CN1596899A - Dexamehasone palmitate freeze-dried emulsion and its preparation method - Google Patents
Dexamehasone palmitate freeze-dried emulsion and its preparation method Download PDFInfo
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Abstract
A freeze-dried emulsion of dexamethasone palmitate contains dexamethasone palmitate, oil phase, emulsifier, stabilizer, pH regulator and freeze-drying protector.
Description
Technical field:
The present invention relates to medical technical field, exactly it is a kind of Limethason freeze-dried emulsion and preparation method thereof.
Background technology:
Rheumatoid arthritis (Rheumatoid arthritis, RA), osteoarthritis is a kind of common chronic inflammatory joint disease.The medicine of this class disease of treatment is mainly steroidal class and nonsteroidal at present, because the determined curative effect of steroidal class medicine is the treatment necessary article of critically ill patient, its effect is that non-steroidal drug can not be displaced.At present, the dosage form of the steroidal drug on the market is mainly two big classes, and a class is the solution-type injection of (comprising freeze-dried powder), and another kind of is the suspendible injection.The former can " intravenous injection ", " intramuscular injection ", " joint cavity injection ", but elimination speed is fast, can not be in blood, keep valid density for a long time in the tissue, and do not have targeting; And the latter can not " intravenous injection " administration, because the suspension type Chinese medicine belongs to crystallographic, particle size is inconsistent, the coarse injustice of particle surface, so when joint cavity injection, bigger to local irritation, inject and can cause the local symptom aggravation after 4～6 hours, it is uncomfortable that part patient can feel, and clinical practice is limited.(2000 the 1st phases the 4th of comparison " the disease control magazine " volume of violent Wang Cuiqin Limethason of Zhao Yun and prednisolone acetate local injection treatment rheumatoid arthritis), dexamethasone is a present most widely used clinically class steroid hormone class medicine, its dosage form also comprises two big classes, liquid drugs injection and dexamethasone acetate suspendible pin as dexamethasone phosphate ester sodium, after the lucky rich pharmacy of Japan (Yoshitomi Pharm) is carried out the Palmic acid esterification with dexamethasone, make the lipid microsphere emulsified injection, commodity are by name: Limethason, route of administration is wide, can " intravenous injection ", " intramuscular injection ", " joint cavity injection ", " epidural space injection ", this dosage form has targeting simultaneously.Researcher is arranged to distributing in the antiinflammation of dexamethasone sodium phosphate (DP) and Limethason lipid microsphere (Lipo-Dpal), the body and curative effect etc. has been carried out animal and clinical trial.Animal experiment: laboratory animal male Wistar rat, do following test respectively: 1. bring out edema in the subcutaneous injection 1% carrageenin salt-water liquid 0.1ml of the right back claw of Mus place, go into the Lipo-Dpal or the DP of various dose behind the 30min in tail vein injection, detect the inhibition percentage rate of edema behind the 5h; 2. under the Mus butt, implanted the filter paper (diameter 6mm) of 7% formaldehyde dipping,, taken off the swollen and filter paper weighing of bud, and marked ED in the 8th day respectively through the quiet injection thing of tail in 7 days by suppressing percentage rate in the 5th, 6
503. inject the 6ml air to cause air bag in the Mus back of the body, in air bag, inject 2% carrageenin salt-water liquid behind the 24h and bring out granuloma,, injected Lipo-Dpal or DP, downcut the granuloma weighing, and marked ED in the 8th day in 7 days with granulomatous suppression ratio in the 5th, 6
504. after right crus of diaphragm side surface behind the female Mus injects 0.05ml adjuvant drug (the liquid Paraffin suspension that contains Mycobacterium butyricum 0.6mg) and brings out arthritis, in the 11st day quiet injection thing, every other day once, and totally three times, measure left foot after the 18th day, mark ED
