CN108283628A - A kind of anticancer drug microcapsule formulation and preparation method thereof - Google Patents
A kind of anticancer drug microcapsule formulation and preparation method thereof Download PDFInfo
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- CN108283628A CN108283628A CN201810362873.5A CN201810362873A CN108283628A CN 108283628 A CN108283628 A CN 108283628A CN 201810362873 A CN201810362873 A CN 201810362873A CN 108283628 A CN108283628 A CN 108283628A
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61K9/4816—Wall or shell material
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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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
Abstract
The invention belongs to pharmaceutical preparations technology fields, are related to a kind of anticancer drug microcapsule formulation, and in particular to a kind of Ni Lapani microcapsule formulations and preparation method thereof.The present invention is added polyvinyl alcohol and Ni Lapani micro-capsules is made, be then uniformly mixed micro-capsule and other auxiliary materials, be prepared into Ni Lapani microcapsule formulations using main ingredient Ni Lapani and auxiliary material boric acid as capsule core material.The microcapsule formulation drugloading rate of the present invention is big, and encapsulation rate is good, considerably improves the stability of Ni Lapani, reduces the adverse reaction of Ni Lapani, and drug is made steadily to discharge in vivo, preferably plays the effect of Ni Lapani, is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical preparations technology fields, are related to a kind of anticancer drug microcapsule formulation, and in particular to a kind of Buddhist nun's drawing
Pa Buddhist nun's microcapsule formulation and preparation method thereof.
Technical background
Oophoroma is the primary cause of death of U.S.'s gynecological tumor, is the fifth-largest reason of female cancer death, only not
The oophoroma women of foot 40% can cure.The incidence of oophoroma with age, 60-70 age bracket incidence highests,
Middle position diagnosis of age 63 years old, 70% is progressive stage disease when diagnosing.The morbidity of oophoroma may be related with the following aspects：Cancer
Disease morbidity external factor (including the carcinogens such as chemistry, physics, biology)；Pathogenesis of cancer internal factor (including it is immune function, interior
Secretion, heredity, mental element etc.) and dietetic nutrition imbalance and bad life habits etc..Mostly occur in the woman of climacteric
Female.35 years old or more the multiple epithelial ovarian cancers of person, and young and childhood women is mostly reproduction cell class malignant tumour.
Malignant tumor of ovary especially epithelioma is difficult to early detection, etiology unknown, in addition to inherited ovarian, without one
Grade precautionary measures advocate that early diagnosis is early controlled, and strives for early detection lesion at present, and the research in relation to early diagnosing is in progress.
PARP is that one kind is widely present in the catalysis ribosylating cell ribozymes of poly ADP in eukaryocyte, at least contains 17 kinds
Hypotype, wherein PARP-1 most studies.PARP-1 is primarily involved in DNA damage reparation, rapid to consume after induction damage is activated
Intracellular a large amount of nicotinamide adenine dinucleotide are ribosylating to itself and other target point proteins progress play ADP, and then repair damage
Wound.PARP inhibitor is mainly used for treatment breast by inhibiting DNA of tumor cell injury repair, promoting tumour cell that apoptosis occurs
Gland cancer, oophoroma, prostate cancer and cancer of pancreas etc. possess the genetic cancer of identical " rogue's gene ".
Ni Lapani (Niraparib) is a kind of novel oral PARP-1 inhibitor researched and developed by Merck (Merck)
(being taken over by Tesaro companies after 2012) is primarily directed to the cancer of BRCA1/2 gene mutations, such as oophoroma and mammary gland
Cancer.It is respectively 3.8nM/2.1nM that Ni Lapani inhibits IC50 to PARP-1/PARP-2.Enter clinical research within 2008, for multiple
The oophoroma of the oophoroma of hair property germline BRCA mutation and sporadic non-BRCA missings.Currently, Tesaro announces Niraparib needles
To three phase clinical datas of advanced ovarian cancer, extremely good curative effect is presented.Oral Niraparib is primary daily, " middle position nothing
Be in progress life span " it is 21 months, and the patient of control group (using chemotherapy) has obtained notable extension for 5.5 months.It is expected that
Niraparib sale peak values can reach annual 2000000000 dollars.
