CN109330995B - Pellet coated with short-acting hypoglycemic agent and preparation method thereof - Google Patents
Pellet coated with short-acting hypoglycemic agent and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention relates to a pellet for encapsulating short-acting hypoglycemic drugs and a preparation method thereof, wherein the pellet is composed of a pellet core containing high-osmotic active substances and a controlled release layer containing water-insoluble substances, the diameter of the pellet is 1.0-2.5mm, or an intermediate layer is arranged between the pellet core and the pellet core, and the drugs exist in the pellet core or/and the intermediate layer.
Description
Technical Field
The invention relates to a pellet preparation and a preparation method thereof, in particular to an osmotic pump pellet coated with insoluble short-acting hypoglycemic drug and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
Diabetes is a large disease of the affected population, and it is estimated that about 15.5 million people worldwide have diabetes, and 90% of the population are type ii diabetes. Aiming at type II diabetes, small molecular chemical medicine preparations are mainly taken to resist the rise of blood sugar and maintain the stability of the blood sugar. At present, most of hypoglycemic micromolecule chemical drugs are insoluble drugs, such as non-sulfonamide drugs, repaglinide, nateglinide and pioglitazone are all insoluble drugs, and are all common tablets for oral administration at present, and gastrointestinal absorption is poor, so that the bioavailability is low. And the medicine needs to be frequently taken before meals every day, so that the compliance of patients is poor, the phenomena of missing and taking less medicine exist, the treatment scheme is difficult to accurately execute, and the curative effect of the diseases is reduced or the disease progress delaying effect is poor. For example: the short-acting hypoglycemic medicine repaglinide is sold in the domestic market as common tablets and dispersible tablets, wherein, Noohilong (Boringer Invitrogen, Germany) is imported repaglinide common tablets, the dosage is 1 mg/tablet, and domestic manufacturers have Jiangsu Howesson pharmacy, 0.5 mg/tablet, Beijing Wansheng pharmaceutical industry, 1 mg/tablet; all are common tablets, and need to be administered for multiple times a day.
In order to reduce the number of times of administration, the reports on sustained-release and controlled-release dosage forms have been published so far as follows:
wei He et al (International Journal of pharmaceuticals 478 (2015) 297) 307) prepared repaglinide into a hydrophilic gel matrix tablet, and prolonged the drug release time to 12 h. Chao Qin et al (International Journal of pharmaceuticals 466 (2014) 276-285) prepares repaglinide into osmotic pump tablets, and prolongs the drug release time to 24 h. The machine types are all tablets and have the defect of single dosage.
NILESH SAINDANE et al (Journal of Pharmaceutical Sciences, Vol. 101, 3169-3179 (2012)) disclose in 2012 osmotic pump pellet technology to prepare glipizide pellets, wherein the controlled release drug is for 24h, a pellet core of sucrose-starch is adopted, a drug layer adopts dichloromethane-methanol as a solvent, a controlled release layer adopts cellulose acetate, a solvent is a dichloromethane and 2-propanol combined solvent, and a pellet drug layer and a controlled release layer are prepared by a coating pan. In the above dosage forms, the tablet is a single dosage form drug. The core of the pill adopts sucrose-starch, and both the sucrose and the starch can increase the blood sugar of the diabetic and are not beneficial to regulating the blood sugar; the coating pan is adopted to prepare the drug layer and the controlled release layer, so that the problems of nonuniform coating and mutual adhesion among the pellets are easily caused for the pellets, and the preparation efficiency is not high. The organic solvent is not beneficial to environmental protection, cannot be produced in large scale and is easy to explode.
CN103211787A discloses a glipizide film-controlled sustained-release pellet capsule, wherein a sustained-release coating film of the pellet adopts Eurdragit RL 30D as a film-forming material, a pellet core contains high-expansibility sodium carboxymethyl starch, and other pharmaceutically acceptable excipients commonly used for sustained-release pellets, preferably microcrystalline cellulose, lactose and sodium dodecyl sulfate, wherein the percentage of the sodium carboxymethyl starch in the pellet core accounts for 5-20% of the weight of the pellet core. The slow-release coating film comprises Eurdagit RL 30D, a plasticizer triethyl citrate and an anti-sticking agent talcum powder, the proportion of the Eurdagit RL 30D, the plasticizer triethyl citrate and the anti-sticking agent talcum powder is preferably 30: 3: 4, and the weight increase of the coating is preferably 17-36%. Because the pellet core containing the carboxymethyl starch sodium with high water-swelling property can obviously swell after absorbing water, the slow-release coating is expanded, the thickness is thinned, the aperture of the water-permeable micropores is enlarged, the permeability is improved, and the permeability reduction caused by membrane aging is compensated, so that the release speed in the middle and later periods is basically constant, the residue in the later period is small, and the stable release performance can be always kept in the validity period. In the patent, glipizide is a poorly soluble drug, and is placed in a pill core, so that incomplete drug release can be caused, and in addition, the drug is difficult to absorb even after being released; a pore-foaming agent is not added in the sustained-release membrane, so that the drug release performance is reduced; no auxiliary material for increasing the release power of the medicine is added in the pill core, so that a slow release system mainly based on diffusion is caused, and the medicine release is incomplete in the later period.
