CN112870156A - Etoricoxib in-situ gel and preparation method thereof - Google Patents
Etoricoxib in-situ gel and preparation method thereof Download PDFInfo
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- CN112870156A CN112870156A CN202110318928.4A CN202110318928A CN112870156A CN 112870156 A CN112870156 A CN 112870156A CN 202110318928 A CN202110318928 A CN 202110318928A CN 112870156 A CN112870156 A CN 112870156A
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- etoricoxib
- situ gel
- gel
- poloxamer
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- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 title claims abstract description 111
- 229960004945 etoricoxib Drugs 0.000 title claims abstract description 111
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000001879 gelation Methods 0.000 title description 15
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 31
- 229920001400 block copolymer Polymers 0.000 claims abstract description 31
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 31
- 239000000843 powder Substances 0.000 claims abstract description 18
- 239000003906 humectant Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 229920001993 poloxamer 188 Polymers 0.000 claims description 15
- 229940044519 poloxamer 188 Drugs 0.000 claims description 15
- 229920001992 poloxamer 407 Polymers 0.000 claims description 15
- 229940044476 poloxamer 407 Drugs 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- 238000000338 in vitro Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- 230000008961 swelling Effects 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- 230000001186 cumulative effect Effects 0.000 claims description 4
- 230000003628 erosive effect Effects 0.000 claims description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000008859 change Effects 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 abstract description 7
- 229920001983 poloxamer Polymers 0.000 abstract description 7
- 229960000502 poloxamer Drugs 0.000 abstract description 7
- 230000007704 transition Effects 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 5
- 231100000956 nontoxicity Toxicity 0.000 abstract description 4
- 238000013268 sustained release Methods 0.000 abstract description 4
- 238000013270 controlled release Methods 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract description 3
- 230000014759 maintenance of location Effects 0.000 abstract description 3
- 230000002441 reversible effect Effects 0.000 abstract description 3
- 230000002459 sustained effect Effects 0.000 abstract description 3
- 239000000499 gel Substances 0.000 description 108
- 238000012360 testing method Methods 0.000 description 18
- 239000007788 liquid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000008213 purified water Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
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- 238000013461 design Methods 0.000 description 5
- 206010067484 Adverse reaction Diseases 0.000 description 4
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- 238000005303 weighing Methods 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
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- 238000007873 sieving Methods 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
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- 230000014509 gene expression Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940124279 traditional non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000003643 water by type Substances 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The application belongs to the technical field of medicines, and particularly relates to etoricoxib powder in-situ gel and a preparation method thereof. Wherein the etoricoxib in-situ gel comprises the following raw material components in parts by weight: 6-10 parts of etoricoxib, 20-30 parts of polyethylene glycol block copolymer, 1881-2 parts of poloxamer, 40715-20 parts of poloxamer and 1-2 parts of humectant. The etoricoxib in-situ gel belongs to a temperature sensitive type, and can generate reversible phase state transition between sol and gel when the temperature change is sensed. Therefore, the composition can exist in the form of solution before administration, and has convenient administration and accurate dosage; after administration, the gel can be transformed into semisolid gel along with the rise of temperature in vivo, has long retention time at the administration part, has good drug sustained and controlled release performance, and is very suitable to be used as a local administration carrier. Meanwhile, the preparation has the advantages of convenient medicine storage, no toxicity, high biocompatibility of biological tissues, good medicine stability and the like.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to etoricoxib powder in-situ gel and a preparation method thereof.
Background
Etoricoxib, a selective cyclooxygenase-2 inhibitor, has anti-inflammatory, analgesic and antipyretic effects, and can be used for treating acute and chronic osteoarthritis, as well as acute gouty arthritis. Etoricoxib serving as a COX-2 (cyclooxygenase-2) inhibitor can reduce the risks of peptic ulcer, perforation and bleeding of gastrointestinal tracts compared with the traditional non-steroidal anti-inflammatory drugs (NSAIDS), has no sulfonamide group, and has higher safety for patients with sulfanilamide allergy. Etoricoxib obviously reduces common adverse reactions of non-steroidal anti-inflammatory drugs (NSAIDs), including gastrointestinal mucosa injury, liver and kidney toxicity, allergic reaction, blood system abnormality and the like.
At present, etoricoxib preparation has complex process and high administration difficulty, is easy to cause adverse reactions, and can cause digestive tract ulcer, cardiovascular damage, renal function damage and the like when the administration is improper.
