WO2023024126A1 - 一种含伏立康唑的眼用凝胶剂及其制备方法与应用 - Google Patents

一种含伏立康唑的眼用凝胶剂及其制备方法与应用 Download PDF

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WO2023024126A1
WO2023024126A1 PCT/CN2021/115661 CN2021115661W WO2023024126A1 WO 2023024126 A1 WO2023024126 A1 WO 2023024126A1 CN 2021115661 W CN2021115661 W CN 2021115661W WO 2023024126 A1 WO2023024126 A1 WO 2023024126A1
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voriconazole
gel
ophthalmic gel
ophthalmic
injection
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French (fr)
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戴向荣
丁领振
李刚
李小羿
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兆科药业（合肥）有限公司
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a voriconazole-containing ophthalmic gel and a preparation method and application thereof.
  • Fungal keratitis (Fungal Keratitis, FK) is a kind of corneal lesion with high blinding rate caused by pathogenic fungal infection.
  • the disease is more common in vegetative trauma (branches, straws, straws, etc.), after removal of corneal foreign bodies such as soil and sand.
  • vegetative trauma branches, straws, straws, etc.
  • glucocorticoids and antibiotics and the popularity of wearing contact lenses, its incidence has increased.
  • Fungal keratitis is one of the major blinding eye diseases in developing countries such as China and India. According to the etiology of fungal keratitis, the main pathogenic genus of fungal keratitis in China is Fusarium, accounting for 70% of the infection cases ⁇ 80%, followed by Aspergillus and Candida. The symptoms of eye irritation in the early stage of infection are generally mild, and the course of the disease develops slowly compared with bacterial keratitis, but the combination of bacterial infection or abuse of glucocorticoids will make the condition aggravate rapidly. The clinical symptoms are foreign body sensation or tingling in the eye, blurred vision, and a small amount of discharge can be seen on eye examination.
  • Fungal keratitis is treated with topical antifungal agents such as natamycin, fluconazole, amphotericin B, and voriconazole.
  • topical antifungal agents such as natamycin, fluconazole, amphotericin B, and voriconazole.
  • natamycin and amphotericin B have low bioavailability and poor corneal penetration, and fluconazole has no effect on the main pathogenic bacteria of fungal keratitis, Fusarium spp. sensitive, which limits their clinical application.
  • Natamycin It is the first ophthalmic topical antifungal drug approved by the US FDA. It has a broad antifungal spectrum, including Fusarium, Aspergillus, Acremonium, Penicillium, and Bispora genera and Candida, etc. Natamycin has poor water solubility, and its 50g/L suspension is stable and can adhere to the cornea well. It is painless to use and has no secondary corneal damage. Its disadvantage is that it is expensive.
  • Fluconazole 10 domestic companies have launched fluconazole eye drops. Fluconazole can inhibit cytochrome P450-dependent enzymes, block the synthesis of ergosterol in the cell membrane, destroy the membrane permeability, and eventually the fungus dies. The disadvantage is that the main pathogenic genus of the disease: Fusarium is not sensitive to fluconazole, so we should be vigilant when choosing drugs.
  • Amphotericin B The concentration of AmB solution for topical application is 1.5-3g/L. It should be freshly prepared with sterile water for injection, and should be stored at low temperature and away from light. It should be used dropwise every 30-60 minutes. The main side effects are Corneal toxicity may occur. There are also eye ointments of 5-20 g/L in topical preparations, which are no longer recommended because subconjunctival injection can produce severe toxic reactions.
  • Voriconazole is a derivative of fluconazole, and its in vitro antibacterial activity is 50-100 times that of fluconazole. In vitro activity studies have shown that voriconazole has high antibacterial activity against Aspergillus, Candida and Fusarium, with MIC90 of 0.25 ⁇ 0.5 ⁇ g ⁇ mL -1 , 0.25 ⁇ 0.5 ⁇ g ⁇ mL -1 and 1 ⁇ 4 ⁇ g ⁇ mL -1 respectively . 1 . And it is one of the few effective drugs against Scedosporium apices. The intrastromal injection of voriconazole is safe and effective, with no obvious complications in the short term.
