CN117357520A - Pharmaceutical composition for relieving pain of osteoarthritis of companion animals and application thereof - Google Patents
Pharmaceutical composition for relieving pain of osteoarthritis of companion animals and application thereof Download PDFInfo
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- CN117357520A CN117357520A CN202210764950.6A CN202210764950A CN117357520A CN 117357520 A CN117357520 A CN 117357520A CN 202210764950 A CN202210764950 A CN 202210764950A CN 117357520 A CN117357520 A CN 117357520A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 41
- 241001465754 Metazoa Species 0.000 title claims abstract description 20
- 201000008482 osteoarthritis Diseases 0.000 title claims abstract description 15
- HZVLFTCYCLXTGV-UHFFFAOYSA-N 1-[2-[4-(2-ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea Chemical compound CCC1=NC2=C(C)N=C(C)C=C2N1C(C=C1)=CC=C1CCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 HZVLFTCYCLXTGV-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229950004517 grapiprant Drugs 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000004094 surface-active agent Substances 0.000 claims abstract description 23
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 12
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 11
- -1 polyoxyethylene Polymers 0.000 claims description 13
- 235000006708 antioxidants Nutrition 0.000 claims description 11
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- 206010061218 Inflammation Diseases 0.000 claims description 7
- 125000005456 glyceride group Chemical group 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
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- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 3
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- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 2
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
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- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
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- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
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- 229940069328 povidone Drugs 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 229960000984 tocofersolan Drugs 0.000 claims description 2
- 235000004835 α-tocopherol Nutrition 0.000 claims description 2
- 239000002076 α-tocopherol Substances 0.000 claims description 2
- 241000282465 Canis Species 0.000 claims 1
- 241000283073 Equus caballus Species 0.000 claims 1
- 241000282324 Felis Species 0.000 claims 1
- 241001529936 Murinae Species 0.000 claims 1
- 239000003907 antipyretic analgesic agent Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
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- 229960005150 glycerol Drugs 0.000 claims 1
- 229940057917 medium chain triglycerides Drugs 0.000 claims 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims 1
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- 229940057847 polyethylene glycol 600 Drugs 0.000 claims 1
- 239000000693 micelle Substances 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 6
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- 239000004530 micro-emulsion Substances 0.000 description 6
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- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 4
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention aims to provide a pharmaceutical composition for relieving pain of osteoarthritis of companion animals and application thereof. The active ingredient of the pharmaceutical composition is grapiprant, and the pharmaceutical composition also contains a solvent, a surfactant and an antioxidant. According to the invention, the micelle is formed in the animal body according to the preferable formula proportion, so that the oral bioavailability of the grapiprant in treating osteoarthritis of companion animals is effectively improved, and the solubility of the active ingredients is better improved. The preparation method is simple, the administration is convenient, safe and effective.
Description
Technical Field
The invention belongs to the technical field of veterinary chemical preparations, and particularly relates to a pharmaceutical composition for relieving pain of osteoarthritis of companion animals and application thereof.
Background
Currently, non-steroidal anti-inflammatory drugs at home and abroad mainly use Cyclooxygenase (COX) inhibitors, and the non-steroidal anti-inflammatory drugs achieve the aim of reducing prostaglandin production by inhibiting cyclooxygenase, so that pain and inflammation are inhibited, but prostaglandins have wider physiological functions, such as regulating vasodilation, supporting platelet functions and the like, inhibit adverse reactions caused by cyclooxygenase, usually have side effects of gastrointestinal tracts and even bring about serious adverse reactions in the aspects of kidneys and livers, and the adverse reactions are not hoped to be seen.
GRAPIPRANT (GRAPIPRANT) is a novel non-steroidal anti-inflammatory drug that is an EP4 receptor inhibitor that can specifically block EP4 receptors directly, thereby blocking prostaglandin E2-induced pain and inflammation.
Although studies have demonstrated the safety of grapiprant in cats, its use in the clinic is greatly limited due to its low oral bioavailability in cats of less than 40% and poor solubility (Irene Sartini, mario giorgi. Grapiprant: A snapshot of the current knowledge [ J ], wiley,2021 (44): 679-688). The development of a pharmaceutical composition and formulation that effectively provides solubility and bioavailability of grapiprant is a major problem in the art that needs to be addressed.
Disclosure of Invention
In order to solve the technical problems, the invention provides a pharmaceutical composition for relieving pain of osteoarthritis of companion animals, which has the advantages of good stability, convenient administration, safety and effectiveness, and greatly improves the solubility of the grapiprant and the bioavailability thereof in vivo.
The technical scheme of the invention is as follows:
in a first aspect of the present invention there is provided a pharmaceutical composition comprising an imidazole derivative of formula (I) or a salt or solvate thereof.