Disclosure of Invention
The application aims to provide an etoricoxib powder in-situ gel and a preparation method thereof, and aims to solve the problems of complex process, high administration difficulty and easiness in causing adverse reactions of the existing etoricoxib preparation to a certain extent.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the application provides an etoricoxib in-situ gel, which comprises the following raw material components in parts by weight:
in a second aspect, the application provides a preparation method of etoricoxib powder in-situ gel, which comprises the following steps:
dissolving the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 in the formula ratio in a solvent, and swelling to obtain clear and transparent blank in-situ gel;
and mixing the etoricoxib and the humectant in the formula amount with the blank in-situ gel to obtain the etoricoxib in-situ gel.
The etoricoxib in-situ gel provided by the first aspect of the application is formed by taking 6-10 parts of etoricoxib as an active ingredient, 20-30 parts of polyethylene glycol block copolymer, 1881-2 parts of poloxamer, 40715-20 parts of poloxamer as a matrix and 1-2 parts of a humectant. The etoricoxib in-situ gel belongs to a temperature sensitive type, and can generate reversible phase state transition between sol and gel when the temperature change is sensed. Therefore, the composition can exist in the form of solution before administration, and has convenient administration and accurate dosage; after administration, the gel can be transformed into semisolid gel along with the rise of temperature in vivo, has long retention time at the administration part, has good drug sustained and controlled release performance, and is very suitable to be used as a local administration carrier. Meanwhile, the preparation has the advantages of convenient medicine storage, no toxicity, high biocompatibility of biological tissues, good medicine stability and the like.
According to the preparation method of etoricoxib powder in-situ gel provided by the second aspect of the application, the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 in the formula amount are dissolved in water at the temperature of 0-4 ℃, and the clear and transparent blank in-situ gel is obtained by swelling, wherein the temperature condition is favorable for the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 to be dissolved in water, the mixture is in a liquid state, and the components are favorably and fully swelled. And then mixing the etoricoxib, the humectant and the blank in-situ gel according to the formula amount, and obtaining the etoricoxib in-situ gel. The preparation method of etoricoxib powder in-situ gel has the advantages of simple process, simplicity and convenience in operation, and easiness in realization of industrial large-scale production and application.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In the present invention, the term "and/or" describes the association relationship of the associated objects, and means that there may be three relationships, for example, a and/or B, which may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the present invention, "at least one" means one or more, "a plurality" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items. For example, "at least one (one) of a, b, or c," or "at least one (one) of a, b, and c," may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, and c may be single or plural, respectively.
It should be understood that, in various embodiments of the present invention, the sequence numbers of the above-mentioned processes do not mean the execution sequence, some or all of the steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its function and inherent logic, and should not constitute any limitation to the implementation process of the embodiments of the present invention.
The terminology used in the embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the examples of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weight of the related components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present invention as long as it is in accordance with the description of the embodiments of the present invention. Specifically, the mass in the description of the embodiments of the present invention may be a mass unit known in the chemical industry field such as μ g, mg, g, kg, etc.
The first aspect of the embodiment of the application provides an etoricoxib in-situ gel, which comprises the following raw material components in parts by weight:
the etoricoxib in-situ gel provided by the first aspect of the application is formed by taking 6-10 parts of etoricoxib as an active ingredient, 20-30 parts of polyethylene glycol block copolymer, 1881-2 parts of poloxamer, 40715-20 parts of poloxamer as a matrix and 1-2 parts of a humectant. The etoricoxib in-situ gel belongs to a temperature sensitive type, and can generate reversible phase state transition between sol and gel when the temperature change is sensed. Therefore, the composition can exist in the form of solution before administration, and has convenient administration and accurate dosage; after administration, the gel can be transformed into semisolid gel along with the rise of temperature in vivo, has long retention time at the administration part, has good drug sustained and controlled release performance, and is very suitable to be used as a local administration carrier. Meanwhile, the preparation has the advantages of convenient medicine storage, no toxicity, high biocompatibility of biological tissues, good medicine stability and the like.
