Oxtriphylline延緩製劑及極低劑量Procaterol HCl固體製劑之研究

Abstract

第一部份 Oxtriphylline (OTP) 是theophylline的choline膽鹼鹽類，較口服的 aminophylline溶解度更好也更安定，吸收的狀況也比較穩定，而且對胃黏膜的刺激性小。臨床上常與吸入性的支氣管擴張劑合併使用，作為治療氣喘的第一線藥物。 氣喘是一種無法完全根治的疾病，因此病人必需長期的服用藥物以控制病情不會或延緩惡化。但是以常用於治療氣喘的theophylline為例，由於藥物的半衰期短以及有效治療濃度範圍小，要經常的投予（每日3-4次）因此使用上非常的不方便，又難控制藥物血中濃度不會超過最高治療濃度，若將本類藥物製成緩釋劑型使其維持較長的有效治療濃度，且因為藥物緩慢釋出對於超過最高治療濃的風險也可以低。故有其意義。 在藥劑學上可作為緩釋的作法主要是以基質（matrix）和膜的控釋為主，而這兩種方式所使用的材質多為聚合物，例如親水性的聚合物可藉膨脹和溶解形成一透明層延緩藥物釋出，而半透膜的方式則是僅允許水分子進入，因為內壓增加使藥物從預先製成的孔洞釋放出來；但是在更早以前即有研究者利用蠟質鈍性的特質做為藥物控制的研究。白蠟和鯨蠟醇在藥劑學上常被用於軟膏或者糖衣錠的磨光，由於它們的融點低，且為鈍性物質因此被選為在本研究中使用。在這個研究當中，被蠟質塗覆的粉體將作粉體的基本分析，例如：藥物的含量，粉體粒徑分布，粉體的流動性等，作為以熱融包覆法將熔融的蠟液噴灑在粉體上的可行性評估。從此之外，包覆蠟質的粉體被壓製成錠片後分析其緩釋的性質，並以溶離數學模型試著去分析其控釋的機制，當一系列的基礎研究結束之後，根據實驗所蒐集到的數據作為開發一最適化處的依據，並以原廠Parke-Davis公司出品的Choledylâ SA 400 mg/Tab 為對照品。 第二部份 Procaterol HCl一種強效同時具選擇性的腎上腺素乙二型激動劑，臨床上用於治療支氣管氣喘、慢性支氣管炎、肺氣腫諸疾患之氣道閉塞性障礙等。本藥品的口服吸收快速且完全，通常投與劑量只有數十微克，例如兒童的劑量是10-25 mg成人則為50-100 mg。雖然本藥品很少副作用的報告，但是仍有少數個案是和腎上腺素乙一型有關的心臟顫動，而這種副作用的報告和使用的劑量是有關的，因此對極低劑量的藥劑而言藥物的均勻性是絕對重要的。傳統的固體製劑之藥物製造技術，包括粉末的混合和濕式造粒，這對低劑量的藥物常是造成藥品不均勻的原因，雖然在製程上嚴格管控仍難免有此一問題的發生。 近年來，有關pellets的劑型研究被大量發表，它有許多的優點例如：改善藥品的均勻度，作成控釋的模式，以及具有良好的外觀。本研究即是研究以pellets的製劑方法，免除了混合和造粒的步驟，評估藥物均勻性是否良好。此處我們選擇用流動床噴霧的方式，先將procaterol HCl溶解在三種不同重量百分濃度的親水性聚合物 (HPMC)溶液中，再噴霧塗覆在不同尺寸的糖芯上，藉由外觀的觀察和藥劑學特性的分析（含量分析、均一性分析、溶離試驗）評估本研究所製得之procaterol HCl pellets與對照藥品Meptin-mini錠的差異。再從中找出與對照藥品有相似藥劑學特性的實驗組進一步作生體相等的研究，實驗是以雙盲、隨機、交叉設計進試驗，以自行開發的LC/MS/MS分析方法作血漿檢品的分析，由血漿中藥物濃度與時間的關係可計算出兩種藥品的藥物動力學參數，經由統計分析方法的檢定，確認本劑型的設計和製程方式是否合適製得一符合臨床使用的藥品。

