CN101810706A - Preparation method of garden burnet solid preparation with low dose - Google Patents
Preparation method of garden burnet solid preparation with low dose Download PDFInfo
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- CN101810706A CN101810706A CN 201010170742 CN201010170742A CN101810706A CN 101810706 A CN101810706 A CN 101810706A CN 201010170742 CN201010170742 CN 201010170742 CN 201010170742 A CN201010170742 A CN 201010170742A CN 101810706 A CN101810706 A CN 101810706A
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Abstract
The invention discloses a preparation method of a garden burnet solid preparation with low dose. The preparation method comprises the following steps of: (1) taking 1 to 10 parts by weight of garden burnet and pulverizing into fine powder; (2) taking 90 to 99 parts by weight of auxiliary materials, wherein the auxiliary materials comprise sucrose and starch; (3) taking part of the sucrose and the starch in the step (2) and preparing an adhesive; (4) mixing the fine powder obtained in the step (1) and the residual auxiliary materials in the step (2) to obtain an mixture; (5) adding the prepared adhesive into the mixture obtained in the step (4), granulating, drying, pulverizing and then mixing; and (6) granulating by using the residual part of the adhesive and/or water or the ethanol solution with the volume concentration of 5 to 40 percent, drying, sieving and then preparing a tablet, a capsule, a pill or granules. The garden burnet preparation obtained by the method has uniform content of the garden burnet, quick disintegration, good curative effect and safe, effective and controllable clinical use.
Description
Technical field
The present invention relates to a kind of preparation method of garden burnet solid preparation with low dose, belong to field of pharmaceutical preparations.
Background technology
Radix Sanguisorbae is the Rosaceae herbaceos perennial.Radix Sanguisorbae is as conventional Chinese medicine, has the effect that skin ulcer is held back in cooling blood for hemostasis, clearing heat, releasing toxin, removing swelling, and modern study shows: Radix Sanguisorbae has hemostasis, antiinflammatory, promotion wound healing, many-sided pharmacologically active such as antibiotic, and the effect with treatment leukopenia.
The prescription that the WS-11020 of drug and food Surveillance Authority of the People's Republic of China (PRC) (ZD-1020)-No. 2002 drug standard discloses DIYU SHENGBAI PIAN is: Radix Sanguisorbae 5g, and sucrose 32g, dextrin 47g, starch 16g makes 1000; The DIYU SHENGBAI PIAN standard (" method for making " item among the WS-11020 (ZD-1020)-200 (2) disclosed burnet for raising white cell piece preparation method down is: " and get Radix Sanguisorbae, be ground into fine powder, add starch, sucrose and dextrin; mixing, make granule, drying; tabletting, sugar coating or film-coat, promptly." this method only is simply to have put down in writing supplementary material mixing, granulation.This product belongs to low dose of solid preparation, every Radix Sanguisorbae protogenic medicinal powder that only contains 5mg, the unit's of accounting for sheet heavy 5%.This means that 5 parts of relatively poor relatively Radix Sanguisorbae protogenic medicinal powder of flowability must carry out uniform mixing with 95 parts pharmaceutic adjuvant in big production, in fact the difficulty of its mix homogeneously is bigger.Simultaneously, show that about the basis and the clinical research data of DIYU SHENGBAI PIAN DIYU SHENGBAI PIAN clinical administration dosage directly influences its clinical efficacy, promptly must take in dosage by strict control medicine, just can obtain the curative effect of good leukocyte increasing.
And the uniformity of active constituent content is to guarantee to be applied to people intravital every or every or every medicine after big the production in the medicament; employed sample has identical material base when carrying out preparation process research, quality standard research, medicine stability research, preclinical study, clinical experimental study with it; guarantee that safety of medicine is effectively crucial; the defective difference that tends to cause active constituent content in different batches even same batch, the same unit dose package of the active constituent content uniformity in the medicine is for the patient brings bad consequence.When taking active constituent content pharmaceutical preparation not up to standard, can't obtain the curative effect of expection probably such as patient when severe disease; If other patients take the medicine that active constituent content differs greatly for a long time, also can't obtain the normal therapeutic effect of this medicine.Therefore, guarantee the uniform distribution of active component Radix Sanguisorbae in the burnet for raising white cell flake products, effectively significant to ensureing this product clinical drug safety.
The CN90108019 Chinese patent application discloses " a kind of preparation method of new type sanguisorba pharmaceutical ".This application has not only been announced the preparation method of low content Rhizoma sanguisorbae preparation: Radix Sanguisorbae crude drug powder 50g (or 100g) and Icing Sugar 400g, starch 450g (or 400g), add magnesium stearate 10g or Pulvis Talci 25g, reuse 10% starch slurry 180ml mixes, and granulates, drying, the technology of tabletting;
This application has also been announced the preparation method of high-load Rhizoma sanguisorbae preparation: Radix Sanguisorbae crude drug powder 5000g and Radix Sanguisorbae thick paste 5000g, Icing Sugar 1070g starch 1430g are mixed and made into soft material, dry, break into fine powder, an amount of with 50% ethanol, 16# granulates, drying, granulate adds the technology of tabletting behind 1% magnesium stearate or 3% Pulvis Talci.
In the preparation method of this patent application low content Rhizoma sanguisorbae preparation, since the content of Radix Sanguisorbae only account for sheet heavy 5%～10%, and be that the crude drug powder directly is used as medicine, its effective ingredient uniform distribution situation is very poor, experimental results show that: the qualified tablet of uniformity of dosage units that can't obtain Radix Sanguisorbae through above-mentioned simple mixing and preparation technology.
