CN111281868A - Application of rotigotine microspheres in preparation of medicine for treating inflammatory pain - Google Patents
Application of rotigotine microspheres in preparation of medicine for treating inflammatory pain Download PDFInfo
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- CN111281868A CN111281868A CN202010229732.3A CN202010229732A CN111281868A CN 111281868 A CN111281868 A CN 111281868A CN 202010229732 A CN202010229732 A CN 202010229732A CN 111281868 A CN111281868 A CN 111281868A
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- 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
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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]
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Abstract
The invention discloses application of rotigotine microspheres in preparation of a medicament for treating inflammatory pain. Rotigotine is a dopamine receptor agonist, and the long-acting slow-release microspheres of the rotigotine are capable of obviously prolonging the withdrawal latency of rat hindpaws after carrageenan inflammation to thermal stimulation and mechanical stimulation and inhibiting the expression of inflammatory tissue PGE2, so that the rotigotine microspheres have an analgesic effect on inflammatory pain, can be used for treating the movement symptoms of the Parkinson's disease and treating pain of the Parkinson's disease or accompanied diseases, and can maintain the analgesic effect for 4 days after one-time administration.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to application of rotigotine microspheres in preparation of a medicine for treating inflammatory pain.
Background
Rotigotine is a non-ergot dopamine receptor agonist, and produces an antiparkinson effect by agonizing dopamine D3/D2/D1 receptors. Rotigotine exhibits significant antiparkinsonian and neuroprotective effects in 6-hydroxydopa and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine induced primate and rodent parkinsonian models, and continuous administration of rotigotine reduces the incidence of motor complications compared to pulsatile administration of levodopa and rotigotine.
Rotigotine sustained release microspheres (LY 03003) for injection developed by green leaf pharmacy has already completed phase I clinical trials and exempted phase II clinical trials in China and America respectively, and is currently starting phase III clinical trials in China. The rotigotine microspheres are prepared by embedding rotigotine in a biodegradable lactic-glycolic acid copolymer, and the medicament is continuously and stably released in a certain period through intramuscular injection administration to form continuous and stable stimulation to dopamine receptors, so that the continuous dopaminergic stimulation treatment of the Parkinson disease is realized. The rotigotine microspheres are clinically applied to patients with early primary Parkinson, improve the motor symptoms of the patients, relieve the 'on-off' effect easily caused by drug treatment of the patients with Parkinson, and obviously improve the motor complications easily caused by patients with late Parkinson disease.
Patients with Parkinson's disease have motor symptoms such as bradykinesia, resting tremor, abnormal gait and muscular tension, but also have non-motor symptoms such as gastrointestinal dysfunction, pain, low blood pressure, hyperhidrosis, depression, anxiety, sleep disorder and the like. Pain is one of the common non-motor symptoms of parkinson's disease, and the overall prevalence in parkinson's patients is reported in the literature to be between 40% and 80%. The manifestations of Parkinson's pain include musculoskeletal pain, dystonic pain, radicular pain, central pain, and the like.
At present, research on rotigotine mainly comprises preparation methods, analysis methods, applications and novel preparations of rotigotine and derivatives thereof, and effects of the rotigotine on Parkinson disease, Parkinson superposition syndrome, depression and the like caused by dopaminergic nervous system injury, and the research on the analgesic effect of the rotigotine microsphere preparation is not reported.
Disclosure of Invention
The invention provides application of rotigotine microspheres in preparation of a medicament for treating inflammatory pain, so that a treatment basis is provided for pain of Parkinson's disease or accompanied diseases while rotigotine microspheres treat motor symptoms of the Parkinson's disease.
In order to achieve the purpose, the invention adopts the technical scheme that:
application of rotigotine microspheres in preparation of medicines for treating inflammatory pain.
Preferably, the human dosage of the rotigotine microspheres is 1.59-6.35 mg/kg.
Preferably, the human dose of the rotigotine microspheres is 6.35 mg/kg.
Preferably, the rotigotine microspheres have analgesic effect after intramuscular injection.
Preferably, the inflammatory pain is non-motor symptom pain in parkinson's disease patients.
Preferably, the inflammatory pain is pain associated with rheumatoid and rheumatoid arthritis in patients with parkinson's disease.
Has the advantages that: the invention provides application of rotigotine microspheres in preparation of a medicament for treating inflammatory pain, so that a treatment basis is provided for pain of Parkinson's disease or accompanied diseases while rotigotine microspheres treat motor symptoms of the Parkinson's disease.
