CN112294778A - Oseltamivir phosphate sustained-release pellet capsule and preparation method thereof - Google Patents
Oseltamivir phosphate sustained-release pellet capsule and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/5089—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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Abstract
The invention provides an oseltamivir phosphate sustained-release pellet capsule and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an oseltamivir phosphate sustained-release pellet capsule and a preparation method thereof.
Background
Oseltamivir phosphate (oseltamivir phosphate), chemical name is (3R,4R,5S) -4-acetamido-5-amino-3- (1-ethyl propoxy) -1-cyclohexene-1-Carboxylic acid ethyl ester phosphate of formula C16H31N2O8P has a structural formula of
Oseltamivir phosphate is a novel Neuraminidase (NA) inhibitor, has extremely high selectivity, can be used for treating and preventing influenza virus infection, bronchitis, pneumonia, general pain and fever accompanied with the infection, and is especially effective for influenza A and B viruses. Oseltamivir is marketed in switzerland in 1999, and a large number of clinical practices prove that oseltamivir has the advantages of high efficiency, difficult drug resistance, good patient tolerance and high safety, and is widely used for preventing and treating influenza in clinic.
At present, the oseltamivir phosphate dosage forms comprise granules, capsules and dry suspensions, only granules and capsules are sold in China, wherein the capsules sold in China are quick-release dosage forms, the dissolution is complete within 30 minutes, no oseltamivir phosphate pellet and sustained-release dosage form are sold in the market at present, and the research on the oseltamivir phosphate pellet and the sustained-release dosage form is lacked in the prior art.
Disclosure of Invention
The invention adopts a method of combining uncoated pellets and sustained-release coated pellets to prepare the oseltamivir phosphate sustained-release pellet capsule.
The invention provides an oseltamivir phosphate sustained-release pellet capsule which is characterized in that: the pellet coating agent comprises uncoated pellets and coated pellets, wherein the uncoated pellets comprise active ingredients, a filling agent and an adhesive, the coated pellets are obtained by coating the uncoated pellets with a coating material, and the mass ratio of the uncoated pellets to the coated pellets is 0.5-1.5: 1.
Preferably, the filler is one or more of microcrystalline cellulose, corn starch, pregelatinized starch and lactose, wherein the mass ratio of the active ingredients to the filler is 1-5: 2-4. .
Preferably, the adhesive is one or more of povidone, ethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose, wherein the mass ratio of the active ingredients to the adhesive is 1-5: 2-5.
Preferably, the coating material is one or more of cellulose acetate, ethyl cellulose or acrylic resin, wherein the mass ratio of the active ingredient to the coating material is 4-10: 1-4.
Preferably, the coating material is an aqueous ethylcellulose dispersion.
The invention also provides a method for preparing the oseltamivir phosphate sustained-release pellet capsule, which is characterized by comprising the following steps of:
(1) weighing active ingredients, a filling agent and an adhesive according to a formula, preparing a soft material, and preparing an uncoated pellet by extrusion, spheronization and drying processes.
(2) And (2) coating and drying the uncoated pellets prepared in the step (1) by using a coating material in a fluidized bed.
(3) And (3) filling the uncoated pellets prepared in the step (1) and the coated pellets prepared in the step (2) into a capsule shell according to the mass ratio of 0.5-1.5: 1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
Preferably, in the rounding process in the step (1), the rounding rotating speed is 300-800 r/min, and the air inlet amount is 8-20 m3H; the drying process adopts fluidized bed drying, wherein the air inlet temperature of the fluidized bed is 60-70 ℃, and the air volume is 80-120 m3And h, drying time is 0.5-1 hour.
Preferably, the air inlet temperature of the fluidized bed in the step (2) is 55-65 ℃, the atomization pressure is 0.2-0.5 MPa, and the spray flow of the coating material is 1-3 ml/min.
Preferably, after the coating material is sprayed in the step (2), the coating material is continuously dried for 0.5 to 1 hour, and then the coating material is sieved to obtain pellets of 20 to 40 meshes.
Preferably, the method for preparing the oseltamivir phosphate sustained-release pellet capsule is characterized by comprising the following steps of:
(1) weighing active ingredients, a filling agent and an adhesive according to a formula to prepare a soft material, performing extrusion, rounding and drying processes by an extruder, a rounding machine and a fluidized bed,preparing uncoated pellets, wherein the extrusion speed is 10-30 r/min, and the extrusion sieve plate: 0.4-0.8 mm; the rotational speed of the rolling circle is 300-800 r/min, and the air inlet amount is 8-20 m3H; the air inlet temperature of the fluidized bed is 60-70 ℃, and the air volume is 80-120 m3And h, drying for 0.5-1 h.
