Eye drop oil type pharmaceutical composition

Abstract

An eye drop type pharmaceutical composition comprising lipids, white petrolatum, and liquid paraffin, wherein the ophthalmic pharmaceutical composition comprises 3 to 500 milligrams of lipids, 100 to 250 milligrams of white petrolatum, and 1 to 797 milligrams of liquid paraffin per gram.

Description

Technical Field

[0001] This application claims the priority of U.S. Provisional Application No. 63 / 442,153, filed in the United States on January 31, 2023, the entire content of which is incorporated herein by reference. This application relates to ophthalmic drugs, and in particular, it is an eye drop oil formulation that does not contain preservatives and has no eye irritation.

Background Art

[0002] The normal ocular surface is covered with tears, which play a role in providing lubrication and protection to the eyes and are called the "tear film". The tear film structure can be divided into three layers, namely, the mucin layer, the aqueous layer, and the lipid layer (Figure 1) from the inside to the outside. The mucin layer can increase the viscosity of the tears and help the water stay on the surface of the eyes. The aqueous layer provides a smooth optical refractive surface for vision, maintains the moisture of the eyes, and the outermost lipid layer can prevent excessive evaporation of tears, assist in eye lubrication, and maintain the integrity of the tear film. If any one layer is missing, the tear film becomes unstable and causes dry eye symptoms.

[0003] In 1995, the National Eye Institute (NEI) of the United States divided dry eye into two types: deficient aqueous production (i.e., aqueous-deficient dry eye) and over evaporation (i.e., lipid-deficient dry eye). According to the research in Cornea. 2012 May, 31(5):472-8, the cause of many dry eyes is not insufficient tear secretion. 86% of dry eye patients have lipid-deficient dry eye due to meibomian gland dysfunction, and only 14% of patients have simple aqueous-deficient dry eye. According to the statistics of the GlobalData database, currently, the drug treatment for dry eye still mainly uses artificial tears in many countries around the world, and there is a lack of drugs on the market to meet the needs of lipid-deficient dry eye patients.

[0004] Common dosage forms for ophthalmic medications include eye drops, ophthalmic suspensions, and ophthalmic ointments. Eye drops are aqueous eye drops, and aqueous formulations are susceptible to microbial contamination. Generally, multi-dose packaging contains preservatives, and preservative-free eye drops can only be sold in single-use packaging, which is expensive and hinders widespread use. Long-term and frequent use of eye drops containing preservatives can worsen chronic eye inflammation and corneal cell damage. Furthermore, eye drops can wash away the lipid layer of the tear film, destroying its integrity and potentially leading to the formation or worsening of dry eye. Some eye drops contain trace amounts of lipids, which are claimed to mimic the tear film's composition, but adding surfactants to such formulations to dissolve the lipids in water can actually burden the eyes.

[0005] Furthermore, active pharmaceutical ingredients used in the eye are insoluble in water and can only be formulated as ophthalmic suspensions or ophthalmic ointments. Ophthalmic suspensions have similar problems to eye drops, and require shaking before use. If not shaken sufficiently, the active ingredient may be unevenly distributed, potentially leading to insufficient therapeutic effect or, in some cases, an excessive dosage. Ophthalmic ointments are packaged in hoses and require the ointment to be pressed into the lower eyelid before use, making them inconvenient for elderly patients to use themselves. Moreover, they can cause blurred vision and a foreign body sensation after use, affecting daily life.

[0006] Because eye drops can affect the stability of the tear film and care must be taken regarding the damage to the eyes from preservatives, ophthalmic suspensions have similar problems to eye drops, plus the risk of uneven content. Ophthalmic ointments are difficult to apply and can cause various discomforts after use, such as impaired vision or a feeling of a foreign body. These eye medications currently on the market clearly have drawbacks in terms of use, so there is an urgent need to develop new dosage forms for ophthalmic medications. The ability to alleviate dry eye and to further add water-insoluble active drug components as an ophthalmic drug platform is an important issue that this application seeks to solve. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In view of the shortcomings faced by related technologies, this application provides an eye drop oil-type pharmaceutical composition which is less irritating to the eye, free of preservatives, does not impair vision after use, can be placed in a common multi-dose reusable eye drop bottle, and is easy to use. The eye drop oil-type pharmaceutical composition of this application effectively prevents water dispersion and loss of the tear film, alleviates dry eye, and can be further enhanced with water-insoluble active drug components to represent another new option in the plateau of ophthalmic drug formulations. [Means for solving the problem]

[0008] The object of this application is to provide an eye drop type pharmaceutical composition comprising lipids, white petrolatum, and liquid paraffin, wherein each gram of this pharmaceutical composition contains 3 to 500 milligrams of lipids, 100 to 250 milligrams of white petrolatum, and 1 to 797 milligrams of liquid paraffin.