In view of this, a new dosage form with reduced administration frequency, high bioavailability and safe administration is needed for insoluble short-acting hypoglycemic drugs.
Disclosure of Invention
The invention aims to solve the defects of the prior art, provides an osmotic pump pellet coated with insoluble short-acting hypoglycemic drug, which applies the osmotic pump drug release principle to control the release speed of the drug so as to achieve the purposes of improving the bioavailability of the insoluble drug and reducing the drug taking times of patients, and also provides a preparation method thereof.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the technical subject is as follows:
a pellet loaded with a short-acting hypoglycemic drug, said pellet consisting of a pellet core containing a highly osmotically active substance and a controlled release layer containing a water-insoluble substance, said pellet having a diameter of 1.0-2.5mm, said drug being present in said pellet core; preferably, the short-acting hypoglycemic agent is selected from: any one or combination of more than two of repaglinide, nateglinide and pioglitazone.
Further, the pellet comprises a pellet core containing a high-permeability active substance, a middle layer coated outside the pellet core and a controlled release layer containing a water-insoluble substance coated outside the middle layer, the diameter of the pellet is 1.0-2.5mm, and the drug is present in the pellet core and/or the middle layer; preferably, the short-acting hypoglycemic agent is selected from: any one or combination of more than two of repaglinide, nateglinide and pioglitazone.
Further, the pellet core comprises a high-permeability active substance, a pellet forming agent and a slow-release retarding additive, wherein the mass ratio of the high-permeability active substance to the pellet forming agent to the slow-release retarding additive is 50-90: 9.5-45: 0.5-5;
preferably, the high osmotic activity substance includes, but is not limited to, saccharides, salts, inorganic small molecular substances and high molecular compounds; preferably, the saccharide is selected from one or more of lactose, fructose, sucrose, glucose, mannitol and xylitol; preferably, the salts are selected from sodium chloride or potassium chloride; preferably, the inorganic small molecule substance is selected from one or a combination of more than two of tartaric acid, fumaric acid, malic acid, citric acid or adipic acid;
preferably, the pellet forming agent is selected from microcrystalline cellulose or starch;
preferably, the macromolecular compound is selected from one or the combination of more than two of cyclodextrin, B-cyclodextrin, hydroxypropyl-B-cyclodextrin or sulfobutyl-B-cyclodextrin; preferably, the slow release retarding additive is selected from HPMC, PVP, CMC-Na or PVA.
Further, the controlled release layer comprises a water-insoluble substance, a plasticizer and a pore-foaming agent, wherein the mass ratio of the water-insoluble substance to the pore-foaming agent is 2:3-3: 1;
preferably, the water-insoluble substance is selected from water-insoluble coating materials, preferably cellulose acetate, ethyl cellulose, insoluble acrylic resin, cellulose acetate phthalate or hydroxypropyl cellulose phthalate, or any one or more combination of the above substances; the plasticizer is selected from triethyl citrate; preferably, the pore-forming agent is selected from one or a combination of more than two of hypromellose, sodium dodecyl sulfate, sodium chloride, lactose, mannitol, fructose, xylitol, fumaric acid, adipic acid, malic acid or citric acid.
Further, the intermediate layer comprises a solid dispersion carrier;
preferably, the material is selected from one or the combination of two or more of povidone, hypromellose, sodium dodecyl sulfate, poloxamer F127, poloxamer F68, polyethylene glycol, soluplus or killidon VA 64.
Further, an isolation layer is arranged between the middle layer and the controlled release layer, the isolation layer comprises gastric-soluble coating powder and HPMC, and the weight of the coating is increased by 1.5-2.5%.
Further, the pellet comprises the following components in parts by weight:
(1) pill core
1-20 parts of a short-acting hypoglycemic drug;
50-500 parts of a permeable active substance;
10-100 parts of a pellet forming agent;
0.5-5 parts of slow release retarder;
(2) controlled release layer
20-80 parts of water-insoluble substances;
0.004-0.1 part of plasticizer;
10-70 parts of a pore-foaming agent.
Further, the pellet comprises the following components in parts by weight:
(1) pill core
1-20 parts of a short-acting hypoglycemic drug;
50-500 parts of a permeable active substance;
10-100 parts of a pellet forming agent;
0.5-5 parts of slow release retarder;
(2) intermediate layer
1-20 parts of short-acting hypoglycemic micromolecule medicine;
10-200 parts of a solid dispersion carrier;
(3) controlled release layer
20-80 parts of water-insoluble substances;
0.004-0.1 part of plasticizer;
10-70 parts of a pore-foaming agent.
