CN117503703B - A levodopa nasal spray and its preparation method and application - Google Patents
A levodopa nasal spray and its preparation method and application Download PDFInfo
- Publication number
- CN117503703B CN117503703B CN202311494072.1A CN202311494072A CN117503703B CN 117503703 B CN117503703 B CN 117503703B CN 202311494072 A CN202311494072 A CN 202311494072A CN 117503703 B CN117503703 B CN 117503703B
- Authority
- CN
- China
- Prior art keywords
- nasal spray
- levodopa
- liquid
- drug
- nasal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 135
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Classifications
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- 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]
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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Abstract
The invention discloses a levodopa nasal spray and a preparation method and application thereof. The levodopa nasal spray comprises levodopa or pharmaceutically acceptable salts thereof, an absorption promoter, a suspending agent, an antioxidant, a wetting agent and a bacteriostatic agent; the levodopa nasal spray improves the stability of levodopa in a liquid preparation, and the drug is directly delivered to an olfactory region through a nasal route after administration, bypasses a blood brain barrier, improves the absorption efficiency of the drug at the brain, quickly takes effect, reduces administration dosage, and is used for treating parkinsonism and improving the occurrence of symptom fluctuation. The levodopa nasal spray has proper viscosity, can effectively increase drug olfactory region deposition, improve nasal-brain delivery efficiency, and effectively treat parkinson's disease.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a levodopa nasal spray and a preparation method and application thereof.
Background
Parkinson's Disease (PD) is a common neurodegenerative disease, and is a relatively high number of patients; the pathogenesis of the disease is more and the mechanism is more, and the disease is a comprehensive pathogenic result, the main pathological change is that dopamine (Dopamine, DA) can be lost from neurons at the compact part of substantia nigra and Louis are formed into small bodies, the main biochemical change is that the striatum area lacks dopamine, and the dopamine is unbalanced in acetylcholine transmitters, so that the acetylcholine function is relatively hyperfunctional. The main symptoms of clinical patients are motor symptoms such as bradykinesia, resting tremor, myotonia and dysgestion, and the like, and non-motor symptoms such as dysolfaction, constipation, sleep disorder and the like, and currently common treatment means comprise drug treatment, operation treatment, rehabilitation treatment and the like, but cannot be cured, only symptoms can be relieved, and the life quality of the patients can be improved, so that the treatment needs attention.
The medicine for treating PD disease mainly comprises dopamine (levodopa, dopamine receptor agonist, etc.) and choline (benzomarie hydrochloride, benzatropine mesylate, propiconazole hydrochloride, etc.). Wherein, levodopa (Levodopa, LDA) is a metabolic precursor of dopamine, and peripherally supplemented levodopa can be converted into dopamine through blood brain barrier through decarboxylation of dopa decarboxylase in brain, thereby playing a role of substitution therapy, being the standard therapy of parkinsonism and the most effective symptomatic therapeutic drug in parkinsonism drug therapy. In addition, levodopa is unstable in a wet state and is susceptible to oxidation. Currently, most of the preparations related to levodopa worldwide are solid preparations such as levodopa tablets, capsules, granules and inhalants which are administered by oral route. However, only 1% of the medicine can be transported to the striatum tissue in the brain to be converted into dopamine through neutral amino acid carrier after being taken orally, so that the medicine has slow effect, low bioavailability and large administration dosage. More than 95% of levodopa is converted into dopamine by decarboxylase widely distributed in peripheral tissues, resulting in adverse reactions such as cardiovascular diseases and gastrointestinal diseases, etc., and after long-term large-dose application, patients also generate On/Off phenomenon. In addition, PD patients develop dysphagia as motor function deteriorates with the progression of the disease, which then in these patients further increases the difficulty of oral ingestion of levodopa. There is therefore also a need for an alternative route of administration of levodopa.
In comparison, the nasal administration preparation can directly deliver the medicine from the olfactory region to the brain, bypasses the blood brain barrier, has the obvious advantages of quick effect, improvement of the brain entering efficiency of the levodopa, reduction of administration dosage, avoidance of gastrointestinal reaction and the like. There are a number of nasal formulations for central nervous system disorders such as zolmitriptan nasal spray for migraine treatmentAnd sumatriptan nasal sprayBuprenorphine tartrate nasal spray (Butorphanol) for pain relief) And fentanyl citrate nasal sprayDiazepam nasal spray for epilepsy treatmentMidazolam nasal sprayNasal spray of esketamine for treating depressionAll have been approved by the FDA to be marketed, and the feasibility and the clinical prospect of the levodopa nasal administration route for treating the Parkinson's disease are fully demonstrated.