  • voriconazole Compared with traditional antifungal drugs, the stability, safety, effectiveness, broad antibacterial spectrum and corneal permeability of voriconazole have been significantly improved. Studies have shown that voriconazole is safe and effective in the treatment of fungal keratitis without complications. However, so far, there is no ophthalmic preparation of voriconazole on the market, and its marketed dosage form is an injection, which cannot be administered by eye drops by the patient, and the compliance in ophthalmology clinical application is not good (long-term medication, intrastromal injection). As in the prior art, the patent application number 201810913082.7 discloses an eye drop containing voriconazole.
  • the present invention provides a voriconazole-containing ophthalmic gel and its preparation method and application.
  • the ophthalmic gel can make voriconazole adhere to the cornea, maintain the effective therapeutic concentration of voriconazole, and prolong the effective treatment time , reduce the frequency of administration, improve patient compliance; improve the solution stability of voriconazole, increase the retention rate of the preparation at the site of action, and improve the bioavailability of voriconazole.
  • the invention provides an ophthalmic gel containing voriconazole, which comprises the following ingredients in weight percent: 0.5%-2% voriconazole, 10%-30% solubilizer, 20%-30% gel matrix, 1%-4 % lubricant, and the balance is water for injection.
  • the ophthalmic gel further includes a pH regulator, and the pH regulator is hydrochloric acid or sodium hydroxide.
  • the pH value of the ophthalmic gel is 4-7.4.
  • the solubilizer is sodium sulfobutylbeta cyclodextrin.
  • the gel matrix is one or more of poloxamer 407, poloxamer 188, and sodium alginate.
  • the lubricant is one of polyvinyl alcohol, polyethylene glycol 4000, and polyethylene glycol 6000.
  • the present invention also provides a preparation method of ophthalmic gel containing voriconazole, comprising the following steps:
  • the invention also provides the application of the ophthalmic gel containing voriconazole in the preparation of medicine for treating fungal keratitis.
  • the positive progress effect of the present invention is:
  • Ophthalmic gel of the present invention is a kind of thermosensitive gel, is the liquid that can flow freely at room temperature, and phase transition can take place at 31 ⁇ 37 °C, forms a kind of semi-solid gel (as shown in Figure 1 ), can adhere to the cornea and stay in the eye, maintain the effective therapeutic concentration of voriconazole, continue to exert the therapeutic effect of voriconazole, prolong the effective treatment time, reduce the frequency of administration, and improve patient compliance. Avoid eye drops flowing through the nasolacrimal duct to the mouth, resulting in a bitter taste.
  • the ophthalmic gel of the invention improves the solution stability of the voriconazole, increases the retention rate of the preparation at the action site, and improves the bioavailability of the voriconazole.
  • Fig. 1 is the contrast figure of ophthalmic gel state under different temperatures
  • Fig. 2 is the release curve of voriconazole ophthalmic gel.
  • An ophthalmic gel containing voriconazole comprising the following components by weight percentage: 0.5%-2% voriconazole, 10%-30% solubilizer, 20%-30% gel base, 1%-4% lubricant, The balance is water for injection.
  • Ophthalmic thermosensitive gel is a special liquid, which undergoes a phase transition at a certain temperature and becomes semi-solid, has a special touch, and is as transparent as a liquid. Its advantages are strong adhesion, not easy to flow out, and long duration of drug effect. Moreover, the eyes will not be blurred during the medication, and it is convenient to use. Its usage is for external use, and it is dripped into the conjunctival sac when used.
  • ophthalmic gels in ophthalmology, such as antiviral antibiotics or artificial tears, which are mainly composed of drugs and gel-like media.
  • the gel can play the role of adhesion, can adhere to the surface of the cornea and conjunctiva, make the action time of the drug more durable, relatively reduce the frequency of dripping the drug, increase people's compliance, and make the drug achieve better effects.
  • Eye gel has no irritation to the eyes, cornea, and conjunctiva, and is actually another state of eye drops or ointment. It has a wider application in ophthalmology and is more widely used than eye drops because it is used less often and patients are more adaptable.
