CN101491643B - Medicine preparation for treating cancer and preparation method thereof - Google Patents
Medicine preparation for treating cancer and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a medical preparation for treating cancer and a preparation method thereof. The medical preparation is prepared from Iphigenia indica, climbing nightshade, Epimedium brevicornum, radix sophorae falvescentis, angelica, Atractylodes macrocephala, ginseng and proper auxiliary materials and adopts the following method: taking and grinding the angelica and the ginseng into fine powder for standby; adding water and decocting other medical materials; combining decoction which is subjected to filtration and concentration; adding the fine powder for evenly mixing and drying; and then preparing a dispersible tablet preparation. The prepared product has the efficacies in tonifying Qi, nourishing the blood, invigorating the spleen, promoting fluid, nourishing Yin, strengthening Yang, inhibiting the tumor and resisting the cancer; and the medicine is used for assisted treatment of cancer of middle and late stage and qi-blood deficiency patients whose leucocyte is reduced caused by radiation and chemo-treatments, and has obvious effect.
Description
Technical field:
The present invention is a kind of pharmaceutical preparation for the treatment of cancer and preparation method thereof, belongs to technical field of Chinese medicine.
Technical background:
Cancer is that the mankind are threatened one of the most serious disease.The Seedling doctor is referred to as " Testudinis " to the cancer enclosed mass, and Miao is referred to as " ripple " or " broadcasting ".Clinically mainly show as, the affected part enclosed mass, become thin, disease such as weak angel, cancer pain.Seedling doctor thinks the formation of " Testudinis ", mainly is outer being subjected to due to evil poison and the interior damage, because the human body self insufficiency of vital energy and blood is subjected to external evil poison harm, injures people's bromhidrosis, blood, water and forms gradually.Depressed stasis then becomes " Testudinis " (enclosed mass), cancer pain; Impairment of QI, weak angel; Blood trouble is hindered water, and human body loses supports, and of a specified duration then becomes thin.Through theory, this class disease mostly is cold and hot complication according to Seedling doctor guiding principle, by " calentura is cold to be controlled, and cold febrile disease is controlled " principle, controls and should share by cold and hot medicine; Also there are many Chinese medicines to be used for the treatment of cancer in the prior art; These medicines have certain therapeutical effect.
Summary of the invention:
The objective of the invention is to: a kind of pharmaceutical preparation for the treatment of cancer and preparation method thereof is provided; According to the theory of Seedling medicine, the application has researched and developed the pharmaceutical preparation of treatment cancer.In prescription research, " Ga Gongchu " (Pseudobulbus Cremastrae Seu Pleiones) property of use is chilly, and the mildly bitter flavor suffering is gone into hot warp, and is slightly poisonous, and tool heat-clearing and toxic substances removing, dispersing swelling and dissipating binds, tumor-inhibiting anticancer function are principal agent. It is cold " to add and lose in the Europe " (Herba Solani Lyrati) property, and bitter in the mouth is gone into hot warp, and is slightly poisonous, tool clearing away heat-damp and promoting diuresis, removing toxic substances and promoting subsidence of swelling, anti-cancer function; (Radix Sophorae Flavescentis) property is cold " to add Gong Shan ", and bitter in the mouth is gone into hot warp, the function heat clearing and damp drying; " Jia Exi " (Herba Epimedii) is hot in nature, and it is peppery to distinguish the flavor of, and goes into fast warp, half of warp, tool kidney-replenishing, raise immunity; The Radix Angelicae Sinensis property and flavor of peppery and warm, blood-supplementing blood-nourishing; Rhizoma Atractylodis Macrocephalae hardship, sweet, temperature, invigorating the spleen and benefiting QI, dampness diuretic, hidroschesis; The sweet little hardship of Radix Ginseng is flat, and QI invigorating, spermatogenesis are calmed the nerves; Above-mentioned Six-element is accessory drugs altogether.All medicines share, the tool benefiting qi and nourishing blood, and spleen invigorating is promoted the production of body fluid, yin nourishing invigorating YANG, the merit of tumor-inhibiting anticancer.
The present invention is directed to prior art, except having studied the preparation of making by Pseudobulbus Cremastrae Seu Pleiones, Herba Solani Lyrati, Herba Epimedii, Radix Sophorae Flavescentis, Radix Angelicae Sinensis, the Rhizoma Atractylodis Macrocephalae, gone back primary study with the dropping pill formulation dosage form of these medical materials preparation and its molding, preparation technology; The micropill of making in the invention, dispersible tablet, disintegrative are good, and the bioavailability height is particularly suitable for the old people and swallow tablet or the inconvenient patient of capsule take; Soft capsule preparation provided by the invention forms drug blockage in soft gel coat, solved medicine and met damp and hot problem of unstable, can also cover adverse drug taste, abnormal smells from the patient, can play the effect that increases stability, improves bioavailability; Granule good mouthfeel provided by the invention does not need disintegrate, absorbs soon taking convenience; The tablet that provides, capsule have enriched the scope of dosage form selection.
The present invention constitutes like this: calculate according to weight, it is to be made into drop pill with Pseudobulbus Cremastrae Seu Pleiones 100-600g, Herba Solani Lyrati 100-500g, Herba Epimedii 100-500g, Radix Sophorae Flavescentis 100-500g, Radix Angelicae Sinensis 100-500g, Rhizoma Atractylodis Macrocephalae 100-300g, Radix Ginseng 50-200g.Say accurately: calculate according to weight, it is the drop pill of making by Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g.
The preparation method of the pharmaceutical preparation of described treatment cancer: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water 1-5 time, and each 0.5-3 hour, collecting decoction filtered, and concentrates, and adds above-mentioned fine powder, mixing, and drying is made different preparations then respectively.
Drop pill in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Get the extract powder portion, two parts of two parts of PEG6000 and polyoxyethylene monostearate S-40, mix homogeneously fuses in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 5cm drip footpath 2.5mm/2mm, mix 75 ℃ of ointment temperature, liquid coolant height 65cm, promptly.
Capsule in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃, be ground into fine powder, incapsulate, make 1000, promptly.
Granule in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃, with the Icing Sugar mixing, to granulate, drying is made 1000g, promptly.
Dispersible tablet in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Get PPVP3.0g and lemon yellow mixing, get 3/4 with the extract powder mix homogeneously, make binding agent with 1% K30 anhydrous alcohol solution, 40 order system material, granulate remain 1/4 the PPVP and the mixed powder of lemon yellow mixing and are added in the particle that makes, tabletting, promptly.
Pellet in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Add an amount of starch, with 60% ethanol and 1.2% soybean oil system soft material, the soft material that makes micropill mechanism ball, wet feed pushed the 0.8mm sieve aperture, and the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings, crossing 16～20 mesh sieves selects ball or merges above-mentioned four kinds of clear paste, spray drying, wet-milling granulation molding, mould placed add the great achievement ball in the coating pan, medicated powder: water is 1: 1, and the coating pan rotating speed is 42r/min, capping, select ball, promptly.
Soft capsule in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Press medication amount: substrate amount=1: 1.3 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: 3g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity＜40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2 hours of the typing of rolling, and 22 ℃ of baking temperatures, dry relative humidity should be lower than 40%, and drying time is at 24～48 hours, promptly.
Tablet in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder when being concentrated into relative density and being 25 ℃, mixing, drying is pulverized, add microcrystalline Cellulose 22g, use 60% alcohol granulation, drying, granulate adds magnesium stearate 1.5g, mixing, tabletting, coating, promptly.
