmaceutical composition comprising: a hydrophobic therapeutic
agent; and a carrier, said carrier comprising: at least one
hydrophilic surfactant; and at least one hydrophobic surfactant,
said hydrophilic and hydrophobic surfactants being present in
amounts such that upon mixing with an aqueous solution the carrier
forms a clear aqueous dispersion of the hydrophilic and hydrophobic
surfactants containing the hydrophobic therapeutic agent, said
composition being substantially free of triglycerides; and
administering said dosage form to said animal.
137. The method of claim 136, wherein the dosage form is a capsule,
a cream, a lotion, an ointment, a suppository, a paste or a
gel.
138. The method of claim 136, wherein the dosage form is
administered by an oral, parenteral, topical, transdermal, ocular,
pulmonary, vaginal, rectal or transmucosal route.
139. The method of claim 136, wherein the animal is a mammal.
140. The method of claim 139, wherein the mammal is a human.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to drug delivery systems, and
in particular to pharmaceutical compositions for the improved
delivery of hydrophobic compounds.
BACKGROUND
[0002] Hydrophobic therapeutic agents, i.e., therapeutic compounds
having poor solubility in aqueous solution, present difficult
problems in formulating such compounds for effective administration
to patients. A well-designed formulation must, at a minimum, be
capable of presenting a therapeutically effective amount of the
hydrophobic compound to the desired absorption site, in an
absorbable form. Even this minimal functionality is difficult to
achieve when delivery of the hydrophobic therapeutic agent requires
interaction with aqueous physiological environments, such as
gastric fluids and intestinal fluids. Pharmaceutical compositions
for delivery of such hydrophobic therapeutic agents must carry the
hydrophobic compound through the aqueous environment, while
maintaining the hydrophobic compound in an absorbable form, and
avoiding the use of physiologically harmful solvents or
excipients.
[0003] A number of approaches to formulating hydrophobic
therapeutic agents for oral or parenteral delivery are known. One
well-known approach uses surfactant micelles to solubilize and
transport the therapeutic agent. Micelles are agglomerates of
colloidal dimensions formed by amphiphilic compounds under certain
conditions. Micelles, and pharmaceutical compositions containing
micelles, have been extensively studied and are described in detail
in the literature; see, e.g., Remington's Pharmaceutical Sciences,
17.sup.th ed. (1985), the disclosure of which is incorporated
herein in its entirety. In aqueous solution, micelles can
incorporate hydrophobic therapeutic agents in the hydrocarbon core
of the micelle, or entangled at various positions within the
micelle walls. Although micellar formulations can solubilize a
variety of hydrophobic therapeutic agents, the loading capacity of
conventional micelle formulations is limited by the solubility of
the therapeutic agent in the micelle surfactant. For many
hydrophobic therapeutic agents, such solubility is too low to offer
formulations that can deliver therapeutically effective doses.
[0004] Another conventional approach takes advantage of the
increased solubility of hydrophobic therapeutic agents in oils
(triglycerides). Hydrophobic therapeutic agents, while poorly
soluble in aqueous solution, could be sufficiently lipophilic that
therapeutically effective concentrations of the therapeutic agents
can be prepared in triglyceride-based solvents. Thus, one
conventional approach is to solubilize a hydrophobic therapeutic
agent in a bioacceptable triglyceride solvent, such as a digestible
vegetable oil, and disperse this oil phase in an aqueous solution.
The dispersion may be stabilized by emulsifying agents and provided
in emulsion form. Alternatively, the therapeutic agent can be
provided in a water-free formulation, with an aqueous dispersion
being formed in the in vivo gastrointestinal environment. The
properties of these oil-based formulations are determined by such
factors as the size of the triglyceride/therapeutic agent colloidal
particles and the presence or absence of surfactant additives.
[0005] In simplest form, a triglyceride-containing formulation
suitable for delivering hydrophobic therapeutic agents through an
aqueous environment is an oil-in-water emulsion. Such emulsions
contain the hydrophobic therapeutic agent solubilized in an oil
phase which is dispersed in an aqueous environment with the aid of
a surfactant. The surfactant may be present in the oil-based
formulation itself, or may be a compound provided in the
gastrointestinal system, such as bile salts, which are known to be
in vivo emulsifying agents. The colloidal oil particles sizes are
relatively large, ranging from several hundred nanometers to
several microns in diameter, in a broad particle size distribution.
Since the particle sizes are on the order of or greater than the
wavelength range of visible light, such emulsions, when prepared in
an emulsion dosage form, are visibly "cloudy" or "milky" to the
naked eye.
[0006] Although triglyceride-based pharmaceutical compositions are
useful in solubilizing and delivering some hydrophobic therapeutic
agents, such compositions are subject to a number of significant
limitations and disadvantages. Emulsions are thermodynamically
unstable, and colloidal emulsion particles will spontaneously
agglomerate, eventually leading to complete phase separation. The
tendency to agglomerate and phase separate presents problems of
storage and handling, and increases the likelihood that
pharmaceutical emulsions initially properly prepared will be in a
less optimal, less effective, and poorly-characterized state upon
ultimate administration to a patient. Uncharacterized degradation
is particularly disadvantageous, since increased particle size
slows the rate of transport of the colloidal particle and digestion
of the oil component, and hence the rate and extent of absorption
of the therapeutic agent. These problems lead to
poorly-characterized and potentially harmful changes in the
effective dosage received by the patient. Moreover, changes in
colloidal emulsion particle size are also believed to render
absorption more sensitive to and dependent upon conditions in the
gastrointestinal tract, such as pH, enzyme activity, bile
components, and stomach contents. Such uncertainty in the rate and
extent of ultimate absorption of the therapeutic agent severely
compromises the medical professional's ability to safely administer
therapeutically effective dosages.
[0007] A further disadvantage of triglyceride-containing
compositions is the dependence of therapeutic agent absorption on
the rate and extent of lipolysis. Although colloidal emulsion
particles can transport hydrophobic therapeutic agents through the
aqueous environment of the gastrointestinal tract, ultimately the
triglyceride must be digested and the therapeutic agent must be
released in order to be absorbed through the intestinal mucosa. The
triglyceride carrier is emulsified by bile salts and hydrolyzed,
primarily by pancreatic lipase. The rate and extent of lipolysis,
however, are dependent upon several factors that are difficult to
adequately control. For example, the amount and rate of bile salt
secretion affect the lipolysis of the triglycerides, and the bile
salt secretion can vary with stomach contents, with metabolic
abnormalities, and with functional changes of the liver, bile
ducts, gall bladder and intestine. Lipase availability in patients
with decreased pancreatic secretory function, such as cystic
fibrosis or chronic pancreatitis, may be undesirably low, resulting
in a slow and incomplete triglyceride lipolysis. The activity of
lipase is pH dependent, with deactivation occurring at about pH 3,
so that the lipolysis rate will vary with stomach contents, and may
be insufficient in patients with gastric acid hyper-secretion.
Moreover, certain surfactants commonly used in the preparation of
pharmaceutical emulsions, such as polyethoxylated castor oils, may
themselves act as inhibitors of lipolysis. Although recent work
suggests that certain surfactant combinations, when used in
combination with digestible oils in emulsion preparations, can
substantially decrease the lipolysis-inhibiting effect of some
common pharmaceutical surfactants (see, U.S. Pat. No. 5,645,856),
such formulations are still subject to the other disadvantages of
pharmaceutical emulsions and triglyceride-based formulations.
[0008] Yet another approach is based on formation of
"microemulsions." Like an emulsion, a microemulsion is a liquid
dispersion of oil in water, stabilized by surfactants. The
microemulsion particles are smaller than those of an emulsion,
rendering the microemulsion essentially optically clear.
Microemulsions, however, are thermodynamically stable, and are not
subject to the particle agglomeration problems of conventional
emulsions. It is generally believed that microemulsions are
micelle-like particles, having an essentially micellar structure
but containing a distinct oil phase in the micelle "core". These
micelle-like particles are often referred to as "swollen micelles",
a term which emphasizes their close relationship to true micellar
particles. Despite their close relationship to micelles,
microemulsions function quite differently in drug delivery systems.
The majority of hydrophobic therapeutic agents are lipophilic, and
have greater solubility in triglycerides than in surfactants. As a
result, the hydrophobic therapeutic agent in a microemulsion-based
delivery system is preferentially solvated in the triglyceride
phase, which is in turn encapsulated in the swollen micelle. The
preferential partitioning in the triglyceride phase results in
higher loading capacities than in comparable micelle-based systems,
but at the cost of introducing into the delivery system the
lipolysis-dependence and other disadvantages associated with the
presence of triglycerides. In addition, the larger size of
microemulsion particles, relative to true micelles, results in a
slower rate of particle diffusion, and thus a slower rate of
therapeutic agent absorption.
[0009] Thus, there is a need for pharmaceutical compositions that
overcome the limitations of conventional micelle formulations, but
without suffering from the disadvantages of triglyceride-containing
formulations.
SUMMARY OF THE INVENTION
[0010] It is therefore an object of the present invention to
provide pharmaceutical compositions capable of solubilizing
therapeutically effective amounts of hydrophobic therapeutic
agents.
[0011] It is another object of the invention to provide
pharmaceutical compositions that are homogeneous and
thermodynamically stable.
[0012] It is yet another object of the invention to provide
pharmaceutical compositions having a small and narrow particle size
distribution.
[0013] It is still another object of the invention to provide
pharmaceutical compositions of a hydrophobic therapeutic agent that
are not dependent upon lipolysis for bioabsorption.
[0014] It is still another object of the invention to provide
methods of treating a patient with a hydrophobic therapeutic
agent.
[0015] It is still another object of the invention to provide less
greasy pharmaceutical compositions for topical/transdermal
delivery.
[0016] In accordance with these and other objects and features, the
present invention provides pharmaceutical compositions for improved
delivery of hydrophobic therapeutic agents. In one embodiment, the
present invention provides a triglyceride-free pharmaceutical
composition including a hydrophobic therapeutic agent and a
carrier. The carrier includes a hydrophilic surfactant and a
hydrophobic surfactant in amounts such that upon dilution with an
aqueous solution such as simulated gastrointestinal fluids the
carrier forms a clear aqueous dispersion of the hydrophilic and
hydrophobic surfactants containing the hydrophobic therapeutic
agent.
[0017] In another embodiment, the present invention provides a
clear aqueous dispersion containing a hydrophilic surfactant, a
hydrophobic surfactant and a hydrophobic therapeutic agent. The
dispersion is substantially free of triglycerides.
[0018] In another embodiment, the present invention relates to a
triglyceride-free pharmaceutical composition which includes a
hydrophilic surfactant and a hydrophobic surfactant in amounts such
that upon dilution with an aqueous solution a clear aqueous
dispersion is formed, a first amount of a hydrophobic therapeutic
agent solubilized in the clear aqueous dispersion, and a second
amount of the hydrophobic therapeutic agent that remains
non-solubilized but dispersed.
[0019] In another embodiment, the present invention relates to
methods of increasing the rate and/or extent of absorption of
hydrophobic therapeutic agents by administering to a patient a
pharmaceutical composition of the present invention.
[0020] These and other objects and features of the present
invention will become more fully apparent from the following
description and appended claims, or may be learned by the practice
of the invention as set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] In order to illustrate the manner in which the above-recited
and other advantages and objects of the invention are obtained, a
more particular description of the invention briefly described
above will be rendered by reference to the specific embodiments
shown in the appended drawings. Understanding that these drawings
depict only typical embodiments of the invention and are not
therefore limiting of its scope, the invention will be described
and explained with additional specificity and detail through the
use of the accompanying drawing, in which:
[0022] FIG. 1 shows the enhanced bioabsorption of a hydrophobic
therapeutic agent in the compositions of the present invention,
relative to a commercial formulation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] The present invention overcomes the problems described above
characteristic of conventional formulations such as micelle
formulations, emulsions, and microemulsions, by providing unique
triglyceride-free pharmaceutical compositions. Surprisingly, the
present inventors have found that compositions including a
combination of a hydrophilic surfactant and a hydrophobic
surfactant can solubilize therapeutically effective amounts of
hydrophobic therapeutic agents without recourse to the use of
triglycerides, thereby avoiding the lipolysis dependence and other
disadvantages of conventional formulations. Use of these
formulations results in an enhanced rate and/or extent of
absorption of the hydrophobic therapeutic agent.
[0024] A. Pharmaceutical Compositions
[0025] In one embodiment, the present invention provides a
pharmaceutical composition including a carrier and a hydrophobic
therapeutic agent. The carrier includes a hydrophilic surfactant
and a hydrophobic surfactant in amounts such that upon dilution
with an aqueous solution the carrier forms a clear aqueous
dispersion of the hydrophilic and hydrophobic surfactants
containing the hydrophobic therapeutic agent. It is a particular
feature of the present invention that the carrier is substantially
free of triglycerides, thereby providing surprising and important
advantages over conventional, triglyceride-containing
formulations.
[0026] 1. Surfactants
[0027] The carrier includes at least one hydrophilic surfactant and
at least one hydrophobic surfactant. As is well known in the art,
the terms "hydrophilic" and "hydrophobic" are relative terms. To
function as a surfactant, a compound must necessarily include polar
or charged hydrophilic moieties as well as non-polar hydrophobic
(lipophilic) moieties; i.e., a surfactant compound must be
amphiphilic. An empirical parameter commonly used to characterize
the relative hydrophilicity and hydrophobicity of non-ionic
amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB"
value). Surfactants with lower HLB values are more hydrophobic, and
have greater solubility in oils, while surfactants with higher HLB
values are more hydrophilic, and have greater solubility in aqueous
solutions.
[0028] Using HLB values as a rough guide, hydrophilic surfactants
are generally considered to be those compounds having an HLB value
greater than about 10, as well as anionic, cationic, or
zwitterionic compounds for which the HLB scale is not generally
applicable. Similarly, hydrophobic surfactants are compounds having
an HLB value less than about 10.
[0029] It should be appreciated that the HLB value of a surfactant
is merely a rough guide generally used to enable formulation of
industrial, pharmaceutical and cosmetic emulsions. For many
important surfactants, including several polyethoxylated
surfactants, it has been reported that HLB values can differ by as
much as about 8 HLB units, depending upon the empirical method
chosen to determine the HLB value (Schott, J. Pharm. Sciences,
79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide
containing block copolymers (PLURONIC.RTM. surfactants, BASF
Corp.), the HLB values may not accurately reflect the true physical
chemical nature of the compounds. Finally, commercial surfactant
products are generally not pure compounds, but are complex mixtures
of compounds, and the HLB value reported for a particular compound
may more accurately be characteristic of the commercial product of
which the compound is a major component. Different commercial
products having the same primary surfactant component can, and
typically do, have different HLB values. In addition, a certain
amount of lot-to-lot variability is expected even for a single
commercial surfactant product. Keeping these inherent difficulties
in mind, and using HLB values as a guide, one skilled in the art
can readily identify surfactants having suitable hydrophilicity or
hydrophobicity for use in the present invention, as described
herein.
[0030] The hydrophilic surfactant can be any hydrophilic surfactant
suitable for use in pharmaceutical compositions. Such surfactants
can be anionic, cationic, zwitterionic or non-ionic, although
non-ionic hydrophilic surfactants are presently preferred. As
discussed above, these non-ionic hydrophilic surfactants will
generally have HLB values greater than about 10. Mixtures of
hydrophilic surfactants are also within the scope of the
invention.
[0031] Similarly, the hydrophobic surfactant can be any hydrophobic
surfactant suitable for use in pharmaceutical compositions. In
general, suitable hydrophobic surfactants will have an HLB value
less than about 10. Mixtures of hydrophobic surfactants are also
within the scope of the invention.
[0032] The choice of specific hydrophobic and hydrophilic
surfactants should be made keeping in mind the particular
hydrophobic therapeutic agent to be used in the composition, and
the range of polarity appropriate for the chosen therapeutic agent,
as discussed in more detail below. With these general principles in
mind, a very broad range of surfactants is suitable for use in the
present invention. Such surfactants can be grouped into the
following general chemical classes detailed in the Tables below.
The HLB values given in the Tables below generally represent the
HLB value as reported by the manufacturer of the corresponding
commercial product. In cases where more than one commercial product
is listed, the HLB value in the Tables is the value as reported for
one of the commercial products, a rough average of the reported
values, or a value that, in the judgment of the present inventors,
is more reliable. It should be emphasized that the invention is not
limited to the surfactants in the following Tables, which show
representative, but not exclusive, lists of available
surfactants.
[0033] 1.1. Polyethoxylated Fatty Acids
[0034] Although polyethylene glycol (PEG) itself does not function
as a surfactant, a variety of PEG-fatty acid esters have useful
surfactant properties. Among the PEG-fatty acid monoesters, esters
of lauric acid, oleic acid, and stearic acid are most useful. Among
the surfactants of Table 1, preferred hydrophilic surfactants
include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate,
PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate,
PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. Examples of
polyethoxylated fatty acid monoester surfactants commercially
available are shown in Table 1.
