KR20100022200A - Development of mastic indicated for imflammatory bowel disease (ibd) applied with colon targeting drug delivery system(dds) - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing Pistacia lentiscus is provided to intensively elute mastic or mastic chios in colon and enhance efficiency of drug. CONSTITUTION: A pharmaceutical formulation for treating Ulcerative Colitis and Crohn Disease contains mastic as an active ingredient, which is stable at Ph 1-6 and dissolved at pH 6.8-8. The pharmaceutical formulation is manufactured by: mixing excipient and disintegrant to form granule; drying the granule; and granulating the granule with lubricant to obtain tablet or capsules.

Description

Development of Mastic indicated for Imflammatory Bowel Disease (IBD) applied with colon targeting Drug Delivery System (DDS)}

The present invention relates to a pharmaceutical composition and a drug delivery system targeting the large intestine to use the extract of Mastic belonging to the Pistacia lentiscus of the Mediterranean Chios island as a therapeutic agent for colitis.

First, mastic is a toothpaste composition that has been used for the prevention and treatment of periodontitis, and has been used as a gastric ulcer treatment for Helicobacter pylori. KR1020027017953 is a cosmetic skin care composition containing a mastic gum has been filed by Unilever Envelope PCT and provides the anti-aging benefits to alleviate skin aging. In toothpaste composition containing the mastic of KR1020070043174, it is possible to maintain more powerful oral cleanliness than conventional toothpaste by using mastic which has the effect of suppressing the sterilization and survival for various oral bacteria.

U.S. Patent No. 20040037790 discloses oral compositions containing Japanese and Chinese herbal medicines, oral methods for preparing and oral hygiene, and natural products from Japan and China using oral hygiene method in Japanese and Chinese herbal remedy. It relates to compositions for oral hygiene using.

In US Patent No. 05073445 (Mastic and caulking compositions and composite articles) and US Patent No. 04983426 (Tiecoat for use with mastic coating applications) are inventions for the application of Mastic. Japanese Patent Application No. 2001128643 describes a Soft Capsule Enclosing Mastic Oil Solution, which is difficult to penetrate the gastric mucosa, and thus it is difficult to maintain a continuous action on Helicobacter pylori. Although it is difficult, Mastic has been developed as a gastric ulcer drug by including it in the soft capsule. Although the application and use of Chios mastic is not widely used, it has been mainly used for periodontitis, gastric ulcer and health function, but it has not been used as a treatment for colitis.

In addition, the colon targeting drug delivery system in Samyang Corp. KR 10-0212432-0000 (1) the nucleus is composed of drugs, disintegration aids and conventional excipients, (2) the outer membrane coating the nucleus is decomposed by bacteria in the large intestine A polyvalent metal ion complex and a plasticizer of pectinate having a molecular weight of 250,000 or more, wherein the dextran or xylan is physically bound in an amount of less than 50% relative to the total weight of the pectinate and the dextran or xylan, Colonic drug delivery compositions are characterized in that they are coated with 15-30% by weight, 10-1000 thick.

KR 10-0186907-0000 relates to a drug delivery system for delivering a drug to the large intestine, wherein the polysaccharide salt solution containing at least one polysaccharide that can be decomposed in the drug and the large intestine is prepared by treating with a metal ion aqueous solution. The colorectal drug delivery system uses biodegradable and biocompatible materials, and a technique is described that enables the efficient delivery of drugs to sugar using colon enzymes without being affected by individual differences in intestinal transit time.

KR 10-0425028-0000 relates to a colon selective drug delivery composition and a colon selective drug delivery agent capable of selectively delivering a bioactive substance to a specific part of the large intestine, and more particularly, to a first polysaccharide that is degraded by colon enzyme and Prepared by mixing a second polysaccharide at a pH of 7 or higher, such colon selective drug delivery composition may comprise a drug, nutrient, diagnostic agent or mixture thereof in combination with the polysaccharide composition. Since the colon-selective drug delivery composition provided in the present invention can be decomposed only by colon enzymes, the drug is selectively delivered only to the large intestine without releasing the drug from the upper gastrointestinal tract, and the drug delivery ratio is controlled by controlling the mixing ratio of the composition or the thickness of the agent. It is described that there is an advantage of selecting a large intestine site as a destination point.

Ajinomoto's WO2006JP317062 (Colonic DeliveryType Therapeutic Agent For Inflammatory Bowel Disease) uses dextran-based functional foods to be absorbed into the large intestine and WO 2006/085075 (Colonic delivery of active agents) cross-links pectin beads with calcium A technique targeted at the large intestine by cross-linking to form polyethyleneimine and an endothelial system is described.

