Pharmaceutical composition for eye drop oil dosage form

Abstract

A pharmaceutical composition for an eye drop oil dosage form, comprising a lipid, white petrolatum, and liquid paraffin. Each gram of the ophthalmic pharmaceutical composition comprises 3-500 mg of a lipid, 100-250 mg of white petrolatum and 1-797 mg of liquid paraffin.

Description

T41 0.001 wt% 15 wt% 20 wt% 64.999 wt% of liquid paraffin T42 0.01 wt% 5 wt% 25 wt% 69.99 wt% of liquid paraffin T43 0.01 wt% 3 wt% 25 wt% 71.99 wt% of liquid paraffin T44 0.1 wt% 30 wt% - 69.9 wt% of canola oil T45 0.1 wt% 30 wt% - Combination of 39.9 wt% of liquid paraffin and 30 wt% of canola oil T46 0.1 wt% - - Combination of 69.9 wt% of liquid paraffin and 30 wt% of soybean oil T47 0.1 wt% - - Combination of 69.9 wt% of liquid paraffin and 30 wt% of lanolin oil T48 0.1 wt% - - Combination of 69.9 wt% of liquid paraffin and 30 wt% of olive oil T49 0.1 wt% - - Combination of 69.9 wt% of liquid paraffin and 30 wt% of corn oil 0089] Eye irritation evaluation Table 13 Transmittance and Corresponding Eye Irritation Measured by In vitro Test of Biological Liquid Film Group Transmittance (%) Eye Irritation T34 99.1 No eye irritation T35 98.6 No eye irritation T36 98.1 No eye irritation T37 99.8 No eye irritation T38 98.3 No eye irritation T39 96.3 No eye irritation T40 100.0 No eye irritation T41 100.0 No eye irritation T42 99.6 No eye irritation T43 98.8 No eye irritation T44 82.9 Low eye irritation T45 91.3 No eye irritation T46 86.7 Low eye irritation T47 91.0 No eye irritation T48 87.8 Low eye irritation T49 89.2 Low eye irritation Comparative Example 1 58.2 High eye irritation

[0090] From the results in Table 13, it can be seen that the tacrolimus-containing pharmaceutical compositions for eye drop oil dosage form of the present invention have a transmittance higher than 80%, so they are low-irritating or even non-irritating to the eyes, and the tacrolimus-containing pharmaceutical compositions of eye drop oil dosage form of T34 to T43 have a transmittance higher than 95%. In contrast, the commercially available tacrolimus-containing eye drops in Comparative Example 1 have a transmittance of only 58.2%, so they are obviously highly irritating to the eyes.

[0091] This demonstrates that, compared to the commercially available tacrolimus-containing eye drops with high eye irritation, the tacrolimus-containing pharmaceutical compositions for eye drop oil dosage form of the present invention do have a better effect of avoiding eye irritation.

