WO2008031286A1 - Composition pharmaceutique contenant une inclusion de cyclodextrine/paclitaxel et procédé de fabrication - Google Patents

Composition pharmaceutique contenant une inclusion de cyclodextrine/paclitaxel et procédé de fabrication Download PDF

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WO2008031286A1
WO2008031286A1 PCT/CN2006/002693 CN2006002693W WO2008031286A1 WO 2008031286 A1 WO2008031286 A1 WO 2008031286A1 CN 2006002693 W CN2006002693 W CN 2006002693W WO 2008031286 A1 WO2008031286 A1 WO 2008031286A1
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Prior art keywords
cyclodextrin
paclitaxel
sulfobutyl
ethanol
hydroxypropyl
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PCT/CN2006/002693
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English (en)
French (fr)
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Yong Ren
Jianfeng Gao
Shuqin Yu
Ling Wu
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Nanjing Normal University
Nanjing Huge-Ring Medicine Technology Development Co., Ltd
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Application filed by Nanjing Normal University, Nanjing Huge-Ring Medicine Technology Development Co., Ltd filed Critical Nanjing Normal University
Priority to JP2009526996A priority Critical patent/JP5087086B2/ja
Priority to EP06791258A priority patent/EP2075010A4/en
Priority to US12/440,792 priority patent/US8426385B2/en
Publication of WO2008031286A1 publication Critical patent/WO2008031286A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the invention relates to a pharmaceutical composition, in particular to an inclusion compound containing paclitaxel, hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin and its common medicinal auxiliary materials Pharmaceutical composition, and a method of preparing the composition. Background technique
  • Paclitaxel (trade name Taxol) is a diterpenoid isolated from the bark of Txus brevifolia, molecular formula C 47 H 51 N0 24 , molecular weight 853. 92, chemical name: (2S, 5R, 7S, 10R ,13S)-10,20-bis(acetoxy)-2-benzoyloxy-1,7-dihydroxy-9-oxo-5,20-epoxy taxane-11-ene-13 -Based (3S)-3-benzoylamino-3-phenyl-D-lactate. Paclitaxel is a white or off-white crystalline powder, which is relatively stable under the conditions of pH 4-8, and has high fat solubility.
  • the clinical application of paclitaxel is injection.
  • the existing paclitaxel injection is prepared from 1:1 (V/V) polyoxyethylene castor oil/anhydrous ethanol to prepare a colorless viscous concentrated solution (5 ml solution containing paclitaxel 30 mg).
  • Paclitaxel injection is made of polyoxyethylene castor oil/anhydrous ethanol as a vehicle.
  • the incidence of clinical allergic reaction is high. It needs to be treated with anti-allergic reaction.
  • the dexamethasone 10 mg is taken orally before 12 h and 6 h before administration.
  • 20 mg of diphenhydramine was given intramuscularly for 30 ⁇ 60 min
  • intravenous cimetidine 300 mg or ranitidine 50 mg was given to prevent adrenaline in patients with allergic reactions.
  • paclitaxel injections cannot be formulated, filled, and injected in a polyvinyl chloride plastic container or injection container to prevent the solvent from reacting with the container to form other sensitizers.
  • the diluent is stored in a glass or polypropylene plastic container, and a specially equipped polyethyl ester injection device can also be used.
  • a specially equipped polyethyl ester injection device can also be used.
  • paclitaxel administration technology mainly focuses on liposome, combination solvent, cyclodextrin, emulsion, nanoparticle, chelation, microsphere and other technologies.
  • Cyclodextrin has special molecular inclusion function plus recent injection. With the clinical application of cyclodextrin derivatives, the research of cyclodextrin-paclitaxel inclusion technology has developed rapidly.
  • cyclodextrin extracts for paclitaxel preparations are mainly: acetyl-cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, bridged bicyclodextrin, ⁇ - Cyclodextrin, methyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, succinyl-methyl- ⁇ -cyclodextrin, anion- ⁇ -cyclodextrin Polymers and the like, wherein ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin are cyclodextrin materials which have been clinically used in various drug injection forms, and the above other cyclodextrins are not currently used for clinical injection applications. Report.
  • cyclodextrin Due to the structural specificity of cyclodextrin and the special requirements of paclitaxel application, its valuable cyclodextrin-paclitaxel system should be mainly embodied in: inclusion strength, solubilization range, pharmacy stability, chemical stability, package Study on the activity of paclitaxel and changes in side effects.
  • paclitaxel has a large molecular volume, it has been found that cyclodextrin can still be used in different degrees with paclitaxel, and its incorporation intensity and specific conditions such as solvent, temperature, material type, especially cyclodextrin structure type The material ratio is directly related. Therefore, different research methods will lead to different conclusions.
  • R m log (l/R f - l) where R m is a function of the drug, mobile phase and cyclodextrin concentration, extrapolating the relationship curve to zero (no mobile phase and cyclodextrin),
  • the absolute migration retention of the object is R m .
  • the cyclodextrin in pure water also has a good effect on the solubilization of paclitaxel.
  • the paclitaxel in aqueous solution of hydroxypropyl- ⁇ -cyclodextrin can reach a solubility of 3.4 mg/ml in about 50% concentration (J Pharm Sci, 1995, 84: 1223-1229), is the best result reported so far.
  • the use of tetraethylenepentamine bridged bicyclodextrin can solubilize paclitaxel to 2.0mg/ml
  • cyclodextrin solubilization is related to the cyclodextrin species, and also to the paclitaxel-cyclodextrin ratio.
  • the stability of paclitaxel was improved and the activity was improved to some extent.
  • Fluorescence spectroscopy showed that the bridged cyclodextrin with a cyclodextrin spacing of 16.1 A had a ⁇ 7 ] ⁇ 1 relative to ⁇ -cyclodextrin and paclitaxel.
  • the inclusion constant, the prepared 1:1 molecule is more stable than the inclusion complex, and the paclitaxel composition has no change.
  • the drug-tumor cell time course can be significantly prolonged (Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2001, 39: 13-18); Studies have shown that due to the increased solubility of paclitaxel can increase the extracellular paclitaxel concentration, which is beneficial to the drug through the cell membrane, the solubilization of cyclodextrin has a retention or enhance activity on paclitaxel (Bioorganic & Medicinal Chemistry Letters 5 2002, 12: 1637-1641); After adding paclitaxel to cyclodextrin, a stable preparation solution containing a small amount of organic solvent or additive (HU P9701945; CN1281373/ZL98811010.5) can be prepared, and the solubility of 1:50 cyclodextrin solution paclitaxel reaches 1.5.
  • an inclusion preparation prepared with acetyl- ⁇ -cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin can significantly reduce the existing paclitaxel Cardiovascular and respiratory toxic side effects of the agent (polyoxyethylene castor oil / anhydrous ethanol solvent). The study also found that inclusion can also effectively reduce the side effects of paclitaxel itself.
  • CN1589157 discloses a paclitaxel/hydroxypropyl- ⁇ -cyclodextrin composition and a preparation method thereof, and the invention employs 45 g of hydroxypropyl a ratio of basal- ⁇ -cyclodextrin, 30 mg of paclitaxel, 100 ml of water, dissolving the paclitaxel in ethanol, and then adding the aqueous solution of hydroxypropyl- ⁇ -cyclodextrin to prepare an inclusion compound, however, up to 1:
  • the paclitaxel/cyclodextrin mass ratio of 1500 makes this technique difficult to use in clinical practice; HU P9701945 uses a lower proportion of cyclodextrin, but the reported solubilization effect is not significant; the example disclosed in USP 6284746 is paclitaxel 11.6
  • An organic solvent such as decyl alcohol, acetonitrile or ethyl acetate.
