CN102008476A - Hydroxypropyl-beta-cyclodextrin inclusion of strychnine and preparation method thereof - Google Patents

Abstract

The invention discloses a hydroxypropyl-β-cyclodextrin inclusion compound of strychnine and a preparation method thereof. The inclusion compound is composed of strychnine and hydroxypropyl -β-cyclodextrin is prepared under the preferred inclusion process, and the experimental results show that the hydroxypropyl-β-cyclodextrin inclusion compound of strychnine provided by the present invention has a high inclusion rate and drug loading Large amount, good stability, can significantly improve the water solubility of strychnine, the solubility in water is more than 20 times that of strychnine, and can significantly improve the bioavailability of strychnine after administration, and has the ability to reduce The role of strychnine toxicity, clinical medication is safer.

Description

Hydroxypropyl-β-cyclodextrin inclusion compound of strychnine and preparation method thereof

technical field

The invention relates to the technical field of pharmaceutical preparations, in particular to a cyclodextrin inclusion compound of strychnine and a preparation method thereof.

Background technique

Strychnine is the main active alkaloid contained in the traditional Chinese medicine Strychnium. Pharmacological studies have shown that strychnine is one of the most promising active ingredients in Strychnium alkaloids: ①Anti-tumor experiments show that Strychnine The activity of strychnine is significantly higher than strychnine, strychnine nitrogen oxides, iso- strychnine and other alkaloid components in strychnine; ②Analgesic and anti-inflammatory tests also show that strychnine has definite Analgesic and anti-arthritis effects, but strychnine has no anti-arthritis and analgesic effects.

Strychnine is a fat-soluble drug, and its solubility in water is relatively low (less than 2 mg/mL), which is not conducive to the preparation of its preparation and its bioavailability after administration. For example, in the preparation process of strychnine gel, due to the low solubility, strychnine will be precipitated from the hydrogel matrix, which limits the increase of drug concentration. Another example is that it is necessary to add a large amount of co-solvents to make injections. The potential toxicity of co-solvents may bring hidden dangers to clinical use. According to reports, the bioavailability of oral and transdermal administration of strychnine is only 30~35%. Moreover, experiments have shown that strychnine has adverse reactions such as central nervous system toxicity while exerting tumor or analgesic and anti-inflammatory effects.

In recent years, a number of strychnine preparations aimed at solving the problems of solubility and bioavailability have been reported, such as microemulsions, liposomes, nanoparticles, etc., such as Chinese invention patent: 200510026516.4, which discloses a nano Strychnine liposome transdermal spray preparation and its preparation method and application, 200810236293.8 discloses a strychnine complex phospholipid liposome and its preparation method and application in pharmacy, 200910235087.X discloses a Nuxychnium total alkaloid sustained-release dropping pills and its preparation method, 02148438.4 discloses a Nuxychnium sustained-release preparation and its preparation method, 200510026515.X discloses a nano strychnine liposome and its preparation method, 01100654.4 discloses a nano strychnium preparation drug and its preparation method, etc., but the above preparation process is generally complicated, and there is no research report on strychnine hydroxypropyl-β-cyclodextrin inclusion technology.

Contents of the invention

Purpose of the invention: the purpose of the invention is to solve the deficiencies in the prior art, to provide a kind of good solubility, high bioavailability, good safety strychnine hydroxypropyl-β-cyclodextrin inclusion compound and its Preparation.

Technical scheme: in order to realize above object, the technical scheme that the present invention takes is:

A hydroxypropyl-β-cyclodextrin inclusion compound of strychnine, which is prepared by the following method:

Weigh hydroxypropyl-β-cyclodextrin and dissolve it in water, add strychnine solution dropwise under stirring, stir and mix, and dry to obtain hydroxypropyl-β-cyclodextrin inclusion compound of strychnine, The weight ratio of strychnine and hydroxypropyl-β-cyclodextrin used therein is 1:1-100.

