CN111939137A - Compound tablet containing atazanavir and ritonavir and preparation method thereof - Google Patents
Compound tablet containing atazanavir and ritonavir and preparation method thereof Download PDFInfo
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- CN111939137A CN111939137A CN201910404096.0A CN201910404096A CN111939137A CN 111939137 A CN111939137 A CN 111939137A CN 201910404096 A CN201910404096 A CN 201910404096A CN 111939137 A CN111939137 A CN 111939137A
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- atazanavir
- ritonavir
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61P31/18—Antivirals for RNA viruses for HIV
Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a compound tablet containing atazanavir and ritonavir and a preparation method thereof. The method solves the problems of poor thermal stability and poor water solubility of the ritonavir in the compound tablet by using a hot-melt extrusion technology, researches and designs the atazanavir compound tablet which has the advantages of simpler process exposition and control and better bioavailability, and is biologically equivalent to single atazanavir and ritonavir, thereby simplifying the medication mode, improving the compliance of patients and reducing the drug resistance risk.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a compound tablet containing atazanavir and ritonavir and a preparation method thereof.
Background
Atazanavir was developed by Behcet-Meissnobo corporation (Bristol-Myers Squibb), ritonavir was developed by ABBVIE, and a combination of atazanavir and ritonavir was developed by MATRIX LABS LTD and EMCURE PHARMS LTD, and was approved by the FDA for initial treatment of HIV-1 infected individuals as part of a combination therapy.
It has been reported that about 40% of active substances, which play a major pharmacological activity in drugs, are poorly water-soluble. The slightly soluble drug (poorly water-soluble drug) has low solubility in water, so the drug is difficult to be absorbed by the body, the elimination speed in the body is high, and the bioavailability is poor. At present, it is increasingly difficult to find a drug having a new chemical structure, and even if a new drug candidate is found, the drug candidate cannot be marketed due to the defect of poor water solubility, which is about four times or so. It is reported that approximately $ 650 million of drugs worldwide per year cause severe imbalance in the ratio of treatment cost to efficacy due to poor bioavailability. However, in fact, many drugs with poor water solubility have strong biological activity and good curative effect in the fields of treating tumors, cardiovascular diseases and the like. Therefore, how to improve the solubility and absorption rate of the drug is always a hot spot and a difficult point of pharmaceutical research, and the development of new formulation technology and dosage form is urgently needed to solve the problem. Currently, there are several methods that can improve the solubility and dissolution rate of poorly water-soluble drugs in pharmaceutical research, such as adding a cosolvent, a solubilizer, and a hydrophilic medium; preparing into solid dispersion or inclusion; forming a particulate dispersion system to form a co-dispersion; the particle size of the medicine is reduced, and the medicine is prepared into micron or even nano particles and the like. In these formulation means, different drugs often have different effects, and different drugs are not suitable for all means.
Although the atazanavir and ritonavir compound preparation is a good anti-HIV drug, the problems still exist, namely the ritonavir is poor in thermal stability and low in solubility in neutral media such as water, and the water is just the most suitable medium for evaluating the non-bioequivalence in a dissolution test.
Disclosure of Invention
The invention aims to overcome the defects, researches and designs the compound preparation of the atazanavir, which has simpler process difficulty, equipment condition, simpler process parameter control and better bioavailability, and is biologically equivalent to the single-tablet atazanavir and the ritonavir, thereby simplifying the medication mode, improving the compliance of patients, reducing the drug resistance risk and effectively improving the thermal stability of the ritonavir.
The invention provides an atazanavir and ritonavir compound tablet and a preparation method thereof.
The structural formula of atazanavir is as follows:
the structural formula of ritonavir is as follows:
the technical scheme of the compound tablet containing atazanavir and ritonavir is as follows:
a compound tablet containing atazanavir and ritonavir comprises an auxiliary material component and a packaging component, wherein the weight ratio of the atazanavir to the ritonavir is 3: 1; the auxiliary material components comprise a binder, a disintegrant, a filler, a lubricant, a colorant, a solubilizer and a glidant; the packaging components comprise yellow Opadry, a high-density polyethylene bottle, a bottle cap, a drying agent and an antioxidant.
