CN102475888A - Transdermally absorbed medicine comprising adjuvant-containing pharmaceutical microparticle and adjuvant-containing water for skin use - Google Patents
Transdermally absorbed medicine comprising adjuvant-containing pharmaceutical microparticle and adjuvant-containing water for skin use Download PDFInfo
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Abstract
The invention relates to a transdermally absorbed medicine comprising adjuvant-containing pharmaceutical microparticles and adjuvant-containing water for skin use, which is consisted of an individually-packaged skin pharmaceutical preparation that contains one or more solid pharmaceutical adjuvants, is insoluble in water and has a D90 particle size of 0.1-10 mum, and individually-packaged water containing one or more water-soluble pharmaceutical adjuvants.
Description
Technical field:
The present invention relates to a kind of dermatologic thing, by containing one or more skin pharmaceutic adjuvants and being insoluble in the dermatologic thing of water and form jointly as independent packing with the water that packing separately contains adjuvant.
Background technology:
Scytitis such as eczema (eczema), allergic dermatitis (allergic dermatitis), atopic dermatitis (atopic dermatitis) urticaria (Urticaria) etc. all are to be caused allergy and caused scytitis by certain allergen.
In the percutaneous drug delivery system; Skin is that medicine gets into intravital main barrier, discovers and has only the only a few medicine to have good skin permeability, and most medicines are difficult for passing human body skin, and this is effective; Barrier optionally, fat-soluble comparatively speaking higher medicine passes epidermis more easily.The treatment dermatosis; Modal preparation type is the Transdermal absorption administration, transdermal drug delivery system or transdermal formulation (transdermal thrapeutic systems, transdermal drug delivery systems; Be called for short TTS; TDDS): be meant in the skin surface administration, make medicine pass through skin, get into the novel form that the body circulation produces whole body or local therapeutic effects with constant rate of speed (or near constant rate of speed).Its advantage applies exists: drug absorption does not receive factor affecting such as pH in the digestive tract, food, transhipment time; Avoid liver first-pass effect; Overcome because of absorbing the too high untoward reaction that causes of too fast generation blood drug level; The sustainable Control injection speed, flexible administration etc., common transdermal drug delivery system comprises cataplasma, ointment, liniment, gel etc.
But because above-mentioned preparation need add a large amount of adjuvants; These adjuvants might produce various untoward reaction to skin; For example some patient can produce allergic symptom to adjuvant, and especially the adult is thinner for the infant skin below 2 years old, and there is stimulation in adjuvants such as the long-chain fat in unguentum, the gel, ethanol, antibacterial to skin; So be prone to irritated crowd and the infant below 2 years old to part, should reduce the use of excipient substance as far as possible.Comparing the conditioned water for skin suspensoid with common transdermal absorption formulation such as cataplasma, ointment, liniment, gel is main with water mainly, and other adjuvant proportions are less, especially are fit to be prone to irritated crowd and child.
There is a kind of difficulty of galenic pharmacy in the conditioned water for skin suspensoid through Transdermal absorption, if the suspendible particle is bigger, then can't pass through epidermal tissue; If the suspendible particle is too small like nanoscale; But compare with macroparticle, the small-particle specific surface area is big, has higher surface energy; Therefore this system makes the molecule on small-particle surface break away from small-particle for reduce its surface energy as far as possible, is adsorbed onto the macroparticle surface through solution diffusion.Finally, small-particle diminishes gradually and macroparticle is grown up gradually, i.e. the Ostwald ripening phenomenon.The speed of Ostwald ripening is mainly by molecular diffusion and surface action decision.Suspended particles is because its particle size distribution is inhomogeneous; So especially obvious ((Welin-Berger K of Ostwald ripening phenomenon; Bergenstahl B.Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase [J] .Int J Pharm; 2000,200 (2): 249-260.).
