Eye-drop oil type pharmaceutical composition

Abstract

The invention relates to a pharmaceutical composition for an eye drop dosage form. The pharmaceutical composition comprises a lipid, white soft paraffin and liquid paraffin. Each gram of the ophthalmic pharmaceutical composition comprises 3 to 500 milligrams of lipid, 100 to 250 milligrams of white soft paraffin and 1 to 797 milligrams of liquid paraffin.

Description

A kind of pharmaceutical composition of eye drop oil dosage form

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 442,153, filed in the United States on January 31, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application relates to an ophthalmic drug, in particular to an eye drop oil dosage form which is free of preservatives and has no eye irritation. Background Art

[0004] The surface of the normal eyeball is covered with a layer of tears, providing lubrication and protection for the eye. This layer is called the "tear film." The tear film structure can be subdivided into three layers: from the inside out, the mucus layer, the water layer, and the oil layer (Figure 1). The mucus layer increases the viscosity of the tears, helping them to remain on the surface of the eye. The water layer provides a smooth optical refractive surface for vision and keeps the eye moist. The outermost oil layer prevents excessive tear evaporation, helps lubricate the eye, and maintains the integrity of the tear film. The absence of any of these layers results in an unstable tear film, leading to dry eye symptoms.

[0005] In 1995, the National Eye Institute (NEI) of the United States classified dry eye into two major categories: deficient aqueous production (i.e., aqueous dry eye) and over-evaporation (i.e., oil-deficient dry eye). According to a study published in Cornea. 2012 May; 31(5): 472-8, most dry eye syndromes are not caused by insufficient tear secretion. Up to 86% of dry eye patients suffer from meibomian gland dysfunction leading to over-evaporation (oil-deficient dry eye), while only 14% suffer from simple insufficient tear production (aqueous dry eye). According to statistics from the GlobalData database, artificial tears are still the main medication for dry eye in most countries around the world, and there is a lack of medications specifically tailored to the needs of patients with oil-deficient dry eye.

[0006] Common dosage forms of ophthalmic medications include eye drops, ophthalmic suspensions, and eye ointments. Eye drops are aqueous eye drops, which are susceptible to microbial contamination. Multi-dose packaging typically contains preservatives. Preservative-free eye drops can only be packaged in single-use, disposable packaging, which is expensive and hinders widespread use. Long-term and frequent use of preservative-containing eye drops may aggravate chronic eye inflammation and corneal cell damage. Furthermore, eye drops may also wash away the lipid layer of the tear film, disrupting its integrity and leading to the development or worsening of dry eye. Although some eye drops contain trace amounts of lipids, claiming to mimic the composition of the tear film, these preparations require the addition of surfactants to dissolve the lipids in water, which in turn burdens the eyes.

[0007] Furthermore, some active pharmaceutical ingredients for ophthalmic use are insoluble in water and can only be formulated as ophthalmic suspensions or ophthalmic ointments. In addition to the same issues as eye drops, ophthalmic suspensions must be shaken before use. Failure to shake the ointment thoroughly can lead to uneven distribution of the active ingredient, resulting in insufficient efficacy and sometimes an overdose. Ophthalmic ointments are packaged in soft tubes and need to be squeezed into the lower eyelid, making them difficult for elderly patients to use on their own. They can also cause blurred vision and a foreign body sensation, impacting daily life.

[0008] Eye drops may affect tear film stability and require attention to preservatives that may harm the eyes. Ophthalmic suspensions share the same issues as eye drops but also carry the risk of uneven content. Eye ointments are difficult to apply and can obstruct vision or cause discomfort, such as a foreign body sensation. These common ophthalmic dosage forms currently on the market all have significant shortcomings. Therefore, there is an urgent need to develop a new ophthalmic dosage form that can not only alleviate dry eye symptoms but also serve as an ophthalmic drug platform for the addition of water-insoluble active pharmaceutical ingredients. This is an important issue addressed by this application.

