Emulsion compositions for polyfunctional active ingredients

• US 6,720,001 B2
• Filed: 10/18/1999
• Issued: 04/13/2004
• Est. Priority Date: 10/18/1999
• Status: Expired due to Fees

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Chen, Feng-Jing, Patel, Mahesh V.
• Primary Examiner(s): KIM, VICKIE Y
• Application Number:
  US09/420,159
• Publication Number:
  US 20020107265A1
• Time in Patent Office: 1,639 Days
• Field of Search: 514/937, 514/570, 514/458, 424/45, 424/400, 424/450, 424/451, 424/455
• US Class Current: 424/455
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides pharmaceutical oil-in-water emulsions for delivery of polyfunctional active ingredients. The emulsions include an aqueous phase, an emulsifier, and an oil phase, wherein the oil phase includes a structured triglyceride that is substantially free of triglycerides having three C₆-C₁₂ fatty acid moieties, or a combination of a long chain triglyceride and a polarity-enhancing polarity modifier. The present invention also provides methods of treating an animal with a polyfunctional active ingredient, using dosage forms of the pharmaceutical emulsions.

Claims

1. A stabilized pharmaceutical oil-in-water emulsion for delivery of a polyfunctional drug, wherein the emulsion has a mean particle diameter of less than about 5 μ

m and consists essentially of;

(a) a therapeutically effective amount of a polyfunctional drug selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, antiarrhythimic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetic agents, anti-epileptic agents, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplostic agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytics, sedatives, hypnotics, neuroleptic agents, β

-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonism agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, muscle relaxants, anti-anginal agents, sex hormones, stimulants, cytokines, peptidomimetics, proteins, peptides, toxoids, antibodies, vaccines, nucleosides, nucleotides, nucleic acids, DNA, RNA, oligonucleotides, oligodeoxynucleotides, and combinations thereof;

(b) an aqueous phase;

(c) an oil phase consisting essentially of

(i) a mixture of structured triglycerides having one medium chain fatty acid (MCFA) group and at least one long chain fatty acid (LCFA) groups, wherein the total amount of fatty groups of the oil phase having a carbon chain length of from 6-12 carbons atoms is less than about 30% and the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than 10% by weight, based on the total weight of the fatty acid groups of the oil phase, and

(ii) a polarity modifier effective to facilitate the incorporation of the polyfunctional drug into the emulsion, wherein the polarity modifier is selected from the group consisting of inorganic acids and inorganic; and

(d) an amount of an emulsifier effective to provide a stabilized emulsion suitable for parenteral administration, wherein the emulsifier is selected from the group consisting of ceramides, mixed chain phospholipids, cationic lipids, oligolipids, phospholipids, carnitines, sphingosines, sphingomyelins, glycolipids, lipoproteins, apoproteins, amphiphilic proteins, amphiphilic peptides, amphiphilic synthetic polymers, and combinations thereof.

2. The pharmaceutical emulsion of claim 1, wherein the polyfunctional drug is hydrophobic and has an intrinsic aqueous solubility of less than about 1 mg/mL.

3. The pharmaceutical emulsion of claim 2, wherein the polyfunctional drug has an intrinsic aqueous solubility of less than about 0.1 mg/mL.

4. The pharmaceutical emulsion of claim 1, wherein the polyfunctional drug is hydrophilic and has an octanol/water partition coefficient of less than about 100.

5. The pharmaceutical emulsion of claim 4, wherein the polyfunctional drug has an octanol/water partition coefficient of less than about 10.

6. The pharmaceutical emulsion of claim 1, wherein the oil phase is substantially free of triglycerides having three fatty acid groups with a carbon chain length of from 6 to 12 carbon atoms.

7. The pharmaceutical emulsion of claim 1, wherein the oil phase further comprises a vegetable oil, a fish oil, an animal fat, a hydrogenated vegetable oil, a partially hydrogenated vegetable oil, a semi-synthetic triglyceride, a synthetic triglyceride, or a mixture thereof.