1TABLE 1 PEG-Fatty Acid Monoester Surfactants COMPOUND COMMERCIAL
PRODUCT (Supplier) HLB PEG 4-100 monolaurate Crodet L series
(Croda) >9 PEG 4-100 monooleate Crodet O series (Croda) >8
PEG 4-100 monostearate Crodet S series (Croda), Myrj Series >6
(Atlas/ICI) PEG 400 distearate Cithrol 4DS series (Croda) >10
PEG 100,200,300 Cithrol ML series (Croda) >10 monolaurate PEG
100,200,300 Cithrol MO series (Croda) >10 monooleate PEG 400
dioleate Cithrol 4DO series (Croda) >10 PEG 400-1000 Cithrol MS
series (Croda) >10 monostearate PEG-1 stearate Nikkol MYS-1EX
(Nikko), Coster 2 K1 (Condea) PEG-2 stearate Nikkol MYS-2 (Nikko) 4
PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg .RTM. 200
ML (PPG), Kessco .RTM. 9.3 PEG 200ML (Stepan), LIPOPEG 2L (LIPO
Chem.) PEG-4 oleate Mapeg .RTM. 200 MO (PPG), Kessco .RTM. 8.3
PEG200 MO (Stepan), PEG-4 stearate Kessco .RTM. PEG 200 MS
(Stepan), 6.5 Hodag 20 S (Calgene), Nikkol MYS-4 (Nikko) PEG-5
stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleate Nikkol TMGO-5
(Nikko) 9.5 PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco .RTM.
PEG 300 MO (Stepan), 8.5 Nikkol MYO-6 (Nikko), Emulgante A6
(Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4 PEG-6 laurate
Kessco .RTM. PEG300 ML (Stepan) 11.4 PEG-7 laurate Lauridac 7
(Condea) 13 PEG-6 stearate Kessco .RTM. PEG300 MS (Stepan) 9.7
PEG-8 laurate Mapeg .RTM. 400 ML (PPG), LIPOPEG 13 4DL(Lipo Chem.)
PEG-8 oleate Mapeg .RTM. 400 MO (PPG), Emulgante 12 A8 (Condea)
PEG-8 stearate Mapeg .RTM. 400 MS (PPG), Myrj 45 12 PEG-9 oleate
Emulgante A9 (Condea) >10 PEG-9 stearate Cremophor S9 (BASF)
>10 PEG-10 laurate Nikkol MYL-10 (Nikko), Lauridac 10 13 (Croda)
PEG-10 oleate Nikkol MYG-10 (Nikko) 11 PEG-10 stearate Nikkol
MYS-10 (Nikko), Coster K100 11 (Condea) PEG-12 laurate Kessco .RTM.
PEG 600ML (Stepan) 15 PEG-12 oleate Kessco .RTM. PEG 600MO (Stepan)
14 PEG-12 ricinoleate (CAS #9004-97-1) >10 PEG-12 stearate Mapeg
.RTM. 600 MS (PPG), Kessco .RTM. 14 PEG 600MS (Stepan) PEG-15
stearate Nikkol TMGS-15 (Nikko), Koster K15 14 (Condea) PEG-15
oleate Nikkol TMGO-15 (Nikko) 15 PEG-20 laurate Kessco .RTM. PEG
1000 ML (Stepan) 17 PEG-20 oleate Kessco .RTM. PEG 1000 MO (Stepan)
15 PEG-20 stearate Mapeg .RTM. 1000 MS (PPG), Kessco .RTM. 16 PEG
1000 MS (Stepan), Myrj 49 PEG-25 stearate Nikkol MYS-25 (Nikko) 15
PEG-32 laurate Kessco .RTM. PEG 1540 ML (Stepan) 16 PEG-32 oleate
Kessco .RTM. PEG 1540 MO (Stepan) 17 PEG-32 stearate Kessco .RTM.
PEG 1540 MS (Stepan) 17 PEG-30 stearate Myrj 51 >10 PEG-40
laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40 (Croda)
17.4 PEG-40 stearate Myrj 52, Emerest .RTM. 2715 (Henkel), >10
Nikkol MYS-40 (Nikko) PEG-45 stearate Nikkol MYS-45 (Nikko) 18
PEG-50 stearate Myrj 53 >10 PEG-55 stearate Nikkol MYS-55
(Nikko) 18 PEG-100 oleate Crodet O-100 (Croda) 18.8 PEG-100
stearate Myrj 59, Arlacel 165 (ICI) 19 PEG-200 oleate Albunol 200
MO (Taiwan Surf.) >10 PEG-400 oleate LACTOMUL (Henkel), Albunol
400 >10 MO (Taiwan Surf.) PEG-600 oleate Albunol 600 MO (Taiwan
Surf.) >10
[0035] 1.2 PEG-Fatty Acid Diesters
[0036] Polyethylene glycol fatty acid diesters are also suitable
for use as surfactants in the compositions of the present
invention. Among the surfactants in Table 2, preferred hydrophilic
surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20
distearate, PEG-32 dilaurate and PEG-32 dioleate. Representative
PEG-fatty acid diesters are shown in Table 2.
2TABLE 2 PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIAL
PRODUCT (Supplier) HLB PEG-4 dilaurate Mapeg .RTM. 200 DL (PPG),
Kessco .RTM. PEG 7 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4
dioleate Mapeg .RTM. 200 DO (PPG), 6 PEG-4 distearate Kessco .RTM.
200 DS (Stepan.sub.-- 5 PEG-6 dilaurate Kessco .RTM. PEG 300 DL
(Stepan) 9.8 PEG-6 dioleate Kessco .RTM. PEG 300 DO (Stepan) 7.2
PEG-6 distearate Kessco .RTM. PEG 300 DS (Stepan) 6.5 PEG-8
dilaurate Mapeg .RTM. 400 DL (PPG), Kessco .RTM. PEG 11 400 DL
(Stepan), LIPOPEG 4 DL (Lipo Chem.) PEG-8 dioleate Mapeg .RTM. 400
DO (PPG), Kessco .RTM. PEG 8.8 400 DO (Stepan), LIPOPEG 4 DO (Lipo
Chem.) PEG-8 distearate Mapeg .RTM. 400 DS (PPG), CDS 400 (Nikkol)
11 PEG-10 dipalmitate Polyaldo 2PKFG >10 PEG-12 dilaurate Kessco
.RTM. PEG 600 DL (Stepan) 11.7 PEG-12 distearate Kessco .RTM. PEG
600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg .RTM. 600 DO (PPG),
Kessco .RTM. 600 10 DO(Stepan) PEG-20 dilaurate Kessco .RTM. PEG
1000 DL (Stepan) 15 PEG-20 dioleate Kessco .RTM. PEG 1000 DO
(Stepan) 13 PEG-20 distearate Kessco .RTM. PEG 1000 DS (Stepan) 12
PEG-32 dilaurate Kessco .RTM. PEG 1540 DL (Stepan) 16 PEG-32
dioleate Kessco .RTM. PEG 1540 DO (Stepan) 15 PEG-32 distearate
Kessco .RTM. PEG 1540 DS (Stepan) 15 PEG-400 dioleate Cithrol 4DO
series (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda)
>10
[0037] 1.3 PEG-Fatty Acid Mono- and Di-ester Mixtures
[0038] In general, mixtures of surfactants are also useful in the
present invention, including mixtures of two or more commercial
surfactant products. Several PEG-fatty acid esters are marketed
commercially as mixtures or mono- and diesters. Representative
surfactant mixtures are shown in Table 3.
3TABLE 3 PEG-Fatty Acid Mono- and Diester Mixtures COMMERCIAL
COMPOUND PRODUCT (Supplier) HLB PEG 4-150 mono, dilaurate Kessco
.RTM. PEG 200-6000 mono, dilaurate (Stepan) PEG 4-150 mono,
dioleate Kessco .RTM. PEG 200-6000 mono, dioleate (Stepan) PEG
4-150 mono, distearate Kessco .RTM. 200-6000 mono, distearate
(Stepan)
[0039] 1.4 Polyethylene Glycol Glycerol Fatty Acid Esters
[0040] Suitable PEG glycerol fatty acid esters are shown in Table
4. Among the surfactants in the Table, preferred hydrophilic
surfactants are PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30
glyceryl oleate.
4TABLE 4 PEG Glycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT
(Supplier) HLB PEG-20 glyceryl laurate Tagat .RTM. L (Goldschmidt)
16 PEG-30 glyceryl laurate Tagat .RTM. L2 (Goldschmidt) 16 PEG-15
glyceryl laurate Glycerox L series (Croda) 15 PEG-40 glyceryl
laurate Glycerox L series (Croda) 15 PEG-20 glyceryl stearate
Capmul .RTM. EMG (ABITEC), 13 Aldo .RTM. MS-20 KFG (Lonza) PEG-20
glyceryl oleate Tagat .RTM. O (Goldschmidt) >10 PEG-30 glyceryl
oleate Tagat .RTM. O2 (Goldschmidt) >10
[0041] 1.5. Alcohol-Oil Transesterification Products
[0042] A large number of surfactants of different degrees of
hydrophobicity or hydrophilicity can be prepared by reaction of
alcohols or polyalcohols with a variety of natural and/or
hydrogenated oils. Most commonly, the oils used are castor oil or
hydrogenated castor oil, or an edible vegetable oil such as corn
oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or
almond oil. Preferred alcohols include glycerol, propylene glycol,
ethylene glycol, polyethylene glycol, sorbitol, and
pentaerythritol. Among these alcohol-oil transesterified
surfactants, preferred hydrophilic surfactants are PEG-35 castor
oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH
40), PEG-25 trioleate (TAGAT.RTM. TO), PEG-60 corn glycerides
(Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel
oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50
hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric
glycerides (Labrasol), and PEG-6 caprylic/capric glycerides
(Softigen 767). Preferred hydrophobic surfactants in this class
include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor
oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil.RTM. M
2125 CS), PEG-6 almond oil (Labrafil.RTM. M 1966 CS), PEG-6 apricot
kernel oil (Labrafil.RTM. M 1944 CS), PEG-6 olive oil
(Labrafil.RTM. M 1980 CS), PEG-6 peanut oil (Labrafil.RTM. M 1969
CS), PEG-6 hydrogenated palm kernel oil (Labrafil.RTM. M 2130 BS),
PEG-6 palm kernel oil (Labrafil.RTM. M 2130 CS), PEG-6 triolein
(Labrafil.RTM. M 2735 CS), PEG-8 corn oil (Labrafil.RTM. WL 2609
BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond
glycerides (Crovol A40). The latter two surfactants are reported to
have HLB values of 10, which is generally considered to be the
approximate border line between hydrophilic and hydrophobic
surfactants. For purposes of the present invention, these two
surfactants are considered to be hydrophobic. Representative
surfactants of this class suitable for use in the present invention
are shown in Table 5.
5TABLE 5 Transesterification Products of Oils and Alcohols COMPOUND
COMMERCIAL PRODUCT (Supplier) HLB PEG-3 castor oil Nikkol CO-3
(Nikko) 3 PEG-5, 9, and 16 ACCONON CA series (ABITEC) 6-7 castor
oil PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikkol 11 CO-20
TX (Nikko) PEG-23 castor oil Emulgante EL23 >10 PEG-30 castor
oil Emalex C-30 (Nihon Emulsion), 11 Alkamuls .RTM. EL 620
(Rhone-Poulenc), Incrocas 30 (Croda) PEG-35 castor oil Cremophor EL
and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35
(Henkel) PEG-38 castor oil Emulgante EL 65 (Condea) PEG-40 castor
oil Emalex C-40 (Nihon Emulsion), 13 Alkamuls .RTM. EL 719
(Rhone-Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14
PEG-56 castor oil Eumulgin .RTM. PRT 56 (Pulcra SA) >10 PEG-60
castor oil Nikkol CO-60TX (Nikko) 14 PEG-100 castor oil Thomley
>10 PEG-200 castor oil Eumulgin .RTM. PRT 200 (Pulcra SA) >10
PEG-5 hydrogenated Nikkol HCO-5 (Nikko) 6 castor oil PEG-7
hydrogenated Simusol .RTM. 989 (Seppic), Cremophor 6 castor oil WO7
(BASF) PEG-10 hydrogenated Nikkol HCO-10 (Nikko) 6.5 castor oil
PEG-20 hydrogenated Nikkol HCO-20 (Nikko) 11 castor oil PEG-25
hydrogenated Simulsol .RTM. 1292 (Seppic), Cerex ELS 11 castor oil
250 (Auschem SpA) PEG-30 hydrogenated Nikkol HCO-30 (Nikko) 11
castor oil PEG-40 hydrogenated Cremophor RH 40 (BASF), Croduret 13
castor oil (Croda), Emulgin HRE 40 (Henkel) PEG-45 hydrogenated
Cerex ELS 450 (Auschem Spa) 14 castor oil PEG-50 hydrogenated
Emalex HC-50 (Nihon Emulsion) 14 castor oil PEG-60 hydrogenated
Nikkol HCO-60 (Nikko); Cremophor 15 castor oil RH 60 (BASF) PEG-80
hydrogenated Nikkol HCO-80 (Nikko) 15 castor oil PEG-100 hydro-
Nikkol HCO-100 (Nikko) 17 genated castor oil PEG-6 corn oil
Labrafil .RTM. M 2125 CS (Gattefosse) 4 PEG-6 almond oil Labrafil
.RTM. M 1966 CS (Gattefosse) 4 PEG-6 apricot Labrafil .RTM. M 1944
CS (Gattefosse) 4 kernel oil PEG-6 olive oil Labrafil .RTM. M 1980
CS (Gattefosse) 4 PEG-6 peanut oil Labrafil .RTM. M 1969 CS
(Gattefosse) 4 PEG-6 hydrogenated Labrafil .RTM. M 2130 BS
(Gattefosse) 4 palm kernel oil PEG-6 palm kernel oil Labrafil .RTM.
M 2130 CS (Gattefosse) 4 PEG-6 triolein Labrafil .RTM. M 2735 CS
(Gattefosse) 4 PEG-8 corn oil Labrafil .RTM. WL 2609 BS
(Gattefosse) 6-7 PEG-20 corn Crovol M40 (Croda) 10 glycerides
PEG-20 almond Crovol A40 (Croda) 10 glycerides PEG-25 trioleate
TAGAT .RTM. TO (Goldschmidt) 11 PEG-40 palm Crovol PK-70 >10
kernel oil PEG-60 corn Crovol M70(Croda) 15 glycerides PEG-60
almond Crovol A70 (Croda) 15 glycerides PEG-4 caprylic/capric
Labrafac .RTM. Hydro (Gattefosse), 4-5 triglyceride PEG-8
caprylic/capric Labrasol (Gattefosse),Labrafac CM 10 >10
glycerides (Gattefosse) PEG-6 caprylic/capric SOFTIGEN .RTM. 767
(Huls), Glycerox 19 glycerides 767 (Croda) Lauroyl macrogol-32
GELUCIRE 44/14 (Gattefosse) 14 glyceride Stearoyl macrogol GELUCIRE
50/13 (Gattefosse) 13 glyceride Mono, di, tri, tetra
SorbitoGlyceride (Gattefosse) <10 esters of vegetable oils and
sorbitol Pentaerythrityl Crodamol PTIS (Croda) <10
tetraisostearate Pentaerythrityl Albunol DS (Taiwan Surf.) <10
distearate Pentaerythrityl Liponate PO-4 (Lipo Chem.) <10
tetraoleate Pentaerythrityl Liponate PS-4 (Lipo Chem.) <10
tetrastearate Pentaerythrityl Liponate PE-810 (Lipo Chem.), <10
tetracaprylate/ Crodamol PTC (Croda) tetracaprate Pentaerythrityl
Nikkol Pentarate 408 (Nikko) tetraoctanoate Also included as oils
in this category of surfactants are oil-soluble vitamins, such as
vitamins A, D, E, K, etc. Thus, derivatives of these vitamins, such
as tocopheryl PEG-1000 succinate (TPGS, available from Eastman),
are also suitable surfactants.
[0043] 1.6. Polyglycerized Fatty Acids
[0044] Polyglycerol esters of fatty acids are also suitable
surfactants for the present invention. Among the polyglyceryl fatty
acid esters, preferred hydrophobic surfactants include polyglyceryl
oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), and
polyglyceryl-10 trioleate. Preferred hydrophilic surfactants
include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L),
polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10
mono, dioleate (Caprol.RTM. PEG 860). Polyglyceryl polyricinoleates
(Polymuls) are also preferred hydrophilic and hydrophobic
surfactants. Examples of suitable polyglyceryl esters are shown in
Table 6.
