CN103330680A - Nano drug transdermal preparation and preparation method thereof - Google Patents
Nano drug transdermal preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a nano drug transdermal preparation belonging to the pharmacy field, and a preparation method thereof. A preparation process of the preparation comprises the steps of preparing the drug into a nano drug; then preparing the nano drug into a hydrogel transdermal preparation, an ointment transdermal preparation or a microneedle transdermal preparation. The nano drug transdermal preparation prepared by selecting proper materials such as a gel matrix, an ointment matrix, a microneedle matrix, a promoter and the like and preparation method of the transdermal preparation is convenient for use, has very good biocompatibility and relatively high bioavailability, and can increase adaptability of patients. The nano drug transdermal preparation can reduce drug resistance of diseased cells and has good curative effect. The preparation method provided by the invention can be applied in the preparation of various drug transdermal preparations.
Description
Technical field
The present invention relates to the pharmaceutical technology field, specifically, is Nano medication preparation capable of permeating skin and preparation method thereof.
Background technology
Pharmaceutical industry is from drug discovery, and to Clinical Application, last link is pharmaceutical preparation.Wherein some medicine needs long term administration to cure, and some needs topicals such as targeting.Reach these purposes, crude drug must be prepared into corresponding dosage form.For external local lesion, need local body surface administration, as child's hemangioma disease, only need topical.
Hemangioma is the common a kind of disease of child, and the ewborn infant sickness rate is 2%～3%, and sickness rate was about 10% in 0～1 years old, and premature labor or light partially neonate sickness rate are about 20%～30%.Operative treatment, laser therapy etc. are arranged at present, but these methods all there is toxic and side effects in various degree." New England's medical science " magazine in 2008 has reported that oral Propranolol (propranolol) can play better curative effect, but there is potential heart toxic and side effects in oral Propranolol.The liniment of external, ointment or gel be topical as required, improves the medicine local concentration, the release of prolong drug or diffusion process, and toxicity is low, rapid-action and easy to use.Chinese patent application CN201210420731.2, January 16 2013 Shen Qing Publication day, a kind of propranolol hydrochloride gel for the treatment of infant superficial vein tumor is disclosed, owing to be that single propranolol hydrochloride molecule plays therapeutical effect, for tumor, be easy to produce drug resistance, cause no longer working, even the treatment failure.
Attack the problem of being unable to for a long time in order to overcome this, need a kind of new pharmaceutical preparation, can not only solve the problem of the potential heart toxic and side effects that Propranolol exists, directly kill tumor cell and be unlikely to produce drug resistance.Except Propranolol, but for the medicine of other skin-penetrating therapeutics, also be necessary to be prepared into such preparation capable of permeating skin.
Summary of the invention
The objective of the invention is provides a kind of Nano medication preparation capable of permeating skin and preparation method thereof at deficiency of the prior art.By medicine is made Nano medication, then Nano medication is prepared into aqueogel, ointment formulation and micropin preparation, the granular nanometer medicine is easily by cellular uptake, and can not produce drug resistance.The preparation method of this preparation capable of permeating skin can be applied in the preparation of various drug transdermal preparations.
For achieving the above object, the technical scheme taked of the present invention is:
A kind of Nano medication preparation capable of permeating skin, the preparation method of described Nano medication preparation capable of permeating skin may further comprise the steps:
(1) medication preparation is become Nano medication, the percentage by weight of described medicine in Nano medication is 0.1%～90%, is preferably 10%～50%, and the particle diameter of described Nano medication is 10～5000 nanometers, is preferably 10～500 nanometers;
(2) Nano medication of step (1) preparation being dispersed in weight percent concentration according to the weight ratio of 1:1～1:10 is in 0.5%～80% the hydrogel solution, the concentration of hydrogel solution is preferably 5%～30%(w/w), add penetration enhancer simultaneously, antiseptic and wetting agent, fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 4～12 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps can repeat 1～4 time in order, place 0～4 ℃ of preservation to obtain Nano medication hydrogel preparation capable of permeating skin at last again, blending manner can be selected emulsifying, vortex or ultrasonic, mixing time are preferably 1～5 minute; Or
The Nano medication of step (1) the preparation weight ratio according to 1:1～1:10 is dispersed in the ointment base, namely obtain Nano medication ointment preparation capable of permeating skin behind the mix homogeneously, dispersing mode can be selected emulsifying, vortex or ultrasonic, jitter time is preferably 1～5 minute, and described ointment base is selected from a kind of in water-soluble base, greasing base or the emulsion-type substrate; Or
The Nano medication of step (1) preparation is attached on the micropin surface according to the weight ratio of 1:1～1:10 or be loaded in micropin inner or with the abundant mixing of micropin material after water and in the micropin mould, obtain Nano medication micropin preparation capable of permeating skin.
The preparation of the Nano medication described in the step (1) may further comprise the steps: with medicine dissolution in water, add the porous nano granule then, stirring makes medicine fully be adsorbed in the porous nano granule, centrifugal removal supernatant, fully washing again, lyophilizing forms Nano medication then.
Described nano-particle is organic nanometer granule or inorganic nanoparticles, one or more in optional self-polystyrene nano-particle, cross-linking dextran nano-particle, nano SiO 2 particle, titania nanoparticles, hydroxyapatite nanoparticle, ferroferric oxide nano granules, ferric oxide particle, gold nano grain, aluminium sesquioxide nano-particle, calcium carbonate nano granule, calcium phosphate nanoparticles, magnesium carbonate nano-particle, magnesium hydroxide nanoparticles or the silver nano-grain.
