CN115177599B - Afatinib maleate microcapsule powder and preparation method and application thereof - Google Patents
Afatinib maleate microcapsule powder and preparation method and application thereof Download PDFInfo
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- CN115177599B CN115177599B CN202211024533.4A CN202211024533A CN115177599B CN 115177599 B CN115177599 B CN 115177599B CN 202211024533 A CN202211024533 A CN 202211024533A CN 115177599 B CN115177599 B CN 115177599B
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- afatinib maleate
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- afatinib
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- 229960001686 afatinib Drugs 0.000 title claims abstract description 158
- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 USNRYVNRPYXCSP-JUGPPOIOSA-N 0.000 title claims abstract description 155
- 239000003094 microcapsule Substances 0.000 title claims abstract description 108
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Classifications
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
- A61K9/5057—Gelatin
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and relates to afatinib maleate microcapsule powder, a preparation method and application thereof, wherein 30-55 parts of afatinib maleate, 10-24 parts of acacia, 10-24 parts of gelatin, 12-30 parts of maltodextrin and 2-5 parts of sucrose are respectively taken, and are subjected to liquid preparation, dissolution, mixing, suction filtration, homogenization, gelatin mixing, pH value adjustment to 4+/-0.2, stirring until the liquid color is uniform, stirring termination, cooling to obtain emulsion, spray drying and powder collection, thus obtaining afatinib maleate microcapsule powder, and the afatinib maleate microcapsule powder is prepared into tablets.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and relates to afatinib maleate microcapsule powder, a preparation method and application thereof.
Background
Afatinib maleate is a potent, irreversible dual inhibitor of the second representative skin growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER 2) tyrosine kinase developed by bringenaghan (Boehringer Ingelheim) in germany, and its principle of action is to inhibit the activity of the tyrosine kinase irreversibly by a Michaelreaction with the thiol group of cysteine 797 in EGFR, interrupting downstream information conduction, thereby preventing cancer cell growth and inducing apoptosis. Clinically, the traditional Chinese medicine composition is used for treating diseases such as Non-small cell lung cancer (Non-small celllungcancer, NSCLC), colorectal cancer, breast cancer, head and neck cancer and the like.
In the prior art, in order to reduce the generation of impurities caused by hydrolysis or oxidation reaction of afatinib maleate in the production and preparation process as far as possible, the possibility of adopting wet tabletting is abandoned, a powder direct tabletting method or a dry granulating tabletting method is usually adopted, and then a hot melting granulating method is also disclosed for tabletting. The publication number is: the Chinese patent application of CN 105456222A, namely an afatinib maleate tablet and a preparation method thereof, adopts a powder direct compression method to prepare the tablet, has simple process and simple and convenient operation, but the afatinib maleate is in a thin needle-shaped form, so that the random arrangement and length of needles cause smaller bulk density and poorer flowability, and the direct compression method is adopted to prepare the tablet, thus easily causing top crack or lamination and poor compressibility of the tablet during a direct compression process, and simultaneously reducing the content uniformity of the tablet. The publication number is: the Chinese patent application No. 106074427A discloses an afatinib maleate tablet and a preparation method thereof, wherein the tablet is prepared by adopting a dry granulation tabletting method, so that the fluidity is improved, but the dry granulation is carried out under the action of mechanical force, the quality control of the granulation process is difficult, the repeatability of the granule property is poor, fine powder is easy to generate, the prepared granules are generally hard and irregular, the friability of the pressed tablet is high, and the pitting phenomenon is easy to occur. The other publication number is: the Chinese patent application No. 107260698B discloses a preparation method of afatinib maleate tablets, which adopts a hot-melting granulation method to prepare tablets, wherein calcium sulfate is added to improve the integrity of the granules, and calcium sulfate is added to improve the compressibility of the tablets, but the hot-melting granulation method needs to strictly control the heat exposure condition and the heating duration of afatinib maleate.
The microencapsulation technology is a technology for embedding a liquid or solid product (capsule core material) into a microcapsule with the diameter of 1-5000 mu m (usually 5-250 mu m) by using natural or synthetic polymer film forming materials (capsule materials), and is widely applied to the fields of medicines, foods, pesticides, feeds, cosmetics, dyes, adhesives, copying papers and the like, and the process of preparing the microcapsule is called microencapsulation technology, which is called microencapsulation for short. The use of microencapsulation technology in the field of pharmaceutical formulations has also been for over fifty years old, primarily for external use initially, and thereafter has evolved into mucosal administration, as well as oral and intramuscular/subcutaneous administration formulations. The microcapsule used in the medicine field is mainly a slow-release microcapsule, and after the medicine (a capsule core material) and a polymer film-forming material (a capsule material) are embedded into the microcapsule, the medicine is released at a specific position in vivo in a proper speed and for a continuous time in a form of diffusion, permeation and the like, so that the purpose of exerting the medicine effect to a greater extent is achieved. In addition, drug microencapsulation has the following advantages: preventing the drug from being destroyed or irritated in the gastrointestinal tract; masking the bad smell of the medicine; prevent the volatilization loss of the medicine; solidifying the liquid drug for transportation, application and storage; avoiding the incompatibility of compound preparation; sustained release, controlled release and targeted delivery of drugs; the bioavailability of the medicine is improved; encapsulation of bioactive substances such as living cells, vaccines, etc. does not cause loss of activity or denaturation.
