CN106176619B - Andrographolide enteric-coated pellet positioning preparation - Google Patents
Andrographolide enteric-coated pellet positioning preparation Download PDFInfo
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- CN106176619B CN106176619B CN201510478607.5A CN201510478607A CN106176619B CN 106176619 B CN106176619 B CN 106176619B CN 201510478607 A CN201510478607 A CN 201510478607A CN 106176619 B CN106176619 B CN 106176619B
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- 239000008188 pellet Substances 0.000 title claims abstract description 148
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 112
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 112
- 238000002360 preparation method Methods 0.000 title claims description 41
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 9
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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Abstract
An andrographolide enteric-coated targeted pellet is characterized by consisting of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0; the weight ratio of andrographolide to polymer a is 1: 2-1: 0.2, the weight of the drug layer is increased by 20 to 100 percent; the enteric coating contains polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the weight of the coating layer is increased by 5-30 wt%.
Description
Technical Field
The invention relates to a medicinal preparation, in particular to an andrographolide enteric-coated pellet positioning preparation.
Background
Andrographolide (molecular formula C20H30O5) is diterpene lactone compound extracted from herba Andrographitis of Acanthaceae, and is one of main effective components of herba Andrographitis; has the efficacies of clearing away heat and toxic material, diminishing inflammation and relieving pain, and is known as natural antibiotic medicine. The composition is diterpene lactone compound, and has the advantages of low side effect, good anti-inflammatory effect, wide source, low price, etc. when used as plant extract.
Recent studies have found that andrographolide is very effective in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. The colon is positioned in the latter half of the digestive tract, the medicine is difficult to reach the colon when the common oral preparation is administrated, and the enema administration is inconvenient and painful, so that the technology of targeting preparations of the intestinal tract, particularly the colon, is developed at present. An oral colon-specific drug delivery system (ocdds) is a localized drug delivery system that does not release drugs in the first half of the gastrointestinal tract, such as the stomach and duodenum, and that starts to release drugs after the drugs are transported to the ileocecal part, thereby exerting local or systemic therapeutic effects. The commonly used techniques for OCSDS include pH-dependent, enzymatic degradation, and time-dependent.
The pH dependent type realizes colon-specific release by utilizing the pH value difference of various parts of the gastrointestinal tract of a human body. The stomach of a healthy person has the lowest pH of 1-3, the duodenum of 4-6, the jejunum of 6-7, the ileum of 7-7.5, and the colon of 7-8.
The current commonly used enteric materials have different pH values, the first one is that the enteric materials begin to dissolve at the pH value of more than or equal to 5.5, the second one begins to dissolve at the pH value of more than or equal to 6.0, and the third one begins to dissolve at the pH value of more than or equal to 7.0. At present, the pH-dependent colon targeting preparation basically adopts a third enteric polymer to coat the medicament, so that the medicament can be released from the upper half part of the gastrointestinal tract to the ileocecal part without being released. This technique is described in Chinese patents CN1981743, CN101209246 and CN 103315959. However, clinical studies show that the difference in gastrointestinal pH between individuals is large, and that there is also a gap between patients with inflammatory bowel disease and healthy people. The colonic pH of patients with inflammatory bowel disease is lower than that of healthy people. Therefore, when the polymer is used alone, the drug is not released in the body of a patient and is directly excluded from the body.
Regarding the andrographolide enteric targeting preparation, the enzyme degradation type localization technology is reported in the prior art. Coating andrographolide on the blank pellet core to obtain drug-loaded pellet, and coating water-insoluble polymer containing monosaccharide pore-forming agent on the surface. The polymer membrane is not released in stomach and small intestine, monosaccharide in the membrane is degraded by colonic enzyme after reaching colon to form pore canal, and the medicine is gradually dissolved and released. Although this technique overcomes the drawbacks of pH-dependent inter-individual variation, it also has problems, mainly because the monosaccharide used, such as guar gum, etc., dissolves in water, so that the drug is released from the pores left by the dissolution of the monosaccharide molecules after entering the body, and it is difficult to secure the drug amount to the colon. In addition, the monosaccharide molecular structure is rigid and embedded among the polymer chains, so that the extensibility of the polymer chains is influenced, the integrity of the polymer film is damaged, the coating film is fragile and easy to break, and the film is in danger of breaking in advance under gastrointestinal peristalsis in the transportation process.
Disclosure of Invention
Aiming at the problems, the product adopts a special pH-dependent technology, namely 2 pH-dependent polymers are combined for use, so that the human body with different colon pH values can achieve enteric targeting, particularly the colon targeting purpose, and the details are as follows:
the andrographolide enteric targeting pellet is characterized by consisting of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0; the weight ratio of andrographolide to polymer a is 1: 2-1: 0.2, preferably 1: 1.5-1.0.5, the weight of the drug layer a is increased by 20-100 wt%, preferably 30-80 wt%; the enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the weight of a coating layer is increased by 5 to 30 weight percent, preferably 8 to 20 weight percent, and most preferably 10 to 18 weight percent.
