CN101301476B - Hydrophobic cyclodextrin clathrate and preparation and use thereof - Google Patents

Abstract

The present invention provides a hydrophobic cyclodextrin clathrate compound with a slow release effect, which is made by mixing a tert-butyl alcohol solution of hydrophobic cyclodextrin and a water phase solution containing hydrophilic medicine. The volume ratio of the tert-butyl solution to the water phase solution is 1 to 100:3. The mol mass ratio of the cyclodextrin to the hydrophilic medicine is 1 to 10:1. The present invention also discloses a method for preparing the clathrate compound. The method comprises the steps of: preparing the hydrophobic cyclodextrin tert-butyl alcohol solution and the water phase solution of the hydrophilic medicine; mixing both solutions into a single phase solution; and, drying, etc. The present invention also discloses an application of the cyclodextrin clathrate compound in pharmacy. Compared with the ordinary release preparations, the clathrate compound formed by the hydrophobic cyclodextrin and the water-soluble medicine is capable of reducing the solubility and digestion velocity of the water-soluble medicine and postponing the release of the medicine. The process is simple, convenient in operation, short in period, low in energy dissipation, and suitable for industrialized production, and has no residue of organic solvent.

Description

A kind of hydrophobic cyclodextrin inclusion compound and its preparation method and application

technical field

The invention belongs to the field of pharmaceutical preparations in medical engineering, and in particular relates to a hydrophobic cyclodextrin inclusion compound with a slow-release effect and a preparation method and application thereof.

Background technique

In recent years, the continuous development of cyclodextrin (CD) derivatives has broadened the application of cyclodextrin in the field of pharmacy. There are a large number of primary and secondary hydroxyl groups in the cyclodextrin molecule. These hydroxyl groups (especially the 2, 3 and 6-position hydroxyl groups) can be used as chemical structure modification points, and groups with different properties (methyl, ethyl, etc.) can be replaced by substitution reactions. , hydroxypropyl, hydroxyethyl, acetyl, etc.) into the CD molecule, and the introduction of these groups does not affect the capacity of the central hole to accommodate guest molecules, but improves some of the physicochemical properties and inclusion of CD ability.

At present, the mainly used CD derivatives are divided into three types: hydrophilic, hydrophobic and ionic. Hydrophilic derivatives mainly include methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin and the like. They have greater water solubility in water, and except for methyl-substituted cyclodextrins which have greater surface tension, the other species have better biocompatibility. Hydrophobic derivatives mainly include diethyl-β-cyclodextrin (DE-β-CD), triethyl-β-cyclodextrin (TE-β-CD), alkyl substituted-β-cyclodextrin ( C2～C18-β-CD), etc. They are generally water-insoluble, soluble in organic solvents, and have surface tension. Ionic cyclodextrins mainly include carboxymethyl-β-cyclodextrin (CME-β-CD), sulfo-β-cyclodextrin (S-β-CD), etc., and their solubility changes with pH. According to the physical and chemical properties of different CD derivatives, hydrophilic cyclodextrins can be used as carriers for quick-acting preparations; hydrophobic cyclodextrins can be used as carriers for sustained-release preparations; amphiphilic cyclodextrins can be used as carriers for microparticle drug delivery systems. Modification material is also a good target preparation carrier. Substituting the hydroxyl groups at the 2, 3, and 6 positions of β-CD with alkyl or acyl groups, because the hole group changes from hydrophilic to hydrophobic, thus expanding the hydrophobic space of cyclodextrin, so that β-cyclodextrin changes from hydrophilic to hydrophobic. Water becomes hydrophobic; during the inclusion process, the hydrophobic part of the guest molecule (hydrophilic drug) enters the hydrophobic cavity of cyclodextrin to form an insoluble inclusion compound. Therefore, the hydrophobic cyclodextrin inclusion compound can reduce the solubility and dissolution rate of some easily soluble drugs in water, and play a sustained release role. At present, the research on hydrophilic β-CD derivatives such as methylation and hydroxypropylation is relatively in-depth in this field, but there are relatively few technical reports on the use of hydrophobic cyclodextrins as pharmaceutical excipients, and no use of other β-CD derivatives has been reported. A technical report on inclusion materials as sustained release formulations.

