WO2024001587A1 - Levodopa composition microparticles for intranasal delivery, preparation method therefor and use thereof - Google Patents

Levodopa composition microparticles for intranasal delivery, preparation method therefor and use thereof Download PDF

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Publication number
WO2024001587A1
WO2024001587A1 PCT/CN2023/094671 CN2023094671W WO2024001587A1 WO 2024001587 A1 WO2024001587 A1 WO 2024001587A1 CN 2023094671 W CN2023094671 W CN 2023094671W WO 2024001587 A1 WO2024001587 A1 WO 2024001587A1
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levodopa
preparation
atomizer
microparticles
droplets
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PCT/CN2023/094671
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French (fr)
Chinese (zh)
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吴铎
严珅
刘旋
张盛宇
尹全义
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苏州大学
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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 present invention relates to the technical field of pharmaceutical preparations, and in particular to a levodopa composition microparticle for nasal delivery and its preparation method and application.
  • brain diseases such as Parkinson's disease, Alzheimer's disease, and brain tumors
  • brain diseases have brought major challenges to the life and health of our people.
  • the low efficiency of drug targeting to the brain is a key bottleneck. This is mainly related to the existence of the physiological structure of the human blood-brain barrier, which prevents almost all macromolecule drugs and 95% of small molecule drugs from entering the brain, significantly reducing the number of drugs. Bioavailability in the brain, thus affecting the treatment of brain diseases such as Parkinson's disease.
  • Levodopa is a white or off-white crystalline powder that is odorless and tasteless. It is a small molecule drug and has no pharmacological activity. It is converted into dopamine under the action of dopa decarboxylase and exerts pharmacological effects. It can cross the blood-brain barrier. , is used as the gold standard for the treatment of Parkinson's disease.
  • the levodopa molecule has a bisphenol structure and is unstable in nature. It is easily oxidized and deteriorates, and it oxidizes and darkens rapidly in the presence of moisture. Therefore, its liquid dosage form has poor storage stability.
  • levodopa/carbidopa tablets are mainly available on the market. They are absorbed through the gastrointestinal tract and enter the systemic blood circulation. They further pass through the blood-brain barrier and reach the brain to exert therapeutic effects. Parkinson's patients take levodopa tablets orally for a long time. It will lead to a decrease in treatment response, such as an off period (OFF period) of at least 2 hours per day, which is the drug ineffective period. At this time, the patient needs to receive other administration methods as auxiliary treatment.
  • Nasal administration is simple and convenient because of its rapid drug absorption, rapid onset of action, and no liver first-pass effect. The drug can be absorbed through the nasal mucosa in the olfactory area and directly and quickly delivered to the brain. It has attracted widespread attention by bypassing the blood-brain barrier to achieve efficient treatment of central nervous system diseases.
  • the complex geometry of the nasal cavity hinders drug delivery to the target area.
  • the clearance mechanism of cilia in the nasal cavity makes the residence time of particles short, and the tightly connected nasal mucosa limits the permeability of drugs.
  • the main preparation methods of levodopa microparticles for nasal delivery include dry grinding, spray drying, double emulsification method, ion gel method, etc. These traditional processes often produce polydisperse particles with a wide distribution of properties in the same batch of production, with poor repeatability and low yields.
  • the technical problem to be solved by the present invention is to provide a levodopa composition microparticle for nasal delivery.
  • the microparticles provided by the present invention have high nasal cavity delivery and deposition efficiency.
  • the present invention provides a method for preparing levodopa composition microparticles for nasal delivery, including:
  • the precursor liquid is atomized using an atomizer to obtain droplets; the size of the droplets is 30 to 300 ⁇ m;
  • the auxiliary material in step A) is one of hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl- ⁇ -cyclodextrin.
  • the mass ratio of levodopa and excipients is 9:1 to 1:9.
  • the total mass concentration of levodopa and excipients in the precursor liquid of step A) is 0.1% to 5%.
  • step B) is selected from a pressure atomizer, a two-fluid atomizer, an ultrasonic atomizer and a microfluidic atomizer, and the initial droplet size is adjusted to 30-300 ⁇ m.
  • the spray drying parameters in step C) are:
  • the tower inlet temperature is 120 ⁇ 230°C, and the outlet temperature is 60 ⁇ 100°C.
  • the aerodynamic particle size of the particles is 10 ⁇ m to 35 ⁇ m, and the deposition rate in the olfactory area is greater than 10%.
  • the present invention provides levodopa composition particles for nasal delivery, which are prepared by the preparation method described in any of the above technical solutions.
  • the invention provides a levodopa group prepared by any one of the above preparation methods.
  • the present invention provides a nasal delivery product, including the levodopa composition particles described in the above technical solution.
  • the present invention provides a method for preparing levodopa composition particles for nasal delivery, which includes: A) dissolving levodopa and auxiliary materials to obtain a precursor liquid; B) atomizing the precursor liquid The liquid droplets are atomized to obtain liquid droplets; the size of the liquid droplets is 30 to 300 ⁇ m; C) the liquid droplets are spray-dried to obtain microparticles.
  • the present invention uses one of hydroxypropyl methylcellulose, polyvinylpyrrolidone and hydroxypropyl- ⁇ -cyclodextrin as an auxiliary material, uniformly mixes it with the drug in different proportions to prepare a precursor liquid, and obtains the size through spray drying technology.
  • Controllable, performance-adjustable levodopa composition particles the aerodynamic particle size of the particles is 10 ⁇ m to 35 ⁇ m, and has high nasal delivery and deposition efficiency.
  • the drug can be evenly dispersed in the carrier matrix in an amorphous form, Significantly improve the dissolution/release behavior of poorly water-soluble drugs in the nasal cavity, and maintain the long-term storage stability of the drug, solving the problem that the liquid dosage form of levodopa is unstable and susceptible to interference by factors such as light, heat, oxygen, moisture, etc. and loses its biological activity.
  • Technical bottleneck the aerodynamic particle size of the particles is 10 ⁇ m to 35 ⁇ m, and has high nasal delivery and deposition efficiency.
  • the drug can be evenly dispersed in the carrier matrix in an amorphous form, Significantly improve the dissolution/release behavior of poorly water-soluble drugs in the nasal cavity, and maintain the long-term storage stability of the drug, solving the problem that the liquid dosage form of levodopa is unstable and susceptible to interference by factors
  • Figure 1 is a scanning electron microscope image of spray-dried levodopa microparticle samples prepared from commercial levodopa API and different excipient types and excipient ratios;
  • Figure 2 shows the X-ray powder diffraction pattern and differential scanning calorimetry of spray-dried levodopa particulate samples prepared from commercial levodopa API and different excipient types and excipient ratios;
  • Figure 3 is a scanning electron microscope image of a spray-dried levodopa composition particle sample after storage for 1 day, 1 week and 1 month respectively;
  • Figure 4 is the X-ray powder diffraction pattern of spray-dried levodopa composition particulate samples after storage for 1 day, 1 week and 1 month respectively;
  • Figure 5 shows the adhesion force-distance curve of spray-dried levodopa microparticle samples prepared from commercial levodopa API and different excipient types and excipient ratios, and the adhesion force histogram of different samples;
  • Figure 6 shows the in vitro release curve of spray-dried levodopa microparticle samples prepared from commercial levodopa API and different excipient types and excipient ratios.
  • all spray-dried microparticles containing excipients can significantly increase the release rate of levodopa, reflecting the advantages of spray-drying amorphous solid dispersions in the presence of excipients;
  • Figure 7 is a graph showing the regional deposition fraction of the spray-dried levodopa particulate sample in each part of the nasal cast. It can be seen from the figure that samples with aerodynamic particle sizes in the range of 10 ⁇ m to 35 ⁇ m have a deposition rate of more than 10% in the olfactory region and have high nasal cavity delivery and deposition efficiency.
  • the present invention provides a levodopa composition microparticle for nasal delivery, its preparation method and application.