The afatinib maleate tablet is used as a molecular targeting antitumor drug, has the characteristics of strong pertinence, quick drug effect, less side effect and the like compared with a common treatment mode, can form higher concentration around a tumor target, improves the curative effect and simultaneously inhibits the occurrence of toxic and side effects, thereby reducing the damage to normal cell tissues. Therefore, whether the medicine can penetrate cell membranes after entering a human body or not can combine with a cancer-causing site on the targeting selection molecular level, so that tumor cells die specifically, and the targeting selection molecular level is the key of afatinib maleate anti-tumor. The research and development of a chemotherapeutic drug release system with better in-vivo dispersing, penetrating and dissolving effects can further improve the therapeutic effect of the drug, and has important significance for realizing efficient and safe tumor treatment, so that a set of proper microencapsulation preparation technology is necessary for afatinib maleate drugs, the efficient and stable drug release rate of the drugs is enhanced, and the bioavailability of the drugs is improved. There are no reports on the preparation of afatinib maleate medicaments by using a microencapsulation technology.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides the afatinib maleate microcapsule powder, the preparation method and the application thereof, and the obtained microcapsule powder has stable quality, uniform content, good in-vitro and in-vivo dissolution behavior, the influence of environmental factors on the medicine is reduced, the stability is enhanced, the use amount of auxiliary materials is reduced, the purity of afatinib maleate in the medicine is relatively improved, the efficient and stable medicine release rate is realized, and the side effect is reduced.
In order to achieve the above purpose, the invention is achieved by the following technical scheme:
the preparation method of the afatinib maleate microcapsule powder comprises the following steps:
(1) Taking: according to the weight portions, 30 to 55 portions of afatinib maleate, 10 to 24 portions of acacia, 10 to 24 portions of gelatin, 12 to 30 portions of maltodextrin and 2 to 5 portions of sucrose are separated for standby;
(2) Preparing liquid: adding water into acacia to prepare an acacia water solution;
(3) Dissolving: adding the afatinib maleate into the Arabic gum aqueous solution to dissolve, so as to obtain an initial mixed solution;
(4) Mixing: adding the maltodextrin and the sucrose into the primary mixed solution, and stirring until the maltodextrin and the sucrose are fully mixed to obtain a mixed solution;
(5) And (3) suction filtration: putting the mixed solution into a suction filter for suction filtration, and separating filtrate for later use;
(6) Homogenizing: preheating the filtrate to 8085 ℃, and placing the filtrate into a homogenizer to be homogenized at the temperature of 8085 ℃ to obtain microemulsion;
(7) Complex coacervation into vesicles: adding gelatin into the microemulsion, regulating the pH value to 480.2, stirring until the liquid color is uniform, stopping stirring, and cooling to 5085 ℃ to obtain emulsion;
(8) And (5) atomizing and drying: and (3) spray-drying the emulsion, and collecting powder to obtain afatinib maleate microcapsule powder.
Preferably, in the step (1), the afatinib maleate is screened through a 40-mesh screen for later use before being separated.
Preferably, in the step (1), the mass ratio of the acacia, the gelatin, the maltodextrin and the sucrose is 24:24:30:5.
Preferably, in the step (2), the mass ratio of the acacia to the water in the acacia aqueous solution is 1:19.
Preferably, in the step (6), the homogenization condition is that the homogenization is carried out 3 times or 6 min/time at 11000rpm under 40MPa pressure.
Preferably, in the step (7), glacial acetic acid or dilute hydrochloric acid is used for adjusting the pH value.
Preferably, in the step (8), relevant parameters of spray drying are 34-37mL/min of feed flow, 20-25% of feed concentration and 16085 ℃ of air inlet temperature.
Further, the feed flow rate is 35mL/min, the feed concentration is 20%, and the air inlet temperature is 160 ℃.
The invention also provides application of the afatinib maleate microcapsule powder, which is used for preparing afatinib maleate tablets.
Compared with the prior art, the invention has the following beneficial effects:
(1) The influence of the temperature and the relative humidity of environmental factors on the afatinib maleate medicament is reduced, the stability of the medicament is enhanced, and the medicament is convenient to store and transport;
(2) The afatinib maleate microcapsule powder has stable quality, uniform content and good in-vitro dissolution behavior;
(3) Compared with tablets prepared by pressing through a conventional method, the microcapsule powder has good fluidity, reduces the use amount of auxiliary materials, relatively improves the purity of afatinib maleate in the tablets, has high-efficiency and stable release rate, and reduces side effects;
(4) The invention combines the complex coacervation preparation process and the spray drying process, avoids introducing the emulsifier and other impurities, can effectively avoid the dry powder from agglomerating in the powder collecting device during spray drying, does not collide with other materials during subsequent tabletting, has simple preparation method, and is more suitable for mass production.
Drawings
FIG. 1 is a graph showing the results of screening and examining the wall material composition ratio in example 1 of the present invention
FIG. 2 is a graph showing the results of screening and examining the dosage of the core material according to example 2 of the present invention
FIG. 3 is a graph showing the results of examining the effect of the feed flow rate on the encapsulation efficiency of the microcapsule powder in example 5 of the present invention
FIG. 4 is a graph showing the results of examining the effect of the feed concentration on the encapsulation efficiency of the microcapsule powder in example 6 of the present invention
FIG. 5 is a graph showing comparative investigation results of dissolution characteristics of afatinib maleate microcapsule tablets and ordinary tablets of the present invention
Detailed Description
The invention will now be described in further detail with reference to specific examples and pharmacokinetic tests, which are intended to illustrate, but not to limit, the invention, and not to limit the invention to the following examples. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Considering that the powder particles of the afatinib maleate medicine need to be unified when the afatinib maleate microcapsule powder is prepared, the distribution of the medicine in the afatinib maleate microcapsule powder prepared in this way is more uniform and the quality is better. Thus, afatinib maleate was screened through a 40 mesh screen for use.
Example 1
The rationality of the wall material component ratios is positively correlated with the stability of the microcapsules prepared from the wall material embedded core material capsules, so that the preferable range of the wall material component ratios can be screened by examining the embedding rate of each wall material component ratio.
