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Polyamino acid’s application in drug controlled release system

Posted Date : 21/12/2011  Click : 658
Review of Tang Guping Chen Qiqi.
(Department of pharmaceutical analysis, Department of pharmacy, Zhejiang University, Hangzhou 310031, China)
Poly amino acid is a kind of polymer material with good biocompatibility, which has a unique application in the field of controlled drug release. In this paper, we briefly review the types, side chain modification, formulation, structure and biocompatibility of amino acid materials in controlled release drugs.
Keywords poly amino acid modified dosage form biocompatibility
Application of Poly-amino-acid in Drug Controlled Release Systems
Tang Guping  ChenQiqi

( Department of Pharmacy , Zhejiang University, Hangzhou 310031 )

Abstract  Poly-amino-acid is one of the polymers with good biocompatibility. It has a special use in the field of controlledrelease drug. In this article are reviewed the types, modification, dosage forms, structure and biocompatility of poly-amino-acid.
Key words PolVmer-amino-acid ModificationDosageformsBiocompatility
1 Introduction
Controlled release formulation is the domestic and foreign scholars are interested in drug delivery system, including polymeric carrier drugs, oral vaccine target to control release system and protein or polypeptide drugs polymer release system and Research on them has become one of the frontiers in the field of pharmacology, material science, biochemistry etc. multi interdisciplinary. Europe and the United States and other developed countries for controlled-release materials research is very warm, polyester, poly (amino acid, poly phosphate, poly acid anhydride, polyacrylamide (PAM) and hydrophilic gel etc. are the object of study, which typical bio compatible materials poly (amino acids) is one of them. Through the same amino acid in homopolymerization or different amino acid copolymerized, functional side chain radical type backbone, to bond the drug to the material, or combined with storage or skeleton and drug, by changing the material of the hydrophobicity, charge and acid-base method to regulate the progress of drug diffusion velocity and material degradation. In terms of amino acid materials, it is necessary for the human body, can be degraded, metabolism by the body absorption and excretion, with other materials can not be compared to the advantages of. Amino acid material has been used as a suture material, artificial skin, etc., in the drug controlled release field has been widely used in family planning, anti-tumor and other drugs. In this paper, the types, modification, dosage forms and structures of poly amino acids in controlled release drugs were reviewed in this paper.
2 amino acid material
2.1 poly glutamic acid material
In the early 1970s, research group of the University of Utah leader Kim is successfully synthesized poly (glutamic acid) materials, with amino propanol as the side chain radicals, by covalent binding mode will be widely used in the clinical steroidal contraceptive norethisterone keying material, and the release in vitro and in vivo release test, norethindrone content was determined by radioimmunoassay method, the releasing time of up to 300 days. The results showed that the degradation of poly glutamic acid could be degraded into a single body, which was not retained in the organism. Therefore, the study of poly glutamic acid and the modification and utilization of the materials have been paid attention by people. Shows that the Hirahayashi[1] of polyglutamic acid material can be as a carrier of cyclophosphamide for cancer chemotherapy, animal experiments also prove galactosyl (Galactose button poly glutamic acid (GAI-PIGA) is a excellent liver can be biodegradable drug carrier and its application in liver disease drug has prospect. The other derivative, 2-, is a liver targeted drug delivery carrier with a combination of an -2- and a poly glutamic acid group, an oxygen - based acetyl group and a poly glutamic acid group. HashidaMitsuuru[2] will 3-hydroxypropyl access poly glutamic acid materials on after, the drug Natrexone, 3 - acetic acid -Natrexone, 3 - ~ (14) - butyl acetate acid Natrexone to covalently binding to the material and drug access rate was 33.8%. The in vitro release experiment for up to 28 days. (3 hydroxypropyl) - D - glutamic acid and (3-hydroxypropyl) L-glutamic acid copolymer and, and ethanolamine 1 -, 5 - amino pentanol and 1, 8 Yassin amino as cross linking agent synthesized 11 kinds of membrane materials, on the synthesis of polymer membrane of enzymes in vitro experimental solution (37 DEG C for, pH 7.4, artificial cells humoral pseudo extra-cellular fluid and PECF) prepared by Yasuyoshi Miyachi[3] prove the release of the degradation rate in line with the Michaelis Menten release rules, and enzyme concentration related. Shan Da Xian synthesized poly (2-hydroxyethyl) - glutamate [4], in acetonitrile and dimethyl formamide in the mixed solution, using bicyclic ethyl carbodiimide (DCC) shrink and norethindrone three ketone oxime bond on the material, drug access rate was 22.8%, and the release curves were fitted to a single exponential model: LG (Y infinity - y):1.686-0.147t (r = 0.99) and release rate constants K=0.335 Days-1. The drug suspension was injected into guinea pigs and released 15 d, and the drug content was measured in the urine of guinea pigs by CSHPLC.
