CN108392638A - A kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound and the nasal spray containing it - Google Patents
A kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound and the nasal spray containing it Download PDFInfo
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- CN108392638A CN108392638A CN201810311579.1A CN201810311579A CN108392638A CN 108392638 A CN108392638 A CN 108392638A CN 201810311579 A CN201810311579 A CN 201810311579A CN 108392638 A CN108392638 A CN 108392638A
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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Abstract
The present invention relates to a kind of Triamcinolone acetonide cyclodextrin super molecule inclusion compound and contain its nasal spray.The present invention in cyclodextrin molecular cavity mainly by Triamcinolone acetonide molecule inclusion in forming super molecule inclusion compound, again in preparation prescription binder and after pharmaceutically acceptable carrier mixes in proportion, using method for preparing water solution obtained solution type nasal medicine composition, increase drug solubility and uniformity, spreadability is good when use, for treating allergic rhinitis.
Description
Technical field
The present invention relates to a kind of nasal pharmaceutical formulations, and in particular to a kind of solution-type Triamcinolone acetonide-cyclodextrin oversubscription attached bag
Close object nasal spray and preparation method thereof.
Background technology
Cyclodextrin (Cyclodextrins, abbreviation CDs) be multiple glucose molecules by α-Isosorbide-5-Nitrae glucosides key connection at
A series of natural cyclic oligosaccharides.The structure of cyclodextrin is truncated hollow cone structure, and conical cavity depth about 0.79nm has similar
The property of surfactant, the preparation to form super molecule inclusion compound with drug molecule non-covalent bond provide advantageous condition.
In numerous kinds cyclodextrin, α-, β-and γ-CDs are most common, are made of respectively 6,7 and 8 glucose units.Wherein β-CDs
Yield highest, price is generally the least expensive, therefore applies wide.But due to the shortcomings of β-CDs renal toxicitys are big, haemocylolysis is strong, scientist
Synthesize a series of beta-cyclodextrin derivatives, at present hydroxypropyl-β-cyclodextrin (Hydroxypropyl- β-cyclodextrin,
HP- β-CD) and Sulfobutyl ether β _ cyclodextrin (Sulfobutylether- β-cyclodextrin, SBECD) it is more common.Therefore, more
Super molecule inclusion compound is generated using beta-cyclodextrin derivative with drug molecule to carry to increase drug solubility and stability
High drug absorption covers smell, controls the release of drug, mitigate locally and systemically toxicity and improve drug permeability etc..
Triamcinolone acetonide (CAS:76-25-5, Triamcinolone Acetonide) it is a kind of potent glucocorticoid, be
Treat the choice drug of allergia, allergic rhinitis.Since the dissolubility of Triamcinolone acetonide is poor, therefore the song listed both at home and abroad at present
An Naide nasal sprays are suspension, mix uneven after drug shaking, and drug uniformity is poor, and fails fundamentally
Solve the problems, such as that Triamcinolone acetonide dissolubility is poor.
Invention content
In view of the disadvantages such as Triamcinolone acetonide solubility is small, bioavilability is low, an object of the present invention is that design is a kind of molten
Liquid type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound and nasal spray.
The second object of the present invention is to provide a kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound and nasal spray
Preparation method.
The technical solution adopted by the present invention is：A kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound, with Triamcinolone acetonide and ring
Dextrin is active ingredient, by Triamcinolone acetonide in the cavity of cyclodextrin molecular, forms Triamcinolone acetonide-cyclodextrin oversubscription attached bag
Close object.
Preferably, above-mentioned Triamcinolone acetonide-cyclodextrin super molecule inclusion compound, the cyclodextrin are alpha-cyclodextrin, β-ring
Dextrin or gamma-cyclodextrin.
It is furthermore preferred that above-mentioned Triamcinolone acetonide-cyclodextrin super molecule inclusion compound, the beta-cyclodextrin is hydroxy propyl-Beta-
Cyclodextrin (HP- β-CD) and Sulfobutyl ether β _ cyclodextrin (SBECD).