In the etoricoxib powder in-situ gel, poloxamer 407(P407) is a temperature-sensitive in-situ gel material, and single P407 cannot meet the requirements of a preparation at a gelling temperature, mechanical strength or biological viscosity. On this basis, poloxamer 188(P188) and P407 are added for compatibility in the embodiment of the application, so that the gelling temperature and the mechanical strength can be effectively improved, but the biological viscosity still cannot meet the requirements of the preparation. Therefore, the embodiment of the application adds the polyethylene glycol block copolymer which is a high molecular material, and the three raw materials of the P188, the P407 and the polyethylene glycol block copolymer are used in a compatible manner, so that the gelling temperature and the mechanical strength are improved, and the defects of poor biological viscosity and the like are overcome. Therefore, the etoricoxib powder in-situ gel has the characteristics of proper gelling temperature, mechanical strength, biological viscosity, biocompatibility and the like, is convenient to administer, has no toxicity, can reduce the adverse reaction of a patient, and improves the compliance. Can also be used for positioning administration, quickly reaching action target and improving curative effect.
The application discovers, through example research, that the gelation temperature of the etoricoxib in-situ gel is reduced along with the increase of the content of the P407 prescription. If the gelation temperature of the etoricoxib in-situ gel is too high, the in-situ gel cannot be rapidly formed at the administration part after administration, so that the drug is lost; if the gelation temperature of the etoricoxib in-situ gel is too low, gelation can be generated when the etoricoxib in-situ gel is not used under the condition of higher ambient temperature in summer, and the administration is also not facilitated. Thus, the present application generally combines P407 with P188 to overcome the disadvantage of too low a gelling temperature. The gelation temperature increases along with the increase of the content of the P188 prescription, and the gelation temperature can meet the requirements of the preparation; however, when the preparation is molded later, the mechanical strength, the biological viscosity, and the like cannot satisfy the requirement of the preparation molding. Furthermore, the third matrix is added for combined use, the polyethylene glycol block copolymer can be used for preparing a temperature-sensitive preparation, and researches show that in the etoricoxib in-situ gel, the gelation temperature changes along with the increase of the formula content of the polyethylene glycol block copolymer, but the increase range is small, so that the requirements of the preparation are met, and the defects of insufficient mechanical strength, excessive biological viscosity and the like of the mixed preparation of the first two matrixes are overcome. However, if the concentration of the polyethylene glycol block copolymer in the etoricoxib in-situ gel is too high, the gel viscosity is reduced, and the flow and displacement during coating are easily caused.
In some embodiments, the etoricoxib powder in-situ gel comprises the following raw material components in parts by weight:
in some embodiments, the etoricoxib in-situ gel has a gelation temperature of 30-35 ℃, is close to the temperature of a human body, and can realize the phase state transition of the etoricoxib in-situ gel through the temperature of the human body after administration. When the temperature is lower than 30-35 ℃, the etoricoxib powder in-situ gel is in a flowing liquid state, so that the etoricoxib powder is convenient to store and transport and convenient to administer, and the dosage is more accurate; when the temperature is higher than 30-35 ℃, the etoricoxib in-situ gel is changed from a liquid state to a hydrogel semi-solid state when the temperature is raised, so that the etoricoxib in-situ gel has long residence time at the medicine application part and better drug sustained-release control performance.
In some embodiments, the etoricoxib in-situ gel has a gel viscosity of 60-65 cps at 25 ℃, and the viscosity enables the etoricoxib in-situ gel to be well combined with an application site after administration, be bonded with biological tissues and have good compatibility.
In some embodiments, the etoricoxib in situ gel of the present application has an erosion time of not less than 4 hours. In some embodiments, the in vitro cumulative release rate of the etoricoxib in-situ gel is 4-4.5 h. According to the etoricoxib in-situ gel, the erosion time and the in-vitro accumulated release degree of the etoricoxib in-situ gel fully ensure the drug slow release effect of the etoricoxib in-situ gel, and the drug durability is improved, so that the curative effect is improved.
In some embodiments, the moisturizer of the present application is selected from the group consisting of: at least one of glycerin, ethylene glycol, propylene glycol, chitosan and hyaluronic acid, and the humectants can further improve the compatibility of the etoricoxib powder in-situ gel and biological tissues.
In some embodiments, the etoricoxib in situ gel of the present application comprises 46.1% by mass of the polyethylene glycol block copolymer, 4.3% by mass of poloxamer 188, and 31.2% by mass of poloxamer 407.
In some embodiments, the etoricoxib in-situ gel further comprises water with a mass percentage of 2% -10%, and the water provides a better swelling condition for the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407, so that the etoricoxib in-situ gel can perform liquid-hydrogel semisolid conversion with temperature.