Subject matter two
The invention provides a pellet coated with a short-acting hypoglycemic drug as the technical subject, wherein the material of the pellet core is added with a proper solution to prepare soft pellets, the soft pellets are extruded by a spheronizer, and the extruded pellets have a sieve plate with the pore diameter of 0.4-1.5mm and are dried; adding adhesive into the material of the middle layer to prepare solution, preparing the middle layer of the pellet core by fluidized bed bottom spraying or centrifugal disc type method, controlling the thickness of the middle layer at 0.1-1mm, and drying; dissolving the material of the isolating layer with water, preparing the isolating layer by a fluidized bed bottom spraying or centrifugal disc type method, drying for 2 hours by a fluidized bed after the weight is increased by 2 percent, and controlling the air inlet temperature to be between 40 and 45 ℃; and then, preparing the material of the controlled release layer into aqueous dispersion by using water as a solvent, and coating, wherein the weight gain is 3-15%.
Further, the method specifically comprises the following steps:
(1) preparing the core of the pill
A. Sieving the active substance and pellet forming agent with 80 mesh sieve, and mixing;
B. preparing the slow release retarder into 5-15 wt% of aqueous solution;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. sending the soft talents obtained in the step CExtruding out of a rolling machine to form strips, then rolling the round pellet cores by the rolling machine, wherein the diameter of an extrusion sieve plate is 0.4-1.5mm, and then drying in a 60 ℃ drying oven for 6 hours, the water content is less than 2%, and the hardness of the pellet cores is 10-17kg cm-2；
(2) Coated controlled release coating film
A. And (3) placing the pellets obtained in the step (2) in a fluidized bed instrument, and coating a controlled release coating layer. The air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 35-45 ℃, the weight is increased by 3-15% (W/W), and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
Preferably, the core pellet comprises an intermediate layer comprising a drug:
A. mixing the medicine, the solid dispersion material and the adhesive in the prescription amount, and sieving with a 60-80 mesh sieve for later use;
B. dissolving the material obtained in the step A by using a 10% PVP k30 ethanol solution (ethanol: water =1:1, w/w), and placing at 30 ℃ for later use;
C. and C, preparing the drug layer of the pill core from the liquid obtained in the step B by a fluidized bed bottom spraying or centrifugal disc method, wherein the thickness of the drug layer is 0.1-1mm, the temperature of the fluidized bed is set between 30-45 ℃, and then the solution is dried in an oven at 60 ℃ for 12 hours to obtain the drug-containing pellets.
Preferably, the middle layer containing medicine is wrapped with isolation coat, water is used as solvent, when the weight is increased by 2%, the drying is continued for 2h, and the hot air temperature of the fluidized bed is maintained between 40-45 ℃.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
the osmotic pump pellet preparation for encapsulating the insoluble short-acting hypoglycemic drug has the advantages that the specific formula composition, the proportion and the preparation process are adopted, the overall synergistic effect is realized, the solubility and the absorption degree of the drug in gastrointestinal fluid can be obviously improved, the bioavailability is improved, the drug can play the role of controlled release and long-acting release, and the drug administration frequency is reduced and the bioavailability is improved.
The osmotic pump pellet preparation for encapsulating the insoluble short-acting hypoglycemic drug solves the problem of coating weight increment of a fluidized bed in the preparation process by the specific formula composition, proportion and preparation process, avoids the irritation of the drug to the stomach, meets the requirements on appearance, component content and drug release, and has high pellet qualification rate. More importantly, the osmotic pump pellet preparation for encapsulating the insoluble short-acting hypoglycemic drug can greatly improve the placement stability and improve the bioavailability of patients with weak gastric acid.
The osmotic pump pellet preparation for encapsulating the insoluble short-acting hypoglycemic drug is characterized in that the insoluble short-acting hypoglycemic drug is designed into a solid dispersion pellet core or a solid dispersion drug layer, and is combined with a large amount of osmotically active substances in a sustained-release pellet core for use, so that the insoluble short-acting hypoglycemic drug is not influenced by the pH, food and peristalsis of the gastrointestinal tract, but does not stimulate the physiological function and structure of the gastrointestinal tract, and has a 24-hour controlled-release behavior.
The osmotic pump pellet preparation for encapsulating the insoluble short-acting hypoglycemic drug is a multi-unit system, the release curve of the drug depends on the overall release behavior of the pellet, the stability and the continuity of drug release of the pellets among batches are improved, and the consistency of the drug effect of patients is enhanced.
The osmotic pump pellet preparation for encapsulating the insoluble short-acting hypoglycemic drug, which is prepared by the invention, can be packed and taken in a dosage form, is beneficial to adjusting the dosage, flexibly changes the dosage scheme, and is different from the existing osmotic pump tablet which is difficult to adjust the dosage and is not beneficial to the change of the dosage scheme.
