CN108815129A - A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace - Google Patents
A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace Download PDFInfo
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Abstract
The present invention relates to miscellaneous Shandong amine nanocrystal oral solid drug compositions of a kind of grace and its preparation method and application.Nanotechnology is applied to the miscellaneous Shandong amine raw material of grace by inventor, to prepare the miscellaneous Shandong amine nanocrystal of grace, and then prepares oral solid formulation.Experiment results proved works well.By a series of test, it is finally obtained the preparation process of the miscellaneous Shandong amine nanocrystal of grace, has obtained the miscellaneous Shandong amine nanocrystal raw material of water-soluble good grace.And the selection being further made up of auxiliary material, it is suppressed that the miscellaneous Shandong amine nanocrystal of grace is prepared into normal oral solid pharmaceutical preparation by the degradation of amido bond and lactam bond in bulk pharmaceutical chemicals.Test proves, the miscellaneous Shandong amine oral solid formulation dissolved corrosion of grace prepared by this technology be improved significantly, and then its bioavilability is similarly obtained raising.Hydrolysis impurity is inhibited simultaneously, and stability is improved, this preparation process is simple, quality controllable, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace
And its preparation method and application.
Background technique
Prostate cancer refers to the epithelial malignancy occurred in prostate.WHO in 2004《Urinary system and male genetic
Organ tumor pathology and science of heredity》Middle prostate cancer histological type includes gland cancer (acinar adenocarcinoma), duct adenocarcinoma, urothelium
Cancer, squamous cell carcinoma, adenosquamous carcinoma.Wherein adenocarcinoma of the prostate accounts for 95% or more, and therefore, the prostate cancer usually described in us is exactly
Refer to adenocarcinoma of the prostate.
Prostate-cancer incidence has an apparent geographical and racial difference, Australia/New Zealand, the Caribbean and this bear
It receives and ties up subregion highest, Asia and North African Area are lower.In world wide, prostate-cancer incidence is in all malignant tumours of male
In occupy second.In the U.S., the disease incidence of prostate cancer alreadys exceed lung cancer, becomes first tumour for endangering men's health, according to
American Cancer Society's estimation, U.S.'s prostate cancer morbidity patient's number in 2013 reach 238590 people, account for all pernicious swollen in male
The 28% of tumor, but death toll slightly decreases, and 32050 people from 2010 are reduced to 29720 people in 2013.In Europe,
New hair cases for prostate cancer about 382000 people in 2008, cause more than 90000 name deaths for 2008.
Ascendant trend is presented well below American-European countries in the disease incidence of Asia prostate cancer in recent years, and increases and compare Europe
U.S. developed country is more rapid.From 30, the whole nation that national treatment and prevention of tumour research office/whole nation tumour Register collects
Registral data show that the prostate cancer incidence of 1988-1992 is 1.96/10 ten thousand populations, and 1993-1997 is
3.09/10 ten thousand populations, 1998-2002 are 4.36/10 ten thousand populations.According to the latest data of National Cancer Center, prostate cancer is certainly
As the highest tumour of disease incidence in urinary system from 2008, disease incidence in 2009 reaches 9.92/10 ten thousand, pernicious in male
The 6th is arranged in tumor incidence ranking, the death rate reaches 4.19/10 ten thousand, and the 9th is arranged in all male malignancies.According to
Worldwide investigation result in 2012, it can also be seen that prostate cancer occurs significantly rising in the disease incidence of China, 1988-
The growth rate of the annual prostate-cancer incidence of China is 2.1% during 1994, and has been arrived between 1994-2002, prostate cancer
Disease incidence rises to 13.4% every year.
Androgen receptor (androgen receptor, AR) plays extremely important work in the generation, development of prostate cancer
With research shows that castration resistance type prostate cancer still relies on the effect of AR.Androgen receptor belongs to nuclear receptor superfamily.AR packet
Containing 918 amino acid, there is similar structure and function with other nuclear receptors, it is made of three important structural domains, respectively
It is DNA binding domain (DNA binding domain, DBD), ligand binding domain (ligand binding domain, LBD) and nitrogen
It holds binding domain (N-terminal domain, NTD), is connected between DBD and LBD by a hinge area (Hinge).It is present in
The LBD of AR carbon teminal is the site of AR and ligand binding, determines specificity of the ligand in conjunction with AR, ligand in conjunction with LBD to
Activate AR.Liang Ge transcriptional activation function area, i.e., the 1 (activation of activation functional areas in NTD structural domain have been determined in AR
Function 1, AF1) and LBD structural domain in highly conserved hydrophobic pocket activate functional areas 2 (AF2).
