CN104162167A - Tamibarotene cyclodextrin or cyclodextrin derivative clathrate and preparation method thereof - Google Patents
Tamibarotene cyclodextrin or cyclodextrin derivative clathrate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a tamibarotene cyclodextrin or cyclodextrin derivative clathrate which is prepared from tamibarotene and cyclodextrin or a cyclodextrin derivative, the molar ratio of tamibarotene to cyclodextrin or cyclodextrin derivative is 1:1-1:100, and the preparation method is as follows: the cyclodextrin or cyclodextrin derivative is added to a solvent to produce a solution or suspension, and then the tamibarotene is added for stirring, grinding or ultrasonic mixing to obtain the tamibarotene cyclodextrin or cyclodextrin derivative clathrate; or the cyclodextrin or cyclodextrin derivative is put in a colloid mill or mortar, a solvent is added for stirring to make a paste, then the tamibarotene is added into the paste for grinding for 1-5 hours to obtain a homogeneous thick paste, and the tamibarotene cyclodextrin or cyclodextrin derivative clathrate is obtained by filtration, concentration or freeze drying. The invention also discloses a tamibarotene-containing composition. The tamibarotene cyclodextrin or cyclodextrin derivative clathrate improves the solubility and dissolution rate of the tamibarotene, has good water solubility, less vascular stimulation, quick disintegration, higher bioavailability and other characteristics.
Description
Technical field
The present invention relates to Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, its preparation method, the pharmaceutical composition that contains Tamibarotene cyclodextrin or cyclodextrin derivant clathrate and the purposes in preparing medicine.Belong to medical technical field.
Background technology
Tamibarotene (Tamibarotene, Am80), chemistry 4-[(5 by name, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2) carbamyl] benzoic acid.It is colourless prism or white crystalline powder, is soluble in oxolane and dichloromethane, water insoluble.Its structural formula is as follows:
Tamibarotene is the new selective retinoic acid α receptor promoter of Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan (Nippon Shinyaku) exploitation, is applicable to the treatment of acute promyelocytic leukemia relapsed or stubborn sexually transmitted disease (STD).Tamibarotene tablet, in June, 2005 in Japan listing (trade name: Amnolake), there is the features such as efficient, low drug resistance and side effect be little.But because it is insoluble in water, with ordinary preparation oral administration, absorption difference, bioavailability is lower, has therefore limited its application.
Medicine can be increased to the dissolubility of medicine with cyclodextrin inclusion compound, improve the bioavailability of medicine, in addition all right: to increase medicine stability; Cover the bad smell of medicine; Reduce zest or the toxic and side effects of some drugs; Regulating drug rate of releasing drug; Promote medicine per mucous membrane absorption etc.There is at present multiple cyclodextrin clathrate launch, but there are no the report of the cyclodextrin clathrate about Tamibarotene.
Summary of the invention
For above-mentioned prior art, water insoluble for solving in prior art Tamibarotene, oral absorption is poor, the technical problem that is difficult to oral or drug administration by injection, the invention provides Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, with and preparation method thereof, and the pharmaceutical composition that contains Tamibarotene cyclodextrin or cyclodextrin derivant clathrate and the purposes in preparing medicine.
The present invention is achieved by the following technical solutions:
Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, be by Tamibarotene, and cyclodextrin or cyclodextrin derivative make, the molecule mol ratio of Tamibarotene and cyclodextrin or cyclodextrin derivative is 1:1～1:100, preferred 1:1～1:10, dosage form is solid dosage forms or liquid dosage form.
Described cyclodextrin includes but not limited to alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, preferably beta-schardinger dextrin-.
Described cyclodextrin derivative includes but not limited to hydroxyethyl-β-cyclodextrin, HP-β-CD, dihydroxypropyl-beta-schardinger dextrin-, first group-beta-cyclodextrin, glucose-cyclodextrin, maltose-cyclodextrin, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin, sulfoalkyl-cyclodextrin, preferably HP-β-CD.
The preparation method of described Tamibarotene cyclodextrin or cyclodextrin derivant clathrate is: cyclodextrin or cyclodextrin derivative are joined in solvent, make concentration and be the cyclodextrin of 1～90% (mass percent) (preferably 30～90%) or solution or the suspension of cyclodextrin derivative, then add Tamibarotene, stirring, grinding or ultrasonic mixing, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate (solution or suspension) of liquid.
