CN114767636B - Itraconazole pellets, preparation method and itraconazole pellet capsule - Google Patents
Itraconazole pellets, preparation method and itraconazole pellet capsule Download PDFInfo
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- CN114767636B CN114767636B CN202210371493.4A CN202210371493A CN114767636B CN 114767636 B CN114767636 B CN 114767636B CN 202210371493 A CN202210371493 A CN 202210371493A CN 114767636 B CN114767636 B CN 114767636B
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title claims abstract description 105
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 105
- 239000008188 pellet Substances 0.000 title claims abstract description 98
- 239000002775 capsule Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000000230 xanthan gum Substances 0.000 claims abstract description 33
- 229920001285 xanthan gum Polymers 0.000 claims abstract description 33
- 229940082509 xanthan gum Drugs 0.000 claims abstract description 33
- 235000010493 xanthan gum Nutrition 0.000 claims abstract description 33
- 239000011247 coating layer Substances 0.000 claims abstract description 19
- 239000006187 pill Substances 0.000 claims abstract description 19
- 230000008961 swelling Effects 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 19
- 239000006185 dispersion Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000005507 spraying Methods 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 8
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 125000000185 sucrose group Chemical group 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 abstract description 5
- 230000008025 crystallization Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- 230000001133 acceleration Effects 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000005070 ripening Effects 0.000 description 2
- -1 1H-1, 2, 4-triazol-1-yl-methyl Chemical group 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 206010005098 Blastomycosis Diseases 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- 208000014260 Fungal keratitis Diseases 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 208000007027 Oral Candidiasis Diseases 0.000 description 1
- 206010033767 Paracoccidioides infections Diseases 0.000 description 1
- 201000000301 Paracoccidioidomycosis Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010041736 Sporotrichosis Diseases 0.000 description 1
- 208000007712 Tinea Versicolor Diseases 0.000 description 1
- 206010056131 Tinea versicolour Diseases 0.000 description 1
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000003929 dermatomycosis Diseases 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- 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
- A61P31/10—Antimycotics
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to an itraconazole pellet, a preparation method and an itraconazole pellet capsule. The itraconazole micro-pill provided by the invention comprises a pill core and a coating layer coated on the surface of the pill core, wherein the coating layer contains itraconazole and xanthan gum in a swelling state. The swelling state xanthan gum can obviously promote the compactness of the coating layer, effectively block the influence of environmental factors such as high temperature, high humidity and the like on the inside of the pellet, thereby avoiding the recrystallization of itraconazole and inhibiting the crystallization phenomenon, and therefore, the itraconazole pellet has better stability.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an itraconazole pellet, a preparation method and an itraconazole pellet capsule.
Background
Itraconazole, i.e., (±) -cis-4- [4- [ [2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazol-1-yl-methyl) -1, 3-dioxolan-4-yl ] methoxy ] -1-piperazinyl ] phenyl ] -2, 4-dihydro-2- (1-methylpropyl) -3H-1,2, 4-triazol-3-one, is a broad spectrum antifungal compound useful for the treatment of conditions known for systemic fungal infections such as aspergillosis, candidiasis, cryptococcoid meningitis, histoplasmosis, sporotrichosis, paracoccidioidomycosis, coloring mycosis, blastomycosis, vulvovaginal candidiasis, dermatologic/ophthalmic tinea versicolor, dermatomycosis, mycotic keratitis, oral candidiasis, and onychomycosis caused by dermatophytes and/or yeast.
Itraconazole pellets are a common formulation of itraconazole, but in the process of implementing the present invention, the inventors of the present invention found that the existing itraconazole pellets have poor stability due to the existence of crystallization phenomenon.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect of poor stability of the conventional itraconazole pellets, so as to provide the itraconazole pellets, the preparation method and the itraconazole pellet capsules.
Therefore, the invention provides an itraconazole pellet, which comprises a pellet core and a coating layer coated on the surface of the pellet core, wherein the coating layer contains itraconazole and xanthan gum, and the xanthan gum is in a swelling state.