The testosterone of male is mainly by testicular secretion, and furthermore adrenal gland can also be secreted on a small quantity.In prostata tissue, 90%
Testosterone is catalyzed by 5α-reductase and generates dihydrotestosterone (DHT), and biological activity ratio's testosterone is stronger, growth and hair to prostate
It educates and plays an important role.Under normal circumstances, androgen receptor is present in cytoplasm and with heat shock protein (Hsp 90) etc.
In conjunction with the tertiary structure for being suitable for androgen combination that formation is stable.When endogenous androgens occur, Hsp90 is released, AR's
The change of LBD rear occurred conformation in conjunction with androgen, and along with the dimerization and phosphorylation of AR, cause AR to be activated.Thus
The AR- androgen compound of formation enters nucleus and identifies corresponding androgen response element, raises other modulins altogether,
And active transcription complex is formed, start the transcription of AR target gene.Antagonist can be with endogenic androgen competitively
In conjunction with AR, but not cause related gene transcription and subsequent biological effect.
Almost CRPC (castration-resistant prostate cancer) patient of one third is since AR overexpression or gene are expanded
Increasing causes AR high to express, and AR signal path is still in verified castration resistance type prostate cancer in research in the past few years
It plays a role.Therefore, targeting AR signal path is still significant.
According to the difference of chemical structure, AR inhibitor can be divided into steroid AR antagonist and nonsteroidal AR antagonist.
Cyproterone acetate is the representative of steroid AR antagonist, oral administration biaavailability and selection due to such drug
Property is poor, adverse reaction caused by cross action is also easy to produce, to limit its clinical application.And the mouth of non-steroidal AR inhibitor
It is relatively high to take bioavilability, and has higher selectivity to AR, therefore become the main side of research and development antiandrogen
To.
Before 2010, Docetaxel is for the only effective treatment side of metastatic castration resistance type prostate cancer
Method.6 drugs are approved for the treatment of the prostate cancer of castration resistance, the inhibitor including CYP17 in succession after 2010
The miscellaneous Shandong amine (Enzalutamide) of abiraterone (Abiraterone), androgen receptor antagonists grace, cytotoxic drug kappa
He matches (Cabazitaxel) and a vaccine (Sipuleucel-T), an antibody (Denosumab).
Currently, the AR inhibitor listed in the drug of column gland cancer before the treatment has the Flutamide of the first generation
(flutamide), the miscellaneous Shandong amine of the grace of Bicalutamide (R-bicalutamide) and Nilutamide (nilutamide) and the second generation
(enzalutamide), the LDB of AR is acted on.It is also extremely similar with the miscellaneous Shandong amine structure of grace in clinical investigation phase
The micromolecular inhibitors such as the ODM-201 of Apalutamide and ORION company research and development.
The miscellaneous Shandong amine of grace, molecular weight 464.44, molecular formula C21H16F4N4O2S is by Medivation company and Astellas
(Astellas) a kind of androgen receptor inhibitor of company's cooperative development, the entitled 4- [3- [4- cyano -3- (fluoroform of chemistry
Base) phenyl] -5,5- dimethyl -4- oxo -2- thioketones -1- imidazolidinyl] the fluoro- N-methyl-benzamide of -2-, in August, 2012 obtains
FDA approval is obtained, is resistant to prostate cancer for treating the advanced stage male's castration for having spread or having recurred.Listing dosage form is soft-gelatin
Capsule, specification 40mg.It is daily primary, each taking 4, amount to 160mg.
The miscellaneous Shandong amine structure formula of grace is as follows：
The miscellaneous Shandong amine of grace is androgen receptor inhibitor, can competitively inhibit the combination of androgen and receptor, and energy
Inhibit the interaction of the nuclear translocation and this receptor and DNA of androgen receptor.The miscellaneous Shandong amine of experiment in vitro studies have shown that grace can
Inhibit the proliferation of prostate gland cancer cell and induces its death, in the model experiment of Prostate Carcinoma of Mice heterograft, the miscellaneous Shandong of grace
Amine can reduce gross tumor volume.The major metabolite of the miscellaneous Shandong amine of grace is the miscellaneous Shandong amine of N- demethyl grace, is shown in vitro and grace
The similar inhibitory activity of miscellaneous Shandong amine.