Most of the commercially available treatments for colitis are monoclonal antibodies that suppress the inflammatory response of the immune system. Classically, 5-ASA, mesalazine, sarazopyrine and adrenal cortex prednisolone (corticosteroid-series prednisolone), and budesonide. The technical problem to be achieved in the present invention is to provide a therapeutic agent containing a mastic (Chios Mastic or Mastic) as an active ingredient that uses a natural raw material as a low toxicity and no harmful reactions even when taking chronic gastrointestinal diseases. have.

Since the large intestine belongs to the lower organs in our body, it is difficult to reach effective blood concentrations due to absorption by the upper organs in general rapid-release preparations. Thus, developing a drug delivery system targeting the large intestine allows certain drugs to be directly eluted and absorbed into the lesions, helping to heal the disease.

The colon targeting system consists of two parts to reach the large intestine by using the internal and external separate components to sustain the release of the internal main components and sensitivity to external pH changes in the body. The external constituent shells maintain a stabilized system in the upper organs and in the large intestine disintegrate the shells to induce sustained release of particles, the major constituents of the interior. The outer shell is a coating made of a polymer such as acrylic resin using a gelatin capsule to form a stable outer shell by cross-linking quaternary ammonium and gelatin so that it does not dissolve at high pH at the top. It is a system. Each of the internal components of the outer membrane is intended to obtain optimized drug dissolution by controlling two rate-controlled stages of drug release by forming sustained-release granules using matrix decomposition by ionic complexes or enzymes. Accordingly, the pharmaceutical composition of the two components to confirm the drug dissolution pattern to derive the best results in vitro (in vitro) for the treatment of colitis. This need has been solved by the present invention.

In the present invention, a colitis targeting drug delivery system using a mattic (mastic) has two components, namely, a rate-limiting step of inducing release of the drug by ion complexation and decomposition by a hydrophilic polymer and colon bacteria. The above problem has been solved by regulating the delivery of the drug carrier to the large intestine and providing a continuous release system of the drug in the large intestine.

By developing colon target drug delivery system containing Mastic or Mastic chios, stable composition of outer membrane to reach the main disease area and control to release the drug slowly at targeting site Slow release of drugs in the large intestine by using pectin, which is sensitive to degradation by ionic complexation and sustained release (SR) -type hydrophilic polymers and pectinolytic enzymes, as a matrix To further increase the effectiveness of the drug. The disintegration / swelling / dissolution of the two components of the core and the outer membrane is the rate-limiting step in controlling the release of the drug.

The present invention is mixed with an excipient and a disintegrant, and mixed with a granulating agent to form granules, then dried, mixed with a glidant and granulated, then compressed into tablets or to fill in capsules To prepare capsules;

Separately, the coating agent and the plasticizer are dissolved in a solvent to prepare an oil-based coating solution, and then the uncoated tablet or the capsule is prepared by coating the coating solution and drying it, which is stable at pH 1 to 6, and disintegrates at pH 6.8 to 8. It provides a pharmaceutical preparation for the treatment of colitis (Ulcerative Colitis (UC)) and Crohn Disease (CD) containing a mastic (Mastic) as a main component. The large intestine is a lower organ of the gastrointestinal tract, in which the drug is dissolved in the upper part and the absorption is poor, and the present invention provides a system for intensively eluting the drug only in the large intestine by using a drug carrier or a drug delivery system. A pharmaceutical composition targeting the large intestine and a colon targeting drug delivery system using the same are provided.

Excipients are controlled to react in-house using calcium chloride and at least two excipients selected from anionic polysaccharides selected from sodium alginate, highly substituted pectin, low substituted pectin, chitosan and hydroxypropylmethylcellulose.

In the present invention, the composition ratio of the anionic polysaccharide and calcium chloride is controlled in a ratio of 1: 1 to 3.

As the disintegrant, at least one selected from camelos and crospovidone is used.

Eudragit is used as the coating agent, triethyl citrate is used as the plasticizer, and at least one selected from ethanol and water is used as the solvent.

In the present invention, it is preferable to adjust the mastic as the active ingredient in the tablet or capsule to contain 100 to 1,000 mg.

In the present invention, the viscosity of the anionic polysaccharide is preferably adjusted to 100 cps to 4,000 cps.

In the present invention, the coating thickness is preferably adjusted to 3 to 5% of the total tablets or capsules by dry weight.

The invention is explained in more detail by the following examples.

Example  1 (Preparation of Internal Components)

According to the above embodiment, each component is precisely weighed and then mixed or granulated.