And in the preparation method of high-load Rhizoma sanguisorbae preparation, the amount of active component Radix Sanguisorbae medicated powder and thick paste thereof account for total sheet heavy 80%, but since the prescription in used the higher thick paste of a large amount of stickinesses, the disintegrative of gained tablet is relatively poor.
Can't realize the uniform distribution of garden burnet solid preparation with low dose active component Radix Sanguisorbae better too even the preparation method of the high-load Rhizoma sanguisorbae preparation in this application is used for preparing the preparation of low content (5%-10%) Rhizoma sanguisorbae preparation.Reason be this method the system soft material after directly with its pulverizing, the step that lacks soft material granulation, in fact this step is granulated by sieving Radix Sanguisorbae medicated powder and adjuvant is carried out fruitful mixing, and the uniform distribution of the middle active component of low dosage Rhizoma sanguisorbae preparation is had indispensable effect.
To sum up, the disclosed method for preparing the low dosage Rhizoma sanguisorbae preparation of prior art can not realize the low dosage Rhizoma sanguisorbae preparation active component---Radix Sanguisorbae is evenly distributed on the technique effect in the preparation.
Summary of the invention
At above technological deficiency, the invention provides a kind of preparation method of new garden burnet solid preparation with low dose.
Said method comprising the steps of:
1., get 1-10 weight portion Radix Sangusorbae powder and be broken into 65～200 purpose fine powders;
2., get the adjuvant of 90-99 weight portion, described adjuvant comprises sucrose and starch;
3., get step in 2. part sucrose and starch to adopt milk cooking process preparation quality concentration be 10%～50% binding agent 10～40 weight portions;
4., with step 1. gained fine powder and step 2. in remaining adjuvant mix more than 30 minutes, mixture;
5., the binding agent of the 11-30 weight portion that step is 3. made adds step 4. in the mixture of gained then, cross 12～50 mesh sieves granulate, dry and be ground into 50～200 purpose fine powders, remix is more than 10 minutes, mixture;
6., with step 5. the gained mixture with the alcoholic solution of the step remaining binding agent of 3. made binding agent and/or water or 5%～40% volumetric concentration granulate, dry, sieve, make tablet, capsule, pill or granule then.
In the inventive method, as embodiment preferred, the 1. middle Radix Sanguisorbae of described step is the 5-10 weight portion; The 2. middle adjuvant of step is a weight portion 95-90 weight portion.
In the method for the invention, as embodiment preferred, the adjuvant of described step in 2. also includes but not limited to a kind of, two or more combination in dextrin, microcrystalline Cellulose, magnesium stearate and the silicon dioxide.For example, the adjuvant of step in 2. is sucrose, dextrin and starch; For example, the adjuvant of step in 2. is sucrose, dextrin, starch and magnesium stearate; Also for example, the adjuvant of step in 2. is sucrose, starch and microcrystalline Cellulose, or is sucrose, starch, microcrystalline Cellulose and silicon dioxide.
The consumption of various adjuvants such as sucrose, starch, dextrin, microcrystalline Cellulose and silicon dioxide and magnesium stearate described in the inventive method can adopt this area consumption commonly used, but in order to realize the present invention better, the present invention further preferred described sucrose is 8～40 weight portions, starch is 5.8～29 weight portions, dextrin is 0～59 weight portion, and microcrystalline Cellulose is 0～52 weight portion; Further preferred described sucrose is 27～40 weight portions, and starch is 12～25 weight portions, and dextrin is 30～59 weight portions, and microcrystalline Cellulose is 0 weight portion.
In the inventive method, the concentration of the binding agent that the 2. middle milk cooking process of described step makes can be the concentration of this area routine, and preferred concentration of the present invention is 10%～50%; More preferably 24%.
In the preparation method of the present invention, as embodiment preferred, described step is 5. middle granulates with the binding agent of 11-30 weight portion, further the binding agent of preferred 19 weight portions; Described step is 6. middle granulates the binding agent of further preferred remaining 6 weight portions with remaining binding agent.
Drying after step described in the inventive method is granulated in 6., the method for sieving, be prepared into then tablet, capsule, granule are this area conventional method, and those skilled in the art can determine in conjunction with the present invention and this area general knowledge; But in order to realize the present invention better, that step of the present invention is granulated in 6. is dry, sieve, preferred mistake 16～22 mesh sieves, optimum 20～22 mesh sieves of crossing.
In the preparation method of the present invention, as embodiment preferred, the 1. middle Radix Sanguisorbae of described step is 5 weight portions; Step 2. in adjuvant be 95 weight portions, and described adjuvant is the sucrose of 32 weight portions, the starch of the dextrin of 47 weight portions and 16 weight portions.
Equally, as the preferred embodiment of the invention, the incorporation time of step in 4. is 30 minutes-10 hours, preferred 30 minutes-1 hour, and especially preferred 30 minutes; The incorporation time of step in 5. is 10 minutes-10 hours, preferred 10 minutes-1 hour, and especially preferred 10 minutes.
The mixing that 1.-6. preparation method of the present invention relates in the step, mixed method that it adopted and equipment are the mixed method of this area routine, the present invention does not have special requirement, those skilled in the art can determine in conjunction with the present invention and this area general knowledge, wherein, for example as preferred, the mixing of step in 4. adopts equivalent to increase progressively mixing method.
In the preparation method of the present invention, further preferably said method comprising the steps of:
1. get 5 weight portion Radix Sangusorbae powders and be broken into 65～200 purpose fine powders;
2. get the adjuvant of 95 weight portions, described adjuvant comprises 47 parts in 32 parts of sucrose, 16 parts of starch and dextrin;
3. getting 2 parts of 4 parts of the sucrose of step in 2. and starch, to adopt milk cooking process preparation quality concentration be 24% binding agent 25 weight portions;
4. with step 1. gained fine powder and step 2. in remaining adjuvant mixed 30 minutes, mixture;
5. the binding agent of 19 then that step is 3. made weight portions adds step 4. in the mixture of gained, cross 12～50 mesh sieves granulate, dry and be ground into 50～200 purpose fine powders, remix 10 minutes, mixture;
6. with step 5. the gained mixture with the binding agent of remaining 6 weight portions granulate, dry, sieve, make tablet, capsule, pill or granule then.
