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Hydroxypropyl Methyl Cellulose (HPMC) is a type of cellulose mixed ether that has rapidly increased in yield, dosage, and quality in recent years. It is a non-ionic cellulose mixed ether made from cotton and wood through processes such as alkalization, epoxypropane, and chloromethane etherification.
HPMC has good dispersion, emulsification, thickening, bonding, water retention, and adhesive retention properties. It is soluble in water and can also be dissolved in less than 70% ethanol and acetone. Special structured HPMC can also be directly soluble in ethanol. HPMC can be widely used as a film coating, sustained-release agent, and adhesive for pharmaceutical preparations, as well as its thickening, dispersion, and emulsification properties. It is widely used in various fields such as petrochemical, building materials, ceramics, textiles, food, daily chemicals, synthetic resins, pharmaceuticals, coatings, and electronics.
The production process of HPMC can be divided into two categories: gas-phase method and liquid-phase method. At present, developed countries such as Europe, America, and Japan are more adopting the gas phase process, using wood pulp as the raw material (cotton pulp is used for producing high viscosity products), and the alkalization and etherification are carried out in the same reaction equipment. The main reaction is a horizontal reactor, with a center horizontal stirring shaft and a side rotating flying knife specially designed for Cellulose Ether production inside, which can achieve good mixing effect.
The global HPMC production capacity accounts for 70% of the non ionic cellulose ether production capacity. Multinational enterprises such as Dow Chemical in the United States, Shinyue in Japan, Hercules/Ashland in the United States, and Samsung in South Korea are currently the main suppliers in the world's largest HPMC high-end market.
The main application fields of HPMC in China also involve architecture, coatings, food, medicine, ceramics, daily chemical products, polymer polymerization, etc. However, the overall quality of HPMC products for pharmaceutical grade and polymer polymerization cannot compare with foreign countries, and many key technologies are still in the hands of developed countries such as Europe, America, and Japan. However, through application research comparison and process equipment transformation, the gap between domestic products and them has gradually narrowed, and some product indicators have exceeded.
Solid dispersion (SD) systems have been extensively used to increase the dissolution and bioavailability of poorly water-soluble drugs. To circumvent the limitations of polyvinylpyrrolidone (PVP) dispersions, HPMC E5 was applied in the formulation process and scaling-up techniques, simultaneously. In this study, SD of nimodipine (NMP) and corresponding tablets were prepared through solvent method and fluid bed granulating one step technique, respectively. Discriminatory dissolution media were used to obtain reliable dissolution results. Meanwhile, the stability study of SDs was investigated with storage under high temperature and humidity conditions. Moreover, the solubility of SDs was measured to explore the effect of carriers. The preparations were characterized by DSC, PXRD, and FTIR. Dramatical improvements in the dissolution rate of NMP were achieved by the ingenious combination of the two polymers. Binary NMP/PVP/HPMC-SDs released steadily, while the dissolution of single NMP/PVP-SDs decreased rapidly in water. The fluid-bed tablets (FB-T) possessed a similar dissolution behavior to the commercial Nimotop&#; tablets. The characterization patterns implied that NMP existed in an amorphous state in our SDs. Furthermore, the results of stability tests suggested a better stability of the binary SDs. A special cooperative effect of PVP and HPMC was discovered on dissolution characteristics of NMP SDs and tablets, which could be extended to other drugs henceforth. Finally, the bioavailability of FB-T was evaluated in beagle dogs with Nimotop&#; as the reference, and the results showed a higher AUC 0&#;12h value for FB-T.
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NMP is known as a dihydropyridine calcium channel blocker applied in the treatment of patients with subarachnoid hemorrhage [1]. As a class II drug in the Biopharmaceutics Classifcation Scheme, NMP has a high permeability, but a poor solubility in water, which leads to a low bioavailability and limited clinical efficacy [2]. For such drugs, drug release is an imperative and limiting step [3]. And improving the release profile of these drugs could make it possible to enhance their bioavailability [4]. Therefore, various advanced approaches such as salt formation, particle size reduction and complexation have been exploited to enhance the dissolution rate [5]. Notably, solid dispersion is considered as a promising strategy to raise dissolution profile of sparingly soluble drugs [6&#;8].
Most often, amorphous organic polymers such as PVP, polyethylene glycol (PEG) and various cellulose derivatives are capable of forming the amorphous solid solutions [4,9]. Particularly, SD prepared with relative high proportions of PVP tends to perform a higher drug solubility and release rate than those with high proportions of drug [7 10,11]. Meanwhile, the chain length of PVP plays a crucial part in the dissolution rate of the scattered drug from its SD formulation [4,12]. However, PVP exhibits a quick inhibition to the precipitation of the drug from the supersaturated solution, the drug may precipitate out faster than that prepares with HPMC, performing a sharp decrease of the dissolution rate in less than an hour, while the drug with HPMC showed a smooth release for more than an hour [13,14]. Due to its swelling and dissolution properties in aqueous solution, HPMC is of great importance as a water soluble polymer carrier in controlling the release of drug from SD system, which is probably related to the formation of soluble complexes between the water-soluble polymers and insoluble drug [15]. HPMC is commonly used on account of its effects on both crystal growth inhibition and extension of supersaturated conditions [16]. Moreover, Yamashita et al. reported that SD formulations with HPMC have been adopted to improve in vivo drug absorption [17]. Possibly, it is expected that SDs with HPMC could exhibit a better stability.
Unexpectedly, despite all that super advantages, the number of commercial products resulting from SD strategies is relatively low [18]. It is primarily imputed to the manufacturing difficulties, the poor stability problems, and the scale-up problems of the SDs. From a commercial point of view, the most common SD product is tablet, which is the most preferred preparation ascribed to its obvious virtues and high patients compliance [19,20]. Therefore, in order to realize the scale-up of SD, the approach of fluid bed granulation is utilized to formulate NMP tablets, which is an efficient strategy to solve above problems, form solid dispersion, and even achieve the pharmacoeconomics. Also, the granules obtained from this technique exhibit excellent flowability, compressibility and composition uniformity [21&#;23].
In this article, a series of solid dispersions and tablets with PVPs and HPMC have been developed to select a proper ratio of drug and carrier by the standard of higher drug solubility, release rate and good stability. The first purpose of present work is to investigate if the PVP and HPMC could affect the release rate of NMP with the usage of differentiating media, simultaneously, as Suziki and Sunada reported that both HPMC and PVP exhibited a high compatability with nifedipine [14]. Phosphate buffer (pH 4.5) with 0.05% SDS (37&#;±&#;0.5&#;°C) was selected as the discriminatory dissolution medium for the formulation screening, which have been proven its excellent discriminating power to evaluate the relationship between in vitro dissolution and in vivo absorption [24,25]. Also, purified water was used as the other powerful discriminatory dissolution medium which could help select better formulations and predict carriers&#; potency of inhibiting crystallizing because the commercial Nimotop&#; tablets could release well in it [25]. Then, the stability of single PVP-SDs and binary SDs was analyzed in high temperature and high humidity. Based on the results of SDs, NMP tablets were formulated by fluid bed technique to achieve the scale-up. Finally, the behavior of NMP tablets in vivo was compared with Nimotop&#; in beagle dogs.
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