[0009] Summary of the Invention

[0010] In response to the shortcomings of the related art, the present application provides a pharmaceutical composition in the form of an eye drop oil. This pharmaceutical composition is low in eye irritation, preservative-free, and does not cause blurred vision after use. It can be packaged in a typical multi-dose, reusable eye drop bottle for ease of use. The present pharmaceutical composition in the form of an eye drop oil can effectively prevent water loss from the tear film, alleviate dry eye symptoms, and can be further supplemented with insoluble active pharmaceutical ingredients, offering a new alternative to ophthalmic drug formulation platforms.

[0011] The present application aims to provide a pharmaceutical composition in the form of an eye drop oil, comprising: a lipid, white petrolatum, and liquid paraffin. Each gram of the pharmaceutical composition comprises 3-500 mg of lipid, 100-250 mg of white petrolatum, and 1-797 mg of liquid paraffin.

[0012] To achieve the aforementioned application purpose, the lipid comprises medium-chain triglyceride (MCT), soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), and lanolin.

[0013] To achieve the aforementioned application purpose, the lipid is a medium chain triglyceride.

[0014] To achieve the aforementioned application purpose, each gram of the pharmaceutical composition comprises 3-500 mg of lipid, 100-250 mg of white soft paraffin, and 300-797 mg of liquid paraffin.

[0015] To achieve the aforementioned application purpose, each gram of the pharmaceutical composition contains 3-300 mg of lipid, 100-240 mg of white soft paraffin, and 500-797 mg of liquid paraffin.

[0016] To achieve the aforementioned application purposes, the pharmaceutical composition may be added with active pharmaceutical ingredients.

[0017] To achieve the aforementioned application purpose, the active pharmaceutical ingredient comprises mineral oil, steroids, tetracycline, macrocyclic antibiotics, prostaglandins, carbonic anhydrase inhibitors, immunosuppressants or other active pharmaceutical ingredients that are poorly soluble in water.

[0018] For the purpose of the aforementioned application, the steroid comprises Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate or Hydrocortisone Acetate.

[0019] For the purpose of the aforementioned application, the tetracycline comprises doxycycline hyclate, tetracycline HCl or minocycline HCl.

[0020] To achieve the aforementioned application purpose, the macrocyclic antibiotic comprises erythromycin or azithromycin.

[0021] To achieve the aforementioned application purpose, the prostaglandin includes Latanoprost, Latanoprost Bunod, Travoprost, and Bimatoprost.

[0022] To achieve the aforementioned application purpose, the carbonic anhydrase inhibitor comprises Brinzolamide.

[0023] To achieve the aforementioned application purpose, the immunosuppressant comprises tacrolimus or sirolimus.

[0024] To achieve the aforementioned application purpose, the other poorly water-soluble active pharmaceutical ingredients include rebamipide, Omega 3, Nepafenac, Besifloxacin HCl, Selenium Disulfide, Vitamin A or Cyclosporin.

[0025] Another object of the present application is to develop an ophthalmic pharmaceutical composition for use in preparing a drug for treating, preventing or improving dry eye, especially oil-deficient dry eye, which is caused by meibomian gland dysfunction.

[0026] In summary, the present application provides an eye drop oil, which is a new dosage form of an ophthalmic pharmaceutical composition. Compared with the current technology, it has the following advantages: 1. It will not destroy the stability of the tear film like eye drops, and is highly safe for long-term use. 2. Compared with eye ointments, the ophthalmic composition of the present application is contained in a general eye drop bottle, which is convenient to use, has low eye irritation, and will not cause blurred vision after use. 3. It can effectively prevent the loss of water from the tear film, treat, prevent or improve dry eye, and meet the treatment needs of patients with excessive tear evaporation (oil-deficient dry eye). 4. Active pharmaceutical ingredients that are difficult to dissolve in water can be added as an ophthalmic drug platform. 5. There is no need to add preservatives, reducing preservative-related side effects. 6. The stability is better than commercially available products. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is a schematic diagram of the tear film;

[0028] Figure 2 shows the change in tear volume one hour after medication. DETAILED DESCRIPTION

[0029] Example 1 Irritation and Viscosity Detection

[0030] The viscosity and biofilm (% T) data were used to confirm and evaluate whether the ophthalmic pharmaceutical composition of the present application had good viscosity and low eye irritation.

