Porous drug matrices and methods of manufacture thereof

• US 6,645,528 B1
• Filed: 10/23/2000
• Issued: 11/11/2003
• Est. Priority Date: 05/27/1999
• Status: Expired due to Term

• Current Assignee: Acusphere Incorporated
• Original Assignee: Acusphere Incorporated
• Inventors: Khattak, Sarwat, Randall, Greg, Straub, Julie, Chickering, Donald E. III, Bernstein, Howard
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/694,407
• Time in Patent Office: 1,114 Days
• Field of Search: 424/484, 424/489, 428/402, 514/951-52
• US Class Current: 424/489
• 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: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/923 Cell culture

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 (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. 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 which comprises a wetting agent and microparticles of a drug,

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

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

3. The composition of claim 2 wherein the porous matrix is in an aqueous medium.

4. The composition of claim 3 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, conjugated estrogens, 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, finasteride, quetiapine fumarate, 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, cefuroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.

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

6. The composition of claim 5 wherein the drug is selected from the group consisting of ceftriaxone, ketoconazole, ceftazidime, oxaprozin, valacyclovir urofollitropin, famciclovir, flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepan, 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, verapamil, 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.

7. The composition of claim 1 wherein the matrix further comprise an excipient selected from the group consisting of hydrophilic polymers, sugars, tonicity agents, pegylated excipients, and combinations thereof.

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

m.

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

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

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

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

13. The composition of claim 1 wherein the dry powder form of the porous matrix has a TAP density less than or equal to 1.0 g/mL.

14. The composition of claim 1 wherein the dry powder form of the porous matrix has a total surface of greater than or equal to 0.2 m²/g.

15. The composition of claim 1 wherein the mean diameter of the microparticles is between about 0.5 end 5 μ

m.