(2) And (2) coating and drying the uncoated pellets prepared in the step (1) by using a coating material in a fluidized bed, wherein the air inlet temperature of the fluidized bed is 55-65 ℃, the material temperature is controlled at 45-55 ℃, the atomization pressure is 0.2-0.5 MPa, the flow rate of a spray liquid is 1-3 ml/min, after the spraying is finished, the pellets are continuously dried for 0.5-1 hour, and the pellets are sieved to obtain pellets with 20-40 meshes.
(3) And (3) filling the uncoated pellets prepared in the step (1) and the coated pellets prepared in the step (2) into a capsule shell according to the mass ratio of 0.5-1.5: 1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
The invention adopts a method of combining uncoated pellets and sustained-release coated pellets to prepare the oseltamivir phosphate sustained-release pellet capsule, wherein the uncoated pellets play a role of quick release and can reach effective blood concentration in a short time, and the sustained-release coated pellets are slowly released at the later stage, so that the blood concentration is kept stable and effective for a long time, and the oseltamivir phosphate sustained-release pellet capsule has obvious clinical value.
Drawings
Fig. 1 is a dissolution curve diagram of the oseltamivir phosphate sustained-release pellet capsule, the pure coated pellet and the tamiflu capsule.
Detailed Description
To facilitate understanding, the present application will now be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the application are shown. This application may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Example 1
Weighing 100g of oseltamivir phosphate, 60g of microcrystalline cellulose, 20g of lactose and 100g of hydroxypropyl methylcellulose K100M 40, preparing a soft material by using 160g of 2% hydroxypropyl methylcellulose E5 solution as an adhesive, extruding the soft material at the speed of 20 rpm, and extruding a sieve plate with the thickness of 0.6 mm; the extruded material is rounded for 1 minute at 800 revolutions per minute, then the rotational speed is adjusted to 300 revolutions per minute, the rounding is continued for about 5 minutes, and the air inlet amount is controlled to be 8-15 m3H, drying the pellets in a fluidized bed with the inlet air temperature of 65 ℃ and the air volume of 120m3And h, drying for about 40 minutes, screening the dried pellets, and taking the pellets of 20-40 meshes.
Coating the uncoated pellets by a fluidized bed, wherein the coating liquid is 267g of ethyl cellulose aqueous dispersion (with the solid content of 15 percent), and the coating parameters are as follows: the air inlet temperature of the fluidized bed is 60 ℃, the material temperature is controlled to be 45-55 ℃, the atomization pressure is 0.2-0.5 MPa, the flow rate of the spray liquid is 2ml/min, the coating is finished after the weight increase of the coating meets the requirement, and the coating is continuously dried for 40 minutes to obtain the coated pellets.
The uncoated pellets and the coated pellets are filled according to the mass ratio of 0.5:1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
Example 2
Weighing 40g of oseltamivir phosphate, 20g of microcrystalline cellulose, 60g of corn starch and 100g of hydroxypropyl methylcellulose K100M 80, uniformly mixing, preparing a soft material by using 140g of 5% povidone K30 solution as an adhesive, extruding the soft material at the speed of 10 revolutions per minute, and extruding a sieve plate with the thickness of 0.4 mm; and rounding the extruded material at 700 revolutions per minute for 1 minute, then adjusting the rotation speed to 300 revolutions per minute, continuing rounding for about 5 minutes, controlling the air inlet amount to be 8-15 m3/h, drying the pellets in a fluidized bed at the air inlet temperature of 60 ℃ and the air amount of 120m3/h for about 30 minutes, and screening the dried pellets to obtain pellets of 20-40 meshes.
Coating the uncoated pellets by a fluidized bed, wherein the coating liquid is 100g of cellulose acetate (solid content is 10 percent), and the coating parameters are as follows: the air inlet temperature of the fluidized bed is 55 ℃, the material temperature is controlled to be 45-55 ℃, the atomization pressure is 0.2-0.5 MPa, the flow rate of the spray liquid is 1ml/min, the coating is finished after the weight increase of the coating meets the requirement, and the coating pellet is continuously dried for 30 minutes to obtain the coated pellet.