A kind of preparation method of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound, includes the following steps：
1) triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes to about 5.0 μm of average grain diameter, maximum
Grain size is no more than 50 μm, and particle size 90% is less than 15 μm, obtains Triamcinolone acetonide micro mist；
2) cyclodextrin is dissolved in appropriate distilled water and ethyl alcohol, under 25-55 DEG C, 200r/min, heating stirring dissolving adds
Enter appropriate Triamcinolone acetonide micro mist, continue after stirring 1h, suitable quantity of water is added and includes 1-3h, stops heating stirring, is filtered to remove insoluble
Filtrate is removed ethyl alcohol in revolving on Rotary Evaporators, super molecule inclusion compound aqueous solution is obtained, by super molecule inclusion compound aqueous solution by object
After pre-freeze, in 12h is lyophilized in freeze drier, Triamcinolone acetonide-cyclodextrin super molecule inclusion compound is obtained.
A kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, including above-mentioned Triamcinolone acetonide-ring paste
Smart super molecule inclusion compound, binder, pH adjusting agent, osmotic pressure regulator, preservative and water are mixed.
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, is wrapped by weight percentage
It includes, 0.01-0.1% Triamcinolone acetonides, 1.0-5.0% cyclodextrin, 1.5-2.5% binders, 4-6% osmotic pressure regulators,
0.010-0.022% preservatives and excess water, it is 4-5 that the dosage of pH adjusting agent, which is adjusting pH value,.
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, the solution-type are bent
An Naide-cyclodextrin super molecule inclusion compound nasal spray have 270-350 millis osmolality/liter osmotic pressure.
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, the solution-type are bent
An Naide-cyclodextrin super molecule inclusion compound nasal spray pH value is 5.
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, the binder are
Hydroxypropyl methyl cellulose (HPMC).
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, the osmotic pressure tune
Section agent is DEXTROSE ANHYDROUS.
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, the preservative are
Benzalkonium chloride.
Preferably, above-mentioned solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, the pH adjusting agent
For 0.1M hydrochloric acid.
A kind of preparation method of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, includes the following steps：
1) triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes to about 5.0 μm of average grain diameter, maximum
Grain size is no more than 50 μm, and particle size 90% is less than 15 μm, obtains Triamcinolone acetonide micro mist.
2) cyclodextrin is dissolved in appropriate distilled water and ethyl alcohol, in 25-55 DEG C, preferably 50 DEG C, under 200r/min, heating is stirred
Dissolving is mixed, appropriate Triamcinolone acetonide micro mist is added, is continued after stirring 1h, suitable quantity of water is added and includes 1-3h, preferably 2h, stops heating and stirs
It mixes, is filtered to remove insoluble matter, filtrate is removed into ethyl alcohol in revolving on Rotary Evaporators, obtains Triamcinolone acetonide-cyclodextrin oversubscription attached bag
Close object aqueous solution.
3) binder, osmotic pressure regulator and preservative are dissolved in deionized water, qs pH adjuster, stirring is added
Uniformly, mixed solution is obtained；
4) merge Triamcinolone acetonide-cyclodextrin super molecule inclusion compound aqueous solution that step 2) obtains and the mixing that step 3) obtains
Solution, after stirring evenly plus excess water, adjusting pH to 4-5 stir evenly, obtain solution-type Triamcinolone acetonide-cyclodextrin oversubscription attached bag
Close object nasal spray.
The advantageous effect of the present invention compared with the existing technology is：
1. the present invention, as reaction dissolvent, overcomes Triamcinolone acetonide in ethanol solution using distilled water and alcohol mixed solution
It is precipitated and loses the technological deficiency of bulk pharmaceutical chemicals, and inclusion rate is better than polishing and ultrasonic method, easy to operate, mild condition is stablized
Property and repeatability are preferable, more conducively industrialized production.Phase solubility experiment shows HP- β-CD and SBECD for Triamcinolone acetonide
SBECD is better than to the solubilization of Triamcinolone acetonide with solubilization and HP- β-CD.The nasal spray of the present invention overcomes the country
The Triamcinolone acetonide nasal spray in outer market is suspension, and uneven, the poor defect of drug uniformity is mixed after drug shaking.