  • Persons skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it. It should be pointed out in particular that all similar substitutions and modifications are obvious to those skilled in the art, and they all fall within the protection scope of the present invention.
  • the methods and applications of the present invention have been described through preferred embodiments. Relevant persons can obviously modify or appropriately change and combine the methods and applications herein without departing from the content, spirit and scope of the present invention to implement and apply the present invention.
  • Invent technology is embodiedopa composition microparticle for nasal delivery, its preparation method and application.
  • the present invention provides a method for preparing levodopa composition microparticles for nasal delivery, including:
  • the precursor liquid is atomized using an atomizer to obtain droplets; the size of the droplets is 30 to 300 ⁇ m;
  • the preparation method of levodopa composition microparticles for nasal delivery provided by the present invention firstly dissolves levodopa and auxiliary materials to obtain a precursor liquid.
  • the auxiliary material of the present invention is one of hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl- ⁇ -cyclodextrin.
  • the present invention does not limit the dissolution, and it is preferably magnetic at 35°C to 40°C. Just stir to dissolve; the present invention does not limit the specific stirring speed, which can be 500 to 700 rpm.
  • the mass ratio of levodopa and excipients is preferably 9:1-1:9; more preferably 8:2-2:8; most preferably 7:3-3:7; including but Not limited to 1:1, 1:2, 2:1.
  • the total mass concentration of levodopa and excipients is preferably 0.1% to 5%; more preferably 0.2% to 4%; most preferably 0.3% to 3%.
  • the precursor liquid is atomized using an atomizer to obtain droplets.
  • the atomization in the present invention is preferably carried out in an atomizer.
  • the present invention does not limit the above-mentioned specific atomizer. It can be homemade in this laboratory, such as application number 201410677942.3; it can be commercially available.
  • the atomizer of the present invention is selected from a pressure atomizer, a two-fluid atomizer, an ultrasonic atomizer or a microfluidic atomizer, and the initial droplet size is controlled to be 30 to 300 ⁇ m.
  • the liquid storage tank is connected to the atomizer through a conduit to atomize the precursor liquid into fine uniform droplets.
  • the size of the liquid droplets prepared by the present invention is preferably 30-300 ⁇ m; more preferably, it is 35-280 ⁇ m.
  • the present invention interacts with each other through the mass ratio of the above-mentioned levodopa and auxiliary materials, the total mass concentration range of levodopa and auxiliary materials, and the parameters of atomization.
  • the above-mentioned components interact, functionally support each other, and have mutually related technical features.
  • the above-mentioned whole Only with this solution can particles with controllable size within a specific range be prepared, and the technical effects of the present invention be achieved.
  • the droplets are spray dried to obtain particles.
  • the spray drying parameters are: the tower inlet temperature is 120-230°C, and the outlet temperature is 60-100°C; more preferably, the tower inlet temperature is 130-220°C, and the outlet temperature is 65-95°C.
  • the aerodynamic particle size of the particles of the present invention is 10 ⁇ m to 35 ⁇ m, and the deposition rate in the olfactory area is greater than 10%.
  • the drug release rate of the microparticles of the present invention can reach 80% in 60 minutes.
  • the present invention uses the above-mentioned specific spray drying parameters such as the settings of the tower inlet temperature and outlet temperature, combined with the above-mentioned atomization parameters, the above-mentioned mutually related technical features, and the above-mentioned overall scheme to prepare levodopa within a specific range.
  • the particle size of the composition is controllable and the shape is regular. It is a solid raisin-like particle with a smooth surface.
  • the particle size range meets the actual needs for delivery to the olfactory area of the nasal cavity.
  • the present invention provides levodopa composition particles for nasal delivery, which are prepared by the preparation method described in any of the above technical solutions.
  • the present invention has a clear description of the above preparation method, which will not be described in detail here.
  • the invention provides a levodopa group prepared by any one of the above preparation methods.
  • microparticles prepared by the above method of the present invention can be used to prepare nasal delivery products, including but not limited to nasal delivery drugs.
  • nasal delivery products including but not limited to nasal delivery drugs.
  • the inventor does not limit this.
  • the present invention provides a nasal delivery product, including the levodopa composition particles described in the above technical solution.
  • the above-mentioned nasal delivery product provided by the present invention includes the above-mentioned levodopa composition microparticles. It may also include pharmaceutically acceptable ingredients, which are not limited here.
  • the present invention uses one of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl- ⁇ -cyclodextrin as an auxiliary material, and uniformly mixes it with the drug in different proportions to prepare a precursor liquid, which is processed by microfluidic spray drying technology. After treatment, the aerodynamic particle size of the microparticles is 10 ⁇ m ⁇ 35 ⁇ m, which has high nasal delivery and deposition efficiency.
  • the drug can be evenly dispersed in the carrier matrix in an amorphous form. The data shows that the prepared amorphous solid dispersion can Significantly improve the dissolution/release behavior of poorly water-soluble drugs. It also maintains the long-term storage stability of the drug, and solves the technical problem that the levodopa solution dosage form is unstable and susceptible to interference by factors such as light, heat, oxygen, moisture, etc. and thus loses drug activity.
  • the present invention adopts microfluidic spray drying technology and controls the size, morphology, density and other powder properties of dried levodopa particles by regulating the precursor liquid formula, spray drying temperature, feed pressure and other process parameters.
  • This method is simple to operate, low in cost, fast and highly reproducible. It can prepare levodopa composition particles of different sizes, morphologies and densities (see Table 1) according to the actual needs suitable for nasal delivery of particles, and can be prepared with other particles. Compared with technology, it has obvious advantages.
  • the levodopa composition microparticles for nasal delivery provided by the present invention, its preparation method and application are described in detail below in conjunction with the examples.
  • levodopa was dissolved in 397.6g deionized water, magnetically stirred at 40°C until completely dissolved, the stirring speed was 600rpm, and then filtered through a 0.22 ⁇ m syringe filter to obtain a mass fraction of 0.6% and a mass ratio of 1: 1. 1:2, 2:1 mixed solutions of levodopa/hydroxypropyl methylcellulose, levodopa/polyvinylpyrrolidone, and levodopa/hydroxypropyl- ⁇ -cyclodextrin.
  • step (2) Combine the pure levodopa, levodopa/hydroxypropyl methylcellulose, levodopa/polyvinylpyrrolidone, and levodopa/hydroxypropyl- ⁇ -cyclodextrin prepared in step (1) Pour the precursor liquid into the liquid storage tank, connect it to the microfluidic atomizer through a catheter, and atomize the precursor liquid into fine uniform droplets through the atomizer with a hole diameter of 75 ⁇ m.
  • the atomization pressure is 0.3kg/cm 3 .
  • the operating vibration frequency of the device is 8000Hz and the amplitude is 15Vpp.
  • the size-controllable particles obtained by spray drying the droplets in step (2) have a tower inlet temperature of 186°C, an outlet temperature of 67°C, and a hot air flow setting range of 280L/min.
  • a laboratory-level microfluidic spray drying tower uses a 75 ⁇ m microfluidic atomizer to prepare levodopa composition particles, whose physical and chemical properties are shown in Table 1.
  • the pure levodopa particles prepared by the present invention are spherical particles with a smooth surface.
  • the prepared levodopa composition particles After adding excipients and co-spraying with levodopa, the prepared levodopa composition particles have controllable size, regular morphology and smooth surface.
  • the raisin-shaped solid particles ( Figure 1) have a particle size range that meets the actual needs for delivery to the nasal olfactory area.
  • the degree of crystallization of pure levodopa spray-dried particles is low.
  • the differential scanning calorimeter diagram shows that the sample has a recrystallization peak and is very unstable. After one day of storage, obvious crystalline materials appear on the surface of the particles, indicating that recrystallization occurs.
  • Test method First calibrate the probe to calculate the elastic coefficient, and then add 10 ⁇ L of pre-prepared simulated nasal mucus (also known as mucin solution, containing 95% water, 2% mucin, and 3% sodium chloride ) in the slide, use the contact mode to make the probe contact the mucin solution and lift it up quickly, and then continue to lower the needle to connect the tip of the probe with the mucin solution and the tip fixed on the slide with double-sided tape. The particles are lifted after contact, and the force curve is obtained using the AFM platform testing software. The measured force curve can then be analyzed through the NanoScopeAnalysis 1.7 software and the adhesion force value can be calculated.