  • the active ingredient is voriconazole.
  • Voriconazole is a derivative of fluconazole, and its in vitro antibacterial activity is 50-100 times that of fluconazole. In vitro activity studies have shown that voriconazole has high antibacterial activity against Aspergillus, Candida and Fusarium, with MIC90 of 0.25-0.5 ⁇ g mL-1, 0.25-0.5 ⁇ g mL-1 and 1-4 ⁇ g mL-1, respectively. 1. And it is one of the few effective drugs against Scedosporium apices. The intrastromal injection of voriconazole is safe and effective, with no obvious complications in the short term. Based on the ophthalmic gel containing voriconazole as 100%, the active ingredient voriconazole is added in an amount of 0.5% to 2%, preferably 0.8% to 1.5%, more preferably 1%.
  • solubilizer in the ophthalmic gel of the present invention, contain solubilizer, described solubilizer is preferably sulfobutylbeta cyclodextrin sodium, voriconazole is added in the solubilizer solution of sulfobutylbeta cyclodextrin sodium, the solubilizer The solvent enhances the solubility and solution stability of the active ingredient. Based on the ophthalmic gel containing voriconazole as 100%, the added amount of sulfobutylbeta cyclodextrin sodium is 10%-30%, preferably 15%-25%, more preferably 20%.
  • the ophthalmic gel of the present invention contains a gel matrix, which can play the role of sustained release and further stability enhancement. Under the same conditions, there is a big difference between adding gel matrix and not adding, and the release curve of the active ingredient and the viscosity of the preparation are significantly different. This effect is related to the residence time, bioavailability and release time of voriconazole in the cornea.
  • the gel matrix is one or more of Poloxamer 407, Poloxamer 188, and sodium alginate. Based on the ophthalmic gel containing voriconazole as 100%, the added amount of the gel matrix is 20%-30%, preferably 23%-27%, more preferably 25%.
  • the ophthalmic gel of the present invention contains a lubricant.
  • the lubricant can not only enhance the lubricating effect on the eyes, but also enhance the stability of voriconazole in aqueous solution.
  • the lubricant is one of polyvinyl alcohol, polyethylene glycol 4000, and polyethylene glycol 6000. Based on the ophthalmic gel containing voriconazole as 100%, the weight percentage of the lubricant is 1%-4%, preferably 2%-3%, more preferably 2.5%.
  • a pH regulator is used to adjust the pH range of the ophthalmic gel to 4-7.4, preferably, the pH range is 4.5-6.5.
  • the pH regulator is preferably hydrochloric acid or sodium hydroxide.
  • the concentration of the hydrochloric acid or sodium hydroxide solution is preferably 1N.
  • the present invention also provides a preparation method of ophthalmic gel containing voriconazole, comprising the following steps:
  • the specific sterilization condition adopted in the sterilization process is 121° C. for 10 to 20 minutes, preferably 15 minutes.
  • the invention also provides the application of the ophthalmic gel containing voriconazole in the preparation of medicine for treating fungal keratitis.
  • the present embodiment provides a kind of ophthalmic gel containing voriconazole, and the prescription is composed as follows:
  • the present embodiment provides a kind of ophthalmic gel containing voriconazole, and the prescription is composed as follows:
  • composition w/v(%)
  • Voriconazole 1 Sodium sulfobutylbeta cyclodextrin 20
  • Poloxamer 407 20 polyvinyl alcohol 1 1N sodium hydroxide solution Adjust pH to 6.5 Water for Injection add to full
  • the present embodiment provides a kind of ophthalmic gel containing voriconazole, and the prescription is composed as follows:
  • Voriconazole 1.5 Sodium sulfobutylbeta cyclodextrin 30 sodium alginate 20 polyethylene glycol 4000 2 1N sodium hydroxide solution Adjust pH to 6.5 Water for Injection add to full
  • the present embodiment provides a kind of ophthalmic gel containing voriconazole, and the prescription is composed as follows:
  • composition w/v(%)
  • Voriconazole 1 Sodium sulfobutylbeta cyclodextrin 20
  • Poloxamer 407 twenty two polyethylene glycol 6000 2 1N sodium hydroxide solution Adjust pH to 7.4 Water for Injection add to full
  • Poloxamer 407 and polyethylene glycol 6000 were added to water for injection with 50% of the prescription volume, placed under refrigeration to dissolve completely, and a clear and transparent gel matrix solution was obtained;
  • composition of the prescription is as follows:
  • composition w/v(%)
  • Voriconazole 0.5 Sodium sulfobutylbeta cyclodextrin 10 polyvinyl alcohol 1 1N hydrochloric acid solution Adjust pH to 4.5 Water for Injection add to full
  • the dissolution and release assay method (general rule 0913 third method) was used to detect the release of voriconazole in the above-mentioned Examples 1-4 and Comparative Examples.
