niacin - aaps_poster_niacin

# T3248 Table 1. Formulations for tablets used in study. Formulation: A B C D Niacin (mg) 250 500 750 1000 Polymer (mg) 300* 100 112.5 100 Electrolyte (mg) 100 25 56.25 50 Lubricant (mg) 10 13 18.75 23.5 * Denotes different polymer selection Table 2. Summaryofpowder characterizat ions. Niacin: Fine Powder USP, Lonza Granular USP, Zetapharm Agglomerated, Niacin (Lonza) Flowability Functions: Angle of Repose (Deg.)* 50.0 39.85 39.03 Aerated Bulk Density (g/cc) 0.289 0.801 0.345 Packed Density (g/cc) 0.651 0.838 0.517 Compressi bility (%) 55.6 4.4 33.2 Angle of Spatula (Deg.)* 76.5 38.3 71.4 Cohesiveness (%) 5.1 98.8 13.8 Degree of Flowability Bad Normal Not Good Total Flowability INDEX 34.0 62.5 49.0 Floodability Functions: Angle of Fall (Deg.)* 34.40 33.23 24.95 Angle of Difference (Deg.) 15.6 6.6 14.1 Dispersibility (%) 19.1 6.3 13.2 Degree of Floodability Tends to flush Tends to flush Fairly High Total Floodabilit y INDEX 58.5 53.25 66.5 *Degree readings are the average value of three separate readings per ASTM standards. Table 3. Variations on components of Formulation A & B (table 1) F ormulation Niacin Polymer Electrolyte Lubrican t A +/- 10% Unchanged Unchanged Unchanged A Unchanged +/- 10% Unchanged Unchanged A Unchanged Unchanged +/- 10% Unchanged A Unchanged Unchanged Unchanged +/- 10% B +/- 10% Unchanged Unchanged Unchanged B Unchanged +/- 10% Unchanged Unchanged B Unchanged Unchanged +/- 10% Unchanged B Unchanged Unchanged Unchanged +/- 10% Table 4. Tablet characteristics. Example of Formulation A (table 1) Formula A Hardness (kP) Friability (% ) Hardness (kP) Friability (% ) Time Point Accelerated Accelerated Ambient Ambient 0 (months)* - - 14.49 0.114 4 (months) 12.48 0.110 14.14 0.070 5 (months) 11.66 0.063 13.79 0.004 *Note: Exam performed at 1 month after date of manufacture. Conclusion The matrix style delivery system utilized by the reference-listed product involves th e combination of a hydrophilic polymer and granulating binder in order to limit the diffusion of the niacin out of the tablet. A use patent for the active ingredient and a formulation patent on th e combination of HPMC, PVP and niacin for the purpose of controlled delivery effectively limited competition within the market. In order to offer a product that could satisfy the generic drug market, a delivery system that utilizes a different system, processes and materials needed to be developed. This novel matrix system allowed for sufficient control in a cost effective manner, when compared to other available technologies in drug delivery. We were successful in producing a tablet that combines the advantages of an immediate release roduct’s cost and manufacturing processes, with the precision and ruggedness of a pharmaceutical controlled delivery system. Results suggest this monolithic formulation is capable of delivering high drug load with minimum burst over 12 hours, utilizing a mechanism of polymer-electrolyte hydration in this obust and directly compressible high drug load system. This formulation trial was able to provide an example of a novel controlled delivery monolithic tablet that addresses the unique issues associated with iacin. We were able to provide an example of a modified solid oral dosage form that delivers high loads of niacin in a highly controlled fashion and does not infringe with any existing process patents, and demonstrates the capability to mimic the in vitro release characteristics of the reference-listed drug and offer improved release characteristics. The advantages this formulation would have over the current eference listed drug are significant: the cost of manufacture and improved release characteristics could enhance consumer compliance and efficacy of the finished dosage form. Acknowledgements This work was supported and possible due to the relationship between Nutraceutix, Inc. and Temple University. Dr. Reza Fassihi, Professor of Biopharmaceutics and Industrial Pharmacy at the Temple University school of Pharmacy, was the innovator res ponsible for Patent No. 6,090,411. Dr. Fassihi’s innovations around logical and effective drug delivery on the industrial scale has enhanced his contributions to the science of pharmacy and earned him the respect of his peers in the industry. Nutraceutix and Temple University share the combined vision of continued application of academic innovations to explore and enhance the pharmaceutical industry. Niacin indicative stability studies The indicative stability of the finished exhibit tablets was very positive. Neither the performance of the delivery system (graph 6), nor the tablet characteristics were significantly affected at either storage condition over the 5-month period (table 4). We anti cipate that the manufacture of these formulations on a commercial scale will