CN118001278A - Bilastine freeze-dried ball composition and preparation method thereof - Google Patents
Bilastine freeze-dried ball composition and preparation method thereof Download PDFInfo
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- CN118001278A CN118001278A CN202311654064.9A CN202311654064A CN118001278A CN 118001278 A CN118001278 A CN 118001278A CN 202311654064 A CN202311654064 A CN 202311654064A CN 118001278 A CN118001278 A CN 118001278A
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- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 title claims abstract description 109
- 229960004314 bilastine Drugs 0.000 title claims abstract description 109
- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 68
- 239000003814 drug Substances 0.000 claims abstract description 60
- 239000008188 pellet Substances 0.000 claims abstract description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000004108 freeze drying Methods 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003223 protective agent Substances 0.000 claims abstract description 11
- 238000007710 freezing Methods 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 239000008213 purified water Substances 0.000 claims description 20
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 14
- 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 claims description 13
- 239000004376 Sucralose Substances 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000796 flavoring agent Substances 0.000 claims description 12
- 235000013355 food flavoring agent Nutrition 0.000 claims description 12
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 12
- 235000019408 sucralose Nutrition 0.000 claims description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims description 11
- 239000001116 FEMA 4028 Substances 0.000 claims description 11
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 11
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 11
- 229960004853 betadex Drugs 0.000 claims description 11
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 10
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 8
- 239000011324 bead Substances 0.000 claims description 8
- 238000007599 discharging Methods 0.000 claims description 8
- 230000008014 freezing Effects 0.000 claims description 8
- 238000004806 packaging method and process Methods 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 229950008882 polysorbate Drugs 0.000 claims description 5
- 229920000136 polysorbate Polymers 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 17
- 238000010521 absorption reaction Methods 0.000 abstract description 11
- 238000000465 moulding Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 23
- 238000009472 formulation Methods 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 229910000838 Al alloy Inorganic materials 0.000 description 6
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 210000000214 mouth Anatomy 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000024780 Urticaria Diseases 0.000 description 3
- 239000008351 acetate buffer Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960000443 hydrochloric acid Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 201000010435 allergic urticaria Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 238000001007 flame atomic emission spectroscopy Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a bilastine freeze-dried ball composition and a preparation method thereof, and the bilastine freeze-dried ball composition and the preparation method thereof provided by the invention are adopted, and the composition comprises the following components in parts by weight: 20 parts of bilastine, 1-5 parts of framework propping agent, 70-90 parts of freeze-drying protective agent, 3-5 parts of solubilizer, 1-2 parts of corrigent and 1-2 parts of pH value regulator, and the bilastine freeze-dried balls prepared through the process steps of liquid medicine preparation, quick-freezing molding, freeze-drying and the like can be disintegrated in water at 37 ℃ for 6-10 seconds, and have shorter disintegration time and higher dissolution rate than the existing related marketed preparations; in addition, when the bilastine freeze-dried pellet is used under the same application condition, the absorption rate and the onset rate of the bilastine freeze-dried pellet are higher than those of the existing related marketed preparations, so that the problems of slow absorption, slow onset of action, low bioavailability and the like in the application process of bilastine tablets and oral liquid are effectively solved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and relates to a bilastine freeze-dried pellet composition and a preparation method thereof.
Background
Bilastine is a non-sedating long acting antihistamine that selectively antagonizes peripheral H1 receptors, but has no affinity for muscarinic receptors and low affinity for other receptors. Is suitable for treating allergic rhinitis and urticaria, including adult and teenagers aged 12 years and older. The curative effect is similar to that of cetirizine, fexofenadine and desloratadine. Currently, the medicines on the market are bilastine tablets and bilastine oral liquid.
The chemical structural formula of the bilastine is shown as follows, and the molecular formula of the bilastine is C 28H37N3O3.
Bilastine tablet was developed by Spanish FAES FARMA (original name: fabrica Espanola de ProductiosQuimicos y FarmaceuticosSA) and is mainly used for treating allergic rhinoconjunctivitis (seasonal and perennial) and urticaria, and was approved by European Union for marketing in 10 European countries such as United kingdom, spanish, germany, denmark, bulgaria, sweden, etc. Bilastine tablet is suitable for allergic rhinitis, urticaria, and pruritus accompanied with skin diseases (eczema, dermatitis, and skin pruritus).
