Title:  Bioadhesive solid dosage form

United States Patent:  6,303,147

Assignee:  Janssen Pharmaceutica, N.V. (Beerse, BE)

Filed:  June 19, 1998

PCT NO:  PCT/EP96/05884

102(e) Date:  June 19, 1998

PCT PUB. Date:  July 10, 1997

Foreign Application Priority Data:  Dec 27, 1995[EP] (95203649)

The present invention is concerned with bioadhesive pharmaceutical compositions comprising a pharmaceutically effective amount of an active ingredient, from 80% to 98.8% (w/w/) pre-gelatinized starch, and from 1% to 10% (w/w) of a hydrophilic matrix forming polymer, characterized in that the composition further comprises from 0.2% to 5% (w/w) alkaliC_16-22 alkyl fumarate as a lubricant; solid dosage forms such as tablets which are suitable for oral, nasal, rectal and vaginal administration; processes of preparing the compositions and solid dosage forms.

Description of the Invention

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.RTM., 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_16-22 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.RTM.) 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 (acetazolamide, frusemide, hydrochlorothiazide, isosorbide); anti-Parkinsonian drugs (bromocryptine mesylate, levodopa, selegiline HCl); enzymes; essential oils (anethole, anise oil, caraway, cardamom, cassia oil, cineole, cinnamon oil, clove oil, coriander oil, dementholised mint oil, dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil, neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint, terpineol, thyme); gastro-intestinal agents (cimetidine, cisapride, clebopride, diphenoxylate HCl, domperidone, famotidine, lansoprazole, loperamide HCl, loperamide oxide, mesalazine, metoclopramide HCl mosapride, olsalazine, omeprazole, ranitidine, rabeprazole, ridogrel, sulphasalazine); haemostatics (aminocaproic acid); lipid regulating agents (lovastatin, pravastatin, probucol, simvastatin); local anaesthetics (benzocaine, lignocaine); opioid analgesics (buprenorphine HCl, codeine, dextromoramide, dihydrocodeine); parasympathomimetics (galanthamine, neostigmine, physostymine, tacrine, donepezil, ENA 713 (exelon), xanomeline); vasodilators (amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine, oxpentifylline, pentaerythritol tetranitrate).

The compositions according to the present invention are best presented as dosage forms suitable for oral, nasal, rectal or vaginal administration. To that purpose they are shaped as a tablet, preferably with a surface area sufficient to ensure effective bioadhesion to mucosa. Flat, disc shaped tablets are particularly preferred.

For oral applications, several buccal tablets have been developed. In imitation of the miconazole tablet described in Eur. J. Clin. Pharmacol. (1992) 43: 137-140, a similar miconazole tablet using sodium stearyl fumarate was prepared, but--as described below--now on an industrial scale. Said tablet comprises by weight based on the total weight of the tablet:

10% microfine miconazole nitrate;

82.8% drum dried waxy maize starch;

2% sodium stearyl fumarate;

5% carbomer 974 P; and

0.2% colloidal anhydrous silica.

In addition two tablets comprising respectively 1% and 5% of the active ingredient miconazole nitrate, and 91.8% and 87.8% drum dried waxy maize starch were prepared as well.

A buccal tablet comprising the triamcinolone (in imitation of Teijin's Aftach.RTM.) was also prepared. This tablet comprises by weight based on the total weight of the tablet

1% microfine triamcinolone;

91.8% drum dried waxy maize starch;

2% sodium stearyl fumarate;

5% carbomer 974 P; and

0.2% colloidal anhydrous silica.

The compositions according to the present invention can be prepared on a small scale by a wet-granulation process comprising the steps of

intimately mixing the active ingredient, the pre-gelatinized starch, and optionally the hydrophilic matrix forming polymer, until homogenous in a suitable mixer,

wetting the thus obtained mixture with a pharmaceutically acceptable non-aqueous solvent,

pressing the wet mixture through a sieve having a maze width ranging from 1% to 1.8 mm;

drying the granulate; and

mixing the dried granulate with sodium stearyl fumarate and optionally the glidant.

In order to prepare tablets, the process is followed by the further step of

compressing the granulate with lubricant and optional glidant, into tablets.

However, this process is not amenable to large-scale production because of the disintegration of the granulate during the drying process in e.g. a fluid bed drier. Tablets can be prepared, however, by a dry process comprising the steps of:

intimately mixing the active ingredient, the pre-gelatinized starch and the hydrophilic matrix forming polymer in the dry state;

compacting the thus obtained mixture into a sheet;

breaking the sheet into a granules;

sieving the granules;

blending the granulate with the lubricant and optionally the glidant; and

compressing the blend into tablets.

In this process, the blending steps can conveniently be conducted in art-known planetary mixers. Similarly, the dry compaction is conveniently conducted in art-known compaction machines at a force in the range of 4 to 15 kN, preferably in the range of 6 to 8 kN. The final compression step can be conducted at pressures ranging from 1500 to 3000 kg.cm^-2, in particular in the range of 1600 to 2000 kg.cm^-2.

The present invention is meant to extend to and include the products obtainable by the foregoing process.

The present invention also concerns the use of 0.2% to 5% (w/w) sodium stearyl fumarate as a lubricant and 80% to 98.8% (w/w) pre-gelatinized starch, 1 to 10% hydrophilic matrix forming polymer for the manufacture of a bioadhesive dosage form.

The buccal tablets according to the present invention can be administered as follows. A tablet is placed on the gingiva, preferably in the region of the upper canines, and is fixed by gently pressing on the cheek for 1 minute. The tablet then is preferably moistened with the tongue to prevent sticking of the tablet to the cheek.

The gingiva seem to be the best site or application because of the long-adhesion time (about 9 hours) and the slow clearance rate from the oral cavity.

Claim 1 of 12 Claims

I claim:

1. A bioadhesive pharmaceutical composition comprising a pharmaceutically effective amount of an active ingredient, from 80% to 98.8% w/w pre-gelatinized starch, and from 1% to 10% w/w of a hydrophilic matrix forming polymer, characterized in that the composition further comprises from 0.2% to 5% w/w alkali C_16-22 alkyl fumarate as a lubricant.

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