The preparation of the Nano medication described in the step (1) may further comprise the steps: medicine dissolution is formed pharmaceutical aqueous solution in water, pharmaceutical aqueous solution is transferred in the Polyethylene Glycol aqueous solution then, fully behind the mixing in refrigerator pre-freeze, lyophilizing afterwards obtains Nano medication with dichloromethane dissolving Polyethylene Glycol and the centrifugal Polyethylene Glycol of removing again; Or
Pharmaceutical pack is rolled in liposome, the polymer nano granules forms Nano medication; Or
Medicine dissolution is formed pharmaceutical aqueous solution in water, medicine is separated out with the form of nano-particle obtain Nano medication by adding bad solvent; Or
Medicine is pulverized instrument with micropowder to be pulverized and directly is prepared into Nano medication.
The preparation of the Nano medication described in the step (1) may further comprise the steps: with medicine dissolution in water, then with the dichloromethane solution stirring and evenly mixing that contains polylactic acid-glycolic guanidine-acetic acid-Polyethylene Glycol, transfer in the polyvinyl alcohol water solution and carry out homogenate, form the Nano medication micelle.
Gel-type vehicle in the hydrogel solution described in the step (2) is selected from polyvinyl alcohol, polyvinylpyrrolidone, ethyl cellulose, Polyethylene Glycol, the carboxyl ethylene copolymer, methylcellulose, sodium carboxymethyl cellulose, cross-linked sodium polyacrylate, polylactic acid-polyglycol-polylactic acid polymer, polyethylene glycol-lactic acid-polyethylene glycol polymer, polylactic acid-glycolic guanidine-acetic acid-polyethylene glycol-lactic-co-glycolic acid polymer, polyethylene glycol-lactic-co-glycolic acid-polyethylene glycol polymer, sodium alginate, starch, glycerol, in the gelatin one or more.
Penetration enhancer described in the step (2) is selected from a kind of in menthol, sodium tetradecyl sulfate, geraniol, anethole or the decyl methyl sulfoxide, described antiseptic is selected from a kind of in sodium benzoate, chlorobutanol, benzalkonium bromide, sorbic acid, ethyl hydroxybenzoate or the butoben, and described wetting agent is glycerol, propylene glycol or the mixture of the two.
Ointment base described in the step (2) is selected from one or more in tristerin, stearic acid, Cera Flava, lanoline, vaseline, paraffin, silicone, Oleum menthae, eucalyptus oil, vegetable oil, gelatin or the sodium carboxymethyl cellulose.
Micropin described in the step (2) refers to metal micro-needle, inorganic micropin or polymer micro needle, and described inorganic micropin refers to the inorganic silicon micropin.
Described medicine comprises small-molecule drug and macromolecular drug, described small-molecule drug is selected from Propranolol, amycin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine, semustine, cisplatin, etoposide, camptothecine and derivant thereof, phenesterin, paclitaxel and derivant thereof, Docetaxel and derivant thereof, vinblastine, vincristine, zitazonium, piposulfan, cyclophosphamide, flutamide and derivant thereof, prednisone, rapamycin, ciclosporin, levofloxacin, a kind of in ofloxacin or the epinastine hydrochloride, described macromolecular drug is selected from erythropoietin, recombinant human granulocyte colony stimulating factor, granulocyte-macrophage colony stimutaing factor, vaccine, interferon, growth hormone, insulin, epidermal growth factor, fibroblast growth factor, transforming growth factor, insulin-like growth factor, vascular endothelial cell growth factor, PDGF, endothelial cell growth factor (ECGF), nerve growth factor, bone-derived growth factor, bone morphogenetic protein(BMP), tissue polypeptide antigen, antibody, blood coagulation factor VIII, plasma thromboplastin component, genetic factor, antisense nucleotide, a kind of in microRNA or the gene.
The invention has the advantages that:
The first, the present invention has selected the preparation method of materials such as suitable gel-type vehicle, ointment base, micropin material, penetration enhancer and preparation capable of permeating skin, the envelop rate height of the Nano medication preparation capable of permeating skin of preparation, can reach more than 90%, overcome the toxic and side effects that general administrations such as oral or injection bring, especially in treatment child hemangioma disease, can overcome the toxic and side effects that the administration of Propranolol whole body brings;
The second, adopt the inventive method can prepare Nano medication hydrogel preparation capable of permeating skin, Nano medication ointment preparation capable of permeating skin, Nano medication micropin preparation capable of permeating skin, these dosage forms can be controlled according to different state of an illness needs, and preparation process is free from environmental pollution, preparation capable of permeating skin is easy to use, have good biocompatibility and high bioavailability, improve patient's adaptability;
Three, adopt the inventive method to prepare the Nano medication preparation capable of permeating skin, can make medicine in whole process of preparation and therapeutic process, keep high activity and non-inactivation, greatly reduce that medicine is prominent to be released, the medicine that discharges can efficiently be absorbed by sick cell the part, thereby reduce the toxic and side effects of medicine itself, can be applied in the preparation of various drug transdermal preparations;
Four, the preparation method of Nano medication preparation capable of permeating skin of the present invention, can apply in the adjuvant preparation of the preparation of pharmaceutical preparation of various topical therapeutics and vaccine, especially the angiomatous topical therapeutic of infant, can improve the efficient of tumor cell ingestion of drugs, because tumor cell absorbs the granular nanometer medicine easily, in case absorbed Nano medication, can make the GP albumen of tumor cell be difficult to efflux medicine, direct kill tumor cell, and be unlikely to produce drug resistance.
