The liquid composition includes alginic acid or its pharmaceutically recognized salt, and very small amounts of polysaccharides.

Abstract

The present invention relates to a liquid-phase composition containing alginic acid or a pharmaceutically acceptable salt thereof and a colloidal polysaccharide, the composition being suitable as a medical biomaterial for tissue restoration used to elevate mucosal tissue of stomach, bowels, or the like when the mucosal tissue is subjected to endoscopic excision, and more specifically, to a liquid-phase composition, which is a medical pharmaceutical composition to be injected into the submucosal layer in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), wherein the liquid-phase composition contains alginic acid having a weight average molecular weight of 100,000 to less than 200,000 or a pharmaceutically acceptable salt thereof, and a colloidal polysaccharide. According to the present invention, the liquid-phase composition can be effectively used as a local submucosal injection agent which superbly sustains injection-induced elevation of mucous membranes during endoscopic mucosal resection or endoscopic submucosal dissection.

Description

Liquid composition containing alginic acid or a pharmaceutically acceptable salt thereof and colloidal polysaccharide

[0001] The present invention relates to a liquid composition containing alginic acid or a pharmaceutically acceptable salt thereof and a colloidal polysaccharide, which is suitable as a biomaterial for medical tissue repair used to elevate mucosal tissues such as those of the stomach or intestines when the tissues are endoscopically resected.

[0002] The advancement of endoscopy and the expansion of regular health screenings have led to a significant increase in the diagnosis of small adenomas and cancers. The diversity of endoscopes and their accessories, along with advances in endoscopic technology, have led to the adoption of various endoscopic treatment modalities, including endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), endoscopic mucosal destruction, and endoscopic photodynamic therapy (EPDT), for local treatment of lesions previously reliant on surgical intervention.

[0003] Endoscopic mucosal resection (EMR) is a procedure that facilitates the removal of mucosal lesions by locally injecting an appropriate solution into the submucosal layer, then capturing and energizing the lesion with a snare. EMR is generally used to remove lesions less than 2 cm in size or to remove larger lesions piecemeal. The injected solution tends to dissipate quickly, flat and depressed lesions are more difficult to capture than protruding ones, and large or inaccessible lesions are more difficult to remove.

[0004] Since the late 1990s, the importance of en bloc and complete resection has been recognized, leading to the development and use of endoscopic submucosal dissection (ESD) using an insulation-tipped electrosurgical knife (IT knife). Currently, with ESD technically feasible, both conventional EMR and ESD are feasible for lesions less than 1 cm in size. Even for lesions 1-2 cm in size, ESD is considered first if en bloc resection is difficult, and ESD is generally recommended for lesions larger than 2 cm. However, in practice, the surgical method should be determined by considering the advantages of EMR, such as its simplicity and shortened procedure time, and the high complication rate and high skill requirement of ESD.

[0005] The most commonly used submucosal infusion solution is a mixture of saline, epinephrine, and indigo carmine. In some cases, high-viscosity, high-osmolarity submucosal infusion solutions (sodium hyaluronate or glycerol mixtures) are used to prolong the duration of submucosal elevation, but these solutions incur additional costs. Consequently, the development of less expensive alternatives is being sought, and alginate salts are attracting attention as such agents.

[0006] However, in order to maintain a satisfactory level of mucosal elevation using sodium alginate solution, the solution must not leak out easily from the tissue, so a relatively high molecular weight solution needed to be used. Consequently, sodium alginate with a high molecular weight had the problem of being relatively difficult to discharge through a needle.

[0007] In particular, when administering a local medication for the purpose of forming a mucosal elevation in the performance of EMR or ESD of the upper or lower digestive tract, 23G or 25G endoscopic puncture needles are standardly used, and one of the characteristics required for a composition for submucosal injection is that it can easily pass through these endoscopic puncture needles.

[0008] Prior art literature may include the following patent documents, and the entire contents of the following patent documents are hereby cited and incorporated as prior art in this specification.

[0009] <Prior Art Literature>

[0010] (Patent Document 1) International Patent Publication No. 2015-009035 (January 22, 2015)

[0011] (Patent Document 2) International Patent Publication No. 2016-043547 (March 24, 2016)

[0012] (Patent Document 3) International Patent Publication No. 2013-077357 (May 30, 2013)

[0013] The present invention aims to provide a composition that can replace expensive sodium hyaluronate as a composition for submucosal injection, while maintaining a long-lasting mucosal elevation effect and allowing easy passage through an endoscopic needle when performing EMR or ESD.

