CN102397527A - Pharmaceutical composition and application thereof - Google Patents
Pharmaceutical composition and application thereof Download PDFInfo
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- CN102397527A CN102397527A CN2010102853284A CN201010285328A CN102397527A CN 102397527 A CN102397527 A CN 102397527A CN 2010102853284 A CN2010102853284 A CN 2010102853284A CN 201010285328 A CN201010285328 A CN 201010285328A CN 102397527 A CN102397527 A CN 102397527A
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- interferon
- recombinant human
- aretigenin
- alpha
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a pharmaceutical composition and application thereof, wherein the composition contains arctigenin and interferon. The invention also provides a microemulsion preparation and an injection containing the pharmaceutical composition, and application of the pharmaceutical composition in preparing medicines for treating leukemia. Compared with single medicine, the medicine composition provided by the invention has a synergistic effect in treating leukemia.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and application thereof, particularly a kind of pharmaceutical composition and application aspect the treatment leukemia thereof that contains aretigenin and interferon.
Background technology
Cancer is that current serious influences human health, threatens one of principal disease of human life.Acute leukemia is a kind of common blood system malignant disease, and leukemia is occupied the first five position in each age mortality of malignant tumors of the whole nation, in child and the crowd below 35 years old, holds pride of place.Leukemic treatment generally can be divided into the inducer remission treatment and alleviate two Main Stage of back treatment, and the latter can further be divided into after treatment again and keep two stages of treatment.The purpose of inducer remission treatment is promptly the leukaemia to be reduced as far as possible, makes the hematopoietic function recovery of bone marrow normal, reaches the standard of alleviating fully.Alleviating fully is that the leukaemic does not have hemorrhage heating and Anemia, and life normally or normal basically.The purpose of alleviating the back treatment is consolidation and the intensive treatment that continues the long period through adopting, and further eliminates leukaemia remaining in the body, prevents leukemia relapse, prolongs and alleviates and life span, strives for curing leukemia.After alleviating fully, still need adopt positive consolidation and intensive treatment and continue quite over a long time (2-3).Becoming human acute myeloid leukemia therapeutic scheme commonly used in the world is the scheme that cytosine arabinoside+anthracene nucleus or anthraquinone based chemotherapy medicine are formed, but this therapeutic scheme toxic and side effects is big, brings very big misery to patient.
Interferon is multi-functional cytokine, by interferon inducers stimulation reticuloendothelial system, macrophage, the lymphocyte of virus and other kinds and a kind of glycoprotein that somatic cell produced.This albumen has multiple biological activity, comprises antiproliferative, antiviral, immunomodulating and induction of differentiation.
Find three types of α, β, γ at present on mankind altogether: alpha-interferon is produced by leukocyte, and interferon beta is produced by fibroblast, and interferon gamma is to be produced by the lymphocyte in the immune system.All this all is effective viral inhibitors for three kinds, and has certain antitumaous effect.Alpha-interferon is a cytokine of using the widest treatment tumor clinically.It is through direct anti-tumour cell proliferative and adjusting body's immunity performance antitumor action.Beta-interferon has obvious or stronger inhibited proliferation to human brain cell strain and the strain of people's malignant melanoma cell, to the effect of obvious suppression tumor body propagation is all arranged after nude mice subcutaneous vaccination glioblastoma cell strain, Glioblastoma cell strain, glioblastoma multiforme cell strain, the strain of people's malignant melanoma cell.Adult's intramuscular injection or quiet administration, each (1～6) * 10
6Unit/m
2, in normal saline 2ml dissolving back intramuscular injection, or be dissolved in normal saline or 5% glucose injection, 250～500ml, in 1 hour, drip off, one day 1 time, logotype 10 days, interval repeated in 3～5 days, and annotating 30 altogether is a course of treatment.The biological activity of gamma interferon comprises: the antigenic expression of MHC II class such as mononuclear cell, macrophage, BMDC, SF, vascular endothelial cell, sternzellen are induced in (1), make it participate in the identifying of specific immunity; (2) promote LPS stimulated in vitro mouse B cell IgG secretion 2a, reduce the generation of IgG1, IgG2b, IgG3 and IgE; Inhibition is by the inductive mouse B cell propagation of IL-4, and IgG1 and IgE produce and Fc ε RII expresses, and promote the propagation of the inductive human B cell of SAC; (3) collaborative IL-2 induces LAK active, promotes T cell IL-2R to express; (4) induce acute phase protein synthetic, induce the myeloid cell differentiation.
Though interferon has been used to treat inflammatory, viral and proliferative disease, comprises leukemia, it has many side effect, comprise local injection reaction, influenza appearance syndrome and depression etc., and these side effect increases the weight of with dosage.Exactly because many leukemic treatments need the interferon of higher dosage, the increase of dosage has increased the weight of toxic and side effects again, so a lot of patient is impatient at and compelled TD.Therefore, need and to unite to improve treatment leukemia curative effect, to reduce the chemical compound of toxic and side effects with interferon,, will produce important meaning the treatment of leukemia patient if can further obtain to reduce dosage, minimizing administration frequency.
For example, in multiple sclerosis therapy (MS treatment), some chemical compounds of uniting use with beta-interferon will reduce potentially the beta-interferon administration dosage, alleviate the side effect that produces by beta-interferon.But these conjoint therapies may not necessarily can alleviate side effect.For example, comprise that the acetic acid lattice draw the therapeutic alliance for thunder and alpha-interferon not improve the clinical score with the mice of EAE treatment.To seek the chemical compound of uniting use with interferon be very necessary in the hope of obtaining to promote curative effect, make side effect reduce to minimum work simultaneously so carry out, and difficulty also is sizable.
Aretigenin (arctigenin) is a Lignanoids compounds, derives from the Chinese medicine Fructus Arctii.Have antibiotic significantly, antiviral, antitumor, anti-paf receptor and calcium antagonistic activity.Wang Lu etc. are at " arctigenin is induced human leukemia cell's effect of apoptosis and mechanism " (Acta Pharmaceutica Sinica; 2008 the 43rd the 5th phases of volume; The 542-547 page or leaf) literary composition discloses arctigenin and can bring into play cytotoxicity through cell death inducing, thereby suppresses the propagation of the capable leukemia K 562 of chronic granulocyte.But there is not scientific evidence to show that aretigenin and interferon therapy leukemia have synergic effect so far.