2.2 poly aspartate
And glutamic acid compared to aspartic acid in the structure less a methylene group, but in the aggregate is not the same, glutamic acid polymerization is not a ring polymerization and synthesis steps are more, the route is complex, in the synthesis process in need of phosgene poisonous gas. The ASP is much simpler, only need concentrated phosphoric acid catalysis, in the 180 degree vacuum polymerization can be amide ring, with neutral, weak acid, alkali and other groups can open ring, and become a multi-functional material. Antoni in 1974 reported a potential plasma substitute alpha, beta poly - (2-hydroxyethyl) - DL asparagine (Phea), and derives the its in aqueous and ionic solution Mark-Hawink equation [5]. After the study, this kind of substitute is a kind of polymer carrier PHEA. German scholar Claudia S.Leopold using polyaspartamide carrier by DCC condensation and colonic drug dexamethasone (dexamethasone, DX) dexamethasone combined with in the materials [6], the molecular weight of the material is 30000, drug access rate is 10% (w / W). The degradation half-life of pH4.5 and 6.5 of the cultured mucosa and muscle tissue was 114d and 2.8d (37 C). Gaetano Giammona research group of Italy Palermo University of polyasparamide studied [7] years of alpha, beta poly (2- - hydroxyethyl) -DL- asparagine (PHEA) and alpha, beta poly (2- amide) -DL- asparagine (PAHy) is studied, especially the physical and chemical properties of the material the drug, bond has done the work of system, modification of side chain material, made of cross-linked materials, hydrogel materials were investigated, the antibacterial peptide (Ofloxacin), to two (Diflunisal), Nai Pusheng - SA (Naproxen, NAP), Bloven (Ketoprofen KPN) ketone, 4- amino -1- beta arabinofuranosyl -2-H pyridone (Arac), anti-inflammatory drugs, anti-inflammatory drugs (Suprofen) (4-biphenylaceticacid BPAA), Bloven (Ibuprofen), isoniazid (Isoniazid), the infrared spectrum, of prodrugs synthesized by differential thermal analysis and powder X-ray The drug was made into different dosage forms, and the in vitro and in vivo release experiments were carried out. B.Zore research group of poly asparagine materials for the system research [8] DOPA (DOPA) bonded to the Phea material, the synthesis of Phea of molecular weight of the polymer is 548 x 104, L-dopa medication access rate was 17.4% (w / W), the PHEA-L-Dopa drug made microspheres and in artificial cerebral spinal fluid to do the in vitro release experiment (pH 6.0). At the same time, B.Zore also of poly asparagine made side chain modification, 5 bromo 2 deoxyuridine glycosides (5-bromo-2- deoxyuridine, bromodeoxyuridine (BrdU) bonded on the modification of materials, modified materials and bonding agents were characterized. Research group of Chen Qi Qi of poly asparagine for the many years of research and [9.10], materials and key on the length of the side chain based drugs, different size, different drug receiving rate of the prodrug of the release experiments. The key drugs are 18- methyl acetylene, acetylene, acetylene, acetylene, acetylene, acetyl salicylic acid, Bloven, Nai Pusheng and so on nearly twenty kinds. The material was prepared by the modification of hydrophilic and hydrophobic properties. The biocompatibility of the material was determined, and the function and metabolism of the material in the living body were studied. Peter R. Byron study revealed that alpha and beta poly - (2-hydroxyethyl) DL asparagine on lung with target to which side chain radical 2-hydroxyethyl has the material traction, stranded on the efficacy of lung [11], therefore the bonding drug for treatment of lung can release slowly in the lesion site, labeled fluorophene Fluorophore fungicide is bonded to the Phea material and pulmonary perfusion in mice, the maximum absorption rate Vmax about 180 g or 0.027 g mol/h.
