The New Progress and Outlook of Oral Colon-specific Drug Delivery System for Treating Cancer Renhan Dong1, 2,a, Mingcui Wang3, b, Faqin Dong3,c,* School of Public Health, University of Hong Kong,Hong Kong999077,P. R. China
1
404 Hospital ofMianyang,Mianyang 621010, P. R. China
2
Southwest University of Science and Technology, Mianyang 621010, P. R. China
3
sxffxll@163.com,b13689670026@163.com,cfqdong@swust.edu.cn
a
Abstract The morbidity of colon cancer is increasingly frequent in past years. Although quite a few researches about colon targeted drugs have achieved certain results and there are quite a few drugs for treatment at present, insufficient of dosage form and function still exists. The paper will give an outlook about a kind of multi-functional colon targeted delivery system. Keywords Oral Colon-Specific Drug; Colon Cancer; Treating; Prospects
Introduction Colon cancer as the common malignant tumor in digestive tract is seriously threatening the health of human beings. With the development of medicine, current treatment for colorectal cancer has gradually diversified. In addition to surgical treatment, the multi-type drug therapy plays an important role in the treatment of colorectal cancer[1]. Targeted therapy is a kind of therapy that combines therapy drug with drug carrier system, delivering the drug to specific target organs to play the curative effect under the function of specific-oriented mechanism. At present, there are biophysical targeted drug delivery preparation, biochemical targeted drug delivery preparation, biological immunity targeted drug delivery preparation, double and multi-targeted drug delivery preparations. Targeted mechanism can be divided into active targeted drugs and passive targeted drugs; it can also be divided into single-targeted drugs and multi-targeted drugs based on the target[2,3]. Due to some specific traits, colon targeted drug is developed. For example, the pH value of physiological environment of colon parts is 6.5-7.5; there are more than 400 kinds of beneficial flora; protein and peptide hydrolysis enzyme concentration and activity are lower than other sections of the digestive tract and they creep slowly; drugs in this part transit and stay for a long time, and the penetration resistance of macromolecular is smaller in colonic wall than in the small intestine. Drugs for Treating Cancer NCCN (National Comprehensive Cancer Network) currently recommended four drugs for colon cancer treatment, which were 5-Fluorouracil, Capectabine, Oxaliplatin and Irinotecan. These drugs make up several kinds of joint programs, including FOLFOX, IFL, FOLFIRI, CAPOX and classic 5 - FU/CF combos, which can be used for the clinical treatment of colon cancer. 5-Fluorouracil Fluorouracil or 5-FU is a drug that is a pyrimidine analog used in the treatment of cancer. It is a suicide inhibitor, working through irreversible inhibition of thymidylate synthase and belongs to the family of drugs called the International Journal of Advance in Medical Science, Vol. 3, No. 1—May 2015 2327-7238/15/01 025-8 Š 2015 DEStech Publications, Inc. doi:10.12783/ams.2015.0301.03
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antimetabolites. Fluorouracil has been used systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers. The chemotherapy agent 5-FU, which has been used against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication. Thymidylate synthase methylatesdeoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly divides cancerous cells and undergo cell death via thymineless death. Calcium folinate provides an exogenous source of reduced folinates and hence stabilise the 5-FU-TS complex hence enhancing 5-FU's cytotoxicity[4]. Capecitabine Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of numerous cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the body. It has been used in the treatment of colorectal, breast, gastric and oespphageal cancer. Capecitabine is metabolised to 5-FU which in turn is a thymidylate synthase inhibitor, hence inhibiting the synthesis of thymidine monophosphate (ThMP), the active form of thymidine which is required for the de novo synthesis of DNA and RNA during gene expression. Oxaliplatin Oxaliplatin (pronounced ox-ally-plat-in), marketed as Eloxatin by Sanofi, is a platinum-based antineoplastic agent used in cancer chemotherapy. The compound features a square planar platinum(II) center. In contrast to cisplatin and carboplatin, oxaliplatin features the bidentate ligand 1,2-diaminocyclohexane in place of the two monodentate ammine ligands. It also features a bidentate oxalate group. According to in vivo studies, oxaliplatin fights carcinoma of the colon through non-targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cancer cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA,which prevent DNA replication and transcription, causing cell death. Oxaliplatin is used for treatment of colorectal cancer, typically along with folinic acid and fluorouracil in a combination known as FOLFOX. Oxaliplatin has been compared with other platinum compounds used for advanced cancers, such as cisplatin and carboplatin. Irinotecan Irinotecan is a drug used for the treatment of cancer. Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin. Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan. Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription. Raltitrexed Raltitrexed is an antimetabolite drug used in cancer chemotherapy. It is an inhibitor of thymidylate synthase, and is manufactured by AstraZeneca. Raltitrexed has been used in the treatment of colorectal cancer since 1998. It may also be used in the treatment of malignant mesothelioma. Raltitrexed is chemically similar to folic acid and in the class of chemotherapy drugs called folate antimetabolites, which inhibit one or more of three enzymes that use folate[5] and deriavtives as substrates: DHFR, GARFT and thymidylate synthase. Raltitrexed is fully active after polyglutamylation, which allows cellular retention of the drug. By inhibiting Thymidylate synthase (TS), thus formation of precursor pyrimidine nucleotides, raltitrexed