Further, by the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate lyophilization spraying is dry or distillation and concentration except desolventizing, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate of solid.
Preferably, before lyophilization, first that the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate is concentrated, the concentration that is concentrated into dextrin or cyclodextrin derivative is 10～50% (mass percents).
The present invention also provides another preparation method: cyclodextrin or cyclodextrin derivative are placed in to colloid mill or mortar, add appropriate suitable solvent to stir, become pastel, then Tamibarotene is added in pastel, grind 1～5 hour, obtain the viscous pastes of homogeneous, filter, concentrate or lyophilization, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate of solid.
In above-mentioned two kinds of preparation methoies, described solvent (dissolving the suitable solvent of cyclodextrin or cyclodextrin derivative) is selected from one or more the mixture in water, ethanol, methanol, propanol, isopropyl alcohol, ethylene glycol, glycerol, acetone, preferred water.
Described while adding Tamibarotene, directly add tamibarotene solid, or with appropriate organic solvent (dehydrated alcohol), dissolve Tamibarotene and obtain after Tamibarotene solution, then add.
The present invention also provides a kind of compositions that comprises medicine Tamibarotene, comprises Tamibarotene cyclodextrin or cyclodextrin derivant clathrate prepared by said method, and acceptable carrier on pharmacopedics.
The dosage form of the described compositions that comprises medicine Tamibarotene, includes but not limited to the liquid dosage forms such as injection, liquid drugs injection, powder pin, oral liquid, syrup (by the directly preparation of the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate); The many kinds of solids dosage forms (Tamibarotene cyclodextrin or cyclodextrin derivant clathrate by solid are made) such as tablet, capsule, granule, dispersible tablet, oral cavity disintegration tablet, buccal tablet.
In the described compositions that comprises medicine Tamibarotene, single dose specification is for containing active medicine Tamibarotene 0.1～1000mg, and preferably single dose specification is for containing active medicine Tamibarotene 1～100mg.
Preferably, the described compositions that comprises medicine Tamibarotene, dosage form is injection, in injection, Tamibarotene cyclodextrin or cyclodextrin derivant clathrate are specially Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion, concentration is 0.01～3% (g/ml), and the pH value of injection is 3～10; In injection, can contain the pH adjustment agent such as sodium chloride, glucose isosmoticity regulator and hydrochloric acid, sodium hydroxide.
Preferably, the described compositions that comprises medicine Tamibarotene, dosage form is injectable powder, Tamibarotene cyclodextrin or cyclodextrin derivant clathrate are specially Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion, pH value after injectable powder dissolves is 3～10, can contain the pH such as the proppants such as mannitol, lactose and hydrochloric acid, sodium hydroxide and adjust in injectable powder.
Beneficial effect of the present invention is: by cyclodextrin or cyclodextrin derivative, Tamibarotene is carried out to enclose, Tamibarotene molecule is embedded in the tubular structure of cyclodextrin or cyclodextrin derivative molecule, become the clathrate of Tamibarotene cyclodextrin or cyclodextrin derivative, thereby improved dissolubility and the rate of dissolution of Tamibarotene.
Tamibarotene cyclodextrin of the present invention or cyclodextrin derivant clathrate, make this active component of Tamibarotene directly apply to solid, liquid dosage form with the form of clathrate.Cyclodextrin or cyclodextrin derivative are the water solublity pharmaceutic adjuvants that a kind of toxicity is less, and Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate with it, prepared are suitable for making plurality of liquid preparation and solid preparation.Tamibarotene cyclodextrin of the present invention or cyclodextrin derivant clathrate, there is good water solubility, feature that blood vessel irritation is little, be particularly useful for making liquid preparation, solved Tamibarotene water solublity low, can not be directly used in liquid dosage form, especially the technical problem of injection type.In addition, owing to having improved water solublity, the solid preparation of preparing with it has that disintegrate is fast, stripping good, bioavailability high, is more conducive to clinical practice.
Accompanying drawing explanation
The DSC collection of illustrative plates of Fig. 1: Am80, HP-β-CD and both mixture, Am80 clathrate.
Fig. 2: the stripping curve figure of Am80 clathrate and Am80 crude drug.
