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Chitinamine is a polysaccharide composed of glucosamine and acetylglucosamine polymers, which can be obtained by partially deacetylating chitin in the chitin. It is also found naturally in certain microorganisms and yeasts. The term chitosan refers to a series of chitin polymers with different molecular weights (50 kDa to 2000 kDa), viscosity and degree of deacetylation (40% to 98%). Chitin is insoluble in neutral and alkaline solutions, but can form salts with inorganic and organic acids such as glutamic acid, hydrochloric acid, lactic acid, and acetic acid. The amino group of the polymer is protonated, and the soluble polysaccharide produced is positively charged. The most commonly used chitosan salts are glutamate and hydrochloride.

Chinese name: Chitin
Composition: Glucosamine, acetylglucosamine polymers
Place of existence: Naturally found in certain microorganisms and yeasts

Nature: Insoluble in neutral and alkaline solutions; soluble in water
Use: Powder tabletting auxiliary, control dosage form, medicinal, etc.
Classification: Polysaccharide

Chitin

Chitinamine salt is soluble in water and its solubility depends on the degree of deacetylation and pH. Chitosamine with a lower degree of deacetylation (40%) is soluble in solutions up to pH 9, while about 85% of deacetylation is only soluble in solutions below pH 6.5. Adding salt to the solution can significantly affect the solubility of chitin. The higher the ionic strength, the lower the solution. The viscosity of the chitosan solution increases as the concentration of chitosan increases, and the viscosity decreases as the temperature increases. Viscosity also increases as the degree of deacetylation of chitosan increases, because high and low degrees of deacetylation of chitosan have different molecular conformations. Chitosamine molecules with high degree of deacetylation are highly ionized and have a more flexible chain-like stretch conformation. And the chitin molecule with low degree of deacetylation has a stripe or curled conformation due to the low degree of ionization.

Chitin use

Chitosan tablets

Chitosan has extremely excellent properties as an auxiliary material for direct compression of powders. Adding chitin to common excipients (mannitol, lactose or starch) can reduce the angle of repose and improve the flowability of the mixed powder. The chitosan was mixed with lactose and propranolol hydrochloride and directly compressed. The dissolution test results showed that the release was zero order. If chitin is added to the tablet at a concentration higher than 5%, as a disintegrant, the effect is better than corn starch and microcrystalline cellulose. The disintegration effect of chitosan depends on the degree of crystallinity, degree of deacetylation, molecular weight and particle size. Upadrashta and others found that chitosan is also an excellent tablet binder. Compared with other excipients, the order of the binding effect is as follows: hydroxypropyl methylcellulose>; Su Na. Another advantage of chitin is that it may be used for the administration of ulcer-prone drugs such as aspirin. In fact, the polysaccharide's gelling properties at low pH and its resistance to acids and ulcers make this polymer prevent stomach irritation of certain active compounds. Kawashima et al. Prepared aspirin tablets containing chitin. The presence of chitin resulted in slow release of aspirin, reducing the most common side effect of aspirin, gastric irritation. Acikgoz and other studies found that chitosan can reduce the irritation of gastric mucosa by another anti-inflammatory drug, diclofenac sodium.

Chitosan controlled release dosage form

In the pharmaceutical industry, the possibility of chitin for the development of controlled release drug delivery systems has been widely explored. This is because it has unique polymeric cationic properties, gelling properties and film-forming properties. These drug delivery systems should be able to control the rate of drug delivery, prolong the duration of effective treatment, and possibly target drug delivery to specific sites. A number of drug delivery systems have been reported in the literature, including microparticle systems, controlled release frameworks, erosive frameworks, and controlled release gel systems.