The New Progress and Outlook of Oral Colon-specific Drug Delivery System for Treating Cancer
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prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells. Inhibition of L1210 cell growth in culture IC50 = 9 nm, is one of the strongest antimetabolites in use[6]. Combined Utilization of Drugs The version of NCCN (2007. 1) is the latest guideline for colon cancer clinical diagnosis and treatment. It embodies the latest progress and trend of the diagnosis and treatment of colon cancer. It provides several programs of drug combination, such as FOLFOX, IFL, FOLFIRI, CAPOX and typical 5-FU/CF. Along with the continuous renewal of clinical trial data, however, the choices of chemotherapy regimens change. As the confirmation of the advantage of 5 - FU venous continuous infusion, classical Mayo clinic scheme began to exit the stage. And as capecitabine curative effect is equal to 5-FU/CF scheme chemotherapy, while side effects is small, CapeOX scheme began to enter the choice of the clinical treatment. Irinotecanscheme has higher toxicity in the treating dosage, but its effect for terminal cancer treatment,which does not demand survival condition, has been recognized by everyone. And oxaliplatin is definitely the first colon cancer chemotherapy, because it doesn't start the chemotherapy in treating colorectal cancer. ColonTargeted Drug Systems and Characteristics Colon targeted drug can be further divided into: the pH-dependent type, flora trigger type, bio- adhesion type, time delay type, pressure-dependent type, pulse type, directly targeted at the colon macrophages and M-cell type, organic acids induced type, self-tuning type, micro-sponges and combined colonic drug delivery systems and so on. The PH-dependent Colonic Delivery System The pH values of the various parts of the digestive tract are as follows: stomach is 0.9-1.5, small intestine is 6.0-6.8, and the colon is 6.5-7.5. The pH-dependent colonic drug delivery system is designed based on a particular pH in the colon; it selects the pH-sensitive material as a carrier and controls its amount, then transits drugs to the colon site to locate the release. Preparation of pH-sensitive polymer coating is constrained by the polymer solubility factors, so its shortcoming is vulnerable to the impact of food and intestinal pH changes; but it also has advantages, such as it's one of the easiest way to the colonic targeted, and its advantages also including low cost and preparation convenience[7]. Flora TriggerType Colonic Drug Delivery System It is also known as enzyme triggered drug delivery system. It is the enzyme produced by colonic flora, degrading the polymer material to release drug and acting on the coated material of drug release. Enzymatic colon delayed release formulations mainly use the colon memory in the specific polysaccharide enzymes and glycosidase, making polysaccharides as a carrier, to prepare the "Polysaccharide - Drug" precursor drugs or to coat; in another case, it can form a prodrug through the combination of the azo bond, or use coated material containing azo bond to coat and prepare hydrogel skeleton preparation. Because of its strong targeted, it also has attracted wide attention and research home and abroad. Bioadhesive Colonic Drug Delivery System This drug delivery system maximally avoids drug contacting with the digestive juice, improving the local drug's concentration, bioavailability and stability. Thus, drug release and absorption rate are more accurate. Currently, non-specific carriers used in bioadhesive are alginate, cellulose derivatives, dextran, gelatin, pectin, chitosan[8], etc. Bioadhesive system has many advantages in the application, such as toxic side effects, relatively low cost, high local drug concentration in the control of bioavailability and controlled drug release. At present, researches about some particulate dosage formulations are relatively active, such as liposomes, microcapsules, microspheres, nanoparticles and so on. Delay Colon Drug Delivery System Normally, in the stomach and small intestine segment, the transit time of a substance is relatively a constant (3 to 4
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h). For this reason, it designs a new drug delivery technology pulse delivery system, ensuring that the drug starts to release after leaving the stomach 3 ~ 4 hours. The release rate depends on the solubility of the drug instead of the pH value of the outside world. According to the physiological factor that colon absorbs drug slowly, it makes use of delaying type accessories to control drug releasing in the colon. However, there are many factors influence the release of drugs targeted and its local bioavailability, it develops slowly. Pressure-dependent Colon Delivery System The system is designed based on the characteristics of the colon under the intestinal pressure. It produces pressure on human gastrointestinal motility. In the stomach and small intestine, because of a lot of digestive juice which buffers pressure the object suffers, the water is absorbed in the colon, and intestinal peristalsis produces a direct pressure on the object, thus the objects are easily broken. The pressure dependent colonic drug delivery system is safe and bioavailability, so it is a kind of colon targeted drug delivery system with bright future. Pulse Colonic Drug Delivery System By