  • HU71251 only solubilized the alcohol to 0.05mg/ml in a 1-20 times molar ratio of various cyclodextrins;
  • HU65835 obtained a 20-fold molar ratio (about 31 times the mass ratio) of the branched cyclodextrin to obtain the purple alcohol Dissolved to an effect of about 0.32 mg/ml.
  • cyclodextrin-incorporated paclitaxel has been very active, there are no formulations of cyclodextrin-incorporated paclitaxel, and the safety of cyclodextrin is one of the main reasons. It has been proven to be able to inject.
  • Dextrin and cyclodextrin derivatives are only ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin (Expert Opin Drug Deliv, 2005 Mar; 2(2) : 335 - 51 ), hydroxypropyl- ⁇ -cyclodextrin has been studied in the improvement of paclitaxel dosage form, but sulfobutyl- ⁇ -cyclodextrin has not been reported yet. Other cyclodextrins are not yet fully safe. Sexual evidence, so the practical application of technology is more difficult.
  • the main drawbacks of the prior art are: low solubility of paclitaxel in the preparation (non-linear effect of cyclodextrin solubilization), poor stability of pharmaceutics, precipitation after precipitation, paclitaxel/cyclodextrin If the concentration of the organic solvent is too high, the residual ratio is high, and the concentration of the cyclodextrin is too large, the basic requirements of the paclitaxel preparation cannot be obtained.
  • the selection of new varieties of cyclodextrin with excellent performance and systematic research on inclusion technology is the hope of changing this situation.
  • the object of the present invention is to overcome the difficulties in the research of cyclodextrin-containing paclitaxel in the prior art, including: low solubility of paclitaxel in the preparation; poor pharmacy stability; excessive paclitaxel/cyclodextrin ratio; Solvents, etc., to achieve technological breakthroughs in this field, to provide a cyclodextrin paclitaxel stable inclusion complex with high paclitaxel solubility and pharmaceutical stability, low cyclodextrin ratio, low organic solvent residue, in order to achieve clinical use .
  • the present invention will also provide a process for the preparation of such a clathrate.
  • the technical solution of the present invention is: a pharmaceutical composition containing a cyclodextrin/paclitaxel inclusion compound, which is composed of paclitaxel, cyclodextrin and a medicinal auxiliary, wherein the mass ratio of paclitaxel to cyclodextrin is 1:10 to 150.
  • the cyclodextrin is: hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfonate a mixture of basal- ⁇ -cyclodextrin in any ratio; the stability constant of cyclodextrin-containing paclitaxel Ka - SSQeM-i MdM" 1 .
  • the pharmaceutical composition containing the cyclodextrin/paclitaxel inclusion compound refers to a composition obtained by the following preparation method:
  • hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin with hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin In a pure aqueous solution of the mixture, a solution of paclitaxel in ethanol is added dropwise (or the cyclodextrin, paclitaxel and pure water are first mixed, and ethanol is slowly added dropwise with stirring until the system is completely dissolved, which is an equivalent step of the same effect);
  • the filtrate is decompressed to remove ethanol to obtain a liquid clathrate; After removing the ethanol under reduced pressure, the water is removed under reduced pressure and dried to obtain a solid clathrate.
  • the pharmaceutical composition containing the cyclodextrin/paclitaxel inclusion compound prepared by the above method has a residual ethanol content of less than 2%.
  • the invention adopts sulfobutyl- ⁇ -cyclodextrin or hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin to be mixed with a paclitaxel raw material solution with an appropriate amount of ethanol under the condition of an aqueous solution, and the added ethanol can promote the package cooperation.
  • the ethanol is removed (the residual amount of ethanol is less than 2%), and a stable paclitaxel/cyclodextrin inclusion compound is prepared, and the inclusion compound is compounded with a common medicinal auxiliary material to prepare a clinically usable inclusion drug.
  • the composition thereby improving the solubility of paclitaxel, increasing stability, reducing side effects, and obtaining paclitaxel products having clinical application value.
  • the preparation of clathrates is the key to the technology of the present invention.
  • hydroxypropyl- ⁇ -cyclodextrin is a non-ionized neutral derivative
  • sulfobutyl- ⁇ -cyclodextrin is an ionized derivative
  • the pharmaceutically acceptable sulfobutyl- ⁇ -cyclodextrin is a 6-7 substituted product (SBE 7 -P-CD, trade name Captisol).
  • SBE 7 -P-CD trade name Captisol
  • HP-SBE-p-CD hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin
  • the present invention improves the paclitaxel preparation by using sulfobutyl- ⁇ -cyclodextrin or hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin (mass ratio 1:10-150), wherein the low ratio prepared is 1: 25 (mass ratio) inclusion compound can make paclitaxel solubility 9 ⁇ 10 mg / ml, solid inclusion complex diluted more than 500 times can be stably stored 12 More than an hour, and it is chemically stable, has high pharmacy stability, and is less irritating, and has important application value.
  • the technical solution of the above-mentioned solution and which is also the task of the second invention of the present invention is: a method for preparing a pharmaceutical composition containing a cyclodextrin/paclitaxel inclusion compound, the steps are as follows,
  • hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin with hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin In a pure aqueous solution of the mixture, a solution of paclitaxel in ethanol is added dropwise (or the cyclodextrin, paclitaxel and pure water are first mixed, and ethanol is slowly added dropwise with stirring until the system is completely dissolved, which is an equivalent step of the same effect);
  • the filtrate is decompressed to remove ethanol to obtain a liquid paclitaxel inclusion compound
  • the paclitaxel inclusion compound has an ethanol content of less than 2%.
  • the specific steps of the method for preparing a cyclodextrin/paclitaxel inclusion compound-containing pharmaceutical composition of the present invention are:
  • cyclodextrin with a 1:25 ratio of paclitaxel: cyclodextrin ratio, which means: hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, or sulfobutyl- ⁇ -cyclodextrin , or a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin mixed with 2-10 times of pure water, slowly adding the ratio of paclitaxel and ethanol with stirring
  • the prepared solution, the amount of ethanol may be the same amount of paclitaxel to 10 times the mass of paclitaxel can be dissolved into the degree, when adding paclitaxel, the room temperature can also be heated and stirred between 25 - 65 ° C, stirred to form an inclusion compound, 0.2 ⁇ Filtration was carried out on a 0.4 ⁇ 4 ⁇ pore filter, and then
  • the solid inclusion compound prepared by the invention has high water solubility and is easy to dissolve without adding other auxiliary solvents, and the prepared aqueous solution has small side effects of hemolysis and is suitable for clinical use.
  • the solid inclusion compound containing the clinically administered dose of 30 mg of paclitaxel can be kept stable within a few days after being diluted with the physiological saline for injection by 10-500 times.
  • the solid clathrate is diluted with a conventional injectable pharmaceutical excipient solution to a suitable concentration and sterilized, and the resulting composition solution is ready for injection.
  • D 2 0 is the solvent of the sulfobutyl- ⁇ -cyclodextrin starting material and the inclusion complex H, C-COSY ( 13 C, l R correlation spectrum) comparison results, inclusion complex in the cyclodextrin glucose ring H- The 3 and H-5 protons ( ⁇ 4.1 to 3.4) shifted significantly to the high field (Fig. 1), indicating that the benzoyl side chain group of the paclitaxel molecule was incorporated into the cyclodextrin.
  • the cyclodextrin structure is characterized by a hydrophobic cavity with high electron density ("Cyclodextrin Chemistry", Science Press 2001, P135), a drug molecule chromophore (such as phenyl) that enters the hydrophobic cavity (inclusion).
  • the ⁇ -electron transition is induced by the high electron density of the cyclodextrin hydrophobic cavity, which causes the change of ultraviolet light.
  • the UV absorption of the determination system is an effective method to judge the inclusion.
