CN1199635C - Capsule and its preparing process and application - Google Patents
Capsule and its preparing process and application Download PDFInfo
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- CN1199635C CN1199635C CN 00124811 CN00124811A CN1199635C CN 1199635 C CN1199635 C CN 1199635C CN 00124811 CN00124811 CN 00124811 CN 00124811 A CN00124811 A CN 00124811A CN 1199635 C CN1199635 C CN 1199635C
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Abstract
The present invention relates to a capsule, a preparation method and an application of the capsule. The capsule comprises a layer of water insoluble polymer and a layer of intestinal soluble pH sensitive polymer, wherein the water insoluble polymer is coated at the inner wall of the shell body of the capsule, and the intestinal soluble pH sensitive polymer is coated on the outer wall of the shell body of the capsule. A medicine action system of the capsule of the present invention is characterized in that medicines is dissolved and diffused in colon for the colon to absorb at low speed; the time of the capsule which moves to the colon is fixed to prevent the system from releasing the medicines in advance. With the advantages of obvious effects of position and timing, high safety and wide application of packed medicines, the capsule can be used for controllable releasing medicines for colon medicine action systems, and especially for biological gene engineering medicines, such as human granular leukocyte colony stimulating factors, etc.
Description
The present invention relates to the packing technique of biological medicine, particularly a kind of capsule body and its production and use.
Oral colon positioning feed system (Oral colon-specific drug deliverysystem) belongs to drug delivery system (Drug delivery system, DDS) category, because its this system of specific physical chemical property can discharge drug conveying to human body colon position, and does not have release on digestive tract top.
Oral colon positioning feed system (hereinafter to be referred as the colon administration system) is mainly used in the following aspects [Chinese Pharmaceutical Journal, 1997,32:1]:
1. local therapeutic effects, colon is the frequently-occurring disease organ, common disease has constipation, crohn (Crohn ' sdisease), ulcerative colitis, colon cancer and intestinal infection disease.General medicine with the ordinary preparation form oral after, before arriving colon, will absorb or degraded at gastrointestinal.Rectally (suppository or enema) can not make medicine arrive transverse colon and ascending colon, and uses inconvenient.The colon administration system is not only easy to use, the patient easily accepts, and most of medicine discharges at the colon position and do not enter blood circulation, and medicine can be scattered in whole colon by higher concentration, treatment to intestinal tract disease is very favourable, and has reduced the whole body toxic and side effects.
2. improve the oral administration biaavailability of macromolecular drug such as protein and polypeptide.The main cause that the polypeptide drug oral administration biaavailability is low is that medicine is destroyed by polypeptidase in gastric acid and the small intestinal, also since the big water solublity height of the general molecular weight of polypeptide difficulty pass through small bowel, and content generally in small intestinal the time of staying short, have only 3 ~ 5 hours.The colonic environment is neutral, the enzyme of degraded polypeptide seldom, and content is the optimal absorption environment of polypeptide drugs oral administration in chronic (20 ~ 35 hours) that colonic stops.
3. delay pharmaceutical release time or pulsatile administration.The time that arrives colon behind the drug oral is longer, the some diseases that influenced by the division of day and night is had better therapeutical effect, as asthma, arthritis, angina pectoris etc.These diseases are through being everlasting time-division in morning outbreak or increase the weight of.
Colon locating administrated systems technology [foreign medical science pharmacy fascicle, 1999, the 26:225 of present document (treatise, patent) report; Drug Delivery, 1995,2:81; Drugs ofToday, 1999,35:537; U.S. Pat 6004583; US5866619; US5849327; US5681584; WO9528963A1] mainly concentrate on following aspect:
1. prodrug design.Colonic has the fungal component of more kind and quantity, and they produce miscellaneous enzyme, comprises azo enzyme, glycosidase, cyclodextrinase.Medicine is made the prodrug that has special function keys, and it is not absorbed in small intestinal, is subjected to the decomposition of enzyme and discharges the prototype medicine gradually after being transported to colon.The 5-aminosalicylic acid of treatment ulcerative colitis is made into sulfasalazine and Olsalazine utilizes this principle exactly.That the polypeptide class is prepared into the synthetic technology of prodrug is very difficult but find, and very likely can cause the polypeptide active forfeiture.
