Hydrazaline hydrochloride pellets and method of preparation

Embodiments of a hydrazaline hydrochloride composition for treatment of hypertension in humans each provide sustained release of hydralazine hydrochloride administered in the form of pellets, granules and tablets. Methods of preparation are disclosed.

BACKGROUND OF THE DISCLOSURE

Field of the Disclosure

The disclosure relates to a method of preparing a controlled release pharmaceutical formulation of hydralazine hydrochloride pellets which are used in the treatment of hypertension in humans.

SUMMARY OF THE DISCLOSURE

An embodiment of the disclosure meets the needs presented above by generally comprising a sustained release hydralazine hydrochloride composition in the form of pellets, granules and tablets.

DESCRIPTION OF THE PREFERRED EMBODIMENT

With reference now to the drawings, and in particular toFIGS. 1 through 6thereof, a new hydralazine hydrochloride pharmaceutical composition embodying the principles and concepts of an embodiment of the disclosure and will be described.

The present invention is further illustrated by the examples provided in the charts within the drawingFIGS. 5 through 9, 10 through 13, 14 through 15, and 16 through 18.

The composition is provided with a core of sugar spheres each having a size between 750 microns and 810 microns layered with a drug layer containing hydrazaline hydrochloride, a separating layer, an enteric layer comprising an enteric polymer and then a top layer. The end product can be administered over a span of 12-24 hours.

In the sample formulations shown inFIGS. 5 through 9, a process of making the hydrazaline hydrochloride composition begins with drug layering by preparation of a first coating solution of a slurry of hydralazine hydrochloride in a solution of hydroxy propyl methyl cellulose in isopropyl alcohol or a solution of polyvinyl pyrrolidine K 30 in isopropyl alcohol or a solution of polyvinyl pyrrolidine K 30 in purified water or a solution of starch in purified water. Sugar spheres of 750-810 microns in size form a core. Depending on the particular formulation the sugar spheres or microcrystalline cellulose spheres or starch spheres are preheated to about 35 degrees Celsius with gentle movement in a fluid bed coater and then sprayed with the first coating solution prepared above, while more air drying is introduced and fluidization intensified. Spray rate, air throughput and inlet air temperature are adjusted in such a way that the core bed reaches a temperature about 35 degrees Celsius. Over wetting of the cores is to be avoided as it may cause conglomeration. The pellets formed are then dried in a tray drier at about 45 degrees Celsius to a moisture content of less than three percent. The dried pellets are sized on a sifter to remove agglomerates, broken pellets, and fine powder. The pellets are then ready for coating.

A second solution of ethyl cellulose, stearic acid and hydroxy propyl methyl cellulose is prepared in an adequate quantity of isopropyl alcohol. Alernatively, the second coating solution is eudragit and stearic acid is prepared in an adequate quantity of isopropyl alcohol. Yet another alternative second coating solution is guar gum/xanthane gum and stearic acid prepared in an adequate quantity of purified water. The drug pellets are preheated to about 35 degrees Celsius with gentle movement in a fluid bed coater, and then sprayed with the second coating solution, while more drying air is introduced and fluidization intensified. Spray rate, air throughput and inlet air temperature are adjusted in such a way that the core bed reaches a temperature of about 35 degrees Celsius. Over wetting is to be avoided as it may cause agglomeration. After a complete of the second coating solution is consumed, the fluidization is reduced for a brief post-drying period. The resulting pellets are then dried in a tray drier at about 45 degrees Celsius to a moisture content of less than three percent. The resulting pellets are sized on a sifter to remove agglomerates, broken pellets and fine powder. After checking weight of the resulting pellets and noting down the yield they are ready to fill in capsules.

In variations of the invention represented inFIGS. 10 through 13, the composition of hydrazaline hydrochloride is made using the following process. Hydralazine hydrochloride is mixed with manitol, povidone K-30, lactose and microcrystalline cellulose then passed through 30 mesh screen producing a blend. The blend is mixed for between 8 and 12 minutes and granulated with starch paste. The resulting wet mass is passed through a #18 sieve to produce granules. The granules are dried at 60 degrees Celsius in a hot air oven for between 25 and 30 minutes after which the granules are passed through a #22 sieve. The sized granules are then blended with magnesium stearate for between 8 and 12 minutes and compressed into tablets.

The tablets are coated with ten percent sorbitol. Various components of the coating solution are added to the solvent in a sequential manner. Each component added is allowed to dissolve prior to adding the next component. To coat, the tablets are placed in a coating pan. The pan is rotated between 15 and 18 revolutions per minute. The coating is performed using a spray gun at a spray rate of three to five ml per minute. The atomization pressure is kept at 1 kg per square cm while outlet temperature was kept between 40 and 45 degrees Celsius. Coating is continued until a desired weight gain of between 9 and 11 percent.

In variations of the invention represented inFIGS. 14 and 15, the composition of hydrazaline hydrochloride is made using the following process. Hydrazaline hydrochloride core tablets are prepared by polysaccharide (lactulose), disintegrant and lubricant by a conventional direct compression method. The core tablets are coated with pH 5.6 depended polymer followed by enteric polymer at a pH above 7.0. The top layer contains a eudragit polymer pH above 7.0 which will not break or dissolve at the stomach but pass to the duodenum, jejunum and ileum followed by the large intestine.

In variations of the invention represented by exemplary formulations inFIGS. 16 through 18, the composition of hydrazaline hydrochloride is made using the following process. A slurry of hydrazaline hydrochloride is prepared in a solution of hydroxy propyl methyl cellulose in isopropyl alcohol or a solution of polyvinyl pyrrolidine K 30 in isopropyl alcohol. Sugar spheres (size 60#80) are preheated to about 35 degrees Celsius with gentle movement in a fluid bed coater and then sprayed with one of the coating solutions as disclosed above, while more drying air is introduced and fluidization intensified. Dried pellets produced are sized with mesh #40 and #50 to provide micro pellets. The micro pellets are coated with hydroxy propyl methyl cellulose as a barrier coating and followed by an enteric coating of a solution of eudragit and PEG 6000 in an adequate quantity of either purified water or isopropyl alcohol. The coated micro pellets are then ready to be formed into tablets prepared by a multiple unit pellet system along with diluent, disintegrant, and lubricants in a conventional manner followed by film coating.

In use, each preparation provides a sustained release of a therapeutic dose of hydrazaline hydrochloride for treatment of hypertension in humans.