CN1546169A - Transnasal inhalant dry powder of calcitonin and its preparation - Google Patents
Transnasal inhalant dry powder of calcitonin and its preparation Download PDFInfo
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- CN1546169A CN1546169A CNA2003101174657A CN200310117465A CN1546169A CN 1546169 A CN1546169 A CN 1546169A CN A2003101174657 A CNA2003101174657 A CN A2003101174657A CN 200310117465 A CN200310117465 A CN 200310117465A CN 1546169 A CN1546169 A CN 1546169A
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Abstract
A thyrocalcitonin inhalant and its preparation process, wherein the dried powder inhalant is made of emulsifying nanometer drug containing agglomerate and carrying agent, wherein the former comprises 0.1-55% of thyrocalcitonin, 0.5-50% of adhesive agent, 5-50% of surface active agent, 2-30% of grease, 0-10% of cosurfactant, and 0-90% of thinning agent.
Description
Technical field
The present invention relates to a kind of calcitonin per nasal Foradil Aerolizer formoterol fumarate and preparation method.
Background technology
Along with biotechnology and engineered development, increasing polypeptide and protein medicaments are used for clinical treatment, and the most biologically active of polypeptide drug is all unstable to multiple factors such as heat and enzymes, so the normal drug administration by injection that adopts.But secular drug administration by injection brings great misery to the patient, and needs special injection technique, and the patient is difficult to autonomous administration, the finished product height, and medical expense is big.Therefore, both at home and abroad the pharmacy worker is devoted to the research of the non-injecting pathway of polypeptide drug always, as nasal cavity, rectum, oral, lung, eye, Transdermal absorption etc.In above-mentioned route of administration, nasal-cavity administration is the most possible non-injection administration approach that breaks through of protein medicaments.
The applicant has applied for the patent of invention of " a kind of salmon calcitonin snuff and preparation method " February 27 calendar year 2001 to Patent Office of the People's Republic of China, and its application number is: 01105431.X.This technology adopts the bioadhesion technology that the material of salmon calcitonin and tool bioadhesive is compound, uses vesicle type doser.But this powder inhalation still exists weak point, and behind the medicine dissolution, the polarity that tool is certain is difficult to the lipid layer through nasal membrane, cause its bioavailability not high, and the absorption difference after the administration is bigger.
Summary of the invention
First purpose of the present invention is to improve on the basis of above-mentioned former patented technology, providing a kind of can increase the absorption rate of polypeptide drug calcitonin, saturating mucosa ability, improves the calcitonin per nasal Foradil Aerolizer formoterol fumarate of the bioavailability of drug nasal administration.
Second purpose of the present invention is to provide a kind of preparation method of calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention.
First purpose of the present invention is achieved in that calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention is made up of the self-emulsifying nanometer pastille agglomerate of 1-99% and the carrier of 1-99%, described self-emulsifying nanometer pastille agglomerate is made up of the calcitonin of 0.1-55%, the gel adhesive agent of 0.5-50%, the surfactant of 5-50%, the grease of 2-30%, the cosurfactant of 0-10%, the diluent of 0-90%, the powder diameter of described self-emulsifying nanometer pastille agglomerate is 10-150um, but meets the w/o/w emulsion droplet that self emulsifying behind the aqueous medium becomes nanoscale size; Described carrier is made up of the gel adhesive agent of 0-10%, the water-insoluble adhesive agent of 0-20%, the diluent of 70-100%, the lubricant of 0-1%; The percentage composition of aforementioned each component is weight percentage.
The gel adhesive agent is for absorbing water and form the macromolecular material of gel among the present invention, select a kind of in the macromolecular material, amylodextrin class material of gelatin substance, the synthetic of natural extract or several for use, the gelatin substance of described natural extract such as alginate, arabic gum, Lac, chitosan, tragakanta, pectin, agar etc., the macromolecular material of described synthetic such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose etc., described amylodextrin class material is starch and derivant thereof, α, beta, gamma-cyclodextrin and derivant etc. thereof.The gelatin substance of the preferred natural extract of gel adhesive agent among the present invention is as chitosan and derivant thereof.