In the embodiment, the afatinib maleate medicine passing through a 40-mesh screen is taken as a core material, the acacia, gelatin, maltodextrin and sucrose are selected to form wall materials, 100 parts by weight of the wall materials are 50 parts by weight, 120 parts by weight of the wall materials are 25 parts by weight, 150 parts by weight of the wall materials are 100 parts by weight, 50 parts by weight, 150 parts by weight, 120 parts by weight, 25 parts by weight, 120 parts by weight and 150 parts by weight are 100 parts by weight, 50 parts by weight, 100 parts by weight, 6 groups by weight are specifically arranged, 3 parallel experiments are respectively, the acacia is added with water according to the mass ratio of the acacia to water of 1:19, the acacia is prepared into an aqueous solution of the acacia, the acacia maleate medicine with the same amount as the wall materials is added, the acacia is fully mixed, and then the acacia is pumped and filtered after the maltodextrin and the sucrose are added, the filtrate is preheated to 80 ℃, the filtrate is put into a homogenizer to be subjected to homogenization at 50MPa for 5000rpm for 6min 1 time, the gelatin is added, the pH value of the mixture is 4.2, the mixture is stirred until the liquid color is evenly, the mixture is cooled until the liquid color is stopped, the mixture is cooled until the liquid color is cooled until the mass ratio is 1:19, and the maleic acid is dry at 50 mL/30 mL, and the air inlet concentration is 30% is obtained by spraying, and the micro-capsule powder is prepared. The embedding rate of each wall material is measured by ultraviolet spectrophotometry, and the average value of each group is taken, and the specific measuring method is as follows:
drawing an afatinib maleate standard curve: dissolving afatinib maleate standard substances in ethanol to prepare 1mg/mL, 3mg/mL, 5mg/mL, 6mg/mL and 9mg/mL standard solutions respectively, measuring a frontal surface diagram of the standard solutions with the concentration of 5mg/mL under an ultraviolet spectrophotometer, selecting the maximum absorption wavelength, measuring absorbance values of five groups of standard solutions with each concentration under the absorption wavelength, and fitting and drawing an afatinib maleate standard curve by taking the afatinib maleate concentration as an X axis and taking the absorbance value of each standard solution with the maximum absorption wavelength as a Y axis.
Sample solution preparation: weighing a sufficient amount of afatinib maleate microcapsule powder, leaching with absolute ethyl alcohol, drying filter residues, grinding, placing into a conical flask, adding purified water, stirring, filtering, repeatedly washing, filtering and drying the obtained aqueous solution, and grinding into powder; precisely weighing 5g of powder, placing into a conical flask with 100mL of absolute ethyl alcohol, vibrating for 10min by ultrasonic waves, standing for 24h, precisely weighing 1mL, placing into a 25mL volumetric flask, fixing the volume by using the absolute ethyl alcohol, and shaking uniformly to obtain a sample solution.
Measuring the absorbance value of each sample solution by using an ultraviolet spectrophotometer, comparing the absorbance value with a standard curve prepared by using a standard solution to obtain the mass of afatinib maleate in the microcapsule, and measuring the embedding rate of each wall material, wherein the specific calculation formula is as follows:
the results of the investigation are shown in Table 1 and FIG. 1:
table 1 results table of investigation of embedding rate of each wall material component ratio
As can be seen from the results shown in table 1 and fig. 1, the wall material with a better embedding rate (the embedding rate is close to 80% or more than 80%) has a composition ratio ranging from 150:120:100:25 to about 120:120:150:25, and the optimal ratio is 120:120:150:25, namely 24:24:30:5.
Example 2
In this example, experiments were performed by taking the optimal proportioning scheme obtained in example 1, and setting the core material content to be 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% and 80% by taking the wall material components, and determining the embedding rate and drug loading rate of each group by the same method as the ultraviolet spectrophotometry described in example 1, and screening the preferred range of afatinib maleate drug loading rate by combining the investigation of the embedding rate and drug loading rate, and the investigation results are shown in table 2 and fig. 2.
Wherein, the drug loading formula is:
TABLE 2 results of investigation of the effect of the dosage on the microcapsule powders
From the results shown in Table 2 and FIG. 2, the preferred range of the afatinib maleate dosage of 30% -55% and the most preferred afatinib maleate dosage of 50% can be selected in combination with the production cost comprehensive consideration.
Example 3
The present example was examined for the conditions of homogeneous emulsions during production, and was specifically examined by the following 2 experiments:
(1) Preliminary investigation of homogeneity conditions
According to the weight parts, 50 parts of afatinib maleate, 20 parts of acacia, 20 parts of gelatin, 25 parts of maltodextrin and 5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; and adding afatinib maleate into the Arabic gum aqueous solution to be fully dissolved, adding maltodextrin and sucrose, stirring until the materials are fully mixed, putting into a suction filter for suction filtration, and separating filtrate to be used as a investigation sample.
Preheating the filtrate to 8085 ℃, setting the temperature of a homogenizer to 8085 ℃ and the homogenizing pressure to 40MPa, wherein the setting of the examined homogenizing conditions in the embodiment comprises: 5000rpm for 6 min/1 times, 6000rpm for 6 min/1 times, 70000 rpm for 6 min/1 times, 5000rpm for 6 min/1 times, 8000rpm for 6 min/2 times, 5000rpm for 6 min/2 times, 9000rpm for 6 min/2 times, 10000rpm for 6 min/2 times, 11000rpm for 6 min/3 times, 11000rpm for 6 min/4 times, and observing whether the emulsion has a delamination phenomenon or not, and using a fully automatic viscosimeter IVS600-2S (Ubbelohde viscometer) to obtain the optimal homogenization conditions for further examining the optimal value of the homogenization times. The test results are shown in Table 3.
TABLE 3 preliminary examination results table of homogeneity conditions
From the results shown in Table 3 above, it can be seen that: the emulsion is only homogenized once, so that the emulsion is difficult to fully and uniformly emulsify, and the emulsion stability of the emulsion is low; when the homogenization condition exceeds 9000rpm for 6 min/time for 2 times, the homogenized emulsion has better stability, and the emulsion is not layered; the viscosity of the emulsion is optimal when the homogenization conditions are 11000rpm for 6 min/3 or more. Therefore, the most preferred single homogenization condition is 11000rpm for 6min.
