CN109806238A - A kind of preparation method of Indomethacin colon drug delivery pellet - Google Patents
A kind of preparation method of Indomethacin colon drug delivery pellet Download PDFInfo
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- CN109806238A CN109806238A CN201910203654.7A CN201910203654A CN109806238A CN 109806238 A CN109806238 A CN 109806238A CN 201910203654 A CN201910203654 A CN 201910203654A CN 109806238 A CN109806238 A CN 109806238A
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Abstract
The present invention discloses a kind of preparation method of Indomethacin colon drug delivery pellet, comprising steps of 1) 8-12g enzyme degradation agent is added to 35-45ml distilled water, obtained enzyme degraded solutions are stirred evenly after swelling；2) 26-32g hydrophobicity retarding agent is added into enzyme degraded solutions, it is stirring while adding, after mixing disperse 5-10g Indomethacin in, obtain containing drug solns；3) it will be slowly dropped into the gelling agent that concentration is 0.03-0.08g/mL containing drug solns through injection needle, gelling is formed by curing gel ball；4) stand 25-35min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet with distilled water, and drained at room temperature, in 50-70 DEG C of baking oven, dry 35-45min to obtain the final product.Pellet of the present invention can avoid its irritation to gastrointestinal tract in colon released medicine, while can be used for the treatment and prevention of colon cancer.
Description
Technical field
The present invention relates to a kind of preparation methods of Indomethacin colon drug delivery pellet, belong to field of pharmaceutical preparations.
Background technique
Indomethacin (Indomethacin, IND) is artificial synthesis of indole acetogenin, has apparent antipyretic town
Bitterly anti-inflammatory anti rheumatism action is mainly used for the treatment of various rheumatism and rheumatoid arthritis, all vertebra inflammation and cancer pain etc..Its
It is curative for effect, absorb fast, bioavilability height.In recent years, the study found that IND has the antitumor action of wide spectrum, epidemiology
Data is shown, can prevent or reduce the disease incidence of colon cancer, and some researches show that IND can inhibit to human colon cancer cell line
The expression of HCT116 protein can also inhibit human colon cancer cell (the HCT116 and SW480) growth for not expressing cyclooxygenase
Deng, therefore certain effect is played in the complex treatment of colon cancer, take the incidence and death that can reduce colon cancer for a long time
Rate.The treatment of colon cancer at present is mainly based on operation, while purposive combination radiation and chemotherapy, since IND can be one
Determine the lesion for inhibiting colon cancer in degree, but common oral preparation and percutaneous drug administration preparation etc. be because drug is not easy to reach disease position,
Lead to the toxic side effects such as the low, gastrointestinal reaction of drug effect.
In recent years, oral colon-specific drug delivery system (oral colon-specific drug delivery system,
OCDDS it) is concerned, drug can be located in colon and released the drug.It can be improved colon local drug concentration, improve and treat
Effect is conducive to treat colon local patholoic change, such as Crohn's disease, ulcerative colitis, colon cancer.According to different principle colon
Targeted drug delivery system can be divided into following five class: time control type, pH dependent form, comprehensive time controlled type, pressure dependence type and enzymatic hydrolysis or
Bacterial degradation type.Wherein since colon is there are a large amount of bacterium and unique enzyme system, the preparation made of enzyme degradability material
It is degraded after reaching colon and discharges drug, achieve the purpose that positioning release medicine, more commonly used chitosan, pectin etc..Due to fruit
Glue is not destroyed under the conditions of Human Physiology by stomach and small intestine, and is degraded in colon by pectase, with metal ion such as Ga2+With
Zn2+The shortcomings that discharging in stomach, small intestine because of its water solubility can be overcome Deng in conjunction with after, be more used for colon released medicine
In system.
Summary of the invention
In view of the above existing problems in the prior art, the present invention provides a kind of preparation sides of Indomethacin colon drug delivery pellet
Method, the pellet can avoid its irritation to gastrointestinal tract in colon released medicine, at the same can be used for the treatment of colon cancer with
Prevention.
To achieve the goals above, a kind of preparation method for Indomethacin colon drug delivery pellet that the present invention uses, specifically
The following steps are included:
1) preparation of enzyme degraded solutions: 8-12g enzyme degradation agent is added into 35-45ml distilled water, is sufficiently stirred after swelling
Mix uniformly obtained enzyme degraded solutions；
2) containing the preparation of drug solns: 26-32g hydrophobicity retarding agent, side being added into enzyme degraded solutions made from step 1)
Edged stirring, after mixing disperse 5-10g Indomethacin in, obtain containing drug solns；
3) dripping pellet: it is 0.03-0.08g/mL that step 2), which is made, and is slowly dropped into concentration through injection needle containing drug solns
Gelling agent in, gelling be formed by curing gel ball；
4) pellet is dry: standing 25-35min afterwards after dripping, decompression filters, obtains gel microsphere, cleaned with distilled water micro-
Ball, drained at room temperature, in 50-70 DEG C of baking oven, dry 35-45min is to get Indomethacin pellet.
