CN106139161A - A kind of roflumilast clathrate and solid preparation thereof - Google Patents
A kind of roflumilast clathrate and solid preparation thereof Download PDFInfo
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- CN106139161A CN106139161A CN201610662530.1A CN201610662530A CN106139161A CN 106139161 A CN106139161 A CN 106139161A CN 201610662530 A CN201610662530 A CN 201610662530A CN 106139161 A CN106139161 A CN 106139161A
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- 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
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Abstract
The invention discloses a kind of roflumilast clathrate and solid preparation thereof, wherein roflumilast clathrate is made up of roflumilast and inclusion agents, and the mass ratio of roflumilast and inclusion agents is 1:6～10.Described inclusion agents is selected from beta cyclodextrin or hydroxypropyl beta cyclodextrin.Roflumilast clathrate of the present invention and pharmaceutic adjuvant are prepared as oral solid formulation, have the advantages that dissolution is fast, good stability, bioavailability are high, the problem such as solve that roflumilast dosage is little, low-solubility is caused pharmacy mixing is uneven and dissolution rate is slow.
Description
One, technical field
The present invention relates to a kind of roflumilast clathrate and solid preparation thereof, belong to pharmaceutical technology field.
Two, background technology
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, hereinafter referred to as COPD)
It is a kind of chronic bronchitis with airflow obstruction feature and (or) emphysema, pulmonary heart disease can be further development of and breathing declines
The common chronic disease exhausted.Abnormal inflammatory reaction with harmful gas and deleterious particle is relevant, and disability rate and case fatality rate are the highest, entirely
More than 40 years old sickness rate up to 9～10% of ball.
COPD is closely related with chronic bronchitis and emphysema, and bronchial asthma is not belonging to COPD.Chronic bronchitis
Referring to after except other known reason of chronic cough, patient coughs every year, eliminates the phlegm more than 3 months, and continuous 2 years persons.Lung qi
Swell and refer to that pulmonary's terminal bronchiole fortune end air cavity the most lasting abnormal expansion occurs and with alveolar wall and bronchiolar destruction
And without obvious pulmonary fibrosis.When flow limitation occur in chronic bronchitis, emphysema patient's pulmonary function test, and can not be complete
Entirely can the inverse time, then can diagnose COPD.If patient only has chronic bronchitis and (or) emphysema, and airless is limited, the most not
COPD can be diagnosed as.If only cough, the chronic bronchitis of symptom of eliminating the phlegm, this is the high-risk period of COPD.If COPD
Can not get correct treatment, systemic disease can be developed into, as some patients can develop into pulmonary heart disease, respiratory failure, lung heart and brain
Disease, and organs function is impaired.
Roflumilast (Roflumilast) is a kind of oral selectivity phosphodiesterase 4 (PDE4) inhibitor, this medicine
Have been proven to suppress the inflammation relevant with COPD, be first medicine for serious symptom COPD novel therapeutic.Also be for
The first oral anti-inflammatory treatment medicine that COPD patient develops specially, is used for treating principal characteristic chronic obstructive pulmonary disease.
The chemical name of roflumilast is 3-(ring the third methoxyl group)-N-(3,5-bis-chloro-4-pyridine radicals)-4-(difluoromethoxy
Base) Benzoylamide, structural formula is as follows:
Roflumilast is the most insoluble in water, and dissolubility is about 0.55 μ g/ml, in the dissolving of other different pH buffer
Degree is all in the range of 0.45 μ g/ml～0.65 μ g/ml, and for insoluble drug, its bioavailability depends on that roflumilast is from solid
Dissolution in body preparation.Therefore, roflumilast is prepared as solid preparation and need to solve the dissolution problem of solid preparation product.
CN101171005A discloses a kind of compositions containing roflumilast, it is characterised in that after roflumilast micronization
Being dried prepared through bed spray with other pharmaceutic adjuvants, the method needs Roflumilast raw material is carried out micronization processes, work
Skill is complicated, and equipment requirements is high, and material loss is big.
CN103127011A discloses a kind of Roflumilast tablet and preparation method thereof, by roflumilast comminution by gas stream micronization
After, direct and adjuvant mixed pressuring plate, but this product specification is less, and main constituent only accounts for 0.77%, the raw material after comminution by gas stream and adjuvant
Granularity difference is big, it is difficult to mix homogeneously, is easily layered in tableting processes, and comminution by gas stream exists increase equipment investment, loss of material
Greatly, equipment cleaning difficulty etc. problem.