[0031] Viscosity evaluation method: using microVISC TM Viscometer test (in accordance with USP <914> The viscosity of water for injection (WFI) is 0.894, and the viscosity of the reference ointment 2 is 2537.7 (as shown in Table 5), which can be used as a reference for the fluidity of eye drops. Viscosity is a resistance to flow within a viscous liquid and can be considered the friction of the fluid itself. Viscosity primarily arises from the mutual attraction between molecules, so substances with lower viscosities flow more easily. The lower the viscosity value, the better the fluidity. After instillation into the eye, it will not cause blurred vision or affect visual clarity. Furthermore, the ointment can be stored in standard eye drop bottles, making it more convenient for patients to use than tube-type eye drops.

[0032] Biofilm assessment method: Based on the Organization for Economic Co-operation and Development (OECD) Chemical Testing Specification No. 496, "In vitro Macromolecular Test Method for Identifying Chemicals Inducing Serious Eye Damage and Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage," in vitro testing of biofilms simulates the eye irritation potential of chemicals. Irritancy is assessed by observing the chemical reaction of macromolecules with irritants and the resulting turbidity of the solution caused by protein denaturation.

[0033] The test method involves mixing the drug and reagent to denature the protein, resulting in a turbid solution. Transmittance is then measured using a UV spectrophotometer (manufacturer: Hitachi; model: U-2900) according to the United States Pharmacopeia (USP) specifications for transmittance. The transmittance of each group at a wavelength of approximately 405 nm is shown in Table 1 below. Transmittance can be used to assess the degree of eye irritation, with higher transmittance indicating lower irritation and lower transmittance indicating higher irritation. Specifically, a transmittance greater than 90% is considered non-irritating, a transmittance greater than 80% and less than or equal to 90% is considered low irritating, a transmittance greater than 70% and less than or equal to 80% is considered moderate irritating, and a transmittance less than or equal to 70% is considered high irritating.

[0034] This application discloses an ophthalmic pharmaceutical composition comprising a medium-chain triglyceride, white soft paraffin, and liquid paraffin. Viscosity and biofilm irritation (% T) data for compositions with varying component ratios as shown in Tables 1-3 confirm that these compositions exhibit good fluidity and low eye irritation.

[0035] The content of white soft paraffin in the ophthalmic pharmaceutical composition was fixed, while the contents of MCT and liquid paraffin were varied. According to the results in Table 1, when the MCT content was varied, the transmittance of the ophthalmic pharmaceutical compositions with MCT contents ranging from 3 to 500 mg / g was greater than 90%, indicating that they were non-irritating to the eyes. However, the viscosity of the ophthalmic pharmaceutical compositions with formulations T10 and T11 was acceptable, suggesting that high MCT content (greater than 500 mg / g) may affect visual clarity and make eye drops difficult to dispense from the eye dropper bottle.

[0036] Table 1. Ophthalmic pharmaceutical compositions containing MCT in different proportions

[0037] To determine whether MCT and liquid paraffin could be replaced with other lipids, the ophthalmic pharmaceutical composition maintained the same levels of white soft paraffin and liquid paraffin, while lipids selected from soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), and lanolin were added. The results in Table 2 show that the ophthalmic pharmaceutical composition exhibited a transmittance greater than 90% regardless of the lipid type, demonstrating its non-irritating properties. The composition also exhibited good flowability, did not blur vision, and did not affect visual clarity.

[0038] Table 2. Ophthalmic pharmaceutical compositions of different lipids

[0039] The MCT content in the ophthalmic pharmaceutical composition was fixed while the white soft paraffin and liquid paraffin contents were varied. According to the results in Table 3, the transmittance was greater than 85% for compositions with a white soft paraffin content of 100-250 mg / g, indicating minimal eye irritation. However, the viscosity of the ophthalmic pharmaceutical composition with formulation T23 was acceptable, suggesting that a high white soft paraffin content (greater than 250 mg / g) could blur vision and affect visual clarity.