As a preferred option, the strychnine hydroxypropyl-β-cyclodextrin inclusion compound mentioned above, the weight ratio of strychnine and hydroxypropyl-β-cyclodextrin used is 1:1 ~30; as a more preferred technical solution, the weight ratio of strychnine and hydroxypropyl-β-cyclodextrin used is 1:1~20. The present invention screens out the weight ratio of strychnine and hydroxypropyl-β-cyclodextrin through a large number of experimental studies, and adopts the optimal dosage ratio of strychnine and hydroxypropyl-β-cyclodextrin obtained in the present invention, It can ensure a high inclusion rate and increase the drug loading capacity.

As a preferred version, the above-mentioned hydroxypropyl-β-cyclodextrin inclusion compound of strychnine, strychnine uses ethanol or acetone as solvent, and the weight of strychnine used and the weight of strychnine used The volume ratio of ethanol or acetone is 1:2~10, strychnine has good solubility in ethanol and acetone,

The hydroxypropyl-β-cyclodextrin inclusion compound of strychnine described in the present invention can be prepared from the hydroxypropyl-β-cyclodextrin inclusion compound of strychnine and a pharmaceutically acceptable carrier Drugs in the form of powder injections, injections, oral solutions, topical gels, ointments, sprays, or nasal drops.

The inclusion compound of strychnine hydroxypropyl-β-cyclodextrin provided by the present invention is subjected to sterile filtration and freeze-drying after depyrogenation to obtain strychnine hydroxypropyl-β-cyclodextrin for injection Inclusion complex powder injection. The strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the invention can be directly freeze-dried to prepare powder injection without adding a freeze-drying protective agent, and has higher safety performance.

When the strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the present invention is made into an injection, take the strychnine hydroxypropyl-β-cyclodextrin inclusion compound, add physiological saline to dissolve and then add activated carbon , stir evenly, heat at 80°C for 30 minutes, filter, adjust the pH value, filter with a vertical fusing glass funnel or other filter until clear, fill, and sterilize at 100 to 115°C for 30 minutes to make an injection. 

When making the strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the present invention into an oral liquid, dissolve the extracts of each raw material in distilled water, filter, add syrup, adjust the pH value, and make an oral liquid .

The preparation method of strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the invention comprises the following steps:

First weigh 1 part of strychnine, dissolve it in an organic solvent to obtain a strychnine solution, and set aside, then weigh 1 to 100 parts of hydroxypropyl-β-cyclodextrin, dissolve it in distilled water, and dissolve it in distilled water at 20 to Add strychnine solution dropwise to hydroxypropyl-β-cyclodextrin aqueous solution under constant temperature magnetic stirring at 60°C for clathration, continue stirring for 0.5~3 hours after the dropwise addition, and dry to obtain strychnine Base hydroxypropyl-β-cyclodextrin inclusion complex.

As a preferred version, the preparation method of the hydroxypropyl-β-cyclodextrin inclusion compound of strychnine described above, the strychnine solution is ethanol or acetone solution of strychnine, strychnine The weight of sub-alkali and the volume ratio of ethanol or acetone are 1:2~10. The ratio of hydroxypropyl-β-cyclodextrin (weight) to water (volume) used is 1:2~10.

As a further preferred option, the preparation method of the hydroxypropyl-β-cyclodextrin inclusion complex of strychnine described above, after inclusion of strychnine hydroxypropyl-β-cyclodextrin, also passes through micropores The unincluded free strychnine drug is removed by membrane filtration, and then dried to obtain strychnine hydroxypropyl-β-cyclodextrin inclusion compound.

As a preferred version, the above-mentioned preparation method of the hydroxypropyl-β-cyclodextrin inclusion compound of strychnine, after adding the strychnine solution dropwise to the aqueous solution of hydroxypropyl-β-cyclodextrin, Ultrasonic oscillation is used for inclusion, or grinding is used to promote inclusion and improve inclusion efficiency.

As a preferred solution, after the inclusion complex of strychnine and hydroxypropyl-β-cyclodextrin is completed, the hydroxypropyl-β-cyclodextrin inclusion compound of strychnine is obtained by spray drying or vacuum drying.

