KR20090081083A - Eye drop composition containing alginic acid compound and its manufacturing method - Google Patents

Abstract

The present invention relates to a composition that can be administered to the eye as a therapeutic agent for corneal conjunctival epithelial disorders, and more particularly, to an ophthalmic composition containing an alginate compound which is a hydrophilic natural extracting polymer, and a preparation method thereof.

The present invention can be effectively applied to prevent and treat eye diseases such as corneal and conjunctival epithelial disorders without topical effects of repeated administration of existing anti-inflammatory drugs, using alginate compounds, which are hydrophilic natural extracting polymers, to be effectively applied for topical application. Can be.

Description

Eye drop composition containing alginic acid compound and its manufacturing method {EYE COMPOSITION COMPRISING ALGINIC ACID BASED COMPOUNDS AND METHOD OF PREPARING THE SAME}

The present invention relates to a composition containing a pharmaceutically acceptable alginic acid compound as a pharmacologically active ingredient and which can be administered to the eye as a therapeutic agent for corneal conjunctival epithelial disorders.

The cornea and conjunctiva of the eye tissues are epithelial tissues exposed to the outside and are easily damaged by external factors. The method of healing the damage of local area caused by various external factors is pharmacologically acting on the affected area, and aims to prevent the secondary damage of the tissue by inflammation and to increase the rate of tissue regeneration. The causes of inflammation include pathogenic microbial infections, chemical infiltration of substances causing inflammation, allergies, irritable autoimmune diseases, and physical wounds.

Corneal epithelial damage according to various causes such as corneal epithelial erosion, corneal epithelial disorders, as well as corneal ulcers (eg, ulcers of the corneal stroma) and infectious eye diseases. In addition, the use of soft contact lenses makes it difficult to distribute a sufficient layer of water on the lens surface, which can lead to poor corneal epithelial disorders due to poor spreading of the lipid layer.

Steroidal anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used. Steroidal anti-inflammatory drugs consist of glucocorticoids of saccharides with adrenal cortical hormone action. Nonsteroidal anti-inflammatory drugs mainly refer to drugs with cycloxygenase (COX) inhibitory action and have a mechanism of inhibiting the production of prostaglandin at the site of inflammation. Long-term absorption of the two drug groups can be accompanied by various metabolic side effects such as changes in the blood, immune system, and inflammatory response.These drugs include dexamethasone, fluorometholone, prednisolone, bromfenac, diclofenac, prubiprofen, Ketorolac and the like.

However, long-term ocular administration of steroid drugs as an eyedrop anti-inflammatory agent may cause side effects such as glaucoma, cataracts, and bacterial conjunctivitis, thereby limiting the period of use for eye drops. In addition, prolonged administration of nonsteroidal drugs results in side effects such as epithelial disorders, corneal thickness reduction, infiltration, ulceration, and perforation.

Therefore, there is a need for a study on the development of eye drops that can eliminate the side effects of long-term use of such anti-inflammatory drugs.

An object of the present invention is to treat a conjunctival epithelial disorder, and to develop a drug for the prevention and treatment of epithelial tissue injury through intraocular small trauma, hydrophobic surgery and wearing hard contact lenses, and to develop a single agent or a combination eyedrop composition. It is providing the eyedrop using the alginic acid compound especially, and its manufacturing method.

The present invention is an eye drop composition comprising an alginate compound as an active ingredient, the content of the alginic acid compound is 0.001 to 10% (w / v) based on the total composition, the viscosity of the alginic acid compound is the active substance 1 Provided are an eye drop composition and a method for preparing the same, wherein the composition is 5 to 500 centipoise at 25 ° C. and has a prophylactic or therapeutic effect on corneal conjunctival epithelial disorders.

Hereinafter, the present invention will be described in detail.

In particular, the present invention relates to a method for the development and preparation of a medicament comprising the active substance having a specific molecular weight range for the development of a medicament for wound healing in the eye.

Alginic acid is a macromolecule material extracted from brown algae, which forms a cell wall by reacting with calcium and magnesium salts, and is useful industrially and variously through biological processes and chemical treatments. For example, sodium alginate is used in the food industry, the paper industry, the dye industry and the textile industry. In particular, alginic acid and sodium alginate in the medical field are natural polymers that are harmless to the human body and are used as a component of dental model materials, and they inhibit and release hemostatic agents, radioactive elements and harmful metals using fibrous precipitates produced by competitive reaction with calcium salts. It is utilized in. In the pharmaceutical aspect, it is used as an additive of various drugs by using the thickening and coagulation characteristics of sodium alginate, and shows the possibility of use as a matrix for sustained-release preparations. Alginates and alginic acid esters are known to have excellent solubility and stability in physical and chemical aspects, and are used as gastric mucosal protective effect agents by administering in the gastrointestinal tract with good epithelial adhesion. Its effects are in the treatment and prevention of excessive gastric acid, stomach, duodenal ulcer, acute gastritis, hemostasis, platelet aggregation, and the promotion of fibrin formation.

Alginate compounds used in the present invention is a water-soluble high molecular material such as hyaluronic acid, the advantage of the present invention lies in the safety of the prevention and treatment of eye diseases. In addition, the composition containing the pharmacologically active substance of the present invention is intended for topical use in the occurrence of anterior ocular trauma, and excludes or reduces the side effects that generally occur when a steroidal drug is prescribed for a long period of time and improves the growth effect of cells. You can increase it. In particular, since it can be used for corneal epithelium and has very high tolerability without hypersensitivity, it is particularly important when used as an ophthalmic drug. Application examples of topical active agents of the present invention are generally used for dermatological diseases and general mucosal diseases, especially mucosal diseases of the oral cavity and nasal cavity, oral administration of external vascular diseases, and skin application. It is not limited.

In the path of light transmission to the retina, the cornea, a transparent tissue, plays a major role in the refraction and transmission of light. The growth of corneal cells is differentiated from basal cells to superficial cells, and in normal eyes, it is known that about 1 to 2 weeks have elapsed until the drop of superficial cells. The incidence distribution of anterior segment trauma is mainly targeted to the cornea and eyelids, and its cause can be divided into chemical damage and physical damage, and the physical damage can be divided into external foreign matter and surgical damage. have. The loss of the corneal epithelium is mainly targeted by the surface and wing cell layers. The adjacent epithelial cells slide and cover the epithelial defects and have a mechanism to heal by mitosis of the basal cells. Among these healing mechanisms, the inflammatory response is known to be caused by the infiltration of white blood cells into the injury site through the limbus, and the steroid system is prescribed as a drug that suppresses excessive inflammatory response. Generally, steroid wound healing eye drops are known to reduce inflammatory cell infiltration and prevent the release of proteolytic enzymes for the first 10 days. Necrosis of the corneal stromal layer is known to promote the breakdown of the collagen fibers and to inhibit the damage site repair process. In particular, long-term administration is known to cause glaucoma, cataracts, bacterial conjunctivitis, and the like.

When the alginic acid compound of the present invention is used as an ophthalmic composition containing a pharmacologically active substance (active ingredient) for ophthalmic treatment, tissues in the eye, in particular, are formed by forming a gel having good adhesion at the site of damage to corneal conjunctival epithelial cells. It protects the corneal epithelial layer and induces growth, and promotes fibrin production of the cells, thereby promoting tissue production of the damaged area to help repair the damaged area. In addition, complex eye drops of anti-inflammatory drugs and alginate compounds can increase anti-inflammatory effects and reduce the content of existing anti-inflammatory drugs, which is valuable for reducing side effects of long-term repeated administration of anti-inflammatory drugs.

Therefore, the ophthalmic composition containing the alginic acid compound of the present invention as an active ingredient has a prophylactic or therapeutic effect against corneal conjunctival epithelial disorders. In particular, it is of particular value as a keratoconjunctival epithelial disorder drug that reduces the side effects of long-term use of existing steroid or nonsteroidal drugs.

The alginic acid compounds usable in the present invention are one or more of pharmaceutically acceptable alginic acid, alginic acid salts, alginic acid esters and the like, and preferably sodium alginate, propylene glycol alginic acid and the like can be used.

Alginates and alginic acid esters are cream (white or pale yellowish white) powders, soluble in water, and the hydrated solution is a mucus. The basic structure of the alginate is represented by the following Chemical Formula 1, and β- (1 → 4) -D-mannuronic acid (M unit, 1C conformation) and α- (1 → 4) -L-gluuronic acid (guluronic) acid: G unit, C1 conformation) consists of linear copolymers in which monomers are linked in a proportion to the glycosidic bonds. Alginate and alginate esters are generally used at a molecular weight of about 25,000 to 1,000,000, and the ratio of guluronic acid (G unit) to mannuronic acid (M unit) is 20:80 to 80:20. Range.

[Formula 1]

Alginate, commonly called alginate, becomes a water-soluble polymer when the monovalent cations are bonded and dissolved in water. The overall structure of alginate is a linear copolymer in which two monomers are bonded in a proportion. The reaction of divalent cations with alginates causes a change in the geometry of the molecules of the polymer. In particular, the portion containing the G unit than the portion connected only to the M unit is present in the form of a bent chain, when the fibers of the bent chain form, it has a diamond-shaped structure called an egg box (Egg box). Such reactions occur in proportion to the concentration of divalent cations and are known to form temporarily or permanently. The presence of low concentrations of divalent ions in solution results in liquids with high viscosity or thixotropy, and high concentrations of divalent ions cause gelation. Depending on the object to be extracted and the method of acquisition, G units are present in the polymer in different proportions, depending on the proportion of divalent cations, reactivity, and gel strength. When G unit is present at a high ratio, it forms a hard gel, so that the patient may feel a foreign body when instilled, which is an important factor in the commercial value of the ophthalmic composition.

Alginate and alginic acid ester or alginic acid used in the present invention is a high-purity raw material with sufficient removal of pyrogenic substances, proteins and nucleic acids, and also meets US Pharmacopeia and European Pharmacopoeia standards and is esterified with sodium salts. . The raw material is a white or pale yellow powder, and it is preferable to use a low molecular weight alginate or alginic acid ester in consideration of eye drops of the patient. In particular, the alginic acid compound of the present invention has an average molecular weight of 25,000 to 1,000,000, more preferably 30,000 to 50,000.

In addition, considering the divalent cations present in the eye, the ratio of G: M units of alginate and alginic acid esters used in the present invention is preferably in the range of 20:80 to 50:50, more preferably 20: One in the range of 80 to 35:65 can be used.

In the ophthalmic composition of the present invention, the viscosity is set according to the kind of pharmacologically active substance, the concentration in the drug, the concentration of the electrolyte in the eye, and the use thereof. Relative medium / high concentrations of drugs are ideal for wound healing by eye surgery or foreign bodies and for reducing foreign material inflammation or irritable immune responses.

Therefore, the viscosity of the drug as a therapeutic agent for keratoconjunctival epithelial disorder is 0.5 to 50 centistokes, more preferably 1 to 35 centistokes. In setting such a viscosity, the viscosity of a composition consisting of an alginic acid compound used in the present invention, a complex composition of an alginate compound and an anti-inflammatory drug, or a composition in which another thickener (polymer) is mixed with the alginic acid compound should be considered. Based on these criteria, the concentration of the pharmacologically active substance and the concentration of the thickener (polymer) are determined.

The viscosity of the alginic acid compound of the present invention is preferably 5 to 500 centipoise at 25 ° C., more preferably 10 to 400 centipoise, based on 1% of the active substance. In the present invention, the content as a therapeutic agent for keratoconjunctival epithelial disorder is 0.001 to 10% (w / v) based on the total composition, preferably 0.3 to 5% (w / v).

As described above, the alginic acid compound of the present invention reacts with a divalent cation to form a hard gel, which forms a hard gel depending on the concentration of the divalent cation in the electrolyte ions in the tear layer. In some cases, the patient may feel a foreign body feeling.

In order to solve this problem, the formulation of different types of polymers is mixed to form a lattice structure between the alginate polymers, thereby forming a relatively soft gel during drug administration. This improves the feeling of foreign matter through the polymer compound that the patient feels, and can also increase the same or different drug efficacy by the polymer.

In the present invention, the polymer material that can be used together with the alginic acid compound includes celluloses (β-1,4-glucan), chitins (β-1,4-N-acetylglucosamine), and xylenes (β-1). Fibrous sugar polymers such as, 3-xsilane), agars, carrageenans, chondroitins, dermatans, kertans, and glycuronans One or more types of reticular sugar polymers, such as (Glycuronans), are mentioned.

Preferably, the polymer material is selected from the group consisting of hyaluronic acid, sodium hyaluronate, hydroxypropylmethylcellulose, gellan gum, dextran, xanthan gum, povidone, polyvinyl alcohol, sodium carboxymethylcellulose, and sodium chondroitin. More than one species can be used.

More preferably, at least one of hyaluronic acid or sodium hyaluronate having an average molecular weight of 400,000 to 1,500,000 or hydroxypropylmethylcellulose having an average molecular weight of 10,000 to 500,000 may be used as the polymer material.

In consideration of the gelling phenomenon of the alginic acid compound of the present invention, the content ratio of the alginic acid compound and the polymer may be used in a weight ratio of about 1: 0.001 to 1:20, preferably about 1: 0.01 to 1:10.

Therefore, the content of the polymer material may be 0.001 to 20% (w / v), preferably 0.01 to 10% (w / v) based on the total composition.

In the present invention, in the case of the composite formulation further comprising an alginate compound and a polymer material such as sodium hyaluronate or hydroxymethyl cellulose, a gel is formed in a lattice shape having a cavity, and thus softer than an ophthalmic composition comprising only the alginate compound which is a fibrous substance. It is more preferable because it can give eye drops.

In addition, the eye drop composition of the present invention may further include one or more selected from the group consisting of anti-inflammatory drugs and steroidal or nonsteroidal anti-inflammatory drugs.

As the anti-inflammatory drug in the present invention, dexamethasone, fluorometholone, prednisolone, bromfenac, diclofenac, prubipropene, ketorolac, salts thereof, and the like can be used. Preferably, the anti-inflammatory drug is dexamethasone 0.01 to 2.0% (w / v), fluorometholone 0.01 to 2.0% (w / v), prednisolone 0.01 to 5.0% (w / v), bromfenac 0.001 to 1.0% (w / v), diclofenac 0.05-1.0% (w / v), frubiprofen 0.005-0.5% (w / v), ketorolac 0.005-1.0% (w / v), and salts thereof At least one selected from, and more preferably fluorometholone and diclofenac can be used.

In general, steroidal compounds are topical steroids, such as corticosteroids, are commonly used to treat anti-inflammatory inflammation of the eye, in particular to treat inflammatory conditions in the eyelids or ocular conjunctiva, cornea and anterior of the eye. Nonsteroidal anti-inflammatory eye drops have been used for the prevention of postoperative inflammatory symptoms and intraoperative / surgical complications during cataract surgery due to their potent prostaglandin biosynthesis. Numerous complications are associated with long-term administration of steroid drugs, including subepithelial cataract formation, increased intraocular pressure, secondary eye infection, delayed corneal wound healing, uveitis, dysphagia, temporary eye discomfort and sewage. In the ocular administration of nonsteroidal anti-inflammatory drugs, most anti-inflammatory drugs have irritation of the mucous membranes and eyes, accompanied by strong eye pain and even metabolic disorders.

The ophthalmic composition added by lowering the commercial concentration of the steroidal or nonsteroidal compound to the alginic acid compound and the alginic acid compound and the available high molecular compound of the present invention can further reduce or eliminate the serious side effects described above, and thus has further technical value.

Meanwhile, the eye drop composition of the present invention may further include one or more adjuvants selected from the group consisting of preservatives, isotonic agents, stabilizers, buffers and pH adjusting agents. The auxiliary agents are those conventionally used in the art to which the present invention pertains, and are not particularly limited because they vary depending on the respective purposes, and follow the general pH, osmotic pressure and viscosity ranges of the ophthalmic composition.

However, in consideration of the effect on the active ingredients, it is preferable to add in an amount of 0.001 to 20% (w / v) based on the total composition, preferably in an amount of 0.01 to 10% (w / v).

Alginate compounds, particularly sodium alginate, as the pharmacologically active substance in the present invention are affected by other auxiliary ingredients such as preservatives, isotonic agents, stabilizers, etc., since the pH is between 6.4 and 8.0 when fully hydrated. Accordingly, the pH of the composition may be adjusted to between 5.0 and 8.0, more preferably between 6.0 and 7.0, by the use of pH adjusting agents such as hydrochloric acid, sodium hydroxide, and buffers in a range that minimizes the effects of the main components over time.

In addition, tears are the same as the osmotic pressure of 0.9% (w / v) sodium chloride solution corresponding to physiological saline, including high molecular weight, glycoproteins, minerals (vitamine, etc.) and inorganic salts. The ophthalmic composition of the present invention is preferably adjusted to about 290 mOsmol / kg osmotic pressure of physiological saline when administered to the eye, the range is 270 to 310 mOsmol / kg. The osmotic pressure-controlling material of the sodium alginate and alginic acid ester composition used in the present invention is at least one selected from the group consisting of D-sorbitol, glycerin, concentrated glycerin, mannitol and maltitol syrup and ionic substances, and the composition ratio thereof is used in one volume isotonic agent. The weight ratio is about 0.5 to 20%, preferably 1 to 10%.

In particular, sodium etetate (0.05 to 0.2% (w / v)) and ε-aminocaproic acid (0.01 to 0.05% (w / v)), anhydrous as stabilizers added to form natural polymers into aqueous eye drops At least one selected from the group consisting of sodium sulfate (0.01 to 0.2% (w / v)), ascorbic acid (0.02 to 0.5% (w / v)), citric acid (0.3 to 2.0% (w / v)), etc. Can be.

In the present invention, as a preservative, benzalkonium chloride 0.002 to 0.1% (w / v), cerimide 0.002 to 0.01% (w / v), chimerosal 0.001 to 0.01% (w / v), chlorobutanol 0.25 to 0.5% (w / v), polyhexamethylene biguanide 0.002 to 0.1% (w / v), paraoxybenzoic acid alkyl methyl, paraoxybenzoic acid ethyl, paraoxybenzoic acid propyl or paraoxybenzoic acid butyl 0.001 to 0.05% (w / v), At least one selected from the group consisting of dihydroacetic acid 0.001 to 0.1% (w / v), chlorocresol 0.0001 to 0.05% (w / v), and chlorohexidine 0.001 to 0.01% (w / v) can be used. have.

The present invention also relates to alginic acid compounds, cellulose (β-1,4-glucan), chitin (β-1,4-N-acetylglucosamine), and xylan (β-1,3-xsilane). ), Agars, Carrageenans, Chondroitins, Chondroitins, Dermatans, Kertans, and Glycuronans. Mixing the polymer material in a mixing ratio of 1: 0.05 to 1: 20 based on the weight ratio, wherein the content of the alginic acid compound in the mixture obtained is 0.001 to 10% (w / v); It provides a method for producing an eye drop composition having a kinematic viscosity of 0.5 to 50 centipoise.

The preparation method of the present invention also includes preparing a solution of an alginic acid compound, preparing a solution of a polymer material having dry eye treatment activity or eye drop healing activity, and mixing the two solutions. Can be configured. In the production method of the present invention may include a step of filtering after the mixing step.

In particular, the ophthalmic composition of the present invention is subjected to a sterilization process using a 0.2 ㎛ filter paper filter (Sartorious, Cellulose Acetate membrane filter, φ = 1.2 ㎛), by applying a cartridge filter applied to the actual product in terms of formulation technology of the composition Can be aseptic.

The present invention provides an ophthalmic composition comprising an alginate compound which is a pharmaceutically acceptable natural polymer material, thereby preparing a viscoelastic natural polymer drug having excellent healing effect on small wounds, minor surgery, and wounds caused by chemical damage. can do.

Preferred examples are provided to aid the understanding of the present invention, but the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited to the following examples.

Example  1-8: Sodium alginate  Preparation of eye drops containing composition

As shown in Table 1 below, a composition for eye drops containing sodium alginate was prepared according to the following preparation method.

In Example 1, 0.01 g of benzalkonium chloride and 0.1 g of sodium etate were completely dissolved in 90 mL of sterile purified water, and 0.1 g of sodium alginate was added to fully hydrate. 0.6 g of sodium dihydrogen phosphate and 0.06 g of sodium dihydrogen phosphate were administered to adjust pH and osmotic pressure. Then, 100 mL of sterile purified water and filtered aseptically with a 0.2 ㎛ filter.

Sodium alginate of Table 1 is a compound consisting of 30:70 ratio of guluronic acid (guluronic acid) and mannuronic acid (mannuronic acid), a white or pale yellow powder. The active substance had a viscosity of about 20 to 150 centipoise when preparing a 1% solution in consideration of eye drops of a patient, and a low molecular weight alginate having a molecular weight of 30,000 to 80,000 was used. The pharmacologically active substance of the present invention is a raw material of high purity in which exothermic substances, proteins and nucleic acids are sufficiently removed, and is a raw material that meets the US Pharmacopeia and European Pharmacopoeia standards, and sodium has a salt structure.