The pharmaceutical composition also comprises a pharmaceutically acceptable carrier, in particular a solvent, a surfactant and an antioxidant. Preferably, the imidazole derivative compound of formula (I) is grapiprant. The carrier has pharmaceutical properties, is nontoxic in the dosage range of the formulation, and is compatible with imidazole derivative compounds.
The pharmaceutical composition comprises the following components in percentage by mass: 0.2 to 5 percent of grapiprant, 20 to 95 percent of solvent, 15 to 70 percent of surfactant and 0.001 to 0.1 percent of antioxidant.
Preferably, the pharmaceutical composition comprises the following components in percentage by mass: 0.5 to 2 percent of grapiprant, 40 to 80 percent of solvent, 15 to 55 percent of surfactant and 0.005 to 0.02 percent of antioxidant.
Preferably, the dosage ratio of the solvent to the surfactant in the pharmaceutical composition is less than or equal to 5:1.
Preferably, the solvent in the pharmaceutical composition of the present invention is one or more of polyethylene glycol (200, 300, 400 or 600), glycerol, azone, ethanol, propylene glycol, propylene carbonate, diethylene glycol monoethyl ether, corn oil, medium chain triglyceride, glycerol monolinoleate, glycerol monooleate. Further preferably, the solvent is selected from diethylene glycol monoethyl ether, polyethylene glycol 400.
Preferably, the surfactant in the pharmaceutical composition of the present invention is a nonionic surfactant or a zwitterionic surfactant, and includes one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol stearate 15, polyethylene glycol-32 stearate, tween 80, polyethylene glycol caprylic capric glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, poloxamer, sodium dodecyl sulfate, and povidone. Further preferred surfactants are polyethylene glycol caprylic capric glyceride.
Preferably, the antioxidant in the pharmaceutical composition of the invention is one or more of tartaric acid, citric acid, ascorbic acid, isoascorbic acid, propyl gallate, sodium metabisulfite, BHA, BHT and alpha-tocopherol. Further preferred antioxidants are BHA.
The pharmaceutical composition is a nonaqueous and non-oil solution system, and after entering the gastrointestinal tract environment, the pharmaceutical composition contacts with the aqueous environment to form a stable and easily-absorbable micelle system.
The medicine composition with the preferable formula proportion can effectively dissolve the grapiprant and has more reasonable medicine carrying rate.
The micelle system is a system which forms a sphere shape, a rod shape and a lamellar shape inside after the surfactant reaches a certain concentration in an aqueous environment, wherein one end of the micelle system is outwards provided with a hydrophilic group, the other end of the micelle system is inwards provided with a hydrophobic group, the grapiprant which is not easy to dissolve in water is wrapped in the micelle system, and the hydrophilic group contacts water to realize the solubilization effect.
Preferably, the pharmaceutical composition of the present invention forms a stable micellar system when the ratio of solvent to surfactant is less than or equal to 5:1.
In another aspect, the invention provides application of the pharmaceutical composition containing the grapiprant in preparing analgesic drugs for treating osteoarthritis and inflammation of companion animals, relieving fever and pain related to surgery and treating certain tumors.
The companion animals include, but are not limited to, dogs, cats, rabbits, birds, mice, horses, etc., preferably the companion animals are dogs and cats, and more preferably the companion animals are cats.
The osteoarthritis pain assessment means comprises: evaluation of pain scores of pets by pet owners, imaging observation, behavior observation and the like.
Preferred routes of administration of the pharmaceutical compositions of the invention are oral, and dosage forms include, but are not limited to, oral solutions, oral suspensions; more preferably, the dosage form is an oral solution in a container (e.g., syringe) that can accurately measure the medicinal solution.
The beneficial effects are that:
1. the medicine composition has good stability and easy storage, and the solution is still clear after 50 times, 100 times, 200 times and 500 times dilution and is not precipitated after being placed for a period of time.
2. The pharmaceutical composition of the invention can form a microemulsion or micelle system, and micelle is formed in the gastrointestinal tract of animals according to the preferable composition proportion; the requirement of forming a stable micelle system in vivo can be met by a small proportion of surfactant, the aim of solubilization is achieved, and the problem of low bioavailability of oral grapiprant in companion animals is effectively solved. At the same time, there is no risk of crystal transformation compared with solid preparations.
3. The pharmaceutical composition can be effectively used for relieving pain and treating inflammation of osteoarthritis of companion animals, is convenient to administer, has higher density than aqueous solution because the preferable formula is a microemulsion or micelle system, is easy to reside in the oral cavity, is not easy to overflow, and has no palatability problem.