[0009] To achieve the aforementioned objectives of the application, the lipids herein include medium-chain triglycerides (MCT), soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), and wool oil.

[0010] To achieve the aforementioned objective of the application, the lipid in this case is a medium-chain triglyceride.

[0011] To achieve the aforementioned objectives of the application, this pharmaceutical composition contains 3 to 500 milligrams of lipid, 100 to 250 milligrams of white petrolatum, and 300 to 797 milligrams of liquid paraffin per gram.

[0012] To achieve the aforementioned objectives of the application, this pharmaceutical composition contains 3 to 300 milligrams of lipid, 100 to 240 milligrams of white petrolatum, and 500 to 797 milligrams of liquid paraffin per gram.

[0013] To achieve the aforementioned objectives of the application, an active drug component may be added to this pharmaceutical composition.

[0014] To achieve the aforementioned objectives of the application, the active drug component includes mineral oil, steroids, tetracyclines, macrolide antibiotics, prostaglandins, carbonic anhydrase inhibitors, immunosuppressants, or other active drug components that are poorly soluble in water.

[0015] To achieve the aforementioned objectives of the application, this steroid comprises loteprednol etabonate, betamethasone, dexamethasone, fluoroometholone, prednisolone acetate, or hydrocortisone acetate.

[0016] To achieve the aforementioned objectives of the application, this tetracycline comprises polycyclocycline hydrochloride (doxycycline hyclate), tetracycline hydrochloride (tetracycline HCl), or minocycline hydrochloride (minocycline HCl).

[0017] To achieve the aforementioned objectives of the application, this macrolide antibiotic comprises erythromycin or azithromycin.

[0018] To achieve the aforementioned objectives of the application, this prostaglandin comprises latanoprost, latanoprostene bunod, travoprost, and bimatoprost.

[0019] To achieve the aforementioned objectives of the application, this carbonic anhydrase inhibitor comprises a brinzolamide.

[0020] To achieve the aforementioned objectives of the application, this immunosuppressant comprises tacrolimus or sirolimus.

[0021] To achieve the aforementioned objectives of the application, the other water-insoluble active drug components include rebamipide, omega 3, nepafenac, besifloxacinHCl, selenium disulfide, vitamin A, or cyclosporine.

[0022] Another object of this application is to develop ophthalmic pharmaceutical compositions for use in manufacturing drugs that treat, prevent or improve dry eye, particularly oil-deficient dry eye, which is caused by dysfunction of the meibomian glands. [Effects of the Invention]

[0023] Taking the above into consideration, the present application provides an eye drop, which is a new dosage form of ophthalmic pharmaceutical composition and has the following advantages compared with the current technology. 1. It does not impair the stability of the tear film like eye drops and is highly safe for long-term use. 2. Compared with eye ointment, the ophthalmic composition of the present application is contained in a general eye drop bottle, is easy to use, has low ocular irritation, and does not cause blurred vision after use. 3. It can effectively prevent the water dissipation of the tear film, treat, prevent, or improve dry eye, and meet the treatment needs of patients with excessive tear evaporation type (oil-deficient dry eye). 4. An active drug component poorly soluble in water can be added to serve as an ophthalmic drug platform. 5. There is no need to add preservatives, reducing the side effects related to preservatives. 6. It has better stability than commercial products.

Brief Description of the Drawings

[0024] [Figure 1] It is a schematic diagram of the tear film. [Figure 2] It is the change amount of tears 1 hour after dosing.

Modes for Carrying Out the Invention

[0025] Example 1 Detection of Irritation and Viscosity By checking the data of viscosity and biological liquid film (%T of light transmittance), it is evaluated whether the ophthalmic pharmaceutical composition of the present application has good viscosity and low ocular irritation.