The dosage of the bilastine tablet for adults is 1 time per day, and 20mg is orally taken every empty stomach. The bilastine tablet has the problems of low dissolution rate, slow absorption, slow onset of action, low bioavailability and the like.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a bilastine freeze-dried pellet composition and a preparation method thereof, and the problems of slow absorption, slow onset of action, low bioavailability and the like existing in the application process of a bilastine tablet are solved by preparing the bilastine freeze-dried pellet with high dissolution rate.
To achieve the purpose, the invention provides a bilastine freeze-dried ball composition, which comprises the following components in parts by weight: 20 parts of bilastine, 1-5 parts of framework propping agent, 70-90 parts of freeze-drying protective agent, 3-5 parts of solubilizer, 1-2 parts of flavoring agent and 1-2 parts of pH value regulator.
Further, the skeleton propping agent is one or a combination of any several of gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone.
Further, the lyoprotectant is polylactide glycolide.
Further, the molar ratio of lactide to glycolide in the polylactide glycolide is 60:40-40:60.
Further, the solubilizer is selected from one or a combination of any of beta cyclodextrin, polysorbate and sodium dodecyl sulfate.
Further, the flavoring agent is selected from one or a combination of any of sucralose, steviosin and edible essence.
Further, the pH regulator is one or the combination of two of hydrochloric acid and citric acid.
Furthermore, the skeleton propping agent of the composition adopts hydroxypropyl methylcellulose, the freeze-drying protective agent adopts hydroxypropyl methylcellulose, the solubilizer adopts beta cyclodextrin, the flavoring agent adopts sucralose, and the pH value regulator adopts hydrochloric acid;
The composition comprises the following components in parts by weight: 20 parts of bilastine, 3-3.5 parts of hydroxypropyl methylcellulose, 78-82 parts of polylactide glycolide (the molar ratio of lactide to glycolide is 60:40-40:60), 4-5 parts of beta-cyclodextrin, 1.5-2 parts of sucralose and 1.5-2 parts of hydrochloric acid.
The invention also provides a preparation method of the bilastine freeze-dried pellet composition, which comprises the following steps:
(1) Preparing a liquid medicine: dissolving the framework propping agent in purified water, stirring to form a uniform solution, adding a freeze-drying protective agent, a solubilizer, bilastine, a pH value regulator and a flavoring agent into the obtained solution, stirring until the framework propping agent is fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to prepare a liquid medicine;
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: placing the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 15-25 Pa, and keeping for 150 minutes; then heating to-20 to-15 ℃ and keeping for 100 minutes; heating to-15-0 deg.c for 100 min, heating to 5-10 deg.c for 100 min, heating to 20-25 deg.c for 100 min, and heating to 25-35 deg.c for 150 min;
(4) And (5) releasing pressure, discharging from the box, and sequentially carrying out cold aluminum packaging, blanking and batch number printing.
Further, the bilastine freeze-dried spheres prepared by the preparation method disintegrate in water at 37 ℃ within 6-10 seconds.
The bilastine freeze-dried ball composition and the preparation method thereof have the beneficial effects that the bilastine freeze-dried ball composition comprises the following components in parts by weight: 20 parts of bilastine, 1-5 parts of framework propping agent, 70-90 parts of freeze-drying protective agent, 3-5 parts of solubilizer, 1-2 parts of corrigent and 1-2 parts of pH value regulator, and the bilastine freeze-dried balls prepared through the process steps of liquid medicine preparation, quick-freezing molding, freeze-drying and the like can be disintegrated in water at 37 ℃ for 6-10 seconds, and have shorter disintegration time and higher dissolution rate than the existing related marketed preparations; in addition, when the bilastine freeze-dried pellet is used under the same application condition, the absorption rate and the onset rate of the bilastine freeze-dried pellet are higher than those of the existing related marketed preparations, so that the problems of slow absorption, slow onset of action, low bioavailability and the like in the application process of bilastine tablets and oral liquid are effectively solved. Meanwhile, in view of the fact that the bilastine preparation prepared by the method is a freeze-dried ball, the bilastine preparation is convenient to carry, water is not needed for taking, and compliance of patients is better.
Drawings
Fig. 1 is a flow chart of a preparation method of a bilastine freeze-dried pellet composition according to an embodiment of the invention.
FIG. 2 is a graph showing the dissolution of the bilastine freeze-dried pellet prepared in the example of the present invention and a reference formulation in a 0.1mol/L hydrochloric acid solution.
FIG. 3 is a graph showing the dissolution of the bilastine lyophilized pellet prepared in the examples of the present invention and a reference formulation in acetate buffer at pH 4.5.
