CN101991720A - Jiechangning target-oriented drug delivery preparation and application thereof - Google Patents
Jiechangning target-oriented drug delivery preparation and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicine, relating to a Jiechangning target-orientated drug delivery preparation and an application thereof. The prescription of the related colon target-oriented drug delivery preparation consists of pollen typhae and false loosestrife. The medicinal materials are prepared into the colon target-oriented tablets, pills, or pellets, capsules, suspension granules and the like through the technologies of solvent extraction, purification, preparation molding, coating and the like. The oral drug delivery is used for the treatment of the colitis. Compared with the existing preparation, the novel preparation has the following advantages that: 1. the colon target-oriented drug delivery preparation completely eliminates the inconvenience and the pain caused by the clysis drug delivery of the existing preparations for external use; 2. through the production of the oral solid preparation, the quality standard is enhanced significantly, and the product quality is ensured; and 3. the target-oriented drug delivery preparation for the treatment of the colitis facilitates the increasing of the drug delivery frequencies, enhances the local medicine concentration and the contacting time, thereby enhancing the curative effect.
Description
Technical field
The invention belongs to field of medicaments, relate to peaceful targeting drug administration preparation of a kind of colon and purposes.The prescription of the colon targeting drug administration preparation that relates to is made up of Pollen Typhae and Herba Ludwigiae Prostratae two flavors, medical material is by solvent extraction, refining, technology such as preparations shaping and coating is made preparations such as segmented intestine targeted enteric coated tablet, pill or micropill, capsule and mix suspension grain agent, and oral administration is used for the treatment of colitis.
Background technology
Chronic colitis is meant that colorectum causes the inflammatory edema of intestinal because of various pathogenesiss, and ulcer, hemorrhage pathological changes are a kind of chronic intestinal tract diseases with tendency of recurrence.Be divided into specificity according to pathogenesis, the colitis of obvious cause is promptly arranged, non-specific is the not clear colitis of pathogenesis.Specificity colitis is common dysentery, tuberculosis of colon, amebic dysentery, radiation rectitis etc.; Nonspecific colonitis has ulcerative colitis, clone disease etc.It is nonspecific that the most clinical alleged chronic colitiss of colitis refer to more, shows as: based on diarrhoea, serious every day 10～30 times, discharge and contain blood, pus and mucous feces, with paroxysmal abdominal pain, based on lower-left stomachache.Chronic colitis can betide any age, but with 20～40 years old for seeing more.Generally speaking, serious symptom is invaded scope with colon and the inflammation degree is relevant.The general mode that all distributes with seriality of inflammation is expanded to proximal colonic from rectum, and the most normal position of involving is rectum, straight-sigmoid colon, left side colon.But minority can be the segmental distribution respectively at descending colon and sigmoid colon, may see the rectum infringement once in a while.Primary disease is comparatively serious produces many complication, causes peritonitis as perforation of colon ulcer, and pathological changes corrodes trunk and can cause hyperhematosis to produce anemia, and long-term diarrhea causes anal infection, and the minority case can produce canceration.
China's treatment at present is light, the most frequently used medicine of moderate colitis remains aminosallcylic acid class medicine and glucocorticoid medicine, has rapid-action, recent clinical remission rate advantages of higher, but easily recurrence after the drug withdrawal, the long-term prescription untoward reaction increases, and part intractable patient curative effect is unsatisfactory.The curative effect of this medicine is directly proportional with untoward reaction and consumption.Report is arranged, oral sulfasalazine every day (SASP) 4 grams, effective percentage is not as good as 50%, 10～15% patients are arranged approximately because of the untoward reaction drug withdrawal, take medicine every day and surpass 4 grams, effective percentage improves, but untoward reaction can reach 37.5%, major side effects for headache, feel sick, erythra, anemia, bone marrow depression and reversibility forfeiture fertility.The intravenously administrable toxic and side effects is bigger, and immunosuppressant is bigger to the hemopoietic function of bone marrow influence, in use wants the periodic review hemopoietic function of bone marrow.Therefore, Western medicine exists curative effect undesirable, erious adverse reaction, shortcoming such as relapse rate height after the drug withdrawal.
In order to improve curative effect, adopt the retention enema administration clinically, be beneficial to medicine and directly contact with the colonic pathological change position long period.But colon clysis needs the medical work personnel of professional experiences, gives patient, family members, and medical workers etc. cause trouble, especially cause suffering to patient, and patient often is difficult to adhere to treatment.Therefore, the colon targeting drug administration preparation that searching is more convenient effectively, untoward reaction is few becomes the emphasis of ulcerative colitis research.
The treatment by Chinese herbs ulcerative colitis is the characteristic of Chinese medicine, is widely used at present, and has obtained certain effect.Decoction, injection, tablet, capsule, suppository or the enema etc. made with Chinese medicine use also more general.For example, XILEI SAN, the knot soup of bursting, colon are peaceful etc. all proves improving symptom or the mucosa pathological changes has certain curative effect.But because of disease typing disunity, the deficiency that many in addition pharmaceutical dosage forms exist, medication lacks targeting, causes the curative effect repeated authentication relatively poor.
It is found that before 20 years after oral aperient has only the arrival large intestine and just bring into play the effect for the treatment of ulcerative colitis.Therefore, people have produced interest to colon targeting drug administration, and constantly develop various colon targeting drug administration system.The Patent data of disclosed Chinese medicine target administration, the have 200410061015.5 Chinese medicine enteric coated preparation patent of (application numbers, down with) relates to a kind of eight flavor XILEI SAN oral formulations and colon-targeted orally-administered preparation and preparation methoies; 200510020807.2 patents are arranged, and relating to a kind of is peaceful targeting preparation of oral colon of forming of feedstock production and preparation method thereof by American-cockroach-extract, is used for the treatment of ulcerative colitis; 03114407.1 patent relates to a kind of herbal polysaccharide is passed drug carrier as colon application; 200410052029.0 patent, relate to a kind of Herba Sophorae alopecuroidis total bases extract in preparation ulcerative colitis medicine application and the preparation method of colon targeting preparation; 200410061015.5 patents are arranged, relate to eight flavor XILEI SAN oral formulations and colon-targeted orally-administered preparation and preparation methoies; 200410040960.7 patents are arranged, relate to by being a kind of pharmaceutical composition for the treatment of ulcerative colitis that feedstock production forms and its production and use with Chinese medicine astragalus, Radix Sophorae Flavescentis; 200510121000.8 patents are arranged, relate to a kind of intestine target medicinal controlled release fiber and preparation method thereof; 93105769.8 patent is arranged, relate to enteric hollow capsules.
