CN102641237B - Curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration and preparation method thereof - Google Patents

Abstract

The invention discloses a curcumin microemulsion ion-sensitive in-situ gel preparation for nasal administration, which uses curcumin as a raw material drug, adopts surfactant, co-surfactant, oil phase, and gellan gum solution, wherein each group The parts by weight of points are as follows: 0.5～8 parts of curcumin, oil phase: 4～25.6 parts, surfactant: 17～46.4 parts, cosurfactant 17～46.4 parts, gellan gum solution: 20～50 parts, The mass concentration of the gellan gum solution is 0.1% to 1.0%. Preparation method: first mix the oil phase, surfactant and co-surfactant with electromagnetic stirring, vortex oscillation or ultrasonic method, then add curcumin, fully stir to dissolve, then dropwise add gellan gum solution, and continue stirring to obtain Curcumin microemulsion ion-sensitive in situ gel nasal formulation. After nasal administration of the microemulsion ion-sensitive in-situ gel of the present invention, the drug can reach the brain target site through two paths, the nose-brain direct pathway and the systemic circulation pathway, so that the curcumin can exert a therapeutic effect on the brain tissue.

Description

Nasally administered curcumin microemulsion ion-sensitive in situ gel preparation and preparation method thereof

technical field

The invention relates to a curcumin microemulsion ion-sensitive in-situ gel preparation for nasal administration and a preparation method thereof.

Background technique

Curcumin (Cur) is a natural phenolic compound extracted from plants of the genus Curcuma longa L. in the family Zingiberaceae. Many brain diseases such as Haimer's disease and Parkinson's disease. Curcumin has also entered the clinical research stage for the treatment of Alzheimer's disease. Due to the poor solubility of curcumin in water, the oral bioavailability is extremely low, only 1%. The curative effect of local diseases is an urgent problem to be solved.

The method of transporting drugs to the brain through nasal administration has been paid more and more attention by researchers. The olfactory nerve is distributed in the olfactory area of the nasal cavity, and the sieve hole is distributed on the cribriform bone plate under the mucosa, and the olfactory nerve reaches the olfactory bulb of the brain through the sieve hole. Drugs can reach the brain tissue directly from the nasal cavity through the olfactory nerve pathway and the trigeminal nerve pathway. The drug enters the blood circulation through the abundant capillaries in the respiratory area, or enters the blood circulation through the lamina propria of the olfactory area, and then circulates across the BBB and enters the brain tissue. However, due to the clearance of nasal cilia, the residence time of the drug in the nasal cavity is shortened, which affects the absorption of the drug. As an ion-sensitive gel matrix, gellan gum is a research hotspot in the field of pharmacy. Timolol maleate ophthalmic gelling solution based on gellan gum has been approved by the US FDA. Gelan collagen site gel is easy to prepare, and can be combined with ions in the drug site, such as the nasal cavity or eyes, to form a viscous semi-solid preparation, which has a strong affinity for mucosal tissue and a long residence time, which is conducive to the absorption of drugs.

Contents of the invention

The purpose of the present invention is to overcome above-mentioned deficiencies in the prior art, provide a kind of curcumin microemulsion ion-sensitive in-situ gel preparation for nasal administration and its preparation method.

To achieve the above object, the present invention adopts the following technical solutions:

A curcumin microemulsion ion-sensitive in-situ gel preparation for nasal cavity administration, which uses curcumin as a raw material drug, and adjuvant surfactants, co-surfactants, oil phases, and gellan gum solutions, wherein the weight of each component The parts are as follows: curcumin 0.5-8 parts, oil phase: 4-25.6 parts, surfactant: 17-46.4 parts, co-surfactant 17-46.4 parts, gellan gum solution: 20-50 parts, gellan gum The concentration of the solution is 0.1% to 1.0%.

The surfactant is selected from: Solutol HS15 (polyethylene glycol stearate 15), Labrasol (caprylic capric macrogol glyceride), Cremophor EL (castor oil polyoxyethylene 35 ether), emulsifier OP (Alkylphenol and ethylene oxide condensate) or Tween80 (Tween 80).

The cosurfactant is selected from: 1,2-propanediol, ethanol, PEG400, Transcutol HP (diethylene glycol monoethyl ether

) or Plurol Oleique CC497 (polyglyceryl oleate).

The oily phase is selected from: ethyl oleate, castor oil, Capryol 90 (propylene glycol monocaprylate), isopropyl myristate or Labrafil M1944 CS (macroglycerol oleate).

The mass concentration of the gellan gum solution is between 0.1% and 1.0%.

The formulation for nasal administration is a solution.

The curcumin microemulsion ion-sensitive in-situ gel nasal preparation is prepared by the following method: firstly mix the oil phase, surfactant, co-surfactant with electromagnetic stirring, vortex oscillation or ultrasonic mode, Then add curcumin, fully stir to dissolve, then dropwise add gellan gum solution, and continue to stir to obtain curcumin microemulsion ion-sensitive gel nasal preparation in situ.

In the present invention, the solubility of curcumin in water is only 11ng/ml, so it is prepared into a microemulsion preparation to improve the solubility of the medicine. In order to avoid the barrier effect of the blood-brain barrier on drugs entering the brain, so that curcumin can enter the brain tissue more to play the role of treating brain diseases, it is used as a nasal preparation. In the preparation prepared by the invention, the drug content of the curcumin can reach 40-80 mg/ml, which significantly improves the solubility of the curcumin. The particle size of the microemulsion ion-sensitive in-situ gel is less than 100nm, which is beneficial to promoting the absorption of drugs in the nasal mucosa when used for nasal cavity administration.

