Tacrolimus ophthalmic composition as well as preparation and application thereof

Abstract

The invention provides a tacrolimus ophthalmic composition as well as preparation and application thereof, the tacrolimus ophthalmic composition comprises an active ingredient tacrolimus and an auxiliary material polyvinyl alcohol, and the weight-average molecular weight of the polyvinyl alcohol is 17kDa-25kDa. The ophthalmic composition tacrolimus is reasonable in particle size range, good in preparation stability and more suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the medical field, and in particular to a tacrolimus ophthalmic composition and a preparation method and application thereof. Background Art

[0002] Tacrolimus is a macrolide immunosuppressant, which is widely used in clinic to prevent rejection of organ transplantation and treat autoimmune diseases. In the field of ophthalmology, it has been used to treat immune-related eye diseases after corneal transplantation. Tacrolimus has a large molecular weight and is insoluble in water, so it is difficult for it to penetrate the cornea, conjunctiva, sclera and other eye tissues to produce effective drug concentrations, and its bioavailability is low. In the prior art, tacrolimus is made into a suspension to improve its bioavailability.

[0003] The selection of dispersants has an important influence on the particle size control and stability of suspension eye drops. CN106727298A discloses a tacrolimus suspension eye drop, in which a high molecular weight polymer (such as polyvinyl alcohol, polyethylene oxide, povidone, etc.) with a molecular weight of more than 100 kDa is used as a dispersant. The viscosity is very high, and bead milling is required to control the particle size. Tacrolimus is a biological preparation and is sensitive to temperature. The heat generated during the grinding process easily degrades tacrolimus. This defect will be more apparent during the industrialized production process, and the drug safety and effectiveness cannot be met. Therefore, it is urgent to develop a tacrolimus suspension eye drop with a stable preparation and more suitable for process production. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a tacrolimus ophthalmic composition and its preparation and use.

[0005] The first aspect of the present invention provides a tacrolimus ophthalmic composition, which comprises tacrolimus as an active ingredient and polyvinyl alcohol as an auxiliary material, wherein the weight average molecular weight of the polyvinyl alcohol is 17 kDa to 25 kDa.

[0006] The second aspect of the present application also provides a method for preparing the tacrolimus ophthalmic composition as described above, comprising the following steps: adding an API solution to a dispersion system to obtain a tacrolimus suspension; wherein the API solution is an anhydrous ethanol solution of tacrolimus; and the dispersion system is an aqueous solution of polyvinyl alcohol and sodium chloride.

[0007] The third aspect of the present application also provides use of the tacrolimus ophthalmic composition as described above in the preparation of a medicament for treating vernal keratoconjunctivitis.

[0008] The positive and progressive effects of the present invention are:

[0009] (1) Polyvinyl alcohol as a thickener and stabilizer has an important influence on the particle size control and stability of tacrolimus suspension. The polyvinyl alcohol with a specific molecular weight (17 kDa to 25 kDa) used in this application can obtain a preparation with a suitable particle size range and good preparation stability.

[0010] (2) Tacrolimus is unstable at high temperatures and cannot be sterilized by terminal moist heat sterilization, while suspension eye drops cannot be sterilized by 0.2 μm filtration.

[0011] The present application obtains a tacrolimus sterile suspension having a particle size that meets the requirements and a stable preparation by dissolving the tacrolimus raw material with ethanol and filtering and sterilizing it, and further screening and determining to select a polyvinyl alcohol and sodium chloride dispersion system for recrystallization. In particular, when the polyvinyl alcohol is 17kDa to 23kDa and 7.2 to 9 equivalents, the number of homogenization times required during preparation is small, and the obtained preparation has excellent stability, and there is no phenomenon that may seriously affect the quality of the drug, such as particle size increase, particle aggregation, and impurity exceeding the limit, within the validity period, and it is more suitable for industrial production.

[0012] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION

[0013] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0014] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0015] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0016] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0017] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0018] In a specific embodiment, the weight average molecular weight of the polyvinyl alcohol is 17 kDa to 25 kDa, for example 17 kDa, 18 kDa, 19 kDa, 20 kDa, 21 kDa, 22 kDa, 23 kDa, 24 kDa or 25 kDa, preferably 20 kDa to 23 kDa, more preferably 20 kDa to 22 kDa.