第一部份 Oxtriphylline (OTP), choline theophylline, is more soluble and more stable than oral aminophylline and less irritant to the gastric mucosa. It has been widely used as supportive therapy with inhaled bronchodilatros and in consequence this may have obscured its value as a first-line drug in asthma. In general, the treatment of maintenance was necessary for relief of symptoms associated with respiratory disorders. But the treatment of pulmonary function impairment is complicated because of the multiple doses daily with appropriate therapy and plasma concentrations of theophylline are not enabled control. Sustained release formulations of drugs are specifically designed to prolong in vivo therapeutic concentration of drug appropriately to reduce side effects, minimize dosing frequency, and to improve patient compliance. Some devices like as matrix and membrane-controlled dosage for sustained release dosage forms have been developed. Polymers were used extensively in sustained and controlled formulations since they were able to provide properties such as swelling ability, solubility and semi-permeability. In fact waxy materials have demonstrated to be able to retard drug release even before synthetic polymers were used as retardant materials in pharmaceutical manufacture. The depressing ability against the drug permeation of waxy materials was considered as a result of their hydrophobic properties. The ways to prepare a formulation of sustained properties with waxy material included spray-congealing of drug/molten wax slurries, solvent evaporation, tumbling melt granulation, high-shear melt granulation, hot-melt extruded method, and fluidized hot melt coating method. In the present investigation fluidized hot melt coating method was chosen as the study technique. The fluidized hot melt coating method which we developed is one of method that can provide with advantages of simple, efficient, less costly, easy clean and better quality control. Since the coating material is applied in its molten state hence no necessary to use solvents during coating. Furthermore, it is no need to concern water moisture. White wax and cetyl alcohol, as the base of ointment for topical use and as poblishing material for sugar-coated tablet, were chosen as the hot melt coating materials due to their lower molten temperatures and inert properties. In present study, the characteristics of wax-coated OTP granules, ie., drug content, particle size distribution, and flowability were analyzed for evaluation the hot-melt coating method whether was feasibility. The OTP granules were compacted to tablets and the release profile of OTP in each formulation was quantitated using an automated dissolution tester equipped with UV-spectrophotometer. A number of mathematical model, such as the zero release model, and the Korsmeyer-Peppas model, have been used to analyze drug release from different compositions of dosage forms. 第二部份 Procaterol hydrochloride, a potent sympathomimetic agent and a selective beta-2 adrenergic receptor agonist, is used to treat reversible bronchospastic disease. Procaterol HCl can be absorbed rapidly and completely after oral administration. It is given at microgram level. The dosage of asthma is 10-25 mg for children and 50-100 mg for adult per day. Although the incidences of adverse events associated with the use of procaterol HCl are relatively low, it’s effects on beta-1 receptors leading to myocardic side effects still a serious concern clinically. These adverse events are known to be dose dependent, therefore, the dose uniformity of procaterol HCl preparations is an important factor to minimize the incidence of such events. Heterogeneous distribution of active components and other excipients is usually observed when traditional wet granulation procedures were used to produce an extremely low dose solid preparation. It is more common to see if the production processes were under a worse controlled condition. However, these mishap was hard to evade completely, especially to produce an extremely low-dose (＜100 mg) preparations. Therefore, it is necessary to develop a manufacturing method to improve product qualities for low dose products such as preparations of procaterol HCl. Use of spherical pellets for prepare a dosage form was extensively studied and to show that spherical pellets exhibit good characteristics such as dosing uniformity improvement, controlled-release properties, and nice appearance in general. A convenient and reliable method to prepare procaterol HCl oral dosage form at an extremely low dosage (25 mg) is presented in this study. The pellets of procaterol HCl was prepared by using with hydroxypropyl methylcellulose (PharmacoatÒ 606) in aqueous solution with a concentration of 2.0、5.0, and 10.0 % (w/w) was chosen as coating agent accordingly and spray-coating on sugar spheres (Nu-pareil PG 20/25). The surface morphology of coated and non-coated pellets was observed by scanning electron microscopy. The procaterol HCl pellets were filled in capsule (no. 4) which the unit dose was 25 mg procaterol HCl, was examined by weight variation, content uniformity, assay, and dissolution test, and compared to the results of a commercial available product of the same low dosage, i.e., MeptinÒ-mini tablet. The results of these quality assurance items were satisfied and indicated the product has a quality similar to MeptinÒ-mini tablet. A randomized, balanced, two-sequence, two-period, crossover clinical trial was carried out for twenty-four male subjects to evaluate the pharmacokinetic parameters of the capsule and the tablet after oral administration 75 mg of procaterol HCl. The values of AUC0®16h, AUC0®¥, Cmax, and MRT values obtained for both preparations had no significant difference (P > 0.05). It is confirmed that the pellets capsule received in this study is bioequivalent with MeptinÒ-mini tablet.