The water-insoluble adhesive agent be for can absorb water but water-fast macromolecular material among the present invention, as a kind of of microcrystalline Cellulose, ethyl cellulose, methylcellulose, low-substituted hydroxypropyl cellulose, acrylic resin etc. or several.
Surfactant is selected a kind of in Polysorbate, poloxamer, Myrij (Mjri), Brij (Brij), lecithin, soybean phospholipid, sodium lauryl sulphate, glyceryl monostearate, sucrose ester, the polyoxyethylene castor oil condensation substance or several for use among the present invention.
Cosurfactant is a kind of in the macromolecular material, ethanol, propylene glycol of gelatin substance, the synthetic of natural extract or several among the present invention, the gelatin substance of described natural extract is selected alginate, arabic gum, Lac, chitosan, tragakanta, pectin, agar etc. for use, the high score material selection hydroxypropyl emthylcellulose of described synthetic, hydroxypropyl cellulose, carboxymethyl cellulose etc.
Grease is selected vegetable oil such as Semen sojae atricolor wet goods, artificial oil such as the C of natural extract for use among the present invention
6～C
16Fatty glyceride etc., at C
6～C
16Fatty glyceride in preferred decanoyl/octanoyl glycerides.
Diluent is selected a kind of in starch and derivant, lactose, mannitol, sorbitol, cyclodextrin and the derivant thereof or several for use among the present invention.
Second purpose of the present invention is achieved in that preparation method of the present invention comprises the following steps:
(1) preparation microemulsion hydrogel: calcitonin and gel adhesive agent are dissolved in the suitable quantity of water respectively or jointly, treat that gel adhesive agent swelling fully after, with both mixing and add water to formula ratio and get the pastille hydrogel, standby; After surfactant, cosurfactant, grease, diluent mixed in proportion, with aforementioned swelling pastille hydrogel mixing completely, promptly get the microemulsion hydrogel of tool bioadhesive, the consisting of of non-water section (weight percentage) in this microemulsion hydrogel, calcitonin 0.1-55%, gel adhesive agent 0.5-50%, surfactant 5-50%, grease 2-30%, cosurfactant 0-10%, diluent 0-90%, the weight ratio of non-water section and water is 1: 2-20;
(2) preparation self-emulsifying nanometer pastille agglomerate: with the microemulsion hydrogel after lyophilizing in 10-30 hour or directly carrying out spray drying, it is that the powder of 10-150um promptly gets self-emulsifying nanometer pastille agglomerate that sieve is got particle diameter, the weight of self-emulsifying nanometer pastille agglomerate consists of, calcitonin 0.1-55%, gel adhesive agent 0.5-50%, surfactant 5-50%, grease 2-30%, cosurfactant 0-10%, diluent 0-90%;
(3) preparation carrier: after getting the lubricant mixing of diluent, 0-1% of water-insoluble adhesive agent, the 70-100% of gel adhesive agent, the 0-20% of 0-10%, make soft material with suitable amount of adhesive, crossing 30 mesh sieves granulates, putting 50-70 ℃ of oven drying takes out after 20 minutes to 1 hour, cross 40 mesh sieve granulate, put 50-70 ℃ of oven for drying, cross 100～400 mesh sieves promptly;
(4) preparation per nasal Foradil Aerolizer formoterol fumarate: get the self-emulsifying nanometer pastille agglomerate of 1-99% and the carrier of 1-99% and mix, make in every gram powder and contain calcitonin 1500-8000IU, be sub-packed in the vesicle by required dosage, promptly get calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention.
In preparation method of the present invention, the preparation process of carrier is identical with the technology of 01105431.X number former patent application, gel adhesive agent in the carrier of the present invention is promptly corresponding to the bioadhesive material in the former patent application carrier, diluent can be accepted powder body corresponding to the physiology in the former patent application carrier, lubricant is the material that improves flowability of carrier, can be a kind of in magnesium stearate, sodium benzoate, bright (different bright) propylhomoserin, the sodium lauryl sulphate, and a kind of in the water-insoluble adhesive agent among the present invention of the microcrystalline Cellulose in the former patent application carrier.
