Stable penehyclidine hydrochloride ophthalmic preparation

Abstract

The invention provides a stable penehyclidine hydrochloride ophthalmic preparation, liquid medicine of the ophthalmic preparation is placed in a combined packaging container, and the combined packaging container comprises an inner layer container and an outer layer container; wherein the inner-layer container comprises a semi-permeable material, and the inner-layer container defines an accommodating space for the ophthalmic preparation; the outer-layer container is made of a multi-layer material containing polyester, aluminum and polyethylene; the inner-layer container is separably arranged in the outer-layer container; the ophthalmic preparation comprises penehyclidine hydrochloride, a phosphate buffer agent, an osmotic pressure regulator and a thickening agent. By adopting the penehyclidine hydrochloride ophthalmic preparation disclosed by the invention, adverse reaction between the ophthalmic preparation and oxygen, humidity or other factors of an external environment can be prevented, so that an ideal pH range of the preparation is maintained, and the content of impurities in an extract is greatly reduced.

Description

Technical Field

[0001] This invention relates to pharmaceutical packaging containers, and more specifically, to a stable ophthalmic preparation of pentoxyverine hydrochloride. Background Technology

[0002] Penehyclidine hydrochloride, chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinine cycloane hydrochloride, molecular formula C 20 H 29 NO2·HCl, molecular weight 351.92, chemical structural formula:

[0003]

[0004] Pentylcholine hydrochloride, as a potent and selective anticholinergic drug, can bind to M and N cholinergic receptors and selectively act on M1, M3, N1, and N2 receptors. It has a strong anticholinergic effect on both peripheral and central nerves, but has no effect on M2 receptors. This avoids the tachycardia caused by atropine's lack of M receptor subtype selectivity and the blocking of the presynaptic membrane M2 receptor regulatory function.

[0005] In previous research, the inventors developed a novel ophthalmic preparation of pentoxyverine hydrochloride (see patent applications 202211231475.2 and 202211223507.4), which showed good efficacy for eye diseases such as myopia or amblyopia. However, during long-term storage, the inventors discovered that the quality stability of the ophthalmic preparation of pentoxyverine hydrochloride changed depending on the packaging container. Therefore, this invention investigated this issue and developed a novel packaging container for the ophthalmic preparation of pentoxyverine hydrochloride, thereby obtaining a stable ophthalmic preparation of pentoxyverine hydrochloride. Summary of the Invention

[0006] This invention addresses the problem of degradation impurity E, which arises from the oxidative degradation of the active ingredient in pentoxyverine hydrochloride ophthalmic formulations during long-term storage. This impurity has potential genotoxicity. Its chemical name is 2-cyclopentyl-2-phenylacetaldehyde, and its chemical structural formula is:

[0007]

[0008] Furthermore, since the material particles of the inner container immerse themselves in the contents of the ophthalmic preparation, the content of leachate impurities in the ophthalmic preparation increases, thereby affecting the product quality of the ophthalmic preparation. The purpose is to provide a combined packaging container that can reduce the generation of leachate impurities in ophthalmic preparations, thereby improving the stability of pentoxyverine ophthalmic preparations.

[0009] Therefore, in a first aspect, the present invention provides an ophthalmic preparation of pentoxyverine hydrochloride. According to an embodiment of the present invention, the ophthalmic preparation is disposed in a combined packaging container, the combined packaging container comprising: an inner container and an outer container; wherein, the inner container comprises a semi-permeable material, the inner container defining a space for containing the ophthalmic preparation; the outer container is a multilayer material containing polyester, aluminum, and polyethylene; the inner container is detachably disposed within the outer container; the ophthalmic preparation comprises pentoxyverine hydrochloride, a phosphate buffer, an osmotic pressure regulator, and a thickener.

[0010] The pentoxyverine hydrochloride ophthalmic formulation of the present invention can maintain ideal chemical composition and properties during long-term storage, and can significantly reduce the content of extractive impurities, impurity B and impurity E. This is very important for ensuring the long-term stability, safety and efficacy of the solution, and further helps to ensure that it meets the stringent drug regulatory requirements.