The filler is at least one of lactose monohydrate, pregelatinized starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium silicate and mannitol; the disintegrant is at least one of pregelatinized starch, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, microcrystalline cellulose, and hydroxypropyl cellulose.
The adhesive is at least one of copovidone, pregelatinized starch, povidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose; the lubricant is at least one of calcium silicate, magnesium stearate, colloidal silicon dioxide and sodium stearyl fumarate.
The colorant is yellow ferric oxide or other lakes; the solubilizer is at least one of sorbitan monolaurate, sodium dodecyl sulfate and Tween.
The packaging components comprise yellow Opadry, a high-density polyethylene bottle, a bottle cap, a drying agent and an antioxidant.
The weight ratio of the atazanavir to the ritonavir in the compound tablet containing the atazanavir and the ritonavir is 3:1, and the compound tablet comprises the following components in percentage by weight:
name weight ratio
15-25% of atazanavir sulfate
8.5 to 10.5 percent of lactose monohydrate
3-4.5% of pregelatinized starch
3 to 8 percent of crospovidone
2 to 4 percent of calcium silicate
0.02-0.05% of yellow iron oxide
0.3 to 1.5 percent of magnesium stearate
Ritonavir 5-8%
30 to 45 percent of polyvidone
1 to 3 percent of colloidal silicon dioxide
3-5% of sorbitan monolaurate (span 20)
5-9% of anhydrous calcium hydrogen phosphate
0.5 to 1.5 percent of sodium stearyl fumarate
Proper amount of purified water
The weight ratio of the atazanavir to the ritonavir in the compound tablet containing the atazanavir and the ritonavir is 3:1, and the compound tablet comprises the following components in percentage by weight:
name weight ratio
15-25% of atazanavir sulfate
7.5 to 12 percent of microcrystalline cellulose
3-6% of pregelatinized starch
4-10% of croscarmellose sodium
2 to 4 percent of calcium silicate
0.02-0.05% of yellow iron oxide
Ritonavir 5-8%
30 to 45 percent of polyvidone
1 to 3 percent of colloidal silicon dioxide
3 to 5.5 percent of sorbitan monolaurate (span 20)
5-9% of anhydrous calcium hydrogen phosphate
0.3 to 1.5 percent of magnesium stearate
Proper amount of purified water
The preparation method of the compound tablet containing the atazanavir and the ritonavir comprises the following steps:
(a) preparation of atazanavir total mixed granules: weighing raw materials, sieving for later use, mixing atazanavir, lactose monohydrate, pregelatinized starch internally added and povidone internally added uniformly, granulating by a wet method, drying, adding pregelatinized starch externally, adding crospovidone, calcium silicate and yellow iron oxide uniformly, adding magnesium stearate, and mixing uniformly to obtain atazanavir total mixed granules;
(b) preparation of ritonavir total mixed granules: weighing raw materials, sieving for later use, uniformly mixing ritonavir, copovidone and internally added colloidal silicon dioxide, adding sorbitan monolaurate, uniformly mixing, and preparing an extrudate by adopting a hot-melt extrusion process: arranging a conveying section, a melting section and a mixing section of a hot-melt extruder, wherein the temperature of the metering section is 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃, preheating for 30 minutes, then placing the mixture into the hot-melt extruder to prepare an extrudate at the screw speed of 100 plus 300rpm, straightening the extrudate with a 0.5mm screen, adding colloidal silicon dioxide, adding calcium hydrogen phosphate to mix uniformly, adding sodium stearyl fumarate to mix uniformly to obtain ritonavir total mixed particles;
(c) preparation of the compound tablet: tabletting the atazanavir total mixed granules and the ritonavir total mixed granules by adopting a capsule-shaped punch die and a double-layer tablet press, wherein the atazanavir is arranged in one layer and the ritonavir is arranged in the other layer; and (3) performing film coating by using a high-efficiency coating machine, wherein coating liquid is Opadry, and then packaging a finished product, and sealing and storing.
The other preparation method of the compound tablet containing the atazanavir and the ritonavir comprises the following steps:
(1) preparation of atazanavir granules: weighing raw materials, sieving for later use, mixing atazanavir, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, granulating by wet method, drying, and grading with 1.0mm screen.