yield the same results as the exhibit batch in performance and stability. The shelf life of this formulation should be equivalent to other commercially available controlled release tablets and capsules. Niacin release studies The physical form of niacin used did not significantly affect the in vitro dissolution profile. We were able to produce equivalent dissolution profiles with b oth the fine powder, granular and agglomerated niacin (graph 1) when compared to the reference listed drug. Dissolution trials utilized various physiologically significant dissolution media in order to simulate the conditions the formulation may come into contact with during transit through the gut. The in vitro release of the niacin was not significantly affected by the pH of the dissolution media (graph 2) and maintained equivalent performance when compared to the reference-listed drug. These results indicate that the delivery within this novel formulation will be capable of high levels of precision and p erformance equal to other environmentally independent systems like osmotic pumps. Dissolution trials were also run at various paddle speeds in order to vary the hydrodynamic effects and challenge the ruggedness of the formulation. Results indicate that there is no significant difference in the in vitro dissolution profiles regardless of the paddle rpm (graph 3), which supports the enhanced performance of the delivery system. The increase in hydrodynamics typically increases the erosional impact on the dissolution of the active ingredient. Th e dissolution profiles at the higher rpm’s are not significantly different from each other, wit h exception to the slowest rpm (graph 3). T his formulation offers improved release performance in a highly robust and rugged system that is capable of release independent from the environment or other physical effects that occur with the GI. In order to test the flexibility and forgiveness of the formulation, the individual components were altered (table 3) to simulate potential problems in processing that may lead to poor content uniformity. The in vitro dissolution profiles were monitored and compared to the unaltered formulatio n. The rate of release did not significantly change with alterations of the formula (graph 4 & 5) however, the amplitude was affected in the cases where the active ingredient was increased or reduced when compared to the original formulation. T he formulation is capable of handling changes, as high as 20%, which supports its flexibility and forgiveness on the manufacturing scale. The formulation demonstrates that it has the capability to handle slight variations that may occur during processing and allows for simple process troubleshooting. The in vitro release studies demonst rrated the robustness and ruggedness of this formulation. This formulation will enable the efficient manufacture, on an industrial scale, of controlled release niacin tablets capable of mimicking the in vitro release characteristics of the reference listed drug and other current niacin preparations. Independence of the environment provides evidence to the improved release when compared to simple matrix style diffusion limited formulations. The a bility to self-correct and be independent of erosional forces alludes to the precision of this formulation. The flexibility and forgiveness demonstrates the ease of manufacture and further enhances the robustness and ruggedness of the formulation. In these studies it was demonstrated that the form of the active niacin (powder versus granular) significantly affected the flow characteristics of the finished blends. The fine and powdered forms exhibited high cohesive properties and had a tendency to flush (table 2). T he bulk and packed densities of the fine powder differed significantly when compared to the granular material which had a much tighter correlation. The fine powder caused the finished blend to “rat - hole” or adhere to the hopper wall leaving an opening in the center portion of the bulk powder during the tablet trials performed on the rotary press. By granulating the fine powdered niacin, we were a ble to reduce the difference between bulk and tapped densities and lower the resulting compressibil ity of the powdered niacin (table 2). This significantly affected the powder flow properties and enhanced the finished blends’ tableting properties. The agglomerated and granular material was much more free flowing as shown by the increase in the flowability index (table 2) and had fewer tendencies to “rat - hole” or accumulate within the hopper during tableting. Development of a High Dru g Load Monolithic Contr olle d R elease Oral Delivery Sys tem for Niacin: A Novel Appr oach S. Turner, M. Hite, C . Federici Nutr aceutix, Inc. Redmond, WA. 980 52 and R . Fassihi Ph .D. Schoo l of Phar macy, Temple