[0011] According to embodiments of the present invention, the pentoxyverine hydrochloride ophthalmic formulation may further include at least one of the following additional technical features:

[0012] According to embodiments of the present invention, the semi-permeable material is selected from low-density polyethylene resin or polypropylene resin. Through extensive experiments, the inventors have found that using low-density polyethylene resin or polypropylene resin can effectively ensure product quality and relatively reduce the content of leachate impurities in the drug solution. This is crucial for ensuring the long-term stability, safety, and efficacy of pentoxyverine hydrochloride ophthalmic preparations.

[0013] It should be noted that the "semi-permeable" nature described in this invention refers to a material possessing a certain degree of air permeability or water permeability. Specifically, it refers to the material's properties that allow a portion of gas or water vapor to pass through the container surface into or out of the container. Semi-permeable containers are widely used for packaging pharmaceutical preparations, such as plastic soft bags for injections, plastic bottles for eye drops, nasal drops, and plastic ampoules. Commonly used semi-permeable container materials include high-density polyethylene, low-density polyethylene, polypropylene, and polyester. Polyester is a general term for thermoplastic saturated polyesters, represented by PET, including PBT, PEN, PCT, and their copolymers.

[0014] Semi-permeable containers, due to their inherent material properties, possess a certain degree of water and air permeability. According to General Chapter 9001 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, pharmaceutical preparations packaged in semi-permeable containers should be tested under conditions of 40℃±2℃ and relative humidity of 25%±5%. Ophthalmic preparations, due to their usage characteristics, have certain requirements regarding the hardness of the inner packaging container. Furthermore, to prevent the leaching of small-molecule volatile organic compounds, semi-volatile organic compounds, plasticizers, and other substances from the semi-permeable container into the medication, which could lead to safety issues, the inventors conducted material screening tests for the inner container under the aforementioned conditions. Ultimately, low-density polyethylene resin or polypropylene resin was used to prepare the eye drop bottle, which serves as the inner container for the combined packaging container.

[0015] According to an embodiment of the present invention, the low-density polyethylene resin is selected from at least one of 2420H, 2421H, 2422H, 2423H, 2424H, 2425H, 2426H, 3020D, LD18D, LD19D, LD20D, LD21D, LD22D, LD23D, LD24D, LD25D and LD26D.

[0016] According to an embodiment of the present invention, the polypropylene resin is at least one of the following: B4808, B4901, B4902, B4908, EPC30G, EPC30R-H and EPS30R.

[0017] According to embodiments of the present invention, the type of the low-density polyethylene resin is selected from 2420H, 2426H, 3020D and / or LD26D.

[0018] According to an embodiment of the present invention, the polypropylene resin is of type B4808 and / or EPC30G.

[0019] The inventors of this invention discovered that when the solution of an ophthalmic preparation is placed in an inner container, the content of certain substances, such as impurities B, E, and leachate impurities, continuously increases during the placement process, especially the content of leachate impurities, which increases significantly. To effectively prevent these impurities from affecting product quality, the inventors used an outer container of a specific material to isolate the inner container, effectively ensuring the stability of product quality.

[0020] According to embodiments of the present invention, the outer container comprises a pharmaceutical composite film containing polyester, aluminum, and polyethylene. Through extensive research, the inventors unexpectedly discovered that using a composite film with a specific structure can effectively control changes in leachates and related substances in ophthalmic preparations under accelerated testing conditions for up to 6 months. Specifically, it reduces the content of impurities B and E, as well as leachates from the inner container, while maintaining the stability of the liquid preparation. It is speculated that the properties of small-molecule volatile organic compounds, semi-volatile organic compounds, plasticizers, and easily oxidized substances in the inner packaging material are altered due to the influence of environmental factors such as high temperature, oxygen content, moisture, and the contact with the pharmaceutical solution. Some of these components leach and enter the pharmaceutical solution, forming leachate impurities. By selecting the specific outer container of the present invention, the level of leachates from the packaging material can be significantly reduced. This allows ophthalmic preparations to maintain ideal chemical composition and properties during long-term storage, which plays a crucial role in ensuring the long-term stability, safety, and efficacy of pentoxyverine hydrochloride ophthalmic preparations.