The miscellaneous Shandong amine of grace is white crystalline solid powder, non-hygroscopic, due to the strong hydrophobic grouping such as trifluoromethyl in structure
In the presence of water-soluble very poor.
It can be seen that from above-mentioned chemical structure and easily occur to hydrolyze drop there are amido bond and lactam bond in the miscellaneous Shandong amine molecule of grace
Solution.
This compound belongs to BCS classification II, is poorly water-soluble, the high drug of permeability of cell membrane.
Due to the water solubility that the miscellaneous Shandong amine of grace is very poor, commercialized product uses the form of soft capsule, bulk pharmaceutical chemicals is dissolved in pungent
In acyl hexanoyl polyoxyglyceride (Caprylocaproyl Polyoxylglycerides), solution is formed, it is filling in soft-gelatin
In capsule.Preparation entirety bioavilability is higher, reaches 84.2%.But soft capsule preparation still has certain limitation.Example
The patient for being such as not suitable for digestive tract ulcer takes, and due to the introducing of oil-based solvent, to avoid its rancid, certain antioxygen need to be added
Agent, is added BHA (Butylated Hydroxyanisole) in the miscellaneous Shandong amine soft capsule of grace and BHT (Butylated Hydroxytoluene) is used as antioxidant.Last soft capsule
Production is a continuous process, and labor intensity is larger, product before gained is packed, easy adhesion, leakage, to influence final production
The quality and yield of product.
In Japan, has the miscellaneous Shandong amine oral solid formulation listing of grace, company develops by Astellas, using solid dispersions
The acetic acid hydroxypropyl methylcellulose succinate of the miscellaneous Shandong amine of grace and three times quality is dissolved in acetone by technology, after spray drying, grace
Miscellaneous Shandong amine is scattered in acetic acid hydroxypropyl methylcellulose succinate with unformed shape, is formed solid dispersions, is added collapse later
Agent is solved, the auxiliary materials such as lubricant are tabletted.Due to the use of acetone in technique, environmental protection and organic solvent residual be it is still necessary to
The problem of solution.
Nanocrystal technology, that is, prepare nano medicine crystal, is a kind of novel medicine for increasing insoluble drug solubility
Approach.It, can by reducing diameter of aspirin particle to nanoscale with according to Noyes-Whitney and Freundlich-Ostwald equation
Significantly increasing medicament saturation solubility and dissolution rate, to improve its bioavilability.Developed country has developed at present
The several nano medicine crystal preparation varieties in city, show good development prospect and market potential.
Summary of the invention
As described above, the miscellaneous Shandong aqueous amine dissolubility of grace is poor, ordinary solid preparation after oral administration, absorbs bad, bioavilability
It is poor.And there are amido bonds and lactam bond, easily generation hydrolytic degradation in molecule.
Based on this, inventor has obtained a kind of oral administration solid drug of miscellaneous Shandong amine nanocrystal of grace by further investigation design
Composition, the composition are prepared into common stomach dissolution type tablet or capsule by certain technique.
The oral solid drug composition of the miscellaneous Shandong amine nanocrystal of grace, it is hydrophilic by the miscellaneous Shandong amine nanocrystal of main ingredient grace
Polymer, surfactant, disintegrating agent, glidant and lubricant composition.It is further prepared into as follows common soluble in the stomach
Type solid pharmaceutical preparation：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) purified water is taken, the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1), hydrophilic polymer, surfactant sequentially adds high-pressure homogeneous
In machine, under a certain pressure, homogeneous obtains the miscellaneous Shandong amine nanocrystal suspension of grace；
3) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 2) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
4) the miscellaneous Shandong amine nanocrystal of grace obtained by step 3) is taken, disintegrating agent, glidant are sequentially added, lubricant is uniformly mixed, obtains grace
Miscellaneous Shandong amine nanocrystal combines object；
5) step 4) resulting composition, tabletting are taken, film coating obtains the miscellaneous Shandong amine nanocrystal tablet of grace；
6) step 4) resulting composition is taken, is fitted into hard capsule case, the miscellaneous Shandong amine nanocrystal hard capsule of grace is obtained；
It is characterized in that, hydrophilic polymer is polyvinyl alcohol in the pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, surface is living
Property agent be tyloxapol, disintegrating agent is crospovidone, and glidant is colloidal silicon dioxide, and lubricant is magnesium stearate.
