CN115245501A - Mesalazine enteric sustained-release pellet with pulse release function and preparation method thereof - Google Patents
Mesalazine enteric sustained-release pellet with pulse release function and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a mesalazine enteric sustained-release pellet with pulse release and a preparation method thereofThe preparation method is as follows. The sustained-release pellet comprises a sustained-release drug-loaded pellet core and a quick-release drug-loaded layer, wherein the sustained-release drug-loaded pellet core comprises the following components in parts by mass: 0.3 to 0.7 portion of mesalazine, 0.05 to 0.55 portion of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.05 to 0.25 portion of microcrystalline cellulose, 0.05 to 0.35 portion of hydroxypropyl methylcellulose and 0.01 to 0.05 portion of colloidal silicon dioxide; the quick-release drug-loaded layer comprises the following components in parts by mass: 0.3 to 0.5 portion of mesalazine and povidone K 30 0.05 to 0.35. The sustained-release pellet releases less than 3 percent of drug in the stomach for 2 hours, greatly reduces the stimulation to the stomach, can release part of drug quickly when reaching the drug release part, quickly reaches the blood concentration, prolongs the release time of the drug, improves the compliance of patients and achieves the use period of once-a-day administration.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a mesalazine enteric sustained-release pellet with pulse release and a preparation method thereof.
Background
Mesalazine is an anti-inflammatory drug used to treat inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. The current preparations on the market at home comprise enteric-coated tablets, sustained-release granules, sustained-release tablets and suppositories.
Mesalazine exerts an anti-inflammatory effect on the intestinal tract by inhibiting the synthesis of prostaglandins that cause inflammation and the formation of leukotrienes, an inflammatory mediator. Mesalazine is very easily absorbed and metabolized in the human body, but only acts locally by contacting intestinal inflammatory mucosa, loses curative effect when entering the systemic circulation, and generates nephrotoxicity when being taken for a long time. Patients with ulcerative colitis have to receive long-term treatment to prevent the recurrence of inflammation.
In the prior art of pharmaceutical preparations, the common sustained-release preparation has the disadvantages that part of active ingredients are absorbed into blood circulation in the stomach and the front small intestine, so that the effective dose reaching the pathological intestinal tract is reduced; the common enteric-coated preparation has the defects that the medicine is released and absorbed quickly in the intestinal tract, the medicine release is not stable, the toxic and side effects are great, and multiple times of administration are required.
Therefore, mesalazine preparation with both delayed (enteric) and slow release characteristics appears on the market. APRISO produced by SALIX PHARMS approved by FDA in 2008 TM (mesalamine) extended-release capsules are marketed, which are designed as enteric sustained-release pellets, and which start sustained release only at a pH of 6 or more. The enteric sustained-release preparation has the advantages of reduced absorption of drug in stomach and front small intestine, stable drug release, and improved therapeutic effectAnd the administration frequency can be reduced, and the compliance of patients is improved. In addition, the enteric sustained-release pellet is a dosage dispersion type dosage form, and one dose is composed of a plurality of dispersed pellet units, so that compared with the currently used sustained-release tablet, the enteric sustained-release pellet has the following advantages: (1) The distribution area of the micro-pills in the body is large, and the micro-pills are widely and uniformly distributed in the intestinal tract in unit form after being taken, so that overlarge local concentration of the medicine is avoided, and the irritation and adverse reaction of the medicine are reduced. (2) The pellet is not affected by food delivery rhythm in intestinal tract, has uniform release, small inter-individual bioavailability difference, and higher bioavailability than sustained release tablet. (3) The drug release area is more constant than that of the sustained-release tablet, meanwhile, the drug release behavior of the pellets is the sum of the drug release behaviors of the pellets forming one dose, and the error or defect of the preparation of the individual pellets can not seriously affect the drug release behavior of the whole preparation, so the controlled release tablet is superior to the sustained-release tablet in the aspects of the reproducibility and the consistency of the drug release rule and the medication safety.
