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WO2025098365A1 - 一种左旋多巴鼻喷雾剂及其制备方法及应用 - Google Patents

一种左旋多巴鼻喷雾剂及其制备方法及应用 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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French (fr)
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

一种左旋多巴鼻喷雾剂及其制备方法及应用。左旋多巴鼻喷雾剂包括左旋多巴或其药学上可接受的盐、吸收促进剂、助悬剂、抗氧剂、润湿剂、抑菌剂，提高了左旋多巴的稳定性，增加了药物嗅区沉积，提高了鼻-脑递送效率，可有效治疗帕金森症，同时改善其症状波动的发生，具有适宜的黏度。

Description

一种左旋多巴鼻喷雾剂及其制备方法及应用 技术领域
本发明属于生物医药技术领域，具体涉及一种左旋多巴鼻喷雾剂及其制备方法及应用。
背景技术
帕金森症(Parkinson's disease，PD)是一种常见的神经系统退行性疾病，患病人数较多；该病的发病原因和机理较多，是综合性致病结果，主要病理改变为黑质致密部位多巴胺(Dopamine，DA)能神经元丢失和路易小体形成，其主要生化改变为纹状体区缺乏多巴胺，多巴胺于乙酰胆碱递质失衡，导致乙酰胆碱功能相对亢进。临床患者的主要症状有运动迟缓、静止性震颤、肌强直和姿势平衡障碍等运动症状，同时伴嗅觉障碍、便秘、睡眠障碍等非运动症状，目前常用治疗手段包括药物治疗、手术治疗、康复治疗等，但无法治愈，只能缓解症状、改善患者生活质量，其治疗亟需重视。
用于PD疾病治疗的药物主要有多巴胺类(左旋多巴、多巴胺受体激动剂等)与胆碱类(盐酸苯海索、甲磺酸苯扎托品、盐酸丙环定等)。其中，左旋多巴(Levodopa，LDA)是多巴胺的代谢前体，外周补充的左旋多巴可通过血脑屏障在脑内经多巴脱羧酶脱羧转变为多巴胺，从而发挥替代治疗的作用，是帕金森症的标准疗法，也是帕金森药物治疗中最有效的对症治疗药物。此外，左旋多巴在潮湿状态下不稳定，易发生氧化。目前，在全球范围内，与左旋多巴相关的制剂多为经口服途径给药的左旋多巴片剂、胶囊剂、颗粒剂、吸入剂等固体制剂。但其口服后仅有1％能经中性氨基酸载体转运至脑内纹状体组织转化为多巴胺而发挥作用，起效缓慢，生物利用度低，给药剂量大。超过95％的左旋多巴被广泛分布于外周组织中的脱羧酶转化为多巴胺，导致不良反应如心血管疾病与胃肠道疾病等，长期大剂量应用后，患者还会产生“On/Off”现象。此外，由于运动功能随着疾病的发展而恶化，PD患者会出现吞咽困难，随后在这些患者中，吞咽困难进一步使口服摄入左旋多巴难度大幅增加。因此还需一种左旋多巴施用的替代途径。
相较而言，鼻腔给药制剂可将药物自嗅区直接递送至大脑，绕过血脑屏障，具有快速起效，提高左旋多巴的入脑效率，降低给药剂量，避免胃肠反应等显著优势。目前已 有多种用于中枢神经系统疾病的鼻腔给药制剂上市，如用于治疗偏头痛的佐米曲普坦鼻喷雾剂和舒马曲普坦鼻喷雾剂，用于缓解疼痛的阿片类药物酒石酸布托啡诺鼻喷雾剂(Butorphanol)和枸橼酸芬太尼鼻喷雾剂用于癫痫治疗的地西泮鼻喷雾剂咪达唑仑鼻喷雾剂及用于抑郁症治疗的艾司氯胺酮鼻喷雾剂等均已经FDA批准上市，充分证明了左旋多巴经鼻腔给药途径用于帕金森症治疗的可行性与临床前景。
口服左旋多巴、普拉克索是帕金森病临床治疗中的常用药物。因为多巴胺难以顺利穿透血脑屏障，需为患者补充左旋多巴这一多巴胺的前体。当左旋多巴进至脑部，为多巴胺能神经元所摄取之后，可经脱羧反应转变成多巴胺，从而发挥药理作用。左旋多巴被机体吸收之后，其中95％的药物于外周发生脱羧反应，形成多巴胺，仅有1％的药物穿透血脑屏障，进至脑中。