(2) Preparation of ritonavir granules: weighing raw materials, sieving for later use, uniformly mixing ritonavir, copovidone and internally added colloidal silicon dioxide, adding sorbitan monolaurate, uniformly mixing, and preparing an extrudate by adopting a hot-melt extrusion process: preheating for 30 minutes at the temperature of 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃ of a hot-melt extruder, then placing the mixture into the hot-melt extruder to prepare an extrudate at a screw speed of 100 plus 300rpm, and straightening the extrudate with a 0.5mm screen;
(3) total atazanavir granules: uniformly mixing the atazanavir granules, the ritonavir granules and the added auxiliary materials of pregelatinized starch, the added cross-linked sodium carboxymethyl cellulose, calcium silicate, yellow iron oxide, colloidal silicon dioxide and anhydrous calcium hydrophosphate, adding magnesium stearate, and uniformly mixing; obtaining the total atazanavir mixed granules.
(4) Preparation of the compound tablet: tabletting the atazanavir total mixed granules by adopting a capsule-shaped punch die and a single-layer tabletting machine; and (3) performing film coating by using a high-efficiency coating machine, wherein coating liquid is Opadry, and then packaging a finished product, and sealing and storing.
The invention has the advantages of simpler process difficulty, equipment condition and process parameter control, and is more suitable for industrial batch production.
Detailed Description
The technical scheme of the invention is further detailed and completely explained by combining the embodiment.
Example 1
Name dosage (g)
Atazanavir sulfate 341.7
Lactose monohydrate 142.0
Pregelatinized starch 55.0
Crospovidone 55.0
Calcium silicate 40.0
Yellow iron oxide 0.5
Magnesium stearate 5.8
Ritonavir 100.0
Co-Povidone 560.0
Colloidal silica 23.0
Sorbitan monolaurate (span 20) 60.0
Anhydrous calcium hydrogen phosphate 100.0
Sodium stearyl fumarate 7.0
Proper amount of purified water
Preparation of atazanavir total mixed granule
Weighing raw materials, and sieving for later use: sieving lactose monohydrate, pregelatinized starch and crospovidone together with 30 mesh sieve, sieving the sieved mixture with atazanavir sulfate together with 20 mesh sieve, sieving yellow iron oxide with 100 mesh sieve, sieving the sieved yellow iron oxide, lactose monohydrate, pregelatinized starch, crospovidone and calcium silicate together with 30 mesh sieve, and sieving magnesium stearate with 60 mesh sieve for later use.
341.7g of atazanavir sulfate, 142g of lactose monohydrate, 15g of pregelatinized starch, 15g of crospovidone and purified water are uniformly mixed and granulated, the mixture is dried, the water content is controlled to be 1.2-2.5%, 40g of pregelatinized starch is added, 40g of crospovidone, 40g of calcium silicate and 0.5g of yellow iron oxide are added and mixed for 20 minutes, 5.8g of magnesium stearate is added and mixed for 5 minutes, and the atazanavir total mixed granule is obtained.
Preparation of ritonavir total mixed granule
Weighing raw materials, and sieving for later use: sieving ritonavir with a 20-mesh sieve, sieving copovidone, colloidal silicon dioxide and anhydrous calcium hydrogen phosphate with a 30-mesh sieve, and sieving sodium stearyl fumarate with a 60-mesh sieve for later use.
Taking 100g of ritonavir and 560g of copovidone, adding 8g of colloidal silicon dioxide for premixing, adding 60g of sorbitan monolaurate, uniformly mixing, carrying out extrusion granulation by adopting a hot-melt extrusion process, setting the temperature of a hot-melt extruder to be 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃, preheating for 30 minutes, placing the mixture into the hot-melt extruder to prepare an extrudate at the screw speed of 100-300rpm, carrying out size stabilization on the extrudate by using a 0.5mm screen, adding 15g of colloidal silicon dioxide, adding 100g of anhydrous calcium hydrophosphate, mixing for 20 minutes, adding 7g of sodium stearyl fumarate, and mixing for 5 minutes to obtain the ritonavir total mixed particles.