6TABLE 6 Polyglycerized Fatty Acids COMPOUND COMMERCIAL PRODUCT
(Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7
Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 Nikkol
DGMIS (Nikko) 5-7 isostearate Polyglyceryl-3 oleate Caprol .RTM.
3GO (ABITEC), Drewpol 6.5 3-1-O (Stepan) Polyglyceryl-4 oleate
Nikkol Tetraglyn 1-O (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol
Tetraglyn 1-S (Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-O
(Stepan), Nikkol 9 Hexaglyn 1-O (Nikko) Polyglyceryl-10 Nikkol
Decaglyn 1-L (Nikko) 15 laurate Polyglyceryl-10 oleate Nikkol
Decaglyn 1-O (Nikko) 14 Polyglyceryl-10 Nikkol Decaglyn 1-S (Nikko)
12 stearate Polyglyceryl-6 Nikkol Hexaglyn PR-15 (Nikko) >8
ricinoleate Polyglyceryl-10 Nikkol Decaglyn 1-LN (Nikko) 12
linoleate Polyglyceryl-6 Nikkol Hexaglyn 5-O (Nikko) <10
pentaoleate Polyglyceryl-3 dioleate Cremophor GO32 (BASF) <10
Polyglyceryl-3 Cremophor GS32 (BASF) <10 distearate
Polyglyceryl-4 Nikkol Tetraglyn 5-O (Nikko) <10 pentaoleate
Polyglyceryl-6 dioleate Caprol .RTM. 6G20 (ABITEC); Hodag 8.5
PGO-62 (Calgene), PLUROL OLEIQUE CC 497 (Gattefosse) Polyglyceryl-2
dioleate Nikkol DGDO (Nikko) 7 Polyglyceryl-10 Nikkol Decaglyn 3-O
(Nikko) 7 trioleate Polyglyceryl-10 Nikkol Decaglyn 5-O (Nikko) 3.5
pentaoleate Polyglyceryl-10 Nikkol Decaglyn 7-O (Nikko) 3
septaoleate Polyglyceryl-10 Caprol .RTM. 10G4O (ABITEC); 6.2
tetraoleate Hodag PGO-62 (CALGENE), Drewpol 10-4-O (Stepan)
Polyglyceryl-10 decaisostearate Nikkol Decaglyn 10-IS (Nikko)
<10 Polyglyceryl-101 Drewpol 10-10-O (Stepan), Caprol 3.5
decaoleate 10G10O (ABITEC), Nikkol Decaglyn 10-O Polyglyceryl-10
mono, Caprol .RTM. PGE 860 (ABITEC) 11 dioleate Polyglyceryl
Polymuls (Henkel) 3-20 polyricinoleate
[0045] 1.7. Propylene Glycol Fatty Acid Esters
[0046] Esters of propylene glycol and fatty acids are suitable
surfactants for use in the present invention. In this surfactant
class, preferred hydrophobic surfactants include propylene glycol
monolaurate (Lauroglycol FCC), propylene glycol ricinoleate
(Propymuls), propylene glycol monooleate (Myverol P-O6), propylene
glycol dicaprylate/dicaprate (Captex.RTM. 200), and propylene
glycol dioctanoate (Captex.RTM. 800). Examples of surfactants of
this class are given in Table 7.
7TABLE 7 Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL
PRODUCT (Supplier) HLB Propylene glycol Capryol 90 (Gattefosse),
Nikkol Sefsol 218 <10 monocaprylate (Nikko) Propylene glycol
Lauroglycol 90 (Gattefosse), Lauroglycol <10 monolaurate FCC
(Gattefosse) Propylene glycol Lutrol OP2000 (BASF) <10 oleate
Propylene glycol Mirpyl <10 myristate Propylene glycol ADM
PGME-03 (ADM), LIPO PGMS (Lipo 3-4 monostearate Chem.), Aldo .RTM.
PGHMS (Lonza) Propylene glycol <10 hydroxy stearate Propylene
glycol PROPYMULS (Henkel) <10 ricinoleate Propylene glycol
<10 isostearate Propylene glycol Myverol P-O6 (Eastman) <10
monooleate Propylene glycol Captex .RTM. 200 (ABITEC), Miglyol
.RTM. 840 >6 dicaprylate/dicaprate (Huls), Neobee .RTM. M-20
(Stepan) Propylene glycol Captex .RTM. 800 (ABITEC) >6
dioctanoate Propylene glycol LABRAFAC PG (Gattefosse) >6
caprylate/caprate Propylene glycol >6 dilaurate Propylene glycol
Kessco .RTM. PGDS (Stepan) >6 distearate Propylene glycol Nikkol
Sefsol 228 (Nikko) >6 dicaprylate Propylene glycol Nikkol PDD
(Nikko) >6 dicaprate
[0047] 1.8. Mixtures of Propylene Glycol Esters-Glycerol Esters
[0048] In general, mixtures of surfactants are also suitable for
use in the present invention. In particular, mixtures of propylene
glycol fatty acid esters and glycerol fatty acid esters are
suitable and are commercially available. One preferred mixture is
composed of the oleic acid esters of propylene glycol and glycerol
(Arlacel 186). Examples of these surfactants are shown in Table
8.
8TABLE 8 Glycerol/Propylene Glycol Fatty Acid Esters COMPOUND
COMMERCIAL PRODUCT (Supplier) HLB Oleic ATMOS 300, ARLACEL 186
(ICI) 3-4 Stearic ATMOS 150 3-4
[0049] 1.9. Mono- and Diglycerides
[0050] A particularly important class of surfactants is the class
of mono- and diglycerides. These surfactants are generally
hydrophobic. Preferred hydrophobic surfactants in this class of
compounds include glyceryl monooleate (Peceol), glyceryl
ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul.RTM.
GDL), glyceryl dioleate (Capmul.RTM. GDO), glyceryl mono/dioleate
(Capmul.RTM. GMO-K), glyceryl caprylate/caprate (Capmul.RTM. MCM),
caprylic acid mono/diglycerides (Imwitor.RTM. 988), and mono- and
diacetylated monoglycerides (Myvacet.RTM. 9-45). Examples of these
surfactants are given in Table 9.
9TABLE 9 Mono- and Diglyceride Surfactants COMPOUND COMMERCIAL
PRODUCT (Supplier) HLB Monopalmitolein (Larodan) <10 (C16:1)
Monoelaidin (Larodan) <10 (C18:1) Monocaproin (C6) (Larodan)
<10 Monocaprylin (Larodan) <10 Monocaprin (Larodan) <10
Monolaurin (Larodan) <10 Glyceryl Nikkol MGM (Nikko) 3-4
monomyristate (C14) Glyceryl monooleate PECEOL (Gattefosse), Hodag
GMO-D, 3-4 (C18:1) Nikkol MGO (Nikko) Glyceryl monooleate RYLO
series (Danisco), DIMODAN 3-4 series (Danisco), EMULDAN (Danisco),
ALDO .RTM. MO FG (Lonza), Kessco GMO (Stepan), MONOMULS .RTM.
series (Henkel), TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695
(ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70, and 100 (ADM),
Myverol (Eastman) Glycerol monooleate/ OLICINE (Gattefosse) 3-4
linoleate Glycerol Maisine (Gattefosse), MYVEROL 3-4 monolinoleate
18-92, Myverol 18-06 (Eastman) Glyceryl ricinoleate Softigen .RTM.
701 (Huls), HODAG 6 GMR-D (Calgene), ALDO .RTM. MR (Lonza) Glyceryl
monolaurate ALDO .RTM. MLD (Lonza), Hodag GML 6.8 (Calgene)
Glycerol Emalex GMS-P (Nihon) 4 monopalmitate Glycerol monostearate
Capmul .RTM. GMS (ABITEC), Myvaplex 5-9 (Eastman), IMWITOR .RTM.
191 (Huls), CUTINA GMS, Aldo .RTM. MS (Lonza), Nikkol MGS series
(Nikko) Glyceryl mono-, Capmul .RTM. GMO-K (ABITEC) <10 dioleate
Glyceiyl CUTINA MD-A, ESTAGEL-G18 <10 palmitic/stearic Glyceryl
acetate Lamegin .RTM. EE (Grunau GmbH) <10 Glyceryl laurate
Imwitor .RTM. 312 (Huls), 4 Monomuls .RTM. 90-45 (Grunau GmbH),
Aldo .RTM. MLD (Lonza) Glyceryl citrate/ Imwitor .RTM. 375 (Huls)
<10 lactate/oleate/ linoleate Glyceryl caprylate Imwitor .RTM.
308 (Huls), Capmul .RTM. 5-6 MCMC8 (ABITEC) Glyceryl caprylate/
Capmul .RTM. MCM (ABITEC) 5-6 caprate Caprylic acid mono, Imwitor
.RTM. 988 (Huls) 5-6 diglycerides Caprylic/capric Imwitor .RTM. 742
(Huls) <10 glycerides Mono-and diacetylated Myvacet .RTM. 9-45,
Myvacet .RTM. 9-40, 3.8-4 monoglycerides Myvacet .RTM. 9-08
(Eastman), Lamegin .RTM. (Grunau) Glyceryl monostearate Aldo .RTM.
MS, Arlacel 129 (ICI), LIPO 4.4 GMS (Lipo Chem.), Imwitor .RTM. 191
(Huls), Myvaplex (Eastman) Lactic acid esters of LAMEGIN GLP
(Henkel) <10 mono,diglycerides Dicaproin (C6) (Larodan) <10
Dicaprin (C10) (Larodan) <10 Dioctanoin (C8) (Larodan) <10
Dimyristin (C14) (Larodan) <10 Dipalmitin (C16) (Larodan) <10
Distearin (Larodan) <10 Glyceryl dilaurate Capmul .RTM. GDL
(ABITEC) 3-4 (C12) Glyceryl dioleate Capmul .RTM. GDO (ABITEC) 3-4
Glycerol esters GELUCIRE 39/01 (Gattefosse), 1 of fatty acids
GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06 (Gattefosse) 6
Dipalmitolein (C16:1) (Larodan) <10 1,2 and 1,3-diolein
(Larodan) <10 (C18:1) Dielaidin (C18:1) (Larodan) <10
Dilinolein (C18:2) (Larodan) <10
[0051] 1.10. Sterol and Sterol Derivatives
[0052] Sterols and derivatives of sterols are suitable surfactants
for use in the present invention. These surfactants can be
hydrophilic or hydrophobic. Preferred derivatives include the
polyethylene glycol derivatives. A preferred hydrophobic surfactant
in this class is cholesterol. A preferred hydrophilic surfactant in
this class is PEG-24 cholesterol ether (Solulan C-24). Examples of
surfactants of this class are shown in Table 10.
10TABLE 10 Sterol and Sterol Derivative Surfactants COMPOUND
COMMERCIAL PRODUCT (Supplier) HLB Cholesterol, sitosterol, <10
lanosterol PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10
PEG-30 cholesterol Nikkol DHC (Nikko) >10 Phytosterol GENEROL
series (Henkel) <10 PEG-25 phyto sterol Nikkol BPSH-25 (Nikko)
>10 PEG-5 soya sterol Nikkol BPS-5 (Nikko) <10 PEG-10 soya
sterol Nikkol BPS-10 (Nikko) <10 PEG-20 soya sterol Nikkol
BPS-20 (Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko)
>10
[0053] 1.11. Polyethylene Glycol Sorbitan Fatty Acid Esters
[0054] A variety of PEG-sorbitan fatty acid esters are available
and are suitable for use as surfactants in the present invention.
In general, these surfactants are hydrophilic, although several
hydrophobic surfactants of this class can be used. Among the
PEG-sorbitan fatty acid esters, preferred hydrophilic surfactants
include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan
monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60),
and PEG-20 sorbitan monooleate (Tween-80). Examples of these
surfactants are shown in Table 11.
11TABLE 11 PEG-Sorbitan Fatty Acid Esters COMMERCIAL COMPOUND
PRODUCT (Supplier) HLB PEG-10 sorbitan laurate Liposorb L-10 (Lipo
Chem.) >10 PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI),
Crillet 1 17 (Croda), DACOL MLS 20 (Condea) PEG-4 sorbitan
monolaurate Tween-21 (Atlas/ICI), Crillet 11 13 (Croda) PEG-80
sorbitan monolaurate Hodag PSML-80 (Calgene); >10 T-Maz 28 PEG-6
sorbitan monolaurate Nikkol GL-1 (Nikko) 16 PEG-20 sorbitan
monopalmitate Tween-40 (Atlas/ICI), Crillet 2 16 (Croda) PEG-20
sorbitan monostearate Tween-60 (Atlas/ICI), Crillet 3 15 (Croda)
PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), Crillet 31 9.6
(Croda) PEG-8 sorbitan monostearate DACOL MSS (Condea) >10 PEG-6
sorbitan monostearate Nikkol TS106 (Nikko) 11 PEG-20 sorbitan
tristearate Tween-65 (Atlas/ICI), Crillet 35 11 (Croda) PEG-6
sorbitan tetrastearate Nikkol GS-6 (Nikko) 3 PEG-60 sorbitan
tetrastearate Nikkol GS-460 (Nikko) 13 PEG-5 sorbitan monooleate
Tween-81 (Atlas/ICI), Crillet 41 10 (Croda) PEG-6 sorbitan
monooleate Nikkol TO-106 (Nikko) 10 PEG-20 sorbitan monooleate
Tween-80 (Atlas/ICI), Crillet 4 15 (Croda) PEG-40 sorbitan oleate
Emalex ET 8040 18 (Nihon Emulsion) PEG-20 sorbitan trioleate
Tween-85 (Atlas/ICI), Crillet 45 11 (Croda) PEG-6 sorbitan
tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleate
Nikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440
(Nikko) 13 PEG-20 sorbitan Tween-120 (Atlas/ICI), Crillet 6 >10
monoisostearate (Croda) PEG sorbitol hexaoleate Atlas G-1086 (ICI)
10 PEG-6 sorbitol hexastearate Nikkol GS-6 (Nikko) 3
[0055] 1.12. Polyethylene Glycol Alkyl Ethers
[0056] Ethers of polyethylene glycol and alkyl alcohols are
suitable surfactants for use in the present invention. Preferred
hydrophobic ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4
lauryl ether (Brij 30). Examples of these surfactants are shown in
Table 12.
12TABLE 12 Polyethylene Glycol Alkyl Ethers COMMERCIAL COMPOUND
PRODUCT (Supplier) HLB PEG-2 oleyl ether,oleth-2 Brij 92/93
(Atlas/ICI) 4.9 PEG-3 oleyl ether,oleth-3 Volpo 3 (Croda) <10
PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl
ether,oleth-10 Volpo 10 (Croda), Brij 96/97 12 (Atlas/ICI) PEG-20
oleyl ether,oleth-20 Volpo 20 (Croda), Brij 98/99 15 (Atlas/ICI)
PEG-4 lauryl ether, laureth-4 Brij 30 (Atlas/ICI) 9.7 PEG-9 lauryl
ether >10 PEG-23 lauryl ether, laureth-23 Brij 35 (Atlas/ICI) 17
PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-10 cetyl ether Brij 56
(ICI) 13 PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2 stearyl ether
Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-20
stearyl ether Brij 78 (ICI) 15 PEG-100 stearyl ether Brij 700 (ICI)
>10
[0057] 1.13. Sugar Esters
[0058] Esters of sugars are suitable surfactants for use in the
present invention. Preferred hydrophilic surfactants in this class
include sucrose monopalmitate and sucrose monolaurate. Examples of
such surfactants are shown in Table 13.
13TABLE 13 Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT
(Supplier) HLB Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3
Crodesta F-10 (Croda) Sucrose distearate/ SUCRO ESTER 11
(Gattefosse), 12 monostearate Crodesta F-110 (Croda) Sucrose
dipalmitate 7.4 Sucrose monostearate Crodesta F-160 (Croda) 15
Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10 Sucrose
monolaurate Saccharose monolaurate 15 1695 (Mitsubishi-Kasei)
[0059] 1.14. Polyethylene Glycol Alkyl Phenols
[0060] Several hydrophilic PEG-alkyl phenol surfactants are
available, and are suitable for use in the present invention.
Examples of these surfactants are shown in Table 14.
14TABLE 14 Polyethylene Glycol Alkyl Phenol Surfactants COMMERCIAL
COMPOUND PRODUCT (Supplier) HLB PEG-10-100 nonyl phenol Triton X
series (Rohm & Haas), >10 Igepal CA series (GAF, USA),
Antarox CA series (GAF, UK) PEG-15-100 octyl phenol ether Triton
N-series (Rohm & Haas), >10 Igepal CO series (GAF, USA),
Antarox CO series (GAF, UK)
[0061] 1.15. Polyoxyethylene-Polyoxypropylene Block Copolymers
[0062] The POE-POP block copolymers are a unique class of polymeric
surfactants. The unique structure of the surfactants, with
hydrophilic POE and hydrophobic POP moieties in well-defined ratios
and positions, provides a wide variety of surfactants suitable for
use in the present invention. These surfactants are available under
various trade names, including Synperonic PE series (ICI);
Pluronic.RTM. series (BASF), Emkalyx, Lutrol (BASF), Supronic,
Monolan, Pluracare, and Plurodac. The generic term for these
polymers is "poloxamer" (CAS 9003-11-6). These polymers have the
formula:
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.nH
[0063] where "a" and "b" denote the number of polyoxyethylene and
polyoxypropylene units, respectively.