鼻腔与脑组织间存在着解剖学上的直接联系：鼻腔的嗅粘膜上皮含双极嗅细胞，由其形成的嗅神经穿过筛板进入中枢神经系统的嗅球，因此，鼻腔给左旋多巴后部分药物可经嗅粘膜吸收进入嗅球或脑脊液(CSF)，从而绕过血脑屏障(BBB)直接转运入脑，发挥中枢治疗作用。因此鼻腔给药起效快、脑内生物利用度高、能减少左旋多巴的用量，减少不良反应。
对于鼻脑递送制剂而言，药物在嗅区的吸收量对其药效至关重要。嗅区黏膜的面积极小(1～5cm2)，仅占鼻腔总面积的3％～5％，如何使药物沉积于嗅区，提高药物的递送效率，促进药物在鼻腔黏膜部位的吸收是左旋多巴鼻喷雾剂的研发重点与难点。此外由于左旋多巴潮湿时在空气中极易氧化，目前已上市的左旋多巴液体制剂仅有需要冷冻保存的卡左双多巴肠凝胶(空肠内持续输注)一种，其稳定性是左旋多巴鼻喷雾剂研发的另一难点。
发明内容
本发明第一方面的目的，在于提供一种药物组合物。
本发明第二方面的目的，在于提供上述组合物的制备方法。
本发明第三方面的目的，在于提供上述药物组合物的应用。
本发明第四方面的目的，在于提供十二烷基-β-D-麦芽糖苷作为吸收促进剂在制备左旋多巴药物制剂中的应用。
本发明所采取的技术方案是：
本发明的第一方面，提供一种药物组合物，包括药物、吸收促进剂；所述药物为左 旋多巴和/或多巴丝肼和/或卡比多巴；所述吸收促进剂为十二烷基-β-D-麦芽糖苷、十四烷基-β-D-麦芽糖苷、壳聚糖、蔗糖十二烷酸酯、羧甲基壳聚糖、牛黄胆酸钠中的至少一种。
优选地，所述吸收促进剂为十二烷基-β-D-麦芽糖苷。
优选地，所述药物组合物还包括助悬剂、抗氧剂、润湿剂、抑菌剂中的至少一种。
优选地，所述助悬剂为微晶纤维素-羧甲基纤维素钠RC591或CL611，卡波姆934、940中的至少一种。
优选地，所述微晶纤维素-羧甲基纤维素钠包括微晶纤维素-羧甲基纤维素钠RC591、CL611等。
优选地，所述卡波姆包括卡波姆934、940等。
优选地，所述助悬剂为微晶纤维素-羧甲基纤维素钠RC591。
优选地，所述抗氧剂为抗坏血酸、抗坏血酸棕榈酸酯、焦亚硫酸钠中的至少一种。
优选地，所述抗氧剂为焦亚硫酸钠。
优选地，所述润湿剂可为聚山梨酯、泊洛沙姆中的至少一种。
优选地，所述润湿剂可为聚山梨酯。
优选地，所述聚山梨酯为聚山梨酯80。
优选地，所述抑菌剂为苯扎氯铵、苯扎溴铵、季铵盐类、西曲溴铵、苯氧乙醇、苯甲酸钠、苯乙醇中的至少一种。
优选地，所述抑菌剂为苯扎氯铵。
优选地，所述药物组合物包括：0.5％～20％w/w的药物、1％～3％w/w的助悬剂；0.1％～3％w/w的抗氧剂：0.1％～0.5％w/w的吸收促进剂；0.01％～0.03％w/w的润湿剂；0.01％～0.024％w/w的抑菌剂。
优选地，所述药物组合物(多巴丝肼)包括：0.5％～15％w/w的左旋多巴或其药学上可接受的盐、0.125％～3％w/w的苄丝肼或其药学上可接受的盐；1.0％～2％w/w的助悬剂；0.2％～3％w/w的抗氧剂；0.05％～0.5％w/w的吸收促进剂；0.005％～0.03％w/w的润湿剂；0.005％～0.03％w/w的抑菌剂。
优选地，所述左旋多巴组合物包括：1％～20％w/w的左旋多巴或其药学上可接受的盐、1％～3％w/w的助悬剂；0.1％～3％w/w的抗氧剂：0.1％～0.5％w/w的吸收促进剂；0.01％～0.03％w/w的润湿剂；0.01％～0.024％w/w的抑菌剂。
优选地，所述药物组合物包括：1％～15％w/w的或其药学上可接受的盐、1.2％～ 2％w/w的助悬剂；0.2％～1％w/w的抗氧剂：0.2％～0.3％w/w的吸收促进剂；0.01％～0.03％w/w的润湿剂；0.015％～0.02％w/w的抑菌剂。
优选地，所述药物组合物还包括pH调节剂，用于调节药物组合物pH为5.0～6.5。