[0026] Viscosity evaluation method: Detected using a microVISC® viscometer (USP <914> (Compliant with Pressure Driven Methods) The viscosity of water for injection (WFI) is 0.894, while the viscosity of control product 2's eye ointment is 2537.7 (as shown in Table 5), which can be used as a reference value for the fluidity of eye drops. Viscosity is the resistance to flow within a viscous liquid and can be considered as friction of the fluid itself. Since viscosity mainly originates from the mutual attractive forces between molecules, substances with low viscosity flow relatively easily. The lower the viscosity value, the better the fluidity, the less blurred the vision will be when dropped into the eye, the less it will affect the clarity of vision, and the more convenient it is for patients to use, as it can be dispensed using a standard eye drop bottle rather than hose packaging.

[0027] Biological fluid film evaluation method: In vitro macromolecular test method for identifying chemicals inducing serious eye damage and chemicals not requiring classification for eye irritation or serious eye damage, as published by the Organization for Economic Co-operation and Development (OECD) in Chemical Testing Code No. 496, is used to test biological fluid films in vitro. Using pseudo-chemicals, macromolecules are used to induce a chemical reaction when exposed to irritants, causing the protein to denature and the solution to become cloudy, thereby determining the degree of irritation.

[0028] The detection method involves inducing turbidity in the solution when the chemical is mixed with the reagent, causing the protein to denature. The light transmittance is then measured using a UV spectroluminometer (manufacturer: Hitachi, model: U-2900) according to the standards for light transmittance described in the United States Pharmacopeia (USP). Table 1 below shows the light transmittance for each group under conditions of approximately 405 nanometer wavelength. The level of light transmittance is used to evaluate the degree of ocular irritation; higher light transmittance indicates lower ocular irritation, while lower light transmittance indicates higher ocular irritation. Specifically, a light transmittance greater than 90% is considered non-irritating, a light transmittance greater than 80% but 90% or less is considered mildly irritating, a light transmittance greater than 70% but 80% or less is considered moderately irritating, and a light transmittance of 70% or less is considered highly irritating.

[0029] This application provides an ophthalmic pharmaceutical composition comprising medium-chain triglycerides, white petrolatum, and liquid paraffin. Compositions with different component ratios shown in Tables 1 to 3 were confirmed to have good fluidity and low eye irritation based on viscosity and biofilm irritation (light transmittance %T) data.

[0030] The content of white petrolatum was fixed in the ophthalmic pharmaceutical composition, while the contents of MCT and liquid paraffin were varied. As shown in Table 1, when the MCT content in the ophthalmic pharmaceutical composition was varied, the light transmittance was greater than 90% in all ophthalmic pharmaceutical compositions with an MCT content of 3 to 500 mg / g, and it was judged that there was no irritation to the eye. However, the viscosity of the ophthalmic pharmaceutical compositions of formulations T10 and T11 was still good, and it was judged that a high content of MCT (greater than 500 mg / g) may affect the clarity of vision, and it was also difficult to dispense when placed in an eye drop bottle.

[0031] Table 1, Ophthalmic pharmaceutical compositions with different ratios of MCT

[0032] [Table 1]

[0033] To determine whether MCT and liquid paraffin can be substituted with other lipids, the content of white petrolatum and liquid paraffin was fixed in the ophthalmic pharmaceutical composition, and lipids selected from soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), and wool oil were added. From the results in Table 2, it was determined that by changing the type of lipid in the ophthalmic pharmaceutical composition, the light transmittance was greater than 90% in all cases, there was no irritation to the eye, good fluidity, and no clouding of vision, and no impact on the clarity of visual acuity.

[0034] Table 2, Ophthalmic pharmaceutical compositions of different lipids

[0035] [Table 2]

[0036] The MCT content was fixed in the ophthalmic pharmaceutical composition, while the white petrolatum and liquid paraffin content were varied. From the results in Table 3, when the white petrolatum content was between 100 and 250 mg / g, the light transmittance was greater than 85% in all cases, and it was judged that there was almost no irritation to the eye. However, the viscosity of the ophthalmic pharmaceutical composition of the T23 formulation was still good, and it was judged that a high content of white petrolatum (greater than 250 mg / g) clouded vision and affected the clarity of visual acuity.

[0037] Table 3, Ophthalmic pharmaceutical compositions with different white petrolatum ratios.