[0040] Table 3. Ophthalmic pharmaceutical compositions with different proportions of white soft paraffin

[0041] This ophthalmic pharmaceutical composition is an eye drop oil formulation, characterized by its composition ratios of 3-300 mg / g lipid, 100-250 mg / g white soft paraffin, and 1-797 mg / g liquid paraffin, all of which provide excellent comfort. The subsequent examples are based on the T03 formulation: 100 mg / g MCT, 200 mg / g white soft paraffin, and 700 mg / g liquid paraffin.

[0042] Table 4 shows the dosage forms and package inserts of commercially available ophthalmic products commonly used by dry eye patients. Reference 1 is a commonly used artificial tear solution, and Reference 2 is an eye ointment for eye lubrication. Table 5 compares the viscosity and transmittance of the present ophthalmic pharmaceutical composition with commercially available products. The transmittance of the present ophthalmic pharmaceutical composition with formulation T03, water for injection, Reference 1, and Reference 2 all exceeds 90%, indicating non-irritation to the eyes. Reference 2 has a high viscosity, which is expected to severely blur vision and affect visual clarity. Furthermore, it can only be contained in a tube, making it inconvenient to use.

[0043] Table 4. Dosage forms and ingredients of commercially available products (as indicated on the package insert)

[0044] Table 5. Comparison of the ophthalmic pharmaceutical composition of this case with water for injection and commercially available products

[0045] Example 2 Stability Analysis

[0046] In order to evaluate the stability of the ophthalmic pharmaceutical composition of the present application, the changes in stability were observed using parameters such as moisture content, appearance, specific gravity, viscosity, and acid value.

[0047] The ophthalmic pharmaceutical composition of the present application comprises a mineral oil, a lipid, and white soft paraffin. The lipid is an oil other than mineral oil, and includes, but is not limited to, medium-chain triglycerides, soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), lanolin oil, peanut oil, and castor oil. The lipid in the ophthalmic pharmaceutical composition is primarily composed of medium-chain triglycerides.

[0048] The ophthalmic pharmaceutical composition of the present application comprises 3-500 mg / g lipid, 100-250 mg / g white soft paraffin, and 1-797 mg / g liquid paraffin.

[0049] The preferred formulation of the ophthalmic pharmaceutical composition of the present application comprises 3-300 mg / g lipid, 100-250 mg / g white soft paraffin, and 300-797 mg / g liquid paraffin.

[0050] The optimal formulation of the ophthalmic pharmaceutical composition of the present application comprises 3-300 mg / g lipid, 100-240 mg / g white soft paraffin, and 500-797 mg / g liquid paraffin.

[0051] The following experiments were conducted based on the T03 formula: MCT 100 mg / g, white soft paraffin 200 mg / g, and liquid paraffin 700 mg / g.

[0052] Detection method:

[0053] Appearance: slightly white, fluid eye drops

[0054] Water content: The solvent is 20.0 mL of a mixture of toluene and methanol (7:3), which should not exceed 0.5% (Karl Fischer Moisture Titrator).

[0055] Specific gravity: 0.806~0.870 (weight conversion)

[0056] Acid value: (refer to USP <401> ACID VALUE)

[0057] Accurately weigh approximately 20 g of the test sample and place it in a flask. Add 50 mL of a neutral mixture of ethanol and 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 test sample does not dissolve in the cold solution, connect the flask to a reflux condenser and slowly heat while shaking occasionally until it dissolves. Add 1 mL of phenolphthalein test solution and titrate with 0.05 N potassium hydroxide solution until the solution retains a light red color after shaking for 30 seconds.

[0058] The results in Table 6 show that after three months of accelerated stability testing, the ophthalmic pharmaceutical composition of the present application has a stable composition and no significant change in acid value. It can be stored for a long time and will not deteriorate during storage and sales.

[0059] Table 6. Accelerated stability data

[0060] Example 3 Moisture content test (refer to USP <922> 、 <1112> )

[0061] Water content is divided into water content and water activity. w ), the water content detected includes free water and bound water (also known as fixed water or hydrated water). Among them, only free water has water activity because free water is ordinary water and can be used by microorganisms; while bound water has no solvent function and cannot be used by microorganisms.