[0064] Preferred hydrophilic surfactants of this class include
Poloxamers 108, 188, 217, 238, 288, 338, and 407. Preferred
hydrophobic surfactants in this class include Poloxamers 124, 182,
183, 212, 331, and 335.
[0065] Examples of suitable surfactants of this class are shown in
Table 15. Since the compounds are widely available, commercial
sources are not listed in the Table. The compounds are listed by
generic name, with the corresponding "a" and "b" values.
15TABLE 15 POE-POP Block Copolymers a, b values in COMPOUND
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).su-
b.b(C.sub.2H.sub.4O).sub.aH HLB Poloxamer 105 a = 11 b = 16 8
Poloxamer 108 a = 46 b = 16 >10 Poloxamer 122 a = 5 b = 21 3
Poloxamer 123 a = 7 b = 21 7 Poloxamer 124 a = 11 b = 21 >7
Poloxamer 181 a = 3 b = 30 Poloxamer 182 a = 8 b = 30 2 Poloxamer
183 a = 10 b = 30 Poloxamer 184 a = 13 b = 30 Poloxamer 185 a = 19
b = 30 Poloxamer 188 a = 75 b = 30 29 Poloxamer 212 a = 8 b = 35
Poloxamer 215 a = 24 b = 35 Poloxamer 217 a = 52 b = 35 Poloxamer
231 a = 16 b = 39 Poloxamer 234 a = 22 b = 39 Poloxamer 235 a = 27
b = 39 Poloxamer 237 a = 62 b = 39 24 Poloxamer 238 a = 97 b = 39
Poloxamer 282 a = 10 b = 47 Poloxamer 284 a = 21 b = 47 Poloxamer
288 a = 122 b = 47 >10 Poloxamer 331 a = 7 b = 54 0.5 Poloxamer
333 a = 20 b = 54 Poloxamer 334 a = 31 b = 54 Poloxamer 335 a = 38
b = 54 Poloxamer 338 a = 128 b = 54 Poloxamer 401 a = 6 b = 67
Poloxamer 402 a = 13 b = 67 Poloxamer 403 a = 21 b = 67 Poloxamer
407 a = 98 b = 67
[0066] 1.16. Sorbitan Fatty Acid Esters
[0067] Sorbitan esters of fatty acids are suitable surfactants for
use in the present invention. Among these esters, preferred
hydrophobic surfactants include sorbitan monolaurate (Arlacel 20),
sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80),
sorbitan monostearate, and sorbitan tristearate. Examples of these
surfactants are shown in Table 16.
16TABLE 16 Sorbitan Fatty Acid Ester Surfactants COMPOUND
COMMERCIAL PRODUCT (Supplier) HLB Sorbitan monolaurate Span-20
(Atlas/ICI), Crill 1 (Croda), 8.6 Arlacel 20 (ICI) Sorbitan
monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), 6.7 Nikkol
SP-10 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4
(Croda), 4.3 Crill 50 (Croda) Sorbitan monostearate Span-60
(Atlas/ICI), Crill 3 (Croda), 4.7 Nikkol SS-10 (Nikko) Sorbitan
trioleate Span-85 (Atlas/ICI), Crill 45 (Croda), 4.3 Nikkol SO-30
(Nikko) Sorbitan sesquioleate Arlacel-C (ICI), Crill 43 (Croda),
3.7 Nikkol SO-15 (Nikko) Sorbitan tristearate Span-65 (Atlas/ICI)
Crill 35 (Croda), 2.1 Nikkol SS-30 (Nikko) Sorbitan monoisostearate
Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7 Sorbitan sesquistearate
Nikkol SS-15 (Nikko) 4.2
[0068] 1.17. Lower Alcohol Fatty Acid Esters
[0069] Esters of lower alcohols (C.sub.2 to C.sub.4) and fatty
acids (C.sub.8 to C.sub.18) are suitable surfactants for use in the
present invention. Among these esters, preferred hydrophobic
surfactants include ethyl oleate (Crodamol EO), isopropyl myristate
(Crodamol IPM), and isopropyl palmitate (Crodamol IPP). Examples of
these surfactants are shown in Table 17.
17TABLE 17 Lower Alcohol Fatty Acid Ester Surfactants COMPOUND
COMMERCIAL PRODUCT (Supplier) HLB Ethyl oleate Crodamol EO (Croda),
Nikkol EOO (Nikko) <10 Isopropyl myristate Crodamol IPM (Croda)
<10 Isopropyl palmitate Crodamol IPP (Croda) <10 Ethyl
linoleate Nikkol VF-E (Nikko) <10 Isopropyl linoleate Nikkol
VF-IP (Nikko) <10
[0070] 1.18. Ionic Surfactants
[0071] Ionic surfactants, including cationic, anionic and
zwitterionic surfactants, are suitable hydrophilic surfactants for
use in the present invention. Preferred anionic surfactants include
fatty acid salts and bile salts. Specifically, preferred ionic
surfactants include sodium oleate, sodium lauryl sulfate, sodium
lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate,
and sodium taurocholate. Examples of such surfactants are shown in
Table 18 below. For simplicity, typical counterions are shown in
the entries in the Table. It will be appreciated by one skilled in
the art, however, that any bioacceptable counterion may be used.
For example, although the fatty acids are shown as sodium salts,
other cation counterions can also be used, such as alkali metal
cations or ammonium. Unlike typical non-ionic surfactants, these
ionic surfactants are generally available as pure compounds, rather
than commercial (proprietary) mixtures. Because these compounds are
readily available from a variety of commercial suppliers, such as
Aldrich, Sigma, and the like, commercial sources are not generally
listed in the Table.
18TABLE 18 Ionic Surfactants COMPOUND HLB FATTY ACID SALTS >10
Sodium caproate Sodium caprylate Sodium caprate Sodium laurate
Sodium myristate Sodium myristolate Sodium palmitate Sodium
palmitoleate Sodium oleate 18 Sodium ricinoleate Sodium linoleate
Sodium linolenate Sodium stearate Sodium lauryl sulfate (dodecyl)
40 Sodium tetradecyl sulfate Sodium lauryl sarcosinate Sodium
dioctyl sulfosuccinate [sodium docusate (Cytec)] BILE SALTS >10
Sodium cholate Sodium taurocholate Sodium glycocholate Sodium
deoxycholate Sodium taurodeoxycholate Sodium glycodeoxycholate
Sodium ursodeoxycholate Sodium chenodeoxycholate Sodium
taurochenodeoxycholate Sodium glyco cheno deoxycholate Sodium
cholylsarcosinate Sodium N-methyl taurocholate PHOSPHOLIPIDS
Egg/Soy lecithin [Epikuron .TM. (Lucas Meyer), Ovothin .TM. (Lucas
Meyer)] Lyso egg/soy lecithin Hydroxylated lecithin
Lysophosphatidylcholine Cardiolipin Sphingomyelin
Phosphatidylcholine Phosphatidyl ethanolamine Phosphatidic acid
Phosphatidyl glycerol Phosphatidyl serine PHOSPHORIC ACID ESTERS
Diethanolammonium polyoxyethylene-10 oleyl ether phosphate
Esterification products of fatty alcohols or fatty alcohol
ethoxylates with phosphoric acid or anhydride CARBOXYLATES Ether
carboxylates (by oxidation of terminal OH group of fatty alcohol
ethoxylates) Succinylated monoglycerides [LAMEGIN ZE (Henkel)]
Sodium stearyl fumarate Stearoyl propylene glycol hydrogen
succinate Mono/diacetylated tartaric acid esters of mono- and
diglycerides Citric acid esters of mono-, diglycerides
Glyceryl-lacto esters of fatty acids (CFR ref. 172.852) Acyl
lactylates: lactylic esters of fatty acids calcium/sodium
stearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate
salts Propylene glycol alginate SULFATES AND SULFONATES Ethoxylated
alkyl sulfates Alkyl benzene sulfones .alpha.-olefin sulfonates
Acyl isethionates Acyl taurates Alkyl glyceryl ether sulfonates
Octyl sulfosuccinate disodium Disodium
undecylenamideo-MEA-sulfosuccinat- e CATIONIC Surfactants >10
Hexadecyl triammonium bromide Decyl trimethyl ammonium bromide
Cetyl trimethyl ammonium bromide Dodecyl ammonium chloride Alkyl
benzyldimethylammonium salts Diisobutyl phenoxyethoxydimethyl
benzylammonium salts Alkylpyridinium salts Betaines
(trialkylglycine): Lauryl betaine (N-lauryl,N,N-dimethylglycine)
Ethoxylated amines: Polyoxyethylene-15 coconut amine
[0072] 1.19 Surfactant Concentrations
[0073] The hydrophilic and hydrophobic surfactants are present in
the pharmaceutical compositions of the present invention in amounts
such that upon dilution with an aqueous solution, the carrier forms
a clear, aqueous dispersion of the hydrophilic and hydrophobic
surfactants, containing the hydrophobic therapeutic agent. The
relative amounts of hydrophilic and hydrophobic surfactants are
readily determined by observing the properties of the resultant
dispersion; i.e., when the relative amounts of the hydrophobic and
hydrophilic surfactants are within a suitable range, the resultant
aqueous dispersion is optically clear. When the relative amount of
hydrophobic surfactant is too great, the resulting dispersion is
visibly "cloudy", resembling a conventional emulsion or multiple
phase system. Although a visibly cloudy solution may be potentially
useful for some applications, such a system would suffer from many
of the same disadvantages as conventional prior art formulations,
as described above.
[0074] A convenient method of determining the appropriate relative
concentrations for any hydrophilic surfactant-hydrophobic
surfactant pair is as follows. A convenient working amount of a
hydrophilic surfactant is provided, and a known amount of a
hydrophobic surfactant is added. The surfactants are stirred to
form a homogeneous mixture, with the aid of gentle heating if
desired. The resulting mixture is diluted with purified water to
prepare an aqueous dispersion. Any dilution amount can be chosen,
but convenient dilutions are those within the range expected in
vivo, about a 10 to 250-fold dilution. The aqueous dispersion is
then assessed qualitatively for optical clarity. The procedure can
be repeated with incremental variations in the relative amount of
hydrophobic surfactant added, to determine the maximum relative
amount of hydrophobic surfactant that can be present for a given
surfactant pair.
[0075] Alternatively, the optical clarity of the aqueous dispersion
can be measured using standard quantitative techniques for
turbidity assessment. One convenient procedure to measure turbidity
is to measure the amount of light of a given wavelength transmitted
by the solution, using, for example, a UV-visible
spectrophotometer. Using this measure, optical clarity corresponds
to high transmittance, since cloudier solutions will scatter more
of the incident radiation, resulting in lower transmittance
measurements. If this procedure is used, care should be taken to
insure that the surfactant mixture does not itself absorb light of
the chosen wavelength, as any true absorbance necessarily reduces
the amount of transmitted light and falsely increases the
quantitative turbidity value. In the absence of chromophores at the
chosen wavelength, suitable dispersions at a dilution of 10.times.
should have an apparent absorbance of less than about 0.3,
preferably less than about 0.2, and more preferably less than about
0.1. At a dilution of 100.times., suitable dispersions should have
an apparent absorbance of less than about 0.1, preferably less than
about 0.05, and more preferably less than about 0.01.
[0076] A third method of determining optical clarity and carrier
diffusivity through the aqueous boundary layer is to quantitatively
measure the size of the particles of which the dispersion is
composed. These measurements can be performed on commercially
available particle size analyzers, such as, for example, a Nicomp
particle size analyzer available from Particle Size Systems, Inc.,
of Santa Barbara, Calif. Using this measure, clear aqueous
dispersions according to the present invention have average
particle sizes much smaller than the wavelength of visible light,
whereas dispersions containing excessive relative amounts of the
hydrophobic surfactant have more complex particle size
distributions, with much greater average particle sizes. It is
desirable that the average particle size be less than about 100 nm,
preferably less than about 50 nm, more preferably less than about
30 nm, and still more preferably less than about 20 nm. It is also
preferred that the particle size distribution be mono-modal. As is
shown in more detail in the Examples herein, dispersions having an
undesirably large relative amount of hydrophobic surfactant
typically display bimodal particle size distributions, such
distributions having a small particle size component, typically
less than about 30 nm, and a large particle size component,
typically on the order of 100 nm or more. It should be emphasized
that these particle sizes are appropriate for the carrier particles
in aqueous solution, in the absence of a hydrophobic therapeutic
agent. It is expected that the presence of the hydrophobic
therapeutic agent may result in an increase in the average particle
size.
[0077] Other methods of determining optical clarity or particle
size can be used as desired. Such methods are well know to those
skilled in the art.
[0078] It should be emphasized that any or all of the available
methods may be used to ensure that the resulting aqueous
dispersions possess the requisite optical clarity. For convenience,
however, the present inventors prefer to use the simple qualitative
procedure; i.e., simple visible observation. However, in order to
more fully illustrate the practice of the present invention, all
three of the above measures are used to assess the dispersion
clarity in the Examples herein.
[0079] Although it should be understood that any aqueous dispersion
having the properties described above is within the scope of the
present invention regardless of the specific relative amounts of
hydrophobic and hydrophilic surfactants, it is expected that the
amount of hydrophobic surfactant will generally be less than about
200% by weight, based on the amount of hydrophilic surfactant, and
more specifically, in the range of about 1% to 200%. Further, based
on observations reported in the Examples herein, it is expected
that the amount of hydrophobic surfactant will generally be less
than about 100%, and more specifically in the range of about 5% to
about 100% by weight, or about 10% to about 100% by weight, based
on the amount of hydrophilic surfactant. For some particular
surfactant combinations, cloudy solutions result when the amount of
hydrophobic surfactant is greater than about 60% by weight, based
on the amount of hydrophilic surfactant. A preferred range for
these surfactants is about 1% to about 60%, preferably about 5% to
about 60%, and more preferably about 10% to about 60%. Addition of
optional excipients as described below can further increase the
maximum relative amount of hydrophobic surfactant that can be
used.
[0080] Other considerations well known to those skilled in the art
will further inform the choice of specific proportions of
hydrophobic and hydrophilic surfactants. These considerations
include the degree of bioacceptability of the surfactants, and the
desired dosage of hydrophobic therapeutic agent to be provided. In
some cases, the amount of hydrophobic surfactant actually used in a
pharmaceutical composition according to the present invention will
be less than the maximum that can be used, and it should be
apparent that such compositions are also within the scope of the
present invention.
[0081] 2. Hydrophobic Therapeutic Agents
[0082] Hydrophobic therapeutic agents suitable for use in the
pharmaceutical compositions of the present invention are not
particularly limited, as the carrier is surprisingly capable of
solubilizing and delivering a wide variety of hydrophobic
therapeutic agents. Hydrophobic therapeutic agents are compounds
with little or no water solubility. Intrinsic water solubilities
(i.e., water solubility of the unionized form) for hydrophobic
therapeutic agents usable in the present invention are less than
about 1% by weight, and typically less than about 0.1% or 0.01% by
weight. Such therapeutic agents can be any agents having
therapeutic or other value when administered to an animal,
particularly to a mammal, such as drugs, nutrients, and cosmetics
(cosmeceuticals). It should be understood that while the invention
is described with particular reference to its value in the form of
aqueous dispersions, the invention is not so limited. Thus,
hydrophobic drugs, nutrients or cosmetics which derive their
therapeutic or other value from, for example, topical or
transdermal administration, are still considered to be suitable for
use in the present invention.
