KR20190036370A - Drug Delivery System for Sustained Release Formaulation of Drugs - Google Patents

Abstract

The present invention relates to a drug carrier for sustained-release formulation of drugs, which is capable of releasing drugs, slowly dissociated in a body and collected, in a sustained-release form. More particularly, in the drug carrier for collecting drugs and formulating drugs into a sustained-release formulation, the present invention relates to the drug carrier comprising an ionic conjugate of fucoidan or glycosaminoglycan (GAGs) and polycation.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a drug delivery system for sustained-

The present invention relates to a drug delivery system for sustained-release formulation of a drug, which permits gradual dissociation in the body of a drug to be released in a sustained release form.

Recently, there has been a social trend that the maintenance and promotion of health is more important than the increase of the national income level, the improvement of the quality of life, and the entry into the aging society. Accordingly, effective and economical treatment of various diseases is required. Therefore, a drug delivery system (DDS, Drug Delivery System) that can administer the necessary minimum amount of drugs in necessary time depending on the individual condition, .

If the drug is given in the form of oral administration or injection, the initial blood concentration may be too high to cause side effects. If the administered drug has a short half-life, the drug remains in the blood only for a short period of time, and the activity lasts only for a short time. Therefore, in order to maintain a constant drug concentration in the blood above an effective concentration, administration of two or more times a day is necessary, resulting in an increase in the size of the administration unit, and consequently, the patient's compliance with the medication is reduced.

When the drug is administered as a topical application directly applied to the affected area, such as an ointment, it is directly applied locally to the site where the drug is to be administered. Thus, unlike the case of an oral preparation or an injection, Positive drugs can also be effective. However, the drug for external use is also rapidly released early, and when the half-life is short, it is troublesome to apply the drug frequently. In addition, when the drug is water-soluble, rapid initial release of the drug can not be avoided due to external moisture, sweat, or body fluid of the affected part, and the drug is easily washed away. Especially when the affected area is not the surface of the skin so that the area can not easily be treated by the general public (for example, a wound due to otitis media or surgery), the frequency of visits to the hospital must be increased to cause troublesome treatment and excessive expenditure have.

In order to solve such a problem, many researches have been made on a sustained-release preparation which can release the drug slowly over a long period of time and maintain an effective concentration for a long period of time, and it has been practically used.

As the sustained release agent, an osmotic pressure regulating system, a stagnation system, and a matrix system have been developed and used. Korean Patent Laid-Open No. 10-2001-0073168 discloses that when water is absorbed into a core coated with a semi-permeable membrane containing an active substance and a hydrophilic gel-forming substance, sufficient pressure is generated inside the osmotic membrane, WO2002-036100 discloses a system in which a core containing a water-soluble drug is coated with an insoluble semi-permeable outer layer such as cellulose acetate, a hole is drilled using a laser perforation, Respectively. However, such a system has a large variation in drug release, requires expensive equipment, and thus has a high manufacturing cost. In particular, it can be applied only to oral preparations and can not be applied to external preparations.

The stomach retention system is controlled so that the residence time in the stomach is prolonged so as to be gradually released, so that it can be applied only to oral preparations. Conventional gastric retention systems can be classified into gastric mucosal adhesion system using biodegradable polymer, expansion system using swelling polymer, and floating system using gas generating material.

The matrix system disperses the drug into a hydrophilic or hydrophobic polymer matrix and slowly releases it. The matrix system can be easily and economically produced and can be applied to various formulations. Patent No. 10-1283454 discloses that an ion complex formed of a negatively charged water-soluble drug and a compound containing a polyvalent cation such as Ca ²⁺ is capable of sustained-release of a negatively charged water-soluble drug and is dispersed in a polymer matrix And that it is possible to use it. Patent No. 10-1319420 discloses that an ion complex formed by a compound containing a positively charged drug, a compound containing a polyvalent anion of the PO ₄ series, and a compound containing at least one polyvalent anion selected from heparin is a water-soluble drug Of the present invention can be used as a formulation for sustained-release of the polymer matrix and can also be used in a form dispersed in a polymer matrix. They are designed so that a water-soluble drug precipitated by a polyvalent cation or anion acts in a sustained manner through a process of being water-soluble through ion exchange in a body fluid in which various ions are present. Japanese Patent Application No. 10-1096679 discloses a core-shell microcapsule structure that can be rapidly crosslinked. The active ingredient is supported on the inside or bonded to the outside, and cations prepared by electrospray drying capable of sustained release of the drug Composite particles of anionic polymers and anionic polymers were disclosed.

Fucoidans and Glycosaminoglycan (GAGs, Glycosaminoglycan), both of which are abundant in brown algae such as marine biomaterials, are sulfated polysaccharides having a sticky, viscous structure. Fucoidan helps cholesterol excretion, lowers blood cholesterol levels, prevents vascular disease, and prevents obesity from leading to adult disease. In addition, anti-coagulant, anti-tumor, anti-bacterial, anti-hypertensive, anti-allergic, It is known that there is a 70-80% effect on the healing of digestive system cancer types. Glycosaminoglycan has the effect of improving skin elasticity, alleviating wrinkles, and improving arthritis. If the ionic complex is formed with the drug using the above-mentioned material having physiological effect and completely harmless to the human body, it would be possible to prepare a sustained release preparation in the form of an ion complex even for a drug which does not form a water-soluble salt. In addition, it is not necessary to use a separate carrier or excipient. Therefore, it is possible to keep the size of the tablet small while increasing the concentration of the active ingredient in the preparation of the formulation, The use of drugs will be possible.

Published Japanese Patent Application No. 10-2001-0073168 WO2002-036100 Patent No. 10-1283454 Patent No. 10-1319420 Patent No. 10-1096679

The object of the present invention is to provide a drug delivery system capable of releasing a drug in a sustained manner irrespective of the physical properties of a drug and capable of producing a sustained-release preparation economically since a drug can be made into a sustained- do.

Another object of the present invention is to provide a drug delivery system capable of further enhancing the efficacy of a drug because it has not only excellent biocompatibility but also a useful physiological activity per se.

In order to accomplish the above object, the present invention provides a drug delivery system for drug formulation and drug release by capturing a drug, the drug delivery system comprising an ionic complex of fucoidan or glycosaminoglycan (GAGs) and a polyvalent cation ≪ / RTI >

Fucoidan and glycosaminoglycan are polysaccharides having a sulfate group and are water-soluble polymer compounds. They react with polyvalent cationic salts to form ionic bonds with polyvalent cations, and have a property of being slowly dissociated in a living environment. In other words, fucoidan and glycosaminoglycan were soluble in water, but in fucoidan and glycosaminoglycan in the PBS buffer similar to the living environment, the cumulative dissociation amount until 7 days was gradually dissociated to about 60% level. Therefore, when the drug is contained in the solution during the formation of the ionic conjugate, the drug is trapped in the precipitate of the ionic conjugate, and the drug can be slowly released as the ionic conjugate dissociates in the living environment. Therefore, It can act as a carrier.

The polyvalent cations include Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ , Be ²⁺ , Cr ²⁺ , Co ²⁺ , Mn ²⁺ , Sn ²⁺ , Ni ²⁺ , Al ³⁺ , At least one selected from the group consisting of Cr ³⁺ , Co ³⁺ , Ga ³⁺ , Au ³⁺ , Mn ³⁺ , Ni ³⁺ , Mn ⁴⁺ , Sn ⁴⁺ , Cr ⁶⁺ and Mn ⁷⁺ . In the following examples, fucoidan did not form an ionic bond with Ca ²⁺ , but the formation of a precipitate or the yield of an ionic bond is affected by the content and molecular weight of the sulfate group in fucoidan. However, the kind and concentration of the polyvalent cation which effectively forms a precipitate depending on the characteristics of fucoidan or glucosaminoglycan to be used can be easily selected by those skilled in the art.

 The drug to be captured in the drug delivery system is not limited in its characteristics. That is, it may be formulated as a sustained-release preparation either water-soluble or poorly soluble, and the concentration of the drug to be captured in the drug delivery system may be 0.1 to 70% by weight. As the concentration of the drug increases, the structure of the drug delivery system becomes looser, so that the release rate of the drug increases. When the concentration of the drug decreases, the release rate of the drug decreases.

The drug delivery system of the present invention can be used by itself or in combination with a pharmaceutically acceptable carrier, a forming agent, a diluent, and the like. In particular, it can be used for the formulation of sustained-release preparations or sustained-release preparations of external preparations. Examples of oral formulations include tablets, capsules, granules and powders, and external preparations can be formulated into ointments, powders, gels, patches, creams, and the like, but are not limited thereto.

As described above, according to the drug delivery system of the present invention, since fucoidan or GAGs bind to multivalent cations to form an ionic conjugate, the drug is captured, and the ionic bond gradually dissociates in the body to release the drug. , It can be usefully used as a drug delivery system capable of sustained release formulation irrespective of whether it can form an ionic conjugate.

In addition, the drug delivery system of the present invention is not only harmless to the human body but also exhibits biocompatibility, and can exhibit various physiological activities such as antibacterial, anticancer, antitumor, antiallergic, etc., It can be efficiently used as a drug delivery vehicle.

FIG. 1 is a graph showing the yields of fucoidan and GAGs ionic conjugates and the contents of fucoidan and GAGs in ionic conjugates according to the cation concentration. FIG.
FIG. 2 is a graph showing dissociation characteristics of fucoidan and GAGs ionic complexes. FIG.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these embodiments are merely examples for explaining the content and scope of the technical idea of the present invention, and thus the technical scope of the present invention is not limited or changed. It will be apparent to those skilled in the art that various changes and modifications can be made within the scope of the technical idea of the present invention based on these examples.

[Example]

Example 1: Formation of ion complex

In the following experiments, fucoidan was obtained from Squalene Bull. of Mar. & Fish. Postharvest & Biotech. 10 (2) 2015, 79-87, and glycosaminoglycans were extracted from the skins by extraction based on the process described in KSBB Journal Vol. 18 (3) 180-185 (2003) Respectively.

Ion complexes of fucoidan and glycosaminoglycan were prepared to confirm that fucoidan and glycosaminoglycans (GAGs) could form an ionic conjugate and act as a drug delivery system for sustained release preparations.

First, fucoidan and GAGs were dissolved in ultrapure water at a concentration of 5 wt% to prepare fucoidan aqueous solution and aqueous solution of GAGs. To the fucoidan aqueous solution or GAGs aqueous solution is added Na ₂ HPO ₄ aqueous solution (1, 3, 5 or 7 wt%), CaCl ₂ aqueous solution (1, 3, 5 or 7 wt%) or BaCl ₂ aqueous solution wt%) was added in a 1: 1 volume ratio to observe the precipitation formation. Table 1 summarizes the formation of precipitates of fucoidan and GAGs by reaction with aqueous solutions of the respective salts. As can be seen from the table below, the Na ₂ HPO ₄ aqueous solution formed a weakly brown transparent solution by mixing with fucoidan or GAGs, and no precipitate could be observed. Fucoidan is by mixing with the aqueous solution of BaCl _2, GAGs are to form a precipitate by mixing an aqueous solution of CaCl ₂ or BaCl ₂ aqueous solution.

The precipitated aqueous solution was centrifuged at 1,200 rpm for 1 min to remove the supernatant and washed with excess ultrapure water to remove fucoidan, GAGs or ions not participating in ionic bonding. Finally, the supernatant was removed by centrifugation from the washing solution and lyophilized to prepare an ion conjugated drug delivery system.