Theoretical foundation of the present invention and related experiment are as follows:
Nano-emulsion (Nanoemulsion) is meant that the diameter of emulsion droplet is in a kind of special Emulsion of nanoscale.1985, the microemulsion that Shah proposes is defined as: microemulsion was two kinds of mutual exclusive liquid, thermodynamically stable, isotropic, the transparent dispersion that generates under the effect of surfactant molecule interfacial film.
The surface tension of water is 72mNm
-1, add table activating agent alive therein, can reduce to 30 ~ 40mNm
-1The interfacial tension of oil-water is 50mNm
-1, can reduce to several behind the adding surfactant to tens mNm
-1Suitable or under the situation that suitably cosurfactant (alcohols material) exists, oil-water interfacial tension reduces significantly, when being low to moderate 10 when three's (oil, water, surfactant) ratio
-2MNm
-1The time, promptly form microemulsion.According to multi-component system Gibbs adsorption isotherm:
dσ＝-∑Г
idμ
i＝∑ГiRTdlna
i
σ---interfacial tension;
Г
i---the surperficial excess quantity of component i;
μ
i---the chemical potential of component i
a
i---the activity of solute
In multicomponent system, if surfactant produces positive absorption on the interface, then the increase of its activity ai will make interfacial tension lowering.When the negative value that is low to moderate moment, then sprawl at the interface, generates small dispersant liquid drop, and Interfacial Adsorption more surfactant and cosurfactant are fully consumed until its bulk concentration simultaneously, and surface tension becomes on the occasion of (10 again
-3～10
-4).The present invention is promptly under the support of above-mentioned theory, pass through prescription screening, the three-phase diagram (see figure 1) that has prepared oil phase, water (containing medicine), surfactant phase (surfactant+cosurfactant), gel district and microemulsion region have been determined, in this two zone, containing medicine liquid droplet exists with nanometer size (in the 500nm, more preferably in the 100nm).In area I I, three-phase mixture is can not free-pouring almost transparent semisolid; And in I, then be viscosity and water proximate, free flowable, slightly with or without the liquid of blue-fluorescence.Principal agent calcitonin, grease, surfactant, adhesive agent and diluent be soluble in the aqueous phase respectively in ratio shown in the I and oil phase in, again with the two mixing, promptly get calcitonin nano-emulsion (microemulsion).But easier degraded when medicine exists with liquid form, and prepare, store, transport all inconvenience, so employing lyophilization or spray-dired method are removed the moisture in the microemulsion, but are promptly got the powder body that self emulsifying becomes nanometer liquid, be i.e. self-emulsifying nanometer pastille agglomerate.
When the pastille agglomerate is sucked in the nasal cavity, absorb when liquid formation interfacial tension approaches 0 microemulsion in the tract, medicinal liquid can fully contact with the nasal mucosa surface; Pharmaceutical pack is rolled in the interfacial film of surfactant formation, can increase its stability in nasal cavity; Hydrophilic calcitonin aqueous solution is dispersed into W/O/W type microemulsion in the colloid solution that surfactant-line of oils becomes, increase that it is fat-soluble, makes medicine be easier to see through the lipid bilayer of nasal mucosa and increase its absorption from face.There is abundant lymphatic vessel in the nasal cavity, after the fat-soluble increase of medicine, can enters the body circulation by the lymphsystem absorption, thereby its bioavailability is further enhanced.Add the bioadhesive polymer that is dissolvable in water water formation gel in the microemulsion, medicine can be adhered on the nasal mucosa more muchly, the performance curative effect.Used surfactant and other adjuvant are through the nasal mucosa toxicity test in the preparation, and the result shows, nasal mucosa and nose cilium is not produced infringement and inhibition.
The permeable membrane experiment is as follows:
One. the processing of the plain cyst membrane of chicken: get the plain capsule of new freshly-slaughtered poultry, clean, peel off fat deposit, be soaked in the normal saline standby.
Two. experimental provision: the permeable membrane device is installed as shown in Figure 2, is got the plain cyst membrane of chicken and be cut into suitable size, be fixed between diffuser casing and the receiving chamber, in receiving chamber, inject normal saline and make the probe tube liquid level, the liquid measure that record adds a little more than film.Open magnetic stirring apparatus and constant temperature oil bath, keep constant speed to stir, 37 ℃ of constant temperature pipette 200 μ l calcitonin solution with micropipettor and place diffuser casing, in each point in time sampling 1ml, and replenish fresh normal saline 1ml in receiving chamber.Obtained sample is in time placed refrigerator, to be measured.