After nasal administration of the microemulsion ion-sensitive in-situ gel of the present invention, the drug can reach the brain target site through two paths, the nose-brain direct pathway and the systemic circulation pathway, so that the curcumin can exert a therapeutic effect on the brain tissue.

Description of drawings

Figure 1: Transmission electron micrograph (120,000×) of curcumin microemulsion ion-sensitive in situ gel.

Detailed ways

The present invention will be further elaborated below through specific examples. It should be noted that the following descriptions are only for explaining the present invention and not limiting its content.

Detailed ways:

Example 1:

Weigh 0.7g of Capryol 90, 4.0g of Cremophor EL, and 2.5g of Transcuol HP. After stirring evenly, add 600mg of curcumin. After stirring evenly, add 3g of a solution containing 0.3% gellan gum dropwise, and continue stirring.

Example 2:

Weigh 0.8g of Capryol 90, 5.0g of Solutol HS15, and 2.5g of Transcuol HP. After stirring evenly, add 3g of 0.5% gellan gum solution dropwise, add 450mg of curcumin, and stir well.

Example 3:

Weigh 0.5g of Capryol 90, 3.5g of Solutol HS15, and 2.2g of Transcuol HP. After stirring evenly, add 500mg of curcumin. After stirring evenly, add 3.5g of 0.3% gellan gum solution dropwise and continue stirring.

Example 4:

Weigh 0.6g of Capryol 90, 3.5g of Solutol HS15, and 3.5g of Transcuol HP. After stirring evenly, add 400mg of curcumin. After stirring evenly, add 4g of 0.3% gellan gum solution dropwise and continue stirring.

Take an appropriate amount of the above-mentioned microemulsion gel solution, dilute it with distilled water, dip the above-mentioned solution with a special copper grid for transmission electron microscopy, carry out negative staining with 2% phosphotungstic acid, and then observe it under a transmission electron microscope. The results are shown in Figure 1. The particles of the preparation are spherical or quasi-spherical, the particle diameter is in the range of 30-100nm, and the dispersibility is good.

Test example 1: prepare curcumin microemulsion ion-sensitive in situ gel preparation according to embodiment 4, and carry out pharmacokinetic research in rats:

Preparation of injection: take an appropriate amount of curcumin raw material, add N,N-dimethylacetamide, PEG400 and 5% glucose injection (15%:40%:45%) mixed solvent, mix well and filter to sterilize at 0.22 μm for later use .

Ten healthy Wistar male rats were divided into two groups, 5 in each group. Fasting 12h before administration, free to drink water. Before the experiment, the rats in the nasal administration group were anesthetized, while the injection group was not anesthetized. Rats administered intranasally were placed in a container containing ether and anesthetized by inhalation of ether. After the rats were anesthetized, they were administered nasally with a micro-injector; the injection group was administered by tail vein injection. Then at different time points (0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, 12h), the subclavian sinus blood was collected in an EP tube containing heparin, centrifuged at 4000rm for 15min, and the plasma was collected Store in -20°C refrigerator until testing. Rat plasma samples were extracted with a mixture of ethyl acetate and methanol, redissolved in methanol, and determined for drug content by HPLC.

Experimental results: The absolute bioavailability of curcumin microemulsion ion-sensitive in situ gel preparation nasal administration reached 55.82%, while the absolute bioavailability of curcumin in rats was only about 4.13%, which significantly improved the absorption of the drug. Increased bioavailability of curcumin.

Test Example 2: Prepare curcumin microemulsion ion-sensitive in-situ gel preparation according to Example 4, and conduct research on drug brain tissue distribution in rats:

Thirty healthy Wistar male rats were divided into two groups, 15 in each group. Fasting 12h before administration, free to drink water. Before the experiment, the rats in the nasal administration group were anesthetized, while the injection group was not anesthetized. Rats administered intranasally were placed in a container containing ether and anesthetized by inhalation of ether. After the rats were anesthetized, the in situ gel preparation was dripped into the nasal cavity; the injection group was given by tail vein injection. Then at different time points (0.083, 0.5, 1, 3, 5 hours), the blood collected from the subclavian sinus was placed in an EP tube containing heparin, centrifuged at 4000 rpm for 15 minutes, and the plasma was collected and stored in a -20°C refrigerator for testing. At the same time, the rat cranial cavity was opened immediately, the brain tissue was taken out, rinsed with normal saline, blotted with filter paper, weighed accurately, and placed in a -20°C refrigerator for testing. Rat plasma samples and rat brain tissue samples were processed separately, and the drug content was determined by HPLC.

Results: At the same dose, the AUC of curcumin microemulsion ion-sensitive in situ gel preparation reaching the brain by nasal administration was 568 mg/L*h, and the AUC of injection administration was 183 mg/L*h. The nasal administration of the gel preparation is 3 times the AUC of the injection administration, and the brain targeting index ([AUC _brain /AUC _blood ] _in / [ AUC _brain /AUC _blood ] _iv ) is 6.17, indicating that curcumin enters the brain significantly The dose in the body is beneficial to the treatment of brain diseases.

Claims (1)

1. curcumin microemulsion ion-activited in situ gel preparation, it is characterized in that: obtain by following preparation method: take Capryol 90 0.6g, Solutol HS15 3.5g, Transcuol HP 3.5g, after electromagnetic agitation is even, add curcumin 400mg, after stirring, be added dropwise to 0.3% gellan gum solution 4g, continue stir and get final product.