The microgranule suspensoid belongs to the thermokinetics Unstable Systems, and particle has accumulative trend, to minimize its surface free energy.Because the specific surface area of microgranule is big, so particle is in contact with one another the chance increase of collision, the stronger power that attracts each other of existence between the while particle; Intermolecular force is strong; Particle is easy to take place irreversible aggrengation to reduce its surface energy (Wong J, Brugger A, Khare A; Et al.Suspensions for intravenous (IV) injection:a review ofdevelopment; Preclinical and clinical aspects [J] .Adv Drug Deliv Rev, 2008,60 (8): 939-954; Kesisoglou F, Panmai S, Wu Y.Nanosizing--oral formulation development and biopharmaceutical evaluation [J] .Adv Drug Deliv Rev, 2007,59 (7): 631-644.).
How to solve particle problem of unstable in the microgranule suspensoid; Be to need one of problem that solves in the galenic pharmacy always; But no matter through adding adjuvant, still improve particle structure, can't guarantee that all the microgranule suspensoid Ostwald ripening phenomenon do not occur in the storage life; Especially skin class suspensoid belongs to repeatedly use, the problems referred to above more likely occur.
Summary of the invention:
Through test; The discovery that we are surprised; With suspendible medicine and separated form water; By independent packing contain one or more skin pharmaceutic adjuvants and be insoluble in the dermatologic thing of water, separately the packing water that contains adjuvant is formed jointly, both can form the conditioned water for skin suspensoid through simple concussion in use.This brand-new Transdermal absorption is treated the dosage form of dermatosis; Both can guarantee in use that water suspension can see through the skin treating dermatosis with particulate form; Can store the long period again, avoid occurring the Ostwald ripening phenomenon and cause granule to become big, thereby influence the curative effect of medicine.
The key of technology is that the D90 particle diameter that is insoluble in water of packing is the storage of 0.1-10 μ m dermatologic thing through certain hour separately; Degradation problem under caking, particle aggregation, the dispersibility do not occur, still can pass through simple concussion and form even suspension and be prone to by skin absorbs with the independent water of packing.
We are in research process; After will treating dermopathic drug microparticles and the solid filler mixing, through storing for a long time, drug microparticles can better keep the particle diameter of microgranule; Avoid the phenomenon that occurs luming, in containing the water of surfactant, disperse to form suspension more easily.
In water, add pH regulator agent, viscosity modifier, penetrating agent, surfactant or stabilizing agent and will guarantee better that drug microparticles better forms suspensoid after mixing, help the absorption of medicine on skin, improve curative effect of medication.
Simultaneously these solid filleies can with water mixed process in soluble in water comparatively rapidly, do not influence the formation of suspensoid, can guarantee certain osmotic pressure simultaneously, help the infiltration of suspendible medicine.
In the said medicine adjuvant, do not add antiseptic and antibacterial that preparation for external application to skin often uses, this has all reduced potential threat for easy irritated crowd and child, is of value to the patient.
The particle diameter of indication of the present invention is the D90 particle diameter, and promptly the cumulative particle sizes distribution number of a sample reaches 90% o'clock pairing particle diameter, and to be particle diameter account for 90% less than its granule to its physical significance.
The present invention provides a kind of Transdermal absorption to treat dermopathic pharmaceutical composition, by the D90 particle diameter that contains one or more solid medicinal adjuvants and be insoluble in water as independent packing be 0.1-10 μ m dermatologic thing, the water that contains one or more water-soluble pharmaceutic adjuvants of packing is formed jointly separately.The D90 particle diameter of said dermatologic thing is preferably 1-10 μ m.The particulate form of said dermatologic thing is spherical or type sphere.
Described pharmaceutical composition is characterized in that increasing the utensil of a kind of hybrid medicine and water.