In the preparation process, the aqueous dispersion solution replaces the conventional water-insoluble coating material formulated with organic solvents. The water-insoluble substance and the pore-forming agent are prepared into the aqueous dispersion by an emulsion solvent diffusion method or an emulsion solvent evaporation method, wherein the organic solvent has low residue, the value of the organic solvent is not more than one thousandth, and the aqueous dispersion is environment-friendly and high in safety.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Figure 1 in vitro release profile of repaglinide pellets prepared in example 1 (n = 3);
fig. 2 in vivo pharmacokinetic profiles (n = 3) of repaglinide pellets prepared in example 1 versus commercially available pellets.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail and fully with reference to the following embodiments.
Example 1
An osmotic pump pellet preparation (repaglinide, 3mg 100mg pellet, 105g in total, unit: g) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
repaglinide 1
Lactose (model Granulac 200) 80;
microcrystalline cellulose (type PH 101) 20;
povidone (PVPk 30) 0.5;
(2) the drug layer part
Repaglinide 2;
sodium dodecyl sulfate 1.2;
polyethylene glycol 400048.8;
HPMC (model: K4M) 7.2;
(3) barrier layer section
Gastric coating powder (opadry) 9;
HPMC (model: K4M) 1;
(4) controlled release layer section
Ethyl cellulose (M70) 30;
sodium lauryl sulfate 45;
triethyl citrate 0.004.
The preparation method of the pellet preparation coated with the short-acting hypoglycemic small molecule medicine comprises the following steps:
(1) preparing the core of the pill
A. Taking repaglinide, lactose and microcrystalline cellulose in the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing, wherein the materials are reserved;
B. preparing povidone into 10 percent of water solution;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. extruding the soft material obtained in the step C by a rounding machine to form strips, rounding the round ball cores by the rounding machine, wherein the diameter of an extrusion sieve plate is 0.4mm, and then placing the strips in a 60 ℃ drying oven to dry for 6 hours, the water content is less than 2%, and the hardness of the ball cores is 10-17kg cm-2；
(2) Preparation of drug layer of solid dispersion
A. Mixing repaglinide, sodium dodecyl sulfate, polyethylene glycol 4000 and HPMC in a prescription amount, and sieving the mixture by a 60-80-mesh sieve to obtain a material for later use;
B. dissolving the material obtained in the step A by using a 10% PVP k30 ethanol solution (ethanol: water =1:1, w/w), and placing at 30 ℃ for later use;
C. b, preparing a drug layer of the pill core from the liquid obtained in the step B by a fluidized bed bottom spraying or centrifugal disc method, wherein the thickness of the drug layer is 0.1mm, the temperature of the fluidized bed is set to be 40 +/-5 ℃, and then the solution is dried in an oven at 60 ℃ for 12 hours to obtain drug-containing pellets for later use;
D. c, placing the pellets obtained in the step C into a fluidized bed, coating an isolation coating, continuing drying for 2 hours when the weight of the pellets is increased by 2%, and maintaining the hot air temperature of the fluidized bed between 40 and 50 ℃;
(3) coated controlled release coating film
A. And (3) placing the pellets obtained in the step (2) in a fluidized bed instrument, and coating a controlled release coating layer. The air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 35-45 ℃, the weight is increased by 5g, and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
The pellets produced in this example released 5% -15% of the dose in the immediate release from 0 to 10 minutes, while the controlled release portion released the remainder of the dose with zero order kinetics from 10 to 24 minutes.
Example 2
An osmotic pump micro-pill (Nateglinide 3mg 100mg micro-pill, 130g micro-pill in unit: g) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
nateglinide 1;
lactose (model Granulac 200) 80;
microcrystalline cellulose (type PH 101) 20;
povidone (PVPk 30) 5;
(2) the drug layer part
Nateglinide 2;
3.6 parts of sodium dodecyl sulfate;
Soluplus 196.4；
poloxamer (F127) 7.2;
(3) controlled release layer section
15 parts of sodium chloride;
triethyl citrate 0.004;
The preparation method of the pellet preparation coated with the short-acting hypoglycemic small molecule medicine comprises the following steps:
(1) preparing the core of the pill
A. Taking the formula amount of the permeable active substance, the nateglinide and the pellet forming substance, sieving with a 80-mesh sieve, and uniformly mixing to obtain a material for later use;
B. preparing 15% aqueous solution of adhesive;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. c, extruding the soft pellets obtained in the step C by a rounding machine to form strips, rounding the soft pellets by the rounding machine, placing the extruded sieve plates with the aperture of 1.5mm in a drying oven at the temperature of 60 ℃ for drying for 6 hours, wherein the water content is less than 2 percent, and the hardness of the soft pellets is 10-17kg cm-2；
(2) Preparation of drug layer of solid dispersion
A. Mixing the nateglinide and the solid dispersion material according to the prescription amount, and sieving the mixture with a 80-mesh sieve for later use;
B. dissolving the material obtained in the step A by using a 10% PVP k30 ethanol solution (ethanol: water =1:1, w/w), and placing at 30 ℃ for later use;
C. b, preparing a drug layer of the pill core from the liquid obtained in the step B by a fluidized bed bottom spraying or centrifugal disc method, wherein the thickness of the drug layer is 0.8mm, the temperature of the fluidized bed is set between 30 and 45 ℃, and then the solution is dried in an oven at 60 ℃ for 12 hours to obtain drug-containing pellets for later use;
(3) coated controlled release coating film
A. And (3) placing the pellets obtained in the step (2) in a fluidized bed instrument, and coating a controlled release coating layer. The air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 35-45 ℃, the weight is increased by 15g, and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
The pellets produced in this example released 5% -15% of the dose in the immediate release from 0 to 10 minutes, while the controlled release portion released the remainder of the dose with zero order kinetics from 10 to 24 minutes.