APRISO TM The slow release mechanism is membrane control type, and the preparation steps are as follows: the preparation method comprises the following steps of (1) preparing a medicine-containing pill core by adopting an extrusion spheronization method, (2) coating a slow release film on the medicine-containing pill core by adopting a film coating slow release technology, and controlling the slow release of active ingredients by the slow release film, and (3) controlling the release of the medicine in an intestinal tract by adopting an enteric coating technology on the slow release pill core. The slow release membrane material selected is ethyl acrylate-methyl methacrylate copolymer. However, it is difficult to obtain a sustained-release film with uniform thickness for coating the small-particle-size particles with the film-forming material, and the conventional domestic equipment and process cannot solve the problem.
CN105456223A discloses a mesalazine sustained-release pellet, a preparation method thereof and a mesalazine sustained-release capsule, wherein the method comprises the following steps: mixing 5-aminosalicylic acid, microcrystalline cellulose and an adhesive, and performing an extrusion rounding process to obtain a drug-containing pill core; a material comprising ethyl cellulose is adopted, and a sustained-release coating layer is coated on the pill-containing core; coating an enteric coating layer on the slow-release coating layer by adopting an enteric material and a processing aid to obtain the mesalazine slow-release pellet; the enteric material is methacrylic acid and ethyl acrylate copolymer.
However, the release time of the mesalazine sustained-release pellet can only be maintained for about 12 hours, and the compliance of patients in clinical use is not good.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a mesalazine enteric sustained-release pellet with pulse release and a preparation method thereof. The mesalazine enteric sustained-release pellet provided by the invention releases drug in stomach for 2h by not more than 3%, so that the stimulation to stomach is greatly reduced, partial drug amount can be quickly released when the drug reaches the drug release part of small intestine, the blood drug concentration is quickly reached, meanwhile, the sustained-release pellet prolongs the release time of the drug for 24 hours, the compliance of clinical use of patients is improved, and the use period of once-a-day administration is reached.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a pulse-type released mesalazine enteric-coated sustained-release pellet comprises a sustained-release drug-carrying pellet core and a quick-release drug-carrying layer coated on the sustained-release drug-carrying pellet core, wherein,
the slow-release medicine-carrying pill core comprises the following components in parts by mass:
the quick-release drug-loaded layer comprises the following components in parts by mass:
0.3 to 0.5 portion of mesalazine
Povidone K 30 0.05～0.35。
Further, the fast-release drug-loaded layer also comprises an isolation layer, and the isolation layer is wrapped on the fast-release drug-loaded layer.
As a preferable scheme, the isolation layer comprises the following components in parts by mass:
0.01-0.50 percent of hydroxypropyl methylcellulose
Polyethylene glycol 400.05-0.10
Further, the enteric-coated tablet further comprises an enteric-coated layer, and the enteric-coated layer is wrapped on the isolating layer.
As a preferable scheme, the enteric layer comprises the following components in parts by mass:
methacrylic acid copolymer 0.3-0.55
Furthermore, the enteric layer takes ethanol solution of methacrylic acid copolymer as enteric coating liquid.
Preferably, the methacrylic acid copolymer is a composition of ewing L and ewing S, wherein the mass ratio of ewing L and ewing S is 1:20 to 1:3.
more preferably, the mass ratio of ewing _ L to ewing _ S is 1:20 to 1:10.
the invention also provides a preparation method of the mesalazine enteric sustained-release pellet, wherein the preparation method comprises the following steps:
1) Mixing mesalazine, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide, and performing wet granulation and extrusion spheronization processes to obtain a sustained-release drug-carrying pill core;
2) Adopts mesalazine and polyvidone K 30 And coating a quick-release drug-loading layer on the slow-release drug-loading pellet core to obtain the mesalazine enteric-coated slow-release pellet.
Furthermore, the preparation method also comprises the step of further wrapping an isolation layer on the quick-release drug-loaded layer.
Furthermore, the preparation method also comprises the step of wrapping the enteric-coated layer on the isolating layer.
