2.9.40. Однородность дозированных единиц

Question

Всем известно о межтаблеточной миграции и вариации содержания нитроглицерина в сублингвальных таблетках. По данным нашумевшего исследования Fusari уже через месяц относительное стандартное отклонение содержания нитроглицерина в разных таблетках может достигать 20 % и более, хотя среднее содержание по 20 таблеткам остается в пределах нормы. Требования общей статьи 2.9.40 применяются для всех дозированных лекарственных средств, независимо от дозировки. Основным критерием проверки приемлемости однородности содержания в статье 2.9.40 является приемочное число AV, которое не должно превышать максимально допустимое значение L1=15. В случае с нитроглицерином в процессе хранения в данные рамки просто невозможно вложиться.
Вопрос состоит в следующем: возможно ли обоснование более высокого L1 для спецификации сублингвальных таблеток нитроглицерина во время хранения?

PurGen · Answer

Я вот тут накопал чего то :) Sublingual Nitroglycerin Tablets Waaler et al. have successfully applied the adsorption approach to make sublingual nitroglycerin tablets by direct compression with better content uniformity, lower weight variation, and much higher stability than tablets made from a molding approach. In the molding approach, nitroglycerin will migrate to the surface of a tablet during the drying process. During manufacturing as well as storage, there may be potency loss due to the volatility of nitroglycerin. Tablets can also be made by wet granulation, where drying may also induce unblending. In the direct compression approach, nitroglycerin dissolved in alcohol was first added to MCC, and triturated slowly for about 5 min to assure content uniformity. The powder is left at room temperature for 12 hr with occasional stirring. Then alcohol is evaporated and nitroglycerin becomes adsorbed onto MCC. Afterward, MCC/nitroglycerin is mixed with other excipients to achieve suitable properties for the finished tablets, including solubility and disintegration rate. Ref.: Waaler, T.; Gundersen, H.; Kvaleid, I.; Shangraw, R. The manufacture and evaluation of stabilized nitroglycerin tablets prepared by direct compression. Medd. Nor. Farm. Selsk. 1976, 38, 213–229.