The compound Chinese herbal medicinal ingredients complexity, easily moisture absorption, it is bigger to make oral targeting preparation technical difficulty, since the more than ten years, though some patents and correlational study report are arranged.But because of a variety of causes such as preparation technology are stable inadequately, do not have rational quality control, the animal pharmacology drug effect is not remarkable, clinical efficacy is undesirable etc., most projects still rest on laboratory stage, and the product that reaches industrialization is very few, also do not see the similar products listing at present.
This patent is to serve as the targeting drug administration preparation of prescription basis preparation with colon peaceful (enema).The peaceful standard of colon is recorded in become a full member the 10th of standard of Ministry of Health of the People's Republic of China's ministry standard new drug, and the standard numbering: WS3-033 (Z-24)-95 (Z), the approval number of the drug: (89) are defended the accurate word Z-15 of medicine number, are produced by Jiuzhitang Co., Ltd..The every bottled 5g of specification (ointment), usage and dosage: the cream 5g that gets it filled, be dissolved in 50～80ml eliminating cold for resuscitation water, put retention enema when being chilled to about 37 ℃, be a course of treatment all around greatly after an action of the bowels once every day.Because administration every day, administration time and treatment cycle are longer, and the patient uses very inconvenient.
The publication of being made oral colon administration or colon targeting drug administration preparation by Pollen Typhae and Herba Ludwigiae Prostratae is not seen in inquiry Chinese patent literature retrieval (1985-2009.04), does not see the use patent of the peaceful oral administration treatment of colon colitis yet.
Summary of the invention
Peaceful targeting drug administration preparation of a kind of oral colon and purposes, be serve as to write out a prescription in the basis with colon peaceful (enema), with Pollen Typhae, Herba Ludwigiae Prostratae two flavor Chinese medicines through extract, behind refining, the preparations shaping, reuse acceptable accessories coating is made, and is used for the treatment of acute and chronic colitis.
The purpose of this invention is to provide a kind of is the peaceful targeting drug administration preparation of oral colon made of prescription by Pollen Typhae and Herba Ludwigiae Prostratae, overcomes present enema shortcoming, makes it to become good effect, easy to use, medicine that the patient takes like a shot.The concrete dosage form of medicine comprises solid preparations such as tablet, capsule, mix suspension grain, pill and micropill, by making the medicine that enteric discharges behind the coating, especially is released to main targeting drug administration preparation with colon.
Another object of the present invention provides the colon targeting preparation of oral administration, is used for the treatment of colitis.
Release mechanism according to the different dosing system, the preparation principle of colon targeting preparation of the present invention mainly can be divided into five big classes: pH dependent form medicine-releasing system, enzyme dependent form medicine-releasing system, time lag medicine-releasing system, flora activation system and colon targeted adhesive medicine-releasing system, wherein pH dependent form medicine-releasing system, enzyme dependent form medicine-releasing system, time lag medicine-releasing system are comparatively commonly used in the present invention.
Be insoluble in the less stomach of pH value (pH1～2) liquid and the intestinal fluid (pH6.8) according to enteric adjuvants such as Eudragit S100, and be dissolved in characteristics in the bigger colonic fluid of pH value (pH7.0～8.0), such adjuvant is applied to the peaceful enema of colon makes the peaceful targeting drug administration preparation of oral colon, medicine does not discharge medicine through stomach, small intestinal, discharges medicine then to the dissolving of colon position adjuvant.In order to increase the plasticity of enteric coating, in enteric adjuvant (polymer), add the plasticizer of appropriate amount, as triethyl citrate, dibutyl sebacate and propylene glycol.Enteric polymer mixes the weight ratio scope of using with plasticizer be 30: 1～2: 1.
Utilize the hydrolysis of the enzyme (nitrogen reductase, glycosidase, glucuronidase etc.) that flora produces according to adjuvants such as pectin at colonic, the present invention prepares the peaceful targeting drug administration preparation of colon of enzyme dependent form.Thereby but in colon, there is special pectin decomposing enzyme decompose pectin to discharge medicine owing in stomach, small intestinal, lack corresponding pectase.Pectin mixes by a certain percentage with hypromellose (HPMC), can improve the hydrophilic of pectin, and pectin mixes use with HPMC, and wherein the weight content of HPMC is 10～90%.But both suitable proportionings are carried out coating preparation quality targeting drug administration preparation preferably to preparation.The flora activation system is to utilize the intestinal anaerobe to the saccharoidal fermentation of non-starch, and polysaccharide skeleton or coating are made oral formulations with medicine, reaches the effect that the location discharges.
Arriving colon according to macromolecular materials such as ethyl celluloses through stomach, small intestinal needs time lag principle the present invention of about 6 hours to prepare the peaceful time lag release of colon preparation, locatees release when medicine reaches at colon after oral.The medicine-releasing system that stagnates in the preparation also often adopts the method for comprehensive time-lag effect and gastrointestinal pH difference, to comprehensive time-lag effect and the design of gastrointestinal pH difference, carrier is stable in the sour environment of stomach, do not discharge medicine, in the slow aquation of the pH of small intestinal environment support, the time that guarantees its aquation contains body and can pass through small intestinal, carries medicine and enters colon and discharge.
