WO2015042759A1 - Carboxyméthyl-hydroxypropyl-β-cyclodextrine et son procédé de préparation - Google Patents

Carboxyméthyl-hydroxypropyl-β-cyclodextrine et son procédé de préparation Download PDF

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WO2015042759A1
WO2015042759A1 PCT/CN2013/001333 CN2013001333W WO2015042759A1 WO 2015042759 A1 WO2015042759 A1 WO 2015042759A1 CN 2013001333 W CN2013001333 W CN 2013001333W WO 2015042759 A1 WO2015042759 A1 WO 2015042759A1
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cyclodextrin
hydroxypropyl
carboxymethyl
substitution
product
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PCT/CN2013/001333
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English (en)
Chinese (zh)
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任勇
孙海松
余书勤
张列峰
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南京师范大学
南京仙巨生物技术有限公司
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    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Definitions

  • the present invention relates to a carboxy-methyl and hydroxypropyl mixed-substituted oxime-cyclodextrin derivative carboxymethyl group for pharmaceutical excipients. - Hydroxypropyl cyclodextrin and a process for its preparation. Background technique
  • ⁇ -cyclodextrin is a cyclic oligo natural product obtained by cyclization of cyclodextrin glucan transposase to obtain a cyclic oligosaccharide.
  • the molecules are connected by a glycoside bond to form a frustoconical body having a hollow inner cavity, and 21 hydroxyl groups are distributed around the periphery of the pyramid cavity. Its hydrophobic and extracellular hydrophilic properties make it possible for 3-CD to form a supramolecular (compound) with weak organic molecules.
  • Organic small molecules have improved physical and chemical properties due to the formation of supramolecules, and have high research and application value in agricultural, pharmaceutical, food and cosmetic applications.
  • P-CD solubility of P-CD is small (1.85%), which affects the ability of inclusion and solubilization. It has obvious nephrotoxicity in parenteral administration and has strong hemolysis effect. It is only suitable for oral administration and cannot be used for parenteral administration. Therefore, it is important to modify the ⁇ -CD structure to create new derivatives, improve the solubility and enhance the inclusion ability, and reduce the hemolysis.
  • the pharmaceutically acceptable cyclodextrin derivative must have good water solubility, low hemolytic activity, low toxicity, and inclusion of solubilizing ability. Studies have shown that both hydrophilic hydroxypropyl and sulfobutyl groups are good substituents for the modification of ⁇ -CD, and the derivatives thus prepared are hydroxypropyl- ⁇ -cyclodextrin ( ⁇ - ⁇ -CD) and sulfonate. Butyl- ⁇ -cyclodextrin (SBE--CD) has become a commonly used medicinal cyclodextrin and is widely used in the pharmaceutical and food industries. Carboxymethyl- ⁇ -cyclodextrin (CM-p-CD) is commercially available as a commercially available product, but there are currently no large industrial applications.
  • M 1149 ⁇ nysg-moi 1 )
  • the drug-loading efficiency is high, but the hemolysis effect of the aqueous solution is obvious and the irritating effect is strong
  • the sulfobutyl-e-cyclodextrin is insoluble in the organic solvent, and the molecular weight is relatively high.
  • the drug-loading efficiency is low
  • substituents can significantly enhance the solubility and inclusion capacity of ⁇ -CD derivatives.
  • the change in the type of substituents has little effect on the solubility properties, but the change in inclusion ability and hemolysis
  • the impact is more complicated, and the inclusion ability is related to the type of substituent (including the structure of the material), and also closely related to the structure and functional group type of the encapsulated drug molecule; the change of hemolysis depends on the type of substituent.
  • ⁇ - ⁇ -CD is less hemolytic than maternal ⁇ -CD, and has little change in hemolysis in the wider DS range (2-10).
  • the hemolytic effect of SBE-P-CD decreased significantly and fluctuated greatly with the change of DS.
  • the increase of DS was beneficial to reduce hemolysis.
