CN101112363A - Crosslinking wrapped core slice in vivo for - Google Patents
Crosslinking wrapped core slice in vivo for Download PDFInfo
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- CN101112363A CN101112363A CNA2006100294763A CN200610029476A CN101112363A CN 101112363 A CN101112363 A CN 101112363A CN A2006100294763 A CNA2006100294763 A CN A2006100294763A CN 200610029476 A CN200610029476 A CN 200610029476A CN 101112363 A CN101112363 A CN 101112363A
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Abstract
The invention pertains to the field of pharmaceutical preparation. The invention relates to a cross-linked covered tablet which is used for colon-specific drug delivery. The invention takes a drug-containing tablet as the core, the periphery of which is wrapped with a coating material, and the outer layer coating retarding material adopts the mixture of pectin of the calcium salts/calcium salts with the special amount and high parts by weight; the retarding release effect of the pectin is strengthened through the cross-linked process, so the invention is applicable to the colon-specific drug delivery, in particular to the insoluble drugs. The experimental results show that the invention can retard the release of the drug, so as to achieve the ideal colon-specific drug delivery, at the same time, the invention does not need to use more coating materials, which can significantly save the using amount of the pectin materials. The invention is applicable to the treatments of the diseases with the need of colon-specific drug delivery, such as colitis, colon cancer and other colon diseases.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of colon locating administrated clad sheet that can be used for.Say that more properly the present invention relates to a kind of colon locating administrated system that suppresses the clad sheet form, its ectomesoderm coating has in the crosslinked ability of body, is made up of pectin and high weight portion calcium salt.
Background technology
The compacting clad sheet is that the way parcel by compression moulding blocks the clothing layer around label, play the delay drug release, make medicine be the effect that pulse discharges, be mainly used in the situation that needs the time-delay administration, as control of cardiovascular disorders outbreak in morning, or colon locating administrated with treatment colon local disease.When colon locating administrated when being used for (Colon-specific drug delivery), usually with the natural polysaccharide coating retardance material, the enzyme that relies on the generation of ileocecus flora triggers release (Sinha et al.Eur J Pharm Sci, 2003, the 18:3-18 of medicine; Vandamme et al.Carbohydr Polym, 2002,48:219-231).The pectin of one of poly-polysaccharide is mainly derived from edible plants, has good gelling property, main as gel and thickening agent in food industry, pharmaceuticals industry can be used as the carrier of controlling Atrigel (Li et al.Biomaterials, 2003,24:3333-3343).Because it is safe in utilization, functional, has become a kind of pharmaceutic adjuvant already, records in American Pharmacopeia 24 editions, has the value of further promoting the use of in the medical industry field.Yet because pectin is the hydrophilic polysaccharide material, be easy to corrosion, the effect of control drug release speed is not strong.Control slow release effect preferably for reaching, usually need a large amount of pectin as skeleton or coating material.Such as, with USP pectin is the clad sheet that material is made, and the total consumption of outer coating material reaches about 700mg could obtain conlon targeting release effect (Ashford et al.J Control Release, 1993 preferably, 26:213-220), the therefore final common volume of preparation is bigger.Manage further to improve the control slow release effect of pectin, reduce its consumption, the technical problem that need solve for relevant field.Pectin is made calcium salt, can reduce its hydration rate and corrosion speed, be applied to matrix type or the agent of pressed coated matrix again, can obtain control drug release effect (Rubinstein et al.PharmRes, 1993,10:258-263 preferably; Rubinstein et al.Eur J Pharm Biopharm, 1995,41:291-295).Yet calcium pectinate still is not a pharmaceutic adjuvant, and the degree of cross linking is also wayward, and there is unstability in character, so be difficult to promote the use of.