2. the nasal spray of the present invention increases residence time of the Triamcinolone acetonide in nasal cavity, makes by the way that binder is added
Drug absorption is more abundant.
3. the nasal spray of the present invention adjusts mM osmotic pressure 280~380 by the way that osmotic pressure regulator is added
(mOsmol/L) in range.
4. solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray of the present invention, compared with other preparations, tool
The effect for having immediate effect and positioning can control the allergic phenomenas such as rhiocnesmus, nasal obstruction, rhinorrhea, sneezing, master in a short time after medication
It is positioned at schneiderian membrane, the drug swallowed through pharynx nasalis is seldom, and the rapid metabolization in liver will not occur adrenal cortex function
The adverse reaction of inhibition.
5. solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray of the present invention, not only increases Triamcinolone acetonide
Solubility, and in nasal cavity have better spreadability, absorption of the Triamcinolone acetonide in nasal cavity can be promoted, to improve drug
Bioavilability.
6, solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray of the invention, often presses main ingredient Triamcinolone acetonide
Content is 50-100 μ g.Triamcinolone acetonide-cyclodextrin super molecule inclusion compound grain size<100nm belongs to supermolecule solution, is conducive to song
Absorptions of the An Naide at schneiderian membrane position.
Description of the drawings
Fig. 1 is the DSC collection of illustrative plates of Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds.
Fig. 2 is the DSC collection of illustrative plates of Triamcinolone acetonide-SBECD super molecule inclusion compounds.
Fig. 3 is the infrared light collection of illustrative plates of Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds.
Fig. 4 is the infrared light collection of illustrative plates of Triamcinolone acetonide-SBECD super molecule inclusion compounds.
Fig. 5 is the scanning electron microscope (SEM) photograph of Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds.
Fig. 6 is the scanning electron microscope (SEM) photograph of Triamcinolone acetonide-SBECD super molecule inclusion compounds.
Specific implementation mode
The present invention is described in detail with reference to embodiments.
1 Triamcinolone acetonide of embodiment-cyclodextrin super molecule inclusion compound
(1) (Triamcinolone acetonide-HP- β-CD supermolecules include Triamcinolone acetonide-hydroxypropyl-β-cyclodextrin super molecule inclusion compound
Object)
1) triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes to about 5.0 μm of average grain diameter, maximum
Grain size is no more than 50 μm, and particle size 90% is less than 15 μm, obtains Triamcinolone acetonide micro mist.
2) 33.17g HP- β-CD are dissolved in 15mL distilled water and 5mL ethyl alcohol, in 50 DEG C, under 200r/min, heating is stirred
Dissolving is mixed, 0.9075g Triamcinolone acetonides are added, after continuing stirring 1,15mL water is added and includes 2h, stops heating stirring, is filtered to remove
Filtrate is evaporated off ethyl alcohol in outstanding on Rotary Evaporators, obtains Triamcinolone acetonide-HP- β-CD super molecule inclusion compound aqueous solutions by insoluble matter,
After super molecule inclusion compound aqueous solution pre-freeze, in 12h is lyophilized in freeze drier, Triamcinolone acetonide-HP- β-CD supermolecules inclusion is obtained
Object.
(2) Triamcinolone acetonide-Sulfobutyl ether β _ cyclodextrin super molecule inclusion compound (Triamcinolone acetonide-SBECD super molecule inclusion compounds)
1) triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes to about 5.0 μm of average grain diameter, maximum
Grain size is no more than 50 μm, and particle size 90% is less than 15 μm, obtains Triamcinolone acetonide micro mist.
2) 69.3g SBECD are dissolved in 20mL distilled water and 10mL ethyl alcohol, in 50 DEG C, under 200r/min, heating stirring
0.9075g Triamcinolone acetonides are added in dissolving, after continuing stirring 1,10mL water are added and includes 2h, stops heating stirring, is filtered to remove not
Filtrate is evaporated off ethyl alcohol in outstanding on Rotary Evaporators, obtains Triamcinolone acetonide-HP- β-CD super molecule inclusion compound aqueous solutions by molten object, will
After super molecule inclusion compound aqueous solution pre-freeze, in 12h is lyophilized in freeze drier, Triamcinolone acetonide-SBECD super molecule inclusion compounds are obtained.
(3) it detects
1, Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds and Triamcinolone acetonide-SBECD are measured by differential scanning calorimetry
The heat absorption peak of super molecule inclusion compound, as a result as depicted in figs. 1 and 2, by Fig. 1 and Fig. 2 as it can be seen that the melting peak of Triamcinolone acetonide disappears
It loses, shows that Triamcinolone acetonide is included completely.
2, the infrared spectrum of Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds and Triamcinolone acetonide-SBECD super molecule inclusion compounds
Figure is as shown in Figure 3 and Figure 4, as can be seen from figs. 3 and 4, in super molecule inclusion compound spectrogram, the carbonyl in Triamcinolone acetonide chemical constitution
In 1700cm-1Stretching vibration peak at left and right disappears, and Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds and Triamcinolone acetonide-
The feature of HP- β-CD and SBECD is presented in the entire spectrogram of SBECD super molecule inclusion compounds respectively, almost without the absorption of Triamcinolone acetonide
Peak, this illustrates that Triamcinolone acetonide molecule has been incorporated in the cavity of cyclodextrin.
3, the scanning electron microscope of Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds and Triamcinolone acetonide-SBECD super molecule inclusion compounds
Figure is as shown in Figure 5 and Figure 6, by Fig. 5 and Fig. 6 as it can be seen that the particle shape of Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds is surface
The particle shape of crystal that is concave-convex and having branch-like, Triamcinolone acetonide-SBECD super molecule inclusion compounds is crystal in irregular shape.
(4) inclusion temperature is on the deliquescent influence of Triamcinolone acetonide
Method is with (one) and (two), and the temperature in only changing the step 2), it is respectively 25 DEG C and 37 DEG C to take temperature.As a result such as
Table 1.
It, can by table 1 by measuring influence experiments of the HP- β-CD and SBECD to Triamcinolone acetonide solubility at different temperatures
See, the equilibrium constant of HP- β-CD groups is all higher than the SBECD group equilibrium constants, illustrates that HP- β-CD are excellent to the solubilization of Triamcinolone acetonide
In SBECD.As the temperature increases, HP- β-CD and SBECD increase the solubilization of Triamcinolone acetonide, illustrate that increasing temperature has
Conducive to the generation of super molecule inclusion compound.
Equations of linear regression and equilibrium constant K of the HP- β-CD and SBECD to Triamcinolone acetonide solubility under 1 different temperatures of table
2 solution-type Triamcinolone acetonide-HP- β-CD super molecule inclusion compound nasal sprays of embodiment
Preparation method is as follows：
1, prescription is as follows：
2, triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes.It is average after Triamcinolone acetonide micronizing
Size controlling is at 5.0 μm or so, and maximum particle diameter must not exceed 50 μm, and particle size 90% should be less than 15 μm, be waited for after fineness qualification
With.
3, weighing HP- β-CD by recipe quantity precision adds suitable quantity of water and ethyl alcohol as in eggplant-shape bottle, is stirred with heated at constant temperature magnetic force
It mixes device to stir to dissolve, temperature 50 C, mixing speed 200r/min.Triamcinolone acetonide is weighed by recipe quantity precision, and constant temperature is added
In above-mentioned solution, continue after stirring 1h, stops heating after suitable quantity of water inclusion 2h is added.It is filtered to remove insoluble matter, by filtrate in rotation
Turn to hang on evaporimeter and ethyl alcohol is evaporated off, obtains Triamcinolone acetonide-HP- β-CD super molecule inclusion compound aqueous solutions.
4, HPMC, DEXTROSE ANHYDROUS, benzalkonium chloride are weighed by recipe quantity precision to be dissolved in deionized water, is added appropriate
0.1M hydrochloric acid, stirs evenly, and obtains mixed solution.
5, merge the mixed solution of Triamcinolone acetonide-HP- the β-CD super molecule inclusion compounds aqueous solution and step 4 of step 3, stirring
1650g is added water to after uniformly, is adjusted pH to 5.0, is stirred evenly, obtain solution-type Triamcinolone acetonide-HP- β-CD super molecule inclusion compound noses
Spray.