Ni Lapani (Niraparib) structural formula is as follows：
Ni Lapani capsules went through to list in the U.S. in 2017, and manufacturer is salol company of Thailand of the U.S..Ni Lapa
The most common adverse reaction of Buddhist nun (incidence is greater than or equal to 20%) has nausea, tired (including weakness), vomiting, anaemia, abdomen
Bitterly, dysgeusia, constipation, loss of appetite, diarrhea, blood platelet reduce and pant.Wherein 10% patient due to adverse reaction and
It is discontinued, predominantly fatigue and weakness.Myelodysplastic syndrome/acute myeloid leukemia has occurred in 0.5% patient.Ni La
The higher adverse reaction rate of pa Buddhist nun limits its use.Moreover, its active component of Ni Lapani is free alkali, it is unstable
Fixed, common oral solid formulation is difficult to overcome the problems, such as these.
Micro-capsule is using natural or synthesis high molecular material as cyst membrane, using solid or liquid medicine as capsule core material
Reservoir devices microencapsulation made of package.Medicament microcapsule there are into many advantages, is mainly shown as：1. improving the stabilization of drug
Property；2. making drug that there is sustained release or controlled release properties, targeting；3. covering the bad smell and taste of drug；4. preventing drug from existing
The stimulation of inactivation or reduction to stomach in stomach；5. avoiding the incompatibility of some drugs in compound preparation or being conducive to compound medicine
Compatibility；6. making liquid drug solidification, convenient for storing or various dosage forms being made again etc..Ni Lapani is made into microcapsule formulation, energy
So that drug is steadily discharged in vivo, prevent instantaneous blood concentration excessively high, and then reduces the adverse reaction of Ni Lapani.Meanwhile
Under the package of capsule material, the stability of high drug is improved.
Micro-capsule is a kind of nearly three novel forms to grow up during the last ten years, and that presently, there are drugloading rates is low, encapsulation rate is poor etc. asks
Topic, which has limited being widely used for the method.
Invention content
For problems of the prior art, the present invention provides a kind of Ni Lapani microcapsule formulations.It is raw according to the present invention
The microcapsule formulation drugloading rate of production is big, and encapsulation rate is good, significantly increases the stability of Ni Lapani, and drug is made steadily to release in vivo
It puts, reduces the adverse reaction of Ni Lapani, preferably play the effect of Ni Lapani, be suitble to industrialized production.
The present invention provides a kind of Ni Lapani microcapsule formulations, it is characterised in that it is by main ingredient Ni Lapani and auxiliary material boric acid
Capsule core material, polyvinyl alcohol are that capsule material and other auxiliary materials form, and weight ratio is as follows：
Preferred weight component is as follows：
Wherein, the average grain diameter of the micro-capsule is 10~100 μm.
Other described auxiliary materials are disintegrant and diluent.
The disintegrant is low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, is crosslinked and gathers
It ties up one or more in ketone, microcrystalline cellulose, Plasdone S-630, starch or natural silica gel.
The diluent is calcium monohydrogen phosphate, microcrystalline cellulose, lactose, xylitol, superfine silica gel powder, pregelatinized starch, sweet
Reveal one or more in alcohol, Icing Sugar, sucrose, dextrin, sodium carboxymethylcellulose or starch.
Microcapsule formulation of the present invention is oral solid formulation.
Another object of the present invention is to provide the preparation methods of suitable Ni Lapani microcapsule formulations.
Preparation method provided by the invention can significantly increase the drugloading rate and encapsulation rate of Ni Lapani micro-capsules, significantly
The stability for improving Ni Lapani, reduces the adverse reaction of Ni Lapani, drug is made steadily to discharge in vivo, is suitble to industrialization big
Production, specifically includes following steps：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the disintegrant and diluent of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, common process prepare to get.
In the above method, 3. the capsule material solution is aqueous solution that capsule material mass percent is 5~10% to step.
Inventor is by a series of experimental study, and Ni Lapani and boric acid are capsule core material by final choice, with polyethylene
Alcohol is capsule material, prepares Ni Lapani micro-capsules using spray drying process, suspension coating is carried out to Ni Lapani in fluid bed, and
Dry in thermal current, the micro-capsule drugloading rate of this method mild condition, preparation is big, and encapsulation rate is good, improves the stability of main ingredient, together
When so that drug is steadily discharged in vivo, prevent instantaneous blood concentration excessively high, thereby reduce the adverse reaction of Ni Lapani.
Compared with the prior art, the present invention has the following advantages：
(1) present invention process mild condition, easy to operate, the micro-capsule drugloading rate of preparation is big, and encapsulation rate is good, is suitble to industrialization
Big production.