CN102274222A discloses roflumilast medicinal composition of a kind of high bioavailability and preparation method thereof, will
Be ground under roflumilast and beta-schardinger dextrin-solid state after certain particle size with other adjuvant mixed pressuring plates, medicine under solid state
Real clathrate cannot be obtained with inclusion agents mixed grinding, find after repeated the method, the solid preparation dissolution obtained
It is much slower than commercially available ordinary tablet
Three, summary of the invention
It is desirable to provide a kind of roflumilast clathrate and solid preparation thereof, to be solved technical problem is that raising
The dissolution of roflumilast and bioavailability, to overcome above-mentioned prior art defect.
The present invention is the principle according to intermolecular interaction, with cyclodextrin or derivatives thereof as host molecule, with sieve fluorine
Department is specially for guest molecule, in the presence of solvent by clathration, by roflumilast inclusion to cyclodextrin or derivatives thereof molecule
In, form clathrate.Its dissolution rate being mainly characterized by improve insoluble medicine and dissolubility, and add stablizing of medicine
Property.
Roflumilast clathrate of the present invention, is made up of roflumilast and inclusion agents, roflumilast and the mass ratio of inclusion agents
For 1:6～10.Wherein inclusion agents is selected from beta-schardinger dextrin-or HP-β-CD.
The preparation method of roflumilast clathrate of the present invention, comprises the steps:
Roflumilast is dissolved in acetone, adds the saturated aqueous solution of inclusion agents, stir or ultrasonic inclusion 30min～2h,
Filter, washing with acetone, dry, pulverize and sieve, obtaining roflumilast clathrate.Wherein roflumilast and the quality volume of acetone
Ratio is 1g:10mL.
The present invention solid preparation containing roflumilast clathrate, is that roflumilast clathrate and pharmaceutic adjuvant are prepared as mouth
Oral solid preparation.
Concrete preparation method: roflumilast clathrate and pharmaceutic adjuvant are pressed equal increments method mix homogeneously, wet granulation,
Tabletted or filling capsule.
Described pharmaceutic adjuvant is acceptable excipient in pharmacy.
Described excipient includes one or more in filler, binding agent, disintegrating agent, lubricant.Wherein filler choosing
One or more in lactose, microcrystalline Cellulose, starch, mannitol；Binding agent is selected from hypromellose, hydroxy propyl cellulose
One or more in element, polyvidone, polyvinyl alcohol；Disintegrating agent is selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linked carboxymethyl
One or more in sodium cellulosate, low-substituted hydroxypropyl cellulose；Lubricant selected from magnesium stearate, sodium stearyl fumarate,
One or more in Pulvis Talci, stearic acid.
Each preparation unit 0.5mg Han roflumilast of the present invention solid preparation containing roflumilast clathrate.
Roflumilast clathrate of the present invention, in the preparation dissolution medium of different pH value, its dissolubility is apparently higher than sieve fluorine
The special micropowder of department, the results are shown in Table 1.
Detection method: weigh in a certain amount of Roflumilast raw material medicine and embodiment 1 roflumilast clathrate in conical flask
In, it is separately added into 100ml purified water, under conditions of 25 ± 2 DEG C, shaking is dissolved 30 minutes, and the saturated solution of gained is surveyed through HPLC
Its concentration fixed, obtains dissolubility.
Table 1 dissolubility compares
| Medium | Roflumilast raw material medicine | Roflumilast clathrate in embodiment 1 |
| Water | 0.56μg/ml | 11.33μg/ml |
| Phosphate buffer (pH6.8) | 0.53μg/ml | 10.94μg/ml |
| Acetate buffer (pH4.5) | 0.51μg/ml | 10.03μg/ml |
| 0.1mol/L hydrochloric acid solution | 0.62μg/ml | 13.44μg/ml |
Containing the solid preparation of roflumilast clathrate of the present invention, dissolution is significantly faster than that commercially available ordinary tabletSee Fig. 1.
Solid preparation containing roflumilast clathrate of the present invention and commercially available ordinary tabletThrough stability (temperature
40 DEG C ± 2 DEG C, relative humidity 75% ± 5%) investigate 6 months, detection level, dissolution and have related substance as follows.Knot
The fruit display solid preparation content of the present invention, dissolution have no significant change with there being related substance, and stability is substantially better than commercially available general
Logical sheetThe results are shown in Table 2.
Table 2 roflumilast preparation stability comparative study result
The present invention solves emphatically the water solubility problems of roflumilast, after being prepared as clathrate, and the dissolubility of roflumilast
Increase about 20 times, solve that the absorption that roflumilast solid preparation occurs because dissolubility is low is slow, bioavailability is low
Problem, and preparation method is simple, it is not necessary to special installation.