Oral liquid in the described preparation prepares like this: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder when being concentrated into relative density and being 25 ℃, mixing adds distilled water, 3.0% aspartame, sterilization, promptly.
Among the we, " Ga Gongchu " (Pseudobulbus Cremastrae Seu Pleiones) property of use is chilly, and the mildly bitter flavor suffering is gone into hot warp, and is slightly poisonous, and tool heat-clearing and toxic substances removing, dispersing swelling and dissipating binds, tumor-inhibiting anticancer function are principal agent. It is cold " to add and lose in the Europe " (Herba Solani Lyrati) property, and bitter in the mouth is gone into hot warp, and is slightly poisonous, tool clearing away heat-damp and promoting diuresis, removing toxic substances and promoting subsidence of swelling, anti-cancer function; (Radix Sophorae Flavescentis) property is cold " to add Gong Shan ", and bitter in the mouth is gone into hot warp, the function heat clearing and damp drying; " Jia Exi " (Herba Epimedii) is hot in nature, and it is peppery to distinguish the flavor of, and goes into fast warp, half of warp, tool kidney-replenishing, raise immunity; The Radix Angelicae Sinensis property and flavor of peppery and warm, blood-supplementing blood-nourishing; Rhizoma Atractylodis Macrocephalae hardship, sweet, temperature, invigorating the spleen and benefiting QI, dampness diuretic, hidroschesis; The sweet little hardship of Radix Ginseng is flat, and QI invigorating, spermatogenesis are calmed the nerves; Above-mentioned Six-element is accessory drugs altogether.All medicines share, Synergistic, the tool benefiting qi and nourishing blood, and spleen invigorating is promoted the production of body fluid, yin nourishing invigorating YANG, the merit of tumor-inhibiting anticancer; Medicine is used for the auxiliary treatment of middle and terminal cancer and leukopenia that carcinosis radiotherapy and chemotherapy causes belongs to QI and blood deficiency person.
The present invention is directed to prior art, the micropill, dispersible tablet, the disintegrative that are prepared from by Pseudobulbus Cremastrae Seu Pleiones, Herba Solani Lyrati, Herba Epimedii, Radix Sophorae Flavescentis, Radix Angelicae Sinensis, the Rhizoma Atractylodis Macrocephalae that provide are good, the bioavailability height is particularly suitable for the old people and swallow tablet or the inconvenient patient of capsule take; Soft capsule preparation provided by the invention forms drug blockage in soft gel coat, solved medicine and met damp and hot problem of unstable, can also cover adverse drug taste, abnormal smells from the patient, can play the effect that increases stability, improves bioavailability; Granule good mouthfeel provided by the invention does not need disintegrate, absorbs soon taking convenience; The tablet that provides, capsule have enriched the scope of dosage form selection.
The applicant finds that granule enters in the body with solution state in the process of development granule, compare with oral solid formulation, reduce disintegrating procedue in the body, helped the absorption of this product, shortened onset time greatly, but also there is certain problem in this product granule, is exactly the mouthfeel hardship.The inventor herein intends solving this two problems by adding correctives.
The applicant finds when the development dispersible tablet, pharmacopeia regulation dispersible tablet must disintegrate fully in the 3min in 19 ℃～21 ℃ water, suspension ability, bioavailability, dispersed homogeneous degree etc. are also had higher requirements, and the paste-forming rate of extract of the present invention is very high, viscosity is excessive, hygroscopicity is strong excessively, make and select to require very strict the kind and the consumption of various adjuvants in the moulding process prescription, deviation is arranged slightly, will cause product defective.The diameter of micropill is less than 2.5mm, and class is in particle properties, the bioavailability height,
The applicant is when development product of the present invention, and maximum difficulty is exactly that the extractum hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding and molten diffusing slower.Soft capsule disintegrate in gastrointestinal tract is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the bioavailability height; Semi-transparent soft capsule can protect medicine not to be subjected to the effect of oxygen, light in dampness and the air with packaging material preferably, thereby improves the stability of labile element; So the stability of soft capsule itself and moulding process directly influence the stability of product, be very crucial technology.
In the process of development drop pill, find, substrate polyethylene glycols commonly used is that esterification forms, be the surface-active water-soluble base of a kind of tool (fusing point is 46～51 ℃), dissolubility to insoluble drug is not good, we add S-40 change polyethylene glycols itself and do not have close ester structure and surface-active character, help the absorption of medicine, if but the consumption of S-40 is too high, and can cause product to draw moist enhancing.
Experimental example 1: Study on Forming
(1) drop pill moulding process
(1) screening of substrate
The fusion situation of substrate and principal agent relatively
The result shows, the drop pill stripping that composite interstitial substance makes is very fast, because the esterification of polyethylene glycols substrate forms, be the surface-active water-soluble base of a kind of tool (fusing point is 46～51 ℃), S-40 has changed polyethylene glycols itself and has not had close ester structure and surface-active character, improve the dissolubility of insoluble drug, help the absorption of medicine.
2. drip distance, drip selection fast, temperature
Group temperature/heavy qualification rate/the % of a ℃ distance/cm liquid coolant height/cm ball
1 90 4 65 76.3
2 90 5 70 84.2
3 90 8 75 82.0
4 80 4 70 90.3
5 80 5 75 86.1
6 80 8 65 80.1
7 75 4 75 90.5
8 75 5 65 93.1
9 75 8 70 83.2
The result shows, the optimum condition of preparation drop pill of the present invention: drip to become ball in dimethicone, drip apart from 5cm drip footpath 2.5mm/2mm, mix 75 ℃ of ointment temperature, liquid coolant height 65cm.
(2) dispersible tablet Study on Forming
Dispersible tablet meet water rapidly disintegrate form the water dispersion tablet of uniform sticky suspension, it is poor to have solved former dosage form disintegrative, stripping is shortcoming slowly, and the dispersible tablet that the applicant makes is disintegrate fully in the 3min in 19 ℃～21 ℃ water, and suspension ability is good, bioavailability is high, dispersed homogeneous degree.
1. adjuvant screening
Prescription PPVP (3g) K30 (%) disintegration time/s
Add in adding
1 3/4 1/4 1.5 63
2 2/4 2/4 1.2 37
3 1/4 3/4 1.0 26
40 full doses 0.8 52
5 full doses 0 0.8 35
2. check disintegration
Adopting changes the basket method, and lift disintegration tester, tablet are got 6, observes the situation by screen cloth.Percent of pass height then disintegrative is good, more pleasant bulk absorption.
Group disintegration (s)
1 2 3 4 5 6
1 batch 27 28 30 30 28 29 in tablet of the present invention
2 batches 25 27 31 30 29 27 in tablet of the present invention
3 batches 26 28 34 33 27 29 in tablet of the present invention
The result shows, get PPVP3.0g and lemon yellow mixing, get 2/5 with the extract powder mix homogeneously, K30 anhydrous alcohol solution with 1.5% is made binding agent, 40 order system material, granulate, the PPVP of residue 3/5 and the mixed powder of lemon yellow mixing are added in the particle that makes, tabletting, and the dispersible tablet product that obtains is easy to disintegrate.
(3) pellet Study on Forming
The micropill diameter is less than 2.5mm, and class is in particle properties, the bioavailability height, and the applicant is when development product micropill of the present invention, and maximum difficulty is exactly that hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding.The micropill manufacturing technology and the adjuvant that adopt the applicant's screening to obtain make product be easy to disintegrate, and the bioavailability height is well-behaved.