Summary of the invention
In order to reduce toxic and side effects, to improve interferon to leukemic curative effect; The present invention unites use with aretigenin and interferon; Obtained good expection; The invention provides a kind ofly for this reason, contain active component aretigenin and interferon in this pharmaceutical composition treatment leukemia effectively pharmaceutical composition.The purpose of aretigenin and interferon administering drug combinations is to reduce the dosage of interferon, to obtain efficacious therapy, the side effect that alleviates interferon simultaneously.
The present invention finds that aretigenin has very strong therapeutic effect to leukemia mouse after aretigenin, interferon drug administration by injection are used to treat various types of leukemia mouse models, and wherein the weight ratio of interferon and aretigenin is (3 * 10
-5-0.1): 1, with independent drug administration by injection aretigenin, separately the drug administration by injection interferon is compared and had significant difference, and have the Synergistic treatment activity.The invention provides the leukemic pharmaceutical composition of a kind of treatment, the active component in this pharmaceutical composition is aretigenin and interferon for this reason, and the weight ratio of interferon and aretigenin is (3 * 10
-5-0.1): 1.
Above-mentioned interferon is selected from a kind of in alpha-interferon, beta-interferon and the gamma interferon or has the combination in any of treatment leukemia effect between them.Interferon is meant alpha-interferon, alpha-interferon analog, alpha-interferon derivant, alpha-interferon conjugates, beta-interferon, beta-interferon analog, beta-interferon derivant, beta-interferon conjugates, gamma interferon particularly.Alpha-interferon and beta-interferon gene can pass through for example to point to its beta-interferon analog of oligonucleotide change generation of sudden change, and for example the people recombinates that cysteine lacks or the metathetical analog of cysteine.In addition, amino acid whose identification or location can change through targeting more than one, and proteinic primary amino acid sequence can increase through glycosylation or through other complementarity molecule (like lipid, phosphoric acid and acetyl group).Single amino acids residue in the chain can be modified through oxidation, reduction or other derivation effect.Alpha-interferon or beta-interferon protein cleavable obtain to keep active fragment, and whole protein or its fragment can merge with other peptide and protein (like immunoglobulin).Alpha-interferon and beta-interferon conjugates can represent to comprise the component of the beta-interferon of the polymer coupling that contains polyalkylene glycol moiety that exists with non-natural.Preferred interferon comprises
The alpha-interferon of the alpha-interferon of the alpha-interferon of the alpha-interferon of Alfacon-1, alpha-interferon, alpha-interferon analog, Pegylation, polymeric alpha-interferon, dimerization, the alpha-interferon that closes with the carrier yoke, oral cavity inhalant form, the alpha-interferon of injectable composition form, topical composition form,
Analog,
Analog,
Analog,
Analog,
Analog, Alfacon-1 analog, beta-interferon, Avonex
TM, Betaseron
TM, Betaferon
TM, Rebif
TM, the beta-interferon of beta-interferon analog, the beta-interferon of Pegylation, polymeric beta-interferon, dimerization, beta-interferon, the beta-interferon of oral cavity inhalant form, the beta-interferon of injectable composition form, the beta-interferon of topical composition form, the Avonex that closes with the carrier yoke
TMAnalog, Betaseron
TMAnalog, Betaferon
TMAnalog, Rebif
TMAnalog.Also can use the material that brings out alpha-interferon or beta-interferon generation or simulate alpha-interferon or beta-interferon effect.
The dosage that uses for every kind of interferon with this area professional and technical personnel known and clinical before and those dosage of using in clinical research and the commercial application similar.Owing to the curative effect that has strengthened these chemical compounds of uniting of these chemical compounds and aretigenin chemical compound, so concentration can be lower than the dosage of general use.Really, the purpose of aretigenin chemical compound and interferon administering drug combinations is to reduce the dosage of interferon, to obtain efficacious therapy, the side effect that alleviates interferon simultaneously.
The dosage of alpha-interferon and beta-interferon is known in the art.For example, the dosage that is used to treat the interferon of proliferative disease hairy cell leukemia is 100-3600 ten thousand units, once a day or twice weekly.The dosage of beta-interferon typically is 30 μ g-250 μ g.Avonex
TM, Betaseron
TM, Rebif
TMThe main distinction be that the approach of amount and administration of given beta-interferon is different with frequency.Avonex
TMPreferably with 30 μ g dosage administered intramuscular each time; Betaseron
TMPreferably with the dosage subcutaneous injection administration every other day of 250 μ g; Rebif
TMPreferably with the inferior on every Wendesdays subcutaneous injection administration of the dosage of 44 μ g.
Those of ordinary skills are clear, and the amount of various compositions will depend on these above-mentioned factors in the present composition of the patient being used according to the present invention.The invention provides and promote or strengthen the method for interferon the leukemia therapeutic activity; Described method promptly is co-administered a certain amount of aretigenin and interferon; Aretigenin and interferon simultaneously or jointly carry out administration with various dose and route of administration therapeutic scheme, with enhancing interferon therapy leukaemic's effect (with using interferon separately and comparing).The therapeutic scheme that can adopt comprises: (1) above once a day, once a day, weekly above, weekly, every month once more than or every month once co-administered aretigenin and interferon, be used for leukemic effective treatment; (2) above once a day, once a day, weekly above, weekly, every month once more than or once used aretigenin and interferon simultaneously in every month, be used for leukemic effective treatment.
In addition, in the leukemic pharmaceutical composition of above-mentioned treatment, the dosage of aretigenin intramuscular injection, subcutaneous injection or intravenous drip is 0.01-10mg/kg.
The present invention has also carried out preferably the weight ratio of aretigenin and interferon, is primarily aimed at the screening of this pharmaceutical composition at the curative effect of medication that suppresses propagation and inducing leukemia cell differentiation.Pharmaceutical composition of the present invention is selected but is not limited to the embodiment of following pharmaceutical compositions:
(1) interferon is a recombinant human interferon alpha-2, and the ratio between the amount of recombinant human interferon alpha-2 and the amount of aretigenin is (0.25-500): 1, and the amount of recombinant human interferon alpha-2 representes that with million international units the amount of aretigenin is represented with milligram.