Among Fig. 2,1 is agitator, and 2 is relay, and 3 is receiving chamber, and 4 is diffuser casing, and 5 is heater strip, and 6 is oil bath pan, and 7 are probe, and 8 is the plain cyst membrane of chicken, and 9 is thermometer.
Three. measure: adopt high-efficient liquid phase technique to measure.
The instrument model: Hitachi L6200,
Chromatographic column: chromatographic column: C18 250mm * 4.6mm (5 μ m) (Supelco, Discovery
TM),
Mobile phase A: acetonitrile: 0.0200mol/L tetramethyl ammonium hydroxide solution=15: 10, phosphoric acid is regulated pH value to 2.5,
Mobile phase B: acetonitrile: 0.0222mol/L tetramethyl ammonium hydroxide solution=5: 45, phosphoric acid is regulated pH value to 2.5,
The program eluting, mobile phase A increases to 57% (Mobile phase B is 43%) by 35% initial (Mobile phase B is 65%) through 21 minutes linearities,
Flow velocity: 1.0mL/min,
Ultraviolet detection wavelength: 220nm,
The quantity tube volume: 100 μ L,
Sampling volume: 100 μ L.
Four. the sample configuration:
Sample 1: calcitonin aqueous solution (1.5mg/ml)
Sample 2: the microemulsion (thin up becomes 1mg/ml) before the lyophilizing;
Sample 3: self-emulsifying nanometer pastille agglomerate (being dissolved in water into 1mg/ml);
Five. the permeable membrane result of the test:
The permeable membrane result of the test is seen Fig. 3.By measurement result as seen, for for a kind of biomembrane, the saturating mucosa ability of the microemulsion system of calcitonin is obviously greater than simple aqueous solution, and the transit dose of self-emulsifying nanometer pastille agglomerate is similar to microemulsion before the lyophilizing, but the time of seeing through shifts to an earlier date.
Pointed out by above-mentioned result of the test: the saturating mucosa ability of calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention strengthens, and bioavailability will obtain to improve.
It is as follows that calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention has been carried out irritation test:
1. (52.5-210 that is equivalent to people's dose by weight approximately doubly with the 300IU/ rabbit for calcitonin per nasal Foradil Aerolizer formoterol fumarate, the 18-71 that is equivalent to people's dose approximately by body surface area is doubly) rabbit is carried out nasal cavity spray into administration and carry out the maximum dosage-feeding test, do not see the phenomena of mortality.After the administration 24 hours, put to death animal, take out the local mucous membrane tissue, do not see mucous hyperemia, redness.The maximum dosage-feeding of calcitonin per nasal Foradil Aerolizer formoterol fumarate is the 300mg/ rabbit.
2. calcitonin per nasal Foradil Aerolizer formoterol fumarate (is equivalent to 48 times of people's dose approximately in the 200IU/ rabbit by body surface area, be equivalent to 140 times of people's dose by weight approximately) rabbit is carried out nasal cavity single (single dose is the 200IU/ rabbit) and repeatedly (administration in continuous 7 days, accumulated dose is the 1400IU/ rabbit) spray into administration, carry out the irritant test of nasal membrane, morphology is observed with histopathology and be there is no obviously irritative response and the symptom relevant with medicine.
It is as follows that calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention has been carried out the animal absorption test:
Laboratory animal and administering mode:
18 of rabbits are divided into blank (normal saline) group (6, male and female half and half), the salmon calcitonin per nasal dry powder group (6, male and female half and half) of former patent, salmon calcitonin per nasal dry powder group of the present invention (6, male and female half and half).Raise after 3 days, begin experiment.Water purification is only drunk in experiment fasting in eve.
Dosage: 5IU/kg
Respectively at getting blood 1.0ml before the administration and after the administration in 0.25,0.5,1,1.5,2,2.5,3,3.5,4,6 hour, (3000 rev/mins of separated plasmas, 15 minutes), get mensuration and the enzyme that blood plasma adopts atomic absorption method to carry out blood calcium respectively and exempt from the mensuration that the test kit method is carried out blood drug level.Measurement result is seen Figure 4 and 5.