  • the probe used during the experiment was Si 3 N 4 (tip diameter ⁇ 10nm), the scanning rate was 0.977Hz, and the scanning depth was 20nm.
  • Example 1 Select the levodopa composition particle sample prepared in the above Example 1, and evaluate the levodopa composition through a Franz diffusion cell device (inner diameter 12mm, receptor chamber volume 15mL, TP-6P, Tianjin Pharmacopoeia Standard Instrument Factory, China) combined with simulated nasal fluid.
  • the simulated nasal fluid is prepared by dissolving 7.45g sodium chloride, 1.29g potassium chloride and 0.32g calcium chloride dihydrate in 1000mL deionized water.
  • Test method The receptor chamber of the diffusion cell is filled with simulated nasal fluid and maintained at 34°C through a water bath to simulate the nasal cavity environment. The sink conditions are maintained throughout the experiment.
  • the receptor medium is magnetically stirred to ensure that levodopa well mixed.
  • the levodopa composition microparticle sample prepared in the above Example 1 was selected, and the powder was studied by independently developing a 3D printed nose cast based on the CT scan of the adult male nose, combined with the Bi-Directional TM nasal powder delivery device developed by OptiNose Company. Deposition behavior of body preparations in various parts of the nasal cavity. During the experiment, it was first coated with a methanol solution of 1% v/v Tween 20. After the methanol evaporated, a Tween 20 film was formed to cover the inner wall of the 3D printed nose mold to prevent particles from colliding and bouncing; an appropriate amount was weighed in advance The capsule of the medicinal powder is placed in the drug delivery device.
  • the drug delivery device is inserted into the nose to a depth of 5mm and the drug delivery angle is 60°. Keep the 3D printed nose cast horizontally and use a ventilator to pass the Bi-Directional TM nasal powder drug delivery device in 3 seconds.
  • the airflow carries particles from one side of the nasal cavity into the other side of the nasal cavity; after the experiment, disassemble the nose cast, place each part in a beaker, and wash with water.
  • ultrasound, and collection; then UV spectrophotometry was used to quantify the levodopa drug content at ⁇ 280 nm to clarify the deposition amount of each part.
  • the drug content in the capsule before and after the experiment was quantified to determine the delivery dose, and the deposition efficiency of each part was converted. As well as capsule powder emptying rate, all tests were repeated three times.

Abstract

A preparation method for levodopa composition microparticles for intranasal delivery, comprising: A) dissolving levodopa and an excipient to obtain a precursor liquid; B) atomizing the precursor liquid using an atomizer to obtain droplets, wherein the size of the droplets is 30-300 μm; and C) subjecting the droplets to spray drying to obtain microparticles. One of hydroxypropyl methylcellulose, polyvinylpyrrolidone and hydroxypropyl-β-cyclodextrin is used as the excipient and uniformly mixed with the drug in varying proportions to prepare the precursor liquid. The spray drying technique is used to prepare levodopa composition microparticles with controllable size and adjustable properties. The aerodynamic particle size of the microparticles is 10 μm-35 μm, which ensures high intranasal delivery and deposition efficiency. In addition, the drug can be uniformly dispersed in an amorphous form into a carrier matrix, so that the dissolution/release behavior of the poorly water-soluble drug in the nasal cavity is significantly improved, and the long-term storage stability of the drug is maintained.

Description

一种用于鼻腔递送的左旋多巴组合物微粒及其制备方法和应用Levodopa composition microparticles for nasal delivery and preparation method and application thereof
本申请要求于2022年06月29日提交中国专利局、申请号为202210750856.5、发明名称为“一种用于鼻腔递送的左旋多巴组合物微粒及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application requires priority for the Chinese patent application submitted to the China Patent Office on June 29, 2022, with the application number 202210750856.5 and the invention title "A levodopa composition microparticle for nasal delivery and its preparation method and application" rights, the entire contents of which are incorporated herein by reference.
技术领域Technical field
本发明涉及药物制剂技术领域，尤其是涉及一种用于鼻腔递送的左旋多巴组合物微粒及其制备方法和应用。The present invention relates to the technical field of pharmaceutical preparations, and in particular to a levodopa composition microparticle for nasal delivery and its preparation method and application.
背景技术Background technique
随着人口老龄化，脑部疾病，如帕金森、阿尔兹海默症、脑肿瘤等给我国人民的生命健康带来重大挑战，据统计，2020年我国已有300万帕金森患者，且每年以10万人数逐年递增，但仍缺少优效的临床药物。其中药物脑靶向效率低是关键瓶颈，这主要与人体血脑屏障这一生理结构的存在密切相关，它阻止了几乎所有的大分子药物以及95％的小分子药物进入脑部，显著降低药物在脑部的生物利用度，从而影响了对如帕金森等脑部疾病的治疗。With the aging of the population, brain diseases, such as Parkinson's disease, Alzheimer's disease, and brain tumors, have brought major challenges to the life and health of our people. According to statistics, there will be 3 million Parkinson's patients in my country in 2020, and every year The number of people is increasing year by year to 100,000, but there is still a lack of effective clinical drugs. Among them, the low efficiency of drug targeting to the brain is a key bottleneck. This is mainly related to the existence of the physiological structure of the human blood-brain barrier, which prevents almost all macromolecule drugs and 95% of small molecule drugs from entering the brain, significantly reducing the number of drugs. Bioavailability in the brain, thus affecting the treatment of brain diseases such as Parkinson's disease.
左旋多巴，为白色或类白色的结晶性粉末，无臭、无味，小分子药物，本身无药理活性，在多巴脱羧酶的作用下转化为多巴胺而发挥药理作用，可穿过血脑屏障，是作为治疗帕金森病的黄金标准，但是左旋多巴分子具有临双酚结构，性质不稳定，极易氧化变质，且在水分存在下迅速氧化与变暗，因此其液体剂型储存稳定性差。Levodopa is a white or off-white crystalline powder that is odorless and tasteless. It is a small molecule drug and has no pharmacological activity. It is converted into dopamine under the action of dopa decarboxylase and exerts pharmacological effects. It can cross the blood-brain barrier. , is used as the gold standard for the treatment of Parkinson's disease. However, the levodopa molecule has a bisphenol structure and is unstable in nature. It is easily oxidized and deteriorates, and it oxidizes and darkens rapidly in the presence of moisture. Therefore, its liquid dosage form has poor storage stability.
目前市场上主要以左旋多巴/卡比多巴的片剂为主，经肠胃吸收进入全身血液循环，进一步穿过血脑屏障到达脑部而发挥疗效，帕金森患者长期口服左旋多巴片剂会导致治疗反应的下降，比如出现每天至少2h的关闭期(OFF期)，即药物无效期，此时患者需要接受其它给药方式作为辅助性治疗。而鼻腔给药由于其给药简单方便，药物吸收迅速，起效快，无肝脏首过效应，药物能够通过嗅区的鼻粘膜吸收，直接快速递送至大脑， 绕过血脑屏障，从而实现高效治疗中枢神经系统疾病而受到广泛关注。Currently, levodopa/carbidopa tablets are mainly available on the market. They are absorbed through the gastrointestinal tract and enter the systemic blood circulation. They further pass through the blood-brain barrier and reach the brain to exert therapeutic effects. Parkinson's patients take levodopa tablets orally for a long time. It will lead to a decrease in treatment response, such as an off period (OFF period) of at least 2 hours per day, which is the drug ineffective period. At this time, the patient needs to receive other administration methods as auxiliary treatment. Nasal administration is simple and convenient because of its rapid drug absorption, rapid onset of action, and no liver first-pass effect. The drug can be absorbed through the nasal mucosa in the olfactory area and directly and quickly delivered to the brain. It has attracted widespread attention by bypassing the blood-brain barrier to achieve efficient treatment of central nervous system diseases.
