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WO2025098365A1 - Pulvérisation nasale de lévodopa, son procédé de préparation et son utilisation - Google Patents

Pulvérisation nasale de lévodopa, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025098365A1
WO2025098365A1 PCT/CN2024/130102 CN2024130102W WO2025098365A1 WO 2025098365 A1 WO2025098365 A1 WO 2025098365A1 CN 2024130102 W CN2024130102 W CN 2024130102W WO 2025098365 A1 WO2025098365 A1 WO 2025098365A1
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Prior art keywords
pharmaceutical composition
levodopa
nasal spray
drug
agent
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Chinese (zh)
Inventor
岳霄
张雪娟
汤宇
刘华亮
梁旭霞
吴传斌
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Guangzhou Novaken Pharm Co Ltd
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Guangzhou Novaken Pharm Co Ltd
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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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

Definitions

  • the invention belongs to the technical field of biomedicine, and specifically relates to a levodopa nasal spray and a preparation method and application thereof.
  • Parkinson's disease is a common neurodegenerative disease with a large number of patients.
  • the disease has many causes and mechanisms, and is a comprehensive pathogenic result.
  • the main pathological changes are the loss of dopamine (DA) neurons in the substantia nigra and the formation of Lewy bodies.
  • the main biochemical changes are the lack of dopamine in the striatum, the imbalance of dopamine and acetylcholine transmitters, and the relative hyperfunction of acetylcholine.
  • the main symptoms of clinical patients include motor symptoms such as bradykinesia, resting tremor, muscle rigidity and postural balance disorders, accompanied by non-motor symptoms such as olfactory disorders, constipation, and sleep disorders.
  • commonly used treatments include drug therapy, surgical treatment, rehabilitation treatment, etc., but it cannot be cured, and can only relieve symptoms and improve the quality of life of patients. Its treatment needs urgent attention.
  • the drugs used to treat PD mainly include dopamine (levodopa, dopamine receptor agonists, etc.) and choline (benhexyphenidyl hydrochloride, benztropine mesylate, procyclidine hydrochloride, etc.).
  • levodopa LDA
  • Peripherally supplemented levodopa can pass through the blood-brain barrier and be decarboxylated into dopamine in the brain by dopa decarboxylase, thereby playing a role in replacement therapy. It is the standard treatment for Parkinson's disease and the most effective symptomatic drug in Parkinson's disease drug treatment.
  • levodopa is unstable in a humid state and is prone to oxidation.
  • most preparations related to levodopa are solid preparations such as levodopa tablets, capsules, granules, and inhalers that are administered orally.
  • levodopa tablets, capsules, granules, and inhalers that are administered orally.
  • after oral administration only 1% can be transported to the striatum tissue in the brain through neutral amino acid carriers to be converted into dopamine to exert its effect. It has a slow onset of action, low bioavailability, and a large dosage.
  • More than 95% of levodopa is converted to dopamine by decarboxylases widely distributed in peripheral tissues, leading to adverse reactions such as cardiovascular and gastrointestinal diseases.
  • nasal administration preparations can deliver drugs directly from the olfactory area to the brain, bypassing the blood-brain barrier, and have significant advantages such as rapid onset of action, increased efficiency of levodopa entering the brain, reduced dosage, and avoidance of gastrointestinal reactions.
  • nasal formulations on the market for central nervous system diseases such as zolmitriptan nasal spray for the treatment of migraine.
  • levodopa and pramipexole are commonly used drugs in the clinical treatment of Parkinson's disease. Because dopamine has difficulty penetrating the blood-brain barrier, patients need to be supplemented with levodopa, a precursor of dopamine. When levodopa enters the brain and is taken up by dopaminergic neurons, it can be converted into dopamine through a decarboxylation reaction, thereby exerting its pharmacological effects. After levodopa is absorbed by the body, 95% of the drug undergoes a decarboxylation reaction in the periphery to form dopamine, and only 1% of the drug penetrates the blood-brain barrier and enters the brain.
  • the olfactory mucosal epithelium of the nasal cavity contains bipolar olfactory cells, and the olfactory nerves formed by them pass through the cribriform plate and enter the olfactory bulb of the central nervous system. Therefore, after nasal administration of levodopa, part of the drug can be absorbed through the olfactory mucosa and enter the olfactory bulb or cerebrospinal fluid (CSF), thereby bypassing the blood-brain barrier (BBB) and being directly transported into the brain to exert a central therapeutic effect. Therefore, nasal administration has a fast onset of action, high bioavailability in the brain, and can reduce the dosage of levodopa and reduce adverse reactions.