Preparation of atazanavir and ritonavir compound tablet
Tabletting the prepared atazanavir total mixed granules and ritonavir total mixed granules by adopting a capsule-shaped punch die and a double-layer tablet press, wherein the atazanavir is arranged in one layer and the ritonavir is arranged in the other layer; performing film coating by using a high-efficiency coating machine, selecting Opadry as a coating solution, packaging to obtain a finished product, wherein the finished product of the compound tablet single capsule contains 0.3g of atazanavir and 0.1g of ritonavir, and sealing and storing.
Example 2
Name dosage (g)
Atazanavir sulfate 341.7
Microcrystalline cellulose 162.0
Pregelatinized starch 40.0
Croscarmellose sodium 50.0
Calcium silicate 40.0
Yellow iron oxide 0.5
Ritonavir 100.0
Co-Povidone 560.0
Colloidal silica 23.0
Sorbitan monolaurate (span 20) 80.0
Anhydrous calcium hydrogen phosphate 80.0
Magnesium stearate 12.8
Proper amount of purified water
Preparation of atazanavir granules
Weighing raw materials, and sieving for later use: sieving lactose monohydrate, pregelatinized starch and croscarmellose sodium together with 30 mesh sieve, sieving the sieved mixture with atazanavir sulfate together with 20 mesh sieve, sieving yellow iron oxide with 100 mesh sieve, sieving the sieved yellow iron oxide, lactose monohydrate, pregelatinized starch, microcrystalline cellulose, copovidone and calcium silicate together with 30 mesh sieve, and sieving magnesium stearate and anhydrous calcium bicarbonate with 60 mesh sieve for later use.
341.7g of atazanavir sulfate, 162g of microcrystalline cellulose, 20g of pregelatinized starch, 50g of croscarmellose sodium and purified water are taken, mixed uniformly, granulated and dried, the water content is controlled to be 1.2-2.5%, and the granules are sieved by a 1.0mm screen to obtain the atazanavir granules.
Preparation of ritonavir granules
Weighing raw materials, and sieving for later use: sieving ritonavir with 20 mesh sieve, and sieving copovidone, colloidal silicon dioxide and anhydrous calcium hydrogen phosphate with 30 mesh sieve.
Taking 100g of ritonavir and 560g of copovidone, adding 10g of colloidal silicon dioxide for premixing, adding 80g of sorbitan monolaurate, uniformly mixing, carrying out extrusion granulation by adopting a hot-melt extrusion process, setting the temperature of a hot-melt extruder to be 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃, preheating for 30 minutes, placing the mixture into the hot-melt extruder to prepare an extrudate at a screw speed of 100-300rpm, and grading the extrudate by using a 0.5mm screen to obtain ritonavir granules.
Total atazanavir granules: uniformly mixing the atazanavir granules, the ritonavir granules and the added auxiliary materials of pregelatinized starch, the added crospovidone, calcium silicate, yellow iron oxide, colloidal silicon dioxide and anhydrous calcium hydrophosphate, adding magnesium stearate, and uniformly mixing; obtaining the total atazanavir mixed granules.
Preparation of the compound tablet: tabletting the atazanavir total mixed granules by adopting a capsule-shaped punch die and a single-layer tabletting machine; performing film coating by using a high-efficiency coating machine, selecting Opadry as a coating solution, packaging to obtain a finished product, wherein the finished product single-piece capsule contains 0.3g of atazanavir and 0.1g of ritonavir, and sealing and storing.
Example 3
Name dosage (g)
Atazanavir sulfate 341.7
Lactose monohydrate 140.0
Pregelatinized starch 60.0
Hydroxypropyl cellulose 55.0
Calcium silicate 40.0
Yellow iron oxide 0.5
Magnesium stearate 5.8
Ritonavir 100.0
Co-Povidone 560.0
Colloidal silica 23.0
Sodium dodecyl sulfate 60.0
Anhydrous calcium hydrogen phosphate 100.0
Sodium stearyl fumarate 7.0
Proper amount of purified water
Preparation of atazanavir total mixed granule
Weighing raw materials, and sieving for later use: sieving lactose monohydrate, pregelatinized starch and hydroxypropyl cellulose together with 30 mesh sieve, sieving the sieved mixture with atazanavir sulfate together with 20 mesh sieve, sieving yellow iron oxide with 100 mesh sieve, sieving the sieved yellow iron oxide, lactose monohydrate, pregelatinized starch, hydroxypropyl cellulose and calcium silicate together with 30 mesh sieve, and sieving magnesium stearate with 60 mesh sieve for later use.