Prior art (application number: 200610025389.0), provide a kind of contain high weight portion calcium salt at the body cross-linked pectin skeleton administration system, its basic role principle is: pectin mixes with certain weight ratio with calcium salt, makes pectin/calcium salt skeleton by the current techique means such as the tablet machine pressed disc method of pharmaceutics; After this skeleton system is met water, or after contacting the gastrointestinal tract physiological fluid in vivo, moisture content infiltrates through skeleton, the pectin aquation, and calcium salt dissolving simultaneously also discharges calcium ion; Because a large amount of negative charges of pectin molecule band can be crosslinked by the calcium ion of bivalence, and play the purpose of retardance bulk erosion and drug release.Replace calcium pectinate at the body cross-linking system with pectin/calcium salt admixture, can regulate the crosslinking degree of pectin skeleton easily by the addition of regulating calcium salt, regulate drug release; Under the situation that reaches identical control slow release effect, substitute the controlled release matrix material with a large amount of inorganic salts, help to reduce its consumption, reduce cost.
Summary of the invention
The purpose of this invention is to provide a kind of can be used for colon locating administrated at the crosslinked clad sheet of body.The present invention relates to suppress the colon locating administrated system of clad sheet form, its ectomesoderm coating is made up of pectin and high weight portion calcium salt, has in the crosslinked ability of body.
The essential structure of clad sheet of the present invention is: with the plain sheet of pastille is core, wraps up coating material with pressing around it.Pastille label wherein is an ordinary tablet, and plate core weight is 70-130mg, and tool rapid release feature is applicable to the present invention, there is no special part; The outstanding key that is different from other clad sheets of prior art is: the outer coating retardance material of this clad sheet is the pectin/calcium salt admixture that contains high weight portion calcium salt, therefore has better conlon targeting release effect, volume, cost also reduce, and more help clinical application.
Add heavy dose of calcium salt in the outer coating of the present invention,, make it to reach ideal colon positioning release by strengthen the retardance releasing effect of pectin at the body cross-linking process.
Outstanding technical characterictic of the present invention is the retardation release time of outer coating, and its influence factor mainly comprises pectin/calcium salt ratio in the consumption of coating material and the coatings.
Experimental result shows that the consumption of described coating material is proportional with the final time lag that produces, and promptly consumption is big more, the retardation releasing effect is good more, but consumption is difficult to be degraded at short notice by colonic microflora when too big, medicine is difficult to discharge, and can't embody colonic microflora and trigger the advantage that discharges.The consumption of coating material is preferably 250mg-500mg between 100mg-700mg among the present invention.What need state is that the indication coating material comprises calcium salt wherein herein.If in pectin/weight of calcium salt ratio is 1/1, in the then above-mentioned coating material consumption, the consumption of pectin only accounts for half.
The ratio of pectin/calcium salt is preferably 2/1～2/3 between 5/1～1/3 in the coating material.
In the crosslinked interaction that comes from calcium ion and pectin molecule chain of body, so calcium salt must have the characteristic of meeting water dissolvable, the adoptable calcium salt of the present invention should be water-soluble Ca salt, especially is selected from calcium chloride, calcium acetate, calcium gluconate, lime nitrate, Citric acid calcium, calcium lactate etc.
Implement the present invention, need preparation label earlier, generally do not need particular design, can adopt general tablet manufacturing technology to carry out.But too big in order to prevent that label from crossing the final clad sheet volume of ambassador, label should be designed to the small size sheet of tool rapid release feature for best.Can adopt super-disintegrant such as crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose etc. to promote disintegration of tablet and stripping during concrete enforcement.Its composition generally contains: principal agent, filler such as microcrystalline Cellulose, lactose, disintegrating agent such as crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose, lubricant such as magnesium stearate etc.
When the preparation clad sheet, can't use common tablet manufacturing equipment, need to use the clad sheet production equipment special.The processing of coating material can be adopted mixing, granulating process relevant in the conventional tablet production process.
Provided by the present invention at the crosslinked clad sheet of body, its objective is to reach the retardation drug release, and inspire release down at colonic microflora.Therefore be applicable to the disease treatment that needs colon positioning release, wherein contained drug is an insoluble drug, as (1) treatment colitis, it contains described clad sheet medicine and comprises indomethacin, dexamethasone, budesonide, 5-aminosalicylic acid or ondansetron, selects indomethacin especially; (2) treatment colon cancer, it contains described clad sheet medicine and comprises 5-fluorouracil or Irinotecan; (3) treat other colonic diseases, it contains the protein polypeptide medicine that medicine can select for use colon to absorb described clad sheet.。
The present invention is applied to compacting bag core colon-specific drug delivery system with pectin/calcium salt system, plays preferable retardance releasing effect, reaches ideal colon positioning release, needn't use more bag core material, the use amount of obviously saving pectin material simultaneously.
