Summary of the invention
The present invention provides a kind of new Chinese medicine composition, and the effect that said composition has heat clearing away, detoxifies, invigorates blood circulation is used to treat various acute and chronic leukemias.
Another object of the present invention provides the method for preparing of above-mentioned Chinese medicine composition.
The present invention realizes through following technical scheme:
The present invention is processed by the following weight proportion raw material: Realgar 0.05-0.1 part, Indigo Naturalis 1.5-3 part, Radix Salviae Miltiorrhizae 9-15 part, Borneolum Syntheticum 0.15-0.3 part.
Preferred weight portion proportioning is: 0.08 part of Realgar, 2 parts of Indigo Naturaliss, 12 parts of Radix Salviae Miltiorrhizaes, 0.2 part of Borneolum Syntheticum.
The method for preparing of Chinese medicine composition of the present invention is following:
Radix Salviae Miltiorrhizae water extraction or different concentration ethanol are extracted or water extract-alcohol precipitation, or water vapour distillation volatile oil medicinal residues water extraction or different concentration ethanol extraction or water extract-alcohol precipitation, also can further use the macroporous resin column purification, obtain Radix Angelicae Sinensis extract; Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum are mixed, add appropriate amount of auxiliary materials, be prepared into pharmaceutically acceptable solid orally ingestible, for example capsule, tablet, pill, drop pill etc.
Wherein, the preferred for preparation method of Radix Salviae Miltiorrhizae extract is:
Radix Salviae Miltiorrhizae adds 5 times of water gagings, decocts 2 hours, filters, and filtering residue adds 4 times of water gagings; Fried in shallow oil 1 hour, and filtered, filtering residue discards, and merges filtrating 2 times; Filtrate decompression is concentrated into medicine liquid volume (L) and medical material weight (Kg) than being 1: 0.9-1.1, and add ethanol and make medicinal liquid contain determining alcohol 70%, leave standstill filtration; Being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract.
Another preferred for preparation method of Radix Salviae Miltiorrhizae extract is:
Radix Salviae Miltiorrhizae adds 8 times of amount 70% ethanol extractions, and 2 times, each 1 hour, filter, filtering residue discards, and merges filtrating 2 times, reclaims ethanol, and being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract.
The method for preparing of the preferred drop pill of Chinese medicine composition of the present invention is following:
With Macrogol 4000: polyethylene glycol 6000 adds the fine powder of Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum, mixing in 3: 1 ratio heating and melting; 60-80 ℃ of insulation splashes in the refrigerative simethicone, treats drop pill cooling back taking-up; Drop is clean and wipe simethicone, promptly gets drop pill.
The method for preparing of the preferred pill of Chinese medicine composition of the present invention is following:
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, add proper honey, evenly mixed, the pill agent.
The method for preparing of Chinese medicine composition preferred capsule of the present invention agent is following:
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, add lactose, mixing is used 95% alcohol granulation, and drying incapsulates, and promptly gets capsule.
The method for preparing of another preferred capsule agent of Chinese medicine composition of the present invention is following:
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, and drying incapsulates, and promptly gets capsule.
The method for preparing of the preferred tablet of Chinese medicine composition of the present invention is following:
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, add lactose, mixing is granulated, drying, and the adding magnesium stearate is an amount of, mixing, tabletting, coating promptly gets tablet.