50The result shows that the curative effect of the two on Carrageenan edema acute inflammation model of Lipo-Dpal and DP is identical, but the curative effect of the former PARA FORMALDEHYDE PRILLS(91,95) edema is big 2 times, and is big 5.3 times to the granulomatous antiinflammation of carrageenin.Big 3.3 times to arthritic curative effect.In order to illustrate the curative effect of Lipo-Dpal, further studied Lipo-Dpal and DP the distribution in rat arthritis district, cytophagous picked-up with to phagocytic function, and the influence of superoxide anion release etc.The result shows that Lipo-Dpal has the distribution of high level in the impaired junction of arthritis, higher 1.5 times than DP at 2～6h; Height is about 2 times in 24h, illustrates that Lipo-Dpal concentrates in inflammatory tissue.Mouse ascites fluid phagocyte and Lipo-Dpal or DP are behind In vitro culture 30min, and Lipo-Dpal is higher 7.8 times than DP in picked-up, and the Lipo-Dpal that is absorbed by phagocyte is hydrolyzed into D (dexamethasone) very soon.Lipo-Dpal can significantly suppress phagocyte releasing superoxide anion, and cytophagous chemotaxis of strong inhibition and phagocytosis, and the reason that Lipo-Dpal has remarkable antiinflammatory action has 2 points: 1. this product concentrates in inflammation damaged part, i.e. targeting; 2. the cytophagous function of strong influence.In people's phagocyte, the Dpal that enters after the inflamed sites is hydrolyzed to dexamethasone rapidly.Clinical trial: give the rheumatic arthritis patient Lipo-Dpal or the DP of intravenous injection 1ml respectively with the double-blind method cross matching, by curative effect and side effect evaluation, the Lipo-Dpal group is excellent than the DP group as a result.The literary composition report is arranged, the intraarticular injection Limethason, per 2 weeks, once 4 times was a course of treatment, after finish a course of treatment, obvious effective rate reaches 77%, and the improvement rate is 23%, and total effective rate reaches 100%, morning, deadlock was reduced to 3.2 minutes by average 13.5 minutes, 20 meters walking times reduced to 16 seconds by 33 seconds, and the hydrops disappearance rate reaches 83%, and side effect does not almost have.Other has literary composition report, changes oral prednisone into after three days one of intramuscular injection every day, one week of the course of treatment, and the treatment anaphylactoid purpura, cure rate reaches 80%, and it is 93.3% that rate is always arranged.After Beijing Tongren Hospital is diluted to 20-30ml with these product 1ml (including dexamethasone 2.5mg) with 5% glucose, the preliminary observation of the slow injection for curing ankylosing spondylitis 10 routine clinical efficacies of vein, per 2 weeks 1 time, 4 times is 1 course of treatment.2 weeks check physiochemical indice after the drug withdrawal, observed 3 months the full course of treatment.Finishing back 10 examples as a result 8 weeks all obviously improves.Morning is stiff owing to reduced to 3.5 minutes in equal 42 minutes.20 meters walking times reduced to 10.5 seconds by average 22.5 seconds.Arthralgia is counted and is reduced to 0 by average 6.4.People's Hospital, Sichuan Prov. adds lignocaine 0.5mg with this product 4mg, thyroid local injection treatment chronic lymphocytic thyroiditis, and per 2 weeks 1 time, 6-12 week is 1 course of treatment (an A group).Matched group 8 examples (B group), oral prednisone.In 6～12 weeks, the low person of first adds thyroxine sheet 20～80mg/d in two groups.The result: after two groups of patient's medications, the thyromegaly sign all is clearly better; Thyroglobulin antibody and thyroid microsomal antibody combination rate all obviously descend; Blood T cell subsets CT8 level descends to some extent; A group lymphocytic infiltration is clearly better.The extremely emerging syndrome performance of medicine in various degree all appears in B group, and has 1 routine blood glucose to increase and end treatment.Show that the A group all is better than the B group.Other has report, this product 1ml (containing dexamethasone 2.5mg) intravenous injection, and per 2 weeks, once 3 months was a course of therapy rheumatoid arthritis, and matched group is a dexamethasone, the result: treatment group total effective rate is 95%, and the matched group total effective rate is 50%.21 example recoveries from illness among the 30 routine patients of this product epidural space injection for curing lumbago and skelalgia, 9 examples take a turn for the better.Epidural space injection for curing prolapse of lumbar intervertebral disc has carried out clinical observation to 35 routine patients, and the result shows that the Limethason advantage is obviously more than Diprospan.Chronic