Technology of the present invention is applicable to the conlon targeting release of multiple medicine, and above-mentioned therapeutic use that exemplifies and medicine do not limit technical characterictic of the present invention, and the purpose of giving an example only is to provide some the present invention possible application.
Description of drawings
Fig. 1 indomethacin pectin/calcium chloride is containing release profiles in the colonic contents release medium at the crosslinked clad sheet of body.
Fig. 2 indomethacin pectin/calcium chloride is containing release profiles in the pectase medium (4ml/900ml) at the crosslinked clad sheet of body.
Fig. 3 indomethacin pectin/calcium chloride is containing release profiles in the pectase medium (2ml/900ml) at the crosslinked clad sheet of body.
The different coat weight indomethacin of Fig. 4 pectin/calcium chloride (adds or do not add pectase) at the crosslinked clad sheet of body in the pH gradient media release profiles.
Fig. 5 contains the release profiles of different proportion pectin/calcium chloride at the crosslinked clad sheet of body.
The specific embodiment
Embodiment 1: indomethacin pectin/calcium chloride is at the crosslinked compacting clad sheet of body
The label prescription:
Indomethacin 25mg
Microcrystalline Cellulose 20mg
Lactose 20mg
Polyvinylpolypyrrolidone 5mg
Magnesium stearate 1mg
Amplify by 1000 amounts.
Preparation technology: indomethacin adopts its micronization type, and mean diameter is less than 5 microns, and magnesium stearate is directly used, and other adjuvants are crossed 80 mesh sieves.Precision takes by weighing indomethacin and each adjuvant of recipe quantity, and mix homogeneously in the pony mixer directly is pressed into the label of the about 6mm of diameter on ZDY-1 type single punch tablet machine.Check by relevant regulations in two appendix of Pharmacopoeia of the People's Republic of China version in 2005, the heavy 71mg of sheet, disintegration time is less than 30 seconds, friability 0.22%, hardness (tensile strength) 9.5～12.5kg.The dissolution determination condition is as follows: temperature is 37 ± 0.5 ℃, and dissolution medium is the distilled water that 900ml contains 1% (W/V) sodium lauryl sulphate, and rotating speed is 100 rev/mins.In special time sampling 5ml, 0.4 μ m filtering with microporous membrane, the content of indomethacin in the high effective liquid chromatography for measuring release medium calculates and discharges percent, and the result shows that label discharged 80%, 30 minute of indomethacin total amount in 15 minutes approximately and can discharge and finish.
Clad sheet coating material prescription is as table 1.
Table 1
| The prescription number | Coating material is formed | Coating material weight (mg) | Pectin | Prescription is formed calcium chloride | Sodium chloride | Discharge percentage rate (%) | |
| 0.1M dilute hydrochloric acid (2h) | PH6.8 citrate solution (3h) | ||||||
| 1 2 3 4 5 6 | Pectin/calcium chloride=1/1 | 150 200 250 300 400 500 | 75 100 125 150 200 250 | 75 100 125 150 200 250 | 0 0 0 0 0 0 | 1.02 1.08 1.06 0 0 0 | 48.02 44.23 0.77 0.47 0 0 |
| 7 8 9 10 | Pectin | 150 200 250 300 | 150 200 250 300 | 0 0 0 0 | 0 0 0 0 | 2.22 2.10 1.86 0.84 | Skeleton avalanche skeleton avalanche 1.87 0.75 |
| 11 12 13 | Pectin/sodium chloride=1/1 | 250 300 400 | 125 150 200 | 0 0 0 | 125 150 200 | 0.60 0.18 0.09 | The avalanche of skeleton avalanche skeleton avalanche skeleton |
Amplify by 1000 amounts.