[0062] Reduce water activity (a w ) helps prevent the proliferation of microorganisms in pharmaceuticals. Moisture content testing demonstrates that the formulation of this application has low water activity. Because the ophthalmic pharmaceutical composition of this application is prepared aseptically, no preservatives are required to maintain sterility.

[0063] According to the United States Pharmacopoeia <1112> Regarding the water activity, drugs with a water activity far below 0.75 are the standard for evaluating product stability. Therefore, this can be used to evaluate whether the application does not require the addition of preservatives and will not allow microbial growth.

[0064] Table 7. Moisture content test

[0065] The moisture content test results in Table 7 indicate that the moisture content of the ophthalmic pharmaceutical compositions of the present application at various ratios is consistently below 0.5. This moisture content includes both free and bound water. This means that the free water (water activity) in the ophthalmic pharmaceutical compositions of the present application is significantly lower than the microbially accessible 0.75. Therefore, the ophthalmic pharmaceutical compositions of the present application are effective in preventing microbial proliferation in the drug, eliminating the need for preservatives. Tables 4 and 7 also indicate that, because the artificial tears in Reference 1 are aqueous, they require the addition of a preservative for long-term storage.

[0066] Example 4 This application improves tear secretion

[0067] Fifteen subjects were administered with reference product 1, artificial tears, reference product 2, eye ointment, and the ophthalmic pharmaceutical composition of the present application as test products.

[0068] The ophthalmic pharmaceutical composition of the present application comprises 3-500 mg / g lipid, 100-250 mg / g white soft paraffin, and 1-797 mg / g liquid paraffin.

[0069] The preferred formulation of the ophthalmic pharmaceutical composition of the present application comprises 3-300 mg / g lipid, 100-250 mg / g white soft paraffin, and 300-797 mg / g liquid paraffin.

[0070] The optimal formulation of the ophthalmic pharmaceutical composition of the present application comprises 3-300 mg / g lipid, 100-240 mg / g white soft paraffin, and 500-797 mg / g liquid paraffin.

[0071] The following experiments were conducted based on the T03 formula: MCT 100 mg / g, white soft paraffin 200 mg / g, and liquid paraffin 700 mg / g.

[0072] Fifteen subjects were randomly assigned to three groups for repeated administration, as shown in Table 8. Tear secretion was measured using the Schirmer's test before and one hour after administration to determine whether the ophthalmic pharmaceutical composition of the present application was superior to commercially available products in terms of tear secretion.

[0073] Table 8. Test groups

[0074] Evaluation method: Tear secretion test (Schirmer's Test)

[0075] Baseline (before drug use)

[0076] 1 hour after medication: Calculate the result after measurement and subtract the Baseline value

[0077] Test steps:

[0078] Baseline value: Before medication, Schirmer's test was performed on both eyes of each subject using tear test strips.

[0079] Each subject's left and right eyes were treated with medication according to the groups in Table 8, and then the following steps were followed.

[0080] One hour after drug application, Schirmer's Test was performed on both eyes of each subject.

[0081] After each medication group is completed, you must wait for a one-day drug clearance period before using the next medication group.

[0082] Schirmer's Test tear secretion test results

[0083] A total of 15 subjects were included in the trial results for statistical analysis, and the measured values ​​were averaged. As shown in Table 9, the measured value 1 hour after medication was subtracted from the Baseline result to show whether the tear secretion volume increased or decreased after medication, and the change in the measured data before and after medication was converted into a percentage to further show the ratio of tear increase or decrease. The results showed that the tear secretion volume of the right eye of the first group using the ophthalmic pharmaceutical composition of the present application was significantly greater than that of the left eye using the control product 1 artificial tears 1 hour after medication (p = 0.013). In terms of tear secretion volume, the test results of the left and right eyes of the other medication groups did not reach statistically significant differences. At the same time, according to the test results of the second group, even if the ophthalmic pharmaceutical composition of the present application is used in addition to the control product 1 artificial tears, its tear secretion volume is not significantly better than that of the ophthalmic pharmaceutical composition of the present application alone.

