WO2023020536A1 - 一种药物组合物及其制备方法和应用 - Google Patents

一种药物组合物及其制备方法和应用 Download PDF

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WO2023020536A1
WO2023020536A1 PCT/CN2022/113025 CN2022113025W WO2023020536A1 WO 2023020536 A1 WO2023020536 A1 WO 2023020536A1 CN 2022113025 W CN2022113025 W CN 2022113025W WO 2023020536 A1 WO2023020536 A1 WO 2023020536A1
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parts
pharmaceutical composition
formula
composition according
compound shown
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PCT/CN2022/113025
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English (en)
French (fr)
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王延东
苏映雪
曹琛
周胜安
薛亚萍
吴美容
于垂亮
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广州润尔眼科生物科技有限公司
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Priority to CA3228588A priority Critical patent/CA3228588A1/en
Priority to CN202280055629.9A priority patent/CN117957002A/zh
Priority to AU2022329224A priority patent/AU2022329224A1/en
Priority to KR1020247007852A priority patent/KR20240042650A/ko
Priority to EP22857847.2A priority patent/EP4389131A1/en
Publication of WO2023020536A1 publication Critical patent/WO2023020536A1/zh

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • 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
    • A61P27/12—Ophthalmic agents for cataracts

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition and its preparation method and application.
  • Cataract is an eye disease that occurs on the lens in the eyeball.
  • the cloudiness of the lens is collectively called cataract.
  • Aging, genetics, abnormal metabolism, trauma, radiation, poisoning and local malnutrition can all cause damage to the lens capsule, increase its permeability, lose its barrier function, or lead to metabolic disorders of the lens, denature the lens protein, and form turbidity.
  • the lens of the eyeball changes from transparent to opaque, which affects the light received by the eye, it will affect the vision of the eye.
  • the turbidity of the eyeball is light, the impact on vision is mild. As the degree of turbidity gradually deepens, vision will also decrease, and in severe cases, it will cause blindness.
  • Cataract is one of the most common blinding eye diseases and it is the main cause of blindness. Since the mechanism of cataract formation is still unclear, no breakthrough has been made in drug treatment so far. Therefore, the only sure effective treatment at present is surgical treatment.
  • the clinical drugs for the treatment of cataracts include: 1 aldose reductase inhibitors, such as catalin (catalin, carinyou, catalin), fakolin, bendalysine, etc.; Oxidative damage drugs, such as glutathione, taurine, aspirin, etc.; 3 nutrition and metabolism drugs, such as vitamins, carotenoids, etc.;
  • 1 aldose reductase inhibitors such as catalin (catalin, carinyou, catalin), fakolin, bendalysine, etc.
  • Oxidative damage drugs such as glutathione, taurine, aspirin, etc.
  • 3 nutrition and metabolism drugs such as vitamins, carotenoids, etc.
  • these drugs for treating cataracts can only delay the progression of cataracts, but cannot reverse the condition, thereby treating cataracts. Therefore, clinically, there is a great need for new varieties of ophthalmic external anti-cataract drugs with safety, good curative effect, strong intraocular penetration and stable properties.
  • Lanosterol is an amphiphilic molecule enriched in the lens. It is synthesized by a key cyclization reaction of lanosterol synthase (LSS) in the cholesterol synthesis pathway, which can reduce the abnormal aggregation of lens protein and make it re- regular arrangement to restore crystal transparency. Studies have shown that lanosterol synthase can be detected in the lens. Furthermore, a specific combination of homozygous mutations in lanosterol synthase and farnesyl diphosphate farnesyltransferase 1 (FDFT1) attenuated cholesterol levels in the lens and resulted in cataracts in a Shumiya cataract rat study.
  • LDS lanosterol synthase
  • FDFT1 farnesyl diphosphate farnesyltransferase 1
  • lanosterol can significantly reduce pre-formed lens protein aggregates in vitro and at the cellular level; it has also been confirmed at the in vivo level that lanosterol can reverse the condition of cataracts, and the lens becomes clear and transparent. It is a new molecule for the prevention and treatment of cataracts.
  • WO2020177714 discloses a formulation of a lanosterol prodrug compound, which can relieve cataract symptoms, improve lens transparency and lens GSH-PX activity.
  • the prescription process is complicated to operate, and the stability is poor, it is not easy to store at room temperature, and the patient finds that the comfort is not good when using it. Therefore, there is an urgent need to develop a composition or preparation prescription that is simple in process operation, strong in prescription stability, and more comfortable for patients.
  • the object of the present invention is to provide a pharmaceutical composition and its preparation method and application.
  • the pharmaceutical composition has good light and high temperature stability, and can be used for preparing medicines for preventing or treating cataract or floaters.