Described pharmaceutical composition is characterized in that the dermatologic thing is a glucocorticoid.Said glucocorticoid can be selected from cortisone; Fluorometholone; Dexamethasone; Betamethasone; Prednisolone; Prednisone; Hydrocortisone; Rui Meisonglong (Rimexolone); Loteprednol; Budesonide; Ciclesonide; Alclometasone; Beclometasone; Betamethasone; Chloroprednisone; Clobetasol; Clobetasone; Clocortolone; Chlorine ripple Buddhist nun alcohol; Deflazacort; Desonide; Desoximetasone; Diflorasone; Diflucortolone; Difluprednate; Flucloronide; Flumetasone; Flunisolide; Fluocinolone acetonide; Fluocortolone; Fluperolone; Fluprednidene; Fluprednisolone; Flurandrenolide; Halcinonide; Halogen is his rope doubly; Halometasone; Halopredone; Hydrocortamate; Medrysone; Meprednisone; Methylprednisolone; Mometasone; Paramethasone; Prednicarbate; The ripple prednylidene 21-diethylaminoacetatte; Triamcinolone; Triamcinolone acetonide; Amcinonide; Fluticasone; Desonide; Mazipredone; A kind of chemical compound in the tixocortol or its pharmaceutically useful ester.The consumption of said glucocorticoid is 0.01%～1%.Preferred 0.1%～1%.
Described pharmaceutical composition is characterized in that dermal drug can also be antibiotic.
Described pharmaceutical composition is characterized in that said solid medicinal adjuvant is one or more in surfactant, the solid filler.Said solid filler is one or more in water-soluble saccharide, the aminoacid.Said aminoacid is glycine, threonine, valine, leucine.Said saccharide comprises monosaccharide and/or disaccharide.Said monosaccharide is mannitol, fructose, glucose, and said disaccharide is maltose, trehalose, cellobiose, lactose, sucrose.Said disaccharide is a lactose.Described lactose is alpha-lactose-hydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, the crystallizing and drying lactose.Preferred crystallizing and drying lactose.
Described pharmaceutical composition is characterized in that surfactant in the said solid medicinal adjuvant is one or more in the solid non-ionic surface active agent.
Described pharmaceutical composition is characterized in that said water-soluble pharmaceutic adjuvant comprises one or more in pH regulator agent, viscosity modifier, penetrating agent, surfactant or the stabilizing agent.Preferably include in penetrating agent, the surfactant one or more.
PH regulator agent in said water-soluble pharmaceutic adjuvant is one or more in phosphoric acid and salt, boric acid and salt thereof, citric acid and salt thereof, acetic acid and salt thereof, tartaric acid and salt thereof, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, the tromethane.In preferred acetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, the potassium bicarbonate one or more.
Osmotic pressure regulator in said water-soluble pharmaceutic adjuvant is one or more in glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, the mannitol.The preferred sodium chloride that adopts 0.4%-0.9%.
Viscosity modifier in said water-soluble pharmaceutic adjuvant is one or more in sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxy vinyl polymer, the polyvinyl pyrrolidone, and consumption is 0.1%～2%.
The optional non-ionic surface active agent of surfactant in said water-soluble pharmaceutic adjuvant.Be tween, span, polyoxyethylene hydrogenated Oleum Ricini 60, Polyethylene Glycol-stearate; Macrogol 4000, lecithin, sucrose ester; Polyoxyethylene alkyl ether, one or more in polyoxyethylene polyoxypropylene glycol and analog thereof, poloxamer, the tyloxapol.
Surfactant in said water-soluble pharmaceutic adjuvant is amino acids, lecithin class surfactant.Said amino acid surfactant is sodium lauroyl sarcosine, sodium lauroyl glutamate, cocos nucifera oil acyl sodium glutamate, cocos nucifera oil acyl disodium glutamate, cocos nucifera oil acyl Kaglutam, cocoyl glutamic acid TEA salt, cocos nucifera oil acyl Glycine sodium, cocos nucifera oil acyl glycine potassium, lauroyl (S)-Leucine sodium salt, cocos nucifera oil acyl (S)-Leucine sodium salt, lauroyl leucine potassium, cocos nucifera oil acyl leucine potassium.Said lecithin class surfactant is soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
Stabilizing agent in said water-soluble pharmaceutic adjuvant is a disodiumedetate.Be preferably 0.1%～0.01% disodiumedetate.
Penetrating agent in said water-soluble pharmaceutic adjuvant is one or more in azone, sulfoxide and analog thereof, ethanol, aliphatic alcohol, pyrrolones, fatty acid, menthol, quintessence oil, the Borneolum Syntheticum.