[0083] Specific non-limiting examples of hydrophobic therapeutic
agents that can be used in the pharmaceutical compositions of the
present invention include the following representative compounds,
as well as their pharmaceutically acceptable salts, isomers,
esters, ethers and other derivatives:
[0084] analgesics and anti-inflammatory agents, such as aloxiprin,
auranofin, azapropazone, benorylate, capsaicin, celecoxib,
diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
leflunomide, meclofenamic acid, mefenamic acid, nabumetone,
naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam,
refocoxib, sulindac, tetrahydrocannabinol, tramadol and
tromethamine;
[0085] anthelmintics, such as albendazole, bephenium
hydroxynaphthoate, cambendazole, dichlorophen, ivermectin,
mebendazole, oxamniquine, oxfendazole, oxantel embonate,
praziquantel, pyrantel embonate and thiabendazole;
[0086] anti-arrhythmic agents, such as amiodarone HCl,
disopyramide, flecainide acetate and quinidine sulfate;
[0087] anti-asthma agents, such as zileuton, zafirlukast,
terbutaline sulfate, montelukast, and albuterol;
[0088] anti-bacterial agents, such as alatrofloxacin, azithromycin,
baclofen, benethamine penicillin, cinoxacin, ciprofloxacin HCl,
clarithromycin, clofazimine, cloxacillin, demeclocycline,
dirithromycin, doxycycline, erythromycin, ethionamide,
furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin,
moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin,
ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin,
spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,
sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,
sulphapyridine, tetracycline, trimethoprim, trovafloxacin, and
vancomycin;
[0089] anti-viral agents, such as abacavir, amprenavir,
delavirdine, efavirenz, indivir, lamivudine, nelfinavir,
nevirapine, ritonavir, saquinavir, and stavueline;
[0090] anti-coagulants, such as cilostazol, clopidrogel,
dicoumarol, dipyridamole, nicoumalone, oprelvekin, phenindione,
ticlidopine, and tirofibran;
[0091] anti-depressants, such as amoxapine, bupropion, citalopram,
clomipramine, fluexetine HCl, maprotiline HCl, mianserin HCl,
nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl,
trimipramine maleate, and venlafaxine HCl;
[0092] anti-diabetics, such as acetohexamide, chlorpropamide,
glibenclamide, gliclazide, glipizide, glymepride, miglitol,
pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide
and troglitazone;
[0093] anti-epileptics, such as beclamide, carbamazepine,
clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine,
methoin, methsuximide, methylphenobarbitone, oxcarbazepine,
paramethadione, phenacemide, phenobarbitone, phenytoin,
phensuximide, primidone, sulthiame, tiagabine HCl, topiramate,
valproic acid, and vigabatrin;
[0094] anti-fungal agents, such as amphotericin, butenafine HCl,
butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,
flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole,
natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine
HCl, terconazole, tioconazole and undecenoic acid;
[0095] anti-gout agents, such as allopurinol, probenecid and
sulphin-pyrazone;
[0096] anti-hypertensive agents, such as amlodipine, benidipine,
benezepril, candesartan, captopril, darodipine, dilitazem HCl,
diazoxide, doxazosin HCl, elanapril, eposartan losartan, mesylate,
felodipine, fenolclopam, fosinopril, guanabenz acetate, irbesartan,
isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine,
nimodipine, nisolidipine, phenoxybenzamine HCl, prazosin HCl,
quinapril, reserpine, terazosin HCl, telmisartan, and
valsartan;
[0097] anti-malarials, such as amodiaquine, chloroquine,
chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil
HCl, pyrimethamine and quinine sulfate;
[0098] anti-migraine agents, such as dihydroergotamine mesylate,
ergotamine tartrate, frovatriptan, methysergide maleate,
naratriptan HCl, pizotifen maleate, rizatriptan benzoate,
sumatriptan succinate, and zolmitriptan;
[0099] anti-muscarinic agents, such as atropine, benzhexol HCl,
biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide,
oxyphencylcimine HCl and tropicamide;
[0100] anti-neoplastic agents and immunosuppressants, such as
aminoglutethimide, amsacrine, azathioprine, bicalutamide,
bisanthrene, busulphan, camptothecan, capecitabine, chlorambucil,
cyclosporin, dacarbazine, ellipticine, estramustine, etoposide,
irinotecan, lomustine, melphalan, mercaptopurine, methotrexate,
mitomycin, mitotane, mitoxantrone, mofetil, mycophenolate,
nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus,
tamoxifen citrate, teniposide, testolactone, topotecan HCl, and
toremifene citrate;
[0101] anti-protozoal agents, such as atovaquone, benznidazole,
clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide
furoate, dinitolmide, furzolidone, metronidazole, nimorazole,
nitrofurazone, omidazole and tinidazole;
[0102] anti-thyroid agents, such as carbimazole, paricalcitol, and
propylthiouracil;
[0103] anti-tussives, such as benzonatate;
[0104] anxiolytic, sedatives, hypnotics and neuroleptics, such as
alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,
bromperidol, brotizolam, butobarbitone, carbromal,
chlordiazepoxide, chlormethiazole, chlorpromazine,
chlorprothiocene, clonazepam, clobazam, clotiazepam, clozapine,
diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,
fluopromazine, flupenthixol decanoate, fluphenazine decanoate,
flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam,
medazepam, meprobamate, mesoridiazine, methaqualone, methyl
phenidate, midazolam, molindone, nitrazepam, olanzapine, oxazepam,
pentobarbitone, perphenazine pimozide, prochlorperazine,
pseudo-ephedrine, quetiapine, risperodone, sertindole, sulpiride,
temazepam, thioridazine, triazolam, zolpidem, and zopiclone;
[0105] .beta.-Blockers, such as acebutolol, alprenolol, atenolol,
labetalol, metoprolol, nadolol, oxprenolol, pindolol and
propranolol;
[0106] cardiac inotropic agents, such as amrinone, digitoxin,
digoxin, enoximone, lanatoside C and medigoxin;
[0107] corticosteroids, such as beclomethasone, betamethasone,
budesonide, cortisone acetate, desoxymethasone, dexamethasone,
fludrocortisone acetate, flunisolide, flucortolone, fluticasone
propionate, hydrocortisone, methylprednisolone, prednisolone,
prednisone and triamcinolone;
[0108] diuretics, such as acetazolamide, amiloride, bendrofluazide,
bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid,
frusemide, metolazone, spironolactone and triamterene.
[0109] anti-parkinsonian agents, such as bromocriptine mesylate,
lysuride maleate, pramipexole, robinirole HCl, and tolcapone;
[0110] gastro-intestinal agents, such as bisacodyl, cimetidine,
cisapride, diphenoxylate HCl, domperidone, famotidine,
lanosprazole, loperamide, mesalazine, nizatidine, omeprazole,
ondansetron HCL, rabeprazole sodium, ranitidine HCl and
sulphasalazine;
[0111] histamine H,-receptor antagonists, such as acrivastine,
astemizole, chlophenisamine, cinnarizine, citrizine, clemastine
fumarate, cyclizine, cyproheptadine HCl, dexchlopheniramine,
dimenhydrinate, fexofenadine, flunarizine HCl, loratadine,
meclozine HCl, oxatomide, and terenadine;
[0112] keratolytics, such as acutretin, calciprotiene, calcifediol,
calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids,
targretin, and tazarotene;
[0113] lipid regulating agents, such as atorvastatin, bezafibrate,
cerivistatin, clinofibrate, clofibrate, fenofibrate, fluvastatin,
gemfibrozil, pravastatin, probucol, and simvastatin;
[0114] muscle relaxants, such as dantrolene sodium and tizanidine
HCl;
[0115] nitrates and other anti-anginal agents, such as amyl
nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide
mononitrate and pentaerythritol tetranitrate;
[0116] nutritional agents, such as calcitriol, carotenes,
dihydrotachysterol, essential fatty acids, non-essential fatty
acids, phytonodione, vitamin A, vitamin B.sub.2, vitamin D, vitamin
E and vitamin K.
[0117] opioid analgesics, such as codeine, dextropropyoxyphene,
diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone,
morphine, nalbuphine and pentazocine;
[0118] sex hormones, such as clomiphene citrate, cortisone acetate,
danazol, dihydro epiandrosterone, ethinyloestradiol, finasteride,
fludrocortisone, fluoxymisterone, medroxyprogesterone acetate,
megesterol acetate, mestranol, methyltestosterone, norethisterone,
norgestrel, oestradiol, conjugated estrogens, progesterone,
rimexolone, stanozolol, stiboestrol, testosterone and tibolone;
[0119] stimulants, such as amphetamine, dexamphetamine,
dexfenfluramine, fenfluramine and mazindol;
[0120] and others, such as becaplermin, donepezil HCl,
L-thryroxine, methoxsalen, nerteporfin, physostigmine,
pyridostigmine, raloxifene HCl, sibutramine HCl, sildenafil
citrate, tacrine, tamsulosin HCl, and tolterodine.
[0121] Preferred hydrophobic therapeutic agents include sildenafil
citrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin,
nabumetone, ibuprofen, terbenafine, itraconazole, zileuton,
zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine,
fexofenadine, loratadine, famotidine, paricalcitol, atovaquone,
nabumetone, tetrahydrocannabinol, megesterol acetate, repaglinide,
progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus,
teniposide, paclitaxel, pseudo-ephedrine, troglitazone,
rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, and
pharmaceutically acceptable salts, isomers and derivatives thereof.
Particularly preferred hydrophobic therapeutic agents are
progesterone and cyclosporin.
[0122] It should be appreciated that this listing of hydrophobic
therapeutic agents and their therapeutic classes is merely
illustrative. Indeed, a particular feature, and surprising
advantage, of the compositions of the present invention is the
ability of the present compositions to solubilize and deliver a
broad range of hydrophobic therapeutic agents, regardless of
functional class. Of course, mixtures of hydrophobic therapeutic
agents may also be used where desired.
[0123] 3. Solubilizers
[0124] If desired, the pharmaceutical compositions of the present
invention can optionally include additional compounds to enhance
the solubility of the hydrophobic therapeutic agent in the carrier
system. Examples of such compounds, referred to as "solubilizers",
include:
[0125] alcohols and polyols, such as ethanol, isopropanol, butanol,
benzyl alcohol, ethylene glycol, propylene glycol, butanediols and
isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,
transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene
glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other
cellulose derivatives, cyclodextrins and cyclodextrin
derivatives;
[0126] ethers of polyethylene glycols having an average molecular
weight of about 200 to about 6000, such as tetrahydrofurfuryl
alcohol PEG ether (glycofurol, available commercially from BASF
under the trade name Tetraglycol) or methoxy PEG (Union
Carbide);
[0127] amides, such as 2-pyrrolidone, 2-piperidone,
.epsilon.-caprolactam, N-alkylpyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide, and polyvinylpyrrolidone;
[0128] esters, such as ethyl propionate, tributylcitrate, acetyl
triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate,
.epsilon.-caprolactone and isomers thereof, .delta.-valerolactone
and isomers thereof, .beta.-butyrolactone and isomers thereof;
[0129] and other solubilizers known in the art, such as dimethyl
acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl
pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol
monoethyl ether (available from Gattefosse under the trade name
Transcutol), and water.
[0130] Mixtures of solubilizers are also within the scope of the
invention. Except as indicated, these compounds are readily
available from standard commercial sources.
[0131] Preferred solubilizers include triacetin, triethylcitrate,
ethyl oleate, ethyl caprylate, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl
cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol,
transcutol, propylene glycol, and dimethyl isosorbide. Particularly
preferred solubilizers include sorbitol, glycerol, triacetin, ethyl
alcohol, PEG-400, glycofurol and propylene glycol.
[0132] The amount of solubilizer that can be included in
compositions of the present invention is not particularly limited.
Of course, when such compositions are ultimately administered to a
patient, the amount of a given solubilizer is limited to a
bioacceptable amount, which is readily determined by one of skill
in the art. In some circumstances, it may be advantageous to
include amounts of solubilizers far in access of bioacceptable
amounts in order to maximize the concentration of hydrophobic
therapeutic agent, with excess solubilizer removed prior to
providing the composition to a patient using conventional
techniques, such as distillation or evaporation. Thus, if present,
the solubilizer can be in a concentration of 50%, 100%, 200%, or up
to about 400% by weight, based on the amount of surfactant. If
desired, very small amounts of solubilizers may also be used, such
as 25%, 10%, 5%, 1% or even less. Typically, the solubilizer will
be present in an amount of about 1% to about 100%, more typically
about 5% to about 25% by weight.
[0133] 4. Other Additives
[0134] Other additives conventionally used in pharmaceutical
compositions can be included, and these additives are well known in
the art. Such additives include antioxidants, preservatives,
chelating agents, viscomodulators, tonicifiers, flavorants,
colorants odorants, opacifiers, suspending agents, binders, and
mixtures thereof. The amounts of such additives can be readily
determined by one skilled in the art, according to the particular
properties desired.
[0135] 5. Dosage Forms
[0136] The pharmaceutical compositions of the present invention can
be provided in the form of a solution preconcentrate; i.e., a
composition as described above, and intended to be dispersed with
water, either prior to administration, in the form of a drink, or
dispersed in vivo. Alternatively, the compositions can be provided
in the form of a diluted preconcentrate (i.e., an aqueous
dispersion), a semi-solid dispersion or a solid dispersion. If
desired, the compositions may be encapsulated in a hard or soft
gelatin capsule, a starch capsule or an enteric coated capsule. The
term "enteric coated capsule" as used herein means a capsule coated
with a coating resistant to acid; i.e., an acid resistant enteric
coating. Although solubilizers are typically used to enhance the
solubility of a hydrophobic therapeutic agent, they may also render
the compositions more suitable for encapsulation in hard or soft
gelatin capsules. Thus, the use of a solubilizer such as those
described above is particularly preferred in capsule dosage forms
of the pharmaceutical compositions. If present, these solubilizers
should be added in amounts sufficient to impart to the compositions
the desired solubility enhancement or encapsulation properties.
[0137] Although formulations specifically suited to oral
administration are presently preferred, the compositions of the
present invention can also be formulated for topical, transdermal,
ocular, pulmonary, vaginal, rectal, transmucosal or parenteral
administration, in the form of a triglyceride-free cream, lotion,
ointment, suppository, gel or the like. If such a formulation is
desired, other additives may be included, such as are well-known in
the art, to impart the desired consistency and other properties to
the formulation. The compositions of the present invention can also
be formulated as a spray or an aerosol. In particular, the
compositions may be formulated as a sprayable solution, and such
formulation is particularly useful for spraying to coat a
multiparticulate carrier, such as a bead. Such multiparticulate
carriers are well known in the art.
[0138] 6. Preparation of Pharmaceutical Compositions
[0139] The pharmaceutical compositions of the present invention can
be prepared by conventional methods well known to those skilled in
the art. Of course, the specific method of preparation will depend
upon the ultimate dosage form. For dosage forms substantially free
of water, i.e., when the composition is provided in a
pre-concentrated form for later dispersion in an aqueous system,
the composition is prepared by simple mixing of the components to
form a pre-concentrate. The mixing process can be aided by gentle
heating, if desired. For compositions in the form of an aqueous
dispersion, the pre-concentrate form is prepared, then the
appropriate amount of purified water is added. Upon gentle mixing,
a clear aqueous dispersion is formed. If any water-soluble
additives are included, these may be added first as part of the
pre-concentrate, or added later to the clear aqueous dispersion, as
desired.
[0140] In another embodiment, the present invention includes a
multi-phase dispersion. In this embodiment, a pharmaceutical
composition includes a carrier which forms a clear aqueous
dispersion upon mixing with an aqueous solution, and an additional
amount of non-solubilized hydrophobic therapeutic agent. Thus, the
term "multi-phase" as used herein to describe these compositions of
the present invention means a composition which when mixed with an
aqueous solution forms a clear aqueous phase and a particulate
dispersion phase. The carrier is as described above, and can
include any of the surfactants, hydrophobic therapeutic agents,
solubilizers and additives previously described. An additional
amount of hydrophobic therapeutic agent is included in the
composition. This additional amount is not solubilized by the
carrier, and upon mixing with an aqueous system is present as a
separate dispersion phase. The additional amount is optionally a
milled, micronized, or precipitated form. Thus, upon dilution, the
composition contains two phases: a clear aqueous dispersion of the
hydrophilic and hydrophobic surfactants containing a first,
solubilized amount of the hydrophobic therapeutic agent, and a
second, non-solubilized amount of the hydrophobic therapeutic agent
dispersed therein. It should be emphasized that the resultant
multi-phase dispersion will not have the optical clarity of a
dispersion in which the hydrophobic therapeutic agent is fully
solubilized, but will appear to be cloudy, due to the presence of
the non-solubilized phase. Such a formulation may be useful, for
example, when the desired dosage of a hydrophobic therapeutic agent
exceeds that which can be solubilized in the carrier of the present
invention. The formulation may also contain additives, as described
above.
[0141] One skilled in the art will appreciate that a hydrophobic
therapeutic agent may have a greater solubility in the
pre-concentrate carrier than in the aqueous dispersion, so that
meta-stable, supersaturated solutions having apparent optical
clarity but containing a hydrophobic therapeutic agent in an amount
in excess of its solubility in the aqueous dispersion can be
formed. Such super-saturated solutions, whether characterized as
clear aqueous dispersions (as initially formed) or as multi-phase
solutions (as would be expected if the meta-stable state breaks
down), are also within the scope of the present invention.