(2) interferon is a recombinant human interferon alpha 1 b, and the weight ratio of recombinant human interferon alpha 1 b and aretigenin is (5 * 10
-5～0.1): 1.
(3) interferon is recombinant human interferon beta 1a, and the weight ratio of recombinant human interferon beta 1a and aretigenin is (3 * 10
-5-0.1): 1.
(4) interferon is recombinant human interferon beta 1b, and the weight ratio of recombinant human interferon beta 1b and aretigenin is (5 * 10
-5-0.45): 1.
(5) interferon is a recombinant human interferon gamma, and the ratio between the amount of recombinant human interferon gamma and the amount of aretigenin is 1: (0.3-1200), the amount of recombinant human interferon gamma representes that with million international units the amount of aretigenin is represented with milligram.
The present invention has investigated the compositions dialogue cell strain NB4 of interferon and aretigenin and the influence of MR2 propagation and differentiation through embodiment 26,27; Experimental result shows that each experimental group compares with matched group; The NB4 cell all there is inhibited proliferation, and has significance or utmost point significant difference.Compare with interferon-ALPHA 2a group, Arctiin tuple, low group of interferon-ALPHA 2a compound recipe and the high group of compound recipe have significant difference to the NB4 cell inhibitory effect, and have synergism; Compare with interferon-ALPHA 1b group, Arctiin tuple, low group of interferon-ALPHA 1b compound recipe and the high group of compound recipe have significant difference to the NB4 cell inhibitory effect, and have synergism; Compare with interferon beta 1a group, Arctiin tuple, low group of interferon beta 1a compound recipe and the high group of compound recipe have significant difference to the NB4 cell inhibitory effect, and have synergism; Compare with interferon beta 1b group, Arctiin tuple, low group of interferon beta 1b compound recipe and the high group of compound recipe have significant difference to the NB4 cell inhibitory effect, and have synergism; Compare with interferon gamma group, Arctiin tuple, the low group of interferon gamma compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism.Each experimental group is followed successively by the power of NB4 cell inhibitory effect effect: the low group of interferon compound recipe and the high group＞interferon group of compound recipe＞Arctiin tuple.
Each experimental group is compared with matched group, and the MR2 cell is all had inhibited proliferation, and has significance or utmost point significant difference, and inhibitory action prolongation in time strengthens gradually.Compare with interferon-ALPHA 2a group, Arctiin tuple, low group of interferon-ALPHA 2a compound recipe and the high group of compound recipe have significant difference to the MR2 cell inhibitory effect, and have synergism; Compare with interferon-ALPHA 1b group, Arctiin tuple, low group of interferon-ALPHA 1b compound recipe and the high group of compound recipe have significant difference to the MR2 cell inhibitory effect, and have synergism; Compare with interferon beta 1a group, Arctiin tuple, low group of interferon beta 1a compound recipe and the high group of compound recipe have significant difference to the MR2 cell inhibitory effect, and have synergism; Compare with interferon beta 1b group, Arctiin tuple, low group of interferon beta 1b compound recipe and the high group of compound recipe have significant difference to the MR2 cell inhibitory effect, and have synergism; Compare with interferon gamma group, Arctiin tuple, the low group of interferon gamma compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Each experimental group is followed successively by the power of MR2 cell inhibitory effect effect: the low group of interferon compound recipe and the high group＞interferon group of compound recipe＞Arctiin tuple.
NBT reduction test result shows still to be the MR2 cell for the NB4 cell no matter; Compare with single medicine; The cell NBT positive rate of low group of interferon compound recipe and the high group of compound recipe has significant difference or utmost point significant difference; Compare with single medicine, the low group of interferon compound recipe and high group of group of compound recipe also further show as synergism to the differentiation capability of inducing of NB4 cell and MR2 cell.
Based on above experimental result, the present invention also provides the application of pharmaceutical composition of the present invention in the medicine of preparation treatment inducing leukemia cell differentiation and inhibition Leukemia Cell Proliferation.Active component in the described compositions is aretigenin and interferon, and the weight ratio of interferon and aretigenin is (3 * 10
-5-0.1): 1.
In the application in the medicine of preparation treatment inducing leukemia cell differentiation and inhibition Leukemia Cell Proliferation, described pharmaceutical composition is selected from following pharmaceutical combination:
(1) interferon is a recombinant human interferon alpha-2, and the ratio between the amount of recombinant human interferon alpha-2 and the amount of aretigenin is (0.25-500): 1, and the amount of recombinant human interferon alpha-2 representes that with million international units the amount of aretigenin is represented with milligram.
(2) interferon is a recombinant human interferon alpha 1 b, and the weight ratio of recombinant human interferon alpha 1 b and aretigenin is (5 * 10
-5～0.1): 1.
(3) interferon is recombinant human interferon beta 1a, and the weight ratio of recombinant human interferon beta 1a and aretigenin is (3 * 10
-5-0.1): 1.
(4) interferon is recombinant human interferon beta 1b, and the weight ratio of recombinant human interferon beta 1b and aretigenin is (5 * 10
-5-0.45): 1.
(5) interferon is a recombinant human interferon gamma, and the ratio between the amount of recombinant human interferon gamma and the amount of aretigenin is 1: (0.3-1200), the amount of recombinant human interferon gamma representes that with million international units the amount of aretigenin is represented with milligram.
In addition; The discovery that the inventor is surprised; The dosage of alpha-interferon, beta-interferon and gamma interferon height no matter; Even under the very low situation of their drug dose, this pharmaceutical composition to various leukemia mouse model therapeutic effect all very obviously, and be significantly higher than the interferon such as alpha-interferon, beta-interferon and gamma interferon of the high dose of independent use.