然而鼻腔复杂的几何形状阻碍了药物递送至靶向区域，鼻腔内纤毛的清除机制使得粒子的停留时间短，紧密连接的鼻粘膜限制了药物的渗透性。目前，鼻腔递送左旋多巴微粒主要的制备方法有干法研磨、喷雾干燥、双乳化法、离子凝胶法等。这些传统工艺在同一批生产中往往会产生性能分布广泛的多分散颗粒，且重复性差，产率低。However, the complex geometry of the nasal cavity hinders drug delivery to the target area. The clearance mechanism of cilia in the nasal cavity makes the residence time of particles short, and the tightly connected nasal mucosa limits the permeability of drugs. At present, the main preparation methods of levodopa microparticles for nasal delivery include dry grinding, spray drying, double emulsification method, ion gel method, etc. These traditional processes often produce polydisperse particles with a wide distribution of properties in the same batch of production, with poor repeatability and low yields.
发明内容Contents of the invention
有鉴于此，本发明要解决的技术问题在于提供一种用于鼻腔递送的左旋多巴组合物微粒，本发明提供的微粒具有高鼻腔递送和沉积效率。In view of this, the technical problem to be solved by the present invention is to provide a levodopa composition microparticle for nasal delivery. The microparticles provided by the present invention have high nasal cavity delivery and deposition efficiency.
本发明提供了一种用于鼻腔递送的左旋多巴组合物微粒的制备方法，包括：The present invention provides a method for preparing levodopa composition microparticles for nasal delivery, including:
A)左旋多巴和辅料溶解，得到前驱液；A) Dissolve levodopa and excipients to obtain precursor solution;
B)前驱液采用雾化器雾化，得到液滴；所述液滴的尺寸30～300μm；B) The precursor liquid is atomized using an atomizer to obtain droplets; the size of the droplets is 30 to 300 μm;
C)液滴经喷雾干燥，即得微粒。C) The droplets are spray-dried to obtain particles.
优选的，步骤A)所述辅料为羟丙基甲基纤维素、聚乙烯吡咯烷酮或羟丙基-β-环糊精中的一种。Preferably, the auxiliary material in step A) is one of hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl-β-cyclodextrin.
优选的，步骤A)所述前驱液中，左旋多巴和辅料的质量比为9:1～1:9。Preferably, in the precursor liquid of step A), the mass ratio of levodopa and excipients is 9:1 to 1:9.
优选的，步骤A)所述前驱液中，左旋多巴和辅料的总质量浓度为0.1％～5％。Preferably, the total mass concentration of levodopa and excipients in the precursor liquid of step A) is 0.1% to 5%.
优选的，步骤B)选自压力式雾化器、双流体雾化器、超声雾化器及微流控雾化器，调控初始液滴尺寸为30～300μm。Preferably, step B) is selected from a pressure atomizer, a two-fluid atomizer, an ultrasonic atomizer and a microfluidic atomizer, and the initial droplet size is adjusted to 30-300 μm.
优选的，步骤C)所述喷雾干燥的参数为：Preferably, the spray drying parameters in step C) are:
塔进口温度为120～230℃，出口温度60～100℃。The tower inlet temperature is 120~230℃, and the outlet temperature is 60~100℃.
优选的，所述微粒的空气动力学粒径为10μm～35μm，嗅区沉积率大于10％。Preferably, the aerodynamic particle size of the particles is 10 μm to 35 μm, and the deposition rate in the olfactory area is greater than 10%.
本发明提供了一种用于鼻腔递送的左旋多巴组合物微粒，由上述技术方案任意一项所述的制备方法制备得到。The present invention provides levodopa composition particles for nasal delivery, which are prepared by the preparation method described in any of the above technical solutions.
本发明提供了上述任意一项所述的制备方法制备得到的左旋多巴组 合物微粒在制备鼻腔递送产品中的应用。The invention provides a levodopa group prepared by any one of the above preparation methods. Application of compound microparticles in the preparation of nasal delivery products.
本发明提供了一种鼻腔递送产品，包括上述技术方案所述的左旋多巴组合物微粒。The present invention provides a nasal delivery product, including the levodopa composition particles described in the above technical solution.
与现有技术相比，本发明提供了一种用于鼻腔递送的左旋多巴组合物微粒的制备方法，包括：A)左旋多巴和辅料溶解，得到前驱液；B)前驱液采用雾化器雾化，得到液滴；所述液滴的尺寸30～300μm；C)液滴经喷雾干燥，即得微粒。本发明采用羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟丙基-β-环糊精中的一种作为辅料，与药物以不同比例均匀混合制备成前驱液，通过喷雾干燥技术制得尺寸可控、性能可调的左旋多巴组合物微粒，所述微粒的空气动力学粒径为10μm～35μm，具有高鼻腔递送和沉积效率，此外可将药物以无定形均匀分散在载体基质中，明显改善水溶性差的药物在鼻腔的溶出/释放行为，并保持药物的长期储存稳定性，解决了左旋多巴液体剂型不稳定，易受光、热、氧、水分等因素的干扰而失去生物活性的技术瓶颈。Compared with the existing technology, the present invention provides a method for preparing levodopa composition particles for nasal delivery, which includes: A) dissolving levodopa and auxiliary materials to obtain a precursor liquid; B) atomizing the precursor liquid The liquid droplets are atomized to obtain liquid droplets; the size of the liquid droplets is 30 to 300 μm; C) the liquid droplets are spray-dried to obtain microparticles. The present invention uses one of hydroxypropyl methylcellulose, polyvinylpyrrolidone and hydroxypropyl-β-cyclodextrin as an auxiliary material, uniformly mixes it with the drug in different proportions to prepare a precursor liquid, and obtains the size through spray drying technology. Controllable, performance-adjustable levodopa composition particles, the aerodynamic particle size of the particles is 10 μm to 35 μm, and has high nasal delivery and deposition efficiency. In addition, the drug can be evenly dispersed in the carrier matrix in an amorphous form, Significantly improve the dissolution/release behavior of poorly water-soluble drugs in the nasal cavity, and maintain the long-term storage stability of the drug, solving the problem that the liquid dosage form of levodopa is unstable and susceptible to interference by factors such as light, heat, oxygen, moisture, etc. and loses its biological activity. Technical bottleneck.
附图说明Description of drawings
图1为商用左旋多巴原料药及不同辅料类型及药辅比制备的喷雾干燥左旋多巴微粒样品的扫描电镜图；Figure 1 is a scanning electron microscope image of spray-dried levodopa microparticle samples prepared from commercial levodopa API and different excipient types and excipient ratios;
图2为商用左旋多巴原料药及不同辅料类型及药辅比制备的喷雾干燥左旋多巴微粒样品的X射线粉末衍射图和差式扫描量热图；Figure 2 shows the X-ray powder diffraction pattern and differential scanning calorimetry of spray-dried levodopa particulate samples prepared from commercial levodopa API and different excipient types and excipient ratios;
图3为喷雾干燥左旋多巴组合物微粒样品分别储存1天、1周和1个月后的扫描电镜图；Figure 3 is a scanning electron microscope image of a spray-dried levodopa composition particle sample after storage for 1 day, 1 week and 1 month respectively;
图4为喷雾干燥左旋多巴组合物微粒样品分别储存1天、1周和1个月后的X射线粉末衍射图；Figure 4 is the X-ray powder diffraction pattern of spray-dried levodopa composition particulate samples after storage for 1 day, 1 week and 1 month respectively;
图5为商用左旋多巴原料药及不同辅料类型及药辅比制备的喷雾干燥左旋多巴微粒样品的粘附力-距离曲线图及不同样品的粘附力柱状图；Figure 5 shows the adhesion force-distance curve of spray-dried levodopa microparticle samples prepared from commercial levodopa API and different excipient types and excipient ratios, and the adhesion force histogram of different samples;
图6为商用左旋多巴原料药及不同辅料类型及药辅比制备的喷雾干燥左旋多巴微粒样品的体外释放曲线；由图可知，相比于左旋多巴原料药和纯左旋多巴喷雾干燥微粒，所有含辅料的喷雾干燥微粒均可显著提高左旋多巴释放速率，体现了辅料存在下喷雾干燥无定形固体分散体的优势； Figure 6 shows the in vitro release curve of spray-dried levodopa microparticle samples prepared from commercial levodopa API and different excipient types and excipient ratios. As can be seen from the figure, compared with levodopa API and pure levodopa spray-dried Microparticles, all spray-dried microparticles containing excipients can significantly increase the release rate of levodopa, reflecting the advantages of spray-drying amorphous solid dispersions in the presence of excipients;
图7为喷雾干燥左旋多巴微粒样品在鼻铸形各部分的区域沉积分数图。由图可知，空气动力学粒径处于10μm～35μm范围内的样品，嗅区沉积率大于10％，具有高鼻腔递送和沉积效率。Figure 7 is a graph showing the regional deposition fraction of the spray-dried levodopa particulate sample in each part of the nasal cast. It can be seen from the figure that samples with aerodynamic particle sizes in the range of 10 μm to 35 μm have a deposition rate of more than 10% in the olfactory region and have high nasal cavity delivery and deposition efficiency.