  • the present invention provides a pharmaceutical composition, comprising the following components:
  • the present invention discovers through research that the compound shown in formula I is combined with hydroxypropyl methylcellulose (HPMC), benzalkonium chloride and a pH regulator, which can significantly improve the stability of the compound shown in formula I, thereby obtaining stable quality pharmaceutical composition.
  • HPMC hydroxypropyl methylcellulose
  • benzalkonium chloride benzalkonium chloride
  • a pH regulator which can significantly improve the stability of the compound shown in formula I, thereby obtaining stable quality pharmaceutical composition.
  • the pharmaceutical composition includes the following components in parts by weight:
  • 0.01 ⁇ 4 parts of the compound shown in formula I for example can be 0.01 part, 0.05 part, 0.1 part, 0.3 part, 0.5 part, 0.8 part, 1 part, 1.5 part, 2 parts, 2.5 parts, 3 parts, 3.5 parts or 4 parts parts, etc.), 2 to 12 parts of hydroxypropyl methylcellulose (such as 2 parts, 3 parts, 5 parts, 8 parts, 10 parts or 12 parts, etc.), 0.05 to 0.06 parts of benzalkonium chloride (such as 0.05 parts, 0.052 parts, 0.053 parts, 0.055 parts, 0.056 parts, 0.058 parts or 0.06 parts, etc.) and 1 to 20 parts of pH regulators (such as 1 part, 2 parts, 3 parts, 5 parts, 8 parts, 10, 12, 15, 18 or 20 etc.);
  • the pH of the pharmaceutical composition is 6-8; for example, it can be 6, 6.2, 6.5, 6.8, 7, 7.2, 7.5, 7.8 or 8, etc.
  • the concentration of the compound represented by formula I in the pharmaceutical composition is 0.01-4 mg/mL; preferably 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL or 4 mg/mL.
  • the pH regulator is selected from sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate and phosphoric acid One or a combination of at least two of dipotassium hydrogen.
  • the pharmaceutical composition further includes a solubilizer.
  • the parts by weight of the solubilizer in the pharmaceutical composition are 10-50 parts; for example, it can be 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 45 copies or 50 copies etc.
  • the solubilizer is selected from polysorbate-80, glycerin, hydrogenated castor oil-RH40, polyethylene glycol 400, hydroxypropyl- ⁇ -cyclodextrin and poloxamer 188 One or a combination of at least two.
  • the pharmaceutical composition includes the following components in parts by weight:
  • the present invention provides a pharmaceutical composition, comprising the following components in parts by weight:
  • the particle size of the compound represented by formula I is ⁇ 90 ⁇ m, preferably ⁇ 50 ⁇ m.
  • the particle size distribution of the compound represented by formula I is D90 ⁇ 7 ⁇ m and/or D50 ⁇ 4 ⁇ m.
  • the D 90 particle size of the compound represented by formula I is ⁇ 8 ⁇ m.
  • the D 50 particle size of the compound represented by formula I is ⁇ 3.5 ⁇ m.
  • the dosage form of the pharmaceutical composition is suspension, emulsion or gel, preferably emulsion.
  • the present invention provides a method for preparing the pharmaceutical composition as described in the first aspect or the second aspect, the preparation method comprising: compounding the compound shown in formula I, hydroxypropylmethylcellulose, benzalkonium The ammonium chloride, optional pH regulator and optional solubilizer are uniformly mixed according to the prescription amount to obtain the pharmaceutical composition.
  • “optionally” in the present invention refers to having or not having corresponding components.
  • the component is used in the preparation method; when the pharmaceutical composition does not contain the corresponding component, the component is not used in the preparation method.
  • the preparation method includes the following steps:
  • the preparation method comprises the steps of:
  • solution III is homogeneously circulated with a high-pressure homogenizer to obtain solution IV;
  • the present invention provides a use of the pharmaceutical composition as described in the first aspect or the second aspect in the preparation of a medicament for preventing or treating cataract or floaters.
  • the present invention has the following beneficial effects:
  • the pharmaceutical composition provided by the invention can be used to prevent or treat cataracts and floaters. It is placed under 4500Lx light conditions or 60°C high temperature conditions for 10 days, the pH and osmotic pressure remain stable, and there is no obvious change in related substances and contents. Good light and high temperature stability, can be stored at room temperature, convenient for patients to use. At the same time, the pH and osmotic pressure of the pharmaceutical composition are close to the intraocular environment, the particle size distribution is uniform, and the D 50 particle size does not exceed 3.5 ⁇ m, which can provide patients with good comfort.