Alternatively, the xanthan gum has a molecular weight of 2×10 6 。
Optionally, in the itraconazole pellets, the content of the pellet core is 180 parts by weight and the content of the xanthan gum is 5 to 15 parts by weight with respect to 100 parts by weight of itraconazole.
Optionally, the coating layer further contains a dispersion carrier, and the content of the dispersion carrier is 140 parts by weight relative to 100 parts by weight of itraconazole.
Optionally, the pellet core is selected from sucrose pellet core and/or microcrystalline cellulose pellet core.
Optionally, the dispersion carrier is selected from at least one of hypromellose, carboxymethyl cellulose, or hydroxypropyl cellulose.
Optionally, the particle size of the pill core is 600-710 mu m, and the particle size of the itraconazole micro-pill is 900-1100 mu m.
The invention also provides a preparation method of the itraconazole pellets, which comprises the following operations:
taking a drug-containing suspension, spraying liquid to coat a pill core, and drying to obtain a pellet intermediate, wherein the drug-containing suspension contains itraconazole, xanthan gum and a solvent;
the pellet intermediate is cooked to swell the xanthan gum.
Alternatively, the xanthan gum has a molecular weight of 2×10 6 。
Alternatively, in the drug-containing suspension, the xanthan gum is used in an amount of 5 to 15 parts by weight and the solvent is used in an amount of 2300 parts by volume, relative to 100 parts by weight of itraconazole, wherein the parts by volume are in units of L when the parts by weight are in kg.
Alternatively, in the case of spray coating, the pellet core is used in an amount of 180 parts by weight with respect to 100 parts by weight of itraconazole.
Optionally, the drug-containing suspension further contains a dispersing carrier, wherein the amount of the dispersing carrier is 140 parts by weight relative to 100 parts by weight of itraconazole.
Optionally, the pellet core is selected from a sucrose pellet core and/or a microcrystalline cellulose pellet core.
Optionally, the dispersion carrier is selected from at least one of hypromellose, carboxymethyl cellulose, or hydroxypropyl cellulose.
Optionally, the solvent is at least one selected from ethanol, dichloromethane and water, preferably a mixed solution of ethanol and dichloromethane, and the volume ratio of ethanol to dichloromethane is 8:15.
optionally, the preparation method of the drug-containing suspension comprises the following steps: taking itraconazole and the dispersion carrier, dissolving in a solvent, and adding xanthan gum.
Optionally, the conditions of the spray coating include: the air inlet temperature is 35-40 ℃, and the air outlet temperature is 30-35 ℃.
Optionally, the drying conditions include: the air inlet temperature is 40-45 ℃, the air outlet temperature is 30-35 ℃, and the drying time is 0.5h.
Optionally, the curing conditions include: the curing temperature is 98-102 ℃, the relative humidity is 30-40% RH, and the curing time is 6-10 h.
The invention also provides an itraconazole pellet capsule which contains the itraconazole pellets described in any one of the above or the itraconazole pellets prepared by the preparation method described in any one of the above.
The technical scheme of the invention has the following advantages:
1. the itraconazole micro-pill provided by the invention comprises a pill core and a coating layer coated on the surface of the pill core, wherein the coating layer contains itraconazole and xanthan gum in a swelling state. The swelling state xanthan gum can obviously promote the compactness of the coating layer, effectively block the influence of environmental factors such as high temperature, high humidity and the like on the inside of the pellet, thereby avoiding the recrystallization of itraconazole and inhibiting the crystallization phenomenon, and therefore, the itraconazole pellet has better stability.
2. According to the itraconazole pellets provided by the invention, the coating layer contains the swelling xanthan gum and the specific content of the dispersion carrier, so that the itraconazole drug in the coating layer has a good dissolution environment, and therefore, the itraconazole pellets have higher dissolution rate.