Example 3
An osmotic pump pellet preparation (pioglitazone, specification: 30mg/300mg, 135g pellet) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
b-cyclodextrin 80;
microcrystalline cellulose (type PH 101) 20;
povidone (PVP k30) 1;
(2) the drug layer part
povidone (PVP k30) 2.4;
killidon VA 64 97.6；
HPMC (model: K4M) 14.4;
(3) controlled release layer section
Ethyl cellulose (M70) 30;
triethyl citrate 0.004;
30 parts of sodium dodecyl sulfate;
The preparation method of the pellet preparation coated with the short-acting hypoglycemic small molecule medicine comprises the following steps:
(1) preparing the core of the pill
A. Taking pioglitazone, B-cyclodextrin and microcrystalline cellulose in the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing to obtain a material for later use;
B. preparing povidone into 10% water solution;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. c, extruding the soft pellets obtained in the step C by a rounding machine to form strips, rounding the round pellets by the rounding machine, wherein the diameter of an extrusion sieve plate is 0.4mm, and then drying the strips in a drying oven at the temperature of 60 ℃ for 6 hours, the water content is less than 2%, and the hardness of the pellets is 10-17kg cm-2；
(2) Preparation of drug layer of solid dispersion
A. Taking pioglitazone, sodium dodecyl sulfate, killidon VA 64 and HPMC in the formula amount, mixing and sieving with a 60-80-mesh sieve for later use;
B. dissolving the material obtained in the step A by using a 10% PVP k30 ethanol solution (ethanol: water =1:1, w/w), and placing at 30 ℃ for later use;
C. b, preparing a drug layer of the pill core from the liquid obtained in the step B by a fluidized bed bottom spraying or centrifugal disc method, wherein the thickness of the drug layer is 1mm, the temperature of the fluidized bed is set to be 40 +/-5 ℃, and then the fluid layer is placed in an oven for drying the solvent at 60 ℃ for 12 hours to obtain drug-containing pellets for later use;
(3) coated controlled release coating film
A. And (3) placing the pellets obtained in the step (2) in a fluidized bed instrument, and coating a controlled release coating layer. The air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 35-45 ℃, the weight is increased by 10g, and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
The pellets produced in this example released 5% -15% of the dose in the immediate release from 0 to 10 minutes, while the controlled release portion released the remainder of the dose with zero order kinetics from 10 to 24 minutes.
Example 4
An osmotic pump pellet preparation (repaglinide, 3mg/100mg, 100g pellet) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
repaglinide 1;
80 parts of xylitol;
starch (type PH 101) 20;
povidone (PVPk 30) 2;
(2) the drug layer part
Repaglinide 2;
sodium dodecyl sulfate 1.2;
polyethylene glycol 400060;
HPMC (model: K4M) 9.0;
(3) barrier layer section
Gastric coating powder (opadry) 9;
HPMC (model: K4M) 1;
(4) controlled release layer section
Ethyl cellulose (M70) 30;
triethyl citrate 0.004;
sodium dodecyl sulfate 45;
the preparation method of the pellet preparation coated with the short-acting hypoglycemic small molecule medicine comprises the following steps:
(1) preparing the core of the pill
A. Taking repaglinide, xylitol and starch in the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing, wherein the materials are for later use;
B. preparing povidone into 10 percent of water solution;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. extruding the soft pellets obtained in the step C by a rounding machine to form strips, rounding the round pellets by the rounding machine, placing the extruded sieve plates with the aperture of 0.4-1.5mm in a drying oven at 60 ℃ for drying for 6 hours, wherein the water content is less than 2%, and the hardness of the pellets is 10-17kg cm-2；
(2) Preparation of drug layer of solid dispersion
A. Mixing repaglinide, sodium dodecyl sulfate, polyethylene glycol 4000 and HPMC in a prescription amount, and sieving the mixture by a 60-80-mesh sieve to obtain a material for later use;
B. dissolving the material obtained in the step A by using a 10% PVP k30 ethanol solution (ethanol: water =1:1, w/w), and placing at 30 ℃ for later use;
C. b, preparing a drug layer of the pill core from the liquid obtained in the step B by a fluidized bed bottom spraying or centrifugal disc method, wherein the thickness of the drug layer is 0.5mm, the temperature of the fluidized bed is set to be 40 +/-5 ℃, and then the solution is dried in an oven at 60 ℃ for 12 hours to obtain drug-containing pellets for later use;
(3) coated controlled release coating film
A. And (3) placing the pellets obtained in the step (2) in a fluidized bed instrument, and coating a controlled release coating layer. The air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 40-45 ℃, the weight is increased by 10g, and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
The pellets produced in this example released 5% -15% of the dose in the immediate release from 0 to 10 minutes, while the controlled release portion released the remainder of the dose with zero order kinetics from 10 to 24 minutes.