  • the UV absorption of paclitaxel was significantly enhanced with the increase of cyclodextrin concentration, indicating that paclitaxel has a distinct and strong inclusion complex with the cyclodextrin used in the present invention.
  • the inclusion stability constant Ka is a measure of the degree of inclusion.
  • Ultraviolet spectrophotometry is a common method for determining Ka. Change the concentration of cyclodextrin (cyclodextrin itself without absorption) constant concentration of paclitaxel solution The UV absorption shows a regular change, and the relationship between cyclodextrin concentration (C) and UV absorbance (A) is obtained. The apparent level of cyclodextrin/paclitaxel can be quantitatively calculated from the 1/C and 1/A curves.
  • the stability constant Ka was measured at the same time. The effect of adding ethanol on Ka was measured.
  • the Ka of various cyclodextrins is shown in Table 1. Table 1 The apparent first-order inclusion stability constant of paclitaxel/cyclodextrin Ka CM" 1 ; 234nm )
  • ⁇ -cyclodextrin 413 show that the cyclodextrin used in the present invention has a large inclusion constant Ka, and the presence of ethanol significantly increases the Ka value (enhances the inclusion ability of the cyclodextrin) and thus promotes inclusion.
  • Function not just a solvent.
  • organic solvents compete with drugs, and ethanol usually exhibits the effect of reducing drug Ka.
  • the cyclodextrin-containing paclitaxel used in the present invention still has a large Ka under pure water conditions, which is sufficient to form a stable clathrate, the present invention forms a clathrate.
  • ethanol is removed as much as possible to obtain a pure drug inclusion compound, and the effect of ethanol on the drug is minimized.
  • the use of ethanol to effect the inclusion of paclitaxel to prepare the inclusions is a successful technical basis for the present invention.
  • the various ratios of sulfobutyl- ⁇ -cyclodextrin/paclitaxel, hydroxypropyl-p-butyl- ⁇ -cyclodextrin/paclitaxel were prepared by drying under reduced pressure. Mixture of sulfobutyl- ⁇ -cyclodextrin with hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin/solid inclusion complex of paclitaxel, verified by DTA Solid solids are clathrates rather than simple physical mixtures. Taking sulfobutyl- ⁇ -cyclodextrin/paclitaxel (mass ratio 25:1) as an example, the analysis shows:
  • paclitaxel has a melting peak (decomposition) at 240 ° C
  • cyclodextrin is also a dehydration endothermic peak and a phase change peak at 70-90 ° C and 250-270 ° C, respectively, about 360 ° C for melting Decompose the peak.
  • the physical mixture maintains the endothermic peak characteristics of cyclodextrin and paclitaxel.
  • the dehydration endothermic peak is significantly weakened, the phase transition peak disappears, and the position (temperature) and shape (thermal effect) of other peaks occur. A significant change has occurred, thus indicating that the clathrate has formed.
  • the experiment proves that although more ethanol is used in the preparation process of the present invention, the ethanol residue after purification treatment is small, and the ethanol residue in the clathrate prepared by the low proportion of cyclodextrin (below 1:50) is generally less than 1.0%; A larger proportion of cyclodextrin to prepare clathrates also has less than 2.0% ethanol residue.
  • the large reduction in volatile and irritating ethanol residues provides a favorable guarantee for improving the stability of paclitaxel preparations and reducing side effects such as irritation.
  • a sulfobutyl- ⁇ -cyclodextrin
  • b hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin is highly soluble due to high concentration of cyclodextrin solution (>50%), but basically no Actual use value, therefore, a solubilization test of a cyclodextrin aqueous solution having a concentration of 31% or less was carried out, and the results showed that The cyclodextrin used in the invention has a strong solubilizing effect on paclitaxel.
  • the stability of the pharmaceutical composition includes the chemical stability of the drug and the pharmaceutically stable nature of the composition, and is an essential element for the application of the pharmaceutical composition.
  • HPLC chromatographic conditions column 008 € 18 (250 11111 ⁇ 4.6 awake); mobile phase, sterol: water: acetonitrile (20: 30: 50); flow rate 10 ml / min; detection wavelength 228 nm; determination time: 30.00 minutes ; Detection sensitivity 1.0000 AUFS.
  • paclitaxel starting material paclitaxel/sulfobutyl- ⁇ -cyclodextrin inclusion complex, mass ratio 1: 25
  • paclitaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion complex paclitaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion complex (b, mass ratio 1: 25 )
  • HPLC measurement legend is shown in Figure 3, Figure 4, and the results of each test are shown in Table 4.
  • Solution stability mass ratio 1:25 Solid inclusion compound was prepared into a solution containing paclitaxel 10 mg/ml with physiological saline and isotonic glucose solution, diluted 1 1000 times, and sterilized to prepare different concentrations of injection solution. Continuous observation for 5 hours to 10 days, wherein the stability test results of the physiological saline dilution system of paclitaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion compound are shown in Table 5.
  • the hemolytic activity of the solution prepared with the inclusion compound physiological saline was significantly different from that of the existing paclitaxel preparation.
  • the hemolysis effect of the diluted solution of the solid inclusion compound is slight; the hemolysis effect of the existing paclitaxel preparation diluted to the clinical dose of 0.06 mg/ml is still 15%, and the results are shown in Fig. 5.
  • paclitaxel/cyclodextrin inclusion complex 5 mg/kg dose inhibition rate 94.69% was significantly higher than unconjugated paclitaxel (inhibition rate 82.77%); paclitaxel and paclitaxel/cyclodextrin inclusion complex decreased body weight, but paclitaxel group weight loss was greater than inclusion complex group, the results suggest that paclitaxel After inclusion, the antitumor activity is enhanced and the side effects are reduced.
  • the inclusion compound significantly improves the solubility of paclitaxel (up to 10 mg/ml or more), and the solution can be kept clear and stable for a long time after dilution, and has low hemolytic effect, small toxic and side effects, and good drug activity.
  • the content of solid and liquid samples is stable, the ratio of drug/cyclodextrin is small, and the amount of cyclodextrin in the preparation is low, which is suitable for clinical use.
  • the clathrate of the present invention has less residual organic solvent, which is advantageous for improving the safety of administration.
  • the preparation method is simple, the operation is simple, the cost is low, and there is no environmental pollution.
  • the inclusion complex is stable in nature and has good compatibility with other pharmaceutical excipients, and is convenient for preparation of the preparation.
  • the injection prepared by the inclusion compound has no corrosive components and is non-toxic, and is convenient for clinical use and practical.
  • Figure 1 molar ratio 1: 9 paclitaxel / sulfobutyl- ⁇ -cyclodextrin inclusion complex H, C-COSY (solvent D 2 0, ⁇ 4. 3.4 part);
  • FIG. 2 Ultraviolet absorption scan of paclitaxel at different concentrations of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin in aqueous solution (210 nm ⁇ 296 nm);
  • Figure 3 HPLC chromatogram of paclitaxel/hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin inclusion complex at high temperature (5 days);
  • Figure 4 HPLC chromatogram of the paclitaxel feedstock high temperature test (5 days);
  • Figure 5 Commercially available paclitaxel formulation, paclitaxel/hydroxypropyl-p-butyl- ⁇ -cyclodextrin (HP-SBE-P-CD) inclusion complex, paclitaxel/sulfobutyl- ⁇ -cyclodextrin (SBE-P -CD) a solution of the inclusion compound physiological saline diluted, paclitaxel concentration - hemolysis curve.