Penetrating agent in said water-soluble pharmaceutic adjuvant is one or more in azone, laurocapram, thionyl chloride, decyl methyl sulfoxide, propylene glycol, N-methyl-2-pyrrolidone, 2-pyrrolidone, lauric acid, oleic acid, linoleic acid, linolenic acid, menthol, ledum terpenes, the eucalyptus oil.
Described pharmaceutical composition is characterized in that the method for micronization of said dermatologic thing can adopt spray drying method, fluid bed supersonic airstream comminuting method, high speed polishing, ball-milling method, fluid energy mill method, solvent method, CO
2The supercritical methanol technology preparation.Preferred spray drying method, the CO of adopting
2The preparation of supercritical auxiliary atomizing method.
Described pharmaceutical composition is characterized in that said compositions can adopt the form of single or multiple dosage to pack.The packaged of said single or multiple dosage is the water-tight packing.The packaged of said multidose is the aluminium foil bubble-cap.
Described pharmaceutical composition, the application in preparation treatment human or animal scytitis medicine.
Described pharmaceutical composition, the application in preparation treatment human or animal skin eczema, daylight rash medicine.
Described pharmaceutical composition, the application in the preparation treatment is below 2 years old in the infant scytitis medicine.
Described pharmaceutical composition, diaper rash, seborrheic dermatitis, the atoipc dermatitis of infant are used in the preparation treatment is below 2 years old.
Pharmaceutical composition provided by the invention comprises drug microparticles and the water that contains excipient substance, and both can form the conditioned water for skin suspensoid through simple concussion in use and can keep the stability of certain hour.
Simultaneously because medicine separates packing with water; When the disease degree not simultaneously; Can adjust and join the water Chinese medicine dosage that contains excipient substance; Make single medicine can have multiple dosage in actual use, be convenient to the patient and use, both can form the conditioned water for skin suspensoid through simple concussion in use and can keep the stability of certain hour.Simultaneously because medicine separates packing with water, when the disease degree not simultaneously, can adjust and join the water Chinese medicine dosage that contains excipient substance; Make single medicine can have multiple dosage in actual use; Be convenient to the patient and use, medicine provided by the invention simultaneously, thereby with also can keep the particle diameter of medicine to guarantee that suspendible is stable within a certain period of time after the suspendible water mixes; Therefore also reduce the waste of medicine, met the requirement of low carbon emission reduction.
The specific embodiment
The particle diameter of following embodiment indication is the D90 particle diameter.
Grain diameter measurement instrument: Tianjin, island laser diffraction formula particle size distribution measurement appearance SALD-7101
One, the preparation of Transdermal absorption medicine microgranule
The capsule of embodiment 1 to 10 resulting drug microparticles packing is a plant capsule, and capsule packs with the aluminium foil bubble-cap after the packing.Embodiment 11, the 12 resulting water that contain adjuvant pack with ampoule.
Embodiment 1
The 1g hydrocortisone is dissolved in ethanol, after the filtration, sterilization; The filtrating spray drying, micronization makes particle diameter reach 3 μ m, mixes the back with 1.5g crystallinity lactose that particle diameter is 30 μ m excessively behind 3 mixings of 200 mesh sieves; Be divided in No. 2 capsules, every capsules has hydrocortisone 10mg.Electron microscopic observation drug microparticles type of being is spherical.