The methods for preparing cyclodextrin inclusion compounds mainly include: grinding method, co-precipitation method, saturated aqueous solution method, freeze-drying method, etc. The grinding method is time-consuming, and most of them need to add organic solvents that are harmful to the human body, which is not suitable for industrial production; the co-precipitation method often requires higher temperature and excessive cyclodextrin, which is not suitable for thermally unstable drugs; the saturated aqueous solution method needs to add excessive Cyclodextrin inclusion materials are not suitable for intravenous administration.

The present invention relates to lyophilization of t-butanol/water co-solvent systems. The most commonly used solvent for freeze drying is water. However, due to some special needs, some freeze-drying processes also use tert-butanol/water co-solvent system. Lyophilization using a tert-butanol/water co-solvent system was derived from the original work of Deluca et al. In 1995, Kasraian and Deluca published two articles on Pharmaceutical Research, which proved that the addition of tert-butanol can change the crystallization behavior of ice, accelerate the sublimation rate, and shorten the freeze-drying cycle. In the ensuing 10 years, different researchers published some articles, but these works were limited to the use of tert-butanol/water co-solvent system to optimize the freeze-drying process and solve the problems in freeze-drying. Such as: speed up the sublimation speed, shorten the freeze-drying cycle, improve the stability of the drug in the pre-freezing solution, increase the solubility and dissolution rate of the drug in the pre-freezing solution, improve the reconstitution characteristics of the freeze-dried product, etc.

The stability of some drugs in the tert-butanol/water co-solvent system is significantly improved, such as the prostaglandin E prepared by the tert-butanol/water co-solvent system, the stability of the lyophilized powder is greatly improved compared with the original drug. The current research on the tert-butanol/water co-solvent system has involved the technical fields of liposome freeze-drying and solid nanoparticles. However, there is no research report on the hydrophobic cyclodextrin inclusion complex of tert-butanol/water co-solvent system in the inclusion of hydrophilic drugs.

Contents of the invention

An object of the present invention is to overcome the technical deficiencies of the prior art and provide a hydrophobic cyclodextrin inclusion compound with sustained release effect.

Another object of the present invention is to provide a preparation method of the hydrophobic cyclodextrin inclusion compound with sustained release effect.

Another object of the present invention is to provide the application of the hydrophobic cyclodextrin inclusion compound with sustained release effect in the preparation of pharmaceutical preparations.

The present invention realizes above-mentioned purpose through following technical scheme:

The hydrophobic cyclodextrin inclusion compound with sustained release effect described in the present invention is prepared by drying a single-phase solution formed by mixing a hydrophobic cyclodextrin tert-butanol solution and an aqueous phase solution containing a hydrophilic drug; The volume ratio of the tert-butanol solution to the water phase solution is 1-100:3, and the molar mass ratio of the cyclodextrin to the hydrophilic drug is 1-10:1.

The hydrophobic cyclodextrin refers to: (1) ethylated β-CD derivatives, including 2,6-diethyl-β-CD and 2,3,6-triethyl-β-CD; (2) Acylated β-CD derivatives, including 2,3,6-triacetyl-β-CD, 2,3,6-tripropionyl-β-CD, 2,3,6-tributyryl-β -CD 2,3-Dihexanoyl-β-CD and 2,3,6-trihexanoyl-β-CD; (3) Acetyl-α-cyclodextrin and acetyl-γ-cyclodextrin.

The hydrophilic drug refers to a drug that can be dissolved in tert-butanol/water co-solvent, such as biological macromolecules such as nucleic acid and protein, or a small molecule drug.

The aqueous phase solution refers to the phase of aqueous solution containing buffer salt or excipient.