1, extrudes-the spheronization pill
(1) supplementary product kind and consumption are selected
Wettability test is got two parts of extract powders, a starch that adds, and mixing is put respectively in the flat weighing bottle of having weighed, and accurate the title, decide, and is to measure its hygroscopic capacity under 75.0% condition at 25 ℃ of temperature, relative humidity, the results are shown in Table.
The wettability test result
The result shows that it is rationally feasible to adopt starch to make adjuvant.
(2) system soft material
Get extractum fine powder and starch, soybean oil and ethanol and make soft material with wet granulation process in right amount, make it to reach and hold agglomeratingly, that pinches can loose, standby.Research emphasis concentration of alcohol and soybean oil consumption influence pill, and experimental result sees Table.
Concentration of alcohol is investigated
| Tested number | Concentration of alcohol | System soft material situation |
| 1 | 50% ethanol | Soft material easily bonds |
| 2 | 60% ethanol | Soft material is moderate |
| 3 | 70% ethanol | Soft material viscosity is not enough |
The soybean oil consumption is investigated
| Tested number | The soybean oil consumption | The pill situation |
| 1 | 60% ethanol, 1.0% soybean oil | Soft material viscosity is not enough, can't pill |
| 2 | 60% ethanol, 1.2% soybean oil | Soft material is moderate, suitable pill |
| 3 | 60% ethanol, 1.5% soybean oil | Soft material easily bonds, the pill difficulty |
The result as seen, it is more satisfactory to adopt 60% ethanol, 1.2% soybean oil to be that adhesive is granulated, otherwise is difficult to molding.
(3) pill
The soft material that makes is with micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, and the wet grain of strip cuts off round as a ball, and 50～60 ℃ of drying and mouldings are crossed 16～20 mesh sieves and selected ball.
2, general method for making pill
Because the extruding that the humidification of water and coating pan rotate makes medicated powder be bonded into ball.Because of this product viscosity is bigger, general when making ball, water spray is fast and to add medicated powder speed slow, causes that it is bonding closely the time that then prolongs into ball, makes dry back hard, is unfavorable for the infiltration of moisture and influences molten loosing and the absorbing of medicine.
| Numbering | Coating pan rotating speed (r/min) | Molten loosing the time (min) | Mouldability |
| 1 | 40 | 6.84 | Relatively poor |
| 2 | 42 | 7.21 | Better |
| 3 | 45 | 12.13 | Harder |
| 4 | 50 | 14.25 | Hard |
The result shows that it is optimum that the coating pan rotating speed is selected 42r/min for use.
(4) soft capsule Study on Forming
Soft capsule disintegrate in gastrointestinal tract is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the bioavailability height; Semi-transparent soft capsule can protect medicine not to be subjected to the effect of oxygen, light in dampness and the air with packaging material preferably, thereby improves the stability of labile element; So capsular stability and moulding process are very crucial technology.
(1) supplementary product kind and consumption are selected
1. disperse medium (or claiming substrate) is selected
At fill material and substrate energy mix homogeneously, and under the prerequisite of unobstructed defeated material of energy and pelleting, reduce substrates quantity as far as possible.By test of many times, determine medication amount (g): substrate amount (g)=be advisable at 1: 1.3, experimental result sees Table.
Substrates quantity is investigated
| Medication amount (g): substrate amount (g) | 1∶1.0 | 1∶1.3 | 1∶1.5 |
| Quality of liquid medicine | Viscosity is big, mobile poor | Viscosity, flowability are all good | Differences in viscosity is mobile big |
2. opacifier is selected
The transparent adhesive tape softgel shell easily causes instability, so need to add a certain amount of opacifier.Select titanium dioxide (titanium dioxide) to make opacifier through investigation and can reach effective shaded effect, and steady quality, not with rubber cement and fill material generation chemical change.Its consumption is through investigating with gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: 3g is advisable, and little to the rubber quality influence, the results are shown in Table.
The opacifier consumption is selected
| Usage ratio | The rubber transparency | Rubber cement viscosity (Mas) | Overall merit |
| Gelatin 100g: glycerol 40g: water 100g: titanium dioxide 1g gelatin 100g: glycerol 40g: water 100g: titanium dioxide 2g gelatin 100g: glycerol 40g: water 100g: titanium dioxide 3g gelatin 100g: glycerol 40g: water 100g: titanium dioxide 4g | Translucent translucent opaque | 3.123.193.363.52 | The good inadequately viscosity of the not enough consumption of consumption is bigger |
Quality is more stable after adding opacifier in the capsule formula.
(2) molding technological condition is investigated
1. fill material mixes
Laboratory is got extractum and was pulverized 80 mesh sieves, presses extractum: substrate=add soybean oil at 1: 1.3, use the colloid mill mixing, and evacuation removes bubble, and is standby.
3. batchingization glue is investigated
By aforementioned preferred prescription is gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: the 3g weigh batching with different temperatures glue, the results are shown in Table.
Changing the glue temperature investigates
| Temperature (℃) | Change the glue time (H) | The rubber quality |
| 50 | 6 | Good |
| 60 | 5 | Good |
| 70 | 5 | Good |
| 80 | 5 | Harder |
| 90 | 4 | Rubber has bubble, and is hard |
By the table prompting, it is the most suitable with 60～70 ℃ to change the glue temperature.So batchingization adhesive tape part is: weigh batching, in the inputizations glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirs 5 hours also the while evacuation except that bubble, treat sizing material even after blowing, incapsulate after the filtration in the sizing material bucket of machine.
4. pelleting: the sizing material bucket and the spice bucket of room temperature of insulation are delivered to the capsule machine top, be connected, debug pellet press with machine, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity＜40%.Treat that it is the 400mg/ grain that ball content loading amount is regulated in pellet press debugging back.Survey loading amount once every half an hour in the pelleting process.
(5) granule Study on Forming
The applicant finds that this product makes that the greatest problem of granule is exactly that hygroscopicity is strong, the bitter supplementary product kind of mouthfeel and consumption thereof investigate in development process
Correctives is selected
The Icing Sugar scale
| Tested number | 1 | 2 | 3 | 4 |
| Addition | Do not add adjuvant | Add 2% | Add 3% | Add 4% |
| Mouthfeel | Pained (-) | The sweet slightly bitterness (+) that still has | Sugariness moderate (++) | Cross sweet (+++) |
The result shows, adds 3% Icing Sugar, and mouthfeel is moderate.
(6) pharmacological research
The antitumor action experiment
1.1 influence to murine sarcoma S180
300 of mices, 18-22g, male and female half and half are divided 5 groups at random, preparation high dose group of the present invention (1.557g/kg), middle dosage group (1.035g/kg), low dose group (0.522g/kg) and cyclophosphamide group (0.04g/kg), blank group (equal-volume distilled water).The equal gastric infusion of animal, every day 1 time, continuous 12 days.The same day was put to death animal in drug withdrawal, and torsion balance is weighed.
This experiment repeats three batches, and the result is similar.The results are shown in following table.Preparation of the present invention has the ashamed usefulness of obvious suppression S180 tumor growth, but it is strong to be not so good as the cyclophosphamide effect.