In the preparation method of the present invention, can adopt the method for this area routine that the solid preparation that the present invention prepares is carried out sweet tablet or film coating as required.
In the preparation method of the present invention, can adopt the breaking method of this area routine and equipment that the Radix Sanguisorbae of described step in 1. pulverized, breaking method and equipment do not have special requirement; Radix Sanguisorbae is pulverized 50-200 purpose fine powder is good, further preferably Radix Sangusorbae powder is broken into 80 purpose fine powders.
Equally, in the preparation method of the present invention, can adopt the breaking method of this area routine and equipment with described step 5. in dried mixture pulverize, breaking method and equipment do not have special requirement; Preferred described step cross in 5. 16 mesh sieves granulate, dry and be ground into 80 purpose fine powders.
It is more even that the prepared garden burnet solid preparation of preparation method of the present invention has active constituent content, and disintegration, shorter, better efficacy guaranteed that really the Radix Sanguisorbae uniform content is stable in the Rhizoma sanguisorbae preparation, and is clinical safe in utilization, effective, controlled.
Experimental results show that, the garden burnet solid preparation that preparation method of the present invention obtains causes the minimizing of murine interleukin disease to cyclophosphamide the obvious treatment effect, and the stable curative effect between the constituent parts preparation, treatment level homogeneous, deviation are little, the therapeutic effect there was no significant difference between each preparation unit (P＜0.01).
Description of drawings
Fig. 1 sample point sketch map.
The specific embodiment
Below in the mode of specific embodiment and test example the present invention is further detailed, be limitation of the present invention but should not be construed as.
The preparation of Radix Sanguisorbae tablet
Get Radix Sanguisorbae medical material 5Kg, sucrose 32Kg, dextrin 47Kg, starch 16Kg, the Radix Sanguisorbae pulverizing medicinal materials becomes fine powder to cross 80 mesh sieves, and sucrose is beaten powder too and sieved if any caking, and is standby.
Get starch 2kg and cane sugar powder 4kg, the water milk cooking process is made binding agent 25kg (mass concentration 24%).
Radix Sangusorbae powder is placed the slot type mixing apparatus, be routinely added to remaining 28kg cane sugar powder, 47kg dextrin and 14kg starch, mix 0.5h; The binding agent 19kg that adds boiling, the system soft material, oscillating granulator is crossed 16 mesh sieves and is granulated, and 70-80 ℃ of drying is standby; Pulverized particles becomes fine powder, crosses 80 mesh sieves, mixes 10min, adds remaining 6kg binding agent and an amount of water, the system soft material, and oscillating granulator is crossed 16 mesh sieves and is granulated, 70-80 ℃ of drying, granulate, tabletting wraps film-coat routinely.The every heavy 100mg of sheet contains the 5mg Radix Sanguisorbae.After testing, the Radix Sanguisorbae uniformity of dosage units is qualified.
Radix Sanguisorbae medical material 5kg, sucrose 40kg, dextrin 30kg, starch 25kg, Radix Sanguisorbae crosses 120 mesh sieves respectively, and sucrose is beaten powder too and sieved if any caking, and is standby.
Get cane sugar powder 1kg and starch 3kg, the water milk cooking process is made binding agent 40kg (mass concentration 10%), and is standby.
Radix Sangusorbae powder is placed the slot type mixing apparatus, be routinely added to remaining adjuvant, add the 30kg binding agent behind the mixing 1h, the system soft material, oscillating granulator is crossed 12 mesh sieves and is granulated, 70-80 ℃ of drying; The gained granule is ground into fine powder, crosses 120 mesh sieves, mix 1h; Add remaining 10kg binding agent moistening, the system soft material, oscillating granulator is crossed 16 mesh sieve granulate, 70-80 ℃ of drying, granulate; Tabletting, sugar coating routinely.The every heavy 100mg of sheet, every contains Radix Sanguisorbae 5mg.After testing, the Radix Sanguisorbae uniformity of dosage units is qualified.
Embodiment 3
Radix Sanguisorbae medical material 1kg, sucrose 27kg, dextrin 59kg, starch 12kg, magnesium stearate 1kg, Radix Sanguisorbae crosses 200 mesh sieves, and sucrose is beaten powder too and sieved if any caking, and is standby.
Get cane sugar powder 1.5kg and starch 4.5kg, the water milk cooking process is made binding agent 30Kg, and (mass concentration 20%) is standby.
Radix Sangusorbae powder is placed mixing plant, be routinely added to the residue adjuvant, mix 30min, add the 11kg binding agent, the system soft material, oscillating granulator is crossed 18 mesh sieves and is granulated, 70-80 ℃ of drying; The gained granule is ground into fine powder, crosses 65 mesh sieves, mix 30min; Add remaining 19kg binding agent moistening, the system soft material, oscillating granulator is crossed 18 mesh sieves and is granulated, 70-80 ℃ of drying, granulate; Tabletting, the 100mg/ sheet, every contains Radix Sanguisorbae 1mg.After testing, the Radix Sanguisorbae uniformity of dosage units is qualified.
Radix Sanguisorbae medical material 2kg, sucrose 8kg, microcrystalline Cellulose 4kg, starch 5.8kg, silicon dioxide 0.2kg, Radix Sanguisorbae crosses 100 mesh sieves, and sucrose is beaten powder too and sieved if any caking, and is standby.
