Application of Excipient Technology in Osmotic Pump Preparation
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The purpose of osmotic pump controlled release formulations with zero-order release characteristics obvious, to avoid the fluctuation of plasma concentration caused by the application of other agents has become the current research and development hot spots at home and abroad. This article first describes the release mechanism of osmotic pump release preparation. Due to the inability to generate a uniform solution of poorly soluble drugs, it is not easy to use single-chamber osmotic pumps to prepare constant-flow osmotic pump tablets. This article provides an overview of the commonly used methods for the preparation of osmotic pump drug delivery formulations for poorly soluble drugs. The progress in research on the use of adjuvant technology in the preparation of poorly soluble drug permeable pumps is reviewed. For a long time, people use a variety of methods to regulate drug release rates. Most controlled release formulations are based on a matrix, membrane or osmotic system. In the skeletal system, the drug is embedded in the polymer and, after taking it, the water enters the skeletal system and slowly dissolves into the medium through the scaffolding after the drug has dissolved. In a membrane-controlled system, the drug is wrapped by a layer of controlled release film, The membrane release slowly, but the release of these two kinds of drug delivery system are simple diffusion, so the drug release rate will be affected by the gastrointestinal pH, food and gastrointestinal physiological environment. Osmotic pump controlled release formulation is based on osmotic pressure as the drug release motivation. It has the characteristics of zero-order drug release significantly, to avoid fluctuations in blood concentration caused by other agents and reduce the gastrointestinal and systemic side effects, small changes in the gastrointestinal tract may be small, can improve the safety of drug use and Effectiveness. Therefore, osmotic pump controlled release formulation has become a hot spot in the research and development at home and abroad. With the development of pharmacy basic theory and preparation technology, the research on osmotic pump preparations has been gradually deepened, especially the outstanding contribution of Theeuwex et al [2] in the 1970s, which laid the foundation for osmotic pump-specific osmotic pump preparations in controlled release preparations status. Alza Corporation of the United States is the first company to apply osmotic pump technology and its OROSTM technology is still the highest in the world. Oral osmotic pump formulations have a long history and have been marketed for several products such as oseltamivir (salbutamol) osmotic pump tablets, pseudoephedrine osmotic pump tablets, verapamil hydrochloride osmotic pump tablets and nifedipine controlled release tablets. 1. Structure of osmotic pump formulations According to the structural features, oral osmotic pump formulations can be divided into two categories: single-chamber osmotic pump and multi-chamber osmotic pump. Single-chamber osmotic pump is generally used for soluble drugs, is composed of two parts of the core and the coating film, the core is composed of drugs and substances with high permeability, the coating film is mostly made of cellulose acetate or ethyl cellulose Such as rigid semi-permeable membrane formed by polymer materials, the semi-permeable membrane usually laser or other mechanical force hit a hole as the drug output channel. When used, the hypertonic substance in the core creates a high osmotic pressure after water absorption, thereby releasing the suspension or solution of the drug. Liu et al. Studied the release of single-layer macromolecular osmotic pumps made of nifedipine and polyethylene oxide (PEO), and studied the molecular weight and amount of PEO, the amount of kCl, drug loading, drug release pore size and membrane composition The impact of multiple factors on release was examined. Domestic, Wang Xiaojun [4] propafenone hydrochloride as a model drug to gum arabic-based materials, also made of single-layer osmotic pump controlled release tablets. However, most of these osmotic pumps have some problems such as the zero-order characteristic is not significant enough, the drug release is not complete enough, so it is difficult to replace the double-layer osmotic pump tablets for production practice. Multi-chamber osmotic pump consists of at least two layers: the chamber and the power chamber. Pharmacy is composed of a drug and a soluble adjuvant or drug suspension, the power chamber is made of some swellable polymer materials. When used, the moisture enters the power chamber through the semipermeable membrane, causing the polymer material to swell and expand, thereby squeezing the drug compartment to release the drug from the drug release orifice. Osmotic pump formulations require a large amount of an osmotic pressure enhancer to maintain a constant and constant osmotic pressure. If the normal tablet weight range is exceeded, it is difficult to establish a high concentration and osmotic pressure within the microchip of the tablet core to maintain an effective drug release rate When you need power room. Therefore, multi-chamber osmotic pump for poorly soluble drugs, drugs and drug-containing layer of polymer molecules in the form of a suspension is pushed layer polymer launch release hole to achieve the purpose of constant rate drug release. The successful cases include the nifedipine dual-chamber osmotic pump developed by Bayer AG in Germany and the Vera controlled release tablets designed and developed by Alza Corporation based on the osmotic pump system [5]. It can be said that double-penetration osmotic pump preparation technology is currently the most difficult to make osmotic pump-based formulations of drugs, the most suitable method of industrial production. However, compared with the single-layer osmotic pump, the process is relatively complicated because the core of the tablet is a double-layer tablet and the release hole must be on the side containing the drug layer. The most commonly used polymer in the push layer is polyethylene oxide (PEO). In general, the drug-containing layer of PEO molecular weight of 300000, promoting the layer of PEO molecular weight of 800000, more appropriate; PEO containing drug layer and promote the ionic strength of the layer is proportional to drug release; hydrophilic plasticizer PEG Increase drug release rate, while the hydrophobic plasticizer glycerol triacetate contrast; release pore size of 015-1141mm more suitable. 