To the influence of murine sarcoma S180 growth (X ± S)
1.2 influence to mice ehrlich carcinoma (solid type)
300 of mices, 18-22g, male and female half and half are divided into 54 groups at random, preparation high dose group of the present invention (1.557g/kg), middle dosage group (1.035g/kg), low dose group (0.522g/kg) and cyclophosphamide group (0.04g/kg), blank group (equal-volume distilled water).The equal gastric infusion of animal, every day 1 time, continuous 12 days.The same day was put to death animal in drug withdrawal, and torsion balance is weighed.
Experiment repeats three batches, the results are shown in following table.
The result shows that each dosage group of granule of the present invention can obviously suppress tumor growth.
The influence that granule of the present invention is grown to mice ehrlich carcinoma solid type (X ± S)
1.3 influence to rat liver cancer (H22)
300 of mices, 18-22g, male and female half and half are divided into 5 groups at random, dispersible tablet high dose group of the present invention (1.557g/kg), middle dosage group (1.035g/kg), low dose group (0.522g/kg) and cyclophosphamide group (0.04g/kg), blank group (equal-volume distilled water).The equal gastric infusion of animal, every day 1 time, continuous 12 days.The same day was put to death animal in drug withdrawal, and torsion balance is weighed.Experiment repeats three batches, the results are shown in following table.
The result shows: " preparation of the present invention " each group all has inhibitory action to liver cancer growth, and big or middle dosage group inhibitory action is obvious
The influence that dispersible tablet of the present invention is grown to the rat liver cancer solid type (X ± S)
Rise white experiment
The operating system that following Data Processing in Experiment method adopts: SCOXEVIXV2-3-2; Programming language: SCOFOXBASE+V2-1-1 data base.
2.1, to the influence of leucocytes reduction due to the cyclophosphamide (CY)
Mice is divided into micropill high dose group of the present invention (1.557/kg), middle dosage group (1.035g/kg), low dose group (0.522g/kg) at random, six groups of batilol groups (0.32g/kg), blank group (equal-volume distilled water), CY matched group (equal-volume distilled water), every group 20,18-22g, male and female half and half.Rat is divided into six groups of micropill high dose group of the present invention (1.035g/kg), middle dosage group (0.522g/kg), low dose group (0.261g/kg), batilol group (0.32g/kg), blank group (equal-volume distilled water), CY matched group (equal-volume distilled water) at random, every group 15,180-220g, male and female half and half.The equal gastric infusion of animal, every day 1 time, continuous 12 days, administration the 1st day, except that CY, blank group lumbar injection equal-volume distilled water, the surplus equal intraperitoneal injection of cyclophosphamide (mice, the equal 0.03g/kg of rat) of respectively organizing of base, every day 1 time, for three days on end.Administration the 6th day, the 9th day, the 12nd day is got blood respectively and is carried out numeration of leukocyte.
The influence that micropill of the present invention reduces the caused by cyclophosphamide murine interleukin
Compare * P＜0.05 * * P＜0.01 * * * P＜0.001 with the batilol group
The result: micropill of the present invention has the obvious treatment effect to the leucocytes reduction of caused by cyclophosphamide mice.
The influence that micropill of the present invention reduces the caused by cyclophosphamide rat leukocyte
Compare * P＜0.05 * * P＜0.01 * * * P＜0.001 with the batilol group
The result: micropill of the present invention has the obvious treatment effect to the leucocytes reduction of caused by cyclophosphamide rat.
2.2, to the influence of leucocytes reduction due to the radioactivity
Mice is divided into soft capsule high dose group of the present invention (1.557g/kg), middle dosage group (1.035g/kg), low dose group (0.522g/kg) at random, six groups of batilol groups (0.32g/kg), deep x ray matched group (equal-volume distilled water), blank group (equal-volume distilled water), every group 20,18-22g, male and female half and half.Rat be divided at random soft capsule high dose group of the present invention (1.035g/kg), middle dosage group (0.522g/kg), low dose group (0.261g/kg), batilol group (0.32g/kg),
60Six groups of Co matched group (equal-volume distilled water), blank groups (equal-volume distilled water), 15 every group, 180-220g, male and female half and half.The equal gastric infusion of animal, every day 1 time, continuous 12 days, administration the 1st day, except that the blank group, all the other each groups are all used radiation exposure 1 time, and mice is used deep X-ray irradiation, 40.61 γ/minute, total amount 350 γ, apart from 40cm, 200KV, 150MA; Rat
60The Co gamma-radiation, the 53.26CGY/ branch, total amount 400CGY, apart from 75cm, administration the 6th day, the 9th day, the 12nd day is got blood respectively and is carried out numeration of leukocyte.
Soft capsule of the present invention is to the influence of radioactivity induced mice leucocytes reduction
Compare * P＜0.05 * * P＜0.01 * * * P＜0.001 with the batilol group
The result: soft capsule of the present invention has the obvious treatment effect to the leucocytes reduction of deep x ray induced mice.
The influence that soft capsule of the present invention reduces rat leukocyte due to the radioactivity
Compare * P＜0.05 * * P＜0.01 * * * P＜0.001 with the batilol group
The result: soft capsule of the present invention is right
60The leucocytes reduction of rat has the obvious treatment effect due to the Co gamma-rays.
Immunization experiment
3.1, to the influence of immune organ
Mice is divided into 5 groups, drop pill high dose group of the present invention (0.61g/kg), middle dosage group (0.3g/kg), low dose group (0.16g/kg), prednisone group (0.04g/kg), blank group (equal-volume distilled water), 20 every group, 18-22g, male and female half and half.The equal gastric infusion of animal, every day 1 time, continuous 9 days.Put to death animal after the drug withdrawal in the 24h, weigh, thymus and spleen weight, calculate thymus index and index and spleen index.
Drop pill of the present invention is to the X ± SD that influences of mouse immune organ
| Group | Number of animals | Thymus index (mg/10g) | Index and spleen index (mg/kg) |
| Drop pill of the present invention (height) | 20 | ?63.89±11.32 ** | 62.00±11.23 ** |
| Drop pill of the present invention (in) | 20 | ?61.24±8.55 ** | 51.12±13.87 |
| Drop pill of the present invention (low) | 20 | ?52.35±17.44 | 49.38±10.24 |
| The blank group | 20 | ?40.00±19.21 | 37.77±24.43 |
| The prednisone group | 20 | ?29.28±11.97 | 27.58±15.95 |
Compare with the blank group: * P＜0.05 * * P＜0.01 * * * P＜0.01
The result: drop pill high dose of the present invention has tangible increase to mouse thymus and spleen weight, and dosage has tangible increase to mouse thymus weight in the drop pill of the present invention, compares P＜0.01 with the blank group.
3.2, to the influence of tumor-bearing mice peritoneal macrophage phagocytic function
Mice is divided into 5 groups of tablet high dose group of the present invention (0.61g/kg), middle dosage group (0.3g/kg), low dose group (0.16g/kg), prednisone group (0.04g/kg), blank group (equal-volume distilled water), 20 every group, 18-22g, male and female half and half.The equal gastric infusion of animal, every day 1 time, continuous 9 days, drug withdrawal mouse peritoneal on the same day is only injected 2% chicken erythrocyte suspension 1ml/, puts to death animal after 30 minutes, the normal saline flushing abdominal cavity, getting the abdominal cavity washing liquid drips on slide, 37 ℃ of temperature are incubated 30 minutes after stain sheets, and oily mirror is 200 macrophage/sheets of counting down, calculate phagocytic percentage and phagocytic index.