In order better to express the form of this pharmaceutical composition, the present invention has prepared the microemulsion formulation of this pharmaceutical composition.Described microemulsion formulation can prepare according to conventional method for preparing, and the mean diameter of the microemulsion formulation of preparation is 15-80nm.Described ejection preparation can prepare according to conventional formulation.The present invention has also studied the microemulsion formulation dialogue cell strain NB4 of pharmaceutical composition provided by the invention and the influence of MR2 propagation and differentiation; Result of the test has obtained unexpected effect, is suppressing all to obtain good synergism aspect Leukemia Cell Proliferation and the inducing leukemia cell differentiation.
In a word, pharmaceutical composition provided by the invention is compared with prior art, has following outstanding advantage:
The first, prior art mostly adopts the administration successively successively in order of two or more cancer therapy drugs, and the present invention is prepared into a kind of pharmaceutical preparation administration simultaneously with two kinds of cancer therapy drugs, greatly makes things convenient for the patient to use, and has improved the compliance of disease treatment.
The second, to compare with single medicine or other drug combination, pharmaceutical composition provided by the invention has significant synergism aspect the treatment leukemia.
The 3rd, this pharmaceutical composition has outstanding characteristics.From the natural plants Fructus Arctii, extract the aretigenin that obtains, toxicity is low, and in case use with the interferon combination; Under the prerequisite that guarantees stronger active anticancer; Can significantly reduce the using dosage of interferon, reduce toxic and side effects, improve the drug resistance of cancer therapy drug.
The specific embodiment
Below further describe the present invention through specific embodiment, the present invention is not limited only to following examples.
Embodiment 1 pharmaceutical composition microemulsion formulation of the present invention
Aretigenin 1g
Recombinant human interferon alpha-2 250MIU
Soybean oil 5g
Polyoxyethylene-23-lauryl ether 20g
1,2-propylene glycol 6g
Preparation technology: take by weighing recipe quantity soybean oil, polyoxyethylene-23-lauryl ether, 1; The 2-propylene glycol; Stir after the mixing, add the dissolving of aretigenin, recombinant human interferon alpha-2 then, also can ultrasonic Treatment with accelerate dissolution; Concentrated solution be must clarify, aretigenin and recombinant human interferon alpha-2 microemulsion concentrate are.Laser granulometry is measured its particle diameter, and mean diameter is 15nm.
Embodiment 2 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon alpha-2 5 * 10
5MIU
Hydrogenation cocos nucifera oil glyceride 5g
Lauroyl Polyethylene Glycol-32-glyceride 20g
1,2-propylene glycol 5g
Polyethylene Glycol 3350 10g
Preparation technology: take by weighing recipe quantity hydrogenation cocos nucifera oil glyceride, lauroyl Polyethylene Glycol-32-glyceride, 1; 2-propylene glycol, Polyethylene Glycol 3350; Stir after the mixing, add the dissolving of aretigenin, recombinant human interferon alpha-2 then, also can ultrasonic Treatment with accelerate dissolution; Concentrated solution be must clarify, aretigenin and recombinant human interferon alpha-2 microemulsion concentrate are.Laser granulometry is measured its particle diameter, and mean diameter is 40nm.
Embodiment 3 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon alpha-2 3000MIU
Safflower oil 15g
Polyoxyethylene-23-lauryl ether 6g
1,2-propylene glycol 10g
Preparation technology is with embodiment 2.Laser granulometry is measured its particle diameter, and mean diameter is 36nm.
Embodiment 4 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 0.1g
Recombinant human interferon alpha 1 b 0.01g
Oleum Gossypii semen 10g
SY-Glyster MSW 750 15g
1,2-propylene glycol 7.5g
Preparation technology: take by weighing recipe quantity Oleum Gossypii semen, SY-Glyster MSW 750,1; The 2-propylene glycol; Stir after the mixing, add the dissolving of aretigenin, recombinant human interferon alpha 1 b then, also can ultrasonic Treatment with accelerate dissolution; Must clarify concentrated solution, be the microemulsion concentrate of aretigenin and recombinant human interferon alpha 1 b.Laser granulometry is measured its particle diameter, and mean diameter is 76nm.
Embodiment 5 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon alpha 1 b 5 * 10
-5g
Soybean oil 20g
SY-Glyster MSW 750 25g
1,2-propylene glycol 5g
Preparation technology is with embodiment 4.Laser granulometry is measured its particle diameter, and mean diameter is 47nm.
Embodiment 6 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon alpha 1 b 0.01g
Soybean oil 32g
SY-Glyster MSW 750 16g
1,2-propylene glycol 8g
Preparation technology is with embodiment 4.Laser granulometry is measured its particle diameter, and mean diameter is 58nm.
Embodiment 7 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon beta 1a 30 μ g
Soybean oil 13g
SY-Glyster MSW 750 9g
1,2-propylene glycol 15g
Preparation technology: take by weighing recipe quantity soybean oil, SY-Glyster MSW 750,1; The 2-propylene glycol; Stir after the mixing, add aretigenin, recombinant human interferon beta 1a dissolving then, also can ultrasonic Treatment with accelerate dissolution; Must clarify concentrated solution, be the microemulsion concentrate of aretigenin and recombinant human interferon beta 1a.Laser granulometry is measured its particle diameter, and mean diameter is 66nm.
Embodiment 8 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon beta 1a 0.01g
Soybean oil 6g
SY-Glyster MSW 750 15g
1,2-propylene glycol 15g
Preparation technology is with embodiment 7.Laser granulometry is measured its particle diameter, and mean diameter is 38nm.
Embodiment 9 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon beta 1a 0.1g
Soybean oil 20g
SY-Glyster MSW 750 15g
1,2-propylene glycol 11g
Preparation technology is with embodiment 7.Laser granulometry is measured its particle diameter, and mean diameter is 44nm.
Embodiment 10 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon beta 1b 0.45g
Soybean oil 5.5g
SY-Glyster MSW 750 7.5g
1,2-propylene glycol 5g
Preparation technology: take by weighing recipe quantity soybean oil, SY-Glyster MSW 750,1; The 2-propylene glycol; Stir after the mixing, add aretigenin, recombinant human interferon beta 1b dissolving then, also can ultrasonic Treatment with accelerate dissolution; Must clarify concentrated solution, be the microemulsion concentrate of aretigenin and recombinant human interferon beta 1b.Laser granulometry is measured its particle diameter, and mean diameter is 56nm.