And filling the uncoated pellets and the coated pellets in a mass ratio of 1:1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
Example 3
Weighing 60g of oseltamivir phosphate, 50g of microcrystalline cellulose, 25g of pregelatinized starch and 80g of ethyl cellulose, uniformly mixing, preparing a soft material by using 150g of 2% hydroxypropyl cellulose solution as an adhesive, extruding the soft material at the speed of 30 revolutions per minute, and extruding a sieve plate to be 0.8 mm; and rounding the extruded material at 800 revolutions per minute for 1 minute, then adjusting the rotation speed to 300 revolutions per minute, continuing rounding for about 5 minutes, controlling the air inlet amount to be 10-20 m3/h, drying the pellets in a fluidized bed for about 40 minutes by setting the air inlet temperature to be 70 ℃ and the air amount to be 120m3/h, and screening the dried pellets to obtain pellets of 20-40 meshes.
Coating the uncoated pellets by a fluidized bed, wherein the coating solution is acrylic resin aqueous dispersion (with the solid content of 10%) 180g, and the coating parameters are as follows: the air inlet temperature of the fluidized bed is 65 ℃, the material temperature is controlled to be 45-55 ℃, the atomization pressure is 0.2-0.5 MPa, the flow rate of the spray liquid is 3ml/min, the coating is finished after the weight increase of the coating meets the requirement, and the coating pellet is continuously dried for 30 minutes to obtain the coated pellet.
The uncoated pellets and the coated pellets are filled according to the mass ratio of 1.5:1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
Example 4
The dissolution curves of the formulation obtained in example 1, the pure coated pellets and the duffy capsule were tested according to dissolution test method 1 (basket method, 100rpm, 37 ℃) in the appendix of the second part of the chinese pharmacopoeia 2015 edition using 900mL of hydrochloric acid solution with ph1.2 as dissolution medium, and the results are shown in fig. 1.
As can be seen from FIG. 1, the coated pellets have good sustained release effect after being filled into capsules, and the sustained release of the drug can reach 24 hours; the release curve is measured after the uncoated pellets and the coated pellets are simultaneously filled into capsules, the uncoated pellets are completely released within about 0.5h (completely similar to the drug dissolution of the tamiflu capsules within 0.5 h), and the subsequent coated pellets are slowly released, so that the drug can be kept in an effective concentration range for a long time, the drug action time is prolonged, and the adverse drug reactions are reduced.
The dissolution rate may indicate the rate of release of the drug from the formulation in the gastrointestinal environment, with lower release rates being reflected in lower Cmax and longer release times on pharmacokinetic data. Compared with the common quick-release capsule, the pellet slow-control capsule prepared by the invention has obviously reduced dissolution rate, and can realize the purposes of reducing Cmax value and prolonging effective blood concentration time compared with the quick-release capsule.
The above-mentioned embodiments only express the embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present application. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, which falls within the scope of protection of the present application. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. An oseltamivir phosphate sustained-release pellet capsule is characterized in that: the pellet coating agent comprises uncoated pellets and coated pellets, wherein the uncoated pellets comprise active ingredients, a filling agent and an adhesive, the coated pellets are obtained by coating the uncoated pellets with a coating material, and the mass ratio of the uncoated pellets to the coated pellets is 0.5-1.5: 1.
2. The oseltamivir phosphate sustained-release pellet capsule according to claim 1, which is characterized in that: the filler is one or more of microcrystalline cellulose, corn starch, pregelatinized starch and lactose, and the mass ratio of the active ingredients to the filler is 1-5: 2-4.
3. The oseltamivir phosphate sustained-release pellet capsule according to claim 1, which is characterized in that: the adhesive is one or more of povidone, ethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose, wherein the mass ratio of the active ingredients to the adhesive is 1-5: 2-5.
4. The oseltamivir phosphate sustained-release pellet capsule according to claim 1, which is characterized in that: the coating material is one or more of cellulose acetate, ethyl cellulose or acrylic resin, and the mass ratio of the active ingredients to the coating material is 4-10: 1-4.
5. The oseltamivir phosphate sustained-release pellet capsule according to claim 4, which is characterized in that: the coating material is ethyl cellulose aqueous dispersion.
6. A method for preparing the oseltamivir phosphate sustained-release pellet capsule of any one of claims 1 to 5, which is characterized by comprising the following steps:
(1) weighing active ingredients, a filling agent and an adhesive according to a formula, preparing a soft material, and preparing an uncoated pellet by extrusion, spheronization and drying processes.
(2) And (2) coating the uncoated pellets prepared in the step (1) by using a coating material through a fluidized bed and drying.
(3) And (3) filling the uncoated pellets prepared in the step (1) and the coated pellets prepared in the step (2) into a capsule shell according to the mass ratio of 0.5-1.5: 1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
7. The method for preparing oseltamivir phosphate sustained-release pellet capsules according to claim 6, wherein the spheronization speed in the spheronization process in the step (1) is 300-800 rpm, and the air inlet volume is 8-20 m3H; the drying process adopts fluidized bed drying, wherein the air inlet temperature of the fluidized bed is 60-70 ℃, and the air volume is 80-120 m3And h, drying time is 0.5-1 hour.