Wherein the polymer a is a methacrylic acid and methyl methacrylate copolymer, preferably a methacrylic acid and methyl methacrylate 1:2 copolymer; the polymer b is a methacrylic acid and ethyl acrylate copolymer, preferably a methacrylic acid and ethyl acrylate 1:1 copolymer.
The polymer a is preferably Eudragit S100 from Eudragit, Egger, Germany, and the polymer b is preferably a Eudragit L series polymer from Eudragit, Germany, most preferably Eudragit L100-55
Wherein the drug layer further comprises plasticizer, antisticking agent, pigment, hydrophilic polymer and surfactant, wherein the surfactant is selected from sodium lauryl sulfate or Tween-80, and is added in an amount of 0-5 wt%, preferably 1-3 wt% of andrographolide.
The plasticizer is selected from one or more of triethyl citrate, dibutyl sebacate, propylene glycol and PEG, and the dosage of the plasticizer is 10 wt% -70 wt%, preferably 10 wt% -20 wt% of the dosage of the polymer a; the antisticking agent is selected from talcum powder in an amount of 25-100 wt%, preferably 30-50 wt% of polymer a or glyceryl monostearate in an amount of 2-20 wt%, preferably 5-10 wt% of polymer a.
The grain diameter of the pellet core is 200-600 microns, preferably 300-500 microns, and the pellet core accounts for 10-70 wt%, preferably 20-60 wt% of the prescription amount. Wherein the pill core is conventional pharmaceutical pill core, preferably blank sucrose pill core or microcrystalline cellulose pill core.
And (4) pill cores: andrographolide: polymer a plasticizer: anti-sticking agent: 200 parts of surfactant, (10-100), (1-15), (1-30) and (0-3);
preferably, the pill core: andrographolide: polymer a plasticizer: anti-sticking agent: 200 parts of surfactant (15-66): (13-74): (2-13.5): 3-27): 0-1.32);
most preferably, the pellet core: andrographolide: polymer a plasticizer: anti-sticking agent: surfactant 200: 200 (20-50): (30-60): (5-10): 5-20): 0.5-1.2);
wherein the enteric coating layer also contains a plasticizer and an antisticking agent, the plasticizer and the antisticking agent are selected as described above, wherein the dosage of the plasticizer is 15 wt% of the polymer b, and the dosage of the antisticking agent is 30 wt% of the polymer b.
The following provides 7 groups of preferred formulations for the pellet core and drug layer:
the andrographolide enteric-coated targeted pellet comprises the following preparation methods:
(1) pill core medicine feeding
A. Dispersing the polymer a in a medicinal solvent, and mechanically stirring to fully dissolve the polymer a; adding auxiliary materials into the polymer a solution; adding andrographolide, and stirring to obtain polymer a coating solution;
B. weighing a blank pellet core, placing the blank pellet core in a fluidized bed, adjusting the air amount to enable the pellet to be in an ideal fluidization state, starting a heating device, starting a peristaltic pump when the temperature of the material reaches a preset value, and enabling the polymer a coating liquid to be atomized and uniformly dispersed on the surface of the blank pellet core through a spray gun to obtain a drug-loaded pellet;
(2) preparation of enteric coating layer
A. Dispersing the polymer b in a medicinal organic solvent or water, mechanically stirring to fully dissolve the polymer b, adding auxiliary materials into the polymer b solution, and uniformly stirring to obtain a polymer b coating solution;
B. coating by adopting fluidized bed equipment, putting the drug-loaded pellets into a fluidized bed bottom spraying device, and uniformly spraying the polymer b coating solution to form an enteric coating layer; the weight increment of the enteric coating layer is 5 to 30 percent by weight.
The preparation method is preferably as follows:
(1) pill core medicine feeding
A. Dispersing the polymer a in medicinal ethanol to ensure that the concentration of the polymer a is 5 wt%, and fully dissolving the polymer a by mechanical stirring; continuously stirring uniformly, and adding a plasticizer, an anti-sticking agent and a surfactant sodium dodecyl sulfate which are used as auxiliary materials into the polymer a solution; adding andrographolide, and stirring to obtain polymer a coating solution;
B. weighing a blank sucrose pellet core of 200-600 microns, placing the blank sucrose pellet core into a fluidized bed, adjusting the air amount to enable the pellet to be in an ideal fluidized state, starting a heating device, keeping the material temperature of the pellet to be 25-35 ℃, starting a peristaltic pump when the material temperature reaches a preset value, and enabling the polymer a coating liquid to be atomized and uniformly dispersed on the surface of the blank pellet core through a spray gun to obtain a drug-loaded pellet;
(2) preparation of enteric coating layer
A. Dispersing the polymer b in medicinal ethanol, stirring by a high-speed shearing machine to fully dissolve the polymer b, adding a plasticizer and an anti-sticking agent which are used as auxiliary materials into the polymer b solution, and stirring uniformly to obtain a polymer b coating solution;
B. coating by adopting fluidized bed equipment, putting the drug-loaded pellets into a fluidized bed bottom spraying device, and uniformly spraying the polymer b coating solution to form an enteric coating layer; the weight increment of the enteric coating layer is 8 to 20 percent by weight.