Embodiment 11 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon beta 1b 5 * 10
-5g
Soybean oil 13.2g
SY-Glyster MSW 750 10.5g
1,2-propylene glycol 7.5g
Preparation technology is with embodiment 10.Laser granulometry is measured its particle diameter, and mean diameter is 48nm.
Embodiment 12 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1g
Recombinant human interferon beta 1b 0.1g
Soybean oil 10g
SY-Glyster MSW 750 8g
1,2-propylene glycol 15g
Preparation technology is with embodiment 10.Laser granulometry is measured its particle diameter, and mean diameter is 57nm.
Embodiment 13 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 0.3mg
Recombinant human interferon gamma 1MIU
Soybean oil 12.0g
SY-Glyster MSW 750 8.5g
1,2-propylene glycol 7.8g
Preparation technology: take by weighing recipe quantity soybean oil, SY-Glyster MSW 750,1; The 2-propylene glycol; Stir after the mixing, add the dissolving of aretigenin, recombinant human interferon gamma then, also can ultrasonic Treatment with accelerate dissolution; Must clarify concentrated solution, be the microemulsion concentrate of aretigenin and recombinant human interferon gamma.Laser granulometry is measured its particle diameter, and mean diameter is 75nm.
Embodiment 14 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 0.1g
Recombinant human interferon gamma 1MIU
Soybean oil 12.5g
SY-Glyster MSW 750 5.0g
1,2-propylene glycol 15.0g
Preparation technology is with embodiment 13.Laser granulometry is measured its particle diameter, and mean diameter is 28nm.
Embodiment 15 pharmaceutical composition microemulsion formulations of the present invention
Aretigenin 1.2g
Recombinant human interferon gamma 1MIU
Soybean oil 6.8g
SY-Glyster MSW 750 15.5g
1,2-propylene glycol 10.5g
Preparation technology is with embodiment 13.Laser granulometry is measured its particle diameter, and mean diameter is 63nm.
Embodiment 16 drug combination injections of the present invention
Aretigenin 1g
Recombinant human interferon alpha-2 500MIU
Sodium chloride 0.85g
1,2-propylene glycol 4.5g
Preparation technology: get the aretigenin and the recombinant human interferon alpha-2 of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 17 drug combination injections of the present invention
Aretigenin 1g
Recombinant human interferon alpha-2 0.25MIU
Sodium chloride 1.75g
1,2-propylene glycol 16g
Preparation technology is with embodiment 16.
Embodiment 18 drug combination injections of the present invention
Aretigenin 1g
Recombinant human interferon alpha 1 b 0.1g
Sodium chloride 2.5g
1,2-propylene glycol 4.5g
Preparation technology: get the aretigenin and the recombinant human interferon alpha 1 b of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 19 drug combination injections of the present invention
Aretigenin 0.01g
Recombinant human interferon alpha 1 b 0.005g
Sodium chloride 1.85g
1,2-propylene glycol 1.8g
Preparation technology: get the aretigenin and the recombinant human interferon alpha 1 b of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 20 drug combination injections of the present invention
Aretigenin 1g
Recombinant human interferon beta 1a 0.1g
Sodium chloride 1.5g
1,2-propylene glycol 6.5g
Preparation technology: get the aretigenin and the recombinant human interferon beta 1a of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 21 drug combination injections of the present invention
Aretigenin 0.01g
Recombinant human interferon beta 1a 0.003g
Sodium chloride 1.95g
1,2-propylene glycol 2.75g
Preparation technology: get the aretigenin and the recombinant human interferon beta 1a of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 22 drug combination injections of the present invention
Aretigenin 1g
Recombinant human interferon beta 1b 0.45g
Sodium chloride 2.5g
1,2-propylene glycol 6g
Preparation technology: get the aretigenin and the recombinant human interferon beta 1b of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 23 drug combination injections of the present invention
Aretigenin 0.01g
Recombinant human interferon beta 1b 0.005g
Sodium chloride 1.85g
1,2-propylene glycol 1.8g
Preparation technology: get the aretigenin and the recombinant human interferon beta 1b of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 24 drug combination injections of the present invention
Aretigenin 0.3mg
Recombinant human interferon gamma 1MIU
Sodium chloride 0.85g
1,2-propylene glycol 1.5g
Preparation technology: get the aretigenin and the paclitaxel of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
Embodiment 25 drug combination injections of the present invention
Aretigenin 1.2g
Recombinant human interferon gamma 1MIU
Sodium chloride 0.85g
1,2-propylene glycol 7.5g
Preparation technology: get the aretigenin and the paclitaxel of recipe quantity, add an amount of distilled water, add 1 again, the 2-propylene glycol fully dissolves, and adds sodium chloride, filtration, embedding, and 100 degrees centigrade of sterilization 30min promptly get.
The influence of embodiment 26 pharmaceutical composition low dose group dialogue cell strain NB4 of the present invention and MR2 propagation and differentiation
1 materials and methods
1.1 material
NB4 cell strain and MR2 cell strain are all available from Rui Jin, Shanghai hospital Blood Research Institute.ATRA is mixed with 10 available from Sigma company with dehydrated alcohol
-3The storage liquid of mol/L, filtration, packing ,-20 ℃ keep in Dark Place.Recombinant human interferon alpha-2, recombinant human interferon alpha 1 b, recombinant human interferon beta 1a, recombinant human interferon beta 1b, recombinant human interferon gamma are available from Shanghai clone Biology high technology Ltd.The anti-people PML of rabbit polyclonal antibody (I is anti-) is purchased the company in Chemicon.Goat-anti rabbit FITC-IgG (II is anti-) purchases the company in KPL.
1.2 cell culture
With NB4, MR2 cell respectively with 1 * 10
6The concentration of/ml is inoculated in the RPMI-1640 culture fluid, under 37 ℃, saturated humidity condition is 5% CO in volume fraction
2Cultivate in the incubator.The cell of getting exponential phase of growth experimentizes.