  • phosphate buffer as the dissolution medium at a temperature of (35 ⁇ 1)°C
  • the release rate of voriconazole in Examples 1-4 in which gel matrix was added was lower than that in the comparative example in which no gel matrix was added. It shows that the ophthalmic gel of the present invention improves the solution stability of voriconazole, slows down the drug release rate, and improves the bioavailability of voriconazole.

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Abstract

一种含伏立康唑的眼用凝胶剂及其制备方法以及在制备治疗真菌性角膜炎药物中的应用，该眼用凝胶剂包括以下重量百分比的成分：0.5％～2％伏立康唑，10％～30％增溶剂，20％～30％凝胶基质，1％～4％润滑剂，余量为注射用水。该眼用凝胶剂能够使伏立康唑粘附在眼角膜，维持伏立康唑的有效治疗浓度，延长有效治疗时间，减少给药频次，提高患者顺应性；提高伏立康唑的溶液稳定性，增加制剂在作用部位的滞留率，提高伏立康唑的生物利用度。

Description

一种含伏立康唑的眼用凝胶剂及其制备方法与应用 技术领域
本发明属于药物制剂领域，特别涉及一种含伏立康唑的眼用凝胶剂及其制备方法与应用。
背景技术
真菌性角膜炎(Fungal Keratitis，FK)是由致病真菌感染引起的致盲率极高的一种角膜病变。本病多见于植物性外伤(树枝、稻草及麦秆等擦伤)，剔除泥土、砂石等角膜异物后。近年来随着糖皮质激素和抗生素的广泛使用，角膜接触镜佩戴的普及，其发病率有增加趋势。
真菌性角膜炎是中国和印度等发展中国家主要的致盲眼病之一，根据真菌性角膜炎的病原学，中国真菌性角膜炎主要致病菌属是镰刀菌属，占感染病例的70％～80％，其次为曲霉菌属和念珠菌属。感染早期眼部刺激症状一般较轻，病程发展相对细菌性角膜炎缓慢，但合并有细菌感染或滥用糖皮质激素会使病情迅速加重。临床症状表现为眼部异物感或刺痛、视物模糊，眼部检查可见有少量分泌物。
现有治疗手段中，由于大多数抗真菌药物在角膜中所能达到的有效药物浓度仅能抑制真菌的生长，并且毒性大，眼部穿透性差,疗效不确定。近年来采取多元化治疗方案，即早期病灶清创联合抗真菌药物治疗，对疗效差的尽早实行手术干预治疗，复发率降到2％以下。但由于角膜移植手术因角膜移植供体材料缺乏，使得该术式的临床应用受到限制。另外，眼角膜移植手术后仍然存在真菌复发的问题，据统计真菌性角膜炎行角膜移植术后，复发的比例在7％～8％。故临床上尚无理想的特效药物和治疗方法。
真菌性角膜炎治疗主要局部使用抗真菌药物，如那他霉素、氟康唑、两性霉素B和伏立康唑。但在治疗角膜深层感染时，那他霉素和两性霉素B较低的生物利用度和较差的角膜穿透性，氟康唑对真菌性角膜炎的主要致病菌属镰刀菌属不敏感，这些限制了它们的临床应用。
那他霉素：是第一种被美国FDA批准生产的眼局部用抗真菌药，抗真菌谱很广，包括镰刀菌属、曲霉菌属、枝顶孢霉属、青霉属、毛双孢属和念 珠菌属等。那他霉素水溶性差，其50g/L的混悬液性质稳定，并能很好地粘附于角膜，使用无痛苦，无继发角膜损伤。其缺点是价格昂贵。