优选地，所述pH调节剂的添加量为0.03％～0.464％。
优选地，所述pH调节剂为枸橼酸/枸橼酸钠，磷酸二氢钠/磷酸氢二钠中的至少一种。
优选地，所述pH调节剂为枸橼酸/枸橼酸钠。
优选地，所述药物组合物还包括渗透压调节剂，用于调节药物组合物渗透压为270-350mOsm/kg。
优选地，所述渗透压调节剂的含量为0％～1.5％。
优选地，所述渗透压调节剂为甘油。
优选地，所述药物组合物还包括水。
优选地，所述左旋多巴为左旋多巴微粉。
优选地，所述左旋多巴微粉的粒径d90为2～20μm。
优选地，所述药物组合物的剂型为喷雾剂。
优选地，所述药物组合物的给药方式为经鼻给药。
优选地，所述喷雾剂可接受的递送体积为100～200μL，左旋多巴的有效递送剂量为10～40mg/spray，临床治疗剂量为10～1000mg/天，其中递送体积根据喷雾装置决定的，递送剂量是药液浓度和递送体积的乘积。
本发明第二方面，提供上述药物组合物的制备方法，包括以下步骤：
S1：将润湿剂加入水中，加入药物混合至分散均匀后得液体1；
S2：将助悬剂加入适量水中，混合至分散均匀后，加入pH调节剂得液体2；
S3：将液体2、抗氧剂、吸收促进剂、抑菌剂、渗透压调节剂加入液体1中，搅拌至混合均匀，即得药物组合物；
优选地，所述方法还包括将药物组合物灌装至鼻喷雾装置中，即得鼻喷雾剂。
本发明的第三方面，提供本发明第一方面所述药物组合物在制备帕金森药物中的应用。
本发明的第四方面，提供十二烷基-β-D-麦芽糖苷在制备左旋多巴和/或苄丝肼和/或卡比多巴鼻喷雾剂中的应用。
本发明的有益效果是：
本发明提供了一种左旋多巴鼻喷雾剂，将十二烷基-β-D-麦芽糖苷作为左旋多巴的吸 收促进剂，并复配助悬剂、抗氧剂、润湿剂、抑菌剂等，提高左旋多巴在液体制剂中的稳定性，给药后本制剂可通过两种通路实现药物吸收：1)部分药物被直接递送至嗅区，绕过血脑屏障，入脑起效；2)部分药物经呼吸区鼻黏膜快速吸收入血，进入全身循环，经血脑屏障后入脑起效。其中经鼻腔途径直接递送至嗅区，绕过血脑屏障，提高脑部药物吸收效率，快速起效，降低给药剂量，用于治疗帕金森症的同时改善症状波动的发生。该左旋多巴鼻喷雾剂具有适宜的黏度，能够有效增加药物嗅区沉积，提高鼻-脑递送效率，有效治疗帕金森症。
附图说明
图1处方F7～F10与处方F11～F14的释放曲线。
图2不同焦亚硫酸钠浓度的制剂60℃放置不同时间的外观(从左至右：焦亚硫酸钠含量为0.2％、0.5％、1％、2％、3％、0％和不含左旋多巴的药液)。
图3不同焦亚硫酸钠浓度的制剂光照放置不同时间的外观(从左至右：焦亚硫酸钠含量为0.2％、0.5％、1％、2％、3％、0％和不含左旋多巴的药液)。
图4 30mm左旋多巴鼻喷雾剂的喷雾过程中的雾滴粒径分布。
图5 60mm左旋多巴鼻喷雾剂的喷雾过程中的雾滴粒径分布。
图6多巴丝肼鼻喷雾剂脑内药时曲线。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本发明的目的、特征和效果。显然，所描述的实施例只是本发明的一部分实施例，而不是全部实施例，基于本发明的实施例，本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例，均属于本发明保护的范围。
以下实施例中所用的左旋多巴为左旋多巴微粉，粒径D90可为2-20μm。粉碎方法如下：
采用JET MILL Lab气流粉碎机，设置进气压力和粉碎压力分别为6.5bar和7.0bar，采用自动进料模式，进料速度为10rpm，投料进行气流粉碎。
左旋多巴微粉的粒径测定：采用马尔文湿法测定微粉后左旋多巴的粒径，测试参数如下：背景/样品测量时间10s，遮光度8％-20％，搅拌转速2000rpm，搅拌时间5min。
左旋多巴及其微粉的粒径分布如表1所示：
表1左旋多巴及其微粉粒径分布