[0021] It should be noted that in the "multilayer material containing polyester, aluminum, and polyethylene" described in this invention, the polyester layer, aluminum layer, or polyethylene layer can be configured as one or more layers; wherein, the total number of polyester, aluminum, and polyethylene layers is 3 to 7 layers; optionally, the total number of polyester, aluminum, and polyethylene layers is 3 to 5 layers. The polyester, aluminum, and polyethylene layers in the multilayer material can be arranged and configured in various ways, such as a three-layer structure of polyester / aluminum / polyethylene, a four-layer structure of polyester / polyethylene / aluminum / polyethylene, or a five-layer structure of polyester / aluminum / polyethylene / aluminum / polyethylene, etc. The "pharmaceutical composite film containing polyester, aluminum, and polyethylene" described in this invention refers to a composite film formed by hot pressing the various layers together.

[0022] According to an embodiment of the present invention, the multilayer material containing polyester, aluminum and polyethylene is a composite material with a 3 to 7-layer structure.

[0023] According to an embodiment of the present invention, the multilayer material containing polyester, aluminum and polyethylene is a composite material with a 3 to 5-layer structure.

[0024] According to embodiments of the present invention, in the multilayer material containing polyester, aluminum, and polyethylene, the polyester layer has a thickness of 8 μm to 20 μm, the aluminum layer has a thickness of 5 μm to 10 μm, and the polyethylene layer has a thickness of 30 μm to 70 μm. Therefore, the content of leachates and related substances in ophthalmic preparations can be significantly reduced during long-term storage, thereby improving the stability of pentoxyverine hydrochloride ophthalmic preparations.

[0025] According to embodiments of the present invention, the polyester layer has a thickness of 10 μm to 15 μm, the aluminum layer has a thickness of 7 μm to 9 μm, and the polyethylene layer has a thickness of 40 μm to 60 μm. Therefore, the content of leachates and related substances in ophthalmic preparations can be significantly reduced during long-term storage, thereby improving the stability of pentoxyverine hydrochloride ophthalmic preparations.

[0026] It should be noted that the thickness of each material layer refers to the sum of the thicknesses of all layers of the same material. For example, "the thickness of the polyester layer is 10μm to 15μm". When there is only one polyester layer, the thickness of the single polyester layer is 10μm to 15μm. When there are multiple polyester layers, the total thickness of the multiple polyester layers is 10μm to 15μm.

[0027] According to an embodiment of the present invention, the multilayer material is obtained by hot-pressing a polyester layer, an aluminum layer, and a polyethylene layer. That is, the multilayer material refers to a composite film formed by hot-pressing the layers together.

[0028] According to an embodiment of the present invention, the mass-volume ratio of pentoxyverine hydrochloride is 0.01% to 2%, the mass-volume ratio of the osmotic pressure regulator is 0.3% to 0.9%, the mass-volume ratio of the thickener is 0.2% to 0.8%, and the concentration of the phosphate buffer in the drug solution is not higher than 50 mM.

[0029] According to embodiments of the present invention, the mass-to-volume ratio of pentoxyverine hydrochloride in the pharmaceutical solution is 0.01% to 1%. For example, it is 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.

[0030] According to an embodiment of the present invention, the concentration of the phosphate buffer in the drug solution is 5 to 50 mM, for example 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM.

[0031] According to an embodiment of the present invention, the concentration of the phosphate buffer in the drug solution is 5-25 mM.

[0032] According to embodiments of the present invention, the osmotic pressure regulator has a mass-to-volume ratio of 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, and 0.9%.