From Fig. 4, Fig. 5 as seen: drug absorption is more rapider than former patent application technology after the salmon calcitonin per nasal dry powder of the present invention administration, absorb more complete, and persistent period basically identical.So this patent can promote more effectively that calcitonin sees through the nasal mucosa barrier, is absorbed into blood, plays a role.
Technique effect of the present invention is: the present invention combines self-emulsifying micro-emulsion technology and bioadhesion technology in the Foradil Aerolizer formoterol fumarate that is applied to respiratory tract administration first, calcitonin is prepared into concentrated microemulsion, compound with macromolecular material again, form the pressed powder of tool bioadhesive, after this medicine feeds nasal cavity, the suction self emulsifying becomes W/O/W, the microemulsion of nanometer size, be easy to see through the barrier of nasal mucosa, blood capillary that enriches in nasal mucosa and lymphatic vessel enter brings into play curative effect in the body, thereby can significantly improve bioavailability of medicament, absorb rapidly, and to the nasal mucosa nonirritant; Expand in pastille agglomerate suction back in addition, can be stranded in for a long time in the nasal mucosa, makes drug absorption and utilize more complete.
Description of drawings
Fig. 1 is the three-phase diagram of oil phase, water, surfactant phase.
Fig. 2 is the permeable membrane installation drawing.
Fig. 3 is the saturating mucosa result of the test figure of calcitonin.
Fig. 4 is blood calcium-time plot behind the nose administration.
Fig. 5 is blood drug level-time plot behind the nose administration.
The specific embodiment
Embodiment one:
Gel adhesive agent chitosan 0.5g is dissolved in 3g (3ml) water, and swelling back fully adds aforesaid salmon calcitonin 0.01g, promptly gets after the dissolving to contain the medicine hydrogel, and is standby; Behind surfactant lecithin 0.1g and polyoxyethylene hydrogenated Oleum Ricini 0.2g, cosurfactant ethanol 0.05g, grease decanoyl/octanoyl glycerides 0.2g, diluent mannitol 0.3g mix homogeneously, after containing medicine hydrogel mixing completely with aforementioned swelling, promptly get the microemulsion hydrogel of tool bioadhesive, place freeze dryer through the 20hr lyophilizing this microemulsion hydrogel, lyophilized products taking-up back sieve is got 100-400 purpose powder, and (particle diameter is 37.5～150um), promptly gets pastille microemulsion agglomerate.With this pastille agglomerate water-soluble after, can get the microemulsion of mean diameter less than 100nm.Get aforementioned gained pastille microemulsion agglomerate 1.31g; tiring in calcitonin is that 5000IU/mg, powder spray dosage are 50IU/ grain or 100,200IU/ grain; mix with embodiment 1 described carrier 25g in the description of No. 01105431 patent; make in every gram powder and contain calcitonin 1500-8000IU; quantitatively be sub-packed in by required dosage in the bubble-cap of dose double, promptly obtain preparation of the present invention.
Embodiment two:
Get salmon calcitonin 1g, chitosan 0.5g, hydroxypropyl emthylcellulose 1g, water 500g, Polysorbate 2g, polyoxyethylene hydrogenated Oleum Ricini 3g, refined soybean oil 5g, lactose 20g by dissolving mixing of the process among the embodiment one or mixing after, spray-dried back sieve is got 100-400 order powder (particle diameter is 37.5～150 μ um), promptly gets pastille microemulsion agglomerate.Get that embodiment 1 described carrier 0.3g mixes in the description of aforementioned gained pastille microemulsion agglomerate 32.5g and No. 01105431 patent, contain calcitonin 1500-8000IU in every gram powder, quantitatively be sub-packed in by required dosage in the bubble-cap of dose double, promptly obtain preparation of the present invention.
