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WO2024159768A1 - Composition pharmaceutique pour forme posologique d'huile pour gouttes oculaires - Google Patents

Composition pharmaceutique pour forme posologique d'huile pour gouttes oculaires Download PDF

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Publication number
WO2024159768A1
WO2024159768A1 PCT/CN2023/119935 CN2023119935W WO2024159768A1 WO 2024159768 A1 WO2024159768 A1 WO 2024159768A1 CN 2023119935 W CN2023119935 W CN 2023119935W WO 2024159768 A1 WO2024159768 A1 WO 2024159768A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
oil
eye
lipid
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/119935
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English (en)
Chinese (zh)
Inventor
郑婉榕
陈怡菁
王又正
吴品润
林秀桦
严婉萍
洪伊珊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
WINSTON MEDICAL SUPPLY CO Ltd
Original Assignee
WINSTON MEDICAL SUPPLY CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by WINSTON MEDICAL SUPPLY CO Ltd filed Critical WINSTON MEDICAL SUPPLY CO Ltd
Priority to AU2023427182A priority Critical patent/AU2023427182A1/en
Priority to CN202380065701.0A priority patent/CN119855610A/zh
Publication of WO2024159768A1 publication Critical patent/WO2024159768A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present application relates to an ophthalmic drug, in particular to an eye drop oil dosage form which does not contain preservatives and has no eye irritation.
  • the surface of the normal eyeball is covered with a layer of tears, which provides lubrication and protection for the eye.
  • This layer is called the "tear film”.
  • the tear film structure can be divided into three layers, namely the mucus layer, the water layer, and the oil layer from the inside to the outside ( Figure 1).
  • the mucus layer increases the viscosity of the tears and helps the water stay 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 evaporation of tears, helps lubricate the eye, and maintains the integrity of the tear film. If any layer is missing, the tear film will be unstable, causing dry eye symptoms.
  • Eye drops are aqueous eye drops, which are easily contaminated by microorganisms.
  • preservatives are added to multi-dose packaging. Eye drops without preservatives can only be made into single-use disposable packaging, but their high price makes them unpopular. Long-term and frequent use of eye drops containing preservatives may aggravate chronic eye inflammation, In addition, eye drops may also wash away the oil layer of the tear film, destroying the integrity of the tear film and leading to the formation or worsening of dry eye.
  • eye drops add trace amounts of oil and claim to simulate the composition of the tear film, such preparations must be supplemented with surfactants to dissolve the oil in water, which in turn causes a burden on the eyes.
  • ophthalmic suspensions or ophthalmic ointments are insoluble in water.
  • ophthalmic suspensions must be shaken before use. If they are not shaken sufficiently, the active ingredient content may be unevenly distributed, resulting in the risk of insufficient efficacy and excessive dosage.
  • Ophthalmic ointments are packaged in soft tubes and need to be squeezed into the lower eyelid when used, which is not conducive to self-use by elderly patients. After use, vision will be blurred and there will be a foreign body sensation, affecting daily life.
  • ophthalmic suspensions not only have the same problems as eye drops, but also have the risk of uneven content. Eye ointments are difficult to apply and can easily obstruct vision or cause discomfort such as a foreign body sensation after use. These common eye drug formulations currently on the market have obvious shortcomings in use. Therefore, it is urgent to develop a new ophthalmic drug formulation that can not only alleviate dry eye syndrome, but also serve as an ophthalmic drug platform to further add active drug ingredients that are poorly soluble in water. This is an important issue that this application intends to solve.
  • the present application provides a pharmaceutical composition in the form of eye drops, which has low eye irritation, no preservatives, and will not cause blurred vision after use, and can be contained in a general multi-dose reusable eye drop bottle for easy use.
  • the pharmaceutical composition in the form of eye drops of the present application can effectively prevent the loss of water from the tear film, alleviate dry eye syndrome, and can further add active pharmaceutical ingredients that are poorly soluble in water, as another new option for the ophthalmic drug preparation platform.
  • the purpose of the present application is to provide a pharmaceutical composition in the form of eye drops, comprising: a lipid, white petrolatum, and liquid paraffin.
  • a pharmaceutical composition in the form of eye drops, comprising: a lipid, white petrolatum, and liquid paraffin.
  • Each gram of the pharmaceutical composition comprises 3 to 500 mg of lipid, 100 to 250 mg of white petrolatum, and 1 to 797 mg of liquid paraffin.