FIG. 4 is a graph showing the dissolution of the bilastine lyophilized pellet prepared in the examples of the present invention and a reference formulation in phosphate buffer having a pH of 6.8.
FIG. 5 is a graph showing the dissolution of the bilastine lyophilized pellet prepared in the examples of the present invention and a reference formulation in purified water.
Detailed Description
The technical solutions of the present invention will be further clearly and completely described below with reference to the accompanying drawings and detailed description, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In this embodiment, a bilastine freeze-dried pellet composition is provided, and the composition comprises the following components in parts by weight: 20 parts of bilastine, 1-5 parts of framework propping agent, 70-90 parts of freeze-drying protective agent, 3-5 parts of solubilizer, 1-2 parts of flavoring agent and 1-2 parts of pH value regulator.
Optionally, the skeleton propping agent is one or a combination of any of gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, and is used for maintaining the shape of the tablet so as to prevent the freeze-dried balls from collapsing after freeze-drying and water loss.
Specifically, the lyoprotectant is poly (lactide-co-glycolide) (PLGA).
Alternatively, the molecular weight of the poly (lactide-co-glycolide) (PLGA) is 6000 to 45000 daltons, preferably 10000 to 30000 daltons, more preferably 10000 to 25000 daltons. The molar ratio of lactide to glycolide in PLGA is 90:10 to 10:90, preferably 75:25 to 25:75, more preferably 60:40 to 40:60, especially 50:50, and the intrinsic viscosity of PLGA is 0.1 to 0.40dL/g, preferably ranging from 0.10 to 0.35dL/g, more preferably 0.10 to 0.30dL/g (VIATELTM DLG 5002A/E).
Optionally, the solubilizer is selected from one or a combination of any of beta cyclodextrin, polysorbate and sodium dodecyl sulfate.
Optionally, the flavoring agent is selected from one or a combination of more than one of sucralose, steviosin and edible essence.
Optionally, the pH regulator is selected from one or two of hydrochloric acid and citric acid, and is used for regulating the pH value of the liquid medicine prepared by adding purified water into the composition to a volume of 1000ml to 3.0-4.0. When the pH of the composition exceeds this pH range, a precipitate phenomenon may exist, thereby affecting the formability of the finished product freeze-drying, resulting in unacceptable product uniformity. In a preferred embodiment, the pH is adjusted to 3.5.
In a preferred embodiment, the skeleton propping agent of the composition adopts hydroxypropyl methylcellulose, the freeze-drying protective agent adopts hydroxypropyl methylcellulose, the solubilizer adopts beta cyclodextrin, the flavoring agent adopts sucralose, the pH value regulator adopts hydrochloric acid, and the composition comprises the following components in parts by weight:
As shown in fig. 1, the preparation method of the bilastine freeze-dried pellet composition provided in the present embodiment includes the following steps:
(1) Preparing a liquid medicine: dissolving the framework propping agent in purified water, stirring to form a uniform solution, adding a freeze-drying protective agent, a solubilizer, bilastine, a pH value regulator and a flavoring agent into the obtained solution, stirring until the framework propping agent is fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to prepare a liquid medicine; and under the action of the pH value regulator, the pH value of the liquid medicine is regulated to 3.0-4.0.
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: placing the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 15-25 Pa, and keeping for 150 minutes; then heating to-20 to-15 ℃ and keeping for 100 minutes; heating to-15-0 deg.c for 100 min, heating to 5-10 deg.c for 100 min, heating to 20-25 deg.c for 100 min, and heating to 25-35 deg.c for 150 min;
(4) And discharging the aluminum alloy from the box after pressure relief, and then sequentially carrying out cold aluminum packaging, blanking and batch number printing.
The following examples are presented to further illustrate embodiments of the invention.
Example 1
The bilastine freeze-dried ball composition comprises the following components in parts by weight:
A method for preparing a bilastine freeze-dried pellet composition in example 1 comprises the steps of:
(1) Preparing a liquid medicine: and dissolving hydroxypropyl methylcellulose in purified water, stirring to form a uniform solution, adding polylactide glycolide (the molar ratio of lactide to glycolide is 50:50), beta-cyclodextrin, bilastine, hydrochloric acid and sucralose into the obtained solution, stirring until the materials are fully and uniformly dissolved, and finally, using the purified water to fix the volume to 1000ml to prepare a liquid medicine, wherein the pH value of the liquid medicine is 3.5.