[0038] [Table 3]

[0039] The ophthalmic pharmaceutical composition of this application is an eye drop oil type, and the component ratios in the range of 3-300 mg / g lipids, 100-250 mg / g white petrolatum, and 1-797 mg / g liquid paraffin all have good comfort. Subsequent examples were made based on the T03 formulation: MCT 100 mg / g, white petrolatum 200 mg / g, and liquid paraffin 700 mg / g.

[0040] Table 4 shows the dosage forms and counterfeit ingredients of commercially available eye drop products commonly used by dry eye patients. Control product 1 is a common commercially available artificial tear solution, and control product 2 is an eye lubricant ointment. Table 5 compares the viscosity and light transmittance of the ophthalmic pharmaceutical composition of this invention with that of commercially available products. The ophthalmic pharmaceutical composition of formulation T03 of this invention has a light transmittance of more than 90% for water for injection, control product 1, and control product 2, and is judged to be non-irritating to the eye. Control product 2 has a high viscosity, which severely clouds vision during use and is judged to affect the clarity of vision, and it is difficult to use as it can only be dispensed with a hose.

[0041] Table 4. Dosage forms and ingredients of commercially available products (based on imitation labeling).

[0042] [Table 4]

[0043] Table 5: Comparison of the proposed ophthalmic pharmaceutical composition with water for injection and commercially available products.

[0044] [Table 5]

[0045] Example 2: Stability Analysis To evaluate the stability of the ophthalmic pharmaceutical composition of this application, changes in stability are observed using parameters such as moisture content, appearance, specific gravity, viscosity, and acid value.

[0046] The formulation of the ophthalmic pharmaceutical composition of this application comprises mineral oil, lipids, and white petrolatum. The lipids are oils, but not mineral oils. These oils include, but are not limited to, medium-chain triglycerides, soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), wool oil, peanut oil, and sesame oil. The lipids in the formulations of the following ophthalmic pharmaceutical compositions are mainly medium-chain triglycerides.

[0047] The formulation of the ophthalmic pharmaceutical composition of this application includes a range of 3 to 500 mg / g of lipids, 100 to 250 mg / g of white petrolatum, and 1 to 797 mg / g of liquid paraffin.

[0048] A preferred formulation of the ophthalmic pharmaceutical composition of this application includes the range of 3 to 300 mg / g of lipids, 100 to 250 mg / g of white petrolatum, and 300 to 797 mg / g of liquid paraffin.

[0049] The optimal formulation of the ophthalmic pharmaceutical composition of this application includes the range of lipids 3 to 300 mg / g, white petrolatum 100 to 240 mg / g, and liquid paraffin 500 to 797 mg / g.

[0050] Based on the T03 formulation: MCT 100 mg / g, white petrolatum 200 mg / g, and liquid paraffin 700 mg / g, the following experiment was conducted.

[0051] Detection method: Appearance: Slightly white, fluid eye drop solution Water content: The water content of a 20.0 mL mixture of toluene and methanol (7:3) solvent must not exceed 0.5% (Karl Fischer Moisture Titrator). Specific gravity: 0.806~0.870 (converted to weighed weight) Acid value: (USP <401> (See ACID VALUE)

[0052] Take approximately 20 g of the sample, weigh it accurately, and place it in a flask. Add 50 mL of a neutral mixture of ethanol and diethyl ether (1:1) (neutralized with phenolphthalein and 0.1 N potassium hydroxide solution or 0.1 N sodium hydroxide solution unless otherwise specified). If the sample does not dissolve in the cold solution, connect the flask to a reflux condenser and heat it slowly, sometimes shaking it until it dissolves. Add 1 mL of phenolphthalein test solution and titrate with 0.05 N potassium hydroxide solution until the solution remains pale red after shaking for 30 seconds.

[0053] Based on the results in Table 6, the 3-month accelerated stability data indicates that the composition of the ophthalmic pharmaceutical composition of this application is stable, the acid value does not change significantly, it can be stored for a long period of time, and it does not deteriorate during storage or sales.

[0054] Table 6, Acceleration Stability Data

[0055] [Table 6]

[0056] Example 3: Moisture content test (USP <922> , <1112> (See reference) Water content is expressed as water content and water activity. w Water can be divided into two types, and the water detected from the water content includes free water and bound water (also called fixed water or hydrated water). Only free water has water activity because free water is ordinary water and can be used by microorganisms, while bound water does not have solvent function and cannot be used by microorganisms.