An andrographolide enteric-coated targeted preparation is prepared by making the above pellet into granule or capsule by conventional method.
Advantageous effects
The application adopts a special pH-dependent technology, namely 2 pH-dependent polymers are used in combination, so that the aim of colon targeting can be achieved for human bodies with different intestinal tract and colon pH values. Firstly, a first enteric material, such as Eudragit L100-55, is coated on the surface of the pellet, so that the drug is not released in the stomach and is dissolved quickly after reaching the duodenum, and a drug layer is exposed. ② the middle drug layer is made of a third enteric material, for example, Eudragit S100 is used as a framework for evenly distributing the drug. When the pellet reaches the duodenum, the drug is gradually dissolved after the outer protective coating is dissolved, but the Eudragit S100 in the drug layer has blocking effect, the drug dissolution release amount is very small under the condition of low pH, and the drug is quickly released only when the pH of the tail end of the small intestine is close to 7.
The andrographolide enteric-coated targeted pellet prepared by the application has a 3-layer structure, a blank inner core, a drug layer and an Eudragit L outer layer. When the pharmaceutical preparation enters the stomach, the first layer of the membrane remains intact due to the pH below 5.5, but after the duodenum the membrane dissolves in a short time, exposing the second layer. The Eudragit S in the second layer has the dual functions of slow release and enteric coating. The andrographolide is uniformly dispersed in Eudragit S. After the outer layer of the duodenum is dissolved, the andrographolide begins to be released when contacting body fluid, but the pH value of the part is low, the dissolution amount of Eudragit S is limited, the drug release amount is small, and the release speed is slow. As the medicine is transferred to the lower half part of the gastrointestinal tract, the pH value is gradually increased, the dissolution speed of Eudragit S is accelerated, and the medicine release speed is gradually increased, so that most of the medicine is released in ileum and colon parts to play a role in intestinal wall inflammation.
The particle size of the core pill core adopted by people is 200-600 microns, and is obviously smaller than that of a common clinical pellet pill core (500-1000 microns), so that the specific surface area of the medicine is favorably improved, the contact area of the medicine and an inflammation part is increased, and the treatment effect of andrographolide on inflammatory bowel diseases is ensured. The pill core accounts for about 10-70 wt% of the prescription.
Eudragit series polymer is used as film material to coat the micro pill, and plasticizer and antisticking agent are added into the prescription. Wherein the plasticizer mainly functions to lower the glass transition temperature and the minimum film forming temperature and can also increase the flexibility of the polymer film. The main function of the anti-sticking agent is to avoid the film from becoming sticky and causing mutual adhesion between the cores.
Surfactants may increase the effect of the emollient.
In vitro release test
In vitro release determination is carried out on the pellets prepared by two of the preferable prescriptions, and the release degree is determined after the enteric targeting pellets equivalent to 150mg of andrographolide are filled into capsules. Adopts a first dissolution method of Chinese pharmacopoeia, the rotating speed is 100 r/min, and salt solutions with different pH values are release media (1000 mL). Sampling according to the specification of Chinese pharmacopoeia, and measuring the drug release amount in different time periods by using HPLC.
The results are shown in the figure, where prescription 1 is the fastest release, prescription 7 is the slowest, and the other prescriptions are in between.
Drawings
FIG. 1 shows the simulation of the cumulative amount of drug released in intestinal juice in phosphate buffer pH6.5
FIG. 2, the cumulative amount of drug released in phosphate buffer pH7.2 simulating colon liquid
Figure 3 mean plasma concentration of andrographolide in plasma after administration in two groups of rats-time curve (n ═ 4)
FIG. 4 is a graph showing the amount of andrographolide distributed in the proximal small intestine after administration to two groups of rats (n ═ 3)
FIG. 5 is a graph showing the amount of andrographolide distributed in the distal small intestine after administration to two groups of rats (n ═ 3)
FIG. 6 is a graph showing the distribution of andrographolide in the colon after administration to two groups of rats (n ═ 3)
Detailed Description
Example 1
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the core is 600 micron blank sucrose core; the plasticizer is triethyl citrate, and the anti-sticking agent is talcum powder; the surfactant is sodium dodecyl sulfate;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 5 wt%.
Example 2
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the pill core is 200 micron microcrystalline cellulose; the plasticizer is dibutyl sebacate, and the anti-sticking agent is glyceryl monostearate; the surfactant is tween 80;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 30 wt%.
Example 3
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the pill core is 400 micron blank sucrose pill core; the plasticizer is propylene glycol, and the antisticking agent is talcum powder; the surfactant is sodium dodecyl sulfate;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 8 wt%.
Example 4
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the pill core is a 500-micron blank sucrose pill core; the plasticizer is propylene glycol, and the antisticking agent is talcum powder;
the enteric coating layer contains Eudragit L30D-55, plasticizer and antisticking agent, wherein the plasticizer and antisticking agent are selected as the above medicinal layer, the dosage of the plasticizer is 15 wt% of Eudragit L30D-55, and the dosage of the antisticking agent is 30 wt% of Eudragit LL 30D-55; the weight gain of the coating is 20 wt%.