Preparation clad sheet: pectin, calcium chloride or the sodium chloride of getting recipe quantity, mixing in the small-sized mixer, spray into 10% polyvinylpyrrolidone alcoholic solution, the system soft material, wet granular pushed 20 mesh sieve system wet granulars, and wet granular was put in 50 ℃ of baking ovens drying 2 hours, 20 mesh sieve granulate, add magnesium stearate by 1% of dried granule gross weight, mixing, standby.Suppress in the clad sheet tablet machine and get.
Press 2005 editions appendix XD regulations of Chinese Pharmacopoeia drug release determination method first method (changeing the basket method) and estimate the release of clad sheet:
1. the release in dilute hydrochloric acid solution and the citrate buffer
Medium is the dilute hydrochloric acid solution of 0.1M of 900ml and the citrate buffer of pH6.8.Rotating speed is 100 rev/mins, and temperature is 37 ± 0.5 ℃.
The result shows, when separately using pectin as the pressed coated granule, when its consumption is 150～200mg, coatings in citrate buffer, dissolve collapse diffusing, when consumption reaches 300mg, still have small amount of drug in the citrate buffer of 0.1M dilute hydrochloric acid solution and pH6.8, to discharge.And when adding sodium chloride in the coated granule, because a little less than the interaction between sodium and the pectin chain, the rate of dissolution of sodium chloride in the citrate buffer of pH6.8 is very fast in addition, coatings in citrate buffer, dissolve collapse diffusing, so can not effectively stop contacting of label and outside medium when adopting pectin/sodium chloride as coated granule.After in coated granule, adding calcium chloride, when the coated granule consumption is 300mg, when wherein the consumption of pectin only is 150mg, just can stop the release of medicine in the 0.1M dilute hydrochloric acid solution, but in the citrate buffer of pH6.8, still have a small amount of release.This may be less with the coatings consumption, and the clothing layer is thin relevant.When continue increasing the consumption to 400 of coated granule～500mg, can stop medicine in the citrate buffer of 0.1M dilute hydrochloric acid solution and pH6.8, to discharge fully.
2. contain the release in the colonic contents medium
Carry out colonic contents induced drug release test after suitably adjusting by the little agar diffusion method of 2005 editions appendix XD of Chinese Pharmacopoeia regulation drug release determination method.The Wistar rat, body weight 200～300g, the normal raising gavages 2% pectin aqueous solution 2ml every day, to induce the activity of rat colon pectase.Gavage 7d continuously, when experiment beginning 30min, put to death rat, open the abdominal cavity, separate caecum, the ligation two ends, be transferred to the citrate buffer of using saturated pH6.5 in advance rapidly, weigh, be diluted to finite concentration standby (w/v) with the citrate buffer of pH6.5, because caecum is an anaerobic environment, so all operations are all carried out under the condition of inflated with nitrogen.Other conditions are with release test in the buffer.Release medium is the citrate buffer that 200mL contains the pH6.5 of 2% or 4% (w/v) rat colon content.At official hour point sampling 1ml, replenish the full fresh dissolution medium that closes of equivalent isothermal nitrogen simultaneously, add 1ml methanol simultaneously and got whole dissolvings of suspended drug particle in the solution to guarantee, centrifugal (6000rpm, 10min), get supernatant liquid filtering, get subsequent filtrate, the HPLC method is measured indomethacin content, calculates the drug release percentage rate.For guarantee the rat colon content in external environment still with body in caecum anaerobic environment basically identical, in entire test, dissolution medium always inflated with nitrogen to guarantee oxygen-free environment.
Coating material is that the release profiles of compacting clad sheet in the rat colon content of 500mg seen accompanying drawing 1.After discharging 16h, compacting clad sheet cumulative release percent in 2% (w/v) and 4% (w/v) rat colon content is respectively 67.64 ± 7.02 and 92.59 ± 7.75, and its cumulative release percent is significantly higher than the release percent (37.64 ± 5.02) that does not add in the colon content.Add in the colonic contents and can make the release time lag of compacting clad sheet obviously shorten, this may be formed calcium pectinate and a residue pectin in the derivative pectase degraded coating skin in the colonic contents, form in coatings and be easy to the fine pore that hydrone passes, the medicine in the dissolving label is diffused in the release medium it.4% (w/v) rat colon content is bigger to the release influence of medicine, drug release is comparatively fast especially in 8～14h, this may with 4% (w/v) rat colon content in contain the higher pectase of concentration, enzyme active higher, promoted the degraded of outer coatings layer, in addition, coatings by with fully the contacting of release medium, calcium pectinate that forms and remaining pectin form behind the gel in by intestinal contents in the enzymatic degradation, and the corrosion of self is also underway.The release of medicine has been accelerated in the Degradation of enzyme and corrosion jointly.