  • the present embodiment provides a kind of pharmaceutical composition, and composition is as shown in the following table:
  • the above-mentioned pharmaceutical composition can be further prepared into an eye drop product through the following steps: sampling to detect pH, osmotic pressure, and content, and subpackaging in a sterile environment with a low-density polyethylene medicinal eye drop bottle after passing the test, each bottle of 5mL medicine liquid.
  • the present embodiment provides a kind of pharmaceutical composition, and composition is as shown in the following table:
  • the above-mentioned pharmaceutical composition can be further prepared into an eye drop product through the following steps: sampling to detect pH, osmotic pressure, and content, and subpackaging in a sterile environment with a low-density polyethylene medicinal eye drop bottle after passing the test, each bottle of 5mL medicine liquid.
  • the present embodiment provides a kind of pharmaceutical composition, and composition is as shown in the following table:
  • the above-mentioned pharmaceutical composition can be further prepared into an eye drop product through the following steps: sampling to detect pH, osmotic pressure, and content, and subpackaging in a sterile environment with a low-density polyethylene medicinal eye drop bottle after passing the test, each bottle of 5mL medicine liquid.
  • the present embodiment provides a kind of pharmaceutical composition, and composition is as shown in the following table:
  • the above-mentioned pharmaceutical composition can be further prepared into an eye drop product through the following steps: sampling to detect pH, osmotic pressure, and content, and subpackaging in a sterile environment with a low-density polyethylene medicinal eye drop bottle after passing the test, each bottle of 5mL medicine liquid.
  • the present embodiment provides a kind of pharmaceutical composition, and composition is as shown in the following table:
  • the above-mentioned pharmaceutical composition can be further prepared into an eye drop product through the following steps: sampling to detect pH, osmotic pressure, and content, and subpackaging in a sterile environment with a low-density polyethylene medicinal eye drop bottle after passing the test, each bottle of 5mL medicine liquid.
  • composition is as shown in the following table:
  • the preparation method of the pharmaceutical composition is the same as in Example 4 except that poloxamer 188 and poloxamer 407 are used instead of glycerin.
  • Photostability test investigate the photostability of the compositions provided by the above-mentioned examples and comparative examples, all samples that carry out photofactor investigations are packaged as commercially available, and placed in the photoincubator MGC-100 under the condition of 4500Lx , samples were taken at 0 days, 5 days, and 10 days, and tested according to the key stability inspection items.
  • the stability inspection items include: character, particle size, particle size distribution, pH value, osmotic pressure, content determination of the compound shown in formula I, and impurity content measurement. The test results are shown in Table 1 below.
  • High temperature stability test observe the high temperature stability of the compositions provided in the above-mentioned examples and comparative examples. Placed in a dry incubator, samples were taken at 0 days, 5 days, and 10 days, and tested according to the key stability inspection items.
  • the stability inspection items include: character, particle size, particle size distribution, pH value, osmotic pressure, content determination of the compound shown in formula I, and impurity content measurement. The test results are shown in Table 1 below.
  • the pharmaceutical composition provided by the present invention is placed under 4500Lx light conditions or 60°C high temperature conditions for 10 days, the pH and osmotic pressure remain stable, and there is no significant change in related substances and contents.
  • the pharmaceutical composition has better light and high temperature stability, can be stored at room temperature, and is convenient for patients to use.
  • the pH and osmotic pressure of the pharmaceutical composition are close to the intraocular environment, the particle size distribution is uniform and the D 50 particle size does not exceed 3.5 ⁇ m, which can provide patients with better comfort.
  • the pH value of the pharmaceutical composition obtained in Comparative Example 1 changed significantly under 4500Lx light conditions or 60°C high temperature conditions, and its stability was poor.
  • the pharmaceutical composition obtained in Comparative Example 1 is a gel, its osmotic pressure cannot be measured, and it does not meet the requirements of the intraocular environment, and the D 50 and D 90 particle sizes are relatively large, and the comfort is poor.
  • the pharmaceutical composition provided by the invention can make black spots and bands in front of the eyes obviously lighten and/or reduce after about 15 days of medication, and improve contrast sensitivity; about 30 days after medication, it can make The black spots and bands in front of the eyes almost disappeared, or even completely disappeared, the visual quality such as contrast sensitivity was significantly improved, and the floaters were basically cured without other side effects.