Example 5
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the pill core is a 500-micron blank sucrose pill core; the plasticizer is PEG, and the anti-sticking agent is talcum powder;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 28 wt%.
Example 6
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the pill core is a 500-micron blank sucrose pill core; the plasticizer is PEG, and the anti-sticking agent is talcum powder;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 15 wt%.
Example 7
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the pill core is a 500-micron blank sucrose pill core; the plasticizer is triethyl citrate, and the anti-sticking agent is talcum powder;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 15 wt%.
Example 8
The andrographolide enteric targeting pellet consists of a blank pellet core, a medicine layer and an enteric coating layer, wherein the medicine layer consists of the following components in percentage by weight:
wherein the core is 600 micron blank sucrose core; the plasticizer is triethyl citrate, and the anti-sticking agent is talcum powder; the surfactant is sodium dodecyl sulfate;
the enteric coating layer contains Eudragit L100-55, plasticizer and antisticking agent, wherein the selection of the plasticizer and the antisticking agent is the same as that of the medicine layer, the dosage of the plasticizer is 15 wt% of the Eudragit L100-55, and the dosage of the antisticking agent is 30 wt% of the Eudragit L100-55; the weight gain of the coating is 8 wt%.
Example 9
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0; the weight ratio of andrographolide to polymer a is 1:2, the weight of the medicine layer is increased by 20 wt%;
the enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 8 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein the polymer a is a copolymer of methacrylic acid and methyl methacrylate; the polymer b is a methacrylic acid and ethyl acrylate copolymer.
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 10
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0; the weight ratio of andrographolide to polymer a is 1: 0.2, the weight gain is 100 wt%; the enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 20 wt%.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
The plasticizer is dibutyl sebacate, and the antisticking agent is glyceryl monostearate
Example 11
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0; the weight ratio of andrographolide to polymer a is 1:1.5, and the weight of the drug layer is increased by 30 wt%; the enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 10 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
Example 12
An andrographolide enteric-coated targeted pellet comprises a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0, plasticizer, antisticking agent, pigment, hydrophilic polymer and surfactant; the ratio of andrographolide to polymer a is 1:2, the weight of the drug layer is increased to 100 wt%; the plasticizer is selected from triethyl citrate, in an amount of 10 wt% of the amount of polymer a; the antisticking agent is selected from talcum powder, and the dosage is 25 wt% of the polymer a.
The enteric coating is polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the weight gain of the coating is 20 percent. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 13
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0, plasticizer and antisticking agent; the weight ratio of andrographolide to polymer a is 1.0.5, and the weight of the drug layer is increased by 80 wt%; the plasticizer is selected from dibutyl sebacate, and the dosage of the plasticizer is 70 wt% of the dosage of the polymer a; the antisticking agent is selected from talcum powder, and the dosage of the antisticking agent is 100 wt% of the polymer a.
The enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 18 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 14
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0, plasticizer and antisticking agent; the weight ratio of andrographolide to polymer a is 1:1, and the weight of the drug layer is increased by 50 wt%; the plasticizer is selected from propylene glycol, and the dosage of the plasticizer is 20 wt% of the dosage of the polymer a; the antisticking agent is selected from talcum powder, and the dosage of the antisticking agent is 30 wt% of the polymer a.
The enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 15 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 15
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0, plasticizer and antisticking agent; the weight ratio of andrographolide to polymer a is 1:1.5, the weight of the medicine layer is increased by 60 wt%; the plasticizer is selected from PEG, and the dosage of the plasticizer is 50 wt% of the dosage of the polymer a; the antisticking agent is selected from talcum powder, and the dosage of the antisticking agent is 80 wt% of the polymer a.
The enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 16 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; the polymer b is methacrylic acid and ethyl acrylate 1:1 copolymer
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 16
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0, plasticizer and antisticking agent; the weight ratio of andrographolide to polymer a is 1:1.5, the weight of the medicine layer is increased by 60 wt%; the plasticizer is selected from PEG, and the dosage of the plasticizer is 50 wt% of the dosage of the polymer a; the antiblocking agent is chosen from glyceryl monostearate, in an amount of 2% by weight of polymer a.
The enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 16 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 17
The andrographolide enteric targeting pellet consists of a blank pellet core, a drug layer and an enteric coating layer, wherein the drug layer comprises: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0, plasticizer and antisticking agent; the weight ratio of andrographolide to polymer a is 1:1.5, the weight of the medicine layer is increased by 60 wt%; the plasticizer is selected from PEG, and the dosage of the plasticizer is 50 wt% of the dosage of the polymer a; the antiblocking agent is chosen from glyceryl monostearate, in an amount of 20% by weight of polymer a.
The enteric coating comprises a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the coating weight gain is 16 wt%. The dosage proportion of the plasticizer and the anti-sticking agent is the same as that of the polymer a in the medicine layer and the plasticizer and the anti-sticking agent.