The preparation step of the miscellaneous Shandong amine nanocrystal of grace is：
1) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
2) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by [0023] section step 1) are scattered in step 1) acquired solution, and suspension concentration is
5%；
3) suspension obtained by step 2) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
4) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 3) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace.
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, unit formulation composition are as follows：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into tablet or capsule as follows
Agent：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition, tabletting are taken, film coating obtains the miscellaneous Shandong amine nanocrystal tablet of grace；
8) step 6) resulting composition is taken, is fitted into appropriate gelatine capsule shell, the miscellaneous Shandong amine nanocrystal hard capsule of grace is obtained.
Present patent application is further illustrated through the following experiment：
Inventor has found the miscellaneous Shandong amine bulk pharmaceutical chemicals poorly water-soluble of grace, while biology benefit in the research process to the miscellaneous Shandong amine preparation of grace
Expenditure is lower.Inventor attempts nanotechnology being applied to the miscellaneous Shandong amine raw material of grace, to prepare the miscellaneous Shandong amine nanocrystal of grace, and then makes
Standby oral solid formulation.Experiment results proved works well.
On the basis of imagination as above, inventor passes through a series of test, is finally obtained the miscellaneous Shandong amine nanocrystal of grace
Preparation process, obtained the miscellaneous Shandong amine nanocrystal raw material of water-soluble good grace.And it is further lower by selection water content
(5%) disintegrating agent of the crospovidone as solid pharmaceutical preparation effectively reduces preparation totality while playing calving disaggregation
Water content finally prepared by the miscellaneous Shandong amine nanocrystal of grace to inhibit the degradation of amido bond and lactam bond in bulk pharmaceutical chemicals
At normal oral solid pharmaceutical preparation.Test proves that the miscellaneous Shandong amine oral solid formulation dissolved corrosion of the grace prepared by this technology obtains
It is obviously improved, and then its bioavilability is similarly obtained raising.Hydrolysis impurity is inhibited simultaneously, and stability is improved, this
Preparation process is simple, quality controllable, is suitable for industrialized production.
Experiment one：Auxiliary material compatibility test
By the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace；The miscellaneous Shandong amine bulk pharmaceutical chemicals of grace respectively with pluronic, sodium taurocholate, tyloxapol, hydroxypropylcellulose,
Polyvinyl alcohol, crospovidone is according to weight ratio 1:5, it is uniformly mixed, the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace and glidant colloidal silicon dioxide,
Magnesium stearate lubricant, film coating agent Opadry is by weight 20:1, be uniformly mixed, set in culture dish respectively booth at<5mm is thick
Thin layer.Sample number into spectrum is respectively A, B, C, D, E, F, G, H, I, J.
Above-mentioned sample is set 60 DEG C respectively, RH20% ± 5%；Illumination 4500Lx ± 500Lx, RH20% ± 5%；Strong striation
It places 10 days under part, was sampled in the 5th day and the 10th day, detect the miscellaneous Shandong amine content of grace and related substance.Detection data such as following table institute
Show.
The miscellaneous Shandong amine bulk pharmaceutical chemicals of 1 grace of table and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
The miscellaneous Shandong amine bulk pharmaceutical chemicals of 2 grace of table and auxiliary material compatibility experiments result to be selected (strong light 4500Lx ± 500Lx, RH20% ±
5%)
It can be seen that selected auxiliary material from the above experimental result to pass through under the conditions of RH20% ± 5% with the miscellaneous Shandong amine of bulk pharmaceutical chemicals grace
60 DEG C of high temperature are crossed, are stored under intense light conditions, compared with the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace, no significant change.That is the miscellaneous Shandong amine of grace and Pu Langni
Gram, sodium taurocholate, tyloxapol, hydroxypropylcellulose, polyvinyl alcohol, crospovidone, colloidal silicon dioxide, magnesium stearate, film
Coating agent Opadry compatibility is good, can with above-mentioned auxiliary material in solid states the following group at composition, and be further prepared into solid
Body preparation.