injury of locomotor system 125 examples are treated with this product local injection by The Second Affiliated Hospital of Nanjing Medical University, treat and carry out the curative effect statistics after 35 days, Limethason group total effective rate is 95.4%, and meticortelone group total effective rate is 81.7%, two group of significant difference (P＜0.05).Zhao Yun waits suddenly and adopts articular cavity or joint surrounding tissue interior injection Limethason and prednisolone acetate that 37 routine rheumatoid arthritiss (RA) are carried out local injection treatment research, the Limethason group is cured 15.8%3 examples after 4 weeks of treatment, produce effects 52.6%, effective 26.3%, total effective rate 94.7%, the prednisolone acetate group cures 5%, produce effects 35%, effective 40%, total effective rate 77.8%.The Limethason group is better than prednisolone acetate group (2000 the 1st phases the 4th of comparison " the disease control magazine " volume of Limethason such as Zhao Yunmeng and prednisolone acetate local injection treatment rheumatoid arthritis), aspect the chronic card pressure of treatment peripheral nerve injury, Limethason is better than glucocorticoid, and (glucocorticoid such as Limethason is pressed the research " Chinese anesthesiology magazine " 1999,19 (11) of functional rehabilitation behind the peripheral nerve injury to chronic card: 668～671).Remove in addition, Limethason can be used for (Limethason local injection treatment subacute thyroiditis observation of curative effect " Tianjin medicine " 1999,27 (1): 39～40 such as " subacute thyroiditis ", " lumbar intervertebral disc prolapse ", " anaphylactoid purpura ", " chronic injury of locomotor system ", " ankylosing spondylitis " " osteoarthritis "; Two kinds of new glucocorticoids to lumbar intervertebral disc prolapse observation of curative effect Medical University Of Chongqing journal 1998,23 (2): 184～185 Limethason advantages obviously more than Diprospan; Limethason and hydrogen are examined treatment anaphylactoid purpura 30 routine observation of curative effect " Sichuan medical science " 1996,17 (5): 315; Limethason local injection treatment chronic injury of locomotor system 125 examples are analyzed " Nanjing Medical University's journal " 1996,16 (6): 589; The curative effect " new drug and clinical " 1996,15 (6): 337～339 of Limethason treatment exophthalmic goiter; The clinical observation " Medical University Of Chongqing's journal " 1996,21 (1) of Limethason epidural space injection for curing lumbago and skelalgia: 71-72; Limethason treatment rheumatoid arthritis observation of curative effect " Binzhou Medical College's journal " 1994,17 (4): 336～337; The local hydrocortisone treatment of chronic lymphocytic thyroiditis is imitated and is observed " CHINESE JOURNAL OF INTERNAL MEDICINE " 1994,33 (10): 692; Limethason treatment osteoarthritis 30 routine clinical efficacy preliminary observations " Capital Medical College's journal " 1994,15 (1): 60～61; The preliminary observation " Beijing medical science " 1993,15 (6) of Limethason treatment ankylosing spondylitis 10 routine clinical efficacies: 326).
In view of the unique formulation characteristic and the curative effect of Limethason emulsion injection, this product is approved for national essential drugs.Consider existing injection poor stability, emulsion droplet is easy to assemble, and high temperature sterilize can damage medicine and adjuvant, we are made into freeze-dried emulsion, experimental result shows that the freeze-dried emulsion of the present invention's preparation has improved the stability of Limethason greatly, sees " embodiment 8 ".
Summary of the invention:
The purpose of this invention is to provide a kind of Limethason freeze-dried emulsion and preparation method thereof, its preparation section is simple, and medicament contg is more controlled, has improved the stability of medicine and additives (adjuvant).For extensive patients provides safer, stable, effective freeze-dried emulsion.Its main technical schemes is that the composition of this freeze-dried emulsion is medicine (Limethason), oil for injection, emulsifying agent, stabilizing agent, pH regulator agent, freeze drying protectant, and all the other are water for injection.Medicine: oil for injection=1: 0～1: 20 (w/w), oil for injection can be the vegetable oil of any kind of, as: one or more mixture in Oleum Glycines, Oleum Camelliae, olive oil, the Flos Carthami wet goods.Granularity is 10nm-1000nm.
