CN103520226B - A kind of pH dependent form conlon targeting hard capsule - Google Patents
A kind of pH dependent form conlon targeting hard capsule Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical preparations, relate to a kind of digestive tract medication preparation, particularly a kind of pH dependent form colon site-specific drug.A kind of pH dependent form conlon targeting hard capsule, comprise hard capsule and the coating membrane thereof of injection of medicine composition, the described coating solution for the formation of coating membrane and consumption thereof are 1 ~ N times: the coating material 2g of following prescription, described coating material is, Eudragit Ⅲ, Eudragit RL100 and/or Eudragit RS 100; Described Eudragit RL100 and/or Eudragit RS 100 accounts for 18 ~ 25% of coating material gross weight; Solvent 92 ~ 98ml also containing plasticizer 2 ~ 3ml, coating material.Hard capsule outermost layer of the present invention is surrounded by macromolecule coating membrane, ensures that the medicine injected is not revealed, and can reach the requirement of colon positioning release.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of digestive tract medication preparation, particularly a kind of pH dependent form colon site-specific drug.
Background technology
Colonic diseases (as colitis, colon cancer etc.) there is no specific medicament at present, and its reason is that drug oral or injection rear arrival colon site concentration are very low.Its bioavailability is low, and main cause is that such medicine has been absorbed or decomposed before entering lesions position colon.Oral colon-specific drug release system (Oral colon-specific drug delivery system, OCDDS) refer to by suitable method, medicine is made to avoid, in Stomach duodenum, jejunum and the release of ileum front end, discharging and a kind of drug-supplying system of performance local or whole body therapeutic effect after being directly transported to human body ileocecus.Colon locating administrated advantage has: improve macromolecular drug as the bioavailability after protein, polypeptide oral administration; Colon drug delivery can some special diseases of locating therapy, as colonic ulcer, Ke Luoshi disease (segmental colon disease), colon cancer, some infectious disease and constipation etc.; After oral colon-target medicine, need certain movement time to arrive colon, can be used for circadian disease.Therefore, the clinical meaning that OCDDS is important has become the Hot Contents of current oral positioning release medicine research.Colon-site specific drug delivery system can be divided into 5 kinds according to the mechanism of action: 1) pressure control medicine-releasing system; 2) pH dependent form medicine-releasing system; 3) time lag type medicine-releasing system; 4) Bacterialtriggered medicine-releasing system or enzyme controlled release durg delivery system; 5) compound medicine-releasing system.
Wherein, pH dependent form medicine-releasing system is according to increasing gradually from mouth to anus pH, and the pH of colon is the highest in whole intestinal segment, the knot enteric material dissolved under using corresponding pH condition, makes preparation just start to discharge medicine within the scope of the pH of colon.At present, domestic and international market has occurred the preparation of many principle design according to this, research comparatively successfully product has 5-aminosalicylic acid conlon targeting sheet, sulfasalazine enteric coatel tablets, budesonide colon-specific pellets.
Oleum Fructus Bruceae (
brucea javanicaseed oil) fatty oil that obtains after Petroleum ether extraction for the dry mature fruit of quassia Fructus Bruceae.Oleum Fructus Bruceae is yellow supernatant liquid, and gas is special, bitter in the mouth, and form primarily of Palmic acid, stearic acid, oleic acid, linoleic acid plus linolenic acid, its mid-oleic reaches 63. 3%.Pharmacological research shows, Oleum Fructus Bruceae has anti-tumor activity widely, as gastric cancer, the esophageal carcinoma, primary hepatocarcinoma, colorectal cancer, cancer of pancreas etc., can suppress multiple cancer cell multiplication, and have the effects such as hypertension and hyperlipemia.