Four, accompanying drawing explanation
Fig. 1 is roflumilast uv absorption figure (solvent: ethanol).
Fig. 2 is beta-schardinger dextrin-uv absorption figure (solvent: ethanol).
Fig. 3 roflumilast and beta-schardinger dextrin-mixture uv absorption figure (solvent: ethanol).
Fig. 4 is sieve fluorine department's beta-schardinger dextrin-spy's clathrate uv absorption figure (solvent: ethanol).
Fig. 5 is embodiment 1 test film and commercially availableStripping curve comparison diagram.
Fig. 6 is embodiment 2 test film and commercially availableStripping curve comparison diagram.
Fig. 7 is embodiment 3 test film and commercially availableStripping curve comparison diagram.
Fig. 8 is embodiment 4 test film and commercially availableStripping curve comparison diagram.
Fig. 9 is embodiment 5 test film and commercially availableStripping curve comparison diagram.
Figure 10 is comparative example 1 test film and commercially availableStripping curve comparison diagram.
Figure 11 is comparative example 2 test film and commercially availableStripping curve comparison diagram.
It can be seen that roflumilast has at absorption maximum, and 213nm at about 213nm, 250nm from Fig. 1 to Fig. 4
At trap relatively 250nm strong about 3 times (Fig. 1)；Beta-schardinger dextrin-does not has obvious uv absorption (Fig. 2) in the range of 200-400nm；Sieve
Fluorine department is special to be had at the relatively 250nm of the trap at absorption maximum, and 213nm with beta-schardinger dextrin-mixture at about 213nm, 250nm
Strong about 3 times (Fig. 3), and roflumilast Benexate Hydrochloride, at 213nm, maximum absorption band disappears, in 200-250nm scope
Show more weak end absorption, with 250nm at the terrace broad absorption band of absworption peak shape (Fig. 4), with roflumilast, beta-schardinger dextrin-
And the uv absorption obvious difference of roflumilast and beta-schardinger dextrin-mixture, demonstrate obvious roflumilast beta-cyclodextrin inclusion compound
The diagnostic characteristics of thing.
It can be seen that use tablet and the commercially available ordinary tablet that the roflumilast clathrate of the present invention prepares from Fig. 5 to Fig. 9Comparing, the Roflumilast tablet dissolution 10min that the present invention prepares is all higher than 50%, and 60min is all higher than 85%；And not
The comparative example test film of inclusion and commercially available ordinary tabletDissolution 10min is respectively less than 45%, and 60min is respectively less than 80%.
These results show that the Roflumilast tablet dissolution rate of the present invention is significantly faster than that commercially available product.
Five, detailed description of the invention
The present invention is described further by the following examples, but not limitation of the present invention.
Embodiment 1:
1, the preparation of roflumilast/Benexate Hydrochloride
Dispensing: roflumilast 1g, beta-schardinger dextrin-9g, acetone 10ml.
Being dissolved in acetone by roflumilast, add the saturated aqueous solution of beta-schardinger dextrin-, ultrasonic inclusion 1h, filter, acetone is washed
Wash, dry, pulverize, cross 80 mesh sieves, obtain roflumilast/Benexate Hydrochloride 7.9g, roflumilast content 12.65%.
2, the preparation of preparation
Roflumilast clathrate step 1 prepared is mixed in following ratio with pharmaceutical aids, prepares tablet and capsule:
Preparation technology:
(1) weigh the roflumilast/Benexate Hydrochloride of recipe quantity, be sequentially added into the breast of recipe quantity by equal increments method
Sugar, microcrystalline Cellulose, polyvinylpolypyrrolidone, mix homogeneously, with 30 POVIDONE K 30 BP/USP 90 aqueous solution soft material, 24 mesh sieves are pelletized；
(2) step (1) gained pellet forced air drying at 50-70 DEG C, 20 mesh sieve granulate；
(3) magnesium stearate lubricant of recipe quantity, mix homogeneously are added；
(4) tabletted or filling capsule.
Embodiment 2:
1, the preparation of roflumilast/Benexate Hydrochloride
Dispensing: roflumilast 1g, beta-schardinger dextrin-10g, acetone 10ml.
Roflumilast is dissolved in acetone, adds in the saturated aqueous solution of beta-schardinger dextrin-, stir inclusion 2h, filter, acetone
Washing, dry, pulverize, and crosses 100 mesh sieves, obtains roflumilast/Benexate Hydrochloride 8.9g, roflumilast content 11.20%.
