Capsule-type eletriptan nasal inhalation powder aerosol and preparation method and application thereofTechnical Field
The invention relates to the technical field of medicinal preparations, and relates to an inhalation powder inhalation, in particular to a capsule-type eletriptan nasal inhalation powder inhalation, and a preparation method and application thereof.
Background
Migraine (migrine) is a common chronic neurovascular disorder manifested by recurrent headaches, autonomic dysfunction, and various combinations of other nervous system symptoms. The attack is often accompanied with a plurality of vegetative nervous system symptoms, such as nausea, vomit, pale complexion, accelerated heart rate, increased respiration, gastrointestinal dysfunction and the like, and the headache is often preceded by visual blurring, flashing, hemianopia, hemifacial numbness, dysphasia, hemianesthesia or hemiparesis and other aura expressions for a plurality of minutes or half an hour. The disease is more common in children and adolescence, the peak of the disease occurs in middle and young age, women are more common, the proportion of male patients to female patients is about 1: 2-3, the prevalence rate in the population is 5% -10%, and the genetic background is common.
The medicines for treating migraine comprise nonspecific analgesics and specific medicines, and the specific medicines mainly comprise triptans. Triptans are a class of drugs that selectively agonize 5-HT receptors. Since 1 st schoppitan of Kurarian Schker company was used for treating migraine in 1990, 6 triptans such as eletriptan, frovatriptan, naratriptan, rizatriptan and levomitriptan were used in clinical practice successively in 2003. Most of the existing medicines for treating migraine are oral preparations of triptan, but the medicines have low bioavailability, slow effect, large dosage and large side effect due to the first pass effect of the liver. The nasal spray of triptan contains citric acid, disodium hydrogen phosphate, purified water and other auxiliary materials, so that nasal mucosa irritation such as dryness, pruritus, burning sensation and the like or discomfort feeling of flowing from a nasal cavity to a throat can be easily caused when the nasal spray is used, and the compliance of the medicine is reduced.
Disclosure of Invention
The invention provides a capsule-type eletriptan nasal inhalation powder inhalation agent which has the advantages of high bioavailability, quick drug absorption and avoidance of liver first-pass effect.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a capsule-type eletriptan nasal inhalation powder aerosol is composed of eletriptan micro powder and carrier micro powder, and is characterized in that the particle size of the raw material micro powder of the eletriptan micro powder is d 10-30 mu m, d 50-10-100 mu m and d 90-30-150 mu m, and the particle size of the carrier micro powder is d 90-20-320 mu m.
Preferably, the fine raw material powder has a particle size of d 10-20 μm, d 50-20-80 μm, and d 90-40-100 μm, and the fine carrier powder has a particle size of d 90-30-200 μm.
More preferably, the fine raw material powder has a particle size of d 10-15 μm, d 50-30 μm, and d 90-50 μm, and the fine carrier powder has a particle size of d 90-50 μm to 150 μm.
Preferably, the carrier is one or more of lactose, glycine, mannitol and sorbitol.
More preferably, the carrier is lactose.
Eletriptan (almotriptan) is a new first-line triptan therapeutic drug, which has the same curative effect as sumatriptan, but has better tolerance and lower price than sumatriptan, and can exert the anti-migraine effect by contracting intracranial vessels and inhibiting neurogenic inflammation. The active components of the medicine can bypass blood brain barrier and directly enter the central nervous system to give full play to the medicine effect, improve the bioavailability, accelerate the medicine absorption and avoid the first pass effect of liver, so the medicine dosage and the medicine taking frequency can be reduced, and the occurrence of adverse effects can be reduced; the powder inhalation only contains lactose which is easy to be absorbed by human body, thus eliminating irritation and discomfort to nasal mucosa and improving treatment compliance.