Process conditions are: inlet temperature is 100 ℃, and outlet temperature is 70 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h
Embodiment 2
1g is dissolved in ethanol with triamcinolone acetonide acetate, after the filtration, and the filtrating spray drying; Micronization makes particle diameter reach 3 μ m; Mix the back with 15g crystallinity lactose that particle diameter is 30 μ m with sterilizing behind 3 mixings of 200 mesh sieves, branch installs in No. 2 capsules, and every capsules has triamcinolone acetonide acetate 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 70 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 3
The 1g beclometasone is dissolved in ethanol, and after the filtration, the filtrating spray drying makes particle diameter reach 3 μ m, mixes with 15g leucine that particle diameter is 30 μ m and sterilizes after 3 mixings of 200 mesh sieves are crossed in the back, and branch installs in No. 2 capsules, and every capsules has beclometasone 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 4
1g is dissolved in ethanol with dexamethasone acetate, and after the filtration, the filtrating spray drying makes particle diameter reach 3 μ m, is that the 15g valine of 30 μ m mixes after the back crosses 3 mixings of 200 mesh sieves with particle diameter, and branch installs in No. 2 capsules, and every capsules has dexamethasone acetate 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 5
1g is dissolved in ethanol with tazarotene, and after the filtration, the filtrating spray drying makes particle diameter reach 3 μ m, is that 15g β-Lactis Anhydrous of 30 μ m mixes and sterilizes after 3 mixings of 200 mesh sieves are crossed in the back with particle diameter, and branch installs in No. 2 capsules, and every capsules has tazarotene 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 6
1g is dissolved in ethanol with ofloxacin, after the filtration, and the filtrating spray drying; Make particle diameter reach 3 μ m; Mixed with 1g sodium lauroyl sarcosine, 1.5g crystallinity lactose that particle diameter is 30 μ m and to sterilize after 3 mixings of 200 mesh sieves are crossed in the back, and divided to install in No. 2 capsules, every capsules has ofloxacin 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 7
1g is dissolved in ethanol with adapalene, and after the filtration, the filtrating spray drying makes particle diameter reach 3 μ m, mixes with 15g crystallinity lactose that particle diameter is 30 μ m and sterilizes after 3 mixings of 200 mesh sieves are crossed in the back, and branch installs in No. 2 capsules, and every capsules has adapalene 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 8
1g is dissolved in ethanol with miconazole nitrate, and after the filtration, the filtrating spray drying makes particle diameter reach 3 μ m, mixes with 15g crystallinity lactose that particle diameter is 30 μ m and sterilizes after 3 mixings of 200 mesh sieves are crossed in the back, and branch installs in No. 2 capsules, and every capsules has miconazole nitrate 1mg.Electron microscopic observation microgranule type of being is spherical.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 9
Utilizing fluid energy mill (using the QM-3A of Nanjing Univ. Instrument Factory) to pulverize micronization the 1g hydrocortisone makes particle diameter reach 3 μ m; Mixed with 1.5g crystallinity lactose that particle diameter is 30 μ m and to sterilize after 3 mixings of 200 mesh sieves are crossed in the back; Be divided in No. 2 capsules, every capsules has hydrocortisone 10mg.The electron microscopic observation microgranule is not for there being the shape of confirming.
Embodiment 10
Utilizing fluid energy mill (using the QM-3A of Nanjing Univ. Instrument Factory) to pulverize micronization the 1g triamcinolone acetonide acetate makes particle diameter reach 3 μ m; Mixed with 15g crystallinity lactose that particle diameter is 30 μ m and to sterilize after 3 mixings of 200 mesh sieves are crossed in the back; Be divided in No. 2 capsules, every capsules has triamcinolone acetonide acetate 1mg.The electron microscopic observation microgranule is not for there being the shape of confirming.
Embodiment 11
EDTA-2Na (disodiumedetate) 0.2g, tween 80 5g,, chlorine sodium carboxymethyl cellulose 2.5g, sodium hydroxide is an amount of, and adding distil water is to 1000g
Compound method: EDTA-2Na, sodium carboxymethyl cellulose, the tween 80 of recipe quantity are dissolved in the 500ml water for injection, stir and dissolve clearly, transfer pH to 6, add the water for injection of surplus, the airtight preservation of sterilization back packing 1ml/ ampoule with sodium hydroxide.
Embodiment 12
EDTA-2Na 0.1g, hydroxypropyl emthylcellulose 4g, laurocapram 2g, soybean lecithin 7g, sodium hydroxide is an amount of, and adding distil water is to 1000g
Compound method: EDTA-2Na, hydroxypropyl emthylcellulose, laurocapram, the soybean lecithin of recipe quantity are dissolved in the 500ml water for injection; Stir and dissolve clearly; Transfer pH to 6 with sodium hydroxide, add the water for injection of surplus, the airtight preservation of sterilization back packing 1ml/ ampoule.