[0084] Table 9. Changes in Schirmer's Test tear secretion one hour after medication

[0085] The results of the Schirmer's Test one hour after medication are presented in a bar graph, which can more intuitively show the change in tear volume, as shown in Figure 2.

[0086] Compared with other commercially available products, the ophthalmic pharmaceutical composition of the present application is significantly superior to the artificial tears of Reference 1, as shown in the tear secretion test results in Table 9. Even if the ophthalmic pharmaceutical composition of the present application is used together with the artificial tears of Reference 1, the effect is not better than that of the ophthalmic pharmaceutical composition of the present application alone. The ophthalmic pharmaceutical composition of the present application has similar effects to the eye ointment of Reference 2. However, according to the fluidity results in Table 5, the ophthalmic pharmaceutical composition of the present application has better fluidity than the eye ointment of Reference 2, can be contained in an eye drop bottle, is more convenient for patients to use, and does not cause blurred vision after use.

[0087] Example 5 Adding active pharmaceutical ingredients to the ophthalmic pharmaceutical composition of the present application

[0088] Due to their poor water solubility, poorly water-soluble active pharmaceutical ingredients have traditionally been formulated into ophthalmic suspensions or ophthalmic ointments. Ophthalmic suspensions not only require the addition of preservatives but also carry the risk of uneven content. Ophthalmic ointments, on the other hand, are difficult to apply and can cause visual impairment, foreign body sensation, and other discomforts. The ophthalmic pharmaceutical composition of the present application, being an oily formulation, can serve as an ophthalmic drug platform, allowing the addition of poorly water-soluble active pharmaceutical ingredients to the formulation for use as an eye drop oil.

[0089] Active pharmaceutical ingredients that are poorly soluble in water include steroids, tetracyclines, macrocyclic antibiotics, prostaglandins, carbonic anhydrase inhibitors (CAIs), immunosuppressants or other active pharmaceutical ingredients that are poorly soluble in water.

[0090] The poorly water-soluble active pharmaceutical ingredient steroids include Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate, and Hydrocortisone Acetate. Loteprednol Etabonate has the worst water solubility and was used as a representative steroid for subsequent experiments.

[0091] Tetracyclines, active pharmaceutical ingredients that are poorly soluble in water, include Doxycycline hyclate, Tetracycline HCl, Minocycline HCl, etc. Among them, Doxycycline hyclate has the worst water solubility and was used as a representative tetracycline in subsequent experiments.

[0092] Macrocyclic antibiotics with poorly water-soluble active pharmaceutical ingredients include erythromycin, azithromycin, etc. Among them, azithromycin has the worst water solubility and was used as a representative macrocyclic antibiotic for subsequent experiments.

[0093] The poorly water-soluble active pharmaceutical ingredient prostaglandin includes Latanoprost, Latanoprostene Bunod, Travoprost or Bimatoprost.

[0094] Carbonic anhydrase inhibitors that are poorly water-soluble active pharmaceutical ingredients include brinzolamide and the like.

[0095] Active pharmaceutical ingredient immunosuppressants that are poorly soluble in water include tacrolimus and sirolimus. Among them, sirolimus has the worst water solubility and was used as a representative immunosuppressant for subsequent experiments.

[0096] Other poorly water-soluble active pharmaceutical ingredients include Rebamipide, Omega 3, Nepafenac, Besifloxacin HCl, Selenium disulfide, Cyclosporin, Vitamin A, etc.

[0097] The aforementioned active pharmaceutical ingredients, such as Cyclosporin, Tacrolimus, Sirolimus, Rebamipide, Omega 3, Selenium Disulfide, and Vitamin A, have the efficacy of preventing, treating, or improving dry eye.

[0098] The aforementioned Doxycycline Hyclate, Erythromycin, Minocycline HCl, Azithromycin, etc. have the efficacy of preventing, treating or improving meibomian gland dysfunction.

[0099] The aforementioned Besifloxacin HCl, Tetracycline HCl, Doxycycline Hyclate, Erythromycin, Minocycline HCl, Azithromycin, etc. have the efficacy of treating bacterial infections.

[0100] The active pharmaceutical ingredients of the aforementioned Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate, Hydrocortisone Acetate, etc. may be steroids.