The compatibility mechanism of pharmaceutical composition of the present invention is following:
The inventor thinks that the leukemic cause of disease mainly is to be caused by " malicious heresy is gone into blood ", and the versatile thermal burn was cloudy after this evil poison got into body, thereby again this malicious heresy was called burning hot heresy, also was referred to as fire-toxin, pyretic toxicity.The internal organs meridians of evil poison invasion human body under certain endogenous cause of ill condition, from outward appearance to inner essence, or poison is from interior and give birth to, inside and outside close poison.If a little less than the few power of evil poison amount then onset is slow, promptly arranged an incubation period, or the course of disease is longer.Evil poison accumulates and amasss in interior, with the passing of time heat-transformation, and the consumption impairment of QI is cloudy, thereby the patient often shows as the syndrome that the cloudy consumption of gas is hindered in early days, and clinical manifestation is a type of deficiency of both QI and YIN, is early stage or light-duty patient; Evil poison injures QI and blood in going into, and the two syndromes of losing of QI and blood occur, belongs to QIXUELIANGXU type; The poison heresy is further deeply invaded nutrient blood, attacks and annotates bone marrow, liver spleen and three warmers, makes imbalance of YIN and YANG, causes hemopoietic organ's dysfunction, and excessive noxious heat performances such as high fever, excessive thirst, epistaxis, a speckle appear in the remarkable outgrowth phenomenon of leukemogenesis cell.Syndromes such as unconsciousness and delirium then appear in pericardium if evil poison caves in, and like untimely treatment, it is cloudy depleted, beyond cure gas to occur, is difficult to treatment.Sb.'s illness took a turn for the worse on this many pro-amphitypy basis and form, also can be very strong because of evil virulence, and perhaps healthy energy extreme deficiency, evil poison is directly invaded nutrient blood, attacks notes bone marrow, and one falls ill promptly sees the excessive noxious heat phenomenon.Accumulate in the evil poison, internal damage by the excessive seven emotions in addition causes the heat immersion of burning, and blood is sticky, and depression and stagnation of QI causes stagnation of QI-blood eventually, and heat is burnt expectorant with fixed attention, and stagnation of QI mental disorder is condensed, then Jian Cheng mass in the abdomen, scrofula, grandular plague and see the enlargement of liver splenic lymph nodes.
The analysis of the leukemic cause of disease course of disease more than the foundation, the treatment leukemia is when being main with heat-clearing and toxic substances removing, blood circulation promoting and blood stasis dispelling is auxilliary.In the drug composition, the mechanism of action of each medicine is following in the present invention:
Realgar: sulfide-based mineral Realgar family Realgar, the main realgar (As2S2) that contains.Suffering, temperature; Poisonous.Return liver, large intestine channel.The detoxifcation parasite killing, removing dampness and eliminating phlegm, preventing the attack (or recurrence) of malaria.Be used for the carbuncle furuncle, snake bite and insect sting, abdominal pain due to worm stagnation, infantile convulsion, malaria.
Indigo Naturalis: dried powder or agglomerate that the leaf of acanthaceous vegetable acanthaceous indigo Baphicacanthus cusia (Nees) Bremek., polygonaceae plant polygonum tinctorium ait. Polygonum tinctorium Ait. or cruciferae isatis Isatis indigoticaFort. or stem and leaf make through processing.Salty, cold.Return Liver Channel.Heat-clearing and toxic substances removing, removing heat from blood, arresting convulsion.Be used for maculae caused by violent heat pathogen, heat in blood is told nosebleed, chest pain hemoptysis, aphtha, mumps, sore throat, pediatric epilepsy scared.
Radix Salviae Miltiorrhizae: hardship is slightly cold.GUIXIN, Liver Channel.Stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, relieving restlessness clears away heart-fire.Be used for menoxenia, the amenorrhea dysmenorrhea, note of the ancient Chinese abdominal mass is gathered, breast ventral spine pain, pyretic arthralgia pain, skin infection swells and ache, dysphoria and insomnia; Hepatosplenomegaly, angina pectoris.
Borneolum Syntheticum: hot, bitter, be slightly cold.GUIXIN, spleen, lung meridian.The refreshment of having one's ideas straightened out, clearing away heat to alleviate pain.Be used for the calentura coma, convulsion is fainted, the apoplexy syncope due to accumulation of phlegm, stagnation of QI sudden syncope, attacked by pestiferous factors stupor, conjunctival congestion, aphtha, laryngopharynx swelling and pain, auditory meatus is suppurated.
Arsenic in China's T&B, is treated chronic myelocytic leukemia (CML) like past application detoxicating tablet of cow-bezoar (containing Realgar) and Realgar as antitumor drug.At the initial stage seventies, China takes the lead in obtaining higher clinical remission rate with arsenic agent treatment acute promyelocytic leukemia (APL).
