Preparation method of azithromycin sustained-release eye drops
阅读说明：本技术 一种阿奇霉素缓释滴眼液的制备方法 (Preparation method of azithromycin sustained-release eye drops ) 是由 不公告发明人 于 2020-05-07 设计创作，主要内容包括：本发明公开了一种阿奇霉素缓释滴眼液的制备方法,通过葡萄糖醛酸改性磷脂乙醇胺获得磷脂乙醇胺衍生物,将磷脂乙醇胺衍生物作为乳化剂制备得到阿奇霉素滴眼液,具有减缓阿奇霉素释放速度的效果；磷脂乙醇胺衍生物的制备条件为：将葡萄糖醛酸和磷脂乙醇胺加入环己烷溶剂中,加入催化剂氯化亚锡,温度120-160℃,回流时间1-6h,反应完成后采用硅胶柱层析法利用1：1-4的氯仿和甲醇的混合溶液洗脱分离得到磷脂乙醇胺衍生物。本发明得到的阿奇霉素滴眼液具有减缓了阿奇霉素的释放速度的效果,以及提高了阿奇霉素在乳化液中的包封率的效果。(The invention discloses a preparation method of azithromycin sustained-release eye drops, which is characterized in that phospholipid ethanolamine derivatives are obtained by modifying phospholipid ethanolamine with glucuronic acid, and the azithromycin eye drops are prepared by taking the phospholipid ethanolamine derivatives as an emulsifier, and have the effect of slowing down the release speed of azithromycin; the preparation conditions of the phospholipid ethanolamine derivative are as follows: adding glucuronic acid and phosphatide ethanolamine into a cyclohexane solvent, adding a catalyst stannous chloride, heating at 120 ℃ and 160 ℃, refluxing for 1-6h, and performing a reaction by a silica gel column chromatography method by using a reaction condition that 1: 1-4 mixed solution of chloroform and methanol is eluted and separated to obtain the phosphatide ethanolamine derivative. The azithromycin eye drops obtained by the invention have the effects of slowing down the release speed of azithromycin and improving the encapsulation rate of azithromycin in emulsion.)
1. A phospholipid ethanolamine derivative has a structural formula as follows:
2. A method for preparing a phospholipid ethanolamine derivative comprises the following steps: adding glucuronic acid and phosphatidylethanolamine into a solvent, adding a catalyst, refluxing at the temperature of 120 ℃ and 160 ℃ for 1-6h, and separating by using an eluent through a silica gel column chromatography after the reaction is finished to obtain the phosphatidylethanolamine derivative; the solvent is cyclohexane, the catalyst is stannous chloride, and the eluent is a mixture of the solvent and the catalyst in a volume ratio of 1: 1-4 of chloroform and methanol.
3. The process for producing a phosphatidylethanolamine derivative according to claim 2, wherein: the addition ratio of the glucuronic acid to the phospholipid ethanolamine is 1: 0.1-1.
4. Use of a phosphatidylethanolamine derivative obtained by the method of any one of claims 2 to 3 for sustained drug release.
5. Use of the phospholipid ethanolamine derivative according to claim 1 for emulsifying a solution.
6. An emulsion comprising a phosphatidylethanolamine derivative as set forth in claim 1.
7. An emulsion according to claim 6, wherein: the content of the phospholipid ethanolamine derivative is 1-5 wt%.
8. Use of an emulsion according to claim 6 in the preparation of eye drops.
9. An azithromycin sustained-release eye drop comprising the emulsion of claim 6.
10. A method for preparing azithromycin sustained-release eye drops as claimed in claim 9, which comprises the following steps: and mixing and emulsifying the oil phase containing the emulsifier phospholipid ethanolamine derivative and the water phase containing the azithromycin to obtain the azithromycin sustained-release eye drops.
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of azithromycin sustained-release eye drops.