Oral levodopa, pramipexole is a common drug in the clinical treatment of parkinson's disease. Because dopamine is difficult to successfully penetrate the blood brain barrier, the patient needs to be supplemented with a precursor of levodopa, which is dopamine. When L-dopa enters the brain, it is taken up by dopaminergic neurons and then converted into dopamine by decarboxylation, thereby exerting pharmacological effects. After the levodopa is absorbed by the body, 95% of the drug undergoes decarboxylation in the periphery to form dopamine, and only 1% of the drug penetrates the blood brain barrier and enters the brain.
There is an anatomically direct link between nasal cavity and brain tissue: the olfactory mucosa epithelium of the nasal cavity contains bipolar olfactory cells, and olfactory nerves formed by the olfactory mucosa epithelium pass through a sieve plate to enter the olfactory bulb of the central nervous system, so that partial medicine after the nasal cavity is given with levodopa can be absorbed into the olfactory bulb or cerebrospinal fluid (CSF) through the olfactory mucosa, and can be directly transported into the brain by bypassing a Blood Brain Barrier (BBB), thereby playing a central therapeutic role. Therefore, the nasal administration has quick effect, high bioavailability in brain, and can reduce the dosage of the levodopa and reduce adverse reactions.
For nasal and brain delivery formulations, the amount of drug absorbed in the olfactory region is critical to its efficacy. The area of the mucous membrane in the olfactory region is extremely small (1-5 cm 2), and only accounts for 3% -5% of the total area of the nasal cavity, so that the medicine is deposited in the olfactory region, the delivery efficiency of the medicine is improved, and the promotion of the absorption of the medicine at the mucous membrane part of the nasal cavity is the research and development focus and difficulty of the levodopa nasal spray. In addition, since levodopa is extremely easily oxidized in air when being moist, the currently marketed liquid preparation of levodopa only has a carbidopa enteric gel which needs to be frozen and preserved(Jejunal continuous infusion) one, its stability is another difficulty in the development of levodopa nasal spray.
Disclosure of Invention
The object of the first aspect of the present invention is to provide a pharmaceutical composition.
The object of the second aspect of the present invention is to provide a process for the preparation of the above composition.
The object of a third aspect of the present invention is to provide the use of the above pharmaceutical composition.
The object of the fourth aspect of the present invention is to provide the use of dodecyl-beta-D-maltoside as an absorption enhancer for the preparation of a pharmaceutical formulation of levodopa.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided a pharmaceutical composition comprising a drug, an absorption enhancer; the medicine is levodopa and/or dopaminzide and/or carbidopa; the absorption promoter is at least one of dodecyl-beta-D-maltoside, tetradecyl-beta-D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan and sodium taurocholate.
Preferably, the absorption enhancer is dodecyl- β -D-maltoside.
Preferably, the pharmaceutical composition further comprises at least one of a suspending agent, an antioxidant, a wetting agent, and a bacteriostatic agent.
Preferably, the suspending agent is at least one of microcrystalline cellulose-sodium carboxymethylcellulose RC591 or CL611, carbomers 934, 940.
Preferably, the microcrystalline cellulose-sodium carboxymethyl cellulose includes microcrystalline cellulose-sodium carboxymethyl cellulose RC591, CL611, etc.
Preferably, the carbomers include carbomers 934, 940, and the like.
Preferably, the suspending agent is microcrystalline cellulose-sodium carboxymethyl cellulose RC591.
Preferably, the antioxidant is at least one of ascorbic acid, ascorbyl palmitate and sodium metabisulfite.
Preferably, the antioxidant is sodium metabisulfite.
Preferably, the wetting agent may be at least one of polysorbate and poloxamer.
Preferably, the wetting agent may be polysorbate.
Preferably, the polysorbate is polysorbate 80.
Preferably, the bacteriostatic agent is at least one of benzalkonium chloride, benzalkonium bromide, quaternary ammonium salts, cetrimide, phenoxyethanol, sodium benzoate and phenethyl alcohol.
Preferably, the bacteriostatic agent is benzalkonium chloride.
Preferably, the pharmaceutical composition comprises: 0.5-20% w/w of drug, 1-3% w/w of suspending agent; 0.1 to 3 percent w/w of antioxidant: 0.1-0.5% w/w of absorption enhancer; 0.01 to 0.03 percent w/w of wetting agent; 0.01 to 0.024 percent of antibacterial agent in w/w.
Preferably, the pharmaceutical composition (dopaminzide) 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% -2% w/w of suspending agent; 0.2-3% w/w of antioxidant; 0.05-0.5% w/w of absorption enhancer; 0.005-0.03% w/w wetting agent; 0.005-0.03% w/w of bacteriostat.
Preferably, the levodopa composition comprises: 1-20% w/w of levodopa or a pharmaceutically acceptable salt thereof, 1-3% w/w of a suspending agent; 0.1 to 3 percent w/w of antioxidant: 0.1-0.5% w/w of absorption enhancer; 0.01 to 0.03 percent w/w of wetting agent; 0.01 to 0.024 percent of antibacterial agent in w/w.