3 solution-type Triamcinolone acetonide-HP- β-CD super molecule inclusion compound nasal sprays of embodiment
(1) dosage for changing HPMC distinguishes 24.75g, 28.875g, 33g, 37.125g, 41.25g, other same embodiments
2 so that HPMC contents are respectively 1.5%, 1.75%, 2.0%, 2.25%, 2.5% by weight percentage, and obtained solution type is bent
An Naide-HP- β-CD super molecule inclusion compound nasal sprays.As a result such as table 2.
2 Triamcinolone acetonide-HP- β-CD super molecule inclusion compound nasal spray viscosity numbers of table
(2) it is respectively 66g, 82.5g, 99g, the other the same as in Example 2 to change the dosage of DEXTROSE ANHYDROUS so that by weight
Percentage anhydrous grape sugared content is respectively 4%, 5%, 6%, obtained solution type Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds
Nasal spray.As a result such as table 3.
3 Triamcinolone acetonide-HP- β-CD super molecule inclusion compound nasal spray osmotic pressure values of table
4 solution-type Triamcinolone acetonide-SBECD super molecule inclusion compound nasal sprays of embodiment
Preparation method is as follows
1, prescription is as follows
2, triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes.It is average after Triamcinolone acetonide micronizing
Size controlling is at 5.0 μm or so, and maximum particle diameter must not exceed 50 μm, and particle size 90% should be less than 15 μm, be waited for after fineness qualification
With.
3, it weighs SBECD by recipe quantity precision and adds suitable quantity of water and ethyl alcohol as in eggplant-shape bottle, with heated at constant temperature magnetic agitation
Device stirs to dissolve, temperature 50 C, mixing speed 200r/min.Triamcinolone acetonide is weighed by recipe quantity precision, and the upper of constant temperature is added
It states in solution, continues after stirring 1h, stop heating after suitable quantity of water inclusion 2h is added.It is filtered to remove insoluble matter, by filtrate in rotation
It is hanged on evaporimeter and steams ethyl alcohol, obtain Triamcinolone acetonide-SBECD super molecule inclusion compound aqueous solutions.
4, HPMC, DEXTROSE ANHYDROUS, benzalkonium chloride are weighed by recipe quantity precision to be dissolved in deionized water, is added appropriate
0.1M hydrochloric acid, stirs evenly, and obtains mixed solution.
5, merge the mixed solution of the Triamcinolone acetonide-SBECD super molecule inclusion compounds aqueous solution and step 4 of step 3, stirring is equal
1650g is added water to after even, is adjusted pH to 5.0, is stirred evenly, obtain solution-type Triamcinolone acetonide-SBECD super molecule inclusion compound nose sprays
Agent.
5 solution-type Triamcinolone acetonide-SBECD super molecule inclusion compound nasal sprays of embodiment
(1) dosage for changing HPMC distinguishes 24.75g, 28.875g, 33g, 37.125g, 41.25g, other same embodiments
4 so that HPMC contents are respectively 1.5%, 1.75%, 2.0%, 2.25%, 2.5% by weight percentage, and obtained solution type is bent
An Naide-SBECD super molecule inclusion compound nasal sprays.As a result such as table 4.
4 Triamcinolone acetonide-SBECD super molecule inclusion compound nasal spray viscosity numbers of table
(2) it is respectively 66g, 82.5g, 99g, the other the same as in Example 4 to change the dosage of DEXTROSE ANHYDROUS so that by weight
Percentage anhydrous grape sugared content is respectively 4%, 5%, 6%, obtained solution type Triamcinolone acetonide-SBECD super molecule inclusion compound noses
Spray.As a result such as table 5.
5 Triamcinolone acetonide-SBECD super molecule inclusion compound nasal spray osmotic pressure values of table
Embodiment 6
(1) droplet measurement
Prepared by Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds nasal sprays and embodiment 4 prepared by measurement embodiment 2
The grain size of Triamcinolone acetonide-SBECD super molecule inclusion compound nasal sprays, as a result such as table 6, as shown in Table 6, the nasal spray grain of preparation
Diameter is smaller, is conducive to absorption of the Triamcinolone acetonide at schneiderian membrane position.