In some embodiments, the etoricoxib in-situ gel of the present application comprises, by mass, 14.1% of etoricoxib, 46.1% of a polyethylene glycol block copolymer, 4.3% of poloxamer 188, 31.2% of poloxamer 407, 2% -10% of water, and glycerin as a humectant.
The etoricoxib in-situ gel of the examples of the application can be prepared by the following method.
A second aspect of the embodiments of the present application provides a method for preparing etoricoxib in-situ gel, which comprises the following steps:
s10, dissolving the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 in a formula ratio in a solvent, and swelling to obtain clear and transparent blank in-situ gel;
s20, mixing the etoricoxib, the humectant and the blank in-situ gel according to the formula amount to obtain the etoricoxib in-situ gel.
According to the preparation method of etoricoxib powder in-situ gel provided by the second aspect of the application, the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 in the formula amount are dissolved in a solvent such as water and the like, and the clear and transparent blank in-situ gel is obtained by swelling, wherein the temperature condition is favorable for the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 to be dissolved in water, the mixture is in a liquid state, and the components are favorably and fully swelled. And then mixing the etoricoxib, the humectant and the blank in-situ gel according to the formula amount, and obtaining the etoricoxib in-situ gel. The preparation method of etoricoxib powder in-situ gel has the advantages of simple process, simplicity and convenience in operation, and easiness in realization of industrial large-scale production and application.
In some embodiments, in step S10, after the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 are added to a solvent such as water and dissolved sufficiently with stirring at a temperature of 0-4 ℃, the mixture is swelled sufficiently at a temperature of 0-4 ℃ and kept in a liquid state, which is beneficial for subsequent mixing with etoricoxib and other components.
In some embodiments, in step S10, the amount of the solvent such as water is 2% to 10% of the total mass of the etoricoxib in-situ gel, and the solvent in the amount can ensure that the components such as the polyethylene glycol block copolymer, the poloxamer 188 and the poloxamer 407 are fully dissolved and swelled, and can avoid the influence of excessive solvent addition on the phase transition of the subsequent etoricoxib in-situ gel.
In some embodiments, in the step S20, etoricoxib in situ gel can be obtained by fully mixing etoricoxib, humectant and blank in situ gel in a formula amount under a stirring state at a temperature of 0-4 ℃.
In order to make the above implementation details and operations of the present application clearly understood by those skilled in the art, and to make the progress of the in situ gel of etoricoxib and the preparation method thereof obvious in the examples of the present application, the above technical solution is illustrated by a plurality of examples below.
Example 1
An etoricoxib in situ gel, which is prepared by the following steps:
1. taking purified water, refrigerating overnight, measuring the amount of the purified water accounting for 10% of the gel matrix content, placing the purified water in an ice-water bath, placing the purified water on a magnetic stirrer, slowly adding accurately weighed P407 (the content is shown in table 1) while stirring, uniformly dispersing, and placing the gel in a refrigerator for storage at 4 ℃ until the gel is fully swelled to obtain clear and transparent blank in-situ gel.
2. And (3) taking a prescription amount of etoricoxib (14.1%), sieving, and uniformly mixing with the blank original taste gel to obtain the etoricoxib in-situ gel.
The in-situ gel gelling temperature of etoricoxib powder with different P407 contents is measured, and the change of the P407 content and the test result are shown in the following table 1:
TABLE 1
From the test results in table 1, with the increase of the content of the P407 formula, the gelation temperature of the etoricoxib in-situ gel decreases, the gel viscosity increases, and the gel strength increases, and if the content of P407 is too small, the mechanical strength and the biological viscosity of the gel cannot meet the requirements. If the gelling temperature is too high, in-situ gel may not be rapidly formed at the administration site after administration, resulting in drug loss; if the gelling temperature is too low, gelling may occur without being used in the case where the ambient temperature is relatively high in summer.
Example 2
An etoricoxib in situ gel which differs from example 1 in that: in step 1, 32% P407 and P188 as contained in table 2 below were added.
The etoricoxib in-situ gel gelling temperature of different P188 contents is measured, and the change of the P188 contents and the test results are shown in the following table 2:
TABLE 2
As can be seen from the test results in Table 2, the combination of P407 and P188 overcomes the disadvantage of too low a gelling temperature. The content of the P407 prescription is fixed, the gelation temperature increases along with the increase of the content of the P188 prescription, the gelation temperature can meet the requirements of the preparation, and the phase transition can be realized at the temperature of a human body. However, the mechanical strength of the etoricoxib in-situ gel is not obviously improved, the mechanical strength needs to be improved, and the biological viscosity is too high.