[0033] According to embodiments of the present invention, the thickener has a mass-to-volume ratio of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, or 0.8%.

[0034] According to an embodiment of the present invention, the phosphate buffer comprises a buffer pair of disodium hydrogen phosphate and sodium dihydrogen phosphate; or the phosphate buffer comprises a buffer pair of dipotassium hydrogen phosphate and potassium dihydrogen phosphate.

[0035] According to embodiments of the present invention, the osmotic pressure regulator includes, but is not limited to, at least one selected from sodium chloride, glucose, glycerol, and sorbitol.

[0036] According to an embodiment of the present invention, the ophthalmic preparation uses a pharmaceutically acceptable thickener to make the viscosity of the prepared ophthalmic preparation below 45 mPa·s, which is within the acceptable range for the human eye, and can effectively control the residence time of the drug in the eye.

[0037] According to embodiments of the present invention, the thickener includes, but is not limited to, at least one selected from hydroxypropyl methylcellulose, polyvinyl alcohol, crospovidone, chitosan, and sodium hyaluronate.

[0038] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0039] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0040] Figure 1 This is a schematic diagram of the inner and outer containers of a combined packaging container according to an embodiment of the present invention;

[0041] Figure 2 This is the spectrum of sample 1 after 6 months of accelerated stability testing according to an embodiment of the present invention;

[0042] Figure 3 The image shows the accelerated stability test spectrum of sample 16 after 6 months according to an embodiment of the present invention. Detailed Implementation

[0043] 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 construed as limiting the present invention.

[0044] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0045] The endpoints and any values ​​of the ranges disclosed herein 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 the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0046] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0047] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0048] In this article, the abbreviation for polyester is PET, the abbreviation for aluminum is AL, and the abbreviation for polyethylene is PE.

[0049] In this article, ND indicates that the substance was not detected.

[0050] In this article, impurity B represents an oxidizing impurity, chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxyquinine-1-oxide), molecular formula C. 20 H 29 NO3, molecular weight 331.46.

[0051] In this article, impurity E represents a degradation impurity, chemical name: 2-cyclopentyl-2-phenylacetaldehyde, molecular formula C 13 H 16 O, with a molecular weight of 188.27, is a potentially genotoxic impurity.

[0052] A schematic diagram of the combined packaging container of the present invention is shown below. Figure 1 As shown, the inner container is an eye drop bottle made of a semi-permeable material, namely low-density polyethylene resin or polypropylene resin. The pentoxyverine hydrochloride ophthalmic preparation is contained within this inner container. The outer container is a polyester / aluminum / polyethylene pharmaceutical composite film. The inner container is placed inside the outer container, and the two are independent of each other. Furthermore, the inner container can be either a multi-dose or single-dose eye drop bottle, as long as it can be placed inside the outer container. Figure 1 The inner container shown is a multi-dose eye drop bottle.

[0053] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0054] Example 1: Different formulations of pentoxyverine hydrochloride ophthalmic preparations

[0055] The method for preparing ophthalmic preparations includes the following steps:

[0056] S1. Take 70% of the total volume of water for injection for ophthalmic preparations, add hydroxypropyl methylcellulose, and cool to below 25°C to obtain preparation solution 1;

[0057] S2. Weigh 20% of the total amount of water for injection, add sodium chloride, pentoxyverine hydrochloride and phosphate buffer solution according to the prescription amount in Table 1, stir until completely dissolved to obtain preparation solution 2;

[0058] S3. After filtering the preparative solution 2 through a 0.22 μm filter membrane, mix it with the preparative solution 1, make up to a certain volume, and stir until the mixture is homogeneous to obtain an ophthalmic preparation. The pH value of the ophthalmic preparation is controlled to be 5.0-7.0.

[0059] S4. Aseptically fill the eye drop bottles using a dispensing method and inspect under light;

[0060] S5. Place the ophthalmic preparations that have passed the light inspection into the outer container and seal it.