using drugs, tracers, electromagnetic or ultrasound sensitive materials and the corresponding polymer materials, microspheres are made. Through vitro monitoring after oral administration, microspheres are induced by electromagnetic or ultrasonic wave in vitro when they arrive at the site of action, releasing the drug to achieve the purpose of release point control. This method is particularly applicable to the treatment of colon cancer chemotherapy. This may fundamentally control the normal gastrointestinal and systemic toxicity of chemotherapy drugs. Directly Targeted to the Colon Macrophages and M Cells in Drug Delivery System Active infection enteritis (IBD) is associated with macrophages and dendritic cells, so it's very important for patients with IBD to control these two types of cells. For the organization and body, damage of this system is very low, and the treatment effect of the disease is higher than the standard level of similar drugs. The system is completed by the use of directly targeted in macrophages and M cells of sugar corticosteroids new microspheres. Directly targeted to the study of colonic macrophages and M cells in drug delivery system is still in its infancy, it has a relatively narrow range of application. Organic Acid-induced Colonic Drug Delivery System The mechanism of this system is that water passes the coated membrane into the drug delivery system by osmosis, and dissolves drugs and organic acids within the drug delivery system, making the coated membrane osmotic pressure increase and prompting drug release. Organic acid-induced colonic drug delivery system may be an alternative pathway for oral controlled release formulations, but it seems very important to select the organic acids. This method should pay attention on the use of a variety of indicators; in particular, we should pay attention to the organic acids' effects on the body in the application. Self-tuning of Colonic Drug Delivery System First, we should combine carboxypeptidase with colon cancer cells, and then hydrolyze the prodrug and free drug to kill cancer cells, for example, methotrexate has a good activity of killing HT-29 cells. The system is highly drugs-oriented, which mainly killing cancer cells and reducing the toxicity of anticancer drugs. Self-tuning colonic drug delivery system is highly targeted. It has no significant toxicity on normal cells, and with high specificity and relatively narrow application. It mainly focuses on killing cancer cells and reducing the toxicity of anticancer drugs in its prospects for the market. Micro-Sponge Colonic Drug Delivery System The micro-sponge (microsponges) is a porous polymer microsphere; it is mostly used for topical administration and oral administration. Micro-sponge has various advantages, such as good liquidity, strong compressibility, easy compressed-tablet, and porosity which make the drugs quick-release in the colon.
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Combined and Applied Colonic Drug Delivery System A successful colon targeted drug system requires that trigger mechanism of drug delivery system solely respond to the specific physiological conditions of the colon. Due to the impact of the gastrointestinal tract food, pH-dependent drugs are able to resist the destruction of the gastric acid, but generic drugs begin to release in the small intestine, and become poor target-oriented. Although human body has relatively stable gastric emptying time, it is difficult to estimate the time of drugs' reaching the colon because of the different formulations of the emptying time. Thus, joint application of drug delivery system has become a hot research at present. The system, with versatility and high degree of accuracy for drug release which makes it complex in actual operation, claims high requirement on all aspects of technology for considerable influencing factors. Excipients for Colon Targeted System Colon targeted preparation is a dosage form based on physiological characteristics of colon. The lack of blood and the sprcial fluid (with plenty of enzymes) demand that the materials of excipients should fit the trait of colon to achieve the therapy goal. The preparations are mainly divided into time dependent type, pH dependent type, microbial sensitive type drug release system. And in recent years, nanometer material becomes a type of excipients for colon targeted system. Its merit of physical and chemical properties makes it a valuable excipient. Time Dependent Excipients for Colon Targeted System Oral drug in the body commonly take 4.5 to 6.5 h before moving to the colon. During this process, it will take 4 to 5 hours in the stomach and small intestine. Coated the drugs with different materials, so as to release the drugs in the controlled speed in colon, is the time dependent colon targeted delivery system. The coated materials that are commonly used are polymers such as hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), cellulose acetate (AC) and Eudragit. HPMC[9] is safe and non-toxic, soluble in water and is generally used as inner hysteresis materials. And the hydrophobic characteristics of EC, AC give them smaller solubility in the stomach. Besides, after reaching the small intestine, it is easy for them to form a membrane aperture, which can release the drugs through. What's more, if change the proportion of various coated materials, the release rate of drugs would be adjusted. PH Dependent Excipients for Colon Targeted System The pH dependent preparation is a drug release system that designed according to the physiological characteristic, which pH is different from each part of the gastrointestinal. The pH of Colon area is 6.4 to 7.0. Different materials have different solubility under different conditions of