SYNERGISTIC BINDER COMPOSITION. METHOD FOR MAKING SAME.

AND TABLETS OF AN ACTIVE AND SAID BINDER HAVING

ADVANTAGEOUS HARDNESS AND FRIABILITY

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to tableting of pharmaceutical, nutritional or vitamin active compounds or compositions, e.g. a poorly compressible drug, and, more particularly, to a new and improved synergistic binder composition and method for making the same, and to processing such actives and binder into tablets of advantageous hardness and friability by direct compression at a suitable compression force.

2. Description of the Prior Art

Many commercial filler materials such as microcrystalline cellulose and silicified microcrystalline cellulose are used in the manufacture of tablets of pharmaceutical, nutritional and vitamin active compounds and compositions. Such materials are described by Tobyn, M.J. in Int. J. of Pharmaceutics, 169, 183-194 (1998). However, actives such as drugs which are difficult to compress require tableting machines which operate at high compression forces to provide tablets of suitable hardness and low friability. Also, large amounts of the filler may be necessary to achieve these results, which, disadvantageously, increases the size of the tablet.

A. Moroni, et al., in U.S. Pat. 6,524,617, described a synergistic binder composition for making pharmaceutical tablets of suitable hardness at low compression force, and low friability, which precluded damage to the tablet upon further processing, and without requiring a substantial increase in the size of the tablet. The Moroni composition included a VP-VA copolymer and microcrystalline cellulose.

Accordingly, it is an object of this invention to provide an improved synergistic binder composition, and method of making the same, for forming tablets of a pharmaceutical, nutritional or vitamin compound or composition, e.g. a poorly compressible drug, by direct compression at a low compression force, which provides tablets having advantageous hardness and low friability.

SUMMARY OF THE INVENTION

Tablets of a pharmaceutical, nutritional or vitamin active compound or compositions, e.g. a poorly compressible drug, are made herein by direct compression using a binder composition of a co-processed copolymer of (a) vinylpyrrolidone (VP) and vinyl acetate (VA), in a suitable wt. ratio of 30-90:70-10, and microcrystalline cellulose (MCC), in a wt. ratio of (a):(b) 1-30:99-70. The invention composition, in the form of an aqueous dispersion, is spray dried at predetermined temperatures and spray rate to provide an excipient binder powder with a desired particle size for such actives. The tablets obtained herein have advantageous hardness and friability, and are processed at an acceptable compression force.

The preferred copolymer in the binder composition of the invention is VP and VA, at a wt. ratio of about 60 wt. % VP and about 40 wt. % VA.

The most preferred binder composition is VP-VA and MCC in a wt. ratio of about 10:90.

In the process of making the binder composition of the invention, an aqueous dispersion of copolymer VP-VA (Plasdone ^® S-630), (International Specialty Products, Inc.) and microcrystalline cellulose, are spray dried under predetermined temperatures and spray rate conditions to produce a binder powder particularly suitable for direct compression of such actives, including poorly compressible drug actives. Preferably spray drying is carried out at an inlet temperature of about 200°-300°C and an outlet temperature of about 75-95°C at a rotary atomizer speed rate of about 12,000 to 24,000 rpm.

Pharmaceutical tablets made by the invention generally include, by wt., 1-85% of an active which may be a poorly compressible drug and 99-15% of the invention co-processed binder powder. Suitably, such drug tablets have a hardness of at least 6 kP and a friability of < 2%.

Tablets are made by direct compression of the binder powders and the active, and, optionally, other excipients typically present in such formulations. Direct compression of the formulation at about 2000 to 7000 lbs provides a tablet having a hardness of about 6-20 kP and a friability of about 1-2%.

DETAILED DESCRIPTION OF THE INVENTION

Actives that can be used in accordance with the present invention are not particularly limited.