  • HP-SBE-P-CD paclitaxel/hydroxypropyl-p-butyl- ⁇ -cyclodextrin
  • SBE-P -CD paclitaxel/sulfobutyl- ⁇ -cyclodextrin
  • Example 1 Mixing 3 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin with 6 ml of pure water, stirring slowly A solution prepared by adding 120 mg of paclitaxel and 3 ml of ethanol was added dropwise, and the mixture was thoroughly mixed until the system was completely dissolved, and filtered through a 0,2 to 0.4 ⁇ filter, and the filtrate 65 was obtained. Ethanol was distilled off under reduced pressure at C. After sterilizing, water was evaporated to dryness under reduced pressure, and the solid was dried under reduced pressure for 48 hours to obtain a white solid clathrate. Refer to Figure 1 to Figure 5 for various parameters.
  • the above powdery clathrate 780 mg (containing paclitaxel 30 mg) is mixed with 250 ml of physiological saline for injection to dissolve into a liquid inclusion composition, which is convenient for injection.
  • Example 2 Basically the same as Example 1, but wherein hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin is
  • Example 3 Basically the same as Example 1, but the paclitaxel therein was 300 mg.
  • Example 4 Basically the same as Example 1, except that the cyclodextrin was sulfobutyl- ⁇ -cyclodextrin.
  • Example 5 Basically the same as Example 2, but the cyclodextrin therein was sulfobutyl- ⁇ -cyclodextrin.
  • Example 6 Basically the same as Example 3, except that the cyclodextrin was sulfobutyl- ⁇ -cyclodextrin.
  • Example 7 Basically the same as Example 1, except that the cyclodextrin was a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-based- ⁇ -cyclodextrin in a mass ratio of 1:1.
  • Example 8 Basically the same as Example 2, except that the cyclodextrin was a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-t-butyl- ⁇ -cyclodextrin in a mass ratio of 1:50.
  • Example 9 Basically the same as Example 3, except that the cyclodextrin was a mixture of sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-n-butyl- ⁇ -cyclodextrin in a mass ratio of 50:1.
  • Example 10 Basically the same as in Example 1, except that cyclodextrin, paclitaxel and 6 ml of pure water were first mixed, and ethanol was slowly added dropwise with stirring until the system was completely dissolved.
  • Example 11 Basically the same as Example 1, except that the obtained powdery clathrate was diluted with an isotonic concentration 3 ⁇ 4 glucose injection.
  • Example 1 '2 Basically the same as Example 1, except that the obtained powdery clathrate was diluted with an isotonic concentration of sucrose injection.

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Description

含有环糊精紫杉醇包合物的药物组合物及其制备方法 技术领域
本发明涉及一种药物组合物， 具体涉及一种含有紫杉醇、 羟丙基 -磺丁 基 -β-环糊精或磺丁基 -β-环糊精的包合物及其与常用药用辅料的药物组合 物， 以及该组合物的制备方法。 背景技术
紫杉醇（Paclitaxel,商品名 Taxol)是由植物短叶紫杉 (Txus brevifolia 树皮分离提取的二萜类化合物， 分子式 C47H51N024 , 分子量 853. 92 , 化 学名： （2S,5R,7S,10R,13S)-10,20-双（乙酰氧基) -2-苯甲酰氧基 -1,7-二羟基 -9-氧 代 -5,20-环氧紫杉烷 -11-烯 -13-基 (3S)-3-苯曱酰氨基 -3-苯基 -D-乳酸酯。紫杉醇 为白色或类白色结晶粉末， 在 pH 4~8 条件下化学性质相对稳定， 本品脂 溶性高 （logP,0/w = 3.5)几乎不溶于水， 不同文献报道的水中溶解度在 0.25 g/ml~0.6(^g/ml 范围，也难溶于多种常用药用溶媒。 大量药理药效实验证 明， 紫杉醇对晚期卵巢癌、 转移性乳腺癌、 黑色素瘤都有显著疗效， 对难治 性卵巢癌和转移性乳腺癌的治愈率高， 对治疗前列腺癌、 胃肠癌、 小细胞 性和非小细胞性肺癌前景良好， 是目前发现的最具抗癌效果的天然抗癌药 物之一。 由于口服难以吸收（口服吸收率 2%~4%)， 紫杉醇的临床应用为注射 给药， 现有的紫杉醇注射液由 1:1 (V/V) 的聚氧乙烯蓖麻油 /无水乙醇配制 成无色粘稠状浓溶液（5ml溶液含紫杉醇 30mg)。使用时先将本品浓溶液稀 释于 500 mL的 0.9 %氯化钠注射液或 5 %葡萄糖注射液或 5 %右旋 酐注射 液中， 稀释成紫杉醇含量约 0.06mg/ml溶液后 （溶媒含量 0.5 % ~ 1.0% ), 确 认 本 用一次性非聚氯乙烯材料的输液瓶和输液管， 并通过 0.22 μπι孔径过滤器过 滤后， 静脉滴注 3 ~ 24 h， 输注剂量为 135 ~ 175 mg/m-2 , 最大耐受剂量为 3 h 内输注225 ~ 240 11¾/111_ 2。