[0061] The formulation ratios of pentoxyverine hydrochloride ophthalmic preparations are shown in Table 1. The percentages in the table represent the mass-to-volume ratio of each raw material to the ophthalmic preparation (unit: g / mL), and the pH values ​​are the measured values ​​for each ophthalmic preparation sample. The combined packaging container consists of two layers: the inner packaging material (inner container) is a single-dose eye drop bottle made of low-density polyethylene resin, material type 2420H; the outer packaging material (outer container) is a polyester / aluminum / polyethylene pharmaceutical composite film with thicknesses of PET12μm / AL9μm / PE60μm (abbreviated as PET12 / AL9 / PE60). The accelerated stability test conditions for pentoxyverine hydrochloride ophthalmic preparations over 6 months were: temperature 40℃±2℃, relative humidity 25%±5%. Related substances were tested using HPLC, with specific conditions shown in Table 2. The results are shown in Table 3, and the chromatogram of sample 1 after 6 months of accelerated stability testing is shown in Table 3. Figure 2 Among them, the retention time of 10.8 min is the impurity B peak, and the retention time of 5.8 min is the leachate impurity peak.

[0062] Experimental Results: During the accelerated stability test, the inner packaging material for the pentoxyverine hydrochloride ophthalmic preparation was a single-dose eye drop bottle made of low-density polyethylene resin (LDPE) type 2420H; the outer packaging material was a polyester / aluminum / polyethylene pharmaceutical composite film with thicknesses of PET12 / AL9 / PE60 for each layer. Within the 6-month accelerated stability test, the product's properties, content, and other quality indicators met the requirements. The pH remained essentially unchanged within the range of 5.0-7.0, and impurities B, E, leachate impurities, and total impurities showed virtually no significant changes, indicating that the product quality remained stable under the 6-month accelerated stability test conditions.

[0063] Table 1. Formulas for Pentoethion Hydrochloride Ophthalmic Preparations

[0064]

[0065] Table 2. Related Substances Testing and Analysis Methods

[0066]

[0067]

[0068] Table 3. Results of stability studies on pentoxyverine hydrochloride ophthalmic formulations

[0069]

[0070] Example 2: Investigation of different types of outer packaging materials

[0071] The preparation method and related substance testing and analysis method of pentoxyverine hydrochloride ophthalmic preparation are described in Example 1. The formulation ratio of pentoxyverine hydrochloride ophthalmic preparation is shown in Table 4. The percentages in the table are the mass-volume ratio of each raw material to the ophthalmic preparation (unit: g / mL), and the pH value is the measured value of each ophthalmic preparation sample. The combined packaging containers consist of two layers, an inner and an outer layer. The inner packaging material is a single-dose eye drop bottle made of low-density polyethylene resin, material type 2420H. The outer packaging material of sample 4 is a polyester / aluminum / polyethylene pharmaceutical composite film with layer thicknesses of PET 8μm / AL 5μm / PE 30μm (abbreviated as PET8 / AL5 / PE30). The outer packaging material of sample 5 is a polyester / polyethylene / aluminum / polyethylene pharmaceutical composite film with layer thicknesses of PET 15μm / PE 30μm / AL 10μm / PE 40μm (abbreviated as PET15 / PE30 / AL10 / PE40). The outer packaging material of sample 6 is a polyester / aluminum / polyethylene / polyethylene / polyethylene pharmaceutical composite film with layer thicknesses of PET 12μm / AL 7μm / PE 30μm / PET 8μm / PE 25μm (abbreviated as PET12 / AL7 / PE30 / PET8 / PE25). The accelerated stability test conditions for pentoxyverine hydrochloride ophthalmic preparations over 6 months were 40℃±2℃ and 25%±5% relative humidity. Related substances were tested using HPLC. The results of the stability test for ophthalmic preparations are shown in Table 5.