Preferably, the pharmaceutical composition comprises: 1 to 15 percent w/w or pharmaceutically acceptable salt thereof, 1.2 to 2 percent w/w of suspending agent; 0.2 to 1 percent of antioxidant in w/w: 0.2-0.3% w/w of absorption enhancer; 0.01 to 0.03 percent w/w of wetting agent; 0.015-0.02% w/w of bacteriostat.
Preferably, the pharmaceutical composition further comprises a pH adjuster for adjusting the pH of the pharmaceutical composition to 5.0-6.5.
Preferably, the addition amount of the pH regulator is 0.03-0.464%.
Preferably, the pH regulator is at least one of citric acid/sodium citrate and sodium dihydrogen phosphate/disodium hydrogen phosphate.
Preferably, the pH regulator is citric acid/sodium citrate.
Preferably, the pharmaceutical composition further comprises an osmolality adjusting agent for adjusting the osmolality of the pharmaceutical composition to 270-350mOsm/kg.
Preferably, the content of the osmotic pressure regulator is 0% -1.5%.
Preferably, the osmolality adjusting agent is glycerol.
Preferably, the pharmaceutical composition further comprises water.
Preferably, the levodopa is a levodopa micropowder.
Preferably, the particle diameter d 90 of the levodopa micro powder is 2-20 μm.
Preferably, the pharmaceutical composition is in the form of a spray.
Preferably, the pharmaceutical composition is administered nasally.
Preferably, the acceptable delivery volume of the spray is 100-200 mu L, the effective delivery dose of the levodopa is 10-40 mg/spray, and the clinical treatment dose is 10-1000 mg/day, wherein the delivery volume is determined by a spray device, and the delivery dose is the product of the concentration of the liquid medicine and the delivery volume.
In a second aspect of the present invention, there is provided a method for preparing the above pharmaceutical composition, comprising the steps of:
S1: adding a wetting agent into water, adding a medicine, and mixing until the medicine is uniformly dispersed to obtain liquid 1;
S2: adding a suspending agent into a proper amount of water, mixing until the suspending agent is uniformly dispersed, and adding a pH regulator to obtain a liquid 2;
S3: adding the liquid 2, the antioxidant, the absorption accelerator, the bacteriostat and the osmotic pressure regulator into the liquid 1, and stirring until the mixture is uniformly mixed to obtain a pharmaceutical composition;
Preferably, the method further comprises filling the pharmaceutical composition into a nasal spray device, i.e. obtaining a nasal spray.
In a third aspect of the invention there is provided the use of a pharmaceutical composition according to the first aspect of the invention in the manufacture of a medicament for use in parkinson's disease.
In a fourth aspect of the invention there is provided the use of dodecyl- β -D-maltoside in the preparation of a nasal spray of levodopa and/or benserazide and/or carbidopa.
The beneficial effects of the invention are as follows:
The invention provides a levodopa nasal spray, which takes dodecyl-beta-D-maltoside as an absorption accelerator of levodopa, and is compounded with a suspending agent, an antioxidant, a wetting agent, a bacteriostat and the like, so that the stability of the levodopa in a liquid preparation is improved, and the preparation can realize drug absorption through two paths after administration: 1) Part of the medicine is directly delivered to the olfactory region, bypasses the blood brain barrier and enters the brain to take effect; 2) Part of the medicines are quickly absorbed into blood through nasal mucosa of respiratory region, enter systemic circulation, and enter brain after passing through blood brain barrier to take effect. The medicine is directly delivered to the olfactory region through the nasal cavity, bypasses the blood brain barrier, improves the absorption efficiency of the brain medicine, has quick action, reduces the administration dosage, and is used for treating the parkinsonism and improving the occurrence of symptom fluctuation. The levodopa nasal spray has proper viscosity, can effectively increase drug olfactory region deposition, improve nasal-brain delivery efficiency, and effectively treat parkinson's disease.
Drawings
The release curves for prescriptions F7-F10 and prescriptions F11-F14 of FIG. 1.
FIG. 2 external appearance of the formulations of different sodium metabisulfite concentrations (from left to right: sodium metabisulfite content 0.2%, 0.5%, 1%, 2%, 3%, 0% and liquid medicine without levodopa) at 60℃for different times.
FIG. 3 appearance of formulations of different sodium metabisulfite concentrations (from left to right: sodium metabisulfite content 0.2%, 0.5%, 1%, 2%, 3%, 0% and liquor without L-dopa) in light-stand for different times.
Figure 4 mist droplet size distribution during spraying of 30mm levodopa nasal spray.