  • the carboxymethyl group can reduce the hemolysis of the product, and the relationship between DS and hemolysis is still unclear. Although the low concentration shows significant hemolysis, it has lower hemolytic properties than HP- ⁇ -CD at high concentrations.
  • the molecular weight of pharmaceutically acceptable cyclodextrin derivatives is also an important factor that must be considered in practical applications.
  • an excessively large molecular weight will make the amount of prescription excipients too high, and the effect of the actual function of the cyclodextrin product becomes an important reason for limiting its practicability.
  • the design and preparation of lower molecular weight cyclodextrin derivatives is not only of great significance, but also one of the technical difficulties in the development of pharmaceutical cyclodextrins. Summary of the invention
  • the technical problem to be solved by the present invention is to improve the water solubility of ⁇ -cyclodextrin and to prepare a ⁇ -cyclodextrin derivative which is safe, effective and has a relatively low molecular weight.
  • the technical method is to introduce two smaller hydrophilic substituents in the ⁇ -cyclodextrin precursor to improve the performance of ⁇ -cyclodextrin, improve product safety, and enhance product practicability.
  • the technical solution of the present invention is:
  • the carboxymethyl-hydroxypropyl-e-cyclodextrin described in the present invention contains a plurality of compounds of the above molecular structure.
  • CH 2 CH(OH)CH 3 , H" means that when R ⁇ OR is CH 2 COO-X, among the 7 R 3 groups in the above structural formula, part of the R 3 group is CH 2 CH(OH CH 3 , another part of the R 3 group is H. The rest of the similar expressions are all this.
  • Carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin can be represented by CMn-HPm-p-CD, the structure of which is carboxymethyl (-CH2COO-X) and 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ) are ether bond-substituted derivatives formed by simultaneous attachment to a cyclodextrin precursor, ie, the cyclodextrin derivative has both a carboxyl group Base and hydroxypropyl two substituent groups.
  • the average number of substituents per mole of ⁇ -cyclodextrin is the average degree of substitution (DS): ⁇ carboxymethyl and m hydroxypropyl.
  • n is the average degree of substitution of carboxymethyl groups
  • m + n - Z is the total average degree of substitution; the mixed substituted product must be nl and ml.
  • the substitution position of the hydroxypropyl or carboxymethyl group of the product is randomly substituted. Derivative of cyclodextrin at position 2, or position 3 or position 6.
  • Carboxymethyl and hydroxypropyl mixed substituted cyclodextrin derivatives abbreviation: carboxymethyl-hydroxypropyl-e-cyclodextrin ), not hydroxypropyl-cyclodextrin and carboxymethyl- a simple mixture of both ⁇ -cyclodextrin.
  • the average degree of substitution n and tn represented by the structural characteristics of the cyclodextrin derivative also contain the actual average value within ⁇ 0.5, and the average degree of substitution for each of the optional derivatives is
  • the carboxymethyl-hydroxypropyl-e-cyclodextrin designed by the present invention is ⁇ -cyclodextrin, ethyl chloroacetate It is prepared by using 1,2-epoxypropionam as a raw material, adding ⁇ -cyclodextrin and a catalytic amount of alkali in water, and adding ethyl chloroacetate and 1,2-epoxypropanoid dropwise after stirring at an appropriate temperature. After purification, a series of designs CMn-HPm-P-CDo can be obtained.
  • the product with the desired degree of substitution can be obtained: with the increase of the reagent ratio, the degree of product substitution. That is to say, it is continuously improved, and the ratio of substitution of reagents is also reduced.
  • the reagent charge can be obtained by adding 2.0 times the molar amount of ethyl chloroacetate (relative to cyclodextrin) and 1.5 times or more by mole of 1,2-epoxypropane.
  • a mixed substitution product of m ⁇ l; a molar amount of 7 times cyclodextrin plus 2 times of ethyl chloroacetate reagent (molar) is the total amount of catalyst base.