Description of drawings
Accompanying drawing 2 is that embodiment 1, Comparative Examples 1 and Comparative Examples 2 gained preparations are to the influence of drug resistance of tumor cell rate.
Accompanying drawing 3 is that embodiment 1, Comparative Examples 1 and Comparative Examples 2 gained preparations are to the influence of nude mice gross tumor volume size.
Accompanying drawing 4 be embodiment 1, Comparative Examples 1 and Comparative Examples 2 gained preparations to the angiomatous treatment situation of eyelid, before A figure was medication, B figure was 1 group of Comparative Examples treatment situation, C figure is 2 groups of treatments of Comparative Examples situation, D figure is that embodiment treats situation for 1 group.
Accompanying drawing 5 is that embodiment 2 gained preparations are to the influence of drug resistance of tumor cell rate.
Accompanying drawing 6 is that embodiment 2 gained preparations are to the influence of nude mice gross tumor volume size.
Accompanying drawing 7 is that embodiment 6 gained preparations are to the influence of drug resistance of tumor cell rate.
Accompanying drawing 8 is that embodiment 6 gained preparations are to the influence of nude mice gross tumor volume size.
Accompanying drawing 9 is that embodiment 8 gained preparations are to the influence of drug resistance of tumor cell rate.
Accompanying drawing 10 is that embodiment 8 gained preparations are to the influence of nude mice gross tumor volume size.
The specific embodiment
Below in conjunction with accompanying drawing the specific embodiment provided by the invention is elaborated.
The preparation (one) of embodiment 1 Propranolol Nano medication hydrogel preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 0.2g Propranolol is dissolved in the 10mL water, add 1g porous silicon dioxide nano granule then, stirring is spent the night and is made Propranolol fully be adsorbed in the silica dioxide granule, centrifugal removal supernatant, fully washing again, lyophilizing forms the Propranolol Nano medication then, and the particle diameter of Nano medication is 20～500 nanometers;
(2) preparation polyvinyl alcohol (molecular weight 40,000) percentage by weight is 12%, Polyethylene Glycol (molecular weight 400) percentage by weight is 1% hydrogel solution;
(3) the Propranolol Nano medication that step (1) is prepared is dispersed in the hydrogel solution of step (2) preparation according to the weight ratio of 1:1, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% menthol and 5% glycerol, ultrasonic mixing 2 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 6 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 2 times in order, place 0～4 ℃ of preservation to obtain Propranolol Nano medication hydrogel preparation capable of permeating skin at last again.
The preparation of Comparative Examples 1 Propranolol hydrogel preparation capable of permeating skin
The small-molecule drug Propranolol directly is prepared into the hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) preparation polyvinyl alcohol (molecular weight 40,000) percentage by weight is 12%, Polyethylene Glycol (molecular weight 400) percentage by weight is 1% hydrogel solution;
(2) accurately taking by weighing a certain amount of Propranolol is dispersed in the hydrogel solution of step (1) preparation, guarantee that the final concentration of Propranolol in the hydrogel preparation capable of permeating skin is the same with the final concentration of Propranolol among the embodiment 1, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% menthol and 5% glycerol, ultrasonic mixing 2 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 6 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 2 times in order, place 0～4 ℃ of preservation to obtain Propranolol hydrogel preparation capable of permeating skin at last again.
The preparation of the common water preparation of Comparative Examples 2 Propranolol Nano medications
The small-molecule drug Propranolol is prepared into the common water preparation of Nano medication, and preparation process is as follows:
(1) accurately taking by weighing the 0.2g Propranolol is dissolved in the 10mL water, add 1g porous silicon dioxide nano granule then, stirring is spent the night and is made Propranolol fully be adsorbed in the silica dioxide granule, centrifugal removal supernatant, fully washing again, lyophilizing forms the Propranolol Nano medication then, and the particle diameter of Nano medication is 20～500 nanometers;
(2) the Propranolol Nano medication that step (1) is prepared is dispersed in the water according to the weight ratio of 1:1; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 6 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 2 times in order, place 0～4 ℃ of preservation to obtain the common water preparation of Propranolol Nano medication at last again.
The common water preparation of Propranolol Nano medication that the Propranolol Nano medication hydrogel preparation capable of permeating skin that embodiment 1 is prepared, the Propranolol hydrogel preparation capable of permeating skin that Comparative Examples 1 prepares and Comparative Examples 2 prepare carries out pattern sign, drug resistance and anticancer test.Figure 1 shows that the scanning electron microscope (SEM) photograph of Propranolol Nano medication, particulate form is good, and the particle diameter of Nano medication is 20～500 nanometers.The medicament good uniformity of embodiment 1 and Comparative Examples 1 preparation is smeared than being easier to, the medicament less stable of Comparative Examples 2 preparations, and drug precipitation is serious.
