[生物医药论文精品]两种苦参素缓释剂型的制备及其相对生物利用度研究

1两种苦参素缓释剂型的制备及其相对生物利用度研究A1A0A3A2A5A4A6A7A8A9A10A11A12A13A14A10A11A15A16A17A18A19A20BEAGLEA21A22A23A24A25A26A27A28A29A30A31A32A33A34A35A36A30A37A38A39A40A41A42A16A43A30EUDRAGITRS30DA44A45A46A47A48A49A4A50A51A52A10A11A12A13A16A53A54A4A6A55A56A57A58A10A11A15A16A30HPLCA59A60A61BEAGLEA21A62A63A7A8A9A10A11A12A13A14A10A11A15A64A65A66A67A68A69A70A8A71A4A72A73A74A53A54A75A76A77A78A24A79A31A16A80A81A82A28A83A84A85A8A86A87A25A26A27A28A29A30A31A32A88A89A88A89A35A90A91A18A19A92A93A94A4A10A11A12A13A24A25A26A27A28A29A30A311031A95A94A4A10A11A15A25A26A27A28A29A30A311176A32A88A96A35A35A97A98A94A4A10A11A4A72A99A65A66A69A70A27A28A100A101A32A102A103A104A35A35A105A106A107A108A109A110A111A112A108A109A110A113A108A114A115A116A117A118A108A116A117A118A108A119A120A121A122A123PREPARATIONOFTHESUSTAINEDRELEASESYSTEMSOFKUSHENINANDSTUDYONTHERELATIVEBIOAVAILABILITYABSTRACTOBJECTIVETOPREPAREKUSHENINSUSTAINEDRELEASEPELLETSANDSUSTAINEDRELEASETABLETS,ANDTOSTUDYTHEBIOAVAILABILITYOFTHESETWOPREPARATIONSINBEAGLEDOGSMETHODSTHEPELLETSWEREPREPAREDANDCOATEDUSINGTHECENTRIFUGATIONCOATINGGRANULATINGEQUIPMENTEUDRAGITRS30DWASUSEDASTHECOATINGMATERIALANDHPMCWASUSEDASTHEMATRIXOFTHESUSTAINEDRELEASETABLETHPLCWASSELECTEDTODETERMINETHECONCENTRATIONOFTHEACTIVEDRUGOXYMATRINEANDITSMETABOLITEMATRINEINPLASMATHEPHARMACOKINETICPARAMETERSANDRELATIVEBIOAVAILABILITYWERECALCULATEDCOMPARINGWITHCONVENTIONALCAPSULESRESULTSTHERELATIVEBIOAVAILABILITYOFOXYMATRINEINSUSTAINEDRELEASEPELLETSANDSUSTAINEDRELEASETABLETSANALYZEDBYNONCOMPARTMENTMODELTHEORYWERE1031AND1176，RESPECTIVELYCONCLUSIONSTWOFORMULATIONSAREBOTHBIOEQUIVALENTWITHTHECONVENTIONALCAPSULESKEYWORDSPHARMACEUTICSSUSTAINEDRELEASEPELLETSSUSTAINEDRELEASETABLETSOXYMARINEMATRINEBIOAVAILABILITY苦参素（KUSHENIN）是从天然植物苦豆子（SOPHORAALOPECUROIDESL）和苦参（SOPHORAFLAVESCENSAIT）中提取的生物碱，是以氧化苦参碱OXYMATRINE，OM为主并含有少量氧化槐果碱的混合碱。此外，苦参碱（MATRINE，M）为豆科植2物苦参的根及广豆根的有效活性成分，它的药理活性与OM类似，二者在一定条件下可以转化，已有文献报道，OM在胃肠道菌群的作用下可被等分子还原成M。NNOHHHHONNOHHHHOXYMATRINE，OMMATRINE，M目前，苦参素已经被确定为治疗病毒性肝炎重点推广工程药物，它能够明显抑制乙肝病毒感染，具有抑制病毒生长繁殖的作用。苦参素目前大量应用于临床，但国内外上市的苦参素制剂主要有软胶囊A124A125A126、输液、速释胶囊、G8892G4568剂A124A127A126和G10267剂，G4590G7092G13543释制剂。G11013于G1866G1319内G9052G19512G2334G15940G7411G17751G11713（15G7942H），G10628有的剂G3423已经G17840G17840G993能G17878合于临床G19668要，G4557于G5942性乙G3423肝炎G5751者G13792G16340，G5332G2469一G7097一G8437G6122G1016G8437的G13543释制剂是G5468有G5529要的。