  • the present invention provides a preparation method of the above carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin, which is prepared by a method of base-catalyzed continuous reaction, and the specific reaction step is one of the following two schemes: 1: Take ⁇ -cyclodextrin and add 2.2 times mass of water and 7.0 times molar amount of base to 0-cyclodextrin, stir to dissolve, and add 7.0 times molar amount of 1,2-epoxypropane to react at room temperature.
  • the parent cyclodextrin is used as a raw material, and the reaction intermediate is mixed and replaced by a continuous feeding reaction step without separation.
  • the present invention provides the pharmaceutical use of any of the above carboxymethyl-hydroxypropyl cyclodextrin, comprising the pharmaceutically acceptable form of carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin
  • the agent is applied to a composition comprising an active molecule preparation.
  • the present invention provides the above oral preparation product containing the carboxymethyl-hydroxypropyl-3-cyclodextrin composition for therapeutic or health care use.
  • the present invention provides a composition of the above carboxymethyl-hydroxypropyl cyclodextrin for use as a non-oral preparation product for therapeutic or health care purposes.
  • the present invention provides the use of any of the above carboxymethyl-hydroxypropyl cyclodextrin as a pharmaceutical adjuvant.
  • the hemolytic effect of the synthesized carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin of the invention is significantly lower than that of the corresponding monosubstituted derivatives ⁇ - ⁇ -CD and CM-p-CD, with low hemolysis rate and substantially no toxicity. . No harmful residues, the product is safe. Not only the product itself has a small hemolysis effect, but also can significantly reduce the hemolysis rate of the encapsulated drug and improve the safety of administration.
  • the product has excellent solubility, solubility in water is 50%, and organic solvent also shows good solubility. It has laid a material foundation for improving the solubility of poorly soluble drugs by inclusion technology, and has a broad prospect in the application of poorly soluble pharmaceutical preparations.
  • the product of the invention has the appropriate ability to contain drugs, and has good inclusion properties for various types of drugs, including polypeptide macromolecules. It has important application value for improving drug solubility, enhancing absorption and improving bioavailability.
  • the carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin prepared by the invention has a moderate average molecular weight, which is equivalent to the molecular weight of the existing product ⁇ - ⁇ -CD, but the hemolytic effect is significantly lower than that of ⁇ - ⁇ -CD, thereby The application feasibility of the product of the invention is greatly improved.
  • the preparation and analysis method of the invention is simple, the preparation yield is high, and the quality is stable.
  • the product of the series was prepared in a weight yield of 100%. Further, the preparation method of the present invention is easy to obtain (commercially available p-CD, 1,2-propylene oxide, ethyl chloroacetate), and the production cost is low. In the preparation process, the feed ratio can be adjusted to obtain the Products that need to be replaced.
  • the product of the invention has stable properties, no toxicity, no flammable and explosive characteristics, no environmental pollution, no deterioration, easy storage and easy transportation.
  • Figure 6 Product differential thermogram: a: ⁇ -CD; b: ⁇ - ⁇ -CD; c: CM-P-CD; d: HP-p-CD/p-CD/CM-p-CD E; CM 2 -HP 6 - -CD
  • Figure 7 HPLC chromatogram of product
  • Figure 8 HPLC chromatogram of three physical mixtures of p-CD, CM-p-CD and ⁇ - ⁇ -CD
  • Figure 9 Artemisinin , CM 3 -HP 6 -p-CD, artemisinin and CM 3 -HP 6 -p-CD physical mixture, CM 3 -HP 6 -P-CD / artemisinin inclusion complex four samples comparison DTA map: a : artemisinin; b: CM 3 -HP 6 -p-CD ; c: artemisinin / CM 3 -HP 6 -p_CD physical mixture; d: CM 3 -HP 6 -P-CD / artemisinin inclusion
  • a three-neck round bottom flask was equipped with a constant pressure funnel, a reflux condenser, and a thermometer. 50 ml of purified water was added thereto, and stirring was started. Then, 0.02 ⁇ 1 ⁇ -cyclodextrin (22.7 g) and 0.3 mol of solid NaOH (12.0) were slowly added thereto with stirring. g), after the system is dissolved, slowly heat, keep 80 ° C, then slowly add 0.08 mol of ethyl chloroacetate (9.8 g), add about 4 h, continue to stir and reflux for 2 h and then cool to room temperature.