8. The pharmaceutical emulsion of claim 1, wherein the oil phase further comprises almond oil;

babassu oil;

borage oil;

black currant seed oil;

canola oil;

castor oil;

coconut oil;

corn oil;

cottonseed oil;

emu oil;

evening primrose oil;

flax seed oil;

grapeseed oil;

groundnut oil;

mustard seed oil;

olive oil;

palm oil;

palm kernel oil;

peanut oil;

rapeseed oil;

safflower oil;

sesame oil;

shark liver oil;

soybean oil;

sunflower oil;

hydrogenated castor oil;

hydrogenated coconut oil;

hydrogenated palm oil;

hydrogenated soybean oil;

hydrogenated vegetable oil;

a mixture of hydrogenated cottonseed oil and hydrogenated castor oil;

partially hydrogenated soybean oil;

a mixture of partially hydrogenated soybean oil and partially hydrogenated cottonseed oil;

glyceryl trioleate;

glyceryl trilinoleate;

glyceryl trilinolenate;

a Ω

3 polyunsaturated fatty acid triglyceride containing oil;

or a mixture thereof.

9. The pharmaceutical composition of claim 1, wherein the oil phase further comprises coconut oil;

corn oil;

olive oil;

palm oil;

peanut oil;

safflower oil;

sesame oil;

soybean oil;

hydrogenated castor oil;

hydrogenated coconut oil;

partially hydrogenated soybean oil;

glyceryl trioleate;

glyceryl trilinoleate;

glyceryl trilinolenate;

a Ω

3 polyunsaturated fatty acid triglyceride containing oil;

or a mixture thereof.

10. The pharmaceutical composition of claim 1, wherein the oil phase further comprises corn oil;

olive oil;

palm oil;

peanut oil;

safflower oil;

sesame oil;

soybean oil;

hydrogenated castor oil;

partially hydrogenated soybean oil;

glyceryl trioleate;

glyceryl trilinoleate;

a Ω

3 polyunsaturated fatty acid triglyceride containing oil;

or a mixture thereof.

11. The pharmaceutical emulsion of claim 1, wherein the total amount of LCFA groups in the oil phase is greater than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase.

12. The pharmaceutical emulsion of claim 11, wherein the total amount of LCFA groups in the oil phase is greater than about 50% by weight, based on the total weight of the fatty acid groups of the oil phase.

13. The pharmaceutical emulsion of claim 1, wherein the emulsifier comprises a phospholipid selected from the group consisting of egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof.

14. The pharmaceutical emulsion of claim 1, which further comprises glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic, a buffering agent, a chelating agent, a colorant, a flavorant, an odorant, an osmotic modifier, a preservative, a solubilizer, a solvent, a tonicifier, a trace element, a viscomodulator, or a mixture thereof.

15. The pharmaceutical emulsion of claim 1, wherein the polyfunctional drug is selected from the group consisting of acarbose;

acyclovir;

acetyl cysteine;

acetylcholine chloride;

alatrofloxacin;

alendronate;

alglucerase;

amantadine hydrochloride;

ambenomium;

amifostine;

amiloride hydrochloride;

aminocaproic acid;

amphotericin B;

antihemophilic factor (human);

antihemophilic factor (poreine);

antihemophilic factor (recombinant);

aprotinin;

asparaginase;

atenolol;

atracurium besylate;

atropine;

azithromycin;

aztreonam;