本发明提供一种用于治疗帕金森的鼻喷雾剂，含有如下成分：
药物活性成分：0.5％～20％w/w；
助悬剂：1％～3％w/w；
抗氧剂：0.1％～3％w/w；
吸收促进剂：0.1％～0.5％w/w；
润湿剂：0.01％～0.03％w/w；
pH调节剂：适量，用于调节喷雾剂pH为5.0～6.5；
渗透压调节剂：适量，用于调节喷雾剂渗透压为270-350mOsm/kg；
抑菌剂：0.01％～0.024％w/w；
纯水：加至100％w/w。
本发明还提供上述鼻喷雾剂的制备方法，包含以下步骤：
S1：通过气流粉碎机对原料药进行粉碎，粉碎压力为5～10bar，进料压力为7～10bar，进料速度为50～65g/min，得药物微粉；
S2：向配液罐中加入适量纯化水及润湿剂，设定搅拌速度为10～20Hz，搅拌3～8min，提高搅拌速度为40～50Hz，在搅拌下加入处方量左旋多巴微粉，加料完成后，继续搅拌20～40min，得液体1；
S3：向另一配液罐中加入适量纯化水，设定搅拌速度为40～50Hz，在搅拌下加入助悬加料完成后，继续搅拌20～40min，设定乳化速度为40～60Hz，均质乳化80～120min，在搅拌下加入pH调节剂，继续乳化20～40min，得液体2；
S4：设定配液罐搅拌速度为40～60Hz，在搅拌下依次将液体2、抗氧剂溶液、吸收促进剂溶液、抑菌剂溶液和渗透压调节剂溶液加入液体1中，设定配液罐压力为约-0.08MPa，开启真空泵，待达到设定压力后，关闭真空泵，搅拌20～40min至混合均匀后，即得左旋多巴混悬液；
S5：将左旋多巴混悬液灌装至高密度聚乙烯瓶中，在氮气环境下轧盖鼻喷雾泵，即得左旋多巴鼻喷雾剂。
实施例1左旋多巴破坏实验
根据左旋多巴美国药典收载的标准，使用USP中含量测定方法对原料药破坏样品 的含量进行检测，考察破坏条件(3.0％过氧化氢分别氧化0.5、1与2h，60℃下3.0％过氧化氢分别氧化0.5、1与2h，130℃高温下分别破坏1、2、4h)下左旋多巴原料药的稳定性。
表2不同条件破坏后左旋多巴含量
结果表明，左旋多巴在高温及氧化下均不稳定。随氧化时间延长，高温放置时间延长，左旋多巴含量逐渐降低。其中60℃下氧化0.5h时，左旋多巴含量降低至92.66％，氧化2h，左旋多巴含量显著降低至74.35％。
实施例2抗氧化剂筛选
以1％浓度的微晶纤维素-羧甲基纤维素钠为助悬剂，以抗坏血酸、抗坏血酸棕榈酸酯、焦亚硫酸钠为候选抗氧剂，分别以种类和用量为处方变量，设计处方(表3、表4)。放置于高温60℃与高湿75％条件下，考察有关物质变化。
表3抗氧化剂筛选处方具体组成