Drawings
FIG. 1: the result of the determination of analgesic effect of rotigotine microspheres on a carrageenan-induced rat inflammatory pain model;
FIG. 2: effect of rotigotine microspheres on the expression of PEG2 in the carrageenan-induced rat model of inflammatory pain.
Detailed Description
For a better understanding of the present disclosure, the following further description is provided in conjunction with the following specific embodiments, but the present disclosure is not limited to the following examples.
A carrageenan induced rat inflammatory pain model is adopted to determine the analgesic effect of rotigotine microspheres, and the steps are as follows:
(1) carrageenan-induced inflammatory pain model in rats, hotplate method, plate method, change in pain withdrawal latencies (HWLs) of rats to thermal and mechanical stimuli: 24 SD male rats (180-220 g) were randomly divided into a blank control group, a model group and a rotigotine microsphere group, and each group had 8 rats. After adaptive feeding for 5 d, the blank control group and the model group are injected with isovolumetric microsphere menstruum intramuscularly, and the rotigotine microsphere group is injected with rotigotine microsphere intramuscularly. 4 d, injecting carrageenan subcutaneously on the left and right foot soles of each rat in the model group and the rotigotine microsphere group except the normal group after intramuscular injection of microsphere menstruum or rotigotine microspheres, measuring HWLs of each group of rats by a hot plate method and a pressing plate method after 3 h, and comparing the change of pain threshold values of each group of rats.
(2) Determination of inflammatory tissue pain-causing substances: at 4 d after administration, carrageenan was injected subcutaneously into the left and right footpads of each rat, and 10% chloral hydrate was intraperitoneally injected at 3 h to kill the rat, which was cut off at 0.5 cm above the ankle joint of the rat hind paw, and the hind footpad of the rat was removed. Shearing tissues at the same parts of rat vola palms, adding a proper amount of precooled phosphate buffer solution, fully homogenizing, and ultrasonically crushing by using an ultrasonic cell crusher. After centrifugation, the supernatant was collected and the level of PGE2 was measured using an ELISA kit.
Example 1: analgesic effect and result of rotigotine microspheres on carrageenan-induced inflammatory pain
Materials and reagents
Rotigotine microspheres (specification: 42 mg/count, made by Shandong green leaf pharmaceutical Co., Ltd.); rotigotine microsphere solvent (self-made by Shandong green leaf pharmaceutical Co., Ltd.); carrageenan (Sigma-Aldrich, USA)
Animals: SPF SD rat, male, weight 180-220 g, provided by Jinan Pengyue laboratory animal Breeding Co., Ltd, quality certificate number: SCXK (lu) 20190003.
The instrument comprises the following steps: YLS-6B Intelligent hotplate instrument (Jinan Yiyan science and technology development Co., Ltd.); model 7200 tenderness machine (UGO Basile, italy); AL204 electronic balance (METTLER, Switzerland)
The thermal stimulation was measured on a YLS-6B intelligent hotplate apparatus, the hotplate temperature was maintained at 52. + -. 0.2 ℃ during the experiment, the ventral surface of the rat hind paw was fully contacted with the hotplate apparatus fixing area, timing was started from the time when the hind paw was contacted with the hotplate, and the hind paw was retracted by the rat's own discretion, and recorded as the thermally stimulated HWLs. HWLs of mechanical stimulation were measured on a model 7200 tonometer, applying a wedge-shaped push rod on the dorsal surface of the hind paw at a loading rate of 30g/s, and recording the time taken for applying force from the wedge-shaped push rod to voluntarily retract the paw in the rat, which was recorded as HWLs of mechanical stimulation. The HWLs were completed within 1-2 min per measurement, and the cut-off time for thermal and mechanical stimulation was 15 s in order to avoid tissue damage.
A rat inflammatory pain model caused by carrageenan is characterized in that 24 SD male rats (180-220 g) are randomly divided into a blank control group, a model group and a rotigotine microsphere group, and each group comprises 8 rats. Equal volume of microsphere solvent is injected into the muscle of the blank control group and the model group, and 40 mg/kg of rotigotine microspheres are injected into the muscle of the rotigotine microsphere group. At 4 d after administration, except for the normal group, the model group and rotigotine microsphere group were injected subcutaneously with 0.1 mL of 2% carrageenan into the left and right footpads of each rat, and HWLs were measured at 3 h in each group of rats by a hot plate method and a platen method.