[0019] In a specific embodiment, the viscosity of the polyvinyl alcohol at 20°C±0.1°C and 4% concentration may be 5-6 mPa·S, preferably 5-5.5 mPa·S.

[0020] In a specific embodiment, the mass ratio of polyvinyl alcohol to tacrolimus is 1:7 to 1:9, for example: 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9, 1:8, 1:8.1, 1:8.2, 1:8.3, 1:8.4, 1:8.5, 1:8.6, 1:8.7, 1:8.8, 1:8.9, 1:9, more preferably 1:7.2 to 1:8, and even more preferably 1:7.4 to 1:8.

[0021] In a specific embodiment, the active ingredient tacrolimus can also be provided in the form of a solvate (such as a hydrate) thereof, for example tacrolimus monohydrate.

[0022] In a specific embodiment, the concentration of tacrolimus in the tacrolimus ophthalmic composition may be 0.3-1 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1 mg / ml is preferably 1 mg / ml.

[0023] In a specific embodiment, the tacrolimus ophthalmic composition may further include other excipients, and the other excipients include one or more of an osmotic pressure regulator, a preservative, a buffer, and a pH regulator.

[0024] In a specific embodiment, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, glycerol, boric acid, and borax, preferably sodium chloride.

[0025] In a specific embodiment, the tacrolimus ophthalmic composition further comprises sodium chloride. The sodium chloride is used to adjust the osmotic pressure of the ophthalmic composition. Preferably, the osmotic pressure of the ophthalmic composition is 280 to 340 mOsm / L, preferably 295 to 309 mOsm / L.

[0026] In a specific embodiment, the tacrolimus ophthalmic composition further comprises sodium chloride, and the mass ratio of the sodium chloride to tacrolimus is 8:1 to 9:1, preferably 8.6:1 to 9:1.

[0027] In a specific embodiment, in the tacrolimus ophthalmic composition, the concentration of sodium chloride is preferably 7-10 mg / ml, such as 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, preferably 8.5 mg / ml.

[0028] In a specific embodiment, the preservative is selected from one or more of benzalkonium bromide, benzalkonium chloride, chlorobutanol, methylparaben, ethylparaben, and propylparaben; preferably, benzalkonium chloride.

[0029] In a specific embodiment, the tacrolimus ophthalmic composition further comprises benzalkonium chloride. Preferably, in the tacrolimus ophthalmic composition, the concentration of benzalkonium chloride is preferably 0.08-0.12 mg / ml, more preferably 0.1 mg / ml.

[0030] In a specific embodiment, the pH adjuster is selected from one or more of sodium hydroxide, hydrochloric acid, phosphoric acid, triethanolamine, sodium carbonate, and sodium bicarbonate; preferably phosphoric acid and / or sodium hydroxide.

[0031] In a specific embodiment, the buffer is selected from one or more of phosphate buffer, acetate buffer, and citrate buffer, preferably a phosphate buffer, such as a buffer system of sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0032] In a specific embodiment, the mass ratio of the buffer to tacrolimus is 1:1.5 to 1:1.6, for example 1:1.51, 1:1.52, 1:1.53, 1:1.54, 1:1.55, 1:1.56, 1:1.57, 1:1.58, 1:1.59, 1:1.6.

[0033] In a specific embodiment, the pH of the tacrolimus ophthalmic composition is preferably 4-6, preferably 4.3-5.5, for example 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5.

[0034] In a specific embodiment, the tacrolimus ophthalmic composition described in the present application further does not contain low-molecular alcohol excipients, such as ethanol, propylene glycol, etc., and the term "not containing" means that they are not added as excipients alone and retained in the finished product, but residual low-molecular alcohols are not excluded (for example, ethanol is used in the preparation process of the tacrolimus ophthalmic composition in the present application, but it is finally removed by reduced pressure distillation, and the residual ethanol is not excluded).