In current existing 'Brucea fruit oil ', oral solid formulation only has oleum fructus bruceae soft capsule (such as colon targeting drug delivery soft capsule disclosed in Chinese invention patent ZL200710031234.2).But the making of soft capsule is more complicated, rubber process and content wrap up and must carry out simultaneously, and compared with hard capsule, the moisture of soft capsule and oxygen permeability are obviously higher, be unfavorable for the storage of medicine, and the easy dehydration of rubber are aging, cause product disintegrate defective.Liquid-tilled hard capsule is as newer a kind of preparation technique, and its advantage also has stability to improve except preparation is relatively convenient, improves bioavailability or reaches slow release object, improves the compliance etc. of patient.Liquid-tilled hard capsule preparation technology is simple, and occupation area of equipment is less, and eliminate dust, loading contrast with traditional powder packing and soft capsule has many advantages.The common soft capsule implant such as oily liquid, solution, suspension or pastel all can fill in hard capsule, but easily there is Seepage, can be solved by the method for sealing.Sealing effectively can shield bad smell and oxygen infiltration, greatly reduces the probability of leakage.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of pH dependent form conlon targeting hard capsule, and this hard capsule outermost layer is surrounded by macromolecule coating membrane, ensures that the medicine injected is not revealed, and can reach the requirement of colon positioning release.
Technical problem to be solved by this invention is achieved by the following technical programs:
A kind of pH dependent form conlon targeting hard capsule, comprise hard capsule and the coating membrane thereof of injection of medicine composition, the described coating solution for the formation of coating membrane and consumption are 1 ~ N of following prescription doubly (concrete multiple needs the quantity of the hard capsule of coating as required to determine, and quantity at most multiple increases):
Coating material 1.5 ~ 2.5g, described coating material is,
Eudragit Ⅲ,
Eudragit RL100 and/or Eudragit RS 100;
Described Eudragit RL100 and/or Eudragit RS 100 accounts for 18 ~ 25% of coating material gross weight;
Solvent 92 ~ 98ml also containing plasticizer 2 ~ 3ml, coating material.
Described coating membrane weight accounts for 3.5 ~ 4.5% of the hard capsule weight of the injection of medicine composition before non-coating.
Described plasticizer is the mixture of at least one in diethyl phthalate or triethyl citrate and Oleum Ricini.
Described solvent is the mixture of dehydrated alcohol and acetone.
When described coating material selection Eudragit Ⅲ, Eudragit RL100, Eudragit RS 100 3 kinds of components, the weight ratio of Eudragit RL100 and Eudragit RS 100 is 1:1.
As the preferred version of technique scheme, the described coating solution for the formation of coating membrane and consumption thereof are 1 ~ N times of following prescription:
Eudragit Ⅲ 1.6g,
Eudragit RL100 0.2g，
Eudragit RS100 0.2g，
Diethyl phthalate or triethyl citrate 1.5ml,
Oleum Ricini 1ml,
Dehydrated alcohol 47.5ml,
Acetone 47.5ml,
Described coating membrane weight accounts for 3.8% of the hard capsule weight of the injection of medicine composition before non-coating.
The ingredient of described injection hard capsule is Oleum Fructus Bruceae.
The present invention has following beneficial effect:
The present invention compares existing Oleum Fructus Bruceae colon targeting drug delivery soft capsule, and processing technology is simpler, and rubber not easily dehydration is aging, and stability improves, and improves bioavailability or reaches slow release object, improves the compliance of patient.
Inventor learns through overtesting, only has Eudragit Ⅲ as the prescription of coating material in prescription, and when coating weight gain is 3.5%, in PH6.8,55min has oil release, and visible solution is muddy, and 3h disintegrate is complete.Increase coating weight gain to 5.0%, the time lengthening of disintegrate, but still in PH6.8 buffer solution the visible solution of 59min muddy, only surplus a small amount of capsule shells after 3h, the complete disintegrate of 32min in PH7.8 buffer solution.Therefore two kinds of coated capsule all can not reach the requirement of colon positioning release.And the present invention is on the basis of Eudragit Ⅲ as major coat material, adds the Eudragit RL100(RL of osmosis type) and Eudragit RS 100 (RS), and through formulation optimization, reach colon positioning release requirement.
