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Process for preparing loteprednol and ophthalmic composition thereof

A technology of loteprednol and composition, which is applied in the direction of drug combination, steroids, drug delivery, etc., can solve the problems that cannot be ruled out, such as refrigerated storage, micronization of raw materials for preparation process and aggregation of eye drops particles, etc.

Active Publication Date: 2019-04-12
深圳市瑞霖医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] None of the above-mentioned documents related to the preparation of loteprednol preparations such as ophthalmic liquid preparations provides an effective preparation process to solve the above-mentioned contradiction between the micronization of the raw material drug and the aggregation of eye drop particles.
In particular, since this ophthalmic liquid pharmaceutical preparation will be exposed to ambient temperatures ranging from 4 to 35°C during storage and circulation, for example, although this preparation does not need to be stored in refrigeration, it cannot be ruled out that some users may choose to purchase it due to personal preference. Store in a refrigerator at around 4°C after entering. This change in ambient temperature may cause new problems for the stability of the physical properties of the suspension drug solution.

Method used

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  • Process for preparing loteprednol and ophthalmic composition thereof
  • Process for preparing loteprednol and ophthalmic composition thereof
  • Process for preparing loteprednol and ophthalmic composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1: prepare loteprednol

[0085] Step 1. Oxidation

[0086]

[0087] In the mixed solution containing 120 milliliters of tetrahydrofuran and 30 milliliters of methanol, add 14.9 grams (40 mmol) of prednisolone, stir to dissolve, add dropwise warm sodium periodate solution (25.7 grams of sodium periodate are dissolved in 100 ml of water), after the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, distilled off tetrahydrofuran and methanol, cooled and suction filtered, washed with water, and dried to obtain 11α, 17β-dihydroxy-3-oxoandroster -1,4-diene-17β-carboxylic acid (Intermediate I) 13 grams, off-white powder, melting point 258-260°C, yield 90.8%.

[0088] Step 2. Condensation

[0089]

[0090] 10 grams of Intermediate I (28.8 mmol) were added to 100 milliliters of water containing 24.2 grams of sodium bicarbonate, stirred and dissolved, then 100 milliliters of dichloromethan...

Embodiment 2

[0099] Embodiment 2: prepare loteprednol

[0100] Step 1. Oxidation

[0101]

[0102] In the mixed solution containing 120 milliliters of tetrahydrofuran and 30 milliliters of methanol, add 14.9 grams (40 mmol) of prednisolone, stir to dissolve, add dropwise warm sodium periodate solution (25.7 grams of sodium periodate are dissolved in 100 ml of water), after the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, distilled off tetrahydrofuran and methanol, cooled and suction filtered, washed with water, and dried to obtain 11α, 17β-dihydroxy-3-oxoandroster 13.3 g of -1,4-diene-17β-carboxylic acid (Intermediate I), an off-white powder with a melting point of 258-261°C.

[0103] Step 2. Condensation

[0104]

[0105] 10 grams of Intermediate I (28.8 mmol) were added to 100 milliliters of water containing 24.2 grams of sodium bicarbonate, stirred and dissolved, then 100 milliliters of dichloromethan...

Embodiment 3

[0114] Embodiment 3: prepare loteprednol

[0115] Step 1. Oxidation

[0116]

[0117] In the mixed solution containing 120 milliliters of tetrahydrofuran and 30 milliliters of methanol, add 14.9 grams (40 mmol) of prednisolone, stir to dissolve, add dropwise warm sodium periodate solution (25.7 grams of sodium periodate are dissolved in 100 ml of water), after the dropwise addition, the reaction mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure, distilled off tetrahydrofuran and methanol, cooled and suction filtered, washed with water, and dried to obtain 11α, 17β-dihydroxy-3-oxoandroster 13.3 g of -1,4-diene-17β-carboxylic acid (Intermediate I), an off-white powder with a melting point of 257-260°C.

[0118] Step 2. Condensation

[0119]

[0120] 10 grams of Intermediate I (28.8 mmol) were added to 100 milliliters of water containing 24.2 grams of sodium bicarbonate, stirred and dissolved, then 100 milliliters of dichloromethan...

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Abstract

The present invention relates to a loteprednol preparation method and an ophthalmic composition of loteprednol, particularly to a loteprednol preparation method, which comprises: dissolving a raw material loteprednol in a first organic solvent to obtain a drug-containing solution, adding a second organic solvent to the obtained solution in a dropwise manner under stirring, continuously stirring, filtering, washing the filter cake by using the second organic solvent, and drying the obtained filter cake in a vacuum oven to obtain the product. The invention further provides a loteprednol bulk drug prepared according to the method, an ophthalmic pharmaceutical composition prepared by using the prepared loteprednol as a bulk drug, and uses of the prepared loteprednol in preparation of drugs for treatment or prevention of ocular inflammations or dry eye. The method of the present invention has excellent pharmaceutical properties, wherein the prepared bulk drug and the preparation have excellent stability.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of glucocorticoid, in particular to a preparation method of glucocorticoid loteprednol etabonate with special physical and chemical properties. The present invention also relates to the preparation of an ophthalmic pharmaceutical composition, especially an ophthalmic suspension, by using the glucocorticoid loteprednol etabonate prepared by the method as a pharmaceutical raw material. The method for preparing the glucocorticoid loteprednol etabonate of the present invention has the excellent technical effects described below. Background technique [0002] Loteprednol (CAS: 82034-46-6, Loteprednol etabonate), commonly known as loteprednol etabonate and loteprednol etabonate, is a new type of corticosteroid steroid developed by Pharmos Corp. Class of anti-inflammatory drugs, its chemical name is 17α-[(ethoxyformyl)oxy]-11β-hydroxy-3-oxoandrost-1,4-diene-17β-carbo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J3/00A61K31/56A61K9/10A61K47/32A61P27/02A61P29/00
CPCA61K9/0048A61K9/10A61K47/32C07J3/005
Inventor 张静刘丰华方子华刘瑄杨玲
Owner 深圳市瑞霖医药有限公司
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