[0014] The present invention has been devised to solve the problems of the prior art,

[0015] The present invention provides a medical pharmaceutical composition for injection into the submucosal layer in endoscopic mucosal resection or endoscopic submucosal dissection, comprising a liquid composition containing alginic acid or a pharmaceutically acceptable salt thereof having a weight average molecular weight of 100,000 or more and less than 200,000, and a colloidal polysaccharide.

[0016] In addition, in the present invention, a liquid composition is provided in which the concentration of alginic acid or a pharmaceutically acceptable salt thereof in the composition is 0.05 w / v% or more and 2.0 w / v% or less.

[0017] In addition, the present invention provides a liquid composition characterized in that the colloidal polysaccharide in the composition includes pectin or a pharmaceutically acceptable salt thereof.

[0018] In addition, in the present invention, a liquid composition is provided in which the concentration of the polysaccharide is 0.01 w / v% or more and 2.0 w / v% or less.

[0019] In addition, in the present invention, a liquid composition is provided in which, on a w / v basis, the alginic acid or a pharmaceutically acceptable salt thereof: pectin or a pharmaceutically acceptable salt thereof = 2 to 8:1.

[0020] In addition, in the present invention, the composition provides a liquid composition having a pH of 5.0 to 8.0 or less.

[0021] In addition, in the present invention, the composition provides a liquid composition having a viscosity of 1.0 to 50.0 centipoise (cps) or less.

[0022] The present invention can be usefully used as a submucosal local injection agent with excellent mucosal elevation duration by injection in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).

[0023] Figure 1 shows a sample manufactured by Example 1, a sample manufactured by Example 2, and a sample manufactured by Example 1 with indigo carmine pigment added thereto for confirmation of visibility.

[0024] Figure 2 shows the appearance of the mucosal elevation height on the resection of a pig observed with the naked eye using samples prepared according to Comparative Example 1, Comparative Example 2, Example 1, and Example 2.

[0025] Figure 3 is a graph showing the results of measuring the height of the mucosal elevation above the resection of a pig for 30 minutes after injection using samples prepared according to Comparative Example 1, Comparative Example 2, Example 1, and Example 2.

[0026] Hereinafter, the present invention will be described in detail.

[0027]

[0028] The present invention is a medical pharmaceutical composition for injection into the submucosal layer in endoscopic mucosal resection or endoscopic submucosal dissection, which is a liquid composition containing alginic acid or a pharmaceutically acceptable salt thereof having a weight average molecular weight of 100,000 or more and less than 200,000, and a colloidal polysaccharide.

[0029] Since the above alginic acid mainly constitutes the cell walls of brown algae, it can be obtained by extraction from brown algae. The above alginic acid has been widely used since ancient times due to its unique physical properties, such as gel-forming ability, high viscosity, and film-forming ability.

[0030] For example, it is used as a stabilizer, viscosifier or gelling agent in various industries including the food industry, printing industry and pharmaceutical industry, and as a raw material for drug delivery systems such as microspheres, beads, microcapsules or tablets, and as a matrix carrier in tissue engineering.

[0031] The above alginic acid is used having a weight average molecular weight of less than 100,000 to 200,000. Although high molecular weight alginic acid has better mucosal elevation persistence than low molecular weight alginic acid, it is difficult to apply to endoscopic surgery because high molecular weight tends to have difficulty passing through an endoscopic puncture needle. Therefore, it is preferable to use alginic acid having a molecular weight of less than 200,000 to improve the fluidity of the injection solution and the drainage ability from the puncture needle. Instead, as will be described later, the problem of lower mucosal elevation persistence compared to when using high molecular weight alginic acid can be overcome by additionally including a colloidal polysaccharide (particularly, pectin) in the above alginic acid.

[0032] The above alginic acid is not particularly limited as long as it satisfies the condition of being "suitable for medical use and having a weight average molecular weight of 100,000 to less than 200,000." The pharmaceutically acceptable salt of alginic acid is not particularly limited, but examples thereof include pharmaceutically acceptable salts among alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), salts of inorganic bases (ammonium salt, etc.), and salts of organic bases (propylene glycol salt, etc.). Among these salts, alkali metal salts of alginic acid are preferable, and sodium alginate is particularly preferable.