Fig. 3: the blood drug level-time plot after Am80 inclusion complex in solution and Am80 crude drug suspension are oral in rat body.
The specific embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1 prepares liquid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion solution
Step is as follows:
(1) take 61mg HP-β-CD, pour 5ml distilled water into, stirring and dissolving.
(2) separately claim Tamibarotene 5mg, add 5ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor stirs 1h with magnetic agitation method at 45 ℃, and vacuum rotary steam is removed ethanol, filters and removes not enclose medicine, obtains Tamibarotene HP-β-CD derivative clathrate solution.
Embodiment 2 prepares solid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1), (2), (3) are with embodiment 1.
(4) Tamibarotene HP-β-CD derivative clathrate solution is carried out to lyophilization again, obtain solid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion.
Embodiment 3 prepares solid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1) take 122mg HP-β-CD, put into mortar, add 2ml distilled water, grind and make into pasty state;
(2) separately take Tamibarotene 10mg, add 2ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor is ground 2 hours, obtain homogeneous pastel, filter, evaporated under reduced pressure, obtains solid Tamibarotene cyclodextrin derivant clathrate.
Embodiment 4 prepares the sodium chloride injection of Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1) take 122mg HP-β-CD, pour in 10ml distilled water, stirring and dissolving, adds 0.5
gtransfusion active carbon, is heated with stirring to 80 ℃, is incubated 15 minutes, filtering decarbonization.
(2) separately take Tamibarotene 10mg, add 10ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor stirs 1h with magnetic agitation method at 45 ℃, observes solution to clear, obtains Tamibarotene HP-β-CD derivative clathrate solution.
(4) inclusion complex in solution moisturizing, to 800ml, adds sodium chloride for injection 7.5g, and regulates pH to 6 with the hydrochloric acid of 0.05M or the sodium hydroxide of 0.05M, and moisturizing, to 1000ml, adds 0.1g injection active carbon, stirs 20 minutes.
(5) the de-charcoal fill of solution, 115 ℃, 30 minutes pressure sterilizings, obtain.
Embodiment 5 prepares the glucose injection of Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1), (2), (3) are with embodiment 4.
(4) take glucose for injection 50g, add water stirring and dissolving and make volume reach 100ml, add 0.1g active carbon, heat micro-boiling 15 minutes, filtering decarbonization, obtains Glucose Liquid.
(5) Glucose Liquid is poured in inclusion complex in solution, and moisturizing, to 800ml, regulates pH to 7 with the hydrochloric acid of 0.05M or the sodium hydroxide of 0.05M, and moisturizing, to 1000ml, adds 0.1g injection active carbon, stirs 20 minutes.
(6) solution carries out coarse filtration, fine straining with filter or sand stick (aperture 1.0 μ m, 0.45 μ m, 0.22 μ m) respectively, then fill, and 115 ℃, 30 minutes pressure sterilizings, obtain.
Embodiment 6 use Tamibarotene hydroxypropyl-beta-cyclodextrin inclusions are prepared aseptic powder injection
Step is as follows:
(1) indoor in sterile working, take 122mg HP-β-CD, be dissolved in water, be settled to 10ml, add 0.1g active carbon, heat micro-boiling 15 minutes, filtering decarbonization.
(2) separately take Tamibarotene 10mg, add 10ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor stirs 1h with magnetic agitation method at 50 ℃, stirs, and vacuum rotary steam is removed ethanol, removes by filter the not medicine of enclose, obtains Tamibarotene HP-β-CD derivative clathrate solution.
(4) inclusion complex in solution moisturizing is to 20ml, crosses 0.22 μ m filter membrane, is sub-packed in the cillin bottle of 5ml (1～2ml/ bottle), inserts in freeze dryer, and lyophilization gland, obtains aseptic powder injection.
Embodiment 7 beta-cyclodextrin inclusion compound Tamibarotene
Step is as follows: take 40g beta-schardinger dextrin-, add 100ml distilled water, be heated to 45 ℃, beta-schardinger dextrin-is dissolved, add with 1g Tamibarotene (using in advance 20ml anhydrous alcohol solution), magnetic agitation, after 2.5 hours, is filtered, lyophilization, obtains beta-schardinger dextrin-Tamibarotene clathrate.