Compared with the prior art, the invention has the following advantages:
the mesalazine enteric sustained-release pellet provided by the invention releases drug in stomach for 2h by not more than 3%, so that the stimulation to stomach is greatly reduced, partial drug amount can be quickly released when the drug reaches the drug release part of small intestine, the blood drug concentration is quickly reached, meanwhile, the sustained-release pellet prolongs the release time of the drug for 24 hours, the compliance of clinical use of patients is improved, and the use period of once-a-day administration is reached.
Drawings
Fig. 1 is a schematic structural diagram of a mesalazine enteric sustained-release pellet of example 1;
fig. 2 is a schematic structural diagram of the mesalazine enteric sustained-release pellet of example 4;
fig. 3 is a schematic structural view of the mesalazine enteric sustained-release pellet of example 7;
fig. 4 is a schematic structural diagram of a mesalazine enteric sustained-release pellet of a comparative example;
in the figures 1, 2, 3 and 4, 1 is a slow-release drug-carrying pill core, 2 is a quick-release drug-carrying layer, 3 is an isolating layer, and 4 is an enteric-coated layer;
fig. 5 is a release profile of mesalazine enteric sustained-release pellets of the present invention and comparative examples.
Detailed Description
The following is a detailed description of the invention, which is intended to further illustrate the invention and not to limit it.
Example 1 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
the slow-release drug-loaded pill core:
quick-release drug-loaded layer:
mesalazine 0.4 parts by mass
Povidone K 30 0.2 part by mass
1 part by mass of 45% ethanol solution
The preparation method comprises the following steps:
1) Preparation of sustained-release drug-loaded pellet core
Mixing mesalazine, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide according to the dosage, adding water to wet uniformly, extruding into strip soft material with the thickness of 1mm by adopting an extrusion rounding machine, and rounding into spherical wet pills with the thickness of about 1 mm; drying the wet pellets at about 60 deg.C; after drying, sieving the sustained-release pill core by using a sieve with the aperture of 0.5mm and 1mm to obtain a sustained-release drug-loaded pill core;
2) Quick-release drug-carrying layer
2.1 Placing a prescribed amount of 45% ethanol solution (temperature 30 deg.C) in a cleaned stirring tank, controlling stirring pressure to be not less than 10psi, and slowly adding prescribed amount of mesalazine and polyvidone K under stirring 30 Stirring for dispersing, cooling to below room temperature, stirring for dispersing to obtain quick-release drug-loaded layer solution;
2.2 Spraying the obtained quick-release drug-loaded layer solution on the sustained-release drug-loaded pellet core obtained in the step 1) in fluidized bed (bottom spraying) coating equipment, and obtaining the mesalazine enteric sustained-release pellet after coating.
The structural schematic diagram of the mesalazine enteric-coated sustained-release pellet of the embodiment is shown in fig. 1, and the sustained-release drug-loaded pellet core 1 and the quick-release drug-loaded layer 2 are arranged from inside to outside in sequence.
Example 2 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
the slow-release drug-loaded pill core:
quick-release drug-loaded layer:
mesalazine 0.3 parts by mass
Povidone K 30 0.05 part by mass
1 part by mass of 45% ethanol solution
The preparation method comprises the following steps:
the same as in example 1.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 1.
Example 3 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
the slow-release drug-loaded pill core:
quick-release drug-loaded layer:
mesalazine 0.5 parts by mass
Povidone K 30 0.35 part by mass
1 part by mass of 45% ethanol solution
The preparation method comprises the following steps:
the same as in example 1.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 1.