[0033] Sodium alginate is a white to light yellow fiber, granule, granule, or powder that is almost odorless and tasteless, and is a bio-derived substance. It increases the adhesiveness and viscosity of foods, promotes emulsion stability, and improves the physical properties and texture of foods. It is used as a stabilizer in ice cream, an adhesive in ketchup, mayonnaise, and sauces, a clarifying agent in sake, a gelling agent, an emulsifier, and a thickener. Sodium alginate is a high molecular weight substance and exists in various grades through a refining process. It becomes viscous when dissolved in water, and the pH of a 1% aqueous solution is 6 to 8, which is almost neutral. (NF 24 pages, 2008). Sodium alginate hardens when it comes into contact with NaCl or in low pH conditions. Due to these properties, sodium alginate has been used as a thickener, etc., and has a structure of the following chemical formula 1.

[0034]

[0035] The concentration of alginic acid or its pharmaceutically acceptable salt included in the composition of the present invention can be appropriately selected. If the solution concentration is too high, its viscosity will also increase, making it difficult to pass through an endoscopic needle. Therefore, low concentrations and viscosity are preferred. On the other hand, if the concentration is too low, the desired mucosal lifting ability may not be achieved.

[0036] Therefore, the concentration of alginic acid or a pharmaceutically acceptable salt thereof included in the composition of the present invention is preferably 0.05 w / v% or more and 2.0 w / v% or less, more preferably 0.05 w / v% or more and less than 1.5 w / v%, and even more preferably 0.05 w / v% or more and 1.0 w / v% or less.

[0037] The polysaccharide used in the present invention is a general term for a single molecule composed of a long chain of monosaccharides linked together by glycosidic bonds. These polysaccharides include alginate, pectic substances, guar gum, dextran, xanthan gum, chitosan, chondroitin, hyaluronic acid, heparin, amylase, amylopectin, glycogen, cellulose, chitin, keratan sulfate, peptidoglycan, etc. In a broad sense, alginate is also included, but in the present invention, alginate and hyaluronic acid are defined as being excluded from polysaccharides in the present invention specification.

[0038] The concentration of the polysaccharide included in the composition of the present invention is preferably 0.01 w / v% or more and 2.0 w / v% or less, more preferably 0.01 w / v% or more and less than 1.0 w / v%, and even more preferably 0.01 w / v% or more and 0.5 w / v% or less.

[0039] Preferred examples of the polysaccharide of the present invention include pectin or a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of pectin are not particularly limited, but include, for example, pharmaceutically acceptable salts of alkali metals (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.).

[0040] Pectic substances include protopectin, pectin, pectic acid, and pectinic acid, which are chemically different polysaccharides mainly composed of high molecular weight acidic polysaccharides formed by the polycondensation of D-galacturonic acid in a normal chain shape, and these can be converted into each other. Pectic substances are linked to each other by bonds mediated by phosphoric acid or arabinose or galactose, and help maintain the shape of cell membranes. Therefore, pectin has all of these properties, and in particular, its gel-forming property is applied to making jams and jellies, and its emulsifying property is widely used as an emulsifying agent for foods, a coating agent for dried confectionery, cosmetics, tooth powder, pastry, and medicines (regulatory agents). In addition, in fruits, protopectin is contained in large quantities in the immature stage, and as the fruit ripens, it breaks down and changes from pectic acid to pectic acid, and then to low-molecular polygalacturonic acid, which determines the firmness of the fruit.

[0041] Pectin is thought to be a linear molecule in which D-galacturonic acid is linked by α-1,4 bonds, and its structure is shown in chemical formula 2 below. Some of the carboxyl groups of galacturonic acid are methyl esterified and some are neutralized by bases, and they mainly form the middle layer of the cell wall.

[0042]

[0043] Defining the structure of pectin is difficult because it can change during extraction, storage, and processing from plants. Pectin has a molecular weight between 50,000 and 150,000 daltons.

[0044] Pectins are classified by their degree of esterification.