3. contain the release in the different pectase buffer systems
Method is basic consistent with 1., release medium is the citrate buffer of 900mL pH6.5, adds 2ml or 4ml pectase Pectinex Ultra SP-L, Pectinex XXL and PectinexSmash XXL (Novo Nocdisk Ferment) respectively in buffer.At official hour point sampling 2ml, replenish the fresh dissolution medium of equivalent isothermal simultaneously, filter, get subsequent filtrate, the HPLC method is measured the content of indomethacin, calculates the drug release percentage rate.
Coated granule is that the release profiles of compacting clad sheet in different pectase buffer systems of 500mg seen accompanying drawing 2,3.Three kinds of pectases also can obviously promote the release of label Chinese medicine, and apparently higher than Pectinex Ultra SP-L and Pectinex XXL, both enzyme activities of back are suitable to the degrading activity of pectin for Pectinex Smash XXL.In the gel of pectase depolymerized pectin and calcium ion formation, the corrosion of skeleton self is also underway.The degraded of enzyme and corrosion have promoted the release of medicine jointly.When the consumption of pectase was reduced to 2ml, release rate of drugs obviously slowed down
4. the release in Gl tract pH surrounding medium
Test by 2005 editions appendix XD regulations of Chinese Pharmacopoeia drug release determination method first method (changeing the basket method).Rotating speed is 100rpm, 37 ± 0.5 ℃ of temperature.Be medium with 900mL 0.1M hydrochloric acid solution earlier, discharge 2h, change the citrate buffer of 900mL pH6.8 into, add 2ml pectase Pectinex UltraSP-L behind the release 3h, discharge 10h.2ml filters in the sampling of official hour point, replenishes the isothermal fresh dissolution medium of equivalent simultaneously, and the HPLC method is measured the content of indomethacin, calculates the compression coated tablets Chinese medicine and discharges percentage rate.
Result such as accompanying drawing 4.Under the situation that does not have pectase, discharge 8h after, when the coated granule consumption when 400mg increases to 500mg, drug release slows down.This may form insoluble calcium pectinate gel with pectin and the calcium chloride in the coated granule under the effect of moisture content, the thicker label Chinese medicine that stoped of formed gel layer expands the result that shape is loose to solute when the coated granule large usage quantity.After discharging 5h adding pectase, the drug release of the compression coated tablets of two kinds of coated granule consumptions is obviously accelerated and discharged shape is similar but then.This may degrade under the effect of enzyme with calcium pectinate, gel layer is destroyed relevant, calcium ion has certain excitation to the activity of pectase in addition, though formed gel layer was thicker when the coated granule consumption was 500mg, the time of enzymolysis clothing layer is longer, but its calcium ion that contains is more relatively simultaneously, and the active of enzyme strengthens relatively, two kinds of effects interact and cause under the condition that enzyme exists, and the clad sheet release behavior that the coated granule of two kinds of consumptions is suppressed is similar.
The release of embodiment 2 different pectin/calcium chloride ratio clad sheet
For further explaination calcium chloride to pectin in the body crosslinked action, compared the release of clad sheet when containing different proportion pectin/calcium chloride in the coatings.
The label prescription is with embodiment 1.
The coating material prescription is as table 2.Press clad sheet preparation method preparation among the embodiment 1.By the preparation of 1000 tablet recipe amounts.Check by correlation technique in two appendix of Pharmacopoeia of the People's Republic of China version in 2005.