  • DTA spectrum 95 'C dehydration endothermic peak, 270 ° C melting point, 300 ⁇ 335 ° C exothermic decomposition.
  • Example 4 It was basically the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate, and 1,2-epoxypropionam were 0.22, 0.04, and 0.05 mol, respectively. The final product yield was 98.5%. The average degree of substitution of carboxymethyl group was 1.2 by 1 H NMR, and the average degree of substitution of hydroxypropyl group was 1.8. The product was abbreviated as CM!-HPz-p-CDa. Example 4
  • Example 2 Basically the same as in Example 1, except that the amounts of NaOH, ethyl chloroacetate, and 1,2-epoxypropionam were 0.22, 0.04, and 0.08 mol, respectively.
  • the yield of the final product was 99.1%.
  • the average degree of substitution of the carboxymethyl group was 1.1 by the 1 H NMR, and the average degree of substitution of the hydroxypropyl group was 3.4.
  • the product was abbreviated as CM!-HPHi-CDa.
  • Example 2 The same as Example 1, except that the amounts of NaOH, ethyl chloroacetate, and 1,2-epoxypropionam were 0.26, 0.06, and 0.06 mol, respectively.
  • the yield of the final product was 100.7%.
  • the average degree of substitution of carboxymethyl group was 1.9 by 1 H NMR, and the average degree of substitution of hydroxypropyl group was 2.2.
  • the product was abbreviated as CM 2 -HPH3-CD.
  • Example 8 the product of potassium salt
  • Example 2 It was basically the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate, and 1,2-epoxypropionam were 0.22, 0.04, and 0.12 mol, respectively.
  • the yield of the product was 106.2%.
  • the average degree of substitution of the carboxymethyl group was 1.3 by the 1 H NMR, and the average degree of substitution of the hydroxypropyl group was 4.6.
  • the product was abbreviated as CMi-HPs-P-CDn.
  • the yield was 110.9%, the average degree of substitution of carboxymethyl group was 2.9 by 1 H NMR, and the average degree of substitution of hydroxypropyl group was 2.8.
  • the product was abbreviated as CM 3 -HP 3 -P-CD.
  • Example 10 was substantially the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate and 1,2-propylene oxide were 0.26, 0.06, and 0.11 mol, respectively.
  • Example 11 is basically the same as Example 1, except that NaOH is changed to KOH, and the amounts of KOH, ethyl chloroacetate, and 1,2-epoxypropionam are 0.62, 0.24, and 0.08 mol, respectively.
  • the product (X K, hydrazine), yield 119.9%, the average degree of substitution of carboxymethyl groups was 5.7 by 1 H NMR, and the average degree of substitution of hydroxypropyl groups was 3.2.
  • Example 12 was substantially the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate, and 1,2-propylene oxide were 0.22, 0.04, and 0.03 mol, respectively.
  • the yield of the product was 93.4%.
  • the average degree of substitution of the carboxymethyl group was 1.4 by the 1 H NMR, and the average degree of substitution of the hydroxypropyl group was 1.3.
  • the product was abbreviated as CMT-HP!-P-CDa.
  • Example 13 was basically the same as Example 1. However, the amounts of NaOH, ethyl chloroacetate and 1,2-epoxypropanone were 0.5, 0.18 and 0.13 mol, respectively.
  • Example 14 was basically the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate and 1,2-propylene oxide were 0.7, 0.24, and 0.03 mol, respectively.
  • the final yield of the product was 113.8%.