1.3MMT method detects the cell proliferation situation
With NB4 and MR2 cell respectively with 5 * 10
4The concentration of/ml is inoculated in 96 well culture plates, and every hole inoculum concentration is 100 μ l.Experimental group adds normal saline, aretigenin, recombinant human interferon alpha-2, recombinant human interferon alpha 1 b, recombinant human interferon beta 1a, recombinant human interferon beta 1b, recombinant human interferon gamma, recombinant human interferon alpha-2+aretigenin, recombinant human interferon alpha 1 b+aretigenin, recombinant human interferon beta 1a+ aretigenin, recombinant human interferon beta 1b+ aretigenin, recombinant human interferon gamma+aretigenin respectively.The final concentration of effective active composition is respectively:
Matched group: the RPMI-1640 culture fluid,
The Arctiin tuple: the final concentration of aretigenin is 0.01mg/ml,
Interferon-ALPHA 2a group: the final concentration of recombinant human interferon alpha-2 is 2.5 * 10
-3MIU/ml,
Interferon-ALPHA 1b group: the final concentration 5 * 10 of recombinant human interferon alpha 1 b
-7Mg/ml,
Interferon beta 1a group: the final concentration 3 * 10 of recombinant human interferon beta 1a
-7Mg/ml,
Interferon beta 1b group: the final concentration 5 * 10 of recombinant human interferon beta 1b
-7Mg/ml,
The interferon gamma group: the final concentration 0.033MIU/ml of recombinant human interferon gamma,
The low group of interferon-ALPHA 2a compound recipe: the final concentration of recombinant human interferon alpha-2+aretigenin is 2.5 * 10
-3The recombinant human interferon alpha-2 of MIU/ml and the aretigenin of 0.01mg/ml,
The low group of interferon-ALPHA 1b compound recipe: the final concentration of recombinant human interferon alpha 1 b+aretigenin is 5 * 10
-7The recombinant human interferon alpha 1 b of mg/ml and the aretigenin of 0.01mg/ml,
The low group of interferon beta 1a compound recipe: the final concentration of recombinant human interferon beta 1a+ aretigenin is 3 * 10
-7The recombinant human interferon beta 1a of mg/ml and the aretigenin of 0.01mg/ml,
The low group of interferon beta 1b compound recipe: the final concentration of recombinant human interferon beta 1b+ aretigenin is 5 * 10
-7The recombinant human interferon beta 1b of mg/ml and the aretigenin of 0.01mg/ml,
The low group of interferon gamma compound recipe: the final concentration of recombinant human interferon gamma+aretigenin is the recombinant human interferon gamma of 0.033MIU/ml and the aretigenin of 0.01mg/ml.
The total measurement (volume) in every hole is 200 μ l.Matched group adds 100 μ lRPMI-1640 culture fluid.After the 1st, 3,5,8 day, detect cell absorbance (A) value with the MIT method, 3 multiple holes are established in every kind of processing, repeat 3 times, get its meansigma methods.(to annotate: changed culture fluid one time to cell in per 3 days. matched group is used the RPMI-1640 culture fluid.Experimental group is with the corresponding RPMI-1640 culture fluid that contains aretigenin, interferon or aretigenin+interferon.)
Inhibitory rate of cell growth=[(matched group average A value-experimental group average A value)/matched group average A value] * 100%.Inhibitory rate of cell growth is represented the inhibited proliferation to the leukaemia, and the high more expression of inhibitory rate of cell growth is strong more to leukaemia's inhibited proliferation.
1.4 the detection of cell differentiation
With NB4 and MR2 cell respectively with 5 * 10
4The concentration of/ml is inoculated in the 25ml culture bottle, and every bottle of inoculum concentration is 5ml.Experimental group adds the active component of above-mentioned concentration respectively, and matched group adds normal saline.Collecting cell after 3 days adopts nitro NBT reduction experiment to detect the differentiation of cell.The centrifugal supernatant that goes adds 0.1% NBT reactant liquor 0.5ml (containing 0.1% NBT and the TPA of 100ng/ml), cultivates the centrifugal supernatants that go of 1h. for 37 ℃; The deposition smear, air-dry, Giemsa-Wright dyeing; The oil mirror amplifies 1000 times of observations down, counts 200 cells, calculates the NBT positive rate.NBT positive rate=(NBT positive cell number/TCS) * 100%.The NBT positive rate is represented the differentiation capability of inducing to NB4 cell and MR2 cell, and the NBT positive rate is high more, and expression induces differentiation capability strong more to NB4 cell and MR2 cell.Repeat 3 times and get its meansigma methods.
1.5PML Protein Detection
Cell culture processes is the same.Collecting cell after 3 days, the centrifugal supernatant that goes, using the PBS dilution is 1 * 10
6The cell suspension of/ml is got the 0.1ml system and is dripped sheet, carries out indirect immunofluorescence experiment immediately.4% paraformaldehyde is 20min fixedly, adds 0.1%TritonX-100 effect 10min.Add 1: 200 and exempt from the anti-PML of anti-people, 37 ℃ of water-bath 1h.Add 1: 10 goat-anti rabbit FITC-IgG, 37 ℃ of water-bath 1h.Add buffering glycerol, the coverslip mounting.Fluorescence microscope is observed down, and (excitation wavelength 488nm) takes pictures.All soak rinsing respectively 2 times behind the fixing and antibody incubation with PBS and BSA-PBS.
1.6 statistical analysis
Calculate the inhibitory rate of cell growth and the NBT positive rate of each experimental group respectively, and respectively each experimental group inhibitory rate of cell growth and NBT positive rate are carried out χ
2Check.If χ
2＞χ
2 0.05.1=3.84, have significant difference property with p＜0.05.
2, experimental result
Each experimental group is compared with matched group, and the NB4 cell is all had inhibited proliferation, and has significance or utmost point significant difference, and inhibitory action prolongation in time strengthens gradually.The growth of NB4 cell obviously receives to press down in the time of the 5th day, and each experimental group is seen table 1 to the growth inhibition ratio of NB4 cell in the time of the 8th day.Compare with interferon-ALPHA 2a group, Arctiin tuple, the low group of interferon-ALPHA 2a compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon-ALPHA 1b group, Arctiin tuple, the low group of interferon-ALPHA 1b compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon beta 1a group, Arctiin tuple, the low group of interferon beta 1a compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon beta 1b group, Arctiin tuple, the low group of interferon beta 1b compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon gamma group, Arctiin tuple, the low group of interferon gamma compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Each experimental group is followed successively by the power of NB4 cell inhibitory effect effect: the interferon compound recipe hangs down group＞interferon group＞Arctiin tuple.