Example 3
An etoricoxib in situ gel which differs from example 1 in that: in step 1, 32% P407, 1% P188 and the polyethylene glycol block copolymer content as in table 3 below were added.
The etoricoxib in-situ gel gelling temperatures of different polyethylene glycol block copolymer contents were measured, and the content change and test results of the polyethylene glycol block copolymers are shown in table 3 below:
TABLE 3
As shown in the test results in Table 3, the gelation temperature changes along with the increase of the formula content of the polyethylene glycol block copolymer, but the increase range is small, so that the requirements of the preparation are met, and the defects of insufficient mechanical strength, high biological viscosity and the like of a poloxamer two-matrix mixed preparation are overcome. However, when the concentration of the polyethylene glycol block copolymer is too high, the gel viscosity is also reduced, and the flow displacement is easily caused during coating.
Example 4
The star point design is the most common second-order design in the effect design curved surface, has the characteristics of less test times, high test precision and the like, and has mature application in the field of pharmacy.
Usually, the test table is arranged in a code form, and is converted into an actual operation value during the test, and the general horizontal values are 0, ± 1, ± λ, wherein 0 is a median and λ is an extremum. Lambda (F)1/4F is the number of factorial design partial experiments, F ═ k2(k is a prime number) or F ═ k2 × 1/2 (typically adopted by more than 5 factors).
After determining ± λ of each factor level, the physical quantities represented by 0, ± 1 are respectively found from the level code. The arrangement of the ± 1,0 levels follows the principle that the difference between any two physical quantities is proportional to the difference between the corresponding codes.
In the screening of the etoricoxib in-situ gel formula in the embodiment of the application, the percentage contents of the polyethylene glycol block copolymer, P188 and P407 are selected, and the polyethylene glycol block copolymer (X) is used by adopting a star point design-effect surface method1)、P188(X2) And P407 (X)3) For the influence factors (independent variables) to be considered, the in vitro release degree (dependent variable) of etoricoxib is used as an evaluation index, 3-factor-5 levels are designed to optimize the prescription, the level code values are respectively +/-1.732, +/-1 and 0, and the specific values are shown in the following table 4:
TABLE 4
Comprehensive analysis and data processing are carried out through Design expert8.0 software, and the etoricoxib in-situ gel with the optimal in-vitro release degree is obtained when the prescription content of the polyethylene glycol block copolymer is 46.1%, the prescription content of P188 is 4.3% and the prescription content of P407 is 31.2%.
Example 5
An etoricoxib in situ gel, which is prepared by the following steps:
1. purified water was taken and refrigerated overnight. Measuring 8.5ml of purified water with the gel matrix content being 10%, placing the purified water in an ice-water bath, placing the purified water on a magnetic stirrer, slowly adding 46.1g, P40731.2g and P1884.3g of polyethylene glycol block copolymer which are accurately weighed while stirring, after uniform dispersion, placing the mixture in a refrigerator for storage at 4 ℃ until full swelling, and obtaining clear and transparent blank in-situ gel.
2. And (3) taking 14.1g of etoricoxib in a prescription amount, sieving, and uniformly mixing with the blank original-taste gel to obtain the etoricoxib in-situ gel.
The prepared etoricoxib powder in situ gel was tested as follows:
1. gelling temperature and gel viscosity: the shear rate of a rotary rheometer (rotor type: 20mm flat plate) is controlled to be 1.0s < -1 >, the temperature rise rate is 1 ℃ min < -1 >, the viscosity value of etoricoxib in-situ gel at 4-40 ℃ is measured, and the inflection point temperature when the viscosity suddenly rises is the gelling temperature. And recording the viscosity at 25 ℃ to obtain the gel viscosity. The test results are shown in table 5 below.
2. And (3) corrosion time: taking 5mL of blank gel liquid, placing the blank gel liquid in a glass test tube (the mass of the blank test tube is W0), weighing the blank gel liquid to be of a fixed mass (W1), placing the blank gel liquid in a constant-temperature water bath oscillator adjusted to be at a proper gelation temperature to be completely gelled, adding 3mL of phosphate buffer saline solution (PBS pH7.0) with the same temperature as that of the gel, oscillating, setting the frequency to be 50Hz, starting timing, pouring all PBS every 30min, weighing the blank gel liquid to be of a fixed mass (Wt), adding the heat-preservation PBS with the same mass as that of the previous step into the glass test tube, transferring 1mL of the taken solution for later use to measure the in-vitro accumulated release rate until the accumulated corrosion amount is more than 95%, and obtaining the loss mass as the corrosion amount Q. Q ═ 100% (W1-Wt)/(W1-W0). The test results are shown in table 5 below.