2, the preparation of preparation
Roflumilast clathrate step 1 prepared is mixed in following ratio with pharmaceutical aids, prepares tablet and capsule:
Preparation technology:
(1) weigh the roflumilast/Benexate Hydrochloride of recipe quantity, be sequentially added into the micro-of recipe quantity by equal increments method
Crystalline cellulose, starch, hypromellose, cross-linking sodium carboxymethyl cellulose and Pulvis Talci, mix homogeneously, with water soft material, 24
Mesh sieve is pelletized；
(2) step (1) gained pellet forced air drying at 50-70 DEG C, 20 mesh sieve granulate；
(3) magnesium stearate lubricant of recipe quantity, mix homogeneously are added；
(4) tabletted or filling capsule.
Embodiment 3:
1, the preparation of roflumilast/hydroxypropyl-beta-cyclodextrin inclusion
Dispensing: roflumilast 1g, HP-β-CD 10g, acetone 10ml.
Roflumilast is dissolved in acetone, adds in the saturated aqueous solution of HP-β-CD, ultrasonic inclusion 2h, mistake
Filter, washing with acetone, dry, pulverize, cross 100 mesh sieves, obtain roflumilast/hydroxypropyl-beta-cyclodextrin inclusion 8.6g, sieve fluorine department
Special content 11.62%.
2, the preparation of preparation
Roflumilast clathrate step 1 prepared is mixed in following ratio with pharmaceutical aids, prepares tablet and capsule:
Preparation technology:
(1) weigh the roflumilast/hydroxypropyl-beta-cyclodextrin inclusion of recipe quantity, be sequentially added into place by equal increments method
The mannitol of side's amount, lactose, PVP K30, carboxymethyl starch sodium, mix homogeneously, with water soft material, 24 mesh sieves are pelletized；
(2) step (1) gained pellet forced air drying at 50-70 DEG C, 20 mesh sieve granulate；
(3) the lubricant sodium stearyl fumarate of recipe quantity, mix homogeneously are added；
(4) tabletted or filling capsule.
Embodiment 4:
1, the preparation of roflumilast/hydroxypropyl-beta-cyclodextrin inclusion
Dispensing: roflumilast 1g, HP-β-CD 6g, acetone 10ml.
Roflumilast is dissolved in acetone, adds in the saturated aqueous solution of HP-β-CD, stir inclusion 1h, mistake
Filter, washing with acetone, dry, pulverize, cross 100 mesh sieves, obtain roflumilast/hydroxypropyl-beta-cyclodextrin inclusion 5.2g, sieve fluorine department
Special content 19.23%.
2, the preparation of preparation
Roflumilast clathrate step 1 prepared is mixed in following ratio with pharmaceutical aids, prepares tablet and capsule:
Preparation technology:
(1) weigh the roflumilast/hydroxypropyl-beta-cyclodextrin inclusion of recipe quantity, be sequentially added into place by equal increments method
Lactose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and the Pulvis Talci of side's amount, mix homogeneously, with water soft material, 24 mesh sieves
Pelletize；
(2) step (1) gained pellet forced air drying at 50-70 DEG C, 20 mesh sieve granulate；
(3) lubricant stearic acid of recipe quantity, mix homogeneously are added；
(4) tabletted or filling capsule.
Embodiment 5:
1, the preparation of roflumilast/hydroxypropyl-beta-cyclodextrin inclusion
Dispensing: roflumilast 1g, HP-β-CD 8g, acetone 10ml.
Roflumilast is dissolved in acetone, adds in the saturated aqueous solution of HP-β-CD, ultrasonic inclusion 1h, mistake
Filter, washing with acetone, dry, pulverize, cross 100 mesh sieves, obtain roflumilast/hydroxypropyl-beta-cyclodextrin inclusion 5.9g, sieve fluorine department
Special content 16.95%.
2, the preparation of preparation
Roflumilast clathrate step 1 prepared is mixed in following ratio with pharmaceutical aids, prepares tablet and capsule:
Preparation technology:
(1) weigh the roflumilast/hydroxypropyl-beta-cyclodextrin inclusion of recipe quantity, be sequentially added into place by equal increments method
The lactose of side's amount, PVP K30, polyvinylpolypyrrolidone, mix homogeneously, with water soft material, 24 mesh sieves are pelletized；
(2) step (1) gained pellet forced air drying at 50-70 DEG C, 20 mesh sieve granulate；
(3) magnesium stearate lubricant of recipe quantity, mix homogeneously are added；
(4) tabletted or filling capsule.