Get cane sugar powder 0.8kg and starch 1.0kg, the water milk cooking process prepares binding agent 4.5kg (mass concentration 40%), and is standby.
Radix Sangusorbae powder is placed the slot type mixing apparatus, add the residue adjuvant, mix 1h, add the 4.5kg binding agent, the system soft material, oscillating granulator is crossed 50 mesh sieves and is granulated, 60～80 ℃ of dryings; The gained granule is ground into fine powder, crosses 100 mesh sieves, mix 1h, add the ethanol moistening of an amount of volumetric concentration 5%, the system soft material, oscillating granulator is crossed 22 mesh sieves and is granulated, 70-80 ℃ of drying, granulate, the capsule of packing into No. 4, the 100mg/ grain contains Radix Sanguisorbae 10mg.After testing, the Radix Sanguisorbae uniformity of dosage units is qualified.
The preparation of Radix Sanguisorbae pill
Get Radix Sanguisorbae medical material 5kg, sucrose 36kg, microcrystalline Cellulose 34kg, starch 24kg, silica 1 kg; Radix Sanguisorbae crosses 80 mesh sieves, and sucrose is beaten powder too and sieved if any caking, and is standby.
Get cane sugar powder 1.5kg and starch 3.5kg, the water milk cooking process prepares binding agent 16.5kg (mass concentration about 30%), and is standby.
Radix Sangusorbae powder is placed the slot type mixing apparatus, add the residue adjuvant, mix 30min, add the 16.5kg binding agent, the system soft material, oscillating granulator is crossed 18 mesh sieves and is granulated, 60～80 ℃ of dryings; The gained granule is ground into fine powder, crosses 200 mesh sieves, mix 1h, add the ethanol moistening of an amount of volumetric concentration 40%, the system soft material, oscillating granulator is crossed 50 mesh sieves and is granulated, 70-80 ℃ of drying, granulate is pressed into piller, routinely sugar coating.Ball heavily is every ball 100mg, and every ball contains Radix Sanguisorbae 5mg.After testing, the Radix Sanguisorbae uniformity of dosage units is qualified.
The preparation of Radix Sanguisorbae granule
Get Radix Sanguisorbae medical material 5kg, sucrose 22kg, microcrystalline Cellulose 52kg, starch 21kg, Radix Sanguisorbae crosses 80 mesh sieves, and sucrose is beaten powder too and sieved if any caking, and is standby.
Get cane sugar powder 2kg and starch 3kg, the water milk cooking process prepares binding agent 10kg (mass concentration 50%), and is standby.
Radix Sangusorbae powder is placed the slot type mixing apparatus, add the residue adjuvant, mix 30min, add the 10kg binding agent, the system soft material, oscillating granulator is crossed 16 mesh sieves and is granulated, 60～80 ℃ of dryings; The gained granule is ground into fine powder, crosses 50 mesh sieves, mix 20min, add the suitable quantity of water moistening, the system soft material, oscillating granulator is crossed 12 mesh sieves and is granulated, 70-80 ℃ of drying, granulate wraps film-coat routinely; With the packing of gained granule, get granule, every bag of 400mg/ bag contains Radix Sanguisorbae 20mg, and after testing, the Radix Sanguisorbae uniformity of dosage units is qualified.
The uniformity of dosage units of the prescription of experimental example one, embodiment 1 effective ingredient Radix Sanguisorbae behind the granule tabletting that once granulation and secondary are granulated and secondary is granulated relatively
1, preparation method:
Preparation granule and tablet: get 3 parts by the prescription of embodiment 1, Radix Sanguisorbae medical material, cane sugar powder are crossed 80 orders respectively, and be with reference to the method boiling of embodiment 1 and use binding agent, standby.
(1) once granulate:
3 parts of Radix Sanguisorbae medical materials of punishment amount are placed 3 platform trough formula mixing apparatus respectively, and the adjuvant that is routinely added to each part remainder separately mixes, and the blended time is respectively 15min, 30min, 1h, 10h; Add binding agent, oscillating granulator is crossed 16 mesh sieves and is granulated, and 70-80 ℃ of airpillow-dry is standby, to be checked; Testing result sees Table 1.
(2) secondary is granulated:
Get the granule of aforementioned mixing 15min preparation, pulverize, cross 80 mesh sieves, be divided into 2 parts, stir 15min respectively, 3h adds residue binding agent and suitable quantity of water moistening, and oscillating granulator is crossed the granulation of 16 mesh sieves respectively, 70-80 ℃ of drying crossed 16～18 mesh sieve granulate, and be standby, to be checked; Testing result sees Table 2
In addition, get the granule of aforementioned mixing 30min preparation, pulverize, cross 80 mesh sieves, be divided into 3 parts, stir 5min respectively, 10min, 3h adds residue binding agent and suitable quantity of water moistening, and oscillating granulator is crossed the granulation of 16 mesh sieves respectively, 70-80 ℃ of drying crossed 16～18 mesh sieve granulate, and be standby, to be checked; Testing result sees Table 3.
(3) tabletting: stir granule that 10min and 3h obtain when granulating for the second time in the table 3 respectively with reference to embodiment one tabletting separately, every heavy 100mg, to be checked.Testing result sees Table 4.
2, detection method: in three layers of the upper, middle and lowers of each storage tank, respectively select 4 totally 12 positions respectively, detect 3 times of dosage take a sample (particular location distribute accompanying drawing 1 as follows) with single, with Ziyuglycoside I index composition serves as to detect index, measures the content uniform distribution situation of Radix Sanguisorbae with reference to the conventional sense method.Uniformity criterion: the relative standard deviation of each point content should satisfy RSD≤7%;
3, experimental result:
Ziyuglycoside I uniformity of dosage units testing result in the granule after table 1 is once granulated
Above-mentioned result of the test shows, mixes all to obtain the qualified granule of Radix Sanguisorbae uniformity of dosage units through 15min, 0.5h, 1h, 10h.