The main component of Realgar is arsenic sulfide, discovers that wherein treating leukemic main compound is realgar (As2S2).Beijing Medical University's hematopathy institute report is with Realgar treatment acute promyelocytic leukemia 38 examples; Wherein 6 examples are to the drug-fast recurrence of multiple medicine patient, and 2 examples are ATRA and the drug-fast recurrence of chemotherapeutics part patient, and 30 examples are alleviated case fully for after the ATRA treatment, reaching in addition; Therapeutic scheme is 1000~1500mgd-1; 2~3 weeks were a course of treatment, and the course of treatment is 2~3 weeks at interval, total 2 years half course of treatment.The result is after Realgar treatment 1~3 course of treatment; 8 examples partially or completely drug-fast patient alleviated fully; 30 examples are accepted the case that Realgar is treated in the complete catabasis, and except that 3 examples withdraw from the treatment because of the side effect of other serious complication or Realgar, all the other 27 examples are continued complete remissions all; All 35 routine patients to 1997 year survival always, actual survival rate was 100% in 3 years.Proved that as far back as people such as Zhou Aixiang in 1981 Realgar treatment leukemia is effective, complete remission rate 72%, part alleviates 28%, total effective rate 100%.Tang in 1998 uses the Chinese patent medicine LIUSHEN WAN, XIHUANG WAN, the zijin troche treatment acute and chronic leukemia that contain Realgar by monarch and obtains certain curative effect.The report utilization is treated acute and chronic leukemia by the pure Chinese medicinal preparation of Chinese prescriptions such as Realgar among the Yang Xins in 1999, and curative effect is better.This result has confirmed the effect that Realgar is cloned into gene level to the high efficiency and the special removing APL of APL treatment.(leukemic mechanism of arsenic agent treatment and clinical practice such as Realgar, the 19th the 2nd phase of volume of PLA's Acta Pharmaceutica Sinica)
The inducing apoptosis of tumour cell of research proof at present is a kind of clearer and more definite and important mechanism of Realgar antitumor action, and different researchers adopts different malignant hematologic disease cells that the mechanism of its inducing apoptosis of tumour cell is furtherd investigate.In apoptotic molecular biology research process, it is found that several genes participates in apoptotic regulation and control, wherein the effect of bcl-2 gene receives much concern.The overexpression of bcl-2 not only can effectively stop the apoptosis that comprises that metabolite accumulation, free radical etc. bring out, and can suppress the apoptosis of many factors (like ray and oncogene) mediation.Some are discovered: the variation of bcl-2 gene family protein expression level can significantly change the impedance of tumor cell line to the induced by chemotherapeutic agents apoptosis.(research of Realgar induced apoptosis in leukemia cell lines, modern tumor medical science the 14th the 1st phase of volume of January in 2006)
In the present invention in the drug composition with Realgar as monarch drug; Utilize the characteristic of its " treating the poisonous disease with poisonous drugs ", as the main medicine that produces therapeutic effect, Indigo Naturalis is got its heat clearing away, detoxifcation, removing heat from blood as ministerial drug effect is to cooperate and to implement the Chinese traditional treatment principle of heat-clearing and toxic substances removing; In addition; Radix Salviae Miltiorrhizae is invigorated blood circulation, and Borneolum Syntheticum is had one's ideas straightened out refreshment altogether for assistant makes, and four medicines share the effect of playing heat-clearing and toxic substances removing, blood circulation promoting and blood stasis dispelling, pain relieving, removing heat from blood altogether.
The effect that Chinese medicine composition of the present invention has heat clearing away, detoxifies, invigorates blood circulation is used to treat various acute and chronic leukemias, like acute leukemia, chronic myelocytic leukemia, polycythemia vera, acute promyelocytic leukemia etc.
Below, foregoing of the present invention is done further to specify through the specific embodiment:
Concrete embodiment
Embodiment 1:
Realgar 0.08kg, Indigo Naturalis 2kg, Radix Salviae Miltiorrhizae 12kg, Borneolum Syntheticum 0.2kg
Radix Salviae Miltiorrhizae adds 5 times of water gagings, decocts 2 hours, filters, and filtering residue adds 4 times of water gagings; Fried in shallow oil 1 hour, and filtered, filtering residue discards, and merges filtrating 2 times; Filtrate decompression is concentrated into 12L, adds ethanol and makes medicinal liquid contain determining alcohol 70%, leaves standstill, and filters; Being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract;
With 20kg Macrogol 4000 and 8kg polyethylene glycol 6000 heating and melting, add the fine powder of Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum, mixing; 60-80 ℃ of insulation splashes in the refrigerative simethicone, treats drop pill cooling back taking-up; Drop is clean and wipe simethicone, promptly gets drop pill.