The invention also provides a preparation method of the capsule-type eletriptan nasal inhalation powder aerosol, which comprises the following steps:
s1, eletriptan micronization: taking an eletriptan raw material, drying at 40-80 ℃ for 0.5-2 hours, and cooling to room temperature; micronizing the raw materials by using a jet mill;
s2, preparation of lactose particles: carrying out superfine grinding on lactose, sieving the lactose by a sieve with 50-100 meshes, putting the sieved lactose into a fluidized bed granulator, granulating by using water or ethanol, controlling the amount of spraying slurry according to the state of granules by controlling the air inlet temperature to be 50-90 ℃, the material temperature to be 40-70 ℃, the spraying speed to be 1-500 g/min and the fan frequency to be 20-40 Hz, continuously drying for 2-30 minutes after the spraying slurry is finished, and controlling the water content to be 0.1-3% to obtain lactose granules; the granulation mode can also adopt high-shear granulation and dry granulation.
S3, mixing: taking micronized eletriptan and lactose particles, and mixing the micronized eletriptan and the lactose particles in an equivalent progressive mode through one of a V-shaped mixer and a three-dimensional mixer at a mixing speed of 2-15 r/min for 5-45 min;
s4, subpackaging: and filling the uniformly mixed powder into capsules by using a trace capsule filling machine to prepare the capsule type eletriptan powder inhalation capsules.
The invention also provides an application of the capsule type eletriptan nasal inhalation powder inhalation: comprises the modes of nasal inhalation and oral inhalation 2, the eletriptan can also exist in the form of physiological salt, the dosage of the powder inhalation is 1-50mg per day, and the inhalation of each dosage is completed by 1-3 capsules.
Preferably, the amount of the dry powder inhalation is 5-30mg per day.
More preferably, the amount of the dry powder inhalation is 10-20mg per day.
After nasal inhalation, eletriptan can directly reach the pain part through nasal brain targeting administration, quickly takes effect, avoids liver first-pass effect, improves bioavailability, avoids liver first-pass effect by direct inhalation, and reduces the dosage of the medicine and side effects caused by large dosage.
The active component in the formula can be eletriptan physiologically acceptable salt, other triptans with the same curative effect, or any combination of the substances, such as eletriptan/sumatriptan succinate, eletriptan or naratriptan and other compound nasal inhalation powder inhalation agents.
By adopting the technical scheme, the blood brain barrier can be bypassed by the eletriptan, so that the bioavailability of the medicine is improved, the medicine is fast to absorb, after nasal inhalation administration, the eletriptan can directly reach a pain part through the nasal brain targeted administration, the effect is fast, the liver first-pass effect is avoided, the bioavailability is improved, the liver first-pass effect is avoided by direct inhalation, the medicine dosage is reduced, and the side effect caused by large dosage is reduced.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without paying creative efforts.
FIG. 1 shows the results of the permeation test in example 1 of the present invention.
Detailed Description
The following further describes embodiments of the present invention with reference to the drawings. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
The formula is as follows: 2g of eletriptan and 15g of lactose, and the total weight is 1000 granules.
Taking 2g of eletriptan, drying at 50 ℃ for 1.5 hours, and cooling to room temperature; micronizing the raw materials by using a jet mill; carrying out superfine grinding on 15g of lactose, sieving by a 60-mesh sieve, putting the sieved lactose into a fluidized bed granulator, granulating by using ethanol, wherein the air inlet temperature is 60 ℃, the material temperature is 45 ℃, the liquid spraying speed is 2 g/min, the fan frequency is 20Hz, and continuously drying for 15min after the spraying is finished.
Taking micronized eletriptan and lactose particles, and mixing in an equivalent progressive mode. The mixing speed is 5 r/min, the mixing time is 20min, and the uniformly mixed powder is filled into capsules by a micro capsule filling machine.
Example 2
The formula is as follows: 4g of eletriptan and 25g of lactose, and preparing 1000 granules.
Taking 4g of eletriptan, drying at 60 ℃ for 1 hour, and cooling to room temperature; micronizing the raw materials by using a jet mill; 30g of lactose is subjected to superfine grinding and then sieved by a sieve of 80 meshes, the sieved lactose is placed in a fluidized bed granulator and granulated by ethanol, the air inlet temperature is 70 ℃, the material temperature is 60 ℃, the liquid spraying speed is 3 g/min, the fan frequency is 30Hz, and after the spraying is finished, the drying is continued for 25 min.