341.7g of atazanavir sulfate, 140g of lactose monohydrate, 20g of pregelatinized starch, 15g of hydroxypropyl cellulose and purified water are taken, mixed uniformly and granulated, dried, the water content is controlled to be 1.2-2.5%, 40g of pregelatinized starch is added, 40g of hydroxypropyl cellulose, 40g of calcium silicate and 0.5g of yellow iron oxide are added, mixed for 20 minutes, 5.8g of magnesium stearate is added, and mixed for 5 minutes, so that the atazanavir total mixed granule is obtained.
Preparation of ritonavir total mixed granule
Weighing raw materials, and sieving for later use: sieving ritonavir with a 20-mesh sieve, sieving copovidone, colloidal silicon dioxide and anhydrous calcium hydrogen phosphate with a 30-mesh sieve, and sieving sodium stearyl fumarate with a 60-mesh sieve for later use.
Taking 100g of ritonavir, 560g of copovidone, adding 8g of colloidal silicon dioxide for premixing, adding 60g of sodium dodecyl sulfate, uniformly mixing, carrying out extrusion granulation by adopting a hot-melt extrusion process, setting the temperature of a hot-melt extruder to be 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and preheating for 30 minutes, placing the mixture into the hot-melt extruder to prepare an extrudate at the screw speed of 100 plus materials and 300rpm, carrying out size stabilization on the extrudate by using a 0.5mm screen, adding 15g of colloidal silicon dioxide, adding 100g of anhydrous calcium hydrophosphate, mixing for 20 minutes, adding 7g of sodium stearyl fumarate, mixing for 5 minutes, and obtaining the ritonavir total mixed particles.
Preparation of atazanavir and ritonavir compound tablet
Tabletting the prepared atazanavir total mixed granules and ritonavir total mixed granules by adopting a capsule-shaped punch die and a double-layer tablet press, wherein the atazanavir is arranged in one layer and the ritonavir is arranged in the other layer; performing film coating by using a high-efficiency coating machine, selecting Opadry as a coating solution, packaging to obtain a finished product, wherein the finished product of the compound tablet single capsule contains 0.3g of atazanavir and 0.1g of ritonavir, and sealing and storing.
Example 4
Name dosage (g)
Atazanavir sulfate 341.7
Mannitol 165.0
Pregelatinized starch 40.0
Croscarmellose sodium 50.0
Calcium silicate 52.8
Yellow iron oxide 0.5
Ritonavir 100.0
Co-Povidone 560.0
Colloidal silica 23.0
Tween 80.0
Anhydrous calcium hydrogen phosphate 80.0
Proper amount of purified water
Preparation of atazanavir granules
Weighing raw materials, and sieving for later use: sieving mannitol, pregelatinized starch and croscarmellose sodium together with 30 mesh sieve, sieving the sieved mixture with atazanavir sulfate together with 20 mesh sieve, sieving yellow iron oxide with 100 mesh sieve, sieving the sieved yellow iron oxide, mannitol, pregelatinized starch, microcrystalline cellulose, copovidone and calcium silicate together with 30 mesh sieve, and sieving anhydrous calcium bicarbonate with 60 mesh sieve for use.
341.7g of atazanavir sulfate, 165g of mannitol, 20g of pregelatinized starch, 50g of croscarmellose sodium and purified water are taken, mixed uniformly, granulated, dried, sieved by a 1.0mm screen, and granulated to obtain atazanavir granules.
Preparation of ritonavir granules
Weighing raw materials, and sieving for later use: sieving ritonavir with 20 mesh sieve, and sieving copovidone, colloidal silicon dioxide and anhydrous calcium hydrogen phosphate with 30 mesh sieve.