Tablet of the present invention is to the X ± SD that influences of Turnover of Mouse Peritoneal Macrophages phagocytic function
| Group | Number of animals | Phagocytic percentage | Phagocytic index |
| Tablet of the present invention (height) | 20 | 60.22±6.23 *** | 71.06±23.22 ** |
| Tablet of the present invention (in) | 20 | 55.34±8.26 ** | 60.35±11.43 * |
| Tablet of the present invention (low) | 20 | 48.43±9.07 | 52.00±10.77 |
| The blank group | 20 | 47.77±6.08 | 49.88±6.25 |
| The prednisone group | 20 | 28.64±7.55 *** | 36.45±7.11 *** |
Compare with the blank group: * P＜0.05 * * P＜0.01 * * * P＜0.01
The result: tablet high dose of the present invention, middle dosage compare P＜0.001, P＜0.01 or P＜0.05 to mouse macrophage phagocytic percentage and the phagocytic index effect of being significantly improved with the blank group.
3.3, to the influence of tumor-bearing mice serum hemolysin antibody
Mice is divided into 5 groups of oral liquid high dose group of the present invention (0.61g/kg), middle dosage group (0.3g/kg), low dose group (0.16g/kg), prednisone group (0.04g/kg), blank group (equal-volume distilled water), 20 every group, 18-22g, male and female half and half.The equal gastric infusion of animal, every day 1 time, continuous 12 days, administration the 3rd day, lumbar injection 5% chicken erythrocyte suspension 0.2ml/ only, drug withdrawal 24h puts to death animal, and it is centrifugal to get blood, and serum dilutes 100 times with normal saline, dilute serum 1ml is mixed with 5% chicken erythrocyte suspension 0.5ml, add 10% complement 0.5ml under 0 ℃ of condition, temperature is incubated after 30 minutes cessation reaction under 0 ℃ of condition, gets supernatant in 721 type spectrophotometer 540nm place's photometry density after centrifugal.
Table 10 oral liquid of the present invention is to the X ± SD that influences of mice hemolytic antibody
| Group | Number of animals | Optical density (od * 100) | The P value |
| Oral liquid of the present invention (height) | 20 | 5.34±3.21 | ＜0.01 |
| Oral liquid of the present invention (in) | 20 | 4.34±2.89 ** | ＜0.01 |
| Oral liquid of the present invention (low) | 20 | 3.38±2.77 | ＜0.05 |
| The blank group | 20 | 1.91±0.75 | |
| The prednisone group | 20 | 0.97±1.13 | ＜0.001 |
The result: oral liquid high dose of the present invention, middle dosage have tangible rising effect to the mice hemolytic antibody, compare P＜0.001, P＜0.01 or P＜0.05 with the blank group.
3.4, influence that carbon granule is cleaned up
Mice is divided into 5 groups of capsule in high dose groups of the present invention (1.557g/kg), middle dosage group (1.035g/kg), low dose group (0.522g/kg), cyclophosphamide group (0.01g/kg), blank group (equal-volume distilled water), every group 20,18-22g, male and female half and half.The equal gastric infusion of animal, every day 1 time, continuous 9 days, each caudal vein injection india ink 0.1ml/10g of 1h after the last administration, respectively at getting blood 20 μ l in 5 minutes, 10 minutes behind the eyeball behind the injection prepared Chinese ink, each adds 0.1% sodium carbonate 2ml, measures optical density with 721 type spectrophotometer 600nm, calculates phagocytic index K value and activate the phagocytic capacity α value.
The influence that capsule of the present invention is cleaned up the mice carbon granule (X ± SD)
Compare with the blank group: * P＜0.05 * * P＜0.01 * * * P＜0.01
The result: capsule in high dose of the present invention, middle dosage is cleaned up function to the mice carbon granule that obvious facilitation is arranged, with the blank group relatively, P＜0.001 or P＜0.01.
Attenuation
100 of mices, 18-22g, male and female half and half, divide 5 groups at random, capsule in high dose group of the present invention (1.557g+ cyclophosphamide 0.1g/kg), middle dosage group (1.035g+ cyclophosphamide 0.1g/kg), low dose group (0.522g+ cyclophosphamide 0.1g/kg) and cyclophosphamide group (0.1g/kg), blank group (equal-volume distilled water).The equal gastric infusion of animal, every day 1 time, continuous 9 days.Drug withdrawal put to death that animal is got blood, bone marrow is counted leukocyte and nucleated cell the same day.
Capsule of the present invention causes the influence (X ± SD) of leukocyte and marrow nucleated cell decreasing to cyclophosphamide
| Group | Dosage (g/kg) | Number of animals (only) | Leukocyte count (* 10 9/L) | Bone marrow nucleated cell (* 10 9/L) |
| Blank | - | 20 | 11.70±1.47 | 60.54±9.34 |
| Cyclophosphamide | 0.1 | 20 | 2.78±0.84 | 25.96±7.64 |
| Ring+medicine I | 3.0 | 20 | 4.04±0.58** | 33.26±7.16* |
| Ring+medicine II | 2.0 | 20 | 3.65±0.36** | 33.74±6.79* |
| Ring+medicine III | 1.0 | 20 | 3.10±0.34** | 25.98±8.93* |
Compare * P＜0.05, * * P＜0.01 with cyclophosphamide.
The result: capsule of the present invention has the toxic reaction of caused by cyclophosphamide and obviously alleviates effect, can resist the minimizing of its leukocyte that causes and nucleated cell.
The acute toxicity test of the capsule preparations of this product
Experiment material
Medicine capsule preparations of the present invention, content are the powder of yellowish-brown
Provide by Guizhou Baixiang Pharmaceutical Co.Being mixed with 25% suspension with distilled water before the test uses.
Two, animal Kunming mouse, 20 ± 2g, male and female half and half, animal housing provides by the Guizhou Prov. Traditional Chinese Medical Research Inst.
Experimental technique and result
60 of mices, male and female half and half are divided into two groups of first, second at random by sex, body weight, behind the fasting 12h, press the 0.4ml/10g gastric infusion, the medication of first group once, second group medication secondary (at interval 2h), dosage is respectively 10g/kg and 20g/kg.1h recovers water and food supply after the medication, observes 7 days.
The results are shown in that respectively to organize mice activity, feed and defecation normal, do not have dead and other anomaly.
Conclusion
The capsule preparations of this product of mouse stomach is not measured the minimum of gastric infusion in prerun, pretend mtd test.The clinical consumption of this product is oral 1.05g/ time, 3 times/day, is equivalent to 0.0525g/kg.d to become body weight for humans 60kg conversion, this is tested maximum consumption and reaches 20g/kg, be 380.95 times of clinical consumption, mice does not all have death and other anomaly after the medication, shows the oral safety non-toxic of this product.
The long term toxicity test of the capsule preparations of this product
Summary
This experimental observation the histological influence of the long-term oral administration of capsule preparations to growth, hemogram, serum biochemistry index and the main organs of rat.The result shows, capsule is given the rat oral medication, and two groups of rats dosage on the one is respectively 8k/kg, 4g/kg, 90 days experimental periods, is equivalent to 3 courses of treatment of clinical application.The experimental session rat generally in order, many-sided index such as body weight sustainable growth, hemogram, blood biochemical, organ coefficient, pathologic finding and matched group relatively all do not have significant difference.After 2 weeks of drug withdrawal, also do not find the untoward reaction of tardy property.