紫杉醇注射剂采用聚氧乙烯蓖麻油 /无水乙醇作溶媒，临床过敏反应发 生率高， 使用时需要作防过敏反应处理， 分别于给药前 12 h、 6 h 口服地塞 米松 10 mg, 用药前 30 ~ 60 min肌注给予 20 mg苯海拉明， 静脉注射西咪替 丁 300 mg或雷尼替丁 50 mg加以预防， 对已发生过敏反应的病人给予注射 肾上腺素对症治疗。 另外， 紫杉醇注射液不能用聚氯乙烯塑料容器或注射容 器配制、 盛装和注射， 以避免溶媒与容器反应生成其他致敏物。 稀释液放置 在玻璃或聚丙烯塑料容器中保存， 也可用专门配备的聚乙酯类注射装置。 虽 然注射紫杉醇致敏的机制至今仍不完全清楚， 但是由于已知另外还有 2个使 用该种溶媒的药物（环孢菌素和鬼臼噻吩甙）也发生相同的过敏反应， 并且 试验也证实蓖麻油本身就能引起狗组织胺释放和低血压 ( Clinical Oncology, 1994; 6 :40 ), 因此， 溶媒蓖麻油的致敏性亦引起人们关注。 近年来， 研究高 效低毒性的不含有蓖麻油成分的药物载体和紫杉醇新型给药技术成为研究 的热点。
目前有关紫杉醇给药技术的研究主要集中于脂质体、组合溶剂、环糊精、 乳剂、 纳米粒、 螯合、 微球等技术， 环糊精由于具有特殊的分子包合功能加 上近年注射用环糊精衍生物的临床应用， 使得环糊精-紫杉醇包合技术研究 有了较快的发展。 目前已经报道用于紫杉醇制剂改进的环糊精品种主要有： 乙酰 一环糊精、 羟丙基 -β一环糊精、 羟丙基 -γ-环糊精、 桥联双环糊精、 α-环 糊精、 甲基 -β-环糊精、 γ-环糊精、 琥珀酰 -甲基 -β-环糊精、 阴离子 -β-环糊精 聚合物等， 其中 α-环糊精和羟丙基- β-环糊精是已经临床用于多种药物注射 剂型的环糊精类材料， 而上述其他环糊精目前还没有临床注射应用的报道。
由于环糊精的结构性能特殊性及紫杉醇应用的特殊要求，其有价值的环 糊精-紫杉醇体系应主要体现于： 包合作用强度、 增溶幅度、 药剂学稳定性、 化学稳定性、 包合后紫杉醇活性及副作用改变等方面的研究。 尽管紫杉醇具 有较大的分子体积，但是研究发现环糊精仍然可以与紫杉醇发生不同程度的 包合作用， 其包合作用强度与具体作用条件如溶剂、 温度、 物料种类尤其是 环糊精结构类型、 物料比例等直接相关， 因此， 不同的研究方法会得出不同 的结论。 采用薄层色谱方法测定 23种抗肿瘤药物加入羟丙基 -β-环糊精（包 合药物）前后薄层比移值 ( Rf )的变化（ International Journal of Pharmaceutics,
1994,108:69-75 )， 由此计算迁移保留值 Rm:
Rm = log (l/Rf - l) 其中， Rm为药物、 流动相及环糊精浓度的函数， 将其关系曲线外推至 零点 （无流动相和环糊精）， 得包合物的绝对迁移保留值 Rm。 （流动相甲醇 浓度 = 0、 环糊精浓度 = 0时， Rm = Rm。， Rm。越小包合物迁移性质变化越大， 包合作用越强）， 结果表明， 23种药物中紫杉醇包合作用最弱 （Rm。最大）， 进一步采用分子空腔较小的 α-环糊精实验， 得相同的结论， 紫杉醇也显示 出最弱的包合能力 ( Journal of Pharmaceutical & Biomedical Analysis, 1995,13:533-541 ); 而采用紫外光语研究 （ Chem. Res. Chinese U. 2005,21: 749-752 )却发现水溶液中羟丙基 -β-环糊精 /紫杉醇显示出较强的包合作用， 包合常数达. 3030Μ-1 ， 其作用以二元包合为主； 相溶解度研究显示 ( International Journal of Pharmaceutics, 1996, 133： 191-201 )， 水溶液中紫杉 醇与环糊精存在以二元包合为主的多级包合， 其 γ-环糊精、 羟丙基 -γ-环糊 精和羟丙基 -β:环糊精的二级包合常数分别为 785 " 1886 jVT1和 7965 ΜΓ1 ， 显示羟丙基 -β-环糊精 /紫杉醇具有强的包合能力， 同时还发现， 加入醇类有 机溶剂各级包合常数都有大幅提高， 也能够显著提高紫杉醇溶解度。 纯水中 环糊精对紫杉醇增溶也有较好效果， 约 50%浓度羟丙基 -β-环糊精水溶液中 紫杉醇可达 3.4mg/ml溶解度（ J Pharm Sci, 1995, 84： 1223-1229 ),是目前报 道的最好结果。 采用四乙烯五胺桥联双环糊精则可增溶紫杉醇到 2.0mg/ml
( CN1440748 ), 环糊精增溶除与环糊精种类有关外， 也与紫杉醇-环糊精比 例相关。 紫杉醇包合后稳定性得到提高、 活性也有不同程度改善， 荧光光谱 研究显示， 环糊精间距 16.1 A的桥联默环糊精相对于 β-环糊精与紫杉醇具 有高达 ΙΟ7 ]^· 1的包合常数， 制备的 1:1分子比包合物稳定性强， 紫杉醇成分 无变化， 包合后能显著延长药物 -肿瘤细胞作用时程（Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2001 , 39: 13-18 )；研究表明由于紫 杉醇溶解度的提高能够增加细胞外紫杉醇浓度， 有利于药物透过细胞膜， 环 糊精的增溶作用对紫杉醇具有保持或增强活性效果（Bioorganic & Medicinal Chemistry Letters52002,12: 1637-1641 ); 紫杉醇加入环糊精后， 可制备含有少 量有机溶剂 或 添加 剂 的 稳定制 剂 溶液 （ HU P9701945 ； CN1281373/ZL98811010.5 ) , 1:50环糊精比例的溶液紫杉醇溶解度达到 1.5mg/ml,采用乙酰 -β-环糊精或羟丙基 -β-环糊精制备的包合制剂可显著降低 现有紫杉醇制剂 （聚氧乙烯蓖麻油 /无水乙醇溶媒） 的心血管和呼吸系统毒 副作用。 研究还发现， 包合作用也可有效降低紫杉醇药物自身的副作用，
( USP 6218374; USP 5804568 )动物实验显示，使用羟丙基 -β-环糊精制备的 紫杉醇包合物注射剂相对乙醇溶解的紫杉醇制剂对注射部位的组织损伤降 低了 2/3。
采用环'糊精进行紫杉醇注射剂的改进研究已有多项技术发明， CN1589157 ( US2005009783 )公开了紫衫醇 /羟丙基 -β-环糊精组合物及其制 备方法， 该发明采用 45g羟丙基 -β-环糊精、 30mg紫衫醇、 100ml水的比例， 将紫衫醇溶解在乙醇中， 然后加入到羟丙基 -β-环糊精的水溶液中制备包合 物， 但是， 高达 1: 1500 的紫杉醇 /环糊精质量比使该技术难以用于临床； HU P9701945 使用较低比例的环糊精， 但是报道的增溶效果不显著； USP 6284746公开的实施例以紫衫醇 11.6 mg 与 2,6-二曱基 -β-环糊精 4g制备 的包合物， 紫衫醇增溶达到 0.9-1.0mg/ml ； USP5684169使用高比例的多种 环糊精加入大量不适合药物用途的如曱醇、 乙腈、 乙酸乙酯等有机溶剂。 HU71251 以多种环糊精 1-20倍摩尔比仅使紫衫醇增溶至 0.05mg/ml； HU65835 采用 20倍摩尔比 （约 31倍质量比） 的支链环糊精获得紫衫醇增溶 到约 0.32mg/ml 的效果。