Ziyuglycoside I uniformity of dosage units testing result in the granule after table 2 secondary is granulated
Result of the test shows, after stirring 15min mixing, granulation, pulverizing the first time, carries out the secondary granulation through stirring 15min and 3h again, all can't obtain the granule of the active constituent content uniformity qualified (RSD＜7%).
Ziyuglycoside I uniformity of dosage units testing result in the granule after table 3 secondary is granulated
Result of the test shows, after stirring for the first time the 30min mixing, granulating, pulverize, carries out secondary through stirring 5min again and granulates, and can't obtain the granule of the uniformity qualified (RSD＜7%); But after stirring for the first time the 30min mixing, granulating, pulverize, again through stirring the granule that 10min or 3h all can obtain the uniformity qualified (RSD＜7%).Wherein, stir before granulating for the second time and stir 10min before 3h granulates for the second time, the content of effective uniformity is not had tangible influence.
Ziyuglycoside I uniformity of dosage units testing result in table 4 tablet
After the granule that described secondary is granulated was pressed into tablet, the effective ingredient Radix Sanguisorbae moved, and the content of effective uniformity is up to specification.Carry out accelerated test according to a conventional method after 6 months, obvious change does not take place in uniformity of dosage units.
4, experiment conclusion:
Wherein, mixing time is 15min in once granulating, and granulating through secondary to obtain the qualified granule of the uniformity; Once the mixing time of Zhi Liing be 30min and more than, can obtain the qualified Rhizoma sanguisorbae preparation of the uniformity more than the restir 10mi n in the secondary pelletization.
The uniformity of dosage units of the prescription of experimental example two, embodiment 3 effective ingredient Radix Sanguisorbae behind the granule tabletting that once granulation and secondary are granulated and secondary is granulated relatively
1, preparation method:
Preparation granule and tablet: get 3 parts by the prescription of embodiment 3, the Radix Sanguisorbae medical material, cross 200 orders, with reference to the method boiling of embodiment 3 and use binding agent, standby.
(1) once granulate:
3 parts of Radix Sanguisorbae medical materials of punishment amount are placed 3 platform trough formula mixing apparatus respectively, and the adjuvant that is routinely added to each part remainder separately mixes, and the blended time is respectively 15min, 30min, 1h, 10h; Add binding agent, oscillating granulator is crossed 18 mesh sieves and is granulated, and 70-80 ℃ of airpillow-dry is standby, to be checked; Testing result sees Table 5.
(2) secondary is granulated:
Get the granule of aforementioned mixing 15min preparation, pulverize, cross 100 mesh sieves, be divided into 2 parts, stir 15min respectively, 3h adds remaining binding agent moistening, and oscillating granulator is crossed the granulation of 18 mesh sieves respectively, and 70-80 ℃ of drying crossed 20～24 mesh sieve granulate, and be standby, to be checked; Testing result sees Table 6
Other gets the granule of aforementioned mixing 30min preparation, pulverizes, and crosses 80 mesh sieves, is divided into 2 parts, stirs 5min respectively, 10min, and 3h adds remaining binding agent moistening, and oscillating granulator is crossed the granulation of 18 mesh sieves respectively, 70-80 ℃ of drying, granulate, standby, to be checked; Testing result sees Table 7.
(3) tabletting: stir granule that 10min and 3h obtain before secondary in the table 7 granulated respectively with reference to embodiment one tabletting separately, every heavy 100mg, to be checked, testing result sees Table 8.
2, detection method: in three layers of the upper, middle and lowers of each storage tank, respectively select 4 totally 12 positions respectively, detect 3 times of dosage take a sample (particular location distribute accompanying drawing 1 as follows) with single, with Ziyuglycoside I index composition serves as to detect index, measures the content uniform distribution situation of Radix Sanguisorbae with reference to the conventional sense method.Uniformity criterion: the relative standard deviation of each point content should satisfy RSD≤7%;
3, experimental result:
Ziyuglycoside I uniformity of dosage units testing result in the granule after table 5 is once granulated
Above-mentioned result of the test shows, mixes all to obtain the qualified granule of Radix Sanguisorbae uniformity of dosage units through 15min, 0.5h, 1h, 10h.
Ziyuglycoside I uniformity of dosage units testing result in the granule after table 6 secondary is granulated
Result of the test shows, after stirring 15min mixing, granulation, pulverizing the first time, carries out the secondary granulation through stirring 15min and 3h again, all can't obtain the granule of the active constituent content uniformity qualified (RSD＜7%).
Ziyuglycoside I uniformity of dosage units testing result in the granule after table 7 secondary is granulated
Result of the test shows, after stirring for the first time the 30min mixing, granulating, pulverize, carries out secondary through stirring 5mi n again and granulates, and can't obtain the granule of the uniformity qualified (RSD＜7%); But after stirring for the first time the 30min mixing, granulating, pulverize, again through stirring the granule that 10min or 3h all can obtain the uniformity qualified (RSD＜7%).Wherein, stir before granulating for the second time and stir 10min before 3h granulates for the second time, the content of effective uniformity is not had tangible influence.
Ziyuglycoside I uniformity of dosage units testing result in table 8 tablet
After the granule that secondary is granulated was pressed into tablet, the effective ingredient Radix Sanguisorbae moved, and uniformity of dosage units is up to specification.Carry out accelerated test according to a conventional method after 6 months, obvious change does not take place in uniformity of dosage units.