  • the lipid comprises medium-chain triglyceride (MCT), soybean oil, corn oil, olive oil, canola oil, sunflower oil, myristic acid Isopropyl acetate (IPM), lanolin.
  • MCT medium-chain triglyceride
  • IPM myristic acid Isopropyl acetate
  • the lipid is a medium chain triglyceride.
  • 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.
  • each gram of the pharmaceutical composition comprises 3-300 mg of lipid, 100-240 mg of white soft paraffin, and 500-797 mg of liquid paraffin.
  • the pharmaceutical composition may be added with active pharmaceutical ingredients.
  • 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.
  • the steroid includes Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate or Hydrocortisone Acetate.
  • the tetracycline includes doxycycline hyclate, tetracycline HCl or minocycline HCl.
  • the macrocyclic antibiotic comprises erythromycin or azithromycin.
  • the prostaglandin includes Latanoprost, Latanoprostene Bunod, Travoprost, and Bimatoprost.
  • the carbonic anhydrase inhibitor comprises Brinzolamide.
  • the immunosuppressant comprises tacrolimus or sirolimus.
  • the other poorly water-soluble active pharmaceutical ingredients include rebamipide, omega 3, nepafenac, besifloxacin HCl, selenium disulfide, vitamin A or cyclosporin.
  • Another object of the present application is to develop an ophthalmic pharmaceutical composition for the preparation of a method for treating, preventing or Use of a drug for improving dry eye, especially oil-deficient dry eye caused by meibomian gland dysfunction.
  • the present application provides an eye drop oil, which is a new dosage form of an ophthalmic pharmaceutical composition.
  • 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.
  • 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 moisture in the tear film, treat, prevent or improve dry eyes, and meet the treatment needs of patients with excessive tear evaporation (oil-deficient dry eyes).
  • Active pharmaceutical ingredients that are poorly soluble 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.
  • Figure 1 is a schematic diagram of the tear film
  • Figure 2 shows the change in tear volume one hour after medication.
  • the viscosity and biofilm (transmittance %T) data are used to confirm and evaluate whether the ophthalmic pharmaceutical composition of the present application has good viscosity and low eye irritation.
  • Viscosity evaluation method Using microVISC TM viscometer (compliant with USP ⁇ 914> Pressure Driven Methods), the viscosity of water for injection (WFI) is 0.894, and the viscosity of reference 2 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 a flow resistance inside a viscous liquid and may be considered as the friction of the fluid itself. Viscosity mainly comes from the mutual attraction between molecules, so substances with lower viscosity are easier to flow. The smaller the viscosity value, the better the fluidity. After dropping into the eyes, it will not cause blurred vision and will not affect the clarity of vision. It can also be stored in a regular eye drop bottle, which is more convenient for patients to use than a soft tube.
  • Biofilm evaluation method Based on the chemical testing specification No. 496 published by the Organization for Economic Co-operation and Development (OECD): 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 tests are conducted on biological liquid films to simulate the irritation of chemicals to the eyes. The irritation level is determined by using the phenomenon that macromolecules react chemically with irritating substances and proteins denature to cause turbidity in the solution.
  • OECD Organization for Economic Co-operation and Development
  • the detection method is that the drug and reagent are mixed to denature the protein, which will cause the solution to become turbid. Then, it is measured by a UV spectrophotometer (manufacturer: Hitachi; model: U-2900) in accordance with the transmittance specifications recorded in the United States Pharmacopeia (USP).
  • the transmittance of each group under the condition of a light wavelength of about 405 nanometers is shown in Table 1 below.
  • the transmittance can be used to evaluate the degree of irritation to the eyes. The higher the transmittance, the lower the eye irritation, and the lower the transmittance, the higher the eye irritation.
  • the transmittance when the transmittance is greater than 90%, it is considered to be non-eye irritation, when the transmittance is greater than 80% and less than or equal to 90%, it is considered to be low eye irritation, when the transmittance is greater than 70% and less than or equal to 80%, it is considered to be moderate eye irritation, and when the light penetration is less than or equal to 70%, it is considered to be high eye irritation.
  • the present application is an ophthalmic pharmaceutical composition, which comprises a medium chain triglyceride, white soft paraffin, and liquid paraffin.