Figure 5 mist droplet size distribution during spraying of 60mm levodopa nasal spray.
Figure 6 is a graph of the nasal spray of dopa and nasal spray for brain administration.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
The levodopa used in the examples below is a levodopa micropowder and the particle size D 90 may be 2-20 μm. The crushing method comprises the following steps:
JET MILL MILL Lab JET MILL is adopted, the air inlet pressure and the crushing pressure are set to be 6.5bar and 7.0bar respectively, an automatic feeding mode is adopted, the feeding speed is 10rpm, and the JET MILL is carried out by feeding.
Determination of the particle size of the levodopa micropowder: the particle size of the levodopa after the micro powder is measured by adopting a Markov wet method, and the test parameters are as follows: background/sample measurement time is 10s, shading degree is 8% -20%, stirring rotation speed is 2000rpm, and stirring time is 5min.
The particle size distribution of levodopa and its micropowder is shown in table 1:
TABLE 1 Levodopa and micropowder particle size distribution
The invention provides a nasal spray for treating parkinsonism, which comprises the following components:
pharmaceutically active ingredients: 0.5-20% w/w;
suspending agent: 1% -3% w/w;
an antioxidant: 0.1% -3% w/w;
absorption promoter: 0.1-0.5% w/w;
wetting agent: 0.01 to 0.03 percent w/w;
pH regulator: proper amount of the water-based spray is used for adjusting the pH of the spray to 5.0-6.5;
Osmotic pressure regulator: a suitable amount for adjusting the osmotic pressure of the spray to 270-350mOsm/kg;
bacteriostat: 0.01-0.024% w/w;
Pure water: to 100% w/w.
The invention also provides a preparation method of the nasal spray, which comprises the following steps:
s1: crushing the crude drugs by an air flow crusher, wherein the crushing pressure is 5-10 bar, the feeding pressure is 7-10 bar, and the feeding speed is 50-65 g/min, so as to obtain drug micro powder;
S2: adding a proper amount of purified water and wetting agent into a liquid preparation tank, setting the stirring speed to be 10-20 Hz, stirring for 3-8 min, increasing the stirring speed to be 40-50 Hz, adding the prescribed amount of levodopa micropowder under stirring, and continuing stirring for 20-40 min after the addition is completed to obtain liquid 1;
s3: adding a proper amount of purified water into another liquid preparation tank, setting the stirring speed to be 40-50 Hz, continuing stirring for 20-40 min after the suspension adding and the charging are completed under stirring, setting the emulsifying speed to be 40-60 Hz, homogenizing and emulsifying for 80-120 min, adding a pH regulator under stirring, and continuing emulsifying for 20-40 min to obtain liquid 2;
S4: setting the stirring speed of a liquid preparation tank to be 40-60 Hz, sequentially adding liquid 2, an antioxidant solution, an absorption accelerator solution, a bacteriostatic agent solution and an osmotic pressure regulator solution into liquid 1 under stirring, setting the pressure of the liquid preparation tank to be about-0.08 MPa, starting a vacuum pump, closing the vacuum pump after the set pressure is reached, and stirring for 20-40 min until the mixture is uniformly mixed to obtain levodopa suspension;
s5: and filling the levodopa suspension into a high-density polyethylene bottle, and rolling a cap nose spray pump in a nitrogen environment to obtain the levodopa nose spray.
EXAMPLE 1 Levodopa destruction assay
According to the standards of the U.S. pharmacopoeia of levodopa, the content of a broken sample of the crude drug is detected by using a USP content measuring method, and the stability of the crude drug of levodopa under breaking conditions (3.0% hydrogen peroxide is respectively oxidized for 0.5, 1 and 2 hours at 60 ℃ and 3.0% hydrogen peroxide is respectively oxidized for 0.5, 1 and 2 hours at 130 ℃ and is respectively broken for 1, 2 and 4 hours) is examined.
TABLE 2 Levodopa content after various conditions are broken
The results show that levodopa is unstable at high temperatures and oxidation. Along with the extension of the oxidation time, the high-temperature standing time is prolonged, and the content of the levodopa is gradually reduced. Wherein when oxidized for 0.5h at 60 ℃, the content of the levodopa is reduced to 92.66%, and when oxidized for 2h, the content of the levodopa is obviously reduced to 74.35%.
EXAMPLE 2 antioxidant screening
The formulation was designed with microcrystalline cellulose-sodium carboxymethylcellulose at 1% concentration as suspending agent, ascorbic acid, ascorbyl palmitate, sodium metabisulfite as candidate antioxidants, and the type and amount of each as formulation variables (tables 3, 4). The temperature was set at 60℃under 75% high humidity to examine the change of the relevant substances.