(2) Examination of the number of homogenization
Preheating filtrate to be emulsified to 8085 ℃, setting the temperature of a homogenizer to 8085 ℃, setting the homogenizing pressure to 40MPa, and carrying out single homogenizing at 11000rpm for 6min, wherein the number of times of homogenizing is 1-4 times, adding gelatin, regulating the pH value of the mixed solution to 4.2 by glacial acetic acid, stirring until the liquid color is uniform, stopping stirring, cooling to 5085 ℃, obtaining emulsion, and spray-drying at the feed flow rate of 30mL/min, the feed concentration of 30% and the air inlet temperature of 150 ℃ to obtain afatinib maleate microcapsule powder.
The entrapment rate was determined by the same method as the ultraviolet spectrophotometry described in example 1.
The calculation formula of the yield is as follows:
the method for measuring the content of afatinib maleate in the emulsion comprises the following steps: before spray drying, a sufficient amount of emulsion is taken, the emulsion is placed in an conical flask, purified water is added for stirring, washing is carried out repeatedly, the obtained aqueous solution is filtered and dried into powder, 5g of powder is placed in the conical flask with 100mL of absolute ethyl alcohol, ultrasonic oscillation is carried out for 10min, standing is carried out for 24h, 1mL is precisely measured, the obtained powder is placed in a 25mL volumetric flask, absolute ethyl alcohol is used for constant volume and shaking is carried out uniformly, and an emulsion sample solution is prepared, and the emulsion sample solution is measured by the same method as the ultraviolet spectrophotometry described in the example 1.
The method for measuring the afatinib maleate content in the actual product comprises the following steps: taking enough afatinib maleate microcapsule powder, grinding the microcapsule powder, placing the microcapsule powder into a conical flask, adding purified water, stirring, repeatedly washing, carrying out suction filtration and drying on the obtained aqueous solution to obtain powder, placing 5g of the powder into a conical flask with 100mL of absolute ethyl alcohol, carrying out ultrasonic oscillation for 10min, standing for 24h, precisely measuring 1mL, placing into a 25mL volumetric flask, carrying out constant volume and shaking with absolute ethyl alcohol, and preparing the microcapsule powder sample solution, and carrying out the same measurement with the ultraviolet spectrophotometry in the embodiment 1.
The measurement results are shown in Table 4.
TABLE 4 examination results of homogenization times to encapsulation efficiency and yield of microcapsule powder
As is apparent from the results shown in table 4, the number of homogenization is positively correlated with the entrapment rate, and the yield is highest when the number of homogenization is 3, but after the number of homogenization exceeds 3, the yield is lowered because the amount of afatinib maleate drug as a core material is oxidized or hydrolyzed increases with the increase of the number of homogenization.
In summary, the homogenization conditions at 40MPa are preferably maintained at 8085 ℃ for 3 times at 11000rpm for 6 min/time.
Example 4
After the investigation experiments described in example 1, example 2 and example 3, the wall material component ratio, the core material addition amount and the homogenization conditions under 40MPa involved in the confirmed afatinib maleate microcapsule powder production step were further examined, and based on this, the present example screened the best homogenization pressure for the influence of the homogenization pressure on the yield and efficiency of afatinib maleate microcapsule powder.
According to the weight parts, 50 parts of afatinib maleate, 20 parts of acacia, 20 parts of gelatin, 25 parts of maltodextrin and 5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 8085 ℃, setting the temperature of a homogenizer to 8085 ℃, setting the homogenization pressures to 30MPa, 35MPa, 40MPa, 45MPa, 50MPa, 55MPa and 60MPa, homogenizing for 3 times at 11000rpm for 6 min/time, measuring the yield and the embedding rate of afatinib maleate microcapsule powder under each homogenization pressure by the same method as in the example 3, and observing the results shown in Table 5.
TABLE 5 results of examination of the effect of homogenizing pressure on the yield and embedding rate of microcapsule powder
The homogenizing pressure has obvious influence on the emulsion, the larger the homogenizing pressure is, the larger the shearing force of the feed liquid is, the more uniform and stable the formed emulsion is, and meanwhile, the surface area of the liquid drop is increased, and the surface energy is improved. Therefore, when the homogenization pressure is higher than a critical value, the surface energy of the liquid drop is too large, so that broken liquid is easy to form and float upwards, the emulsion is layered, and the yield and embedding rate of the formed microcapsule are reduced. From the results shown in Table 5, the optimal homogenization pressure was selected to be 40MPa, since the yield was highest and the entrapment rate was relatively high when the homogenization pressure was 40MPa.
Example 5
The spray drying method is to spray the mixture of the core material and the capsule material through a sample injection pump under the action of compressed air flow to form small liquid drops, and the solvent in the small liquid drops is quickly evaporated in a drying chamber and separated by a vortex separator to obtain the required microcapsule. The spray drying method can dry the solution, emulsion and suspension into powder particles, and avoids the complicated operation processes such as evaporation, crushing and the like. The method can be operated continuously, saves time, is suitable for industrial production, and can avoid introducing impurities such as emulsifying agent and the like.
In the spray drying process, the water is excessively evaporated when the feeding flow is too slow, and the temperature of an air outlet is too high at the moment, so that a core material (afatinib maleate) is oxidized at high temperature, and the yield of afatinib maleate microcapsule powder is reduced; if the feeding flow is too fast, the water evaporation capacity is insufficient, and at the moment, the prepared microcapsule powder cannot form a wall with good compactness and certain strength, so that the embedding rate and yield of the product are reduced, the diameter of the microcapsule particles of the product is large, and the product has poor fluidity and high water content although the product has good water dispersibility and solubility, and is unfavorable for long-term storage of afatinib maleate medicines; and the phenomenon of tower sticking of materials can be caused by too fast and serious feeding flow, so that the powder yield of spray drying is reduced.
Based on this, the present example examined the effect of feed flow rate during spray drying on the embedding rate of the preparation of afatinib maleate microcapsule powder.