Example 5
An osmotic pump pellet preparation (repaglinide, 3mg/100mg, 105g pellet g) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
repaglinide 1;
starch (type PH 101) 20;
povidone (PVPk 30) 1;
(2) controlled release layer section
Acrylic resin (RS-30D) 25;
HPMC （K4M） 15；
triethyl citrate 0.004;
15 of fumaric acid;
the preparation method of the pellet preparation coated with the short-acting hypoglycemic small molecule medicine comprises the following steps:
(1) preparing the core of the pill
A. Taking repaglinide, mannitol, sodium chloride and starch in the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing, wherein the materials are for later use;
B. preparing povidone into 10 percent of water solution;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. c, extruding the soft pellets obtained in the step C by a rounding machine to form strips, rounding the soft pellets by the rounding machine, placing the extruded sieve plates with the aperture of 1mm in a drying oven at the temperature of 60 ℃ for drying for 6 hours, wherein the water content is less than 2 percent, and the hardness of the soft pellets is 10-17kg cm-2；
(2) Coated controlled release coating film
A. And (2) placing the pellets obtained in the step (1) in a fluidized bed instrument, and coating a controlled release coating layer. The air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 40-45 ℃, the weight is increased by 15g, and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
The pellets produced in this example released 5% -15% of the dose in the immediate release from 0 to 10 minutes, while the controlled release portion released the remainder of the dose with zero order kinetics from 10 to 24 minutes.
Example 6
An osmotic pump pellet preparation (repaglinide, 3mg/100mg, 105g pellet) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
repaglinide 1;
60 parts of xylitol;
20 of starch;
povidone (PVPk 30) 5;
(2) the drug layer part
Repaglinide 2;
povidone 8.0;
polyethylene glycol 4000120;
HPMC (model: K4M) 2.0;
(3) controlled release layer section
HPMC （K4M） 8；
triethyl citrate 0.004;
2 parts of citric acid;
the preparation method is the same as example 2.
Example 7
An osmotic pump pellet preparation (repaglinide, 3mg/100mg, 105g pellet) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
repaglinide 2;
lactose (model Granulac 200) 80;
microcrystalline cellulose (type ph 101) 20;
povidone (PVPk 30) 5;
(2) the drug layer part
Repaglinide 1;
8.2 parts of sodium dodecyl sulfate;
polyethylene glycol 4000100;
HPMC (model: K4M) 2.4;
(3) controlled release layer section
Ethyl cellulose (M70) 25;
HPMC （K4M） 15；
triethyl citrate 0.004;
30 parts of sodium dodecyl sulfate;
the preparation method is the same as example 2.
Example 8
An osmotic pump pellet preparation (repaglinide, 3mg, 730g pellet) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
lactose (model G200) 500;
microcrystalline cellulose (type ph 101) 50;
povidone (PVPk 30) 5;
(2) the drug layer part
15 parts of sodium dodecyl sulfate;
polyethylene glycol 4000180;
HPMC (model: K4M) 5;
(3) controlled release layer section
Ethyl cellulose (M70) 30;
HPMC （K4M） 15；
triethyl citrate 0.004;
30 parts of sodium dodecyl sulfate;
the preparation method is the same as example 2.
Example 9
An osmotic pump pellet preparation (repaglinide, 3mg/100mg, 100g pellet) for encapsulating insoluble short-acting hypoglycemic drug
(1) A pill core part:
repaglinide 1;
mannitol 80;
microcrystalline cellulose (type PH 101) 20;
povidone (PVPk 30) 5;
(2) the drug layer part
Repaglinide 2;
7.5 parts of sodium dodecyl sulfate;
Soluplus 80；
HPMC (model: K4M) 5;
(3) controlled release layer section
Ethyl cellulose (M90) 25;
HPMC （K4M） 15；
citric acid triethyl ester
Sodium dodecyl sulfate
The preparation method is the same as example 2.
