CN102204894A - Iodized lecithin enteric capsule preparation and preparation method thereof - Google Patents
Iodized lecithin enteric capsule preparation and preparation method thereof Download PDFInfo
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- CN102204894A CN102204894A CN 201110124914 CN201110124914A CN102204894A CN 102204894 A CN102204894 A CN 102204894A CN 201110124914 CN201110124914 CN 201110124914 CN 201110124914 A CN201110124914 A CN 201110124914A CN 102204894 A CN102204894 A CN 102204894A
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Abstract
The invention relates to an iodized lecithin enteric capsule preparation and a preparation method thereof. The iodized lecithin enteric capsule preparation comprises the main components of 1) iodized lecithin, 2) a disintegrant, 3) an enteric solid dispersion carrier, 4) an excipient, and 5) an enteric capsule which prevents the iodized lecithin from being decomposed and damaged by gastric juice. The iodized lecithin enteric capsule preparation is wrapped by the enteric capsule, so the damage of the gastric juice to the iodized lecithin is avoided; the stimulation of a medicament to gastric mucosa is avoided; the absorption of the medicament through intestinal mucosa is enhanced; the blood concentration is improved; and the medicament effect is enhanced.
Description
Technical field
The present invention relates to a kind of active component is medicament composition capsule preparation of lecithin chelated iodine and preparation method thereof.
Background technology
Decline gradually and some disease of function of human body cause the disorder of body metabolism with advancing age, make retina that a series of pathological changes take place, cause vitreous hemorrhage, muddiness, central retinal vein occlusion etc., severe patient can cause losing one's sight, along with aging society is stepped in the many areas of China gradually, prevent and to treat this class disease particularly important.
Iodine has been used to treat nervous function disease, arteriosclerosis, asthma and thyroid disease etc. in the internal medicine field.In addition, iodine is used as antiinflammatory and antitypy medicine for a long time in field of ophthalmology, especially in retinal diseases, demonstrates goodish clinical effectiveness.Yet the medicine form of most iodide such as potassium iodide, sodium iodide and compound iodine solution all is not suitable for taking, and the untoward reaction of these iodine preparation, mainly is very important to the infringement of stomach.Select suitable carrier to provide the required iodine of treatment pathological changes necessary.
The lecithin chelated iodine utilization easily absorbs, avirulent lecithin is as stable iodophor, makes iodine exist with combining form, thus do not resemble the free-iodine volatile owing to combine with lecithin, easier enter in the body and playing a role.Therefore, lecithin chelated iodine can be brought into play the effect of iodine better and avoid other Operand instability, the GI irritation significant side effects.
Lecithin chelated iodine is brown yellow granule or powder, and special odor is arranged, and is soluble in chloroform, carbon tetrachloride and the benzene; be insoluble to ether and ethanol, in water, form colloid solution, amount of iodine 6.5～7.0%; stable in non-polar solven, but in polar solvent, decompose gradually and discharge iodine.The chemistry of lecithin chelated iodine is by name: two α-(β)-and phospholipid base choline diiodo-, structural formula is:
Molecular formula: C
88H
168O
16N
2P
2I
2
Molecular weight: 1826.06
Lecithin chelated iodine is mainly used in vasospasm retinitis, hemorrhagic retinitis, vitreous hemorrhage, vitreous opacity, central vein closure retinitis and infantile asthma, bronchitis, goiter due to iodine deficiency, iodine deficiency hypothyroidism clinically.
The active substance iodine of lecithin chelated iodine is absorbed into blood with the lecithin of easy absorption easily, but it is subject to stomach acids destroy, and is unstable in gastric juice, and it has special abnormal smells from the patient, makes the patient take inconvenience." number of patent application is 200610012274.8 Chinese patent " discloses lecithin chelated iodine soft capsule and preparation method thereof.It has covered the special odor of lecithin chelated iodine, but can not effectively avoid medicine to be subjected to the destruction of gastric acid, the lecithin chelated iodine enteric coated capsule preparation of the present invention's preparation can avoid medicine to be subjected to the destruction of gastric acid, avoided the zest of medicine to gastric mucosa, strengthened the absorption of medicine by intestinal mucosa, improve blood drug level, strengthened drug effect.Cover the special odor of lecithin chelated iodine simultaneously, make things convenient for the patient to take.