3. According to the preparation method of the itraconazole pellets, provided by the invention, the crystallization problem of the itraconazole pellets can be remarkably improved by combining the xanthan gum and the curing process, and the stability of the itraconazole pellets can be effectively improved. Specifically, the process of ripening can promote compactness of the coating layer of the pellet, and on the other hand, the xanthan gum can be quickly swelled in the ripening process to further promote compactness of the coating layer, so that the coating layer can effectively block the influence of environmental factors such as high temperature, high humidity and the like on the inside of the pellet, and the itraconazole is prevented from being recrystallized under the conditions of high temperature, high humidity and the like, thereby inhibiting crystallization phenomenon of itraconazole, and therefore, the preparation method of the itraconazole pellet can remarkably promote stability of the itraconazole pellet.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
Fig. 1 is a DSC scan of each itraconazole pellet capsule in experimental example 2 of the present invention.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Example 1
The embodiment provides a preparation method of itraconazole pellets, which comprises the following operations:
(1) Taking 0.12kg of itraconazole and 0.168kg of dispersion carrier (hypromellose), dissolving in 2.76L of solvent (mixed solution of ethanol and dichloromethane according to volume ratio of 8:15), adding 0.012kg of xanthan gum after dissolving completely, and obtaining drug-containing suspension after dispersing completely the xanthan gum;
(2) Taking the drug-containing suspension obtained in the operation (1), spraying liquid and coating 0.216kg of pill cores (sucrose pill cores with the particle size of 600-710 mu m) in a fluidized bed, and drying to obtain a pellet intermediate; wherein the air inlet temperature of the spray coating stage is 35-40 ℃, the air outlet temperature is 30-35 ℃, the air inlet temperature of the drying stage is 40-45 ℃, the air outlet temperature is 30-35 ℃ and the time is 0.5h;
(3) And (3) taking the pellet intermediate obtained in the operation (2), and placing the pellet intermediate in a constant temperature and humidity box with the relative humidity of 35% at the temperature of 100 ℃ for curing for 8 hours to obtain the itraconazole pellets.
The itraconazole micro-pill prepared in the embodiment comprises a pill core and a coating layer coated on the surface of the pill core, wherein the coating layer contains itraconazole, a dispersion carrier (hydroxypropyl methylcellulose) and xanthan gum in a swelling state. In the itraconazole pellets, the content of the pellet core (sucrose pellet core) was 180 parts by weight, the content of xanthan gum was 10 parts by weight, and the content of the dispersion carrier (hypromellose) was 140 parts by weight, relative to 100 parts by weight of itraconazole. The particle size of the itraconazole pellets is 900-1100 μm through detection.
Example 2
Itraconazole pellets were prepared according to the method of example 1, except that: in this example, the amount of xanthan gum used was 0.006kg.
In the itraconazole pellets prepared in this example, the content of xanthan gum was 5 parts by weight with respect to 100 parts by weight of itraconazole.
Example 3
Itraconazole pellets were prepared according to the method of example 1, except that: in this example, the amount of xanthan gum used was 0.018kg.
In the itraconazole pellets prepared in this example, the content of xanthan gum was 15 parts by weight with respect to 100 parts by weight of itraconazole.
Example 4
Itraconazole pellets were prepared according to the method of example 1, except that: in this example, the amount of the dispersion medium (hypromellose) used was 0.18kg.
In the itraconazole pellets prepared in this example, the content of the dispersion carrier (hypromellose) was 150 parts by weight based on 100 parts by weight of itraconazole.
Example 5
Itraconazole pellets were prepared according to the method of example 1, except that: the curing temperature in operation (3) of this example was 98℃and the relative humidity was 40% RH, and the curing time was 6 hours.
Example 6
Itraconazole pellets were prepared according to the method of example 1, except that: the curing temperature in operation (3) of this example was 102℃and the relative humidity was 30% RH, and the curing time was 10 hours.
Example 7
Itraconazole pellets were prepared according to the method of example 1, except that: an equal amount of carboxymethyl cellulose was used instead of hydroxypropyl methylcellulose.
Example 8
Itraconazole pellets were prepared according to the method of example 1, except that: equal amounts of hydroxypropyl cellulose were used instead of hydroxypropyl methylcellulose.