  • CSF cerebrospinal fluid
  • the amount of drug absorbed in the olfactory area is crucial to its efficacy.
  • the area of the olfactory mucosa is very small (1-5 cm2 ), accounting for only 3%-5% of the total area of the nasal cavity.
  • How to deposit the drug in the olfactory area, improve the drug delivery efficiency, and promote the absorption of the drug in the nasal mucosa is the research and development focus and difficulty of levodopa nasal spray.
  • levodopa is very easy to oxidize in the air when it is wet
  • the only levodopa liquid preparation currently on the market is the carbidopa intestinal gel that needs to be frozen for storage. (Continuous Intrajejunal Infusion)
  • L-DOPA nasal spray Continuous Intrajejunal Infusion
  • the purpose of the first aspect of the present invention is to provide a pharmaceutical composition.
  • the second aspect of the present invention aims to provide a method for preparing the above composition.
  • the third aspect of the present invention is to provide the use of the above-mentioned pharmaceutical composition.
  • the fourth aspect of the present invention aims to provide the use of dodecyl- ⁇ -D-maltoside as an absorption enhancer in the preparation of levodopa pharmaceutical preparations.
  • the first aspect of the present invention provides a pharmaceutical composition, comprising a drug and an absorption enhancer; the drug is Rotadopa and/or dopamine and/or carbidopa; the absorption enhancer is at least one of dodecyl- ⁇ -D-maltoside, tetradecyl- ⁇ -D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan and sodium taurocholate.
  • the absorption enhancer is dodecyl- ⁇ -D-maltoside.
  • the pharmaceutical composition further comprises at least one of a suspending agent, an antioxidant, a wetting agent, and an antibacterial agent.
  • the suspending agent is at least one of microcrystalline cellulose-sodium carboxymethyl cellulose RC591 or CL611, carbomer 934, 940.
  • the microcrystalline cellulose-sodium carboxymethyl cellulose includes microcrystalline cellulose-sodium carboxymethyl cellulose RC591, CL611 and the like.
  • the carbomer includes carbomer 934, 940 and the like.
  • the suspending agent is microcrystalline cellulose-sodium carboxymethyl cellulose RC591.
  • the antioxidant is at least one of ascorbic acid, ascorbyl palmitate and sodium metabisulfite.
  • the antioxidant is sodium metabisulfite.
  • the wetting agent may be at least one of polysorbate and poloxamer.
  • the wetting agent may be polysorbate.
  • the polysorbate is polysorbate 80.
  • the antibacterial agent is at least one of benzalkonium chloride, benzalkonium bromide, quaternary ammonium salts, cetrimide, phenoxyethanol, sodium benzoate, and phenylethanol.
  • the antibacterial agent is benzalkonium chloride.
  • the pharmaceutical composition comprises: 0.5% to 20% w/w of the drug, 1% to 3% w/w of the suspending agent; 0.1% to 3% w/w of the antioxidant; 0.1% to 0.5% w/w of the absorption enhancer; 0.01% to 0.03% w/w of the wetting agent; and 0.01% to 0.024% w/w of the antibacterial agent.
  • the pharmaceutical composition comprises: 0.5% to 15% w/w of levodopa or a pharmaceutically acceptable salt thereof, 0.125% to 3% w/w of benserazide or a pharmaceutically acceptable salt thereof; 1.0% to 2% w/w of a suspending agent; 0.2% to 3% w/w of an antioxidant; 0.05% to 0.5% w/w of an absorption enhancer; 0.005% to 0.03% w/w of a wetting agent; and 0.005% to 0.03% w/w of an antibacterial agent.
  • the levodopa composition comprises: 1% to 20% w/w of levodopa or a pharmaceutically acceptable salt thereof, 1% to 3% w/w of a suspending agent; 0.1% to 3% w/w of an antioxidant; 0.1% to 0.5% w/w of an absorption enhancer; 0.01% to 0.03% w/w of a wetting agent; and 0.01% to 0.024% w/w of an antibacterial agent.