[0142] The multi-phase formulation can be prepared by the methods
described above. A pre-concentrate is prepared by simple mixing of
the components, with the aid of gentle heating, if desired. It is
convenient to consider the hydrophobic therapeutic agent as divided
into two portions, a first solubilizable portion which will be
solubilized by the carrier and contained within the clear aqueous
dispersion upon dilution, and a second non-solubilizable portion
which will remain non-solubilized. When the ultimate dosage form is
non-aqueous, the first and second portions of the hydrophobic
therapeutic agent are both included in the pre-concentrate mixture.
When the ultimate dosage form is aqueous, the composition can be
prepared in the same manner, and upon dilution in an aqueous
system, the composition will form the two phases as described
above, with the second non-solubilizable portion of the hydrophobic
therapeutic agent dispersed or suspended in the aqueous system, and
the first solubilizable portion of the hydrophobic therapeutic
agent solubilized in the mixed surfactant carrier. Alternatively,
when the ultimate dosage form is aqueous, the pre-concentrate can
be prepared including only the first, solubilizable portion of the
hydrophobic therapeutic agent. This pre-concentrate can then be
diluted in an aqueous system to form a clear aqueous dispersion, to
which is then added the second, non-solubilizable portion of the
hydrophobic therapeutic agent to form a multi-phase aqueous
composition.
[0143] The amount of hydrophobic therapeutic agent included in the
pharmaceutical compositions of the present invention can be any
amount desired by the formulator, up to the maximum amount that can
be solubilized or suspended in a given carrier system. In general,
the amount of hydrophobic therapeutic agent will be about 0.1% to
about 60% by weight, based on the total weight of the
pharmaceutical composition. In another aspect of the invention,
described below, excess hydrophobic therapeutic agent can also be
added, in a multi-phase dispersion.
[0144] B. Methods of Improved Delivery
[0145] In another aspect, the present invention relates to methods
of improving delivery of hydrophobic therapeutic agents in an
animal by administering to the animal a dosage form of the
pharmaceutical compositions described herein. Preferably the animal
is a mammal, and more preferably, a human. It has been found that
the pharmaceutical compositions of the present invention when
administered to an animal enable the hydrophobic therapeutic agent
contained therein to be absorbed more rapidly than in conventional
pharmaceutical compositions. Thus, in this aspect the invention
relates to a method of increasing the rate of and/or extent of
bioabsorption of a hydrophobic therapeutic agent by administering
the hydrophobic therapeutic agent to an animal in the
pharmaceutical compositions described herein.
[0146] C. Characteristics of the Pharmaceutical Compositions
[0147] The dispersions formed upon dilution of the pharmaceutical
compositions of the present invention have the following
characteristics:
[0148] Rapid formation: upon dilution with an aqueous solution, the
carrier forms a clear dispersion very rapidly; i.e., the clear
dispersion appears to form instantaneously.
[0149] Optical clarity: the dispersions are essentially optically
clear to the naked eye, and show no readily observable signs of
heterogeneity, such as turbidity or cloudiness. More
quantitatively, dispersions of the pharmaceutical compositions of
the present invention show a mono-modal distribution of very small
particles sizes, typically 20 nm or less in average diameter;
absorbances of less than about 0.3, typically less than about 0.1,
at 10.times. dilution; and absorbances of less than about 0.1,
typically less than about 0.01, at 100.times. dilution, as
described more fully in the Examples herein. In the multi-phase
embodiment of the compositions described herein, it should be
appreciated that the optical clarity of the aqueous carrier
dispersion phase will be obscured by the dispersed particulate
non-solubilized hydrophobic therapeutic agent.
[0150] Robustness to dilution: the dispersions are surprisingly
stable to dilution in aqueous solution, including aqueous solutions
simulating physiological fluids such as enzyme-free simulated
gastric fluid (SGF) and enzyme-free simulated intestinal fluid
(SIF). The hydrophobic therapeutic agent remains solubilized for at
least the period of time relevant for absorption.
[0151] Triglyceride-free: It is a particular feature of the present
invention that the pharmaceutical compositions are substantially
triglyceride-free. The term "triglyceride" as used herein means
glycerol triesters of C.sub.6 to about C.sub.25 fatty acids. Unlike
conventional compositions such as oil-based solutions, emulsions,
and microemulsions, which rely on the solubilizing power of
triglycerides, the present compositions surprisingly solubilize
hydrophobic therapeutic agents using combinations of substantially
triglyceride-free surfactants.
[0152] As used herein, the term "substantially triglyceride-free"
means compositions which contain triglycerides, if at all, only as
minor components or impurities in surfactant mixtures. It is well
known in the art that commercially available surfactants often are
complex mixtures of compounds. For example, one preferred
surfactant is Capmul.RTM. GMO-K, a widely-used blend of glyceryl
mono- and dioleates. Due to difficulties in separating complex
product mixtures, however, a typical lot of Capmul.RTM. GMO-K, as
reported by the manufacturer's certificate of analysis, contains
the following distribution of glyceryl esters, in percent by weight
based on the total weight of glyceryl esters:
19 Palmitic acid 3.3% Stearic acid 4.0% Oleic acid 81.0% Linoleic
acid 9.7% Linolenic acid 0.3%
[0153] In addition, the surfactant mixture in the particular lot
reported contains 0.10% water and 0.95% free, unesterified
glycerol. These specific percentages are expected to vary,
lot-by-lot, as well, and it is expected that commercial surfactant
products will generally possess similar variability, regardless of
the specific major component and the specific manufacturer. Thus,
the present invention does not include surfactants which contain
triglycerides as an intended component. Indeed, such surfactants
are not common, since triglycerides themselves have no surfactant
properties. However, it should be appreciated that the present
invention does not exclude the use of surfactant products which
contain small amounts of triglycerides as impurities or as
unreacted starting material. It is expected that commercial
mixtures suitable for use in the present invention may contain as
much as 5% triglycerides by weight as unintended components. Thus,
"substantially triglyceride-free" should be understood as meaning
free of added triglycerides, and containing less than 5%,
preferably essentially 0%, triglyceride impurities.
[0154] Without wishing to be bound by theory, it is believed that
the observed properties of the clear, aqueous dispersions formed by
the compositions of the present invention are consistent with, and
best explained by, the formation of mixed micelles of the
hydrophobic and hydrophilic surfactants, with the hydrophobic
therapeutic agent solubilized by the micelles. It should be
emphasized that these dispersions are characterized by the
properties described herein, regardless of the precise microscopic
physical form of the dispersed particles. Nevertheless, in order to
more fully explain the invention, and to illustrate its unexpected
and important advantages, the following discussion is offered in
terms consistent with the theoretical principles believed to be
correct.
[0155] It is believed that the hydrophobic and hydrophilic
surfactants form mixed micelles in aqueous solution. In this model,
each micelle is composed of molecules (or ions) of both the
hydrophilic and hydrophobic surfactants. Depending upon the
detailed three-dimensional structure of the hydrophobic therapeutic
agent, its distribution of polar moieties, if any, its
polarizability in local regions, and other molecule-specific and
complex factors, the hydrophobic therapeutic agent may be
distributed in any part of the micelle, such as near the outer,
more hydrophilic region, near the inner, more hydrophobic region,
or at various points in between. Further, it is known that micelles
exist in dynamic equilibrium with their component molecules, and it
is expected that this equilibrium will include dynamic
redistribution of the hydrophobic therapeutic agent.
[0156] As discussed above, triglyceride-containing formulations
suffer the disadvantage that bioabsorption of the hydrophobic
therapeutic agents contained therein is dependent upon enzymatic
degradation (lipolysis) of the triglyceride components. The
pharmaceutical compositions of the present invention, however, are
substantially free of triglycerides, and thus do not depend upon
lipolysis to enable release of the hydrophobic therapeutic agent
for bioabsorption. The hydrophobic therapeutic agent is in a
dynamic equilibrium between the free compound in solution and the
solubilized compound, thus promoting rapid release.
[0157] The unique pharmaceutical compositions of the present
invention present a number of significant and unexpected
advantages, including:
[0158] Efficient transport: The particle sizes in the aqueous
dispersions of the present invention are much smaller, typically
less than 20 nm, than the larger particles characteristic of
vesicular, emulsion or microemulsion phases, and the particle size
distribution is mono-modal and narrow. This reduced and more
uniform size enables more efficient drug transport through the
intestinal aqueous boundary layer, and through the absorptive brush
border membrane. More efficient transport to absorptive sites leads
to improved and more consistent absorption of hydrophobic
therapeutic agents.
[0159] Non-dependence on lipolysis: The lack of triglyceride
components provides pharmaceutical compositions not dependent upon
lipolysis, and upon the many poorly characterized factors which
affect the rate and extent of lipolysis, for effective presentation
of a hydrophobic therapeutic agent to an absorptive site. Such
factors include the presence of composition components which may
inhibit lipolysis; patient conditions which limit production of
lipase, such as pancreatic lipase secretory diseases; and
dependence of lipolysis on stomach pH, endogenous calcium
concentration, and presence of co-lipase or other digestion
enzymes. The lack of lipolysis dependence further provides
transport which does not suffer from any lag time between
administration and absorption caused by the lipolysis process,
enabling a more rapid onset of therapeutic action and better
bioperformance characteristics. In addition, pharmaceutical
compositions of the present invention can make use of hydrophilic
surfactants which might otherwise be avoided or limited due to
their potential lipolysis inhibiting effects.
[0160] Non-dependence on bile and meal fat contents: Due to the
higher solubilization potential over bile salt micelles, the
present compositions are less dependent on endogenous bile and bile
related patient disease states, and meal fat contents. These
advantages overcome meal-dependent absorption problems caused by
poor patient compliance with meal-dosage restrictions.
[0161] Superior solubilization: The surfactant combinations used in
compositions of the present invention enable superior loading
capacity over conventional micelle formulations. In addition, the
particular combination of surfactants used can be optimized for a
specific hydrophobic therapeutic agent to more closely match the
polarity distribution of the therapeutic agent, resulting in still
further enhanced solubilization.
[0162] Faster dissolution and release: Due to the robustness of
compositions of the present invention to dilution, the hydrophobic
therapeutic agents remain solubilized and thus do not suffer
problems of precipitation of the therapeutic agent in the time
frame relevant for absorption. In addition, the therapeutic agent
is presented in small particle carriers, and is not limited in
dilution rate by entrapment in emulsion carriers. These factors
avoid liabilities associated with the poor partitioning of lipid
solubilized drug in to the aqueous phase, such as large emulsion
droplet surface area, and high interfacial transfer resistance, and
enable rapid completion of the critical partitioning step.
[0163] Consistent performance: Aqueous dispersions of the present
invention are thermodynamically stable for the time period relevant
for absorption, and can be more predictably reproduced, thereby
limiting variability in bioavailability--a particularly important
advantage for therapeutic agents with a narrow therapeutic
index.
[0164] Efficient release: The compositions of the present invention
are designed with components that help to keep the hydrophobic
therapeutic agent solubilized for transport to the absorption site,
but readily available for absorption, thus providing a more
efficient transport and release.
[0165] Less prone to gastric emptying delays: Unlike
triglyceride-containing formulations, the present compositions are
less prone to gastric emptying delays, resulting in faster
absorption. Further, the particles in dispersions of the present
invention are less prone to unwanted retention in the
gastro-intestinal tract.
[0166] Small size: Because of the small particle size in aqueous
dispersion, the pharmaceutical compositions of the present
invention allow for faster transport of the hydrophobic therapeutic
agent through the aqueous boundary layer.
[0167] These and other advantages of the present invention, as well
as aspects of preferred embodiments, are illustrated more fully in
the Examples which follow.
EXAMPLES
Example 1
[0168] Preparation of Compositions
[0169] A simple pre-concentrate of a hydrophobic surfactant and a
hydrophilic surfactant is prepared as follows. Predetermined
weighed amounts of hydrophilic and hydrophobic surfactants are
stirred together to form a homogeneous mixture. For surfactant
combinations that are poorly miscible, the mixture can be gently
heated to aid in formation of the homogeneous mixture. A chosen
hydrophobic therapeutic agent in a predetermined amount is added
and stirred until solubilized. Optionally, solubilizers or
additives are included by simple mixing.
[0170] To form an aqueous dispersion of the pre-concentrate, a
predetermined amount of purified water, buffer solution, or aqueous
simulated physiological solution, is added to the pre-concentrate,
and the resultant mixture is stirred to form a clear, aqueous
dispersion.
Example 2
[0171] Surfactant Combinations Giving Clear Aqueous Dispersions
[0172] Surfactant mixtures giving clear, aqueous dispersions were
prepared according to the method of Example 1. Seven hydrophilic
surfactants and sixteen hydrophobic surfactants were used to
produce approximately one hundred clear aqueous dispersions
suitable for use in the present invention. For simplicity, no
hydrophobic therapeutic agent was included in these compositions,
since it is believed that the presence of the hydrophobic
therapeutic agent does not substantially affect the clear, aqueous
nature of composition. For the same reason, these compositions were
free of additional solubilizers and other additives.
[0173] Multiple solutions were prepared for each surfactant
combination, to determine the approximate maximum amount of
hydrophobic therapeutic agent giving a clear aqueous dispersion
with a given amount of hydrophilic therapeutic agent. Thus, for
each gram of the hydrophilic surfactant, a predetermined amount of
hydrophobic agent was used to prepare a 10.times. aqueous
dispersion. If the dispersion appeared to be optically clear, a new
dispersion was prepared according to Example 1, using a larger
amount of hydrophobic surfactant. Similarly, if the dispersion
appeared to be cloudy, a new dispersion was prepared using a
smaller amount of hydrophobic surfactant. The results are shown in
Table 19.
20TABLE 19 Surfactant Combinations Giving Clear Dispersions
Hydrophilic Surfactant PEG-35 PEG-40H PEG-60 PEG-8 PEG-25 Castor
Oil Castor Oil Polysorbate Polysorbate Corn Oil Capric/ Glyceryl
Hydrophobic (Incrocas (Cremophor -20 80 (Crovol M- Caprylic
trioleate Surfactant 35) RH-40) (Tween 20) (Tween 80) 70)
(Labrasol) (Tagat TO) Glyceryl/Propylene 20 20 20 8 15 25 10 Glycol
Oleate (Arlacel 186) Glyceryl Oleate 15 40 10 12 10 35 10 (Peceol)
Acetylated 80 80 20 15 10 10 10 Monoglycerides (Myvacet 9-45) PEG-6
Corn Oil 50 95 10 10 20 10 10 (Labrafil M2125CS) Sorbitan
Monooleate 25 65 5 5 20 15 10 (Span 80) Sorbitan Monolaurate 30 20
20 10 15 30 10 (Arlacel 20) Polyglyceryl oleate 10 5 35 10 10 35 10
(Plurol Oleique CC497) Propylene Glycol Laurate 10 55 35 20 15 35
10 (Lauroglycol FCC) Glyceryl Caprylate/ 10 50 20 25 25 20 10
Caprate (Capmul MCM) PEG-20 Corn Oil 35 40 40 25 30 90 10 (Crovol
M-40) PEG-20 Almond Oil 30 35 40 25 30 90 10 (Crovol A-40)
Mono/diglycerides of 50 50 60 25 25 30 10 Caprylic Acid (Imwitor
988) PEG-4-lauryl ether 40 45 95 70 * 90 10 (Brij 30) PEG-3-oleyl
ether 20 30 25 20 20 25 10 (Volpo 3) Glyceryl mono/dioleate * 10 *
* 10 25 10 (Capmul GMO-K) Ethyl Oleate 40 60 10 10 60 10 10
(Crodamol EO) *This combination was not tested.
[0174] Each entry in the Table represents the approximate maximum
number of grams of hydrophobic surfactant per 100 g of hydrophilic
surfactant giving acceptable optical clarity. The numbers in the
Table are illustrative only, and it is expected that further
optimization of the surfactant systems with solubilizers,
co-surfactants, and other additives will give still higher
numbers.
Example 3
[0175] Compositions Containing Solubilizers
[0176] The procedure of Example 2 was repeated for compositions
containing PEG-40 hydrogenated castor oil (Cremophor RH 40) as the
hydrophilic surfactant, with eight different hydrophobic
surfactants, and four different solubilizers, to study the effect
of solubilizer on the relative amounts of hydrophobic and
hydrophilic surfactants giving clear aqueous dispersions. In each
case, the amount of solubilizer was held constant at 20% by weight,
based on the total weight of the two surfactants. The results are
shown in Table 20. As in Example 2, the numbers in the Table
represent the approximate maximum number of grams of hydrophobic
surfactant per 100 g of hydrophilic surfactant giving a clear
aqueous dispersion. For convenience, the corresponding entries from
Table 19 (with no solubilizer present) are reproduced in Table 20
in the column labeled "none."