Wherein polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate; polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate.
The plasticizer is triethyl citrate, and the antisticking agent is talcum powder.
Example 18
The preparation method of the pellets described in examples 1-17 comprises the following steps:
1) pill core medicine application:
A. dispersing the polymer a in a certain amount of medicinal organic solvent, and fully dissolving the polymer a by high-speed shearing mechanical stirring; adding a plasticizer and an anti-sticking agent into the polymer solution; adding andrographolide, and stirring; during coating, the mechanical stirring is kept, so that the coating solution is uniform suspension;
B. weighing blank pellet cores, placing the blank pellet cores in a fluidized bed, adjusting the air amount to enable the pellets to be in an ideal fluidization state, starting a heating device, starting a peristaltic pump when the temperature of the material reaches a preset value, and enabling the coating liquid to be atomized and uniformly dispersed on the surfaces of the pellet cores through a spray gun;
2) preparation of enteric coat
A. Dispersing the polymer b in a certain amount of medicinal organic solvent or water, fully dissolving the polymer b by high-speed shearing mechanical stirring, adding a plasticizer into the polymer solution, and uniformly stirring the anti-sticking agent;
B. coating the enteric coating layer on a fluidized bed device, putting the drug-loaded pellets into a bottom spraying device of the fluidized bed, and uniformly spraying the polymer b coating liquid; the weight of the pellet enteric coating film is increased by 5 wt%.
Example 18
The preparation method of the pellets described in examples 1-17 comprises the following steps:
1) pill core medicine application:
A. dispersing the polymer a in a certain amount of medicinal organic solvent, and fully dissolving the polymer a by high-speed shearing mechanical stirring; adding a plasticizer and an anti-sticking agent into the polymer solution; adding andrographolide, and stirring; during coating, the mechanical stirring is kept, so that the coating solution is uniform suspension;
B. weighing blank pellet cores, placing the blank pellet cores in a fluidized bed, adjusting the air amount to enable the pellets to be in an ideal fluidization state, starting a heating device, starting a peristaltic pump when the temperature of the material reaches a preset value, and enabling the coating liquid to be atomized and uniformly dispersed on the surfaces of the pellet cores through a spray gun;
2) preparation of enteric coat
A. Dispersing the polymer b in a certain amount of medicinal organic solvent or water, fully dissolving the polymer b by high-speed shearing mechanical stirring, adding a plasticizer into the polymer solution, and uniformly stirring the anti-sticking agent;
B. coating the enteric coating layer on a fluidized bed device, putting the drug-loaded pellets into a bottom spraying device of the fluidized bed, and uniformly spraying the polymer b coating liquid; the weight gain of the pellet enteric coating film is 30 wt%.
Example 19
The preparation method of the pellets described in examples 1-17 comprises the following steps:
1) pill core medicine application:
A. dispersing the polymer a into a certain amount of medicinal ethanol to ensure that the concentration of the polymer is 5 wt%, and fully dissolving the polymer a by high-speed shearing mechanical stirring; stirring was continued until homogeneous and the plasticizer, antisticking agent and sodium lauryl sulfate surfactant from the table below were added to the polymer solution. Adding andrographolide, and stirring; during coating, the mechanical stirring is kept, so that the coating solution is uniform suspension;
B. 200 micron blank sucrose pellet cores are weighed and placed in a fluidized bed. Regulating the air quantity to make the pellet in an ideal fluidization state, starting a heating device, keeping the material temperature of the pellet at 25 ℃, starting a peristaltic pump when the material temperature reaches a preset value, and atomizing and uniformly dispersing the coating liquid on the surface of the pellet core through a spray gun;
2) preparation of enteric coat
A. Dispersing the polymer b into a certain amount of medicinal ethanol, fully dissolving the polymer b by high-speed shearing mechanical stirring, adding a plasticizer into the polymer solution, and uniformly stirring the anti-sticking agent;
B. coating the enteric coating layer on a fluidized bed device, putting the drug-loaded pellets into a bottom spraying device of the fluidized bed, and uniformly spraying the polymer b coating liquid; the weight gain of the pellet enteric coating film is 8 wt%.
Example 20
The preparation method of the pellets described in examples 1-17 comprises the following steps:
1) pill core medicine application:
A. dispersing the polymer a into a certain amount of medicinal ethanol to ensure that the concentration of the polymer is 5 wt%, and fully dissolving the polymer a by high-speed shearing mechanical stirring; stirring was continued until homogeneous and the plasticizer, antisticking agent and sodium lauryl sulfate surfactant from the table below were added to the polymer solution. Adding andrographolide, and stirring; during coating, the mechanical stirring is kept, so that the coating solution is uniform suspension;
B. a600 micron blank sucrose pellet core is weighed and placed in a fluidized bed. Regulating the air quantity to make the pellet in an ideal fluidization state, starting a heating device, keeping the material temperature of the pellet at 35 ℃, starting a peristaltic pump when the material temperature reaches a preset value, and atomizing and uniformly dispersing the coating liquid on the surface of the pellet core through a spray gun;
2) preparation of enteric coat
A. Dispersing the polymer b into a certain amount of medicinal ethanol, fully dissolving the polymer b by high-speed shearing mechanical stirring, adding a plasticizer into the polymer solution, and uniformly stirring the anti-sticking agent;
B. coating the enteric coating layer on a fluidized bed device, putting the drug-loaded pellets into a bottom spraying device of the fluidized bed, and uniformly spraying the polymer b coating liquid; the weight gain of the pellet enteric coating film is 20 wt%.