[0057] Water activity (a w Lowering the water activity helps prevent the growth of microorganisms in the drug. Water content tests demonstrate that the formulation of this application has low water activity, and because the ophthalmic pharmaceutical composition of this application is manufactured aseptically, sterility can be maintained without the addition of preservatives.

[0058] American Pharmacopoeia <1112> According to the explanation regarding water activity, a chemical with a water activity much lower than 0.75 is used as a criterion for evaluating product stability. Therefore, this application does not require the addition of preservatives and allows for evaluation of whether or not microorganisms will grow.

[0059] Table 7, Moisture content test

[0060] [Table 7]

[0061] From the water content test results in Table 7, it was found that the water content of all ophthalmic pharmaceutical compositions of different ratios in this application was lower than 0.5, and that the water content included both free water and bound water. In other words, the free water (water activity) in the ophthalmic pharmaceutical compositions of this application was much lower than 0.75, which is the level at which microorganisms can utilize it. Therefore, it was found that the ophthalmic pharmaceutical compositions of this application can effectively prevent the growth of microorganisms in the drug, and thus there is no need to add preservatives. From Tables 4 and 7, it was found that since artificial tears of control product 1 are an aqueous formulation, preservatives must be added for long-term storage.

[0062] Example 4: Improvement of tear secretion volume according to the present invention Fifteen subjects were administered one artificial tear solution (control product 1), one ophthalmic ointment (control product 2), and the ophthalmic pharmaceutical composition of this application as test subjects.

[0063] The formulation of the ophthalmic pharmaceutical composition of this application includes a range of 3 to 500 mg / g of lipids, 100 to 250 mg / g of white petrolatum, and 1 to 797 mg / g of liquid paraffin.

[0064] A preferred formulation of the ophthalmic pharmaceutical composition of this application includes the range of 3 to 300 mg / g of lipids, 100 to 250 mg / g of white petrolatum, and 300 to 797 mg / g of liquid paraffin.

[0065] The optimal formulation of the ophthalmic pharmaceutical composition of this application includes the range of lipids 3 to 300 mg / g, white petrolatum 100 to 240 mg / g, and liquid paraffin 500 to 797 mg / g.

[0066] Based on the T03 formulation: MCT 100 mg / g, white petrolatum 200 mg / g, and liquid paraffin 700 mg / g, the following tests were conducted.

[0067] As shown in Table 8, the medication was administered to 15 subjects in three different groups. Tear secretion was detected using Schirmer's Test before and one hour after administration. The purpose of this test was to confirm whether the ophthalmic pharmaceutical composition of this application is superior to commercially available products in its effect on tear secretion.

[0068] Table 8, by test group

[0069] [Table 8]

[0070] Evaluation method: Tear film secretion test (Schirmer's Test) Baseline (before drug use) One hour after medication: Calculate the result after subtracting the baseline after measurement.

[0071] Test steps: Baseline values: Schirmer's Test was performed on both eyes of each subject using tear film test strips before medication administration. Each subject's left and right eyes were administered according to the group shown in Table 8, and then the following steps were taken. Schirmer's Test was performed on both eyes of each subject one hour after administration of the medication. After each treatment group was completed, a one-day drug elimination period was observed before administering the next group.

[0072] Schirmer's Test Tear Fluid Volume Test Results The results of the 15 subjects were incorporated and statistically analyzed, and the numerical values ​​were measured and the average was taken. As shown in Table 9, subtracting the baseline results from the measurements taken one hour after administration showed whether tear secretion increased or decreased after administration, and converting the change in measurement data before and after administration into a percentage further showed the rate of increase or decrease in tear secretion. From the results, it was found that in the first group, the tear secretion one hour after administration was significantly greater in the right eye using the ophthalmic pharmaceutical composition of this application than in the left eye using control product 1 artificial tears (p=0.013), while in the remaining administration groups, the detection results for the left and right eyes in terms of tear secretion did not reach a statistically significant difference. At the same time, from the test results of the second group, it was found that even when control product 1 artificial tears were added to the ophthalmic pharmaceutical composition of this application, the tear secretion was not significantly better than when the ophthalmic pharmaceutical composition of this application was used alone.

[0073] Table 9, Changes in tear secretion volume 1 hour after medication (Schirmer's Test)

[0074] [Table 9]

[0075] By displaying the results of Schirmer's Test one hour after medication as a bar graph, the change in tear volume can be seen more intuitively, as shown in Figure 2.