2.3 poly -L- lysine
In addition to glutamate, aspartate, poly L- lysine (Poly-L-Ly-sme, PLL) is also a research. PLL with positive charge, easily pinocytosis of tumor cell uptake, binding and antitumor drug 5-Fu can be used for the treatment of tumor patients. In addition, there are PLL and Pt (II) key reports, for the treatment of tumor chemotherapy [12]. Poly (L - lysine can directly and tumor cell surface to carry negative charge, leading to cell aggregation and display cytotoxicity and in vivo animal experiment also showed significant anti-tumor activity, but the clustering Yoko toxicity, generally do not directly as an antitumor agent, but as a drug carrier and adjuvant to be studied. Ryser et Al13 studied the activity of poly - L - lysine amino acid and ammonia armor pterin complexes (MTX) of hamster ovarian cell strains CHOWTT and the membrane transport disorder caused by MTX resistance variation, found that complexes can increase variants to MTX intake of 200 times, inhibit cell proliferation activity was increased 100 times.
3 amino acid copolymer
The chemical structure of amino acid has a significant influence on the biodegradability. Therefore, in the copolymer of two amino acids and three amino acids, the type of amino acid and the ratio of the amino acids have great significance to the properties of the copolymer. It is proved that the poly glutamic acid material can be completely degraded into a monomer, and is a low toxic and non irritating substance. So people begin to modify the structure of poly glutamic acid to increase its functionality. In addition, the amino acid in the body is mainly in the enzymatic hydrolysis, the enzymatic hydrolysis of amino acid specificity, a variety of amino acids into the body after polymerization, to provide a number of enzymatic hydrolysis point. Therefore, the ratio of different amino acids in poly amino acids could be regulated, and the enzymatic hydrolysis rate of the materials could be regulated. Deng Xianmo. [14] to R - benzyl-l-glutamate ester PBIG N-carboxyanhydrides as the initial material synthesized by R - benzyl-l-glutamate, the tetrahydrofuran as solvent, alpha amino acid direct phosgene. The yield of r- benzyl -L- glutamic acid was 95.5%, and the molecular weight was more than 100000. Pan Shirong [15] to R - benzyl-l-glutamate synthesis is improved, using sulfuric acid as catalyst and vacuum dewatering, phosgene - benzene liquid phase of preparation of glutamic acid N carbon anhydride, benzene - two oxygen six ring solution polymerization was PBLG, yield was 95.0%, the molecular weight range in the range of 5-35 million. Infrared analysis showed that the configuration of PBLG is alpha helix polypeptide. On the basis of this study, they prepared the leucine - glutamic acid benzyl ester series materials, the proportion of leucine in the polymer respectively 0, 0.30 and 0.50, 0.70 (molar ratio), 18 methyl norethindrone and materials made of microspheres in vitro enzymatic hydrolysis experiment, papain, chain wire bacteria protease, trypsin and trypsin. The prodrug enzyme hydrolysis test. The results showed that the ratio of glutamic acid was higher than that of the material. Subsequently, the three meta copolymer L- leucine -L- glutamic acid methyl ester -L- glutamic acid (PIMGG) polymerization. The test results show that the PLMGG have better physical properties and film performance, is an ideal carrier of drug delivery preparation and in vitro enzyme solution and mice in vivo degradation test. The results showed that the copolymer in glutamic acid group was greater and stronger hydrophilicity, after implantation in vivo swelling than larger, weight retention rate is small, biodegradable large [16]. Tang Guping [17] aspartic acid and glutamic acid series copolymer materials synthesis, the reaction of aspartic acid and glutamic acid cast feed molar ratio was 9:1, 8:2, 7:3, 6:4, 5:5 and, of the synthesized materials were FTIR, DSC, X-ray and in vitro enzyme hydrolysis test, the material of biological compatibility and blood were determined, that the material is non-toxic materials. It has been reported that L- leucine and L- aspartate copolymer, the material implanted in the animal skin after that, the rate of degradation by the material of the hydrophilic and strong, strong hydrophilicity, degradation rate to speed up. Colin and other [18] are made of polymer with different ratio of glutamic acid tyrosine. As a drug carrier, the toxicity, the distribution rate of the body, the rate of cell uptake and the rate of biodegradation were systematically studied. The experiment showed that the material with high content of glutamic acid was accelerated. YouungHunChoiI[19] reported the polyethylene glycol and poly L lysine amino acid graft copolymer as carrier for DNA drug, in which poly L lysine of molecular weight of 25000, and PEG grafted copolymer molar ratio were 5%, 10%, 25%. Yasuyoshi[20] synthesized copolymers (3-hydroxypropyl) - asparagine and L-alanine, copolymer composition and sequence distribution was by simulated body fluid of PECF liquid and papain on materials degradation experiment, all samples in papain were degradation, degradation rate in line with the Michaelis Menten rules, and enzyme concentration.