G7424文参G10043市G2818胶囊“G2350G4584G8900G2159胶囊”（剂量G726G8611G7097G989G8437，G8611G843723G12902，100MG/G12902），G19036G4557G993G2528G5751者，制G3803G1114G1319外释G693012G4579G7114的苦参素G13543释G10267和G13543释G5506G1036，并G17839G15904G1114苦参素G13543释G10267、G13543释G5506G1036的G11468G4557生物G2045用G5242和G1319内外G11468G1863性G11752G12362。实验部分1仪器与试剂氧化苦参碱G4557G10043G2709（中国药G2709生物制G2709G7828定G6164）G727苦参素、苦参素胶囊（G4437G3811G2350G4584G8900G2159药G1006G13941G1233有G19492G1856G2508）G727G5506G7242G13432G13512素（MCC）（G8755G14499G5132G10099市药用G17753G7021G2390）G727EUDRAGITRS30D（G5515国G13611G3994G1856G2508）G727EC、HPMC（上G9035COLORCONG1856G2508）G727G18267G9354G3423G8443G5064G1207（上G9035COLORCONG1856G2508）。BZJ360MG266G3423G2265G15927G17908G12902G7438（G14334天G18108一G19510G2325G1128G11752G12362G6164）G727G20652效液G11468G14406G16901G1214（AUTOSAMPLERL7200,UVVISDETECTERL7420,PUMPL7110）（G7097G7424HITACHIG1856G2508）G727CKCHROMG14406G16901工作G12461（SCIENTIFICSYSTEMINC）。WISTAR大G21748，G1319重180G794220GG727G1593G5259BEAGLEG10368，G1319重10G10215KG（G8796G19463药科大G4410G4466G20576G2172物G4472）。2实验方法321检测OM和M的色谱条件A128A129A130G726G3G14406G16901G7621G726DIAMOSILC18G7621（20046MM，5MID）G727G8981G2172G11468G726乙G14108G8712（2080，含5MMOLL1庚烷磺酸钠，以磷酸调PH值32）G727G7828测波长G726220NMG727G8981速G72610MLMIN1G727G7621温G72640。22苦参素胃肠道吸收部位的确定采用外翻肠囊法，测定G1114250GML1苦参素在大G21748各肠段的吸收情况，结果见FIG1。表明苦参素在大G21748各肠段均有吸收，G7092特定吸收G18108位，符合制成G13543释制剂的基G7424条件。图1FIG123苦参素缓释制剂释放度测定的方法确定考察G1114苦参素G13543释G10267、G13543释G5506G1036在G993G2528G9354出介质中的释G6930G5242，结果可知，OM在蒸馏G8712、PH68磷酸盐G13543冲液和01MOLL1HCLG989种介质的释G6930G5242曲线基G7424一致，为非PH依赖性制剂，故选用900ML蒸馏G8712为释G6930G5242测定介质。OM易G9354于G8712，饱和G9354解G5242G17840G17840大于制剂完全释G6930G7114的浓G5242，满足释G6930G6164G19668漏槽条件，参G10043中国药典G10267剂释G6930G5242测定方法，确定为篮法，转速为100RMIN1。24苦参素缓释片的制备G10267芯的制G3803G726称取处方量苦参素及MCC、HPMC（K100M、K4M），过筛混合，加入粘合剂制软材，过筛制湿颗G12902，干燥2HR，过筛整G12902，加入硬脂酸镁，混匀，压G10267，控制G10267剂硬G5242，即得苦参素G13543释G10267。薄膜G2265G15927G10267的制G3803G726将G10267芯置G2265G15927锅内，将G18267G9354性G8443G5064G1207制成G2265G15927液，G17839G15904G2265G15927，即得。25苦参素缓释微丸的制备251空白丸心的制备取MCCG17878量置于离心G2265G15927G17908G12902G7438中，以G8712为粘合剂，G5332G2172离心G17908G12902G7438使物G7021呈絮状G8981G2172状态后G5332始供粉，此过程G17839G15904至G1036核长至32G79428目。252素丸的制备将主药置于供粉G4472中，称取空白G1036心G17878量于离心G2265G15927G17908G12902G7438中，喷入粘合剂，使离心G4472中的G5506G1036逐渐长大，待供粉G4472中G7092粉末剩余，G1863闭主G7438。收集药G1036，晾干。筛出20G79424目的G5506G1036，G3803用。253包衣微丸的制备4取含药G5506G1036置于离心G4472中转G2172，喷入EUDRAGITRS30DG2265G15927液，至制成具有一定G2265G15927厚G5242的G5506G1036。G5506G1036G2265G15927后，置于烘箱中40热处理。26两种苦参素缓释制剂体外释放度测定和释药机理的研究G1016种苦参素G13543释制剂的G1319外释G6930G5242测定结果见TAB1。