Comparative example 1
Itraconazole pellets were prepared according to the method of example 1, except that: the present comparative example was not subjected to the aging treatment in the operation (3).
Experimental example 1
Itraconazole pellets prepared in examples 1-6 and comparative example 1 were filled into capsules in an amount of 430 mg.+ -. 4%, and each itraconazole pellet capsule and span (batch number KJJ1 HCQ) were subjected to an acceleration test under acceleration conditions (60 ℃ C., 75% RH) for 2 months.
After the acceleration test, taking out each itraconazole pellet capsule, performing a dissolution test according to a dissolution rate measurement method (the first method of the four general rules of the edition 2020 of Chinese pharmacopoeia), taking 900ml of medium solution (hydrochloric acid solution with the pH of 1.0) as a dissolution medium, and operating at the rotating speed of 50 revolutions per minute according to law. Samples were taken at 60 and 120 minutes, respectively, and the dissolution was measured by ultraviolet-visible spectrophotometry (general rule 0401) and the results are shown in Table 1.
Table 1 dissolution of itraconazole pellets capsule after 2 months of accelerated test
| Capsule | Dissolution for 60min, percent | Dissolution for 120min, percent |
| Example 1 | 89.0 | 99.8 |
| Example 2 | 87.5 | 92.0 |
| Example 3 | 78.4 | 96.5 |
| Example 4 | 76.6 | 79.5 |
| Example 5 | 88.8 | 91.3 |
| Example 6 | 79.6 | 94.7 |
| Comparative example 1 | 73.9 | 75.3 |
| Sipinuno | 87.8 | 90.2 |
As can be seen from Table 1, itraconazole pellets prepared by the method of the present invention have high dissolution rate after being prepared into capsules.
Experimental example 2
The capsules prepared from itraconazole pellets of example 1 and comparative example 1, and the raw material of stephanotized schneiderian (lot number KJJ1 HCQ) after the acceleration test of experimental example 1 for 2 months were taken and thermally analyzed by DSC differential scanning calorimetry, specifically as follows:
taking an empty aluminum crucible as a reference substance, weighing 5mg of sample in another crucible, and placing the sample in a differential scanning calorimeter, wherein the heating rate is 10 ℃/min -1 Heating range is 30-250 ℃, nitrogen is 50ml/min -1 The thermal profile was measured in the environment.
The DSC curves obtained by scanning are shown in fig. 1, and it can be seen from fig. 1 that capsules prepared from itraconazole pellets of comparative example 1 and the spe-pinol (lot number KJJ1 HCQ) have melting peaks of itraconazole after 2 months of acceleration test under acceleration condition (60 ℃,75% rh), which means that the amorphous itraconazole in the capsules prepared from itraconazole pellets of comparative example 1 and the spe-pinol (lot number KJJ1 HCQ) have been recrystallized; whereas the capsules prepared from the itraconazole pellets of example 1 showed no melting peak of itraconazole in the DSC scan after 2 months of acceleration test at the acceleration condition (60 ℃,75% rh), which indicates that itraconazole in the capsules prepared from the itraconazole pellets of example 1 remained amorphous.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (8)
1. The itraconazole micro-pill is characterized by comprising a pill core and a coating layer coated on the surface of the pill core, wherein the coating layer contains itraconazole and xanthan gum, and the xanthan gum is in a swelling state;
wherein, in the itraconazole pellets, the content of the xanthan gum is 5-15 parts by weight relative to 100 parts by weight of itraconazole;
the coating layer also contains a dispersion carrier, wherein the content of the dispersion carrier is 140 parts by weight relative to 100 parts by weight of itraconazole, and the dispersion carrier is hypromellose;
the preparation method of the itraconazole pellets comprises the following operations:
taking a drug-containing suspension, spraying liquid to coat a pill core, and drying to obtain a pellet intermediate, wherein the drug-containing suspension consists of itraconazole, xanthan gum, a dispersion carrier and a solvent; the solvent is a mixed solution of ethanol and dichloromethane, and the volume ratio of the ethanol to the dichloromethane is 8:15;
curing the pellet intermediate to swell the xanthan gum, the curing conditions comprising: the curing temperature is 98-102 ℃, the relative humidity is 30-40% RH, and the curing time is 6-10 h.