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: putting the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40+/-2 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 18+/-2 Pa, and keeping for 150 minutes; then heating to-18+/-2 ℃ and keeping for 100 minutes; heating to-10deg.C for 100 min, heating to 6deg.C for 100 min, heating to 22+ -2deg.C for 100 min, and heating to 28+ -2deg.C for 150 min;
(4) And discharging the aluminum alloy from the box after pressure relief, and then sequentially carrying out cold aluminum packaging, blanking and batch number printing.
Example 1 a freeze-dried bilastine pellet was prepared, which disintegrated in water at 37 ℃ for 6 seconds.
Example 2
The bilastine freeze-dried ball composition comprises the following components in parts by weight:
a method for preparing a bilastine freeze-dried pellet composition in example 2, comprising the steps of:
(1) Preparing a liquid medicine: dissolving hypromellose in purified water, stirring to form a uniform solution, adding polylactide glycolide (the molar ratio of lactide to glycolide is 40:60), beta-cyclodextrin, bilastine, a pH value regulator and sucralose into the obtained solution, stirring until the materials are fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to obtain a liquid medicine, wherein the pH value of the liquid medicine is 3.5;
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: putting the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40+/-2 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 18+/-2 Pa, and keeping for 150 minutes; then heating to-18+/-2 ℃ and keeping for 100 minutes; heating to-10deg.C for 100 min, heating to 6deg.C for 100 min, heating to 22+ -2deg.C for 100 min, and heating to 28+ -2deg.C for 150 min;
(4) And discharging the aluminum alloy from the box after pressure relief, and then sequentially carrying out cold aluminum packaging, blanking and batch number printing.
Example 2a freeze-dried ball of bilastine was prepared, which disintegrated in water at 37 ℃ for 10 seconds.
Example 3
The bilastine freeze-dried ball composition comprises the following components in parts by weight:
a method for preparing a bilastine freeze-dried pellet composition in example 3 comprises the steps of:
(1) Preparing a liquid medicine: dissolving hydroxypropyl cellulose in purified water, stirring to form a uniform solution, adding polylactide glycolide (the molar ratio of lactide to glycolide is 60:40), polysorbate, bilastine, hydrochloric acid and sucralose into the obtained solution, stirring until the solution is fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to prepare a liquid medicine, wherein the pH value of the liquid medicine is 3.5;
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: putting the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40+/-2 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 18+/-2 Pa, and keeping for 150 minutes; then heating to-18+/-2 ℃ and keeping for 100 minutes; heating to-10deg.C for 100 min, heating to 6deg.C for 100 min, heating to 22+ -2deg.C for 100 min, and heating to 28+ -2deg.C for 150 min;
(4) And discharging the aluminum alloy from the box after pressure relief, and then sequentially carrying out cold aluminum packaging, blanking and batch number printing.
The freeze-dried bilastine spheres prepared in this example 3 disintegrated in water at 37 ℃ for 8 seconds.
Example 4
The bilastine freeze-dried ball composition comprises the following components in parts by weight:
the preparation method of the bilastine freeze-dried pellet composition in the embodiment 4 comprises the following steps:
(1) Preparing a liquid medicine: dissolving povidone in purified water, stirring to form a uniform solution, adding polylactide-glycolide (the molar ratio of lactide to glycolide is 45:55), sodium dodecyl sulfate, bilastine, citric acid and steviosin into the obtained solution, stirring until the solution is fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to obtain a liquid medicine, wherein the pH value of the liquid medicine is 3.5;
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: putting the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40+/-2 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 18+/-2 Pa, and keeping for 150 minutes; then heating to-18+/-2 ℃ and keeping for 100 minutes; heating to-10deg.C for 100 min, heating to 6deg.C for 100 min, heating to 22+ -2deg.C for 100 min, and heating to 28+ -2deg.C for 150 min;
(4) And discharging the aluminum alloy from the box after pressure relief, and then sequentially carrying out cold aluminum packaging, blanking and batch number printing.
The freeze-dried bilastine spheres prepared in this example 4 disintegrated in water at 37 ℃ for 10 seconds.
Example 5
The bilastine freeze-dried ball composition comprises the following components in parts by weight:
A method for preparing a bilastine freeze-dried pellet composition in example 5, comprising the steps of:
(1) Preparing a liquid medicine: dissolving hydroxypropyl methylcellulose and hydroxypropyl cellulose in purified water, stirring to form a uniform solution, adding polylactide glycolide (the molar ratio of lactide to glycolide is 55:45), beta-cyclodextrin, polysorbate, bilastine, hydrochloric acid and sucralose into the obtained solution, stirring until the solution is fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to obtain a liquid medicine, wherein the pH value of the liquid medicine is 3.5;
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: putting the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40+/-2 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 18+/-2 Pa, and keeping for 150 minutes; then heating to-18+/-2 ℃ and keeping for 100 minutes; heating to-10deg.C for 100 min, heating to 6deg.C for 100 min, heating to 22+ -2deg.C for 100 min, and heating to 28+ -2deg.C for 150 min;
(4) And discharging the aluminum alloy from the box after pressure relief, and then sequentially carrying out cold aluminum packaging, blanking and batch number printing.