表1TAB1将G13543释G5506G1036的G1319外释G6930数据分别按零级、一级、HIGUCHI释药G2172G2159G4410方程G17839G15904处理，结果表明，G13543释G5506G1036的G1319外释药结果符合一级G2172G2159G4410方程（R09938）。从G9354出过程中可以观察到，G9354出前，G5506G1036表G19766G15927G4630G11468G4557G17751G1821G9381，G9354出12H后，G13917G11536可见G5506G1036的G15927G4630G1185G17751为完整，推测释药是以从EUDRAGITRS30D膜的G13870合物G19154G19400分子G4392G19565G6205G6967为主。将G13543释G10267的G1319外释G6930数据分别按零级、一级、HIGUCHI、RITGERPEPPASG8181G3423释药G2172G2159G4410方程G17839G15904处理，结果表明RITGERPEPPASG8181G3423（R09956）、HIGUCHIG8181G3423（R09941）和FIRSTORDERG8181G3423（R09927）释G6930G5242和G7114G19400均有G17751G3921的G11468G1863性。经G11013RITGERPEPPAS方程释药曲线G6323合的K05366，在045G794089G1055G19400，可见释药过程是药物G6205G6967和G20604G7562G9354G15444G1861G2528作用。G11013G16809G20576中观察到G5415G9354出G16809G20576G17839G15904到12G4579G7114以后，G10267剂G1185可G1457G6357G17751为完整的G5430状，G3252此OM的释G6930以G6205G6967为主。3两种苦参素缓释制剂和市售苦参素胶囊的生物利用度及体内外相关性研究以苦参素胶囊为G4557G10043，分别考察苦参素G13543释G10267、G13543释G5506G1036在BEAGLEG10368G1319内的药物G2172G2159G4410特G5461，G2528G7114G4557G14270制苦参素G13543释G10267和G13543释G5506G1036G17839G15904G1114G11468G4557生物G2045用G5242G11752G12362。应用非G19560G4472G2172G2159G4410理G16782，G17902过OM及G1866G1207G16886G1147物MG15892药浓G5242G713G7114G19400G2465G20316G1461G5699得到的药G2172G4410参数和G1319内外G11468G1863性等G6363G7643G4557苦参素G13543释G10267、G13543释G5506G1036质量G17839G15904G1114G16792G1227。31色谱条件G14406G16901条件G252821，G1177将G8981G2172G11468G6925为G726乙G14108G8712（15G72685，VV，含5MMOLL1庚烷磺酸钠，以磷酸调PH值32）。32血浆样品的处理取G15892G898605ML，依G8437加入内G7643G9354液50L，6（W/V）HCLO404ML，G7071G9077混合30S，离心（3000RMIN1）5MIN。上G9177液转G12239至10ML离心G12661中，加20NAOHG9354液04ML，G8707G1235G8503G981G18267（982，V/V）提取G9354液40ML，G7071G9077混合540S，G8712G5191G6403G14645240TIMESMIN115MIN,离心（4000RMIN1）10MIN。吸取有G7438G11468，G6393干，G8543G9207以100LG8981G2172G11468G9354解，G7071G9077混合30S，离心（3000RMIN1）5MIN。取上G9177液20LG17839G7691，G16772G5417G14406G16901图。33给药设计及血样采集331缓释片的给药设计及血样采集G1593G5259BEAGLEG103686G2494，G7393药前G12117G2014712H，G1016G8437G7393药G19400G195607天，G2345剂量G14270G17535G1144G2461G2487G7393G14270制苦参素G13543释G102672G10267（G6221G2507G72620030301，G8611G12902含苦参素150MG）和市G2818G4557G10043胶囊3G12902（G4437G3811G2350G4584G8900G2159药G1006有G19492G1856G2508G11752制，G6221G2507G72620020802，G8611G12902含苦参素100MG），G13485药前G1820取空白G15892，G13485药后025、05、1、15、2、25、3、35、4、6、8、10、12和24H取G15892，前G14163G19757G14045处采G15892G134342ML，置于G9046有肝素的离心G16809G12661中，G12447即于3500RPM条件下，离心10MIN，吸取上G4630G15892G8986，置于G71320G1924箱中G1457G4396，待分G7524。