University, 33 07 N Broad St. Philadelphia PA Purpose. To design a monolithic, solid oral dosage form ca pable of 12-hour near zero-order release delivery of high load niacin preparations. Methods. Three formulations using polyethylene oxide and sodium bicarbonate salts were developed to represent clinically relevant dosage strengths of niacin at 500mg, 750mg, and 1000mg for direct compression tableting and s cale up operation. Dissolution studies were conducted using USP 24 apparatus II, at 50 rpm in 0.1N HCl over 12 hours. Tablet hardness, friability, weight and dry blend characterization were conducted to ensure smooth manufacturability. Results. The physical characteristics of tablets, including friability, content uniformity and hardness were within the USP 24 limits. Near zero-order release over 12-hours was achieved and featured complete elease of the drug at different loading doses using a proportional formula. Conclusions. Results suggest this monolithic formulation is capable of delivering high drug load with minimum burst for 12 ours, utilizing a mechanism of polymer-electrolyte hydration in this robust and directly compressible Characterization of active ingredient Objectives: 1.Develop a formulation capable of controlled release of a highly soluble drug. 2.Develop a formulation capable of high drug load with minimal controlling excipient. www.nutraceutix.com 500mg, 750mg, and 1000mg Niacin CR 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0.0 0 2. 00 4. 00 6.0 0 8. 00 10. 00 12. 00 14.0 0 16. 00 Time (hr) C o r r e c t e d r e l e a s e 1000mg 500mg 750mg Graph 3. Combined in vitro dissolution profiles of finished tablets. Formulation A, compressed at 4 tons (USP 24 apparatus II, 25, 50, 75, 100, 125 rp m’s, 900mL aqueous media at 37 degrees C). 250mg OTC Niacin F22 0.0000 0.2000 0.4000 0.6000 0.8000 1.0000 0. 00 2. 00 4. 00 6. 00 8. 00 10.00 12.00 14.00 16.00 18.00 Time (hr) F r a c t i o n a l r e l e a s e F22 avg, 125rpm F22avg, 25rpm F22 avg, 50rpm F22 avg, 75rpm F22 avg, 100rpm Graph 6. Combined dissolution profiles of exhibit tablet (Formula A) ov er 5 months of storage in ICH conditions for both accelerated and ambient studies. 250mg OTC Niacin, F22 dissolution; 05-22-01 0.0000 0.1000 0.2000 0.3000 0.4000 0.5000 0.6000 0.7000 0.8000 0.9000 1.0000 0. 00 2. 00 4. 00 6. 00 8. 00 10 .00 12 .00 14.00 16 .00 Time (hr) F r a c t i o n a l r e l e a s e F22ambientavgt=2 F22 acceleratedavg t=2 F22 avg, t=0 F22ambientavgt=1 F22 acceleratedavg t=1 F22 avg, t=0 Graph 5. Combined in vitro dissolution profiles of finished tablets. Variation in components of Formulation B (table 3), compressed at 4 tons (USP 24 apparatus II, 50 rpm, 900mL aqueous media at 37 degrees C). OTC Niacin Formula B Variations 0 0.2 0.4 0.6 0.8 1 0. 00 2. 00 4. 00 6. 00 8. 00 10.00 12 .00 14.00 16 .00 Time (hr) F r a c t i o n a l r e l e a s e (+ 20%) Electrolyte (- 20%) Electrolyte (+ 10%) Niacin (- 10%) Niacin F28a avg (+ 10%) Polymer (- 10%) Polymer (+ 10%) Electrolyte (+ 20%) Niacin (- 20%) Niacin (-10%) Electrolyte (+ 20%) Polymer (- 20%) Polymer F28 avg Graph 4. Combined in vitro dissolution profiles of finished tablets. Variation in components of Formulation A (table 3), compressed at 4 tons (USP 24 apparatus II, 50 rpm, 900mL aqueous media at 37 degrees C). OTC Niacin, FA Variations 0 0.2 0.4 0.6 0.8 1 0. 00 2.00 4. 00 6. 00 8. 00 10 .00 12.00 14.00 16.00 18.00 Time (hr) F r a c t i o n a l r e l e a s e (+ 20%) Electrolyte (- 20%) Electrolyte (+ 20%) Polymer (- 20%) Polymer (+ 20%) Niacin (- 20%) Niacin (+ 10%) Electrolyte (- 10%) Electrolyte (- 10%) Polymer (+ 10%) Polymer (+ 10%) Niacin (- 10%) Niacin F22 avg Graph 2. Combined in vitro dissolution profiles of finished tablets. Formulation A, compressed at 4 tons (USP 24 apparatus II, 50 rpm, 900mL aqueous media 0.1 N HCl, pH’s 3.0, 5.4, 6.8, 7.8 at 37 degrees C). 250mg OTC Niacin, F22 0.0000 0.1000 0.2000 0.3000 0.4000 0.5000 0.6000 0.7000 0.8000 0.9000 1.0000 0. 00 2. 00 4. 00 6. 00 8. 00 10.00 12.00 14.00 16.00 18.00 Time (hr) F r a c t i o n a l r e l e a s e Zenith-Goldline, pH 6.8 F22 avg, pH 6.8 Zenith-Goldline, pH 7.8 F22 avg, pH 7.8 F22 avg, pH 3.0 Zenith-Goldline, pH 3.0 F22 avg, pH 5.4 Zenith-Goldline, pH 5.4 F22 avg, 0.1 N HCl Zenith-Goldline, 0.1N HCl Zenith-Goldline, 0.2% SDS F22 avg, 0.2% SDS Graph 1. Combined in vitro dissolution profiles. Formulation A, using fine powder and agglomerated niacin, compressed at 4 tons (USP 24 apparatus II, 50 rpm, 900mL aqueous media pH 7.0 at 37 degrees C.) 500 mg Niacin CDT, F20 & F20a Comparison; 01-22-01 0 0.2 0.4 0.6 0.8 1 0. 00 2. 00 4. 00 6. 00 8. 00 10 .00 12.00 14.00 16 . 00 Time (hr) C o r r e c t e d R e l e a s e Niaspan F20a average Niaspan F20 Average

niacin - aaps_poster_niacin

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