4, experiment conclusion:
Embodiment 3 prescriptions select for use the Radix Sanguisorbae protogenic medicinal powder to produce, and use wet method once to granulate and can't make the uniformity of dosage units of effective ingredient Radix Sanguisorbae in the granule qualified; After wet method was granulated for the second time, the uniformity was qualified; The granule that secondary is granulated is behind tabletting, and the uniformity of dosage units of Radix Sanguisorbae is qualified in the tablet.
Wherein, mixing time is 15min in once granulating, and granulating through secondary to obtain the qualified granule of the uniformity; Once the mixing time of Zhi Liing be 30min and more than, can obtain the qualified Rhizoma sanguisorbae preparation of the uniformity in the secondary pelletization more than the restir 10min.
The prescription of experimental example three embodiment 1 is with reference to " pharmaceutics " (Shenyang Pharmaceutical University, version in 1980: the granule and the tablet content uniformity test of the guidance preparation 698～711)
Get Radix Sanguisorbae and adjuvant by the prescription of embodiment 1, wherein Radix Sanguisorbae and sucrose are crossed 80 orders respectively, and is standby.Get Radix Sangusorbae powder, adjuvant and suitable quantity of water and mix stirring 3 hours, the ethanol that adds an amount of volumetric concentration 10% is made soft material.Use 12～14 mesh sieves, cross 3 times, re-use 16～18 mesh sieves, cross 3 times, get granule, 70～80 ℃ of oven dry, granulate, standby, to be checked.
Method with reference to experimental example 1 is carried out assay, the results are shown in Table 9;
With above-mentioned granule, routine is pressed into tablet, randomly draws 10, with reference to carrying out assay with quadrat method, the results are shown in Table 9;
Table 9
Experiment conclusion: the soft material of embodiment 1 prescription preparation is crossed 12～14 mesh sieves 3 times, cross 16～18 mesh sieves 3 times, can not obtain qualified granule of uniformity and tablet.
Experimental example four embodiment 1 prescription is with reference to the granule and the experiment of tablet content uniformity of the method for making preparation of the disclosed half extractum sheet of ZL90108019.5
Get Radix Sanguisorbae and adjuvant by the prescription of embodiment 1, wherein Radix Sanguisorbae and sucrose are crossed 80 orders respectively, and is standby.Get Radix Sangusorbae powder, adjuvant and suitable quantity of water and stirred 3 hours, make soft material, direct 70～80 ℃ of dryings are ground into fine powder.The ethanol moistening that adds an amount of volumetric concentration 50%, the system soft material is crossed 16 mesh sieves, 70～80 ℃ of oven dry, 16～18 mesh sieve granulate, standby, to be checked.
Method with reference to experimental example 1 is carried out cloud test, the results are shown in Table 10;
Above-mentioned granule routine is pressed into tablet,, the results are shown in Table 10 with reference to carrying out assay with quadrat method;
Table 10
The Rhizoma sanguisorbae preparation of experimental example five experimental examples one, three, four preparations causes the therapeutic effect contrast that murine interleukin reduces to cyclophosphamide
Get 144 of Kunming mouses, male and female half and half are divided into 18 groups at random, 8 every group.Be the normal control group, cyclophosphamide model group, A1～A5 group, B1～B5 group, C1～C5 group, batilol positive controls.Wherein the reagent thing that is subjected to of each group of A1～A5 extracts and obtains in the site at random for 5 from experimental example one preparation tablet respectively; The reagent thing that is subjected to of each group of B1～B5 extracts and obtains in the site at random for 5 from experimental example three preparation tablets respectively; The reagent thing that is subjected to of each group of C1～C5 extracts and obtains in the site at random for 5 from experimental example four preparation tablets respectively.
Except that the normal control group, all the other respectively organize the equal intraperitoneal injection of cyclophosphamide 150ml/kg of mice, cause the leukopenia model.Gave distilled water by 20ml/kg respectively to normal group and cyclophosphamide model control group the same day in the injection cyclophosphamide, the batilol positive controls gives batilol by 100mg/kg; Each group of A1～A5, each group of B1～B5, each group of C1～C5 gives medicine, every day 3 times, gastric infusion, continuous 6 days by the dosage of 1.12g/kg respectively.After 24 hours, the extraction eyeball is got blood, detects total white blood cells (WBC) in the blood, the results are shown in Table 11 after the last administration.
Each Rhizoma sanguisorbae preparation of table 11 causes the influence that murine interleukin reduces to cyclophosphamide
Annotate: compare with normal group,
*P＜0.01,
*P＜0.05
Compare with model group,
△ △P＜0.01,
△P＜0.05
Experiment conclusion:
Model group mice WBC significantly reduces than normal group, and the modeling success is described;
Each group of A1～A5 compares with model group, all has the effect (P＜0.01) of significant leukocyte increasing, and does not have obvious effects difference between each group of A1～A5;
In B1～B5 group, B1, B3, B5 group have the effect (B1 and B3 group P＜0.01, B5 organizes P＜0.05) of significant leukocyte increasing, significantly are lower than B1 group and B3 group (P＜0.01 as calculated) but the B5 group rises white effect; B2, B4 group does not relatively have significant difference with model group, does not rise white effect;
In C1～C5 group, C1, C2, C3, C5 group have the effect (C1 and C2 group P＜0.01, C3, C5 organize P＜0.05) of significant leukocyte increasing, significantly are lower than C1 group and C2 group (P＜0.01 as calculated) but C3 and C5 group rise white effect; The C4 group does not relatively have significant difference with model group, does not rise white effect.