2. pH sensitive polymer coating.The pH value of human body alimentary canal has certain rule.Gastric pH remains on 1～3; Small intestinal is that faintly acid approaches neutrality; The colon position is neutral to alkalescence.With some pH sensitive polymer to drug particles or tablet coating after administration, polymer is stable on digestive tract top, dissolves and release gradually at the colon position.The 5-aminosalicylic acid colon administration preparation of listing adopts this method mostly at present.Acrylic resin is the coating material of using always.But the shortcoming of this method is distal small intestine and has been alkalescence, slightly descends again to colon front end pH value, and the influence of food is also very important.Therefore use the drug-supplying system conlon targeting instability of the method separately.
3. biological degradation polyalcohol coating.This method principle is with 1., the polymer with specific functional groups after the enzyme that colonic is produced by intestinal bacterium decomposes, the destroyed release medicine of coatings.But experiment finds to have only the degraded of water solublity better polymerization thing very fast, again can be but water solublity is too high in the dissolving of small intestinal position, and syntheticly have the polymer of suitable azo bond or glycoside key very uneasy, also to detect its bio-capacitivity.
4. medicine buries in biological degradation polyalcohol.This method requires 3. high to polymer, but rate of releasing drug depends on colonic peristalsis and the intensity that rubs with drug particles to a great extent.
5. time controlled release system.This method mainly utilizes the polymer imbibition promptly to burst coatings release medicine after to a certain degree.This method research early and have than forming technique, as Pulsincap, Oros, Osmet, Time-Clock etc.It begin be not for colon administration custom-designed.Because the time of delivery from the oral cavity to the colon is fixing (8 hours), so this method can be used for colon administration.The 5-aminosalicylic acid and the steroid hormone that are used for the treatment of colitis all have this type of launch.But the emptying time of stomach differs greatly, and dissimilar food is also influential to the suction of gel.Therefore adopt the product drug release time individual variation of this technology bigger separately.
6. reduction-oxidation sensitive polymer; The bioadhesion system; Ion exchange resin.The research of these aspects seldom.
Colon administration systematic research trend is with the multiple technologies combination at present, strengthens the targeting of system.This respect also has more report, and the result shows better than using single technology.When the different technologies modular design, also to take all factors into consideration pharmaceutical properties, material source, technical equipment etc.
Takaya etc. have reported pressure control colon administration capsule (Pressure-controlled colondelivery capsules, PCC) [J Controlled Release, 1998,50:111; JDrug Targeting, 1996,4:59; JControlled Release, 1998,52:119], it is inner surface coating ethyl cellulose (EC) layer at gelatine capsule, interior powder charge thing solution or suspension, and oral back gelatin layer dissolves immediately, this moment, delivery system resembled the balloon of inner filling water, and the film of balloon is exactly an ethyl cellulose.The content of upper gastro-intestinal tract contains washiness, and viscosity is little, and the ethyl cellulose ball has enough intensity and flowability, can tolerate gastrointestinal stress this moment.Because colon is to the heavily absorption of water, the viscosity of enteric cavity content increases, and enteral pressure also increases, when can not tolerating enteral pressure, the ethyl cellulose ball will break, and release medicine wherein.The key of this drug-supplying system is the thickness of ethyl cellulose, if too thin, can promptly discharge medicine in the small intestinal position; If too thick, may discharge medicine and influence drug effect at the colon middle part.Food and human body physiological state are also bigger to the off-position influence of pressure control colon administration capsule.The safety of this drug-supplying system is worth discussion.
In addition, biotech drug developed in nearest 10 years rapidly, had been used for clinical in a large number, typical case's representative has the Filgrastim, insulin, human granulocyte macrophage colony stimulus factor, calcitonin, the human growth hormone, interferon, interleukin, erythropoietin, cyclosporin, various vaccines.Most biotech drugs are polypeptide and protein, because their very difficult absorptions in gastrointestinal tract of previous reasons.Scientist studies have shown that, colon is the optimal site of polypeptide and protein oral absorption, and medicine just helps diffusion and absorption at colon preferably liquid state; But present technical merit is difficult to realize the colon administration of bio-pharmaceutical.
