CN102552131A - Accessory-containing hydrocortisone butyrate divided water suspension medicament for treating dermatopathy - Google Patents
Accessory-containing hydrocortisone butyrate divided water suspension medicament for treating dermatopathy Download PDFInfo
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Abstract
An accessory-containing hydrocortisone butyrate divided water suspension medicament for treating dermatopathy is composed of one or more individually packaged skin pharmaceutical accessories, water-insoluble hydrocortisone butyrate and individually packaged water, wherein the D90 particle size of hydrocortisone butyrate is 0.1-10 micons.
Description
Technical field:
The present invention relates to a kind of dermatologic thing, by forming jointly as the hydrocortisone butyrate of packing separately that contains one or more skin pharmaceutic adjuvants and the water of 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 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 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 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, can't guarantee that all the Ostwald ripening phenomenon does not appear in the microgranule suspensoid; 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 water of packing 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 0.5-10 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.Because separately packing is insoluble in the dermatologic thing of water and contains one or more skin pharmaceutic adjuvants, wherein surfactant can play the effect of moistening in water, make drug microparticles with form suspension more easily after water mixes; Avoid occurring drug microparticles with water mixed process in the phenomenon of the water surface appears swimming in, but because surfactant often has and draws moistly, in storing, can cause the agglomerating phenomenon of drug microparticles with drug microparticles is long-time; Can't form suspensoid with water; So the inventor has added the solid filler, like lactose or/and aminoacid avoids occurring the problems referred to above; 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.
Used water can be provided with product by pharmacy corporation simultaneously, also can be provided by hospital, also can use daily clean water, like cooled warm water of boiled water or normal-temperature water, can reduce cost like this, makes things convenient for the patient to use.
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 as independent packing contain one or more skin pharmaceutic adjuvants and the D90 particle diameter be 0.1-10 μ m hydrocortisone butyrate, the water 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.
The consumption of said hydrocortisone butyrate is 0.01%～0.2%.Preferred 0.05%～0.1%.
Described pharmaceutical composition is characterized in that described adjuvant contains one or more in surfactant, the solid filler.Surfactant in the said adjuvant is one or more in the solid non-ionic surface active agent, and described solid non-ionic surface active agent is one or more in Polyethylene Glycol-stearate, Polyethylene Glycol, sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol and analog thereof, poloxamer, the tyloxapol.
Surfactant in the said adjuvant can also be 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.Said surfactant is preferably SOLEC F soybean lecithin, the S soybean lecithin that Semen sojae atricolor company of U.S. central authorities produces.
Said percentage ratio is the percentage by weight that said composition accounts for pharmaceutical composition.
Described pharmaceutical composition is characterized in that the HLB value 7-12 of surfactant.
Described pharmaceutical composition is characterized in that said solid filler is one or more in water-soluble saccharide, the aminoacid.The said water aminoacid that dissolves in is glycine, threonine, valine.Said water soluble 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 the alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, the crystallizing and drying lactose.Preferred crystallizing and drying lactose.
Described pharmaceutical composition, the water that it is characterized in that said independent packing is aquesterilisa.
Described pharmaceutical composition is characterized in that said hydrocortisone butyrate method of micronization 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, its characteristic is packed in the form that being set forth in hydrocortisone butyrate can single or multiple dosage.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, the application in the preparation treatment is below 2 years old in the diaper rash of infant, seborrheic dermatitis, the atoipc dermatitis.
Pharmaceutical composition provided by the invention is made up of hydrocortisone butyrate microgranule 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, also reduced the waste of medicine simultaneously, meet 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 vial after the packing.