具体实施方式Detailed ways
以下结合具体实施例对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。The principles and features of the present invention are described below with reference to specific embodiments. The examples cited are only used to explain the present invention and are not intended to limit the scope of the present invention.
本发明提供了一种用于鼻腔递送的左旋多巴组合物微粒、其制备方法和应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都属于本发明保护的范围。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。The present invention provides a levodopa composition microparticle for nasal delivery, its preparation method and application. Persons skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it. It should be pointed out in particular that all similar substitutions and modifications are obvious to those skilled in the art, and they all fall within the protection scope of the present invention. The methods and applications of the present invention have been described through preferred embodiments. Relevant persons can obviously modify or appropriately change and combine the methods and applications herein without departing from the content, spirit and scope of the present invention to implement and apply the present invention. Invent technology.
本发明提供了一种用于鼻腔递送的左旋多巴组合物微粒的制备方法，包括：The present invention provides a method for preparing levodopa composition microparticles for nasal delivery, including:
A)左旋多巴和辅料溶解，得到前驱液；A) Dissolve levodopa and excipients to obtain precursor solution;
B)前驱液采用雾化器雾化，得到液滴；所述液滴的尺寸30～300μm；B) The precursor liquid is atomized using an atomizer to obtain droplets; the size of the droplets is 30 to 300 μm;
C)液滴经喷雾干燥，即得微粒。C) The droplets are spray-dried to obtain particles.
本发明提供的用于鼻腔递送的左旋多巴组合物微粒的制备方法首先将左旋多巴和辅料溶解，得到前驱液。The preparation method of levodopa composition microparticles for nasal delivery provided by the present invention firstly dissolves levodopa and auxiliary materials to obtain a precursor liquid.
本发明所述辅料为羟丙基甲基纤维素、聚乙烯吡咯烷酮或羟丙基-β-环糊精中的一种本发明对于所述溶解不进行限定，优选在35℃～40℃下磁力搅拌溶解即可；本发明对于所述具体的搅拌速度不进行限定，可以为500～700rpm。The auxiliary material of the present invention is one of hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl-β-cyclodextrin. The present invention does not limit the dissolution, and it is preferably magnetic at 35°C to 40°C. Just stir to dissolve; the present invention does not limit the specific stirring speed, which can be 500 to 700 rpm.
本发明所述前驱液中，左旋多巴和辅料的质量比优选为9:1～1:9；更优选为8:2～2:8；最优选为7:3～3:7；包括但不限于1:1、1:2、2:1。In the precursor liquid of the present invention, the mass ratio of levodopa and excipients is preferably 9:1-1:9; more preferably 8:2-2:8; most preferably 7:3-3:7; including but Not limited to 1:1, 1:2, 2:1.
具体的，所述前驱液中，左旋多巴和辅料的总质量浓度优选为0.1％～5％；更优选为0.2％～4％；最优选为0.3％～3％。Specifically, in the precursor liquid, the total mass concentration of levodopa and excipients is preferably 0.1% to 5%; more preferably 0.2% to 4%; most preferably 0.3% to 3%.
前驱液采用雾化器雾化，得到液滴。 The precursor liquid is atomized using an atomizer to obtain droplets.
本发明所述雾化优选在雾化器中进行，本发明对上述具体的雾化器不进行限定，可以是本实验室自制的，如申请号201410677942.3；可以是是市售的均可。The atomization in the present invention is preferably carried out in an atomizer. The present invention does not limit the above-mentioned specific atomizer. It can be homemade in this laboratory, such as application number 201410677942.3; it can be commercially available.
本发明所述雾化器选自压力式雾化器、双流体雾化器、超声雾化器或微流控雾化器，调控初始液滴尺寸为30～300μm。The atomizer of the present invention is selected from a pressure atomizer, a two-fluid atomizer, an ultrasonic atomizer or a microfluidic atomizer, and the initial droplet size is controlled to be 30 to 300 μm.
将上述步骤中配制完成的纯左旋多巴、左旋多巴/羟丙基甲基纤维素、左旋多巴/聚乙烯吡咯烷酮、左旋多巴/羟丙基-β-环糊精的前驱液倒入储液罐，通过导管连接雾化器，将前驱液雾化成细小的均一液滴。Pour the precursor solutions of pure levodopa, levodopa/hydroxypropyl methylcellulose, levodopa/polyvinylpyrrolidone, and levodopa/hydroxypropyl-β-cyclodextrin prepared in the above steps. The liquid storage tank is connected to the atomizer through a conduit to atomize the precursor liquid into fine uniform droplets.
本发明制备得到的所述液滴的尺寸优选为30～300μm；更优选为35～280μm。The size of the liquid droplets prepared by the present invention is preferably 30-300 μm; more preferably, it is 35-280 μm.
本发明通过上述左旋多巴和辅料的质量比、左旋多巴和辅料的总质量浓度范围，雾化的参数上述组分上相互作用，功能上彼此相互支持，存在相互关系的技术特征，上述整体的方案才能使得制备得到特定范围内，尺寸可控的微粒，才能达到本发明的技术效果。The present invention interacts with each other through the mass ratio of the above-mentioned levodopa and auxiliary materials, the total mass concentration range of levodopa and auxiliary materials, and the parameters of atomization. The above-mentioned components interact, functionally support each other, and have mutually related technical features. The above-mentioned whole Only with this solution can particles with controllable size within a specific range be prepared, and the technical effects of the present invention be achieved.
液滴经喷雾干燥，即得微粒。具体的，所述喷雾干燥的参数为：塔进口温度为120～230℃，出口温度60～100℃；更优选的，塔进口温度为130～220℃，出口温度65～95℃。The droplets are spray dried to obtain particles. Specifically, the spray drying parameters are: the tower inlet temperature is 120-230°C, and the outlet temperature is 60-100°C; more preferably, the tower inlet temperature is 130-220°C, and the outlet temperature is 65-95°C.
本发明所述微粒的空气动力学粒径为10μm～35μm，嗅区沉积率大于10％。The aerodynamic particle size of the particles of the present invention is 10 μm to 35 μm, and the deposition rate in the olfactory area is greater than 10%.
本发明的微粒在60min药物的释放率可达80％。The drug release rate of the microparticles of the present invention can reach 80% in 60 minutes.
本发明通过上述特定的喷雾干燥参数如塔进口温度、出口温度的设置，结合上述雾化参数，上述在相互关系的技术特征，上述整体的方案才能使得制备得到特定范围内，制备的左旋多巴组合物微粒尺寸可控，形貌规则，为表面光滑的葡萄干状实心微粒，粒径范围满足用于鼻腔嗅区递送的实际需要。The present invention uses the above-mentioned specific spray drying parameters such as the settings of the tower inlet temperature and outlet temperature, combined with the above-mentioned atomization parameters, the above-mentioned mutually related technical features, and the above-mentioned overall scheme to prepare levodopa within a specific range. The particle size of the composition is controllable and the shape is regular. It is a solid raisin-like particle with a smooth surface. The particle size range meets the actual needs for delivery to the olfactory area of the nasal cavity.