[0092] Stability evaluation

[0093] In this test, T34 to T43 and Comparative Example 1 were selected for the stability test. Specifically, the tacrolimus-containing pharmaceutical compositions for eye drop oil dosage form of T34 to T43 and the commercially available tacrolimus-containing eye drops of Comparative Example 1 were placed at 25°C for 1 month, and then at70°C for 3 days. After that, according to the method for testing tacrolimus raw materials specified in USP, the tacrolimus content of each group was detected by high performance liquid chromatography (HPLC-UV; which adopts L1 specification, silica gel particle size of 3 microns, column diameter of 4.6 cm, and length of 15 cm), where the flow rate of the mobile phase of the high performance liquid chromatography is about 1.5 ml / min, the composition formulation of the mobile phase is shown in Table 14 below, and the composition proportion of the mobile phase at different times is shown in Table 15 below. The results of tacrolimus content determination for T34 to T43 and Comparative Example 1 are listed in Table 16 below. Table 14 Mobile Phase Formulation for High Performance Liquid Chromatography Solution A Solution B Solution C Solution D Phosphoric acid at a concentration of 6 mM A solution of acetonitrile and tertiary methyl butyl ether mixed in a volume ratio of 81:19 A solution of solution A and solution B mixed in a volume ratio of 4:1 A solution of solution A and solution B mixed in a volume ratio of 1:4 Table 15 Composition Proportions of Mobile Phase in High Performance Liquid Chromatography at Different Times Time (minute) Composition proportion of mobile phase (%) Solution C Solution D 0 72 28 30 72 28 53 15 85 54 72 28 60 72 28 Table 16 Results of Tacrolimus Determination for T34 to T43 and Comparative Example 1 Group Tacrolimus Content (%) T34 95.4 T35 102.6 T36 98.1 T37 102.3 T38 104.9 T39 103.2 T40 103.7 T41 87.2 T42 96.1 T43 86.4 Comparative Example 1 71.8 0094] From the results in Table 16 above, it can be seen that after the stability test, the tacrolimus content in the pharmaceutical composition for eye drop oil dosage form of T34 to T43 is still higher than 85%, among which the tacrolimus content in T34 to T40 and T42 is higher than 95%. In contrast, for the commercially available tacrolimus-containing eye drops in Comparative Example 1, after the stability test, the tacrolimus content contained therein is only 71.8%, which is significantly lower than the results of the pharmaceutical composition of the present invention. It can be seen therefrom that the tacrolimus-containing pharmaceutical composition for eye drop oil dosage form of the present invention does have a better stability.

[0095] In summary, the present invention provides an eye drop oil, which is an ophthalmic pharmaceutical composition with a novel dosage form. Compared with the prior arts, the ophthalmic composition has the following advantages: 1. Without destroying the stability of the tear film like eye drops, the ophthalmic composition is highly safe for long-term use. 2. Compared with eye ointments, the ophthalmic composition of the present invention is contained in a general eye drop bottle, is convenient to use, has low eye irritation, and will not cause blurred vision after use. 3. The ophthalmic composition can effectively prevent the loss of water from the tear film, treat, prevent or improve dry eye syndrome, and meet the treatment needs of patients with tear over evaporation (lipid deficient dry eye). 4. The ophthalmic composition can be added with water-insoluble active pharmaceutical ingredients and can serve as an ophthalmic drug platform. 5. Because of 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 ophthalmic pharmaceutical compositions containing tacrolimus, it can be seen that the ophthalmic composition of the present invention has a stability better than that of commercially available products.

Claims

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

2. The pharmaceutical composition according to claim 1, wherein the lipid comprises mediumchain triglycerides, soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), lanolin oil, peanut oil, and castor 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 each gram of the pharmaceutical composition comprises 3-300 mg of lipid, 100-250 mg of white petrolatum, and 300797 mg of liquid paraffin.

5. The pharmaceutical composition according to claim 1, wherein each gram of the pharmaceutical composition comprises 3-300 mg of lipid, 100-240 mg of white petrolatum, and 500797 mg of liquid paraffin.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition for eye drop oil dosage form can be added with active pharmaceutical ingredients.

7. The pharmaceutical composition according to claim 6, wherein the active pharmaceutical ingredient comprises mineral oil, steroids, tetracyclines, macrolide antibiotics, prostaglandins, carbonic anhydrase inhibitors, immunosuppressive agents or other water-insoluble active pharmaceutical ingredients.

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 hyclate, 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.5        12. The pharmaceutical composition according to claim 7, wherein the carbonic anhydraseinhibitor comprises brinzolamide.

13. The pharmaceutical composition according to claim 7, wherein the immunosuppressive agent comprises tacrolimus or sirolimus.

14. The pharmaceutical composition according to claim 7, wherein the other water-insoluble 10 active pharmaceutical ingredient comprises 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 syndromes.

16. The use according to claim 15, wherein the dry eye syndrome is over evaporation.15        17. The use according to claim 15, wherein the dry eye syndrome is caused by meibomian glanddysfunction.

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