pH, so materials that are insoluble in the stomach and small intestine but dissolved in colon will be chosen as coated stuff to protect drugs running through the stomach and small intestine and to release in the colon[7]. Commonly used coated material is divided into two types-single and mixed .Single excipients mainly use acrylic resin polymer, which goods is also called Eudragit. Eudragit has a variety of models, such as E, L and S. The better compatibility between the various models, the better film-forming performance, the safety and stability and character of no stimulation make Eudragit quite a popular coated material. Mixed materials can achieve better targeted effect, and different mixing ratio can have different interpretation of the drugs in different pH level, which will effectively overcome the individual differences. Microbial Sensitive Excipients for Colon Targeted System Bacterias in colon can produce many special enzyme systems, which can be used as the ideal target for drugs' releasing. Some of the polymer materials can be degraded under this condition in the colon site, which can be used as drug carrier for the colon controlled release preparation[10]. This type of excipient is divided into the prodrug excipients and skeleton preparations. The carriers of prodrugs are compounds like azo, glucoside, amino acids and cyclodextrin. After combined with the carrier, the molecular weight of the prodrug gets higher, which makes it more hydrophilic as well as the decrease of biological membrane permeability. Generally, this type of conjugate is only sensitive to colon enzyme while no degradation
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Renhan Dong, Mingcui Wang, Faqin Dong
by enzymes in small intestine and stomach.Skeleton preparation use the characteristic that the excipients will be degraded in the body by different enzyme to release drugs in colon, and often use skeleton and coated preparation forms. Excipients that are familiarized are the natural material such as azo compounds, amylose, pectin, melon ear glue, chitosan[11], glucan and chondroitin.They all can be degraded by the intestinal bacterial, which means their good biocompatibility. Nanometer Material for Colon Targeted System Using nanotechnology to make the drug nanocrystallization or to package the drug in the nano-carrier can contain the drug without releasing in the stomach, duodenum, jejunum and ileum front-end. The drug won't release until transported to the cecum, so as to function in the colon or in the whole body.The nanotechnology delivery system can eliminate the effect of physical environment, and prevent drug from destruction or degradation before reaching the colon target. With the characters of nanometer material carrier, which are large specific surface area and high interfacial activity, by modifying the surface of carries, it can avoid the body's immune system to identify or devour, and overcome the biological barriers in the body, so as to realize the colon-specific drug delivery. Due to the small size and the strong adsorption ability, nanoparticles can specifically gather in colon, which can release the drug directly in lesion site, increase the local drug concentration, and improve the compliance of patients with partial colon diseases. At the same time, the drug in the colon slowly releases, functioning in a long term, which is advantageous to the treatment of rhythmic disease. The Method for Targeted Drugs to Increase Bioavailability Targeted Drug Coated Technology At present, there are many coated technologies used, including pH-dependent polymer coated, time-dependent materials coated, polysaccharides or azo polymer coated and other coated technologies. For example, the pellet preparation technology is coated by using novel oral colon targeted film which takes resistant starch acetate (RSA) as film. Polysaccharide Matrix Controlled-release Technology of Targeted Drugs At present, there are guar gum, dextran, pectin, chitosan, cyclodextrin as carriers of the drug delivery system. Of which the delivery system using pectin[8] as its carrier which is widely used in medicine and research. For example, there is a new polymer skeleton coated technology of the mixture of ethyl cellulose and resistant dextrin soluble fiber (Nutriose) is used. Prodrug Technology of Targeted Drugs Prodrug technology is a method which makes active ingredients attaches chemical bonds which can be split by a colon bacterial enzyme to the carrier to form the precursor drugs. In the human gastrointestinal tract, the combined prodrug, with the increase of molecular, the strengthening of hydrophilic and low permeability of biofilm, will not be hydrolyzed by the small intestine or stomach enzyme. It is only sensitive to the colon enzyme and can position accurately. Prodrug mainly includes glycoside prodrug, azoprodrug, and azo double bond targeted adhesion of prodrugs. This technology does not need the drug coated, if it takes budesonide-glucan conjugate compounds as a new budesonide precursor of drugs for the oral colon-specific drug development[12]. Targeted Drugs Bioadhesive Technology Targeted drugs bioadhesive technology uses bioadhesive natural or synthetic polymer materials as drug carriers. Mucosa extends the residence time of drugs through the adhesion between the material and human mucosa in specific parts of the body. In this way, drugs spread into the circulatory system through mucosal in a certain speed and play the efficacy. This technology avoids releasing into the ileocecal disintegration or releasing the drug-containing particles after drug oral administration. What's more, it makes the particle adhere in colonic mucosal surface in the digestive tract to release the drug wrapped in its internal.