As an improvement, the enzyme degradation agent uses one or more of chitosan, pectin, sodium alginate, glucan
Mixing.
As an improvement, the hydrophobicity retarding agent is using in ethyl cellulose, cellulose acetate, phthalic acid titanate esters
One or more of mixing.
As an improvement, the gelling agent is aqueous zinc acetate solution, any in calcium chloride water, calcium sulfate aqueous solution
Kind.
As an improvement, specifically includes the following steps:
1) preparation of enzyme degraded solutions: 9.6g pectin is added into 40ml distilled water, sufficiently the system of stirring evenly after swelling
Obtain pectin solution；
2) containing the preparation of drug solns: 28.80g ethyl cellulose, side edged being added into pectin solution made from step 1)
Stirring, after mixing disperse 7.31g Indomethacin in, obtain containing drug solns；
3) dripping pellet: step 2) is made and is slowly dropped into the acetic acid that concentration is 0.05g/mL through injection needle containing drug solns
In zinc aqueous solution, gelling is formed by curing gel ball；
4) pellet is dry: stand 30min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet with distilled water,
Drained at room temperature, in 60 DEG C of baking oven, dry 40min is to get Indomethacin pellet.
In addition, the present invention also provides a kind of using Indomethacin colon drug delivery pellet made from the preparation method.
Compared with prior art, Indomethacin colon drug delivery pellet produced by the present invention, different from common Indomethacin
Preparation can avoid its irritation to gastrointestinal tract, while can be used for controlling for colon cancer in colon released medicine in this way
It treats and prevents.Indomethacin colon released medicine pellet of the invention is encapsulated rate and tablets in vitro test and proves, encapsulation rate symbol
2015 editions pharmacopoeial requirements are closed, it is good in colon released medicine.
This method is easy to operate, and cost of supplementary product is low, and site specific DDS for colon may be implemented, and plays the work of Indomethacin inhibitor against colon carcinoma cells
With.The pellet of method preparation is near-spherical, and surface is smooth, and it is in brown color, average grain diameter is about 1.8mm, in vitro that form, which is circle,
Release test the result shows that, simulation stomach and intestinal fluid in 5h Accumulation dissolution be 20.13%, simulation colonic fluid in 12h
Accumulation dissolution be 83.02%, meet colon released medicine requirement.
Detailed description of the invention
Fig. 1 is that the dry forward and backward schematic diagram of Indomethacin colon released medicine pellet is made in the embodiment of the present invention 3；Scheming (a) is
Before drying, after figure (b) is dry；
Fig. 2 is that the in-vitro simulated colon drug delivery curve of IND pellet is made in the embodiment of the present invention 3.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention is carried out below further detailed
It describes in detail bright.However, it should be understood that the specific embodiments described herein are merely illustrative of the present invention, it is not limited to this hair
Bright range.
Unless otherwise defined, all technical terms and scientific terms used herein are led with technology of the invention is belonged to
The normally understood meaning of the technical staff in domain is identical, and term as used herein in the specification of the present invention is intended merely to retouch
State the purpose of specific embodiment, it is not intended that in the limitation present invention.
Embodiment 1
A kind of preparation method of Indomethacin colon drug delivery pellet, specifically includes the following steps:
1) preparation of enzyme degraded solutions: 8g chitosan is added into 35ml distilled water, sufficiently the system of stirring evenly after swelling
Obtain chitosan solution；
2) containing the preparation of drug solns: 26g cellulose acetate being added into chitosan solution made from step 1), side edged stirs
Mix, after mixing disperse 5g Indomethacin in, obtain containing drug solns；
3) dripping pellet: step 2) is made and is slowly dropped into the chlorination that concentration is 0.03g/mL through injection needle containing drug solns
Calcium aqueous solution, gelling are formed by curing gel ball；
4) pellet is dry: stand 25min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet with distilled water,
Drained at room temperature, in 50 DEG C of baking oven, dry 45min is to get Indomethacin pellet.
Embodiment 2
A kind of preparation method of Indomethacin colon drug delivery pellet, specifically includes the following steps:
1) preparation of enzyme degraded solutions: 12g glucan is added into 45ml distilled water, sufficiently the system of stirring evenly after swelling
Obtain dextran solution；
2) containing the preparation of drug solns: 32g phthalic acid titanate esters, side being added into dextran solution made from step 1)
Edged stirring, after mixing disperse 10g Indomethacin in, obtain containing drug solns；
3) dripping pellet: step 2) is made and is slowly dropped into the sulfuric acid that concentration is 0.08g/mL through injection needle containing drug solns
Calcium aqueous solution, gelling are formed by curing gel ball；
4) pellet is dry: stand 35min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet with distilled water,
Drained at room temperature, in 70 DEG C of baking oven, dry 35min is to get Indomethacin pellet.