[0101] The active pharmaceutical ingredients of the aforementioned Nepafenac and the like are nonsteroidal anti-inflammatory drugs (NSAIDs).

[0102] The aforementioned active pharmaceutical ingredients such as Brinzolamide, Latanoprost, Latanoprostene Bunod, Travoprost or Bimatoprost have the efficacy of preventing, treating or improving glaucoma.

[0103] Table 10. Experimental results of transmittance, viscosity, and water content of the ophthalmic pharmaceutical composition of the present application with the addition of active pharmaceutical ingredients

[0104] Table 10 shows the experimental results of biofilm irritation (light transmittance), viscosity, and water content of the ophthalmic pharmaceutical compositions of the present application, which were tested for the addition of a poorly water-soluble active pharmaceutical ingredient. The light transmittance of T24 to T33 was greater than 80%, indicating low or no irritation after use. The viscosities of T24 to T33 were all less than 100, indicating good fluidity and suitability for use as eye drops without causing blurred vision. The water content results indicate that the water contents of T24 to T33 were all well below the microbially accessible water content of 0.75. Therefore, the ophthalmic pharmaceutical compositions of the present application are not conducive to microbial growth and therefore do not require the addition of preservatives.

[0105] Example 6: Adding active pharmaceutical ingredients to the eye drop oil dosage form pharmaceutical composition of the present application, taking the addition of tacrolimus as an example

[0106] Appropriate amounts of tacrolimus, liquid paraffin, lipid, and white soft paraffin were placed in a glass beaker, which was then heated to approximately 90° C. and stirred with a magnet until the components were completely dissolved to obtain a uniformly mixed solution. The mixed solution was then continuously stirred and cooled to obtain pharmaceutical compositions in the form of eye drops containing tacrolimus in different proportions as shown in Table 12.

[0107] Comparative Example 1 Commercially available tacrolimus eye drops

[0108] Comparative Example 1 was prepared according to the instructions for commercially available tacrolimus eye drops, the ingredients listed in Table 11. The solution contained 0.1 wt% tacrolimus. The preparation method involved adding 20% ​​water and polyvinyl alcohol to a beaker, heating to 80°C and stirring to dissolve. The temperature was then lowered to 30°C. The tacrolimus was then added and homogenized at 3000 rpm for 15 minutes (main phase). In another beaker, 60% water and the remaining ingredients were added and stirred to dissolve. The main phase was then added to the beaker, and water was added in a fixed amount, stirring thoroughly.

[0109] Table 11. Ingredients of commercially available tacrolimus eye drops package insert

[0110] Table 12. Pharmaceutical compositions containing tacrolimus in the form of eye drops in oil form

[0111] Eye irritation assessment

[0112] Table 13. Light transmittance and corresponding eye irritation measured after in vitro testing of biological liquid films

[0113] As can be seen from the results in Table 13, the transmittance of the tacrolimus-containing eye drop oil formulation pharmaceutical compositions of the present application is all above 80%, and therefore they are low or even non-irritating to the eyes. In particular, the transmittance of the tacrolimus-containing eye drop oil formulation pharmaceutical compositions T34 to T43 is even above 95%. In contrast, the transmittance of the commercially available tacrolimus-containing eye drop solution in Comparative Example 1 is only 58.2%, which is clearly highly irritating to the eyes.

[0114] This demonstrates that, compared to the commercially available tacrolimus-containing eye drops that are highly irritating to the eyes, the tacrolimus-containing eye drop oil formulation of the present application indeed has a better effect in avoiding eye irritation.

[0115] Stability assessment

[0116] This study used T34 to T43 and Comparative Example 1 for stability testing. Specifically, the tacrolimus-containing eye drop oil formulations of T34 to T43 and the commercially available tacrolimus-containing eye drops of Comparative Example 1 were placed in a 25°C environment for one month and then in a 70°C environment for three days. The tacrolimus content of each group was then determined using a high-performance liquid chromatography (HPLC-UV) instrument (using L1 specification, 3-micron silica gel particle size, and a column diameter of 46 cm and length of 15 cm) according to the USP standard for the analysis of tacrolimus raw materials. The flow rate of the HPLC mobile phase 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 at different times is shown in Table 15 below. The tacrolimus content determination results of T34 to T43 and Comparative Example 1 are listed in Table 16 below.