The excipients may be mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, maltose, xylitol, lactose and the like. The addition of excipients has the following advantages: 1. It can be used as a freeze-drying protective agent, and the obtained freeze-dried product has a good shape; 2. It can make the freeze-dried product difficult to absorb moisture and can be stored for a long time; 3. Guarantee certain The drug activity of sensitive drugs helps to complex the drug with cyclodextrin.

The single-phase solution refers to a clear homogeneous solution, and the tert-butanol solution and the aqueous phase solution should be mixed in an appropriate ratio to form a single-phase solution.

The preparation method of the hydrophobic cyclodextrin inclusion compound with sustained release effect of the present invention adopts the tert-butanol/water co-solvent freeze-drying method, through the interaction between hydrophobic cyclodextrin and hydrophilic drug molecules, to generate Supramolecularization of solid clathrates to reduce the dissolution rate of water-soluble drugs.

The preparation method of the hydrophobic cyclodextrin inclusion compound with sustained release effect according to the present invention comprises the following steps:

a, dissolving the hydrophobic cyclodextrin used to form the clathrate in tert-butanol to make a tert-butanol solution of the hydrophobic cyclodextrin;

b. Dissolving the hydrophilic drug to be encapsulated in the aqueous phase solution;

c. According to the molar ratio requirements of cyclodextrin and hydrophilic drug, mix the tert-butanol solution of hydrophobic cyclodextrin and the aqueous phase solution according to the required volume ratio to form a single-phase solution;

d. Drying the single-phase solution to obtain a solid of drug cyclodextrin inclusion compound.

The above steps are carried out in the tert-butanol-water co-solvent system, the hydrophobic cyclodextrin is completely dissolved in the tert-butanol solution of the hydrophobic cyclodextrin, and the hydrophilic drug in the aqueous phase solution is also completely dissolved .

As the drying method, freeze-drying, spray-drying, or reduced-pressure drying can be used, among which freeze-drying is preferred.

Another object of the present invention is to provide the application of hydrophobic cyclodextrin inclusion compound with sustained release effect in pharmacy, specifically to prepare pharmaceutical dosage forms with sustained release effect, which can be made into cyclodextrin inclusion compound Drugs such as metformin hydrochloride, salbutamol sulfate, diltiazem hydrochloride, ciprofloxacin hydrochloride or insulin pharmaceutical preparations can be in the form of tablets, capsules, granules, injections or sterile powders for injection.

The present invention overcomes the technical deficiencies of the prior art and has the following beneficial effects:

1. The present invention provides a new hydrophobic cyclodextrin inclusion compound, and provides its application as an inclusion material for sustained-release preparations. Through the interaction between hydrophobic cyclodextrin and hydrophilic drug molecules, it generates Supramolecularized solid clathrates to reduce the dissolution rate of water-soluble drugs to meet the technical requirements of slow release of water-soluble drugs;

2. In the preparation process of the hydrophobic cyclodextrin of the present invention, the use of harmful solvents can be avoided and solvent residues can be thoroughly removed. Because the vacuum degree during freeze-drying is very low (less than 15pa), tert-butanol in the freeze-dried product obtained There is almost no residue, and tert-butanol is a less toxic solvent. It is generally considered to be a slightly toxic solvent to the human body, and its toxicity is much lower than that of chloroform and methanol;

3. The present invention can fully guarantee the activity of certain sensitive drugs. Since the preparation process is completed at low temperature, the hydrolysis and oxidation of the drug are avoided;

4. The present invention improves the inclusion ability of hydrophobic cyclodextrin;

5. Compared with regular-release preparations, hydrophobic cyclodextrins and water-soluble drugs can reduce the solubility and dissolution rate of water-soluble drugs after forming inclusion complexes, delaying the release of drugs, and the process is simple, easy to operate, and the cycle is short. Low energy consumption, no organic solvent residue, suitable for industrial production.