Experiment purpose
Observe the toxic reaction that the long-term oral capsule of the present invention of rat is produced, to determine clinical application safety.
Experiment material
1. medicine: the capsule of the present invention's preparation, sample is provided by Guizhou Baixiang Pharmaceutical Co, is made into desired concn with its normal saline during experiment, every day matching while using.
2. animal: Wistar kind rat, male and female half and half, male average weight are 101.4 ± 5.8g, female average weight is 78.5 ± 5.4g, animal housing provides by the Guizhou Prov. Traditional Chinese Medical Research Inst, every day water, supply of forage abundance.
3. instrument: Japan produces F-800 blood cell numeration instrument, COBAS MIRA 25-4464 biochemistry analyzer.
Experimental technique
60 of Wister rats, body weight 103～123g is divided into 3 groups at random by body weight, and 20 every group, ♀ ♂ sub-cage rearing, 2 in every cage.Medicine is mixed in feedstuff (feedstuff be the weight of animals 5%), and in feed at 4 o'clock in afternoon, at 8 o'clock next day, animal was fed, and other throws in normal diet, and at 12 o'clock at noon stopped eating, and every day is identical.If 2 medicine groups, high dose group (I group) is 8g/kg Jesus, low amount group (II group) 4g/kgd, and matched group is fed normal diet, continuous 90 days.Drug withdrawal second day, each is organized half animal and gets the tail blood examination and have a blood test and resemble, and gets the carotid artery blood examination and looks into biochemical indicator.Dissect animal, organs such as the heart, liver, spleen, lung, kidney, adrenal gland, gastrointestinal, testis, uterus, ovary, brain are observed, get high dose group and the control rats heart, liver, spleen, lung, kidney are done the pathology histological examination.Second half animal was extremely cutd open in drug withdrawal on the 14th day, did above-mentioned inspection.
The result:
1, the general situation of animal: between administration and withdrawal time, each organizes all no abnormal performance of rat, and hair is smooth, absent lacrimation, sialorrhea image, and behavior and activity, diet, stool urinate all as usual.
2, growth promoter: experimental session is respectively organized the equal sustainable growth of body weight, there was no significant difference (table 1) between group.
3, hemogram: each organizes rat hemogram index all in normal range, there was no significant difference (table 2) between group.
4, blood biochemical: the results are shown in table 3, every index of liver, renal function all in normal range, there was no significant difference between group.
5, internal organs coefficient: the results are shown in table 4, each organizes there was no significant difference between rat.
6, pathologic finding: gross examination of skeletal muscle, each group all has minority animal lungs to present local congestion phenomenon, and other organs are not seen difference.Check pathological section, administration group and matched group are not relatively seen the pathological change relevant with medicine.
After 2 weeks of drug withdrawal, also do not find the untoward reaction of tardy property.
Discuss and conclusion
This experiment is according to " provisions for new drugs approval " " supplementary provisions " and documents such as " study of tcm new drug guides ", and according to capsular clinical consumption, the course of treatment and main pharmacodynamics institute dosage, determine that adopting high dose is 8g/kg/ day, low dose group is 4g/kg/ day, successive administration 3 months has been observed every index on request.The result shows: the continuous gastric infusion of capsule preparations 3 months, rat diet, growth, hematological indices, serum biochemistry are learned the organ coefficient and the pathomorphology inspection of index, main organs (heart, liver, spleen, lung, kidney) and all do not found the overt toxicity reaction, the harmonization of the stomach duodenum is not had the obvious stimulation reaction yet, capsule free of toxic effects in used dosage and administration time is described.
This capsule of table 1 rat long term toxicity test-body weight (X ± SDg)
Table 2 Chinese mugwort capsule for curing rat long term toxicity test-hemogram measurement result (X ± SD)
This capsule of table 3 rat long term toxicity test-hepatic and renal function index determining result (X ± SD)
| Group | Alaninyl transferring enzyme (Ka Menshi unit) | Oxamidic acid. aminotransferase (Ka Menshi unit) | Carbamide ammonia (mmol/L) | Creatinine (u molL) |
| Contrast in 90 days | 31.3±9.98 | 25.0±11.7 | 4.93±0.93 | 56.2±11.0 |
| This I | 25.5±3.62 | 29.1±14.1 | 4.53±0.83 | 48.2±9.72 |
| This II | 27.4±6.29 | 27.21±3.6 | 4.06±0.37 | 47.6±10.1 |
| Contrast in 14 days | 22.0±4.16 | 20.5±3.56 | 4.06±0.82 | 44.5±6.30 |
| This I | 20.6±3.60 | 17.1±2.59 | 4.73±0.96 | 44.2±5.34 |
| This II | 20.9±3.57 | 20.5±3.57 | 4.64±1.16 | 46.2±8.38 |
This capsule of table 4 rat long term toxicity test-internal organs coefficient (X ± SD g/kg)
| Group | The heart | Lung | Liver | Spleen | Kidney | Testis | The uterus |
| Contrast in 90 days | 0.33±0.03 | 0.76±0.07 | 3.49±0.34 | 0.45±0.12 | 0.79±0.04 | 1.03±0.08 | 0.23±0.02 |
| This I | 0.32±0.02 | 0.77±0.10 | 3.48±0.30 | 0.42±0.13 | 0.75±0.06 | 0.91±0.07 | 0.22±0.01 |
| This II | 0.33±0.01 | 0.77±0.11 | 3.46±0.31 | 0.44±0.163 | 0.77±0.03 | 1.00±0.03 | 0.21±0.02 |
| Contrast in 14 days | 0.33±0.02 | 0.73±0.05 | 3.49±0.22 | 0.44±0.11 | 0.68±0.04 | 0.89±0.02 | 0.19±0.02 |
| This I | 0.34±0.02 | 0.72±0.07 | 3.50±0.18 | 0.41±0.10 | 0.71±0.04 | 0.86±0.07 | 0.20±0.01 |
| This II | 0.33±0.02 | 0.73±0.05 | 3.49±0.22 | 0.44±0.11 | 0.68±0.04 | 0.89±0.02 | 0.19±0.02 |
Clinical trial data and clinical operating position:
Capsule for treating leukopenia clinical verification embodiment provided by the invention
Capsule provided by the invention is that Miao ethnic group's folk remedy discovery and arrangement forms, have that heat clearing and damp drying, benefiting qi and nourishing blood, spleen invigorating are promoted the production of body fluid, the effect of yin nourishing invigorating YANG, can suppress tumor growth, cancer is had certain curative effect, can be used for the diseases such as leukopenia that carcinosis radiotherapy and chemotherapy causes.Leukopenia is the syndrome that is caused by multiple reason, and clinical have factors such as (as chemotherapeutic, chemical drugs, radiotherapy etc.) and infection that medicine source property causes, immunity to cause or agnogenio person.Its incidence rate of leukocyte that medicine source property causes is higher, is common in the clinical treatment process.This product has the effect of treatment leukopenia, confirms this medicine safety non-toxic side reaction through pharmacodynamics and toxicologic study, and clinical research is found tumor patient obvious because of radiation or leukopenia caused by cancer chemotherapy disease therapeutical effect.According to Ministry of Public Health " provisions for new drugs approval " requirement, must and have no adverse reaction to its clinical efficacy and verify.Formulate this clinical verification implementation plan with reference to " new Chinese medicine treatment hematopathy clinical drug research guideline ".