Each experimental group is compared with matched group, and the MR2 cell is all had inhibited proliferation, and has significance or utmost point significant difference, and inhibitory action prolongation in time strengthens gradually.The growth of MR2 cell obviously receives to press down in the time of the 5th day, and each experimental group is seen table 1 to the growth inhibition ratio of MR2 cell in the time of the 8th day.Compare with interferon-ALPHA 2a group, Arctiin tuple, the low group of interferon-ALPHA 2a compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon-ALPHA 1b group, Arctiin tuple, the low group of interferon-ALPHA 1b compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon beta 1a group, Arctiin tuple, the low group of interferon beta 1a compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon beta 1b group, Arctiin tuple, the low group of interferon beta 1b compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon gamma group, Arctiin tuple, the low group of interferon gamma compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Each experimental group is followed successively by the power of MR2 cell inhibitory effect effect: the interferon compound recipe hangs down group＞interferon group＞Arctiin tuple.
The NBT positive rate is represented the differentiation capability of inducing to NB4 cell and MR2 cell, and the NBT positive rate is high more, and expression induces differentiation capability strong more to NB4 cell and MR2 cell.NBT reduction test result shows still to be the MR2 cell for the NB4 cell no matter; Compare with single medicine; The cell NBT positive rate of the low group of interferon compound recipe has significant difference or utmost point significant difference; Compare with single medicine, the low group of interferon compound recipe also further shows as synergism to the differentiation capability of inducing of NB4 cell and MR2 cell.Specifically see table 2.
Table 1 interferon and aretigenin compositions are to the influence of NB4 and MR2 cell proliferation
△Compare p＜0.05 with matched group;
△ △Compare p＜0.01 with matched group;
*Compare p＜0.05 with the Arctiin tuple;
*Compare p＜0.01 with the Arctiin tuple;
#Compare p＜0.05 with interferon-ALPHA 2a group;
$Compare p＜0.05 with interferon-ALPHA 1b group;
&Compare p＜0.05 with interferon beta 1a group;
■Compare p＜0.05 with interferon beta 1b group;
▲Compare p＜0.05 with the interferon gamma group.
Table 2 interferon and aretigenin compositions are to the influence of the NBT positive rate of NB4 and MR2 cell
△Compare p＜0.05 with matched group;
△ △Compare p＜0.01 with matched group;
*Compare p＜0.05 with the Arctiin tuple;
*Compare p＜0.01 with the Arctiin tuple;
#Compare p＜0.05 with interferon-ALPHA 2a group;
$Compare p＜0.05 with interferon-ALPHA 1b group;
&Compare p＜0.05 with interferon beta 1a group;
■Compare p＜0.05 with interferon beta 1b group;
▲Compare p＜0.05 with the interferon gamma group.
The influence of embodiment 27 pharmaceutical composition high dose group dialogue cell strain NB4 of the present invention and MR2 propagation and differentiation
1, experimental procedure
With embodiment 26.Just the final concentration with the effective active composition is adjusted into respectively:
Matched group: the RPMI-1640 culture fluid,
The Arctiin tuple: the final concentration of aretigenin is 0.01mg/ml,
Interferon-ALPHA 2a group: the final concentration of recombinant human interferon alpha-2 is 5MIU/ml,
Interferon-ALPHA 1b group: the final concentration 0.001mg/ml of recombinant human interferon alpha 1 b,
Interferon beta 1a group: the final concentration 0.001mg/ml of recombinant human interferon beta 1a,
Interferon beta 1b group: the final concentration 0.0045mg/ml of recombinant human interferon beta 1b,
The high group of interferon-ALPHA 2a compound recipe: the final concentration of recombinant human interferon alpha-2+aretigenin is the recombinant human interferon alpha-2 of 5MIU/ml and the aretigenin of 0.01mg/ml,
The high group of interferon-ALPHA 1b compound recipe: the final concentration of recombinant human interferon alpha 1 b+aretigenin is the recombinant human interferon alpha 1 b of 0.001mg/ml and the aretigenin of 0.01mg/ml,
The high group of interferon beta 1a compound recipe: the final concentration of recombinant human interferon beta 1a+ aretigenin is the recombinant human interferon beta 1a of 0.001mg/ml and the aretigenin of 0.01mg/ml,
The high group of interferon beta 1b compound recipe: the final concentration of recombinant human interferon beta 1b+ aretigenin is the recombinant human interferon beta 1b of 0.0045mg/ml and the aretigenin of 0.01mg/ml,
2, experimental result:
Each experimental group is compared with matched group, and the NB4 cell is all had inhibited proliferation, and has significance or utmost point significant difference, and inhibitory action prolongation in time strengthens gradually.The growth of NB4 cell obviously receives to press down in the time of the 5th day, and each experimental group is seen table 3 to the growth inhibition ratio of NB4 cell in the time of the 8th day.Compare with interferon-ALPHA 2a group, Arctiin tuple, the high group of interferon-ALPHA 2a compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon-ALPHA 1b group, Arctiin tuple, the high group of interferon-ALPHA 1b compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon beta 1a group, Arctiin tuple, the high group of interferon beta 1a compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Compare with interferon beta 1b group, Arctiin tuple, the high group of interferon beta 1b compound recipe has significant difference to the NB4 cell inhibitory effect, and has synergism; Each experimental group is followed successively by the power of NB4 cell inhibitory effect effect: the high group＞interferon group of interferon compound recipe＞Arctiin tuple.