本发明提供了一种用于鼻腔递送的左旋多巴组合物微粒，由上述技术方案任意一项所述的制备方法制备得到。The present invention provides levodopa composition particles for nasal delivery, which are prepared by the preparation method described in any of the above technical solutions.
本发明对于上述制备方法有了清楚的描述，在此不再赘述。The present invention has a clear description of the above preparation method, which will not be described in detail here.
本发明提供了上述任意一项所述的制备方法制备得到的左旋多巴组 合物微粒在制备鼻腔递送产品中的应用。The invention provides a levodopa group prepared by any one of the above preparation methods. Application of compound microparticles in the preparation of nasal delivery products.
本发明上述方法制备得到的微粒可以用于制备鼻腔递送产品，包括但不限于鼻腔递送药物。本发明人对此不进行限定。The microparticles prepared by the above method of the present invention can be used to prepare nasal delivery products, including but not limited to nasal delivery drugs. The inventor does not limit this.
本发明提供了一种鼻腔递送产品，包括上述技术方案所述的左旋多巴组合物微粒。The present invention provides a nasal delivery product, including the levodopa composition particles described in the above technical solution.
本发明提供的上述鼻腔递送产品包括上述左旋多巴组合物微粒。还可以包括药学上可以接受的配料，在此不进行限定。The above-mentioned nasal delivery product provided by the present invention includes the above-mentioned levodopa composition microparticles. It may also include pharmaceutically acceptable ingredients, which are not limited here.
本发明采用羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟丙基-β-环糊精中的一种作为辅料，与药物以不同比例均匀混合制备成前驱液，经过微流控喷雾干燥技术处理后，所述微粒的空气动力学粒径为10μm～35μm，具有高鼻腔递送和沉积效率，此外可将药物以无定形形式均匀分散在载体基质中，数据显示制备的无定形固体分散体可明显改善水溶性差的药物的溶出/释放行为。并保持药物的长期储存稳定性，解决了左旋多巴溶液剂型不稳定，易受光、热、氧、水分等因素的干扰而失去药物活性的技术问题。The present invention uses one of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl-β-cyclodextrin as an auxiliary material, and uniformly mixes it with the drug in different proportions to prepare a precursor liquid, which is processed by microfluidic spray drying technology. After treatment, the aerodynamic particle size of the microparticles is 10 μm ~ 35 μm, which has high nasal delivery and deposition efficiency. In addition, the drug can be evenly dispersed in the carrier matrix in an amorphous form. The data shows that the prepared amorphous solid dispersion can Significantly improve the dissolution/release behavior of poorly water-soluble drugs. It also maintains the long-term storage stability of the drug, and solves the technical problem that the levodopa solution dosage form is unstable and susceptible to interference by factors such as light, heat, oxygen, moisture, etc. and thus loses drug activity.
本发明采用微流控喷雾干燥技术，通过调控前驱液配方和喷雾干燥温度、进料压力等工艺参数，从而达到对干燥后左旋多巴微粒的尺寸、形貌和密度等粉体性质的控制，该方法操作简单，成本较低，快速，可重复性高，能根据适合鼻腔递送微粒的实际需要制备不同尺寸，形貌和密度(见表1)的左旋多巴组合物微粒，与其它微粒制备技术相比，具有明显的优势。The present invention adopts microfluidic spray drying technology and controls the size, morphology, density and other powder properties of dried levodopa particles by regulating the precursor liquid formula, spray drying temperature, feed pressure and other process parameters. This method is simple to operate, low in cost, fast and highly reproducible. It can prepare levodopa composition particles of different sizes, morphologies and densities (see Table 1) according to the actual needs suitable for nasal delivery of particles, and can be prepared with other particles. Compared with technology, it has obvious advantages.
为了进一步说明本发明，以下结合实施例对本发明提供的一种用于鼻腔递送的左旋多巴组合物微粒、其制备方法和应用进行详细描述。In order to further illustrate the present invention, the levodopa composition microparticles for nasal delivery provided by the present invention, its preparation method and application are described in detail below in conjunction with the examples.
实施例1Example 1
按照如下步骤制备左旋多巴组合物微粒：Follow the following steps to prepare levodopa composition microparticles:
(1)称取0.3g左旋多巴溶于99.7g去离子水中，40℃磁力搅拌，直至完全溶解，搅拌速度为600rpm，配制成质量分数为0.3％的左旋多巴溶液。并选择羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟丙基-β-环糊精分别作为药物载体，称取1.2g、0.8g、1.6g载体物质分别对应和1.2g、1.6 g、0.8g左旋多巴溶解于397.6g去离子水中，40℃磁力搅拌，直至完全溶解，搅拌速度为600rpm，后经0.22μm的针头过滤器过滤得到质量分数为0.6％，质量比为1:1、1:2、2:1的左旋多巴/羟丙基甲基纤维素、左旋多巴/聚乙烯吡咯烷酮、左旋多巴/羟丙基-β-环糊精混合溶液。(1) Weigh 0.3g of levodopa and dissolve it in 99.7g of deionized water. Stir magnetically at 40°C until completely dissolved. The stirring speed is 600rpm to prepare a levodopa solution with a mass fraction of 0.3%. Hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl-β-cyclodextrin were selected as drug carriers respectively, and 1.2g, 0.8g, and 1.6g of carrier materials were weighed to correspond to 1.2g and 1.6g respectively. g, 0.8g levodopa was dissolved in 397.6g deionized water, magnetically stirred at 40°C until completely dissolved, the stirring speed was 600rpm, and then filtered through a 0.22μm syringe filter to obtain a mass fraction of 0.6% and a mass ratio of 1: 1. 1:2, 2:1 mixed solutions of levodopa/hydroxypropyl methylcellulose, levodopa/polyvinylpyrrolidone, and levodopa/hydroxypropyl-β-cyclodextrin.
(2)将步骤(1)中配制完成的纯左旋多巴、左旋多巴/羟丙基甲基纤维素、左旋多巴/聚乙烯吡咯烷酮、左旋多巴/羟丙基-β-环糊精的前驱液倒入储液罐，通过导管连接微流控雾化器，将前驱液通过孔径为75μm的雾化器雾化成细小的均一液滴，雾化压力为0.3kg/cm3，雾化器工作振动频率为8000Hz，幅值为15Vpp。(2) Combine the pure levodopa, levodopa/hydroxypropyl methylcellulose, levodopa/polyvinylpyrrolidone, and levodopa/hydroxypropyl-β-cyclodextrin prepared in step (1) Pour the precursor liquid into the liquid storage tank, connect it to the microfluidic atomizer through a catheter, and atomize the precursor liquid into fine uniform droplets through the atomizer with a hole diameter of 75 μm. The atomization pressure is 0.3kg/cm 3 . The operating vibration frequency of the device is 8000Hz and the amplitude is 15Vpp.
(3)步骤(2)中的液滴经喷雾干燥得到的尺寸可控的微粒，其塔进口温度为186℃，出口温度为67℃，热风流量设置范围为280L/min。(3) The size-controllable particles obtained by spray drying the droplets in step (2) have a tower inlet temperature of 186°C, an outlet temperature of 67°C, and a hot air flow setting range of 280L/min.
根据上述左旋多巴组合物微粒的制备方法，实验室级微流控喷雾干燥塔选用75μm的微流控雾化器制得左旋多巴组合物微粒，其物化性质如表1所示。According to the above preparation method of levodopa composition particles, a laboratory-level microfluidic spray drying tower uses a 75 μm microfluidic atomizer to prepare levodopa composition particles, whose physical and chemical properties are shown in Table 1.