Description of drawings

Fig. 1 is the differential scanning calorimetry spectrum of the cyclodextrin inclusion compound of metformin hydrochloride prepared by grinding method, rotary evaporation method and co-solvent freeze-drying method. In the figure, a is the MH raw material drug, b is TA-β-CD, c is the physical mixture of MH/TA-β-CD, d is the grinding method to prepare the MH/TA-β-CD inclusion complex, e is the rotary evaporation method Preparation of MH/TA-β-CD inclusion complex, f is preparation of MH/TA-β-CD inclusion complex by co-solvent freeze-drying method.

Fig. 2 is an X-ray powder diffraction pattern of metformin hydrochloride cyclodextrin inclusion compound prepared by grinding method, rotary evaporation method and co-solvent freeze-drying method. In the figure, a is the MH raw material drug, b is TA-β-CD, c is the physical mixture of MH/TA-β-CD, d is the grinding method to prepare the MH/TA-β-CD inclusion complex, e is the rotary evaporation method Preparation of MH/TA-β-CD inclusion complex, f is preparation of MH/TA-β-CD inclusion complex by co-solvent freeze-drying method.

Fig. 3 is a comparison chart of drug dissolution in vitro in the preparation of metformin hydrochloride cyclodextrin inclusion complex by grinding method, rotary evaporation method and co-solvent freeze-drying method.

Fig. 4 is the cumulative release curve in vitro of the clathrate prepared in Example 1.

Detailed ways

The following examples further describe the present invention so that those skilled in the art can further understand the present invention, but do not limit the present invention in any form.

Example 1

Weigh 40 mg of metformin hydrochloride (MH) and dissolve it in 10 ml of double distilled water, weigh the corresponding stoichiometric 2,3,6-triacetyl-β-cyclodextrin (TA-β-CD) (molar mass ratio is 1:1 ) was dissolved in 10ml of tert-butanol, mixed the aqueous solution and tert-butanol solution, sterilized by 0.22μm microporous membrane filter, packed in 5ml vials, 2ml per bottle, put into a freeze dryer at -40°C for 4 hours, and turned on the vacuum pump , the sample was dried at -40°C for 12 hours once, and the second drying condition was 25°C for 8 hours to obtain metformin hydrochloride cyclodextrin inclusion compound, which was then plugged.

Example 2

Weigh 150 mg of salbutamol sulfate and dissolve it in 10 ml of double distilled water, weigh the corresponding stoichiometric amount of 2,3,6-triethyl-β-cyclodextrin (molar ratio is 1:1) and dissolve it in 20 ml of tert-butanol, and dissolve the aqueous solution Mix with tert-butanol solution, filter and sterilize with 0.22μm microporous membrane filter, pack in 5ml vials, 2ml per bottle, freeze in a freeze dryer at -40°C for 4h, turn on the vacuum pump, and dry the sample at -40°C for 12h once. The secondary drying condition is to dry at 25°C for 8 hours to obtain the inclusion compound of albuterol sulfate cyclodextrin, which is then plugged.

Example 3

Weigh 150 mg of diltiazem hydrochloride and dissolve it in 10 ml of double distilled water, weigh the corresponding stoichiometric amount of 2,3,6-triethyl-β-cyclodextrin (molar ratio is 1:1) and dissolve it in 20 ml of tert-butanol, and dissolve the aqueous solution Mix with tert-butanol solution, filter and sterilize with 0.22μm microporous membrane, pack in 5ml vials, 2ml per bottle, freeze in a freeze dryer at -40°C for 4h, turn on the vacuum pump, and dry the sample at -30°C for 12h once. The secondary drying condition is to dry at 25°C for 8 hours and stoppering.

Example 4

Weigh 200 mg of ciprofloxacin hydrochloride and dissolve it in 10 ml of double distilled water, weigh the corresponding stoichiometric 2,3,6-triacetyl-β-cyclodextrin (molar ratio is 1:3) and dissolve it in 25 ml of tert-butanol, Mix the aqueous solution and tert-butanol solution, filter and sterilize with a 0.22 μm microporous membrane, pack in 5ml vials, 2ml per bottle, put in a freeze dryer at -40°C for 4 hours, turn on the vacuum pump, and dry the sample once at -30°C 12h, the secondary drying condition is 25°C for 8h, and stoppering.

