SPECIFICATIONTabletThe present invention relates to a particular form of pharmaceutical presentation, more specifically a double layer tablet, for use in both the human and veterinary practice.
The double layer tablet according to the present invention is intended for oral use in the treatment of infectious diseases caused by bacteria and provides a simultaneous application, to a patient in need of treatment, of a pro-drug for mecillinam (6 -[(hexahydro - 1 H - azepin -i - yl) - methyleneamino] penicillanic acid) and a pro-drug for ampicillin (6 - (D a - aminophenylacetamido) penacillanic acid).
From the published British patent specification No.
1,405,886 it is known that pre-formulated mixtures of certain penicillins and amidinopenicillanic acid derivatives give rise to an enhanced antibacterial effect when compared with the effect of the individual compounds.
From British patents Nos. 1,215,812 and 1,293,590 it is known that pro-drugs for ampicillin and mecillinam, respectively, in the form of easily hydrolyzable esters, e.g. acyloxyalkyl esters, are particularly valuable for oral application due to the enhancer absorbability of said esters.
Among the easily hydrolyzable esters known from the above mentioned patents are the particularly suitable pivaloyloxymethyl esters of ampicillin and mecillinam, these esters having the generic names, pivampicillin and pivamecillinam, respectively. FromBritish Patents Nos. 1,363,506 and 1,427,139 also the alkoxycarbonyloxyalkyl esters of ampicillin and mecillinam are known to be suitable esters for the said purpose.
When using the first mentioned esters, it is for stability reasons preferred to apply pivmecillinam in form of the water-soluble hydrochloride, whereas it is preferred to use pivampicillin as the sparingly soluble free base because this gives rise to lesser gastro-intestinal side-effects than the corresponding hydrochloride, confer German patent No.
2,349,971.
Following the teachings of published British patent specification No. 1,405,866 in preparing a mixture of pivampicillin and pivmecillinam hydrochloride, this would result in a product with an inferior shelf-life and a prolonged disintegration time, due to the different solubilities of the two components of the composition and interaction between them, unless specific measures are undertaken.
The lesser stability is partly due to the influence of the amino-group of pivampicillin on the pivmecillinam molecule, the latter being subjected to an aminolysis, i.e. a destruction ofthe molecule. The destruction is particularly notable when the composition is stored without special precautions being taken to exclude moisture. The prolonged disintegration time is caused by the simultaneous presence of insoluble pivampicillin and easily soluble pivmecillinam hydrochloride in a tablet matrix. The presence of an auxiliary agent in the form of a disintegrant, typically a starch, has no effect in a tablet containing such mixture. However, a disintegrant is necessaryto disperse the only slightly soluble pivampicillin in the stomach to avoid high local concentrations. Pivmecillinam hydrochloride is easily soluble and needs no disintegrant.On the contrary, pivampicillin and a disinteg rant tend in the presence of pivmecillinam hydrochloride to form a slow release preparation, presumably due to the formation of a matrix from which the pivmecillinam is only slowly liberated.
It has now been shown that it is possible to provide a double layer tablet by which the draw-backs connected with the described mixtures can be avoided. The double layer tablet according to the invention is a two-layertablet in which the first layer contains the pro-drug for ampicillin and the second layer the pro-drug for mecillinam, the layers further containing suitable carriers and/or auxiliary agents.
The present two-layer tablets can be produced on a conventional tabletting machine for this purpose, using a first granulate containing one active ingredient together with carriers and/or auxiliary agents, and a second granulate containing the other active ingredient and the necessary carriers and/or auxili- ary agents. The first granulate is dosed in the correct amount into the die and is slightly pre-compressed, the lower punch is lowered, and the second granulate is dosed into the empty space in the die, and the tablet is finally compressed.
When providing the above granulates for producing the present double layer tablets, due consideration shall be given to the properties ofthe components involved.
Pivampicillin and similar pro-drugs for ampicillin are subjected to destruction of the molecule when brought into contact with organic solvents. As pivampicillin is only slightly soluble in water, an aqueous solution of a water soluble cellulose derivative, e.g. methylcellulose, may be used as granulating agent.
Pivmecillinam hydrochloride and similar prodrugs for mecillinam are easily soluble in water, and it is thus necessary to choose an organic solvent with as little influence on the stability of the pivmecillinam molecule as possible and in which the pivmecillinam hydrochloride is only slightly soluble.