Background
Azithromycin is a semi-synthetic 15-membered macrolide antibiotic, and has the effect of mainly interfering the protein synthesis of sensitive microorganisms to achieve the bacteriostatic effect. Azithromycin has the characteristic of wide antibacterial spectrum compared with erythromycin, is sensitive to various staphylococci, streptococcus, bacilli, mycoplasma and chlamydia, is effective to conjunctival infection caused by various pathogenic bacteria, and is listed as a key medicine for preventing and treating eye infectious diseases such as trachoma conjunctivitis and the like by the world health organization. Azithromycin is stable to acid and has good tolerance, and becomes a first-line medicament for treating infection at present. The ophthalmic medicine solution is mainly absorbed through two ways of cornea and conjunctiva when being dripped into eyes, most of the medicine firstly permeates into aqueous humor through the cornea and then is distributed in peripheral tissues, and a small amount of the medicine enters into eye pigment membrane and vitreous humor through the ways of conjunctiva and sclera, but not firstly enters into the aqueous humor, so the corneal barrier is the primary limiting channel for the medicine to permeate and reach the eyes.
The phospholipidethanolamine, as a member of phospholipid families, is an important component in a cell membrane phospholipid bilayer structure, is important for maintaining the physiological activity of a biological membrane and the normal metabolism of organisms, and is widely distributed in animals, plants and microorganisms. The phosphatide ethanolamine has an emulsifying effect and can be used as an emulsifier; can also be used as a drug carrier to prepare liposome loaded drugs to realize drug slow release. However, due to the specific molecular structure of the phospholipid ethanolamine, the phospholipid ethanolamine has many specific functions, but has many limitations in application, for example, the phospholipid ethanolamine has few hydroxyl groups, poor hydrophilic performance and weak surface active capacity.
The eye drop is dropped on the surface of eye and the medicine is transferred along with the secretion of tears, although it has the advantage of even medicine distribution, because of the blinking of eyelid, the secretion of conjunctival sac tears and the quick discharge from nasolacrimal duct, it has the problems of short detention time and low bioavailability, the contact time between the medicine and cornea in human body is only about 1-2min, the bioavailability of eye is generally less than 10%, sometimes in order to achieve the therapeutic purpose, it needs frequent and high concentration administration, resulting in the decrease of compliance of patient and increase of general adverse reaction. The market needs a new eye drop with good compatibility and long time of pharmaceutical technology.
Disclosure of Invention
1. The invention provides a phosphatide ethanolamine derivative, which comprises phosphorus obtained by reacting glucuronic acid with phosphatide ethanolamine
A lipidethanolamine derivative having the following structural formula:
The invention provides a preparation method of a phospholipid ethanolamine derivative, which comprises the following steps: adding glucuronic acid and phosphatidylethanolamine into a solvent, adding a catalyst, refluxing at the temperature of 120 ℃ and 160 ℃ for 1-6h, and separating by using an eluent through a silica gel column chromatography after the reaction is finished to obtain the phosphatidylethanolamine derivative; cyclohexane is used as a solvent, stannous chloride is used as a catalyst, and the volume ratio of the eluent is 1: 1-4 of chloroform and methanol. Preferably, the amount of glucuronic acid added is 2-10 wt% of the solvent, more preferably, the amount of glucuronic acid added can be 3-8 wt%, for example, 3.5, 4, 4.5, 5, 5.5, 6, 7, 7.5 wt%; the amount of the phosphatidylethanolamine added is 2 to 6 wt% of the solvent, and more preferably, the amount of the phosphatidylethanolamine added may be 3 to 5 wt%, for example, 3.3, 3.5, 4, 4.5, 4.8 wt%. Preferably, the adding ratio of the glucuronic acid to the phospholipid ethanolamine is 1: 0.1-1.
The invention provides an application of a phospholipid ethanolamine derivative in drug slow release and an application in an emulsified solution.
The invention provides an emulsion comprising a phospholipidolamine derivative. Preferably, the content of the phosphatidylethanolamine derivative in the emulsion is 1-5 wt%; more preferably, the composition of the phospholipid ethanolamine derivative may be 1.5 to 4.5 wt%, for example, 2, 2.5, 3, 3.5, 4 wt%.
The invention provides an application of emulsion in the preparation of eye drops.
The invention aims to provide a preparation method of azithromycin sustained-release eye drops, which is characterized in that phospholipid ethanolamine derivatives are obtained by modifying phospholipid ethanolamine with glucuronic acid, and the azithromycin eye drops are prepared by taking the phospholipid ethanolamine derivatives as an emulsifier and have the effect of azithromycin sustained release.