According to the weight parts, 50 parts of afatinib maleate, 20 parts of acacia, 20 parts of gelatin, 25 parts of maltodextrin and 5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 8085 ℃, keeping the homogenization condition at 40MPa for 6 min/time and 3 times at 11000rpm to obtain microemulsion, adding gelatin into the microemulsion, adjusting the pH value to 480.2, stirring until the liquid color is uniform, cooling to 5085 ℃ to obtain emulsion, setting the air inlet temperature of spray drying to 160 ℃, and measuring the embedding rate under each feed flow by the same method as in example 3 when the feed flow of spray drying is respectively 25mL/min, 30mL/min, 35mL/min, 40mL/min and 45mL/min, wherein the measurement results are shown in Table 6 and FIG. 3.
TABLE 6 influence of feed flow on embedding rate investigation results table
From the results shown in table 6 above, it can be derived that: when the feeding flow is 35mL/min, the embedding rate of the afatinib maleate microcapsule powder prepared by spray drying is optimal. From FIG. 3, it can be obtained that the embedding rate of the afatinib maleate microcapsule powder prepared by spray drying is kept at about 84% when the feeding flow is 34-37mL/min, and the encapsulation efficiency is higher at this time. Thus, the preferred range of feed flow rates is 34-37mL/min, with a most preferred feed flow rate of 35mL/min.
Example 6
In the spray drying step of preparing afatinib maleate microcapsule powder, the solid content of the emulsion (also called as feed concentration in the spray drying step) is controlled, so that the formation of the capsule wall and the improvement of compactness are facilitated, meanwhile, the migration of the core material to the surface of the wall material is reduced due to the increase of the viscosity of the system, the core material can be better embedded, and the embedding rate is increased; however, too high a feed concentration means that the emulsion has a high viscosity, which is detrimental to the degree of atomization of the emulsion in the spray dryer, and in severe cases, the emulsion is insufficiently dried due to the large droplet diameter. Based on this, the present example was specifically examined for the effect of the emulsion solids concentration on the entrapment rate during spray drying.
According to the weight parts, 50 parts of afatinib maleate, 20 parts of acacia, 20 parts of gelatin, 25 parts of maltodextrin and 5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 8085 ℃, keeping the homogenization condition at 40MPa for 3 times at 11000rpm for 6 min/time to obtain microemulsion, adding gelatin into the microemulsion, adjusting the pH value to 480.2, stirring until the liquid color is uniform, cooling to 5085 ℃, controlling the solid content by using a rapid emulsion solid content detector, cooling to 5085 ℃ to obtain emulsion, respectively obtaining emulsion with feed concentration of 20%, 22.5%, 25%, 27.5% and 30%, setting the air inlet temperature of 160 ℃, the feed flow of 35mL/min, performing spray drying, collecting powder, and obtaining the afatinib maleate microcapsule powder prepared under the conditions of each solid content, the embedding rate of which is measured and calculated, and the results are shown in table 7 and figure 4.
TABLE 7 results of investigation of the effect of feed concentration on the entrapment rate
From the results shown in table 7 and fig. 4, it is possible to obtain: the embedding rate is better within the range of 20% -25% of the feeding concentration; the most preferred feed concentration is 20% in combination with practical production considerations.
Example 7
According to the weight parts, 50 parts of afatinib maleate, 20 parts of acacia, 20 parts of gelatin, 25 parts of maltodextrin and 5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 80 ℃, keeping the homogenization condition at 40MPa at 80 ℃ for 11000rpm for 6 min/homogenizing for 3 times to obtain microemulsion, adding gelatin into the microemulsion, regulating the PH value to 4.0 by dilute hydrochloric acid, stirring until the liquid color is uniform, stopping stirring, cooling to 5085 ℃, controlling the solid content by using an emulsion solid content rapid detector, regulating the solid content of the emulsion to 20%, cooling to 50 ℃ to obtain emulsion, setting the air inlet temperature of spray drying to 160 ℃, the feed flow to 35mL/min, performing spray drying, and collecting powder to obtain afatinib maleate microcapsule powder.
Example 8
According to the weight parts, 30 parts of afatinib maleate, 10 parts of acacia, 10 parts of gelatin, 12 parts of maltodextrin and 2 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 75 ℃, keeping the homogenization condition at 40MPa at 75 ℃ for 6 min/time at 11000rpm for 3 times to obtain microemulsion, adding gelatin into the microemulsion, regulating the PH value to 3.8 by glacial acetic acid, rapidly stirring, cooling to 45 ℃ to obtain emulsion, regulating the concentration of the emulsion to 20%, setting the air inlet temperature of spray drying to 160 ℃ and the feed flow to 34mL/min, performing spray drying, and collecting powder to obtain afatinib maleate microcapsule powder.
Example 9
According to the weight parts, 40 parts of afatinib maleate, 16 parts of acacia, 16 parts of gelatin, 20 parts of maltodextrin and 3.5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 85 ℃, keeping the homogenization condition at 40MPa at 85 ℃ for 6min at 11000rpm for 3 times to obtain microemulsion, adding gelatin into the microemulsion, regulating the PH value to 4.2 by dilute hydrochloric acid, rapidly stirring, cooling to 55 ℃ to obtain emulsion, regulating the concentration of the emulsion to 20%, setting the air inlet temperature of spray drying to 160 ℃ and the feed flow to 37mL/min, performing spray drying, and collecting powder to obtain afatinib maleate microcapsule powder.
Example 10
According to the weight parts, 55 parts of afatinib maleate, 24 parts of acacia, 24 parts of gelatin, 30 parts of maltodextrin and 5 parts of sucrose which are sieved by a 40-mesh sieve are respectively taken; adding water into acacia gum according to the weight ratio of acacia gum to water of 1:19 to prepare an acacia gum aqueous solution; adding afatinib maleate into the aqueous solution of Arabic gum, fully dissolving, adding maltodextrin and sucrose, stirring to fully mix, putting into a suction filter for suction filtration, separating filtrate, preheating the filtrate to 85 ℃, keeping the homogenization condition at 40MPa at 85 ℃ for 6 min/time at 11000rpm for 3 times to obtain microemulsion, adding gelatin into the microemulsion, regulating the PH value to 4.2 by using dilute hydrochloric acid, rapidly stirring until the liquid color is uniform, stopping stirring, cooling to 55 ℃ to obtain emulsion, regulating the concentration of the emulsion to 20%, setting the inlet air temperature of spray drying to 160 ℃ and the feed flow to 37mL/min, performing spray drying, and collecting powder to obtain afatinib maleate microcapsule powder.
