Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-06-19
2001-10-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S434000, C424S436000, C424S464000, C424S465000, C424S486000, C424S488000
Reexamination Certificate
active
06303147
ABSTRACT:
The present invention is concerned with bioadhesive compositions and solid dosage forms prepared therefrom which have a regular and prolonged release pattern for a locally acting ingredient or also for a systemically acting drug, and which are suitable for oral, nasal, rectal and vaginal administration.
Known bioadhesive solid dosage forms are described, for example, in GB-2,042,888 (Teijin). Those dosage forms comprise an active ingredient, 50 to 95% of a cellulose ether and 50 to 5% of a high molecular weight crosslinked polyacrylic acid (carboxyvinyl polymer, carbomer, carbopol). Commercially available bioadhesive dosage forms are often double-layered (multi-layered) preparations with one adhesive layer and at least one non-adhesive layer (e.g. Teijin's Aftach®, Triamcinolone Acetonide Plastering Tablet).
An improved bioadhesive solid dosage form comprising a mixture of 5% polyacrylic acid (Carbopol 934) with pregelatinized starch (drum-dried waxy maize) was described in EP-0,451,433 and in Eur. J. Clin. Pharmacol. (1992) 43: 137-140. Its main advantages were excellent bioadhesion and the total absence of tissue irritation. The development of a buccal tablet on an industrial scale using these disclosures proved unfeasible because of the impossibility to obtain industrially meaningful quantities of the lubricant sodium benzoate in micronized form (i.e. with a very high specific surface). All attempts to prepare buccal tablets with a non-micronized lubricant or without a lubricant failed. The lubricant proved to be essential in order to compress tablets from a granulate. Without it, the tablets stuck to the punches and dies used. A non-micronized lubricant then had the drawback that it needed to be used in unacceptably high amounts and that as a result thereof it affected such properties as bioavailability, release characteristics, taste and mouthfeel.
Consequently, a different lubricant having acceptable properties was called for. First, it was found that the two problems of taste and mouthfeel could be dealt with by restricting the lubricant used to a water-soluble lubricant. Poorly water-soluble lubricants such as magnesium stearate in combination with the bioadhesive carrier left a soap-like taste in the mouth. All of the problems could be solved satisfactorily by using a water-soluble alkali C
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alkyl fumarate as lubricant, in particular sodium stearyl fumarate. A surprising finding was that the lubricant did not cause any loss of bioadhesion and did not negatively affect the release characteristics of the tablet. Upon further upscaling of the wet granulation process used thus far for preparing tablets from the novel bioadhesive composition, yet another problem was encountered, namely disintegration of the granulate during its drying in e.g. a fluid bed drier. This problem has now been solved by dry compaction of some of the ingredients before compression.
The present invention relates to a bioadhesive pharmaceutical composition comprising a pharmaceutically effective amount of an active ingredient and from 80% to 98.8% (w/w) of a mixture of pre-gelatinized starch, from 1% to 10% (w/w) hydrophylic matrix forming polymer, characterized in that the composition further comprises from 0.2% to 5% (w/w) alkali C
6-22
alkyl fumarate as a lubricant.
Amounts of lubricants below 0.2% cannot be considered effective, whereas their use in amounts in excess of 5% do not further improve the process of compression into tablets, but on the contrary tend to impart undesired properties on the formulations. An amount of about 2% is considered optimal. Preferably, said lubricant is sodium stearyl fumarate which is commercially available in micronized form (Pruv®) and in addition is water-soluble and practically tasteless.
The amount of hydrophilic matrix forming polymer in the bioadhesive compositions according to the present invention in general ranges from 2.5% to 7.5% (w/w), and most preferably is about 5% (w/w). Examples of hydrophilic matrix forming polymers are polyacrylic acid (carbomer), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol and mixtures thereof. Polyacrylic acid and in particular carbomer 974P is useful in ensuring that the dosage forms prepared from the bioadhesive compositions have a regular and prolonged release pattern of the active ingredient. Therefore it is the preferred hydrophilic matrix forming polymer in the bioadhesive compositions according to the present invention.
In order to prevent the abrasion of the granulate during the tablet compression, the composition according to the invention advantageously further comprises a glidant. An example of such a glidant is colloidal anhydrous silica. The amount of glidant can range from 0% to about 1% (w/w) and preferably is about 0.2%.
A preferred composition according to the present invention comprises by weight based on the total weight of the composition:
from 0.001% to 10% active ingredient;
from 80% to 98.8% pre-gelatinized starch;
from 1 to 10% hydrophilic matrix forming polymer;
from 0.2% to 5% sodium stearyl fumarate;
from 0% to 1% glidant.
Suitable active ingredients are those which exert a local physiological effect, as well as those which exert a systemic effect, either following penetrating the mucosa or—in the case of oral administration—following transport to the gastro-intestinal tract with saliva. The bioadhesive dosage forms prepared from the compositions according to the present invention are particularly suitable for active ingredients which exert their activity during an extended period of time. Examples thereof are: analgesic and anti-inflammatory drugs (NSAIDs, acetyl salicylic acid, diclofenac sodium, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, naproxen sodium, paracetamol, piroxicam, tolmetin sodium); anti-arrhythmic drugs (procainamide HCl, quinidine sulphate, verapamil HCl); antibacterial agents (amoxicillin, ampicillin, benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil, cephalexin, chloramphenicol, ciprofloxacin, clavulanic acid, clindamycin HCl, doxyxycline HCl, erythromycin, flucloxacillin sodium, kanamycin sulphate, lincomycin HCl, minocycline HCl, nafcillin sodium, nalidixic acid, neomycin, norfloxacin, ofloxacin, oxacillin, phenoxymethyl-penicillin potassium); anti-coagulants (warfarin); antidepressants (amitriptyline HCl, amoxapine, butriptyline HCl, clomipramine HCl, desipramine HCl, dothiepin HCl, doxepin HCl, fluoxetine, gepirone, imipramine, lithium carbonate, mianserin HCl, milnacipran, nortriptyline HCl, paroxetine HCl); anti-diabetic drugs (glibenclamide); antifungal agents (amphotericin, clotrimazole, econazole, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole nitrate, nystatin); antihistamines (astemizole, cinnarizine, cyproheptadine HCl, flunarizine, oxatomide, promethazine, terfenadine); anti-hypertensive drugs (captopril, enalapril, ketanserin, lisinopril, minoxidil, prazosin HCl, ramipril, reserpine); anti-muscarinic agents (atropine sulphate, hyoscine); antivirals (acyclovir, AZT, ddC, ddI, ganciclovir, loviride, tivirapine, 3TC, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir); sedating agents (alprazolam, buspirone HCl, chlordiazepoxide HCl, chlorpromazine, clozapine, diazepam, flupenthixol HCl, fluphenazine, flurazepam, lorazepam, mazapertine, olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine, risperidone, selfotel, seroquel, sulpiride, temazepam, thiothixene, triazolam, trifluperidol, ziprasidone); anti-stroke agents (lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil, remacemide); anti-migraine drugs (alniditan, sumatriptan); beta-adrenoceptor blocking agents (atenolol, carvedilol, metoprolol, nebivolol, propanolol); cardiac inotropic agents (digitoxin, digoxin, milrinone); corticosteroids (beclomethasone dipropionate, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone); disinfectants (chlorhexidine); diuretics (aceta
Appollina Mary
Berman Alysia
Janssen Pharmaceutica N.V.
Page Thurman K.
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