(2) in the present invention, inventor is creative in Ni Lapani capsule core materials to have used boric acid, makes drug dissolution
Height, and dissolve out steadily, the serious peak valley phenomenon of blood concentration is avoided, the bioavilability of drug is improved, and reduces Buddhist nun
The side effect of La Pani enhances the therapeutic effect of Ni Lapani.
(3) after main ingredient is prepared into micro-capsule by the present invention, avoid drug storage and using when moisture absorption, decomposition etc. ask
Topic, improves the stability of main ingredient, enhances the safety of medication.
Description of the drawings
Fig. 1：The drug of commercially available Ni Lapani capsules and Ni Lapani microcapsule formulations (embodiment 1-3, comparative example 1) is molten
Go out curve graph.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, it is thus understood that these embodiments are only used for
The purpose of illustration, does not limit the scope of the invention, at the same those of ordinary skill in the art according to the present invention done it is apparent
Change and modification be also contained within the scope of the invention.
Embodiment 1：The preparation of Ni Lapani capsules of the present invention
Preparation process：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the Plasdone S-630 and dextrin of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, it is directly filling, obtain this
The Ni Lapani Capsules of Microencapsulated of invention.
Embodiment 2：The preparation of Ni Lapani Capsules of Microencapsulated of the present invention
Preparation process：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the crospovidone and xylitol of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, it is directly filling, obtain this
The Ni Lapani Capsules of Microencapsulated of invention.
Embodiment 3：The preparation of Ni Lapani Capsules of Microencapsulated of the present invention
Preparation process：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the microcrystalline cellulose and pregelatinized starch of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, it is directly filling, it obtains
To the Ni Lapani Capsules of Microencapsulated of the present invention.
Embodiment 4：The preparation of Ni Lapani microcapsule tablets of the present invention
Preparation process：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the low-substituted hydroxypropyl cellulose and lactose of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, direct tablet compressing obtains
To the Ni Lapani microcapsule tablets of the present invention.
Embodiment 5：The preparation of Ni Lapani micro-capsule granules of the present invention
Preparation process：
1. by 120 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 40~50 DEG C；
2. polyvinyl alcohol is added in purified water while stirring, it is configured to the polyethylene that mass percent is 15-25%
Alcoholic solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 20~25r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.0%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the sodium carboxymethyl starch and sucrose of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, pack to get the present invention
Ni Lapani micro-capsule granules.
Comparative example 1：The preparation of Ni Lapani Capsules of Microencapsulated
Preparation process：
1. Ni Lapani is crushed 80 mesh, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization, the temperature of hot-air
Degree is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules；
4. the microcrystalline cellulose and pregelatinized starch of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, it is directly filling, it obtains
To the Ni Lapani Capsules of Microencapsulated of the present invention.
The effect further illustrated the present invention below by way of experimental example：
Experimental example 1：Capsule material screening test
Micro-capsule (microcapsules) system is embedding by solid or liquid medicine packet using natural or synthesis high molecular material
Made of grain size be 5~250 μm of microencapsulation, abbreviation micro-capsule.Depending on preparation method difference, range can be expanded to 0.25~1000
μm。
Encapsulation rate refers to the percentage ratio that the practical content of dispersion in micro-capsule accounts for total dose (i.e. drugloading rate) in microencapsulated sample, that is, makes
The micro-capsule content of dispersion obtained accounts for the percentage of the total content of dispersion of system.Encapsulation rate is higher, shows that the encapsulated degree of drug is better.This reality
We explore the prescription and technological factor that influence micro-capsule preparation using encapsulation rate as one evaluation index of micro-capsule in testing.
The assay method of drugloading rate：
It takes dry micro-capsule appropriate, is pulverized in mortar, is placed in 50mL volumetric flasks, a small amount of 0.4%NaOH solution is added to fill
Dissolving and constant volume, ultrasonic 15min, (0.25 μm) filtering of miillpore filter is divided to measure trap.By the mark under 0.4%NaOH solvents
Directrix curve obtains total dose D1, drugloading rate calculation formula inside and outside micro-capsule：Drugloading rate=(the matter of total dose D1/ micro-capsules inside and outside micro-capsule
Amount) × 100%.