Example 4 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
the quick-release drug-loaded layer is characterized by further comprising an isolating layer on the basis of the embodiment 1, wherein the isolating layer is wrapped on the quick-release drug-loaded layer and comprises the following components:
0.2 part by mass of hypromellose (E5)
Polyethylene glycol 400.08 parts by mass
The preparation method comprises the following steps:
1) Preparation of sustained-release drug-loaded pellet core
Mixing mesalazine, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide according to the dosage, adding water to wet uniformly, extruding into strip soft material with the thickness of 1mm by adopting an extrusion rounding machine, and rounding into spherical wet pills with the thickness of about 1 mm; drying the wet pellets at about 60 deg.C; after drying, sieving the sustained-release pill core by using a sieve with the aperture of 0.5mm and 1mm to obtain a sustained-release drug-loaded pill core;
2) Quick-release drug-carrying layer
2.1 A prescribed amount of 45% ethanol solution (temperature 30 ℃) was placed in a cleaned stirred tank and controlledStirring under pressure of not less than 10psi, and slowly adding formula amount of mesalazine and polyvidone K under stirring 30 Stirring for dispersing, cooling to below room temperature, stirring for dispersing to obtain quick-release drug-loaded layer solution;
2.2 Spraying the obtained quick-release drug-loaded layer solution on the sustained-release drug-loaded pellet core obtained in the step 1) in fluidized bed (bottom spraying) coating equipment, and obtaining the sustained-release drug-loaded pellet core coated with the quick-release drug-loaded layer after coating.
3) Wrapping and isolating layer
3.1 Placing purified water (with the temperature of more than 70 ℃) with the prescription amount of 30% into a cleaned stirring tank, controlling the stirring pressure to be not less than 10psi, slowly adding hydroxypropyl methylcellulose (E5) with the prescription amount into the stirring tank under stirring, stirring and dispersing, then adding purified water at normal temperature with the prescription amount of 70%, stirring and cooling the mixture to be below 40 ℃, adding polyethylene glycol 400 with the prescription amount into the mixture, and stirring the mixture to disperse the mixture to obtain an isolation layer solution;
3.2 Placing the slow-release drug-loaded pellet core wrapped with the quick-release drug-loaded layer in fluidized bed (bottom spraying) coating equipment, spraying the obtained isolation layer solution on the quick-release drug-loaded layer, and obtaining the mesalazine enteric-coated slow-release pellet after coating.
The structural schematic diagram of the mesalazine enteric-coated sustained-release pellet of the embodiment is shown in fig. 2, and the sustained-release drug-loaded pellet core 1, the quick-release drug-loaded layer 2 and the isolation layer 3 are arranged from inside to outside in sequence.
Example 5 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
the quick-release drug-loaded layer based on the embodiment 2 further comprises an isolation layer, wherein the isolation layer is wrapped on the quick-release drug-loaded layer and comprises the following components:
0.01 part by mass of hypromellose (E5)
Polyethylene glycol 400.05 parts by mass
The preparation method comprises the following steps:
the same as in example 4.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 4.
Example 6 preparation of mesalazine enteric sustained-release pellets
The components are as follows:
the quick-release drug-loaded layer is characterized by further comprising an isolating layer on the basis of the embodiment 3, wherein the isolating layer is wrapped on the quick-release drug-loaded layer and comprises the following components:
0.50 part by mass of hypromellose (E5)
Polyethylene glycol 400.10 parts by mass
The preparation method comprises the following steps:
the same as in example 4.
The schematic structural diagram of the mesalazine enteric-coated sustained-release pellet of the embodiment is the same as that of the embodiment 4.
Example 7 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
the enteric-coated tablet further comprises an enteric-coated layer on the isolation layer, wherein the enteric-coated layer comprises the following components in parts by mass:
0.45 part by mass of a methacrylic acid copolymer
Proper amount of 80% ethanol solution
Wherein the methacrylic acid copolymer is a composition of Ewing L100 and Ewing S100, wherein the mass ratio of Ewing L100 and Ewing S100 is 1:15.