Embodiment 2:
Realgar 0.05kg, Indigo Naturalis 2kg, Radix Salviae Miltiorrhizae 12kg, Borneolum Syntheticum 0.2kg
Radix Salviae Miltiorrhizae adds 5 times of water gagings, decocts 2 hours, filters, and filtering residue adds 4 times of water gagings; Fried in shallow oil 1 hour, and filtered, filtering residue discards, and merges filtrating 2 times; Filtrate decompression is concentrated into 12L, adds ethanol and makes medicinal liquid contain determining alcohol 70%, leaves standstill, and filters; Being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract;
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, add proper honey, evenly mixed, the pill agent.
Embodiment 3:
Realgar 0.1kg, Indigo Naturalis 2kg, Radix Salviae Miltiorrhizae 9kg, Borneolum Syntheticum 0.2kg
Radix Salviae Miltiorrhizae adds 8 times of amount 70% ethanol extractions, and 2 times, each 1 hour, filter, filtering residue discards, and merges filtrating 2 times, reclaims ethanol, and being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract;
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, add the 10kg lactose, mixing is used 95% alcohol granulation, and drying incapsulates, and promptly gets capsule.
Embodiment 4:
Realgar 0.08kg, Indigo Naturalis 3kg, Radix Salviae Miltiorrhizae 15kg, Borneolum Syntheticum 0.3kg
Radix Salviae Miltiorrhizae adds 5 times of water gagings, decocts 2 hours, filters, and filtering residue adds 4 times of water gagings; Fried in shallow oil 1 hour, and filtered, filtering residue discards, and merges filtrating 2 times; Filtrate decompression is concentrated into 15L, adds ethanol and makes medicinal liquid contain determining alcohol 70%, leaves standstill, and filters; Being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract;
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, and drying incapsulates, and promptly gets capsule.
Embodiment 5:
Realgar 0.08kg, Indigo Naturalis 1.5kg, Radix Salviae Miltiorrhizae 12kg, Borneolum Syntheticum 0.15kg
Radix Salviae Miltiorrhizae adds 8 times of amount 70% ethanol extractions, and 2 times, each 1 hour, filter, filtering residue discards, and merges filtrating 2 times, reclaims ethanol, and being concentrated into relative density is the thick paste of 1.30-1.35 (50 ℃), drying under reduced pressure (60 ℃ ,-0.08Mpa), promptly get Radix Salviae Miltiorrhizae extract;
Radix Salviae Miltiorrhizae extract, Realgar, Indigo Naturalis, Borneolum Syntheticum powder are broken into fine powder, add the 6kg lactose, mixing is granulated, drying, and the adding magnesium stearate is an amount of, mixing, tabletting, coating promptly gets tablet.
Come further to set forth the beneficial effect of pharmaceutical composition according to the invention through following experiment:
Pharmaceutical composition of the present invention is to the experimentation of portable mouse lymphocyte leukemia (L7212) therapeutical effect
1 materials and methods
1.1 experiment material medicinal liquid of the present invention, propidium iodide, rat anti-mouse monoclonal antibody (anti-CD3-PE, anti-CD4-FITC, anti-CD8-FITC).615 inbred mouses, Mus 5-8 in age week, body weight 18-24g, male and female half and half.Flow cytometer.The L7212 leukemia cell line.
1.2 experimental technique press document (Chu Jianxin, Qi Shuling, Lei Jianling, etc. the foundation of portable mouse leukemia model (L7212) and biological characteristics [J] thereof. Chinese tumor magazine, 1981,3 (4): 287) method is duplicated L7212 leukemia model.Mice is divided into normal control group, normal administration group (Chinese medicine high dose), L7212 model group, L7212 Chinese medicine 1 group of (Chinese medicine high dose) and 2 groups in L7212 Chinese medicine (dosage in the Chinese medicine) at random.2 groups in normal administration group, 1 group in L7212 Chinese medicine and L7212 Chinese medicine give medicinal liquid of the present invention, and (high dose Chinese medicine is the medicinal liquid that contains crude drug 8g/ml; In dosage Chinese medicine be the medicinal liquid that contains crude drug 4g/ml) 0.3ml/ only irritates stomach, normal control group and L7212 model group are given the equal-volume normal saline.Each group every day 1 time, is total to administration 7d all in inoculation gastric infusion next day.