Example 11
The afatinib maleate microcapsule powders prepared in example 7-example 10 were prepared into tablets using conventional tablet drug preparation techniques. The specific preparation steps in this example are as follows:
(1) Finishing the afatinib maleate microcapsule powder by using a swinging finishing machine with an 18-mesh screen for standby;
(2) Total mixing: according to the weight of the particle-sized afatinib maleate microcapsule powder, 15 weight percent of sodium alginate, 0.2 weight percent of micropowder silica gel and 60 weight percent of microcrystalline cellulose are respectively taken, the afatinib maleate microcapsule, the sodium alginate, the micropowder silica gel and the microcrystalline cellulose are put into a mixer and mixed for 15 minutes at 10rpm to obtain a primary mixed material, and the mixed material is added into a hopper mixer again after passing through a low-position rapid particle-sizing machine to be mixed for 10 minutes to obtain a total mixed material;
(3) Pressing the plain tablets: adding the total mixture into a dry granulating machine for dry granulating, calculating tablet weight according to each marked content, tabletting by using a full-automatic rotary tablet press ZP15, setting the main pressure of the tablet press to be 15-30KN, the rotating speed to be 10HZ, the hardness to be 50-90N and the feeding rotating speed to be 40-60rpm, and obtaining afatinib maleate microcapsule tablets;
(4) Coating film, namely accurately weighing coating powder and purified water which are actually required according to the theoretical weight increment of about 8 mg/tablet, pouring the coating solution which is prepared into 12% into a coating pot at room temperature, stirring until the coating solution is completely dissolved, placing the afatinib maleate microcapsule tablet into the coating pot, heating the tablet bed temperature to 40-55 ℃, coating and drying to obtain the afatinib maleate microcapsule tablet.
Experiment 1
The experiment was conducted on the dissolution rate of the afatinib maleate microcapsule tablet prepared in example 11.
The afatinib maleate microcapsule tablets prepared by using the afatinib maleate microcapsule powders obtained in examples 7-10 in example 11 are respectively used as samples with the numbers of A1, A2, A3 and A4; the afatinib maleate tablet (prepared by a dry granulating and tabletting method) obtained in the market is taken as a common tablet S as a control sample, and the dissolution rate is investigated by referring to the second method of the general rule 0931 in the edition 2020 of Chinese pharmacopoeia, and the specific measuring method is as follows:
taking A1, A2, A3 and A4 afatinib microcapsule tablets, taking 900ml of diluted Mcllvainee buffer solution with pH of 4.0 as a dissolution medium, operating according to the law (fourth method of general rule 0931 in the 2020 edition of Chinese pharmacopoeia) at 37 ℃ and 80.5 ℃ for 5 minutes, 10 minutes, 15 minutes, 20 minutes and 30 minutes, simultaneously supplementing the same volume of Mcllvainee buffer solution with the temperature of 37 ℃ and 80.5 ℃ for 20 minutes, immediately filtering the mixture by using a microporous filter membrane with the temperature of 0.45 mu m within 30 seconds, taking clear filtrate, and measuring the content by referring to the rules related to high performance liquid chromatography of the four general rule 0512 in the 2020 edition of Chinese pharmacopoeia and using octadecylsilane bonded silica gel as a filling agent (Welch Ultimate AQ-C18, 150 multiplied by 4.6mm,5 mu m or a chromatographic column with equivalent performance); taking ammonium acetate buffer solution with pH of 3.5 (taking 2.3g of ammonium acetate, adding 1000ml of water for dissolving, uniformly mixing, adjusting the pH value to 3.5 by glacial acetic acid) and methanol (25:75) as a mobile phase; the flow rate is 1.2ml/min; the column temperature is 35 ℃; the detection wavelength was 345nm. Precisely measuring 20 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. The elution amount of each tablet was calculated by the external standard method using the peak area. The limit was 80% of the indicated amount and the test results are shown in Table 8.
Table 8 results of comparative investigation of dissolution characteristics of afatinib maleate microcapsules and conventional tablets
As is clear from the results shown in Table 8, the dissolution rates of the afatinib maleate microcapsule tablets A1, A2, A3 and A4 of the present invention are similar, and all of the tablets meet the above-mentioned regulations.
In order to visually observe the comparison of the elution amounts of the afatinib maleate microcapsule tablets and the common tablets according to the present invention, the average value of the elution amounts of the microcapsule tablets A1, A2, A3, and A4 in the above table 8 was taken, the average value was numbered as microcapsule tablet a, and a graph was drawn with the elution time as the X axis and the elution degree as the Y axis, see fig. 5. As can be seen from the results shown in fig. 5, the dissolution rate of the afatinib maleate microcapsule tablet is obviously higher than that of the common tablet from the first sampling (5 min) to the third sampling (15 min), and the phases from the third sampling (15 min) to the 5 th sampling (30 min) are similar to those of the common tablet and tend to be stable; overall, the avermectin maleate microcapsule tablet disclosed by the invention is faster and smoother to release, which means that compared with the common tablet, the avermectin maleate microcapsule tablet disclosed by the invention has a quicker drug curative effect, can effectively avoid the peak-valley phenomenon of the drug, and can reduce adverse reactions caused by the peak-valley phenomenon of the drug.
Experiment 2
The experiment was conducted on the stability study of the afatinib maleate microcapsule tablets prepared in example 11.