Example 5

Weigh 1mg of insulin and dissolve in 15ml of pH6.86 buffer solution, weigh the corresponding stoichiometric amount of 2,3,6-triacetyl-β-cyclodextrin (molar ratio 1:2) and dissolve it in 5ml of tert-butanol, and dissolve the aqueous solution Mix with tert-butanol solution, stir thoroughly with a magnetic stirrer for 3 hours to form a clear single-phase solution, filter and sterilize with a 0.22 μm microporous membrane, pack in 5ml vials, 2ml per bottle, and put in a freeze dryer at -40°C Freeze for 6 hours, turn on the vacuum pump, dry the sample at -30°C for 12 hours once, and dry at 20°C for 8 hours for the second time, and stopper.

Embodiment 6 Comparative example-grinding method

Weigh 80 mg of metformin hydrochloride and corresponding stoichiometric 2,3,6-triacetyl-β-cyclodextrin (molar ratio is 1:1) and place in a mortar for mixing, add 5 ml of aqueous ethanol (1:1, v /v) Grind to a thick slurry (about 2h). Dry at 40°C, pulverize, pass through an 80-mesh sieve, and finally store in a vacuum desiccator at room temperature.

Embodiment 7 Comparative example-rotary evaporation method

Take by weighing 80 mg of metformin hydrochloride and dissolve in 20 ml of double distilled water, take by weighing corresponding stoichiometric 2,3,6-triacetyl-β-cyclodextrin (molar ratio is 1:1) and dissolve in 20 ml of tert-butanol, the aqueous solution and The tert-butanol solution was mixed, and the obtained clear single-phase solution was rotated to evaporate the precipitate at 40°C. The precipitate was dried at 40°C, pulverized, passed through a 80-mesh sieve, and finally stored in a vacuum desiccator at room temperature.

Embodiment 8 The result that embodiment compares with comparative example

DSC was used to identify MH raw materials, TA-β-CD, physical clathrates, and MH/TA-β-CD clathrates prepared by grinding, rotary evaporation, and co-solvent freeze-drying methods. The migration or disappearance of the characteristic thermodynamic peak position of the substance proves the formation of clathrate. The results of differential scanning calorimetry measurements are shown in Figure 1.

MH bulk drug, TA-β-CD, physical inclusion compound, and MH/TA-β-CD inclusion compound prepared by grinding method, rotary evaporation method and co-solvent freeze-drying method were identified by powder X-ray diffraction method, According to the reduction or disappearance of the characteristic diffraction peak intensity of each substance in the spectrum, the formation of clathrate is proved. The measurement results of X-ray diffraction pattern are shown in Fig. 2 .

According to the second appendix (XD) of Chinese Pharmacopoeia 2005 edition, the release rate of the drug in the inclusion compound was investigated. The preparation method affects the in vitro release behavior of the drug; the preparation of MH/TA-β-CD inclusion complex by co-solvent freeze-drying method is more impressive than the preparation of MH/TA-β-CD inclusion compound by grinding method or rotary evaporation method. Satisfactory release behavior, it can significantly reduce the solubility and release rate of the drug in water, and has a longer sustained release time (about 7h). The comparison results of the in vitro cumulative release curves of the MH/TA-β-CD inclusion compound obtained by the three preparation methods are shown in Figure 3.

Example 9

RS PO和硬脂酸镁，过40目筛混合均匀，采用粉末直接压片，得到盐酸二甲双胍缓释片。Take by weighing the metformin hydrochloride cyclodextrin clathrate that embodiment 1 makes is appropriate, add

RS PO and magnesium stearate were passed through a 40-mesh sieve and mixed evenly, and the powder was directly compressed into tablets to obtain metformin hydrochloride sustained-release tablets.