尽管环糊精包合紫杉醇的研究十分活跃， 但是现在还没有环糊精包合 的紫杉醇制剂上市使用， 其中环糊精的安全性问题是主要原因之一， 目前已 被证明能够注射用的环糊精及环糊精衍生物仅有 α-环糊精、 羟丙基 -β-环糊 精和磺丁基 -β-环糊精 3 种（Expert Opin Drug Deliv, 2005 Mar;2(2): 335 - 51 ), 紫杉醇剂型改进研究中， 羟丙基 -β-环糊精研究较多， 而磺丁基 -β-环糊 精还没有研究报道， 其他环糊精由于还没有充分的安全性证据， 所以技术实 际应用难度较大。 目前已有技术的主要缺陷是： 制剂中紫杉醇溶解度低（环 糊精增溶效果不显著）、 药剂学稳定性较差稀释后即析出沉淀、 紫杉醇 /环糊 精比例过高、 残留高比例的有机溶剂、 使用环糊精浓度过大不能达到紫杉醇 制剂的基本要求等。选用性能优良的环糊精新品种并且开展包合技术的系统 研究是改变这种现状的希望所在。
发明内容
本发明的目的是： 克服现有技术中环糊精包合紫杉醇研究的种种困难， 包括：制剂中紫杉醇溶解度低；药剂学稳定性较差；紫杉醇 /环糊精比例过高； 残留高比例的有机溶剂等， 实现该领域内的技术突破， 提供一种紫杉醇溶解 度和药剂学稳定性都较高、 环糊精比例较低、有机溶剂残留低的环糊精紫杉 醇稳定包合物， 以实现临床使用。 本发明还将提供这种包合物的制备方法。
完成本发明的技术方案是:含有环糊精 /紫杉醇包合物的药物组合物 , 由 紫杉醇、 环糊精与药用辅料组成， 其中紫杉醇与环糊精的质量比为 1 ： 10 ~ 150, 所述的环糊精是： 羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺 丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精任意比例的混合物； 环糊精包合紫 杉醇的稳定常数 Ka - SSQeM-i MdM"1 。
对该包合态药物组合物的进一步限定，所述的含有环糊精 /紫杉醇包合物 的药物组合物， 是指用以下制备方法得到的组合物：
在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与 羟丙基-磺丁基 -β-环糊精的混合物的纯水溶液中， 搅拌下滴加紫杉醇的乙醇 溶液（或先将环糊精、 紫杉醇与纯水混合， 搅拌下緩慢滴加乙醇至体系完全 溶解， 是效果完全相同的等同步骤）；
体系溶解后以 0.2 ~ 0.4μηι微孔滤膜过滤；
滤液减压除乙醇， 得到的液体包合物； 或减压除乙醇后再减压除水， 干燥， 得到的固体包合物。
通过以上方法制备得到的含有环糊精 /紫杉醇包合物的药物组合物，其残 留的乙醇含量小于 2%。
本发明采用磺丁基 -β-环糊精或羟丙基-磺丁基 -β-环糊精在水溶液条件下 与加有适量乙醇的紫杉醇原料溶液混合， 加入的乙醇可促进包合作用， 生成 包合物后除去乙醇（乙醇残留量小于 2% ), 制得稳定的紫杉醇 /环糊精包合 物， 其包合物与常用药用辅料复合， 制备成为可临床使用的包合态药物组合 物， 从而提高紫杉醇的溶解度、 增加稳定性、 降低副作用， 获得具有临床应 用价值的紫杉醇产品。 制备包合物是本发明的技术关键。
目前已经上市且可用于注射用途的环糊精衍生物中，羟丙基 -β-环糊精是 非离子化的中性衍生物，磺丁基 -β-环糊精是离子化的衍生物， 其中药用的磺 丁基 _β_环糊精是 6~7取代的产物（SBE7-P-CD， 商品名 Captisol )。 大量研究 表明 （《药学前沿》， 中国医药科技出版社， 2001: 46-59 )， 磺丁基 -β-环糊精 在安全性， 稳定化， 药物增溶作用及生产制备技术等方面都具有更为显著的 提高， 其优点可以概括为： 高的水溶性（>50g/100g H2O ); 强的包合性能； 无药理活性； 对肾功能无影响； 可用于口服及非口服制剂； 低的 GMP生产 成本和更广的用途。 我们研制开发的羟丙基-磺丁基 -β-环糊精 ( HP-SBE-p-CD )是以羟丙基和磺丁基混合取代的新型环糊精衍生物（CN 1800221A ), 该产品具有优良的性能， 初步实验证明具有很高的安全性。 本 发明采用 （质量比 1: 10 ~ 150 )的磺丁基 -β-环糊精或羟丙基-磺丁基 -β-环糊 精改进紫杉醇制剂， 其中制得的低配比 1 ： 25 (质量比）包合物即可使紫杉 醇溶解度达 9 ~ 10 mg/ml, 固体包合物稀释 500倍以上皆能够稳定保存 12 小时以上， 且化学性质稳定、 药剂学稳定性高， 刺激性小， 具有重要应用价 值。
上述方案实现的关键、 也是本发明的第二发明任务的技术方案是： 含有 环糊精 /紫杉醇包合物的药物组合物的制备方法， 步骤如下，
在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与 羟丙基-磺丁基 -β-环糊精的混合物的纯水溶液中， 搅拌下滴加紫杉醇的乙醇 溶液（或先将环糊精、 紫杉醇与纯水混合， 搅拌下緩慢滴加乙醇至体系完全 溶解， 是效果完全相同的等同步骤)；
体系溶解后以 0.2 ~ 0.4μιη微孔滤膜过滤；
滤液减压除乙醇， 得到液体紫杉醇包合物；
或减压除乙醇后再减压除水， 干燥， 得到固体紫杉醇包合物。
所述的紫杉醇包合物中乙醇含量小于 2%。
更优化和更具体地说，本发明的含有环糊精 /紫杉醇包合物的药物组合物 的制备方法的具体步骤是：
用 1 ： 25 量比的紫杉醇 ： 环糊精比例配制环糊精的纯水溶液， 该溶 液是指： 羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精 与羟丙基-磺丁基 -β-环糊精的混合物与 2 ~ 10倍质量的纯水混合制成的溶液， 搅拌下緩慢加入比例紫杉醇与乙醇配制的溶液， 乙醇用量可以是紫杉醇等量 至 10倍质量以紫杉醇能够溶解为度， 加入紫杉醇时可室温也可在 25 - 65 °C 间加热搅拌， 搅拌加热生成包合物后， 以 0.2 ~ 0.4μιη 4敖孔滤膜过滤， 然后 减压尽量除去乙醇， 得到液体包合物， 或再继续减压除水至尽， 减压真空干 燥后得固体包合物。 本发明制备的固体包合物水溶性高， 易于溶解而不需加入其他助溶剂， 配制的水溶液溶血副作用小， 适宜临床使用。 含有临床给药剂量 30mg紫杉 醇的固体包合物加注射用生理盐水稀释 10-500倍配制成溶液后数天内皆能 够保持稳定。
该固体包合物与常用的含有可注射的药用辅料溶液稀释到适当浓度经 灭菌处理后， 所得的組合物溶液可供注射使用。
包合作用的 ¾r证：
D20为溶剂的磺丁基 -β-环糊精原料与包合物 H,C-COSY ( 13C， lR相关 谱）对照结果， 包合物中环糊精葡糖环内的 H-3和 H-5质子（δ4.1〜3.4 ) 明 显移向高场（附图 1 ),表明紫杉醇分子的苯甲酰基侧链基团被包合进入环糊 精。
紫外光谱实验发现， 水溶液中， 紫杉醇的紫外吸收随环糊精（环糊精自 身无吸收）浓度的变化而发生改变（附图 2 )。
环糊精结构特征是具有高电子密度的疏水空腔（《环糊精化学》， 科学出 版社 2001， P135 ), 进入疏水空腔（包合） 的药物分子发色团 （如苯基） 的 π电子跃迁受环糊精疏水空腔高电子密度的诱导发生改变而引起紫外光 i普的 变化， 测定体系紫外吸收是判断包合作用的有效方法。 紫杉醇紫外吸收随环 糊精浓度的增大而明显增强，说明紫杉醇与本发明使用的环糊精存在明显而 强的包合作用。
包合稳定常数的测定：
包合稳定常数 Ka是包合作用程度的量度， 紫外分光光度法是测定 Ka 的常用方法。 改变环糊精浓度（环糊精自身无吸收）浓度恒定的紫杉醇溶液 紫外吸收呈现规律性变化， 从而获得环糊精浓度 ( C )与紫外吸光度 ( A ) 的关系， 由 1/ C与 1/A关系曲线可定量计算出环糊精 /紫杉醇的表观一级包 合稳定常数 Ka， 同时实验测定了加入乙醇对 Ka的影响变化， 各种环糊精的 Ka见表 1， 表 1 紫杉醇 /环糊精的表观一级包合稳定常数 Ka CM"1; 234nm)