21TABLE 20 Effect of Solubilizer on Hydrophobic Surfactant Amounts
Hydrophilic Surfactant (Cremophor RH40) + 20% Solubilizer PEG-
Glyco- Hydrophobic Surfactant (None) Triacetin Ethanol 400 furol
Glyceryl/Propylene 20 28 25 25 25 Glycol Oleate (Arlacel 186)
Glyceryl Oleate 40 40 42 40 44 (Peceol) Sorbitan Monooleate 65 40
40 25 30 (Span 80) Sorbitan Monolaurate 20 65 * * 65 (Span 20)
PEG-6 Corn Oil 95 95 * 95 * (Labrafil M2125CS) Acetylated 80 80 80
80 80 Monoglyceride (Myvacet 9-45) Ethyl Oleate 60 60 60 * 60
(Crodamol EO) Mono/diglycerides of 50 80 * * 75 Caprylic Acid
(Imwitor 988) *This combination was not tested.
[0177] As is clear from the data in the Table, the effect of added
solubilizer on the relative amount of hydrophobic surfactant that
can be used varies considerably. For some surfactant combinations,
the added solubilizer has a dramatic effect on the amount of
hydrophobic surfactant (e.g., Span 20, Imwitor 988). In other
systems, the effect is moderate (Arlacel 186, Peceol) or negligible
(Crodamol EO, Myvacet 9-45). In the one case of Span 80, the
presence of the solubilizer actually decreases the amount of
hydrophobic surfactant that can be used.
Example 4
[0178] Compositions Containing Solubilizers
[0179] Example 3 was repeated, this time choosing a single
hydrophobic surfactant (Arlacel 186) and three different
hydrophilic surfactants, with addition of either ethanol or
triacetin (20% by weight, based on the total weight of the two
surfactants). The results are shown in Table 21. The corresponding
entry from Table 19 (with no solubilizer present) is included in
Table 21 for reference.
22TABLE 21 Effect of Solubilizer on Hydrophobic Surfactant Amounts
Hydrophobic Surfactant (Arlacel 186) + Hydrophilic 20% Solubilizer
Surfactant (None) Ethanol Triacetin PEG-60 Corn Oil 15 20 20
(Crovol M-70) PEG-35 Castor Oil 20 25 25 (Incrocas 35) Polysorbate
20 20 25 25 (Tween 20)
[0180] In each case, a moderate increase (20%) in the relative
amount of hydrophobic surfactant was observed.
Example 5
[0181] Effect of Solubilizer Concentration
[0182] The procedure of Example 3 was repeated, with the following
differences. A single hydrophilic surfactant (Cremophor RH-40) and
hydrophobic surfactant (Arlacel 186) were chosen, to examine the
effect of increased solubilizer concentration. For each of the four
solubilizers tested at 20% concentrations in Example 3 (Table 20)
plus an additional solubilizer (propylene glycol), compositions
were tested at a solubilizer concentration of 50% by weight, based
on the total weight of the surfactant pair. As in each of the
previous examples, the numbers in Table 22 represent the maximum
hydrophobic surfactant concentration giving a clear aqueous
dispersion. Note that the "0" column in Table 22 reproduces the
numbers shown in Table 19 (no solubilizer), and the "20%" column
reproduces the numbers in Table 20, with the value for propylene
glycol also supplied.
23TABLE 22 Effect of Solubilizer Concentration on Hydrophobic
Surfactant Amounts* Weight Percent of Solubilizer Solubilizer 0 20
50 PEG-400 20 25 25 Propylene Glycol 20 28 30 Triacetin 20 28 25
Ethanol 20 25 30 Glycofurol 20 25 30 *for an Arlacel 186
(hydrophobic)-Cremophor RH-40 (hydrophilic) surfactant pair
[0183] As the Table shows, increasing the amount of solubilizer has
a small to moderate effect on the amount of hydrophobic surfactant
that can be present in a clear aqueous dispersion. It should be
appreciated that the data equivalently show that very large amounts
of solubilizer can be used, without detrimental effect on the
ability of the surfactant system to form a clear, aqueous
dispersion.
Example 6
[0184] Effect of High Solubilizer Concentration and Solubilizer
Mixtures
[0185] Example 5 was repeated, using the same surfactant pair, but
with an 80% concentration of solubilizer, based on the total weight
of the surfactants. The 80% solubilizer was either PEG-400, or a
mixture of PEG-400 and one of three alcohols or polyols. The
results are shown in Table 23, with the numbers in the Table having
the same meaning as in the previous Examples.
24TABLE 23 Large Solubilizer Concentrations and Solubilizer
Mixtures* 60% 60% 60% PEG-400 + PEG-400 + (no 80% PEG-400 + 20%
Propylene 20% solubilizer) PEG-400 20% Glycerol Glycol Isopropanol
20 25 25 25 25 *for an Arlacel 186 (hydrophobic)-Cremophor RH-40
(hydrophilic) surfactant pair
[0186] It is clear from the data in the Table that very high
concentrations of solubilizers, as well as mixtures of
solubilizers, can be used effectively in the clear aqueous
dispersions of the present invention.
Examples 7-12
[0187] Average Particle Size
[0188] In order to more quantitatively characterize the clear
aqueous dispersions of the present invention, particle sizes were
measured for several compositions of the present invention. For
simplicity, the measurement were made for the dispersed carrier, in
the absence of a hydrophobic therapeutic agent. In this Example,
formulations were prepared as in Example 1, and diluted to form
10.times. or 100.times. aqueous dispersions. Each of the resulting
dispersions was observed to be optically clear to the naked eye.
Average particle sizes were measured with a Nicomp Particle Size
Analyzer (Particle Size Systems, Inc., Santa Barbara, Calif.). The
results of these measurements are shown in Table 24.
25TABLE 24 Average Particle Size Ex- Particle am- Sur- Size ple
factant Dilu- Observa- (nm) .+-. No. Formula Ratio* tion tion
S.D.** 7 Tween 80 520 mg 9.6 100X very clear 6.5 .+-. 1.1
Lauroglycol 50 mg solution FCC 8 Tween 80 500 mg 15 10X very clear
8.1 .+-. 1.6 Capmul 73 mg solution MCM 9 Cremophor 530 mg 28 100X
clear 12.4 .+-. 3.0 RH-40 150 mg solution Peceol 10 Cremophor 500
mg 2.0 100X clear 14.7 .+-. 3.0 RH-40 10 mg solution Plurol Oleique
CC497 11 Cremophor 550 mg 36 100X clear 14.3 .+-. 2.5 RH-40 200 mg
solution Lauroglycol FCC 12 Cremophor 500 mg 40 100X clear 12.6
.+-. 2.9 RH-40 200 mg solution Capmul MCM *grams of hydrophobic
surfactant per 100 g of hydrophilic surfactant **standard
deviation
[0189] As the data show, the compositions of the present invention
produce clear, aqueous dispersions, with no visible cloudiness. The
particle size distribution shows very small particles, with average
diameters of from about 6 to about 15 nm. The distribution is
mono-modal, with a standard deviation of approximately 20%,
indicating a highly uniform distribution of very small particles.
This particle size distribution is consistent with a solution of
particles of micellar structure, although the invention is not
limited by any particular theoretical framework.
Comparative Examples C1-C5
[0190] Optical Clarity and Particle Sizes of Compositions Not
Forming Clear Aqueous Dispersions
[0191] For comparison to the clear aqueous dispersions of the
present invention, several compositions were prepared having
hydrophobic surfactant concentrations higher than those suitable
for forming clear aqueous dispersions. These compositions were
prepared by weighing the components and mixing well, with gentle
warming. The compositions were then diluted 10.times. to form
dispersions, and these dispersions were subjected to the particle
size measurements as described in Example 7. The results are shown
in Table 25. For direct comparison with the compositions of the
present invention, Examples 7, 9, 10, 11 and 12 are shown next to
the corresponding comparative compositions.
26TABLE 25 Optical Clarity and Particle Size Example Surfactant
Particle Size (nm)** No. Surfactants Ratio* Observation Mean 1 Mean
2 C1 Tween 80 67 milky 26.6 209 Lauroglycol solution FCC 7 Tween 80
9.6 very clear 6.5 -- Lauroglycol solution FCC C2 Cremophor 67
milky 25 116 RH-40 solution Peceol 9 Cremophor 28 clear 8.1 --
RH-40 solution Peceol C3 Cremophor 67 milky 16.5 102 RH-40 solution
Plurol Oleique CC497 10 Cremophor 2.0 clear 12.4 -- RH-40 solution
Plurol Oleique CC497 C4 Cremophor 69 hazy 17.1 45.3 RH-40 solution
Lauroglycol FCC 11 Cremophor 36 clear 14.3 RH-40 solution
Lauroglycol FCC C5 Cremophor 67 milky 11.6 176 RH-40 solution
Capmul MCM 12 Cremophor 40 clear 12.6 -- RH-40 solution Capmul MCM
*grams of hydrophobic surfactant per 100 g of hydrophilic
surfactant **two means are reported for bimodal distributions
[0192] In addition to the compositions shown in the Table,
compositions containing Tween 80 and Plurol Oleique CC497, Tween 80
and Peceol, and Tween 80 and Capmul MCM were prepared at a
surfactant ratio of 67 g hydrophobic surfactant per 100 g
hydrophilic surfactant. Particle sizes were not measured for these
compositions, but each was observed to form a milky or hazy aqueous
dispersion.
[0193] As the data show, compositions having excessive amounts of
hydrophobic surfactant form milky or hazy solutions, whereas those
of the present invention form clear solutions. In addition, the
particle size distributions of the milky solutions are bimodal, in
contrast to the mono-modal solutions of the corresponding clear
solutions. These bimodal particle size distributions show a first
mode having a small mean particle size of about 12 to about 27 nm,
and a second mode having particle sizes of up to more than 200 nm.
Thus, compositions having excessive hydrophobic surfactant are
heterogeneous (multi-phasic), non-clear dispersions, having a
complex bimodal distribution of particles of two distinct size
ranges. In contrast, compositions of the present invention are
homogeneous (single phase), clear dispersion, having a mono-modal
distribution of very small particle sizes.
Examples 13-42
[0194] Spectroscopic Characterization of Optical Clarity
[0195] The optical clarity of aqueous dispersions of the present
invention was measured spectroscopically. Compositions were
prepared according to Example 1, and diluted to 10.times. and
100.times. solutions. The specific compositions measured also
include a solubilizer, to further illustrate preferred aspects of
the invention. In addition, several of the compositions illustrate
compositions according to the present invention wherein either the
hydrophilic surfactant (Examples 20 and 27) or the hydrophobic
surfactant (Examples 41 and 42) itself is a mixture of
surfactants.
[0196] The absorbance of each solution was measured at 400.2 nm,
using a purified water standard, and the results are shown in Table
26.
27TABLE 26 Spectroscopic Characterization of Optical Clarity
Example Absorbance (400.2 nm) No. Formulation 10X 100X 13 Cremophor
RH-40 430 mg 0.407 0.099 Myvacet 9-45 310 mg Ethyl Alcohol 210 mg
14 Cremophor RH-40 610 mg 0.299 0.055 Peceol 160 mg Ethyl Alcohol
200 mg 15 Cremophor RH-40 540 mg 0.655 0.076 Span 80 260 mg
Triacetin 220 mg 16 Incrocas 35 470 mg 0.158 0.038 Myvacet 9-45 250
mg Ethyl Alcohol 220 mg 17 Incrocas 35 510 mg 0.064 0.009 Imwitor
988 220 mg Triacetin 200 mg 18 Tween 20 570 mg 0.031 0.003
Lauroglycol FCC 140 mg Glycofurol 220 mg 19 Crovol M70 610 mg 0.049
0.006 Crovol M40 120 mg Ethyl Alcohol 200 mg 20 Cremophor RH-40 250
mg 0.028 0.008 Labrasol 250 mg Capmul GMO-K 110 mg Triacetin 100 mg
21 Cremophor RH-40 220 mg 0.114 0.018 Lauroglycol FCC 200 mg Ethyl
Alcohol 75 mg 22 Tween 80 170 mg 0.050 0.008 Capmul MCM 30 mg Ethyl
Alcohol 38 mg 23 Cremophor RH-40 550 mg 0.029 0.006 Capmul MCM 80
mg Ethyl Alcohol 53 mg 24 Cremophor RH-40 230 mg 0.187 0.020 Peceol
70 mg Ethyl Alcohol 54 mg 25 Cremophor RH-40 500 mg 0.028 0.005
Plurol Oleique 10 mg CC497 11 mg Ethyl Alcohol 26 Tween 80 180 mg
0.036 0.003 Lauroglycol FCC 20 mg Ethyl Alcohol 37 mg 27 Tween 80
420 mg 0.036 0.009 Labrasol 330 mg Arlacel 186 54 mg Ethyl Alcohol
140 mg 28 Tagat O2 500 mg 0.077 0.005 PGMG-03 50 mg Ethyl Alcohol
100 mg 29 Incrocas 35 250 mg 0.053 0.005 Gelucire 44/14 150 mg
Triacetin 94 mg 30 Cremophor RH-40 270 mg 0.232 0.047 Labrafil 170
mg Ethyl Alcohol 100 mg 31 Crovol M-70 380 mg 0.064 0.011 Labrafil
50 mg Triacetin 100 mg 32 Cremophor RH-40 300 mg 0.163 0.034 Peceol
110 mg Triacetin 110 mg 33 Tween 20 340 mg 0.038 0.005 Lauroglycol
FCC 110 mg Glycofurol 100 mg 34 Incrocas-35 310 mg 0.101 0.020
Labrafil 110 mg Ethyl Alcohol 100 mg 35 Cremophor RH-40 300 mg
0.908 0.114 Span 80 130 mg Triacetin 100 mg 36 Cremophor RH-40 510
mg 0.039 0.008 Arlacel 186 58 mg Propylene Glycol 55 mg 37
Cremophor RH-40 510 mg 0.440 0.100 Peceol 140 mg Propylene Glycol
58 mg 38 Cremophor RH-40 500 mg 0.411 0.107 Labrafil M2125CS 400 mg
Propylene Glycol 88 mg 39 Cremophor RH-40 550 mg 0.715 0.106 Span
80 220 mg Propylene Glycol 78 mg 40 Cremophor RH-40 500 mg 0.547
0.147 Crodamol 280 mg Propylene Glycol 100 mg 41 Cremophor RH-40
550 mg 0.419 0.055 Labrafil M2125CS 340 mg Span 80 200 mg Ethyl
Alcohol 110 mg 42 Cremophor RH-40 500 mg 0.293 0.260 Labrafil
M2125CS 270 mg Crovol M-40 280 mg Ethyl Alcohol 100 mg
[0197] Ideally, a clear aqueous dispersion should have a very high
transmittance, indicating little scattering of light by large
particles. Absorbance and transmittance are related by the simple
expression
A=-log T
[0198] where A is absorbance, and T is the transmittance expressed
as a decimal. Thus, preferred solutions of the present invention
will have small absorbances. As noted above, in the absence of true
absorption (due to chromophores in solution), suitable clear
aqueous dispersions of the present invention should have an
absorbance at 10.times. dilution of less than about 0.3.
[0199] The data in Table 26 show 30 solutions, 22 of which have
absorbances less than about 0.3 at 10.times. dilution. Of these
solutions, 3 have absorbances between 0.2 and 0.3, 5 have
absorbances between 0.1 and 0.2, and 14 have absorbances less than
0.1. Thus, for the majority of the solutions, absorbance provides
an adequate measure of optical clarity.
[0200] Solutions having absorbances greater than 0.3 may still be
suitable for use in the present invention, as these are observed to
have acceptable optical clarity by visual examination. For these
relatively high absorbance solutions, this simple spectroscopic
measure of optical clarity is inadequate, and other methods are
more well-suited to assessing optical clarity, such as visual
observation and particle size. As an example, Example 37, which
shows an absorbance of 0.440, has a surfactant ratio of 27, well
below the value of 40 shown in Table 19, and is observed to be a
clear solution. This same composition, without the additional
solubilizer, is shown in Example 9 at a surfactant ratio of 28 to
have a mono-modal, narrow particle size distribution, at an average
particle size of 12.4 nm. It should be appreciated that direct
particle size measurement and absorbance measurement are different
ways of assessing optical clarity, and provide alternative criteria
for quantifying clarity. However, it is believed that the simple,
qualitative visual observation of optical clarity is a sufficient
measure of suitable clarity for use in the present invention,
particularly so since compositions outside the scope of the
invention show marked and unmistakable cloudiness without recourse
to quantitative measurement (See, e.g., Comparative Example 1).
Comparative Examples C6-C12
[0201] Spectroscopic Characterization of Compositions Not Forming
Clear Aqueous Dispersions
[0202] For comparison to the clear aqueous dispersions of the
present invention, compositions observed to be milky or cloudy were
characterized by absorption, as in Examples 13-42. Where available,
results for comparable solutions from Examples 13-42 are reproduced
for comparison. In such cases, where a given surfactant combination
is presented in Examples 13-42 more than once (with different
solubilizer concentrations), the composition having the lowest
solubilizer concentration is chosen, to facilitate more direct
comparison. The results are shown in Table 27.