Functional properties of 4 poly amino acid materials
Currently on the study of poly (amino acid material point of view, in addition to the human body must amino acid, good biocompatibility and characteristics and foreign and amino acids with active groups point, whether it is the homopolymerization or copolymerization, it retains some active groups. These groups as functional material with the condition. Therefore, in of poly amino acid material development, on the one hand to find optimal amino acid precursor structure ratio, on the other hand can function for of synthetic materials. In the synthesis process, the material can be opened or type functional groups to make the materials prepared with intelligent and more practical significance. Table 1 lists the various side chain groups and bonding agents used in poly amino acid.

Table 1 kinds of side chain groups and bonded drugs in poly amino acid

Table 1 The properties of side-chain in poly-amino-acid


According to the structure of side chain, the formation of the cantilever (Spacer) of the amino open loop, the drug is treated by chemical treatment, and the polymer material condensation, take off a small molecule substance to form the precursor drug. Generally speaking, under the same drug access rate and side chain longer, faster release rate; due to the steric hindrance effect, the structure of the drug itself also have an impact, the complex structure of the drug easily with long side chains of the parent material combination. Before joining amino propanol and join the appropriate proportion of propylamine, side groups is capable of binding activity of the drug groups, and regulation of hydrophilic and hydrophobic groups, change the material so that the synthesis of hydrophilic and hydrophobic materials in vivo degradation speed change. Galactose group is targeted to the sex groups, so that the material on the liver targeted [11]. Amino ethanol [1,2] has targeted lung, which can be the target material of pulmonary drug. Second amine side groups such as putrescine, ethylenediamine, 1, 8 - Yassin amine, N - succinic acid, shrink glycerin, methacrylic acid, methyl acrylate shrink glycerin [7] is applied to the mesh gel crosslinking agent.

Drug delivery system of 5 amino acid material
In the study of poly amino acid material, parent material modification and side chain spacers are very important factors, but for drug delivery is a can not be ignored link, and it is directly related to the drug release rate, use of biological and effective blood drug concentration. So many forms of administration are also developed. Pan Shi Rong [15] leucine - glutamic acid benzyl ester copolymer carrier was prepared by 18 methyl norethindrone microspheres release system, the microsphere diameter for 82.6 ~ 133 m, in vitro release test showed that, drug release rate and the approximation of the release time of the drug / to check than, the release rate of drug depends mainly on the microspheres by size and diffusion coefficient. Filipoic[18] prepared DOPA microspheres, microspheres with diameters of 200 - 250 m, ZLipon[21] preparing the norethisterone a polyglutamate microspheres, the microsphere diameter for 100 + 80 mu m and drug access rate was 39% and 60%, the molecular weight of material for 230 000, in vitro release 265 days. Tang Guping [21] the acetyl salicylic acid is bonded to the Phea, pressing Cheng Xiaobang (phi 3mm * 5mm, the sterilized mice implanted subcutaneously, in vivo release experiment. The results showed that the rod-shaped implant administration in a certain extent can reduce drug burst release phenomenon, the drug release process from outside to inside layer by layer release, with drugs and materials not to entrapment with but to form chemical bond with, in a certain extent prevented drug and enzyme or humoral contact, so stick agent dosing than suspension administered to ease the drug release rate. Liu Zhenhua [22] with dibutyl amine of the preparation of poly DL asparagine hydrogel materials in tap water, distilled water has larger swelling ratio, in the electrolyte solution and 50% ethanol swelling was significantly lower than that the nonionic hydrogels have the composition of solvent sensitivity, the hydrogels in aqueous 5-fluorouracil. 