The afatinib maleate microcapsule tablets prepared by using the afatinib maleate microcapsule powders obtained in examples 7-10 in example 11 are respectively used as samples with the numbers of A1, A2, A3 and A4; the afatinib maleate tablet (prepared by a dry granulation tabletting method) obtained in the market is taken as a common tablet S to serve as a control sample, and the stability is investigated by referring to the general rule 9001 of the edition of Chinese pharmacopoeia 2020, and the specific measuring method is as follows:
the afatinib maleate and the afatinib maleate common tablet are stored in a constant temperature and humidity box with the speed of 40 ℃/RH75% for 6 months, and the properties, the dissolution rate, the content and the related substances are inspected respectively in the 0 day, the 3 rd month and the 6 th month, wherein the dissolution rate experiment is the same as the experiment 1, the samples are taken at the time of 15min, the related substances and the content are measured by an HPLC method, the total impurities of the related substances are not more than 1%, and the content is not less than 98.0%. The results are shown in Table 9 below.
TABLE 9 Afatinib maleate microcapsule tablet and ordinary tablet stability comparative investigation result table
As shown in Table 9, the appearance and the content of the afatinib maleate microcapsule tablet and the common tablet are basically unchanged in the accelerated experiment process, but the dissolution rate of the common tablet is obviously reduced, the dissolution rate of the related substances is obviously increased, and the dissolution rate of the afatinib maleate microcapsule tablet is smaller than the change of the common tablet, and the increase rate of the related substances is also smaller than that of the common tablet. Based on the above, it can be demonstrated that the afatinib maleate microcapsule tablet prepared by the invention has improved drug stability and prolonged shelf life compared with the common tablet.
Experiment 3
The experiment was conducted on the prepared afatinib maleate microcapsule tablet in example 11 for drainage property examination.
The afatinib maleate microcapsule tablets prepared by using the afatinib maleate microcapsule powders obtained in examples 7-10 in example 11 are respectively used as samples with the numbers of A1, A2, A3 and A4; the method takes the afatinib maleate tablet (prepared by dry granulation and tabletting) obtained in the market as a common tablet S as a control sample, and refers to the guiding principle of the drug hygroscopicity test of four portions 9103 in the year 2020 of Chinese pharmacopoeia for the investigation of hygroscopicity, and the specific measuring method is as follows:
the dried glass weighing bottle with plug (outer diameter 50mm, height 15 mm) was placed in a climatic chamber (set temperature 25 ℃ C. 81 ℃ C., relative humidity 80% 82%) one day before the test, and the weight (m) 1 ) The method comprises the steps of carrying out a first treatment on the surface of the Spreading the sample in the weighing bottle, wherein the sample is about 1mm thick, and precisely weighing (m 2 ) The method comprises the steps of carrying out a first treatment on the surface of the The weighing bottle is opened and is placed under the constant temperature and humidity condition for 24 hours together with the bottle cap; the lid of the weighing flask was closed, and the weight (m 3 ) The weight gain percentage is calculated, and the calculation formula is as follows:
and referring to the national food and drug administration import registration standard (standard number JX 20150037), the moisture content of 0 day and 6 month was measured by the Karl Fischer method, respectively, and the examination results are shown in Table 10.
Table 10 results of comparative investigation of wettability of afatinib maleate microcapsule tablets and general tablets
As can be seen from the results shown in Table 10, the afatinib maleate microcapsule tablets of the present invention have no or almost no hygroscopicity, and the increase in the water content during 0-6 months of storage is significantly less than that of the conventional tablets. The reason is analyzed because the invention prepares the afatinib maleate into the microcapsule powder and then presses the microcapsule powder into the tablet, and the capsule material of the microcapsule powder can protect the afatinib maleate medicament serving as a core material from being contacted with water or hardly contacted with water, thereby reducing the hygroscopicity of the afatinib maleate medicament.
Experiment 4
The experiment evaluates the effect of the afatinib maleate microcapsule tablet of the invention by a pharmacokinetics test of healthy subjects.
44 healthy subjects were selected and randomized into two groups A, B, each group of subjects were orally administered afatinib maleate (40 mg) and afatinib maleate microcapsule tablets in a single dose in a fasting state according to a cross-dosing regimen, with a washout period of 14 days. The clinical study adopts a confirmed liquid chromatography-tandem mass spectrometry (LC-MS/MS) as an analysis method for determining afatinib in human blood plasma to evaluate the clinical effects of the afatinib maleate common tablet and the microcapsule tablet. Analytical methodology linear range of afatinib: 0.250-80.0 ng/mL, and the minimum limit of quantification is 0.250ng/mL.
Subjects were randomly assigned to groups a and B at a 1:1 ratio. Namely 22 subjects in the first period A group are orally taken with afatinib maleate common tablets on an empty stomach; group B22 subjects received oral afatinib maleate microcapsule tablets on an empty stomach. The administration was crossed after 14 days, and the administration dose and the administration mode were the same for both periods. Subjects were fasted overnight without water withdrawal for at least 10 hours per cycle, on the day of each cycle of administration, drinking water (except 240mL of warm water administered during administration) was prohibited for 1 hour before administration to 1 hour after administration, on the morning of the test, 1 piece of afatinib maleate was administered with 240mL of warm water, swallowed without chewing, and after administration, the subjects were examined for their mouth, hands and containers by a researcher to ensure proper administration of the drug.
(1) According to the actual medicine taking group list, the blood concentration data of all the time points of all the subjects are described, and the blood concentration data are statistically described by adopting the number of cases, the arithmetic mean, the standard deviation, the median, the quartile, the maximum value, the minimum value and the variation coefficient.