The specific assay method of encapsulation rate：
By every gram not at the medicine assay of medicine capsule and every gram of encystation as a result, every gram of micro-capsule capsule can be calculated as follows
The content of material：Capsule material weight=every gram of 1- of every gram of micro-capsule is not at the content of dispersion of the micro-capsule of the content of dispersion of micro-capsule/every gram.
Based on the above method, take the drying micro-capsule with above-mentioned equivalent that water is added to vibrate, place 1min, with ensure not at
The drug of micro-capsule is all soluble in water, takes (0.25 μm) filtering of supernatant miillpore filter, measures trap.By the mark under water-soluble matchmaker
Directrix curve obtains the outer dose D2 of capsule, encapsulation rate calculation formula：Encapsulation rate=(the total dose of the outer dose/micro-capsule of the total dose-capsule of micro-capsule)
× 100%=(D1-D2)/D1 × 100%.
1) capsule material type screening test：
Experimenter has found that different capsule materials has an impact the grain size and encapsulation rate of micro-capsule, herein in the course of the research
There is provided battery of tests data, the prescription which sets as：10 parts of Ni Lapani, 2 parts of boric acid, 60 parts of capsule material.
Processing step：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. preparing capsule material solution.
3. capsule material solution is continuously added to fluid bed by the nozzle atomization of fluid bed, atomizing pressure is 0.2~0.4Mpa；
Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating, cooling discharging,
Obtain Ni Lapani micro-capsules.
1 capsule material screening experiment result of table
| Serial number | Capsule material | Encapsulation rate (%) |
| 1 | Polyvinyl alcohol | 98.3 |
| 2 | Gelatin | 44.7 |
| 3 | Starch | 56.5 |
| 4 | Stearic acid | 56.3 |
| 5 | Sodium alginate | 20.1 |
| 6 | Polyethylene glycol | 76.9 |
| 7 | Arabic gum | 58.7 |
| 8 | Polyacrylic acid | 34.0 |
| 9 | Polyvinylpyrrolidone | 85.1 |
| 10 | Polyisobutyl group acrylate | 63.9 |
| 11 | Carboxymethyl cellulose | 42.8 |
| 12 | Hydroxyethyl cellulose | 49.0 |
| 13 | Hydroxypropyl cellulose | 82.0 |
| 14 | Hydroxypropyl methyl cellulose | 62.5 |
| 15 | Dimethylaminoethyl methacrylate | 72.0 |
| 16 | IV type acrylic resin | 36.6 |
| 17 | Methacrylate copolymer | 58.3 |
As it can be seen from table 1 when the capsule material of this test recipe is selected as polyvinyl alcohol, encapsulation rate highest.
2) capsule material dosage screening test：
Experimenter has found that the dosage of capsule material polyvinyl alcohol has shadow to the grain size and encapsulation rate of micro-capsule in the course of the research
Ring, battery of tests data provided herein, the prescription which sets as：10 parts of Ni Lapani, 2 parts of boric acid, polyvinyl alcohol is several
Part.
Processing step：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization,
The temperature of hot-air is 65~75 DEG C；
2. it is in purified water that polyvinyl alcohol is added to 65~75 DEG C while stirring, it is 5-10% to be configured to mass percent
Poly-vinyl alcohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed, atomizing pressure 0.2 by the nozzle atomization of fluid bed
~0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating,
Cooling discharging obtains Ni Lapani micro-capsules.
2 capsule material screening experiment result of table
From table 2 it can be seen that when capsule material dosage is less than 50 parts, encapsulation rate increases as capsule material dosage increases.Work as capsule material
When dosage is more than 50 parts, encapsulation rate reaches preferably and stablizes, and no longer increases with capsule material dosage and increase, therefore overall cost and matter
Amount considers that preferably capsule material dosage is 50-70 parts.
Experimental example 2：Dissolution determination
With reference to dissolution method (two the second methods of annex XC of Chinese Pharmacopoeia version in 2015), rotating speed is 50 turns per minute,
37 DEG C ± 0.5 DEG C of temperature, 0min, 30min, 60min, 120min, 180min, 240min, 300min after dispensing take
Sample samples 10ml, immediately mutually synthermal, same volume the dissolution medium of supplement.Sample is filtered through 0.8um water system miillpore filters,
Primary filtrate 3ml is discarded, subsequent filtrate, HPLC is taken to measure content.By Nip's Ni Lapa open capsule and Examples 1 to 3, comparative example
1 gained Ni Lapani microcapsule formulations carry out dissolution experiment, and corresponding data is shown in Table 3 and Fig. 1.