BCG vaccine;

bacitracin;

becaplemin;

belladona;

bepridil hydrochloride;

bleomycin sulfate;

calcitonin human;

calcitonin salmon;

carboplatin;

capecitabine;

capreomycin sulfate;

cefamandole nafate;

cefazolin sodium;

cefepime hydrochloride;

cefixime;

cefonicid sodium;

cefoperazone;

cefotetan disodium;

cefotaxime;

cefoxitin sodium;

ceftizoxime;

ceftriaxone;

cefuroxime axetil;

cephalexin;

cephapirin sodium;

cholera vaccine;

chorionic gonadotropin;

cidofovir;

cisplatin;

cladribine;

clidinium bromide;

clindamycin and ciprofloxacin;

clodronate;

colistimethate sodium;

colistin sulfate;

corticotropin;

cosyntropin;

cromolyn sodium;

cytarabine;

dalteperin sodium;

danaparoid;

deferoxamine;

denileukin diftitox;

desmopressin;

diatrizoate meglumine and diatrizoate sodium;

dicyclomine;

didanosine;

dirithromycin;

dopamine hydrochloride;

dornase alpha;

doxacurium chloride;

doxorubicin;

etidronate disodium;

enalaprilat;

enkephalin;

enoxacin;

enoxaparin sodium;

ephedrine;

epinephrine;

epoetin alpha;

erythromycin;

esmolol hydrochloride;

factor IX;

famciclovir;

fludarabine;

fluoxetine;

foscarnet sodium;

ganciclovir;

granulocyte colony stimulating factor;

granulocyte-macrophage stimulating factor;

recombinant human growth hormones;

bovine growth hormones;

gentamycin;

glucagon;

glycopyrolate;

gonadotropin releasing hormone and synthetic analogs thereof, gonadorelin;

grepafloxacin;

haemophilus B conjugate vaccine;

Hepatitis A virus vaccine inactivated;

Hepatitis B virus vaccine inactivated;

heparin sodium;

indinavir sulfate;

influenza virus vaccine;

interleukin-2;

interleukin-3;

insulin-human;

insulin lispro;

insulin porcine;

insulin NPH;

insulin aspart;

insulin glargine;

insulin detemir;

interferon alpha;

interferon beta;

ipratropium bromide;

isophosphamide;

Japanese encephalitis virus vaccine;

lamivudine;

leucovorin calcium;

leuprolide acetate;

levofloxacin;

lincomycin and lincomycin derivatives;

lobucavir;

lomefloxacin;

loracarbef, mannitol;

measles virus vaccine;

meningococcal vaccine;

menotropins;

mepenzolate bromide;

mesalamine;

methenamine;

methotrexate;

methscopolamine;

metformin hydrochloride;

metoprolol;

mezlocillin sodium;

mivacurium chloride;

mumps viral vaccine;

nedocromil sodium;

neostigmine bromide;

neostigmine methyl sulfate;

neurontin;

norfloxacin;

oetreotide acetate;

ofloxacin;

olpadronate;

oxytocin;

pamidronate disodium;

pancuronium bromide;

paroxetine;

pefloxacin;

pentamidine isethionate;

pentostatin;

pentoxifylline;

penciclovir, pentagastrin;

phentolamine mesylate;

phenylalanine;

physostigmine salicylate;

plague vaccine;

piperacillin sodium;

platelet derived growth factor-human;

pneumococcal vaccine polyvalent;

poliovirus vaccine inactivated;

poliovirus vaccine live (OPV);

polymyxin B sulfate;

pralidoxime chloride;

pramlintide;

pregabalin;

propaferone;

propantheline bromide;

pyridostigmine bromide;

rabies vaccine;

risedronate;

ribavirin;

rimantadine hydrochloride;

rotavirus vaccine;

salmeterol xinafoate;

sincalide;

small pox vaccine;

sotalol;

somatostatin;

sparfloxacin;

spectinomycin;

stavudine;

streptokinase;

streptozocin;

suxamethonium chloride;

tacrine hydrochloride;

terbutaline sulfate;

thiotepa;

ticarcillin;

tiludronate;

timolol;

tissue type plasminogen activator;

TNFR;

Fc;

TNK-tPA;

trandolapril;

trimetrexate gluconate;

trospectomycin;

trovafloxacin;

tubocurarine chloride;

tumor necrosis factor;

typhoid vaccine live;

urea;

urokinase;

vancomycin;

valacyclovir;

valsarian;

varicella virus vaccine live;

vasopressin and vasopressin;

vecuronium bromide;

vinblastine;

vincristine;

vinorelbine;

warfarin sodium;

yellow fever vaccine;

zalcitabine;

zanamivir;

zoledronate;

zidovudine;

pharmacoutically acceptable salts, isomers, and derivative thereof; and

mixtures thereof.