4. According to the invention, the solvent and the surfactant are uniformly mixed according to the preferred proportion, the antioxidant is added, and the grapiprant is added finally for mixing, so that the preparation method is simple and is suitable for industrial production.
Detailed Description
Example 1-example 8A pharmaceutical composition for analgesic of companion animal osteoarthritis
(1) The formula comprises the following components:
(2) The preparation method comprises the following steps:
the preparation method of the invention comprises the steps of carrying out the steps of (normal temperature) under the stirring condition in the examples 1-8, mixing the solvent and the surfactant according to the prescription amount uniformly in proportion, and adding an antioxidant, finally adding the grapiprant, mixing, and recording the dissolution time of the grapiprant. The results of the grapiprant dissolution time are shown in table 1:
table 1 grapiprant dissolution time
All the components in the embodiment of the invention are micelle systems or microemulsion solutions. From the above results, it can be seen that the dissolution capacity of different solvents and surfactants for grapiprant is different, the dissolution effect of a single solvent is not as good as that of two solvents, and comparison of example 5 and example 6 shows that the same adjuvant type can dissolve grapiprant quickly even with a smaller amount of surfactant; examples 7 and 8 as microemulsion systems, the presence of the oil phase also dissolved the grapiprant very well.
Example 9 stability test
The stability of examples 2, 5, 6, 7 and 8 was examined after they were diluted 50-fold, 200-fold and 500-fold with water and left at room temperature for 5 days. The results are shown in Table 2:
TABLE 2 stability test results
Example 7 as a microemulsion system solution, the presence of an oil phase resulted in delamination of the solution and precipitation of the starting material after a period of standing after high-power dilution; whereas example 8, which is a microemulsion system solution, is relatively stable because the proportion of oil phase is not large. Whereas examples 2, 5 and 6 formed a micellar system upon contact with water, the solutions were stable and no precipitation occurred.
EXAMPLE 10 pharmacokinetic testing
Control groups were prepared: taking water as a solvent, hydrochloric acid and sodium hydroxide as pH value regulators, taking polyoxyethylene ratio sesame oil 35 (EL 35) as a solubilizer, preparing the gladipiran injection under the condition of heating, filling and sterilizing to obtain the final product.
Comparative example groups were prepared: the common grapiprant oral liquid is prepared by taking water as a solvent and tween 80 as a solubilizer under the heating condition.
The test method comprises the following steps: 15-20 healthy Chinese farm cats are selected, the weight of the healthy Chinese farm cats is 2-5 kg, the healthy Chinese farm cats are fasted, and blood is taken and detected at 5min, 15min, 30min, 45min, 1h, 1.5g, 2h, 4h, 6h, 8h, 10h, 24h and 36h according to the dosage of 2mg/kg (the invention of examples 5, 6 and 8 and the comparison group). The results are shown in Table 3:
TABLE 3 pharmacokinetic assay
| Detecting items | Example 5 | Example 6 | Example 8 | Comparative example group | Control group |
| T 1/2 (h) | 4.5 | 4.4 | 4.6 | 4.5 | 5.2 |
| T max (h) | 1.5 | 1.3 | 1.2 | 2.5 | / |
| C max (ng/ml) | 594 | 608 | 599 | 502 | / |
| AUC((μg/ml)·h) | 1053 | 1064 | 1058 | 521 | 1308 |
| F(％) | 80.5 | 81.3 | 80.9 | 39.8 | / |
It can be seen that the absolute bioavailability of example 5, example 6 and example 8 reaches more than 80%, the oral effect is better, and the bioavailability of the comparative example group (using water as solvent) is lower, which indicates that the bioavailability can be greatly improved by the combination of the micelle system formulation. By comparison between example 5 and example 6, it is demonstrated that a small proportion of surfactant formulation achieves the same effect as a large proportion of surfactant formulation in vivo, although the in vitro tyndall phenomenon is weak, with the appropriate adjuvant type.
The formulation of the present invention is preferably a formulation having a small surfactant ratio, considering that an excessively high surfactant ratio may cause foaming more seriously upon transportation or administration.
EXAMPLE 11 clinical efficacy testing
Clinical efficacy trials were performed with examples 2, 6, 8, while placebo without grapiprant was established as a blank.
The evaluation index is a pet owner assessment of pain scores in pets, including gait observations (lameness, joint activity), tenderness, and imaging examinations.
Test animals: the weight of the Chinese garden cat is about 2-4 kg, and each group is selected from 2-3 cats.
The requirement of the selected case: clinical diagnosis of osteoarthritis is 2-3 grades, and blood analysis shows inflammation indication, and pain score is 5-10 grades.