Test two, the selection of polymer and surfactant
The miscellaneous Shandong amine bulk pharmaceutical chemicals of grace are first crushed, cross 200 meshes, partial size by the miscellaneous Shandong amine nanocrystal of the lesser grace of partial size in order to obtain
About 0.074mm.Nanocrystal is prepared using high pressure homogenization technique, to reduce gravitation between particle, partial size is further decreased, needs
Surfactant and polymer is added, different surfaces activating agent and polymer are used herein, under identical homogenizer parameter
(100bar is recycled 3 times) is tested, to determine final suitable surfactant and polymer, with the miscellaneous Shandong of final gained grace
The small person of amine partial size be optimal surfactant and polymer, using laser particle analyzer measure particle size distribution, and choose D50 and
D90 is parameter of measurement, and score (S) is calculated as follows in weight 1: 1, and to be scored at index, score is higher then more excellent：
Score (S)=1/D50+1/D90
Experimental design is as follows：
3 surfactant of table and type of polymer, concentration (w/w, %) screening：
Data as above can be seen that using 2% tyloxapol and the 10% polyvinyl alcohol preparation miscellaneous Shandong amine nanocrystal institute of grace
It is smaller to obtain nanocrystal partial size.
Experiment three, pressure and cycle-index selection
It is determined by afore-mentioned test, 2% tyloxapol and 10% polyvinyl alcohol are optimal conditions.This test is attempted to change homogeneous pressure
Power and cycle-index, to further decrease the miscellaneous Shandong amine nanocrystal partial size of grace.
Test parameters and droplet measurement result are as follows：
Data as above can be seen that using 2% tyloxapol and 10% polyvinyl alcohol, and further be recycled using 100bar
7 homogeneous parameters, the miscellaneous Shandong amine nanocrystal gained nanocrystal partial size of preparation grace are smaller.
Test four, gained nanocrystal partial size score (S)
By test two, three have determined surfactant, polymer and the homogeneous parameter of the preparation miscellaneous Shandong amine nanocrystal of grace.Using
This experimental condition prepares the miscellaneous Shandong amine nanocrystal of three batches of grace, every batch of batch about 5.0g.Partial size is measured with laser particle analyzer and is calculated
Score S, as shown in the table：
Test five, the miscellaneous Shandong amine nanocrystal of fask oscillating method measurement gained grace are water-soluble
Respectively by the miscellaneous Shandong amine crude product of excessive grace (crossing 200 mesh fine powders, partial size about 75um), four three crowdes of miscellaneous Lu Anna of grace of gained of experiment
Meter Jing Ti is separately added into purified water, 0.05%SDS aqueous solution, in 0.5%SDS aqueous solution, is placed in 10ml volumetric flask, seals,
It sets in 37 DEG C of shaking tables of constant temperature and shakes 72 hours, obtain each sample saturated solution.Shaking terminates, and extracts appropriate amount of sample solution, with
The filtration of 100nm miillpore filter, takes subsequent filtrate to measure sample concentration, calculates sample solubility, as a result as shown in the table：
Inhibit the activity of cancer cell multiplication outside experiment six, the miscellaneous Shandong amine nanocrystal of grace and bulk pharmaceutical chemicals powder body
(LNCaP-AR) cell culture of androgen-dependent prostate cancer is being passed through into the processing of glucose activity charcoal containing 10%
The RPMI1640 culture solution of fetal calf serum, culture to cell are in logarithmic growth phase, with trypsin digestion cell and use trypan blue
Decoration method carries out plating cells after counting, and every hole adds 100 μ L cell suspensions, includes 5000 cells.After plating cells 24 hours,
The miscellaneous Shandong amine nanocrystal aqueous suspensions of three batch grace obtained by adding the miscellaneous Shandong amine micro mist of grace and testing four (final concentration of 0.005,
0.025,0.05,0.250,0.5,2.5,5 μM).Three days after addition, the PSA in the supernatant of culture solution is measured by ELISA
(prostate cancer specific antigen) concentration.At room temperature, by culture medium and standard items (200 hole μ L/) in the coated plate of antibody in
With 500rpm to 600rpm incubation 2 hours in plate oscillator.Then, hole is washed 5 times.With measurement buffer by HRP conjugate
It is diluted to 1:20,100 μ L are added into all holes.At room temperature, plate is incubated on the oscillator 30 minutes, and as previously described into
Row washing, adds the TMB (0.4g/L) of 100 μ L.Plate is incubated for 10 minutes on the oscillator, is terminated and reacted with 100 μ L terminate liquids.
Using plate reader at 450nm (have 650nm referring to filter) read plate.After a variety of processing, it is directed to PSA level
The growth differences of LNCaP-AR cell normalize, and determine as measured by MTS.Measurement (tested chemical combination based on seven points
The concentration of object) calculate the IC50 of PSA, as a result it is shown in Table 4.