The hydroxypropyl-β-cyclodextrin inclusion complex of strychnine provided by the invention can be used to prepare anti-inflammatory and analgesic drugs and anti-tumor drugs.

Beneficial effects: Compared with the prior art, the inclusion compound of strychnine hydroxypropyl-β-cyclodextrin provided by the present invention has the following advantages:

1. In the strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the present invention, the inclusion material hydroxypropyl-β-cyclodextrin used is a derivative of β-cyclodextrin and has a cylindrical shape Molecular structure, very soluble in water and no nephrotoxicity, large inclusion capacity, strychnine is included into the cavity in the cyclodextrin molecule by means of intermolecular force to form an inclusion complex, which can significantly improve the quality of strychnine The water solubility of strychnine, the experimental results show that compared with strychnine, the solubility of strychnine hydroxypropyl-β-cyclodextrin inclusion compound can be increased by 20 times, which can significantly improve the administration of strychnine The final bioavailability is not only suitable for the preparation of liquid preparations or injection powders, but also the bioavailability of oral or external preparations prepared by it can be significantly improved; at the same time, when the water solubility of strychnine is increased, it also has the ability to reduce strychnine The effect of the central nervous system toxicity of the subalkine, the drug safety is better. the

2. The strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the present invention is optimized by optimizing the dosage and concentration of strychnine and hydroxypropyl-β-cyclodextrin, and adopting an optimized process The hydroxypropyl-β-cyclodextrin inclusion compound of strychnine was prepared. The experimental results showed that the inclusion rate of strychnine was high, the drug loading capacity was high, and the stability was good. The prepared strychnine hydroxyl The inclusion compound of propyl-β-cyclodextrin can be conveniently prepared into various dosage forms such as powder injection, and is safe for clinical use.

Description of drawings

Fig. 1 is a patch using strychnine, a physical mixture of strychnine and hydroxypropyl-β-cyclodextrin, and a strychnine hydroxypropyl-β-cyclodextrin inclusion compound as raw materials respectively, with Plasma drug concentration-time curve after transdermal administration of 60mg/kg dose to rats.

Detailed ways

The present invention is further illustrated below in conjunction with specific embodiments, should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention, after having read the present invention, those skilled in the art will understand the various equivalent forms of the present invention All modifications fall within the scope defined by the appended claims of this application.

Example 1 Preparation of strychnine hydroxypropyl-β-cyclodextrin inclusion compound

Weigh 1g of strychnine, dissolve it in 6ml of ethanol to obtain strychnine ethanol solution, set aside, take 6g of hydroxypropyl-β-cyclodextrin, grind it into a paste with 12ml of distilled water, then mix the strychnine Add the ethanol solution to the hydroxypropyl-β-cyclodextrin paste for clathration, after the dropwise addition, grind at 40°C for 2 hours, dry in vacuum, and wash away the unclad strychnine drug with dichloromethane , and dry to obtain strychnine hydroxypropyl-β-cyclodextrin inclusion compound.

The obtained strychnine hydroxypropyl-β-cyclodextrin inclusion compound was dissolved in distilled water to prepare a solution with a strychnine concentration of 20 mg/ml, and the inclusion rate was 96%.

Example 2 Preparation of strychnine hydroxypropyl-β-cyclodextrin inclusion compound

First weigh 1g of strychnine, dissolve it in 4ml of ethanol to obtain a strychnine solution, and set aside, then weigh 10g of hydroxypropyl-β-cyclodextrin, dissolve it in 30ml of distilled water, and stir magnetically at a constant temperature of 40°C Add the strychnine solution dropwise to the aqueous solution of hydroxypropyl-β-cyclodextrin for inclusion, continue magnetic stirring for 3 hours after the addition, spray dry, wash away the unincluded drug with chloroform, After drying, the strychnine hydroxypropyl-β-cyclodextrin inclusion compound is obtained.

The obtained strychnine hydroxypropyl-β-cyclodextrin inclusion compound was dissolved in distilled water to prepare a solution with a strychnine concentration of 23 mg/ml, and the inclusion rate was 94%.