In the case of 1, 2, 3 and 4 of the embodiment, as described above, the main ingredient mastic and the excipient are mixed for about 10 minutes, and then the lubricant is mixed and then further mixed for 10 minutes. In the granulation process, the granules are molded using water as the granulating agent as the main component and the mattress component. Separately, the granules are molded by making a granulating solution with 10% PVP 30K. Molded granules are dried overnight at 60 ^° C. to ensure that moisture is less than 3%. The confirmed dry granules were Sieve No. 20 is determined so that the final particle size is about 850 micrometers. Finally, the obtained granules are mixed with a disintegrant and then mixed with a lubricant for 10 minutes. Uncoated tablets are prepared by filling or compressing the mixture obtained in accordance with each example in capsule size # 00.

Example  2 (External Component: Drug Delivery System)

To develop a drug delivery system targeting the large intestine, a coating solution was prepared in the composition of the above example using a commercially available pH dependent polymer base.

First, according to the above example, the exact amount of EUDRAGIT L100 is weighed and dissolved in ethanol as a stirrer to prepare an initial liquid. The oil-based coating solution was prepared by adding 5% of a plasticizer and TEC (Triethylcitrate) to solutions of different concentrations. Coating conditions were carried out by adjusting the respective coating conditions using a modified pan coater (ERWEKA AR402) according to Example 3 below to evaluate the coating state by the surface and uniformity of the capsule.

On the other hand, after diluting the EUDRAGIT FS D30 aqueous dispersion with water by concentration, 5% plasticizer (TEC) was added to adjust the concentration of the water-based coating solution and then using a spray gun (spray-gun) according to Example 4 below. Coating was carried out while adjusting the respective coating conditions.

Example  3 (coating)

Example  4 (coating)

Experimental Example 1

After the capsules containing the prepared mastic were dried, a drug dissolution test was conducted according to the following experimental example in order to evaluate the drug delivery system of pH dependent coating and colon targeting.

Condition of the dissolution test was 2 hours, 4 hours at pH 4.0 at pH 1.2 using an automatic sampling apparatus VK 8000 at 37 ^o eluate from C with 50 rpm pH 1.2, pH 4.0 and pH 6.8 using a Vankel (VK 7000), And the dissolution pattern of the drug was observed for 6 hours at pH 6.8. The collected samples were analyzed using Agilent 1100 series (Agilent Technology).

The results are shown in the following FIGS.

1 is a result of eluting the Chios mastic capsule prepared according to Example 1 at pH 1.2 for 2 hours, pH 4.0 for 4 hours and pH 6.8 for 6 hours. At pH 1.2 and pH 4.0, there was no drug dissolution, and at pH 6.8, the dissolution rates due to differences in the pharmaceutical compositions showed different patterns. As the most optimized composition among them, in the case of sample 6, the main mattress component composed of the drug was slowly released.

FIG. 2 is a graph showing the dissolution mode at pH 6.8 of a persistent chios mastic formulation.

Claims (8)

Mastic is mixed with excipients and disintegrants, mixed with granulating agents to form granules, then dried, mixed with glidants and granulated, then compressed into tablets to prepare uncoated tablets, or by filling into capsules. To prepare; Separately, the coating agent and the plasticizer are dissolved in a solvent to prepare an oil-based coating solution, and then the uncoated tablet or the coating agent is coated with this coating solution, and then dried. A pharmaceutical formulation for treating colitis (Clc) and Crohn Disease (CD), which is stable at pH 1 to 6 and contains Mastic as a main component, characterized by disintegration at pH 6.8 to 8. The method according to claim 1, wherein the excipient is controlled to react in itself using at least two excipients selected from anionic polysaccharides selected from sodium alginate, high substituted pectin, low substituted pectin, chitosan and hydroxypropylmethylcellulose and calcium chloride. Pharmaceutical formulations prepared. The pharmaceutical preparation according to claim 1 or 2, wherein the composition ratio of the anionic polysaccharide and calcium chloride is controlled in a ratio of 1: 1 to 3. The pharmaceutical formulation according to claim 1, which is prepared using at least one selected from camelos and crospovidone as disintegrants. The pharmaceutical composition according to claim 1, which is prepared using Eudragit as a coating agent, triethyl citrate as a plasticizer, and at least one selected from ethanol and water as a solvent. The pharmaceutical preparation according to claim 1, wherein the active ingredient mastic contains 100 to 1,000 mg. The pharmaceutical preparation according to claim 1, wherein the viscosity of the anionic polysaccharide is adjusted to 100 cps to 4,000 cps. The pharmaceutical formulation according to claim 1, wherein the coated thickness is 3 to 5% of the total by dry weight.

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