In order to confirm the content of fucoidan or GAGs in the prepared ionic conjugates, quantitative analysis of sugar was carried out. First, 1 mg of each fucoidan-ion complex and GAGs-ion complex were dissolved in 1 mL of ultrapure water, and 166.5 μl of the solution was collected and placed in a 1.5 ml EP-tube. And 666 μl of sulfuric acid (sulfuric acid 99.9%, Aldrich, USA) to which 25 mM sodium tetraborate (Aldrich, USA) was added. The EP-tube containing the sample was heated at 100 ° C for 10 minutes, cooled at room temperature for 15 minutes, and 166.6 μl of 0.125% carbazole (Carbazole, Sigma, China) reagent was added. The reaction was further heated at 100 ° C for 10 minutes and then cooled at room temperature for 15 minutes to induce carbazole reaction. The contents of each drug were determined using a UV / VIS spectrometer (absorbance 520 nm; Lambda 14, PERKIN ELMER, USA).

FIG. 1 is a graph showing the yield of an ionic complex according to the concentration of each ion solution and the content of fucoidan or GAGs in the ionic conjugate. FIG. In the following Examples, in view of the content of the fucoidan or containing GAGs of the ion concentrations and the actual yield of the ion-ion conjugate conjugate fucoidan _{-BaCl 2 3 wt%, GAGs-} BaCl 2 3 wt%, GAGs unless otherwise noted And 5 wt% of CaCl ₂ were used.

Example 2: Evaluation of dissociation characteristics of ionic bonds

As fucoidan and GAGs were found to form ionic bonds, the dissociation properties of ionic compounds were evaluated to confirm their efficacy as drug carriers in the formation of ionic complexes with drugs.

To this end, 5 mg of the ionic conjugate prepared in Example 1 was added to the EP-tube, and 1 mL of PBS (pH ~ 7.4) buffer solution similar to the environment in the human body was filled in the EP-tube, followed by shaking at 50 rpm in a thermostatic chamber at 37 ° C. On the 1st, 2nd, 3rd, 5th, and 7th days, the supernatant was collected using a centrifuge and the new buffer was filled to collect the samples released into the supernatant. The amount of fucoidan or GAGs eluted in the supernatant was quantitatively analyzed using a UV / VIS spectrometer (Lambda 14, PERKIN ELMER, USA) in the same manner as described in Example 1 and the results are shown in FIG.

As can be seen in FIG. 2, fucoidan and GAGs themselves were all dissociated within 24 hours and released into the supernatant, but the ionic conjugate continued to release even after 7 days. Therefore, when the drug is captured in the ionic complex of fucoidan and GAGs and used as a drug delivery system, it can be formulated into a sustained release preparation irrespective of water solubility or ionic properties.

Claims (4)

A drug delivery system for collecting a drug and formulating the drug into a sustained release preparation,
Wherein the drug carrier is composed of fucoidan or glycosaminoglycan and an ionic conjugate of a polyvalent cation.
The method according to claim 1,
The polyvalent cations include Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ , Be ²⁺ , Cr ²⁺ , Co ²⁺ , Mn ²⁺ , Sn ²⁺ , Ni ²⁺ , Al ³⁺ , Cr ^{3 Wherein} the drug is at least one selected from the group consisting of ⁺ , Co ³⁺ , Ga ³⁺ , Au ³⁺ , Mn ³⁺ , Ni ³⁺ , Mn ⁴⁺ , Sn ⁴⁺ , Cr ⁶⁺ and Mn ⁷⁺ Carrier.
3. The method according to claim 1 or 2,
The drug delivery system according to claim 1, wherein 0.1 to 70% by weight of the drug in the sustained-release preparation is collected.
3. The method according to claim 1 or 2,
Wherein the sustained-release preparation is an oral preparation or an external preparation.

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