" microgranule " mentioned in the following control Example is meant the capsule 's content of corresponding embodiment.
Control Example 1-1
The water that microgranule that embodiment 1 is obtained and embodiment 11 obtain mixes according to the ratio of 10mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 1-2
The water that microgranule that embodiment 1 is obtained and embodiment 12 obtain mixes according to the ratio of 10mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 2-1
The water that microgranule that embodiment 2 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 2-2
The water that microgranule that embodiment 2 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 3-1
The water that microgranule that embodiment 3 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 3-2
The water that microgranule that embodiment 3 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 4-1
The water that microgranule that embodiment 4 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 4-2
The water that microgranule that embodiment 4 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 5-1
The water that microgranule that embodiment 5 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 5-2
The water that microgranule that embodiment 5 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 6-1
The water that microgranule that embodiment 6 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 6-2
The water that microgranule that embodiment 6 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 7-1
The water that microgranule that embodiment 7 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 7-2
The water that microgranule that embodiment 7 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 8-1
The water that microgranule that embodiment 8 is obtained and embodiment 11 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 8-2
The water that microgranule that embodiment 8 is obtained and embodiment 12 obtain mixes according to the ratio of 1mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Two, relevant pharmacodynamics test
Embodiment 15 stability experiments
With embodiment 1-12, control Example 1-1 to 8-2 be divided into embodiment 1-10 group, control Example 1-1 to 8-2 organizes; 11,12 groups every group 500 of embodiment; All the other every group 40 units; At 40 ℃ ± 2 ℃, carry out stability test under the situation of relative humidity 75% ± 5%, respectively at the D90 particle diameter of storage sampling survey medicine in the time of 0 month, 1 month, 3 months; Get 10 units at every turn; Wherein each 10 capsules getting of embodiment 1-10 group are before carrying out the particle diameter test, get 5 capsular medicines and in ampoule, mix, get 5 capsular medicines with water that 5 units that embodiment 11 obtains contain adjuvant respectively and mix in ampoule with the water that 5 units that embodiment 12 obtains contain adjuvant respectively, and measure particle diameter immediately after 10 seconds with descending to shake on hand; Control Example 1-1 to 8-2 group is before carrying out the particle diameter test, with descending concussion to measure particle diameter immediately after 10 seconds on hand.After measuring particle diameter in the time of 3 months; With embodiment 1-10 mix the suspensoid that forms respectively with embodiment 11,12, the suspensoid of control Example 1-1 to 8-2 is added a cover at 40 ℃ ± 2 ℃; Preserve under the situation of relative humidity 45% ± 5% after 24 hours, with descending concussion to carry out the particle diameter test after 10 seconds on hand.
Experimental result is following:
| Control Example 6-1 | 3.7±0.5 | 7.8±2.4 | 18.6±3.3 | 19.1±3.2 |
| Control Example 7-1 | 3.8±0.8 | 9.8±2.8 | 19.6±3.5 | 20.7±3.6 |
| Control Example 8-1 | 3.8±0.6 | 8.6±2.6 | 20.5±3.4 | 20.5±3.3 |
| Control Example 1-2 | 3.7±0.6 | 9.3±2.4 | 19.9±3.2 | 19.9±3.1 |
| Control Example 2-2 | 3.6±0.5 | 9.5±2.4 | 19.7±3.4 | 19.6±3.3 |
| Control Example 3-2 | 3.5±0.6 | 10.1±2.6 | 21.1±3.1 | 21.2±3.2 |
| Control Example 4-2 | 3.7±0.5 | 10.1±2.5 | 22.3±3.4 | 22.3±3.4 |
| Control Example 5-2 | 3.7±0.9 | 8.9±2.3 | 19.8±3.2 | 19.7±3.3 |
| Control Example 6-2 | 3.6±0.5 | 8.7±2.1 | 23.8±3.9 | 23.9±3.7 |
| Control Example 7-2 | 3.9±0.8 | 10.6±2.6 | 22.0±3.8 | 22.1±3.7 |
| Control Example 8-2 | 3.7±0.7 | 9.4±2.5 | 21.6±3.5 | 21.5±3.4 |
Show through above-mentioned experiment; According to the technology among the present invention medicine is separated with the water that contains adjuvant,, mix again during use through storing for a long time; Less to grain diameter influence; After storing 24 hours under the pyritous condition, the D90 particle diameter remains on below the 10 μ m basically, and the drug microparticles profile is that sphere or type spherical ability than the maintenance particle diameter that does not have definite form are better simultaneously.And if with medicine and through forming suspensoid through long-time storage with the water that contains adjuvant, the ability of maintenance particle diameter is relatively poor, particle diameter obviously improves.