TABLE 3 antioxidant screening prescription specific composition
TABLE 4 different antioxidant prescription designs
TABLE 5 substances associated with each prescription for 0 days and 5 days after high temperature and high humidity storage
As shown in Table 5, the impurity content was significantly increased after each formulation was left for 5 days at 60℃and the color of the ascorbic acid group, ascorbyl palmitate group and the formulation without antioxidant was significantly changed to brown yellow, and the oxidation resistance was poor. Further, sodium metabisulfite is preferable as an antioxidant because ascorbic acid itself is unstable and changes in color greatly after oxidation.
EXAMPLE 3 suspension screening
Microcrystalline cellulose-sodium carboxymethylcellulose RC591 and CL611 approved by the FDA for nasal administration are used as suspending agents, the formulation design of the suspending agents is shown in tables 6 and 7, and the content uniformity and the release behavior of the preparation under different suspending agent concentrations are examined.
TABLE 6 suspension screening formulation specific composition
TABLE 7 different suspension formulations
The content uniformity results are shown in Table 8;
TABLE 8 content and content uniformity of different prescriptions
The result shows that the content RSD of each prescription after preparation is less than 2 percent, and meets the requirements. After the mixture is placed for 5 days at normal temperature, the content of each prescription is unchanged, and the content uniformity meets the requirements.
The results of the content of the related substances are shown in Table 9;
TABLE 9 content of substances related to different prescriptions
The result shows that the total impurity content of each prescription is far below 1%, wherein the single impurity content is far below 0.1%, which meets the requirements
The release behavior of each formulation was examined using a transdermal diffusion instrument. The release medium is 9mL of PBS solution with pH of 5.8, the medium temperature is 37+/-0.5 ℃, the sampling volume is 9mL, and the fluid replacement volume is 9mL; the release profile is shown in figure 1.
Fig. 1 shows that prescriptions F7-F14 exhibit rapid release, almost complete release at 24 hours. In addition, as can be seen from comparison of the formulations, the release rate of each formulation increases as the viscosity of the formulation increases, and the cumulative release rate increases. Wherein the release rate of prescription F7 is highest, and the release rate can be more than 60% in 1h, and the cumulative release rate in 24h is more than 90%, preferably as the optimal suspension ratio.
EXAMPLE 4 sodium metabisulfite concentration screening
The liquid medicines were prepared according to Table 10, the concentrations of sodium metabisulfite were 0.2%, 0.5%, 1%, 2% and 3%, and after the liquid medicines were filled in penicillin bottles, the liquid medicines were placed under the conditions of high temperature 60 ℃ and illumination (4500 Lx.+ -. 500 Lx), the appearance was observed, and the content of levodopa and related substances were detected.
Table 10
The results are shown in FIGS. 2-3 and tables 11-14 below.
TABLE 11 Levodopa levels at 60℃for different times for different sodium metabisulfite concentration formulations
TABLE 12 preparation of sodium metabisulfite concentration at 60℃for various times
TABLE 13 Levodopa levels at various sodium metabisulfite concentrations for various times under prescribed light conditions
TABLE 14 preparation of substances with different sodium metabisulfite concentrations for different times under prescribed illumination conditions
The results show that:
1) When the liquid medicine is placed at 60 ℃, the liquid medicine without sodium metabisulfite changes color, when the content of sodium metabisulfite is 0.2-3%, the liquid medicine is placed for 30 days, the color change phenomenon is avoided, the content of levodopa is not changed obviously, and related substances are not increased obviously (figure 2 and tables 11-12).
2) When the sodium metabisulfite liquid medicine is placed under the illumination condition, the color change does not occur, when the sodium metabisulfite content is 0.2-3%, the sodium metabisulfite liquid medicine is placed for 13 days, the color change phenomenon does not occur, the content of the levodopa does not change obviously, and related substances do not increase obviously (figure 3 and tables 13-14).
Example 5 quality assessment of preferred prescriptions
1. The preparation method of the liquid medicine according to the prescription of the table 15 is as follows:
S1: crushing the levodopa bulk drug by using an airflow crusher, wherein the crushing pressure is 7bar, the feeding pressure is 8bar, and the feeding speed is 56g/min, so as to obtain levodopa micro powder;
S2: adding a proper amount of purified water and wetting agent into a liquid preparation tank, setting the stirring speed to be 15Hz, stirring for 5min, increasing the stirring speed to be 45Hz, adding the prescribed amount of levodopa micropowder under stirring, and continuing stirring for 30min after the addition is completed to obtain liquid 1;
S3: adding a proper amount of purified water into another liquid preparation tank, setting the stirring speed to be 45Hz, continuing stirring for 30min after adding the suspending agent under stirring, setting the emulsifying speed to be 50Hz, homogenizing and emulsifying for 100min, adding the pH regulator under stirring, and continuing emulsifying for 30min to obtain liquid 2;
S4: setting the stirring speed of a liquid preparation tank to be 50Hz, sequentially adding liquid 2, an antioxidant solution, an absorption accelerator solution, a bacteriostat solution and an osmotic pressure regulator solution into liquid 1 under stirring, setting the pressure of the liquid preparation tank to be-0.08 MPa, starting a vacuum pump, closing the vacuum pump after the set pressure is reached, and stirring for 30min until the mixture is uniform, thus obtaining the levodopa suspension;
s5: and filling the levodopa suspension into a high-density polyethylene bottle, and rolling a cap nose spray pump in a nitrogen environment to obtain the levodopa nose spray.