  • a medium chain triglyceride white soft paraffin
  • liquid paraffin liquid paraffin
  • the content of white soft paraffin was fixed in the ophthalmic pharmaceutical composition, and the content of MCT and liquid paraffin was changed. According to the results in Table 1, the content of MCT was changed in the ophthalmic pharmaceutical composition.
  • the content of MCT was 3-500 mg/g
  • the transmittance was greater than 90%, which was judged to be non-irritating to the eyes.
  • the viscosity of the ophthalmic pharmaceutical composition of formula T10 and T11 was acceptable, and it was judged that a high content of MCT (greater than 500 mg/g) may affect the clarity of vision, and it is not easy to drip out when contained in the eye drop bottle.
  • the content of white soft paraffin and liquid paraffin in the ophthalmic pharmaceutical composition is fixed, and lipids selected from soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), and lanolin are added.
  • lipids selected from soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), and lanolin are added.
  • the light transmittance is greater than 90% when the type of lipid is changed in the ophthalmic pharmaceutical composition, which is judged to be non-irritating to the eye, and has good fluidity, does not blur vision, and does not affect the clarity of vision.
  • the content of MCT in the ophthalmic pharmaceutical composition was fixed, and the content of white soft paraffin and liquid paraffin was changed. According to the results in Table 3, when the content of white soft paraffin was 100-250 mg/g, the transmittance was greater than 85%, which was judged to be almost non-irritating to the eyes, but the viscosity of the ophthalmic pharmaceutical composition of formula T23 was acceptable, and it was judged that a high content of white soft paraffin (greater than 250 mg/g) would blur vision and affect the clarity of vision.
  • the ophthalmic pharmaceutical composition of the present application is an eye drop oil dosage form, wherein the lipid is 3-300 mg/g, white soft stone
  • the proportion of the ingredients in the range of 100-250 mg/g wax and 1-797 mg/g liquid paraffin has good comfort.
  • the subsequent examples are based on the T03 formula: MCT 100 mg/g, white soft paraffin 200 mg/g, and liquid paraffin 700 mg/g.
  • Table 4 shows the dosage forms and labelled ingredients of commercial ophthalmic products frequently used by patients with dry eyes.
  • Reference product 1 is a commonly used artificial tear on the market
  • reference product 2 is an eye ointment for lubricating the eyeball.
  • Table 5 shows the viscosity and transmittance comparison of the ophthalmic pharmaceutical composition of this case and commercially available products.
  • the transmittance of the ophthalmic pharmaceutical composition of the T03 formula of this case, water for injection, reference product 1, and reference product 2 are all greater than 90%, and it is judged that they are non-irritating to the eyes.
  • Reference product 2 has a high viscosity, and it is judged that it will seriously blur vision when used, affecting the clarity of vision, and it can only be contained in a tube, which is inconvenient to use.
  • the change of stability was observed by using parameters such as water content, appearance, specific gravity, viscosity, and acid value.
  • the ophthalmic pharmaceutical composition of the present application comprises a mineral oil, a lipid, and a White soft paraffin
  • the lipid is an oil but not a mineral oil
  • the oil includes but is not limited to medium chain triglycerides, soybean oil, corn oil, olive oil, canola oil, sunflower oil, isopropyl myristate (IPM), lanolin, peanut oil, castor oil
  • the lipids in the formula composition of the following ophthalmic pharmaceutical composition are mainly medium chain triglycerides.
  • 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.
  • 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.
  • 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.
  • the solvent is 20.0mL of a mixture of toluene and methanol (7:3), which should not exceed 0.5% (Karl Fischer Moisture Titrator)
  • Water content is divided into water content and water activity (a w ).
  • the water detected by 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 has no solvent function and cannot be used by microorganisms.
  • Lowering water activity helps prevent the proliferation of microorganisms in medicines.
  • the water content test can prove that the water activity of the formulation of the present application is low. Since the ophthalmic pharmaceutical composition of the present application is prepared aseptically, no preservatives need to be added to maintain the sterile state.
  • the water content of the ophthalmic pharmaceutical composition of different proportions of the present application is all lower than 0.5, and the water content includes free water and bound water, that is, the free water (water activity) in the ophthalmic pharmaceutical composition of the present application is far lower than 0.75 that can be used by microorganisms. Therefore, the ophthalmic pharmaceutical composition of the present application can effectively prevent the proliferation of microorganisms in the drug, so no preservatives need to be added.
  • Tables 4 and 7 it can also be seen that since the artificial tears of the reference product 1 are aqueous preparations, preservatives must be added for long-term storage.