[0072] Experimental Results: During the accelerated stability test, the inner packaging material of the pentoxyverine hydrochloride ophthalmic formulation was low-density polyethylene resin (2420H), and the outer packaging material was a polyester / aluminum / polyethylene pharmaceutical composite film with membrane structures of PET8 / AL5 / PE30, PET15 / PE30 / AL10 / PE40, and PET12 / AL7 / PE30 / PET8 / PE25. During the accelerated stability test, the product's properties, content, and other quality indicators all met the requirements. The pH value remained essentially unchanged within the range of 5.0-7.0, and there were basically no significant changes in impurities B, E, leachate impurities, and total impurities. This indicates that the product quality remained stable under accelerated conditions for 6 months.

[0073] Table 4. Formulas for Pentylcholine Hydrochloride Ophthalmic Preparations

[0074] Sample 4 Sample 5 Sample 6 Total concentration of buffer 5mM 5mM 5mM Pentyl quinone hydrochloride 0.1％ 0.1％ 0.1％ Hydroxypropyl methylcellulose 0.5％ 0.5％ 0.5％ disodium hydrogen phosphate 0.009％ 0.009％ 0.009％ Sodium dihydrogen phosphate 0.053％ 0.053％ 0.053％ Sodium chloride 0.9％ 0.9％ 0.9％ Water for Injection Add to 5L Add to 5L Add to 5L pH value 6.0 6.0 6.0 Inner packaging material (model) Low-density polyethylene 2420H Low-density polyethylene 2420H Low-density polyethylene 2420H Outer packaging material (model number) PET8 / AL5 / PE30 PET15 / PE30 / AL10 / PE40 PET12 / AL7 / PE30 / PET8 / PE25

[0075] Table 5 shows the stability test results for samples 4, 5, and 6.

[0076]

[0077]

[0078] Example 3: Investigation of different inner packaging materials

[0079] The preparation method and related substance testing methods for pentoxyverine hydrochloride ophthalmic preparations are described in Example 1. The formulation ratios of the pentoxyverine hydrochloride ophthalmic preparations are shown in Table 6. The percentages in the table represent the mass-volume ratio of each raw material to the ophthalmic preparation (unit: g / mL), and the pH value is the measured value of each ophthalmic preparation sample. The combined packaging container consists of two layers. The outer packaging material uses a polyester / aluminum / polyethylene pharmaceutical composite film, with each layer thickness being PET12μm / AL8μm / PE65μm (abbreviated as PET12 / AL8 / PE65). The inner packaging material is a single-dose eye drop bottle, using low-density polyethylene resin or polypropylene resin, with material types LD26D and B4808, respectively. The test results of influencing factors on the ophthalmic preparations are shown in Table 7.

[0080] Experimental Results: The inner packaging material for pentoxyverine hydrochloride ophthalmic preparations uses single-dose pharmaceutical eye drop bottles made of low-density polyethylene resin (LD26D) or polypropylene resin (B4808), and the outer packaging material uses a polyester / aluminum / polyethylene pharmaceutical composite film with a film structure of PET12 / AL8 / PE65. The experimental conditions for influencing factors are a temperature of 50℃±2℃ and a humidity of 75%RH±5%RH. The results of the influencing factor test show that after being placed at a high temperature of 50℃ for 30 days, there are basically no significant changes in impurities B, impurities E, leachate impurities, and total impurities.

[0081] Table 6. Formulation of Pentoxyverine Hydrochloride Ophthalmic Preparations

[0082] Sample 7 Sample 8 Total concentration of buffer 5mM 5mM Pentyl quinone hydrochloride 0.5％ 0.5％ Hydroxypropyl methylcellulose 0.5％ 0.05％ disodium hydrogen phosphate 0.009％ 0.009％ Sodium dihydrogen phosphate 0.053％ 0.053％ Sodium chloride 0.9％ 0.9％ Water for Injection Add to 5L Add to 5L pH value 6.0 6.0 Inner packaging material Low-density polyethylene LD26D Polypropylene B4808 Outer packaging materials PET12 / AL8 / PE65 PET12 / AL8 / PE65