16. The pharmaceutical emulsion of claim 1, wherein the polyfunctional drug is selected from the group consisting of tramadol, celceoxib, etodolac, rofecoxib, oxaprozin, leflunomide, diclofenac, nabumetone, acetyl coenzyme Q10, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutin, rifapentine, trovafloxacin, baclofen, ritonavir, saquinavir, nelfinavir, efavirenz, dicumarol, tirofiban, cilostazol, ticlopidine, clopidogrel, oprelyekin, paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol, repaglinide, glimepiride, pioglitazone, rosiglitazone, troglitazone, glyburide, glipizide, glibenclamide, carbamazenine, fosphenytoin, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenaline, terbinafine, itraconazole, fluconazole, miconazole, lycopene, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, lisinopril, benazepril, nifedipine, nisoldipine, telmisartan, irbesartan, eprosartan, valsartan, candesartan, minoxidil, terazosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizotifen, sumatriptan, zolmitriptan, naratriptan, rizatriptan, aminoglutethimide, busulfan, cyclosporin, mitoxantrone, irinotecan, etoposide, teniposido, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecin, topotecan, nilutanide, bicalutanide, ephedrine, toremifene, atovaquone, furazolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, beclomothasone, budesonide, betamethasone, prednisolone, cisapride, cimetidine, loperamide, famotidine, lansoprazole, rabeprazole, nizatidine, omeprazole, cetirizine, cinnarizine, dexchlorphenirarmine, loratadine, clemastine, fexofenadine, chlorpheniramine, acetretin, tazarotene, calcipotrieno, calcitriol, targretin, ergocalciferol, cholecalciferol, isotretinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinitrate, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dehydroepiandrosterone, medroxyprogesterone, progesterone, rimexolone, megostrol acetate, oestradiol, finasteride, mifepristone, amphetamine, L-thyroxine, tamsulosin, methoxsalen, facrine, donezepil, raloxifene, verteporfrin, sibutramine, pyridostigmine, pharmaceutically acceptable salts, isomers, and derivatives thereof;

and mixtures thereof.

17. A dosage form of the pharmaceutical emulsion of claim 1.

18. The dosage form of claim 17, wherein the dosage form comprises the pharmaceutical emulsion processed by lyophilization, encapsulation, extrusion, homogenization, sonication, melting, solubilizing, evaporation, sterilization, filtration, irradiation, mixing, coating, size reduction, spraying, or a combination thereof.

19. The dosage form of claim 17, which comprises the pharmaceutical emulsion formulated as an injectable, a drink, an eye drop or spray, a nasal drop or spray, a buccal drop or spray, a cervical drop or spray, an inhalant, a lotion, a gel, a liniment, a cream, a paste, a solution, a suppository, an ovule, a wafer, a troche, a sachet, an elixir, a tineture, a douche, an aerosol, a patch, or a combination thereof.

20. The dosage form of claim 17, wherein the dosage form is adapted for parental, enteral, ocular, nasal, sublingual, buccal, topical, intra-cervical, rectal, intramuscular, intra-dermal, pulmonary, transmucosal, intra-thecal, intravenous, intra-arterial, epidural, intra-cavity, intra-organ transdermal, intra-lymphatic, intra-cranular, or intra-lumoral administration, or a combination thereof.

21. The pharmaceutical emulsion of claim 1, having a mean particle diameter of less than about 5 μ

m.