The inhibition (IC50) that the miscellaneous Shandong amine micro mist of 4 grace of table and nanocrystal generate PSA in LNCaP-AR cell
Data as above can be seen that the prepared miscellaneous Shandong amine nanocrystal of three batches of grace and generate to PSA in LNCaP-AR cell
Inhibiting effect, be better than the miscellaneous Shandong amine micro mist of grace.
Test seven, tablet formulation design and dissolution test
Disintegrating agent crospovidone, glidant colloidal silicon dioxide, lubrication is added by main ingredient raw material of the miscellaneous Shandong amine nanocrystal of grace
Agent magnesium stearate, investigates influence of the different amounts crospovidone to the disintegration of tablet, different amounts glidant to tabletting among
The influence of the influence of liquid flowability and different lubricant quantities to compression molding.
| Supplementary material | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| The miscellaneous Shandong amine of grace | 40g | 40g | 40g | 40g |
| Tyloxapol | 16g | 16g | 16g | 16g |
| Polyvinyl alcohol | 80g | 80g | 80g | 80g |
| Crospovidone | 7g | 9g | 8g | 11g |
| Colloidal silicon dioxide | 5g | 3g | 5g | 3g |
| Magnesium stearate | 2g | 2g | 1g | 1g |
| Opadry | Plain piece weight gain 5% | Plain piece weight gain 5% | Plain piece weight gain 5% | Plain piece weight gain 5% |
| Unit formulation weight (g) | 150g | 150g | 150g | 150g |
Preparation process：
1) the miscellaneous Shandong amine nanocrystal of grace is taken, sequentially adds disintegrating agent crospovidone, glidant colloidal silicon dioxide, lubricant is hard
Fatty acid magnesium is uniformly mixed, and obtains the miscellaneous Shandong amine nanocrystal combination object of grace；
2) step 1) resulting composition, tabletting are taken, film coating obtains the miscellaneous Shandong amine nanocrystal tablet of grace；
Dissolution rate detection：
It is that dissolution is situated between with phosphate buffer (pH6.8) 250ml by Chinese Pharmacopoeia two annex dissolution methods of version in 2010
Matter, revolving speed are 75 turns per minute, are operated according to methods, and when through 15 minutes, take solution 10ml to filter, take subsequent filtrate molten as test sample
Liquid is measured with HPLC, Detection wavelength 255nm, measures the miscellaneous Shandong amine tablet of grace in 10min, 15min, 20min, 30min, 45min
Cumulative release amount, the results are shown in Table 1.
| Sample | 10min | 15min | 20min | 30min | 45min |
| Prescription 1 | 5.20 | 12.31 | 40.45 | 66.62 | 88.66 |
| Prescription 2 | 9.99 | 13.07 | 44.35 | 62.66 | 94.53 |
| Prescription 3 | 7.35 | 13.44 | 41.25 | 64.41 | 86.72 |
| Prescription 4 | 8.10 | 12.14 | 44.19 | 64.03 | 86.11 |
The tablet of four prescriptions of gained is analyzed：
1) prescription 3,4 is less since magnesium stearate is added, and in tabletting, occasionally has generation is puckery to rush phenomenon；
2) prescription 2 is more more than prescription 1 since crospovidone amount is added, therefore is disintegrated comparatively fast, and in 45min, cumulative release
Amount is most.
By above-mentioned screening, optimizing prescriptions 2 are optimal prescription.Therefore the miscellaneous Shandong amine nanocrystal tablet of 40mg specification grace is determined
Prescription and preparation process, supplementary material amplify 2 times and 4 times, as 80mg, 160mg specification preparation on year-on-year basis.
| Supplementary material | Specification 1 | Specification 2 | Specification 3 |
| The miscellaneous Shandong amine of grace | 40g | 80g | 160g |
| Tyloxapol | 16g | 32g | 64g |
| Polyvinyl alcohol | 80g | 160g | 320g |
| Crospovidone | 9g | 18g | 36g |
| Colloidal silicon dioxide | 3g | 6g | 12g |
| Magnesium stearate | 2g | 4g | 8g |
| Opadry | Plain piece weight gain 5% | Plain piece weight gain 5% | Plain piece weight gain 5% |
| It is made altogether | 1000 preparation units | 1000 preparation units | 1000 preparation units |
Preparation process is as follows；
1) the miscellaneous Shandong amine nanocrystal of grace is taken, sequentially adds disintegrating agent crospovidone, glidant colloidal silicon dioxide, lubricant is hard
Fatty acid magnesium is uniformly mixed, and obtains the miscellaneous Shandong amine nanocrystal combination object of grace；
2) step 1) resulting composition, tabletting are taken, film coating obtains the miscellaneous Shandong amine nanocrystal tablet of grace；
Based on identical prescription and similar technique, hard capsule is prepared.