A kind of positioning timing effect is remarkable, the extensive capsule body of the high safety powder charge thing scope of application but the purpose of this invention is to provide.
Another object of the present invention provides a kind of preparation method of above-mentioned capsule body.
A further object of the invention provides a kind of purposes of above-mentioned capsule body.
Capsule body of the present invention is included in coated inner wall one deck water insoluble polymer of capsule housing, at outer wall coating one deck enteric pH of capsule housing sensitive polymer.
Wherein, described water insoluble polymer can comprise ethyl cellulose, zein, cellulose acetate and polyvinyl acetate.
Described enteric pH sensitive polymer is for dissolving, be difficult to dissolved substances below pH4 more than the pH5, mostly be natural or synthetic, can comprise acrylic resin, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, phthalic acid ester sugar derivatives and Lac.
Described water insoluble polymer and enteric pH sensitive polymer all can be dissolved in a kind of several frequently seen organic solvent of or arbitrary proportion, comprise ethanol, methanol, acetone, dichloromethane.
Capsule body of the present invention can also comprise that direct employing enteric coated capsule replaces common gelatine capsule, again at outer wall coating one deck enteric pH of capsule housing sensitive polymer.This enteric coated capsule can be dipped conventional capsule or gas fumes is handled in the preparation with formaldehyde, amino combined with outer gelatin molecule makes it to be dissolved in gastric juice, and can dissolve in intestinal juice.With the Algin is that the capsule that main material prepares also has enteric solubility.
Capsule body of the present invention can also be included in the sealing part envelope sealing compound.Described sealing compound can be the concentrated solution of the water insoluble polymer of inside capsule wall, or other has the material of viscosity.
The preparation method of capsule body of the present invention comprises: the water insoluble polymer that will be dissolved in the solvent pours in the body and medicated cap of capsule housing, liquid level of solution is equal with capsule body mouth or medicated cap mouth, evaporate into driedly naturally down at 2-30 ℃, promptly stay one deck clothing film at capsule body and medicated cap inner wall surface; With the body and the medicated cap closure of capsule housing, method is dipped in employing or nebulization is coated in enteric pH sensitive polymer on the capsule outer walls.
Wherein, the method for inside capsule wall coating water insoluble polymer can also adopt bores an aperture with the capsule housing bottom or the top of closure, injects the water insoluble polymer solution of higher concentration, serves as that axle does not stop rotation with two empty lines then, stays a skim until volatilizing.
The method of described capsule outer walls coating all has introduction in general pharmaceutics books, can carry out or adopt special plant equipment by hand, the method for also can referenced patent US4670287 describing.
The thickness of capsule body directly influences capsular intensity and discharges the position of medicine.Because the solubility property of different capsule materials is different with film-strength, and except that polymer, can also add plasticizer, spreading agent, antitack agent, pigment etc. in the capsule material, their physicochemical properties are changed, so the capsule film thickness that the capsule material of different prescriptions obtains has nothing in common with each other, generally in the 100-600 mu m range.
The construction features of capsule body of the present invention is: powder charge thing solution or can become the pharmaceutical composition of liquid under body temperature, capsule body coated inner wall one deck insoluble polymer, outer wall parcel one deck pH sensitive polymer in the capsule; Be not subjected to the influence in gastric juice and gastric emptying time after oral, outer pH sensitive polymer does not dissolve gradually after gastric changes, enters small intestinal, dissolving is complete substantially when arriving the colon position, at this moment capsule body shell attenuation, and be subjected to the big pressure of colonic, capsule body breaks and discharges medicine.