Emulsifying agent: one or more mixture in phospholipid, poloxamer, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethyleneglycol 660 hydroxystearate as a nonionic solubilizer for injection solutions), vitamin E polyethylene glycol succinic acid ester (TPGS) (0%～5%), the Tweens etc., consumption be (0%～5%) (w/v).
Stabilizing agent: one or more mixture in anhydrous sodium sulfite, sodium sulfite, vitamin C, nitrogen, dibenzylatiooluene, alpha-tocopherol, α-tocopheryl acetate, the hydroquinone etc., consumption is 0.01%-1% (w/v).
The pH regulator agent: one or more mixture in sodium hydroxide, sodium acetate, acetic acid, phosphate, hydrochloric acid, the citric acid etc., adjusting pH is 4-9.
Antiseptic: parabens, consumption are 0%-1% (w/v).
Freeze drying protectant: glucide; as: one or more mixture in glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, the polyvinylpyrrolidone (PVP) etc., the content of freeze drying protectant is 4%-40% (W/V).Wherein best of breed is glucose and mannitol, and both proportionings are: 1: 0.01～0.01: 1, best proportioning was: the manufacture method of 1: 0.2～0.2: 1 injection freeze-dried emulsion is as follows:
1) in dosing apparatus, Limethason is dissolved in the oil for injection;
2) emulsifying agent is added in an amount of water for injection, and add stabilizing agent;
3) with 2) under stirring condition, add 1) in (or 1) under stirring condition, add 2) in), in the time of 20 ℃～80 ℃, stir, by even matter instrument, with solution homogenize repeatedly, add an amount of freeze drying protectant, obtain uniform solution; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, get exsiccant Limethason freeze-dried emulsion;
5) freeze-dried emulsion that makes is measured on demand added water, be recovered to Emulsion, drug administration by injection after the hydration vibration.
Freeze drying protectant:, concentrate gradually, and be distributed in around the emulsion droplet with the freezing and crystalline growth of Emulsion as mannitol, trehalose etc., stop the fusion of emulsion droplet; Can suppress the growth of ice crystal, thereby reduce the damage of ice crystal emulsion droplet; Can improve the glass transition temperature of Emulsion, and under certain rate of temperature fall, make Emulsion realize segment glassization, avoid crystalline state curing, reduce the various damages that in common balance freezing method, cause owing to ice-crystal growth; In the Emulsion freezing process, protective agent increases the viscosity of solution, thereby the crystallization process of the water that weakened has reached the purpose of protecting.
The assay of Limethason is analyzed with HPLC:
The chromatographic condition of HPLC is: the chromatographic column octadecylsilane chemically bonded silica
Mobile phase methanol-water (95: 5)
Detect wavelength 238nm
Particle size analyzer: use PSS.NICOMP in this experiment
TM380 as the instrument of measuring particle diameter.
The specific embodiment:
Embodiment 1:
Prescription is formed: Limethason 0.4g, soybean lecithin 5g, anhydrous sodium sodium bisulfate 0.01g become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.4g is dissolved in an amount of ethanol;
2), and add 0.01g anhydrous sodium sodium bisulfate with soybean lecithin for injection and the proper amount of water for injection mix homogeneously of 5g;
3) with 2) under stirring condition, add 1) in, when 20, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.The mannitol of adding 4% makes the medicinal liquid of 100ml as freeze drying protectant; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, get exsiccant Limethason freeze-dried emulsion;
5) will make freeze-dried emulsion and measure adding water for injection on demand, be recovered to Emulsion after the hydration vibration.Particle diameter 10～336nm.
Embodiment 2:
Prescription is formed: Limethason 0.2g, Ovum Gallus domesticus Flavus lecithin 0.5g, injection Oleum Camelliae 0.2g, anhydrous sodium sodium bisulfate 0.01g, 0.01g ethyl hydroxybenzoate, 5g glucose and 1g mannitol become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.2g is dissolved in the 0.2g injection Oleum Camelliae;
2), and add 0.01g ethyl hydroxybenzoate, 0.01g anhydrous sodium sodium bisulfate with injection Ovum Gallus domesticus Flavus lecithin and the proper amount of water for injection mix homogeneously of 0.5g;
3) with 1) under stirring condition, add 2) in, when 40, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Add glucose and mannitol as freeze drying protectant, make the medicinal liquid of 100ml; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, get exsiccant Limethason freeze-dried emulsion;
5) will make freeze-dried emulsion and measure on demand and add the injection water, be recovered to Emulsion after the hydration vibration.Particle diameter 10～625nm.