8. The method for preparing oseltamivir phosphate sustained-release pellet capsules according to claim 6, wherein the air inlet temperature of the fluidized bed in the step (2) is 55-65 ℃, the atomization pressure is 0.2-0.5 MPa, and the spray flow rate of the coating material is 1-3 ml/min.
9. The method for preparing oseltamivir phosphate sustained-release pellet capsules according to claim 8, wherein the coating material is continuously dried for 0.5-1 hour after the spraying in step (2), and then sieved to obtain pellets of 20-40 meshes.
10. The method for preparing oseltamivir phosphate sustained-release pellet capsules according to claim 6, which comprises the following steps:
(1) weighing active ingredients, a filling agent and an adhesive according to a formula to prepare a soft material, and then carrying out extrusion, spheronization and drying processes through an extruder, a spheronizer and a fluidized bed to prepare the uncoated pellet, wherein the extrusion speed is 10-30 r/min, and an extrusion sieve plate: 0.4-0.8 mm; the rotational speed of the rolling circle is 300-800 r/min, and the air inlet amount is 8-20 m3H; the air inlet temperature of the fluidized bed is 60-70 ℃, and the air volume is 80-120 m3And h, drying time is 0.5-1 hour.
(2) And (2) taking the uncoated pellets prepared in the step (1), coating and drying the uncoated pellets by using a coating material through a fluidized bed, wherein the air inlet temperature of the fluidized bed is 55-65 ℃, the material temperature is controlled at 45-55 ℃, the atomization pressure is 0.2-0.5 MPa, the flow rate of a spray liquid is 1-3 ml/min, after the spraying is finished, continuously drying for 0.5-1 hour, and sieving to obtain pellets of 20-40 meshes.
(3) And (3) filling the uncoated pellets prepared in the step (1) and the coated pellets prepared in the step (2) into a capsule shell according to the mass ratio of 0.5-1.5: 1 to prepare the oseltamivir phosphate sustained-release pellet capsule.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202011226788.XA CN112294778A (en) | 2020-11-05 | 2020-11-05 | Oseltamivir phosphate sustained-release pellet capsule and preparation method thereof |
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| CN202011226788.XA CN112294778A (en) | 2020-11-05 | 2020-11-05 | Oseltamivir phosphate sustained-release pellet capsule and preparation method thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030044457A1 (en) * | 2001-07-17 | 2003-03-06 | Joaquina Faour | Drug delivery device containing oseltamivir and an H1 antagonist |
| CN104510723A (en) * | 2013-10-08 | 2015-04-15 | 上海迪赛诺药业有限公司 | Labetalol hydrochloride slow-release capsule and preparation method thereof |
| CN104784155A (en) * | 2015-05-15 | 2015-07-22 | 中国药科大学 | Pramipexole dihydrochloride combined pellet capsule and preparation method thereof |
| US20170173157A1 (en) * | 2014-03-24 | 2017-06-22 | Kashiv Pharma, Llc | Method of manufacturing fine particles suitable for orally disintegrating pharmaceutical dosage forms |
| CN111184762A (en) * | 2020-02-16 | 2020-05-22 | 丁虹 | Solid preparation for cocktail therapy |
| CN111317752A (en) * | 2020-03-31 | 2020-06-23 | 广东龙帆生物科技有限公司 | Medicine for preventing or treating influenza virus infection and application |
-
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- 2020-11-05 CN CN202011226788.XA patent/CN112294778A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030044457A1 (en) * | 2001-07-17 | 2003-03-06 | Joaquina Faour | Drug delivery device containing oseltamivir and an H1 antagonist |
| CN104510723A (en) * | 2013-10-08 | 2015-04-15 | 上海迪赛诺药业有限公司 | Labetalol hydrochloride slow-release capsule and preparation method thereof |
| US20170173157A1 (en) * | 2014-03-24 | 2017-06-22 | Kashiv Pharma, Llc | Method of manufacturing fine particles suitable for orally disintegrating pharmaceutical dosage forms |
| CN104784155A (en) * | 2015-05-15 | 2015-07-22 | 中国药科大学 | Pramipexole dihydrochloride combined pellet capsule and preparation method thereof |
| CN111184762A (en) * | 2020-02-16 | 2020-05-22 | 丁虹 | Solid preparation for cocktail therapy |
| CN111317752A (en) * | 2020-03-31 | 2020-06-23 | 广东龙帆生物科技有限公司 | Medicine for preventing or treating influenza virus infection and application |
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