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Improved low-toxicity high-efficiency orthoester miscible substance pharmaceutical adjuvant, preparation method and local sustained-release drug delivery preparation containing adjuvant

A technology of pharmaceutical excipients and ortho esters, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, etc., can solve problems such as damage to respiratory mucosa, vision, damage, and blindness, and achieve Improve the therapeutic index and compliance, the value of extensive clinical application, the effect of slow and uniform treatment effect

Active Publication Date: 2022-08-05
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the orthoester compound used in this excipient contains methoxy, and its degradation product is methanol, which has potential biological safety risks: methanol is highly toxic and has the greatest impact on the nervous system and blood system of the human body. Toxic reactions will occur after inhalation through the respiratory tract or skin, and its vapor can damage the mucous membrane of the respiratory tract and vision, and cause harm to the human body; the most common symptoms of methanol poisoning include headache, nausea, vomiting, blurred vision, and severe cases can cause blindness and even death , the cranial nerves will also be damaged, resulting in permanent damage, methanol will cause damage to the kidneys after entering the blood, and severe kidney failure will occur

Method used

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  • Improved low-toxicity high-efficiency orthoester miscible substance pharmaceutical adjuvant, preparation method and local sustained-release drug delivery preparation containing adjuvant
  • Improved low-toxicity high-efficiency orthoester miscible substance pharmaceutical adjuvant, preparation method and local sustained-release drug delivery preparation containing adjuvant
  • Improved low-toxicity high-efficiency orthoester miscible substance pharmaceutical adjuvant, preparation method and local sustained-release drug delivery preparation containing adjuvant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Synthesis of orthoester compound 4,4'-(oxybis(methylene))bis(2-ethoxy-1,3-dioxolane)(OE-1')

[0080] Under nitrogen protection, diglycerol (16.6 g, 0.1 mol), triethyl orthoacetate (48.67 g, 0.3 mol) and p-toluenesulfonic acid (344.4 mg, 0.002 mol) were added to the reaction flask, and acetonitrile (150 mL) was added. ) was dissolved and reacted at room temperature overnight. After the acetonitrile was removed by distillation under reduced pressure, the crude product was dissolved in ethyl acetate, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove ethyl acetate and excess triethyl orthoacetate to obtain a colorless oily product. rate of 78.4%, 1 HNMR as figure 1 shown.

Embodiment 2

[0082] Synthesis of orthoester compound 4,4'-(oxybis(methylene))bis(2-propoxy-1,3-dioxolane)(OE-2')

[0083] Under nitrogen protection, diglycerol (16.6 g, 0.1 mol), tripropyl orthoacetate (61.25 g, 0.3 mol) and p-toluenesulfonic acid (344.4 mg, 0.002 mol) were added to the reaction flask, and acetonitrile (150 mL) was added. ) was dissolved and reacted at room temperature overnight. After the acetonitrile was removed by distillation under reduced pressure, the crude product was dissolved in ethyl acetate, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove ethyl acetate and excess triethyl orthoacetate to obtain a colorless oily product. The rate was 76.2%.

Embodiment 3

[0085] Orthoester compound 4,4'-(oxybis(methylene))bis(2-(2-methoxymonomethyl ether polyethylene glycol)-1,3-dioxolane)(OE -3') synthesis

[0086] OE-1' (30.6g, 0.1mol), polyethylene glycol 550 monomethyl ether (165.0g, 0.3mol) and pyridine p-toluenesulfonate (502.6mg, 0.002mol) were added to the reaction flask, and at 135 The reaction was carried out under reduced pressure for 4 hours. The crude product was purified by dialysis using tetrahydrofuran containing a trace amount of triethylamine, the molecular weight cut-off of the used dialysis bag was 1000 Daltons, and the yield was 84.4%.

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Abstract

The invention discloses an improved low-toxicity high-efficiency orthoester miscible pharmaceutical adjuvant, a preparation method thereof and a local sustained-release drug delivery preparation containing the adjuvant, and relates to the field of pharmaceutical adjuvants. The non-methoxy orthoester compound is obtained by mixing and dissolving non-methoxy orthoester compounds (class I and class II) according to different proportions or mixing and dissolving the orthoester compounds (class I or class II) and a biocompatible medical polymer material according to different proportions. The chemical formula I of the class I orthoester compound is shown in the formula I, and the chemical formula II of the class II orthoester compound is shown in the formula II. The invention further provides a preparation method of the pharmaceutic adjuvant and a local sustained-release drug delivery preparation containing the adjuvant. The invention has the following beneficial effects: the biological safety of the medicinal auxiliary material is improved by adjusting the substituent type and length of the orthoester compound, and the properties of the orthoester miscible medicinal auxiliary material before and after improvement are not changed, and all functions and effects of the orthoester miscible medicinal auxiliary material before structure improvement are included but not limited to.

Description

technical field [0001] The invention relates to the field of pharmaceutical excipients, in particular to an improved low-toxicity and high-efficiency orthoester miscible pharmaceutical excipient, a preparation method, and a local sustained-release administration preparation comprising the excipient. Background technique [0002] Pharmaceutical excipients refer to additives and excipients added in the process of producing medicines and formulating prescriptions. They are used in pharmaceutical preparations for the purpose of improving their availability or reducing side effects. Therefore, pharmaceutical excipients can also be interpreted as a general term for all substances whose safety can be guaranteed except the active ingredients. Therefore, the biosafety of pharmaceutical excipients is a necessary prerequisite for their clinical application. [0003] Orthoesters are a class of acid-sensitive degradable materials, which can be used as pharmaceutical excipients for syste...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/06A61K45/00A61K47/10A61K47/22A61K47/32A61K47/34C07D317/34
CPCA61K9/06A61K45/00A61K47/34A61K47/10A61K47/22A61K47/32C07D317/34A61K38/28A61K38/38A61K31/445A61K31/415A61K31/4184A61K31/337A61K9/0014
Inventor 唐汝培闫国卿王鑫
Owner ANHUI UNIVERSITY
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