  • the average degree of substitution of the carboxymethyl group was 5.6 by 1 H NMR, and the average degree of substitution of the hydroxypropyl group was 1.3.
  • the product was abbreviated as CM 6 -HP ⁇ -CD.
  • Example 15 was substantially the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate and 1,2-propylene oxide were 0.26, 0.06, and 0.10 mol, respectively.
  • the final yield of the product was 108.7%.
  • the average degree of substitution of the carboxymethyl group was 1.8 by the 1 H NMR, and the average degree of substitution of the hydroxypropyl group was 3.9.
  • the product was abbreviated as CM 2 -HP 4 -P-CD.
  • Example 16 was substantially the same as Example 1, except that the amounts of NaOH, ethyl chloroacetate, and 1,2-epoxypropionam were 0.45, 0.15, and 0.03 mol, respectively.
  • the yield of the final product was 105.4%.
  • the average substitution degree of carboxymethyl group was 3.8 by 1 H NMR, and the average degree of substitution of hydroxypropyl group was 1.3.
  • the product was abbreviated as
  • Example 17 Inclusion of a product with artemisinin and preparation of a clathrate.
  • CM-p-CD ⁇ 0.0102 ⁇ + 9.5804 0.9957 939.2
  • CM 3 -HP 6 - -CD ⁇ - 0.0069 ⁇ + 10.667 0.9934 1545.9
  • the inclusion constant Ka determination results show that the inclusion ability of CM 3 -HP 6 -P-CD for artemisinin is significantly stronger than the existing product ⁇ - ⁇ - CD and CM-p-CD, CM-HP-p-CD binary substituted cyclodextrin derivatives facilitate drug inclusion, and the corresponding drug inclusion complexes are more stable and easier to manufacture.
  • 10 g of CM 3 -HPH3-CD and 1.70 g of artemisinin were accurately weighed, mixed with an appropriate amount of pure water for 3 hours, and dried under reduced pressure at 50 ° C to obtain a white solid clathrate (molar ratio of 1:1). Take artemisinin, CM 3 -HP 6 -P-CD, artemisinin and CM 3 -HP 6 -P-CD physical mixture,
  • CM 3 -HPH3-CD/artemisinin inclusion complex four samples each about 5.0mg, for differential scanning thermal analysis: ⁇ 1 2 ⁇ 3 reference, range ⁇ 50 ⁇ , temperature range 40 ° C ⁇ 400 ° C, heating rate At 10 ° C / min, the DTA map was obtained (Fig. 9).
  • Solubility determination Artemisinin, artemisinin/HP-p-CD inclusion complex (prepared by the same method, molar ratio 1: 1.16), CM 3 -HP 6 -P-CD/artemisinin inclusion complex Molar ratio 1: 1 ) The solubility of the sample was measured at 25 ° C. Results: Artemisinin Ol lmg'ml- ⁇ CM 3 -HP 6 -P_CD inclusion complex l.OSmg'ml- ⁇ - ⁇ -CD inclusion complex 0.53 Mg'm, CM 3 -HP 6 -p-CD increased the solubility of artemisinin by 9.55 times, while ⁇ - ⁇ -CD only increased the solubility by 4.81 times.
  • the iHNMR spectrum shows: due to the influence of the substituent, the proton of the cyclodextrin glucose ring in the product structure
  • the displacements are interlaced to form a set of multiple peaks (similar to the ⁇ - ⁇ -CD spectrum), rather than as clear and easy to distinguish as ⁇ -CD, the -dH proton of the glucose ring is also superimposed by the doublet in ⁇ -CD.
  • CM 2 -HP 3 -P-CD sample was weighed and mixed with the ganciclovir bulk drug 1.0 g, and added to 4 ml of water for 0.5 h, and then dried under reduced pressure at 45 Torr to obtain 1 g of a powdery product.
