CN102475681A - Separated water suspension medicine for treating dermatosis - Google Patents

Abstract

A separate water suspension medicine for treating dermatosis is composed of the individually packaged water-insoluble D90 medicine with 0.1-10 microns in particle size for skin application and the individually packaged water containing one or more medicinal auxiliary materials for skin application, and features that the D90 particle size of said individually packaged water-insoluble medicine for skin application is preferably 1-10 microns and its particles are spherical or quasi-spherical.

Description

Treat dermopathic separate type water suspension medicine

Technical field:

The present invention relates to a kind of dermatologic thing, is that the dermatologic thing of 0.1-10 μ m, the water of packing separately that contains one or more skin pharmaceutic adjuvants are formed jointly by the water-fast particle diameter as independent packing.

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 can produce various untoward reaction to skin simultaneously, and for example some patient can produce allergic symptom to adjuvant, and especially the adult is thinner for the infant skin below 2 years old; There is stimulation in adjuvants such as the long-chain fat in unguentum, the gel, ethanol 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, water suspension just has similar effects.But preparation as treatment skin; A little less than the drug action of water suspension; Key is that water suspension does not have fat-soluble adjuvant such as lanoline etc., so the percutaneous ability of this kind preparation is relatively poor, so in fact this kind water suspension dosage form is not treating dermatosis through Transdermal absorption.

Simultaneously, also there is a kind of difficulty of preparation in water suspension through Transdermal absorption, if the suspendible particle is bigger; Then can't pass through epidermal tissue,, but compare with macroparticle if the suspendible particle is too small like nanoscale; The small-particle specific surface area is big; Have higher surface energy, so this system is adsorbed onto the macroparticle surface for reduce the molecule disengaging small-particle that its surface energy makes the small-particle surface as far as possible 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 of development; 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, all can't guarantee microgranule suspensoid long preservation; 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; To be made up of jointly the water that contains one or more skin pharmaceutic adjuvants that is 0.1-10 μ m dermatologic thing as the particle diameter of packing separately that is insoluble in water, packs separately, 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 that contains one or more skin pharmaceutic adjuvants of packing.

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.Its physical significance be particle diameter less than it granule account for 90%.

The present invention provides a kind of Transdermal absorption to treat dermopathic pharmaceutical composition, is made up of jointly the water that contains one or more skin pharmaceutic adjuvants that is 0.1-10 μ m dermatologic thing as the D90 particle diameter of packing separately that is insoluble in water, packs separately.The D90 particle diameter that is insoluble in water dermatologic thing of described independent packing is preferably 1-10 μ m, and particulate form is spherical or type sphere.Described pharmaceutical composition can also increase the utensil of a kind of hybrid medicine and water.

Described pharmaceutical composition, the dermatologic thing that it is characterized in that being insoluble in water 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.Preferably from poor efficiency glucocorticoid prednisolone, prednisone, hydrocortisone, methylprednisolone or its pharmaceutically useful salt or ester.The consumption of said glucocorticoid is 0.01%～1%.Preferred 0.1%～1%.

Adjuvant in the water that contains one or more skin pharmaceutic adjuvants of said independent packing comprises one or more in pH regulator agent, osmotic pressure regulator, viscosity modifier, penetrating agent, surfactant or the stabilizing agent.PH regulator agent in the said 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 the said 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 the said 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 the said adjuvant.Be tween 80, 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, consumption is preferably 0.1%～2%.

Stabilizing agent in the said adjuvant is a disodiumedetate.Preferred stabilizing agent is 0.1%～0.01% disodiumedetate.

Penetrating agent in the said adjuvant is one or more in azone, sulfoxide and analog thereof, ethanol, aliphatic alcohol, pyrrolones, fatty acid, menthol, quintessence oil, the Borneolum Syntheticum, is selected from 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 one or more.

Said dermal drug compositions is characterized in that the pH of the water that contains one or more skin pharmaceutic adjuvants of described independent packing is selected from 5-7.

Described pharmaceutical composition; The D90 particle diameter that is insoluble in water that it is characterized in that said independent packing is that the method for micronization of 0.1-10 μ m 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, CO₂The supercritical methanol technology preparation.Said method of micronization adopts spray drying method, CO₂The preparation of supercritical auxiliary atomizing method.

Described pharmaceutical composition is characterized in that said dermatologic thing can adopt the packaged of single or multiple dosage, and 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 is made up of the drug microparticles of independent packing 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, 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.

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 is used the aluminium foil blister package after the packing.