Example 5 a freeze-dried ball of bilastine was prepared, which disintegrated in water at 37 ℃ for 8 seconds.
Comparative example 1 disintegration time test
In order to prepare the bilastine freeze-dried spheres of comparative examples 1-5 and the disintegration time of the related bilastine tablets in the prior art, according to the four-part rule 0921 of pharmacopoeia 2020, the disintegration time of the tablets is examined by using a Tian Dai Fang disintegrator (ZB-1E) and using water at 37 ℃ as a disintegration medium. The disintegration time of examples 1-5 and the reference formulation (bilastine tablets, commercially available foreign formulations Bilaxten, product lot 2892A) are shown in table 1.
TABLE 1 disintegration time of examples 1-5 and control
Comparative example 2 dissolution performance test
In this embodiment, dissolution performance of the bilastine freeze-dried pellet prepared in example 1 and a reference formulation (bilastine tablet, commercially available formulation Bilaxten abroad, product lot No. 2892A) in four medium solutions with different pH values was studied. The dissolution rates of the bilastine freeze-dried pellet prepared in example 1 and the reference formulation in 0.1mol/L hydrochloric acid solution, acetate buffer with pH value of 4.5, phosphate buffer with pH value of 6.8 and purified water are shown in Table 2.
The dissolution profiles of the bilastine freeze-dried pellet prepared in example 1 and the reference formulation in 0.1mol/L hydrochloric acid solution, acetate buffer with pH value of 4.5, phosphate buffer with pH value of 6.8 and purified water are shown in figures 2-5.
As can be seen from table 2 and fig. 2 to 5, the dissolution rate of the bilastine freeze-dried pellet prepared in example 1 in various medium solutions is far faster than that of the reference formulation, and the in vitro dissolution behavior can reflect the in vivo absorption rate, so that the absorption rate and the onset rate of the bilastine freeze-dried pellet prepared in example 1 when used under the same application conditions can be far higher than those of the reference formulation. Moreover, the bilastine freeze-dried pellets prepared in examples 1-4 disintegrated in water at 37 ℃ within 6-10 seconds, and rapidly disintegrated in the mouth, and most of the bilastine freeze-dried pellets entered the gastrointestinal tract along with swallowing, and some of the bilastine freeze-dried pellets were absorbed through the oral cavity, so that the bilastine freeze-dried pellets also had a faster effect than the reference formulation, and the bioavailability of bilastine was effectively improved.
Comparative example 3 pharmacokinetic test
To further study and verify the absorption, onset and bioavailability of the bilastine lyophilized pellet prepared in this embodiment in vivo, the bilastine lyophilized pellet prepared in example 1 (i.e., the test agents in tables 3 and 4) and the reference formulation were subjected to pharmacokinetic studies, and some of the key parameters in the fasting drug time curves (fasting plasma drug concentration-time curves) of the test agent and the reference agent are shown in tables 3 and 4.
TABLE 3 arithmetical mean of part of key parameters in fasting drug curves for test and reference reagents
TABLE 4 geometric mean of some key parameters in fasting drug-time curves for test and reference agents
Wherein, C max -maximum blood concentration; t max -peak time for drug concentration; AUC-area under the time of drug curve; CL-clearance; t 1/2 -half-life; v d -apparent distribution volume; f-bioavailability.