In addition, each of the eye drop compositions prepared in Examples 1 to 8 by measuring a time required for a certain volume flows down the capillary viscometer (Cannon-Fenske Routine viscometer ^ⓡ ) at 30 ℃ conditions to calculate the kinematic viscosity, each pH And osmotic pressure is measured and shown in Table 1 below.

Ingredient Name Content of each component in 100 mL total composition Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 chief ingredient Sodium alginate 0.1g 0.05g 0.2 g 0.3 g 0.4g 0.5g 0.5g 1.0 g Preservative Benzalkonium chloride 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g Stabilizer Sodium Ethate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g pH regulator Sodium hydrogen phosphate 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g Sodium Dihydrogen Phosphate 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g solvent Sterilized Purified Water Quantity Quantity Quantity Quantity Quantity Quantity Quantity Quantity pH 6.5 6.6 6.5 6.6 6.5 6.5 5.6 6.7 Osmotic pressure (mOsmol / kg) 288 289 289 288 290 290 290 288 Viscosity (cst) 2.1 1.4 3.6 5.15 7.35 10.4 9.1 23.6

Example  9-11: Preparation of the eye drop composition using alginic acid esters

To the composition of Table 2 was prepared according to the following eye preparation composition. In 90 mL of sterile purified water, 0.01 g of benzalkonium chloride and 0.1 g of sodium ethate are completely dissolved in this order, and 0.1 g of propylene glycol alginic acid, which is an alginate ester, is sufficiently hydrated. 0.6 g of sodium dihydrogen phosphate and 0.06 g of sodium dihydrogen phosphate were administered to adjust pH and osmotic pressure. Then, 100 mL with sterile purified water and sterile filtered with a 0.2 ㎛ filter.

In addition, the kinematic viscosity was calculated in the same manner as in Example 1, and the respective pH and osmotic pressure were measured and shown in Table 2 below.

Ingredient Name Content of each component in 100 mL total composition Example 9 Example 10 Example 11 chief ingredient Propylene Glycol Alginate 0.1g 0.05g 0.2 g Preservative Benzalkonium chloride 0.01 g 0.01 g 0.01 g Stabilizer Sodium Ethate 0.1g 0.1g 0.1g pH regulator Sodium hydrogen phosphate 0.6g 0.6g 0.6g Sodium Dihydrogen Phosphate 0.06 g 0.06 g 0.06 g solvent Sterilized Purified Water Quantity Quantity Quantity pH 6.7 6.5 6.3 Osmotic pressure (mOsmol / kg) 284 290 294 Viscosity (cst) 1.5 2.5 6.2

Example  12-17: With sodium alginate Sodium hyaluronate  Preparation of eye drops containing composition

To the composition as shown in Table 3 below, an eye drop composition including sodium alginate and sodium hyaluronate was prepared according to the following preparation method.

In Example 12, 0.01 g of benzalkonium chloride and 0.1 g of sodium etate were completely dissolved in 70 mL of sterile purified water, and 0.1 g of sodium alginate was added to fully hydrate. Separately, 0.02 g of sodium hyaluronate was completely dissolved in 20 mL of sterile purified water, and the mixture was added to the solution containing sodium alginate prepared in the first step and mixed well. pH and osmotic pressure were adjusted. Then, 100 mL with sterile purified water and aseptically filtered with a 0.2 ㎛ filter.

The sodium alginate of Table 3 below was the same as that used in Example 1, and the sodium hyaluronate of Table 3 below used a molecular weight of 500,000 to 1,000,000. In addition, the kinematic viscosity was measured in the same manner as in Example 1, and the respective pH and osmotic pressure were measured and shown in Table 3 below.

Ingredient Name Content of each component in 100 mL total composition Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 chief ingredient Sodium alginate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g Subcomponent Sodium hyaluronate 0.02 g 0.01 g 0.005g 0.04g 0.07g 0.1g Preservative Benzalkonium chloride 0.005g 0.005g 0.005g 0.005g 0.005g 0.005g Stabilizer Sodium Ethate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g pH regulator Sodium hydrogen phosphate 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g Sodium Dihydrogen Phosphate 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g solvent Sterilized Purified Water Quantity Quantity Quantity Quantity Quantity Quantity pH 6.6 6.5 6.7 6.5 6.5 6.6 Osmotic pressure (mOsmol / kg) 288 290 287 288 289 288 Viscosity (cst) 2.9 2.4 2.2 4.6 8.9 17.3

Example  18-24: With sodium alginate  Preparation of Eye Drop Composition Containing Hydroxypropylmethylcellulose

To the composition as shown in Table 4, using a hydroxypropylmethylcellulose 2910 having a molecular weight of 20,000 to 80,000 instead of sodium hyaluronate 2910 was completely dissolved by heating to 70 ~ 80 ℃ and then quenched in the solution prepared in the first step Except for the addition, eye drop compositions containing sodium alginate and hydroxypropylmethylcellulose were prepared in the same manner as described in Example 12.

In addition, the kinematic viscosity was measured in the same manner as in Example 1, and the respective pH and osmotic pressure were measured and shown in Table 4 below.