The mensuration of drug resistance of tumor cell rate: with pharmaceutical preparation and cell culture a period of time that embodiment 1, Comparative Examples 1 and Comparative Examples 2 make, total number of cells control is 5 * 10
5～20 * 10
5In the scope, guarantee respectively to organize the consumption unanimity of Propranolol, use Flow cytometry drug-resistant tumor cell number then, resistant rate=(drug-resistant tumor cell number/total tumor cell number) * 100%.Concrete steps are as follows: tumor cell MCF27/A is incubated at and contains 10%(w/w) calf serum, 1%(w/w) penicillin, 2%(w/w) streptomycin, 1%(w/w) in the RPMI21640 culture fluid of Propranolol, 5mg/L amycin, at 37 ℃, 5% CO
2Condition under cultivate.Use trypsinization after the MCF27/A cell grew into for 70%～80% full end, results contain 7 * 10 in each EP pipe approximately in the EP of 1mL pipe
5Individual cell.After PBS cleaning 3 times, the centrifugal supernatant that goes, cell FACS
TMSaturatingization solution is hatched under lucifuge, room temperature, makes cell membrane have more permeability.Cell sap centrifugal 3min under 400g then, the supernatant discarded float.Add 100 μ L JBS21 working solutions after cell cleans 1 time with PBS and under 37 ℃, hatch certain hour, clean 2 times with PBSBN again, discard unconjugated JBS21, avoid non-specific adsorption, add then 100 μ L GAMIF working solutions in 37 ℃ hatch after, clean 3 times with PBSBN, to get rid of the non-specific adsorption that GAMIF was caused.Cell after the processing suspends with 1mL PBS, and 4 ℃ of placements are to be checked.The K562/A cell directly is harvested from the EP pipe of 1mL, and subsequent treatment is with the MCF27/A cell.The cellular control unit of MCF27/A also the same method is handled, and does not just add JBS21 antibody and with the PBSBN replacement of equal volume.Cell under the same treatment condition all detects 2 times.The result as can be seen from Figure, compares ratio 1 and Comparative Examples 2 as shown in Figure 2, and the resistant rate of the Propranolol Nano medication hydrogel preparation capable of permeating skin of embodiment 1 preparation is minimum.
Tumor to nude mice is carried out medication, dips in the pharmaceutical preparation part of embodiment 1, Comparative Examples 1 and Comparative Examples 2 with cotton swab and embrocates, and every day 3 times, 6～8 hours at interval, observes tumor size and changes.The result as shown in Figure 3, the gross tumor volume minimum that embodiment is 1 group.Be used for clinical treatment eyelid hemangioma simultaneously, medication: dip in the pharmaceutical preparation part with cotton swab and embrocate, every day 3 times, 6～8 hours at interval, result such as Fig. 4, it is the fastest to found that the preparation of 1 group of embodiment is cured, and the matched group of Comparative Examples is still better readily good.Illustrate that the antitumous effect of the Propranolol Nano medication hydrogel preparation capable of permeating skin of embodiment 1 preparation obviously is better than the preparation of Comparative Examples 1 and Comparative Examples 2.
The result shows, adopt the inventive method earlier medication preparation to be become Nano medication, further making the hydrogel preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduce Propranolol whole body toxic and side effects, antitumous effect is good and easy to use.
The preparation (two) of embodiment 2 Propranolol Nano medication hydrogel preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 10g Propranolol is dissolved in the 100mL water, add 20g porous hydroxyapatite nano-particle then, stirring is spent the night and is made Propranolol fully be adsorbed in the hydroapatite particles, centrifugal removal supernatant, fully washing again, lyophilizing forms the Propranolol Nano medication then, and the particle diameter of Nano medication is 20～700 nanometers;
(2) preparation polyvinyl alcohol (molecular weight 40,000) percentage by weight is 4%, polyvinyl alcohol (molecular weight 13.6 ten thousand) percentage by weight is 4%, Polyethylene Glycol (molecular weight 400) percentage by weight is 2% hydrogel solution;
(3) the Propranolol Nano medication that step (1) is prepared is dispersed in the hydrogel solution of step (2) preparation according to the weight ratio of 1:5, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% sodium tetradecyl sulfate, 1.5% glycerol and 3.5% propylene glycol, vortex mixing 5 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 4 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 3 times in order, place 0～4 ℃ of preservation to obtain Propranolol Nano medication hydrogel preparation capable of permeating skin at last again.
The Propranolol Nano medication hydrogel preparation capable of permeating skin that embodiment 2 is prepared carries out drug resistance and anticancer test.The mensuration mode of drug resistance of tumor cell rate and antitumous effect Figure 5 shows that the resistant rate of the Propranolol Nano medication hydrogel preparation capable of permeating skin of embodiment 2 preparations with embodiment 1, and as can be seen from Figure, resistant rate is lower.Figure 6 shows that the influence to nude mice gross tumor volume size, the result shows that antitumous effect is better.Adopt the inventive method earlier medication preparation to be become Nano medication, further making the hydrogel preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduces Propranolol whole body toxic and side effects, and antitumous effect is good and easy to use.
The preparation (three) of embodiment 3 Propranolol Nano medication hydrogel preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 10g Propranolol is dissolved in the 100mL water, add 40g porous silver nano-grain then, stirring is spent the night and is made Propranolol fully be adsorbed in the silver nano-grain, centrifugal removal supernatant, fully washing again, lyophilizing forms the Propranolol Nano medication then, and the particle diameter of Nano medication is 10～1000 nanometers;
(2) preparation sodium carboxymethyl cellulose percentage by weight is 8%, polyvinyl alcohol (molecular weight 100,000) percentage by weight is 5%, Polyethylene Glycol (molecular weight 400) percentage by weight is 1.5% hydrogel solution;
(3) the Propranolol Nano medication that step (1) is prepared is dispersed in the hydrogel solution of step (2) preparation according to the weight ratio of 1:10, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% anethole, 2% glycerol and 1.5% propylene glycol, vortex mixing 4 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 10 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 4 times in order, place 0～4 ℃ of preservation to obtain Propranolol Nano medication hydrogel preparation capable of permeating skin at last again.