Combining chitin and its derivatives with other excipients to prepare tablets with controlled release characteristics, it was found that the release rate of the drug is, to some extent, directly related to the amount and type of chitin used, and can be obtained Zero-order release model. Most gel-forming polymers form gels at high pH, so it is clear that chitosan can be used for intestinal controlled release. Theophylline controlled-release tablets were prepared using a chitosan, Carbomer® 934P and citric acid hydrated colloid framework system. It was found that when the amount of chitinamine exceeds 50% of the tablet weight, a non-erodible matrix tablet can be formed, and when the amount is less than 33% At the same time, a quick-release skeleton sheet can be formed. The amount of chitosan is less than 10%, which can be used as a disintegrant. The addition of sodium alginate in the preparation of tablets makes the tablets have a wider range of drug release properties. Citric acid can gelatinize chitosan, which affects the controlled release characteristics. Carbomer reduces the disintegration performance of chitinamine. Akbuga studied the relationship between the release characteristics of chitinamine maleate matrix tablets and the physicochemical properties of the drug, and found that drug solubility, dissociation degree and molecular weight were important influencing factors.

Chitosan gel

Miyazaki et al. Explored the use of chitosan xerogel as a slow-release matrix for poorly soluble drugs such as indomethacin and papaverine hydrochloride. The drug dispersed in the gel showed zero-order release, 40% indomethacin release in pH 7.4 buffer solution for 24 h, and 100% release of papaverine hydrochloride for 24 h in 0.1N HCl. Kristl et al. Also confirmed these results with the release of lidocaine (and its salts) from chitosan hydrated colloids and gels. The degree of deacetylation and the content of chitinamine are important factors affecting the release. The release model of the gel is consistent with zero order kinetics. Knapczyk used 93% and 66% deacetylated chitinamine and lactic acid to prepare gels. It was found that gels prepared with high deacetylated chitinamine were more stable in combination with drugs than gels prepared with low deacetylated chitinamine.

Chitosan promotes dissolution

The dissolution rate of poorly soluble drugs is an important factor affecting drug absorption. It has been found that milling chitin with poorly soluble drugs such as griseofulvin or prednisolone can increase their dissolution performance. For acidic drugs with low solubility, such as indomethacin, the positively charged amino sugar group of chitosan interacts with the negatively charged drug to form a gel, which increases the solubility and controlled release of the drug. Hou et al. Produced granules made of chitosan and indomethacin. The pH granules placed in acidic gastric juice were faster than the granules without lower pH and released the drug at pH 7.5. This is due to the expansion of chitosan at low pH to form a gel. In contrast, if the particles are cross-linked with glutaraldehyde, swelling and gel formation are reduced, and the brown reaches a sustained release effect at intestinal pH.

Chitosan bioadhesion

Takayama et al. Prepared oral tablets with chitin and sodium hyaluronate to study their bioadhesion and release rate of model drugs. It was found that tablets made with only chitin were less adhesive to the mucosa than tablets made with sodium hyaluronate alone or with these two polymers. The release rate of the drug is highly dependent on the weight ratio of chitin in the tablet. The ratio of chitin is between 10% and 60%. A constant release rate can be obtained. When the ratio is higher, the release increases rapidly.

Miyazaki et al. Performed in vivo and in vitro measurements on oral adhesive tablets prepared with chitin and sodium alginate. With the increase of alginic acid content, the bioadhesion in vitro increased, indicating the strong bioadhesion of alginic acid. In vivo tests show that, on the one hand, the tablets adhere tightly to the mucosa of the sublingual area, and on the other hand, the bioavailability of the sublingual drug is significantly improved. In addition, because the bioadhesive system is neither irritating nor unpleasant taste or discomfort, it is easily accepted by patients.

Chitosan for colon administration

Recently, chitin was in capsule form for colon-specific administration of insulin. The chitosan capsules are coated with an enteric coating (hydroxypropyl methylcellulose phthalate) and contain various absorption enhancers and enzyme inhibitors in addition to insulin. It was found that the capsule disintegrated in the colon area, indicating that the disintegration effect was either due to the low pH at the ascending colon (relative to the terminal ileum) or the presence of a microbial enzyme capable of degrading chitin.

Chitosan microspheres and microcapsules

Chitosan microspheres have been widely studied for implantation or oral controlled release drug delivery systems. Generally, such microspheres are prepared by an emulsification cross-linking process or by coordination between macromolecules with opposite charges.