The present invention adopts in the pH dependent form drug-supplying system, acceptable accessories mainly is meant at pH greater than dissolved enteric polymer more than 6.5, common have an acrylic acid II resin, acrylic acid III resin, You Teqi EudragitS100 (methacrylic acid: methyl methacrylate 30: 70), Eudragit FS 30D (methacrylic acid: acrylic acid methyl ester.: methacrylate 1: 1: 1), polyvinyl acetate phthalic acid ester (PVAP), phthalic acid hypromellose ester (HPMCP), hypromellose acetic acid succinate (HPMCAS), Eudragit L, Eudragit RS etc., these adjuvants can be wherein a kind of, also can be arbitrarily several mixture or and plasticizer, the mixture of antiplastering aid etc.
Pectin, calcium pectinate and and hydroxypropyl methylcellulose etc. can be used for preparing enzyme dependent form colon targeting drug administration preparation; Azobenzene polymer, diphenyl diimide and acrylic resin copolymer, glucosan (Dextran) and chitosan (Chitosan), guar gum, chitosan, succinic acid-chitosan and phthalic acid-chitosan etc. can be used for preparing flora dependent form colon targeting drug administration preparation; Glucosan, pectin, chitin, cyclodextrin, cellulose derivative, gelatin, alginate, carbomer etc. can be used for preparing the adhesive type colon targeting drug administration preparation; Ethyl cellulose, kappa wax, Cera Flava, span, HPMC etc. can be used for time lag type colon targeting drug administration preparation.
The peaceful targeting preparation of oral colon provided by the invention also prepares the peaceful enteric targeting of novel colonic coated preparation in conjunction with pH dependent form, time lag type or two kinds of enzyme dependent forms or multiple principle.
Peaceful (enema) the former prescription of colon records become a full member the 10th of standard of portion of Ministry of Health of the People's Republic of China new drug, and by Pollen Typhae 4320g, Herba Ludwigiae Prostratae 864g forms, and is used to make 1000 bottles.The present invention is the new formulation for preparing in conjunction with the modern pharmaceutical technology on this prescription basis, and the preparation method of the peaceful targeting drug administration preparation of colon may further comprise the steps.
The peaceful extractum of colon extracts subtractive process: adopt conventional extraction, process for refining, get Pollen Typhae and Herba Ludwigiae Prostratae in the prescription, add twice of water times 6～8 water boiling and extraction, filter merging filtrate, concentrating under reduced pressure, the semi-finished product thick paste, direct drying under reduced pressure or add suitable adjuvant drying, dry extract; Said extracted concentrated solution also method such as available ethanol precipitation is refining, reclaims ethanol, and is condensed into the thick paste that relative density is 1.30～1.38 (60～65 ℃).
More than extract also Pollen Typhae and Herba Ludwigiae Prostratae can be added water respectively or add alcohol extraction, concentrate, drying obtains extractum or dry extract powder.The advantage of technologies such as extracting respectively, make with extra care can suitably reduce the effective ingredient in the Pollen Typhae such as the loss of isorhamnetin-compositions such as 3-O-new dried orange peel glucosides.
Because easily moisture absorption of Chinese medicine extract adds an amount of acrylic resin II number (adding behind the dissolve with ethanol), starch or betacyclodextrin etc. and carries out drying when extract dry, can reduce the dry extract hygroscopicity.
The peaceful sheet core molding process of colon: according to conventional adjuvant of Chinese medicinal tablet and tablet forming technique, the peaceful label of preparation colon.Such as getting 1 part of dry extract, add 0.5 part of lactose, directly mixed pressuring plate is granulated, and granulate adds 0.02 part of Pulvis Talci again, mixing, tabletting promptly gets label; Also available dry extract adds suitable adjuvant and granulates drying, tabletting with the 5%HPMC alcoholic solution; In order to improve the coating yield rate, the label hardness of tabletting is suitable＞40N, friability＜1%, every contains crude drug 1.3～5.18g.
Capsule for treating colonopathy preparation technology:, get 1 part of extractum (1.37,60～65 ℃ of relative densities) according to conventional adjuvant of Chinese medicinal capsule agent and prepared capsule, add 0.5 part of filler such as starch, sucrose, dextrin etc., drying under reduced pressure is pulverized, directly encapsulated, make every capsules contain crude drug 1.3～5.18g.Extractum and adjuvant also can be made into greater than 80 order granules before encapsulated, and enteric coated back is encapsulated, the also optional enteric coated capsule of the optional common gastric-dissolved capsule of capsule shells.
The peaceful micropill moulding process of colon: prepare peaceful ball of colon or micropill according to the Chinese medicine pellet common process, concrete grammar is: get 1 part of peaceful extractum of colon, add adjuvants such as microcrystalline cellulose or lactose; 65% ethanol is an amount of; the system soft material, the plate hole aperture is selected in pelletize in extruding round as a ball comminutor; every wet ball of scalable contains the amount of crude drug; extrude rotating speed 800～1000r/min, round as a ball rotating speed 1000～1200r/min, 3～10 minutes round as a ball time; wet ball is in 45 ℃ of dryings 4～6 hours, promptly.According to demand, aperture, adjustable imposite hole obtains different big or small ball cores.
Get common label, ball core, granule and capsule, can obtain the peaceful targeting preparation of colon to the suitable enteric coating of its surface coverage.The kind of enteric coating has pH dependent form, enzyme dependent form, time lag type, flora activated form and colon targeted adhesive type, and wherein pH dependent form, enzyme dependent form and time lag release type are comparatively commonly used in the present invention.
The adjuvant of the most frequently used pH dependent form is the enteric coating adjuvant of methacrylic, as the strange S 100 (methacrylic acid: methyl methacrylate of You Te, 30: 70) and the strange FS 30D (methacrylic acid: acrylic acid methyl ester.: methacrylate of You Te, 1: 1: 1), such adjuvant is pH flip-over type colon administration adjuvant for to dissolve in greater than the pH7.0 medium.