Taking micronized eletriptan and lactose particles, and mixing in an equivalent progressive mode. The mixing speed is 10 r/min, the mixing time is 30 min, and the uniformly mixed powder is filled into capsules by a micro capsule filling machine.
Example 3
The formula is as follows: 5g of eletriptan and 40g of lactose, and preparing 1000 granules.
Taking 8g of eletriptan, drying at 60 ℃ for 2 hours, and cooling to room temperature; micronizing the raw materials by using a jet mill; 60g of lactose is subjected to superfine grinding and then is sieved by a 100-mesh sieve, the sieved lactose is placed in a fluidized bed granulator and is granulated by ethanol, the air inlet temperature is 70 ℃, the material temperature is 60 ℃, the liquid spraying speed is 4 g/min, the fan frequency is 40Hz, and after the spraying is finished, the drying is continued for 20 min.
Taking micronized eletriptan and lactose particles, and mixing in an equivalent progressive mode. The mixing speed is 12 r/min, the mixing time is 40 min, and the uniformly mixed powder is filled into capsules by a micro capsule filling machine.
The invention carries out the permeable membrane test according to the following method:
the method comprises the following steps: cutting fresh Bufo siccus mucosa into suitable size, fixing between the supply chamber and the receiving chamber, allowing the mucosa outer surface to face the supply chamber, injecting physiological saline with pH of 5.0 into the receiving chamber to fill, and recording the volume of the solution. Starting a magnetic stirrer and a constant-temperature water bath, keeping constant-speed stirring, keeping constant temperature at 37 ℃, uniformly scattering administration powder on a mucous membrane of a diffusion chamber, spraying a proper amount of physiological saline for wetting, sampling 0.4ml at each time point, and supplementing 0.4ml of physiological saline with the pH value of 5.0 in a receiving chamber. The amount of the membrane permeation of the obtained sample was measured.
Sample preparation: example 1
FIG. 1 shows a schematic view of a
The result of the film penetration test is shown in figure 1, and the determination result shows that the eletriptan nasal inhalation powder inhalation agent has excellent film penetration capability after the processes of prescription optimization, particle size control and the like.
Evaluation of nasal mucociliary (in vitro):
the toads were grouped into groups of 4 each, group 1: physiological saline; group 2: the nasal inhalation aerosol of eletriptan of the invention (example 1, diluted to 2mg/ml with normal saline); group 3: 2% propranolol.
Fixing Bufo siccus on frog board, opening oral cavity, dripping 0.2ml of the above solution on mucous membrane, standing for 20min, cutting 3mm × 3mm palate mucous membrane with surgery, spreading on glass slide after treatment, observing cilia swinging condition of mucous membrane under microscope, placing the glass slide in chromatography cylinder at room temperature, sealing, observing cilia condition at regular intervals until cilia stop swinging, and recording cilia continuous movement time, with the results as shown in Table 1.
TABLE 1 ciliary duration
The experimental results show that: the cilia of group 1 move actively, the number of the cilia swings is large, and the continuous swinging time is 517 +/-15 min; after the nasal inhalation aerosol of eletriptan of the invention is given in group 2, ciliary movement is not affected, and the continuous swinging time is 504 +/-11 min. After the group 3 is dripped with 2% propranolol solution, part of mucous epithelium falls off and cilia do not move during the first observation; the result shows that the eletriptan nasal inhalation powder aerosol has good compatibility with cilia of the nasal cavity, and does not cause damage to cilia swinging.
The experimental results of the other examples were the same.
Determination of evacuation Rate
The emptying rate of the powder aerosol capsules prepared by the implementation 1-3 is measured according to the method disclosed in the general rule 0111 of the four parts of the national pharmacopoeia 2015 edition, and the result is shown in the following table:
| group of | Example 1 | Example 2 | Example 3 |
| Evacuation Rate (%) | 96.2 | 94.8 | 96.3 |
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.