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Abstract

一种药物组合物及其制备方法和应用。所述药物组合物包括如下组分：式I所示化合物、羟丙基甲基纤维素、苯扎氯铵和pH调节剂。所述药物组合物可用于制备预防或治疗白内障的药物。所述药物组合物具有良好的光照和高温稳定性，可以室温保存，便于患者使用，其pH、渗透压接近眼内环境，粒度分布均匀，能够给予患者良好的舒适性。

Description

一种药物组合物及其制备方法和应用 技术领域
本发明属于医药领域，具体涉及一种药物组合物及其制备方法和应用。
背景技术
白内障属于眼睛的疾病，发生在眼球内的晶状体上，晶状体的浑浊统称为白内障。老化、遗传、代谢异常、外伤、辐射、中毒和局部营养不良等都可引起晶状体囊膜损伤，使其渗透性增加，丧失屏障作用，或导致晶状体代谢紊乱，使晶状体蛋白发生变性，形成混浊。如果眼球的晶状体从透明变成不透明，影响到眼睛接收光，就会影响眼睛的视力。在眼球浑浊较轻时对视力的影响较轻，随着浑浊的程度逐渐加深，视力也会随之降低，严重时会导致失明。白内障是最常见的致盲眼病之一，它是导致失明的主要因素。由于白内障形成的机制尚不明确，药物治疗至今未取得突破性进展。因此，目前唯一确定有效的治疗方法就是手术治疗。
尽管白内障手术方式的不断进步为白内障的治疗提供了巨大的帮助，但手术治疗的治愈率仍然远远低于发生率，存在发生严重并发症的可能。另一方面，白内障的手术治疗成本十分高昂，会给患者和医疗保险体系带来巨大的负担。因此药物的防治起到举足轻重的作用。
目前，临床上针对白内障的治疗药物包括：①醛糖还原酶抑制剂，如卡他林(卡他灵、卡林优、白内停)、法可林、苄达赖氨酸等；②抗氧化损伤药物，如谷胱甘肽、牛磺酸、阿司匹林等；③营养代谢类药物，如维生素类、类胡萝卜素等；④中药复方包括石斛夜光丸、杞菊地黄丸、石决明散等。但这些治疗白内障的药物经长期临床试验证实，只能延缓白内障的病情恶化，不能使病情逆转，从而治疗白内障。 因此，临床上非常需要安全、疗效好、眼内穿透力强、性质稳定的新品种眼科外用抗白内障药物。
羊毛甾醇是富集于晶状体内的两亲性分子，它是由羊毛甾醇合酶(LSS)在胆固醇合成途径中的一个关键的环化反应来合成，能够降低晶状体蛋白的异常聚集，使其重新规则排列从而恢复晶体透明。已有研究表明，在晶状体中可以检测到羊毛甾醇合酶。此外，在Shumiya白内障大鼠研究中，羊毛甾醇合酶和法尼基二磷酸法尼基转移酶1(FDFT1)的纯合突变特定组合可以减轻晶状体中胆固醇的水平，并导致白内障。此外，羊毛甾醇在体外和细胞水平可以显著降低预形成的晶状体蛋白质聚集体；在体内水平也证实，羊毛甾醇可以使白内障的病情逆转，晶状体变的澄清透明，是预防和治疗白内障的新分子。
WO2020177714公开了一种羊毛甾醇前药化合物的制剂处方，其可以减轻白内障症状、提高晶状体透明度以及晶状体GSH-PX活性。但是该处方工艺操作复杂，且稳定性较差，不易常温保存，而且患者在使用时发现舒适度欠佳。因此，临床上急需要开发一种工艺操作简单，处方稳定性强，并且对于患者来说舒适性更好的组合物或制剂处方。
发明内容
针对现有技术存在的不足，本发明的目的在于提供一种药物组合物及其制备方法和应用。该药物组合物具有良好的光照和高温稳定性，可用于制备预防或治疗白内障或飞蚊症的药物。
为达此目的，本发明采用以下技术方案：
第一方面，本发明提供一种药物组合物，包括如下组分：
式I所示化合物、羟丙基甲基纤维素、苯扎氯铵和pH调节剂；
Figure PCTCN2022113025-appb-000001
本发明通过研究发明，将式I所示化合物与羟丙基甲基纤维素(HPMC)、苯扎氯铵和pH调节剂配合，能够显著提高式I所示化合物的稳定性，从而获得质量稳定的药物组合物。
在本发明一些实施方式中，所述药物组合物包括如下重量份数的组分：
式I所示化合物0.01～4份(例如可以是0.01份、0.05份、0.1份、0.3份、0.5份、0.8份、1份、1.5份、2份、2.5份、3份、3.5份或4份等)、羟丙基甲基纤维素2～12份(例如可以是2份、3份、5份、8份、10份或12份等)、苯扎氯铵0.05～0.06份(例如可以是0.05份、0.052份、0.053份、0.055份、0.056份、0.058份或0.06份等)和pH调节剂1～20份(例如可以是1份、2份、3份、5份、8份、10份、12份、15份、18份或20份等)；