Nishioka et al. Prepared glutaraldehyde cross-linked chitinamine microspheres containing cisplatin. The encapsulation efficiency of the drug increased significantly with the increase of the chitin and chitin content, and the sustained release effect increased with the increase of the chitin content from 1% to 5%, and the increase of the chitin content from 0% to 1.5%. Jameela et al. Prepared similar microspheres containing mitoxantrone. The degree of cross-linking can be used to effectively control the drug release. At high cross-linking levels, only about 25% of the drug is released from the microspheres at 36 days. Microspheres are not biodegradable in rat muscle. Akbuga et al. Prepared fast urine microspheres using a W / O emulsification system. The properties of the microspheres are affected by the preparation factors such as the concentration and type of chitosan, drug concentration, and cross-linking process. The polypeptide salmon calcitonin was encapsulated with tripolyphosphonic acid crosslinked microspheres and released slowly over 27 days. Mi et al. Used interfacial acetylation and spray hardening to prepare chitinamine microspheres, and used chitosan with molecular weights of 70 kDa, 700 kDa, and 2000 kDa to prepare oxytetracycline-containing microspheres. The experimental results show that the higher the molecular weight of chitosan, the greater the sustained-release effect of the drug. Aideh et al. Prepared similar chitosan microspheres encapsulated with insulin, and ascorbyl palmitate was cross-linked on the microsphere surface. The release rate of the drug is determined by the amount of chitin in the microspheres, which can be released continuously for up to 80 hours. Recently, chitosan microspheres cross-linked with polyanionic sodium tripolyphosphate and polyethylene oxide-polypropylene oxide copolymers have been proposed as carriers for oral administration of proteins and vaccines. Antigen release is slow, with only 20% of tetanus toxoid being released in 18 days. Chitosan microspheres can also be prepared by the emulsification-ion gel method, which can increase the pH of the emulsion system and make the chitinamine insoluble.

Oppositely charged polyelectrolytes act rapidly in solution, often forming insoluble precipitates. This principle is used in the preparation of chitosan microspheres, thus avoiding the use of cross-linking agents. Polk et al. Reacted chitinamine and sodium alginate in the presence of calcium chloride to form microcapsules with a polyelectrolyte complex membrane. The release rate of albumin in the microcapsules depends on the concentration of alginic acid and the molecular weight of chitin. The release rate of albumin decreases with the increase of these two factors. Remunan Lopez et al. Prepared chitinamine gel coacervate microspheres using the same principle. Recently, Liu et al gelled chitosan with sodium alginate and freeze-dried to prepare porous microspheres. Interleukin-2 diffuses from an external drug aqueous solution and binds to pre-formed microspheres. The drug was found to be released from the microspheres in a sustained release manner. Due to the slow release of cytokinin, the drug stimulates inhalation of cytotoxic T lymphocytes (CTL) more effectively than free drugs.

Chitin wound healing agent

The scientific basis of the effectiveness of chitin in promoting wound healing was first reported in 1978. The chitosan acetate film that contacts and protects the wound has the advantages of good oxygen permeability, strong water absorption, and slow enzyme (lysozyme) degradation, so it can avoid the need for repeated applications. Treatment of various dog tissues with chitin solution results in inhibition of fibrous tissue formation and promotes tissue regeneration. Significant progress has been made in the development of veterinary wound healing agents. Japan's Sunfive Inc. has started to develop and market a chitosan cotton (Chitopak TMC) and a chitosan suspension (Chitofine TMS). 3M has marketed a human wound healing agent (TegasorbTM?) Containing chitin as an adjuvant.

Chitosan promotes absorption

Illum et al. First proposed that chitosan can perform transmucosal absorption of polar small molecules and peptides and protein drugs. In the sheep model, they found that the addition of chitin to a nasal insulin prescription caused the plasma glucose level to drop to 43% of the original level, compared to 83% of the original prescription without chitosan. At the same time, plasma insulin levels increased from 34 m IU / 1 to 191 mIU / l, and AUC increased 7-fold. Similar results were obtained for other small molecular weight drugs, such as morphine and anti-migraine drugs polarized in nature, and peptides such as calcitonin, desmopressin, goserelin, parathyroid hormone and leucine Prorelin. Results from studies on human volunteers confirm the results of the sheep trial.