Bag cake tablet recipe and fundamental property thereof when containing different calcium chloride amount in table 2 coating material
| The prescription number | Coating is formed (mg) | Sheet heavy (mg) | Tensile strength (kg) | Friability (%) | Clad sheet thick (mm) | Clad sheet diameter (mm) | |
| | Calcium chloride | ||||||
| 14 15 16 17 | 200 200 200 200 | 0 50 100 200 | 271.2 321.7 373.2 473.0 | 6.5 7.2 6.8 7.0 | 0.10 0.05 0.04 0.06 | 3.99 4.53 4.78 5.30 | 10.0 10.0 10.0 10.0 |
The release test method is with embodiment 1.
Releasing curve diagram such as accompanying drawing 5.
The result shows: do not add calcium chloride in the coating material, only can keep about 3 hours release time lag, but after adding calcium chloride, discharge time lag and then can extend to more than 6 hours, and rate of release slows down with the amount increase of calcium chloride in the coating.Because calcium chloride is the extremely strong inorganic salt of water solublity, generally in preparation prescription, add calcium chloride and can quicken drug release, not only do not quicken the release of medicine herein, reduced the rate of release of pectin clad sheet on the contrary greatly, be enough to show calcium chloride to pectin material in the body crosslinked action.Its blockage effect significantly is better than not adding the simple pectin skeleton of calcium chloride.
The present invention describes by above description and embodiment, more than is described as nonrestrictively, does not limit claim scope of the present invention.
Claims (5)
1. one kind is used for colon locating administrated at the crosslinked clad sheet of body, with the plain sheet of pastille is core, be enclosed with coating material around it, it is characterized in that, pastille label weight wherein is 70～130mg, coating material is the pectin/calcium salt admixture that contains high weight portion calcium salt, and its consumption is 100mg～700mg, and wherein the ratio of pectin/calcium salt is 5/1～1/3.
2. be used for colon locating administratedly by claim 1 is described, it is characterized in that described coating material consumption is 250mg～500mg at the crosslinked clad sheet of body.
3. describedly be used for colon locating administratedly by claim 1 or 2, it is characterized in that the ratio of pectin/calcium salt is 2/1～2/3 in the described coating material at the crosslinked clad sheet of body.
By claim 1 described be used for colon locating administrated at the crosslinked clad sheet of body, it is characterized in that, it contains the awkward soluble drug of medicine described clad sheet, is selected from indomethacin, dexamethasone, budesonide, 5-aminosalicylic acid, ondansetron 5-fluorouracil or Irinotecan or protein polypeptide medicine.
5. be used for colon locating administratedly by claim 1 is described, it is characterized in that at the crosslinked clad sheet of body, described clad sheet its to contain medicine be indomethacin.
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| CNA2006100294763A CN101112363A (en) | 2006-07-27 | 2006-07-27 | Crosslinking wrapped core slice in vivo for |
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| CNA2006100294763A CN101112363A (en) | 2006-07-27 | 2006-07-27 | Crosslinking wrapped core slice in vivo for |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972232A (en) * | 2010-11-01 | 2011-02-16 | 山东大学 | Eudragit S100 coated curcumin pectin microsphere and preparation method thereof |
| CN103622928A (en) * | 2013-11-27 | 2014-03-12 | 广西大学 | Preparation method and application of pectin-base carrier material |
| CN107998152A (en) * | 2017-12-14 | 2018-05-08 | 乐普制药科技有限公司 | A kind of probiotics tablets of colon release |
| CN112877152A (en) * | 2021-02-06 | 2021-06-01 | 濮阳宏业环保技术研究院有限公司 | Coated sodium percarbonate material and preparation method and application thereof |
-
2006
- 2006-07-27 CN CNA2006100294763A patent/CN101112363A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972232A (en) * | 2010-11-01 | 2011-02-16 | 山东大学 | Eudragit S100 coated curcumin pectin microsphere and preparation method thereof |
| CN103622928A (en) * | 2013-11-27 | 2014-03-12 | 广西大学 | Preparation method and application of pectin-base carrier material |
| CN107998152A (en) * | 2017-12-14 | 2018-05-08 | 乐普制药科技有限公司 | A kind of probiotics tablets of colon release |
| CN112877152A (en) * | 2021-02-06 | 2021-06-01 | 濮阳宏业环保技术研究院有限公司 | Coated sodium percarbonate material and preparation method and application thereof |
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