[0035] In a specific embodiment, the tacrolimus ophthalmic composition described herein is a suspension eye drop.

[0036] In a specific embodiment, in the tacrolimus ophthalmic composition, the particle size D50 of the tacrolimus microparticles is less than 1 μm, for example, less than 0.9 μm, 0.8 μm, 0.7 μm, 0.6 μm, or 0.5 μm.

[0037] In a specific embodiment, in the tacrolimus ophthalmic composition, the particle size D90 of tacrolimus microparticles is less than 2.5 μm, for example, less than 2.4 μm, 2.3 μm, 2.2 μm, 2.1 μm, 2.0 μm, 1.9 μm, 1.8 μm, 1.7 μm, 1.5 μm, 1.4 μm, 1.3 μm, 1.2 μm, 1.1 μm, 1.0 μm.

[0038] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application further comprises the step of adding other excipients. The other excipients include one or more of the osmotic pressure regulator, preservative, buffer, and pH regulator described above.

[0039] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application further comprises a high-speed shearing process.

[0040] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application further comprises a homogenization process.

[0041] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application further comprises a step of adjusting the pH.

[0042] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application further comprises the step of removing ethanol by distillation under reduced pressure.

[0043] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application further comprises the step of adding water for injection to make up the volume.

[0044] In a specific embodiment, the tacrolimus ophthalmic composition described in the present application is prepared by the following preparation method: adding the API solution to the dispersion system to obtain a tacrolimus suspension, adding the other excipients, high-speed shearing, homogenization, adjusting the pH, and adding water for injection to make up the volume; wherein the API solution is an anhydrous ethanol solution of tacrolimus; and the dispersion system is an aqueous solution of polyvinyl alcohol and sodium chloride.

[0045] In a specific embodiment, the tacrolimus ophthalmic composition described in the present application is prepared by the following preparation method: adding the prepared API solution to the dispersion system to obtain a tacrolimus suspension, adding the other excipients, high-speed shearing, homogenization, adjusting the pH, vacuum distillation to remove ethanol, and adding water for injection to make up the volume; wherein the API solution is an anhydrous ethanol solution of tacrolimus; and the dispersion system is an aqueous solution of polyvinyl alcohol and sodium chloride.

[0046] In a specific embodiment, in the method for preparing the tacrolimus ophthalmic composition described in the present application, the weight volume of tacrolimus and anhydrous ethanol is 160-500 mg / ml, preferably 250-500 mg / ml.

[0047] In a specific embodiment, in the method for preparing the tacrolimus ophthalmic composition described in the present application, the volume ratio of the API solution to the dispersed system is 1:130-400, preferably 1:200-400.

[0048] In a specific embodiment, the concentration of polyvinyl alcohol in the dispersed system is 8-12 mg / ml, for example 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml or 12 mg / ml, preferably 10 mg / ml.

[0049] In a specific embodiment, the method for preparing the tacrolimus ophthalmic composition described in the present application comprises the following steps:

[0050] Step 1) preparing an API solution by dissolving tacrolimus in anhydrous ethanol;

[0051] Step 2) preparing a dispersion system, adding polyvinyl alcohol and sodium chloride into purified water to obtain a dispersion system;

[0052] Step 3) adding the API solution prepared in step 1 dropwise to the dispersed system in step 2 to obtain solution A;

[0053] Step 4) adding benzalkonium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate to solution A and stirring until completely dissolved to obtain solution B;

[0054] Step 5) high-speed shearing and homogenizing solution B to obtain solution C;

[0055] Step 6) adjusting the pH of solution C to 5-5.5, and removing ethanol by distillation under reduced pressure;

[0056] Step 7) Add water to make up the volume.

[0057] In a specific embodiment, provided is the use of the tacrolimus ophthalmic composition in the preparation of a medicament for treating vernal keratoconjunctivitis for which the anti-allergic treatment effect is not obvious.

[0058] The numerical range in the present invention may be understood to include all values ​​(including integers or decimals) within the range and the cited endpoints, and also include the values ​​defining the range and the values ​​adjacent to the range. For example, a person skilled in the art will understand that a change of 5% (e.g., 4%, 3%, 2%, 1%) of the upper or lower limit of the point value cited in this application may also be applicable and covered by this application.

[0059] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0060] Unless otherwise stated, the various embodiments or embodiments of different preferred levels described in this application can be arbitrarily combined.

[0061] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0062] Example 1 Screening of dispersant polyvinyl alcohol models

[0063] The following preparation process was used to prepare tacrolimus suspension eye drops:

[0064] Step 1: Prepare API solution by dissolving tacrolimus monohydrate (500 mg as tacrolimus) in 1.0 ml of anhydrous ethanol;

[0065] Step 2: Preparation of a dispersion system: dissolve polyvinyl alcohol (3600 mg) and sodium chloride (4300 mg) in 400 mL of purified water to obtain a dispersion system (heat to dissolve);

[0066] Step 3: adding the API solution prepared in step 1 dropwise to the dispersed system prepared in step 2 to obtain solution A;

[0067] Step 4: Add benzalkonium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate to solution A, and stir until completely dissolved to obtain solution B;

[0068] Step 5: High-speed shearing and homogenization of solution B to obtain solution C;

[0069] Step 6: Adjust the pH of solution C to 4.3-5.5, and remove ethanol by distillation under reduced pressure;

[0070] Step 7: Add water to make up to 500ml;

[0071] The particle size distribution of the prepared tacrolimus suspension eye drops and the data of 6-month accelerated stability (temperature 40°C ± 2°C, relative humidity 25% ± 5%) and the corresponding phenomena are shown in Table 1 below

[0072] Table 1

[0073]

[0074]

[0075] *Under the same homogenization pressure and rate, Example 1b was homogenized 30 times, and other examples were homogenized 10 times (the following examples are homogenized 10 times unless otherwise specified).

[0076] The viscosity of polyvinyl alcohol is closely related to the molecular weight. The larger the molecular weight, the higher the viscosity. This is because the interaction force between the macromolecular segments is enhanced, resulting in increased flow resistance. Polyvinyl alcohol 2-5 with a molecular weight of 17-25 kDa (viscosity of 5-6 mPa·S) has the best dispersion effect and is easier to obtain a tacrolimus suspension with a reasonable particle size and stable formulation.

[0077] Example 2

[0078] The remaining steps are the same as those in Example 1, except that polyvinyl alcohol 5 is selected in step 2 and its dosage is adjusted to 3500 mg to obtain tacrolimus suspension eye drops.

[0079] Example 3

[0080] The remaining steps are the same as those in Example 1, except that polyvinyl alcohol 3 is selected in step 2 and its dosage is adjusted to 3500 mg to obtain tacrolimus suspension eye drops.

[0081] Example 4

[0082] The remaining steps are the same as those in Example 1, except that polyvinyl alcohol 4 is selected in step 2 and its dosage is adjusted to 4000 mg to obtain tacrolimus suspension eye drops.

[0083] Example 5

[0084] The remaining steps are the same as those in Example 1, except that polyvinyl alcohol 4 is selected in step 2 and its dosage is adjusted to 4500 mg to obtain tacrolimus suspension eye drops.

[0085] Example 6

[0086] The steps are the same as those in Example 1, except that the amount of anhydrous ethanol in step 1 is adjusted to 2 ml, and the amount of polyvinyl alcohol 3 selected in step 2 is adjusted to 3800 mg.

[0087] Example 7

[0088] The steps are the same as those in Example 5, except that the amount of anhydrous ethanol in step 1 is adjusted to 3 ml.

[0089] The particle size distribution and 6-month accelerated stability (temperature 40°C ± 2°C, relative humidity 25% ± 5%) data and corresponding phenomena of the tacrolimus suspension eye drops prepared in Examples 2 to 7 are shown in Table 2 below.