The tablet that the granulating process of the low dosage Rhizoma sanguisorbae preparation that experimental example six, ZL90108019 announce prepares carries out Determination of Content Uniformity
The prescription and the technology of the low dosage Rhizoma sanguisorbae preparation of announcing according to ZL90108019 are prepared: get Radix Sanguisorbae crude drug powder 50g, Icing Sugar 400g, starch 450g, add magnesium stearate 10mg, add 10% starch slurry 180ml mixing, granulation, drying again, granulate, tabletting, the heavy 90mg/ sheet of sheet, every is equivalent to contain the about 5mg of crude drug.Method with reference to experimental example 1 is measured content of effective in granule and the tablet respectively, and the result sees table 12:
Particulate uniformity of dosage units result in table 12ZL90108019 low dosage Rhizoma sanguisorbae preparation and the pelletization thereof
Experiment conclusion: the content of effective deviation is very big in the tablet that granule and compacting obtain, and uniformity of dosage units is all defective.
Experimental example seven, embodiment 1, experimental example three and six, and the disintegration time comparison of pressing the tablet of DIYU SHENGBAI PIAN standard (WS-11020 (ZD-1020)-2002) preparation
The tablet of the tablet of embodiment 1 and experimental example three is the identical prescription of employing but is prepared from through different process that other gets the ZL90108019 low dosage Radix Sanguisorbae tablet of preparation in the experimental example six;
In addition, by DIYU SHENGBAI PIAN standard (WS-11020 (ZD-1020)-2002) preparation tablet.
Below to comparing disintegration of these four groups of tablets.
According to " in the Chinese pharmacopoeia version in 2005 disintegration inspection technique, the disintegration time of above-mentioned four groups of tablets is measured.Surpass 15min because of the tablet of experimental example three has 1 disintegration time when measuring for the first time, should get 6 retrials in addition by the pharmacopeia guideline.The result sees table 13.
The disintegration time data of the tablet of the tablet of table 13 embodiment 1 and experimental example three
| ??①??(min) | ??②??(min) | ??③??(min) | ??④??(min) | ??⑤??(min) | ??⑥??(min) | |
| |
??3 | ??2.5 | ??3 | ??3 | ??3.5 | ??3 |
| Experimental example three preparation tablets | ??12 | ??13 | ??12 | ??17 | ??14 | ??13 |
| Experimental example three preparation tablets ' | ??12 | ??12 | ??16 | ??12 | ??16 | ??13 |
| Embodiment six preparation tablets | ??14 | ??20 | ??17 | ??12 | ??18 | ??13 |
| By DIYU SHENGBAI PIAN standard (WS-11020 (ZD-1020)-2002) preparation tablet | ??8 | ??9 | ??10 | ??9 | ??9 | ??8 |
The all disintegrates in 2.5～3.5min of the tablet of experiment conclusion: embodiment 1 preparation; The average disintegration time of twice mensuration of tablet of experimental example three preparations is 13.5min, and has the disintegration time of tablet to reach 17min and 16min respectively, has all surpassed the disintegration of the 15min of pharmacopeia regulation.Though ZL90108019 low dosage Radix Sanguisorbae tablet has indivedual tablet disintegration times up to specification, its average disintegration time is 15.3min, has surpassed the disintegration of 15min.
The tablet of embodiment 1 is than the tablet of experimental example three, though fill a prescription identical but since embodiment 1 adopted the disclosed specific preparation technology of present patent application, its disintegration time is short, and it is little to fluctuate, absorption that can quick and stable after the patient is taken medicine helps the raising of bioavailability and obtaining of stable drug effect.The tablet and embodiment six tablets (being ZL90108019 low dosage Radix Sanguisorbae tablet) of preparation in the experimental example three, disintegration time is longer, disintegration time fluctuation between the tablet is bigger, and the disintegration time that tablet is arranged surpasses the regulation of Chinese Pharmacopoeia, be unfavorable for the absorption of medicine, be unfavorable for that this medicine brings into play its due curative effect.
By the tablet of DIYU SHENGBAI PIAN standard (WS-11020 (ZD-1020)-2002) preparation, disintegration time is qualified, but the disintegration of tablet time of relative embodiment one preparation is longer.
Half extractum sheet disintegration time of preparation method gained is measured in experimental example eight, No. 90108019 patent applications of ZL
Half extractum tablet recipe and the technology announced according to ZL90108019 are prepared: Radix Sanguisorbae crude drug powder 5000g and Radix Sanguisorbae thick paste 5000g, Icing Sugar 1070g starch 1430g are mixed and made into soft material, dry, break into fine powder, an amount of with 50% ethanol, 16# granulates, drying, granulate adds tabletting behind 1% magnesium stearate or 3% Pulvis Talci.
In addition, with reference to the disclosed half extractum tablet recipe sampling of ZL90108019, but adjusting process is promptly directly granulated behind the soft material for making first, tabletting, and the disintegration time of mensuration tablet.Be specially: get Radix Sanguisorbae crude drug powder 5000g and Radix Sanguisorbae thick paste 5000g, Icing Sugar 1070g starch 1430g, mix routinely, it is an amount of to add 50% ethanol, makes soft material, and 16# granulates, drying, and granulate adds tabletting behind 1% magnesium stearate or 3% Pulvis Talci.Why to adopt the purpose of " system soft material then beat powder make soft material, granulation and tabletting more again " be for solving the problem of half extractum sheet disintegrative difference to half extractum sheet among the ZL90108019.
Another purpose of this section is may think for the auditor: the scheme of " beating powder behind the system soft material and making soft material, granulation and tabletting more again " to solution homogeneity disclosed by the invention among the ZL90108019 provides the technology enlightenment, proposes to give counterevidence; Be that the former half extractum sheet principal agent of ZL90108019 accounts for 80%, energy is mixing well, and this scheme is really for solving the disintegrative problem.
Method with reference to experimental example six is measured disintegration time, the results are shown in following table 14.