[0083] Table 7. Results of Experimental Testing on Influencing Factors

[0084]

[0085] Experimental Example 1:

[0086] The preparation method and related substance testing methods for pentoxyverine hydrochloride ophthalmic preparations are described in Example 1. The formulation ratios of the pentoxyverine hydrochloride ophthalmic preparations are shown in Table 8. The percentages in the table represent the mass-volume ratio of each raw material to the ophthalmic preparation (unit: g / mL), and the pH value is the measured value of each ophthalmic preparation sample. The combined packaging container consists of two layers: the inner packaging material is a single-dose eye drop bottle made of low-density polyethylene resin or polypropylene resin, with the material types shown in Table 8; the outer packaging material uses aluminum foil bags, high-barrier bags with oxygen absorbers, or no outer packaging material. The accelerated stability test conditions for pentoxyverine hydrochloride ophthalmic preparations over 6 months were 40℃±2℃ and 25%±5% relative humidity. Related substance testing was performed using HPLC, and the results of the ophthalmic preparation stability test are shown in Table 9.

[0087] Experimental Results: During the accelerated stability test, when the inner packaging material of the pentoxyverine hydrochloride ophthalmic preparation was low-density polyethylene resin or polypropylene resin, and the outer packaging material was aluminum foil packaging bag (mainly for light protection) or high-barrier bag + oxygen absorber (mainly for oxygen isolation), impurities B, E, and leachate all increased significantly, indicating that the form and structure of the outer packaging material have a significant impact on product quality. When the pentoxyverine hydrochloride ophthalmic preparation did not use an outer packaging material, due to the water and air permeability of the semi-permeable container material, the product content continuously increased and exceeded the quality standard limit, and leachate appeared during the accelerated stability test. This indicates that when the pentoxyverine hydrochloride ophthalmic preparation is packaged in a semi-permeable eye drop bottle, it must be used in combination with an outer packaging material to significantly reduce the impurity content of the ophthalmic preparation.

[0088] Table 8. Formulation composition of ophthalmic preparations

[0089]

[0090] Table 9 shows the stability test results of samples 9-12.

[0091]

[0092]

[0093] Experimental Example 2:

[0094] The preparation method and related substance analysis methods for pentoxyverine hydrochloride ophthalmic preparations are described in Example 1. The formulation ratios of the pentoxyverine hydrochloride ophthalmic preparations are shown in Table 10. The percentages in the table represent the mass-volume ratio of each raw material to the ophthalmic preparation (unit: g / mL), and the pH values ​​are the measured values ​​for each ophthalmic preparation sample. The combined packaging container consists of two layers, inner and outer. The inner packaging material is a single-dose eye vial, made of low-density polyethylene resin or polypropylene resin; specific material models are shown in Table 10. The outer packaging material uses a polyester / aluminum / polyethylene pharmaceutical composite film, with each layer thickness being PET 20μm / AL 5μm / PE 30μm (abbreviated as PET20 / AL5 / PE30, and so on). The accelerated stability test conditions for the pentoxyverine hydrochloride ophthalmic preparations over 6 months were 40℃±2℃ and 25%±5% relative humidity. Related substance analysis was performed using HPLC. The stability test results for the ophthalmic preparations are shown in Table 11. The chromatogram of sample 16 after 6 months of accelerated stability testing is shown in Table 11. Figure 3 As shown, the impurity with a retention time of 5.6 min is the leachate impurity, the impurity peak with a retention time of 10.7 min is the B peak, and the impurity peak with a retention time of 12.2 min is the E peak.