332缓释微丸的给药设计及血样采集G1593G5259BEAGLEG103686G2494G1319重（1015KG），G7393药前G12117G2014712HR，G8939G1940G7411为7天，G1016G2620G7411G19555G7438G1144G2461G2487G7393苦参素G13543释G5506G1036胶囊2G12902（G8611G12902含苦参素150MG）和苦参素G7234G17902胶囊3G12902（G8611G12902含苦参素100MG），G13485药前G1820取空白G15892，G13485药后025、05、1、15、2、25、3、4、5、6、8、10、12、24取G15892，前G14163G19757G14045处采G15892G134343ML，置于G9046有肝素的离心G16809G12661中，G12447即于4000RMIN1条件下，离心10MIN，吸取上G4630G15892G8986，置于G71320G1924箱中G1457G4396，待分G7524。34药物动力学参数的计算苦参素G13543释G10267、G13543释G5506G1036、市G2818胶囊的主要药G2172G4410参数（MEANSD）见TAB2、3，药G7114曲线见FIG2、3。表2TAB2图2FIG2表3TAB3图3FIG335相对生物利用度以G13491G16757G11709结果中的G15892药浓G5242G713G7114G19400曲线下G19766G12227AUC0数据G16757G12651，G14270制G13543释G5506G1036G4557G11468G2528剂量的G7234G17902胶囊的G11468G4557生物G2045用G5242FR（OM）63785/36441001031G727以OM和M的浓G5242合G16757，G11013G1856G5347G16757G12651得出FR（OMM）（3785/2645641/248）/3644/2645567/2481001020。G14270制G13543释G10267G4557G11468G2528剂量的市G2818G10267的G11468G4557生物G2045用G5242FR（OM）2219727以OM和M的浓G5242合G16757，G11013G1856G5347G16757G12651得出FR（OMM）（2219/2643059/248）/1887/2642758/2481001089。36氧化苦参碱转化为苦参碱的转化率G14270制G13543释G5506G1036的苦参碱转化G10587为613G705，G13543释G10267的苦参碱转化G10587为596G705，G1016G8437测得的市G2818胶囊的苦参碱转化G10587分别为617，611G705。37生物等效性评价G11013方G5058分G7524G13491G16757G16757G12651，G14270制苦参素G13543释G10267、G13543释G5506G1036与市G2818胶囊的OM和M的AUC0在制剂G19400、G2620G7411G19400、G1022G1319G19400均G7092显G14891性G5058G5334（PG730005），G13792与市G2818胶囊的TMAX、CMAX在制剂G19400有显G14891性G5058G5334（PG728005），但在G2620G7411G19400、G1022G1319G19400均G7092显G14891性G5058G5334（PG730005）。在方G5058分G7524的基G11796上G4557AUC0G17839G15904G2464G2345G1403TG7828G20576和90置G1461G2318G19400分G7524，结果表明G2475G16809制剂G13543释G5506G1036和G13543释G10267的OM的AUC0与参G8616制剂市G2818胶囊的OM的AUC0G8616值的90置G1461G2318G19400分别为1127869和1132858G727G2475G16809制剂G13543释G5506G1036和G13543释G10267的M的AUC0与参G8616制剂市G2818胶囊的M的AUC0G8616值的90置G1461G2318G19400分别为1077806和1084817，均在80125的G14551G3272G1055内。故以AUC0为G16792G1227G6363G7643，G1016种G14270制G13543释制剂与市G2818胶囊生物等效。4结论1G11013离G1319外翻肠囊G4466G20576结果，可知苦参素在大G21748各肠段均有吸收，G7092特G5334性吸收G18108位，符合制成G13543释制剂的基G7424条件。2G14270制的G1016种苦参素G13543释制剂，G1319外释G6930均可G6357G1350512H，G1866释G6930G5242符合要G8726。G14270制G13543释G10267的药物释G6930曲线G17839G15904数G4410G8181G3423G6323和，G1866释药G7438制为G726G6205G6967和G9354G15444G2339G2528作用释药，以G6205G6967G7438制为主。G14270制G13543释G5506G1036的G1319外释药结果符合一级G2172G2159G4410方程，推测释药是以G6205G6967为主。3G4557G14270制G13543释G10267、G13543释G5506G1036以市G2818胶囊为G4557G10043G11752G12362G1114二者在BEAGLEG10368G1319内的药物G2172G2159G4410过程和G11468G4557生物G2045用G5242。