The preparation (four) of embodiment 4 Propranolol Nano medication hydrogel preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 2g Propranolol is dissolved in the 10mL water and forms pharmaceutical aqueous solution, then pharmaceutical aqueous solution being transferred to 10mL concentration is 5%(w/w) Polyethylene Glycol (molecular weight 8000) aqueous solution in, abundant mixing, then-80 ℃ of refrigerator pre-freezes 12 hours, lyophilizing afterwards, obtain Nano medication with dichloromethane dissolving Polyethylene Glycol and the centrifugal Polyethylene Glycol of removing again, the particle diameter of Nano medication is 50～5000 nanometers;
(2) preparation polyvinyl alcohol (molecular weight 40,000) percentage by weight is 12%, Polyethylene Glycol (molecular weight 400) percentage by weight is 1% hydrogel solution;
(3) the Propranolol Nano medication that step (1) is prepared is dispersed in the hydrogel solution of step (2) preparation according to the weight ratio of 1:8, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% menthol and 5% glycerol, ultrasonic mixing 2 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 6 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 1 time in order, place 0～4 ℃ of preservation to obtain Propranolol Nano medication hydrogel preparation capable of permeating skin at last again.
The preparation (five) of embodiment 5 Propranolol Nano medication hydrogel preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 10g Propranolol is dissolved in the 60mL water, then with to contain polylactic acid-glycolic guanidine-acetic acid-Polyethylene Glycol concentration be 10%(w/w) the dichloromethane solution stirring and evenly mixing, transferring to polyvinyl alcohol concentration is 5%(w/w) aqueous solution in and carry out homogenate, form the Nano medication micelle;
(2) preparation polyvinyl alcohol (molecular weight 40,000) percentage by weight is 4%, polyvinyl alcohol (molecular weight 13.6 ten thousand) percentage by weight is 4%, Polyethylene Glycol (molecular weight 400) percentage by weight is 2% hydrogel solution;
(3) the Propranolol Nano medication micelle that step (1) is prepared is dispersed in the hydrogel solution of step (2) preparation according to the weight ratio of 1:4, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% sodium tetradecyl sulfate and 5% propylene glycol, vortex mixing 5 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 4 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 3 times in order, place 0～4 ℃ of preservation to obtain Propranolol Nano medication hydrogel preparation capable of permeating skin at last again.
The Propranolol Nano medication hydrogel preparation capable of permeating skin that embodiment 3, embodiment 4 and embodiment 5 are prepared carries out drug resistance and anticancer test.The mensuration mode of drug resistance of tumor cell rate and antitumous effect is with embodiment 1, and the result shows that the resistant rate of the Propranolol Nano medication hydrogel preparation capable of permeating skin of preparation is lower, and antitumous effect is better.Adopt the inventive method earlier medication preparation to be become Nano medication, further making the hydrogel preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduces Propranolol whole body toxic and side effects, and antitumous effect is good and easy to use.
The preparation (one) of embodiment 6 Propranolol Nano medication ointment preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication ointment preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 10g Propranolol is dissolved in the 50mL water, add the cross linked porous glucosan nano-particle of 20g then, stirring is spent the night and is made Propranolol fully be adsorbed in the cross-linking dextran granule, centrifugal removal supernatant, fully washing again, lyophilizing forms the Propranolol Nano medication then, and the particle diameter of Nano medication is 500～2000 nanometers;
(2) get tristerin, stearic acid, vaseline, heating paraffin and be molten into oil phase, in addition glycerol and water are heated to 90 ℃, add the dissolving of sodium lauryl sulphate and ethyl hydroxybenzoate again and obtain water, water is slowly poured in the oil phase, stir while adding, condensation obtains ointment base;
(3) the Propranolol Nano medication that step (1) is prepared is dispersed in the ointment base of step (2) preparation according to the weight ratio of 1:9, fully obtains Propranolol Nano medication ointment preparation capable of permeating skin behind the mixing.
The Propranolol Nano medication ointment preparation capable of permeating skin that embodiment 6 is prepared carries out drug resistance and anticancer test.The mensuration mode of drug resistance of tumor cell rate and antitumous effect Figure 7 shows that the resistant rate of the Propranolol Nano medication ointment preparation capable of permeating skin of embodiment 6 preparations with embodiment 1, and as can be seen from Figure, resistant rate is lower.Figure 8 shows that the influence to nude mice gross tumor volume size, the result shows that antitumous effect is better.Adopt the inventive method earlier medication preparation to be become Nano medication, further making the ointment preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduces Propranolol whole body toxic and side effects, and antitumous effect is good and easy to use.
The preparation (two) of embodiment 7 Propranolol Nano medication ointment preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication ointment preparation capable of permeating skin, and preparation process is as follows:
(1) accurately take by weighing the 8g Propranolol and grind with micropowder pulverizing instrument, obtaining particle diameter is the Propranolol Nano medication of 500～2000 nanometers;
(2) Camphora, Mentholum mixed grinding are made it congruent melting, with Oleum menthae, eucalyptus oil mix homogeneously, vaseline, paraffin, Cera Flava are heated to 110 ℃ removes moisture in addition, is chilled to 70 ℃ after the mixing then, add fragrant wet goods and stir, cooling at last obtains ointment base;
(3) the Propranolol Nano medication that step (1) is prepared is dispersed in the ointment base of step (2) preparation according to the weight ratio of 1:9, fully obtains Propranolol Nano medication ointment preparation capable of permeating skin behind the mixing.