氟康唑：国内已经上市了10家氟康唑滴眼液。氟康唑能够抑制细胞色素P450依赖酶，阻断细胞膜合成麦角甾醇，破坏膜通透性，最终真菌死亡。缺点是对该病的主要致病菌属：镰刀菌属对氟康唑不敏感，选用药物时要警惕。
两性霉素B(AmB)：局部应用的AmB溶液浓度为1.5～3g/L，应用灭菌注射用水新鲜配制,且要低温和避光保存，每30～60min滴用1次，其副作用主要是可能出现角膜毒性。局部制剂还有5～20g/L的眼膏，因结膜下注射可产生严重的毒性反应而不再推荐使用。
伏立康唑：伏立康唑为氟康唑的衍生物，体外抗菌活性是氟康唑的50～100倍。体外活性研究表明，伏立康唑对曲霉菌、假丝酵母菌和镰刀菌有高度的抗菌活性，MIC90分别为0.25～0.5μg·mL -1、0.25～0.5μg·mL -1和1～4μg·mL -1。而且是为数不多抗尖端赛多孢子菌的有效药物。采用角膜基质内注射伏立康唑，是安全有效的，短期内无明显并发症。
伏立康唑的稳定性、安全性、有效性、抗菌谱广及角膜渗透性较传统抗真菌药物有了明显改善，研究表明伏立康唑对真菌性角膜炎的治疗是安全有效的、无并发症。但是，目前为止，并没有伏立康唑的眼用制剂上市，其上市剂型为注射剂，患者无法自行滴眼给药，在眼科临床应用的顺应性不好(长期用药，角膜基质内注射)。如现有技术中，申请号为201810913082.7的专利公开了一种含伏立康唑的滴眼液，临床施用时，需要在闭眼的同时，用手指轻轻按压内眼角，以防止眼内的药液流走。如果药液流走，需要重新补滴，造成药物生物利用度的浪费。另外，药液通过鼻泪管流到口腔会有苦涩的味道。
因此，如何提供一种能够使伏立康唑粘附在眼角膜，维持伏立康唑的有效治疗浓度，延长有效治疗时间，减少给药频次，提高患者顺应性；提高伏立康唑的溶液稳定性，增加制剂在作用部位的滞留率，提高伏立康唑的生物利用度是目前本领域技术人员迫切需要解决的技术问题。
发明内容
有鉴于此，本发明提供了一种含伏立康唑的眼用凝胶剂及其制备方法与应用，该眼用凝胶能够使伏立康唑粘附在眼角膜，维持伏立康唑的有效治疗浓度，延长有效治疗时间，减少给药频次，提高患者顺应性；提高伏立康唑的溶液稳定性，增加制剂在作用部位的滞留率，提高伏立康唑的生物利用度。
为了解决上述技术问题，本发明的技术方案如下：
本发明提供了一种含伏立康唑的眼用凝胶剂，包括以下重量百分比的成分：0.5％～2％伏立康唑，10％～30％增溶剂，20％～30％凝胶基质，1％～4％润滑剂，余量为注射用水。
优选的，所述眼用凝胶剂还包括pH调节剂，所述pH调节剂为盐酸或氢氧化钠。
优选的，所述眼用凝胶剂的pH值为4-7.4。
优选的，所述增溶剂为磺丁基倍他环糊精钠。
优选的，所述凝胶基质为泊洛沙姆407、泊洛沙姆188、海藻酸钠中的一种或几种。
优选的，所述润滑剂为聚乙烯醇、聚乙二醇4000、聚乙二醇6000中的一种。
本发明还提供了一种含伏立康唑的眼用凝胶剂的制备方法，包括以下步骤：
a)将增溶剂溶于处方量30％-50％的注射用水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将凝胶基质与润滑剂加入处方量30％～50％的注射用水，溶解完全，得到澄清透明的凝胶基质溶液；
c)将伏立康唑药液加入凝胶基质溶液中，用pH调节剂调节pH至4～7.4，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌10～20分钟，得到无菌的伏立康唑眼用凝胶剂。
本发明还提供了一种含伏立康唑的眼用凝胶剂在制备治疗真菌性角膜炎药物中的应用。
与现有技术相比，本发明的积极进步效果在于：