Embodiment three:
After getting salmon calcitonin 0.01g, hydroxypropyl emthylcellulose 1g, water 20g (20ml), Polysorbate 0.4g, Brij 0.2g, refined soybean oil 0.3g, lactose 1g and pressing process dissolving mixing or mixing among the embodiment one, sieve is got 100-400 order powder (particle diameter is 37.5～150 μ um) after lyophilization in 20 hours, promptly gets pastille microemulsion agglomerate.Get aforementioned gained pastille microemulsion agglomerate 2.91g and carrier and be angle of repose and mix, contain calcitonin 1500-8000IU in every gram powder, quantitatively be sub-packed in by required dosage in the bubble-cap of dose double, promptly obtain preparation of the present invention less than 40 ° lactose 15g.
Embodiment four:
Get aforesaid salmon calcitonin 0.01g, hydroxypropyl emthylcellulose 1g, polyoxyethylene hydrogenated Oleum Ricini 0.5g, water 30g (30ml), poloxamer 0.1g, refined soybean oil 0.5g, lactose 2g, press the process dissolving mixing among the embodiment one, after lyophilization in 30 hours, sieve is got 100-400 order powder, promptly get pastille microemulsion agglomerate, getting aforementioned gained pastille microemulsion agglomerate 4.11g and carrier and be angle of repose mixes less than 40 ° pregelatinized Starch 20g, quantitatively be sub-packed in by required dosage in the bubble-cap of dose double, promptly obtain preparation of the present invention.
Embodiment five:
Get aforesaid salmon calcitonin 1g, hydroxypropyl emthylcellulose 0.1g, water 10g (10ml), polyoxyethylene hydrogenated Oleum Ricini 1g, Polysorbate 1g, after decanoyl/octanoyl glycerides 1.5g presses process dissolving mixing or mixing among the embodiment one, sieve is got 100-400 order powder (particle diameter is 37.5～150 μ um) after lyophilization in 15 hours, promptly gets pastille microemulsion agglomerate.Get aforementioned gained pastille microemulsion agglomerate 4.6g and carrier and be angle of repose and mix, contain calcitonin 1500-8000IU in every gram powder, quantitatively be sub-packed in by required dosage in the bubble-cap of dose double, promptly obtain preparation of the present invention less than 40 ° lactose 455.4g.
Embodiment six:
Get aforesaid salmon calcitonin 19g, chitosan 0.5g, water 700g, Polysorbate 4g, polyoxyethylene hydrogenated Oleum Ricini 6g, ethanol 0.05g, refined soybean oil 5g, by behind dissolving mixing of the process among the embodiment one or the mixing, spray-dried back sieve is got 100-400 order powder (particle diameter is 37.5～150 μ um), promptly gets pastille microemulsion agglomerate (theoretical value is 34.50g).Get that embodiment 1 described carrier 25g mixes in the description of aforementioned gained pastille microemulsion agglomerate and No. 01105431 patent, contain calcitonin 1500-8000IU in every gram powder, quantitatively be sub-packed in by required dosage in the bubble-cap of dose double, promptly obtain preparation of the present invention.
Embodiment seven:
The consumption of each raw material is as follows in the present embodiment:
Salmon calcitonin 0.1g,
The gel adhesive agent: arabic gum 25g, chitosan 25g,
Water 300g,
Surfactant: soybean phospholipid 2g, polyoxyethylene hydrogenated Oleum Ricini 3g,
Grease: refined soybean oil 3g,
Diluent: sorbitol 41.9g,
Carrier: lactose 50g.
Preparation method is with embodiment one.
Embodiment eight:
The consumption of each raw material is as follows in the present embodiment:
Salmon calcitonin 0.5,
The gel adhesive agent: agar 0.5g,
Water 500g,
Surfactant: sodium lauryl sulphate 20g, glyceryl monostearate 20g, sucrose ester 10g,
Grease: refined soybean oil 30g,
Diluent: cyclodextrin 19g,
Carrier: lactose 50g,
Preparation method is with embodiment one.
Embodiment nine:
The consumption of each raw material is as follows in the present embodiment:
Salmon calcitonin 0.5g,
The gel adhesive agent: Lac 4.5g,
Water 800g,
Surfactant: Myrij 3g,
Grease: decanoyl/octanoyl glycerides 2g,
Diluent: sorbitol 90g
Carrier: lactose 12g.
Preparation method is with embodiment one.