Embodiment 1
The 0.2g hydrocortisone butyrate is dissolved in ethanol; After the filtration, sterilization, filtrating spray drying; Micronization makes particle diameter reach 3 μ m; Mixed with 1g sodium lauroyl sarcosine, 1.5g crystallinity lactose that particle diameter is 30 μ m after the back crosses 3 mixings of 200 mesh sieves, and be divided in No. 2 capsules, every capsules has hydrocortisone butyrate 2mg.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 hydrocortisone butyrate; After the filtration; The filtrating spray drying, micronization makes particle diameter reach 3 μ m, and the 12g sodium lauroyl glutamate, the 15g crystallinity lactose that are 30 μ m with particle diameter mix the back with sterilizing behind 3 mixings of 200 mesh sieves; Divide to install in No. 2 capsules, every capsules has hydrocortisone butyrate 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 0.5g hydrocortisone butyrate is dissolved in ethanol; After the filtration; The filtrating spray drying makes it particle diameter and reaches 3 μ m, mixes the back with 13g lauroyl (S)-Leucine sodium salt, 15g crystallinity lactose that particle diameter is 30 μ m and sterilizes behind 3 mixings of 200 mesh sieves excessively; Divide to install in No. 2 capsules, every capsules has hydrocortisone butyrate 0.5mg.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
0.5g is dissolved in ethanol with hydrocortisone butyrate; After the filtration, the filtrating spray drying makes particle diameter reach 2.5 μ m; With particle diameter be the 15g crystallinity lactose of 30 μ m; And the SOLEC F soybean lecithin of Semen sojae atricolor company of the U.S. of 13g central authorities mixes after the back crosses 3 mixings of 200 mesh sieves, divides to install in No. 2 capsules, and every capsules has hydrocortisone butyrate 0.5mg.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 hydrocortisone butyrate; After the filtration, the filtrating spray drying makes particle diameter reach 3 μ m; With particle diameter be the 15g crystallinity lactose of 30 μ m; And the S soybean lecithin of Semen sojae atricolor company of the U.S. of 10g central authorities mixes and sterilizes after 3 mixings of 200 mesh sieves are crossed in the back, divides to install in No. 2 capsules, and every capsules has hydrocortisone butyrate 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 hydrocortisone butyrate; After the filtration; The filtrating spray drying makes particle diameter reach 3 μ m, mixes the back with 1g sodium lauroyl sarcosine, 1.5g crystallinity lactose that particle diameter is 30 μ m and sterilizes behind 3 mixings of 200 mesh sieves excessively; Divide to install in No. 2 capsules, every capsules has hydrocortisone butyrate 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
0.5g is dissolved in ethanol with hydrocortisone butyrate; After the filtration; The filtrating spray drying makes particle diameter reach 3 μ m, mixes the back with 12g sodium lauroyl glutamate, 15g crystallinity lactose that particle diameter is 30 μ m and sterilizes behind 3 mixings of 200 mesh sieves excessively; Divide to install in No. 2 capsules, every capsules has hydrocortisone butyrate 0.5mg.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 hydrocortisone butyrate; After the filtration; The filtrating spray drying makes particle diameter reach 3 μ m, mixes the back with 13g lauroyl (S)-Leucine sodium salt, 15g crystallinity lactose that particle diameter is 30 μ m and sterilizes behind 3 mixings of 200 mesh sieves excessively; Divide to install in No. 2 capsules, every capsules has hydrocortisone butyrate 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 0.2g hydrocortisone butyrate makes 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; Be divided in No. 2 capsules, every capsules has hydrocortisone butyrate 2mg.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 hydrocortisone butyrate makes particle diameter reach 3 μ m; Mixed with 12g sodium lauroyl glutamate, 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 hydrocortisone butyrate 1mg.The electron microscopic observation microgranule is not for there being the shape of confirming.
Control Example 1-1
Microgranule that embodiment 1 is obtained and water for injection mix according to the ratio of 2mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 1-2
According to the method for embodiment 1 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 2mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 2-1
Microgranule that embodiment 2 is obtained and water for injection mix 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
According to the method for embodiment 2 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 1mg/ml, mix, 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 water for injection obtain mixes according to the ratio of 0.5mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 3-2
According to the method for embodiment 3 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 0.5mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 4-1
Microgranule that embodiment 4 is obtained and water for injection mix according to the ratio of 0.5mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 4-2
According to the method for embodiment 4 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 0.5mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 5-1
Microgranule that embodiment 5 is obtained and water for injection mix 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
According to the method for embodiment 5 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 1mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 6-1
Microgranule that embodiment 6 is obtained and water for injection mix 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
According to the method for embodiment 6 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 1mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 7-1
Microgranule that embodiment 7 is obtained and water for injection mix according to the ratio of 0.5mg/ml, and sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 7-2
According to the method for embodiment 7 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 0.5mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Control Example 8-1
Microgranule that embodiment 8 is obtained and water for injection mix 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
According to the method for embodiment 8 obtain not with blended microgranule of excipient substance (only containing medicine) and the ratio of water for injection according to 1mg/ml, mix, sterilization is with ultrasonic wave concussion airtight preservation of packing 1ml/ ampoule after 30 seconds.