本发明的眼用凝胶剂是一种温敏凝胶剂，在室温下是可以自由流动的液体，在31～37℃下可以发生相转变，形成一种半固体凝胶剂(如图1所示)，可以粘附于眼角膜而滞留在眼部，维持伏立康唑的有效治疗浓度，持续发挥伏立康唑的治疗作用，延长有效治疗时间，减少给药频次，提高患者顺应性。避免滴眼液通过鼻泪管流到口腔，产生苦涩的味道。
本发明的眼用凝胶剂提高了伏立康唑的溶液稳定性，增加制剂在作用部位的滞留率，提高伏立康唑的生物利用度。
附图说明
图1为不同温度下眼用凝胶剂状态比对图；
图2为伏立康唑眼用凝胶剂释放曲线。
具体实施方式
一种含伏立康唑的眼用凝胶剂，包括以下重量百分比的成分：0.5％～2％伏立康唑，10％～30％增溶剂，20％～30％凝胶基质，1％～4％润滑剂，余量为注射用水。
眼用温敏凝胶是一种特殊的液体，在一定温度下发生相变，成半固体，具有特殊的触感，而且像液体那样透明。它的优势是附着力强，不易流出，药效持续时间长。而且用药期间眼睛不会模糊，使用方便。它的用法是外用，使用时滴入结膜囊中。
眼用凝胶在眼科中有很多种类型，像抗病毒的抗生素或者人工泪液都有凝胶制剂，主要由药物和凝胶状介质所相结合。凝胶能起到黏附性的作用，能黏附在角膜和结膜表面，使药物的作用时间更加持久，相对减少药物的滴用次数，增加人的依从性，使药物达到更好的作用。眼用凝胶对眼部或者角膜、结膜没有刺激，实际上是眼药水或者眼药膏的另一种状态。在眼科有更广泛的应用，比眼药水的使用范围更广，因为其使用的次数更少，患者的适应性更好。
本发明眼用凝胶剂中，其活性成分为伏立康唑。伏立康唑为氟康唑的衍生物，体外抗菌活性是氟康唑的50～100倍。体外活性研究表明，伏立康唑 对曲霉菌、假丝酵母菌和镰刀菌有高度的抗菌活性，MIC90分别为0.25～0.5μg·mL-1、0.25～0.5μg·mL-1和1～4μg·mL-1。而且是为数不多抗尖端赛多孢子菌的有效药物。采用角膜基质内注射伏立康唑，是安全有效的，短期内无明显并发症。以含伏立康唑的眼用凝胶剂百分量为100％计，活性成分伏立康唑的添加量为0.5％～2％，优选为0.8％～1.5％，更优选为1％。
本发明眼用凝胶剂中，含有增溶剂，所述增溶剂优选为磺丁基倍他环糊精钠，将伏立康唑加到磺丁基倍他环糊精钠的增溶剂溶液中，该增溶剂增强了活性成分的溶解度与溶液稳定性。以含伏立康唑的眼用凝胶剂百分量为100％计，磺丁基倍他环糊精钠的添加量为10％～30％，优选为15％～25％，更优选为20％。
本发明眼用凝胶剂中，含有凝胶基质，能够起到缓释与进一步稳定性增强的作用。相同条件下，加入凝胶基质和不加入有很大区别，活性成分的释放曲线以及制剂粘度有明显不同，该效果与伏立康唑在眼角膜的滞留时间、生物利用度以及释放时间有关。优选的，本发明中，所述凝胶基质为泊洛沙姆407、泊洛沙姆188、海藻酸钠中的一种或几种。以含伏立康唑的眼用凝胶剂百分量为100％计，凝胶基质的添加量为20％～30％，优选为23％～27％，更优选为25％。
本发明眼用凝胶剂中，含有润滑剂。润滑剂不仅能够增强在眼部润滑效果，还能够增强伏立康唑在水溶液中稳定性。优选的，本发明中，润滑剂为聚乙烯醇、聚乙二醇4000、聚乙二醇6000中的一种。以含伏立康唑的眼用凝胶剂百分量为100％计，所述润滑剂重量百分比为1％～4％，优选为2％～3％，更优选为2.5％。
本发明眼用凝胶剂中，采用pH调节剂调节眼用凝胶剂pH范围为4-7.4，优选地，pH范围为4.5-6.5。所述pH调节剂优选为盐酸或氢氧化钠。所述盐酸或氢氧化钠溶液的浓度优选为1N。
本发明还提供了一种含伏立康唑的眼用凝胶剂的制备方法，包括以下步骤：
a)将增溶剂溶于处方量30％～50％的注射用水中，搅拌溶解完全，加入伏 立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将凝胶基质与润滑剂加入处方量30％～50％的注射用水，溶解完全，得到澄清透明的凝胶基质溶液；