Embodiment ten:
The consumption of each raw material is as follows in the present embodiment:
Salmon calcitonin 1g,
The gel adhesive agent: chitosan 25g,
Water 700g,
Surfactant: Myrij 40g,
Cosurfactant: propylene glycol 10g,
Grease: decanoyl/octanoyl glycerides 24g,
Carrier: lactose 5g.
Preparation method is with embodiment one.
Claims (10)
1. calcitonin per nasal Foradil Aerolizer formoterol fumarate, it is characterized in that: form by the self-emulsifying nanometer pastille agglomerate of 1-99% and the carrier of 1-99%, described self-emulsifying nanometer pastille agglomerate is made up of the calcitonin of 0.1-55%, the gel adhesive agent of 0.5-50%, the surfactant of 5-50%, the grease of 2-30%, the cosurfactant of 0-10%, the diluent of 0-90%, the powder diameter of described self-emulsifying nanometer pastille agglomerate is 10-150um, but meets the w/o/w emulsion droplet that self emulsifying behind the aqueous medium becomes nanoscale size; Described carrier is made up of the gel adhesive agent of 0-10%, the water-insoluble adhesive agent of 0-20%, the diluent of 70-100%, the lubricant of 0-1%; The percentage composition of aforementioned each component is weight percentage.
2. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 1, it is characterized in that: described gel adhesive agent is for absorbing water and form the macromolecular material of gel, select the gelatin substance of natural extract for use, the macromolecular material of synthetic, a kind of in the amylodextrin class material or several, the gelatin substance of described natural extract is an alginate, arabic gum, Lac, chitosan, the tragakanta, pectin, agar, the macromolecular material of described synthetic is a hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, described amylodextrin class material is starch and derivant thereof, α, beta, gamma-cyclodextrin and derivant thereof.
3. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 2 is characterized in that: the gelatin substance of the preferred natural extract of described gel adhesive agent.
4. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 1, it is characterized in that: described water-insoluble adhesive agent be for can absorb water but water-fast macromolecular material, selects a kind of in microcrystalline Cellulose, ethyl cellulose, methylcellulose, low-substituted hydroxypropyl cellulose, the acrylic resin or several for use.
5. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that: described surfactant is a kind of in Polysorbate, poloxamer, Myrij, Brij, lecithin, soybean phospholipid, sodium lauryl sulphate, glyceryl monostearate, sucrose ester, the polyoxyethylene castor oil condensation substance or several.
6. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 1, it is characterized in that: described cosurfactant is a kind of in the macromolecular material, ethanol, propylene glycol of gelatin substance, the synthetic of natural extract or several, the gelatin substance of described natural extract is alginate, arabic gum, Lac, chitosan, tragakanta, pectin, agar, and the high score material of described synthetic is hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose.
7. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that: described grease is vegetable oil, the C of natural extract
6～C
16Fatty glyceride.
8. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 7 is characterized in that: the preferred decanoyl/octanoyl glycerides of described grease.
9. calcitonin per nasal Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that: described diluent is a kind of in starch and derivant, lactose, mannitol, sorbitol, cyclodextrin and the derivant thereof or several.