Embodiment 3
A kind of preparation method of Indomethacin colon drug delivery pellet, specifically includes the following steps:
1) preparation of enzyme degraded solutions: 9.6g pectin is added into 40ml distilled water, sufficiently the system of stirring evenly after swelling
Obtain pectin solution；
2) containing the preparation of drug solns: 28.80g ethyl cellulose, side edged being added into pectin solution made from step 1)
Stirring, after mixing disperse 7.31g Indomethacin in, obtain containing drug solns；
3) dripping pellet: step 2) is made and is slowly dropped into the acetic acid that concentration is 0.05g/mL through injection needle containing drug solns
In zinc aqueous solution, gelling is formed by curing gel ball；
4) pellet is dry: stand 30min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet with distilled water,
Drained at room temperature, in 60 DEG C of baking oven, dry 40min is to get Indomethacin pellet.
IND pellet is made with embodiment 3 and carries out performance measurement.
Fig. 1 is that the dry forward and backward schematic diagram of Indomethacin colon released medicine pellet is made in the embodiment of the present invention 3；Scheming (a) is
Before drying, glomeration, canescence, surface is smooth, and average grain diameter is 4.1mm or so；After scheming (b) for drying, average grain diameter is
1.8mm left and right.
Pellet entrapment efficiency determination:
Appropriate pellet is taken to pulverize, accurately weighed 1.0g is packed into the bag filter after activating, and both ends sealing is placed in
In 50mL volumetric flask with phosphate buffer (containing 0.1%SDS, 0.1% pectase) constant volume of pH5.0, in constant temperature oscillator
On under conditions of 37.5 DEG C, 100r/min, shake 12h, take its solution, 0.45 μm of filtering with microporous membrane discards primary filtrate,
It takes 20 μ l of its subsequent filtrate to inject liquid chromatograph, records chromatogram, the encapsulation rate of pellet is calculated according to following formula.
Contained IND amount/dosage × 100% in encapsulation rate=pellet
Optimal prescription verifying:
It repeats to prepare three batches of IND pellet samples as described in Example 3, and carries out tablets in vitro investigation, the results are shown in Table 1.
1 embodiment 3 of table prepares the verification result of pellet
Analytical table 1 is it is found that three batches of samples meet the expected requirements, and the preparation process is reasonable, stable, feasible.It is obtained
The wet pellet glomeration of IND, canescence, surface is smooth, and average grain diameter is 4.1mm or so；Pellet average grain diameter after drying is
1.8mm left and right.
In-vitro simulated colon drug delivery is investigated:
Precision weighs 1.0g pellet, in the bag filter after being put into activation, both ends sealing, by 2015 editions annex XD of Chinese Pharmacopoeia
Defined the second method of release combination Bag filter method carries out the release test of conversion medium.Temperature is (37 ± 0.5) DEG C, and revolving speed is
75r/min, dissolution medium 250mL.Hydrochloric acid solution that simulate the gastric juice is pH1.0 (containing 0.1%SDS), simulated intestinal fluid are
Phosphate buffer that the phosphate buffer (contain 0.1%SDS) of pH6.8, simulation colonic fluid are pH5.0 (containing 0.1%SDS,
0.1% pectase).2h is discharged in simulate the gastric juice first, taking-up, which is transferred in simulated intestinal fluid, to be continued to discharge 5h, is finally transferred to mould
Continue to discharge 12h in quasi- colonic fluid.5mL is sampled every 1h and supplements corresponding dissolution medium, 0.45 μm of filtering with microporous membrane,
Primary filtrate is discarded, 20 μ l of its subsequent filtrate is taken to inject liquid chromatograph, records chromatogram, peak area is counted, calculates the accumulation of drug
Release, and drug release profiles are drawn, it the results are shown in Table 2, Fig. 2.
The tablets in vitro result of 2 IND pellet of table
Analytical table 2, Fig. 2 are it is found that IND pellet produced by the present invention, pellet accumulation of 5h in simulation stomach and intestinal fluid are released
Degree of putting is 20.13%, and the Accumulation dissolution of 12h is 83.02% in simulation colonic fluid.