Suitable pharmaceutical nutritional and vitamin actives include, but are not limited to: abacavir sulfate, acebutolol, acetaminophen, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, albumin, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, amprenavir, ascorbic acid, aspartame, astemizole, atazanavir, atenolol, acemetacin, azithromycin, azithromycin dihydride, beclomethasone, benserazide, benzalkonium hydroxide, benzocaine, benzole acid, betametasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazolin, cefixime, cefotaxime, ceftazidine, ceftriaxone, cefuroxime, chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone, choline, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, clotrimazole, clozapine, codeine, colestyramine, coenzyme Q10, cromoglycic acid, cyanocobalamin, cyclosporin, cyproterone, delavirdine mesylate, desipramine, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphene,

diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, doxorubicin hydrochloride, dronabinol, efavirenz, emtricitabine, enalapril, enrofloxacin, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, ezetimibe, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, fexofenadine hydrochloride, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flutamide, fosamprenavir, fosamprenavir calcium, furosemide, gancyclovir, gemfibrozil, gentamicin, ginkgo biloba, glibenclamide, glipizide, Glycyrrhiza Glabra, guaifenesin, guanabenz, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, hydroxytetracycline, ipratropium hydroxide, ibuprofen, imipenem, indinavir sulfate, indomethacin, iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, itraconazole, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lamivudine, lecithin, levocamitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, lisinopril, loperamide, lopinavir, loratadine, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamins and minerals, nystatin, N-methylephedrine, nadolol, naftidrofuryl, naproxen, nelfinavir mesylate, neomycin, nevirapine, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantoprazole, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, phenylephrine, phenylpropanolamine, phenytoin, pioglitazone hydrochloride, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, proglumetacin, propafenone, propranolol, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, ribavirin, riboflavin, ritonavir, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, saquinavir, simvastatin, somatropin, sotalol, spironolactone, stavudine,

sucralfate, sulbactam, sulfamethoxazole, sulphasalazine, sulpiride, tamoxifen, tegafur, tenofovir disoproxil fumarate, tenoxicam, teprenone, terazosin, terbinafine hydrochloride, terbutaline, terfenadine, theophylline, thiamine, tiaprofenic acid, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valgancyclovir hydrochloride, valproic acid, vancomycin, verapamil, vitamin E, zalcitabine, zidovudine, zotepine.

The invention will now be illustrated in more detail by reference to the following examples.

EXAMPLE 1

An aqueous dispersion of a binder composition of VP-VA copolymer (60:40 by wt.) and MCC, in a wt. ratio of 1-30:99:70, and a solids content of about 15-30%, were spray dried in a laboratory scale disc or nozzle spray dryer at an inlet temperature of 200-300 ⁰ C and an outlet temperature of 75-95 ⁰ C, at an atomizer speed rate of 12,000-24,000 rpm. Powders of a free- flowing binder composition were collected. The powders had a mean particle size of about 20-120 μ.

EXAMPLE 2

The free-flowing binder powders obtained in Example 1 were admixed with a poorly compressible drug (acetaminophen) at a wt. ratio of 50:20 drug:binder with the remainder of the formulation being comprised of filler (27%), a disintegrant (2%), a glidant (0.5%), and a lubricant (0.5%). Formulations of the spray dried binder composition and drug ready for direct compression into tablets are given in Table 1 below. Runs 1-3 for such formulations were made using spray dried powders of VP-VA (Plasdone ^® S-630) and MCC, at various wt. ratios, while runs 4-5 (controls) were made using only physical blends of these materials. The results in Table 2 show that the invention runs 1-3 had a substantially increased tablet hardness and decreased friability as compared to control runs 4-5.

TABLE 1 Drug Formulations of Invention and Controls

TABLE 2

Physical Properties of Drug Tablets of Formulations of Table 1

While the invention has been described with particular reference to certain embodiments thereof, it will be understood that changes and modifications may be made which are within the skill of the art. Accordingly, it is intended to be bound only by the following claims, in which: