HK40005358A - Eye-drop composition for lowering intraocular pressure - Google Patents

Description

Ophthalmic composition for reducing intraocular pressure

Technical Field

The present invention relates to ophthalmic compositions comprising latanoprost (latanoprost), polyoxyethylene 40 hydrogenated castor oil, and sorbitol.

Background

Glaucoma is one of the leading causes of blindness worldwide, with cataracts and diabetic retinopathy, and is approximately 2% of the population of the mouth, such that glaucoma is considered to be one of the most common ophthalmic diseases. Glaucoma is characterized by damage to the optic nerve with loss of retinal ganglion cells. Glaucoma presents with elevated intraocular pressure, not only the most important symptom, but the only treatable symptom, among several risk factors.

Adalimumab (Xalatan) using latanoprost as an active ingredient is a representative therapeutic agent for glaucoma, which shows an intraocular pressure-lowering effect, and it is the first prostaglandin analog (PGA) -based Drug, approved by the Food and Drug Administration (FDA) in 1996. In prostaglandin based products, prida contains the highest concentration of benzalkonium chloride (BAK, 0.02% w/v) which is not only used for the purpose of obtaining preservative effect, but also for the purpose of dissolving and stabilizing latanoprost.

However, preservatives such as benzalkonium chloride have been reported to be toxic to corneal epithelial cells and to retard epithelial cell regeneration (J Korea Ophthalmol Soc 2010; 51(8): 1113-. Therefore, in order to avoid the side effect of using eye drops, it is preferable to reduce the concentration of a preservative (such as benzalkonium chloride) as much as possible. Since glaucoma drugs need to be administered for a long period of time, there is a need to develop a therapeutic agent for lowering intraocular pressure, which does not contain a preservative such as benzalkonium chloride.

Furthermore, the entitlements should be stored protected from light and stored under refrigerated conditions of 2 ° to 8 ℃, since the entitlements are not stable at room temperature despite the use of benzalkonium chloride. Therefore, storage conditions for easy access are not convenient for glaucoma patients who need long-term administration. Therefore, there is a need to develop a stable latanoprost ophthalmic solution that is sufficient for storage at room temperature.

Formulations using latanoprost as an active ingredient have disadvantages in that the storage stability of such formulations at room temperature is reduced, and thus the appearance of related substances such as impurities, degradation products, and the like may be increased. Furthermore, if a relevant substance is present, the reduction in the permeation amount of the active ingredient may be as much as the relevant substance. Therefore, there is a need for efforts to develop latanoprost eye drop compositions that are stable and produce smaller amounts of related substances.

In addition, there is a latanoprost eye drop which can be stored at room temperature and contains a large amount (5%) of a nonionic surfactant (polyoxyethylene 40 hydrogenated castor oil, HCO-40). However, this commercial product is also known to be cytotoxic to the eyeball (J Biochem Pharmacol Res.2014.12 months 1 days; 2(4): 175-.

On the other hand, latanoprost (one of prostaglandin derivatives) is a prodrug of latanoprost acid (a pharmaceutically effective form in vivo). Latanoprost is more permeable to the eye and less burning sensation than latanoprost acid, so latanoprost acid is administered in the form of a prodrug (i.e., latanoprost). When latanoprost permeates into the cornea (eye), it is converted to latanoprost acid to achieve the effect of lowering intraocular pressure. However, if latanoprost is converted to latanoprost acid before penetrating into the cornea (in the formulation), the drug penetration amount decreases, and thus the drug efficacy may be lowered, and side effects such as burning sensation and the like may occur. Therefore, it is required to develop a stable preparation (European Journal of pharmaceuticals and biopharmaceuticals 2015; 95:203-214) which can reduce the amount of latanoprost acid.

Therefore, the present inventors have endeavored to realize the development of stable latanoprost eye drops, which can be stored at room temperature, and identified that the latanoprost eye drops containing sorbitol have stability improvement over a long period of time even in the case of not containing benzalkonium chloride (i.e., regardless of whether benzalkonium chloride is contained or not), thereby completing the present invention.

Documents of the prior art

Non-patent document

J Korean Ophthalmol Soc 2010；51(8):1113-1120

J Biochem Pharmacol Res.2014.12 months and 1 day; 2(4):175-184

European Journal of Pharmaceutics and Biopharmaceutics 2015；95:203-214

Detailed Description

Technical problem

It is an object of the present invention to provide an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil, and sorbitol.

It is a further object of the present invention to provide an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil and sorbitol, wherein the amount of sorbitol is 4.0 to 6.0 w/v% of the total composition.

It is another object of the present invention to provide an ophthalmic composition for reducing intraocular pressure comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil and sorbitol, wherein the amount of sorbitol is 4.0 to 6.0 w/v% of the total composition.

It is still another object of the present invention to provide a method for reducing ocular pressure comprising the step of administering an ophthalmic composition for reducing ocular pressure comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil and sorbitol to an individual.

It is a further object of the present invention to provide a method for preventing or treating elevated intraocular pressure, ocular hypertension and glaucoma, wherein the method comprises the step of administering an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil and sorbitol to an individual.

It is yet another object of the present invention to provide a method for preparing an ophthalmic composition for enhancing the stability of latanoprost, wherein the method comprises the step of mixing latanoprost, polyoxyethylene 40 hydrogenated castor oil and sorbitol.

Technical scheme

In one aspect to solve the above objects, the present invention provides an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil and sorbitol, wherein the amount of sorbitol is 4.0 to 6.0 w/v% of the total composition.

The ophthalmic composition according to the present invention is prepared by appropriately mixing the components, and has the following advantages: compared with other commercially available eye drops on the market, the eye drop has excellent transmittance and storage stability; the intraocular pressure reducing effect is maintained; and producing smaller amounts of the relevant substances.

In the present invention, "latanoprost" is a prostaglandin analog which is effective in lowering intraocular pressure, such as lowering ocular hypertension or preventing ocular hypertension. Prostaglandin analogs include bimatoprost (bimatoprost), tafluprost (defluproprost), travoprost (travoprost), unoprost (unoprost), and the like, as well as latanoprost.

Latanoprost may be included in a therapeutically effective amount for the purpose of lowering intraocular pressure. For the purpose of the present invention, the amount of latanoprost may be 0.001 to 0.05 w/v%, particularly 0.002 to 0.01 w/v%, and more particularly 0.005 w/v%, based on the total amount of the ophthalmic composition, but is not limited thereto.

The ophthalmic composition of the present invention shows an effect of lowering intraocular pressure due to its nature comprising latanoprost, and thus such composition can be usefully used for preventing or treating ocular pressure elevation, ocular hypertension, glaucoma, or any symptoms associated therewith.

In the preparation of ophthalmic formulations, the use of benzalkonium chloride to stabilize latanoprost compositions has been disclosed, but it is also known that the use of benzalkonium chloride may cause side effects that show toxicity to corneal epithelial cells. Further, compositions that can be stored at room temperature by adjusting the pH of the formulation have been disclosed, but administration of a formulation with a low pH can be a cause of sensory eye irritation. Therefore, in order to solve the above-mentioned problems, the present inventors have prepared an ophthalmic composition (having a pH similar to that of tear film) having excellent stability and reduced side effects even without benzalkonium chloride (i.e., regardless of whether benzalkonium chloride is contained) by containing polyoxyethylene 40 hydrogenated castor oil and sorbitol as constituent components of an ophthalmic preparation.

In the present invention, "polyoxyethylene 40 hydrogenated castor oil" is a solubilizer, and is also referred to as PEG-40 hydrogenated castor oil, which is the name of International Nomenclature Cosmetic Ingredient (INCI), wherein Cosmetic Ingredient is the name given internationally by the Personal Care Products Council (PCPC), i.e., the former Cosmetic, Toiletry and perfume Association (CTFA).

In the present invention, polyoxyethylene 40 hydrogenated castor oil may be used in combination with HCO-40 or Cremophor RH40 (in the same sense). Polyoxyethylene 40 hydrogenated castor oil may show the same effect as a surfactant, which is used to solubilize water-insoluble substances.

The amount of polyoxyethylene 40 hydrogenated castor oil may be 0.3 to 2.0 w/v%, particularly 0.3 to 1.0 w/v%, more particularly 0.4 to 0.7 w/v%, and especially more particularly 0.5 to 0.6 w/v% of the total ophthalmic composition of the present invention.

At too high a concentration, nonionic surfactants such as the polyoxyethylene 40 hydrogenated castor oil may cause side effects by causing irritation to the corneal epithelial layer. Therefore, it is preferable to contain a small amount of a nonionic surfactant.

In one experimental example of the present invention, an ophthalmic composition prepared by varying the amount of polyoxyethylene 40 hydrogenated castor oil was maintained under stress (stress) conditions (55 ℃ and 75% relative humidity) for four weeks, and then its transmittance was measured. As a result, if the amount of polyoxyethylene 40 hydrogenated castor oil is less than or equal to about 1.0 w/v% of the total composition, it can be seen that both the initial transmittance and the transmittance after storage are excellent. On the other hand, if the amount of polyoxyethylene 40 hydrogenated castor oil is 2.0 w/v%, it can be seen that the initial transmittance is very low (table 3).

Further, in one experimental example of the present invention, an ophthalmic composition prepared by varying the amount of polyoxyethylene 40 hydrogenated castor oil was maintained under stress conditions for four weeks, and then the amount of latanoprost thereof was measured. As a result, if the amount of polyoxyethylene 40 hydrogenated castor oil is greater than or equal to about 0.3 w/v% of the total composition, it can be seen that the amount of latanoprost is maintained at a certain level after storage. On the other hand, if the amount of polyoxyethylene 40 hydrogenated castor oil is 0.05 w/v% and 0.1 w/v% of the total composition, it can be seen that the amount of latanoprost after storage is reduced, and thus its stability becomes remarkably low (table 4).

In the present invention, "sorbitol" is a sugar alcohol having 6 hydroxyl groups, and is also referred to as D-sorbitol or D-glucitol.

In one experimental example of the present invention, after storing a composition not containing sorbitol, it was determined that the stability thereof was low due to the decrease in the amount of latanoprost, and thus it can be seen that sorbitol is a constituent ingredient for enhancing the stability of an ophthalmic composition (table 4 and example 5).

The amount of sorbitol may be 4.0 to 6.0 w/v%, particularly 4.0 to 5.0 w/v%, more particularly 4.1 to 4.7 w/v%, preferably about 4.4 w/v%, and most preferably 4.41 w/v% of the total ophthalmic composition.

In preparing the compositions of the present invention, a D-sorbitol solution may be used to include sorbitol in the composition. In the case of using the D-sorbitol solution, the input amount of the D-sorbitol solution may be adjusted by considering the amount of sorbitol contained in the D-sorbitol solution, so that a desired amount of sorbitol may be contained in the total composition. In particular, the D-sorbitol solution may be a D-sorbitol solution in which the content of sorbitol is 70% (w/w), but is not limited thereto.

In particular, if the concentration of the D-sorbitol solution contained in the total ophthalmic composition is 70% (w/w), the D-sorbitol solution may be contained in an amount of 6.3 w/v% of the total composition of 70% (w/w).

In one experimental example of the present invention, an ophthalmic composition containing sorbitol and an ophthalmic composition containing no sorbitol were maintained under stress conditions (55 ℃ and RH 75%) for 4 weeks, and then the latanoprost content thereof was measured, and the amount of related substances produced therefrom was measured. As a result, it can be seen that the ophthalmic composition comprising sorbitol maintains a high content of latanoprost, thus indicating that such composition exhibits excellent storage stability (table 4 and fig. 5). Furthermore, it can be seen that there is a small amount of the related substances produced, which has an adverse effect on the stability and quality of the ophthalmic composition (table 5 and fig. 6).

Further, in one embodiment of the present invention, an ophthalmic composition prepared by varying the amount of sorbitol contained in the composition is maintained under stress conditions (55 ℃ and RH 75%) for four weeks, after which the amount of latanoprost and related substances is measured. As a result, as the amount of sorbitol becomes higher, it can be seen that the content of latanoprost becomes higher (table 4), and the content of the produced related substances becomes lower (table 5 and fig. 6).

On the other hand, sorbitol can act as an isotonic agent, while hypertonic eye drops can cause damage to cells. Thus, considering an osmolality of the tear film of about 300mOsmol/kg, it is preferred that the amount of sorbitol should not exceed 6 w/v% of the total ophthalmic composition. Furthermore, if the amount of sorbitol is high, in particular more than 10 w/v% and more in particular more than 7 w/v% of the total ophthalmic composition, the amount of related substances produced during storage increases and may therefore not be suitable for the preparation of ophthalmic compositions.

In the present invention, the ophthalmic composition may further comprise a stabilizer. In the case of further comprising a stabilizer, the ophthalmic composition of the present invention may have a great improvement in its physical and chemical stability. The stabilizer hydrates in an aqueous solvent to form a certain bonding structure in which oil droplets of the eye drop are made into a gel network, so that the stabilizer can impart viscosity to the eye drop and serves to physically stabilize the eye drop. The stabilizer may include: cellulose-based compounds including carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and the like; polyethylene-based compounds including polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), and the like; acrylic acid-based compounds including carbomer and the like; gum base compounds including gellan gum (gellan gum), xanthan gum, and the like; polysaccharides including Hyaluronic Acid (HA), sodium hyaluronate, sodium alginate, dextran, etc.; any combination thereof; and the like. In particular, the stabilizer may be a carbomer.

In the present invention, the ophthalmic composition may further comprise a pH adjuster, an isotonic agent, a preservative, a buffer solution, and the like.

The ophthalmic compositions of the present invention have a pH suitable for administration to the eye, wherein the pH can be adjusted by methods known to those skilled in the art to obtain an appropriate pH.

The pH of the ophthalmic composition of the present invention may be particularly 5.5 or more, and more particularly 6.5 to 7.5.

As the pH adjuster, sodium hydroxide, hydrochloric acid, or the like can be used. The pH adjusting agent may be used in such a way that it is added in the amount required to obtain the appropriate pH by methods known to those skilled in the art.