Test eight：Accelerated stability experiment in 6 months
The miscellaneous Shandong amine preparation (embodiment 1-6) of grace and Astellas is taken to produce 7 groups of samples of the commercially available soft capsule of 40mg specification (containing packaging)
Number A-G sets 40 DEG C ± 2 DEG C to product respectively respectively, stores 12 months under the conditions of 75% ± 5%RH, respectively at 0 month, January, and March, 6
Month, relevant nature (dissolution determination method is with test seven) is measured by sampling, obtains corresponding data, as shown in the table December：
5 embodiment of table is compared with commercial particulate agent sample stability
According to the miscellaneous Shandong amine piece of grace prepared by embodiment 1-6 prescription of the present invention and technique it can be seen from upper table data
Agent and capsule, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environment, after storage in 12 months, content, related substance has
Changed, but content, more than 98.5%, for largest single impurity matter less than 0.5%, total impurities are below 1.5%, 45min dissolution rate
Remain within 90% or more；Correspond, the commercially available miscellaneous Shandong amine soft capsule of 40mg grace through acceleration 12 months storage after,
Content falls to approximately 95%, and largest single impurity matter rises to greater than 1.1%, and total impurities are then more than 5.0%, 45min dissolution rate than 0 month
Sample slightly reduces, and only 31.78%.
Based on analysis as above, accelerating item according to the miscellaneous Shandong amine preparation of grace prepared by embodiment prescription of the present invention and technique
Under part, the data after storage 12 months shows, and stability is significantly better than commercially available soft capsule, i.e., prescription through the invention with
The stability of the miscellaneous Shandong amine preparation of grace is remarkably reinforced in technique, while by above-mentioned test it is found that the Dissolution behaviours of its preparation
It is significantly improved.So that the present invention has substantive distinguishing features outstanding and marked improvement, and there is practicability.
Specific embodiment
Beneficial effects of the present invention are further illustrated by following experiment.But it is not limited to following embodiments, this field
Technical staff on the basis of the present invention made by, do not depart from the equivalent substitute or transformation of substantive content of the present invention, also this
Within the protection scope of invention.
The 1 miscellaneous Shandong amine tablet of 40mg specification grace of embodiment prepares (unit：g)
Prescription：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into tablet as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, tabletting, film coating, coating weight gain 5% obtains the miscellaneous Shandong amine nanocrystal tablet of grace.
The 2 miscellaneous Shandong amine tablet of 80mg specification grace of embodiment prepares (unit：g)
Prescription：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into tablet as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, tabletting, film coating, coating weight gain 5% obtains the miscellaneous Shandong amine nanocrystal tablet of grace.
The 3 miscellaneous Shandong amine tablet of 160mg specification grace of embodiment prepares (unit：g)
Prescription：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into tablet as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, tabletting, film coating, coating weight gain 5% obtains the miscellaneous Shandong amine nanocrystal tablet of grace.
The 4 miscellaneous Shandong amine hard capsule of 40mg specification grace of embodiment prepares (unit：g)
Prescription：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into hard capsule as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, is fitted into appropriate gelatine capsule shell, the miscellaneous Shandong amine nanocrystal capsule of grace is obtained.
The 5 miscellaneous Shandong amine hard capsule of 80mg specification grace of embodiment prepares (unit：g)
Prescription：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into hard capsule as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, is fitted into appropriate gelatine capsule shell, the miscellaneous Shandong amine nanocrystal capsule of grace is obtained.
The 6 miscellaneous Shandong amine hard capsule of 160mg specification grace of embodiment prepares (unit：g)
Prescription：
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, is further prepared into hard capsule as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous Shandong amine nanocrystal suspension of grace obtained by step 4) is taken, spray drying obtains the miscellaneous Shandong amine nanocrystal of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, is fitted into appropriate gelatine capsule shell, the miscellaneous Shandong amine nanocrystal capsule of grace is obtained.