Example 10 determination of in vitro Release of pellets coated with short-acting hypoglycemic Agents in accordance with the invention
According to the first method of the supplement XD of the fourth part of the pharmacopeia of 2015 edition, a dissolution rate measuring device (the first method of the supplement XD of the second part of the pharmacopeia of 2015 edition) is adopted, 900ml of artificial gastric juice with the pH value of 1.2 contains 0.5 percent of sodium dodecyl sulfate as a release medium, the water temperature is 37 ℃, the rotating speed is 100 r/min, 5ml of solution is taken when the operation is carried out for 1h and 2h according to the method, and the solution is filtered and supplemented with the medium with the same temperature and volume. And (4) injecting 20 mu l of filtrate into a chromatograph, recording a chromatogram, and calculating the release degree of repaglinide.
After 2h the medium was adjusted to pH6.8 for artificial intestinal juice containing 0.5% sodium lauryl sulfate, after 30 minutes 5ml of solution was taken, with the same volume of medium at the same temperature. And (3) filtering the sample, injecting 20 mu l of the filtered sample into a chromatograph, recording a chromatographic peak, and calculating the release degree of repaglinide. And (5) taking, supplementing and filtering the solution 2h, 4h, 6h, 10h and 24h after the solution is changed, and calculating the release degree of the repaglinide.
The high performance liquid chromatography method comprises the following steps: the chromatographic column is an octadecylsilane chemically bonded silica packing column; the mobile phase is 0.02mol/L disodium hydrogen phosphate buffer (10% phosphoric acid solution to adjust pH to 6.5) -methanol (700: 30); detection wavelength: 243 nm;
preparing a repaglinide reference substance: taking 20mg of repaglinide reference substance, precisely weighing, placing in a 50ml measuring flask, adding a methanol solution for dissolving, and fixing the volume. Precisely measuring 1.0ml to 10ml measuring bottles, diluting the mobile phase to scale, and preparing the reference solution containing 40 mu g of repaglinide in each 1 ml.
As a result: in normal gastric juice: simulated gastric juice environment pH1.2, containing sodium dodecyl sulfate (0-2 h); artificial intestinal juice (2-24 h) simulating the intestinal juice environment with pH of 6.8; the release rate of repaglinide is 2.5, 25, 37, 48 and 63% in 2, 4, 6, 8 and 12 hours, and 93% in 24 hours; 1. RSD is less than 10% in 2h, and RSD released in the rest time is less than 5%; see fig. 1. The result shows that the pellet in vitro release of the repaglinide osmotic pump presents an obvious controlled release characteristic, the pellet is verified to be zero-order release by a fitting equation, the release lasts 24 hours, and finally 93% in 24 hours, while the common repaglinide tablet releases 85% in 25min, and presents an obvious quick release characteristic.
Example 11 in vivo pharmacokinetic experiments
Three rats are selected and divided into two groups, one group is given with the pellet preparation provided in example 1, the other group is given with a commercially available common tablet, grinding is carried out, 0.5% CMC-Na solution is added for suspension, then the stomach filling is carried out, 0.5ml of orbital inner canthus venous blood is taken at 0min, 15 min, 30 min, 60min, 2h, 4h, 6h, 8h, 12h and 24h, and the supernatant is taken for standby after 10min of centrifugation at 4000 rpm. After 200. mu.l of the taken supernatant was subjected to liquid-liquid extraction with ethyl acetate, nitrogen was evaporated, the mobile phase was redissolved in 100. mu.l, the concentration of the drug was measured by HPLC-UV, the concentration of the drug at each time point was calculated by a standard curve equation, and a pharmacokinetic curve chart was drawn, as shown in FIG. 2.
As a result, the in vivo pharmacokinetics of the home-made pellets showed lower C than the commercial formulationmax420ng/ml, lower than 510ng/ml for the commercial formulation; self-made preparation AUC0-t4569 ng/h/ml, which is higher than 2854 ng/h/ml of the commercial preparation, and shows that the self-made preparation has obvious drug slow-release effect.
Investigation test 1
The pellet core and the drug layer were prepared according to the formulation and preparation method of example 1, with test group 1-1 not coated with barrier coating, and test group 1-2 coated with barrier coating, specifically, 100g of pellet core was taken, with or without barrier coating, and then coated with controlled release coating film. After the controlled release coating is dried, the membrane is taken out for determination, and parameters such as diameter, drug content, pellet yield, time taken for coating the controlled release coating and the like are included. The results show that the time for coating the controlled release coating is shortened after the barrier coating is added, and the dosage, yield and drug content of the coating solution have obvious advantages, and are shown in table 1:
investigation test 2
The pellet cores and drug layers were prepared according to the pellet core formulation of table 2 and the preparation method of example 1, specifically, 100g of pellet cores were taken, barrier coated, and then coated with a controlled release coating film, according to the method of example 1. The release rates of the different pellet core formulations were determined according to the in vitro release rate method. The result shows that the zero-order release of the osmotic substance, the pill core forming agent, the retarder and the medicament of the pill core plays an important role, the osmotic substance is increased, the forming agent is reduced, the medicament has an obvious zero-order medicament release characteristic, and the retarder plays an obvious role in regulating the release of the medicament. The controlled release effect of the insoluble drug can be achieved through proper compatibility of the three components, which is specifically shown as follows:
TABLE 2
Through the adjustment test of the composition of the pellet core, the high-permeability active substance, the pellet forming agent and the slow release retardant are found to be all the above. The pellet forming agent can promote the pill forming on one hand, and can coordinate the influence degree of the retarder and the high-osmotic active substance on the other hand, so that the release speed is more gentle.