One, diagnostic criteria
1, chemotherapy or radiotherapy history are arranged.
2, the peripheral blood leukocyte sum is double below 4000/ μ l.The neutrophilic granulocyte absolute value is between 1000-1800/ μ l.
3, be easy to flu, dizzy weak, extremity are aching and limp.
Two, case is selected
(1), include case in:
1, be the main object of observation with adult patients, the men and women takes into account.
2, based on the inpatient, and the out-patient that partly can finish every observation index.
3, reduced to tumor patient below the 4000/ μ l through total white blood cells after radiotherapy or the chemotherapy.
(2), get rid of case:
Advance to fail in the phase whole blood or blood products person.
Used the Chinese medicine and western medicine person of function of increasing leukocyte.
Three, observation item
Safety observation
1, checks urine, stool for routine, liver function, renal function (blood urea nitrogen, serum creatinine etc.) before, during and after the treatment.
2, observe the untoward reaction of medicine to systems such as digestion, breathing, cardiovascular, nerve, urinary system, skins.
Health giving quality is observed
1, to general symptom treatment, as dizzy, weak, diseases such as whole body is aching and limp, insomnia and dreamful sleep, low grade fever.
2, observe hemoglobin (Hb) (gram/dl), erythrocyte (RBC), leukocyte count (WBC) and classification before and after the treatment.
3, before the treatment, back bone marrow smear is (hyperplasia degree, hematopoietic cell ratio and form change) relatively.
Should observe and write down every index according to plan in detail during the treatment.
Four, verification method
Clinical verification is intended carrying out in 2-3 hospital, observes 100 examples altogether, and other establishes matched group 30 examples, and sex, age, disease time and state of an illness weight and treatment group are approximate.Take random packet.Contrast medicinal batilol+leucogen.
Five, usage, consumption and the course of treatment
The treatment group: the capsule of oral the present invention's preparation, each 1.35 grams, every day three times, 7 is a course of treatment.
Matched group: 20 milligrams/time of 20 milligrams/time+leucogens of oral batilol, every day three times.Two medicines share, and the course of treatment is consistent with the treatment group.
Six, curative effect is judged
Treatment back is with numeration of leukocyte evaluation curative effect of medication, divides produce effects, effective, invalid three grades.
(1) produce effects
Numeration of leukocyte and classification recover normal range (＞5000/ μ l).
(2) effective
Numeration of leukocyte is treated preceding raising 100% or is risen to more than the 3000/ μ l.And granulocyte absolute value＞1500/ μ l.
(3) invalid
Leukocyte count does not have obviously and increases.
Seven, analysis, statistical disposition and evaluation
Clinical verification should gather and array data, but can not alter observed and recorded arbitrarily after finishing, and the brief summary report should be write out by each clinical verification unit.Gather by clinical responsible department and to check checking unit, general introduction, physical data, verification method, judgement, observation index, judgement criterion of therapeutical effect, treatment and result's (comprising form and model case), discussion and result.Should verify the result according to this in the discussion, to capsular function provided by the invention cure mainly, subject range, dosage regimen, the course of treatment, curative effect (observing effectively above result), safety, untoward reaction (comprising processing method) etc. draw a conclusion.And, product is made objective evaluation according to its clinical meaning.
The capsule for treating leukopenia clinical verification of the present invention preparation is summed up: according to the clinical verification of No.1 Hospital of Guiyang Traditional Chinese Medicine College's oncology and Song Zhencai: " ethnic drug " the Chinese mugwort capsule for curing (capsule preparations of the present invention's preparation, its trade name: the Chinese mugwort capsule for curing) " be the oral capsule that develops by Miao ethnic group's folk remedy.Have that heat clearing and damp drying, benefiting qi and nourishing blood, spleen invigorating are promoted the production of body fluid, the effect of yin nourishing invigorating YANG, can suppress tumor growth, cancer is had certain curative effect, can be used for the diseases such as leukopenia that carcinosis radiotherapy and chemotherapy causes.Confirm this medicine safety non-toxic side reaction through Pharmacodynamic test of active extract and toxicologic study, clinical research is found tumor patient obvious because of radiation or leukopenia caused by cancer chemotherapy disease therapeutical effect.Clinical verification plan requirement according to No. 27 file Chinese mugwort of Guizhou Province Department of Public Health Qianweiyaozhi (95) capsule for curing, we have carried out clinical verification to 130 examples because of the leukopenia patient that chemicotherapy causes, the result shows that " Chinese mugwort capsule for curing " reaches 87.28% to the leukopenia total effective rate that chemicotherapy causes ".
Clinical data
One, diagnostic criteria
According to " new Chinese medicine treatment hematopathy clinical drug research guideline " is diagnosis basis.The object of observation is that the secondary total white blood cells is lower than normal value (4.0 * 10 before the clinical verification
9/ l), the contrast index is leukocyte value of detecting second time.
Two, case is selected
(1), include case in:
1, be the main object of observation with adult patients, the men and women takes into account.
2, based on the inpatient, and the out-patient that partly can finish every observation index.
3, reduced to tumor patient below the 4000/ μ l through total white blood cells after radiotherapy or the chemotherapy.
4, the inpatient and the out-patient that can finish every observation index.
(2), get rid of case:
1, advances to fail in the phase whole blood or blood products person.
2, used the Chinese medicine and western medicine person of function of increasing leukocyte.
Three, physical data
Observe 130 examples altogether, have 95 examples to be the inpatient.Its promising outpatient service can be looked into patient, male's 76 examples, and women's 54 examples, at minimum 20 years old of age, maximum 71 years old, each age group distributed and the sex situation sees Table 1.
Pulmonary carcinoma 27 examples wherein, nasopharyngeal carcinoma 9 examples, thyroid carcinoma 6 examples, malignant lymphosarcoma 13 examples, esophageal carcinoma 12 examples, rectal cancer 8 examples, cancer of pancreas 3 examples, protopathy mammary cancer 19 examples, cervical cancer 8 examples, colon cancer 11 examples, carcinoma of endometrium 2 examples, carcinoma of vulva 1 example, malignant melanoma 4 examples, ovarian cancer 6 examples, renal carcinoma 1 example.
Radiotherapy person's 53 examples in the above case, chemotherapy person's 49 examples, radiotherapy plus chemotherapy person's 21 examples, agnogenio person's 7 examples.Whole cases are divided into treatment and organize 100 examples, matched group 30 examples.
Table 1 Chinese mugwort capsule for curing clinical verification physical data
Four, Therapeutic Method
The treatment group: oral Chinese mugwort capsule for curing, each 1.35 grams, every day three times, 7 is a course of treatment.Observe two courses of treatment.
Matched group: 20 milligrams/time of 20 milligrams/time+leucogens of oral batilol, every day three times.Two medicines share, and the course of treatment is consistent with the treatment group.
Five, observation index
According to data clinical verification plan requirement, fill in observed and recorded in detail.
(1) safety observation
1, checks urine, stool for routine, liver function, renal function (blood urea nitrogen, serum creatinine etc.) before, during and after the treatment.
2, observe the untoward reaction of medicine to systems such as digestion, breathing, cardiovascular, nerve, urinary system, skins.
(2) health giving quality is observed
1, to general symptom treatment, as dizzy, weak, diseases such as whole body is aching and limp, insomnia and dreamful sleep, low grade fever.