1.3 observation index (1) life span is calculated with formula (T-C)/C * 100%, increase in life span T is a treatment group The average survival time natural law, and C is a matched group The average survival time natural law.(2) PBL sum and differential counting, the differential counting of bone marrow nucleated cell smear, liver, spleen, thymus index.(3) mensuration of residual leukemic cell is pressed document (Zheng Dexian; Wu Kefu, Chu Jianxin. modern experimental hematology research method and technology [M]. Beijing: combined publication society of China Concord Medical Science University of Beijing Medical University, 1999; 510) method adopts the biological implantation test to detect.(4) press cell generation cycle document (Jiang Bo, Zhang Yali, Zhou Dianyuan. molecular biology common experimental method [M]. Beijing: method People's Medical Officer Press 1996,118), detect with flow cytometer.T lymphocyte subset the crowd detect with flow cytometer.
1.4 the statistical procedures measurement data is represented with
, adopts the t check.
2 results
Relatively see table 1 2.1 respectively organize life span.The result shows in the 1st, the 2 batch of experiment that the L7212 Chinese drug-treated group all prolongs (p<0.05 or 0.01) to some extent than L7212 model group life span, and life span difference does not have significance (p>0.05) between 1,2 groups of groups of L7212 Chinese medicine.
Table 1 is respectively organized life span relatively
Compare * p<0.05, * * p<0.01 with the L7212 model group.Down together.
Relatively see table 2 2.2 respectively organize PBL counting and classification.The result shows L7212 model group and the obviously rising on the 5th after inoculation of 1 group of mice PBL counting of L7212 Chinese medicine, but difference does not have significance (p>0.05).Inoculation back the 8th day, visible a large amount of leukaemias in two groups of mice peripheral blood films, and 1 group of leukaemia's percentage ratio of L7212 Chinese medicine is lower than L7212 model group (p<0.01).
The PBL counting respectively organized by table 2 and leukaemia's percentage ratio compares
Relatively see table 3 2.3 respectively organize bone marrow leukemia cells percentage ratio.A small amount of leukaemia has appearred in inoculation back the 5th day in the mouse bone marrow cells, but two groups of results close (p>0.05).Inoculation back the 8th day, leukaemia's percentage ratio is starkly lower than the L7212 model group in 1 group of mouse bone marrow cells of L7212 Chinese medicine, but because the routine number of observation is few, the end takes statistics.
Table 3 is respectively organized bone marrow leukemia cells percentage ratio relatively
2.4 respectively organized liver, spleen, thymus index relatively after L7212 model group and the L7212 Chinese medicine 1 winding kind the 5th day, the live mice (6) that kills and liver, the index and spleen index close (p>0.05) of the dead mice of leukemia (4 batches, totally 44).Spleen, the thymus index close (p>0.05) of normal administration group mice.
Residual leukemic cell mensuration result compares the L7212 model group and 1,2 groups of mice life spans of L7212 Chinese medicine compare not statistically significant 2.5 respectively organize.
Relatively see table 4 2.6 respectively organize the proliferation of bone marrow cells period profile.The result shows that normal matched group of 1 group of bone marrow cells in mice G2/G1 of L7212 Chinese medicine ratio and L7212 model group reduce.
Table 4 is respectively organized proliferation of bone marrow cells period profile relatively
Compare △ P<0.05 with the normal control group.Down together
2.7 respectively organize spleen, the t lymphocyte subset crowd relatively sees table 5.L7212 group mouse spleen t lymphocyte subset crowd CD3+, CD4+, CD8+ percentage ratio are lower than normal group more, and CD4+/CD8+ ratio is lower than not administration group (normal control group, L7212 model group) more.
Table 5 is respectively organized spleen, t lymphocyte subset crowd relatively
3 conclusions
This experiment shows that pharmaceutical composition of the present invention has better curative effect to leukemia, because of its life span that can prolong the L7212 leukemia mouse, reduces leukaemia's in its peripheral blood ratio, so this side is objective effective to the treatment leukemia.