[0095] Experimental Results: During the accelerated stability test, the ophthalmic formulation of pentoxyverine hydrochloride used low-density polyethylene resin and polypropylene resin as inner packaging materials, and polyester / aluminum / polyethylene pharmaceutical composite film as outer packaging material. Different structures of the outer packaging material were screened, resulting in six structures: PET20 / AL5 / PE30, PET14 / AL7 / PE40, PET10 / AL9 / PE50, PET12 / AL4 / PE60, PET6 / AL4 / PE20, and PET25 / AL12 / PE80. Except for the PET12 / AL5 / PE30 structure... Apart from L4 / PE60, PET6 / AL4 / PE20, and PET25 / AL12 / PE80, the contents of impurities B, E, and leachates in ophthalmic preparations packaged with other outer packaging materials did not show a significant increase. This indicates that a PET thickness of less than 8 μm, an aluminum foil layer thickness of less than 5 μm, or a polyethylene layer thickness of less than 30 μm in the outer packaging material structure all have a certain impact on product quality and stability. Furthermore, a PET thickness of more than 20 μm, an aluminum foil layer thickness of more than 10 μm, or a polyethylene layer thickness of more than 70 μm all have a certain impact on product quality and stability. Therefore, the preferred composition for this material is a polyester thickness of 8 μm–20 μm, an aluminum thickness of 5 μm–10 μm, and a polyethylene thickness of 30 μm–70 μm, with a preferred composition of a polyester thickness of 10–15 μm, an aluminum thickness of 7 μm–9 μm, and a polyethylene thickness of 40 μm–60 μm.

[0096] Table 10 Formulation Composition of Ophthalmic Preparations

[0097]

[0098] Table 11 shows the stability test results for samples 13-18.

[0099]

[0100]

[0101]

[0102] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0103] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A pentoethione hydrochloride ophthalmic preparation, characterized in that, The ophthalmic preparation is placed in a combined packaging container, which includes an inner container and an outer container. in, The inner container comprises a semi-permeable material and defines a space for containing the ophthalmic preparation. The outer container is a multi-layered material containing polyester, aluminum and polyethylene; The inner container is detachably disposed within the outer container; The ophthalmic preparation includes pentoxyverine hydrochloride, phosphate buffer, osmotic pressure regulator and thickener.

2. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 1, characterized in that, The semi-permeable material is selected from low-density polyethylene resin or polypropylene resin.

3. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 1, characterized in that, The outer container comprises a pharmaceutical composite film containing polyester, aluminum, and polyethylene.

4. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 1, characterized in that, The multilayer material containing polyester, aluminum and polyethylene is a composite material with a 3 to 7-layer structure.

5. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 4, characterized in that, The multilayer material containing polyester, aluminum and polyethylene is a composite material with a 3 to 5-layer structure.

6. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 1, characterized in that, In the multilayer material containing polyester, aluminum and polyethylene, the thickness of the polyester layer is 8μm to 20μm, the thickness of the aluminum layer is 5μm to 10μm, and the thickness of the polyethylene layer is 30μm to 70μm.

7. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 6, characterized in that, In the multilayer material containing polyester, aluminum and polyethylene, the thickness of the polyester layer is 10μm to 15μm, the thickness of the aluminum layer is 7μm to 9μm, and the thickness of the polyethylene layer is 40μm to 60μm.

8. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 6 or 7, characterized in that, The multilayer material is obtained by hot pressing a polyester layer, an aluminum layer, and a polyethylene layer.

9. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 1, characterized in that, The mass-volume ratio of the pentoxyverine hydrochloride is 0.01% to 2%, the mass-volume ratio of the osmotic pressure regulator is 0.3% to 0.9%, the mass-volume ratio of the thickener is 0.2% to 0.8%, and the concentration of the phosphate buffer in the solution is not higher than 50 mM.

10. The ophthalmic formulation of pentoxyverine hydrochloride according to claim 1, characterized in that, The phosphate buffer comprises a buffer pair of disodium hydrogen phosphate and sodium dihydrogen phosphate; or The phosphate buffer comprises a buffer pair of dipotassium hydrogen phosphate and potassium dihydrogen phosphate.

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