[0076] Compared to other commercially available products, the ophthalmic pharmaceutical composition of this application is clearly superior to the artificial tears of control product 1, as shown in the tear secretion test results in Table 9. Adding the ophthalmic pharmaceutical composition of this application to the artificial tears of control product 1 is not more effective than using the ophthalmic pharmaceutical composition of this application alone. The ophthalmic pharmaceutical composition of this application has almost the same effect as the eye ointment of control product 2. However, according to the fluidity results in Table 5, the ophthalmic pharmaceutical composition of this application has better fluidity than the eye ointment of control product 2. It was found that when placed in an eye drop bottle, it is easy for patients to use and does not cause clouding of vision after use.

[0077] Example 5: An active drug component is added to the ophthalmic pharmaceutical composition of this application. Because active drug components that are poorly soluble in water have poor water solubility, conventionally only ophthalmic suspensions or ophthalmic ointments could be manufactured. However, ophthalmic suspensions require the addition of preservatives and carry the risk of uneven content distribution. In contrast, ophthalmic ointments are difficult to apply and can cause various discomforts after use, such as impaired vision or a foreign body sensation. The ophthalmic pharmaceutical composition of this application is an oily formulation and can therefore be used as an ophthalmic drug platform. By adding the water-poorly soluble active drug component to this platform, it can be used as an ophthalmic oil formulation.

[0078] Active drug components that are poorly soluble in water include steroids, tetracyclines, macrolide antibiotics, prostaglandins, carbonic anhydrase inhibitors (CAIs), immunosuppressants, or other active drug components that are poorly soluble in water.

[0079] The active drug components that are poorly soluble in water include steroids such as loteprednol etabonate, betamethasone, dexamethasone, fluorometholone, prednisolone acetate, and hydrocortisone acetate. Loteprednol etabonate had the worst water solubility, and subsequent experiments were conducted using representative steroids with this characteristic.

[0080] Tetracycline, an active drug component that is poorly soluble in water, includes Doxycycline hyclate, Tetracycline HCl, and Minocycline HCl. Doxycycline hyclate has the worst water solubility, and subsequent experiments were conducted using tetracycline, a representative example of this type of tetracycline.

[0081] Macrolide antibiotics, which have poor water solubility, include erythromycin and azithromycin. Azithromycin showed the worst water solubility, and subsequent experiments were conducted on representative macrolide antibiotics.

[0082] The active drug components prostaglandins, which are poorly soluble in water, include latanoprost, latanoprostene bunod, travoprost, or bimatoprost.

[0083] Carbonic anhydrase inhibitors, which are active drug components that are poorly soluble in water, include Brinzolamide and others.

[0084] The active drug components of immunosuppressants that are poorly soluble in water include tacrolimus and sirolimus, and sirolimus had the worst water solubility. Subsequent experiments were conducted using representative immunosuppressants of this type.

[0085] Other active drug components that are poorly soluble in water include Rebamipide, Omega 3, Nepafenac, Besifloxacin HCl, Selenium disulfide, Cyclosporin, and Vitamin A.

[0086] The aforementioned active drug components, such as cyclosporin, tacrolimus, sirolimus, rebamipide, omega 3, selenium disulfide, and vitamin A, have the effect of preventing, treating, or improving dry eye.

[0087] The aforementioned Doxycycline Hyclate, Erythromycin, Minocycline HCl, Azithromycin, etc., have the effect of preventing, treating, or improving dysfunction of the meibomian glands of the eye.

[0088] The aforementioned Besifloxacin HCl, Tetracycline HCl, Doxycycline Hyclate, Erythromycin, Minocycline HCl, and Azithromycin are effective in treating bacterial infections.

[0089] The active drug component, such as loteprednol etabonate, betamethasone, dexamethasone, fluorometholone, prednisolone acetate, or hydrocortisone acetate, may be a steroid.

[0090] The active drug components of Nepafenac and other similar substances are nonsteroidal anti-inflammatory drugs (NSAIDs).

[0091] The active drug components mentioned above, such as Brinzolamide, Latanoprost, Latanoprostene Bunod, Travoprost, or Bimatoprost, have drug effects that prevent, treat, or improve glaucoma.

[0092] Table 10. Experimental results of adding the light transmittance, viscosity, and water content of the active drug component to the ophthalmic pharmaceutical composition of this application.