Adopt the characteristics of the drug-supplying system of capsule body of the present invention to be: 1. medicine can only be absorbed by the body with the solution molecule state, and the colonic amount of liquid is seldom, if medicine with the solid state administration, even discharge at colonic, can not fine dissolving and absorption; That is to say that medicine is the rate-limiting step that absorbs in intracolic dissolving and diffusion.2. two kinds of controlled-release technology combinations.It is more fixing that small intestine contents moves to the time of colon, and we adopt pH sensitive polymer " identification " system to begin to enter small intestinal, and dissolving substantially before arriving colon.The capsule material gelatin also can very fast dissolving simultaneously.Because moisture content is absorbed in a large number in the colonic contents, pressure is discharged medicine much larger than small intestinal so the insoluble film of drug-supplying system can crush.Because the existence of pH sensitive polymer and insoluble polymer duplicature is arranged at the small intestinal position, the system strength ratio is big when arriving colon, and the system that prevented shifts to an earlier date release.
Content in the capsule can be a liquid, comprises homogeneous phase and heterogeneous liquid, semisolid or solid, and the latter two should become less fluid of viscosity or solution under body temperature.
Capsule body of the present invention is applicable to the controllable release medicine of colon administration system, biological gene engineering medicine particularly is as Filgrastim, erythropoietin, insulin, calcitonin, interferon, human granulocyte macrophage colony stimulus factor, human growth hormone, interleukin, cyclosporin, various vaccines etc.
Because the colon administration system is in pharmaceutically special role, the kind of powder charge thing is also a lot of in the capsule body of the present invention, comprises anti-inflammatory drug, calm sleeping medicine, antitumor drug, antiulcerative, anthelmintic, anti-asthmatic, antimicrobial drug, cardiovascular drug, antiallergic agent, amcinonide and biotech drug etc.Specifically medicine for example: 5-amino salicylate, ibuprofen, naproxen, salicylic acid, indomethacin, piroxicam, acetaminophen, caffeine, stable, estazolam, phenobarbital, triazolam, ammonia metopon, 5-fluorouracil, methotrexate, cyclophosphamide, fluorouracil, amycin, vincristine, cisplatin, cimetidine, ranitidine, famotidine, omeprazole, lansoprazole, sucralfate, albendazole, albuterol, metronidazole, penicillin, cephalosporin, tetracycline, erythromycin, gentamycin, clindamycin, sulfadiazine, berberine, isoniazid, rifampicin, fluconazol, clotrimazole, acyclovir, levamisole, nitroglycerin, nifedipine, nimodipine, amlodipine, captopril, chlorphenamine, diphenhydramine, loratadine, cortisone, dexamethasone.
Can also be contained in health product, nourishing additive agent that the colon position discharges its special role and function in the capsule body of the present invention.For example treat constipation hemp seed oil, improve the enteric microorganism environment active bacteria formulation, can by intestinal bacteria fermentation decompose produce human body must nutrient substance, as vitamin.
Adopt capsule body of the present invention, the placement method when medicine is solution can be similar with general pharmaceutical capsules placement method, promptly directly drug solution injected in the capsule body sealing of reuse capsule cap; Will be coated with the last layer sealing compound in capsule body (medicated cap) open end edge when wherein capsule is closed spills to prevent drug solution; Sealing compound can be concentrated solution or other material with viscosity of inside capsule wall coating material.The packaging process of drug solution also can bore an aperture at the capsule cap top after the capsule closure, by aperture drug solution is injected capsule with syringe, the above-mentioned sealing compound sealing of top aperture reuse.
Some medicine is in the solution state instability, or difficulty is made aqueous solution, can they with have the material of preference temperature sensitivity (promptly below body temperature, be solid-state or semisolid, be in a liquid state more than the body temperature) or fusing point a little less than body temperature, room temperature under for solid-state material mixing or make solid dispersion.The former is as cocoa butter, the latter such as cetomacrogol 1000.If medicine is to exist with solid state, then their packaging process is identical with capsule completion method commonly used.Semi-solid medicament can pour into syringe or with reference to the method that US4497157 describes.