Example 21
The preparation method of the pellets described in examples 1-17 comprises the following steps:
1) pill core medicine application:
A. dispersing the polymer a into a certain amount of medicinal ethanol to ensure that the concentration of the polymer is 5 wt%, and fully dissolving the polymer a by high-speed shearing mechanical stirring; stirring was continued until homogeneous and the plasticizer, antisticking agent and sodium lauryl sulfate surfactant from the table below were added to the polymer solution. Adding andrographolide, and stirring; during coating, the mechanical stirring is kept, so that the coating solution is uniform suspension;
B. 400 micron blank sucrose pellet cores are weighed and placed in a fluidized bed. Regulating the air quantity to make the pellet in an ideal fluidization state, starting a heating device, keeping the material temperature of the pellet at 32 ℃, starting a peristaltic pump when the material temperature reaches a preset value, and atomizing and uniformly dispersing the coating liquid on the surface of the pellet core through a spray gun;
2) preparation of enteric coat
A. Dispersing the polymer b into a certain amount of medicinal ethanol, fully dissolving the polymer b by high-speed shearing mechanical stirring, adding a plasticizer into the polymer solution, and uniformly stirring the anti-sticking agent;
B. coating the enteric coating layer on a fluidized bed device, putting the drug-loaded pellets into a bottom spraying device of the fluidized bed, and uniformly spraying the polymer b coating liquid; the weight of the pellet enteric coating film is increased by 15 wt%.
Example 21
The pellets in examples 1-17 are prepared into conventional granules or capsules.
Example 22
Comparison of pharmacokinetics of andrographolide drop pill and andrographolide enteric-coated pellet preparation
1. Test article and preparation
Andrographolide standard (Chinese medicine biological product identification institute, purity: 98.7%, batch number: 110797-;
the andrographolide enteric-coated pellet is prepared according to the prescription and the preparation method of example 1 and example 18;
the andrographolide dripping pill and andrographolide enteric-coated pellet have substantially the same main component content.
2. Grouping and administration of laboratory animals and plasma sample collection
The 8 Wistar rats are divided into two groups randomly, and andrographolide dropping pills and andrographolide enteric-coated pellet preparations are respectively administrated by intragastric gavage according to 100mg/kg (calculated by andrographolide). Blood samples were collected at 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h after administration and stored frozen at-20 ℃.
3. Test method
3.1 analytical Instrument
The American applied biosystems liquid phase mass spectrometry system API 4000Qtrap (containing 2 Islands LC-20AD pump, SIL-20AC constant temperature autosampler, CTO-20A column oven, CBM-20A controller, ESI and APCI interface ion source, analysis Software 1.5.2 chromatographic workstation); WatersQuattro Premier XE/Acquity UPLC (Masslynx V4.1 chromatography workstation) system for ultra-high pressure liquid mass spectrometry.
3.2 plasma sample treatment
100 mu L of the plasma sample of the rat to be administered is put into a plastic EP tube, 10 mu L of internal standard solution (1.0 mu g/mL of ginkgolide) is added, 10 mu L of methanol/water (1:1) solution is added, the mixture is fully vortexed for 1min, 500 mu L of ethyl acetate is added, the mixture is fully vortexed for 3min and is then centrifuged at 15000r/min for 10min, 400 mu L of supernatant solution is taken, nitrogen is used for drying, 100 mu L of methanol/water (1:1) solution is used for vortexing for 1min, and 10 mu L of supernatant sample is taken and injected.
3.3LC-MS/MS conditions
3.3.1 chromatographic conditions
3.3.2 Mass Spectrometry conditions (negative ion detection mode)
4. Results of the experiment
The mean plasma concentration of andrographolide in the plasma after administration-time curves are shown in figure 3. The DAS3.0 software was used to calculate the main pharmacokinetic parameters of andrographolide in plasma after administration in two groups of rats (see table 1, table 2). The results of pharmacokinetic experiments show that the andrographolide enteric-coated pellet preparation shows obvious absorption retardation and T thereofmaxAbout 5.4 times of the dripping pill, and has statistical difference (P)<0.05), and the blood concentration of rats within 4 hours after the enteric-coated pellet preparation is administrated is less than that of the dripping pill group, no obvious burst release exists, CmaxIs also smaller than the dripping pill group, and the average retention time (MRT) of andrographolide in the enteric-coated pellet group is also obviously longer than that of the dripping pill group (P)<0.05) substantially corresponding to the pharmacokinetic profile of the colon targeted formulation.
