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Levodopa nasal dry powder for treating Parkinson's dyskinesia and preparation method thereof

A technology of levodopa nasal dry powder and levodopa, which is applied in directions such as medical preparations without active ingredients, medical preparations containing active ingredients, powder delivery, etc., can solve the problem of limited nasal volume, unstable levodopa and easy Degradation, can not meet and other problems

Active Publication Date: 2022-05-27
SHANGHAI MODERN PHARMA ENG INVESTIGATION CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Nasal administration is mostly a liquid preparation, but levodopa is unstable and easy to degrade in aqueous solution
Simultaneously, the volume of the nasal cavity is limited, the maximum volume of a single nasal administration is 150ul, and levodopa is slightly soluble in water (about 4mg / ml), which cannot satisfy its high-dose administration (minimum oral dose 50mg, single dose of lung inhalation) 42mg) dissolution requirements

Method used

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  • Levodopa nasal dry powder for treating Parkinson's dyskinesia and preparation method thereof
  • Levodopa nasal dry powder for treating Parkinson's dyskinesia and preparation method thereof
  • Levodopa nasal dry powder for treating Parkinson's dyskinesia and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of levodopa nasal dry powder:

[0039] Ⅰ. Weigh 2.5g of L-dopa, put it in a sealed container with 2.5g of any methylated-β-cyclodextrin (RM-β-CD), mix well, dry the mixture in an oven at 80°C for 0.5h, take it out and set it to dry Cool down to room temperature in the machine; in an environment with relative humidity < 50%, put the mixture into the agate ball milling cavity of a German flying ball mill, add grinding beads, and perform planetary ball milling after sealing. After 10 minutes, it was stopped for 10 minutes, and the cycle was repeated 72 times. The total grinding time was 12 hours. After grinding, carry out subpackaging under the condition of <50% RH to obtain the levodopa nasal dry powder (I) for the treatment of Parkinson's dyskinesia;

[0040] Ⅱ. Weigh 2.5g of levodopa in the same way, respectively mix with 2.5g of polyvinylpyrrolidone 30 (PVP K30), 2.5g of hydroxypropyl-β-cyclodextrin (HP-β-CD), 2.5g of α-cyclodextrin (α-CD) and 2.5g sodium...

Embodiment 2

[0046] Weigh 2.5g of levodopa and place them in 2.5g of any methylated-β-cyclodextrin (RM-β-CD) and 2.5g of dimethyl-β-cyclodextrin (DM-β-CD) respectively. In a sealed container, mix well, vacuum dry at 80°C for 0.5h, take it out and put it in a desiccator to cool to room temperature; in an environment with relative humidity < 50%, put the mixture into the agate ball milling chamber of a German flying ball mill, add grinding beads, and seal it. Then carry out planetary ball milling, set the ball milling speed to 500 rpm, centrifugal force 4 kg, stop 10 min after grinding for 10 min, cycle 12 times, and the total grinding time is 2 h. After grinding, carry out sub-packaging under the condition of <50% RH, respectively obtain the levodopa nasal dry powder I (containing RM-β-CD) and II (containing DM-β) for the treatment of Parkinson's dyskinesia. -CD);

[0047] The dissolution experiment was carried out with reference to the method in Example 1, and the dissolution curve of lev...

Embodiment 3

[0049] Optimization of nasal dry powder formulation:

[0050] Weigh 4.5, 3.5, and 2.5 g of levodopa, respectively, and place them in a sealed container with 0.5, 1.5, and 2.5 g of any methylated-β-cyclodextrin, mix well, and dry the mixture in an oven at 80°C for 0.5 h. Cool down to room temperature in the machine; in an environment with relative humidity < 50%, put the mixture into the agate ball milling cavity of a German flying ball mill, add grinding beads, and carry out planetary ball milling after sealing. After 10 minutes, it was stopped for 10 minutes, and the cycle was repeated 12 times. The total grinding time was 2 hours.

[0051] The dissolution test of L-dopa dry powder containing different proportions of RM-β-CD was carried out according to the method of Example 1, and was compared with the dissolution of L-dopa by ball milling alone in Example 1.

[0052] Results The dissolution rate of L-dopa dry powder with 50% RM-β-CD content was significantly higher than th...

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Abstract

The invention discloses a levodopa nasal dry powder for treating Parkinson's dyskinesia and a preparation method thereof, the levodopa nasal dry powder is a mixture obtained by co-grinding or co-crushing levodopa and a carrier, or a mixture obtained by co-grinding or co-crushing levodopa, a carrier and other auxiliary components; and the carrier is hydroxypropyl beta-cyclodextrin (HP-beta-CD), alpha-cyclodextrin, methylated-beta-cyclodextrin, sodium alginate or lactose. According to the levodopa dry powder preparation disclosed by the invention, levodopa is rapidly absorbed into blood through a nose to achieve relatively high bioavailability and plasma concentration, so that dyskinesia caused by a switching effect is rapidly relieved, and the problems of instability of levodopa and the like caused by a solution preparation are solved. A subsequent animal pharmacokinetic test proves that the co-ground material can achieve the effect of being rapidly absorbed into blood, which means that the dyskinesia caused by the Parkinson's switch effect is possibly rapidly relieved.

Description

technical field [0001] The present invention relates to a dry powder preparation for nasal administration containing levodopa active components and a preparation method thereof. Background technique [0002] Parkinson's disease (PD), also known as tremor palsy, is a common neurodegenerative disease in middle-aged and elderly people. The main lesions are in the substantia nigra and striatum. The slow loss of substantia nigra dopaminergic neurons results in a marked decrease in striatal dopamine (DOPA), resulting in motor symptoms such as stiffness, bradykinesia, tremors, and postural disturbances. According to the World Health Organization, the annual incidence of Parkinson's disease is 9.7-13.8 per 100,000 people, with the highest incidence among people aged 50-60. [0003] Levodopa is the gold standard for the treatment of Parkinson's disease. However, the intermittent use of dopa nergic drugs for a long time is prone to "switching phenomenon". The switching phenomenon ...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K9/72A61K31/198A61K47/40A61K47/26A61P25/16
CPCA61K9/146A61K9/145A61K9/0043A61K9/0075A61K31/198A61P25/16Y02A50/30
Inventor 吴闻哲侯惠民杨阳张琪陈洪月
Owner SHANGHAI MODERN PHARMA ENG INVESTIGATION CENT
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