The Propranolol Nano medication ointment preparation capable of permeating skin that embodiment 7 is prepared carries out drug resistance and anticancer test, the mensuration mode of drug resistance of tumor cell rate and antitumous effect is with embodiment 1, the result shows that employing the inventive method becomes Nano medication with medication preparation earlier, further making the ointment preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduce Propranolol whole body toxic and side effects, antitumous effect is good and easy to use.
The preparation (one) of embodiment 8 Propranolol Nano medication micropin preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication micropin preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 5g Propranolol is dissolved in the 20mL water, then with to contain polylactic acid-glycolic guanidine-acetic acid-Polyethylene Glycol concentration be 5%(w/w) the dichloromethane solution stirring and evenly mixing, transferring to polyvinyl alcohol concentration is 5%(w/w) aqueous solution in and carry out homogenate, form the Nano medication micelle;
(2) the Propranolol Nano medication micelle that step (1) is prepared is dispersed in the polyvinyl alcohol micropin solution according to the weight ratio of 1:4, water behind the mix homogeneously in the micropin mould, be put into-80 ℃ of pre-freezes then 10 hours, transfer in 4 ℃ of refrigerators and thaw, 3 times repeatedly, final drying obtains Propranolol Nano medication micropin preparation capable of permeating skin.
The Propranolol Nano medication micropin preparation capable of permeating skin that embodiment 7 is prepared carries out drug resistance and anticancer test.The mensuration mode of drug resistance of tumor cell rate and antitumous effect Figure 9 shows that the resistant rate of the Propranolol Nano medication micropin preparation capable of permeating skin of embodiment 8 preparations with embodiment 1, and as can be seen from Figure, resistant rate is lower.Figure 10 shows that the influence to nude mice gross tumor volume size, the result shows that antitumous effect is better.Adopt the inventive method earlier medication preparation to be become Nano medication, further making the micropin preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduces Propranolol whole body toxic and side effects, and antitumous effect is good and easy to use.
The preparation (two) of embodiment 9 Propranolol Nano medication micropin preparation capable of permeating skin
The small-molecule drug Propranolol is prepared into Nano medication micropin preparation capable of permeating skin, and preparation process is as follows:
(1) accurately takes by weighing the 20mg Propranolol and be prepared into polysaccharide Propranolol nano-particle, the preparation of polysaccharide nano-particle sees Chinese patent for details: application number 200610029127.1, patent name are " the low temperature aqueous phase-aqueous phase emulsion prepares the method for protein-polysaccharide vitreous sustained-release micro-spheres ";
(2) the Propranolol Nano medication of step (1) preparation is dispersed in according to the weight ratio of 1:4 contain 10%(w/w) empty micropin, 2.5%(w/w) glycerol and 0.5%(w/w) in the aqueous solution of sodium benzoate, soaked 10 hours behind the mix homogeneously, lyophilizing obtains Propranolol Nano medication micropin preparation capable of permeating skin then.
The Propranolol Nano medication micropin preparation capable of permeating skin that embodiment 9 is prepared carries out drug resistance and anticancer test, the mensuration mode of drug resistance of tumor cell rate and antitumous effect is with embodiment 1, the result shows that employing the inventive method becomes Nano medication with medication preparation earlier, further making the micropin preparation capable of permeating skin again can topical treatment, can overcome the drug resistance of tumor cell, reduce Propranolol whole body toxic and side effects, antitumous effect is good and easy to use.
The preparation of embodiment 10 auxin Nano medication hydrogel preparation capable of permeating skin
The macromolecular drug auxin is prepared into Nano medication hydrogel preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 10g auxin is dissolved in the 100mL water, add 40g porous hydroxyapatite nano-particle then, stirring is spent the night and is made auxin fully be adsorbed in the hydroxyapatite nanoparticle, centrifugal removal supernatant, fully washing again, lyophilizing forms the auxin Nano medication then, and the particle diameter of Nano medication is 500～1000 nanometers;
(2) preparation sodium carboxymethyl cellulose percentage by weight is 8%, polyvinyl alcohol (molecular weight 100,000) percentage by weight is 5%, Polyethylene Glycol (molecular weight 400) percentage by weight is 1.5% hydrogel solution;
(3) the auxin Nano medication that step (1) is prepared is dispersed in the hydrogel solution of step (2) preparation according to the weight ratio of 1:10, add whole weight percent concentration simultaneously and be 0.5% sodium benzoate, 1% anethole, 2% glycerol and 1.5% propylene glycol, vortex mixing 4 minutes; Fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 10 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps repeat 4 times in order, place 0～4 ℃ of preservation to obtain auxin Nano medication hydrogel preparation capable of permeating skin at last again.
The preparation of embodiment 11 auxin Nano medication ointment preparation capable of permeating skin
The macromolecular drug auxin is prepared into Nano medication ointment preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 10g auxin is dissolved in the 50mL water, add the cross linked porous glucosan nano-particle of 20g then, stirring is spent the night and is made auxin fully be adsorbed in the cross-linking dextran granule, centrifugal removal supernatant, fully washing again, lyophilizing forms the auxin Nano medication then, and the particle diameter of Nano medication is 500～2000 nanometers;
(2) get tristerin, stearic acid, vaseline, heating paraffin and be molten into oil phase, in addition glycerol and water are heated to 90 ℃, add the dissolving of sodium lauryl sulphate and ethyl hydroxybenzoate again and obtain water, water is slowly poured in the oil phase, stir while adding, condensation obtains ointment base;
(3) the auxin Nano medication that step (1) is prepared is dispersed in the ointment base of step (2) preparation according to the weight ratio of 1:9, fully obtains auxin Nano medication ointment preparation capable of permeating skin behind the mixing.