Embodiment 16 in-vitro percutaneous permeability tests
Experimental program:
After getting 3 monthly age healthy rats and rat anesthesia execution in 10 day age; Eliminate belly wool with shears; Take off undamaged skin, remove subcutaneous tissue, be individually fixed in the liberation port of Franz diffusion cell after cleaning; Add the pH7.4 phosphate buffer in the receiving chamber and make release medium, keep endodermis to contact closely with solution.Get the 0.1ml medicinal liquid and be coated on the skin, regulate water-bath and make outer jacket layer temperature constant in (37 ± 1) ℃, mixing speed is 100rpm, draws release medium 4ml respectively at 0,0.15,0.5,0.75,1,1.5,2 hour, adds equivalent PBS liquid simultaneously.Discharge liquid and confirm concentration C i, try to achieve drug per unit area accumulation transit dose Q:Q=CiV/A according to following formula with the method for Chinese Pharmacopoeia version in 2010
In the formula, Q is a drug per unit area accumulation transit dose, and Ci is the drug level in the release medium in the t time, and V is the receiving chamber volume, and A is the skin diffusion area.With Q and C the time is carried out linear regression respectively, try to achieve permeability (J/ μ g.h
-1)
The preparation of experiment medicine: with embodiment 1-12, control Example 1-1 to 8-2 be divided into embodiment 1-10 group, control Example 1-1 to 8-2 organizes; Embodiment 11-12 organizes 500 every group; All the other every group 40 units at 40 ℃ ± 2 ℃, carry out stability test under the situation of relative humidity 75% ± 5%; Store after 3 months, wherein each 20 capsules getting of embodiment 1-10 group carry out permeability test.
Before carrying out permeability test; Embodiment 1-10 organizes every group and gets 10 capsular medicines and water that 10 units that embodiment 11 obtains contain adjuvant and in ampoule, mix, get 10 capsular medicines and mix in ampoule with the water that 10 units that embodiment 12 obtains contain adjuvant, and with on hand down concussion be coated on immediately on the 3 monthly age healthy rat skins after 20 seconds; Control Example 1-1 to 8-2 group is before carrying out permeability test, with descending concussion to be coated on immediately on the 3 monthly age healthy rat skins after 10 seconds on hand.
Likewise, 10 day age rat skin carry out same test.
Experimental result is following:
Through above-mentioned experiment; Can find out that the bigger control Example infiltration rate of particle diameter is obviously lower; And the less embodiment infiltration rate of particle diameter is higher; Especially obviously improve for the thin rat infiltration rate in 10 day age of skin, can explain that suspensoid among the present invention more adapts to give skin thin child.
Claims (10)
1. a Transdermal absorption is treated dermopathic pharmaceutical composition, by the D90 particle diameter that contains one or more solid medicinal adjuvants and be insoluble in water as independent packing be 0.1-10 μ m dermatologic thing, the water that contains one or more water-soluble pharmaceutic adjuvants of packing is formed jointly separately.
2. pharmaceutical composition as claimed in claim 1 is characterized in that the dermatologic thing is a glucocorticoid.