The results of measuring the API content, viscosity, osmotic pressure, pH, sedimentation stability, spray performance, etc. of the levodopa nasal spray are shown in table 16.
TABLE 15
Table 16
The results show that the preparation meets the requirements of the nasal preparation item of the 2020 edition of Chinese pharmacopoeia.
2. Delivered dose uniformity investigation
The liquid medicine is filled into high-density polyethylene bottles, a nasal spray pump is covered by rolling under the nitrogen environment, and the delivery dosage of 10 bottles of samples in the same batch is detected according to the FDA guiding principle and the requirements of Chinese pharmacopoeia 2020, and the results are shown in Table 17.
TABLE 17
The results show that the delivery dosages of the first spray and the last spray (60 th spray) of 10 times are 98.44% and 98.25% of the marked amount respectively, so that the medicine can be stably delivered, and the requirements of Chinese pharmacopoeia 2020 edition and FDA guiding principle are met.
3. Particle size distribution of mist droplets
The particle size of the spray droplets of the levodopa nasal spray at 30mm and 60mm was measured by a Sympatec laser particle sizer (HELOS & SPRAYER TM), the lens was R5, the contact pressure was 60N, and the measurement time was 150ms.
The spraying process of nasal sprays can be divided into three phases, the formation phase, the stabilization phase and the dissipation phase: the formation stage is the spray formation stage, the concentration of fog drops is rapidly increased, and the particle size is also rapidly increased; the particle size of the fog drops reaches a peak value and remains stable in the stable period; the concentration of fog drops is rapidly reduced in the dissipation period, and the particle size is greatly fluctuated. As shown in fig. 4 to 5, the stability period of the levodopa nasal spray is 20% to 50%, so that the stability period of the levodopa nasal spray is taken as the stability period of the levodopa nasal spray, and the particle size of the mist drops in the stability period of the nasal spray is detected by adopting a three-stage method.
4. Particle size of mist droplets in stationary phase
The droplet size of the levodopa nasal spray at the stationary phase of 30mm and 60mm was measured by Sympatec laser particle sizer (HELOS & SPRAYER TM), lens R5, trigger pressure 60N, stationary phase 20% -50%, results are shown in table 18.
TABLE 18
The results show that the spray particle size in and among the bottles of the present formulation is relatively stable at distances of 30mm and 60 mm.
5. Amount of fine mist drop
A new generation of medicinal disc impactor (NGI) is adopted to examine the content of the medicine carried by the fine mist drops of the nasal spray, the airflow speed is 15L/min, the volume of a glass expansion chamber is 5L, the sample injection amount is 4 presses, the time between pressing is 5s, and the precooling is carried out for 90min at 3.5 ℃; the results are shown in Table 19.
TABLE 19
The results show that the content of the levodopa nasal spray per pressing of mist drops smaller than 10 mu m is extremely low and smaller than 0.1% of the marked amount, and meets the requirements of the FDA guidelines.
EXAMPLE 6 in vivo pharmacokinetic behavior investigation
1. The pharmacokinetic behaviors of the levodopa nasal spray after nasal administration, oral administration of a commercial preparation and oral inhalation administration of the levodopa inhalation powder spray are studied, and the absorption and metabolism behaviors of the levodopa in blood plasma after administration are examined. The preparation method of the self-made levodopa inhalation powder spray comprises the following steps:
a) The prescription design is as in table 20:
table 20 homemade levodopa inhalation powder spray
B) Preparation
Adding levodopa micropowder for 3 times by adopting a layer-by-layer lamination method, adding 4.4g of lactose ML001 into a centrifuge tube, adding 0.6g of micronization API, uniformly mixing, then sequentially adding 0011.2 g of lactose ML, 0.7g of micronization API, mixing, 1.2g of lactose MLO, 0.7g of micronization API, mixing, and manually mixing for 20min after 001.2 g of lactose ML, thus obtaining the levodopa inhalation powder spray.