  • Example 4 The present application improves tear secretion
  • test products 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.
  • 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.
  • 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.
  • 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.
  • the medication was repeated in three groups with 15 subjects, as shown in Table 8.
  • the tear secretion was tested by Schirmer's Test before and one hour after medication. The purpose of the test was to confirm whether the ophthalmic pharmaceutical composition of the present application has a better effect on tear secretion than the commercial product.
  • the left and right eyes of each subject were medicated according to the groups in Table 8, and then the following steps were followed.
  • Schirmer’s Test was performed on both eyes of each subject.
  • the ophthalmic pharmaceutical composition of the present application is significantly superior to the artificial tears of reference product 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 product 1, the effect will not be 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 product 2, but 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 product 2, and can be contained in an eye drop bottle for easier use by patients, and there will be no blurred vision after use.
  • Example 5 Adding active pharmaceutical ingredients to the ophthalmic pharmaceutical composition of the present application
  • ophthalmic suspensions may also have the risk of uneven content; and ophthalmic ointments are difficult to apply and may obstruct vision or cause discomfort such as foreign body sensation after use.
  • the ophthalmic pharmaceutical composition of the present application is an oily preparation and can be used as an ophthalmic drug platform to which active pharmaceutical ingredients that are poorly soluble in water can be added and used in the form of eye drops.
  • the poorly water-soluble active pharmaceutical ingredients include steroids, tetracyclines, macrocyclic antibiotics, prostaglandins, carbonic anhydrase inhibitors (CAI), immunosuppressants or other poorly water-soluble active pharmaceutical ingredients.
  • the poorly water-soluble active pharmaceutical ingredient steroids include Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate, Hydrocortisone Acetate, etc. Among them, Loteprednol Etabonate has the worst water solubility and was used as a representative steroid for subsequent experiments.
  • the poorly water-soluble active pharmaceutical ingredients tetracycline include Doxycycline hyclate, Tetracycline HCl, Minocycline HCl, etc.
  • Doxycycline hyclate has the worst water solubility and was used as a representative of tetracycline for subsequent experiments.
  • Macrocyclic antibiotics with poorly 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.
  • Active pharmaceutical ingredients that are poorly soluble in water include prostaglandins such as Latanoprost, Latanoprostene Bunod, Travoprost or Bimatoprost.
  • Poorly water-soluble active pharmaceutical ingredients carbonic anhydrase inhibitors include Brinzolamide and the like.
  • Active pharmaceutical ingredient immunosuppressants that are poorly soluble in water include Tacrolimus, Sirolimus, etc. Among them, Sirolimus has the worst water solubility and was used as a representative immunosuppressant for subsequent experiments.
  • the aforementioned active pharmaceutical ingredients Cyclosporin, Tacrolimus, Sirolimus, Rebamipide, Omega3, Selenium Disulfide, Vitamin A, etc. have the effect of preventing, treating or improving dry eye syndrome.
  • the aforementioned Doxycycline Hyclate, Erythromycin, Minocycline HCl, Azithromycin, etc. have the effects of preventing, treating or improving meibomian gland dysfunction.
  • the aforementioned Besifloxacin HCl, Tetracycline HCl, Doxycycline Hyclate, Erythromycin, Minocycline HCl, Azithromycin, etc. have the effect of treating bacterial infections.
  • the aforementioned active pharmaceutical ingredients such as Loteprednol Etabonate, Betamethasone, Dexamethasone, Fluorometholone, Prednisolone Acetate, and Hydrocortisone Acetate may be steroids.
  • the active pharmaceutical ingredients of the aforementioned Nepafenac and other drugs are nonsteroidal anti-inflammatory drugs (NSAIDs).
  • the aforementioned Brinzolamide, Latanoprost, Latanoprostene Bunod, Travoprost or Active pharmaceutical ingredients such as Bimatoprost have the efficacy of drugs for preventing, treating or improving glaucoma.
  • the light transmittance of T24 to T33 is higher than 80%, which means low irritation or no irritation after use; the viscosity of T24 to T33 is less than 100, and the fluidity is good. It can be used as an eye drop formulation without causing blurred vision after use; from the water content results, it can be seen that the water content of T24 to T33 is far lower than the water content that can be utilized by microorganisms, which is 0.75. Therefore, the ophthalmic pharmaceutical composition of the present application is not conducive to the growth of microorganisms, so no preservatives need to be added.