Chitosan can be applied in the form of a simple solution (concentration 0.5 to 1.0%), or chitosan microspheres can be prepared by spray drying. Compared with the chitin solution, this powder formulation has a stronger promotion effect on drug transport through the cell membrane. In sheep model tests, for peptide drugs (goserelin, leuprolide, and parathyroid hormone), the bioavailability of chitin powder and microspheres reached 20 to 40%. The results of the clinical trials also confirmed the results of the animal trials.

Consistent with nasal absorption studies, Rentel et al. Reported that chitosan can also promote the transmucosal absorption of the peptide drug 9? Deglycinamide? 8? Arginine vasopressin solution administered to the intestine of rats. Later experiments showed that the effect of chitin on the penetration of mannitol by Caco2 cells depends on the degree of deacetylation and the molecular weight of chitin. Recently, it has also been reported that chitosan solution can increase intestinal absorption of buserelin by 50%. Chitin derivatives have similar absorption-promoting effects. N? Trimethylchitosan chloride has better water solubility, so it is easier to prepare solid oral dosage forms than chitosan itself. Studies on solid dosage forms containing chitin are less successful due to the slow dissolution of chitin in powder form. Rat and pig model tests on peptides such as insulin and calcitonin have yielded similar results.

Chitin Related Information

Recently, it has been reported that chitin (most likely due to its absorption-promoting effect) can be used as a material to enhance the immune response of vaccines through transmucosal routes such as nasal administration. When administered through the nasal cavity or by injection, chitosan itself cannot produce a humoral immune response. Gill et al. Reported that the pertussis vaccine containing the antigen hemagglutinin filaments (FHA) and pertussis toxoid or FHA only, was administered nasally with chitin in combination with intraperitoneal injection to obtain plasma IgG levels similar to those administered intraperitoneally. Very high levels of secreted IgA are obtained. In contrast, injectable formulations that do not contain chitosan have no detectable IgA levels in nasal wash fluids, and nasal prescriptions that do not contain chitin have low IgA levels. A chitosan-containing influenza vaccine was administered nasally and found to have a similarly high immune response boost compared to subcutaneous injections.

Different research groups have extensively studied the mechanism of chitinamine promoting drug transmucosal transport, which is believed to be the temporary opening of tight junctions on the cell membrane to allow polar drugs to pass and the result of bioadhesion. The ? scintillation method clearly shows that chitin is bioadhesive. The control solution, chitin solution, and chitin powder were applied to the nasal cavity of human volunteers, and the nasal clearance time was 25, 40, and 80 minutes, respectively. The pulse tracking study further showed that the transmucosal absorption promotion effect of chitin was short-lived, and the effect decreased after 30 to 45 minutes after solution administration. The effect of chitin on model cell membranes summarized that chitin was likely to interact with the open structure of the tight junction due to its positive charge, as seen in the decline of ZO? 1 protein and the cytoskeleton protein FActin from filamentous Into a spherical structure.

Chitosan toxicology test

Chitin has recently been approved as a food additive in Japan, Italy and Finland. Applications for inclusion of chitin in the European Pharmacopoeia have been considered. A series of toxicity studies were performed on chitin, including the effect on the frequency of cilia movement after 28 days of application of guinea venom. Toxicity is negligible in all tests. A 10-day subacute toxicity study in rabbits showed no macro or micro effects on organs or tissues. The sweetness clearance test found that after using chitin on the nasal cavity daily, human mucous ciliary clearance was not affected. Chitosan has been reported to have an oral toxicity of 16 g / kg body weight (LD50?).

Chitosan conclusion

This article outlines the application of chitosan as a pharmaceutical excipient in the pharmaceutical industry. For example, it is used as a disintegrant for direct compression of powders, for the production of controlled release solid dosage forms or to improve the dissolution of drugs. The microspheres and microcapsules prepared with chitin are used in the delivery system of hormonal drug implantation, which can control the drug release for a long time. Recently, the promotion of transmucosal absorption of chitin has been developed, especially for nasal and oral mucosal delivery of polar drugs including peptides and proteins, and administration of vaccines. These characteristics, as well as its very safe toxicity characteristics, make chitosan an exciting and promising excipient in the pharmaceutical industry.