Embodiment 3:
Prescription is formed: Limethason 0.2g, poloxamer (F68) 1g, injection olive oil 1g, anhydrous sodium sulfite 0.1g become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.2g is dissolved in the 1g injection olive oil;
2) with poloxamer and the proper amount of water for injection mix homogeneously of 1g;
3) with 2) under stirring condition, add 1) in, in the time of 60 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.It is 4～5 that hydrochloric acid, sodium hydroxide are regulated pH, and the sucrose of adding 40% is as freeze drying protectant, and water for injection adds to 100ml; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) moisture is removed in lyophilization, gets exsiccant Limethason Limethason freeze-dried emulsion;
5) make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Particle diameter 20～731nm.
Embodiment 4:
Prescription is formed: Limethason 0.2g, tween 80 1g, injection soybean oil 2g, vitamin C 0.1g, 0.01g ethyl hydroxybenzoate and 0.001g propylparaben become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.2g is dissolved in the 2g injection soybean oil;
2), and add 0.01g ethyl hydroxybenzoate and 0.001g propylparaben with tween 80 and the proper amount of water for injection mix homogeneously of 1g;
3) with 2) under stirring condition, add 1) in, in the time of 40 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.The trehalose of adding 8% is as freeze drying protectant, and it is 6～7 that sodium acetate, acetic acid are regulated pH, makes medicinal liquid 100ml altogether; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, get exsiccant Limethason freeze-dried emulsion;
5) will make freeze-dried emulsion and measure on demand and add water, after the hydration vibration, be recovered to Emulsion; Particle diameter 80～960nm.
Embodiment 5:
Prescription is formed: Limethason 0.2g, Ovum Gallus domesticus Flavus lecithin 1g, 0.5g HS15, injection soybean oil 4g, vitamin C 0.1g, 0.01g ethyl hydroxybenzoate and 0.001g propylparaben, 5g mannitol and 5g glucose become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.2g is dissolved in the 4g injection soybean oil;
2) with Ovum Gallus domesticus Flavus lecithin 1g, 0.5g HS15 and proper amount of water for injection mix homogeneously;
3) with 1) under stirring condition, add 2) in, in the time of 40 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Add the manna alcohol and glucose as freeze drying protectant, it is 7～8 that citric acid, sodium hydroxide are regulated pH, makes medicinal liquid 100ml altogether; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, inflated with nitrogen gets exsiccant Limethason freeze-dried emulsion;
5) will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Particle diameter 60～1000nm.
Embodiment 6:
Prescription is formed: Limethason 0.2g, soybean lecithin 1g, 0.5g vitamin E polyethylene glycol succinic acid ester (TPGS), injection safflower oil 1g, alpha-tocopherol 0.1g, 0.1g ethyl hydroxybenzoate, 8g xylitol become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.2g is dissolved in 1g injection safflower oil, the 0.1g alpha-tocopherol;
2) with soybean lecithin 1g, 0.5g vitamin E polyethylene glycol succinic acid ester (TPGS) and proper amount of water for injection mix homogeneously;
3) with 2) under stirring condition, add 1) in, when 40, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Add xylitol as freeze drying protectant, it is 8-9 that phosphoric acid, sodium hydroxide are regulated pH, makes medicinal liquid 100ml altogether; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, get exsiccant Limethason freeze-dried emulsion;
5) will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Particle diameter 10～810nm.
Embodiment 7:
Prescription is formed: Limethason 0.2g, 5g vitamin E polyethylene glycol succinic acid ester (TPGS), injection soybean oil 1g, dibenzylatiooluene 0.1g, vitamin C 0.1g, 1g mannitol and 5g glucose become 100ml altogether.