The normal plasticizer that adds reduces vitrification point and minimum film formation temperature in the coating solution; The organic solution of You Teqi S100 needs 10-30% plasticizer (dry weight of pressing polymer calculates), and suitable manufacturing methods has: triethyl citrate, dibutyl sebacate and propylene glycol.You Teqi FS 30D is a kind of flexible polymer, and good filming is arranged, and can add plasticizer again, and small amount of plasticizer can increase the flexibility of film sometimes, improves preparation process.For example: the film breakage during for fear of the enteric coated particles tabletting can add the flexibility that an amount of plasticizer increases film.
Consider the easy moisture absorption of Chinese medical concrete, coating of the present invention mainly adopts the organic solution coating, especially the bottom coating.The top layer coating can adopt water suspension.Common organic solvent is ethanol, propylene glycol and acetone soln, can be used for various oral solid formulations commonly used, as: the enteric coating of tablet, piller, micropill, capsule, soft capsule, drop pill and granule.You Teqi S100 carries out the suitable covering amount of coating with organic solution: tablet, capsule are every square centimeter of surface area 6～100mg; Piller, granule are 6～60% of its weight.Polymer overmold amount and their surface texture, mechanical strength is relevant with drug solubility.
The appropriate level of solid material is 10～15% in organic coating solution, and the sheet bed tempertaure of granule coating (organic solution coating) is 25～30 ℃ in fluid bed, 30～35 ℃ of the sheet bed tempertaures of coating in the coating pan.According to distinct device and environment, above parameter can suitably be adjusted, to reach best coating effect.
You Teqi S100 is the anionic polymer of methacrylic acid and methyl methacrylate, is insoluble to gastric juice, and is also water insoluble, in the available bases and form soluble-salt; They are dissolved in isopropyl alcohol and so on organic solvent, are mixed with coating solution and can form antacid enteric thin film.
Below be the prescription commonly used of label enteric coating: the strange S10040g of You Te, dibutyl sebacate 4g, Pulvis Talci 10g, isopropyl alcohol 246g, acetone 300g; Preparation method: isopropyl alcohol and acetone are mixed into mixed solvent, the strange S100 of You Te is dissolved in an amount of solvent, and Pulvis Talci and dibutyl sebacate added in an amount of solvent, with refiner homogenize 10 minutes, pour in the strange S100 solution of You Te, in the coating process, continue to stir.More than spraying suspension solids content 9%, spraying suspension polymer content 6.7%.In coating solution, also suitable microcrystalline Cellulose can be added, the wearing and tearing of label corner can be reduced.But the microcrystalline Cellulose consumption is too much, can increase the permeability of coating, influences the effect of coating.
To coatings such as micropill, granule and tablets, also often adopt the method for carrying out surface coatings behind the bottom coating again.Bottom coating prescription: the strange L100300g of You Te, triethyl citrate 30g, Pulvis Talci 70g, isopropyl alcohol 4200g, solids content 8.6% in the coating solution, and polymer content 6.5% in the coating solution.Preparation method: the strange L of You Te is dissolved in acetone, adds Pulvis Talci and triethyl citrate,, suspension is poured in the strange L100 solution of You Te, continue in the coating process to stir, bottom coating weightening finish scope 6～60% with homogenizer homogenize 10 minutes.
The prescription that the top layer coatings is commonly used: the strange S100 180g of You Te, Pulvis Talci 160g, magnesium stearate 50g, titanium dioxide 50g, polyethylene glycol 6000 25g, isopropyl alcohol/acetone (1: 1) 3035g, solids content 13.3% in the coating solution, and polymer content 5.9% in the coating solution.The strange S100 of preparation method: You Te is dissolved in an amount of solvent, with Pulvis Talci, and magnesium stearate, titanium dioxide and pigment are poured in an amount of solvent, pour Polyethylene Glycol organic solution again into, and this suspension is used about 10 minutes of homogenizer homogenize.With the strange S100 of You Te or pour in the suspension, continue in the coating process to stir.
Coating method: label places coating pan, rotates coating pan, with pneumatic spray gun the coating suspension is sprayed on 25～30 ℃ the label.Adjust hydrojet speed, intake and inlet temperature make that spray operation can continue to carry out.In the coating process, the sheet bed tempertaure maintains 25～30 ℃, and tablet can smooth and easyly flow.In coating solution, add an amount of antiplastering aid as: Pulvis Talci, magnesium stearate etc. can avoid tablet inter-adhesive.In case adhesion occurs, should suspend hydrojet, treat the tablet surface drying, tablet recovers the smooth and easy hydrojet that continues again when mobile.Packaging technique parameter commonly used: pre-thermal endurance 3 minutes, 40～50 ℃ of inlet temperature, 20～25 ℃ of sheet bed tempertaures, 10～30 rev/mins of pot rotating speeds, atomization air pressure 0.5bar.
Granule of the present invention, micropill can be packed into and be carried out enteric coating behind the conventional capsule, and the strange L30D-55 of You Te is used for the enteric coating of hard capsule.Hard capsule can carry out coating in the coating pan of ordinary coating pot or improvement, for fear of dehydration the glue shell is become fragile, and capsule can be preheated to more than 25 ℃; Hydrojet speed is controlled with peristaltic pump, and coating solution should continue to stir in the coating process, in order to avoid precipitation produces.Temperature of charge remains on 25～28 ℃ in the coating process, helps obtaining uniform thin film; The hydrojet condition should strictly be monitored, and overdrying can make the glue shell become fragile.When polymer carboxyl and capsule shells respond, the glue shell phenomenon that becomes fragile also can appear, can coat one deck sealing coat sometimes earlier to avoid this phenomenon.
The operating parameter of capsule coating, common No. 0, No. 1, No. 2 capsules, the spraying enteric coat layer, coating is gained in weight and is every square centimeter of 6～60mg polymer, common equipment rotation coating pan, dry air volume 0.8～1.0m
3/ minute, 30～35 ℃ of inlet temperature, 20～22 ℃ of temperature of charge, atomizing whiff pressure 0.8～1.0bar, 200～250 minutes coating time, hydrojet speed 1.8～2.0g/ branch/kg capsule.