所述药物组合物的pH为6-8；例如可以是6、6.2、6.5、6.8、7、7.2、7.5、7.8或8等。
在本发明一些实施方式中，所述药物组合物中式I所示化合物的浓度为0.01-4mg/mL；优选为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/mL、1mg/mL、2mg/mL、3mg/mL或4mg/mL。
在本发明一些实施方式中，所述pH调节剂选自氢氧化钠、盐酸、枸橼酸钠、枸橼酸、硼酸、硼砂、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾和磷酸氢二钾中的一种或至少两种的组合。
在本发明一些实施方式中，所述药物组合物还包括增溶剂。
在本发明一些实施方式中，所述药物组合物中增溶剂的重量份数 为10～50份；例如可以是10份、15份、20份、25份、30份、35份、40份、45份或50份等。
在本发明一些实施方式中，所述增溶剂选自聚山梨酯-80、甘油、氢化蓖麻油-RH40、聚乙二醇400、羟丙基-β-环糊精和泊洛沙姆188中的一种或至少两种的组合。
在本发明一些实施方式中，所述药物组合物包括如下重量份数的组分：
式I所示化合物2份、羟丙基甲基纤维素6份、硼酸16.5份、硼砂2份和苯扎氯胺0.05份；
或者，式I所示化合物2份、羟丙基甲基纤维素6份、聚山梨酯-80 40份、硼酸16份、硼砂1.6份和苯扎氯胺0.05份；
或者，式I所示化合物2份、羟丙基甲基纤维素6份、氢化蓖麻油-RH40 10份、硼酸17份、硼砂1.7份和苯扎氯胺0.05份。
第二方面，本发明提供一种药物组合物，包括如下重量份数的组分：
式I所示化合物2份、羟丙基甲基纤维素6份、甘油25份和苯扎氯胺0.05份；
或者，式I所示化合物2份、羟丙基甲基纤维素6份、氢化蓖麻油-RH40 10份、聚山梨酯-80 40份、甘油25份和苯扎氯胺0.05份。
在本发明一些实施方式中，式I所示化合物的粒径＜90μm，优选≤50μm。
在本发明一些实施方式中，式I所示化合物粒度分布为D90≤7μm和/或D50≤4μm。
在本发明一些实施方式中，式I所示化合物的D 90粒径＜8μm。
在本发明一些实施方式中，式I所示化合物的D 50粒径≤3.5μm。
在本发明一些实施方式中，所述药物组合物的剂型为混悬剂、乳剂或凝胶剂，优选为乳剂。
第三方面，本发明提供一种如第一方面或第二方面所述的药物组合物的制备方法，所述制备方法包括：将式I所示化合物、羟丙基甲基纤维素、苯扎氯铵、任选地pH调节剂和任选地增溶剂按处方量混合均匀，得到所述药物组合物。
需要说明的是，本发明中所述“任选地”是指有或者没有对应的组分。当药物组合物中含有对应的组分时，则制备方法中使用该组分；当药物组合物中不含对应的组分时，则制备方法中不使用该组分。
在本发明一些实施方式中，所述制备方法包括如下步骤：
(1)用注射用水溶解羟丙基甲基纤维素，得溶液I；
(2)用注射用水溶解处方量的除羟丙基甲基纤维素和式I所示化合物之外的组分，然后加入到所述溶液I中，混合均匀，得溶液II；
(3)取处方量的式I所示化合物，加入所述溶液II中，混合均匀，得溶液III；
(4)将所述溶液III用注射用水定容至全量，得到所述药物组合物。
优选地，所述制备方法包括如下步骤：
(1)用注射用水溶解羟丙基甲基纤维素，搅拌使其完全溶解，得溶液I；
(2)用注射用水溶解处方量的除羟丙基甲基纤维素和式I所示化合物之外的组分，然后加入到所述溶液I中，加注射用水至90％处方量，搅拌均匀，得溶液II；
(3)取处方量的式I所示化合物，加入所述溶液II中，得溶液III；
(4)将所述溶液III用高压均质机进行均质循环，得溶液IV；
(5)将所述溶液IV用注射用水定容至全量，得到所述药物组合物。
第四方面，本发明提供一种如第一方面或第二方面所述的药物组 合物在制备预防或治疗白内障或飞蚊症的药物中的应用。
与现有技术相比，本发明具有以下有益效果：
本发明提供的药物组合物能够用于预防或治疗白内障、飞蚊症，其在4500Lx光照条件或60℃高温条件下放置10天，pH、渗透压保持稳定，有关物质和含量无明显变化，具有良好的光照和高温稳定性，可以室温保存，便于患者使用。同时，该药物组合物的pH、渗透压接近眼内环境，粒度分布均匀且D 50粒径不超3.5μm，能够给予患者良好的舒适性。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述具体实施方式仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1