Technology:
1) in dosing apparatus, Limethason 0.2g is dissolved in the 1g injection soybean oil;
2) with 5g vitamin E polyethylene glycol succinic acid ester (TPGS) and proper amount of water for injection mix homogeneously;
3) with 2) under stirring condition, add 1) in, in the time of 40 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Add the manna alcohol and glucose as freeze drying protectant, make medicinal liquid 100ml altogether; Cross the degerming of 0.22um microporous filter membrane, 100 grades aseptic subpackaged down.
4) remove moisture through lyophilization, inflated with nitrogen gets exsiccant Limethason freeze-dried emulsion;
5) will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Particle diameter 10～360nm.
Embodiment 8:
Stability test.Place 40 ℃ of calorstats to investigate 3 months in sample, measure medicament contg with HPLC,
The results are shown in Table 1.
Table 1: stability test result
Content (%) emulsion embodiment 2 embodiment 3 embodiment 5 embodiment 7
0 time 98.8 99.6 99.1 98.5 98.7
After March 89.3 98.9 99.2 98.8 98.3
Hence one can see that, and the stability of freeze-dried emulsion is better than normal injection.
Embodiment 9: the pharmacology antiinflammatory action
According to teaching material " antiinflammatory of glucocorticoid is tested ", through preliminary experiment, it is undesirable to find to cause scorching back 4 hours execution mice survey swelling degree gained data, changes 2 hours into so will cause the scorching time.Mice is divided six groups at random by body weight, male and female half and half, and lumbar injection, dosage are equivalent to dexamethasone 0.039ug/g:A group, normal saline; The B group, 2 groups of embodiment; The C group, 3 groups of embodiment; The D group, 5 groups of embodiment; The E group, 7 groups of embodiment.The two sides causes inflammation before and after being applied to left ear with dimethylbenzene in 40 minutes after the administration; Each group is put to death mice causing scorching back 2 hours, is that the card punch of 8mm is located to take off auricle in the ears symmetry and weighed with diameter then, and left and right sides auricle weight difference is the swelling degree.Data see Table 2.
Table 2 pharmacological experimental data
Heavy (g) swelling degree (g) of heavy (g) auris dextra of group left side ear
A group 0.0296+-0.0037 0.0156+-0.0043 0.0140
B group 0.0280+-0.0017 0.0179+-0.0019 0.0101
C group 0.0273+-0.0036 0.0180+-0.0034 0.0093
D group 0.0278+-0.0035 0.0190+-0.0029 0.0088
E group 0.0287+-0.0045 0.0181+-0.0022 0.0106
By experimental data as seen, the Limethason preparation has tangible antiinflammatory action.
Claims (5)
1, a kind of Limethason freeze-dried emulsion; it is characterized in that: contain effective doses of dexamethasone cetylate in the dried frozen aquatic products as effective ingredient, and contain oil phase, emulsifying agent, stabilizing agent, pH regulator agent, antiseptic or do not contain antiseptic, freeze drying protectant pharmaceutic adjuvant.
2, a kind of Limethason freeze-dried emulsion according to claim 1, it is characterized in that: medicine: oil for injection=1: 0～1: 20 (w/w), described oil for injection can be vegetable oil or its mixture of Oleum Glycines, Oleum Camelliae, olive oil, Flos Carthami wet goods any kind of, and consumption is 0～5%; Emulsifying agent is: one or more in 0%～5% egg yolk lecithin or soybean phospholipid (w/v), 0%～5% poloxamer (w/v), 0%～5% HS15 (Polyethylene glycol 660 hydroxystearate), 0%～5% vitamin E polyethylene glycol succinic acid ester (TPGS), 0%～1% the Tweens (w/v); The pH regulator agent is one or more in hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, phosphoric acid, sodium phosphate, citric acid, the sodium citrate etc., and the pH scope is 4～9; Stabilizing agent is: one or more in sodium sulfite, sodium sulfite, vitamin C, nitrogen, dibenzylatiooluene, alpha-tocopherol, α-tocopheryl acetate, the hydroquinone etc.; Freeze drying protectant is: glucide, as: one or more in glucose, lactose, galactose, fructose, dextran, mannitol, sorbitol, xylose, xylitol, sucrose, trehalose, the polyvinylpyrrolidone etc., protectant consumption is 2%～40% (w/v); Antiseptic is: parabens (0%～0.5%).The particle size range of institute's antigalactic is 10nm～1um.