Male SD rats (180-220 g) were kept in SPF environment, fed with free food and water, fasted for 12h before the experiment, 15 rats were randomly divided into 5 groups of 3, and each group was given levodopa tablet (25 mg/kg), methodological tablet (20 mg/kg), self-made levodopa inhalation powder spray (10 mg/kg), self-made levodopa nasal spray (5 mg/kg) and self-made levodopa nasal spray (10 mg/kg), respectively. Continuous orbital blood collection is carried out at time points of 2min, 5min, 10min, 15min, 30min, 1h, 2h, 4h and 6h after administration, the content of levodopa and dopamine in blood plasma is detected, and the calculation results of pharmacokinetic parameters are shown in tables 21 and 22;
TABLE 21 plasma Levodopa levels in rats
TABLE 22 rat plasma dopamine levels
The results show that the concentration of levodopa and dopamine in plasma after administration of each group of rats is significantly higher than that of the levodopa tablet group in the plasma AUC 0-6h after nasal spray (10 mg/kg) nasal administration at 1/5 dose as follows. The concentration of levodopa in the blood plasma of a levodopa nasal spray and the dosage of the drug administered are linear, and the Cmax and AUC of the levodopa in the blood plasma increase with the increase of the dosage of the drug administered.
In addition, after the levodopa nasal spray is administrated through nose, the content of dopamine in blood plasma is similar to that of the methodological tablet, and is far lower than that of a levodopa tablet group, so that the safety is higher, and side effects after the levodopa administration are expected to be reduced.
2. The tissue distribution of the levodopa nasal spray after nasal administration and oral administration of the commercial preparation was studied, and the absorption and metabolic behavior of levodopa in brain tissues after administration was examined.
Male SD rats (180-220 g) were kept in SPF environment, fed with free food and water, fasted for 12h before the experiment, 15 rats were randomly divided into 5 groups of 3, and each group was given levodopa tablet (25 mg/kg), methoba tablet (20 mg/kg), self-made levodopa nasal spray (5 mg/kg) and self-made levodopa nasal spray (10 mg/kg) respectively. Rats were sacrificed at time points of 2min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, 6h post-dose, brain tissue was completely dissected, and brain tissue was pressed: adding the homogenate in the ratio of homogenate=1:4, homogenizing in ice bath, and detecting the content of levodopa and dopamine in the brain tissue homogenate, wherein the calculation result of the pharmacokinetic parameters is shown in tables 23-24;
Table 23 rat brain tissue dopamine content (subtracted basal) (n=3)
Table 24 rat brain tissue levodopa content (n=3)
The results show that the levodopa nasal spray is rapidly absorbed after nasal administration and enters the brain, the peak time is 10-15min, which is faster than that of a methodological oral administration group (T max =60 min), and under the 1/2 administration dosage, the AUC 0-6h of the onset drug (dopamine) is similar to that of the methodological tablet group, and the equivalent curative effect can be expected to be achieved under the 1/2 dosage, the administration dosage of the levodopa can be reduced, and the safety is improved.
In addition, after the levodopa nasal spray is administrated, the AUC 0-6h of dopamine in the brain is far higher than that of a levodopa tablet group at the administration dosage of 1/5, and the effectiveness is obviously improved.
EXAMPLE 7 in vivo absorption-promoting study of DDM pharmacokinetic behavior investigation
The absorption promoting effect of dodecyl-beta-D-maltoside (DDM) on the drug was evaluated by performing pharmacokinetic studies on levodopa nasal spray with or without DDM.
Wherein the nasal spray (without DDM) was prescribed as in table 25,
Table 25 formulation design for DDM-free Levodopa nasal spray
The preparation method of the DDM-free levodopa nasal spray according to the prescription of the table is the same as that of the levodopa nasal spray in the specific embodiment.
Experimental animals and modes of administration were as above, and the results are shown in tables 26-29;
table 26 rat brain tissue dopamine content (subtracted basal) (n=3)
Table 27 rat brain tissue levodopa content (n=3)
Table 28 plasma Levodopa content in rats
TABLE 29 plasma dopamine levels in rats
The results show that the addition of DDM (dodecyl-beta-D-maltoside) significantly promotes the absorption of levodopa, improves the peak time of the plasma of the levodopa from 120min to 15min, and improves the AUC 0-6 h of dopamine in brain from 3875 ng/mL/min to 14189 ng/mL/min.