Taking 100g of ritonavir, 560g of copovidone, adding 10g of colloidal silicon dioxide for premixing, adding 80g of tween, uniformly mixing, carrying out extrusion granulation by adopting a hot-melt extrusion process, setting the temperature of a hot-melt extruder to be 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃, preheating for 30 minutes, placing the mixture into the hot-melt extruder to prepare an extrudate at a screw speed of 100 plus 300rpm, and carrying out size stabilization on the extrudate by using a 0.5mm screen to obtain ritonavir particles.
Total atazanavir granules: uniformly mixing the atazanavir granules, the ritonavir granules and the added auxiliary material of pregelatinized starch, the added crospovidone, calcium silicate, yellow iron oxide, colloidal silicon dioxide and anhydrous calcium hydrophosphate, adding the calcium silicate and uniformly mixing; obtaining the total atazanavir mixed granules.
Preparation of the compound tablet: tabletting the atazanavir total mixed granules by adopting a capsule-shaped punch die and a single-layer tabletting machine; performing film coating by using a high-efficiency coating machine, selecting Opadry as a coating solution, packaging to obtain a finished product, wherein the finished product single-piece capsule contains 0.3g of atazanavir and 0.1g of ritonavir, and sealing and storing.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (9)
1. A compound tablet containing atazanavir and ritonavir comprises an auxiliary material component and a packaging component, and is characterized in that the weight ratio of the atazanavir to the ritonavir is 3: 1; the auxiliary material components comprise a binder, a disintegrant, a filler, a lubricant, a colorant, a solubilizer and a glidant; the packaging components comprise yellow Opadry, a high-density polyethylene bottle, a bottle cap, a drying agent and an antioxidant.
2. The compound tablet of claim 1, wherein the filler is at least one of lactose monohydrate, pregelatinized starch, microcrystalline cellulose, anhydrous dibasic calcium phosphate, calcium silicate, mannitol; the disintegrant is at least one of pregelatinized starch, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, microcrystalline cellulose, and hydroxypropyl cellulose.
3. The compound tablet of claim 1, wherein the binder is at least one of copovidone, pregelatinized starch, povidone, hydroxypropyl cellulose, and hypromellose; the lubricant is at least one of calcium silicate, magnesium stearate, colloidal silicon dioxide and sodium stearyl fumarate.
4. The compound tablet of claim 1, wherein the colorant is yellow iron oxide or other lake; the solubilizer is at least one of sorbitan monolaurate, sodium dodecyl sulfate and Tween.
5. The compound tablet of claim 1, wherein the packaging component is yellow opadry, high density polyethylene bottle, bottle cap, desiccant, antioxidant.
6. The combination tablet of claim 1, wherein the weight ratio of atazanavir to ritonavir in the combination tablet containing atazanavir and ritonavir is 3:1, and the components and the ratio are as follows:
name weight ratio
15-25% of atazanavir sulfate
8.5 to 10.5 percent of lactose monohydrate
3-4.5% of pregelatinized starch
3 to 8 percent of crospovidone
2 to 4 percent of calcium silicate
0.02-0.05% of yellow iron oxide
0.3 to 1.5 percent of magnesium stearate
Ritonavir 5-8%
30 to 45 percent of polyvidone
1 to 3 percent of colloidal silicon dioxide
3-5% of sorbitan monolaurate (span 20)
5-9% of anhydrous calcium hydrogen phosphate
0.5-1.5% of sodium stearyl fumarate.
7. The combination tablet of claim 1, wherein the weight ratio of atazanavir to ritonavir in the combination tablet containing atazanavir and ritonavir is 3:1, and the components and the ratio are as follows:
name weight ratio
15-25% of atazanavir sulfate
7.5 to 12 percent of microcrystalline cellulose
3-6% of pregelatinized starch
4-10% of croscarmellose sodium
2 to 4 percent of calcium silicate
0.02-0.05% of yellow iron oxide
Ritonavir 5-8%
30 to 45 percent of polyvidone
1 to 3 percent of colloidal silicon dioxide
3 to 5.5 percent of sorbitan monolaurate (span 20)
5-9% of anhydrous calcium hydrogen phosphate
0.3-1.5% of magnesium stearate.