Two, relevant pharmacodynamics test
Stability experiment
With embodiment 1-10, control Example 1-1 to 8-2 be divided into embodiment 1-10 group, control Example 1-1 to 8-2 organizes; Every group of 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, and each capsule mixes in ampoule with 1ml water for injection, and with descending concussion to measure particle diameter immediately after 20 seconds 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 20 seconds on hand.After measuring particle diameter in the time of 3 months; With embodiment 1-10 mix the suspensoid that forms respectively with water for injection, 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.
Wherein 5 embodiment such as embodiment 1-2,2-2,3-2,4-2,5-2,6-2,7-2,8-2 are not owing to add surfactant; When measuring 0 month data, find that most of drug particle swims on the water surface, when measuring 1 month particle diameter; Still can't guarantee the even of product; Can cause the homogeneity of medicine to guarantee like this,, no longer carry out long-term stable experiment so there has not been use value in this embodiment.
Experimental result is following:
Show through above-mentioned experiment; According to the technology among the present invention the medicine that contains adjuvant is separated packing with water,, mix again during use through storing for a long time; Less to grain diameter influence; After storing 24 hours under the pyritous condition, it is better relatively that the D90 particle diameter keeps 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.
In-vitro percutaneous permeability test
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) degree, mixing speed is 100rpm, respectively at 0,0.15,0.5,0.75,1,1.5,2 hour absorption release medium 4ml, 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 1-10, control Example 1-1 to 8-1 be divided into embodiment 1-10 group, control Example 1-1 to 8-1 organizes; Every group of 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 capsules and make an experiment, and each capsule mixes in ampoule with 1ml water for injection, 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 with descending concussion to be coated on immediately on the 3 monthly age healthy rat skins after 10 seconds on hand, is coated with dose and sees the following form before carrying out permeability test.
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 as independent packing contain one or more skin pharmaceutic adjuvants and the D90 particle diameter be the hydrocortisone butyrate of 0.1-10 μ m, the water of packing is formed jointly separately.
2. pharmaceutical composition as claimed in claim 1, the consumption that it is characterized in that said hydrocortisone butyrate is 0.01%～0.2%.
3. pharmaceutical composition as claimed in claim 1 is characterized in that described adjuvant contains one or more in surfactant, the solid filler.
4. pharmaceutical composition as claimed in claim 3 is characterized in that surfactant in the said adjuvant is one or more in the solid non-ionic surface active agent.
5. pharmaceutical composition as claimed in claim 3 is characterized in that the surfactant in the said adjuvant is amino acids, lecithin class surfactant.
6. pharmaceutical composition as claimed in claim 3 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 water soluble saccharide is a lactose.
8. the pharmaceutical composition described in claim 1 is characterized in that said hydrocortisone butyrate thing method of micronization 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, its characteristic is that the hydrocortisone butyrate of 0.1-10 μ m can adopt the form of single or multiple dosage to pack at said one or more skin pharmaceutic adjuvants and the D90 particle diameter of containing.
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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| CN2010105568944A CN102552131A (en) | 2010-11-23 | 2010-11-23 | Accessory-containing hydrocortisone butyrate divided water suspension medicament for treating dermatopathy |
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| CN2010105568944A CN102552131A (en) | 2010-11-23 | 2010-11-23 | Accessory-containing hydrocortisone butyrate divided water suspension medicament for treating dermatopathy |
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2010
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Application publication date: 20120711 |