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Targeted Drugs Silica Particles Vector Technology First, attach drug covalently bond to silica particles (5 ~ 10Οm), then wrap the enteric coated. Thus, it can make the drug deliver to the colon. If the cecum infected by parasites swallow the silica gel particles attached nitroimidazole, it helps killing the parasite. Targeted Drugs Porosity Osmotic This drug preparation makes traditional drug package wrapped microporous semipermeable membrane and enteric polymer to form porosity osmotic bilayer tablet. It can reduce the cost price without laser drilling. Applications of Colon Targeted System The colon-specific drugs used in the clinical treatment of cancer are reported rarely. But in other treating area, clinical colon-specific drug delivery has a unique advantage compared with conventional drug delivery methods. For example, the treatments for chronic colitis, ulcerative colitis or regional enteritis often use steroid medicines combined with other anti-inflammatory medications. Oral taking or intravenous injection of steroid medicines like dexamethasone or meprednisone prone to systemic adverse reactions, such as immune suppression, Cushingoid syndrome and bone destruction, etc. making these drugs into colon targeted medicines rarely find out adverse reactions in the common treatment dosage, and also greatly reduce the incidence of adverse reactions in the high dosage. Recently, colon targeted medicines on the market are metronidazole colon-specific enteric-coated tablets (capsules), tinidazole colon-specific enteric-coated tablets(capsules) and so on, with only few varieties. But along with the development of the preparation technology and the high polymer material, it is quite possible that more colon-specific preparations will spring up in the clinical treatment or on the market. Deficiencies in the Targeted Drug Applications and Research According to the special physiological environment of the colon parts, a variety of colon targeted drug delivery systems and their excipients are developed. They have certain advantages in the colon-positioning, but there are also several insufficiencies. Time-delay type drug delivery system receives many internal and external factors, so there are few examples of separate application. Coated prescription of pH-dependent drug delivery system requires research according to the characteristics of different drugs; in addition, release is affected by individual differences and many other factors, so the effect of the colon needs to be improved. The bacterial enzyme-triggered drug delivery system needs to address the safety of the synthetic polymer, natural polymer hydrophobicity and expansion issues. Because the pressure of human colon is influenced by various factors and varies greatly, instance of separate application of the pressure release system is also relatively small. Organic acids induced type is also limited because of its selection. So, we need to find a selection and optimize pH-dependent targeted drugs with a feature of more efficient, safe, convenience and economic by combining western medicines, Chinese medicines and nano materials, such as multi-functional colon targeted drug. Research Significance and Objective of Colon Targeted Drug Coated preparation is easier than the skeleton preparation, the degradation mechanism of the coated film is multi-faceted, preparation of membrane coated should take full account of pH value, flora and single-coated media and other factors, only in this way can formulations be ensured to achieve the best release. What’s more, the coated tablet is safer and more stable than injection production, and easier for sufferers to take. However, there are still some shortages of the single-layer colon targeted drug. One of the most important is that single-layer coated may not target perfectly. Besides, directly releasing in colon may reduce the absorption of the main drug. According to limitations of single-layer colon targeted drug delivery method, developed joint applied colon
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targeted drug delivery system has its advantages. To some extent, it can change or reduce the adverse effects of a single system, and also improve the stability and reliability of colon targeted drug delivery system. What’s more, it is combined with nano-materials technology to develop multi-functional coated colon targeted drugs. ACKNOWLEDGEMENT
This work was supported by the internship funding of 404 Hospital.We are grateful to Professor Zongning Yin,Jia Yang, Yong Yu(China School of Pharmacy, Sichuan University) and Chief physician Jianjun Deng for the assistance. REFERENCE
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