The half extractum sheet that table 14ZL90108019 announces compares with the disintegration time of the half extractum sheet that obtains through " disposable system soft material granulation, tabletting "
| ??①??(min) | ??②??(min) | ??③??(min) | ??④??(min) | ??⑤??(min) | ??⑥??(min) | |
| The half extractum sheet that ZL90108019 announces | ??12 | ??13 | ??13 | ??14 | ??12 | ??12 |
| The half extractum sheet that " granulation, tabletting behind the disposable system soft material " obtains | ??30 | ??36 | ??28 | ??40 | ??31 | ??47 |
| The half extractum sheet that obtains after " disposable system soft material granulation, tabletting " | ??40 | ??29 | ??35 | ??38 | ??46 | ??33 |
The half extractum sheet disintegration time that experiment conclusion: ZL90108019 announces all in 15min, meets " the standard of Chinese pharmacopoeia version in 2005.And adopt identical prescription, and the disintegration of tablet that directly granulate behind the system soft material, tabletting obtains is very poor, between 28min～47min, and the former standards of pharmacopoeia that surpasses.After human body is taken, be difficult to absorb.
Claims (14)
1. the preparation method of a garden burnet solid preparation with low dose is characterized in that, said method comprising the steps of:
1. get 1-10 weight portion Radix Sangusorbae powder and be broken into 65～200 purpose fine powders;
2. get the adjuvant of 90-99 weight portion, described adjuvant comprises sucrose and starch;
3. get step in 2. part sucrose and starch to adopt milk cooking process preparation quality concentration be the binding agent 10-40 weight portion of 10%-50%;
4. with step 1. gained fine powder and step 2. in remaining adjuvant mix more than 30 minutes, mixture;
5. get the 3. made binding agent 11-30 weight portion of step then and add step 4. in the mixture of gained, cross 12～50 mesh sieves granulate, dry and be ground into 50-200 purpose fine powder, remix is more than 10 minutes, mixture;
6. with step 5. the gained mixture with the alcoholic solution of the 3. made binding agent rest parts of step and/or water or 5%-40% volumetric concentration granulate, dry, sieve, make tablet, capsule, pill or granule then.
2. preparation method according to claim 1 is characterized in that, described adjuvant also comprises a kind of, two or more combination in dextrin, microcrystalline Cellulose, magnesium stearate and the silicon dioxide.
3. preparation method according to claim 2 is characterized in that, the 1. middle Radix Sanguisorbae of described step is the 5-10 weight portion; The 2. middle adjuvant of step is the 95-90 weight portion.
4. preparation method according to claim 3 is characterized in that, described sucrose is the 8-40 weight portion; Starch is the 5.8-29 weight portion; Dextrin is the 0-59 weight portion; Microcrystalline Cellulose is the 0-52 weight portion.
5. preparation method according to claim 4 is characterized in that, described sucrose is the 27-40 weight portion; Starch is the 12-25 weight portion; Dextrin is the 30-59 weight portion; Microcrystalline Cellulose is 0 weight portion.
6. preparation method according to claim 5 is characterized in that, it is 24% binding agent 25 weight portions that the starch that 3. described step comprises the sucrose of getting 4 weight portions of step in 2. and 2 weight portions is made mass concentration by milk cooking process.
7. preparation method according to claim 6 is characterized in that, 5. described step is got the 3. made binding agent of step of 19 weight portions and granulated.
8. preparation method according to claim 7 is characterized in that, 6. described step is got the 3. made binding agent of step of 6 weight portions and granulated.
9. preparation method according to claim 8 is characterized in that, the 1. middle Radix Sanguisorbae of described step is 5 weight portions; Step 2. in adjuvant be 95 weight portions, and described adjuvant is the sucrose of 32 weight portions, the starch of the dextrin of 47 weight portions and 16 weight portions.
10. preparation method according to claim 9 is characterized in that, the incorporation time of step in 4. is 30 minutes-10 hours; The incorporation time of step in 5. is 10 minutes-10 hours.
11. preparation method according to claim 10 is characterized in that, the incorporation time of step in 4. is 30 minutes-1 hour, preferred 30 minutes; The incorporation time of step in 5. is 10 minutes-1 hour, preferred 10 minutes.
12. preparation method according to claim 11 is characterized in that, said method comprising the steps of:
1. get 5 weight portion Radix Sangusorbae powders and be broken into 65-200 purpose fine powder;
2. get the adjuvant of 95 weight portions, described adjuvant comprises 47 parts in 32 parts of sucrose, 16 parts of starch and dextrin;
3. getting 2 parts of 4 parts of the sucrose of step in 2. and starch, to adopt milk cooking process preparation quality concentration be 24% binding agent 25 weight portions;
4. with step 1. gained fine powder and step 2. in remaining adjuvant mixed 30 minutes, mixture;
5. get the 3. made binding agent of the step of 19 weight portions then and add step 4. in the mixture of gained, cross the 12-50 mesh sieve granulate, dry and be ground into 50～200 purpose fine powders, remix 10 minutes, mixture;
6. with step 5. the gained mixture with the 3. made binding agent of the step of 6 weight portions granulate, dry, sieve, make tablet, capsule, pill or granule then.
13. preparation method according to claim 12 is characterized in that, described step is ground into 80 purpose fine powders in 1.; 5. middle 16 mesh sieves excessively of step are granulated, and crushed after being dried becomes 80 purpose fine powders.
14., it is characterized in that making during step 6. sugar coating or film-coat behind tablet, capsule, pill or the granule according to each described method of claim 1-13.
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| 《成都医药》 19951231 余秀枝等 健脾消积片制备工艺的改进 108-109 1-14 第21卷, 第2期 * |
| 《时珍国医国药》 20000229 凌解春等 影响中草药片剂质量几个因素 124-125 1-14 第11卷, 第2期 * |
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