[0117] Table 14. Formulation of mobile phase for high performance liquid chromatography

[0118] Table 15. Composition ratio of mobile phase in HPLC at different times

[0119] Table 16. Tacrolimus assay results for T34 to T43 and Comparison 1

[0120] As shown in Table 16, after stability testing, the tacrolimus content in the eye drop oil formulation pharmaceutical compositions of T34 to T43 remained above 85%. Specifically, the tacrolimus content in T34 to T40 and T42 all exceeded 95%. In contrast, the commercially available tacrolimus-containing eye drops of Comparative Example 1, after stability testing, contained only 71.8% tacrolimus, significantly lower than the result of the pharmaceutical composition of the present application. This demonstrates that the tacrolimus-containing eye drop oil formulation pharmaceutical composition of the present application indeed possesses superior stability.

[0121] In summary, the present application provides an eye drop oil, which is a new dosage form of an ophthalmic pharmaceutical composition. Compared with the existing technology, it has the following advantages: 1. It will not destroy the stability of the tear film like eye drops, and is highly safe for long-term use. 2. Compared with eye ointments, the ophthalmic composition of the present application is contained in a general eye drop bottle, which is convenient to use, has low eye irritation, and will not cause blurred vision after use. 3. It can effectively prevent the loss of water from the tear film, treat, prevent or improve dry eye, and meet the treatment needs of patients with excessive tear evaporation (oil-deficient dry eye). 4. Active pharmaceutical ingredients that are difficult to dissolve in water can be added as an ophthalmic drug platform. 5. Due to the low water content and low water activity, there is no need to add preservatives, avoiding preservative-related side effects. 6. From the results of the ophthalmic pharmaceutical composition containing tacrolimus, it can be seen that the stability of this case is better than that of commercially available products.

Claims

1. A pharmaceutical composition in the form of an eye drop oil, comprising: a lipid, white soft paraffin, and liquid paraffin, wherein each gram of the ophthalmic pharmaceutical composition comprises 3-500 mg of lipid, 100-250 mg of white soft paraffin, and 1-797 mg of liquid paraffin.

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), lanolin, peanut oil, and castor oil.

3. The pharmaceutical composition according to claim 1, wherein The lipids are medium chain triglycerides.

4. The pharmaceutical composition according to claim 1, wherein Each gram of the pharmaceutical composition contains 3-300 mg of lipid, 100-250 mg of white soft paraffin, and 300-797 mg of liquid paraffin.

5. The pharmaceutical composition according to claim 1, wherein Each gram of the pharmaceutical composition contains 3-300 mg of lipid, 100-240 mg of white soft paraffin, and 500-797 mg of liquid paraffin.

6. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition in the form of eye drops can be added with active pharmaceutical ingredients.

7. The pharmaceutical composition according to claim 6, wherein The active pharmaceutical ingredient comprises mineral oil, steroids, tetracycline, macrocyclic antibiotics, prostaglandins, carbonic anhydrase inhibitors, immunosuppressants or other active pharmaceutical ingredients that are poorly soluble in water.

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

9. The pharmaceutical composition according to claim 7, wherein The tetracycline comprises Doxycycline Hyclate, Tetracycline HCl or Minocycline HCl.

10. The pharmaceutical composition according to claim 7, wherein The macrocyclic 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 contains Tacrolimus or Sirolimus.

14. The pharmaceutical composition according to claim 7, wherein The other poorly water-soluble active pharmaceutical ingredients include Rebamipide, Omega 3, Nepafenac, Besifloxacin HCl, Selenium Disulfide, Vitamin A or Cyclosporin.

15. Use of the pharmaceutical composition according to claim 1 for preparing a drug for treating, preventing or improving dry eye.

16. The use according to claim 15, wherein This dry eye syndrome is caused by excessive tear evaporation.

17. The use according to claim 15, wherein This dry eye syndrome is caused by meibomian gland dysfunction.

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