TABLE 5
As can be seen from the test results in Table 5, the prepared etoricoxib in-situ gel has proper gelling temperature, gel viscosity and erosion time, is easy to be smeared on an affected part, is easy to generate phase change and is adhered to the affected part.
3. In vitro cumulative release assay:
chromatographic conditions Waters C18column (4.6 mm. times.150 mm, 3.5 μm); detection wavelength: 235 nm; column temperature: 40 ℃; flow rate: 0.7ml/min, injection volume: 10 μ l. 0.02mol/L sodium dihydrogen phosphate solution (pH adjusted to 3 with 2% phosphoric acid solution) -acetonitrile (68: 27, V/V) was used as a mobile phase.
Preparation of control solutions: an appropriate amount of etoricoxib reference substance is precisely weighed, dissolved by acetonitrile-water (1: 1, V/V) and prepared into a solution containing 0.1mg/ml of etoricoxib as a reference solution.
Preparation of a test solution: precisely weighing the product, adding appropriate amount of acetonitrile-water solution, performing strong ultrasound for 60min to dissolve and quantitatively dilute, making into 0.1mg/ml solution, and filtering to obtain test solution.
The determination method comprises the following steps: precisely sucking 10 μ l of each of the reference solution and the sample solution, injecting into liquid chromatograph, and measuring. The results of the tests are shown in Table 6 below (cumulative release,%).
TABLE 6
The test results in Table 6 show that the in vitro accumulative release rate reaches the release end point within 4-4.5 h, and the drug release effect is good. Compared with the traditional tablet, the etoricoxib in-situ gel has the advantages of uniform drug dispersion, convenient administration and realization of slow release.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. The etoricoxib in-situ gel is characterized by comprising the following raw material components in parts by weight:
2. the etoricoxib in-situ gel according to claim 1, which comprises the following raw material components in parts by weight:
3. the etoricoxib in situ gel according to claim 1 or 2, wherein the etoricoxib in situ gel has a gelling temperature of 30-35 ℃.
4. The etoricoxib in situ gel according to claim 1 or 2, wherein the gel viscosity of the etoricoxib in situ gel is 60-65 cps at 25 ℃.
5. The etoricoxib in situ gel according to claim 1 or 2, wherein the etoricoxib in situ gel has an erosion time of not less than 4 h;
and/or the in-vitro cumulative release degree of the etoricoxib in-situ gel is 4-4.5 h.
6. The etoricoxib in situ gel of claim 1 or 2, wherein the humectant is selected from the group consisting of: at least one of glycerol, ethylene glycol, propylene glycol, chitosan, and hyaluronic acid.
7. The etoricoxib in situ gel according to claim 1, wherein the etoricoxib in situ gel comprises 14.1% by mass, 46.1% by mass of the polyethylene glycol block copolymer, 4.3% by mass of poloxamer 188 and 31.2% by mass of poloxamer 407;
and/or the etoricoxib powder in-situ gel further comprises 2-10% of water by mass.
8. A method for preparing etoricoxib powder in-situ gel according to any one of claims 1 to 7, which comprises the following steps:
dissolving the polyethylene glycol block copolymer, poloxamer 188 and poloxamer 407 in the formula ratio in a solvent, and swelling to obtain clear and transparent blank in-situ gel;
and mixing the etoricoxib and the humectant in the formula amount with the blank in-situ gel to obtain the etoricoxib in-situ gel.
9. The preparation method of etoricoxib in-situ gel according to claim 8, wherein the polyethylene glycol block copolymer, the poloxamer 188 and the poloxamer 407 in the formula amount are added into a solvent to be dissolved under the stirring state at the temperature of 0-4 ℃, and are swelled under the temperature of 0-4 ℃.
10. A process for the preparation of etoricoxib in situ gel according to claim 8 or 9 wherein the solvent is selected from water;
and/or the dosage of the solvent is 2-10% of the total mass of the etoricoxib in-situ gel.
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