  • the pharmaceutical composition comprises: 1% to 15% w/w of or a pharmaceutically acceptable salt thereof, 1.2% to 2% w/w suspending agent; 0.2% to 1% w/w antioxidant; 0.2% to 0.3% w/w absorption promoter; 0.01% to 0.03% w/w wetting agent; 0.015% to 0.02% w/w antibacterial agent.
  • the pharmaceutical composition further comprises a pH adjuster for adjusting the pH of the pharmaceutical composition to 5.0-6.5.
  • the added amount of the pH adjuster is 0.03% to 0.464%.
  • the pH adjuster is at least one of citric acid/sodium citrate and sodium dihydrogen phosphate/disodium hydrogen phosphate.
  • the pH adjuster is citric acid/sodium citrate.
  • the pharmaceutical composition further comprises an osmotic pressure regulator for adjusting the osmotic pressure of the pharmaceutical composition to 270-350 mOsm/kg.
  • the content of the osmotic pressure regulator is 0% to 1.5%.
  • the osmotic pressure regulator is glycerol.
  • the pharmaceutical composition further comprises water.
  • the levodopa is levodopa micropowder.
  • the particle size d 90 of the levodopa micropowder is 2 to 20 ⁇ m.
  • the pharmaceutical composition is in the form of a spray.
  • the pharmaceutical composition is administered nasally.
  • the acceptable delivery volume of the spray is 100-200 ⁇ L
  • the effective delivery dose of levodopa is 10-40 mg/spray
  • the clinical therapeutic dose is 10-1000 mg/day
  • the delivery volume is determined by the spray device, and the delivery dose is the product of the drug solution concentration and the delivery volume.
  • the present invention provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps:
  • the method further comprises filling the pharmaceutical composition into a nasal spray device to obtain a nasal spray.
  • the third aspect of the present invention provides use of the pharmaceutical composition of the first aspect of the present invention in the preparation of Parkinson's disease drugs.
  • the fourth aspect of the present invention provides the use of dodecyl- ⁇ -D-maltoside in the preparation of levodopa and/or benserazide and/or carbidopa nasal spray.
  • the present invention provides a levodopa nasal spray, wherein dodecyl- ⁇ -D-maltoside is used as the nasal spray of levodopa.
  • the drug absorption promoter is compounded with a suspending agent, an antioxidant, a wetting agent, an antibacterial agent, etc. to improve the stability of levodopa in the liquid preparation.
  • the preparation can achieve drug absorption through two pathways: 1) part of the drug is directly delivered to the olfactory area, bypassing the blood-brain barrier, and entering the brain to take effect; 2) part of the drug is quickly absorbed into the blood through the nasal mucosa in the respiratory area, enters the systemic circulation, and enters the brain after passing through the blood-brain barrier to take effect.
  • the levodopa nasal spray has a suitable viscosity, can effectively increase the deposition of drugs in the olfactory area, improve the nose-brain delivery efficiency, and effectively treat Parkinson's disease.
  • Fig. 1 Release curves of formulations F7-F10 and F11-F14.
  • Figure 2 shows the appearance of preparations with different sodium metabisulfite concentrations after being placed at 60°C for different periods of time (from left to right: solutions with sodium metabisulfite contents of 0.2%, 0.5%, 1%, 2%, 3%, 0% and no levodopa).
  • Figure 3 shows the appearance of preparations with different sodium metabisulfite concentrations after exposure to light for different periods of time (from left to right: solutions with sodium metabisulfite contents of 0.2%, 0.5%, 1%, 2%, 3%, 0% and no levodopa).
  • Fig. 6 The intracerebral drug-time curve of dopamine nasal spray.
  • the levodopa used in the following examples is levodopa micropowder, and the particle size D 90 may be 2-20 ⁇ m.
  • the pulverization method is as follows:
  • a JET MILL Lab air flow mill was used with the air inlet pressure and crushing pressure set to 6.5 bar and 7.0 bar respectively.
  • the automatic feeding mode was adopted with a feeding speed of 10 rpm, and the materials were fed for air flow crushing.
  • Determination of particle size of levodopa micropowder The particle size of levodopa after micropowder was determined by the Malvern wet method, and the test parameters were as follows: background/sample measurement time 10s, shading 8%-20%, stirring speed 2000rpm, stirring time 5min.