c)将伏立康唑药液加入凝胶基质溶液中，用pH调节剂调节pH至4～7.4，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌10～20分钟，得到无菌的伏立康唑眼用凝胶剂。
本发明制备工艺中，对灭菌工艺采用的具体的灭菌条件为121℃进行10～20分钟，优选为15分钟。
本发明还提供了一种含伏立康唑的眼用凝胶剂在制备治疗真菌性角膜炎药物中的应用。
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例对本发明进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
本实施例提供了一种含伏立康唑的眼用凝胶剂，处方组成如下：
处方组成 w/v(％)
伏立康唑 0.5
磺丁基倍他环糊精钠 10
泊洛沙姆407 25
泊洛沙姆188 5
聚乙烯醇 1
1N盐酸溶液 调pH至4.5
注射用水 加至全量
制备工艺：
a)将磺丁基倍他环糊精钠溶于处方量40％的水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将泊洛沙姆407、泊洛沙姆188、聚乙烯醇加入处方量50％的注射用水，放置于冷藏条件下溶解完全，得到澄清透明的凝胶基质溶液；
c)将伏立康唑药液加入凝胶基质溶液中，用1N盐酸溶液调节pH至4.5，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌10分钟，得到无菌的伏立康唑眼用凝胶剂。
实施例2
本实施例提供了一种含伏立康唑的眼用凝胶剂，处方组成如下：
处方组成 w/v(％)
伏立康唑 1
磺丁基倍他环糊精钠 20
泊洛沙姆407 20
聚乙烯醇 1
1N氢氧化钠溶液 调pH至6.5
注射用水 加至全量
制备工艺：
a)将磺丁基倍他环糊精钠溶于处方量50％的水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将泊洛沙姆407与聚乙烯醇加入处方量40％的注射用水，放置于冷藏条件下溶解完全，得到澄清透明的凝胶基质溶液；
c)将伏立康唑药液加入凝胶基质溶液中，用1N氢氧化钠溶液调节pH至6.5，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌15分钟，得到无菌的伏立康唑眼用凝胶剂。
实施例3
本实施例提供了一种含伏立康唑的眼用凝胶剂，处方组成如下：
处方组成 w/v(％)
伏立康唑 1.5
磺丁基倍他环糊精钠 30
海藻酸钠 20
聚乙二醇4000 2
1N氢氧化钠溶液 调pH至6.5
注射用水 加至全量
制备工艺：
a)将磺丁基倍他环糊精钠溶于处方量50％的水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将海藻酸钠与聚乙二醇4000加入处方量40％的注射用水，放置于冷藏条件下溶解完全，得到澄清透明的凝胶基质溶液；
c)将伏立康唑药液加入凝胶基质溶液中，用1N氢氧化钠溶液调节pH至6.5，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌15分钟，得到无菌的伏立康唑眼用凝胶剂。
实施例4
本实施例提供了一种含伏立康唑的眼用凝胶剂，处方组成如下：
处方组成 w/v(％)
伏立康唑 1
磺丁基倍他环糊精钠 20
泊洛沙姆407 22
聚乙二醇6000 2
1N氢氧化钠溶液 调pH至7.4
注射用水 加至全量
制备工艺：