Ingredient Name Content of each component in 100 mL total composition Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 chief ingredient Sodium alginate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g Subcomponent Hydroxypropyl methylcellulose 2910 0.2 g 0.01 g 0.05g 0.1g 0.4g 0.8 g 1.0 g Preservative Benzalkonium chloride 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g Stabilizer Sodium Ethate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g pH regulator Sodium hydrogen phosphate 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g Sodium Dihydrogen Phosphate 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g solvent Sterilized Purified Water Quantity Quantity Quantity Quantity Quantity Quantity Quantity pH 6.5 6.6 6.5 6.4 6.5 6.6 6.7 Osmotic pressure (mOsmol / kg) 286 288 290 288 288 290 286 Viscosity (cst) 2.5 1.9 2.1 2.2 3.0 3.7 3.8

Example  25 ~ 31: containing various polymers Sodium alginate  Complex Eye Drop Composition

An ophthalmic composition was prepared according to the method described in Examples 12 and 18 by changing the type of polymer instead of sodium hyaluronate. The polymer type, other components and contents used are as described in Table 5 below.

In addition, the kinematic viscosity was measured in the same manner as in Example 1, and the respective pH and osmotic pressure were measured and shown in Table 5 below.

Ingredient Name Content of each component in 100 mL total composition Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 chief ingredient Sodium alginate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g Subcomponent Gellan gum 0.1g - - - - - - Dextran 70 - 0.1g - - - - - Xanthan Gum - - 0.1g - - - - PovidoneK-25 - - - 0.1g - - - Polyvinyl alcohol - - - - 0.1g - - Carboxymethyl Cellulose Sodium - - - - - 0.1g - Chondroitin Sodium - - - - - - 0.1g Preservative Benzalkonium chloride 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g 0.01 g Chimerosal - - - - - - 0.003g Stabilizer Sodium Ethate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g pH regulator Sodium hydrogen phosphate 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g Sodium Dihydrogen Phosphate 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g solvent Sterilized Purified Water Quantity Quantity Quantity Quantity Quantity Quantity Quantity pH 6.5 6.7 6.6 6.7 6.6 5.2 6.7 Osmotic pressure (mOsmol / kg) 285 287 290 290 288 283 290 Viscosity (cst) 3.0 2.1 4.1 2.1 2.1 3.6 2.1

Example  32-40: containing various supplements Sodium alginate  Complex Eye Drop Composition

According to the method described in Example 1, an ophthalmic composition further comprising an adjuvant with a composition as shown in Table 6 was prepared, the kinematic viscosity was measured, and the respective pH and osmotic pressure were measured. .

Ingredient Name Content of each component in 100 mL total composition Example 32 Example 33 Example 34 Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 chief ingredient Sodium alginate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.3 g 0.5g Osmotic pressure regulator Sorbitol - - - 6.5g 6.5g 6.5g 6.5g 6.5g 6.5g Concentrated glycerin 25 g - - - - - - - - Mannitol - 50 g - - - - - - - Maltitol syrup - - 90 g - - - - - - Preservative Benzalkonium chloride 0.01 g 0.01 g 0.01 g - - 0.01 g 0.01 g 0.01 g 0.01 g Polyhexamethylene Biguanide - - - 0.0005g - - - - - Chlorobutanol - - - - 0.3 g - - - - Stabilizer Sodium etate 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g ε-aminocaproic acid - - - - - 0.05g - - - pH regulator Sodium hydrogen phosphate 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g 0.6g Sodium Dihydrogen Phosphate 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g 0.06 g solvent Sterilized Purified Water Quantity Quantity Quantity Quantity Quantity Quantity Quantity Quantity Quantity pH 6.5 6.6 6.7 6.5 6.7 6.6 6.5 6.4 6.5 Osmotic pressure (mOsmol / kg) 289 289 290 288 287 289 289 290 288

Example  41-46: Anti-inflammatory  Drug-containing Sodium alginate suspension  Eye Drop Composition

According to the method described in Example 1 above, various anti-inflammatory properties with a composition as shown in Table 7 below A drug-added sodium alginate suspension ophthalmic composition was prepared.

The types, other components, and contents of the anti-inflammatory drugs used are as shown in Table 6 below, and the following anti-inflammatory drugs were used raw materials that meet the US Pharmacopoeia and European Pharmacopoeia standards.

Ingredient Name Content of each component in 100 mL total composition Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 chief ingredient Sodium alginate 0.05g 0.05g 0.1g 0.05g 0.05g 0.1g Fluorometholone 0.02 g - - - - - Dexamethasone - 0.05g - - - - Predinisolone Acetate - - 0.1g - - - Brompenac - - - 0.05g - - Diclofenac - - - - 0.05g - Pruviprofen - - - - - 0.015 Preservative Benzalkonium chloride 0.005g 0.01 g 0.004g 0.005g - - Chlorobutanol - - - - 0.5g Timerosal - - - - - 0.005g Stabilizer Sodium Ethate 0.01 g 0.01 g 0.01 g 0.02 g 0.05g 0.01 g Dissolution aids Polysorbate 80 0.005g - 0.01 g 0.1g - - Tyroxapol - 0.05g - - - - Caster oil - - - - 5 g - pH regulator Boric acid - - - Quantity Quantity - borax - - - Quantity - - Hydrochloric acid - Quantity - - - Quantity Sodium hydroxide - Quantity - - - Quantity Sodium hydrogen phosphate Quantity - Quantity - - - Sodium Dihydrogen Phosphate Quantity - Quantity - - - solvent Sterilized Purified Water Quantity Quantity Quantity Quantity Quantity Quantity

Experimental Example  1: Effect of Wound Healing on Corneal Epithelial Cell Disorder

Nine males of 2.3-3.0 kg of New Zealand white rabbits, healthy and without eye diseases and abnormalities, were selected as experimental animals. The rabbits used for the experiments were bred in the kennel and used dry feed for water and rabbits, and were managed in accordance with the Regulation on the Use of Experiment Animals and Breeding Management (Regulation No. 116 of the Korean Food and Drug Administration).