the preparation method comprises the following steps:
1) Preparation of sustained-release drug-loaded pellet core
Mixing mesalazine, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide according to the dosage, adding water to wet uniformly, extruding into strip soft material with the thickness of 1mm by adopting an extrusion rounding machine, and rounding into spherical wet pills with the thickness of about 1 mm; drying the wet pellets at about 60 deg.C; after drying, sieving the sustained-release pill core by using a sieve with the aperture of 0.5mm and 1mm to obtain a sustained-release drug-loaded pill core;
2) Quick-release drug-carrying layer
2.1 Placing a prescribed amount of 45% ethanol solution (temperature 30 deg.C) in a cleaned stirring tank, controlling stirring pressure to be not less than 10psi, and slowly adding prescribed amount of mesalazine and polyvidone K under stirring 30 Stirring for dispersing, cooling to below room temperature, stirring for dispersing to obtain quick-release drug-loaded layer solution;
2.2 Spraying the obtained quick-release drug-loaded layer solution on the slow-release drug-loaded pill core coated with the isolation layer obtained in the step 2) in a fluidized bed (bottom spraying) coating device to obtain a slow-release drug-loaded pill core coated with the quick-release drug-loaded layer after coating is finished;
3) Wrapping and isolating layer
3.1 Placing purified water (with the temperature of more than 70 ℃) with the prescription amount of 30% into a cleaned stirring tank, controlling the stirring pressure to be not less than 10psi, slowly adding hydroxypropyl methylcellulose (E5) with the prescription amount into the stirring tank under stirring, stirring and dispersing, then adding purified water at normal temperature with the prescription amount of 70%, stirring and cooling the mixture to be below 40 ℃, adding polyethylene glycol 400 with the prescription amount into the mixture, and stirring the mixture to disperse the mixture to obtain an isolation layer solution;
3.2 Spraying the obtained solution of the isolating layer on the quick-release drug-loaded layer in fluidized bed (bottom spraying) coating equipment to obtain a slow-release drug-loaded pellet core coated with the isolating layer and the quick-release drug-loaded layer after coating is finished;
4) Coated with enteric layer
4.1 ) dissolving Eiteqi L100 and Eiteqi S100 in 80% ethanol solution to obtain enteric coating solution;
4.2 Placing the sustained-release drug-loaded pellet core coated with the isolating layer and the quick-release drug-loaded layer in fluidized bed (bottom spraying) coating equipment, spraying the obtained enteric coating solution on the isolating layer, and obtaining the mesalazine enteric sustained-release pellet after coating.
The structural schematic diagram of the mesalazine enteric-coated sustained-release pellet of the embodiment is shown in fig. 3, and the sustained-release drug-loaded pellet core 1, the quick-release drug-loaded layer 2, the isolation layer 3 and the enteric layer 4 are sequentially arranged from inside to outside.
Example 8 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
a) Sustained-release drug-loaded pill core
b) Quick-release drug-loaded layer
Mesalazine 0.45 parts by mass
Povidone K 30 0.1 part by mass
1 part by mass of 45% ethanol solution
c) Insulating layer
0.02 part by mass of hypromellose (E5)
Polyethylene glycol 400.08 parts by mass
d) Enteric layer
0.45 part by mass of a methacrylic acid copolymer
Proper amount of 80% ethanol solution
The methacrylic acid copolymer is a composition of Ewing L100 and Ewing S100, wherein the mass ratio of the Ewing L100 to the Ewing S100 is 1:20.
the preparation method comprises the following steps:
the same as in example 7.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 7.
Example 9 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
a) Sustained-release drug-loaded pill core
b) Quick-release drug-loaded layer
Mesalazine 0.40 parts by mass
Povidone K 30 0.1 part by mass
1 part by mass of 45% ethanol solution
c) Insulating layer
0.02 part by mass of hypromellose (E5)
Polyethylene glycol 400.08 parts by mass
d) Enteric layer
0.45 part by mass of a methacrylic acid copolymer
Proper amount of 80% ethanol solution
The methacrylic acid copolymer is a composition of Ewing L100 and Ewing S100, wherein the mass ratio of the Ewing L100 to the Ewing S100 is 1:10.
the preparation method comprises the following steps:
the same as in example 7.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 7.