[0045] In high (methyl) ester, or HM-pectin, a relatively high proportion of carboxyl groups form methyl esters, and the remaining carboxylic acid groups exist as free acids or ammonia, potassium, calcium, or sodium salts. The properties of HM-pectin can vary depending on the degree of esterification and polymerization. Pectin in which less than 50% of the carboxylic acid units appear as methyl esters is usually called low (methyl) ester, or LM-pectin. Low ester pectin is generally obtained by treating high ester pectin under slightly acidic or alkaline conditions.

[0046] Amidated pectin is produced as a high-ester pectin through an alkaline de-esterification process using ammonia. In this type of pectin, some of the remaining carboxylic acid groups are converted to acid amides. The properties of amidated pectin can vary depending on the ratio of ester and amide units and the degree of polymerization. Commercial pectin is usually mixed with sugar for standardization purposes, and some types may also contain buffering salts to adjust pH or tailor desired properties.

[0047] In the above composition, the ratio of alginic acid or a pharmaceutically acceptable salt thereof: pectin or a pharmaceutically acceptable salt thereof may be 2 to 8:1 on a w / v basis. As will be understood through the examples and experimental examples described below, if the pectin content is too low outside the above ratio, the mucosal elevation effect may be insufficient, and conversely, if the pectin content is too high, there may be a concern that the discharge performance through a puncture needle may deteriorate.

[0048] The solvent included in the composition of the present invention is not particularly limited, as long as it is a pharmaceutically acceptable solvent. Examples include water (preferably water for injection) and physiological saline. Furthermore, to adjust the pH of the composition, preferably to a pH of 5.0 to 8.0, a buffer such as a phosphate buffer may be included.

[0049] The composition of the present invention may contain other pharmaceutically active ingredients, stabilizers, emulsifiers, buffers, isotonic agents, preservatives, analgesics, colorants, binders, lubricants, suspending agents, antioxidants, pH regulators, dispersants, solubilizers, dissolving agents, and solubilizing aids, as long as they do not adversely affect the effects of the invention.

[0050] The composition of the present invention may contain a pharmaceutically acceptable pigment, such as indigo carmine, to enhance visibility. Coloring the composition not only makes it easier to clearly see the area injected submucosally, but also makes it easier to clearly see that the composition has been injected into the submucosal layer. This contributes to improved operability and safety in EMR and ESD.

[0051] The composition of the present invention is injected into the lower layer of the mucosa in EMR or ESD. The mucosa is not particularly limited, and examples thereof include digestive mucosa (e.g., oral mucosa, digestive tract mucosa, etc.), respiratory mucosa (e.g., nasal septum mucosa, etc.), and urogenital mucosa (e.g., bladder mucosa, vaginal mucosa, uterine mucosa, etc.), with digestive mucosa being preferred.

[0052] Among digestive mucosa, the digestive tract mucosa is preferred. Examples of digestive tract mucosa include the esophageal mucosa, gastric mucosa, duodenal mucosa, and colonic mucosa.

[0053] The composition of the present invention is a composition for use in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). During surgery, the composition is injected into the submucosal layer of a site where epithelial elevation is desired. When the composition of the present invention is injected into the submucosal layer, the alginic acid or a pharmaceutically acceptable salt thereof described above remains at the injection site, thereby elevating the mucosal portion. To prevent leakage of the composition and ensure injection into the desired site, the injection is preferably performed using a syringe. By injecting the composition and elevating the mucosa around the lesion, medical treatment of the lesion becomes easier, thereby enabling more rapid and reliable removal of the lesion.

[0054] The dosage of the composition of the present invention is appropriately set depending on the size or location of the lesion and is not limited, but when applied to human EMR or ESD, approximately 5 to 60 mL is injected.

[0055] The composition of the present invention may be provided as a packaged injection containing some or all of its components in a syringe, or as a packaged injection that can be diluted and mixed immediately before use. By supplying the composition in this form, immediate injection can be performed during surgery simply by attaching an endoscopic injection needle to the tip of the syringe. If the stability of alginic acid or a pharmaceutically acceptable salt thereof is compromised by an added component, the component may be provided in a formulation that can be mixed on-site immediately before the procedure.

[0056] The liquid composition for endoscopic use of the present invention can be preferably used for resection of mucosal tissues such as the stomach or intestines. That is, the endoscopic puncture needle is injected into the submucosal layer where resection of polyps, cancer, etc. is planned to occur, thereby elevating the site to be resected, and this elevated portion is resected using a snare (a wire-shaped loop) or needle knife.