2, observe hemoglobin (Hb) (gram/dl), erythrocyte (RBC), leukocyte count (WBC) and classification before and after the treatment.
3, before the treatment, back bone marrow smear is (hyperplasia degree, hematopoietic cell ratio and form change) relatively.
Observed result
Efficacy assessment standard is formulated standard according to leukocyte curative effect of medication in " treatment hematopathy clinical drug research guideline ", divides produce effects, effective, invalid three grades.
One, the efficacy result of Chinese mugwort capsule for curing treatment group
The treatment group is totally 100 examples, and total effective rate is 89%.The data tabulate statistics sees Table 2.
Table 2 Chinese mugwort capsule for curing treatment group curative effect statistical table
Two, Chinese mugwort capsule for curing treatment group and matched group curative effect are relatively
In the Chinese mugwort capsule for curing clinical verification process, matched group and treatment group are taked random packet.Basic condition is approximate, and two groups of curative effects of clinical observation result relatively see Table 3.
Table 3 treatment group and matched group curative effect are relatively
The result shows that the total effective rate of the leukopenia card of secondary is 89% after the Chinese mugwort capsule for curing treatment radiotherapy.Matched group (batilol adds the leucogen) is 66.67%, and treatment group and matched group be P＜0.001 relatively.
Three, Chinese mugwort capsule for curing drug treatment and therapeutic effect relationship
Case totally 89 examples are organized in 100 examples effectively in treatment, total white blood cells and neutral classification numerical value all have and increase after one course of treatment of medication, all effective case reaches effectively above standard after second course of treatment, show that the Chinese mugwort capsule for curing leukogenic effect promptly occurs in medication after 7 days, to rise white effect better along with the increase of the course of treatment, for clinical rational drug use provides foundation.
Four, untoward reaction
Do not see in the case untoward reaction or toxic and side effects are arranged.
Brief summary
The result who observes 130 examples through clinical verification shows, the Chinese mugwort capsule for curing is imitated the contour painting that rises of the caused leukopenia of chemicotherapy, total effective rate is 89%, its curative effect is better than matched group (batilol+leucogen) P＜0.001, in 100 routine treatment groups, produce effects, effective case be totally 89 examples, reaches effectively above clinical development standard.The curative effect and the course of treatment are proportional, for clinical rational drug use provides foundation.
In sum, the Chinese mugwort capsule for curing is effective preparation for the treatment of the leukopenia that causes after the tumor radiotherapy chemotherapy, and it has the characteristics of instant effect, safety non-toxic.
The specific embodiment
Embodiments of the invention 1: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing when being concentrated into relative density and being 25 ℃, drying is ground into fine powder, incapsulates, make 1000, promptly get capsule, oral, one time 3,3 times on the one, every the dress 0.35g.
Embodiments of the invention 2: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃, with the Icing Sugar mixing, to granulate, drying is made 1000g, promptly gets granule.
Embodiments of the invention 3: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Get PPVP3.0g and lemon yellow mixing, get 3/4 with the extract powder mix homogeneously, make binding agent with 1% K30 anhydrous alcohol solution, 40 order system material, granulate remain 1/4 the PPVP and the mixed powder of lemon yellow mixing and are added in the particle that makes, tabletting promptly gets dispersible tablet.
Embodiments of the invention 4: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Add an amount of starch, with 60% ethanol and 1.2% soybean oil system soft material, the soft material that makes micropill mechanism ball, wet feed pushed the 0.8mm sieve aperture, and the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings, crossing 16～20 mesh sieves selects ball or merges above-mentioned four kinds of clear paste, spray drying, wet-milling granulation molding, mould placed add the great achievement ball in the coating pan, medicated powder: water is 1: 1, and the coating pan rotating speed is 42r/min, capping, select ball, promptly get micropill
Embodiments of the invention 5: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Press medication amount: substrate amount=1: 1.3 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: 3g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity＜40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2 hours of the typing of rolling, and 22 ℃ of baking temperatures, dry relative humidity should be lower than 40%, and promptly got soft capsule at 24～48 hours drying time.
Embodiments of the invention 6: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merges three decoctions, filtration, the thick paste of 1.12-1.15 adds above-mentioned fine powder, mixing, drying when being concentrated into relative density and being 25 ℃; Get the extract powder portion, two parts of two parts of PEG6000 and polyoxyethylene monostearate S-40, mix homogeneously fuses in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 5cm drip footpath 2.5mm/2mm, mix 75 ℃ of ointment temperature, liquid coolant height 65cm promptly gets drop pill.
Embodiments of the invention 7: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder when being concentrated into relative density and being 25 ℃, mixing, drying is pulverized, add microcrystalline Cellulose 22g, use 60% alcohol granulation, drying, granulate adds magnesium stearate 1.5g, mixing, tabletting, coating promptly gets tablet.
Embodiments of the invention 8: Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g, Radix Ginseng 100g, get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements decoct with water three times, and 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 adds above-mentioned fine powder when being concentrated into relative density and being 25 ℃, mixing adds distilled water, 3.0% aspartame, and sterilization promptly gets oral liquid
Embodiments of the invention 9: Pseudobulbus Cremastrae Seu Pleiones 100g, Herba Solani Lyrati 100g, Herba Epimedii 100g, Radix Sophorae Flavescentis 100g, Radix Angelicae Sinensis 100g, Rhizoma Atractylodis Macrocephalae 100g, Radix Ginseng 50g get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and be standby; All the other Six-elements decoct with water 0.5 hour, and decocting liquid filters, and concentrate, and add above-mentioned fine powder, mixing, and drying, pill promptly gets pill.
Embodiments of the invention 10: Pseudobulbus Cremastrae Seu Pleiones 600g, Herba Solani Lyrati 500g, Herba Epimedii 500g, Radix Sophorae Flavescentis 500g, Radix Angelicae Sinensis 500g, Rhizoma Atractylodis Macrocephalae 300g, Radix Ginseng 200g get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and be standby; All the other medical materials decoct with water 5 times, and each 3 hours, collecting decoction filtered, and concentrates, and adds above-mentioned fine powder, mixing, and drying adds syrup, promptly gets syrup.
Claims (1)
1. pharmaceutical preparation for the treatment of cancer is by Pseudobulbus Cremastrae Seu Pleiones 450g, Herba Solani Lyrati 350g, Herba Epimedii 300g, Radix Sophorae Flavescentis 350g, Radix Angelicae Sinensis 300g, Rhizoma Atractylodis Macrocephalae 250g and Radix Ginseng 100g and adjuvant preparation; It is characterized in that: get Radix Angelicae Sinensis 100g, Radix Ginseng is worn into fine powder, and is standby; All the other Six-elements: remaining Radix Angelicae Sinensis and Pseudobulbus Cremastrae Seu Pleiones, Herba Solani Lyrati, Herba Epimedii, Radix Sophorae Flavescentis and the Rhizoma Atractylodis Macrocephalae decoct with water three times, 2 hours for the first time, 1 hour for the second time, 1 hour for the third time, merge three decoctions, filter, the thick paste of 1.12-1.15 when being concentrated into relative density and being 25 ℃, add above-mentioned fine powder, mixing, drying; Get the extract powder portion, two parts of two parts of PEG6000 and polyoxyethylene monostearate S-40, mix homogeneously fuses in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 5cm drip footpath 2.5mm/2mm, mix 75 ℃ of ointment temperature, liquid coolant height 65cm promptly gets dropping pill formulation.
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