3. pharmaceutical composition as claimed in claim 2 is characterized in that glucocorticoid can be selected from doubly a kind of chemical compound or its pharmaceutically useful ester in his rope, halometasone, halopredone, hydrocortamate, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone, prednicarbate, ripple prednylidene 21-diethylaminoacetatte, triamcinolone, triamcinolone acetonide, amcinonide, fluticasone, desonide, mazipredone, the tixocortol of cortisone, fluorometholone, dexamethasone, betamethasone, prednisolone, prednisone, hydrocortisone, Rui Meisonglong (Rimexolone), loteprednol, budesonide, ciclesonide, alclometasone, beclometasone, betamethasone, chloroprednisone, clobetasol, clobetasone, clocortolone, chlorine ripple Buddhist nun alcohol, deflazacort, desonide, desoximetasone, diflorasone, diflucortolone, difluprednate, flucloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocortolone, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, halcinonide, halogen.
4. pharmaceutical composition as claimed in claim 3, the consumption that it is characterized in that said glucocorticoid is 0.01%～1%.
5. the pharmaceutical composition described in claim 1 is characterized in that said solid medicinal adjuvant is one or more in the solid filler.
6. the pharmaceutical composition described in claim 5 is characterized in that the solid filler is one or more in water-soluble saccharide, the aminoacid.
7. pharmaceutical composition as claimed in claim 6 is characterized in that said saccharide is a lactose.
8. the pharmaceutical composition described in claim 1 is characterized in that the method for micronization of said dermatologic thing can adopt spray drying method, fluid bed supersonic airstream comminuting method, high speed polishing, ball-milling method, fluid energy mill method, solvent method, CO
2The supercritical methanol technology preparation.
9. the pharmaceutical composition described in claim 1 is characterized in that said compositions can adopt the form of single or multiple dosage to pack.
10. like arbitrary described pharmaceutical composition in the claim 1 to 9, treat the application in human or animal's scytitis medicine in preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105567994A CN102475888A (en) | 2010-11-23 | 2010-11-23 | Transdermally absorbed medicine comprising adjuvant-containing pharmaceutical microparticle and adjuvant-containing water for skin use |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105567994A CN102475888A (en) | 2010-11-23 | 2010-11-23 | Transdermally absorbed medicine comprising adjuvant-containing pharmaceutical microparticle and adjuvant-containing water for skin use |
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| CN102475888A true CN102475888A (en) | 2012-05-30 |
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| CN2010105567994A Pending CN102475888A (en) | 2010-11-23 | 2010-11-23 | Transdermally absorbed medicine comprising adjuvant-containing pharmaceutical microparticle and adjuvant-containing water for skin use |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474063A (en) * | 2015-08-27 | 2017-03-08 | 重庆华邦制药有限公司 | A kind of aerosol for external use containing desonide |
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| CN1973827A (en) * | 2006-12-15 | 2007-06-06 | 北京化工大学 | Prepn process of superfine inhaled glucocorticoid medicine powder |
| WO2008065451A2 (en) * | 2006-11-29 | 2008-06-05 | Malvern Cosmeceutics Limited | Compositions comprising macromolecular assemblies of lipid and surfactant |
| CN101443018A (en) * | 2006-01-27 | 2009-05-27 | 伊兰制药国际有限公司 | Sterilized nanoparticulate glucocorticosteroid formulations |
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2010
- 2010-11-23 CN CN2010105567994A patent/CN102475888A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101443018A (en) * | 2006-01-27 | 2009-05-27 | 伊兰制药国际有限公司 | Sterilized nanoparticulate glucocorticosteroid formulations |
| WO2008065451A2 (en) * | 2006-11-29 | 2008-06-05 | Malvern Cosmeceutics Limited | Compositions comprising macromolecular assemblies of lipid and surfactant |
| CN1973827A (en) * | 2006-12-15 | 2007-06-06 | 北京化工大学 | Prepn process of superfine inhaled glucocorticoid medicine powder |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106474063A (en) * | 2015-08-27 | 2017-03-08 | 重庆华邦制药有限公司 | A kind of aerosol for external use containing desonide |
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Application publication date: 20120530 |