The percent that the present invention mixes with 1:1 with the percent of the percent of coating weight gain, RL, RS and RL and RS carries out single factor exploration, understand the change of these factors to the impact of the disintegration time of coated capsule, and pass through orthogonal test, determine best coating fluid prescription, the hard capsule using this coating solution to carry out coating to obtain, in the buffer solution of pH7.8, the average disintegration time needed is 52min, is better than all results of orthogonal test.
Detailed description of the invention
Self-control Oleum Fructus Bruceae hard capsule, only puts into Oleum Fructus Bruceae in hard capsule and there will be leakage of oil very soon, therefore will seal after hard capsule charge of oil.According to the record (Chinese invention patent ZL200710031234.2) of prior art, and through the proof of preliminary experiment, Eudragit Ⅲ has disintegrate in the buffer solution of PH6.8, in the buffer solution of PH7.8, very fast disintegrate is complete, but seal using Eudragit Ⅲ as coating material, hard capsule is intact oil-proof, and therefore the major coat material of coating solution of the present invention still adopts Eudragit Ⅲ.Eudragit Ⅲ is the copolymer reacted with the ratio of 1:2 by methacrylic acid and methyl methacrylate.In prescription, Eudragit Ⅲ originates from Lianyun Harbour Wan Tai medical material company limited.
Eudragit RL100(is hereinafter referred to as RL) and Eudragit RS 100 (hereinafter referred to as RS) be the acrylic resin (originating from German Degussa company) of two kinds of osmosis types.
Oleum Fructus Bruceae pH dependent form conlon targeting hard capsule preparation method is:
Oleum Fructus Bruceae is loaded in hard capsule, each dress 0.6ml, lock capsule.In coating pan, carry out coating by coating fluid prescription of the present invention after lock capsule, ventilate under room temperature evaporating solvent, and the hard capsule after coating carries out aging more than 12 hours at the baking oven of 40 DEG C, then carries out slaking test.Require that coating membrane is even, smooth.
Ifs vitro disintegration is tested: according to the regulation in 2010 editions Chinese Pharmacopoeias, coating hard capsule after aging is placed in Intelligent disintegration tester, allow capsule slaking test 2 hours in the hydrochloric acid solution of 9 → 1000 respectively, slaking test 3 hours in PH6.8 phosphate buffer solution, disintegrate 1 hour in PH7.8 phosphate buffer solution.Require the not disintegrates or do not discharge in hydrochloric acid solution and PH6.8 phosphate buffer solution of the hard capsule after coating, and in PH7.8 phosphate buffer solution in 1 hour disintegrate completely or release completely.
1. coating fluid prescription optimization experiment:
table
1
this experiment
9
individual prescription
| Prescription is numbered | |||||||||
| Eudragit Ⅲ (g) | 1.80 | 1.64 | 1.50 | 1.80 | 1.64 | 1.50 | 1.80 | 1.64 | 1.50 |
| Eudragit RL100（g） | 0.2 | 0.36 | 0.50 | / | / | / | 0.1 | 0.18 | 0.25 |
| Eudragit RS100（g） | / | / | / | 0.2 | 0.36 | 0.50 | 0.1 | 0.18 | 0.25 |
| Diethyl phthalate (ml) | 1.5 | 1.5 | 1.5 | 1.5 | 1.5 | 1.5 | 1.5 | 1.5 | 1.5 |
| Oleum Ricini (ml) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| Dehydrated alcohol (ml) | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 |
| Acetone (ml) | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 | 47.5 |
The ifs vitro disintegration situation of the Oleum Fructus Bruceae pH dependent form conlon targeting hard capsule after each coating fluid prescription coating of table 1 is in table 2:
table
2
ifs vitro disintegration experimental result
| Prescription is numbered | |||||||||
| PH1 | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate | 2h not disintegrate |
| PH6.8 | 109min has disintegrate | 3h not disintegrate | 3h not disintegrate | 82min has disintegrate | 3h not disintegrate | 3h not disintegrate | 136min has and collapses | 3h not disintegrate | 3h not disintegrate |
| PH7.8 | 50min collapses entirely | 64min collapses entirely | 57min collapses entirely | 36min collapses entirely | 52min collapses entirely | 58min collapses entirely | 45min collapses entirely | 56min collapses entirely | 67min collapses entirely |
| Remarks | Film is intact | Pericarpium Citri Reticulatae | Film is intact | Film is intact | Film is intact | Film is intact | Film is intact | Film is intact | Film is intact |
As shown in Table 2, the coating material of prescription 1-3 is Eudragit Ⅲ and Eudragit RL100, wherein, the percentage by weight of Eudragit RL100 accounts for 10%, 18%, 25% of coating material respectively, the ifs vitro disintegration result display of prescription 1-3, can not reach conlon targeting requirement when the ratio of Eudragit RL100 is 10%, may be that 18% and 25% reaches conlon targeting requirement substantially because the amount of Eudragit Ⅲ is comparatively large in prescription.