表4不同抗氧剂处方设计
表5高温及高湿放置0天与5天的各处方有关物质
结果如表5，可以看出，60℃条件，各处方放置5天后，杂质含量明显升高，此外抗坏血酸组、抗坏血酸棕榈酸酯组与未加抗氧剂处方颜色明显变化为棕黄色，抗氧化性能不佳。此外由于抗坏血酸自身不稳定，氧化后颜色变化较大，故优选焦亚硫酸钠作为抗氧剂。
实施例3助悬剂筛选
以FDA批准用于鼻腔给药的微晶纤维素-羧甲基纤维素钠RC591与CL611为助悬 剂，助悬剂处方设计见表6、表7，考察不同助悬剂浓度下制剂的含量均匀度和释放行为。
表6助悬剂筛选处方具体组成
表7不同助悬剂处方设计
含量均匀度结果见表8；
表8不同处方含量及含量均匀度

结果表明，各处方制备完成后含量RSD小于2％，符合要求。常温放置5天后，各处方的含量未发生变化，且含量均匀度符合要求。
有关物质含量结果见表9；
表9不同处方的有关物质含量
结果表明，各处方的总杂含量远低于1％，其中各单杂含量远低于0.1％，符合要求
采用透皮扩散仪对各处方的释放行为进行考察。释放介质为9mL pH5.8的PBS溶液，介质温度为37±0.5℃，取样体积为9mL，补液体积为9mL；释放行为曲线见图1。
图1显示，处方F7～F14表现为快速释放，在24h时几乎完全释放。此外，对比各处方可见，随处方黏度增大，各处方释放速率加快，累积释放度增加。其中处方F7释放速率最高，1h可释放超过60％，24h累积释放度超过90％，优选其作为最佳助悬剂 比例。
实施例4焦亚硫酸钠浓度筛选
按表10配制药液，焦亚硫酸钠浓度分别为0.2％、0.5％、1％、2％和3％，将上述药液灌装于西林瓶后，放置于高温60℃和光照(4500Lx±500Lx)条件下，观察其外观，检测左旋多巴含量和有关物质。
表10
结果如下图2-图3和表11-14。
表11不同焦亚硫酸钠浓度处方60℃放置不同时间的左旋多巴含量
表12不同焦亚硫酸钠浓度处方60℃放置不同时间的有关物质