Among the organic solvents used within the pharmaceutical technique, isopropanol and acetone are suitable and isopropanol is the preferred solvent because of the risks of explosion connected with the use of large amounts of acetone.
As cellulose derivative it is preferred to use hydroxypropylcellulose because of its solubility in isopropanol.
For filmcoating the final tablets, an agent should be used which results in a strong, tenacious film.
Thus, it is preferred to use hydroxypropylmethylcellulose dissolved in an aqueous solution of an alkanol, e.g. ethanol.
A double layer tablet as provided above has shown to be stable, easily disintegratable, providing a good bioavialability ofthe two active components.
It is well suited for clinical practice.
Another embodiment of a two-layer tablet would be a tablet with a core of the first active ingredientand a coating containing the second active ingredient, but this embodiment might be less appropriate in case that the amounts used ofthe two activeingredients are of the same magnitude, due to difficulties in the correct centering of the core with ensuing uneven thickness of and risk of cracking of the coating during storage and handling of the finalproduct.
The two-layertablet according to the invention is thus the most suitable form of simultaneously administering the two active components. This pharmaceutical technique makes it possible to vary the proportions of the two active components bet weeneg. 1:5 to 5:1.
The invention will be further illustrated by twoExamples which, however, shall not in any way be considered limiting the scope of the invention.
Example 1Preparation of 100,000 tabletsManufacturing formulaPivampicillin ........................................ 25.00 kgPivmecillinam hydrochloride .................... 20.00 kg Hydroxypropylcellulose ...... 0.07 kg Lactose ........................................ ...... 6.00 kgMagnesium stearate .................................. 0.50 kgMethylcellulose ........................................ 0.30 kgStarch, (Sta-Rx 15008) ................................ 5.40 kg Hydroxypropylmethylcellulose ................. 1.00 kg Manulacturing processPivampicillin and a part of the starch are wet granulated with an aqueous solution of methylcellulose.The "fluid bed" dried granulate is mixed with the remainder of the starch and with 1% magnesium stearate. This granulate is used as the first (lower)layer in a two-layertablet.
Pivmecillinam hydrochloride and lactose are wetgranulated with a solution of hydroxypropylcellulose in isopropanol. The "fluid-bed" dried granulateis mixed with magnesium stearate, and is used as the second (upper) layer in atwo-layertablet.
The tablets are compressed with:Total fill weight: 580 mg/tabletFirst layer, fill weight: 310 mg/tabletSecond layer, fill weight: 270 mg/tabletPunch size: circular 12 mm diameter, convex surfaces.
The tablets are filmcoated in a "fluid bed" equipment with hydroxypropylmethylcellulose dissolvedin ethanol:water, 25:75. The filmcoated tablets aredried at35-40"C for 9 hours.
Example 2Preparation of 100,000 tabletsManufacturing formulaPivampicillin ........................................ 25.00 kgPivmecillinam hydrochloride .................... 20.00 kgHydroxypropylcellulose ............................. 0.50 kgCellulose microcrystalline ......................... 10.00 kgMagnesium stearate 0.50 kg Methylcellulose 0.30 kg Starch (Sta-Rx 1500#)...................... 3.60 kg Carboxymethylstarch ................................. 1.80 kgHydroxypropylmethylcellulose ................. 1.00 kgManufacturing process:Pivampicillin and a partofthe starch are wet granulated with an aqueous solution of methylcellulose. The dried granulate is mixed with the remainder of the starch, the carboxymethyl starch, and with 1% magnesium stearate. This granulate is used as the first (lower) layer in a two-layertablet.
Pivmecillinam hydrochloride is wet granulated with hydropropylcellulose dissolved in isopropanol.
The dried granulate is mixed with microcrystalline cellulose and magnesium stearate and is used as the second (upper) layer in a two layertablet.
The tablets are compressed with:Total fill weight: 617 mg/tabletFirst layer, fill weight: 310 mg/tabletSecond layer, fill weight: 307 mg/tabletPunch size: Circular, 12 mm diameter, convex surfaces.
The tablets are filmcoated in a "fluid-bed" equipment with hydroxypropylmethylcellulose dissolved in ethanol:water25:75.
The coated tablets are dried at 35"C for 9 hours.