选取纯左旋多巴微粒以及药辅比为2:1的喷雾干燥左旋多巴组合物微粒样品于T＝20±2℃、RH＝15±5％的条件下，分别存储1天、1周和1个月，并分别记录每个时间节点样品的扫描电镜及X射线粉末衍射数据。Select pure levodopa microparticles and spray-dried levodopa composition microparticle samples with a drug-adjuvant ratio of 2:1 and store them under the conditions of T=20±2℃ and RH=15±5% for 1 day, 1 week and 1 month, and record the scanning electron microscope and X-ray powder diffraction data of the samples at each time point.
结果如下：本发明制备的纯左旋多巴微粒，为表面光滑的球形微粒，而加入辅料与左旋多巴共喷后，制备的左旋多巴组合物微粒尺寸可控，形貌规则，为表面光滑的葡萄干状实心微粒(图1)，粒径范围满足用于鼻腔嗅区递送的实际需要。由图2可知，纯左旋多巴喷雾干燥微粒结晶程度较低，差式扫描量热图表明该样品具有重结晶峰，非常不稳定，在储存一天后，微粒表面有明显晶体物质出现，发生重结晶来达到稳定的晶体形式。而本发明制备的左旋多巴组合物微粒均以无定形形式存在，在T＝22±2℃、RH＝15±5％的条件下储存稳定性较好，在分别存储1天、1周、1个月，微粒表面未出现明显晶体物质(图3)，且X射线粉末衍射图显示微粒样品仍保持无定形(图4)，药物货架期延长，表明左旋多巴组合物微粒可以无定形形式稳定存在。 The results are as follows: the pure levodopa particles prepared by the present invention are spherical particles with a smooth surface. After adding excipients and co-spraying with levodopa, the prepared levodopa composition particles have controllable size, regular morphology and smooth surface. The raisin-shaped solid particles (Figure 1) have a particle size range that meets the actual needs for delivery to the nasal olfactory area. As can be seen from Figure 2, the degree of crystallization of pure levodopa spray-dried particles is low. The differential scanning calorimeter diagram shows that the sample has a recrystallization peak and is very unstable. After one day of storage, obvious crystalline materials appear on the surface of the particles, indicating that recrystallization occurs. Crystallize to achieve a stable crystal form. The levodopa composition particles prepared by the present invention all exist in amorphous form and have good storage stability under the conditions of T=22±2°C and RH=15±5%. They are stored for 1 day, 1 week, and After 1 month, no obvious crystalline material appears on the surface of the microparticles (Figure 3), and the X-ray powder diffraction pattern shows that the microparticle sample remains amorphous (Figure 4). The shelf life of the drug is extended, indicating that the levodopa composition microparticles can be in amorphous form. Stable existence.
实施例2Example 2
选取上述实施例1中所制备左旋多巴组合物微粒样品，通过原子力显微镜(Atomic force microscope，AFM，Dimension Icon，Bruker，美国)测量微粒与模拟鼻腔粘液之间的粘附力来评价微粒的粘膜粘附性能。测试方法：首先将探针进行校准以计算获取弹性系数，而后滴加10μL预先配制的模拟鼻腔粘液(又名粘蛋白溶液，含有95％的水、2％的粘蛋白、3％的氯化钠)于载玻片中，采用接触模式下针使得探针与粘蛋白溶液接触后迅速抬起，然后继续下针将粘有粘蛋白溶液的探针尖端与利用双面胶固定在载玻片上的微粒接触后抬起，利用AFM平台测试软件来获取力曲线，随后可通过NanoScopeAnalysis 1.7软件对所测力曲线进行分析并计算得粘附力数值。实验过程中所使用的探针为Si3N4(针头直径<10nm)，扫描速率为0.977Hz，扫描深度为20nm。Select the levodopa composition microparticle sample prepared in the above Example 1, and measure the adhesion between the microparticles and simulated nasal mucus through an atomic force microscope (AFM, Dimension Icon, Bruker, USA) to evaluate the mucosa of the microparticles. Adhesion properties. Test method: First calibrate the probe to calculate the elastic coefficient, and then add 10 μL of pre-prepared simulated nasal mucus (also known as mucin solution, containing 95% water, 2% mucin, and 3% sodium chloride ) in the slide, use the contact mode to make the probe contact the mucin solution and lift it up quickly, and then continue to lower the needle to connect the tip of the probe with the mucin solution and the tip fixed on the slide with double-sided tape. The particles are lifted after contact, and the force curve is obtained using the AFM platform testing software. The measured force curve can then be analyzed through the NanoScopeAnalysis 1.7 software and the adhesion force value can be calculated. The probe used during the experiment was Si 3 N 4 (tip diameter <10nm), the scanning rate was 0.977Hz, and the scanning depth was 20nm.
结果如下：从图5中可知，与左旋多巴原料药相比，含有环糊精的微粒与模拟鼻粘液之间的粘附力基本保持不变，而含有羟丙基甲基纤维素及聚乙烯吡咯烷酮的微粒与模拟鼻粘液之间的粘附力明显提升，且随着聚合物含量的提高，微粒的粘附性逐渐增强。此外，在相同的药辅比下，羟丙基甲基纤维素对微粒粘附力的影响比聚乙烯吡咯烷酮更加明显。The results are as follows: As can be seen from Figure 5, compared with levodopa API, the adhesion between microparticles containing cyclodextrin and simulated nasal mucus remains basically unchanged, while the adhesion between particles containing hydroxypropyl methylcellulose and poly The adhesion between vinylpyrrolidone particles and simulated nasal mucus is significantly improved, and as the polymer content increases, the adhesion of the particles gradually increases. In addition, at the same drug-to-excipient ratio, hydroxypropyl methylcellulose has a more obvious effect on particle adhesion than polyvinylpyrrolidone.
实施例3Example 3
选取上述实施例1中所制备左旋多巴组合物微粒样品，通过Franz扩散池装置(内径12mm，受体室体积15mL，TP-6P，天津药典标准仪器厂，中国)结合模拟鼻液来评估左旋多巴微粒体外释放性能。其中模拟鼻液是由7.45g氯化钠，1.29g氯化钾和0.32g二水合氯化钙溶于1000mL去离子水中配制而成。测试方法：扩散池的受体室中充满模拟鼻液，并通过水浴加热维持在34℃以模拟鼻腔内环境，且在整个实验过程中保证漏槽条件，受体介质磁力搅拌以确保左旋多巴混合均匀。准确称量10mg左旋多巴组合物微粒样品，均匀的撒在已用模拟鼻液浸润并置于Franz扩散池供体室及受体室之间的醋酸纤维素膜上(孔径0.45μm，上海兴亚净化材料厂，中国)，随后向供体室中加入0.5mL模拟鼻液以促进药粉在整个膜表面的均匀铺展和润湿。在一定的时间间隔内，从受体室中移取 200μL溶液，并同时补充相同体积的新鲜模拟鼻液介质，并排除多余气泡。在λ＝280nm处用紫外分光光度法(DR6000，哈希公司，美国)测定提取样品中的左旋多巴含量。每个样品重复测试3次。Select the levodopa composition particle sample prepared in the above Example 1, and evaluate the levodopa composition through a Franz diffusion cell device (inner diameter 12mm, receptor chamber volume 15mL, TP-6P, Tianjin Pharmacopoeia Standard Instrument Factory, China) combined with simulated nasal fluid. In vitro release properties of DOPA microparticles. The simulated nasal fluid is prepared by dissolving 7.45g sodium chloride, 1.29g potassium chloride and 0.32g calcium chloride dihydrate in 1000mL deionized water. Test method: The receptor chamber of the diffusion cell is filled with simulated nasal fluid and maintained at 34°C through a water bath to simulate the nasal cavity environment. The sink conditions are maintained throughout the experiment. The receptor medium is magnetically stirred to ensure that levodopa well mixed. Accurately weigh 10 mg of the levodopa composition particle sample, and sprinkle it evenly on the cellulose acetate membrane that has been infiltrated with simulated nasal fluid and placed between the donor chamber and the recipient chamber of the Franz diffusion cell (pore size 0.45 μm, Shanghai Xing Asia Purification Materials Factory, China), and then added 0.5 mL of simulated nasal fluid into the donor chamber to promote the uniform spreading and wetting of the drug powder on the entire membrane surface. Removed from the receptor chamber at certain intervals 200 μL solution, and at the same time add the same volume of fresh simulated nasal fluid medium, and eliminate excess air bubbles. The levodopa content in the extracted samples was determined using UV spectrophotometry (DR6000, Hach Company, USA) at λ = 280 nm. Each sample was tested in duplicate 3 times.