  • the present invention provides a nasal spray for treating Parkinson's disease, comprising the following ingredients:
  • Active pharmaceutical ingredient 0.5% to 20% w/w;
  • Suspending agent 1% to 3% w/w;
  • Antioxidant 0.1% to 3% w/w;
  • Absorption enhancer 0.1% to 0.5% w/w
  • Wetting agent 0.01% to 0.03% w/w
  • pH adjuster appropriate amount, used to adjust the pH of the spray to 5.0-6.5;
  • Osmotic pressure regulator appropriate amount, used to adjust the osmotic pressure of the spray to 270-350mOsm/kg;
  • Antibacterial agent 0.01% to 0.024% w/w;
  • Purified water add to 100% w/w.
  • the present invention also provides a method for preparing the above-mentioned nasal spray, comprising the following steps:
  • S5 Fill the levodopa suspension into a high-density polyethylene bottle and cap the nasal spray pump under a nitrogen environment to obtain the levodopa nasal spray.
  • the USP content determination method is used to destroy the raw material sample
  • the content of levodopa was tested to investigate the stability of the levodopa raw material under the destruction conditions (3.0% hydrogen peroxide oxidation for 0.5, 1 and 2 h, 3.0% hydrogen peroxide oxidation at 60°C for 0.5, 1 and 2 h, and high temperature of 130°C for 1, 2 and 4 h).
  • the formula (Table 3 and Table 4) was designed with 1% microcrystalline cellulose-sodium carboxymethyl cellulose as suspending agent, ascorbic acid, ascorbyl palmitate, and sodium metabisulfite as candidate antioxidants, and the type and dosage as prescription variables.
  • the formula was placed under high temperature 60°C and high humidity 75% to observe the changes of related substances.
  • Microcrystalline cellulose-sodium carboxymethyl cellulose RC591 and CL611 approved by FDA for nasal administration were used as suspension aids.
  • the formulation designs of the suspending agent and the suspending agent are shown in Tables 6 and 7. The content uniformity and release behavior of the preparations at different suspending agent concentrations were investigated.
  • the release behavior of each prescription was investigated using a transdermal diffusion instrument.
  • the release medium was 9 mL of PBS solution with a pH of 5.8, the medium temperature was 37 ⁇ 0.5 °C, the sampling volume was 9 mL, and the rehydration volume was 9 mL; the release behavior curve is shown in Figure 1.
  • Figure 1 shows that prescriptions F7 to F14 exhibit rapid release, with almost complete release at 24 hours.
  • the viscosity of the prescription increases, the release rate of each prescription increases, and the cumulative release increases.
  • prescription F7 has the highest release rate, with more than 60% released in 1 hour and a cumulative release of more than 90% in 24 hours. It is preferred as the best suspending agent Proportion.
  • S5 Fill the levodopa suspension into a high-density polyethylene bottle and cap the nasal spray pump under a nitrogen environment to obtain the levodopa nasal spray.
  • the above-mentioned drug solution was filled into a high-density polyethylene bottle, and the nasal spray pump was capped under a nitrogen environment. According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 edition, the delivery dose of 10 bottles of samples from the same batch was tested. The results are shown in Table 17.
  • the spray droplet size of the levodopa nasal spray at 30 mm and 60 mm was measured by a Sympatec laser particle size analyzer (HELOS & SPRAYER TM ), with an R5 lens, a trigger pressure of 60 N, and a measuring time of 150 ms.
  • HELOS & SPRAYER TM Sympatec laser particle size analyzer
  • the spray process of nasal spray can be divided into three stages: formation period, stabilization period and dissipation period: formation period is the spray formation stage, the droplet concentration increases rapidly and the particle size increases rapidly; during the stabilization period, the droplet size reaches a peak and remains stable; during the dissipation period, the droplet concentration decreases rapidly and the particle size fluctuates greatly.
  • the stabilization period of levodopa nasal spray is 20% to 50%, so this is the stabilization period of levodopa nasal spray, and the three-stage method is used to detect the droplet size of the nasal spray during the stabilization period.
  • Sympatec laser particle size analyzer (HELOS & SPRAYER TM ) was used to measure the droplet diameter of levodopa nasal spray at 30 mm and 60 mm during the stable period.
  • the lens was R5, the trigger pressure was 60 N, and the stable period was 20% to 50%. The results are shown in Table 18.
  • the drug content of fine droplets of nasal spray was investigated using a new generation pharmaceutical disk impactor (NGI).
  • NTI new generation pharmaceutical disk impactor
  • the air flow rate was 15 L/min
  • the volume of the glass expansion chamber was 5 L
  • the injection volume was 4 presses
  • the interval between each press was 5 s
  • the preheating temperature was set at 3.5 °C. Cool for 90 minutes; the results are shown in Table 19.