Example 10 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
a) Sustained-release drug-loaded pill core
b) Quick-release drug-loaded layer
Mesalazine 0.35 parts by mass
Povidone K 30 0.1 part by mass
1 part by mass of 45% ethanol solution
c) Insulating layer
0.02 part by mass of hydroxypropyl methylcellulose
Polyethylene glycol 400.08 parts by mass
d) Enteric layer
0.45 part by mass of a methacrylic acid copolymer
Proper amount of 80% ethanol solution
The methacrylic acid copolymer is a composition of Ewing L100 and Ewing S100, wherein the mass ratio of the Ewing L100 to the Ewing S100 is 1:3.
the preparation method comprises the following steps:
the same as in example 7.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 7.
Example 11 preparation of Mesalazine enteric sustained-release pellets
The components are as follows:
a) Sustained-release drug-loaded pill core
b) Quick-release drug-loaded layer
Mesalazine 0.40 parts by mass
Povidone K 30 0.2 part by mass
1 part by mass of 45% ethanol solution
c) Insulating layer
0.03 part by mass of hypromellose (E5)
Polyethylene glycol 400.09 parts by mass
d) Enteric layer
0.50 parts by mass of methacrylic acid copolymer (Equidz L100)
Proper amount of 80% ethanol solution
The preparation method comprises the following steps:
the same as in example 7.
The structure schematic diagram of the mesalazine enteric sustained-release pellet of the embodiment is the same as that of the embodiment 7.
Comparative example
The components are as follows:
the slow-release drug-loaded pill core:
isolation layer:
0.2 part by mass of hypromellose (E5)
Polyethylene glycol 400.08 parts by mass
Enteric layer:
0.45 part by mass of a methacrylic acid copolymer
Proper amount of 80% ethanol solution
Wherein the methacrylic acid copolymer is a composition of ewt chi L100 and ewt chi S100, wherein the mass ratio of ewt chi L100 and ewt chi S100 is 1:15.
the preparation method comprises the following steps:
1) Preparation of sustained-release drug-loaded pellet core
Mixing mesalazine, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide according to the dosage, adding water to wet uniformly, extruding into strip soft material with the thickness of 1mm by adopting an extrusion rounding machine, and rounding into spherical wet pills with the thickness of about 1 mm; drying the wet pellets at about 60 deg.C; after drying, sieving the sustained-release pill core by using a sieve with the aperture of 0.5mm and 1mm to obtain a sustained-release drug-loaded pill core;
2) Wrapping and isolating layer
2.1 Placing purified water (with the temperature of more than 70 ℃) with the prescription amount of 30% into a cleaned stirring tank, controlling the stirring pressure to be not less than 10psi, slowly adding hydroxypropyl methylcellulose (E5) with the prescription amount into the stirring tank under stirring, stirring and dispersing, then adding purified water at normal temperature with the prescription amount of 70%, stirring and cooling the mixture to be below 40 ℃, adding polyethylene glycol 400 with the prescription amount into the mixture, and stirring the mixture to disperse the mixture to obtain an isolation layer solution;
2.2 Spraying the obtained solution of the isolating layer on the sustained-release drug-loaded pill core in fluidized bed (bottom spraying) coating equipment to obtain the sustained-release drug-loaded pill core coated with the isolating layer after coating;
3) Coated with enteric layer
3.1 ) dissolving Eiteqi L100 and Eiteqi S100 in 80% ethanol solution to obtain enteric coating solution;
3.2 Placing the sustained-release pill core coated with the isolating layer in fluidized bed (bottom spraying) coating equipment, spraying the obtained enteric coating solution on the isolating layer, and coating to obtain the mesalazine enteric sustained-release pellet.
The structural schematic diagram of the mesalazine enteric-coated sustained-release pellet of the comparative example is shown in fig. 4, and the sustained-release drug-carrying pellet core 1, the isolation layer 3 and the enteric layer 4 are sequentially arranged from inside to outside.
Test example 1 Release test
In order to examine the release condition of the mesalazine enteric-coated sustained-release pellet in the human gastrointestinal tract, the release degree is measured by adopting a pH medium which is converted by simulating the human gastrointestinal tract.
Samples of mesalazine enteric sustained-release pellets for testing were prepared in example 1, example 4, example 7 and comparative example, respectively.