Osteoarthritis grading requirements: first, slight narrowing of the joint space occurs mainly, and there is little osteophyte formation and slight hardening; second, mainly a moderate narrowing of the joint space occurs, and moderate bony spur formation and moderate hardening of the subchondral bone; tertiary, mainly with hardened bone, changes in the neoplasm, particularly because of the resulting spallation of the articular, cartilage surface, resulting in relative friction of the underlying cartilage surface, bone and bone mass, resulting in changes in bone mass. But this case does not occur with bone loss; fourth, severe subchondral bone sclerosis and changes in bone cysts occur, and narrowing of the joint space and even disappearance of the joint space occurs, resulting in deformity of varus and valgus of the knee.
Pain score: referring to CSOM scoring criteria (https:// cvm. Ncsu. Edu/research/labs/clinical-sciences/comparative-pain-research/clinical-metric-instruments /) -customer specific outcome assessment, when CSOM scoring is performed, the pet owner needs to select three events for which the pet owner does not perform or does not perform recently, evaluate each item, score the evaluation, and finally obtain a total score by the sum of the three evaluation scores, wherein the total score ranges from 3 points (normal) to 15 points (high damage), and after the test is finished, the total score is evaluated to be reduced by more than or equal to 2 points, namely the treatment is considered successful.
Wherein, each item in the CSOM evaluation table has a score range of 0 to 4 points, and the score evaluation criteria are as follows:
score 0 (no problem): can move freely like a normal cat, and has no difficulty in performing the activities which are difficult to finish before, and the whole body is light.
Score 1 (weak lesions): it can be observed that not extremely painful, the pet owner can perceive the discomfort, but not by others, and weak injuries can only be noticeable to the pet owner.
Score 2 (moderate injury): it is observed that not excessive or extreme pain is perceived by both pet owners and others as uncomfortable, moderate pain.
Score 3 (severe injury): very severe pain can be observed, causing significant discomfort, and all people can perceive strong discomfort, requiring veterinary assessment of the condition.
Score 4 (high injury): this activity cannot be completed, which is a recently impossible activity for the pet.
Dosage of administration: according to 2mg/kg, the medicine is taken once daily for 28 days continuously.
The results of the clinical effect test after 28 days are shown in Table 4:
TABLE 4 evaluation of clinical effects
The above results illustrate: in clinical use, the example 2, the example 6 and the example 8 can reduce the inflammation and pain of the bone joint, and have obvious effects.
Claims (10)
1. A pharmaceutical composition for pain relief of osteoarthritis in companion animals, comprising grapiprant or a salt or a solvent compound thereof, characterized by further comprising a solvent, a surfactant, and an antioxidant.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises the following components in percentage by mass: 0.2 to 5 percent of grapiprant, 20 to 95 percent of solvent, 15 to 70 percent of surfactant and 0.001 to 0.1 percent of antioxidant.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition comprises the following components in percentage by mass: 0.5 to 2 percent of grapiprant, 40 to 80 percent of solvent, 15 to 55 percent of surfactant and 0.005 to 0.02 percent of antioxidant.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the ratio of solvent to surfactant in the pharmaceutical composition is less than or equal to 5:1.
5. A pharmaceutical composition according to any one of claims 1-3, wherein the solvent in the pharmaceutical composition is one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, glycerol, azone, ethanol, propylene glycol, propylene carbonate, diethylene glycol monoethyl ether, corn oil, medium chain triglycerides, glycerol monolinoleate, glycerol monooleate.
6. A pharmaceutical composition according to any one of claims 1-3, wherein the surfactant in the pharmaceutical composition is one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol stearate 15, polyethylene glycol-32 stearate, tween 80, polyethylene glycol caprylic capric glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, poloxamer, sodium dodecyl sulfate, povidone.
7. A pharmaceutical composition according to any one of claims 1-3, wherein the antioxidant in the pharmaceutical composition is one or more of tartaric acid, citric acid, ascorbic acid, isoascorbic acid, propyl gallate, sodium metabisulfite, BHA, BHT, alpha-tocopherol.
8. Use of a pharmaceutical composition for analgesic of osteoarthritis in a companion animal as claimed in any one of claims 1-3 in the manufacture of an analgesic medicament for analgesic of osteoarthritis in a companion animal for treatment of inflammation, surgical related antipyretic analgesic, tumour treatment.
9. The use of a pharmaceutical composition according to claim 8 wherein the companion animal is a canine, a feline, a rabbit, a bird, a murine, or an equine.
10. The use of a pharmaceutical composition according to claim 8, wherein the route of administration of the drug is oral.
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| CN202210764950.6A CN117357520A (en) | 2022-06-29 | 2022-06-29 | Pharmaceutical composition for relieving pain of osteoarthritis of companion animals and application thereof |
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