[0090] Table 2

[0091]

[0092] Example 8 Scale-up production

[0093] Step 1: Prepare API solution by dissolving tacrolimus monohydrate (5 kg based on tacrolimus) in 12 L of anhydrous ethanol;

[0094] Step 2: Preparation of a dispersion system: dissolving polyvinyl alcohol (38 kg) and sodium chloride (43 kg) in 3.8 tons of purified water to obtain a dispersion system (heating to dissolve);

[0095] Step 3: adding the API solution prepared in step 1 dropwise to the dispersed system prepared in step 2 to obtain solution A;

[0096] Step 4: Add benzalkonium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate to solution A, and stir until completely dissolved to obtain solution B;

[0097] Step 5: Shear solution B at high speed and homogenize to obtain solution C;

[0098] Step 6: Adjust the pH of solution C to 4.3-5.5, and remove ethanol by distillation under reduced pressure;

[0099] Step 7: Add water to 5 tons

[0100] Step 8: Packaging.

[0101] The 6-month stability data are shown in Table 3 below.

[0102] Table 3

[0103]

[0104]

[0105] Osmotic pressure molar concentration ratio: The osmotic pressure molar concentration ratio of the test solution and 0.9% (g / ml) sodium chloride standard solution is called the osmotic pressure molar concentration ratio.

[0106] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0107] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A tacrolimus ophthalmic composition, characterized in that: The ophthalmic composition comprises tacrolimus as an active ingredient and polyvinyl alcohol as an auxiliary material, wherein the weight average molecular weight of the polyvinyl alcohol is selected from 17 kDa to 25 kDa.

2. The tacrolimus ophthalmic composition according to claim 1, characterized in that The weight average molecular weight of the polyvinyl alcohol is 18 kDa to 23 kDa.

3. The tacrolimus ophthalmic composition according to claim 1, characterized in that: The weight average molecular weight of the polyvinyl alcohol is 20 kDa to 23 kDa.

4. The tacrolimus ophthalmic composition according to claim 1, characterized in that The mass ratio of tacrolimus to polyvinyl alcohol is 1:7 to 1:

9.

5. The tacrolimus ophthalmic composition according to claim 1, characterized in that The mass ratio of tacrolimus to polyvinyl alcohol is 1:7.2 to 1:8, preferably 1:7.4 to 1:

8.

6. The tacrolimus ophthalmic composition according to claim 1, characterized in that: The ophthalmic composition further comprises one or more of an osmotic pressure regulator, a preservative, a buffer, and a pH regulator.

7. The tacrolimus ophthalmic composition according to claim 6, characterized in that: The osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, glycerol, boric acid, and borax; and / or, The preservative is selected from one or more of benzalkonium bromide, benzalkonium chloride, chlorobutanol, methylparaben, ethylparaben, and propylparaben; and / or, The pH regulator is selected from one or more of sodium hydroxide, hydrochloric acid, phosphoric acid, triethanolamine, sodium carbonate, and sodium bicarbonate; and / or, The buffer is selected from one or more of phosphate buffer, acetate buffer and citrate buffer.

8. A method for preparing the tacrolimus ophthalmic composition according to any one of claims 1 to 7, characterized in that: The method comprises the following preparation steps: adding an API solution into a dispersion system to obtain a tacrolimus suspension; wherein the API solution is an anhydrous ethanol solution of tacrolimus; and the dispersion system is an aqueous solution of polyvinyl alcohol and sodium chloride.

9. The preparation method according to claim 8, characterized in that: The weight volume of tacrolimus and anhydrous ethanol is 160-500 mg / ml, preferably 250-500 mg / ml; and / or, the volume ratio of the API solution to the dispersed system is 1:130-400, preferably 1:200-400; and / or, the preparation method further comprises the step of adding other excipients to the tacrolimus microparticle suspension; and / or, the preparation method further comprises the step of high-speed shearing; and / or, The preparation method further comprises a homogenization step; and / or, The preparation method further comprises the step of adjusting pH; and / or, The preparation method further comprises the step of removing ethanol by distillation under reduced pressure; and / or, The preparation method further comprises the step of adjusting the volume with water for injection.

10. Use of the tacrolimus ophthalmic composition according to any one of claims 1 to 7 and the tacrolimus ophthalmic composition prepared by the preparation method according to claim 8 or 9 in preparing a medicament for treating vernal keratoconjunctivitis.

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