As the isotonic agent, at least one selected from the group consisting of: glycerin, mannitol, sodium chloride, potassium chloride, boric acid, borax, etc., but is not limited thereto, wherein the amount thereof may range from 0.01 to 10.0 w/v%, particularly from 0.1 to 3.0 w/v%, relative to the amount of the total composition.

Preservatives of the present invention may include: quaternary ammonium compounds including benzalkonium chloride, benzethonium chloride, cetonitium chloride, polyquaternium-1 (e.g. benzalkonium chloride, and cetonitum chloride), and polyquaternium-1) Etc.; guanidine-based compounds including PHMB, chlorohexidine (chlorohexidine), and the like; chlorobutanol; mercury-based preservatives including thimerosal (thilomesal), phenylmercuric acetate, phenylmercuric nitrate, and the like; and an oxidizing preservative, a bagIncluding stabilized oxychloro complexes (e.g. of the type) Alkyl parabens (e.g., methyl Paraben (PM)), and the like.

Preservatives may be used by taking into account the side effects of eye drops, wherein the amount of preservative may range from 0.001 to 0.5 w/v% of the amount of the total composition.

As the buffer of the present invention, a buffer for eye drops can be used without limitation, wherein acetate buffer, citrate buffer, phosphate buffer (e.g., disodium hydrogen phosphate or a hydrate thereof, and sodium dihydrogen phosphate or a hydrate thereof), boric acid buffer (such as boric acid or a salt thereof), and the like can be used, but is not limited thereto. The amount of the buffer used may be appropriately selected by those skilled in the art, and may be used in an amount of 0.001 to 10 w/v%, particularly 0.01 to 5.0 w/v%, and more particularly 0.1 to 2.0 w/v%, with respect to the amount of the total composition.

In the present invention, the ophthalmic composition may be characterized by not comprising a co-gelling agent/co-solubilizer.

"Cogelling/co-solubilizing agents" are common components used in the preparation of eye drops and can be used to achieve a desired level of viscosity and enhance dissolution of the active ingredient. Typically, co-gelling/co-solubilizing agents include polymers, such as polyethylene glycol (PEG), and vinyl derivatives, including polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP).

In one experimental example of the present invention, it was determined that a composition not containing PEG4000 has excellent storage stability and a small amount of the related substances produced, and thus it can be seen that a composition can be provided in which the active ingredient thereof is solubilized, and which is stable and has an excellent intraocular pressure lowering effect even without containing a co-gelling agent/co-solubilizing agent such as PEG 4000.

Further, the ophthalmic composition of the present invention not only shows an effect of reducing side effects such as a feeling of irritation caused by a foreign substance, which may occur upon administration of eye drops without containing a co-gelling agent/co-solubilizing agent, but also shows an excellent feeling of instillation as compared with a composition simultaneously containing PEG 4000.

Furthermore, the ophthalmic composition may be characterized by comprising no benzalkonium chloride (BAK) at all or only a small amount of benzalkonium chloride as solubilizer. The inclusion of only a small amount of benzalkonium chloride (BAK) means that there is no need to include a large amount of benzalkonium chloride (which, as in the case of the lida, contains an excess of benzalkonium chloride as a solubilizing agent), and also means that a minimum amount of benzalkonium chloride can be included to obtain preservative capability.

Preferably, the ophthalmic compositions of the present invention should not contain benzalkonium chloride.

If the ophthalmic composition of the present invention comprises benzalkonium chloride as a preservative, said benzalkonium chloride may be comprised in an amount of 0.001 to 0.01 w/v% of the amount of the total composition.

"benzalkonium chloride" is a nitrogen cationic surfactant belonging to quaternary ammonium salts, and may be generally contained in an eye drop composition to function as a preservative, but may show side effects such as toxicity and the like if contained in an amount of a certain level or more.

In one experimental example of the present invention, the storage stability at room temperature of a commercially available eye drop containing benzalkonium chloride and an ophthalmic composition of the present invention containing no benzalkonium chloride were compared. As a result, it can be seen that: although considerable amounts of benzalkonium chloride are contained for solubilization and stabilization, commercially available eye drops cannot ensure storage stability at room temperature, whereas the ophthalmic composition of the present invention has excellent storage stability at room temperature. Furthermore, it can be seen that the ophthalmic composition of the present invention can reduce the side effects caused by long-term administration of eye drops by containing no benzalkonium chloride at all or by containing only the minimum amount of benzalkonium chloride required as a preservative, and can ensure stability even without containing benzalkonium chloride (fig. 1 and 2).

Furthermore, in one experimental example of the present invention, the amounts of latanoprost acid produced were compared between a commercially available eye drop containing benzalkonium chloride and the ophthalmic composition of the present invention, respectively, after storage under room temperature storage conditions. As a result, it can be seen that the amount of latanoprost acid produced by the ophthalmic composition of the present invention was reduced by at least 5 times as compared to the commercial eye drops (fig. 3).

Thus, the ophthalmic composition of the present invention shows excellent stability under storage conditions, since it not only maintains a high content of latanoprost, but also a small amount of latanoprost acid, even in the absence of benzalkonium chloride (i.e. whether or not benzalkonium chloride is included).

The ophthalmic compositions of the present invention may also contain an active compound. The active compound may be a medicament for the treatment and/or prevention of ophthalmic diseases such as ocular hypertension and/or glaucoma and the like. The active compound may be a drug for increasing aqueous humor release; a medicament for reducing aqueous humor production; and a drug for reducing intraocular pressure.

The active compound may be a prostaglandin based compound or a derivative thereof, a cholinergic agonist, β -an adrenergic antagonist (e.g., timolol), a carbonic anhydrase inhibitor (e.g., dorzolamide), or β -an adrenergic agonist (e.g., dipivefrin), but is not limited thereto, and may be a compound conventionally used in the art for lowering intraocular pressure.

In another aspect, the present invention may provide a method for preparing an ophthalmic composition for enhancing the stability of latanoprost, wherein the method comprises the step of mixing latanoprost, polyoxyethylene 40 hydrogenated castor oil, and sorbitol.

The amount of sorbitol may be 4.0 to 6.0 w/v%, particularly 4.0 to 5.0 w/v%, and more particularly 4.1 to 4.7 w/v% of the total ophthalmic composition of the present invention.

In the present invention, "latanoprost", "polyoxyethylene 40 hydrogenated castor oil" and "sorbitol" are the same as described above.

The method for preparing an ophthalmic composition may further comprise the step of adding a pharmaceutically acceptable additive or carrier. Such a pharmaceutical additive or carrier may be added during the preparation of the ophthalmic composition without other limitations, but should preferably be added after latanoprost is completely mixed into the composition.

Furthermore, in another aspect, the present invention provides a method for reducing intraocular pressure, the method comprising the step of administering an ophthalmic composition to an individual. The present invention provides methods for preventing or treating elevated intraocular pressure, ocular hypertension, and glaucoma, the methods comprising the step of administering an ophthalmic composition to an individual.

In the present invention, "individual" may mean all animals including humans, which suffer from or may suffer from elevated intraocular pressure. The animal may be not only a human but also a mammal such as a cow, a horse, a sheep, a pig, a goat, a camel, an antelope, a dog, a cat, etc., which are required to treat a symptom similar to the increase in intraocular pressure, but is not limited thereto.

In the present invention, "administration" means introducing the ophthalmic composition of the present invention into a patient by an appropriate method, and the administration route of the present invention is topical administration to the eyeball, because the composition is an ophthalmic composition. The method for reducing intraocular pressure according to the present invention comprises administering the ophthalmic composition of the present invention in a therapeutically effective amount. The compositions of the present invention may be administered in a pharmaceutically effective amount. By pharmaceutically effective amount is meant an amount sufficient to treat the disease at a reasonable risk/benefit ratio applicable to medical treatment and not causing side effects, wherein an effective dosage level may be determined according to factors including: patient health, disease type, severity, drug activity, sensitivity to drug, method of administration, time of administration, route and rate of excretion, period of treatment, drug combined or co-administered, and other well known factors in the medical arts. In particular, such compositions may be administered in a divided manner at certain time intervals from once to several times per day, depending on the decision of a doctor or pharmacist, and each administration may be administered in an amount of 0.01ml to 0.1ml, but is not limited thereto.

Furthermore, in another aspect, the present invention provides the use of an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol for lowering intraocular pressure. The present invention provides the use of an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol for the prevention or treatment of elevated intraocular pressure, ocular hypertension and glaucoma.

In the present invention, "latanoprost", "polyoxyethylene 40 hydrogenated castor oil", "sorbitol", and the like are the same as described above.

Furthermore, in another aspect, the present invention provides the use of an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol in the manufacture of a medicament for lowering intraocular pressure. The present invention provides the use of an ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol in the manufacture of a medicament for the prevention or treatment of elevated intraocular pressure, ocular hypertension and glaucoma.

In the present invention, "latanoprost", "polyoxyethylene 40 hydrogenated castor oil", "sorbitol", and the like are the same as described above.

Advantageous effects

The ophthalmic composition according to the present invention can be used valuably as an eye drop for lowering intraocular pressure, which exhibits an excellent effect of lowering intraocular pressure, excellent transmittance, storage stability and instillation feeling; side effects are reduced; ensuring the long-term storage stability at room temperature; is stable even at high temperatures; and is easy to store.

Brief Description of Drawings

Fig. 1 is a graph showing the stability of the composition of example 1 upon storage at room temperature (25 ℃ and RH 40%) for 24 months.

Figure 2 is a graph comparing stability between the composition of example 1 and belidas according to shelf life.

Figure 3 is a graph comparing the amount of latanoprost acid produced between the composition of example 1 and alisda according to shelf life.

Fig. 4 is a photograph of transmittance between the compositions of comparative examples 3 and 4 and the composition of comparative example 1.

Fig. 5 is a graph showing the amount of decrease in the content of the main component (latanoprost) of the compositions of examples 1, 2, 5, 8, and 9 during storage.

Fig. 6 is a graph showing the amounts of related substances produced by the compositions of examples 1, 2 and 10 during storage.

Fig. 7 is a graph showing the amount of change in intraocular pressure (IOP) in one day according to administration of the composition of example 1.

Figure 8 is a graph showing IOP over 25 days according to administration of the composition of example 1.

Detailed Description

Hereinafter, the configuration and effect of the present invention will be described in more detail by way of examples. However, the following examples are provided only to illustrate the present invention, and thus the contents of the present invention are not limited thereto.

Experimental example 1: storage stability test of the composition of example 1 and of Adita

Storage stability at room temperature was compared between the eye drop composition of example 1 and the pteridan (i.e., a commercially available eye drop containing latanoprost). The main components and amounts of the composition of example 1 above are shown in table 1 below, and such compositions were prepared as follows. Sorbitol, polyoxyethylene 40 hydrogenated castor oil (Cremophor RH40) and latanoprost were dissolved in water for injection according to the amounts described in table 1 below. Sodium edetate hydrate (sodium EDTA) and carbomer 974P were dissolved in other water for injection according to the amounts described in table 1 below, and the pH thereof was adjusted by sodium hydroxide. Thereafter, an ophthalmic composition is prepared by mixing the two prepared solutions together.

On the other hand, when preparing an ophthalmic composition, a D-sorbitol solution may be used for sorbitol. In this case, the amount of the D-sorbitol solution added to the composition may be adjusted by considering the corresponding sorbitol content in the D-sorbitol solution, so that the amount of sorbitol therein may be the same as the amount shown in table 1 below.

[ Table 1]

The storage stability of the composition and the eye drop was compared by measuring the change in latanoprost content under the condition of storage at room temperature (25 ℃ and RH 40%), respectively, according to the lapse of the storage period.

Specifically, the content of latanoprost was analyzed by High Performance Liquid Chromatography (HPLC), wherein the conditions thereof were as follows:

(1) mobile phase composition: the composition ratio of 50 percent of phosphate buffer solution and 50 percent of acetonitrile

(2) Velocity of mobile phase: 0.7 to 1.0mL/min

(3) Column: l1 with particle size of 5 μm and 4.6 × 250mm

As a result, with the composition of example 1, it was determined that the initial content of latanoprost was maintained and its stability was ensured for at least 24 months even after storage under room temperature storage conditions for 6 months (fig. 1). On the other hand, for aptida, it was determined that the latanoprost content decreased to 93.4% within three months after storage and then to less than 90.0% upon long-term storage, indicating lower stability as a drug stored at room temperature (fig. 2).

Therefore, it was confirmed that the ophthalmic composition of example 1 described above has excellent storage stability compared to the commercial advantages of adata.

Experimental example 2: experiment of occurrence of Latanoprostolic acid in the composition and Adita of example 1

The amount of latanoprost acid produced was compared between the composition of example 1 of experimental example 1 above and the belidade according to the storage period.

Specifically, the amount of latanoprost acid produced was analyzed by HPLC, wherein the conditions thereof were as follows:

(1) mobile phase composition: mobile phase gradient conditions between phosphate buffer and acetonitrile over time.

(2) Velocity of mobile phase: 0.5 to 0.8mL/min

(3) Column: chiral column with particle size of 3 μm and 4.6 × 250mm

As a result, for the composition of example 1, it was determined that only 0.2% of latanoprost acid was produced within 6 months after storage even under the condition of storage at room temperature. On the other hand, for the adata, it was determined that 1.1% of latanoprost acid was produced within 6 months after storage, indicating that at least 5-fold more latanoprost acid was produced compared to the composition of example 1 (fig. 3).

Therefore, for the eye drop composition of example 1 described above, it was determined that the amount of produced latanoprost acid was appropriate according to product standards, and the amount of produced latanoprost acid was significantly low compared to that of talloda.

Experimental example 3: experiment of transmittance under stress condition

The ophthalmic compositions of examples and comparative examples in the following table 2 were stored under stress conditions (55 ℃ and RH 75%) for 4 weeks, and then the transmittance of the compositions was measured.

Eye drop compositions of examples 2 to 4 in the following table 2 were prepared by the same method as shown in experimental example 1, and the composition of comparative example 1 was prepared as follows. PEG4000, sorbitol, polyoxyethylene 40 hydrogenated castor oil (Cremophor RH40) and latanoprost were dissolved in water for injection according to the amounts described in table 2 below. Sodium edetate hydrate (sodium EDTA) and carbomer 974P were dissolved in other water for injection according to the amounts described in table 2 below, and the pH thereof was adjusted by sodium hydroxide. Thereafter, a composition is prepared by mixing the two prepared solutions together.