Ka
环糊精 -
¾0 60% EtOH
磺丁基 -β-环糊精 5396 9367
羟丙基-磺丁基 -β-环糊精 14121 19722
羟丙基 -β-环糊精 1325 4646
β-环糊精 413 结果显示， 本发明使用的环糊精具有较大的包合常数 Ka， 而且乙醇的 存在显著提高了 Ka值（增强环糊精的包合能力）因而具有促进包合的作用， 而不仅仅是助溶剂。 一般情况下， 有机溶剂与药物竟争包合， 乙醇通常表现 为降^ ^药物 Ka的效应。 与羟丙基 -β-环糊精不同， 由于純水条件下本发明使 用的环糊精包合紫杉醇仍然具有较大的 Ka , 足以生成稳定的包合物， 因而 本发明在包合物形成后将乙醇尽量去除， 以获得较纯净的药物包合物， 尽可 能降低乙醇对药物产生的影响。利用乙醇对紫杉醇包合作用的影响制备包合 物是本发明成功的技术基础。
包合物制备及
采用加入适量乙醇使包合充分以后，再减压除去经干燥制备了多种比例 的磺丁基 -β-环糊精 /紫杉醇， 羟丙基-礅丁基 -β-环糊精 /紫杉醇， 磺丁基 -β-环 糊精与羟丙基-磺丁基 -β-环糊精的混合物 /紫杉醇的固体包合物， DTA实验证 实固体物为包合物而非简单的物理混合物。 以磺丁基 -β-环糊精 /紫杉醇（质 量比 25 ： 1 )为例分析说明：
称取紫杉醇、磺丁基 -β-环糊精、 紫杉醇与磺丁基 -β-环糊精物理混合物、 包合物共四种样品各约 5.0mg， 进行差示扫描热分析： A1203参比， 量程 ±50μν, 升温范围 30°C ~ 400°C， 升温速率 10°C/min, 得 DTA图谱。 结果表 明： 紫杉醇在 240°C有一熔融峰（分解）； 环糊精在 70-90°C和 250-270°C处 也各分别为脱水吸热峰和相变峰， 约 360 °C为熔融分解峰。 物理混合物保持 了环糊精和紫杉醇的吸热峰特征， 而包合物图谱上， 脱水吸热峰显著减弱， 相变峰基本消失， 其他各峰的位置（温度）和形状（热效应）都发生了明显 变化， 因此说明包合物已形成。
包合物中的残留乙醇：
包合物 iHNMR显示微弱的乙醇甲基峰，由乙醇曱基峰（t ,δ= 1.10941 ) 与环糊精特征峰（H-1峰， d,8= 5.18258-5.05405 )的积分面积比计算出多批 制备包合物中的乙醇残留量（％)， 结果见表 2， 紫杉醇 /环糊精固体包合物中乙醇残留量
包合物批号 环糊精 * 药物 /环糊精比 乙醇残留量（％)
20060128 a 1 : 50 0.43
20060131 b 1 : 50 0.51
20060306 a 1 : 30 0.37
20060318 b 1 : 30 0.22
20060608 b 1 : 25 0.21
20060629 a 1 : 25 0.27
20060730 a + b 1： 25: 25 0.37 20060812 b 1： 100 1.26
*: a=磺丁基 -β-环糊精; b =羟丙基-磺丁基 -β-环糊精
实验证明， 本发明技术制备过程中虽然使用较多乙醇， 但经纯化处理后 乙醇残留很少， 低比例环糊精（1 ： 50以下）制备的包合物中乙醇残留一般 低于 1.0%; 较大比例环糊精制备包合物也仅有不足 2.0% 的乙醇残留。挥发 性、 刺激性强的乙醇残留量的大幅降低， 为提高紫杉醇制剂稳定性、 降低刺 激等副作用提供了有利保障。
包合增溶试验：
标准曲线： 以乙醇溶液配制 0.225mg/ml 的紫杉醇母液， 纯净水稀释成 0.25 g/ml ~ 2.25 g/ml系列溶液， 234nm下测定紫外吸收 A, 以 A对浓度 C ( mg/ml )作图得标准曲线（A= 393.2C-0.0123; r =0.9998 λ
用纯净水配制不同 ％ 浓度的环糊精溶液， 加入紫杉醇原料药， 于 25°C士 1°C振荡 72h，过滤，静置，定量移取适量的滤液，纯净水稀释，于 234nm 处测定紫外吸收， 由标准曲线得紫杉醇溶解度， 见表 3
表 3 紫杉醇在环糊精溶液中的溶解度
环糊精 * (浓度％) 溶解度（mg/ml) 增溶倍数
0 0.000589 1 a ( 25 ) 9.324 15540 a ( 31 ) 10.182 16971 b ( 31 ) 11.177 18629
*: a =磺丁基 -β-环糊精; b =羟丙基-磺丁基 -β-环糊精 由于高浓度环糊精溶液（>50% )增溶作用虽强， 但基本无实际使用价 值， 因此， 进行了 31% 以下浓度环糊精水溶液的增溶试验， 结果显示， 本 发明使用的环糊精对紫杉醇有极强的增溶作用。
样品稳定性：
药物组合物的稳定性包括药物的化学稳定性及組合物的药剂学稳定性 质， 是药物組合物得以应用的基本要素。
固体包合物稳定性
HPLC法色谱条件： 色谱柱008€18 (250 11111^ 4.6醒)； 流动相， 曱醇: 水:乙腈 (20： 30： 50); 流速 l.O ml/min; 检测波长 228nm; 测定时间： 30.00 分钟； 检测灵敏度 1.0000AUFS。
样品：紫杉醇原料；紫杉醇 /磺丁基 -β-环糊精包合物 ,质量比 1： 25 ) ; 紫杉醇 /羟丙基-磺丁基 -β-环糊精包合物（b，质量比 1： 25 )
取紫杉醇原料和包合物若干， 均分 3份为试验样品， 分别进行光照、 高 温和高湿度加速试验：
1 ) 光照试验 样品置于透明密封容器中， 放在装有日光灯的光照箱内， 在 4500 ±500LX光照度的条件下放置 5天，取样检查分析， 结果与 0天样品 比较。
2 ) 高温试验 样品分别置于密封洁净容器中， 在 60°C的温度下放置 5天， 取样检查分析， 结果与 0天样品比较。
3 ) 高湿度试验 样品分别置于恒湿密闭器 中于 25°C、 相对湿度 90士 5% 条件下放置 5天， 取样检查分析， 结果与 0天样品比较。
HPLC测定图例见附图 3, 附图 4, 各试验结果见表 4,
表 4 5天加速试验的样品含量测定结果
样 品 含 量（％) 0天 光照 1¾温 高湿 紫杉醇原料 99.748 90.346 91.569 89.336 包合物 a 99,746 97.035 96.476 96.141 包合物 b 99,736 96.786 97.255 96.022 加速试验条件下， 紫杉醇原料颜色略变深， 含量下降较明显； 包合物外观颜 色无改变， 含量降低很少， 杂质基本无变化。 结果显示， 固体包合物中紫杉 醇化学性质稳定， 包合技术对提高紫杉醇稳定性效果明显。
包合物溶液及药物稳定性
(1) 溶液稳定性 质量比 1:25 固体包合物分别用生理盐水、 等渗葡 糖液配制成含紫杉醇 10mg/ml的溶液， 再稀释 1 1000倍， 灭菌处理制成不 同浓度注射液、 连续观察 5 小时 ~ 10天， 其中对紫杉醇 /羟丙基-磺丁基 -β- 环糊精包合物的生理盐水稀释体系的稳定性观察试验结果见表 5，
表 5 环糊精包合紫杉醇注射液的溶液状态 药物浓度 溶液状态 *
稀释倍数 ： mg/ml
0小时 5小时 10小时 15小时 20小时 2天 4天 6天 10天
1倍 5.00 + + + + + - - - -
10倍 1.00 + + + + + + + + +
20倍 0.50 + + + + + + + + +
50倍 0.20 + + + + + + + + +
100倍 0.10 + + + + + + + + +
500倍 0.02 + + + + + + + + +
1000倍 0.01 + + + + + + + + +
* +： 澄清无沉淀 ； - ： 产生沉淀或浑浊
( 2 ) 溶液中的紫杉醇稳定性试验（含量测定）