As an experimental group applied to rabbits, Example 4 (0.3% sodium alginate), Example 12 (0.1% sodium alginate and 0.02% sodium hyaluronate), Example 18 (0.1% sodium alginate and 0.2% hydroxypropylmethylcellulose) And an eye drop composition prepared according to Example 41 (0.05% sodium alginate and 0.02% fluorometholone), and a fluorometholone 0.1% suspension composition was used as a control. In addition, a group treated with saline (0.9% NaCl) was set as the experimental group. The experimental group was set up to measure the natural healing ability of the cornea and did not receive any other drug ('Effect of Topical Na-Hyaluronan on Hemidesmosome Formation in n-Heptanol-Induced Corneal Injury', JH Chung, et al., (1998) Ophthalmic Res . 30, 96-100).

As a specific experimental method, in a breeding environment set at a constant temperature (23 ± ° C.) and humidity (50 ± 0%), localized anesthesia with 0.4% benosinate hydrochloric acid was applied to purified New Zealand white rabbits for 2 weeks. A round filter paper (5.5 mm diameter) sufficiently wetted with n-heptanol was contacted with the central portion of the cornea for 2 minutes to remove the corneal epithelium, causing damage. After washing with 2 mL of saline for 2 minutes, the compositions of the experimental, control and experimental groups were instilled 5 minutes after the induction of corneal injury, and then three times daily (50 μl / once). One day after the injury, the eyes were stained with 1% Rose Bengal stain solution once a day, and then washed with 0.9% sterile saline solution, and the area of the corneal epithelial damage was measured by photographing. Observed daily.

As described above, the method using 0.4% hydrobenzoic acid as the local anesthetic agent is applied directly to the mucous membrane or skin so that only the surface is anesthetized, and the sensory disappears from 0.5 to 3 minutes after application of the local anesthetic and lasts up to 30 to 60 minutes. Known. Application of local anesthetics is characterized by facilitating the diagnosis of the eye by inducing tissue contraction from vasoconstriction.

As a result of observation of corneal epithelial damage through photography, the corneal damage ratio is calculated as the ratio of the area value of the stained portion with the dye solution and the total area of the pupil, and the recovery power is expressed as a relative value of the damage area ratio on the day of observation. It is shown in Table 8 below. In addition, the measurement results for the blank test and the experimental group 1 is shown graphically in Figure 1, the measurement results for the blank test, Experimental group 2 and the control is shown in Figure 2, and the actual observation picture is shown in Figures 3a to 3g.

Damage area ratio (%) 1 day 2 days 3 days 4 days 5 days 6 days 7 days 8th Blank test Saline (0.9% NaCl) 100.0 73.8 63.5 59.8 45.8 21.4 9.0 0.0 Experimental Group 1 Example 4 100.0 61.0 34.1 14.6 9.8 4.9 0.0 - Example 12 100.0 77.0 39.3 14.4 2.0 0.0 - - Example 18 100.0 74.6 39.8 18.6 3.9 0.0 - - Experimental Group 2 Example 41 100.0 59.3 40.0 6.2 0.0 - - - Control Fluorometholone0.1% 100.0 70.0 47.5 42.5 42.5 27.5 25.0 15.0

*

As can be seen from Table 8, FIGS. 1, 2, and 3A to 3G, immediately after the ocular angle and conjunctival injury caused by n-heptanol, a similar degree of damage was obtained in all groups of all groups. Subsequently, it was observed that the area of the damaged part was reduced by treating the compositions of the blank, experimental and control groups, respectively.

As the experimental group, the wound healing effect of the eye drop compositions prepared according to Examples 4, 9, 15 and 41 of the present invention was observed to be superior to the fluorometholone composition of the blank test group and the control group. In particular, more than three days, four days or more, the wound healing effect was confirmed to continue with excellent performance. In the case of the control group, fluorometholone was shown to have a lower healing effect than the blank test group due to the long-term administration, which may be presumed to be a problem due to side effects of changes in the immune system following long-term administration.

Therefore, all of the eye drop compositions of the present invention prepared according to Examples 4, 9, 15, and 41 were able to confirm that the excellent therapeutic performance of eye diseases without exertion of side effects even during long-term dosing. In particular, as in Examples 12 and 18, when using a suitable polymer (sodium hyaluronate, hydroxymethyl cellulose, etc.) in combination with the composition using only sodium alginate, lattice-like smooth gel structure even if the concentration of sodium alginate is low As the biocompatibility is increased by forming, it can be seen that an excellent synergistic effect is shown with respect to the therapeutic effect.