Summary of the invention:
The present invention aims to provide a kind of stable, effective in vivo lecithin chelated iodine enteric with capsule preparation, thereby makes it that good bioavailability and curative effect be arranged.
Lecithin chelated iodine enteric coated capsule preparation of the present invention comprises lecithin chelated iodine, disintegrating agent, and enteric solubility solid dispersion carrier, excipient and conduct protection lecithin chelated iodine are not decomposed and destructive enteric coated capsule by gastric juice.
Above-mentioned disintegrating agent is selected from Sodium Hydroxymethyl Stalcs, crosslinked Sodium Hydroxymethyl Stalcs, low substituent group hydroxypropyl cellulose, one or more in polyvinylpolypyrrolidone and the starch.
Above-mentioned enteric solubility solid dispersion carrier is selected from one or more in Hydroxypropyl Methylcellulose Phathalate, polyacrylic resin L100-55, polyacrylic resin L30D-55, polyacrylic resin L100 and the cellulose acetate-phthalate.
Above-mentioned excipient is selected from one or more in filler, binding agent and the lubricant.
Above-mentioned filler is selected from one or more in lactose, microcrystalline Cellulose, starch, pregelatinized Starch, dextrin, mannitol, glucose, sorbitol, the sucrose.
Described binding agent is selected from one or more in polyvidone, hydroxypropyl emthylcellulose, ethyl cellulose and the methylcellulose.
Above-mentioned lubricant is selected from one or more in micropowder silica gel, hydrogenated vegetable oil, Pulvis Talci, calcium stearate, magnesium stearate, zinc stearate and the stearic acid.
The preferred constituent of the present invention (by weight) is: 1 part of lecithin chelated iodine, 200～500 parts in enteric solubility solid dispersion carrier, 30～100 parts of disintegrating agents, 600～1500 parts of excipient.
The further preferred constituent (by weight) of the present invention is: 1 part of lecithin chelated iodine, 400 parts of cellulose acetate-phthalates, 40 parts of Sodium Hydroxymethyl Stalcses, 800 parts of lactose, 550 parts of microcrystalline Cellulose.
The present invention also comprises a kind of preparation method of lecithin chelated iodine enteric coated capsule preparation, comprises following steps:
A. take by weighing lecithin chelated iodine, solid dispersion carrier, the disintegrating agent of recipe quantity, join stirring and evenly mixing in the ethanol water of debita spissitudo, evacuation rotary evaporation solvent, preparation solid dispersion.
B. with prepared solid dispersion drying, sieve, conventional method prepares granule or directly incapsulates with pharmaceutics auxiliary materials and mixing commonly used, must the lecithin chelated iodine enteric coated capsule.
Below data further specify beneficial effect of the present invention by experiment:
One, stability study
1, produces checking
By " Good Manufacturing Practice and Quality Control of Drug " requirement this product embodiment 1 has been carried out three batches of production technology checkings, the checking result shows this product prescription rationally, and preparation technology is feasible, can guarantee product quality.The results are shown in Table 1.
Table 1 is produced the checking result
2, accelerated test
Get three batches of production-scale samples of pilot scale of this product, all adopt the listing packing.Under 40 ℃ ± 2 ℃ of temperature, relative humidity RH75% ± 5% accelerated test condition, placed 6 months, respectively at January, February, March, sampling in June, investigate the situation of change of the important indicators such as character, disintegration, content of test specimen by the assay method of this product quality standard, and every index of the result that will investigate and 0 month compares.The result shows that this product was placed 6 months under above-mentioned accelerated test condition, its every important quality index and relatively do not have significant change in 0 month, and prompting this product quality is basicly stable.
3, long term test
Get three batches of production-scale samples of pilot scale of this product, all adopt the listing packing.Place the chamber that keeps sample of 25 ℃ ± 2 ℃ of temperature, relative humidity RH 60% ± 10%, respectively at March, June, JIUYUE, December, sampling in the 18th month, the 24th month, the 36th month, the assay method of pressing this product quality standard is investigated the situation of change of important indicators such as the character of test specimen, disintegration, content, long term test 24th month with increase the inspection of microbial limit the 36th the end of month, and every index of the result that will investigate and 0 month compares.The result shows that this product was placed 36 months under above-mentioned long term test condition, its every important quality index and relatively do not have significant change in 0 month, and prompting this product quality is basicly stable.