TABLE 1 Primary pharmacokinetic parameters of rats in Andrographolide enteric-coated pellet formulation group
TABLE 2 Primary pharmacokinetic parameters of Andrographolide drop pill group rats
Example 23
Comparison of intestinal tissue distribution of andrographolide dripping pill and andrographolide enteric-coated pellet
1. Test article and preparation
Andrographolide standard (China institute for identification of pharmaceutical and biological products, purity: 98.7%, batch No. 110797-,
the andrographolide enteric-coated pellet is prepared according to the prescription and the preparation method of example 1 and example 18;
the andrographolide dripping pill and andrographolide enteric-coated pellet have substantially the same main component content.
2. Grouping and administration of laboratory animals and plasma sample collection
Dividing 30 rats into 2 preparation groups (andrographolide enteric-coated pellet preparation and andrographolide dripping pill) randomly, setting 5 time point groups (3 groups) in each preparation group, respectively gavaging the andrographolide dripping pill and the andrographolide enteric-coated pellet preparation according to 100mg/kg (calculated by andrographolide), killing the rats after administration for 0.5, 1.5, 4, 8 and 24 hours, rapidly collecting the tissues of the proximal small intestine, the distal small intestine and the colon of the rats, cleaning, weighing, homogenizing with physiological saline (the tissue weight/g: physiological saline/mL is 1:2), and freezing and storing at 20 ℃.
3. Test method
3.1 analytical Instrument
A combination system of UPLC-30A ultra-fast liquid chromatograph (Shimadzu, Japan) and AB SCIEX 5500QRTAP mass spectrometry (AB applied biosystems, USA).
3.2 tissue sample treatment
Taking 100 mu L of each intestinal tissue sample, adding 100 mu L of internal standard (digoxin 100ng/mL), 100 mu L of methanol-water (1:1), 2mL of ethyl acetate, whirling for 3min, centrifuging at 12500rpm/min, taking supernatant, drying by blowing nitrogen, redissolving 100 mu L of methanol-water (1:1), whirling for 1min, taking supernatant, and injecting 10 mu L of sample.
3.3LC-MS/MS conditions
3.3.1 chromatographic conditions
The column was ACQUITY UPLC BEH Shield RP 18(1.7 μm, 2.1X 100mm), the mobile phase was 0.1% formic acid water-methanol (47%: 53%), the flow rate was 0.4mL/min
3.3.2 Mass Spectrometry conditions (negative ion detection mode)
※The excimer ion is [ M + HCOO]-Form(s) of
4. Results of the experiment
Tissue distribution maps of andrographolide in the proximal small intestine, distal small intestine, and colon after administration to two groups of rats are shown in fig. 4-6. The results show that after the andrographolide enteric-coated pellet preparation and the andrographolide dropping pill preparation are taken, the distribution quantity of the andrographolide pellet group in the small intestine near end and the small intestine far end within 1.5h is less than that of the andrographolide dropping pill group, and certain distribution delay is shown. In the colon, the distribution amount of andrographolide at each time point of the enteric-coated pellet group is obviously higher than that of the dripping pill group, and the andrographolide enteric-coated pellet group can be preliminarily proved to have certain intestinal targeting property.
Claims (9)
1. An andrographolide enteric-coated targeted pellet is characterized by comprising a blank pellet core, a drug layer and an enteric coating layer; the medicine layer contains: andrographolide, polymer a dissolved under the condition that the pH value is more than or equal to 7.0; the weight ratio of andrographolide to polymer a is 1: 2-1: 0.2, the weight of the drug layer is increased by 20 to 100 percent; the enteric coating contains a polymer b dissolved under the condition that the pH value is more than or equal to 5.5, and the weight of the coating layer is increased by 5-30 wt%; the polymer a is a 1:2 copolymer of methacrylic acid and methyl methacrylate, and the polymer b is a 1:1 copolymer of methacrylic acid and ethyl acrylate; the drug layer also contains a plasticizer, an antisticking agent and a surfactant, and the enteric coating layer also contains a plasticizer and an antisticking agent.
2. The pellet of claim 1, wherein the plasticizer is selected from the group consisting of triethyl citrate, dibutyl sebacate, propylene glycol, PEG in an amount of 10 wt% to 70 wt% of the amount of polymer a; the antisticking agent is selected from talcum powder in 25-100 wt% of polymer a or glyceryl monostearate in 2-20 wt% of polymer a.
3. The pellet of claim 1, wherein the pellet core has a particle size of 200-600 microns, and the pellet core accounts for 10-70 wt% of the prescription amount.
4. The pellet of claim 2, wherein the dosage ratio of the pellet core is: andrographolide: polymer a plasticizer: anti-sticking agent: surfactant 200: (10-100):(10-100):(1-15):(1-30):(0-3).
5. The pellet of claim 4, wherein the core: andrographolide: polymer a plasticizer: anti-sticking agent: the surfactant is 200 (15-66) (13-74) (2-13.5) (3-27) (0-1.32).