3, a kind of Limethason freeze-dried emulsion according to claim 2 is characterized in that: the proportioning of medicine and oil for injection can be medicine: oil for injection=1: 1～1: 10 (w/w).
4, a kind of Limethason freeze-dried emulsion according to claim 2, it is characterized in that: freeze drying protectant can be the combination of glucose and mannitol, and both proportionings are: 1: 0.01～0.01: 1.
5, a kind of preparation method of Limethason freeze-dried emulsion as claimed in claim 1 is characterized in that: medicinal liquid is lyophilized into solid by adding protective agent, before the use; add the injection water as required; through the hydration vibration, be recovered to Emulsion, its preparation process is as follows:
1, in dosing apparatus, Limethason is dissolved in the oil for injection;
2, emulsifying agent is added in an amount of water for injection, and add stabilizing agent;
3, with 2) under stirring condition, add 1) in or 1) under stirring condition, add 2) in, in the time of 20 ℃-60 ℃, stir, by even matter instrument, with solution homogenize repeatedly, obtain uniform solution;
4, add an amount of freeze drying protectant, remove moisture, get exsiccant Limethason freeze-dried emulsion through lyophilization;
5, the freeze-dried emulsion that makes is measured the adding sterilized water for injection on demand, be recovered to Emulsion, drug administration by injection after the hydration vibration.
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Cited By (6)
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| CN102391342A (en) * | 2011-09-20 | 2012-03-28 | 海南灵康制药有限公司 | Dexamethasone palmitate compound and preparation method thereof |
| CN102526078A (en) * | 2010-12-15 | 2012-07-04 | 重庆华邦制药股份有限公司 | Compound betamethasone suspension injection and preparation method thereof |
| CN104706574A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Dexamethasone palmitate fat emulsion concentrated solution, preparation method and application thereof |
| CN105250221A (en) * | 2014-07-14 | 2016-01-20 | 天津药物研究院 | Licopyrinobuter dry emulsion and preparation method thereof |
| CN112516091A (en) * | 2020-06-15 | 2021-03-19 | 和舆(苏州)医药科技有限公司 | Dexamethasone sodium phosphate freeze-dried powder injection |
| CN116077669A (en) * | 2022-12-15 | 2023-05-09 | 中南大学湘雅医院 | Glucocorticoid nano-lipid carrier for treating arthralgia, preparation method and application thereof |
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2004
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| CN102526078B (en) * | 2010-12-15 | 2015-12-02 | 重庆华邦制药有限公司 | Compound betamethasone suspension injection and preparation method thereof |
| CN102391342A (en) * | 2011-09-20 | 2012-03-28 | 海南灵康制药有限公司 | Dexamethasone palmitate compound and preparation method thereof |
| CN102391342B (en) * | 2011-09-20 | 2012-11-21 | 海南灵康制药有限公司 | Dexamethasone palmitate compound and preparation method thereof |
| CN104706574A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Dexamethasone palmitate fat emulsion concentrated solution, preparation method and application thereof |
| CN105250221A (en) * | 2014-07-14 | 2016-01-20 | 天津药物研究院 | Licopyrinobuter dry emulsion and preparation method thereof |
| CN105250221B (en) * | 2014-07-14 | 2018-06-19 | 天津药物研究院 | A kind of Licopyrinobuter dried emulsifier and preparation method thereof |
| CN112516091A (en) * | 2020-06-15 | 2021-03-19 | 和舆(苏州)医药科技有限公司 | Dexamethasone sodium phosphate freeze-dried powder injection |
| CN112516091B (en) * | 2020-06-15 | 2022-03-29 | 和舆(苏州)医药科技有限公司 | Dexamethasone sodium phosphate freeze-dried powder injection |
| CN116077669A (en) * | 2022-12-15 | 2023-05-09 | 中南大学湘雅医院 | Glucocorticoid nano-lipid carrier for treating arthralgia, preparation method and application thereof |
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