The results are shown in FIG. 1, where A is rat left plantar hotplate HWLs; b is rat right plantar hot plate HWLs; c is left plantar pressboard HWLs of rats; d is rat right plantar pressboard HWLs. The model rats had significantly reduced HWLs in both hind paws to thermal and mechanical stimulation compared to the blank control group: (P<0.001), which indicates that the model of inflammatory pain is successfully molded. Both hindpaws of rotigotine rats significantly increased both thermal and mechanical stimulated HWLs compared to the model group (r) ((r))P<0.001), showing that the rotigotine microspheres have obvious analgesic effect on inflammatory pain. (Note: compared to blank control group. about. P ><0.001; compared with the model group, # # # P<0.001）；
Example 2: determination result of rotigotine microspheres on pain-causing substances of carrageenan-caused inflammatory pain inflammatory tissues
Materials and reagents
Rotigotine microspheres (specification: 42 mg/count, made by Shandong green leaf pharmaceutical Co., Ltd.); rotigotine microsphere solvent (self-made by Shandong green leaf pharmaceutical Co., Ltd.); chloral hydrate (national chemical agents, ltd.); carrageenan (Sigma-Aldrich, USA); rat PGE2 ELISA kit (Shanghai enzyme-linked biotechnology, Inc.)
Animals: SPF SD rat, male, weight 180-220 g, provided by Jinan Pengyue laboratory animal Breeding Co., Ltd, quality certificate number: SCXK (lu) 20190003.
The instrument comprises the following steps: VCX130PB ultrasonicator (SONICS corporation, usa); AL204 electronic balance (METTLER, switzerland); SpectraMax M3 multifunctional microplate reader (Molecular Devices, USA); beckman Allegra X-22R high speed centrifuge (Beckman Coulter, USA)
Three groups of rats of example 1 were administered in groups and molded, then sacrificed with 10% chloral hydrate, and cut off at 0.5 cm from the ankle joint of the hind paw of the rat, and the hind plantar aspect of the foot of the rat was removed. Shearing tissues at the same parts of rat vola palms, adding a proper amount of precooled phosphate buffer solution, fully homogenizing, and ultrasonically crushing by using an ultrasonic cell crusher. After centrifugation, the supernatant was collected and the level of PGE2 was measured using an ELISA kit.
The effect of rotigotine microspheres on PEG2 expression in rat inflamed tissue in a model of inflammatory pain due to carrageenan is shown in figure 2. Increased levels of PGE2 in the model group compared to the blank control group (P<0.001). Significantly reduced rotigotine microsphere group PGE2 levels compared to the model group (P<0.001). The rotigotine microspheres are shown to play a significant analgesic role in the inflammatory pain induced by the carrageenan by reducing the expression of the pain-causing substance PGE2 at the inflammatory part. (Note: compared to blank control group. about. P ><0.001; compared with the model group, # # # P<0.001）。
Claims (6)
1. Application of rotigotine microspheres in preparation of medicines for treating inflammatory pain.
2. The use of rotigotine microspheres according to claim 1 in the preparation of a medicament for the treatment of inflammatory pain, wherein the human dose of rotigotine microspheres is 1.59-6.35 mg/kg.
3. Use of rotigotine microspheres according to claim 2 in the preparation of a medicament for the treatment of inflammatory pain, wherein the human dose of rotigotine microspheres is 6.35 mg/kg.
4. The use of rotigotine microspheres according to claim 2 in the preparation of a medicament for the treatment of inflammatory pain, wherein the rotigotine microspheres have an analgesic effect after intramuscular injection.
5. Use of rotigotine microspheres according to claim 1 in the preparation of a medicament for the treatment of inflammatory pain, wherein the inflammatory pain is pain in non-motor symptoms of parkinson's disease patients.
6. The analgesic effect of rotigotine microspheres according to claim 1, wherein the inflammatory pain is pain associated with rheumatic and rheumatoid arthritis in patients with Parkinson's disease.
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| CN202010229732.3A CN111281868A (en) | 2020-03-27 | 2020-03-27 | Application of rotigotine microspheres in preparation of medicine for treating inflammatory pain |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112569226A (en) * | 2020-12-22 | 2021-03-30 | 烟台大学 | New application of rotigotine in preparation of medicine for resisting acute liver injury |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112569226A (en) * | 2020-12-22 | 2021-03-30 | 烟台大学 | New application of rotigotine in preparation of medicine for resisting acute liver injury |
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Application publication date: 20200616 |