4, conclusion (of pressure testing)
Result of the test shows, this product adopts simulation listing packing, under 40 ℃ ± 2 ℃ of temperature, relative humidity RH75% ± 5% accelerated test condition, placed 6 months, under 25 ℃ ± 2 ℃ of temperature, relative humidity RH 60% ± 10% long term test condition, placed 36 months, every important quality index and relatively do not have significant change in 0 month shows that this product quality is basicly stable.
The effect duration of tentative this product is 36 months (3 years).
Two, pharmaceutical research
According to the pharmaceutical research to this product, the result is as follows:
(1) in rabbit and the adult male body, lecithin chelated iodine is absorbed into that the form with inorganic iodine works behind the blood.Then in conjunction with human thyroid and to owing to lack goiter patient that iodine causes or child's hypothyroidism works.
(2) lecithin chelated iodine can promote the amphiblestroid Tissue respiration of rabbit, promotes amphiblestroid metabolism.
(3) lecithin chelated iodine can quicken the minor fluctuations of ERG (electroretinogram) rhythm and pace of moving things sample of adult white rabbit.This effect is the most obvious when to the iodine preparation amount being 18 μ g/kg/ days, and treats effect in three months continuously and strengthen.
(4) in anaphylaxis uvea (tunica uvea) inflammation or the uveitic two kinds of experiments of fulminant, tangible antiinflammatory action and the effect that improves ERG are arranged all to rabbit.
(5) Cavia porcellus, mice and rat, this product can strengthen the effect of adrenergic relaxing smooth muscle in the isolated tracheal, strengthens the inhibitory action of acetylcholine in the ileum that exsomatizes, and suppresses passive allergy, the level of cAMP and cGMP in the rising body fluid suppresses the edema that carrageenin causes.In clinical trial, also be proved to be effective to baby's bronchial asthma.Find that also it can reduce serum IgE level in the body, improve level and the cAMP/cGMP ratio of cAMP, cGMP, can also improve the irritability of autonomic nerve and beta receptor, the reactivity of trimethoquinol anti-asthmatic is had remarkable potentiation.
Three, PC-I bioavailability clinical research
This test adopt gas chromatography determination 18 men's health experimenters intersect single oral dose at random and be subjected to reagent lecithin chelated iodine capsule (to be subjected to test preparation, Shaanxi Zheng Kang medication chemistry company limited is developed) and contrast medicine lecithin chelated iodine sheet (reference preparation, the first medicine Industry Co., Ltd produces,) concentration of lecithin chelated iodine in the different blood plasma constantly, draw blood drug level-time graph, and, ask the bioavailability of calculating relevant pharmacokinetic parameter and being subjected to test preparation according to blood drug level-time data.
18 health volunteers are by interior extrapolation method at random respectively behind oral test preparation and each 9mg of reference preparation (1.5mg/ sheet or grain), the T of lecithin chelated iodine in the blood plasma
MaxBe respectively 1.028 ± 0.19h (means standard deviation, down together) and 1.028 ± 0.19h; C
MaxBe respectively 2.72 ± 0.87 and 2.56 ± 0.92 μ g/mL; T
1/2keBe respectively 34.41 ± 13.6 and 42.85 ± 27.79h; Calculate AUC with trapezoidal method
0-tBe respectively 18.29 ± 4.34 and 17.39 ± 4.72 μ gh/mL, AUC
0-∞Be respectively 44.99 ± 17.25 and 49.06 ± 24.81 μ gh/mL; With AUC
0-tCalculate, the capsular relative bioavailability average out to 106.7 ± 13.3% of lecithin chelated iodine is with AUC
0-∞Calculate, the lecithin chelated iodine capsule is to bioavailability average out to 102.8 ± 32.9%.