6 solution-type Triamcinolone acetonide cyclodextrin super molecule inclusion compound nasal spray particle size values of table
(2) ovality measures
Prepared by Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds nasal sprays and embodiment 4 prepared by measurement embodiment 2
The ovality of Triamcinolone acetonide-SBECD super molecule inclusion compound nasal sprays, as a result such as table 7, as shown in Table 7, cross circular section is ellipse
Circularity is small, keeps liquid and nasal cavity contact area more uniform, absorbs more abundant.
The measurement result of 7 solution-type Triamcinolone acetonide cyclodextrin super molecule inclusion compound nasal spray ovality of table
(3) the solution-type Triamcinolone acetonide cyclodextrin super molecule inclusion compound nasal spray and city of comparative example 2 and 4 gained
Triamcinolone acetonide nasal spray (Nasacorts AQ) effect experiment sold.
1, experimental animal：Healthy guinea pig 50, half male and half female, 500 ± 50g of weight
2, modeling method：3 are randomly selected by gender and is only used as Normal group, and remaining cavy is made as model group
Mould, model group animal instill 10%TDI olive oil solutions, 12.5 μ L/ of dosage with micro sample adding appliance from cavy bilateral nostril
Kg, one time a day, continuous 7 days.As table 8 passes through the whether successful (index detection method of neurological deficit score judgment models：Behaviouristics is commented
Point：At once to 30min observation animal behavior scorings after excitation.It is scored using superposition quantization,>5 points indicate modeling success).After 7 days
Next day of being changed to 1 time, (gives 10%TDI olive oil solutions for 15 minutes after to physiological saline or medicine, maintains sensitization shape
State, until drug therapy terminates).
Table 8
3, grouping and administration：In modeling administration start within the 8th day the successful cavy of modeling is randomly divided into 8 groups, every group 3
Only, be divided into 9 groups, be normal group (giving physiological saline) respectively, negative model control group (giving physiological saline), Qu An how
Moral-cyclodextrin super molecule inclusion compound nasal spray (Triamcinolone acetonide-HP- β-CD super molecule inclusion compounds nasal sprays and Triamcinolone acetonide-
SBECD super molecule inclusion compounds nasal spray) low, middle and high dose groups, positive controls (Nasacort groups).Each group difference simultaneously
Drug or solvent are given according to dosage and method shown in table 9,1 time a day, continuous use 14 days.
9 Triamcinolone acetonide cyclodextrin super molecule inclusion compound nasal spray of table treats cavy allergic rhinitis dosage table
4, methods of sample collection：Animal behavior is excited with 10%TDI olive oil solution collunariums within 1 hour after last time is administered
It learns and changes, observe animal situation.Animal is put to death after 30 minutes, is removed nose surrounding skin, is taken schneiderian membrane, it is molten in 10% formalin
It is fixed in liquid.It makes pathological section sample and carries out pathological examination under light microscopic.
5, experimental result：There is typical allergic symptom in the made AR animal patterns of the technology of the present invention, and modeling is after a week, it is seen that
Cavy, sneezing, wipes nose number and nasal secretion obviously increases.The source of an allusion is presented compared with normal group in cavy nasal mucosal tissue
The pathological change of type illustrates that modeling method is reliably effective.Administration group cavy pathological section the result shows that, Triamcinolone acetonide cyclodextrin is super
Molecular clathrate nasal spray has dose-dependence to the therapeutic effect of rhinitis, and with the increase of dosage, schneiderian membrane fills
Phenomena such as blood, telangiectasis, mitigates or disappears.
Claims (10)
1. a kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound, which is characterized in that with Triamcinolone acetonide and cyclodextrin be effectively at
Point, by Triamcinolone acetonide in the cavity of cyclodextrin molecular, form Triamcinolone acetonide-cyclodextrin super molecule inclusion compound.
2. a kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound according to claim 1, which is characterized in that the ring
Dextrin is alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin.