The preparation of embodiment 8 beta-cyclodextrin inclusion compound Tamibarotene oral capsules
Step is as follows: take beta-cyclodextrin inclusion compound Tamibarotene 5g, itself and 20g lactose are mixed by equivalent multiplication method, with water dissolution HPMC, as binding agent soft material processed, 20 mesh sieves are granulated, dry at 60 ℃, 30 mesh sieve granulate for dry granule, carry out intermediate check, by encapsulated containing active medicine 2mg/ grain, sampling observation, subpackage, obtains.
The preparation of embodiment 9 beta-cyclodextrin inclusion compound Tamibarotene oral tablets
Step is as follows: take beta-cyclodextrin inclusion compound Tamibarotene 2g, itself and 8g lactose and 0.5g carboxymethyl starch sodium mixed by equivalent multiplication method, with water dissolution HPMC as binding agent soft material processed, 20 mesh sieves are granulated, dry at 60 ℃, 30 mesh sieve granulate for dry granule, add micropowder silica gel 0.1g, be mixed evenly, by containing active medicine 2mg/ sheet tabletting, carry out intermediate check, encapsulated, sampling observation, subpackage, obtains.
Experiment 1
The physical mixed of getting respectively appropriate Tamibarotene, HP-β-CD, Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion (by example 2 gained), Tamibarotene and HP-β-CD (takes 5mg Tamibarotene, 61mg HP-β-CD, in mortar, be ground, obtain) totally four parts carry out differential scanning calorimetry.Wherein programming rate is 5 ℃/min, and sweep limits is 20～500 ℃, and test result as shown in Figure 1.As can be seen from the figure, Tamibarotene has a sharp-pointed feature endothermic peak at 231 ℃; HP-β-CD has a larger feature endothermic peak 360 ℃ of left and right; The physical mixture of Tamibarotene and HP-β-CD is respectively having an absworption peak at 217 ℃, 289 ℃ respectively, is the stack peak of Tamibarotene and hydroxypropyl cyclodextrin, may be the peak position difference slightly that both influencing each other causes them; Tamibarotene clathrate all disappears with the peak of 360 ℃ of left and right at 231 ℃, only 325 ℃ of left and right, has an absworption peak, shows that Tamibarotene and hydroxypropyl-beta-cyclodextrin inclusion form.
Experiment 2
Take respectively each six parts of Tamibarotene 2mg, Tamibarotene clathrates appropriate (embodiment 2 preparations, containing Tamibarotene 2mg).According to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia), measure, take purified water 900ml as dissolution medium, temperature is (37 ± 0.5) ℃, rotating speed (100 ± 1) r/min.In 3,7,10,15,20,30,45min samples 5ml, 0.45um filtering with microporous membrane, get subsequent filtrate 2mL, adopt UV method to measure trap, according to the standard curve of setting up, calculate its accumulative releasing degree, take the time as abscissa, accumulation dissolution be vertical coordinate draw Tamibarotene and clathrate thereof stripping curve as shown in Figure 2.As seen from the figure, the dissolution rate of Tamibarotene clathrate Chinese medicine and dissolution, all apparently higher than Tamibarotene crude drug, illustrate that the Tamibarotene clathrate of preparation can obviously improve the stripping of medicine.
Experiment 3
Get 6 of Wistar rats, body weight 200 ± 20g, is divided at random two groups and (for examination, organizes a gavage and give Tamibarotene suspension; For examination, organize two groups of gavages and give Tamibarotene clathrate (by example 2 gained); Dosage is 20mg/kg, and every group parallel three, fasting 12h before experiment, freely drinks water.For examination group and matched group before administration and 0.25 after administration, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24h, from jugular sinus, get blood, add in the centrifuge tube of processing through heparin sodium, the centrifugal 10min of 4000rpm, the accurate 0.1ml supernatant of drawing, add 0.2ml acetonitrile, vortex vibration 30s, the centrifugal 10min of 12000rpm, get the filtering with microporous membrane of 0.22 μ m for supernatant, obtain the plasma sample of different time points, get 20 μ l sample introductions and analyze (utilizing high performance liquid chromatogram to measure), utilize DAS2.0 to process data, draw the blood drug level-time plot in rat body, as shown in Figure 3.Wherein, the AUC of Tamibarotene clathrate and Tamibarotene is respectively 54.812,21.541 (mg/L*h), Cmax is respectively 9.314,2.017 (mg/L), known, Tamibarotene is made after clathrate, bioavailability obviously increases, and can reduce thus the dosage of medicine, thereby can reduce the toxic and side effects of medicine.