According to pectin in colon by the zymolytic characteristics of colon, this product can adopt the suspension coating of adjuvants such as pectin, HPMC, make enzyme dependent form colon targeting drug administration preparation, for example, pectin and hypromellose (HPMC) are mixed and made into the water suspension of 3-15%, pectin mixes use with HPMC, wherein the weight content of HPMC is 10～90%, adds the bonding that suitable Pulvis Talci, silicon dioxide etc. can improve the coating process.
According to the characteristics of water-insoluble material ethyl cellulose materials such as (EC), also can be made into the enteric coating of time lag release type; Adopt carbomer, starch pelletizing forming, enteric coated then, after the enteric coating dissolving, the carbomer suction produces stronger adhesion and sticks on the colon position, thereby reaches the effect that colon discharges medicine, and said preparation is the adhesive type colon location preparation.
Outside enteric coating, spray 2～5% HPMCP 3～6% solution again, can increase the preparation acid accumulator resistance, guarantee that preparation discharges still less under one's belt.HPMCP dissolving method: in container, add quantitative solvent, under stirring, slowly add HPMCP and stir that to place 20～50 minutes be solubilized.HPMCP consumption: be generally 6～10% of label weight.Used organic solvent: ethanol, acetone, acetone (1/1), ethanol/water (8/2) equal solvent.
Get 6 of this product, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopt the device of dissolution method (appendix X C second method), putting respectively in six different stripping rotors, is release medium with 0.1mol/L hydrochloric acid solution 200ml, and rotating speed is that per minute 50 changes, operation in accordance with the law, after 2 hours, to get solution 5ml and filter, filtrate is as need testing solution (1); The 0.2mol/L sodium radio-phosphate,P-32 solution 50ml that adds 37 ℃ then, mixing is 6.8 ± 0.05 with the pH value of 2mol/L sodium hydroxide solution regulator solution, record release medium volume continued to operate in accordance with the law and clock, after 2 hours, get solution 5ml and filter, as need testing solution (2); And the pH value with 2mol/L sodium hydroxide solution regulator solution is 7.8 ± 0.05 in process container, record release medium volume, continue to operate in accordance with the law and clock, after 4 hours, getting solution 5ml filters, as need testing solution (3), measure according to high performance liquid chromatography (two appendix VI of Chinese Pharmacopoeia version in 2005 D).
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are filler; Acetonitrile-water (15: 85) is a mobile phase; The detection wavelength is 254nm, and number of theoretical plate calculates by isorhamnetin-3-O-neohesperidoside peak should be not less than 1000.
The preparation of need testing solution is respectively at the sampling of regulation sample point, and the filtering with microporous membrane of 0.45um is got subsequent filtrate as need testing solution.It is an amount of that the preparation precision of reference substance solution takes by weighing in the phosphorus pentoxide vacuum drying apparatus isorhamnetin-3-O-neohesperidoside reference substance of dry 36 hours, add dissolve with methanol to scale, it is an amount of that precision is measured above-mentioned solution, be diluted to the solution close with release medium respectively, promptly with need testing solution concentration.
Accurate respectively reference substance solution and the need testing solution drawn of algoscopy injects chromatograph of liquid, and the record chromatogram, relatively calculates promptly with the assay value with the calculated by peak area burst size by external standard method, and measurement result sees the following form.
The external accumulative total of the peaceful targeting enteric coatel tablets of table 1 colon discharges the measurement result (%) with isorhamnetin-3-O-neohesperidoside
| Release medium | Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 |
| 0.1mol/L hydrochloric acid solution (2 hours) | 0 | 0 | 0 | 0 | 0 | 0 |
| PH 6.8 buffer solution (2 hours) | 20.4 | 14.2 | 20.8 | 12.7 | 15.0 | 17.5 |
| PH 7.8 phosphate buffers (4 hours) | 95.5 | 93.2 | 98.9 | 98.0 | 94.2 | 96.4 |
The result shows from table 1, the peaceful targeting enteric coatel tablets of colon of the present invention discharge seldom in the hydrochloric acid of 0.1mol/L, less than 10%, total burst size is less than 30% in the hydrochloric acid of 0.1mol/L and pH 6.8 phosphate buffers, almost all discharge in the colon, reach comparatively ideal targeting releasing effect, medicine discharges greater than 70% in pH 7.8 phosphate buffers.
By above-mentioned enteric coatel tablets assay method, get 6 capsules (every capsules contains crude drug 2.6g), measure with method, the results are shown in Table 2.
The external accumulative total of the peaceful targeting enteric coated capsule of table 2 colon discharges the measurement result (%) with isorhamnetin-3-O-neohesperidoside
| Release medium | Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 |
| 0.1mol/L hydrochloric acid solution (2 hours) | 0 | 0 | 0 | 0 | 0 | 0 |
| PH 6.8 buffer solution (2 hours) | 15.4 | 15.8 | 18.6 | 15.2 | 10.5 | 17.9 |
| PH 7.8 phosphate buffers (4 hours) | 97.5 | 99.3 | 94.8 | 96.7 | 93.0 | 96.2 |
By above-mentioned enteric coatel tablets assay method, get micropill 0.7g (being equivalent to crude drug 5.18g), the accurate title, decide, and puts respectively in six cups, measures release, the results are shown in Table 3.
The external accumulative total of the peaceful targeting enteric coated micropill of table 3 colon discharges the measurement result (%) with isorhamnetin-3-O-neohesperidoside
| Release medium | Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 |
| 0.1mol/L hydrochloric acid solution (2 hours) | 0 | 0 | 0 | 0 | 0 | 0 |
| PH 6.8 buffer solution (2 hours) | 12.7 | 20.3 | 14.7 | 15.2 | 12.3 | 15.0 |
| PH7.8 phosphate buffer (4 hours) | 95.9 | 96.8 | 98.6 | 97.3 | 92.2 | 97.0 |
By above-mentioned enteric coatel tablets assay method, get mix suspension grain 4g (being equivalent to crude drug 5.18g), the accurate title, decide, and puts respectively in six cups, measures release, the results are shown in Table 4.
The external accumulative total of the peaceful targeting enteric coated particles of table 4 colon discharges the measurement result (%) with isorhamnetin-3-O-neohesperidoside
| Release medium | Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 |
| 0.1mol/L hydrochloric acid solution (2 hours) | 0 | 0 | 0 | 0 | 0 | 0 |
| PH 6.8 buffer solution (2 hours) | 20.4 | 19.1 | 23.6 | 20.7 | 20.0 | 24.6 |
| PH 7.8 phosphate buffers (4 hours) | 100.3 | 98.8 | 98.2 | 96.8 | 99.5 | 102.4 |
Result of the test shows, the drug release of targeting drug administration preparation of the present invention (in isorhamnetin-3-O-new dried orange peel glucosides) in the hydrochloric acid of 0.1mol/L all less than 10%, total burst size discharges summation greater than 70% less than 30% at phosphate buffer (pH 7.8～8.0) in the hydrochloric acid of 0.1mol/L and pH 6.8 phosphate buffers.
The release of targeting drug administration preparation of the present invention also can adopt Self-control method and other methods to measure, and the difference of assay method does not influence Seeking for Right of the present invention.
Each coated preparation has been carried out the discrimination test of isorhamnetin-3-O-neohesperidoside and typhaneoside by 2005 editions one appendix VI B of Chinese Pharmacopoeia: get this product coated preparation (being equivalent to the 5.18g crude drug), grind, the overtime extraction of adding distil water 30 minutes, filter, filtrate evaporate to dryness, residue add ethyl acetate 10ml, heating makes dissolving, filter, filtrate is concentrated into about 0.5ml, as need testing solution.Other gets isorhamnetin-3-O-neohesperidoside and typhaneoside reference substance, adds ethanol respectively and makes the solution that every 1ml contains 0.5mg, in contrast product solution.According to thin layer chromatography (appendix VI B) test, draw each 10 μ l of need testing solution and reference substance solution, put respectively on same silica GF254 lamellae, (5: 3: 1: 1) be developing solvent, expansion was taken out with ethyl acetate-butanone-formic acid-water, dry, put under the ultra-violet lamp (254nm) and inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
This preparation employing isorhamnetin-3-O-neohesperidoside and typhaneoside are as the assay index of quality standard.Measure according to high performance liquid chromatography (05 edition one appendix VI D of Chinese Pharmacopoeia), chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Acetonitrile-water (15: 85) is a mobile phase; The detection wavelength is 254nm.Number of theoretical plate calculates by isorhamnetin-3-O-neohesperidoside peak and typhaneoside should be not less than 1000.
The preparation precision of reference substance solution takes by weighing isorhamnetin-3-O-neohesperidoside, the typhaneoside reference substance is an amount of, and accurate the title decides, and adds methanol respectively and makes the solution that every 1ml contains 25 μ g, promptly.
This product an amount of (being equivalent to crude drug 2.6g) is got in the preparation of need testing solution, and accurate the title decides, and puts in the 25ml measuring bottle, add methanol 20ml, supersound process (power 250W, frequency 20kHz) 30 minutes is put cold, add methanol to scale, shake up, filter, the accurate absorption in subsequent filtrate 5ml to the 25ml measuring bottle, add methanol to scale, promptly.
Accurate respectively absorption reference substance solution of algoscopy and need testing solution are an amount of, inject chromatograph of liquid, measure, that is, four kinds of different preparation measurement results see Table 5.
The content of isorhamnetin in the different coated preparations of table 5 (in crude drug 5.18g)-3-O-neohesperidoside and typhaneoside
| Different coated preparations | Isorhamnetin-3-O-neohesperidoside (mg) | Typhaneoside (mg) |
| The peaceful coated tablet of colon | 5.6 | 3.8 |
| The peaceful coating capsule of colon | 7.2 | 4.4 |
| The peaceful coated micropill of colon | 6.7 | 4.2 |
| The peaceful coating mix suspension grain of colon | 6.3 | 3.9 |
Because the place of production, the source difference in the Pollen Typhae, wherein active constituent content differs greatly, and some can reach more than 20 times.Preparation of the present invention is 1～40mg in the amount that is equivalent to the 5.18g crude drug and contains isorhamnetin-3-O-neohesperidoside, and containing isorhamnetin-3-O-neohesperidoside amount by every gram crude drug is 0.19～7.7mg; Preparation is 0.5～30mg in the amount that is equivalent to the 5.18g crude drug and contains typhaneoside, and the amount that contains typhaneoside by every gram crude drug is 0.1～5.8mg.
Preparation of the present invention is a kind of colon targeting drug administration preparation, be used for causing inflammatory edema, ulcer, the hemorrhage pathological changes of intestinal, specificity and non-specific chronic intestinal tract disease with tendency of recurrence because of various pathogenesiss, clinical manifestation is: contain blood, pus and mucous feces with diarrhoea, discharge, with paroxysmal abdominal pain.This product also can be used for functional chronic colitis, as irritable bowel syndrome etc.Finished product does not dissolve in the stomach of pH value 1～3 substantially, not release, discharges on a small quantity at the small intestinal of pH value 6.8; Have only preparation to reach the colon of pH value 7～8, the drug coating layer begins dissolving and discharges medicine, directly contacts with intestinal, helps the intestinal surface texture and absorbs the drug, and accelerates pathological tissues and replys normal.Preparation of the present invention has solved the defective of coloclysis administration position restriction, adopts the drug targeting administration, and easy to use, dosage is little, better effects if, determined curative effect.
The outstanding advantage of the present invention and former preparation comparison is: 1. the peaceful targeting preparation of colon has thoroughly changed inconvenient and painful that the administration of former preparation external coloclysis brings; 2. by making oral solid formulation, quality standard obviously improves, and product quality is guaranteed; 3. the targeting drug administration preparation of treatment colitis conveniently increases administration number of times, improves local drug concentration and time of contact, thereby improves curative effect.