8. The method for preparing a compound tablet according to any one of claims 1 to 6, comprising the steps of:
preparation of atazanavir total mixed granules: weighing raw materials, sieving for later use, mixing atazanavir, lactose monohydrate, pregelatinized starch internally added and povidone internally added uniformly, granulating by a wet method, drying, adding pregelatinized starch externally, adding crospovidone, calcium silicate and yellow iron oxide uniformly, adding magnesium stearate, and mixing uniformly to obtain atazanavir total mixed granules;
preparation of ritonavir total mixed granules: weighing raw materials, sieving for later use, uniformly mixing ritonavir, copovidone and internally added colloidal silicon dioxide, adding sorbitan monolaurate, uniformly mixing, and preparing an extrudate by adopting a hot-melt extrusion process: arranging a conveying section, a melting section and a mixing section of a hot-melt extruder, wherein the temperature of the metering section is 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃, preheating for 30 minutes, then placing the mixture into the hot-melt extruder to prepare an extrudate at the screw speed of 100 plus 300rpm, straightening the extrudate with a 0.5mm screen, adding colloidal silicon dioxide, adding calcium hydrogen phosphate to mix uniformly, adding sodium stearyl fumarate to mix uniformly to obtain ritonavir total mixed particles;
preparation of the compound tablet: tabletting the atazanavir total mixed granules and the ritonavir total mixed granules by adopting a capsule-shaped punch die and a double-layer tablet press, wherein the atazanavir is arranged in one layer and the ritonavir is arranged in the other layer; and (3) performing film coating by using a high-efficiency coating machine, wherein coating liquid is Opadry, and then packaging a finished product, and sealing and storing.
9. A method of preparing a compound tablet according to any one of claims 1 to 5 or 7, comprising the steps of:
(1) preparation of atazanavir granules: weighing raw materials, sieving for later use, mixing atazanavir, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium uniformly, granulating by wet method, drying, and grading with 1.0mm screen;
(2) preparation of ritonavir granules: weighing raw materials, sieving for later use, uniformly mixing ritonavir, copovidone and internally added colloidal silicon dioxide, adding sorbitan monolaurate, uniformly mixing, and preparing an extrudate by adopting a hot-melt extrusion process: preheating for 30 minutes at the temperature of 40-70 ℃, 60-90 ℃, 80-110 ℃, 110-140 ℃ and 110-140 ℃ of a hot-melt extruder, then placing the mixture into the hot-melt extruder to prepare an extrudate at a screw speed of 100 plus 300rpm, and straightening the extrudate with a 0.5mm screen;
(3) total atazanavir granules: uniformly mixing the atazanavir granules, the ritonavir granules and the added auxiliary materials of pregelatinized starch, the added cross-linked sodium carboxymethyl cellulose, calcium silicate, yellow iron oxide, colloidal silicon dioxide and anhydrous calcium hydrophosphate, adding magnesium stearate, and uniformly mixing; obtaining the total atazanavir mixed granules;
(4) preparation of the compound tablet: tabletting the atazanavir total mixed granules by adopting a capsule-shaped punch die and a single-layer tabletting machine; and (3) performing film coating by using a high-efficiency coating machine, wherein coating liquid is Opadry, and then packaging a finished product, and sealing and storing.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910404096.0A CN111939137A (en) | 2019-05-16 | 2019-05-16 | Compound tablet containing atazanavir and ritonavir and preparation method thereof |
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| CN201910404096.0A CN111939137A (en) | 2019-05-16 | 2019-05-16 | Compound tablet containing atazanavir and ritonavir and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652811A (en) * | 2022-03-25 | 2022-06-24 | 乐普制药科技有限公司 | Compound tablet containing nelmavir and ritonavir |
| CN114668737A (en) * | 2022-03-02 | 2022-06-28 | 乐普制药科技有限公司 | Compound bilayer tablet containing ritonavir pellets for treating novel coronavirus |
-
2019
- 2019-05-16 CN CN201910404096.0A patent/CN111939137A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114668737A (en) * | 2022-03-02 | 2022-06-28 | 乐普制药科技有限公司 | Compound bilayer tablet containing ritonavir pellets for treating novel coronavirus |
| CN114652811A (en) * | 2022-03-25 | 2022-06-24 | 乐普制药科技有限公司 | Compound tablet containing nelmavir and ritonavir |
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Application publication date: 20201117 |