2.1 Polymer compounds A poorly soluble drug and a dissolved polymer can form the appropriate viscosity together into a core, can improve drug dissolution. When the water through the semipermeable membrane infiltration into the heart, the heart of the polymer material rapid hydration with the drug to form a homogeneous suspension with a certain viscosity, and use of polymer dissolved when the swelling pressure and osmotic pressure to the formation of The release of the suspension from the drug release pores, the release behavior in line with Poiseuille's law. Janicki et al [6] were isosorbide dinitrate and gum arabic, povidone and polyethylene glycol mixed tablets, and then cellulose acetate and EurdgitS100 as a coating material coating, the film in a Side made 800-1400μm release hole. In vitro release studies showed that the release of the main drug within 7 hours increased with the heart weight increase, showing nearly zero release characteristics. 2.2 β cyclodextrin inclusion technology as a solubilization technology β cyclodextrin inclusion technology is commonly used to improve the solubility of insoluble drugs, one of the methods, the resulting inclusion complex is widely made of various preparations, cyclodextrin package The same technology applies to osmotic pump formulations. Okimoto et al [8] used testosterone, prednisolone [7] and chlorpromazine [8] as a model drug to compare their effects on 7m-β-CD and HP- CD) made of osmotic pump controlled release tablets. It was found that the inclusion complex formed by (SBE) 7m-β-CD had larger binding constants than the osmotic pump tablet with HP-β-CD as excipient for (SBE) 7m- , Made of osmotic pump controlled release tablets release stable and complete. However, (SBE) 7m-β-CD is a newly developed β-CD derivative. At present, only a small amount of β-CD derivatives are synthesized and there is no product on the market. However, the process for preparing osmotic pump tablets by this method is simple and simple, , Has a good application prospects. 2.3 drug salvage poorly soluble drug salification, the drug solubility increases, more suitable for the preparation of osmotic pump tablets, such as the indometacine sodium salt prepared indomethacin osmotic pump tablets. There are many insoluble drugs are also used in the form of salt, such as methylphenidate, amitriptyline, etc. [9-11], their salts can be prepared directly with water-soluble drugs osmotic pump tablets. However, the solubility of some drugs is too large, so that the drug can not control the release, not suitable for the preparation of osmotic pump tablets. At this point can be added to block the control, such as ZenterGM [12], respectively, with NaCl and positive ion exchange resin to diltiazem hydrochloride surrounded in them, slowing the release of drugs, so that the drug was zero release; the drug salt Preparation of osmotic pump is currently a more applied method. In particular, the relatively large dose of insoluble drugs can be made into salt, the coating film to control the release of drugs, so you can reduce the amount of excipients for the convenience of the patient. 2.4 The addition of acid and alkaline substances Many poorly soluble drugs have a dependence on the solubility of insoluble in neutral water drugs, under certain acidic or alkaline conditions can often have some solubility, suitable for making single-layer osmotic pump , Such as haloperidol [13] osmotic pump tablets, haloperidol water solubility of less than 011mg? ML-1, the osmotic pressure is almost zero, adding carboxylic acid type penetration enhancers, can increase the drug solubility and membrane Intrinsic pressure. Tombre et al in the preparation of glipizide reverse osmosis membrane type controlled release capsules, also added to the capsule coated trometamol or N-methyl glucosamine to adjust the solubility of glipizide. Due to the relatively large solubility of the commonly used acid-base buffer salts, they release faster and lead to incomplete release of the main drug. However, this method has a certain scope of application can not be applied to all drugs, and sometimes due to excessive release of acid-base substances, the drug release is not complete. 3 conclusions Difficult-to-soluble drugs into osmotic pump formulations ideas and methods varied, but more cases are several methods, a few aspects of the integrated application, can effectively be a poorly soluble drug made of zero-order release Significant drug characteristics, but also complete release of osmotic pump controlled release formulations. Although the reported design methods are very sophisticated, most of them have some limitations and it is difficult to completely replace the double-layer osmotic pump used in industrial production. Therefore, it is still an important direction in the research field of osmotic pump controlled release formulations that how to make insoluble drugs into controlled-release osmotic pump formulations with simple process, stable drug release performance and suitable for industrialized production.