The specific embodiment
The preparation of the peaceful targeting enteric coatel tablets of embodiment 1 colon
Get Pollen Typhae 432g, Herba Ludwigiae Prostratae 86.4g adds the water extraction 2 times of 8 times of amounts, and each 1.5 hours, merging filtrate, be concentrated into suitable density 1.02 (60 ℃), add the equivalent ethanol precipitation, filter, reclaim ethanol, continue to be concentrated into about 1.36 (65 ℃) of relative density, get extractum and weigh 68 grams, cooling, standby; Get above-mentioned extractum, add lactose 34g, drying under reduced pressure gets dry extract, waves granulation, adds Pulvis Talci 1.5 grams, mixing, and tabletting gets plain sheet, and total sheet heavily is 62.5g, and every contains crude drug 2.6g.The strange S100 40g of the preparation of coating suspension: You Te, dibutyl sebacate 4g, Pulvis Talci 10g, isopropyl alcohol 246g, acetone 300g; Preparation method: isopropyl alcohol and acetone are mixed into mixed solvent, get half solvent with the strange S100 dissolving of You Te, Pulvis Talci and dibutyl sebacate added in second half solvent, with refiner homogenize 10 minutes, pour in the strange S100 solution of You Te, in the coating process, continue to stir.
In the coating process, the sheet bed tempertaure maintains 25 ℃, and tablet can smooth and easyly flow (adding the special-shaped blank of about 500g in addition to improve the rollability of tablet).In coating solution in the process in case adhesion occurs, should suspend hydrojet, treat the tablet surface drying, tablet recovers the smooth and easy hydrojet that continues again when mobile.The packaging technique parameter: pre-thermal endurance 3 minutes, 45 ℃ of inlet temperature, 25 ℃ of sheet bed tempertaures, 10～30 rev/mins of pot rotating speeds, atomization air pressure 0.5MPa, 45 ℃ of dryings 4 hours, coating divides and gets coated tablet, coated tablet gross weight 76.5g, weightening finish 22.4%.Other gets phthalic acid hypromellose ester (HPMCP) 50g, adds the 1000g acetone solution, the same coating, 45 ℃ of dryings 4 hours, the heavy 85.8g of coated tablet, total augment weight 37.3%.
The preparation of the peaceful targeting enteric coated capsule of embodiment 2 colons
Get Pollen Typhae 432g, Herba Ludwigiae Prostratae 86.4g, the ethanol extraction of doubled amount 2 times, each 1 hour, merging filtrate filtered, and reclaims ethanol, is concentrated into about 1.37 (65 ℃) of relative density, and get extractum and weigh 54 grams, cooling, standby; Get above-mentioned extractum, with sucrose 27g, drying under reduced pressure gets dry extract, waves granulation, and mixing is adorned enteric coated capsule No. 0, and every capsules contains crude drug 2.6g.
The strange S100 180g of the preparation of coating suspension: You Te, Pulvis Talci 150g, magnesium stearate 50g, titanium dioxide 50g, polyethylene glycol 6000 25g, isopropyl alcohol/acetone (1: 1) 3000g, solids content 13.3% in the coating solution, and polymer content 5.9% in the coating solution.The strange S100 of preparation method: You Te is dissolved in an amount of solvent, with Pulvis Talci, and magnesium stearate, titanium dioxide and pigment are poured in an amount of solvent, pour Polyethylene Glycol organic solution again into, and this suspension is used about 10 minutes of homogenizer homogenize.With the strange S100 of You Te or pour in the suspension, continue in the coating process to stir.
Get capsule in the rotation coating pan (adding a certain amount of blank adjuvant capsule), dry air volume per minute 0.8m
3, 35 ℃ of inlet temperature, 22 ℃ of temperature of charge, atomizing whiff pressure 0.8MPa, 250 minutes coating time, hydrojet speed 1.8g/ branch/kg, the coating capsule is in 45 ℃ of dryings 4 hours, capsule weightening finish 9.4%.
The peaceful targeting enteric coated micropill of embodiment 3 colons
Get Pollen Typhae 2160g, Herba Ludwigiae Prostratae 432g adds ethanol extraction 2 times, reclaims ethanol, each 1 hour, concentrates and makes relative density 1.37 (60 ℃) extractum 262g; Get the peaceful extractum of colon; add lactose 131 grams, 65% ethanol is an amount of, the system soft material; pelletize in extruding round as a ball comminutor; the plate hole aperture contains about crude drug 0.13g every wet ball, extrudes rotating speed 850r/min; round as a ball rotating speed 1000r/min; 5 minutes round as a ball time, wet ball is in 45 ℃ of dryings 5.5 hours, the 235g micropill.
Bottom coating prescription: the strange L10030g of You Te, triethyl citrate 3g, Pulvis Talci 7g, isopropyl alcohol 420g, preparation method: the strange L of You Te is dissolved in an amount of solvent, and Pulvis Talci and triethyl citrate were added in an amount of solvent, with homogenizer homogenize 10 minutes, suspension is poured in the strange L100 solution of You Te, continued in the coating process to stir.The heavy 278g of bottom coated micropill, weightening finish 18.6%.Top layer coating prescription, preparation method and coating method are with embodiment 1, and the heavy 336.5g of last micropill increases weight 43.2%.Other gets phthalic acid hypromellose ester (HPMCP) 25g, adds the 500g acetone solution, with embodiment 1 coating, and 45 ℃ of dryings 4 hours, heavy at last 355g, total augment weight 51.1%.