Main pharmacokinetic parameters (C
Max, AUC
0-t) through to the laggard capable variance analysis of number conversion, adopt sided t-check and (1-2 α) confidence interval method to carry out evaluation of bioequivalence.The result shows, is subjected to the AUC of test preparation
0-t90% confidence interval is 101.0%～111.1% of a reference preparation relevant parameter, is subjected to test preparation AUC
0-∞90% examination confidence interval is 86.0%～112.1% of a reference preparation relevant parameter, is subjected to test preparation C
Max90% confidence interval be 98.1%～118.3% of reference preparation relevant parameter, be subjected to test preparation T
Max90% confidence interval be 100%～100% of reference preparation relevant parameter.Statistic analysis result shows: biological agent equivalence in two kinds of preparation bodies.
Clinical research is the result show: the commercially available prod (lecithin chelated iodine sheet) that this product and the Japanese first medicine Industry Co., Ltd produce has bioequivalence.And this product adopts enteric coated capsule parcel lecithin chelated iodine, can avoid lecithin chelated iodine to be subjected to the destruction of gastric acid, and to the stimulation of gastric mucosa, has strengthened the absorption of medicine by intestinal mucosa, has improved blood drug level, has strengthened drug effect.Cover the special odor of lecithin chelated iodine simultaneously, make things convenient for the patient to take.
Four, PC-I complex degraded test
One .pH is to the influence of PC-I complex degraded
Take by weighing 1 gram PC-I complex, adding 20ml 95% ethanol is moistening, adds people 80ml purified water under the magnetic agitation, drips 1: 1 aqueous hydrochloric acid solution and transfers to pH value about 1.0 (matched group PH is adjusted to 7).Stir and got supernatant 10ml filtration in 30 minutes, add chloroform 1.0ml again, dense hydrogen peroxide 1.0ml jolting 2-3 minute, leaves standstill back chloroform layer colour developing, result such as Fig. 1
Two. the degraded of PC-I complex is measured under the different pH
Take by weighing 1 gram PC-I complex, adding 20ml 95% ethanol is moistening, adds people 80ml purified water under the magnetic agitation, drips 1: 1 aqueous hydrochloric acid solution and transfers to pH value about 1.0 (matched group PH is adjusted to 7).Every interval was got supernatant 10.0ml (1/10 volume) in 10 minutes and is filtered (replenishing isopyknic purified water simultaneously) under stirring, with the constant-current titration of 0.005mol/L silver nitrate.Every 1ml silver nitrate titration liquid is equivalent to the iodine of 0.635mg.A determines titration end-point according to two appendix VII of Chinese Pharmacopoeia version in 2005.With Δ
2E/ Δ V
2For doing coordinate, be abscissa with V, curve plotting.Volume during the curve zero passage is titration end-point.According to the decomposition amount of the volume calculation PC-I complex of titration end-point silver nitrate, thereby obtain the dissociate percentage rate of sample under condition of different pH.Result such as table 2
The table 2 lecithin chelated iodine percentage rate that dissociates
Three. conclusion:
Draw from above result, lecithin chelated iodine (PH=1.0) degraded under acid condition destroys serious, will directly have influence on the drug effect of medicine.If use enteric coated capsule bag medicine carrying thing, can avoid gastric acid directly to contact medicine and medicine is damaged and degrades, thereby improve stability of drug and effectiveness.
The advantage of lecithin chelated iodine enteric coated capsule of the present invention is that it has avoided medicine to be subjected to the destruction of gastric acid, has avoided the zest of medicine to gastric mucosa, has strengthened the absorption of medicine by intestinal mucosa, has improved blood drug level, has strengthened drug effect.Cover the special odor of lecithin chelated iodine simultaneously, make things convenient for the patient to take.
Figure of description:
Fig. 1 PH is to the influence of PC-I complex degraded, a: experimental group pH=1; B: matched group pH=7
The specific embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Preparation technology:
A. take by weighing the lecithin chelated iodine of recipe quantity, cellulose acetate-phthalate and Sodium Hydroxymethyl Stalcs join stirring and evenly mixing in the ethanol water of debita spissitudo, evacuation rotary evaporation solvent, preparation solid dispersion.
B. with prepared solid dispersion drying, cross 100 mesh sieves, the lactose and the microcrystalline Cellulose that take by weighing recipe quantity are simultaneously crossed 100 mesh sieves respectively.