采用上述相同的样品和 HPLC 色谱条件，取紫杉醇原料和包合物若干, 用流动相（pH = 6.50 )溶解， 超声 30分钟后稀释 100倍， 静置， 分别于 0、 2、
4、 6、 8 小时取样测定 HPLC谱,
表 6 含水溶液中样品含量随时间的变化
含 量（％)
样 品
0小时 2小时 4小时 6小时 8小时 紫杉醇原料 99.745 99.700 99.577 99.648 99.608 包合物 a 99.736 99.740 99.717 99.687 99.702 包合物 b 99.748 99.718 99.630 99.627 99.605 各样品在含水溶液中， 化学性质稳定， 含量基本不变。
溶血作用试险：
(参考文献： 国家食品药品监督管理局 《化学药物刺激性、 过敏性和溶 血性研究技术指导原则》， 2005, 3, 18; 国家药品监督管理局 《中药注射剂 研究的技术要求》， 1999， 11 , 12 )
包合物生理盐水配制的溶液的溶血性与现有紫杉醇制剂对比具显著差 异。 固体包合物稀释的溶液溶血作用轻微； 现有紫杉醇制剂稀释至临床给药 0.06mg/ml的 浓度条件下溶血作用仍然达 15% , 结果见附图 5 。 体内抑瘤作用：
20±2g雄性昆明小鼠右腋窝皮下接种 lxl07/ml S18。细胞 0.2ml (2xl06 个细胞)实体瘤模型， 紫杉醇及紫杉醇 /环糊精包合物样品溶液腹腔给药 7天， 实验条件下， 紫杉醇 /环糊精包合物 5mg/kg剂量抑瘤率 94.69% 明显高于未 包合的紫杉醇（抑瘤率 82.77% ) ； 紫杉醇及紫杉醇 /环糊精包合物对动物体 重均有降低， 但紫杉醇组体重降低大于包合物组， 结果提示， 紫杉醇包合后 抑瘤活性增强而毒副作用得到降低。 本发明的优点：
包合物显著提高了紫杉醇溶解度（达 10mg/ml以上）， 溶液稀释后能够 长时间保持清澈稳定， 且溶血作用低、 毒副作用小， 药物活性好。
紫杉醇与环糊精包合后，固态、液态样品含量稳定，药物 /环糊精比例小、 制剂中环糊精用量低， 适宜用于临床。
本发明的包合物有机溶剂残留少， 有利于提高用药安全性。
制备方法简单、 操作简便、 成本低且无环境污染。 包合物性质稳定、 与 其他药用辅料相容性好， 便于制剂的制备。
包合物制备的注射液无腐蚀性成分、无毒害，临床使用方便、实用性强。 附图说明
图 1:摩尔比 1 : 9紫杉醇 /磺丁基 -β-环糊精包合物 H,C-COSY (溶剂 D20, δ4. 3.4部分）；
图 2:水溶液中不同羟丙基-磺丁基 -β-环糊精浓度下的紫杉醇紫外吸收扫 描图 （210nm ~ 296nm );
图 3: 紫杉醇 /羟丙基-磺丁基 -β-环糊精包合物高温试验（ 5天）的 HPLC 色谱图；
图 4: 紫杉醇原料高温试验（ 5天）的 HPLC色谱图；
图 5:市售紫杉醇制剂、紫杉醇 /羟丙基-横丁基 -β-环糊精（HP-SBE-P-CD ) 包合物、 紫杉醇 /磺丁基 -β-环糊精（SBE-P-CD )包合物生理盐水稀释的溶液， 紫杉醇浓度-溶血作用曲线图。
具体实施方式
实施例 1: 将 3g羟丙基-磺丁基 -β-环糊精与 6ml纯水混合， 搅拌下緩慢 滴加 120 mg紫杉醇与 3ml乙醇配制的溶液，充分混合搅拌至体系完全溶解， 以 0,2 ~ 0.4μπι 孔滤膜过滤， 滤液 65。C下减压蒸除乙醇， 灭菌处理后减压 蒸除水分至干， 固体物继续减压干燥 48小时， 即得白色固体包合物。 其各 种参数请参照图 1〜图 5。
上述粉状包合物 780 mg (含紫杉醇 30mg )与 250 ml 注射用生理盐水 混合即溶解成为液态包合组合物， 该溶液可方便用于注射。
实施例 2: 与实施例 1基本相同， 但其中的羟丙基-磺丁基 -β-环糊精为
4.5g与 15ml纯水混合， 紫杉醇为 30 mg。
实施例 3: 与实施例 1基本相同， 但其中的紫杉醇为 300 mg。
实施例 4:与实施例 1基本相同，但其中的环糊精采用磺丁基 -β-环糊精。 实施例 5:与实施例 2基本相同，但其中的环糊精采用磺丁基 -β-环糊精。 实施例 6:与实施例 3基本相同，但其中的环糊精采用磺丁基 -β-环糊精。 实施例 7: 与实施例 1基本相同， 但其中的环糊精采用磺丁基 -β-环糊精 与羟丙基- 于基 -β-环糊精质量比 1 ： 1的混合物。
实施例 8: 与实施例 2基本相同， 但其中的环糊精采用磺丁基 -β-环糊精 与羟丙基-横丁基 -β-环糊精质量比 1 ： 50的混合物。
实施例 9: 与实施例 3基本相同， 但其中的环糊精采用磺丁基 -β-环糊精 与羟丙基-續丁基 -β-环糊精质量比 50 ： 1的混合物。 - 实施例 10: 与实施例 1基本相同， 但先将环糊精、 紫杉醇与 6ml纯水 混合， 搅拌下緩慢滴加乙醇至体系完全溶解。
实施例 11 : 与实施例 1基本相同，但得到的粉状包合物用等渗浓度 ¾葡 萄糖注射液稀释。 实施例 1'2: 与实施例 1基本相同，但得到的粉状包合物用等渗浓度的杲 糖注射液稀释。

Claims

权 利 要 求 书
1、 一种含有环糊精 /紫杉醇包合物的药物组合物， 由紫杉醇、 环糊精与 药用辅料组成， 其中紫杉醇与环糊精的质量比为 1 ： 10 ~ 150, 所述的环糊 精是： 羟丙基-磺丁基爷环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与 羟丙基-磺丁基 -β-环糊精任意比例的混合物； 环糊精包合紫杉醇的稳定常数 Ka = 5396M -1〜 14121Μ·1 。
2、 按照权利要求 1所述的含有环糊精 /紫杉醇包合物的药物组合物， 其 特征在于，所述的含有环糊精 /紫杉醇包合物的药物组合物，是指用以下制备 方法得到的组合物： 在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺 丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精的混合物的纯水溶液中 , 搅拌下滴 加紫杉醇的乙醇溶液， 体系溶解后以 0.2 ~ 0.4μηι微孔滤膜过滤， 滤液减压 除乙醇， 然后再减压除水， 干燥， 得到的固体包合物， 或减压除乙醇后得到 的液体包合物。
3、按照权利要求 1或 2所述的含有环糊精 /紫杉醇包合物的药物组合物， 其特征在于， .所述的包合物中乙醇含量小于 2% 。
4、 一种权利要求 1所述的含有环糊精 /紫杉醇包合物的药物组合物的制 备方法， 步骤如下， 在羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺 丁基 -β-环糊精与羟丙基-磺丁基 -β-环糊精的混合物的純水溶液中， 搅拌下滴 加紫杉醇的乙醇溶液；
体系溶解后以 0.2 ~ 0.4μιη微孔滤膜过滤， 滤液减压除乙醇， 得到液体 包合物， 或减压除乙醇后再减压除水， 干燥， 得到的固体包合物； 所得的包 合物中乙醇含量不高于 2%。
5、 按照权利要求 4所述的含有环糊精 /紫杉醇包合物的药物組合物的制 备方法， 其特征在于， 具体步骤是：
用 1 ： 25质量比的紫杉醇 .· 环糊精配制环糊精的纯水溶液， 该溶液是 指： 羟丙基-磺丁基 -β-环糊精， 或磺丁基 -β-环糊精， 或磺丁基 -β-环糊精与羟 丙基-磺丁基 -β-环糊精的混合物与 2 ~ 10倍质量的纯水混合制成的溶液， 搅 拌下緩慢加入比例紫杉醇与可溶解紫杉醇的适量乙醇配制的溶液，加入紫杉 醇时在室温或在 25 ~ 65°C间加热搅拌， 搅拌加热生成包合物后， 以 0.2 ~ 0.4μηι £孔滤膜过滤， 然后减压尽量除去乙醇， 得到液体包合物， 或再继续 减压除水至尽， 减压真空干燥后得固体包合物。
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