  • the pharmacokinetic behavior of three administration routes namely, nasal administration of levodopa nasal spray, oral administration of commercial preparations, and oral inhalation administration of levodopa inhalation powder, was studied to investigate the absorption and metabolic behavior of levodopa in plasma after administration.
  • the preparation method of homemade levodopa inhalation powder is as follows:
  • the levodopa powder was added three times by layer-by-layer method. 4.4 g lactose ML001 was added to the centrifuge tube, and 0.6 g micronized API was added and mixed evenly. Then 1.2 g lactose ML001 and 0.7 g micronized API were added in sequence. The mixture was mixed with 1.2 g of lactose MLO1 and 0.7 g of micronized API, and then 1.2 g of lactose ML001 was manually mixed for 20 min to obtain levodopa inhalation powder.
  • mice Male SD rats (180-220g) were raised in an SPF environment and were free to eat and drink. They were fasted for 12 hours before the experiment. Fifteen rats were randomly divided into five groups, with three rats in each group, and given levodopa tablets (25 mg/kg), medopa tablets (20 mg/kg), homemade levodopa inhalation powder (10 mg/kg), homemade levodopa nasal spray (5 mg/kg) and homemade levodopa nasal spray (10 mg/kg), respectively. Continuous orbital blood sampling was performed at 2min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, and 6h after administration to detect the levels of levodopa and dopamine in plasma. The pharmacokinetic parameter calculation results are shown in Tables 21 and 22;
  • the plasma levodopa concentration of the levodopa nasal spray was linearly related to the administration dose, and the Cmax and AUC of levodopa in plasma increased with the increase of the administration dose.
  • the AUC 0-6h of dopamine in the brain was much higher than that of the levodopa tablet group, and its effectiveness was significantly improved.
  • the DDM-free levodopa nasal spray was prepared according to the prescription in the above table, and the preparation method was the same as the preparation method of the levodopa nasal spray in the specific embodiment.
  • the plasma peak time of levodopa was increased from 120min to 15min, and the AUC 0-6h of dopamine in the brain was increased from 3875ng/mL ⁇ min to 14189ng/mL ⁇ min.
  • S5 Fill the dobase hydrazine suspension into a high-density polyethylene bottle and cap the nasal spray pump under a nitrogen environment to obtain the dobase hydrazine nasal spray.
  • the DDM-free dopamine hydrazine nasal spray was prepared according to the above prescription, and the preparation method was the same as the preparation method of the dopamine hydrazine suspension nasal spray in the specific embodiment.

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Abstract

L'invention concerne une pulvérisation nasale de lévodopa, son procédé de préparation et son utilisation. La pulvérisation nasale de lévodopa comprend de la lévodopa ou un sel pharmaceutiquement acceptable de celle-ci, un activateur d'absorption, un agent de suspension, un antioxydant, un agent mouillant et un agent antimicrobien. La pulvérisation nasale de lévodopa améliore la stabilité de la lévodopa, augmente le dépôt de région olfactive du médicament, améliore l'efficacité d'administration nasale-cérébrale, peut traiter efficacement la maladie de Parkinson tout en réduisant l'apparition de fluctuations symptomatiques, et a une viscosité appropriée.