a)将磺丁基倍他环糊精钠溶于处方量40％的水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将泊洛沙姆407与聚乙二醇6000加入处方量50％的注射用水，放置于冷藏条件下溶解完全，得到澄清透明的凝胶基质溶液；
c)将伏立康唑药液加入凝胶基质溶液中，用1N氢氧化钠溶液调节pH至7.4，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌20分钟，得到无菌的伏立康唑眼用凝胶剂。
对比例
处方组成如下：
处方组成 w/v(％)
伏立康唑 0.5
磺丁基倍他环糊精钠 10
聚乙烯醇 1
1N盐酸溶液 调pH至4.5
注射用水 加至全量
制备工艺：
a)将磺丁基倍他环糊精钠溶于处方量50％的水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
b)将聚乙烯醇加入处方量40％的注射用水，放置于冷藏条件下溶解完全，得到澄清透明的辅料溶液；
c)将伏立康唑药液加入辅料溶液中，用1N氢氧化钠溶液调节pH至6.5，用注射用水定重至全量，混合均匀；
d)灌装后，采用121℃，灭菌15分钟，得到无菌的伏立康唑眼用溶液。
效果实施例
参照2020年版《中国药典》(四部)溶出度与释放度测定法(通则0913第三法)，检测上述实施例1-4及对比例中伏立康唑的释放度。以磷酸盐缓冲液为溶出介质，温度为(35±1)℃，检测30、60、90、120、180、240分钟时溶出液中伏立康唑，计算累积释放度。绘制释放度曲线，结果如图2所示。加入凝胶基质的实施例1-4中伏立康唑的释放速度要低于不加入凝胶基质的对比例。说明本发明的眼用凝胶剂提高了伏立康唑的溶液稳定性，减缓药物释放速率，提高伏立康唑的生物利用度。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (8)

  1. 一种含伏立康唑的眼用凝胶剂，其特征在于，包括以下重量百分比的成分：0.5％～2％伏立康唑，10％～30％增溶剂，20％～30％凝胶基质，1％～4％润滑剂，余量为注射用水。
  2. 根据权利要求1所述的含伏立康唑的眼用凝胶剂，其特征在于，还包括pH调节剂，所述pH调节剂为盐酸或氢氧化钠。
  3. 根据权利要求2所述的含伏立康唑的眼用凝胶剂，其特征在于，所述眼用凝胶剂的pH值为4-7.4。
  4. 根据权利要求1所述的含伏立康唑的眼用凝胶剂，其特征在于，所述增溶剂为磺丁基倍他环糊精钠。
  5. 根据权利要求1所述的含伏立康唑的眼用凝胶剂，其特征在于，所述凝胶基质为泊洛沙姆407、泊洛沙姆188、海藻酸钠中的一种或几种。
  6. 根据权利要求1所述的含伏立康唑的眼用凝胶剂，其特征在于，所述润滑剂为聚乙烯醇、聚乙二醇4000、聚乙二醇6000中的一种。
  7. 一种如权利要求1-6任意一项所述含伏立康唑的眼用凝胶剂的制备方法，其特征在于，包括以下步骤：
    a)将增溶剂溶于处方量30％-50％的注射用水中，搅拌溶解完全，加入伏立康唑原料，搅拌溶解完全，得伏立康唑药液；
    b)将凝胶基质与润滑剂加入处方量30％～50％的注射用水，溶解完全，得到澄清透明的凝胶基质溶液；
    c)将伏立康唑药液加入凝胶基质溶液中，用pH调节剂调节pH至4～7.4，用注射用水定重至全量，混合均匀；
    d)灌装后，采用121℃，灭菌10～20分钟，得到无菌的伏立康唑眼用凝胶剂。
  8. 一种如权利要求1-6任意一项所述含伏立康唑的眼用凝胶剂在制备治疗真菌性角膜炎药物中的应用。
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