The peaceful targeting enteric of embodiment 4 colons mix suspension grain
Get Pollen Typhae 2160g, add 6 times of ethanol extractions 2 times, reclaim ethanol, drying under reduced pressure gets thick extractum; Other gets Herba Ludwigiae Prostratae 432g, decocts with water to extract 2 times, is evaporated to suitable density 1.02～(60～65 ℃) at 1.03 o'clock, add the equivalent ethanol precipitation, filter, reclaim ethanol to thick paste, merge 275g altogether with above-mentioned thick paste, add equivalent sucrose, 65～70 ℃ of drying under reduced pressure dryings, granulate, fine powder adds ethanol and granulates in right amount again, drying gets 40～80 order granule 368g at last, and is standby.Coating method is with embodiment 1, and the heavy 517g of coated granule increases weight 40.8%.Other gets phthalic acid hypromellose ester (HPMCP) 25g, adds the 500g acetone solution, with embodiment 1 coating, and 45 ℃ of dryings 4 hours, the heavy 535g of final granule, weightening finish 45.4% is sieved, and collects 80～40 order granules, and is standby.
Other gets the cane sugar powder and the dextrin of equivalent, and it is an amount of to add 5% starch slurry, granulates, dry sugared granule; Get standby coated granule portion, 3 parts of sugaring granules mix, and promptly get the peaceful targeting enteric of colon mix suspension grain.
Although the present invention is described by specific specific embodiments, this area professional can carry out some to it and corresponding change such as improve and replenish, and these improve and additional ought to comprising within the scope of the invention.
Claims (9)
1. peaceful targeting drug administration preparation of colon and purposes, be serve as to write out a prescription in the basis with colon peaceful (enema), with the oral targeting drug administration preparation of Pollen Typhae, Herba Ludwigiae Prostratae two flavor Chinese medicines, be used for the treatment of colitis through extracting, making with the acceptable accessories coating again behind refining, the preparations shaping.
2. the peaceful targeting drug administration preparation of colon according to claim 1 is characterized in that described targeting drug administration preparation is tablet for oral administration, pill or micropill, capsule and mix suspension grain agent.
3. the peaceful targeting drug administration preparation of colon according to claim 1 is characterized in that described acceptable accessories comprises one or more at pH dissolved enteric adjuvant more than 6.5.
4. according to claim 1 and the peaceful targeting drug administration preparation of 3 described colons, it is characterized in that pH is mainly acrylic acid II resin greater than dissolved enteric adjuvant more than 6.5, acrylic acid III resin, You Teqi EudragitS100 (methacrylic acid: methyl methacrylate 30: 70), Eudragit FS 30D (methacrylic acid: acrylic acid methyl ester.: methacrylate 1: 1: 1), polyvinyl acetate phthalic acid ester (PVAP), phthalic acid hypromellose ester (HPMCP), hydroxypropyl emthylcellulose acetic acid succinate (HPMCAS), Eudragit L, Eudragit RS etc.
5. according to claim 1, the peaceful targeting drug administration preparation of 2 described colons, it is characterized in that described targeting drug administration preparation drug release rate (in isorhamnetin-3-O-new dried orange peel glucosides) in the hydrochloric acid of 0.1mol/L (2 hours) less than 10%, (2 hours) discharge total amount less than 30% in the hydrochloric acid of 0.1mol/L and pH 6.8 phosphate buffers, and (4 hours) discharge total amount greater than 70% in pH 7.8～8.0 phosphate buffers.
6. according to claim 1, the peaceful targeting drug administration preparation of 2 described colons, it is characterized in that adopting isorhamnetin-3-O-neohesperidoside and typhaneoside is that reference substance carries out the thin layer chromatography evaluation, and the result is positive.
7. the peaceful targeting drug administration preparation of colon according to claim 1, it is characterized in that described preparation is 1～40mg in the amount that is equivalent to the 5.18g crude drug and contains isorhamnetin-3-O-neohesperidoside, the amount that contains isorhamnetin-3-O-neohesperidoside by every gram crude drug is 0.19～7.7mg.
8. according to claim 1, the peaceful targeting drug administration preparation of 7 described colons, it is characterized in that described preparation is 0.5～30mg in the amount that is equivalent to the 5.18g crude drug and contains typhaneoside, the amount that contains typhaneoside by every gram crude drug is 0.1～5.8mg.
9. the purposes of the peaceful targeting drug administration preparation of colon according to claim 1 is characterized in that colon rather is prepared into oral tablet, pill, capsule and mix suspension grain agent, is used for the treatment of colitis.
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| CN102432737A (en) * | 2011-09-07 | 2012-05-02 | 张绍国 | Controlled-release enteric acrylic resin latex and preparation method thereof |
| CN106214658A (en) * | 2016-08-29 | 2016-12-14 | 北京英茂药业有限公司 | A kind of compound coating pre-mixing agent and preparation method thereof |
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- 2009-08-14 CN CN2009101682100A patent/CN101991720A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102432737A (en) * | 2011-09-07 | 2012-05-02 | 张绍国 | Controlled-release enteric acrylic resin latex and preparation method thereof |
| CN102432737B (en) * | 2011-09-07 | 2015-02-25 | 张绍国 | Controlled-release enteric acrylic resin latex and preparation method thereof |
| CN106214658A (en) * | 2016-08-29 | 2016-12-14 | 北京英茂药业有限公司 | A kind of compound coating pre-mixing agent and preparation method thereof |
| CN106214658B (en) * | 2016-08-29 | 2019-05-03 | 北京英茂药业有限公司 | A kind of compound coating pre-mixing agent and preparation method thereof |
| CN106236736A (en) * | 2016-09-26 | 2016-12-21 | 安徽省逸欣铭医药科技有限公司 | Beclomethasone enteric-coated sustained-release tablet and preparation method thereof |
| CN107929325A (en) * | 2017-11-29 | 2018-04-20 | 四川好医生攀西药业有限责任公司 | A kind of suppository containing American cockroach and preparation method thereof |
| CN111374962A (en) * | 2018-12-28 | 2020-07-07 | 内蒙古京新药业有限公司 | Enteric coated preparation of periplaneta americana extract and preparation method thereof |
| CN111374962B (en) * | 2018-12-28 | 2022-08-23 | 内蒙古京新药业有限公司 | Enteric coated preparation of periplaneta americana extract and preparation method thereof |
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Application publication date: 20110330 |