28TABLE 27 Comparative Spectroscopic Characterization Example
Absorbance (400.2 nm) No. Formulation 10X 100X C6 Tween 80 100 mg
2.938 2.827 Lauroglycol FCC 67 mg 26 Tween 80 180 mg 0.036 0.003
Lauroglycol FCC 20 mg Ethyl Alcohol 37 mg C7 Tween 80 100 mg 0.980
0.932 Capmul MCM 67 mg 22 Tween 80 170 mg 0.050 0.008 Capmul MCM 30
mg Ethyl Alcohol 38 mg C8 Cremophor RH-40 100 mg 2.886 1.595 Plurol
Oleique CC497 67 mg 25 Cremophor RH-40 500 mg 0.028 0.005 Plurol
Oleique CC497 10 mg Ethyl Alcohol 11 mg C9 Cremophor RH-40 100 mg
2.892 1.507 Peceol 67 mg 24 Cremophor RH-40 230 mg 0.187 0.020
Peceol 70 mg Ethyl Alcohol 54 mg C10 Cremophor RH-40 100 mg 1.721
0.491 Capmul MCM 67 mg 23 Cremophor RH-40 550 mg 0.029 0.006 Capmul
MCM 80 mg Ethyl Alcohol 53 mg C11 Tween 80 100 mg 1.585 1.357
Plurol Oleique CC497 67 mg C12 Tween 80 100 mg 2.849 2.721 Peceol
67 mg
[0203] The data in the Table demonstrate that the clear aqueous
dispersions of the present invention show very different absorptive
behavior from compositions having excessive hydrophobic surfactant
concentrations, having apparent absorbances (through scattering
losses) lower by at least a factor of ten, and in some cases by a
factor of more than one hundred.
Examples 43 and 44
[0204] Solubility of a Polyfunctional Hydrophobic Therapeutic
Agent
[0205] The enhanced solubility of a typical polyfunctional
hydrophobic therapeutic agent, cyclosporin, in the pharmaceutical
compositions of the present invention was measured using a
conventional "shake flask" method. Compositions were prepared and
diluted to 10.times. and 100.times. as in Example 1, without
including the therapeutic agent. The solutions were then provided
with an excess of cyclosporin, and agitated to allow the
cyclosporin to achieve an equilibrium partitioning between the
solubilized phase and the non-solubilized dispersion phase.
Concentration of the solubilized cyclosporin was then determined
using standard HPLC techniques, optimized for the quantitative
detection of cyclosporin. The results are shown in Table 28.
29TABLE 28 Solubility of Cyclosporin in Clear Aqueous Dispersions
Ex- ample Solubility (.mu.g/mL) No. Carrier Composition 10X
Dilution 100X Dilution 43 Cremophor RH-40 430 mg 13,205 1,008
Myvacet 9-45 321 mg Ethyl Alcohol 210 mg 44 Cremophor RH-40 540 mg
11,945 1,127 Span 80 260 mg Triacetin 220 mg
[0206] This Example demonstrates the dramatically enhanced
solubility of a hydrophobic therapeutic agent in the pharmaceutical
compositions of the present invention.
Comparative Examples C13-C16
[0207] Solubility of a Polyfunctional Hydrophobic Therapeutic
Agent
[0208] For comparison, the solubility experiment of Examples 43-44
was performed on four standard aqueous solutions. The first
comparison solution was purified water with no additives. Next, a
standard simulated intestinal fluid (SIF) was used, to simulate the
in vivo conditions to be encountered by the hydrophobic therapeutic
agent. A third solution was prepared with simulated intestinal
fluid, plus an additional aliquot of 20 mM sodium taurocholate (a
bile salt); this solution is designated SIFB in Table 29. Finally,
a fourth solution was prepared with simulated intestinal fluid, 20
mM sodium taurocholate, and 5 mM lecithin; this solution is
designated SIFBL. The 20 mM bile salt and 5 mM lecithin
concentrations are believed to be representative of the average
concentration of these compounds encountered in the
gastrointestinal tract. As in the previous Examples, these
comparison solutions were equilibrated with cyclosporin using the
shake flask method, and analyzed by HPLC. The results of these
measurements are presented in Table 29.
30TABLE 29 Solubility of Cyclosporin in Aqueous Solutions Example
No. Solution Solubility (.mu.g/mL) C13 Water 6 C14 SIF 6 C15 SIFB
49 C16 SIFBL 414 43-44 (average at 10X) present invention
12,575
[0209] As the Table indicates, the solubility of the polyfunctional
hydrophobic therapeutic agent in the compositions of the present
invention is far greater than its solubility in aqueous and
gastrointestinal aqueous solutions.
Examples 45-49
[0210] Solubility of a Lipophilic Hydrophobic Therapeutic Agent
[0211] The enhanced solubility of a typical lipophilic hydrophobic
therapeutic agent, progesterone, in the pharmaceutical compositions
of the present invention was measured as described in Examples
43-44. The results are shown in Table 30.
31TABLE 30 Solubility of Progesterone in Clear Aqueous Dispersions
Ex- ample Solubility (.mu.g/mL) No. Carrier Composition 10X
Dilution 100X Dilution 45 Cremophor RH-40 1000 mg 1100 200 Arlacel
186 120 mg Propylene Glycol 110 mg 46 Cremophor RH-40 1000 mg 1240
140 Peceol 240 mg Propylene Glycol 120 mg 47 Cremophor RH-40 1000
mg 1760 190 Labrafil M2125CS 800 mg Propylene Glycol 180 mg 48
Cremophor RH-40 1000 mg 1360 160 Span 80 350 mg Propylene Glycol
140 mg 49 Cremophor RH-40 1000 mg 1720 190 Crodamol EO 600 mg
Propylene Glycol 160 mg
[0212] This Example demonstrates the dramatically enhanced
solubility of a hydrophobic therapeutic agent in the pharmaceutical
compositions of the present invention.
Comparative Examples C17-C20
[0213] Solubility of a Lipophilic Hydrophobic Therapeutic Agent
[0214] For comparison, the solubility experiment of Comparative
Examples C13-C16 was repeated, using progesterone instead of
cyclosporin. The results of these measurements are presented in
Table 31.
32TABLE 31 Solubility of Progesterone in Aqueous Solutions Example
No. Solution Solubility (.mu.g/mL) C17 Water 6 C18 SIF 7-10 C19
SIFB 32-40 C20 SIFBL 80 45-49 (average at 10X) present invention
1436
[0215] As the Table indicates, the solubility of the lipophilic
hydrophobic therapeutic agent in the compositions of the present
invention is far greater than its solubility in aqueous and
gastrointestinal aqueous solutions.
Examples 50-57
[0216] Aqueous Dilution Stability of Compositions Containing a
Polyfunctional Hydrophobic Therapeutic Agent
[0217] Compositions according to the present invention were
prepared, with a typical polyfunctional hydrophobic therapeutic
agent, cyclosporin, as the therapeutic agent. The compositions were
prepared as described in Example 1, except that the ingredients
were added in the order listed in Table 32. The pre-concentrates
were diluted 100.times. with purified water, and a visual
observation was made immediately after dilution. The solutions were
then allowed to stand 6 hours to assess dilution stability, then
the cyclosporin concentration in solution was measured, using a
drug-specific HPLC assay. The results are shown in Table 32.
33TABLE 32 Dilution Stability of Polyfunctional Therapeutic Agents
Cyclosporin Example Concen- No. Composition Observation tration* 50
Cremophor RH-40 430 mg clear solution 121 Myvacet 9-45 310 mg Ethyl
Alcohol 210 mg Cyclosporin 99 mg 51 Cremophor RH-40 610 mg clear
solution 99 Peceol 160 mg Ethyl Alcohol 200 mg Cyclosporin 100 mg
52 Cremophor RH-40 540 mg clear solution 114 Span 80 260 mg
Triacetin 220 mg Cyclosporin 97 mg 53 Incrocas 35 470 mg clear
solution 96 Myvacet 9-45 250 mg Ethyl Alcohol 220 mg Cyclosporin
100 mg 54 Cremophor RH-40 660 mg clear solution 105 Arlacel 186 120
mg Propylene Glycol 100 mg Ethanol 100 mg Cyclosporin 100 mg 55
Cremophor RH-40 550 mg clear solution 102 Arlacel 186 120 mg
Propylene Glycol 450 mg Cyclosporin 100 mg 56 Cremophor RH-40 580
mg clear solution 108 Arlacel 186 120 mg Propylene Glycol 100 mg
Ethanol 100 mg Cyclosporin 100 mg 57 Gelucire 44/14 120 mg clear
solution 108 Incrocas 35 200 mg (at 37.degree. C.) Glycofurol 100
mg Cyclosporin 100 mg
[0218] * as a percentage of the initial cyclosporin
concentration
[0219] The data in the Table indicate that large amounts of a
polyfunctional hydrophobic therapeutic agent can be solubilized in
the compositions of the present invention to produce clear, aqueous
dispersions. These dispersions show no instability effects, such as
hydrophobic therapeutic agent precipitation or particle
agglomeration, upon standing.
Examples 58-74
[0220] Aqueous Dilution Stability of Compositions Containing a
Lipophilic Hydrophobic Therapeutic Agent
[0221] Compositions according to the present invention were
prepared, with a typical lipophilic hydrophobic therapeutic agent,
progesterone, as the therapeutic agent. The compositions were
prepared and analyzed as in Examples 50-57, and the results are
shown in Table 33.
34TABLE 33 Dilution Stability of Lipophilic Therapeutic Agents
Proges- terone Example Concen- No. Composition Observation tration*
58 Cremophor RH-40 1000 mg very clear 99.1 Arlacel 186 120 mg
solution Propylene Glycol 110 mg Progesterone 48 mg 59 Cremophor
RH-40 1000 mg very clear 99.3 Peceol 240 mg solution Propylene
Glycol 120 mg Progesterone 48 mg 60 Cremophor RH-40 1000 mg very
clear 100.2 Labrafil 800 mg solution Propylene Glycol 180 mg
Progesterone 45 mg 61 Cremophor RH-40 1000 mg very clear 97.2 Span
80 350 mg solution Propylene Glycol 140 mg Progesterone 50 mg 62
Cremophor RH-40 1000 mg very clear 98.4 Crodamol EO 600 mg solution
Propylene Glycol 160 mg Progesterone 48 mg 63 Cremophor RH-40 540
mg clear solution 104.4 Labrafil M2125CS 350 mg Ethyl Alcohol 200
mg Progesterone 42 mg 64 Cremophor RH-40 570 mg very slight tang
106.1 Ethyl Oleate 260 mg blue color Ethyl Alcohol 200 mg solution
Progesterone 42 mg 65 Cremophor RH-40 600 mg very slight tang 104.6
Peceol 210 mg blue color Triacetin 210 mg solution Progesterone 42
mg 66 Cremophor RH-40 600 mg very clear 97.7 Capmul MCM 200 mg
solution Triacetin 200 mg Progesterone 44 mg 67 Cremophor RH-40 590
mg clear solution 102.3 Span 80 270 mg Triacetin 210 mg
Progesterone 41 mg 68 Crovol M-70 760 mg very clear 104.6 Labrafil
M2125CS 100 mg solution Triacetin 200 mg Progesterone 43 mg 69
Tween 20 610 mg very slight tang 98.0 Imwitor 988 300 mg blue color
Triacetin 200 mg solution Progesterone 45 mg 70 Tween 20 670 mg
very clear 96.3 Lauroglycol FCC 170 mg solution Glycofurol 200 mg
Progesterone 43 mg 71 Incrocas 35 620 mg very clear 99.5 Labrafil
M2125CS 220 mg solution Ethyl Alcohol 200 mg Progesterone 43 mg 72
Incrocas 35 660 mg very clear 105.9 Span 20 160 mg solution Ethyl
Alcohol 210 mg Progesterone 41 mg 73 Cremophor RH-40 980 mg very
clear 103.7 Arlacel 186 130 mg supernatant Propylene Glycol 110 mg
Progesterone 110 mg 74 Cremophor RH-40 520 mg very clear 103.1
Labrafil 400 mg supernatant Propylene Glycol 110 mg Progesterone
100 mg *as a percentage of the initial progesterone
concentration
[0222] The data in the Table indicate that a lipophilic hydrophobic
therapeutic agent can be solubilized in the compositions of the
present invention to produce clear, aqueous dispersions. These
dispersions show no instability effects, such as hydrophobic
therapeutic agent precipitation or particle agglomeration, upon
standing.
Example 75
[0223] Enhancement of Bioabsorption
[0224] Studies were performed to establish that the clear aqueous
dispersions of the present invention facilitate an increased rate
of bioabsorption of the hydrophobic therapeutic agent contained
therein. The studies used a rat model with perfused intestinal loop
along with cannulation of the mesenteric vein. This unique
methodology enabled assessment of the "true" absorption potential
free of any systemic metabolic interference.
[0225] A representative preconcentrate of the present invention
containing a cyclosporin hydrophobic therapeutic agent was used.
The composition had the following formulation:
35 Cyclosporine 0.140 g Cremophor RH-40 0.41 g Arlacel 186 0.29 g
Sodium taurocholate 0.26 g Propylene glycol 0.46 g
[0226] For this experiment, the preconcentrate was diluted with an
isotonic aqueous HEPES buffer rather than purified water. The
resultant solution was spiked with radioactive active and perfused
through isolated ileal lumen segment of known length and diameter.
Loss of radioactivity from the lumenal side and appearance of
radioactivity in the mesenteric blood from the other side was
monitored as an indicator of absorption.
Experimental Details
[0227] Young adult (275-300 g) male Sprague Dawley rats were used.
The procedures were consistent with those reported by Winne et al.,
"In vivo studies of mucosal-serosal transfer in rat jejunum",
Naunyn-Schmeideberg's Arch. Pharmacol., 329, 70 (1985).
[0228] Jugular vein cannulation: the animal was anesthetized using
2% halothane in 98% oxygen via a halothane vaporizer (Vapomatic, A.
M. Bickford, Inc., NY). An opening in the jugular vein was made
with a 21 ga needle and a jugular cannula consisting of a 4 cm
segment of silastic tubing connected to polyethylene tubing was
inserted in the jugular vein and secured with cyanoacrylate glue.
For the donor rat, approximately 20 mL of blood was freshly
collected in the presence of heparin (1,000 units) and the
collected blood was infused at a rate of 0.2 mL/min through the
jugular vein in the experimental rat to replenish blood
sampling.
[0229] Intestine cannulation: after the animal was anesthetized,
its body temperature was maintained at 37.degree. C. using a
heating pad. A vertical midline incision of approximately 3 cm was
made through the skin to expose the small intestine. Approximately
6-10 cm segment of ileum was located. Using electro-cautery, a
small incision was made at the ends of the segment and the lumenal
contents were flushed with saline maintained at 37.degree. C. Two
1.5 cm notched pieces of Teflon tubing were inserted into the
intestinal lumen at each incision and tightened using 4-0 silk. A
warm isotonic buffer was passed through the intestine using a 50-mL
syringe. These Teflon cannula were used to perfuse the drug
solution through the isolated intestinal segment using a syringe
pump.
[0230] Mesenteric vein cannulation: the mesenteric vein draining
blood from the resulting isolated mesenteric cascade venules was
then cannulated using a 24 ga IV catheter and secured in place
using 4-0 silk sutures. The cannula was then connected to a
polyethylene tubing 25 cm long where the blood was collected in a
vial kept under the animal level. Blood samples were collected
continuously over 60 min. The infusion of blood via the jugular
vein was initiated to replenish blood loss. The animal was then
killed by a lethal injection of Phenobarbital after completion of
the experiment.
[0231] The experiment was performed twice using the compositions of
the present invention as the drug carrier, and twice using a
commercial cyclosporin microemulsion formulation for comparison
(NeOral.RTM.). For each formulation, the results of the two trials
were averaged. The results are presented graphically in FIG. 1.
[0232] FIG. 1 shows the accumulated radioactivity
(.mu.Ci/cm.sup.2.mu.Ci) in mesenteric blood as a function of time,
over the course of 60 minutes, for the pharmaceutical compositions
of the present invention (filled squares) and a commercial
cyclosporin formulation (filled circles). As the Figure shows, the
bioabsorption of the hydrophobic therapeutic agent exceeds that of
the commercial formulation at the earliest measurement point, and
continues to increase relative to the commercial formulation over
the course of the measurement interval. At the final measurement
point (60 min), the bioabsorption of the hydrophobic therapeutic
agent from the compositions of the present invention exceeds that
of the commercial formulation by nearly 100%.
[0233] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims
rather than by the foregoing description. All changes which come
within the meaning and range of equivalency of the claims are to be
embraced within their scope.
* * * * *