  • Weigh the appropriate amount of ganciclovir inclusion compound dissolve in glucose injection, filter with 0.2 ⁇ filter, and prepare 100ml of inclusion compound injection of ganciclovir concentration 1.0mg_m.
  • the invention adopts HP-p-CD, CM-p-CD and ⁇ -CD as control, and carries out in vitro experiments of CM-HP_p_CD on insulin incorporation, promotion of Caco-2 cell insulin in vitro, and cytotoxicity.
  • CM-HP-p-CD has a stronger inclusion of insulin and promotes transmembrane transport of insulin, and is essentially non-toxic to membrane cells.
  • CM-HP-P-CD has a good hypoglycemic ability to promote insulin.
  • the control ⁇ - ⁇ -CD can be used not only as a preparation for chemical drugs, but also as a carrier for excellent protein macromolecular drugs, thus greatly expanding the application field of ⁇ - ⁇ -CD.
  • Intensive strength Preparation and properties of carboxymethyl-hydroxypropyl cyclodextrin and peptide type drug-insulin inclusion compound.
  • the CM 2 -HP 6 -p-CD of the present invention is measured by the commercially available HP-P-CD, CM_p_CD and ⁇ -CD as the control, and the apparent inclusion constant Ka of insulin is determined. The results are shown in the following table:
  • the cells were seeded in 12-well Transwell (1.12 cm 2 , 0.4 ⁇ ), the plate density was 2 ⁇ 10 5 'mL- 1 , and the medium added to the apical and basal ends was 0.5 mL and 1.5 mL, respectively, and the cells were cultured for about 3 weeks. Fusion differentiation.
  • HBSS was used to wash away the metabolites adhering to the cell surface, and the permeation amount of sodium fluorescein did not exceed 4. ⁇ g-hr l -cm- 2 , and the TEER value was about 500 Q'cm- 2 .
  • the Apical side chamber (referred to as the A side) was added with 15 Il ⁇ mL- 1 insulin and clathrate solution, and 1.5 mL HBSS was added to the Basolateral side chamber (B side) below the membrane, and the temperature was 50 rmin- 1 at 37 °C. Incubate on an air shaker, sample 0.5 ml from the BL pool at 30, 60, 90, 120, 150 min, and immediately add an equal amount of HBSS; determine the insulin content in the sample by HPLC. Repeat 3 times for each experiment. The penetration of insulin (in IU) versus time (t) gives the insulin penetration curve.
  • CM 2 - HP 6 - -CD > CM- -CD> HP- -CD>p-CD the order is exactly the same as their insulin inclusion constant.
  • CM 2 -HIVP-CD prepared according to the invention has the strongest effect of enhancing insulin penetration and translocation.
  • Example 21 Preparation of carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin and flavonoid drug-puerarin and hemolysis test. Weigh accurately 10g of the CM 3 -HP 3 -P-CD of the present invention is uniformly mixed with 2.8g of puerarin (molar ratio of 1:1), melted at 60 ° C, heated at a temperature of 1 h, and then cooled at 25 ° C.
  • the product of the present invention can easily prepare a clathrate compound for the polyphenolic flavonoid drug, and it is not necessary to add any solvent auxiliary agent in the preparation process, and is particularly suitable for the preparation of the sensitive drug clathrate.
  • CM 2 -HP 5 -p-CD inclusion complex mass ratio 5: 1
  • the inclusion complex 6g dissolved in NaCl injection filtered with 0.2 ⁇ filter, prepared into 500ml of injection of puerarin concentration Z.Omg.ml- 1
  • hemolysis test (literature method: "Guidelines for Drug Research Technology (2005)", Chinese medicine Science and Technology Press, 2006, P116-132) No obvious hemolysis (hemolytic rate ⁇ 5%) was observed, and the common commercial puerarin injection (puerarin concentration S.Omg'ml- 1 ) with the same concentration was observed. Hemolysis (hemolytic rate 09%). Tests have shown that the use of the CM-HP-P-CD prepared by the present invention can effectively reduce the hemolysis of the drug, thereby enhancing the safety of the clinical drug.
