Porous drug matrices and methods of manufacture thereof

• US 20050048116A1
• Filed: 08/24/2004
• Published: 03/03/2005
• Est. Priority Date: 05/27/1999
• Status: Abandoned Application

• Current Assignee: Acusphere Incorporated
• Original Assignee: Acusphere Incorporated
• Inventors: Altreuter, David, Khattak, Sarwat, Straub, Julie, Randall, Greg, Chickering, Donald E. III, Bernstein, Howard
• Application Number:
  US10/924,642
• Publication Number:
  US 20050048116A1
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution and hydrophilic or hydrophobic excipients that stabilize the drug and inhibit crystallization, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. Hydrophobic or hydrophilic excipients may be selected to stabilize the drug in crystalline form by inhibiting crystal growth or to stabilize the drug in amorphous form by preventing crystallization. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid-compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

Claims

1. A pharmaceutical composition comprising a porous matrix formed of a hydrophilic or hydrophobic excipient and microparticles of a drug,

wherein the microparticles have a mean diameter between about 0.1 and 5 μ

m and a total surface area greater than about 0.5 m²/mL, and

wherein the dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and having a total surface area of greater than or equal to 0.2 m²/g.

2. The pharmaceutical composition of claim 1 comprising between 1 and 95% drug by weight in combination with at least one hydrophilic or hydrophobic excipient which enhances the rate of drug dissolution, stabilizes the drug in crystalline form by inhibiting crystal growth or stabilizes the drug in amorphous form by preventing crystallization.

3. The pharmaceutical composition of claim 1 comprising between about 5 and 60% drug.

4. The pharmaceutical composition of claim 1 comprising one or more hydrophobic or hydrophilic excipients selected from the group consisting of polymers, amino acids, sugars, preservatives, wetting agents, tonicity agents, pegylated excipients, and combinations thereof.

5. The pharmaceutical composition of claim 1 wherein the excipient is hydrophobic or hydrophilic amino acid.

6. The composition of claim 1 wherein the drug is a low aqueous solubility drug.

7. The composition of claim 1 wherein the drug is a low aqueous solubility drug, wherein the porous matrix upon contact with an aqueous medium yields microparticles having a mean diameter between about 0.1 and 5 μ

m and a total surface area greater than about 0.5 m²/mL, and

wherein the dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and having a total surface area of greater than or equal to 0.2 m²/g.

8. The composition of claim 1 wherein the drug is selected from the group consisting of albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, estrogens conjugated, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, omeprazole, rubitecan, amlodipine besylate/benazepril hydrochloride, etodolac, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D₃ and related analogues, finasteride, quetiapine fulmarate, alprostadil candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine, flumazenil, risperidone, carbemazepine, carbidopa/levodopa, ganciclovir, saquinavir, amprenavir, carboplatin, glyburide, sertraline hydrochloride, rofecoxib carvedilol, halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone, imiquimod, simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride, mofafinil, azithromycin, clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone maleate, diclofenac sodium, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan, diazapam, loratadine, toremifene citrate, thalidomide, dinoprostone, mefloquine hydrochloride, trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin, etodolac, triamcinolone acetate, estradiol, ursodiol, nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide, famotidine, nifedipine, prednisone, cefuiroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.

9. The composition of claim 1 wherein the drug is water-soluble.

10. The composition of claim 1 wherein the drug is selected from the group consisting of ceftriaxone, ketoconazole, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, fluticasone, budesonide, flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepam, follitropin, glipizide, omeprazole, fluoxetine, lisinopril, levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, bupropion, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betaxolol, bleomycin sulfate, dexfenfluramine, diltiazem, fentanyl, flecainid, gemcitabine, glatiramer acetate, granisetron, lamivudine, mangafodipir trisodium, mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast, octreotide acetate, olopatadine, paricalcitol, somatropin, sumatriptan succinate, tacrine, verapainil, nabumetone, trovafloxacin, dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone, enoxaparin, fluconazole, lansoprazole, terbinafine, pamidronate, didanosine, diclofenac, cisapride, venlafaxine, troglitazone, fluvastatin, losartan, imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin, and ipratropium.

11. The composition of claim 1 wherein the mean diameter of the microparticles is between about 1 and 5 μ

m.

12. The composition of claim 1 wherein the microparticles are suspended in an aqueous solution suitable for parenteral administration.

13. The composition of claim 1 wherein the matrix is processed into tablets or capsules suitable for oral administration.

14. The composition of claim 1 wherein the matrix is formed into suppositories suitable for vaginal or rectal administration.

15. The composition of claim 1 wherein the matrix is in a dry powder form suitable for pulmonary administration.

16-33. -33. (Canceled)