2. Itraconazole pellets according to claim 1, wherein the content of the pellet core is 180 parts by weight with respect to 100 parts by weight of itraconazole in the itraconazole pellets;
the pellet core is selected from sucrose pellet core and/or microcrystalline cellulose pellet core.
3. Itraconazole pellets according to claim 1 or 2, wherein the pellet core has a particle size of 600-710 μm and the itraconazole pellets have a particle size of 900-1100 μm.
4. A method for preparing itraconazole pellets according to claim 1, comprising the following steps:
taking a drug-containing suspension, carrying out liquid spraying coating on a pill core, and drying to obtain a pellet intermediate, wherein the drug-containing suspension consists of itraconazole, xanthan gum, a dispersion carrier and a solvent, the dosage of the xanthan gum is 5-15 parts by weight relative to 100 parts by weight of itraconazole, the content of the dispersion carrier is 140 parts by weight, and the dispersion carrier is hypromellose; the solvent is a mixed solution of ethanol and dichloromethane, and the volume ratio of the ethanol to the dichloromethane is 8:15;
curing the pellet intermediate to swell the xanthan gum, the curing conditions comprising: the curing temperature is 98-102 ℃, the relative humidity is 30-40% RH, and the curing time is 6-10 h.
5. The method of claim 4, wherein in the drug-containing suspension the solvent is used in an amount of 2300 parts by volume, wherein the parts by volume are in units of L when the parts by weight are in kg;
in the case of spray coating, the pellet core is used in an amount of 180 parts by weight relative to 100 parts by weight of itraconazole;
the pellet core is selected from sucrose pellet core and/or microcrystalline cellulose pellet core.
6. The method of claim 4, wherein the method of preparing the drug-containing suspension comprises:
taking itraconazole and the dispersion carrier, dissolving in a solvent, and adding xanthan gum.
7. The method according to any one of claims 4 to 6, wherein the conditions for spray coating comprise: the air inlet temperature is 35-40 ℃, and the air outlet temperature is 30-35 ℃;
and/or, the drying conditions include: the air inlet temperature is 40-45 ℃, the air outlet temperature is 30-35 ℃, and the drying time is 0.5h.
8. Itraconazole pellet capsule, characterized by containing itraconazole pellets according to any one of claims 1-3 or itraconazole pellets prepared by the preparation method according to any one of claims 4-7.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1244796A (en) * | 1997-03-26 | 2000-02-16 | 詹森药业有限公司 | Pellets having a core coated with an antifungal and a polymer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1244796A (en) * | 1997-03-26 | 2000-02-16 | 詹森药业有限公司 | Pellets having a core coated with an antifungal and a polymer |
Non-Patent Citations (6)
| Title |
|---|
| Meixia Zheng等.Development of hydroxypropyl methylcellulose film with xanthan gum and its application as an excellent food packaging bio-material in enhancing the shelf life of banana.《Food Chemistry》.2021,第374卷第1-8页. * |
| Nishant Kumar等.Polysaccharide-based component and their relevance in edible film/coating: a review.《Nutrition & Food Science》.2019,第49卷(第5期),第793-823页. * |
| 伊曲康唑PVP微丸制备及体外溶出实验;孙伟张, 曾仁杰, 张勤, 于波涛, 王丹;西南国防医药(第05期) * |
| 周蕊;刘文一;吕竹芬;杨晖;陈燕忠.枸橼酸钾缓释微丸的制备及其质量考察.药学与临床研究.2016,(第01期),全文. * |
| 孙伟张,曾仁杰,张勤,于波涛,王丹.伊曲康唑PVP微丸制备及体外溶出实验.西南国防医药.2005,(第05期),全文. * |
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