6. The pellet of claim 4, wherein the pellet core: andrographolide: polymer a plasticizer: anti-sticking agent: the surfactant is 200 (20-50) (30-60) (5-10) (5-20) (0.5-1.2).
7. A process for the preparation of pellets according to claims 1 to 6, characterized by the following steps:
(1) pill core medicine feeding
A. Dispersing the polymer a in a medicinal solvent, and mechanically stirring to fully dissolve the polymer a; adding auxiliary materials into the polymer a solution; adding andrographolide, and stirring to obtain polymer a coating solution;
B. weighing a blank pellet core, placing the blank pellet core in a fluidized bed, adjusting the air amount to enable the pellet to be in an ideal fluidization state, starting a heating device, starting a peristaltic pump when the temperature of the material reaches a preset value, and enabling the polymer a coating liquid to be atomized and uniformly dispersed on the surface of the blank pellet core through a spray gun to obtain a drug-loaded pellet;
(2) preparation of enteric coating layer
A. Dispersing the polymer b in a medicinal organic solvent or water, mechanically stirring to fully dissolve the polymer b, adding auxiliary materials into the polymer b solution, and uniformly stirring to obtain a polymer b coating solution;
B. coating by adopting fluidized bed equipment, putting the drug-loaded pellets into a fluidized bed bottom spraying device, and uniformly spraying the polymer b coating solution to form an enteric coating layer; the weight increment of the enteric coating layer is 5 to 30 percent by weight.
8. The process for preparing pellets according to claim 7, comprising the steps of:
(1) pill core medicine feeding
A. Dispersing the polymer a in medicinal ethanol to ensure that the concentration of the polymer a is 5 wt%, and fully dissolving the polymer a by mechanical stirring; continuously stirring uniformly, and adding a plasticizer, an anti-sticking agent and a surfactant sodium dodecyl sulfate which are used as auxiliary materials into the polymer a solution; adding andrographolide, and stirring to obtain polymer a coating solution;
B. weighing a blank sucrose pellet core of 200-600 microns, placing the blank sucrose pellet core into a fluidized bed, adjusting the air amount to enable the pellet to be in an ideal fluidized state, starting a heating device, keeping the material temperature of the pellet to be 25-35 ℃, starting a peristaltic pump when the material temperature reaches a preset value, and enabling the polymer a coating liquid to be atomized and uniformly dispersed on the surface of the blank pellet core through a spray gun to obtain a drug-loaded pellet;
(2) preparation of enteric coating layer
A. Dispersing the polymer b in medicinal ethanol, stirring by a high-speed shearing machine to fully dissolve the polymer b, adding a plasticizer and an anti-sticking agent which are used as auxiliary materials into the polymer b solution, and stirring uniformly to obtain a polymer b coating solution;
B. coating by adopting fluidized bed equipment, putting the drug-loaded pellets into a fluidized bed bottom spraying device, and uniformly spraying the polymer b coating solution to form an enteric coating layer; the weight increment of the enteric coating layer is 8 to 20 percent by weight.
9. An andrographolide enteric-coated targeted preparation, which is characterized in that the pellet of claim 1 is prepared into granules or capsules.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1233170A (en) * | 1996-10-11 | 1999-10-27 | 普罗克特和甘保尔公司 | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| CN102552171A (en) * | 2012-03-02 | 2012-07-11 | 北京科信必成医药科技发展有限公司 | Andrographolide colon-targeted micropellet and preparation method thereof |
| CN103142492A (en) * | 2013-02-01 | 2013-06-12 | 北京科信必成医药科技发展有限公司 | Controlled release pellet preparation and its preparation method |
| CN103908535A (en) * | 2014-03-19 | 2014-07-09 | 锦州博泽医药科技开发有限公司 | Enteric capsule containing andrographolide |
-
2015
- 2015-08-06 CN CN201510478607.5A patent/CN106176619B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1233170A (en) * | 1996-10-11 | 1999-10-27 | 普罗克特和甘保尔公司 | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| CN102552171A (en) * | 2012-03-02 | 2012-07-11 | 北京科信必成医药科技发展有限公司 | Andrographolide colon-targeted micropellet and preparation method thereof |
| CN103142492A (en) * | 2013-02-01 | 2013-06-12 | 北京科信必成医药科技发展有限公司 | Controlled release pellet preparation and its preparation method |
| CN103908535A (en) * | 2014-03-19 | 2014-07-09 | 锦州博泽医药科技开发有限公司 | Enteric capsule containing andrographolide |
Non-Patent Citations (2)
| Title |
|---|
| pH-dependent colon targeted oral drug delivery system methacrylic acid copolymers I.Manipulation of drug release using Eudragit L100-55 and Eudragit S100 combinations;M. Zahirul I. Khan et al.;《Journal of Controlled Release》;19991231;第58卷;第215-222页 * |
| 穿心莲内酯结肠靶向片的制备及体外释放性能评价;单春燕等;《新疆医科大学学报》;20110131;第31卷(第01期);第36-40页 * |
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