10. the preparation method of the described calcitonin per nasal of claim 1 Foradil Aerolizer formoterol fumarate is characterized in that comprising the following steps:
(1) preparation microemulsion hydrogel: calcitonin and gel adhesive agent are dissolved in the suitable quantity of water respectively or jointly, treat that gel adhesive agent swelling fully after, with both mixing and add water to formula ratio and get the pastille hydrogel, standby; After surfactant, cosurfactant, grease, diluent mixed in proportion, with aforementioned swelling pastille hydrogel mixing completely, promptly get the microemulsion hydrogel of tool bioadhesive, the consisting of of non-water section (weight percentage) in this microemulsion hydrogel, calcitonin 0.1-55%, gel adhesive agent 0.5-50%, surfactant 5-50%, grease 2-30%, cosurfactant 0-10%, diluent 0-90%, the weight ratio of non-water section and water is 1: 2-20;
(2) preparation self-emulsifying nanometer pastille agglomerate: with the microemulsion hydrogel after lyophilizing in 10-30 hour or directly carrying out spray drying, it is that the powder of 10-150um promptly gets self-emulsifying nanometer pastille agglomerate that sieve is got particle diameter, the weight of self-emulsifying nanometer pastille agglomerate consists of, calcitonin 0.1-55%, gel adhesive agent 0.5-50%, surfactant 5-50%, grease 2-40%, cosurfactant 0-50%, diluent 0-90%;
(3) preparation carrier: after getting the lubricant mixing of diluent, 0-1% of water-insoluble adhesive agent, the 70-100% of gel adhesive agent, the 0-20% of 0-10%, make soft material with suitable amount of adhesive, crossing 30 mesh sieves granulates, putting 50-70 ℃ of oven drying takes out after 20 minutes to 1 hour, cross 40 mesh sieve granulate, put 50-70 ℃ of oven for drying, cross 100～400 mesh sieves promptly;
(4) preparation per nasal Foradil Aerolizer formoterol fumarate: get the self-emulsifying nanometer pastille agglomerate of 1-99% and the carrier of 1-99% and mix, make in every gram powder and contain calcitonin 1500-8000IU, be sub-packed in the vesicle by required dosage, promptly get calcitonin per nasal Foradil Aerolizer formoterol fumarate of the present invention.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101174657A CN1546169A (en) | 2003-12-16 | 2003-12-16 | Transnasal inhalant dry powder of calcitonin and its preparation |
| PCT/CN2004/001363 WO2005058289A1 (en) | 2003-12-16 | 2004-11-26 | A method of preparing intranasal dry powders inhalant of calcitonin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101174657A CN1546169A (en) | 2003-12-16 | 2003-12-16 | Transnasal inhalant dry powder of calcitonin and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1546169A true CN1546169A (en) | 2004-11-17 |
Family
ID=34337813
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2003101174657A Pending CN1546169A (en) | 2003-12-16 | 2003-12-16 | Transnasal inhalant dry powder of calcitonin and its preparation |
Country Status (2)
| Country | Link |
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| CN (1) | CN1546169A (en) |
| WO (1) | WO2005058289A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100400097C (en) * | 2005-08-22 | 2008-07-09 | 上海医药工业研究院 | Insulin liquid formulations for nose administration |
| CN104208029A (en) * | 2013-05-30 | 2014-12-17 | 上海医药工业研究院 | Vaccine composition powder preparation used for nose and preparation method thereof |
| CN115920010A (en) * | 2022-09-27 | 2023-04-07 | 深圳大佛药业股份有限公司 | Salmon calcitonin composition spray and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118453519A (en) * | 2024-05-28 | 2024-08-09 | 南京康舟医药科技有限公司 | Salmon calcitonin nasal spray preparation and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
| CN1179723A (en) * | 1995-08-15 | 1998-04-22 | 旭化成工业株式会社 | Mucosal preparation containing physiologically active peptide |
| WO2001056594A1 (en) * | 2000-02-04 | 2001-08-09 | Unigene Laboratories, Inc. | Nasal calcitonin formulations |
| CN1193745C (en) * | 2001-02-27 | 2005-03-23 | 国家医药管理局上海医药工业研究院 | Salmon calcitonin snuff and its prepn |
-
2003
- 2003-12-16 CN CNA2003101174657A patent/CN1546169A/en active Pending
-
2004
- 2004-11-26 WO PCT/CN2004/001363 patent/WO2005058289A1/en active Application Filing
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100400097C (en) * | 2005-08-22 | 2008-07-09 | 上海医药工业研究院 | Insulin liquid formulations for nose administration |
| CN104208029A (en) * | 2013-05-30 | 2014-12-17 | 上海医药工业研究院 | Vaccine composition powder preparation used for nose and preparation method thereof |
| CN104208029B (en) * | 2013-05-30 | 2017-06-06 | 上海医药工业研究院 | A kind of nose vaccine combination powder preparation and preparation method thereof |
| CN115920010A (en) * | 2022-09-27 | 2023-04-07 | 深圳大佛药业股份有限公司 | Salmon calcitonin composition spray and preparation method thereof |
| CN115920010B (en) * | 2022-09-27 | 2023-09-19 | 深圳大佛药业股份有限公司 | Salmon calcitonin composition spray and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| WO2005058289A1 (en) | 2005-06-30 |
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