EXAMPLE 8 dopa serazide nasal spray
1. Preparation of dopa hydrazine nasal spray
The ratio ranges of the components in the dopa-silk hydrazine nasal spray are shown in table 30:
Table 30 composition of the dopa hydrazine nasal spray formulation
Subsequent experiments were performed using the formulation shown in table 31 to prepare a dopa-hydrazine nasal spray:
table 31 preferred DOPASILAZINE nasal spray formulation
The preparation method comprises the following specific steps:
S1: crushing raw materials of the levodopa and the benserazide by using an airflow crusher, wherein the crushing pressure is 7bar, the feeding pressure is 8bar, the feeding speed is 56g/min, and the d90 of the levodopa and benserazide micro powder is 2-20 mu m;
S2: adding a proper amount of purified water and wetting agent into a liquid preparation tank, setting the stirring speed to be 15Hz, stirring for 5min, increasing the stirring speed to be 45Hz, adding prescribed amounts of levodopa micro powder and benserazide micro powder under stirring, and continuing stirring for 30min after the addition is completed to obtain liquid 1;
S3: adding a proper amount of purified water into another liquid preparation tank, setting the stirring speed to be 45Hz, continuing stirring for 30min after adding the suspending agent under stirring, setting the emulsifying speed to be 50Hz, homogenizing and emulsifying for 100min, adding the pH regulator under stirring, and continuing emulsifying for 30min to obtain liquid 2;
S4: setting the stirring speed of a liquid preparation tank to be 50Hz, adding liquid 2, an antioxidant solution, an absorption enhancer solution and a bacteriostatic agent solution into liquid 1 in sequence under stirring, setting the pressure of the liquid preparation tank to be-0.08 MPa, starting a vacuum pump, closing the vacuum pump after the set pressure is reached, and stirring for 30min until the materials are uniformly mixed to obtain the multi-filigree hydrazine suspension;
s5: and filling the dopa hydrazine suspension into a high-density polyethylene bottle, and rolling a cap nose spray pump under a nitrogen environment to obtain the dopa hydrazine nose spray.
2. In vitro evaluation of dopa-wire hydrazine nasal spray
1) The content of the prepared milbezide nasal spray is detected, and the viscosity, osmotic pressure, pH, sedimentation stability, spray performance and the like are examined, and the results are shown in Table 32.
Table 32 quality evaluation of dopa filthy nasal spray
The results show that the preparation meets the requirements of the nasal preparation item of the 2020 edition of Chinese pharmacopoeia.
2) Delivered dose uniformity investigation
According to the FDA guiding principle and the requirements of Chinese pharmacopoeia 2020, carrying out delivery dose uniformity investigation on the levodopa and benserazide compound nasal spray, and detecting the delivery dose of 10 bottles of samples in the same batch, wherein the results are shown in tables 33-34;
TABLE 33 detection of levodopa in dopa-hydrazine nasal spray
TABLE 34 content of dopa filzosin nasal spray per benserazide
The results show that the delivery dosages of the first spray and the last spray (60 th spray) of 10 times are 98.23% and 98.48% of the marked amount respectively, so that the medicine can be stably delivered, and the requirements of Chinese pharmacopoeia 2020 edition and FDA guiding principle are met.
3. Pharmacokinetic studies of dopa-serazide nasal sprays
The trabeculozine nasal spray without dodecyl-beta-D-maltoside (DDM) was subjected to pharmacokinetic studies to evaluate the intracerebral delivery performance of the trabeculozine nasal spray and the absorption promoting effect of DDM on the drug.
The prescription of nasal sprays (without DDM) is shown in table 35.
Table 35 formulation design of DDM free dopa serazide nasal spray
The preparation method of the DDM-free dopa hydrazine nasal spray according to the prescription of the table is the same as that of the dopa hydrazine suspension nasal spray in the specific embodiment.
2) The tissue distribution of the nasal spray of dopa and the nasal spray of dopa without DDM was studied to investigate the absorption and metabolic behavior of dopa hydrazine in brain tissue after administration.
Male SD rats (180-220 g) were kept in SPF environment, fed with free food and water, fasted for 12h before the experiment, 15 rats were randomly divided into 2 groups of 3, and self-made dopa hydrazine nasal spray (20 mg/kg) and self-made DDM free dopa hydrazine nasal spray (20 mg/kg) were administered respectively. Rats were sacrificed at time points of 2min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, 6h post-dose, brain tissue was completely dissected, and brain tissue was pressed: homogenate=1:4, homogenate is added in the ice bath, the amine content in the brain tissue homogenate is detected, and the calculation result of the pharmacokinetic parameters is shown in fig. 6 and table 36;
table 36 rat brain tissue levodopa content (n=3)
The results show that the addition of DDM (dodecyl-beta-D-maltoside) significantly promotes the absorption of levodopa, increases the peak concentration of levodopa from 209ng/mL to 227ng/mL, and increases the AUC0-6h of levodopa in the brain from 45462 ng/mL.min to 50464 ng/mL.min.
The present invention has been described in detail in the above embodiments, but the present invention is not limited to the above examples, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
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| CN112955134A (en) * | 2018-07-19 | 2021-06-11 | 英倍尔药业股份有限公司 | Respiratory delivery of levodopa and dopa decarboxylase inhibitors for the treatment of parkinson's disease |
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