3 drug-eluting curve data of table
| The title time | 0min | 30min | 60min | 120min | 180min | 240min | 300min |
| Commercially available Ni Lapani capsules (%) | 0 | 58.8 | 84.3 | 90.8 | 90.9 | 92.2 | 92.1 |
| Embodiment 1 (%) | 0 | 10.0 | 20.2 | 39.6 | 59.9 | 80.2 | 99.9 |
| Embodiment 2 (%) | 0 | 9.8 | 19.2 | 38.6 | 58.1 | 77.2 | 98.0 |
| Embodiment 3 (%) | 0 | 9.9 | 20.5 | 39.7 | 59.7 | 80.4 | 100.4 |
| Comparative example 1 (%) | 0 | 7.1 | 16.2 | 34.9 | 55.9 | 73.2 | 73.3 |
It can be seen that from table 3 and Fig. 1：Dissolution rate of the embodiment of the present invention is high, and stripping curve is steady；Comparative example is not
Using boric acid is used, as capsule core material, dissolution is steady, but dissolution rate is poor；Commercially available Ni Lapani capsules are non-microcapsule formulation, are dissolved out
Soon, it dissolves out unstable.Dissolution determination result further demonstrates the microcapsule formulation that boric acid and raw material are prepared as capsule core material, molten
Out-degree is high, and dissolution is steady.
Experimental example 3：The Ni Lapani microcapsule formulation influence factors experiment of the present invention
By Capsules of Microencapsulated and 1 gained micro-capsule capsule of comparative example obtained by commercially available Ni Lapani capsules, embodiment 1-3
Agent, by 2015《Chinese Pharmacopoeia》Two annex bulk pharmaceutical chemicals carry out influence factor examination with pharmaceutical preparation stability test guideline
It tests.Hot test：Example and comparative examples are placed 10 days at a temperature of setting 60 DEG C, are sampled in the 5th day and the 10th day, by steady
Qualitative high spot reviews project is detected.High humidity test：Example and reference substance are set and place 10 under RH92.5% ± RH5%
It, sampled in the 5th day and the 10th day, is detected by stability high spot reviews project.Strong illumination is tested：Example and right
It is placed in the lighting box equipped with fluorescent lamp, is placed 10 days under conditions of illumination is 4500lx ± 500lx, in the 5th according to embodiment
It was sampled with the 10th day, was detected by stability high spot reviews project；Influence factor test result is shown in Table 4.
4 influence factor test result of table
As can be seen from Table 4：Embodiment impurity content is low, and dissolution rate is stablized, and product quality is without bad trend；Comparison is implemented
There are unfavorable trend, stability is poor for example impurity and dissolution rate；Commercially available Ni Lapani capsules are non-microcapsule formulation, impurity and dissolution rate
There are bad trend, stability is poor.The superiority of the present invention is further demonstrated above.
Experimental example 4：Accelerated test study on the stability：
By Capsules of Microencapsulated and 1 gained micro-capsule capsule of comparative example obtained by commercially available Ni Lapani capsules, embodiment 1-3
Agent is placed under same packaging and is placed in storage 6 months in the climatic chamber of 40 DEG C/RH75%, respectively at 0 month and 6th month
When carry out dissolution rate and the investigation in relation to substance respectively.It is measured with HPLC methods in relation to substance and dissolution rate, the results are shown in Table 5.
5 accelerated test study on the stability result of table
As shown in table 5, during accelerated test, the dissolution rate of commercially available Ni Lapani capsules obviously becomes smaller, and related substance is bright
It is aobvious to become larger；And the dissolution of the Capsules of Microencapsulated of the present invention does not change substantially, the increase in relation to substance is also than commercially available capsule
Agent is much smaller, illustrates that the microcapsule formulation prepared by the present invention can improve the stability of drug, extends the shelf life of preparation.It is related
The control of substance is conducive to control the adverse reaction of drug.
Experimental example 6：Draw moist investigation
Experimenter devises draws moist test, and drug draws moist measurement and refers to reference to 2010 editions formulary drug hygroscopicity tests
It leads the method in principle and draws the wet standard for increasing weight and defining.Test environment conditions are (25 ± 2) DEG C, relative humidity 75% ± 5%
Climatic chamber.Draw moist change with the opposite moisture absorption weightening variation characterization drug of capsule.Measuring compares city
The hygroscopic variation of Capsules of Microencapsulated of Ni Lapani capsules and the present invention is sold, concrete outcome is shown in Table 6.