The characteristics of this experiment is according to IND prepares enzyme degradation-type oral colon-specific drug release pellet and investigates its body outer osmotic
0.6% pectase is added in simulation colonic fluid to simulate the flora environment in colon, to evaluate more scientificly in characteristic, selection
The release behaviour in vitro of pellet.The IND colon drug delivery pellet has apparent site specific DDS for colon effect, is Indomethacin for treating
Colonic pathological change provides theoretical foundation.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement or improvement etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (6)
1. a kind of preparation method of Indomethacin colon drug delivery pellet, which is characterized in that specifically includes the following steps:
1) preparation of enzyme degraded solutions: 8-12g enzyme degradation agent is added into 35-45ml distilled water, is sufficiently stirred after swelling equal
Even obtained enzyme degraded solutions；
2) containing the preparation of drug solns: 26-32g hydrophobicity retarding agent, side edged being added into enzyme degraded solutions made from step 1)
Stirring, after mixing disperse 5-10g Indomethacin in, obtain containing drug solns；
3) dripping pellet: step 2) is made and is slowly dropped into the glue that concentration is 0.03-0.08g/mL through injection needle containing drug solns
In solidifying agent, gelling is formed by curing gel ball；
4) pellet is dry: standing 25-35min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet, room with distilled water
Drained under temperature, in 50-70 DEG C of baking oven, dry 35-45min is to get Indomethacin pellet.
2. a kind of preparation method of Indomethacin colon drug delivery pellet according to claim 1, which is characterized in that described
Enzyme degradation agent uses the mixing of one or more of chitosan, pectin, sodium alginate, glucan.
3. a kind of preparation method of Indomethacin colon drug delivery pellet according to claim 1, which is characterized in that described to dredge
Aqueous retarding agent uses the mixing of one or more of ethyl cellulose, cellulose acetate, phthalic acid titanate esters.
4. a kind of preparation method of Indomethacin colon drug delivery pellet according to claim 1, which is characterized in that the glue
Solidifying agent is any one of aqueous zinc acetate solution, calcium chloride water, calcium sulfate aqueous solution.
5. a kind of preparation method of Indomethacin colon drug delivery pellet according to claim 1, which is characterized in that specific packet
Include following steps:
1) preparation of enzyme degraded solutions: 9.6g pectin is added into 40ml distilled water, sufficiently stirs evenly obtained fruit after swelling
Sol solution；
2) containing the preparation of drug solns: 28.80g ethyl cellulose is added into pectin solution made from step 1), it is stirring while adding,
In after mixing dispersing 7.31g Indomethacin in, obtain containing drug solns；
3) dripping pellet: step 2) is made and is slowly dropped into the zinc acetate water that concentration is 0.05g/mL through injection needle containing drug solns
In solution, gelling is formed by curing gel ball；
4) pellet is dry: standing 30min afterwards after dripping, decompression filters, obtains gel microsphere, clean pellet, room temperature with distilled water
Under it is drained, in 60 DEG C of baking oven, dry 40min is to get Indomethacin pellet.
6. a kind of using Indomethacin colon drug delivery pellet made from any one of the claim 1-5 preparation method.
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| CN201910203654.7A CN109806238A (en) | 2019-03-18 | 2019-03-18 | A kind of preparation method of Indomethacin colon drug delivery pellet |
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| CN201910203654.7A CN109806238A (en) | 2019-03-18 | 2019-03-18 | A kind of preparation method of Indomethacin colon drug delivery pellet |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110384688A (en) * | 2019-08-14 | 2019-10-29 | 新疆农业大学 | 5 FU 5 fluorouracil oral colon-specific drug delivery system and preparation method thereof |
| CN111450049A (en) * | 2020-05-11 | 2020-07-28 | 中国药科大学 | Preparation method of micro hydrogel with colon-specific delivery |
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| CN104367588A (en) * | 2014-11-29 | 2015-02-25 | 山西医科大学 | Dexamethasone, pectin and zinc combined gel oral colon-specific drug delivery pellet |
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| US20070190153A1 (en) * | 2004-03-05 | 2007-08-16 | Jonathan Farber | Delivery systems for non-steroidal anti-inflammatory drugs (nsaids) |
| CN1857732A (en) * | 2006-03-31 | 2006-11-08 | 复旦大学 | In vivo cross-linked pectin skeleton administration system containing calcium salt in great weight portions |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110384688A (en) * | 2019-08-14 | 2019-10-29 | 新疆农业大学 | 5 FU 5 fluorouracil oral colon-specific drug delivery system and preparation method thereof |
| CN110384688B (en) * | 2019-08-14 | 2023-03-17 | 新疆农业大学 | 5-fluorouracil oral colon-specific drug delivery system and preparation method thereof |
| CN111450049A (en) * | 2020-05-11 | 2020-07-28 | 中国药科大学 | Preparation method of micro hydrogel with colon-specific delivery |
| CN111450049B (en) * | 2020-05-11 | 2021-06-25 | 中国药科大学 | Preparation method of micro hydrogel with colon-specific delivery |
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