[0093] [Table 10]

[0094] From the experimental results of biofilm irritation (light transmittance), viscosity, and water content of the ophthalmic pharmaceutical composition of this application, as shown in Table 10, with the addition of an active drug component that is poorly soluble in water, it was found that the light transmittance of T24 to T33 was higher than 80%, indicating low irritation or no irritation after use; the viscosity of T24 to T33 was all less than 100, indicating good fluidity, allowing it to be formulated as an eye drop oil type, and that vision did not become cloudy after use; and from the water content results, it was found that the water content of T24 to T33 was all much lower than the water content of 0.75 that is usable by microorganisms, indicating that the ophthalmic pharmaceutical composition of this application is unfavorable for microbial growth, and therefore there is no need to add a preservative.

[0095] Example 6: An active drug component is added to the eye drop oil-type pharmaceutical composition of this application, with the addition of tacrolimus being an example.

[0096] After placing appropriate amounts of tacrolimus, liquid paraffin, lipids, and white petrolatum components into a glass beaker, the mixture was heated to approximately 90°C and stirred with a magnet until a mixed solution was obtained in which all components were completely dissolved and uniformly mixed. Then, while continuing to stir, the mixed solution was cooled to obtain tacrolimus-containing eye drop type pharmaceutical compositions in the different ratios shown in Table 12.

[0097] Comparative Example 1: Commercially available tacrolimus-containing eye drops Comparative Example 1 was prepared from a imitation component of a commercially available tacrolimus-containing eye drop solution, the components of which are shown in Table 11, and it contains 0.1 wt% tacrolimus. The preparation method involved adding 20% ​​water and polyvinyl alcohol to a beaker, heating to 80 degrees Celsius, stirring and dissolving, then cooling to 30 degrees Celsius, adding tacrolimus, and stirring at 3000 rpm for 15 minutes to form a homogeneous mixture (main component phase). In another beaker, 60% water and the remaining components were added and stirred and dissolved, the main component phase was added, water was added and quantified, and the mixture was uniformly stirred.

[0098] Table 11. Ingredients used to mimic commercially available tacrolimus-containing eye drops.

[0099] [Table 11]

[0100] Table 12. Tacrolimus-containing eye drop oil-type pharmaceutical compositions

[0101] [Table 12]

[0102] Eye irritation evaluation Table 13. Light transmittance and corresponding ocular irritation measured after in vitro testing of biological fluid membranes.

[0103] [Table 13]

[0104] The results in Table 13 show that the light transmittance of all tacrolimus-containing eye drop oil-type pharmaceutical compositions of this application is higher than 80%, indicating that they are all low-irritation and even non-irritating to the eye. In particular, the light transmittance of the tacrolimus-containing eye drop oil-type pharmaceutical compositions T34 to T43 is even higher than 95%, while in contrast, the light transmittance of the commercially available tacrolimus-containing eye drop solution in Comparative Example 1 was only 58.2%, clearly indicating that it is highly irritating to the eye.

[0105] This demonstrates that the tacrolimus-containing eye drop oil-type pharmaceutical composition of this application is indeed optimally effective in avoiding eye irritation compared to commercially available tacrolimus-containing eye drops that are highly irritating to the eye.

[0106] Stability evaluation This study performed stability tests on T34 to T43 and Comparative Example 1. Specifically, the tacrolimus-containing ophthalmic oil-type pharmaceutical compositions T34 to T43 and the commercially available tacrolimus-containing ophthalmic solution of Comparative Example 1 were left in an environment of 25°C for one month, then left in an environment of 70°C for three days. Subsequently, according to the tacrolimus raw material testing method specified in the USP, the tacrolimus content of each group was detected using high-performance liquid chromatography (HPLC-UV, L1 standard, silica gel particle size 3 microns, column diameter 4.6 cm, length 15 cm). Here, the mobile phase flow rate of the high-energy liquid chromatography was approximately 1.5 ml / min. The composition of the mobile phase is shown in Table 14 below, and the composition ratio of the mobile phase for different time periods is shown in Table 15 below. The results of the tacrolimus content measurement for T34 to T43 and Comparative Example 1 are shown in Table 16 below.

[0107] Table 14. Formulation of mobile phase for high-energy liquid chromatography.