本实施例提供一种药物组合物，成分如下表所示：
成分 用量(g)
式I所示化合物 2.0
HPMC 6.0
硼酸 16.5
硼砂 2
苯扎氯铵 0.05
水 定容至1000mL
本实施例中所述药物组合物的制备方法如下：
(1)先用10％的煮沸注射用水将羟丙甲纤维素溶解，加入适量冷注射用水，搅拌使其完全溶解，得溶液I；
(2)用适量的注射用水，搅拌溶解处方量的硼酸、硼砂和苯扎氯铵，然后加入溶液I中，加入注射用水至90％处方量，搅拌均匀，得溶液II；
(3)称取处方量的式I所示化合物，加入溶液II中，用高剪切乳化机以10000r/min的速度分散10分钟，分散均匀，得溶液III；
(4)将溶液III用高压均质机以250bar的压力均质循环一次，收集药液，并用适量无菌注射用水冲洗高压均质机管路，收集冲洗液，与药液合并，得溶液IV；
(5)用无菌注射用水将溶液IV定容至全量。
上述药物组合物可进一步经如下步骤制备成滴眼液产品：取样检测pH、渗透压、含量，合格后用低密度聚乙烯药用滴眼剂瓶在无菌环境中分装，每瓶5mL药液。
实施例2
本实施例提供一种药物组合物，成分如下表所示：
成分 用量(g)
式I所示化合物 2.0
HPMC 6.0
聚山梨酯-80 40
硼酸 16
硼砂 1.6
苯扎氯铵 0.05
水 定容至1000mL
本实施例中所述药物组合物的制备方法如下：
(1)先用10％的煮沸注射用水将羟丙甲纤维素溶解，加入适量冷注射用水，搅拌使其完全溶解，得溶液I；
(2)用适量的注射用水，搅拌溶解处方量的硼酸、硼砂和苯扎氯铵，然后加入溶液I中，边搅拌边缓慢加入处方量的聚山梨酯-80，加入注射用水至90％处方量，搅拌均匀，得溶液II；
(3)称取处方量的式I所示化合物，加入溶液II中，用高剪切乳化机以10000r/min的速度分散10分钟，分散均匀，得溶液III；
(4)将溶液III用高压均质机以250bar的压力均质循环一次，收集药液，并用适量无菌注射用水冲洗高压均质机管路，收集冲洗液，与药液合并，得溶液IV；
(5)用无菌注射用水将溶液IV定容至全量。
上述药物组合物可进一步经如下步骤制备成滴眼液产品：取样检测pH、渗透压、含量，合格后用低密度聚乙烯药用滴眼剂瓶在无菌环境中分装，每瓶5mL药液。
实施例3
本实施例提供一种药物组合物，成分如下表所示：
成分 用量(g)
式I所示化合物 2.0
HPMC 6.0
氢化蓖麻油-RH40 10
硼酸 17
硼砂 1.7
苯扎氯铵 0.05
水 定容至1000mL
本实施例中所述药物组合物的制备方法如下：
(1)先用10％的煮沸注射用水将羟丙甲纤维素溶解，加入适量冷注射用水，搅拌使其完全溶解，得溶液I；
(2)用适量的注射用水，搅拌溶解处方量的硼酸、硼砂和苯扎氯铵，然后加入溶液I中，边搅拌边缓慢加入处方量的氢化蓖麻油-RH40，加入注射用水至90％处方量，搅拌均匀，得溶液II；
(3)称取处方量的式I所示化合物，加入溶液II中，用高剪切乳化机以10000r/min的速度分散10分钟，分散均匀，得溶液III；
(4)将溶液III用高压均质机以250bar的压力均质循环一次，收集药液，并用适量无菌注射用水冲洗高压均质机管路，收集冲洗液， 与药液合并，得溶液IV；
(5)用无菌注射用水将溶液IV定容至全量。
上述药物组合物可进一步经如下步骤制备成滴眼液产品：取样检测pH、渗透压、含量，合格后用低密度聚乙烯药用滴眼剂瓶在无菌环境中分装，每瓶5mL药液。
实施例4
本实施例提供一种药物组合物，成分如下表所示：
成分 用量(g)
式I所示化合物 2.0
HPMC 6.0
甘油 25
苯扎氯铵 0.05
水 定容至1000mL
本实施例中所述药物组合物的制备方法如下：
(1)先用10％的煮沸注射用水将羟丙甲纤维素溶解，加入适量冷注射用水，搅拌使其完全溶解，得溶液I；
(2)用适量的注射用水，搅拌溶解处方量的苯扎氯铵，然后加入溶液I中，边搅拌边缓慢加入处方量的甘油，加入注射用水至90％处方量，搅拌均匀，得溶液II；
(3)称取处方量的式I所示化合物，加入溶液II中，用高剪切乳化机以10000r/min的速度分散10分钟，分散均匀，得溶液III；