Comparative example 1:
1, prescription 6:(recipe quantity is 1000)
2, preparation technology:
(1) microcrystalline Cellulose 102, lactose, magnesium stearate are dried 4 hours under the conditions of 80 DEG C, standby；
(2) beta-schardinger dextrin-of recipe quantity and roflumilast are placed in container, mix homogeneously, be ground to granularity 80 μm ±
10 μm, standby；
(3) microcrystalline Cellulose 102 of (2) item and recipe quantity, lactose, magnesium stearate are mixed homogeneously；
(4) tabletting.
Comparative example 2:
1, prescription 7:(recipe quantity is 1000)
2, preparation technology:
(1) by the PVP K30 of recipe quantity, pregelatinized Starch, starch, lactose mix homogeneously, add in wet granulator；
(2) roflumilast 95% ethanol weighing recipe quantity is configured to the solution that concentration is 25mg/ml；
(3) adding in wet granulator by (2) item, soft material processed, 24 mesh granulations, forced air drying at 50-70 DEG C, 20 mesh sieves are whole
Grain；
(4) magnesium stearate lubricant of recipe quantity, mix homogeneously are added；
(5) tabletting.
Embodiment 6: dissolved corrosion measures
Example 1-5, comparative example 1-2 item and commercially available ordinary tablet respectivelyMeasure molten according to following condition
Trip is, the results are shown in Table 3.
Leaching condition:
Method: Chinese Pharmacopoeia version four general rules 0,931 second method in 2015
Medium: water 1000ml
Rotating speed: 50rpm
Temperature: 37 DEG C ± 0.5 DEG C
Sampling time point: 10min, 20min, 30min, 45min, 60min, 90min, 120min
Testing conditions:
Agilent 1100 high performance liquid chromatograph
Chromatographic column: Agilent TC C18 (150 × 4.6mm, 5 μm)
Flowing phase: acetonitrile-water (65: 35)
Detection wavelength: 215nm
Column temperature: 25 DEG C
Flow velocity: 1.0ml/min
Sample size: 100 μ l
Table 3 stripping curve result
Result shows: in embodiment 1-5, the dissolution rate of compositions is faster than commercially available ordinary tabletComparative example 1 He
Comparative example 2 test film dissolution dissolution rate is considerably slower than commercially available ordinary tablet
Claims (8)
1. a roflumilast clathrate, it is characterised in that:
Being made up of roflumilast and inclusion agents, the mass ratio of roflumilast and inclusion agents is 1:6～10.
Roflumilast clathrate the most according to claim 1, it is characterised in that:
Described inclusion agents is selected from beta-schardinger dextrin-or HP-β-CD.
Roflumilast clathrate the most according to claim 1, it is characterised in that be prepared via a method which to obtain:
Roflumilast is dissolved in acetone, adds the saturated aqueous solution of inclusion agents, stirring or ultrasonic inclusion 30min～2h, filter,
Washing with acetone, dry, pulverize and sieve, and obtains roflumilast clathrate.
Roflumilast clathrate the most according to claim 3, it is characterised in that
Roflumilast is 1g:10mL with the mass volume ratio of acetone.
5. the solid preparation containing the roflumilast clathrate described in claim 1, it is characterised in that:
Being that roflumilast clathrate and pharmaceutic adjuvant are prepared oral solid formulation, each preparation unit contains roflumilast
0.5mg。
Solid preparation the most according to claim 5, it is characterised in that:
Described pharmaceutic adjuvant is the excipient accepted in pharmacy.
Solid preparation the most according to claim 6, it is characterised in that:
Described excipient includes one or more in filler, binding agent, disintegrating agent, lubricant.
Solid preparation the most according to claim 7, it is characterised in that:
One or more in lactose, microcrystalline Cellulose, starch, mannitol of described filler；
One or more in hypromellose, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol of described binding agent；
Described disintegrating agent is selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low substituted hydroxy-propyl fiber
One or more in element；
One or more in magnesium stearate, sodium stearyl fumarate, Pulvis Talci, stearic acid of described lubricant.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107126420A (en) * | 2017-05-09 | 2017-09-05 | 上海信谊万象药业股份有限公司 | A kind of high-dissolution fenofibrate and preparation method thereof |
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| CN107126420A (en) * | 2017-05-09 | 2017-09-05 | 上海信谊万象药业股份有限公司 | A kind of high-dissolution fenofibrate and preparation method thereof |
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