The ophthalmic composition of the present invention is safe for the prevention and treatment of eye diseases, in particular, can be used locally in the occurrence of anterior ocular trauma, and may be used initially for the purpose of treatment by using a steroidal or nonsteroidal drug in combination. In addition, by using an anti-inflammatory drug in addition to the eye drop composition of the present invention, it is possible to exclude or reduce the side effects caused by long-term prescription of the anti-inflammatory drug in the existing, it is possible to increase the growth effect of the cells Therefore, it can be said that the industrial applicability is very large.

1 is a graph showing the damage area ratio over time after the induction of corneal epithelial damage for the blank test and experimental group 1 in Experimental Example 1 of the present invention.

Figure 2 is a graph showing the damage area ratio over time after the induction of corneal epithelial damage for the blank test, control group, and experimental group 2 in Experimental Example 1 of the present invention.

Figure 3a to 3g is a photograph showing a change in the damage portion over time after inducing corneal epithelial damage in Experimental Example 1 of the present invention.

Claims (15)

As an eye drop composition containing an alginic acid compound as an active ingredient, The content of the alginic acid compound is 0.001 to 10% (w / v) based on the total composition, the viscosity of the alginic acid compound is 5 to 500 centipoise at 25 ℃ based on 1% of the active substance, An eye drop composition having a prophylactic or therapeutic effect on an epithelial disorder. The eye drop composition according to claim 1, wherein the alginic acid compound is at least one selected from the group consisting of alginic acid, alginate, and alginic acid esters. The eye drop composition according to claim 1, wherein the average molecular weight of the alginic acid compound is 25,000 to 1,000,000. The eye drop composition according to claim 1, wherein a ratio of mannuronic acid and gluuronic acid, which are the binding units of the alginic acid compound, is 80:20 to 50:50. According to claim 1, Cellulose (β-1,4-glucan), chitin (β-1,4-N-acetylglucosamine), xylan (β-1,3-xsilane), agar Add at least one polymer material selected from the group consisting of Agars, Carrageenans, Chondroitins, Dermatans, Kertans, and Glycuronans. Eyedrop composition comprising a. The method of claim 5, wherein the polymer material is selected from the group consisting of hyaluronic acid, sodium hyaluronate, hydroxypropylmethylcellulose, gellan gum, dextran, xanthan gum, povidone, polyvinyl alcohol, sodium carboxymethylcellulose, and sodium chondroitin. Eyedrop composition which is 1 or more types. The eye drop composition according to claim 6, wherein the polymer material is at least one selected from the group consisting of hyaluronic acid and sodium hyaluronate having an average molecular weight of 400,000 to 1,500,000. The eye drop composition according to claim 6, wherein the polymer material is at least one hydroxypropylmethylcellulose having an average molecular weight of 10,000 to 100,000. The eye drop composition according to claim 6, wherein the content of the polymer material is 0.01 to 10% (w / v) based on the total composition. The eye drop composition according to claim 1, further comprising at least one selected from the group consisting of anti-inflammatory drugs and steroidal or nonsteroidal anti-inflammatory drugs. 11. The method according to claim 10, wherein the anti-inflammatory drug is dexamethasone 0.01 to 2.0% (w / v), fluorometholone 0.01 to 2.0% (w / v), prednisolone 0.01 to 5.0% (w / v), bromfenac 0.001 to 1.0% (w / v), diclofenac 0.05-1.0% (w / v), frubiprofen 0.005-0.5% (w / v), ketorolac 0.005-1.0% (w / v), and salts thereof Eye drop composition is one or more selected from the group consisting of. 12. The method according to any one of claims 1 to 11, wherein the preservative, tonicity agent, stabilizer, antioxidant, and pH adjusting agent is selected from 0.002 to 5.0% (w / The composition for eye drop further comprising in the content of v). The method of claim 12, wherein the preservative is benzalkonium chloride 0.002 to 0.1% (w / v), cetridide 0.002 to 0.01% (w / v), chimerosal 0.001 to 0.01% (w / v), chlorobutanol 0.25 to 0.5% (w / v), polyhexamethylene biguanide 0.002 to 0.1% (w / v), paoxybenzoic acid methyl, paoxybenzoic acid ethyl, paoxybenzoic acid propyl or butyl paoxybenzoic acid 0.0001 to 0.05% (w / v) v), dihydroacetic acid 0.0001 to 0.1% (w / v), chlorocresol 0.0001 to 0.05% (w / v), and chlorohexidine 0.001 to 0.01% (w / v) Eye drop composition. Alginate compounds, celluloses (β-1,4-glucans), chitin (β-1,4-N-acetylglucosamine), xylans (β-1,3-xsilanes), and agars (Agars), Carrageenans, Chondroitin (Chondroitins), Dermatans, Kertans, and glycuronans (Glycuronans) at least one selected from the group consisting of Mixing based on a mixing ratio of 1: 0.05 to 1:20 on the basis of The content of the alginic acid compound in the mixture obtained above is 0.001 to 10% (w / v), the kinematic viscosity of the mixture obtained above is 0.5 to 50 centistokes, and has a prophylactic or therapeutic effect on keratoconjunctival epithelial disorders. Method for producing an ophthalmic composition. The method of claim 14, Preparing an alginate compound solution, Preparing a solution of the active polymeric material for treating eye drops, Mixing the two solutions, and Mixing the anti-inflammatory drug with the alginic acid compound solution or another active high molecular substance and alginic acid compound mixture A method for producing an ophthalmic composition having a prophylactic or therapeutic effect on a conjunctival epithelial disorder comprising a.

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