The coating material of prescription 4-6 is Eudragit Ⅲ and Eudragit RS100, the percentage by weight of Eudragit RS100 accounts for 10%, 18%, 25% of coating material respectively, the ifs vitro disintegration result display of prescription 4-6, conlon targeting requirement can not be reached when the ratio of Eudragit RS100 is 10%, may be that 18% and 25% reaches conlon targeting requirement substantially because the amount of Eudragit Ⅲ is comparatively large in prescription.
The coating material of prescription 7-9 is Eudragit Ⅲ, Eudragit RL100 and Eudragit RS100 tri-kinds, the percentage by weight of the mixture of Eudragit RL100 and Eudragit RS100 accounts for 10%, 18%, 25% of coating material respectively, and both weight ratios are 1:1.The ifs vitro disintegration result display of prescription 7-9, the ratio that Eudragit RL100 mixes with Eudragit RS100 can not reach conlon targeting requirement 10% time.The coated capsule of 18% and 25% can reach requirement substantially.
2. coating weight gain is tested the impact of disintegration:
Coating weight gain is important influence factor in film coating.Coating weight gain affects the thickness of coatings, large protecting medicine of increasing weight, but disintegration time is long, and the little disintegration time that increases weight is short, but not good to the protected effect of medicine, easily in pH6.8 buffer solution or even in hydrochloric acid solution, occurs disintegrate.Three levels of selected coating weight gain are: 2%; 4%; 6%.
The coating fluid prescription of coating weight gain experiment: Eudragit Ⅲ 1.6g; Eudragit RL100 0.6g; Diethyl phthalate 1.5ml; Oleum Ricini 1ml; Dehydrated alcohol 47.5ml, acetone 47.5ml.It the results are shown in following table 1:
table
3
coating weight gain is on the impact of disintegrate situation
| Level | PH1 | PH6.8 | PH7.8 | Remarks |
| 2% | 45min has disintegrate | There is disintegrate | 22min | Film is intact |
| 4% | 2h not disintegrate | 3h not disintegrate | 60min | Film is intact |
| 6% | 2h not disintegrate | 3h not disintegrate | 102min | Film is intact |
Result shows, and the coating membrane 2% time that increases weight can not protect capsule substantially, may be because coating membrane is imperfect or due to the osmosis of the Eudragit RL100 in prescription; Weightening finish more than 4% can reach requirement substantially, but disintegration time is partially long.