结果表明G726与市G2818胶囊G11468G8616，G1016种G14270制G13543释制剂可明显G19489G1314G9052G19512速G10587G5132数（KE），G5322长药物在G1319内的G9052G19512G2334G15940G74117（T1/2）和G5191均G9394G11053G7114G19400（MRT）G727G13543释G5506G1036与G13543释G10267中OM的G11468G4557生物G2045用G5242分别为1031和1176，将G1207G16886为M的OM与原G5430药物OM加和后，G6164得全G18108OM的G11468G4557生物G2045用G5242分别为1020和1089。4经方G5058分G7524，与市G2818胶囊G11468G8616，G1016G13543释制剂在OM和M的AUC0在制剂G19400、G2620G7411G19400、G1022G1319G19400均G7092显G14891性G5058G5334（PG730005）G727G13792与市G2818胶囊的TMAX、CMAX在制剂G19400有显G14891性G5058G5334（PG728005），但在G2620G7411G19400、G1022G1319G19400均G7092显G14891性G5058G5334（PG730005）G727G16840明G1016G13543释制剂在G10368G1319内G15892药浓G5242G5191G12295、G6357G1049。5在方G5058分G7524的基G11796上G4557AUC0G17839G15904G2464G2345G1403TG7828G20576和90置G1461G2318G19400分G7524，G1016种G14270制G13543释制剂T的AUC（OM和M）与参G8616制剂市G2818胶囊的AUCG8616值的90置G1461G2318G19400均在80125的G14551G3272G1055内。故以AUC0为G16792G1227G6363G7643，G1016种G14270制G13543释制剂与市G2818胶囊生物等效。G1000G1319内外G11468G1863性良G3921，G16840明G1319外释G6930G5242测定方法可作为衡量生物G2045用G5242的G6363G7643。6G11752G12362结果表明，BEAGLEG10368G2487G7393OM后G13434有60左右的OM在G1319内G1207G16886为M。5讨论1G11013于OM的极性G17751大，G1000结构特殊，在参考文献的基G11796上，采用G1114离子G4557G14406G16901法G2528G7114测定OM和M，G17902过G6925变G8981G2172G11468中有G7438G11468和G8712G11468的G8616例来分G7524G1319内G7691G2709，并选择G1114二者的G2528系物槐果碱为内G7643，该方法重G10628性G3921、灵敏G5242G20652。2文献报道G1114OM在胃肠道菌群的作用下可被等分子G1207G16886成M，但在大G21748离G1319外翻肠囊法G4466G20576中并未G7828测到M，分G7524G1866原G3252可能为G726G4466G20576过程中肠内菌群G3252G9177G8939G13792被破坏G6122G4466G20576G17839G15904的G7114G19400G993足，G7092法使OM在2H内被还原为M并被吸收入G8986膜G4630。3G1016G14270制G13543释制剂经G1319内G4466G20576G16792G1227均为以AUC0A131为G16792G1227G6363G7643的生物等效制剂，与市G2818胶囊G11468G8616可明显G19489G1314G9052G19512速G10587G5132数（KE），G5322长药物在G1319内的G9052G19512G2334G15940G7411（T1/2）和G5191均G9394G11053G7114G19400（MRT），减少G5751者G7393药G8437数，提G20652G5751者的顺应性G727G19489G1314CMAX，减少负G2465应的G2469生，提G20652G5751者的耐G2475性。与G13543释G5506G1036G11468G8616，G13543释G10267具有成G7424G17751G1314，工艺简G2345，G17878用于G5132规的生G1147设G3803和工艺条件，G7438械化程G5242G20652等优点G727与G13543释G10267G11468G8616，G13543释G5506G1036具有G1319G12227G4579，易于G7393用，提G20652药物与胃肠道的接触G19766G12227，避免G4557胃粘膜的刺激G1000G2475到G9052化道输送G20147物节律的影响也G17751少。G1016种制剂的G11752制成功为G5751者提供G1114更多的选择。