Drawing for the different capsules of table 6 is moist
| Sample | It is opposite to draw wet weightening/% (n=3) | Draw moist evaluation |
| Commercially available Ni Lapani capsules | 4.00 | Have draw it is moist |
| Embodiment 1 | 0.10 | Do not have draw it is moist |
| Embodiment 2 | 0.09 | Do not have draw it is moist |
| Embodiment 3 | 0.09 | Do not have draw it is moist |
| Comparative example 1 | 0.15 | Do not have draw it is moist |
By table 6 as it can be seen that commercially available Ni Lapani capsules are moist with drawing, and Ni Lapani is prepared into micro-capsule, then filling
At capsule, draw moist reduction, this solves the problems, such as the moisture absorption of capsule during storage.It can be seen that by Ni Lapani systems
For at micro-capsule, the stability of main ingredient is not only increased, and enhance the safety of Ni Lapani preparation medications.
Claims (10)
1. a kind of Ni Lapani microcapsule formulations, it is characterised in that it is capsule core material, poly- second by main ingredient Ni Lapani and auxiliary material boric acid
Enol is that capsule material and other auxiliary materials form, and weight ratio is as follows：
2. Ni Lapani microcapsule formulations as described in claim 1, which is characterized in that each component weight ratio is as follows：
3. Ni Lapani microcapsule formulations as described in claim 1, which is characterized in that the average grain diameter of the micro-capsule be 10~
100μm。
4. Ni Lapani microcapsule formulations as described in claim 1, which is characterized in that other described auxiliary materials are disintegrant and dilute
Release agent.
5. Ni Lapani microcapsule formulations as claimed in claim 4, which is characterized in that the disintegrant is that low-substituted hydroxypropyl is fine
Tie up element, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, microcrystalline cellulose, Plasdone S-630, starch
Or it is one or more in natural silica gel.
6. Ni Lapani microcapsule formulations as claimed in claim 4, which is characterized in that the diluent is calcium monohydrogen phosphate, micro-
Crystalline cellulose, lactose, xylitol, superfine silica gel powder, pregelatinized starch, mannitol, Icing Sugar, sucrose, dextrin, sodium carboxymethylcellulose
Or it is one or more in starch.
7. Ni Lapani microcapsule formulations as described in claim 1, which is characterized in that the microcapsule formulation is oral administration solid system
Agent.
8. Ni Lapani microcapsule formulations as claimed in claim 7, which is characterized in that preparation method includes the following steps：
1. by 80 mesh of Ni Lapani and boric acid co-grinding, it is placed in fluid bed, is passed through hot-air, be allowed to suspension fluidization, heat is empty
The temperature of gas is 65~75 DEG C；
2. polyvinyl alcohol is added to while stirring in 65~75 DEG C of purified water, it is the poly- of 5-10% to be configured to mass percent
Glycohol solution.
3. capsule material poly-vinyl alcohol solution is continuously added to fluid bed by the nozzle atomization of fluid bed, atomizing pressure is 0.2~
0.4Mpa；Conveying speed is 15~20r/min；Solution persistently enters the wind drying after having sprayed, until moisture<1.5%, stop heating, it is cold
But it discharges, obtains Ni Lapani micro-capsules；
4. the disintegrant and diluent of Ni Lapani micro-capsules and recipe quantity are uniformly mixed, common process prepare to get.
9. Ni Lapani microcapsule formulations as claimed in claim 8, which is characterized in that 3. the capsule material solution is capsule material to step
The aqueous solution that mass percent is 5~10%.
10. a kind of preparation method of Ni Lapani microcapsule formulations as claimed in claim 8 or 9.
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| CN201810362873.5A CN108283628B (en) | 2018-04-20 | 2018-04-20 | Anticancer medicine microcapsule preparation and its preparing method |
| CN202010910601.1A CN111991366A (en) | 2018-04-20 | 2018-04-20 | Preparation method of nilapanib microcapsule preparation |
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| CN109875977A (en) * | 2019-03-13 | 2019-06-14 | 安庆瑄宇医药科技有限公司 | A kind of Ni Lapani anticancer drug and preparation method thereof |
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| US20230201122A1 (en) * | 2021-12-23 | 2023-06-29 | Boston Scientific Medical Device Limited | Chemoembolic compositions and methods of treatment using them |
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