(4)将溶液III用高压均质机以250bar的压力均质循环一次，收集药液，并用适量无菌注射用水冲洗高压均质机管路，收集冲洗液，与药液合并，得溶液IV；
(5)用无菌注射用水将溶液IV定容至全量。
上述药物组合物可进一步经如下步骤制备成滴眼液产品：取样检测pH、渗透压、含量，合格后用低密度聚乙烯药用滴眼剂瓶在无菌 环境中分装，每瓶5mL药液。
实施例5
本实施例提供一种药物组合物，成分如下表所示：
成分 用量(g)
式I所示化合物 2.0
HPMC 6.0
氢化蓖麻油-RH40 10
聚山梨酯-80 40
甘油 25
苯扎氯铵 0.05
水 定容至1000mL
本实施例中所述药物组合物的制备方法如下：
(1)先用10％的煮沸注射用水将羟丙甲纤维素溶解，加入适量冷注射用水，搅拌使其完全溶解，得溶液I；
(2)用适量的注射用水，搅拌溶解处方量的苯扎氯铵，然后加入溶液I中，边搅拌边缓慢加入处方量的氢化蓖麻油-RH40、聚山梨酯-80和甘油，加入注射用水至90％处方量，搅拌均匀，得溶液II；
(3)称取处方量的式I所示化合物，加入溶液II中，用高剪切乳化机以10000r/min的速度分散10分钟，分散均匀，得溶液III；
(4)将溶液III用高压均质机以250bar的压力均质循环一次，收集药液，并用适量无菌注射用水冲洗高压均质机管路，收集冲洗液，与药液合并，得溶液IV；
(5)用无菌注射用水将溶液IV定容至全量。
上述药物组合物可进一步经如下步骤制备成滴眼液产品：取样检测pH、渗透压、含量，合格后用低密度聚乙烯药用滴眼剂瓶在无菌环境中分装，每瓶5mL药液。
对比例1
提供一种药物组合物，成分如下表所示：
成分 用量(g)
式I所示化合物 2.0
HPMC 6.0
泊洛沙姆188 16
泊洛沙姆407 205
苯扎氯铵 0.05
水 定容至1000mL
所述药物组合物的制备方法除使用泊洛沙姆188和泊洛沙姆407代替甘油外，其他与实施例4相同。
稳定性测试：
(1)光照稳定性试验：考察上述实施例和对比例提供的组合物的光照稳定性，所有进行光照因素考察的样品均按市售包装，在4500Lx条件下的光照培养箱MGC-100中放置，分别于0天、5天、10天取样，按稳定性重点考察项目进行检测。稳定性考察项目包括：性状、粒度、粒度分布、pH值、渗透压、式I所示化合物含量测定、杂质含量测定，检测结果如下表1所示。
(2)高温稳定性试验：察上述实施例和对比例提供的组合物的高温稳定性，所有进行高温因素考察的样品均按市售包装，在60℃条件下的101-1A数显式电热干燥恒温箱中放置，分别于0天、5天、10天取样，按稳定性重点考察项目进行检测。稳定性考察项目包括：性状、粒度、粒度分布、pH值、渗透压、式I所示化合物含量测定、杂质含量测定，检测结果如下表1所示。
表1
Figure PCTCN2022113025-appb-000002
Figure PCTCN2022113025-appb-000003
Figure PCTCN2022113025-appb-000004
从表1的实验结果可以看出，本发明提供的药物组合物在4500Lx光照条件或60℃高温条件下放置10天，pH、渗透压保持稳定，有关物质和含量无明显变化，比对比例提供的药物组合物具有更好的光照和高温稳定性，可以室温保存，便于患者使用。同时，该药物组合物的pH、渗透压接近眼内环境，粒度分布均匀且D 50粒径不超3.5μm，能够给予患者更好的舒适性。
而对比例1得到的药物组合物在4500Lx光照条件或60℃高温条件下pH值均变化较明显，稳定性较差。且对比例1得到的药物组合物为凝胶剂，其渗透压无法测定，也不符合眼内环境的要求，且D 50、 D 90粒径偏大，舒适性较差。
治疗效果测试
选取9名患有飞蚊症的患者，自确诊日起，每日分别施用实施例1提供的药物组合物四次，每次2滴，于第15日、第30日复诊，观察患者飞蚊症的治疗效果，具体如下表2所示：
表2
Figure PCTCN2022113025-appb-000005
Figure PCTCN2022113025-appb-000006
Figure PCTCN2022113025-appb-000007
从表2的治疗效果可以看出，本发明提供的药物组合物用药15天左右就能使眼前黑点、条带明显变浅和/或减少，改善对比敏感度；用药30天左右，能够使眼前黑点、条带几乎消失，甚至完全消失，对比敏感度等视觉质量明显改善，飞蚊症基本治愈，且无其他副作用。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (16)