The transmittance of the composition was measured by a UV spectrophotometer (Shimazu), and the transmittance (T550%) was measured at 550nm by using purified water as a blank.

[ Table 2]

As a result of measuring the transmittance of the composition, the composition of example 2 showed a high initial transmittance of 90% or more, while the composition of comparative example 1 showed a very low initial transmittance of 20% or less. Furthermore, for the composition of comparative example 1, a transmission of 15% within 4 weeks after storage was determined, which was reduced by at least 75% compared to the composition of example 2 (table 3). Further, for the compositions of examples 3 and 4, it was determined that the transmittance was reduced by about 4% and 8%, respectively, after 4 weeks of storage, compared to the initial value, while the transmittance of the composition of example 2 was consistently maintained at a level of 98% even under stress conditions (fig. 4 and table 3). Further, when initial transmittances between the two compositions were compared, it was determined that low transmittance was shown in the case of containing a large amount of HCO-40 as shown in example 4, and very low transmittance was shown in the case of containing a large amount of HCO-40 and PEG4000 as shown in comparative example 1 (table 3).

Thus, it can be seen that the components of the ophthalmic composition and their amounts are constituents which affect the turbidity in the properties of the composition and its turbidity over time.

[ Table 3]

Experimental example 4: experiment of storage stability under stress conditions

The ophthalmic compositions of examples in the following table 4 were prepared by the same method as shown in the above experimental example 1, and then filled into LDPE eye drop containers, and then stored under stress conditions (55 ℃ and RH 75%) for 4 weeks. Thereafter, the content of latanoprost in the composition was measured by the same method as shown in the above experimental example 1.

As a result, for the composition of example 5 containing no sorbitol, it was determined that the content of latanoprost became too low to ensure the stability of the ophthalmic composition after 4 weeks of storage, but the higher the amount of sorbitol, the higher the amount of latanoprost, thus indicating that the stability of the composition was excellent (table 4 and fig. 5). On the other hand, for the composition of example 1, it was determined that the content of latanoprost was 90% or more, thereby ensuring the most excellent stability. In addition, for the compositions of examples 6 to 8 in which the amount of HCO-40 was 0.1% or less, the contents of latanoprost were determined to be 59.4%, 70.2%, and 83.7%, respectively, thus ensuring lower stability (table 4).

Thus, it can be seen that sorbitol and HCO-40 are constituents that affect the stability of latanoprost, which is the active component of the ophthalmic composition.

[ Table 4]

Experimental example 5: experiment of appearance of related substance under stress condition

The compositions of examples in the following table 5 were prepared by the same method as shown in the above experimental example 1, and the amounts of the related substances produced were measured after storage for 4 weeks under stress conditions (55 ℃ and RH 75%). The amount of the produced related substance was measured by the following method.

In particular, the amount of the relevant substances was analyzed by HPLC, wherein the conditions thereof were as follows:

(1) mobile phase composition: the composition ratio of 50 percent of phosphate buffer solution and 50 percent of acetonitrile

(2) Velocity of mobile phase: 0.3 to 0.5mL/min

(3) Column: chiral column with particle size of 3 μm and 4.6 × 250mm

[ Table 5]

As a result, it was determined that the amount of the related substance produced was 2.86% for the composition of example 5 containing no sorbitol, but it was determined that the amount of the related substance produced was reduced to 0.83% for the composition of example 1 containing about 4.4 w/v% sorbitol, thus indicating that the amount of the related substance produced was at least 3 times lower than that of the composition containing no sorbitol after storage under stress conditions, and that the amount of the related substance was reduced by at least about 1.6 times even compared to the composition of example 10 (fig. 6). This means that the amount of the relevant substance is reduced by about 40% compared to the amount of the relevant substance produced from the composition of example 10.

Therefore, if sorbitol is included in the ophthalmic composition, it is determined that the amount of the related substance produced is decreased. If the amount of sorbitol is at least 4.0 w/v%, in particular about 4.4 w/v%, of the total composition, it is determined that the amount of the relevant substance produced is significantly reduced.

Experimental example 6: experiments on intraocular pressure (IOP) changes

The intraocular pressure (IOP) lowering effect was compared between the eye drop composition of the present invention and other compositions. The animal model of induced glaucoma used in Experimental example 6 was prepared according to a known method (Eitan Z. Rath (2011), ISBN: 978-.

In particular, rabbits with induced glaucoma are classified as: positive control group (G1); the eye drop composition administration group of example 1 (G2) prepared according to the above experimental example 1; the ulida administration group (G3); and the Monoprest administration group (G4), then each drug was administered once a day (9 pm) for 4 weeks. Monoprot administration groups were dosed by using a Monoprot (laboratories Thea) product containing 0.005 w/v% latanoprost, large amounts (5%) of HCO-40 and PEG 4000.

After the first administration, intraocular pressure was measured for each time zone (9 pm, 10 pm, 11 pm, 0 am, 1 pm, 4 pm, 7 pm, 9 pm, 1 pm and 9 pm) by using a tonometer. Thereafter, the intraocular pressure was measured every other day.

As a result of measuring intraocular pressure in each time zone after the first administration, for the group to which the eye drop composition of example 1 was administered (G2), it was determined that the intraocular pressure value was reduced by about 0.5 to 1.5mmHg from 10:30 in the afternoon to 5 am on the next day as compared with the monopost administration group (G4), thus showing a more excellent effect of reducing intraocular pressure (fig. 7). From the results, it can be seen that the composition of example 1 exhibited a more excellent effect of lowering the initial intraocular pressure than the Monoprost administration group (G4).

Further, in consideration of more increase in intraocular pressure during sleep, it can be seen that the eye drop composition of example 1 shows a greater effect in lowering intraocular pressure in the nighttime interval (where intraocular pressure is highest), thus indicating that the composition of example 1 shows a more excellent effect in lowering intraocular pressure and treating glaucoma.

As a result of measuring the amount of change in ocular pressure in 25 days, it was confirmed that the composition of the present invention can be stored at room temperature and also shows an effect of lowering ocular pressure equivalent to that of cherida (cold storage), which is administered to many patients for a long period of time as a therapeutic agent for ocular hypertension and glaucoma. Furthermore, it was confirmed that the administration group (G2) of the composition of the present invention showed a faster intraocular pressure lowering effect than the monopost administration group (G4) (fig. 8). As can be seen from the results, the composition of the present invention showed a much faster intraocular pressure lowering effect, thus showing an excellent effect.

As can be seen from the present experimental examples, the ophthalmic composition of the present invention shows similar or superior intraocular pressure lowering effect as compared with other eye drop compositions on the market.

Although specific portions of the present invention have been described in detail above, it will be apparent to those skilled in the art that such detailed description is merely illustrative of exemplary embodiments and should not be construed as limiting the scope of the invention.

It is therefore to be understood that the invention is defined by the appended claims and their equivalents.

Claims (14)

1. An ophthalmic composition comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol, wherein the amount of sorbitol is 4.0 to 6.0 w/v% of the total composition.

2. The ophthalmic composition of claim 1, wherein the sorbitol is in an amount of 4.1 to 4.7 w/v% of the total composition.

3. The ophthalmic composition according to claim 1, characterized in that the composition does not comprise a co-gelling/co-solubilizing agent.

4. The ophthalmic composition of claim 1, wherein the amount of polyoxyethylene 40 hydrogenated castor oil is from 0.3 to 1.0 w/v% of the total composition.

5. The ophthalmic composition of claim 1, wherein the amount of polyoxyethylene 40 hydrogenated castor oil is 0.5 w/v% of the total composition.

6. The ophthalmic composition of claim 1, wherein the amount of said latanoprost is from 0.001 to 0.05 w/v% of the total composition.

7. The ophthalmic composition of claim 1, wherein the composition further comprises an active compound.

8. The ophthalmic composition of claim 1, wherein the composition is a composition for reducing intraocular pressure.

9. The ophthalmic composition according to claim 8, wherein the composition is used for lowering intraocular pressure such that the composition is used for preventing or treating elevated intraocular pressure, ocular hypertension, glaucoma or ophthalmic diseases related thereto.

10. An ophthalmic composition for reducing intraocular pressure comprising latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol, wherein the amount of polyoxyethylene 40 hydrogenated castor oil is from 0.3 to 1.0 w/v% and the amount of sorbitol is from 4.0 to 6.0 w/v% of the total composition, such that the ophthalmic composition is stabilized.

11. An ophthalmic composition comprising latanoprost and polyoxyethylene 40 hydrogenated castor oil (HCO-40), wherein sorbitol is comprised as an alternative stabilizer to polyoxyethylene 40 hydrogenated castor oil.

12. A method for stabilizing latanoprost, comprising the step of mixing latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol, wherein the amount of polyoxyethylene 40 hydrogenated castor oil is 0.3 to 1.0 w/v% of the total composition prepared according to the above steps.

13. A process for the preparation of an ophthalmic composition for enhancing the stability of latanoprost comprising the step of mixing latanoprost, polyoxyethylene 40 hydrogenated castor oil (HCO-40) and sorbitol, wherein the amount of sorbitol is 4.0 to 6.0 w/v% of the total composition.

14. A method for lowering intraocular pressure, the method comprising the step of administering to an individual a composition according to one of claims 1 to 11.