Claims (10)
1. the preparation method of a Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, it is characterized in that: cyclodextrin or cyclodextrin derivative are joined in solvent, make concentration and be 1～90% cyclodextrin or solution or the suspension of cyclodextrin derivative, then add Tamibarotene, stirring, grinding or ultrasonic mixing, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate of liquid;
The molecule mol ratio of described Tamibarotene and cyclodextrin or cyclodextrin derivative is 1:1～1:100;
Described cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin;
Described cyclodextrin derivative is selected from hydroxyethyl-β-cyclodextrin, HP-β-CD, dihydroxypropyl-beta-schardinger dextrin-, first group-beta-cyclodextrin, glucose-cyclodextrin, maltose-cyclodextrin, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin, sulfoalkyl-cyclodextrin.
2. the preparation method of Tamibarotene cyclodextrin according to claim 1 or cyclodextrin derivant clathrate, it is characterized in that: by the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate lyophilization spraying is dry or distillation and concentration except desolventizing, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate of solid.
3. the preparation method of a Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, it is characterized in that: cyclodextrin or cyclodextrin derivative are placed in to colloid mill or mortar, add solvent to stir, become pastel, then Tamibarotene is added in pastel, grind 1～5 hour, obtain the viscous pastes of homogeneous, filter, concentrated or lyophilization, obtains Tamibarotene cyclodextrin or cyclodextrin derivant clathrate.
4. according to the Tamibarotene cyclodextrin described in claim 1 or 2 or 3 or the preparation method of cyclodextrin derivant clathrate, it is characterized in that: described solvent is selected from one or more the mixture in water, ethanol, methanol, propanol, isopropyl alcohol, ethylene glycol, glycerol, acetone.
5. according to the Tamibarotene cyclodextrin described in claim 1 or 2 or 3 or the preparation method of cyclodextrin derivant clathrate, it is characterized in that: described in while adding Tamibarotene, directly add tamibarotene solid, or with organic solvent dissolution Tamibarotene, obtain after Tamibarotene solution, then add; Described organic solvent is dehydrated alcohol.
6. the Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate that utilize the preparation method of the Tamibarotene cyclodextrin described in any one in claim 1～5 or cyclodextrin derivant clathrate to prepare.
7. a compositions that comprises Tamibarotene, is characterized in that: comprise Tamibarotene cyclodextrin claimed in claim 6 or cyclodextrin derivant clathrate, and acceptable carrier on pharmacopedics.
8. the compositions that comprises Tamibarotene according to claim 7, is characterized in that: described in comprise medicine Tamibarotene the dosage form of compositions be injection, liquid drugs injection, powder pin, oral liquid, syrup, tablet, capsule, granule, dispersible tablet, oral cavity disintegration tablet or buccal tablet.
9. the compositions that comprises Tamibarotene according to claim 7, it is characterized in that: described in comprise medicine Tamibarotene the dosage form of compositions be injection, in injection, Tamibarotene cyclodextrin or cyclodextrin derivant clathrate are specially Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion, concentration is 0.01～3%, and the pH value of injection is 3～10.
10. the compositions that comprises Tamibarotene according to claim 7, it is characterized in that: described in comprise medicine Tamibarotene the dosage form of compositions be injectable powder, Tamibarotene cyclodextrin or cyclodextrin derivant clathrate are specially Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion, and the pH value after injectable powder dissolves is 3～10.
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| EP3752159A4 (en) * | 2018-02-13 | 2021-11-24 | Transgenex Nanobiotech, Inc. | Novel crystalline forms of tamibarotene for treatment of cancer |
| CN115337291A (en) * | 2021-05-14 | 2022-11-15 | 香港大学 | Dry powder formulations of tamibarotene for pulmonary and intranasal delivery |
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| EP3752159A4 (en) * | 2018-02-13 | 2021-11-24 | Transgenex Nanobiotech, Inc. | Novel crystalline forms of tamibarotene for treatment of cancer |
| CN115337291A (en) * | 2021-05-14 | 2022-11-15 | 香港大学 | Dry powder formulations of tamibarotene for pulmonary and intranasal delivery |
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