  1. 一种药物组合物，其特征在于，所述药物组合物包括如下组分：
    式I所示化合物、羟丙基甲基纤维素、苯扎氯铵和pH调节剂；
    Figure PCTCN2022113025-appb-100001
  2. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物包括如下重量份数的组分：
    式I所示化合物0.01～4份、羟丙基甲基纤维素2～12份、苯扎氯铵0.05～0.06份和pH调节剂1～20份，所述药物组合物的pH为6-8。
  3. 根据权利要求2所述的药物组合物，其特征在于，所述药物组合物中式I所示化合物的浓度为0.01-4mg/mL，进一步优选为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/mL、1mg/mL、2mg/mL、3mg/mL或4mg/mL。
  4. 根据权利要求2所述的药物组合物，其特征在于，所述pH调节剂选自氢氧化钠、盐酸、枸橼酸钠、枸橼酸、硼酸、硼砂、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾和磷酸氢二钾中的一种或至少两种的组合。
  5. 根据权利要求1或2所述的药物组合物，其特征在于，所述药物组合物还包括增溶剂。
  6. 根据权利要求5所述的药物组合物，其特征在于，所述药物组合物中增溶剂的重量份数为10～50份。
  7. 根据权利要求5所述的药物组合物，其特征在于，所述增溶剂选自聚山梨酯-80、甘油、氢化蓖麻油-RH40、聚乙二醇400、羟丙基-β-环糊精和泊洛沙姆188中的一种或至少两种的组合。
  8. 根据权利要求1-7任一项所述的药物组合物，其特征在于，所述药物组合物包括如下重量份数的组分：
    式I所示化合物2份、羟丙基甲基纤维素6份、硼酸16.5份、硼砂2份和苯扎氯胺0.05份；
    或者，式I所示化合物2份、羟丙基甲基纤维素6份、聚山梨酯-80 40份、硼酸16份、硼砂1.6份和苯扎氯胺0.05份；
    或者，式I所示化合物2份、羟丙基甲基纤维素6份、氢化蓖麻油-RH40 10份、硼酸17份、硼砂1.7份和苯扎氯胺0.05份。
  9. 一种药物组合物，其特征在于，所述药物组合物包括如下重量份数的组分：
    式I所示化合物2份、羟丙基甲基纤维素6份、甘油25份和苯扎氯胺0.05份；
    或者，式I所示化合物2份、羟丙基甲基纤维素6份、氢化蓖麻油-RH40 10份、聚山梨酯-80 40份、甘油25份和苯扎氯胺0.05份。
  10. 根据权利要求1-9任一项所述的药物组合物，其特征在于，式I所示化合物的粒径＜90μm。
  11. 根据权利要求10所述的药物组合物，其特征在于，式I所示化合物的粒径≤50μm。
  12. 根据权利要求11所述的药物组合物，其特征在于，式I所示化合物粒度分布为D90≤7μm和/或D50≤4μm。
  13. 根据权利要求1-12任一项所述的药物组合物，其特征在于，所述药物组合物的剂型为混悬剂、乳剂或凝胶剂，优选为乳剂。
  14. 一种如权利要求1-13任一项所述的药物组合物的制备方法，其特征在于，所述制备方法包括：将式I所示化合物、羟丙基甲基纤维素、苯扎氯铵、任选地pH调节剂和任选地增溶剂按处方量混合均匀，得到所述药物组合物。
  15. 根据权利要求14所述的制备方法，其特征在于，所述制备 方法包括如下步骤：
    (1)用注射用水溶解羟丙基甲基纤维素，得溶液I；
    (2)用注射用水溶解处方量的除羟丙基甲基纤维素和式I所示化合物之外的组分，然后加入到所述溶液I中，混合均匀，得溶液II；
    (3)取处方量的式I所示化合物，加入所述溶液II中，混合均匀，得溶液III；
    (4)将所述溶液III用注射用水定容至全量，得到所述药物组合物。
  16. 一种如权利要求1-13任一项所述的药物组合物在制备预防或治疗白内障或飞蚊症的药物中的应用。
PCT/CN2022/113025 2021-08-18 2022-08-17 一种药物组合物及其制备方法和应用 WO2023020536A1 (zh)

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