  • IR spectrum of KBr pellets of different substituted carboxymethyl-hydroxypropyl-P-cyclodextrin products prepared by the present invention is compared with ⁇ -CD, and the CM-HP-p-CD products are 2969cm- 1 and 1461cm.
  • - 1 has significant absorption (antisymmetric stretching vibration of hydroxypropyl group and symmetric bending vibration absorption), and 1420 cm- 1 and 1617 cm- 1 peaks indicate the presence of a carboxymethyl substituent.
  • the products of different degrees of substitution of carboxymethyl-hydroxypropyl cyclodextrin prepared by the invention are all white amorphous powdery solids, which are easy to absorb moisture, and the products still contain 4% ⁇ 11% of inclusion water after sufficient drying. All products are thermally decomposed without a fixed melting point, and the decomposition point is gradually increased in the range of 230X to 280 °C as the degree of substitution (increase in molecular weight) increases.
  • the sample (e) features: 90 ° C or less is wider than p-CD, CM-p-CD and ⁇ - ⁇ -CD.
  • Table 2 the partial product substitution degree prepared by the present invention obtained by iH NMR is shown in Table 2:
  • the carboxymethyl-hydroxypropyl-3-cyclodextrin prepared by the invention has the similar solubility characteristics of ⁇ - ⁇ -CD, and the series products are highly soluble in water, dilute acid/dilute lye, and also very soluble in methanol. / Ethanol aqueous solution, soluble in pure methanol / pure ethanol, difficult to dissolve or insoluble in common organic solvents such as n-hexane, ethyl acetate, chloroform, acetone, etc., the solubility properties of the products with different degrees of substitution are basically no difference.
  • the solubility of carboxymethyl-hydroxypropyl-e-cyclodextrin in pure ethanol can be more than 2.5 times that of hydroxypropyl-sulfobutylcyclodextrin. Good solubility characteristics will be very beneficial for high fat-soluble drug inclusion complexes. Preparation, research and development of new systems for improving the performance of poorly soluble drugs Agent products have important application value.
  • the solubility test results using CM 3 -HP 3 -p-CD as an example are shown in the table below.
  • the carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin prepared by the present invention is a carboxymethyl and hydroxypropyl mixed-substituted cyclodextrin derivative instead of hydroxypropyl- ⁇ -cyclodextrin.
  • the CD has significantly different HPLC chromatographic characteristics, making it easy to identify the products of the invention.
  • Chromatographic conditions column Amino column (4.6mm x 250mm, 5 m); Refractive detector; Mobile phase: Acetonitrile: Water (67: 33); Flow rate: l.Oml/min; Column temperature 30 °C. Accurately weigh P_CD, CM--CD.
  • the product of the invention is a product of mixed substitution of hydroxypropyl and carboxymethyl, instead of hydroxypropyl cyclodextrin and carboxymethyl - A simple physical mixture of ⁇ -cyclodextrin.
  • the carboxymethyl-hydroxypropyl-3-cyclodextrin of the invention is obtained by reacting ⁇ -cyclodextrin with ethyl chloroacetate and 1,2-epoxypropanone in a strong base in an aqueous solution, and the system impurities are residual Base-catalyzed hydrolysates of ⁇ -cyclodextrin and reagents: glycolic acid and 1,2-propanediol, using dialysis purification technology to adjust ⁇ , can greatly reduce the residual amount of ⁇ -cyclodextrin and 1,2-propanediol
  • the glycolic acid has a small molecular weight and exists in the form of an anion to be more easily removed, so that the carboxymethyl-hydroxypropyl cyclodextrin product of the invention has high purity and good product dissolution and inclusion properties, and is significantly low.