[0057] Hereinafter, the present invention will be described in more detail with examples.

[0058] It is to be made clear that the following examples are intended only to provide a detailed explanation of the invention and are not intended to limit the scope of the rights.

[0059] Example 1

[0060] Sodium alginate having a weight average molecular weight of approximately 130,000 to 150,000 was prepared as a 0.08 w / v% aqueous solution, and then 0.02 w / v% pectin was added, and an isotonic agent, a buffer or a pH adjuster, and a stabilizer were added. The aqueous solution had a pH of 7.0±0.5, an osmotic pressure of 285.0±15.0 mOsm, and a viscosity of 2.5±0.5 cps. The mixture was stirred until completely dissolved. The composition was filtered through a 0.2 ㎛ filter, placed in a vial capped with a rubber cap and an aluminum ring, and sterilized at 121°C for 20 minutes.

[0061] The sample manufactured by Example 1, the sample manufactured by Example 2, and the sample manufactured by Example 1 with indigo carmine pigment added for confirmation of visibility are shown in Fig. 1.

[0062] Example 2

[0063] Sodium alginate having a weight average molecular weight of approximately 130,000 to 150,000 was prepared as a 0.06 w / v% aqueous solution, and then 0.015 w / v% pectin was added, and an isotonic agent, a buffer or a pH adjuster, and a stabilizer were added. The aqueous solution had a pH of 7.0±0.5, an osmotic pressure of 280.0±10.0 mOsm, and a viscosity of 2.5±0.5 cps. The mixture was stirred until completely dissolved. The composition was filtered through a 0.2 ㎛ filter, placed in a vial capped with a rubber cap and an aluminum ring, and sterilized at 121°C for 20 minutes.

[0064] Comparative Example 1

[0065] 0.4 w / v% sodium hyaluronate solution

[0066] Comparative Example 2

[0067] Normal Saline (NS)

[0068]

[0069] Experimental example

[0070] Mucosal elevation assessment

[0071] The mucosal elevation height above the resection of a pig was visually observed using the samples prepared according to Comparative Example 1, Comparative Example 2, Example 1, and Example 2. The mucosal elevation height was visually observed 5 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes after submucosal injection, as shown in Fig. 2, and the results (average values ​​of measurements repeated three times each) are shown in Table 1 and Fig. 3.

[0072]

[0073] As a result, the mucosal elevation was maintained even 30 minutes after injection.

[0074]

[0075] Endoscopic needle drainage smoothness evaluation

[0076] The above 10 mL of the sample was filled into a 10 mL syringe (jig) holding an endoscopic puncture needle (needle diameter: 23 G), and the piston of the syringe was pressed at a constant speed of 0.2 mm / sec to eject the sample from the tip of the endoscopic puncture needle, and the magnitude of the force (Kgf) applied was measured. The measurement (small tabletop tester: KANA, IM-010) was repeated three times, and the results were averaged and shown in Table 2 below.

[0077]

[0078] The present invention is a composition that maintains a raised state even after 30 minutes, has a discharge power superior to that of a sodium hyaluronate solution, and is as practical as the discharge power of a saline solution, and is thus an optimal composition suitable for EMR or ESD.

Claims

1. A pharmaceutical liquid formulation suitable for submuscular injection for use in laparoscopic or endoscopic removal of large tumors without incisions in the abdomen, for medical applications, comprising alginic acid with an average molecular weight of 100,000 to 150,000 or its pharmaceutically acceptable salts, and a very small polysaccharide in which the alginic acid or its pharmaceutically acceptable salt is present, and pectin or its pharmaceutically acceptable salt.

1. The liquid composition of claim 1 in which alginic acid or its pharmaceutically acceptable salts are present at a concentration of 0.05% (m³ / v) to 2.0% (m³ / v).

2. The liquid composition of claim 1 in which very small polysaccharides are incorporated with pectin or its pharmaceutically acceptable salts.

3. The liquid composition of claim 1 in which polysaccharides are present at a concentration of 0.01% (m³ / v) to 2.0% (m³ / v). 5.Liquid composition according to claim 1 in which the composition has a pH of 5.0 to 8.0; Liquid composition according to claim 1 in which the composition has a viscosity of 1.0 to 50.0 centipoise (cps);