PCT/CN2024/130102 2023-11-09 2024-11-06 Pulvérisation nasale de lévodopa, son procédé de préparation et son utilisation Pending WO2025098365A1 (fr)

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CN202311494072.1 2023-11-09
CN202311494072.1A CN117503703B (zh) 2023-11-09 2023-11-09 一种左旋多巴鼻喷雾剂及其制备方法及应用

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CN117503703B (zh) * 2023-11-09 2024-11-22 广州新济药业科技有限公司 一种左旋多巴鼻喷雾剂及其制备方法及应用
CN118593475B (zh) * 2024-06-06 2025-07-25 暨南大学 用于治疗帕金森病的组合物、鼻喷雾剂及其制备方法
CN119700724A (zh) * 2024-12-31 2025-03-28 中国医学科学院生物医学工程研究所 一种用于治疗慢性阻塞性肺病和哮喘的雾化吸入制剂及其制备方法

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101797243A (zh) * 2010-03-23 2010-08-11 广东药学院 一种含有左旋多巴和冰片的组合物及其应用
CN101926785A (zh) * 2009-06-18 2010-12-29 北京科信必成医药科技发展有限公司 一种治疗帕金森病的药物控释制剂及其制备方法
CN106619490A (zh) * 2017-01-19 2017-05-10 云南白药集团无锡药业有限公司 一种左旋多巴透皮贴剂及其制备方法
CN108553416A (zh) * 2018-06-14 2018-09-21 五邑大学 一种含有左旋多巴和盐酸苄丝肼的缓释混悬制剂及其制备方法
CN111801141A (zh) * 2018-01-05 2020-10-20 英倍尔药业股份有限公司 通过精密鼻装置的左旋多巴粉末的鼻内递送
CN112955134A (zh) * 2018-07-19 2021-06-11 英倍尔药业股份有限公司 用于治疗帕金森氏病的左旋多巴和多巴脱羧酶抑制剂的呼吸道递送
CN113784703A (zh) * 2019-05-16 2021-12-10 株式会社新日本科学 经鼻施予用粉末制剂及其制造方法
CN115068617A (zh) * 2022-06-27 2022-09-20 辽宁天融生物科技有限公司 一种脑靶向药物组合物、给药制剂及其制备方法
CN115707462A (zh) * 2021-08-19 2023-02-21 沈阳药科大学 一种提高脑靶向的左旋多巴组合物及其应用
CN117503704A (zh) * 2023-11-09 2024-02-06 广州新济药业科技有限公司 一种作用于中枢神经系统的鼻喷雾剂及其制备方法及应用
CN117503703A (zh) * 2023-11-09 2024-02-06 广州新济药业科技有限公司 一种左旋多巴鼻喷雾剂及其制备方法及应用
CN118593475A (zh) * 2024-06-06 2024-09-06 暨南大学 用于治疗帕金森病的组合物、鼻喷雾剂及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2457580A1 (fr) * 2004-08-25 2012-05-30 The UAB Research Foundation Activateurs de l'absorption pour l'administration de médicaments
SE538425C2 (en) * 2014-09-04 2016-06-21 Lobsor Pharmaceuticals Ab Pharmaceutical compositions comprising levodopa, carbidopa and a comt inhibitor and method of administration thereof
CN111643493B (zh) * 2020-05-26 2023-01-10 上海京新生物医药有限公司 一种高浓度左旋多巴制剂及其制备方法及其应用

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101926785A (zh) * 2009-06-18 2010-12-29 北京科信必成医药科技发展有限公司 一种治疗帕金森病的药物控释制剂及其制备方法
CN101797243A (zh) * 2010-03-23 2010-08-11 广东药学院 一种含有左旋多巴和冰片的组合物及其应用
CN106619490A (zh) * 2017-01-19 2017-05-10 云南白药集团无锡药业有限公司 一种左旋多巴透皮贴剂及其制备方法
CN111801141A (zh) * 2018-01-05 2020-10-20 英倍尔药业股份有限公司 通过精密鼻装置的左旋多巴粉末的鼻内递送
CN108553416A (zh) * 2018-06-14 2018-09-21 五邑大学 一种含有左旋多巴和盐酸苄丝肼的缓释混悬制剂及其制备方法
CN112955134A (zh) * 2018-07-19 2021-06-11 英倍尔药业股份有限公司 用于治疗帕金森氏病的左旋多巴和多巴脱羧酶抑制剂的呼吸道递送
CN113784703A (zh) * 2019-05-16 2021-12-10 株式会社新日本科学 经鼻施予用粉末制剂及其制造方法
CN115707462A (zh) * 2021-08-19 2023-02-21 沈阳药科大学 一种提高脑靶向的左旋多巴组合物及其应用
CN115068617A (zh) * 2022-06-27 2022-09-20 辽宁天融生物科技有限公司 一种脑靶向药物组合物、给药制剂及其制备方法
CN117503704A (zh) * 2023-11-09 2024-02-06 广州新济药业科技有限公司 一种作用于中枢神经系统的鼻喷雾剂及其制备方法及应用
CN117503703A (zh) * 2023-11-09 2024-02-06 广州新济药业科技有限公司 一种左旋多巴鼻喷雾剂及其制备方法及应用
CN118593475A (zh) * 2024-06-06 2024-09-06 暨南大学 用于治疗帕金森病的组合物、鼻喷雾剂及其制备方法

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