(2) By usingNon-compartmental modeling (NCA module) of software version 8.0 calculates pharmacokinetic parameters of each subject after administration of the test and reference formulations to obtain study drugKinetic (PK) parameters. The primary PK parameters are C max (highest observed blood concentration), AUC 0-t (area under blood concentration-time curve from zero to last measurable concentration), AUC 0-in (area under the plasma concentration-time curve over time from zero to infinity); secondary PK parameters were: t (T) max 、t 1/2 、λ z 、AUC _％Extrap 、F、CL/F、V d /F。
The calculation method of the pharmacokinetic parameters is as follows: c (C) max And T max All expressed by measured values; AUC (AUC) 0-t Calculating by a trapezoid method; AUC (AUC) 0-inf ＝AUC 0-t +C t /λ z (t is the sampling time of the last time of actually measuring the blood concentration, ct is the last time of actually measuring the sample concentration, lambda z is the end elimination rate constant obtained by the straight line part at the end of the logarithmic concentration-time curve, the optimal curve of the elimination phase is obtained by the least square method, and the slope is multiplied by 2.303 to obtain lambda z A value); t is t 1/2 ＝ln2/λ z ；CL/F＝d/AUC 0-inf (d is the dosage administered); v (V) d /F＝CL/F/λ z ；F＝AUC 0-t (test preparation) /AUC 0-t (reference preparation) ×100％；AUC _％Extrap ＝[(AUC 0-inf -AUC 0-t )/AUC 0-inf ]×100％。
The list describes PK parameters for all subjects, with arithmetic mean, standard deviation, median, quartile, maximum, minimum, geometric mean calculated for each parameter, test results are shown in tables 11, 12. Table 11 shows the general tablet postpharmacokinetic parameters (PKPS) of afatinib maleate administered singly to subjects, and Table 12 shows the tablet postpharmacokinetic parameters (PKPS) of afatinib maleate administered singly to subjects, C in both tables max The highest blood concentration observed; AUC (AUC) 0-t Area under the plasma concentration-time curve from zero to the last measurable concentration; AUC (AUC) 0-inf Area under the plasma concentration-time curve for the time from zero to infinity.
TABLE 11-1 Subjects single oral afatinib maleate general posttablet pharmacokinetic parameters (PKPS)
TABLE 11-2 Subjects single oral afatinib maleate general posttablet pharmacokinetic parameters (PKPS)
TABLE 12-1 Subjects single oral afatinib maleate microencapsulated tablet postpharmacokinetic parameters (PKPS)
TABLE 12-2 Subjects single oral afatinib maleate microencapsulated tablet postpharmacokinetic parameters (PKPS)
As can be seen from tables 11 and 12, the afatinib maleate microcapsule tablet provided by the invention is easier to absorb compared with a common tablet, and the drug peak concentration reaches the effective concentration in a shorter time, so that the afatinib maleate microcapsule tablet has high-efficiency and stable drug release rate, further improves the drug effect of the product, and has better effect than the common afatinib maleate tablet.
In conclusion, the experimental results show that the drug effect and the stability of the afatinib maleate drug are improved by preparing afatinib maleate into microcapsule powder and then preparing afatinib maleate microcapsule tablets, and simultaneously, the hygroscopicity of afatinib maleate in the shelf life is effectively reduced, the shelf life of the afatinib maleate drug preparation can be prolonged, and the drug safety of afatinib maleate is enhanced.
The above examples are only preferred embodiments of the present invention, and it should be noted that the above preferred embodiments should not be construed as limiting the invention, and the scope of the invention should be defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations should and are intended to be comprehended within the scope of the invention.
Claims (10)
1. The preparation method of the afatinib maleate microcapsule powder is characterized by comprising the following steps of:
(1) Taking: respectively taking 30-55 parts of afatinib maleate, 10-24 parts of acacia, 10-24 parts of gelatin, 12-30 parts of maltodextrin and 2-5 parts of sucrose for later use according to parts by weight;
(2) Preparing liquid: adding water into acacia to prepare an acacia water solution;
(3) Dissolving: adding the afatinib maleate into the Arabic gum aqueous solution, and dissolving to obtain an initial mixed solution;
(4) Mixing: adding the maltodextrin and the sucrose into the primary mixed solution, and stirring until the maltodextrin and the sucrose are fully mixed to obtain a mixed solution;
(5) And (3) suction filtration: putting the mixed solution into a suction filter for suction filtration, and respectively taking filtrate for later use;
(6) Homogenizing: preheating the filtrate to 80+/-5 ℃, and placing the filtrate into a homogenizer to be homogenized at the temperature of 80+/-5 ℃ to obtain microemulsion;
(7) Complex coacervation into vesicles: adding gelatin into the microemulsion, regulating the pH value to 4+/-0.2, stirring until the liquid color is uniform, stopping stirring, and cooling to 50+/-5 ℃ to obtain emulsion;
(8) And (5) atomizing and drying: and (3) spray-drying the emulsion, and collecting powder to obtain afatinib maleate microcapsule powder.
2. The preparation method of afatinib maleate microcapsule powder according to claim 1, wherein the step (1) is carried out by sieving afatinib maleate with a 40-mesh screen before taking the afatinib maleate microcapsule powder.
3. The preparation method of afatinib maleate microcapsule powder according to claim 1, wherein the mass ratio of gum arabic, gelatin, maltodextrin and sucrose in the step (1) is 24:24:30:5.
4. The method for preparing afatinib maleate microcapsule powder according to claim 1, wherein the mass ratio of gum arabic to water in the aqueous solution of gum arabic in step (2) is 1:19.
5. The method for preparing afatinib maleate microcapsule powder according to claim 1, wherein the homogenizing condition in step (6) is homogenizing 3 times at 11000rpm under 40MPa pressure for 6 min/time.
6. The process for preparing afatinib maleate microcapsule powder according to claim 1, wherein in step (7), glacial acetic acid or dilute hydrochloric acid is used to adjust the pH.
7. The method for preparing afatinib maleate microcapsule powder according to claim 1, wherein the relevant parameters of the spray drying in the step (8) are 34-37mL/min of feed flow, 20% -25% of feed concentration and 160+ -5 ℃ of air inlet temperature.
8. The method for preparing afatinib maleate microcapsule powder according to claim 7, wherein the feeding flow is 35mL/min, the feeding concentration is 20%, and the air inlet temperature is 160 ℃.
9. An afatinib maleate microcapsule powder, which is characterized in that: prepared by the preparation method of the afatinib maleate microcapsule powder in any of claims 1-8.
10. An application of afatinib maleate microcapsule powder is characterized in that: use of the afatinib maleate microcapsule powder of claim 9 for the preparation of afatinib maleate tablets.
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