表13不同焦亚硫酸钠浓度处方光照条件下放置不同时间的左旋多巴含量
表14不同焦亚硫酸钠浓度处方光照条件下放置不同时间的有关物质
结果显示：
1)60℃放置下，不含焦亚硫酸钠药液发生变色，焦亚硫酸钠含量为0.2％～3％时，放置30天，无变色现象，左旋多巴含量无明显变化，有关物质无明显增长(图2和表11-12)。
2)光照条件放置下，不含焦亚硫酸钠药液发生变色，焦亚硫酸钠含量为0.2％～3％时，放置13天，无变色现象，左旋多巴含量无明显变化，有关物质无明显增长(图3和表13-14)。
实施例5优选处方的质量评价
1、根据表15处方制备药液并灌装，制备方法如下：
S1：通过气流粉碎机对左旋多巴原料药进行粉碎，粉碎压力为7bar，进料压力为8bar，进料速度为56g/min，得左旋多巴微粉；
S2：向配液罐中加入适量纯化水及润湿剂，设定搅拌速度为15Hz，搅拌5min，提高搅拌速度为45Hz，在搅拌下加入处方量左旋多巴微粉，加料完成后，继续搅拌30min，得液体1；
S3：向另一配液罐中加入适量纯化水，设定搅拌速度为45Hz，在搅拌下加入助悬加料完成后，继续搅拌30min，设定乳化速度为50Hz，均质乳化100min，在搅拌下加入pH调节剂，继续乳化30min，得液体2；
S4：设定配液罐搅拌速度为50Hz，在搅拌下依次将液体2、抗氧剂溶液、吸收促进剂溶液、抑菌剂溶液和渗透压调节剂溶液加入液体1中，设定配液罐压力为-0.08MPa，开启真空泵，待达到设定压力后，关闭真空泵，搅拌30min至混合均匀后，即得左旋多巴混悬液；
S5：将左旋多巴混悬液灌装至高密度聚乙烯瓶中，在氮气环境下轧盖鼻喷雾泵，即得左旋多巴鼻喷雾剂。
检测左旋多巴鼻喷雾剂API含量、黏度、渗透压、pH、沉降稳定性、喷雾性能等，结果如表16。
表15
表16
结果显示该制剂符合中国药典2020版鼻用制剂项下要求。
2、递送剂量均一性考察
将上述药液灌装至高密度聚乙烯瓶，在氮气环境下轧盖鼻喷雾泵，按FDA指导原则和中国药典2020版要求，检测10瓶同批次样品的递送剂量，结果如表17。
表17
结果表明其10次首喷和末喷(第60喷)的递送剂量分别为标示量的98.44％和98.25％，可稳定递送药物，符合中国药典2020版和FDA指导原则要求。
3、雾滴粒度分布
采用Sympatec激光粒度仪(HELOS&SPRAYERTM)测定左旋多巴鼻喷雾剂在30mm和60mm的喷雾雾滴粒径，镜头为R5，触动压力60N，测量时间为150ms。
鼻喷雾剂的喷雾过程可划分为形成期、稳定期和消散期三个阶段：形成期即喷雾形成阶段，雾滴浓度快速升高，粒径也迅速增大；稳定期时雾滴粒径达到峰值并保持稳定；消散期时雾滴浓度迅速下降，粒径波动巨大。据图4-图5所示，左旋多巴鼻喷雾剂的稳定期为20％～50％，因此以此为左旋多巴鼻喷雾剂的稳定阶段，采用三阶段法检测鼻喷雾剂的稳定期雾滴粒径。
4、稳定期雾滴粒径
采用Sympatec激光粒度仪(HELOS&SPRAYERTM)测定左旋多巴鼻喷雾剂在30mm和60mm的稳定期雾滴粒径，镜头为R5，触动压力60N，稳定期为20％～50％，结果如表18。
表18
结果显示，在30mm和60mm的距离下，本制剂的瓶内和瓶间喷雾粒径较为稳定。
5、微细雾滴量
采用新一代药用圆盘撞击器(NGI)考察鼻喷雾剂的微细雾滴载药含量，气流流速为15L/min，玻璃膨胀室容积为5L，进样量为4揿，每揿间隔时间5s，设置3.5℃预 冷90min；结果如表19所示。
表19
结果显示，左旋多巴鼻喷雾剂每揿小于10μm雾滴的含药量极低，小于标示量的0.1％，符合FDA指导原则要求。
实施例6体内药动学行为考察
1、对左旋多巴鼻喷雾剂经鼻给药、市售制剂经口给药和左旋多巴吸入粉雾剂经口吸入给药三种给药途径给药后的药动学行为进行研究，考察给药后左旋多巴在血浆中的吸收与代谢行为。自制左旋多巴吸入粉雾剂的制备方法如下：
a)处方设计如表20：
表20自制左旋多巴吸入粉雾剂
b)制备
采用层层叠加法分3次加入左旋多巴微粉，在离心管中加入4.4g乳糖ML001，加入0.6g的微粉化API混合均匀，然后依次加入乳糖ML0011.2g，微粉化API 0.7g混 合，乳糖MLO1 1.2g,微粉化API 0.7g混合，乳糖ML001 1.2g后手动混合20min，即得到左旋多巴吸入粉雾剂。
雄性SD大鼠(180-220g)，饲养于SPF环境中，自由进食和饮水，实验前禁食12h，将15只大鼠随机分为5组，每组3只，分别给予左旋多巴片(25mg/kg)、美多芭片(20mg/kg)、自制左旋多巴吸入粉雾剂(10mg/kg)、自制左旋多巴鼻喷雾剂(5mg/kg)和自制左旋多巴鼻喷雾剂(10mg/kg)。在给药后2min、5min、10min、15min、30min、1h、2h、4h、6h时间点进行持续眼眶取血，检测血浆中左旋多巴和多巴胺含量，药动学参数计算结果如表21和表22；
表21大鼠血浆左旋多巴含量
表22大鼠血浆多巴胺含量
结果表明，各组大鼠给药后血浆中左旋多巴和多巴胺浓度随时间变化曲线和药动学参数如下，在1/5给药剂量下，鼻喷雾剂(10mg/kg)鼻腔给药后左旋多巴在血浆中的AUC0-6h远高于左旋多巴片组。左旋多巴鼻喷雾剂的血浆左旋多巴浓度和给药剂量呈线性关系，血浆中左旋多巴的Cmax和AUC随给药剂量增大而升高。
此外，左旋多巴鼻喷雾剂经鼻给药后，血浆中多巴胺的含量与美多芭片相近，远低 于左旋多巴片组，安全性更高，有望降低左旋多巴给药后的副反应。
2、对左旋多巴鼻喷雾剂经鼻给药、市售制剂经口给药两种给药途径给药后的组织分布进行研究，考察给药后左旋多巴在脑组织中的吸收与代谢行为。
雄性SD大鼠(180-220g)，饲养于SPF环境中，自由进食和饮水，实验前禁食12h，将15只大鼠随机分为5组，每组3只，分别给予左旋多巴片(25mg/kg)、美多芭片(20mg/kg)、自制左旋多巴鼻喷雾剂(5mg/kg)和自制左旋多巴鼻喷雾剂(10mg/kg)。在给药后2min、5min、10min、15min、30min、1h、2h、4h、6h时间点处死大鼠，完整剥离脑组织，按脑组织：匀浆液＝1:4的比例加入匀浆液在冰浴下匀浆，检测脑组织匀浆中左旋多巴和多巴胺含量，药动学参数计算结果如表23-24所示；
表23大鼠脑组织多巴胺含量(已扣除基底)(n＝3)
表24大鼠脑组织左旋多巴含量(n＝3)
结果显示，左旋多巴鼻喷雾剂经鼻给药后，快速吸收，进入脑内，其达峰时间为10-15min，快于美多芭口服给药组(Tmax＝60min)，且在1/2给药剂量下，起效药物(多巴胺)的AUC0-6h与美多芭片组相近，有望在1/2剂量下，达到同等疗效，可降低左旋多 巴的给药剂量，提高安全性。
此外，左旋多巴鼻喷雾剂给药后，在1/5给药剂量下，其脑内多巴胺的AUC0-6h远高于左旋多巴片组，有效性显著提高。
实施例7 DDM体内促吸收作用研究体内药动学行为考察
对有无十二烷基-β-D-麦芽糖苷(DDM)的左旋多巴鼻喷雾剂进行药动学研究，评价DDM对药物的吸收促进作用。
其中鼻喷雾剂(无DDM)的处方设计如表25，
表25无DDM左旋多巴鼻喷雾剂处方设计
按上表处方制备无DDM左旋多巴鼻喷雾剂，制备方法同具体实施方式中左旋多巴鼻喷雾剂的制备方法。
实验动物和给药方式同上，结果如表26-表29所示；
表26大鼠脑组织多巴胺含量(扣除基底)(n＝3)