belka · Answer

М-да, вопрос качества таблеток нитроглицерина (НГ) проблематичен в свете современных фармакопейных требований (должна заметить весьма категоричных) Европейской фармакопеи и соответственно ДФУ. «Особенность» или, вернее сказать, специфичность производства сублингвальных таблеток НГ и проблема качества – вопросы древние; еще в 60-е годы прошлого века производитель оригинальных таблеток Nitrostat (Pfizer) (http://www.pfizer.com/files/products/uspi_nitrostat.pdf) изучал причины вариаций НГ и пути их решений. В книге Pharmaceutical dosage forms - Tablets Vol.1 описаны причины и возможные пути решения специфических вариаций НГ.Nitroglycerin tablets potentially can lose potency in four ways: loss to the atmosphere by evaporation, intertablet migration, sorption by package materials, and chemical decomposition.Chemical Decomposition Although chemical stability is normally not a problem with conventional nitroglycerin tablets. both polyethylene glycol 400 and povidone (molecular weight ~35,000), which are used to stabilize content uniformity, may accelerate the hydrolysis of nitroglycerin. Chemical decomposition via hydrolysis is illustrated by the data in Table 4 for nitroglycerin-providone-lactose systems. Both l,2-dinitroglycerin and l,3-dinitroglycerin were present in the aged samples in roughly equal amounts. Dinitroglycerin content is expressed as weight percent of the total nitroglycerin compounds. Within the uncertainty of the data, both the nitroglycerin loss and the dinitroglycerin content were independent of the povidone concentration above a weight ratio of 0.6. Although the thin-layer chromatographic assay is only semiquantitative, the data demonstrate that a significant fraction of the nitroglycerin loss was due to hydrolysis of the trinitroester to dinitroglycerin species. The high-temperature stability of tablets containing povidone is compared with that of other formulations in Table 5. Potency loss at high temperature was significantly greater with the povidone-containing formulation. Analysis by thin-layer chromatography howed significant amounts of the 1,2- and 1,3-dinitroglycerin species in the aged povidone formulation but only trace amounts in the other formulations, Although povidone-containing tablets show poor high-temperature stability, the stability at 25°C is satisfactory (approximately 3 to 4% potency loss per year). Polyethylene glycol 400 has also been shown to accelerate potency loss of nitroglycerin from tablets and from solution. However, tablets with satisfactory stability have been formulated with PEG 400 at weight ratio of glycol to nitroglycerin of 0,85. This apparent anomaly is resolved when stability is examined as a function of the weight ratio of PEG 400 to nitroglycerin. It appears that below a weight ratio of approximately 1, PEG does not significantly affect the stability of nitroglycerin, but at high weight ratios (~2), PEG 400 causes extensive hydrolysis of nitroglycerin even at 25°C. Таблицы 4 и 5 в прикрепленных файлах внизу.Исследования показали, что добавления повидона (поливинилпирролидона, с молекулярной массой ~ 35000 ) или ПЭГ 400 приводит к стабилизации содержания при хранении. При добавлении ПЭГ 400 к раствору НГ увеличивает потери НГ. При хранении в упаковке из полиэтилена высокой плотности не наблюдается потери НГ в таблетках, в отличие от упаковки из винила или полиэтилена низкой плотности.IV. COMPRESSED SUBLINGUAL TABLETS The requirements for sublingual tablets are speed of absorption and a correspondingly rapid physiological response, which are normally best achieved with a rapidly soluble molded tablet. However, compressed sublingual tablets have also been prepared which disintegrate quickly and allow the active ingredient to dissolve rapidly in the saliva-and to be available for absorption without requiring the complete solution of all the ingredients of the formulation, Erythrityl tetranitrate, isosorbide dinitrate, and isoproterenol hydrochloride are marketed as compressed tablets for sublingual use. Compressed nitroglycerin tablets have been described in the literature; formulations for these tablets contain large amounts of cellulosic material and may also contain lubricants, glidants, flavors, coloring agents, and stabilizers. Compared to molded tablets, compressed tablets of this type normally have less weight variation and better content uniformity. The USP requirement for the uniformity of dosage units is met if each of the 10 tablets tested lies within the range of 85.0 to 115.0% of label claim and the relative standard deviation is less than or equal to 6.0%. If one unit is outside the 85,0 to 115.0% range and no unit is outside 75.0 to 125.0% of label claim, an additional 20 tablets are tested, and the requirements are met if not more than one out of 30 tablets is outside the 85.0 to 115.0 % range but none lies outside of 75.0 to 125.0% of label claim and the relative standard deviation of the 30 dosage units does not exceed 7.8%. The tablets are also harder and less fragile, thereby avoiding weight and potency loss that occur by the erosion of the molded target edges.Example 4: Nitroglycerin Tablets (0.3 mg, Direct-Compression)IngredientQuantity per tabletNitroglycerin (10% of microcrystalline cellulose)3.0 mgMannitol2.0 mgMicrocrystalline cellulose29.0 mgFlavorq.s.Sweetenerq.s.Coloring agentq.s.Compressed nitroglycerin tablets were reported to have a rapid disintegration time of from 3 to 7 sec by the USP method for sublingual tablets, as well as rapid response time as measured by an increase in pulse rate of 10 to 13 beats/min within 3 min in human volunteers. However, in some clinical patients, these compressed tablets did not appear to disintegrate or release the medication for absorption. In these subjects, the compressed tablets either gave no response or gave a delayed response when compared with molded tablets.Example 5: Nitroglycerin Tablets (0.3 mg, Granulation)IngredientQuantity per tabletMicrocrystalline cellulose21.00 mgAnhydrous lactose5.25 mgStarch, USP3.00 mgColoring agentq.s.Povidone0.30 mgNitroglycerin (as the spirit)0.30 mgCalcium stearate0.15 mgBlend the excipients and the coloring agent, and granulate with an ethanol solution of povidone and nitroglycerin. After the granulation is dried and milled, it is blended with the calcium stearate and compressed.Perhaps insufficient saliva is present to allow complete removal of nitroglycerin from the absorbent cellulose. A strong negative psychological effect resulting from the presence of undissolved cellulose in the patient's mouth has also been suggested as the reason for product failure. The methods for evaluation of compressed sublingual tablets are the same as those given for molded sublingual tablets.Pharma, обратите внимание на требования USP 32 к монографии Nitroglycerin sublingual tablets: критерии приемлемости диапазона расширены по тесту "Однородность дозирования" в сравнении с требованиями общей статьи . А если конкретно, то требования по тесту «Uniformity of dosage units” следующие: значения 10 таблеток должны находиться в диапазоне 75-135% , если одно значение выпадает из данного диапазона, но находиться в 60-150%, то проводят испытания на дополнительных 20 таблетках; ни одно значение из 20 таблеток не должно выходить из лимитов 75-135%.Что касается безоговорочных требований Eur.Ph. к показателю «Однородность дозируемых единиц», то я обратилась к одному из экспертов Eur.Ph. (EDQM) с просьбой разрешения ситуации с сублингвальными таблетками НГ. Об ответе сообщу.https://pharm-community.com/wp-content/uploads/2017/01/table-5.gifhttps://pharm-community.com/wp-content/uploads/2017/01/table-4.gif

belka · Answer

Как обещала, ответ из ЕР. Strictly speaking, if your product fulfills the criteria for applying the content uniformity test or mass variation test, you must show that the fomulation complies with the limits.