Embodiment 1

The 1g hydrocortisone is dissolved in ethanol, after the filtration, the filtrating spray drying, micronization makes particle diameter reach 3 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, is divided in No. 3 capsules, and every capsules has hydrocortisone 10mg.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 2

1g is dissolved in ethanol with triamcinolone acetonide acetate, after the filtration, and the filtrating spray drying, micronization makes it particle diameter and reaches 3 μ m, and with sterilizing behind 3 mixings of 200 mesh sieves, branch installs in No. 3 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

1g is dissolved in ethanol with beclometasone, and after the filtration, the filtrating spray drying makes it particle diameter and reaches 3 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, divides to install in No. 3 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 it particle diameter and reaches 2.5 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, divides to install in No. 3 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 it particle diameter and reaches 3 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, divides to install in No. 3 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, and after the filtration, the filtrating spray drying makes it particle diameter and reaches 3 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, divides to install in No. 3 capsules, and 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 it particle diameter and reaches 3 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, divides to install in No. 3 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 it particle diameter and reaches 3 μ m, sterilizes after crossing 3 mixings of 200 mesh sieves, divides to install in No. 3 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

Utilize fluid energy mill (use the QM-3A of Nanjing Univ. Instrument Factory) to pulverize micronization the 1g hydrocortisone and make it particle diameter and reach 3 μ m, sterilize after crossing 3 mixings of 200 mesh sieves, be divided in No. 3 capsules, every capsules has hydrocortisone 10mg.The electron microscopic observation microgranule is not for there being the shape of confirming.

Embodiment 10

Utilize fluid energy mill (use the QM-3A of Nanjing Univ. Instrument Factory) to pulverize micronization the 1g triamcinolone acetonide acetate and make it particle diameter and reach 3 μ m, sterilize after crossing 3 mixings of 200 mesh sieves, be divided in No. 3 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, sodium chloride is an amount of, sodium carboxymethyl cellulose 2.5g, poloxamer 0.5g, sodium hydroxide is an amount of, and adding distil water is to 1000g

Compound method: EDTA-2Na, sodium carboxymethyl cellulose, the poloxamer of recipe quantity are dissolved in the 500ml water for injection; Stir and dissolve clearly; Transfer pH to 5.5 with sodium hydroxide, transfer to wait with sodium chloride and ooze the water for injection that the back adds surplus, the airtight preservation of packing 1ml/ ampoule after the sterilization.

Embodiment 12

EDTA-2Na 0.1g, sodium chloride is an amount of, hydroxypropyl emthylcellulose 4g, N-methyl-2-pyrrolidone 5g, sodium hydroxide is an amount of, and adding distil water is to 1000g

Compound method: EDTA-2Na, hydroxypropyl emthylcellulose, the N-methyl-2-pyrrolidone of recipe quantity are dissolved in the 500ml water for injection; Stir and dissolve clearly; Transfer pH to 5.5 with sodium hydroxide, transfer to wait with sodium chloride and ooze the water for injection that the back adds surplus, the airtight preservation of packing 1ml/ ampoule after the sterilization.

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; 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%, 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:

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

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 with the method for Chinese Pharmacopoeia version in 2010; Try to achieve drug per unit area accumulation transit dose Q:Q=CiV/A according to following formula; 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; 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; Get 10 capsular medicines and in ampoule, mix, get 10 capsular medicines with water that 10 units that embodiment 11 obtains contain adjuvant respectively and mix in ampoule with the water that 10 units that embodiment 12 obtains contain adjuvant respectively, and with on hand down concussion be coated on immediately on the 3 monthly age healthy rat skins after 10 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 in this more adapts to give skin thin child.

Claims (10)

1. a Transdermal absorption is treated dermopathic pharmaceutical composition, is made up of jointly the water that contains one or more skin pharmaceutic adjuvants that is 0.1-10 μ m dermatologic thing as the D90 particle diameter of packing separately that is insoluble in water, packs separately.

2. pharmaceutical composition as claimed in claim 1 is characterized in that the D90 particle diameter that is insoluble in water dermatologic thing of packing is 1-10 μ m separately.

3. pharmaceutical composition as claimed in claim 1, the dermatologic thing that it is characterized in that being insoluble in water is a glucocorticoid.

4. pharmaceutical composition as claimed in claim 3 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.

5. pharmaceutical composition as claimed in claim 4, the consumption that it is characterized in that said glucocorticoid is 0.01%～1%.

6. the pharmaceutical composition described in claim 1 is characterized in that adjuvant in the water that contains one or more skin pharmaceutic adjuvants of said independent packing comprises one or more in pH regulator agent, osmotic pressure regulator, viscosity modifier, penetrating agent, surfactant or the stabilizing agent.

7. the pharmaceutical composition described in claim 1; The D90 particle diameter that is insoluble in water that it is characterized in that said independent packing is that the method for micronization of 0.1-10 μ m 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, CO₂The supercritical methanol technology preparation.

8. the pharmaceutical composition described in claim 1 is characterized in that said dermatologic thing can adopt the packaged of single or multiple dosage.

9. like arbitrary described pharmaceutical composition among the claim 1-8, treat the application in human or animal's scytitis medicine in preparation.

10. like arbitrary described pharmaceutical composition among the claim 1-8, the application in the preparation treatment is below 2 years old in the infant scytitis medicine.