Example 3 Preparation of strychnine hydroxypropyl-β-cyclodextrin inclusion compound

First weigh 1g of strychnine and dissolve it in 10ml of acetone to obtain a solution of strychnine in acetone for later use, then weigh 20g of hydroxypropyl-β-cyclodextrin, dissolve it in 40ml of distilled water, and stir at 40°C Add the strychnine solution dropwise to the aqueous solution of hydroxypropyl-β-cyclodextrin for inclusion, continue ultrasonic oscillation for 1.5 hours after the dropwise addition, freeze-dry, wash away the unincluded drug with ether, and dry , That is, strychnine hydroxypropyl-β-cyclodextrin inclusion compound. Dissolve the clathrate with distilled water, filter, add syrup, adjust the pH value, and make oral liquid.

Example 4 Preparation of strychnine hydroxypropyl-β-cyclodextrin inclusion compound

First weigh 10g of strychnine and dissolve it in 20ml of ethanol to obtain a strychnine ethanol solution for later use, then weigh 100g of hydroxypropyl-β-cyclodextrin, dissolve it in 1000ml of distilled water, and stir at 50°C Add the strychnine solution dropwise to the aqueous solution of hydroxypropyl-β-cyclodextrin for clathrate. After the dropwise addition, stir clathrate at 50°C for 5 hours to obtain clathrate solution. Use 0.45 micron microporous Membrane filtration, in a 100-level purification workshop, use a 0.22 micron microporous membrane to filter, sub-package, freeze-dry, cap, and pack to obtain a freeze-dried powder.

Example 5 Preparation of strychnine hydroxypropyl-β-cyclodextrin inclusion compound

First weigh 2g of strychnine and dissolve it in 10ml of ethanol to obtain a strychnine ethanol solution for later use, then weigh 50g of hydroxypropyl-β-cyclodextrin, dissolve it in 300ml of distilled water, and stir at 50°C Add the strychnine solution dropwise to the aqueous solution of hydroxypropyl-β-cyclodextrin for clathrate. After the dropwise addition, ultrasonically oscillate clathrate for 2 hours to obtain the clathrate solution, and filter it with a 0.45 micron microporous membrane , and then vacuum-dried to obtain strychnine hydroxypropyl-β-cyclodextrin inclusion compound.

Take the prepared strychnine hydroxypropyl-β-cyclodextrin inclusion compound, add swollen and mixed polyethylene glycol (PVA), sodium carboxymethylcellulose (CMC-Na), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) mixed matrix, coating, drying, cutting, and making into patches.

Example 6

The bioavailability of the strychnine hydroxypropyl-β-cyclodextrin inclusion compound prepared in Example 5 was evaluated. The patches made of strychnine, the physical mixture of strychnine and hydroxypropyl-β-cyclodextrin, and the inclusion complex of strychnine and hydroxypropyl-β-cyclodextrin as raw materials, the content Both were 3mg/cm ² , and were pasted on the abdomen of rats at a dose of 60mg/kg. The blood drug concentration at different time points after administration was determined by HPLC. Each patch used 6 rats for pharmacokinetic experiments. The three kinds of patches The results of comparison of the drugs are shown in Fig. 1. The results in Fig. 1 show that after 10 hours of administration, the blood drug concentration of the strychnine hydroxypropyl-β-cyclodextrin inclusion complex patch reaches the maximum value, and by The experimental results showed that the relative bioavailability after administration of strychnine hydroxypropyl-β-cyclodextrin inclusion complex as raw material was 186.19% of that of the patch directly using strychnine as raw material. The blood concentration of strychnine and hydroxypropyl-β-cyclodextrin physical mixture was significantly increased, but the blood concentration of strychnine and hydroxypropyl-β-cyclodextrin physical mixture patch did not increase significantly, indicating that strychnine and hydroxypropyl-β-cyclodextrin The cyclodextrin can promote the transdermal absorption of strychnine and improve the bioavailability after it is prepared as an inclusion compound. The above experiments also show that the strychnine hydroxypropyl-β-cyclodextrin inclusion compound provided by the present invention has good water solubility, high bioavailability, smaller clinical dosage, and after the water solubility increases, it can improve horse The drug loading of chrysantrine in the patch.