[0108] [Table 14]

[0109] Table 15. Composition ratio of different time intervals for mobile phases in high-energy liquid chromatography.

[0110] [Table 15]

[0111] Table 16, Tacrolimus measurement results for T34 to T43 and Comparison 1

[0112] [Table 16]

[0113] From the results in Table 16 above, after stability testing, the tacrolimus content in the ophthalmic oil-type pharmaceutical compositions T34 to T43 was all higher than 85%, and the tacrolimus content in T34 to T40 and T42 was all higher than 95%. In contrast, the commercially available tacrolimus-containing ophthalmic solution of Comparative Example 1 contained only 71.8% tacrolimus after stability testing, which is significantly lower than the results for the pharmaceutical composition of this application. Thus, it was found that the tacrolimus-containing ophthalmic oil-type pharmaceutical composition of this application has better stability.

[0114] In summary, this application provides an eye drop oil, a novel ophthalmic pharmaceutical composition in a new dosage form, which has the following advantages compared to current technology: 1. It does not impair the stability of the tear film like eye drops, and is highly safe for long-term use. 2. Compared to eye ointments, the ophthalmic composition of this application comes in a standard eye drop bottle, is easy to use, has low ocular irritation, and does not cause blurred vision after use. 3. It can effectively prevent water dispersion and loss of the tear film, treat, prevent, or improve dry eye, and can meet the treatment needs of patients with excessive tear evaporation (oil-deficient dry eye). 4. It can be used as an ophthalmic drug platform by adding an active drug component that is poorly soluble in water. 5. Due to its low water content and low water activity, there is no need to add preservatives, thus avoiding side effects associated with preservatives. 6. Results from the tacrolimus-containing ophthalmic pharmaceutical composition showed that this invention is more stable than commercially available products.

Claims

1. A pharmaceutical composition in the form of an eye drop oil, comprising lipids, white petrolatum, and liquid paraffin, wherein the pharmaceutical composition comprises 3 to 500 milligrams of lipids, 100 to 250 milligrams of white petrolatum, and 1 to 797 milligrams of liquid paraffin per gram.

2. The pharmaceutical composition according to claim 1, wherein the lipids include medium-chain triglycerides, soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), wool oil, peanut oil, and bellflower oil.

3. The pharmaceutical composition according to claim 1, wherein the lipid is a medium-chain triglyceride.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 3 to 300 milligrams of lipid, 100 to 250 milligrams of white petrolatum, and 300 to 797 milligrams of liquid paraffin per gram.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 3 to 300 milligrams of lipid, 100 to 240 milligrams of white petrolatum, and 500 to 797 milligrams of liquid paraffin per gram.

6. The pharmaceutical composition according to claim 1, wherein an active drug component may be added to the eye drop oil type pharmaceutical composition.

7. The pharmaceutical composition according to claim 6, wherein the active drug component comprises mineral oil, steroids, tetracyclines, macrolide antibiotics, prostaglandins, carbonic anhydrase inhibitors, immunosuppressants, or other active drug components that are poorly soluble in water.

8. The pharmaceutical composition according to claim 7, wherein the steroid comprises Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate, or Hydrocortisone Acetate.

9. The pharmaceutical composition according to claim 7, wherein the tetracycline comprises doxycycline hydroxylate, tetracycline HCl, or minocycline HCl.

10. The pharmaceutical composition according to claim 7, wherein the macrolide antibiotic comprises erythromycin or azithromycin.

11. The pharmaceutical composition according to claim 7, wherein the prostaglandin comprises latanoprost, latanoprostene bunod, travoprost, or bimatoprost.

12. The pharmaceutical composition according to claim 7, wherein the carbonic anhydrase inhibitor comprises brinzolamide.

13. The pharmaceutical composition according to claim 7, wherein the immunosuppressant comprises Tacrolimus or Sirolimus.

14. The pharmaceutical composition according to claim 7, wherein the other active drug component that is poorly soluble in water comprises Rebamipide, Omega 3, Nepafenac, Besifloxacin HCl, Selenium Disulfide, Vitamin A, or Cyclosporin.

15. An application for manufacturing a drug that treats, prevents, or improves dry eye as described in claim 1.

16. The use according to claim 15, wherein the dry eye is a type of dry eye caused by excessive tear evaporation.

17. The use according to claim 15, wherein the dry eye is due to dysfunction of the meibomian glands.

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