结果如下：由图6可知，相比于左旋多巴原料药和纯左旋多巴喷雾干燥微粒，所有含辅料的喷雾干燥微粒均可显著提高左旋多巴释放速率，体现了辅料存在下喷雾干燥无定形固体分散体的优势。The results are as follows: It can be seen from Figure 6 that compared with levodopa API and pure levodopa spray-dried particles, all spray-dried particles containing excipients can significantly increase the release rate of levodopa, which reflects the inefficiency of spray drying in the presence of excipients. Advantages of Shaped Solid Dispersions.
实施例4Example 4
选取上述实施例1中所制备左旋多巴组合物微粒样品，通过自主研发基于成人男性鼻子CT扫描图的3D打印鼻铸形，结合OptiNose公司研发的Bi-DirectionalTM鼻粉给药装置，研究粉体制剂在鼻腔各部分的沉积行为。实验过程中，首先用1％v/v吐温20的甲醇溶液涂覆，待甲醇挥发后形成吐温20薄膜覆盖在3D打印鼻铸形的内壁，以防微粒碰撞弹跳；将预先称取适量药粉的胶囊置于给药装置中，控制给药装置插入鼻中深度5mm，给药角度60°，保持3D打印鼻铸形水平放置，用呼吸机通过Bi-DirectionalTM鼻粉给药装置在3s内，以50L/min的气流流速将20mg药粉吹进鼻腔中，气流携带微粒从一侧鼻腔进入另一侧鼻腔中；实验结束后，将鼻铸形拆卸，各个部分置于烧杯中，用水清洗、超声、收集；之后采用紫外分光光度法在λ＝280nm处定量左旋多巴药物含量，明确各个部分的沉积量，同时定量实验前后胶囊中药物含量以确定递送剂量，换算得各个部分的沉积效率以及胶囊中药粉排空率，所有测试均重复三次。The levodopa composition microparticle sample prepared in the above Example 1 was selected, and the powder was studied by independently developing a 3D printed nose cast based on the CT scan of the adult male nose, combined with the Bi-Directional TM nasal powder delivery device developed by OptiNose Company. Deposition behavior of body preparations in various parts of the nasal cavity. During the experiment, it was first coated with a methanol solution of 1% v/v Tween 20. After the methanol evaporated, a Tween 20 film was formed to cover the inner wall of the 3D printed nose mold to prevent particles from colliding and bouncing; an appropriate amount was weighed in advance The capsule of the medicinal powder is placed in the drug delivery device. The drug delivery device is inserted into the nose to a depth of 5mm and the drug delivery angle is 60°. Keep the 3D printed nose cast horizontally and use a ventilator to pass the Bi-Directional TM nasal powder drug delivery device in 3 seconds. Inside, blow 20 mg of medicinal powder into the nasal cavity at an airflow rate of 50L/min. The airflow carries particles from one side of the nasal cavity into the other side of the nasal cavity; after the experiment, disassemble the nose cast, place each part in a beaker, and wash with water. , ultrasound, and collection; then UV spectrophotometry was used to quantify the levodopa drug content at λ = 280 nm to clarify the deposition amount of each part. At the same time, the drug content in the capsule before and after the experiment was quantified to determine the delivery dose, and the deposition efficiency of each part was converted. As well as capsule powder emptying rate, all tests were repeated three times.
结果如下：由图7可知，空气动力学粒径处于10μm～35μm范围内的样品，嗅区沉积率大于10％，具有高鼻腔递送和沉积效率。The results are as follows: It can be seen from Figure 7 that samples with aerodynamic particle sizes in the range of 10 μm to 35 μm have a deposition rate of more than 10% in the olfactory region and have high nasal delivery and deposition efficiency.
表1喷雾干燥左旋多巴微粒样品的物化性质

Table 1 Physicochemical properties of spray-dried levodopa microparticle samples

以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。 The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (10)

  1. 一种用于鼻腔递送的左旋多巴组合物微粒的制备方法，其特征在于，包括：A method for preparing levodopa composition microparticles for nasal delivery, which is characterized by including:
    A)左旋多巴和辅料溶解，得到前驱液；A) Dissolve levodopa and excipients to obtain precursor solution;
    B)前驱液采用雾化器雾化，得到液滴；所述液滴的尺寸30～300μm；B) The precursor liquid is atomized using an atomizer to obtain droplets; the size of the droplets is 30 to 300 μm;
    C)液滴经喷雾干燥，即得微粒。C) The droplets are spray-dried to obtain particles.
  2. 根据权利要求1所述的制备方法，其特征在于，步骤A)所述辅料为羟丙基甲基纤维素、聚乙烯吡咯烷酮或羟丙基-β-环糊精中的一种。The preparation method according to claim 1, characterized in that the auxiliary material in step A) is one of hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl-β-cyclodextrin.
  3. 根据权利要求1所述的制备方法，其特征在于，步骤A)所述前驱液中，左旋多巴和辅料的质量比为9:1～1:9。The preparation method according to claim 1, characterized in that, in the precursor liquid of step A), the mass ratio of levodopa and auxiliary materials is 9:1 to 1:9.
  4. 根据权利要求1所述的制备方法，其特征在于，步骤A)所述前驱液中，左旋多巴和辅料的总质量浓度为0.1％～5％。The preparation method according to claim 1, characterized in that, in the precursor liquid of step A), the total mass concentration of levodopa and auxiliary materials is 0.1% to 5%.
  5. 根据权利要求1所述的制备方法，其特征在于，步骤B)所述雾化器种类为：The preparation method according to claim 1, characterized in that the type of atomizer in step B) is:
    选自压力式雾化器、双流体雾化器、超声雾化器或微流控雾化器，调控初始液滴尺寸为30～300μm。Choose from pressure atomizer, dual-fluid atomizer, ultrasonic atomizer or microfluidic atomizer, and adjust the initial droplet size to 30-300 μm.
  6. 根据权利要求1所述的制备方法，其特征在于，步骤C)所述喷雾干燥的参数为：The preparation method according to claim 1, characterized in that the spray drying parameters in step C) are:
    塔进口温度为120～230℃，出口温度60～100℃。The tower inlet temperature is 120~230℃, and the outlet temperature is 60~100℃.
  7. 根据权利要求1所述的制备方法，其特征在于，所述微粒的空气动力学粒径为10μm～35μm，嗅区沉积率大于10％。The preparation method according to claim 1, characterized in that the aerodynamic particle size of the particles is 10 μm to 35 μm, and the deposition rate in the olfactory zone is greater than 10%.
  8. 一种用于鼻腔递送的左旋多巴组合物微粒，其特征在于，由权利要求1～7任意一项所述的制备方法制备得到。A levodopa composition microparticle for nasal delivery, characterized in that it is prepared by the preparation method described in any one of claims 1 to 7.
  9. 权利要求1～8任意一项所述的制备方法制备得到的左旋多巴组合物微粒在制备鼻腔递送产品中的应用。Application of the levodopa composition particles prepared by the preparation method according to any one of claims 1 to 8 in the preparation of nasal delivery products.
  10. 一种鼻腔递送产品，其特征在于，包括权利要求8所述的左旋多巴组合物微粒。 A nasal cavity delivery product, characterized by comprising the levodopa composition particles according to claim 8.
PCT/CN2023/094671 2022-06-29 2023-05-17 Levodopa composition microparticles for intranasal delivery, preparation method therefor and use thereof WO2024001587A1 (en)

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