Example 7 Toxicity determination of strychnine hydroxypropyl-β-cyclodextrin inclusion compound

The acute toxicity of strychnine hydroxypropyl-β-cyclodextrin inclusion compound prepared in Example 1 and strychnine was compared. Both were dissolved in normal saline to form a solution of the same concentration, and administered by tail vein injection. The measured LD ₅₀ of strychnine hydroxypropyl-β-cyclodextrin inclusion compound and strychnine were respectively 12.2mg/kg and 21.9mg/kg, it proves that strychnine hydroxypropyl-β-cyclodextrin inclusion compound can reduce the toxicity of strychnine, and the clinical medication is safer.

The present invention preferably determines the dosage ratio of strychnine and hydroxypropyl-β-cyclodextrin, and the strychnine in the prepared strychnine hydroxypropyl-β-cyclodextrin inclusion compound It has good water solubility and high bioavailability, and can be prepared into water-soluble preparations such as powder injections.

The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.

Claims (8)

1. a hydroxypropyl-beta-cyclodextrin inclusion compound of strychnine, characterized in that it is prepared by the following method: Weigh hydroxypropyl-β-cyclodextrin and dissolve it in water, add strychnine solution dropwise under stirring, stir and mix, and dry to obtain hydroxypropyl-β-cyclodextrin inclusion compound of strychnine, The weight ratio of strychnine and hydroxypropyl-β-cyclodextrin used therein is 1:1-100. 2. the hydroxypropyl-beta-cyclodextrin clathrate of strychnine according to claim 1, is characterized in that, the weight of strychnine and hydroxypropyl-beta-cyclodextrin used The ratio is 1:1~30. 3. The hydroxypropyl-β-cyclodextrin inclusion compound of strychnine according to claim 1, characterized in that, the strychnine solution is ethanol or acetone solution of strychnine. 4. The hydroxypropyl-β-cyclodextrin clathrate of strychnine described in any one of claims 1 to 3, characterized in that, the hydroxypropyl-β-cyclodextrin of strychnine The clathrate and the pharmaceutically acceptable carrier are prepared into medicines in the form of powder injection, injection, oral liquid, external gel, ointment, spray or nasal drops. 5. the preparation method of the hydroxypropyl-beta-cyclodextrin clathrate of strychnine as claimed in claim 1, is characterized in that, comprises the following steps: First weigh 1 part of strychnine, dissolve it in an organic solvent to obtain a strychnine solution, and set aside, then weigh 1 to 100 parts of hydroxypropyl-β-cyclodextrin, dissolve it in distilled water, and dissolve it in distilled water at 20 to Add strychnine solution dropwise to hydroxypropyl-β-cyclodextrin aqueous solution under constant temperature magnetic stirring at 60°C for clathration, continue stirring for 0.5~3 hours after the dropwise addition, and dry to obtain strychnine Base hydroxypropyl-β-cyclodextrin inclusion complex. 6. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion compound of strychnine according to claim 5, is characterized in that, described strychnine solution is the ethanol of strychnine or Acetone solution, the weight ratio of strychnine to ethanol or acetone is 1:2~10. 7. The preparation method of the hydroxypropyl-beta-cyclodextrin inclusion compound of strychnine according to claim 5, characterized in that, after strychnine hydroxypropyl-beta-cyclodextrin inclusion compound The unincluded free strychnine drug is also removed by microporous membrane filtration, and then dried to obtain strychnine hydroxypropyl-β-cyclodextrin inclusion compound. 8. The preparation method of the hydroxypropyl-beta-cyclodextrin inclusion compound of strychnine according to claim 5, characterized in that, the strychnine solution is added dropwise to the hydroxypropyl-beta-cyclodextrin inclusion complex After the aqueous solution of dextrin is added, ultrasonic vibration is used for clathration.