Further describe the present invention below in conjunction with embodiment
Embodiment one:
Ethyl cellulose is dissolved in dichloromethane: make in 5% solution in the methanol (4: 1), it is filled in No. 1 capsular body medicated cap, at room temperature volatilize naturally.Barium sulfate suspension is injected the capsule body, coat the spissated gel ethyl cellulose of a circle in capsule body opening outer rim, with capsule body medicated cap closure, capsule is put into coating pan after waiting to seal bone dry, with III acrylic resin soln spraying capsule thickness to 400 μ m.Capsule adopts 95 editions Chinese Pharmacopoeia enteric coating drug release determination methods to detect capsular release, and concrete operations and phenomenon are as follows: with the 0.1N hydrochloric acid solution is medium, and capsule was placed 2 hours in the instrument molten, and outward appearance does not have any variation; Take out the back and place in the phosphate buffer of pH7.0, outer capsule layer begins dissolving (comprising acrylate resin layer and gelatin layer), and outer capsule layer is dissolved fully after 3 hours, only stays the ethyl cellulose layer.
Above-mentioned preparation colon site-specific drug is done " barium meal " experiment on healthy human body, prove that this capsule does not break at harmonization of the stomach small intestinal position and discharges medicine, begins to discharge content at the caecum place, discharges substantially at transverse colon front end medicine to finish.
Embodiment two:
Capsule material and process are with embodiment one.Get in the Polyethylene Glycol (PEG) 1000 (containing 0.5% Tween 80) that 100 order 5-aminosalicylic acids (5-ASA) are suspended in heating and melting, put to room temperature (25 ℃), be fills up to capsule No. 0 after will becoming solid 5-ADA-PEG solid mixture to pulverize, make every capsules contain 250 milligrams of 5-ASA.
Above-mentioned capsule delivers medicine to 12 hours Canis familiaris L. of fasting (not prohibiting water) early morning, begins feed after 6 hours.1,2,3,4,5,6,7,8,9,10, extracted 1 milliliter of blood in 12 hours, obtain blood plasma after centrifugal, measure 5-ADA concentration in the blood plasma according to the analytical method of design in advance, when drawing medicine curve as shown in Figure 1, simultaneously and commercially available 5-ADA enteric coated tablet compare.
Fig. 1 curve is blood drug level and a time relation after the different preparation administrations of 5-ADA.---represent conventional capsule, the capsule of capsule body of the present invention is adopted in a representative.
Deliver medicine to Canis familiaris L. with embodiment two, measure leucocyte level (BTL), and contrast with conventional capsule, the result as shown in Figure 2;
Fig. 2 curve is leucocyte level and a time relation after the different preparation administrations of G-CSF.---represent conventional capsule, the capsule of capsule body of the present invention is adopted in a representative.
Embodiment three:
Choose No. 0 capsule and be dissolved in dichloromethane: the ethyl cellulose solution of making in the methanol (4: 1) in 5% solution adds respectively in capsule body and the medicated cap, volatilize organic solvent at normal temperatures, then by spissated ethyl cellulose glue with medicated cap body closure, at the crown end with No. 8 pin drill one apertures, inject granulocyte colony-stimulating factor (G-CSF) solution of about 1 milliliter of 300 μ g/ml with No. 7 syringe needles, topped hole is sealed with concentrated ethyl cellulose rope glue.With capsule manual capsule and dry of dipping in the 5%III acrylic resin soln, get final capsule.
Claims (6)
1, a kind of capsule body is characterized in that being included in coated inner wall one deck water insoluble polymer of common gelatine capsule housing, at outer wall coating one deck enteric PH of capsule housing sensitive polymer;
Wherein, described water insoluble polymer comprises ethyl cellulose, zein, cellulose acetate and polyvinyl acetate;
Described enteric PH sensitive polymer comprises acrylic resin, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, phthalic acid ester sugar derivatives and Lac.
2, capsule body as claimed in claim 1 is characterized in that described water insoluble polymer and enteric PH sensitive polymer all are dissolved in several solvents that comprise a kind of or arbitrary proportion in ethanol, methanol, acetone, the dichloromethane.
3, capsule body as claimed in claim 1 or 2, it is characterized in that also being included in the sealing part envelope has sealing compound; Described sealing compound adopts the concentrated solution of the water insoluble polymer of inside capsule wall.