C. will drop in the multidirectional movement mixer by the equivalent method of going forward one by one by the supplementary material that recipe quantity has taken by weighing, incapsulate behind the mix homogeneously.
Embodiment 2:
Preparation technology embodiment 1
Embodiment 3:
Preparation technology is with embodiment 1
Embodiment 4
Preparation technology is with embodiment 1
Claims (10)
1. lecithin chelated iodine enteric coated capsule preparation, the active component that comprises has 1) lecithin chelated iodine, 2) disintegrating agent, 3) enteric solubility solid dispersion carrier, 4) excipient, 5) do not decomposed and destructive enteric coated capsule as the protection lecithin chelated iodine by gastric juice.
2. according to the lecithin chelated iodine enteric coated capsule preparation of claim 1, wherein said disintegrating agent is selected from Sodium Hydroxymethyl Stalcs, crosslinked Sodium Hydroxymethyl Stalcs, low substituent group hydroxypropyl cellulose, one or more in polyvinylpolypyrrolidone and the starch.
3. according to the lecithin chelated iodine enteric coated capsule preparation of claim 1, it is characterized in that described enteric solubility solid dispersion carrier is selected from one or more in Hydroxypropyl Methylcellulose Phathalate, polyacrylic resin L100-55, polyacrylic resin L30D-55, polyacrylic resin L100 and the cellulose acetate-phthalate.
4. lecithin chelated iodine enteric coated capsule preparation according to claim 1 is characterized in that described excipient is selected from one or more in filler, binding agent and the lubricant.
5. lecithin chelated iodine enteric coated capsule preparation according to claim 4 is characterized in that described filler is selected from one or more in lactose, microcrystalline Cellulose, starch, pregelatinized Starch, dextrin, mannitol, glucose, sorbitol, the sucrose.
6. lecithin chelated iodine enteric coated capsule preparation according to claim 4 is characterized in that described binding agent is selected from one or more in polyvidone, hydroxypropyl emthylcellulose, ethyl cellulose and the methylcellulose.
7. lecithin chelated iodine enteric coated capsule preparation according to claim 4 is characterized in that described lubricant is selected from one or more in micropowder silica gel, Pulvis Talci, magnesium stearate, calcium stearate, zinc stearate and the stearic acid.
8. according to claim 1 and 4 described lecithin chelated iodine enteric coated capsule preparations, it is characterized in that its constituent is: 1 part of lecithin chelated iodine, 200～500 parts in enteric solubility solid dispersion carrier, 30～100 parts of disintegrating agents, 600～1500 parts of excipient.
9. according to the described lecithin chelated iodine enteric coated capsule of claim 9 preparation, it is characterized in that its constituent is:
1 part of lecithin chelated iodine, 400 parts of cellulose acetate-phthalates, 40 parts of Sodium Hydroxymethyl Stalcses, 800 parts of lactose, 550 parts of microcrystalline Cellulose.
10. method for preparing the described lecithin chelated iodine enteric coated capsule of claim 1 preparation is characterized in that comprising following steps:
A. take by weighing lecithin chelated iodine, solid dispersion carrier, the disintegrating agent of recipe quantity, join stirring and dissolving in the ethanol water of debita spissitudo, evacuation rotary evaporation solvent, preparation solid dispersion;
B. with prepared solid dispersion drying, sieve, conventional method prepares granule or directly incapsulates with pharmaceutics auxiliary materials and mixing commonly used, must the lecithin chelated iodine enteric coated capsule.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103127017A (en) * | 2013-03-01 | 2013-06-05 | 南京正宽医药科技有限公司 | Entecavir dispersible tablet and preparation method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861057A (en) * | 2006-06-15 | 2006-11-15 | 宛六一 | Soft capsule contg. lecithin complex iodine and its prepn. method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861057A (en) * | 2006-06-15 | 2006-11-15 | 宛六一 | Soft capsule contg. lecithin complex iodine and its prepn. method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103127017A (en) * | 2013-03-01 | 2013-06-05 | 南京正宽医药科技有限公司 | Entecavir dispersible tablet and preparation method |
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