Example 10

Take by weighing the appropriate amount of salbutamol sulfate cyclodextrin clathrate prepared in implementation 2, add lactose, pass through a 40 mesh sieve and mix evenly, fill capsules to obtain salbutamol sulfate sustained-release capsules.

Example 11

Weigh an appropriate amount of diltiazem hydrochloride cyclodextrin inclusion compound prepared in Example 3, add HPMC and microcrystalline cellulose, dry granulate, add magnesium stearate, mix evenly, and press into tablets to obtain diltiazem hydrochloride sustained-release tablets.

Example 12

The cyclodextrin inclusion complex of ciprofloxacin hydrochloride prepared in Example 4 can be prepared into sterile powder of sustained-release ciprofloxacin hydrochloride for injection according to the general preparation process of sterile powder.

Example 13

The insulin cyclosperm inclusion compound prepared in Example 5 can be made into a sterile insulin powder for injection according to the general sterile powder preparation process.

Claims (9)

1. A hydrophobic cyclodextrin clathrate with slow-release effect is characterized in that the single-phase solution formed by mixing the tert-butanol solution of hydrophobic cyclodextrin and the aqueous phase solution containing hydrophilic medicine is frozen Prepared by drying method; the hydrophilic drug is one of metformin hydrochloride, albuterol sulfate, diltiazem hydrochloride, ciprofloxacin hydrochloride or insulin; the volume ratio of the tert-butanol solution to the aqueous phase solution is 1 to 100 :3, the molar mass ratio of the cyclodextrin to the hydrophilic drug is 1-10:1. 2. The cyclodextrin inclusion compound as claimed in claim 1, characterized in that the cyclodextrin is an ethylated β-cyclodextrin derivative, an acylated β-cyclodextrin derivative or an acetyl-α - Any one or a mixture of two or more cyclodextrins or acetyl-γ-cyclodextrins. 3. The cyclodextrin inclusion compound according to claim 2, characterized in that said ethylated β-cyclodextrin derivative is 2,6-diethyl-β-cyclodextrin or 2,3, 6-triethyl-β-cyclodextrin; the acylated β-cyclodextrin derivatives are 2,3,6-triacetyl-β-cyclodextrin, 2,3,6-tripropionyl- β-cyclodextrin, 2,3,6-tributyryl-β-cyclodextrin 2,3-dihexanoyl-β-cyclodextrin or 2,3,6-trihexanoyl-β-cyclodextrin . 4. The cyclodextrin clathrate as claimed in claim 1, characterized in that said aqueous solution is an aqueous solution containing buffer salts or excipients. 5. cyclodextrin clathrate as claimed in claim 4 is characterized in that described excipient is in mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, maltose, xylitol or lactose Any one or a mixture of two or more. 6. a preparation method of the hydrophobic cyclodextrin inclusion complex with sustained-release effect according to claim 1, characterized in that it comprises the following steps: a, dissolving the hydrophobic cyclodextrin used to form the clathrate in tert-butanol to make a tert-butanol solution of the hydrophobic cyclodextrin; b. Dissolving the hydrophilic drug to be encapsulated in the aqueous phase solution; c. According to the molar ratio requirements of cyclodextrin and hydrophilic drug, mix the tert-butanol solution of hydrophobic cyclodextrin and the aqueous phase solution according to the required volume ratio to form a single-phase solution; d. Drying the single-phase solution to obtain a solid of drug cyclodextrin inclusion compound. 7. The preparation method according to claim 6, characterized in that said drying is freeze-drying. 8. The application of the hydrophobic cyclodextrin inclusion compound with sustained-release effect according to claim 1, characterized in that it is applied to the preparation of metformin hydrochloride, salbutamol sulfate, diltiazem hydrochloride, ciprofloxacin hydrochloride or insulin sustained-release compound. release pharmaceutical preparations. 9. The application according to claim 8, characterized in that the dosage form of the pharmaceutical preparation is tablet, capsule, granule or injection.

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