  • Example 6 Add active pharmaceutical ingredients to the eye drop oil dosage form pharmaceutical composition of the present application to Adding Tacrolimus as an example
  • tacrolimus, liquid paraffin, lipid, and white soft paraffin components are placed in a glass beaker, which is then heated to about 90° C. and stirred with a magnet until the components are completely dissolved to obtain a uniformly mixed solution. The mixed solution is then continuously stirred and cooled to obtain a pharmaceutical composition in the form of eye drops containing tacrolimus in different proportions as shown in Table 12.
  • Comparative Example 1 is prepared according to the instructions of a commercially available tacrolimus eye drop, the ingredients are listed in Table 11, and it contains 0.1wt% tacrolimus.
  • the preparation method is to add 20% water and polyvinyl alcohol (Polyvinyl Alcohol) to a beaker, heat to 80 degrees, stir and dissolve, cool to 30 degrees, then add Tacrolimus and homogenize at 3000rpm for 15 minutes (main component phase), add 60% water and the remaining ingredients to another beaker, stir and dissolve, add the main component phase, add water quantitatively, and stir evenly.
  • Polyvinyl Alcohol Polyvinyl Alcohol
  • the transmittance of the tacrolimus-containing eye drop oil dosage form pharmaceutical compositions of the present application is higher than 80%, and therefore they are low irritation or even non-irritating to the eyes.
  • the transmittance of the tacrolimus-containing eye drop oil dosage form pharmaceutical compositions T34 to T43 is even higher than 95%.
  • the transmittance of the commercially available tacrolimus eye drops in Comparative Example 1 is only 58.2%, which is obviously highly irritating to the eyes.
  • the tacrolimus-containing eye drop oil dosage form pharmaceutical composition of the present application does have a better effect of avoiding eye irritation.
  • This test selected T34 to T43 and Comparative Example 1 for stability test. Specifically, the tacrolimus-containing eye drop oil dosage form pharmaceutical composition of T34 to T43 and the commercially available tacrolimus-containing eye drop of Comparative Example 1 were placed in an environment of 25°C for 1 month, and then placed in an environment of 70°C for 3 days.
  • the tacrolimus content of each group was detected by high performance liquid chromatography (HPLC-UV; it adopts L1 specification, silica gel particle size is 3 microns, column diameter is 46 cm, length is 15 cm), wherein the flow rate of the mobile phase of the high performance liquid chromatography is about 1.5 ml/min, the composition formula 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.
  • the present application provides an eye drop oil, which is a new dosage form of an ophthalmic pharmaceutical composition.
  • 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.
  • 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 moisture in the tear film, treat, prevent or improve dry eye syndrome, and meet the treatment needs of patients with excessive tear evaporation (oil-deficient dry eye syndrome).
  • Active pharmaceutical ingredients that are poorly soluble in water can be added as an ophthalmic drug platform. 5.

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Abstract

L'invention concerne également une composition pharmaceutique pour une forme posologique d'huile pour gouttes oculaires, comprenant un lipide, de la vaseline blanche et de la paraffine liquide. Chaque gramme de la composition pharmaceutique ophtalmique comprend 3 à 500 mg d'un lipide, 100 à 250 mg de vaseline blanche et 1 à 797 mg de paraffine liquide.
PCT/CN2023/119935 2023-01-31 2023-09-20 Composition pharmaceutique pour forme posologique d'huile pour gouttes oculaires Ceased WO2024159768A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2023427182A AU2023427182A1 (en) 2023-01-31 2023-09-20 Pharmaceutical composition for eye drop oil dosage form
CN202380065701.0A CN119855610A (zh) 2023-01-31 2023-09-20 一种滴眼油剂型的医药组合物

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US202363442153P 2023-01-31 2023-01-31
US63/442,153 2023-01-31

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CN (1) CN119855610A (fr)
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Publication number Priority date Publication date Assignee Title
CN117883378A (zh) * 2023-12-21 2024-04-16 艾尔健康眼药(辽宁)有限公司 一种治疗干眼症的他克莫司油性制剂及其制备方法

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CN1638769A (zh) * 2002-03-04 2005-07-13 诺瓦提斯公司 包含子囊霉素的眼用组合物
JP2010120856A (ja) * 2008-11-17 2010-06-03 Santen Pharmaceut Co Ltd 眼科用組成物
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