  • the main impurities and limits to be controlled in the carboxymethyl-hydroxypropyl- ⁇ -cyclodextrin product of the present invention are as follows: Main Impurities in Carboxymethyl-Hydroxypropyl Cyclodextrin Impurity Source Impurity Limit Determination Method Cyclodextrin Residue ⁇ 1.5% HPLC
  • 1,2-propanediol hydrolysate ⁇ 2.5% GC 1 HPLC product contains only traces of glycolic acid (about 10 ⁇ 20ppm) after purification. This impurity is related to the new material of biomedical engineering, lactic acid monoglycolic acid copolymer (PLGA). The degradation products are identical. Extensive research has shown that PLGA has good biocompatibility and biodegradability, and it has good safety. It can be made into artificial catheter, drug delivery carrier, tissue engineering scaffold material, and has been rapidly developed.
  • the ⁇ -cyclodextrin is liable to form a hydrogen bond, and therefore exhibits an extremely high inclusion ability for a drug having a carboxyl group and a hydroxyl group structure. Further determining the inclusion constants of the different degree of substitution products of the present invention and the above drugs, and found that the inclusion constant is about the same as the degree of substitution ( ⁇ ).
  • Tests have shown that the CM-HP-p-CD prepared by the invention not only has a small self-hemolytic effect, but also can effectively reduce the hemolysis of the encapsulated drug and improve the safety of administration.

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  • Polymers & Plastics (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

La présente invention concerne une carboxyméthyl-hydroxypropyl-β-cyclodextrine et son procédé de préparation, la carboxyméthyl-hydroxypropyl-β-cyclodextrine étant un dérivé de β-cyclodextrine substitué à la fois par des groupements carboxyméthyle et hydroxypropyle, le dérivé étant : la n-(2,3,6-O-carboxyméthyl)-m-(2,3,6-O-2-hydroxypropyl)-β-cyclodextrine. Les groupes substitués de chaque mole de cyclodextrine contiennent n groupements carboxyméthyle et m groupements hydroxypropyle, m représentant le nombre de liaisons aux groupements hydroxypropyle dans chaque mole de dérivé de cyclodextrine, à savoir le degré de substitution moyen des groupements hydroxypropyle, et n représentant le nombre de liaisons aux groupements carboxyméthyle dans chaque mole de dérivé cyclodextrine, à savoir le degré de substitution moyen des groupements carboxyméthyle, m représentant un nombre choisi dans la plage allant de 1 à 6 et n représentant un nombre choisi dans la plage allant de 1 à 6. La présente invention agit comme un excipient médical, et présente les caractéristiques de faible propriété hémolytique, de faible toxicité et de solubilité élevée.
PCT/CN2013/001333 2013-09-25 2013-11-04 Carboxyméthyl-hydroxypropyl-β-cyclodextrine et son procédé de préparation WO2015042759A1 (fr)

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WO2018140856A1 (fr) 2017-01-30 2018-08-02 Bio-Rad Laboratories, Inc. Compositions d'émulsion et leurs procédés d'utilisation
FR3075799A1 (fr) * 2017-12-22 2019-06-28 Roquette Freres Procede de modification de matiere polysaccharidique par fonctionnalisation chimique homogene sequencee

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CN104558253A (zh) * 2014-12-19 2015-04-29 福建工程学院 2-O-甲基-6-O-（2-羟丙基）-β-环糊精的绿色合成方法
CN104983784A (zh) * 2015-07-30 2015-10-21 淄博千汇生物科技有限公司 增加葛根黄酮溶解度的方法
CN107573427B (zh) * 2017-10-19 2019-10-15 无锡甜丰食品有限公司 一种羟丙基麦芽糊精的制备方法
CN107540750B (zh) * 2017-10-19 2019-10-15 无锡甜丰食品有限公司 一种羧甲基麦芽糊精的制备方法
CN108503729A (zh) * 2018-03-15 2018-09-07 山东滨州智源生物科技有限公司 一种离子交换树脂作为催化剂用于生产羟丙基倍他环糊精的制备方法

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