16mol/l has good swelling properties and to concentration calculation l.0g gel can be wrapped 2.0g 5-fluorouracil, are expected to be used as an anticancer drug 5-fluorouracil sustained-release material. Giammona[7] with amyl dialdehyde as gum crosslinking agent of prepared poly (alpha, beta (2 - hydroxyethyl) - DL asparagine (Phea) and poly alpha, beta (2 - amine) - DL asparagine (Phea) three-dimensional network hydrogel, 4-amino-1 - beta - arabinofuranosyl 2 (H) pyridone as die plough medicine is prepared into the material, in pH 7.4 phosphate buffer solution for in vitro release, Sprague Dawley rats as experimental animals were biocompatible evaluation and in vivo release experiment. In addition, DMPC is also used to make Giammona liposome by using methyl methacrylate as the gel chain. Using BPAA as a model drug. Byron[11]'s lung targeted drug delivery methods will be PHEA labeled Fluorophore materials by solvent dissolution, the spray directly through an endotracheal tube directly into the respiratory tract, sprayer with a propeller operation. The peak of [15] reported PLMGG sustained-release tablets and sustained-release capsules, and different drugs (18- methyl norethindrone, progesterone and 5- fluorouracil) and different copolymer ratio (molar ratio of 30: 55: 15, 30: 45: 25, 30: 32: 38) sustained-release tablets and capsules of drug release in vitro studies, these results show that drug delivery device has a good sustained-release effect, steady state rate of drug and time release capsule. The release rate of the tablets increase with time and decreases slowly, the drug release rate increased with the drug release in the medium and high drug solubility increases, increases with the content of glutamic acid in the copolymer increased, the pill began to have the impact of the amount of drug release, the steady state after the drug release rate with time decreases slowly, proportional to tl/2, suitable for a release the impact of the amount of drugs such as antitumor drugs, capsule drug release rate has nothing to do with time, Paul Sustained release drug, suitable for the requirements of periodic constant speed drug release, such as contraceptive drugs.
Structure and biocompatibility of 6 amino acid materials
Pan Shirong [15] in the study used FTR found that gamma benzyl -L- glutamate (PIBG) alpha helix polypeptide. In 1652cm-1 for alpha helix and the amide group characteristic absorption frequency and 3289cm-1, 1549cm-1, 1082cm-1, 1120cm-1 for alpha helix amide II (n - N deformation vibration), 3065 for benzene C-H stretching vibration. Giammona[23] is of poly (2-hydroxyethyl) DL asparagine and poly (2 - amine) - DL asparagine in solution form structure analysis, small angle X-ray scanning analysis, indicating that the Phea showed no gauge coiled shape, and pahy is straight tube shaped plane structure distribution, in a certain extent and beta layer spherical protein similar. This kind of rigid structure provides the possibility for PAHy to make the network gel. They of Phea and pahy material the biocompatibility tests, including acute toxicity, subacute toxicity, the materials were implanted in vivo and the animal body weight changes, the hemogram index (SGPT, SGOT, etc.), the maximum tolerance dose of pahy for 4 000mg/Kg. Pan Shi Rong [24] will PLMGG series material samples implanted in mice in vivo for 72 weeks of observation, macroscopic observation of the tissue of the animals showed that materials in 48 weeks remained a wafer shaped, slightly swelling, is made of colourless transparent transformation yellow translucent. Surrounding tissue hyperemia, edema. The dense layer specimens are fibroblasts consisting of layers of coating. Light microscopy can see a large number of lymphocytes, macrophages and a lot of plasma cells and macrophages. Tissue reaction is at the stage of acute inflammation and the stage of chronic reaction. The density of inflammatory cells decreased significantly in the 2 ~12 weeks, and the 12~48 peripheral capsule had obvious fibrosis. There was no significant difference in the control of Msi materials widely used in medicine at present. Weng Lihong [25] was used for detection of polyasparamide modified material biocompatibility. Histopathological experimental observation that, in the implanted site early foreign body reaction, side of the small blood vessels of the 13 part D in liver tissue of mice appear a small amount of inflammatory cells, 34 days after inflammatory cells gradually reduced or disappeared, liver tissue and cell morphology and function basically normal. Domurado[26] will natural dextran and Phea respectively with mannose a-D-, beta l fucose sugar modified after intravenous injection in mice. The experimental results show that Phea modifiers of glucose oxidase in blood clearance less than dextran modified.
7 conclusion
Poly amino acid materials in controlled release drug application has been studied quite intensively, but due to a number of reasons for the real application in clinical is less, the reason with the polymer production on a smaller scale, varieties and specifications is not complete, the price is expensive. From the point of view of industrial production of the control agent, it is needed to produce a qualified product which is sterile, stable and reproducible. It needs a more complex manufacturing process. In addition, it is needed to increase the basic research on the study of the biological degradation preparation. But it can be predicted that with the continuous deepening of the controlled release preparation, some weak links to gradually improve and overcome, poly amino acid material in the field of drug controlled release must have a good prospect.
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