Comparative example 1
The difference from example 1 is that the pellet core does not contain hydroxypropylcellulose, and the in vitro release degree was measured according to the test method of example 10 as follows: drug release data without added blockers: the drug release speed is higher in 2-6h stage, the drug release rate reaches 75% in 6h, and the drug release rate is 56% in 6h with blocker.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (6)
1. A pellet coated with a short-acting hypoglycemic drug is characterized by comprising the following components in parts by weight:
(1) a pill core part:
2 portions of medicine
80 parts of lactose;
20 parts of microcrystalline cellulose;
300.5-5 parts of povidone k;
(2) the drug layer part
1-2 parts of a medicine;
1.2-8.2 parts of sodium dodecyl sulfate;
400048.8-100 parts of polyethylene glycol;
HPMC 2.4-7.2；
(3) barrier layer section
9 parts of gastric-soluble coating powder;
1 part of HPMC;
(4) controlled release layer
20-80 parts of water-insoluble substances;
0.004-0.1 part of plasticizer;
10-70 parts of a pore-foaming agent;
the drug is selected from one of repaglinide and nateglinide.
2. The pellet of claim 1, wherein the water-insoluble material is selected from water-insoluble coating materials.
3. The pellet of claim 1, wherein the water-insoluble substance is selected from one or more of cellulose acetate, ethyl cellulose, insoluble acrylic resin, cellulose acetate phthalate and hydroxypropyl cellulose phthalate.
4. The pellet of claim 1, wherein the plasticizer is selected from triethyl citrate.
5. The pellet of claim 1, wherein the pore-forming agent is selected from hypromellose, sodium dodecyl sulfate, sodium chloride, lactose, mannitol, fructose, xylitol, fumaric acid, adipic acid, malic acid, or citric acid, or a combination of two or more thereof.
6. The preparation method of the pellets coated with the short-acting hypoglycemic drug according to claim 1, which comprises the following steps:
(1) preparing the core of the pill
A. Sieving the medicines, lactose and microcrystalline cellulose in the prescription amount by a sieve of 80 meshes, and uniformly mixing the materials for later use;
B. preparing povidone k30 into 5-15 wt% aqueous solution;
C. mixing the material obtained in the step A and the solution obtained in the step B to prepare a soft material, and placing the soft material in a closed container for 4 hours to uniformly mix the material, the adhesive and the solvent;
D. extruding the soft pellets obtained in the step C by a rounding machine to form strips, rounding the round pellets by the rounding machine, placing the extruded sieve plates with the aperture of 0.4-1.5mm in a drying oven at 60 ℃ for drying for 6 hours, wherein the water content is less than 2%, and the hardness of the pellets is 10-17kg cm-2；
(2) Preparation of the intermediate layer
A. Mixing the medicines, the sodium dodecyl sulfate, the polyethylene glycol 4000 and the HPMC according to the prescription amount, and sieving the mixture by a 60-80-mesh sieve to obtain a material for later use;
B. dissolving the material obtained in the step A by using a 10% PVPk30 ethanol solution (ethanol: water =1:1, w/w), and placing at 30 ℃ for later use;
C. b, preparing a drug layer of the pill core from the liquid obtained in the step B by a fluidized bed bottom spraying or centrifugal disc method, wherein the thickness of the drug layer is 0.01-0.5mm, the temperature of the fluidized bed is set between 30-45 ℃, and then the solution is placed in an oven for drying at 60 ℃ for 12 hours to obtain drug-containing pellets;
(3) wrapping isolation clothes
Taking water as a solvent, continuing drying for 2 hours when the weight is increased by 2%, and maintaining the hot air temperature of the fluidized bed at 40-50 ℃;
(4) coated controlled release coating film
A. Placing the pellets obtained in the step (3) in a fluidized bed instrument, and coating a controlled release coating layer;
the air inlet temperature of the apparatus is 40-50 ℃, the material temperature is 35-45 ℃, the weight is increased by 3-15% (W/W), and the short-acting blood sugar-reducing micro-molecular osmotic pump micro-pill preparation is prepared after drying for 6h at 40 ℃.
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