3. orthogonal experiment screening:
According to monofactorial experimental result, coating weight gain should be greater than 2%, and the amount of RL and RS added should be greater than 10%.Determine investigation factor A(coating weight gain), factor B(RL and RS accounts for the percent of coating material after mixing) and the mixed proportion of factor C(RL and RS) these 3 mixed proportions.Three factors are divided into 3 levels separately, list in table 4.
table
4
factor level table
Adopt L9 (3
3) orthogonal array, according to L9 (3
3) use table, each level of each factor of correspondence is inserted in table, testing program and the results are shown in Table 5.
table
5 L9 (3
3
)
positive quadraturing design test scheme and result
From result, being coating weight gain to the factor had the greatest impact disintegration, is secondly the ratio of RL and RS, is finally the ratio that RL and RS mixture accounts for coating material.The prescription that in orthogonal experiment, result is best is A
3b
1c
3.According to the requirement of disintegrate experiment, choose disintegration time shorter for excellent scheme, i.e. A
3b
3c
1, this scheme ratio that to be ratio that coating weight gain 3.8%, RL and RS mixing accounts for coating material be between 20%, RL and RS is 1:1.
4. the checking of optimum coating prescription
With this prescription (A
3b
3c
1) carrying out three coatings, the coating hard capsule obtained carries out disintegrate experiment respectively, obtains result as table 6:
table
6
prescription is verified
| PH1 | PH6.8 | PH7.8（min） | Remarks | |
| 1 | 2h is without disintegrate | 3h is without disintegrate | 50 | Film is intact |
| 2 | 2h is without disintegrate | 3h is without disintegrate | 52 | Film is intact |
| 3 | 2h is without disintegrate | 3h is without disintegrate | 54 | Film is intact |
The disintegration time that this optimum prescription capsule on average needs is 52min, reaches conlon targeting requirement and is better than all results of orthogonal experiment.
Claims (7)
1. a pH dependent form conlon targeting hard capsule, comprises hard capsule and the coating membrane thereof of injection of medicine composition, it is characterized in that, for the formation of the coating solution of described coating membrane and consumption thereof be 1 ~ N of following prescription doubly:
Coating material 2g, described coating material is,
Eudragit Ⅲ,
Eudragit RL100 and/or Eudragit RS 100;
Described Eudragit RL100 and/or Eudragit RS 100 accounts for 18 ~ 25% of coating material gross weight;
Solvent 92 ~ 98ml also containing plasticizer 2 ~ 3ml, coating material.
2. pH dependent form conlon targeting hard capsule according to claim 1, is characterized in that: described coating membrane weight accounts for 3.5 ~ 4.5% of the hard capsule weight of the injection of medicine composition before non-coating.
3. pH dependent form conlon targeting hard capsule according to claim 1, is characterized in that: described plasticizer is the mixture of at least one in diethyl phthalate or triethyl citrate and Oleum Ricini.
4. pH dependent form conlon targeting hard capsule according to claim 1, is characterized in that: described solvent is the mixture of dehydrated alcohol and acetone.
5. the pH dependent form conlon targeting hard capsule according to claim 1 ~ 4 any one, it is characterized in that: when described coating material selection Eudragit Ⅲ, Eudragit RL100, Eudragit RS 100 3 kinds of components, the weight ratio of Eudragit RL100 and Eudragit RS 100 is 1:1.
6. pH dependent form conlon targeting hard capsule according to claim 1, is characterized in that: the ingredient of described injection hard capsule is Oleum Fructus Bruceae.
7. a pH dependent form conlon targeting hard capsule, comprises hard capsule and the coating membrane thereof of injection of medicine composition, it is characterized in that, for the formation of the coating solution of described coating membrane and consumption thereof be 1 ~ N of following prescription doubly:
Eudragit Ⅲ 1.6g,
Eudragit RL100 0.2g，
Eudragit RS100 0.2g，
Diethyl phthalate or triethyl citrate 1.5ml,
Oleum Ricini 1ml,
Dehydrated alcohol 47.5ml,
Acetone 47.5ml.
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| CN105287427B (en) * | 2015-10-20 | 2017-04-19 | 沈阳红旗制药有限公司 | Semi-solid rifampicin capsule and preparation method thereof |
| CN112022828A (en) * | 2019-06-04 | 2020-12-04 | 绍兴康可胶囊有限公司 | Colon capsule and its preparing process |
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