4, a kind of preparation method as the described capsule body of claim 1-3, it is characterized in that comprising: the water insoluble polymer that will be dissolved in the solvent pours in the body and medicated cap of capsule housing, liquid level of solution is equal with capsule body mouth or medicated cap mouth, evaporate into driedly naturally down at 2-30 ℃, promptly stay one deck clothing film at capsule body and medicated cap inner wall surface; With the body and the medicated cap closure of capsule housing, method is dipped in employing or nebulization is coated in enteric PH sensitive polymer on the capsule outer walls.
5, preparation method as claimed in claim 4, the method employing that it is characterized in that inside capsule wall coating water insoluble polymer is bored an aperture with the capsule housing bottom or the top of closure, inject the water insoluble polymer solution of higher concentration, serve as that axle does not stop rotation with two hole lines then, stay a skim until volatilizing.
6, preparation method as claimed in claim 4, the thickness that it is characterized in that capsule body is in the 100-600 mu m range.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 00124811 CN1199635C (en) | 2000-09-15 | 2000-09-15 | Capsule and its preparing process and application |
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| CN 00124811 CN1199635C (en) | 2000-09-15 | 2000-09-15 | Capsule and its preparing process and application |
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| CN1343488A CN1343488A (en) | 2002-04-10 |
| CN1199635C true CN1199635C (en) | 2005-05-04 |
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| CN 00124811 Expired - Fee Related CN1199635C (en) | 2000-09-15 | 2000-09-15 | Capsule and its preparing process and application |
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Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1322865C (en) * | 2002-11-14 | 2007-06-27 | 北京东方凯恩医药科技有限公司 | Oral colon-positioned medicine composition for curing bacillary dysentery |
| CN1456148A (en) * | 2003-03-26 | 2003-11-19 | 北京东方凯恩医药科技有限公司 | Use of enlerogastric dynamic medicine in preparation of colonic orientation medicinal composition |
| CN103394093B (en) * | 2013-08-11 | 2015-02-18 | 重庆衡生药用胶囊有限责任公司 | Carragheenan and potassium chloride gelled hydroxypropyl methylcellulose enteric-coated hollow capsule |
| CN103417979B (en) * | 2013-08-11 | 2015-02-18 | 重庆衡生药用胶囊有限责任公司 | Hypromellose enteric empty capsule gelated by gellan gum and potassium chloride |
| CN103394092B (en) * | 2013-08-11 | 2015-02-18 | 重庆衡生药用胶囊有限责任公司 | Gellan gum and calcium chloride gelled hydroxypropyl methylcellulose enteric-coated hollow capsule |
| CN103432096B (en) * | 2013-08-11 | 2014-12-24 | 重庆衡生药用胶囊有限责任公司 | Hydroxypropyl methylcellulose enteric empty capsule jellied by carrageenan and potassium citrate |
| CN103417978B (en) * | 2013-08-11 | 2015-02-18 | 重庆衡生药用胶囊有限责任公司 | Hypromellose enteric empty capsule gelated by gellan gum and potassium citrate |
| CN103549162B (en) * | 2013-11-02 | 2014-10-08 | 成都雪樱动物科技实业有限公司 | Novel feed additive and preparation method thereof |
| CN104146982A (en) * | 2014-07-29 | 2014-11-19 | 浙江益立胶囊有限公司 | Hollow enteric capsule |
| CN104922088A (en) * | 2015-06-09 | 2015-09-23 | 绍兴康可胶囊有限公司 | Formula of hard empty capsule encapsulant |
| CN107157949B (en) * | 2017-06-09 | 2021-01-15 | 厦门普罗康客科技有限公司 | Method for sealing inner part of hard capsule and application thereof |
| CN108143724A (en) * | 2018-03-05 | 2018-06-12 | 上海祺宇生物科技有限公司 | A kind of high oxygen-impermeable plant hollow capsule and preparation method thereof |
| CN108261407A (en) * | 2018-03-05 | 2018-07-10 | 上海祺宇生物科技有限公司 | A kind of hypromellose Capsules for being used to suck medicament |
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