The in vitro dissolution behavior and the key parameters of the drug time curve of the bilastine freeze-dried pellet prepared in the comparative example 1 and the reference preparation can be known, and the dissolution rate of the bilastine freeze-dried pellet prepared in the example 1 is far faster than that of the bilastine tablet; the in vitro dissolution behavior reflects the in vivo absorption rate, and the time-of-drug curve parameters in tables 3 and 4 show that, using the same drug concentration for the peak time, the peak blood concentration of the bilastine lyophilized pellet prepared in example 1 (i.e., the maximum blood concentration of the test preparation) is higher than the peak blood concentration of the reference preparation (i.e., the maximum blood concentration of the reference preparation), which is further described: the in vivo absorption speed of the prepared bilastine freeze-dried ball is greater than that of the marketed preparation, and the in vivo onset speed of the prepared bilastine freeze-dried ball is greater than that of the marketed preparation. In addition, the bilastine freeze-dried balls prepared by the embodiment of the invention can be rapidly disintegrated in the mouth, and part of bilastine is absorbed by the oral cavity, so that the effect is faster than that of the marketed preparation, and the bioavailability of the bilastine can be effectively improved. In addition, in view of the bilastine freeze-dried balls prepared in the embodiment of the invention, the bilastine freeze-dried balls are convenient to carry, do not need water for administration, have good taste, can improve the medication compliance of patients, and solve the problem of difficult medication of patients.
The above embodiments are merely illustrative of the present invention and various modifications and variations may be made thereto by those skilled in the art without departing from the spirit and scope of the present invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (10)
1. A bilastine freeze-dried pellet composition, characterized in that the composition comprises the following components in parts by weight: 20 parts of bilastine, 1-5 parts of framework propping agent, 70-90 parts of freeze-drying protective agent, 3-5 parts of solubilizer, 1-2 parts of flavoring agent and 1-2 parts of pH value regulator.
2. A bilastine freeze-dried pellet composition according to claim 1, wherein the skeletal propping agent is selected from one or a combination of any of gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone.
3. A bilastine freeze-dried pellet composition as in claim 1 wherein the lyoprotectant is polylactide glycolide.
4. A bilastine freeze-dried pellet composition according to claim 3, wherein the molar ratio of lactide to glycolide in the polylactideglycolide is from 60:40 to 40:60.
5. A bilastine freeze-dried pellet composition according to claim 1, wherein the solubilising agent is selected from one or a combination of any of beta cyclodextrin, polysorbate, sodium dodecyl sulphate.
6. A bilastine freeze-dried pellet composition as claimed in claim 1 wherein the flavouring agent is selected from one or a combination of any of sucralose, steviosin, flavouring essence.
7. A bilastine freeze-dried pellet composition according to claim 1, wherein the pH adjustor is selected from one or a combination of two of hydrochloric acid and citric acid.
8. The bilastine freeze-dried pellet composition according to claim 1, wherein the composition has a skeleton proppant of hydroxypropyl methylcellulose, a freeze-drying protective agent of hydroxypropyl methylcellulose, a solubilizer of beta cyclodextrin, a flavoring agent of sucralose, and a pH regulator of hydrochloric acid;
The composition comprises the following components in parts by weight: 20 parts of bilastine, 3-3.5 parts of hydroxypropyl methylcellulose, 78-82 parts of polylactide glycolide (the molar ratio of lactide to glycolide is 60:40-40:60), 4-5 parts of beta-cyclodextrin, 1.5-2 parts of sucralose and 1.5-2 parts of hydrochloric acid.
9. A process for the preparation of a bilastine freeze-dried pellet composition according to any one of claims 1 to 8, characterized in that it comprises the steps of:
(1) Preparing a liquid medicine: dissolving the framework propping agent in purified water, stirring to form a uniform solution, adding a freeze-drying protective agent, a solubilizer, bilastine, a pH value regulator and a flavoring agent into the obtained solution, stirring until the framework propping agent is fully and uniformly dissolved, and finally, fixing the volume to 1000ml by using the purified water to prepare a liquid medicine;
(2) And (3) forming: placing the liquid medicine into a liquid nitrogen bead freezing machine, and setting the temperature of liquid nitrogen to be between-180 ℃ and-190 ℃; the liquid medicine is quickly frozen into solid balls after the liquid medicine drops with the volume of 2 ml.
(3) And (3) freeze-drying: placing the solid spheres obtained in the step (2) into a freeze dryer, and keeping the temperature at-40 ℃ for 60 minutes; then vacuumizing to the vacuum degree of 15-25 Pa, and keeping for 150 minutes; then heating to-20 to-15 ℃ and keeping for 100 minutes; heating to-15-0 deg.c for 100 min, heating to 5-10 deg.c for 100 min, heating to 20-25 deg.c for 100 min, and heating to 25-35 deg.c for 150 min;
(4) And (5) releasing pressure, discharging from the box, and sequentially carrying out cold aluminum packaging, blanking and batch number printing.
10. The preparation method of the bilastine freeze-dried pellet composition according to claim 9, wherein the bilastine freeze-dried pellet prepared by the preparation method is disintegrated in water at 37 ℃ within 6-10 seconds.
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