Each experimental group is compared with matched group, and the MR2 cell is all had inhibited proliferation, and has significance or utmost point significant difference, and inhibitory action prolongation in time strengthens gradually.The growth of MR2 cell obviously receives to press down in the time of the 5th day, and each experimental group is seen table 3 to the growth inhibition ratio of MR2 cell in the time of the 8th day.Compare with interferon-ALPHA 2a group, Arctiin tuple, the high group of interferon-ALPHA 2a compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon-ALPHA 1b group, Arctiin tuple, the high group of interferon-ALPHA 1b compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon beta 1a group, Arctiin tuple, the high group of interferon beta 1a compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Compare with interferon beta 1b group, Arctiin tuple, the high group of interferon beta 1b compound recipe has significant difference to the MR2 cell inhibitory effect, and has synergism; Each experimental group is followed successively by the power of MR2 cell inhibitory effect effect: the high group＞interferon group of interferon compound recipe＞Arctiin tuple.
The NBT positive rate is represented the differentiation capability of inducing to NB4 cell and MR2 cell, and the NBT positive rate is high more, and expression induces differentiation capability strong more to NB4 cell and MR2 cell.NBT reduction test result shows still to be the MR2 cell for the NB4 cell no matter; Compare with single medicine; The cell NBT positive rate of the high group of interferon compound recipe has significant difference or utmost point significant difference; Compare with single medicine, the high group of interferon compound recipe also further shows as synergism to the differentiation capability of inducing of NB4 cell and MR2 cell.Specifically see table 4.
Table 3 interferon and aretigenin compositions are to the influence of NB4 and MR2 cell proliferation
△Compare p＜0.05 with matched group;
△ △Compare p＜0.01 with matched group;
*Compare p＜0.05 with the Arctiin tuple;
*Compare p＜0.01 with the Arctiin tuple;
#Compare p＜0.05 with interferon-ALPHA 2a group;
$Compare p＜0.05 with interferon-ALPHA 1b group;
&Compare p＜0.05 with interferon beta 1a group;
■Compare p＜0.05 with interferon beta 1b group.
Table 4 interferon and aretigenin compositions are to the influence of the NBT positive rate of NB4 and MR2 cell
△Compare p＜0.05 with matched group;
△ △Compare p＜0.01 with matched group;
*Compare p＜0.05 with the Arctiin tuple;
*Compare p＜0.01 with the Arctiin tuple;
#Compare p＜0.05 with interferon-ALPHA 2a group;
$Compare p＜0.05 with interferon-ALPHA 1b group;
&Compare p＜0.05 with interferon beta 1a group;
■Compare p＜0.05 with interferon beta 1b group.
Claims (19)
1. a pharmaceutical composition is characterized in that its active component is made up of interferon and aretigenin.
2. pharmaceutical composition as claimed in claim 1, the weight ratio that it is characterized in that described interferon and aretigenin is (3 * 10
-5-0.1): 1.
3. pharmaceutical composition as claimed in claim 2 is characterized in that described interferon is selected from a kind of in alpha-interferon, beta-interferon and the gamma interferon at least.
4. pharmaceutical composition as claimed in claim 3 is characterized in that described alpha-interferon is recombinant human interferon alpha-2 or recombinant human interferon alpha 1 b.
5. pharmaceutical composition as claimed in claim 4; It is characterized in that the ratio between the amount of amount and aretigenin of described recombinant human interferon alpha-2 is (0.25-500): 1; The amount of recombinant human interferon alpha-2 representes that with million international units the amount of aretigenin is represented with milligram.
6. pharmaceutical composition as claimed in claim 4, the weight ratio that it is characterized in that described recombinant human interferon alpha 1 b and aretigenin is (5 * 10
-5-0.1): 1.
7. pharmaceutical composition as claimed in claim 3 is characterized in that described beta-interferon is recombinant human interferon beta 1a or recombinant human interferon beta 1b.
8. pharmaceutical composition as claimed in claim 7 is characterized in that the weight ratio of described recombinant human interferon beta 1a and aretigenin is (3 * 10
-5-0.1): 1.
9. pharmaceutical composition as claimed in claim 7 is characterized in that the weight ratio of described recombinant human interferon beta 1b and aretigenin is (5 * 10
-5-0.45): 1.
10. pharmaceutical composition as claimed in claim 3 is characterized in that described gamma interferon is a recombinant human interferon gamma.
11. pharmaceutical composition as claimed in claim 10; It is characterized in that the ratio between the amount of amount and aretigenin of described recombinant human interferon gamma is 1: (0.3-1200); The amount of recombinant human interferon gamma representes that with million international units the amount of aretigenin is represented with milligram.
12. the application of pharmaceutical composition as claimed in claim 1 in the medicine of preparation treatment inhibition Leukemia Cell Proliferation and inducing leukemia cell differentiation.
13. application as claimed in claim 12 is characterized in that the weight ratio of interferon and aretigenin is (3 * 10 in the described pharmaceutical composition
-5-0.1): 1.
14. application as claimed in claim 12; It is characterized in that described interferon is a recombinant human interferon alpha-2; Ratio between the amount of recombinant human interferon alpha-2 and the amount of aretigenin is (0.25-500): 1; The amount of recombinant human interferon alpha-2 representes that with million international units the amount of aretigenin is represented with milligram.
15. application as claimed in claim 12 is characterized in that described interferon is a recombinant human interferon alpha 1 b, the weight ratio of recombinant human interferon alpha 1 b and aretigenin is (5 * 10
-5～0.1): 1.
16. application as claimed in claim 12 is characterized in that described interferon is recombinant human interferon beta 1a, the weight ratio of recombinant human interferon beta 1a and aretigenin is (3 * 10
-5-0.1): 1.
17. application as claimed in claim 12 is characterized in that described interferon is recombinant human interferon beta 1b, the weight ratio of recombinant human interferon beta 1b and aretigenin is (5 * 10
-5-0.45): 1.
18. application as claimed in claim 12; It is characterized in that described interferon is a recombinant human interferon gamma; Ratio between the amount of recombinant human interferon gamma and the amount of aretigenin is 1: (0.3-1200); The amount of recombinant human interferon gamma representes that with million international units the amount of aretigenin is represented with milligram.
19., it is characterized in that it is microemulsion formulation or injection like the arbitrary described pharmaceutical composition of claim 1-11.
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| CN101049484A (en) * | 2007-05-14 | 2007-10-10 | 郝来勤 | Strong effective Chinese traditional medicine for treating lung cancer and other various cancers |
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