8参考文献1A132A133A134A135A136A137A138A135A139A140A141A142A143A144A145A146A147A148A149A150A151A152A153A154A155A156A152A157A158A150A159A160A161A162A163A164A165A166A167A168A169A170A171A172A143A173A174A173A175A176A177A178A179A180A1352002A13522A1815A182A1833353362A184A185A186A135A132A187A188A143A146A147A189A190A191A192A193A153A157A155A156A194A195A170A196A197A198A199A143A200A201A176A202A1352002A1352A1811A182A18384853A203A204A135A205A206A207A135A208A209A210A142A143A211A212A213A214A215A216A159A192A215A217A218A219A220A221A222A223A224A173A144A145A146A147A148A225A226A143A227A228A229A230A231A202A202A232A1352002A13519A1815A182A183328331表1G13543释制剂中氧化苦参碱的累G16757释G6930量TAB1RESULTSOFACCUMULATIVERELEASEDOMINTHESUSTAINEDRELEASEPREPARATIONSTIME（H）05124681012SUSTAINEDRELEASETABLETS162248379566696793865923SUSTAINEDRELEASEPELLETS132210411624750810851900表2G993G2528制剂中氧化苦参碱的药G2172G4410参数TAB2PHARMACOKINETICPARAMETERSOFOMFROMDIFFERENTPREPARATIONSABPARAMETERSSUSTAINEDRELEASEPELLETSCOMMERCIALCAPSULESSUSTAINEDRELEASETABLETSCOMMERCIALCAPSULESCMAXGML16440909680893340565720869TMAXH350077267075342020192038KEH100635001250395300727008001031002T1/2H1123201180028913125224016AUC0GML1H3785454364422522195111887210AUMC0S14408640148622523587067270929MRTH11772194070531062190385012表3G993G2528制剂中苦参碱的药G2172G4410参数TAB3PHARMACOKINETICPARAMETERSOFMFROMDIFFERENTPREPARATIONSABPARAMETERSSUSTAINEDRELEASEPELLETSCOMMERCIALCAPSULESSUSTAINEDRELEASETABLETSCOMMERCIALCAPSULESCMAXGML1528226865201250045391066TMAXH650281525141833082567151KEH101621018240213100881013003023007T1/2H728372373143540099331141AUC0GML1H56412390556764730595352758325AUMC0S1735325771505431796620274952111306MRTH1343265894265663104765086图1氧化苦参碱在大G21748各肠段的吸收曲线FIG1THEABSORPTIONKINETICPROFILESOFOMACROSSRATEVERTEDGUTSACSA233N5A234A2352A236A237A238A239A240A241A238A239A242A243A244A245A246A247A248A249A250A251A252A253A254A255A6A0A1A2FIG2MEANPLASMACONCENTRATIONTIMEPROFILESOFOMAFTERSINGLEORALADMINISTRATIONOFTHESUSTAINEDRELEASETABLETS,PELLETSANDTHEREFERENCECAPSULESN6ASELFMADESUSTAINEDRELEASEPELLETSANDCOMMERCIALCAPSULES10A3A4A5A7A8A9A10A11A12A13A3A14A9A4A4A14A9A5A15A16A17A18A19A20A21A22A23A23A24A25A24A26A27A28A29A30A31A27A32A33A34A35A36A28A29A34A37A38A24A39A40A23A25A41A16A42A18A43A17A44A18A44A43A45A43A17A46A43A47A46A18A45A43A17A48A47A42A47A45BSELFMADESUSTAINEDRELEASETABLETSANDCOMMERCIALCAPSULESA2353A236A237A238A239A240A241A238A239A242A243A244A245A246A247A250A251A252A253A254A255A6A0A1A2FIG3MEANPLASMACONCENTRATIONTIMEPROFILESOFMAFTERSINGLEORALADMINISTRATIONOFTHESUSTAINEDRELEASETABLETS,PELLETSANDTHEREFERENCECAPSULESN6ASELFMADESUSTAINEDRELEASEPELLETSANDCOMMERCIA