3. a kind of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound according to claim 2, which is characterized in that the β-
Cyclodextrin is hydroxypropyl-β-cyclodextrin and Sulfobutyl ether β _ cyclodextrin.
4. a kind of preparation method of Triamcinolone acetonide-cyclodextrin super molecule inclusion compound described in claim 1, which is characterized in that packet
Include following steps：
1) triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes to about 5.0 μm of average grain diameter, maximum particle diameter
No more than 50 μm, particle size 90% is less than 15 μm, obtains Triamcinolone acetonide micro mist；
2) cyclodextrin is dissolved in appropriate distilled water and ethyl alcohol, under 25-55 DEG C, 200r/min, heating stirring dissolving is added suitable
Triamcinolone acetonide micro mist is measured, is continued after stirring 1h, suitable quantity of water is added and includes 1-3h, stops heating stirring, is filtered to remove insoluble matter, it will
Ethyl alcohol is evaporated off in outstanding on Rotary Evaporators in filtrate, super molecule inclusion compound aqueous solution is obtained, by super molecule inclusion compound aqueous solution pre-freeze
Afterwards, in 12h is lyophilized in freeze drier, Triamcinolone acetonide-cyclodextrin super molecule inclusion compound is obtained.
5. a kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, which is characterized in that the solution-type is bent
An Naide-cyclodextrin super molecule inclusion compound nasal spray, including Triamcinolone acetonide described in claim 1-cyclodextrin oversubscription attached bag
Object, binder, pH adjusting agent, osmotic pressure regulator, preservative and water is closed to be mixed.
6. a kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray according to claim 5, feature
It is, solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray, includes 0.01- by weight percentage
0.1% Triamcinolone acetonide, 1.0-5.0% cyclodextrin, 1.5-2.5% binders, 4-6% osmotic pressure regulators, 0.010-0.022%
Preservative and excess water, it is 4-5 that the dosage of pH adjusting agent, which is adjusting pH value,.
7. a kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray according to claim 5 or 6,
It is characterized in that, solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray has 270-350 milli infiltrations mole
Concentration/liter osmotic pressure.
8. a kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray according to claim 5 or 6,
It is characterized in that, solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray pH value is 5.
9. a kind of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray according to claim 5 or 6,
It is characterized in that, the binder is hydroxypropyl methyl cellulose；The osmotic pressure regulator is DEXTROSE ANHYDROUS；Described
Preservative is benzalkonium chloride；The pH adjusting agent is 0.1M hydrochloric acid.
10. a kind of preparation of solution-type Triamcinolone acetonide-cyclodextrin super molecule inclusion compound nasal spray described in claim 5 or 6
Method, which is characterized in that include the following steps：
1) triamcinolone acetonide raw medicine is placed in airslide disintegrating mill and carries out micronization processes to about 5.0 μm of average grain diameter, maximum particle diameter
No more than 50 μm, particle size 90% is less than 15 μm, obtains Triamcinolone acetonide micro mist；
2) cyclodextrin is dissolved in appropriate distilled water and ethyl alcohol, under 25-55 DEG C, 200r/min, heating stirring dissolving is added suitable
Triamcinolone acetonide micro mist is measured, is continued after stirring 1h, suitable quantity of water is added and includes 1-3h, stops heating stirring, is filtered to remove insoluble matter, it will
Filtrate removes ethyl alcohol in revolving on Rotary Evaporators, obtains Triamcinolone acetonide-cyclodextrin super molecule inclusion compound aqueous solution；
3) binder, osmotic pressure regulator and preservative are dissolved in deionized water, qs pH adjuster is added, stirring is equal
It is even, obtain mixed solution；
4) merge Triamcinolone acetonide-cyclodextrin super molecule inclusion compound aqueous solution that step 2) obtains and the mixing that step 3) obtains is molten
Liquid, after stirring evenly plus excess water, adjusting pH to 4-5 are stirred evenly, and obtain solution-type Triamcinolone acetonide-cyclodextrin supermolecule inclusion
Object nasal spray.
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| CN104971039A (en) * | 2015-07-07 | 2015-10-14 | 上海通用药业股份有限公司 | Medical product containing solution-type triamcinolone acetonide acetate |
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