Claims (10)
1. a kind of oral solid drug composition containing the miscellaneous Shandong amine nanocrystal of grace, by the miscellaneous Shandong amine nanocrystal of main ingredient grace, parent
Aqueous polymer, surfactant, disintegrating agent, glidant and lubricant composition, are further prepared into common stomach as follows
Molten type solid pharmaceutical preparation：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) purified water is taken, the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1), hydrophilic polymer, surfactant sequentially adds high-pressure homogeneous
In machine, under a certain pressure, homogeneous obtains the miscellaneous nanocrystalline suspension of Shandong amine of grace；
3) the miscellaneous nanocrystalline suspension of Shandong amine of grace obtained by step 2) is taken, it is nanocrystalline that spray drying obtains the miscellaneous Shandong amine of grace；
4) the miscellaneous Shandong amine nanocrystal of grace obtained by step 3) is taken, disintegrating agent, glidant are sequentially added, lubricant is uniformly mixed, obtains grace
Miscellaneous Shandong amine nanocrystal combines object；
5) step 4) resulting composition, tabletting are taken, film coating obtains the miscellaneous Shandong amine nanocrystal tablet of grace；
6) step 4) resulting composition is taken, is fitted into hard capsule case, the miscellaneous Shandong amine nanocrystal hard capsule of grace is obtained；Its feature exists
In in the pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace, hydrophilic polymer is polyvinyl alcohol, surfactant Tai Luosha
Pool, disintegrating agent is crospovidone, and glidant is colloidal silicon dioxide, and lubricant is magnesium stearate.
2. the oral solid drug composition as described in claim 1 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The preparation step for stating the miscellaneous Shandong amine nanocrystal of grace is：
1) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
2) it disperses the miscellaneous Shandong amine bulk pharmaceutical chemicals of 200 mesh grace of gained in step 1) acquired solution, suspension concentration 5%；
3) suspension obtained by step 2) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
4) the miscellaneous nanocrystalline suspension of Shandong amine of grace obtained by step 3) is taken, it is nanocrystalline that spray drying obtains the miscellaneous Shandong amine of grace.
3. the oral solid drug composition as claimed in claim 2 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is stated, preparation prescription composition is as follows：
4. the oral solid drug composition as claimed in claim 2 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is stated, preparation prescription composition is as follows：
5. the oral solid drug composition as claimed in claim 2 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is stated, preparation prescription composition is as follows：
6. such as the oral solid drug composition as claimed in claim 3 to 5 containing the miscellaneous Shandong amine nanocrystal of grace, feature
It is, the pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is further prepared into tablet as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous nanocrystalline suspension of Shandong amine of grace obtained by step 4) is taken, it is nanocrystalline that spray drying obtains the miscellaneous Shandong amine of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, tabletting, film coating, coating weight gain 5% obtains the miscellaneous Shandong amine nanocrystal tablet of grace.
7. the oral solid drug composition as claimed in claim 2 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is stated, preparation prescription composition is as follows：
8. the oral solid drug composition as claimed in claim 2 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is stated, preparation prescription composition is as follows：
9. the oral solid drug composition as claimed in claim 2 containing the miscellaneous Shandong amine nanocrystal of grace, which is characterized in that institute
The pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is stated, preparation prescription composition is as follows：
10. the oral solid drug composition containing the miscellaneous Shandong amine nanocrystal of grace as described in claim 7-9 is any, feature
It is, the pharmaceutical composition of the miscellaneous Shandong amine nanocrystal of grace is further prepared into hard capsule as follows：
1) it takes the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace to crush, crosses 200 meshes, it is spare；
2) tyloxapol and polyvinyl alcohol is taken successively to be dissolved in purified water, concentration is 2% and 10%；
3) the miscellaneous Shandong amine bulk pharmaceutical chemicals of grace obtained by step 1) are taken to be scattered in step 1) acquired solution, concentration 5%；
4) suspension obtained by step 3) is added in high pressure homogenizer, is recycled 7 times under the pressure of 100bar, obtains the miscellaneous Lu Anna of grace
Rice crystal suspension；
5) the miscellaneous nanocrystalline suspension of Shandong amine of grace obtained by step 4) is taken, it is nanocrystalline that spray drying obtains the miscellaneous Shandong amine of grace；
6) the miscellaneous Shandong amine nanocrystal of grace obtained by step 5) is taken, disintegrating agent crospovidone, glidant colloidal silica are sequentially added
Silicon, magnesium stearate lubricant are uniformly mixed, and obtain the miscellaneous Shandong amine nanocrystal combination object of grace；
7) step 6) resulting composition is taken, is fitted into appropriate gelatine capsule shell, the miscellaneous Shandong amine nanocrystal capsule of grace is obtained.
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