Dissolution conditions: 750ml of 0.1mol/L hydrochloric acid solution is used as a dissolution medium, the rotating speed is 100 revolutions per minute, and sampling is carried out according to the method for 2 hours. Taking a rotary basket after 2 hours under the term of dissolution amount in acid, immediately immersing the rotary basket into 1000ml of dissolution medium of phosphate buffer solution (pH7.5), continuously operating according to the method, sampling for 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 hours, and immediately supplementing the dissolution medium with the same temperature and the same volume.
And (4) judging a result: the interference of blank auxiliary materials (containing capsule shells) on the dissolution rate measurement is not more than 2.0 percent of the marked amount; the separation degree of an impurity F peak and a mesalazine peak in the system applicability solution is not less than 2.0, and the number of theoretical plates is not less than 2000 calculated according to the mesalazine peak; sample solution is continuously injected for 6 times, the retention time RSD of the mesalazine peak is not more than 2.0%, and the RSD of the mesalazine peak area is not more than 2.0%.
The results of the release test are shown in fig. 5. As can be seen from fig. 5, the mesalazine enteric sustained-release pellet of the embodiment of the invention releases drug in stomach for 2h not more than 3%, greatly reducing the stimulation to stomach, and simultaneously has a pulse-type drug release curve, and releases a part of drug amount after reaching the drug release part, so as to quickly reach the blood concentration, and the subsequent sustained-release pellet core continuously releases, thereby effectively prolonging the time of the effective blood concentration of the drug, improving the accuracy of the drug release position, and simultaneously increasing the compliance of clinical use of patients, and achieving the once-a-day administration frequency. The release time of the mesalazine enteric sustained-release pellet of the comparative example can only be maintained for 12 hours.
Claims (10)
1. A mesalazine enteric-coated sustained-release pellet with pulse release is characterized in that the mesalazine enteric-coated sustained-release pellet comprises a sustained-release drug-carrying pellet core and a quick-release drug-carrying layer wrapped on the sustained-release drug-carrying pellet core, wherein,
the slow-release medicine-carrying pill core comprises the following components in parts by mass:
the quick-release drug-loaded layer comprises the following components in parts by mass:
0.3 to 0.5 portion of mesalazine
Povidone K 30 0.05～0.35。
2. The mesalazine enteric sustained-release pellet according to claim 1, further comprising an isolation layer, wherein the isolation layer is wrapped on the quick-release drug-carrying layer.
3. The mesalazine enteric sustained-release pellet according to claim 2, wherein the isolating layer comprises the following components in parts by mass:
0.01-0.50 percent of hydroxypropyl methylcellulose
0.05 to 0.10 percent of polyethylene glycol.
4. The mesalazine enteric sustained-release pellet according to claim 2 or 3, further comprising an enteric layer, wherein the enteric layer is wrapped on the isolation layer.
5. The mesalazine enteric sustained-release pellet according to claim 4, wherein the enteric layer comprises the following components in parts by mass:
methacrylic acid copolymer 0.3-0.55.
6. The mesalazine enteric sustained-release pellet according to claim 5, wherein the enteric layer is an enteric coating solution prepared from an ethanol solution of methacrylic acid copolymer.
7. The mesalazine enteric sustained-release pellet according to claim 6, wherein the methacrylic acid copolymer is a combination of Eiteqi L and Eiteqi S, wherein the mass ratio of the Eiteqi L to the Eiteqi S is 1:20 to 1:3, preferably 1:20 to 1:10.
8. the preparation method of the mesalazine enteric sustained-release pellet of claim 1, which is characterized by comprising the following steps:
1) Mixing mesalazine, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide, and performing wet granulation and extrusion spheronization processes to obtain the sustained-release drug-loaded pill core;
2) Adopts mesalazine and polyvidone K 30 And coating a quick-release drug-carrying layer on the slow-release drug-carrying pellet core to obtain the mesalazine enteric-coated slow-release pellet.
9. The method of claim 8, further comprising applying a release layer to the immediate release drug-loaded layer.
10. The method of claim 9, further comprising coating an enteric layer on the barrier layer.
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