The preparation of embodiment 12 auxin Nano medication micropin preparation capable of permeating skin
The macromolecular drug auxin is prepared into Nano medication micropin preparation capable of permeating skin, and preparation process is as follows:
(1) accurately taking by weighing the 5g auxin is dissolved in the 20mL water, then with to contain polylactic acid-glycolic guanidine-acetic acid-Polyethylene Glycol concentration be 5%(w/w) the dichloromethane solution stirring and evenly mixing, transferring to polyvinyl alcohol concentration is 5%(w/w) aqueous solution in and carry out homogenate, form auxin Nano medication micelle;
(2) the auxin Nano medication micelle that step (1) is prepared is dispersed in the polyvinyl alcohol micropin solution according to the weight ratio of 1:4, water behind the mix homogeneously in the micropin mould, be put into-80 ℃ of pre-freezes then 10 hours, transfer in 4 ℃ of refrigerators and thaw, 3 times repeatedly, final drying obtains auxin Nano medication micropin preparation capable of permeating skin.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the inventive method; can also make some improvement and replenish, these improvement and replenish and also should be considered as protection scope of the present invention.
Claims (10)
1. a Nano medication preparation capable of permeating skin is characterized in that, the preparation method of described Nano medication preparation capable of permeating skin may further comprise the steps:
(1) medication preparation is become Nano medication, the percentage by weight of described medicine in Nano medication is 0.1%～90%, and the particle diameter of described Nano medication is 10～5000 nanometers;
(2) Nano medication of step (1) preparation being dispersed in weight percent concentration according to the weight ratio of 1:1～1:10 is in 0.5%～80% the hydrogel solution, add penetration enhancer, antiseptic and wetting agent simultaneously, fully be put into 0～4 ℃ of preservation behind the mixing, be put into-40～-20 ℃ of pre-freezes then 4～12 hours, wherein 0～4 ℃ of preservation and-40～-20 ℃ of pre-freeze steps can repeat 1～4 time in order, place 0～4 ℃ of preservation to obtain Nano medication hydrogel preparation capable of permeating skin at last again; Or
The Nano medication of step (1) the preparation weight ratio according to 1:1～1:10 is dispersed in the ointment base, namely obtain Nano medication ointment preparation capable of permeating skin behind the mix homogeneously, described ointment base is selected from a kind of in water-soluble base, greasing base or the emulsion-type substrate; Or
The Nano medication of step (1) preparation is attached on the micropin surface according to the weight ratio of 1:1～1:10 or be loaded in micropin inner or with the abundant mixing of micropin material after water and in the micropin mould, obtain Nano medication micropin preparation capable of permeating skin.
2. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that, the preparation of the Nano medication described in the step (1) may further comprise the steps: with medicine dissolution in water, add the porous nano granule then, stirring makes medicine fully be adsorbed in the porous nano granule, centrifugal removal supernatant, fully washing again, lyophilizing forms Nano medication then.
3. Nano medication preparation capable of permeating skin according to claim 2; it is characterized in that; described nano-particle is organic nanometer granule or inorganic nanoparticles, optional self-polystyrene nano-particle; the cross-linking dextran nano-particle; nano SiO 2 particle; titania nanoparticles; hydroxyapatite nanoparticle; ferroferric oxide nano granules; ferric oxide particle; gold nano grain; the aluminium sesquioxide nano-particle; the calcium carbonate nano granule; calcium phosphate nanoparticles; the magnesium carbonate nano-particle; in magnesium hydroxide nanoparticles or the silver nano-grain one or more.
4. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that, the preparation of the Nano medication described in the step (1) may further comprise the steps: medicine dissolution is formed pharmaceutical aqueous solution in water, pharmaceutical aqueous solution is transferred in the Polyethylene Glycol aqueous solution then, fully behind the mixing in refrigerator pre-freeze, lyophilizing afterwards obtains Nano medication with dichloromethane dissolving Polyethylene Glycol and the centrifugal Polyethylene Glycol of removing again; Or
Pharmaceutical pack is rolled in liposome, the polymer nano granules forms Nano medication; Or
Medicine dissolution is formed pharmaceutical aqueous solution in water, medicine is separated out with the form of nano-particle obtain Nano medication by adding bad solvent; Or
Medicine is pulverized instrument with micropowder to be pulverized and directly is prepared into Nano medication.
5. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that, the preparation of the Nano medication described in the step (1) may further comprise the steps: with medicine dissolution in water, then with the dichloromethane solution stirring and evenly mixing that contains polylactic acid-glycolic guanidine-acetic acid-Polyethylene Glycol, transfer in the polyvinyl alcohol water solution and carry out homogenate, form the Nano medication micelle.
6. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that the gel-type vehicle in the hydrogel solution described in the step (2) is selected from polyvinyl alcohol, polyvinylpyrrolidone, ethyl cellulose, Polyethylene Glycol, the carboxyl ethylene copolymer, methylcellulose, sodium carboxymethyl cellulose, cross-linked sodium polyacrylate, polylactic acid-polyglycol-polylactic acid polymer, polyethylene glycol-lactic acid-polyethylene glycol polymer, polylactic acid-glycolic guanidine-acetic acid-polyethylene glycol-lactic-co-glycolic acid polymer, polyethylene glycol-lactic-co-glycolic acid-polyethylene glycol polymer, sodium alginate, starch, glycerol, in the gelatin one or more.
7. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that, penetration enhancer described in the step (2) is selected from a kind of in menthol, sodium tetradecyl sulfate, geraniol, anethole or the decyl methyl sulfoxide, described antiseptic is selected from a kind of in sodium benzoate, chlorobutanol, benzalkonium bromide, sorbic acid, ethyl hydroxybenzoate or the butoben, and described wetting agent is glycerol, propylene glycol or the mixture of the two.
8. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that the ointment base described in the step (2) is selected from one or more in tristerin, stearic acid, Cera Flava, lanoline, vaseline, paraffin, silicone, Oleum menthae, eucalyptus oil, vegetable oil, gelatin or the sodium carboxymethyl cellulose.
9. Nano medication preparation capable of permeating skin according to claim 1 is characterized in that, the micropin described in the step (2) refers to metal micro-needle, inorganic micropin or polymer micro needle, and described inorganic micropin refers to the inorganic silicon micropin.
10. Nano medication preparation capable of permeating skin according to claim 1, it is characterized in that, described medicine comprises small-molecule drug and macromolecular drug, described small-molecule drug is selected from Propranolol, amycin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine, semustine, cisplatin, etoposide, camptothecine and derivant thereof, phenesterin, paclitaxel and derivant thereof, Docetaxel and derivant thereof, vinblastine, vincristine, zitazonium, piposulfan, cyclophosphamide, flutamide and derivant thereof, prednisone, rapamycin, ciclosporin, levofloxacin, a kind of in ofloxacin or the epinastine hydrochloride, described macromolecular drug is selected from erythropoietin, recombinant human granulocyte colony stimulating factor, granulocyte-macrophage colony stimutaing factor, vaccine, interferon, growth hormone, insulin, epidermal growth factor, fibroblast growth factor, transforming growth factor, insulin-like growth factor, vascular endothelial cell growth factor, PDGF, endothelial cell growth factor (ECGF), nerve growth factor, bone-derived growth factor, bone morphogenetic protein(BMP), tissue polypeptide antigen, antibody, blood coagulation factor VIII, plasma thromboplastin component, genetic factor, antisense nucleotide, a kind of in microRNA or the gene.
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| CN104069484A (en) * | 2014-03-28 | 2014-10-01 | 上海交通大学 | Interferon microneedle, as well as preparation method and application thereof |
| CN104274390A (en) * | 2014-09-04 | 2015-01-14 | 郑家伟 | Timolol long-acting transdermal preparation and application thereof in hemangioma treatment |
| CN104274390B (en) * | 2014-09-04 | 2017-06-13 | 郑家伟 | A kind of long-acting preparation capable of permeating skin of timolol and its application in hemangioma |
| CN107405313B (en) * | 2015-04-06 | 2021-04-13 | 株式会社Lg生活健康 | Soluble microneedle for delivery of poorly soluble drugs |
| CN107405313A (en) * | 2015-04-06 | 2017-11-28 | 株式会社Lg生活健康 | The soluble micropin of insoluble drug transmission |
| CN105641801A (en) * | 2016-02-27 | 2016-06-08 | 浙江理工大学 | Porous hydroxyapatite/gelatin compounded microneedle array patch and preparation method thereof |
| CN105663027A (en) * | 2016-04-01 | 2016-06-15 | 中国人民解放军广州军区武汉总医院 | External preparation containing sirolimus as well as preparation method and application thereof |
| CN105663027B (en) * | 2016-04-01 | 2018-12-18 | 中国人民解放军广州军区武汉总医院 | Sirolimus external preparation, preparation method and the usage |
| CN106422045A (en) * | 2016-09-05 | 2017-02-22 | 中国科学院理化技术研究所 | Flexible slow-release micro-needle patch and preparation method thereof |
| CN107519433A (en) * | 2017-09-02 | 2017-12-29 | 包宝金 | A kind of nail polish for repairing onychomycosis and preparation method thereof |
| CN108721310A (en) * | 2018-06-29 | 2018-11-02 | 佛山科学技术学院 | A kind of adriamycin and Propranolol compound medicament composition and application thereof |
| CN108721310B (en) * | 2018-06-29 | 2020-06-26 | 佛山科学技术学院 | Adriamycin and propranolol compound pharmaceutical composition and application thereof |
| CN109985248A (en) * | 2019-05-20 | 2019-07-09 | 北京农学院 | Methotrexate (MTX) percutaneous dosing part controlled release preparation and its preparation method and application |
| CN109985248B (en) * | 2019-05-20 | 2022-03-15 | 北京农学院 | Methotrexate transdermal administration local controlled release preparation and preparation method and application thereof |
| CN112494421A (en) * | 2020-12-23 | 2021-03-16 | 华中科技大学 | Slow-release soluble microneedle, preparation method and application |
| CN114773629A (en) * | 2022-05-20 | 2022-07-22 | 昆明理工大学 | Preparation method of injectable light-cured hemostatic hydrogel for traumatic brain injury |
| CN114773629B (en) * | 2022-05-20 | 2024-04-12 | 昆明理工大学 | Preparation method of injectable photo-curing hemostatic hydrogel for traumatic brain injury |
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