表27大鼠脑组织左旋多巴含量(n＝3)
表28大鼠血浆左旋多巴含量
表29大鼠血浆多巴胺含量
结果显示，DDM(十二烷基-β-D-麦芽糖苷)的添加，显著促进了左旋多巴的吸收， 将左旋多巴的血浆达峰时间从120min提高至15min，将脑内多巴胺的AUC0-6h从3875ng/mL·min提高至14189ng/mL·min。
上述具体实施方式对本发明作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。
实施例8多巴丝肼鼻喷雾剂
1.多巴丝肼鼻喷雾剂的制备
多巴丝肼鼻喷雾剂中各组分的比例范围如表30所示：
表30多巴丝肼鼻喷雾剂处方组成
采用表31所示处方制备多巴丝肼鼻喷雾剂进行后续实验：
表31优选多巴丝肼鼻喷雾剂处方组成

具体制备步骤如下：
S1：通过气流粉碎机对左旋多巴、苄丝肼原料药进行粉碎，粉碎压力为7bar，进料压力为8bar，进料速度为56g/min，得左旋多巴及苄丝肼微粉，d90为2-20μm；
S2：向配液罐中加入适量纯化水及润湿剂，设定搅拌速度为15Hz，搅拌5min，提高搅拌速度为45Hz，在搅拌下加入处方量左旋多巴微粉、苄丝肼微粉，加料完成后，继续搅拌30min，得液体1；
S3：向另一配液罐中加入适量纯化水，设定搅拌速度为45Hz，在搅拌下加入助悬加料完成后，继续搅拌30min，设定乳化速度为50Hz，均质乳化100min，在搅拌下加入pH调节剂，继续乳化30min，得液体2；
S4：设定配液罐搅拌速度为50Hz，在搅拌下依次液体2、抗氧剂溶液、吸收促进剂溶液和抑菌剂溶液加入液体1中，设定配液罐压力为-0.08MPa，开启真空泵，待达到设定压力后，关闭真空泵，搅拌30min至混合均匀后，即得多巴丝肼混悬液；
S5：将多巴丝肼混悬液灌装至高密度聚乙烯瓶中，在氮气环境下轧盖鼻喷雾泵，即得多巴丝肼鼻喷雾剂。
2.多巴丝肼鼻喷雾剂的体外评价
1)检测制得多巴丝肼鼻喷雾剂的含量、考察黏度、渗透压、pH、沉降稳定性、喷雾性能等，结果如表32所示。
表32多巴丝肼鼻喷雾剂质量评价

结果显示该制剂符合中国药典2020版鼻用制剂项下要求。
2)递送剂量均一性考察
按FDA指导原则和中国药典2020版要求，对左旋多巴+苄丝肼复方鼻喷雾剂进行递送剂量均一性考察，检测10瓶同批次样品的递送剂量，结果如表33-34；
表33多巴丝肼鼻喷雾剂中左旋多巴检测量
表34多巴丝肼鼻喷雾剂每喷苄丝肼含量

结果表明其10次首喷和末喷(第60喷)的递送剂量分别为标示量的98.23％和98.48％，可稳定递送药物，符合中国药典2020版和FDA指导原则要求。
3.多巴丝肼鼻喷雾剂的药代动力学研究
对无十二烷基-β-D-麦芽糖苷(DDM)的多巴丝肼鼻喷雾剂进行药动学研究，评价多巴丝肼鼻喷雾剂的脑内递送性能及DDM对药物的吸收促进作用。
其中鼻喷雾剂(无DDM)的处方设计如表35。
表35无DDM多巴丝肼鼻喷雾剂处方设计
按上表处方制备无DDM多巴丝肼鼻喷雾剂，制备方法同具体实施方式中多巴丝肼混悬鼻喷雾剂的制备方法。
2)对多巴丝肼鼻喷雾剂和无DDM多巴丝肼鼻喷雾剂经鼻给药后的组织分布进行研究，考察给药后多巴丝肼在脑组织中的吸收与代谢行为。
雄性SD大鼠(180-220g)，饲养于SPF环境中，自由进食和饮水，实验前禁食12h，将15只大鼠随机分为2组，每组3只，分别给予自制多巴丝肼鼻喷雾剂(20mg/kg)和自制无DDM多巴丝肼鼻喷雾剂(20mg/kg)。在给药后2min、5min、10min、15min、30min、1h、2h、4h、6h时间点处死大鼠，完整剥离脑组织，按脑组织：匀浆液＝1:4的比例加入匀浆液在冰浴下匀浆，检测脑组织匀浆中胺含量，药动学参数计算结果如图6和表36所示；
表36大鼠脑组织左旋多巴含量(n＝3)
结果显示，DDM(十二烷基-β-D-麦芽糖苷)的添加，显著促进了左旋多巴的吸收，将左旋多巴的达峰浓度从209ng/mL提高至227ng/mL，将脑内左旋多巴的AUC0-6h从45462ng/mL·min提高至50464ng/mL·min。

Claims (10)

  1. 一种药物组合物，包括药物、吸收促进剂；所述药物为左旋多巴和/或苄丝肼和/或卡比多巴或其药学上可接受的盐；
    所述吸收促进剂为十二烷基-β-D-麦芽糖苷、十四烷基-β-D-麦芽糖苷、壳聚糖、蔗糖十二烷酸酯、羧甲基壳聚糖、牛黄胆酸钠中的至少一种。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包括助悬剂、抗氧剂、润湿剂、抑菌剂中的至少一种。
  3. 根据权利要求2所述的药物组合物，其特征在于，所述助悬剂为微晶纤维素-羧甲基纤维素钠、卡波姆中的至少一种；
    优选地，所述抗氧剂为抗坏血酸、抗坏血酸棕榈酸酯、焦亚硫酸钠中的至少一种；
    优选地，所述润湿剂可为聚山梨酯、泊洛沙姆中的至少一种；
    优选地，所述抑菌剂为苯扎氯铵、苯扎溴铵、季铵盐类、西曲溴铵、苯氧乙醇、苯甲酸钠、苯乙醇中的至少一种。
  4. 根据权利要求2所述的药物组合物，其特征在于，所述药物组合物包括：0.5％～20％w/w的药物、1％～3％w/w的助悬剂；0.1％～3％w/w的抗氧剂：0.1％～0.5％w/w的吸收促进剂；0.01％～0.03％w/w的润湿剂；0.01％～0.024％w/w的抑菌剂；
    优选地，所述药物组合物包括：1％～15％w/w的药物、1.2％～2％w/w的助悬剂；
    0.2％～1％w/w的抗氧剂：0.1％～0.3％w/w的吸收促进剂；0.01％～0.03％w/w的润湿剂；0.015％～0.02％w/w的抑菌剂。
  5. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包括pH调节剂，用于调节药物组合物pH为5.0～6.5；优选地，所述药物组合物还包括渗透压调节剂，用于调节药物组合物渗透压为270～350mOsm/kg；优选地，所述药物组合物还包括水。
  6. 根据权利要求1所述的药物组合物，其特征在于，所述药物为药物微粉；优选地，所述药物微粉的粒径D90为2～20μm。
  7. 根据权利要求1～6任一项所述的药物组合物，其特征在于，所述药物组合物的剂型为喷雾剂；优选地，所述药物组合物的给药方式为经鼻给药。
  8. 权利要求7所述的药物组合物的制备方法，包括以下步骤：
    S1：润湿剂加入水中，加入药物，混合至分散均匀后得液体1；
    S2：将助悬剂加入适量水中，混合至分散均匀后均质乳化，加入pH调节剂，得液体2；
    S3：将液体2、抗氧剂、吸收促进剂、抑菌剂、渗透压调节剂加入液体1中，搅拌至混合均匀，即得药物组合物；
    优选地，所述方法还包括将药物组合物灌装至鼻喷雾瓶装置中，即得鼻喷雾剂。
  9. 权利要求1～7任一项所述药物组合物在制备帕金森药物中的应用。
  10. 十二烷基-β-D-麦芽糖苷在制备左旋多巴和/或苄丝肼和/或卡比多巴鼻喷雾剂中的应用。
PCT/CN2024/130102 2023-11-09 2024-11-06 一种左旋多巴鼻喷雾剂及其制备方法及应用 Pending WO2025098365A1 (zh)

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