A preparation method of azithromycin sustained-release eye drops comprises the following steps:
adding the phospholipid ethanolamine derivative into soybean oil, and uniformly mixing to form an oil phase; adding azithromycin, L-cysteine, mannitol and sorbic acid into water, adjusting the pH value to 6.0-7.0, and continuously stirring for 5-30min at 30-50 ℃ to form a water phase; slowly dripping the oil phase into the water phase, continuously stirring at 30-50 deg.C for 10-60min, metering volume, and packaging to obtain azithromycin microemulsion eye drop. Preferably, the addition amount of azithromycin is 0.1-2 wt%. Preferably, the amount of the phospholipid ethanolamine derivative added is 1-6 wt% of the soybean oil. The phospholipid ethanolamine derivative is used as an emulsifier, the phospholipid ethanolamine derivative is added into soybean oil and uniformly mixed to form an oil phase, when a water phase is added, the oil phase is continuously stirred to form an emulsion, two fatty acid chains are arranged in the phospholipid ethanolamine derivative, the interfacial tension of the emulsion is reduced, the flexibility and the firmness of an emulsion interfacial film are improved, and the modified groups such as the fatty acid chains, carboxyl groups, hydroxyl groups, carbonyl groups and the like in the phospholipid ethanolamine derivative slow down the release speed of azithromycin under the van der waals force and embedding action.
Preferably, the addition amount of L-cysteine is 0.04-0.4 wt%; more preferably, L-cysteine may be added in an amount of 0.05 to 0.3 wt%, e.g., 0.06, 0.08, 0.1, 0.15, 0.2, 0.25 wt%. The eye drops are composed of an oil phase as a main carrier, are very easy to oxidize, and are added with L-cysteine as an antioxidant to ensure the stability of the eye drops.
Preferably, mannitol is selected to regulate the osmotic pressure at 260-320 mOsmol/Kg. Human eyes have osmotic pressure, cells are expanded to generate stimulation in hypotonic condition, cells are dehydrated and dried in hypertonic condition, mannitol is selected as an isoosmotic adjusting agent, and the osmotic pressure is adjusted to be 260-320 mOsmol/Kg.
Preferably, sorbic acid is added in an amount of 0.0005 to 0.005 wt%; more preferably, sorbic acid may be added in an amount of 0.0008 to 0.0045 wt%, for example, 0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045 wt%. The eye drops can be opened for multiple times for use, are easily polluted by microorganisms in the using and storing processes, sorbic acid is used for preventing secondary pollution of the microorganisms in the using process, and the acidity can increase the solubility of azithromycin in an aqueous solution, thereby being beneficial to the preparation of emulsion eye drops.
In one embodiment of the invention, during the preparation process of the azithromycin sustained-release eye drops, the alpha-carotene and the hesperidin are added, the alpha-carotene and the hesperidin are dissolved in an oil phase in a solution, form a composite structure with soybean oil and a phospholipid ethanolamine derivative, and form a closely-packed complex film on an interface, so that the viscosity of an emulsion is increased, the movement of azithromycin is inhibited, and the encapsulation rate of the azithromycin is improved.
Preferably, the amount of alpha-carotene added is 0.1-5 wt%; more preferably, the amount of alpha-carotene added is 0.2-4 wt%, e.g., 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5%.
Preferably, the addition amount of hesperidin is 0.1-2 wt%; more preferably, hesperidin is added in an amount of 0.2 to 1.8 wt%, for example, 0.3, 0.5, 0.8, 1, 1.3, 1.5 wt%.
The invention adopts the phosphatide ethanolamine derivative as the emulsifier, and the alpha-carotene and the hesperidin as the additives of the azithromycin eye drops, thereby having the following beneficial effects: the release speed of the azithromycin in the azithromycin eye drops is slowed down, and the encapsulation rate of the azithromycin in the emulsion is improved. Therefore, the azithromycin eye drops have the drug slow-release effect.
Drawings
FIG. 1 is an infrared spectrum of a phosphatidylethanolamine and a phosphatidylethanolamine derivative according to the present invention;
FIG. 2 is a scanning electron microscope image of azithromycin eye drop emulsion of the invention;
FIG. 3 is a drug release rate chart of azithromycin eye drops of the invention;
figure 4 is a graph comparing the encapsulation efficiency of azithromycin eye drops of the invention.
Detailed Description
The technical solution of the present invention is further described in detail below with reference to the following detailed description and the accompanying drawings: