CN102351895A - Fospropofol disodium hydrate, preparation method and purpose thereof - Google Patents
Fospropofol disodium hydrate, preparation method and purpose thereof Download PDFInfo
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- CN102351895A CN102351895A CN2011102263794A CN201110226379A CN102351895A CN 102351895 A CN102351895 A CN 102351895A CN 2011102263794 A CN2011102263794 A CN 2011102263794A CN 201110226379 A CN201110226379 A CN 201110226379A CN 102351895 A CN102351895 A CN 102351895A
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Abstract
The invention relates to a fospropofol disodium hydrate, a preparation method and purpose thereof. The fospropofol disodium hydrate has better stability, higher bioavailability and better drug effect. Besides, the fospropofol disodium hydrate can be prepared into a tablet, a capsule and vein administration preparation to be used in operation anaesthesia.
Description
Technical field:
The invention belongs to medical technical field, relate to the hydrate of first phosphorus propofol disodium.
Technical background:
In nearest 15 years anesthesia treatment, injectable narcotic, especially Propofol, the application of inducing and keeping that is used for general anesthesia has obtained to accept widely.Compare several advantages with propofol vein anesthesia with previous method:,, suffocate or the overpowering odor of VA because patient needn't worry to mask as more being prone to inducing of tolerance; Rapid and predictable recovery; The degree of depth that is easy to regulate anesthesia through the dosage of regulating Propofol; Comparing with the inhalation anesthesia agent has low adverse reaction rate; Anxiety, nausea and vomiting [Padfield NL, Intrduction, history and develpment that minimizing was arranged in the recovery stage of anesthesia; In:Padfield NL (Ed.) Ed.; Total Intravenous Anesthesia, Butterworth Heinemann, Oxford 2000].
Except tranquilizer and narcotic effect, Propofol also has a series of other biology and medical use.For example; It is reported that it is once as Bendectin [McCollum JSC etc., Anesthesia 43 (1988) 239], epilepsy sick medicine [Chilvers CR, Laurie PS; Anesthesia 45 (1990) 995] and antipruritic [Borgeat etc., Anesthesiology 76 (1992) 510].Be lower than HD, can typically observing antiemetic and antipruritic effect when promptly the plasma concns that reaches of Propofol is lower than the dosage of calm and the desired concentration of anesthesia.On the other hand, in the plasma concns scope of broad, can observe antiepileptic activity [Borgeat etc., Anesthesiology 80 (1994) 642].Reported that also the short period of time intravenous injection is lower than Propofol ten minutes effective [Krusz JC etc., Headache, 40 (2000) 224-230] aspect migraine of treating refractory and non-migraine of anaesthesia dosage.Infer that further Propofol can be used as anxiolytic [Kurt etc.; Pol.J.Pharmacol.55 (2003) 973-7], neuroprotective drug [Velly etc.; Anesthesiology 99 (2003) 368-75] and muscle relaxant [O ' Shea etc., J.Neurosci.24 (2004) 2322-7], and because it has antioxidant property in living things system; Thereby can be further used for treating the especially inflammation at respiratory tract position of inflammation, the nerve injury relevant with nerve degeneration or wound with treatment.These illnesss are considered to oxygen production relevant, therefore can treat with inhibitor.For example, referring to the USP 6,254,853 of Hendler etc.
Propofol typically is mixed with oil-in-water emulsion and is used for clinical application.Said preparation has limited preservation period, and responsive to bacterium and fungal contamination, and said bacterium and fungal contamination cause postoperative infection [Bennett SN etc., N Engl J Med 333 (1995) 147].Because said preparation is dense white, can not at first detect the pollution of bacterium or fungi through the visual inspection bottle.
Propofol not only is insoluble in water, and causes pain in the injection site, must alleviate [Dol in SJ usually with local anaesthetics; Drugs and pharmacology, In:N.Padfield, Ed.Total Intravenous Anesthesia; Butterworth Heinemann, Oxford 2000].Because its preparation is a liplid emulsions, so intravenously administrable also causes the disadvantageous hypertriglyceridemia to the patient, the patient [Fulton B. and Sorkin EM, Drugs 50 (1995) 636] of acceptance transfusion especially over a long time.It is shared that the preparation of liplid emulsions more is difficult to other medicine it.Any physical change of said preparation, as fat drip the size variation, can both cause medicine pharmacological property change and cause spinoff, like pulmonary infarction.
As if according to further, the anesthesia induction purposes of Propofol is relevant with apneic high incidence, and this depends on dosage, injection rate and premedicate [Reves JG; Glass, PSA, Lubarsky DA; Nonbarbiturate intravenous anesthetics.In:R.D.Miller etc., Eds, the 5th edition Churchill Livingstone of Anesthesia.; Philadephia, 2000].The breathing consequence of using the Propofol of anesthesia induction dosage comprises that tolerance reduces and breathlessness, and [Bryson etc., Drugs 50 (1995) 520] take place in up to 83% patient for this.Also the Propofol of known inductive dose has significant ypotension effect, and this effect is dosage and plasma concentration-dependent [Reves etc. see on].The ypotension relevant with the peak plasma behind the bolus injection Propofol requires to use controlled infusion pump or inductive bolus injection dosage is dispersed into some little dosage that increase progressively sometimes.And inductive bolus injection dosage can cause unconsciousness in short-term, and this makes Propofol only be suitable for simple treatment.For above-mentioned reasons, Propofol is used to anaesthetize induces and/or keeps generally and must under the situation that the patient is kept watch on by the narcology expert, use, and it has been generally acknowledged that because non-narcotic expert uses the revocable or daily state of an illness is inappropriate.
Except its inducing of being used to anaesthetize with keeping, Propofol also once successfully was used for the part or the regional anesthesia of conscious patient as sedative.Its sedative properties is ground-breaking to be used for making conscious patient to feel uneasy diagnosis aspect such as colonoscopy or imaging operation.Propofol also Ceng Zuowei calmness is used to accept image-forming diagnose or radiocurable children.Nearest development is the calmness that Propofol is used for patient's control.This skill more patient is liked and is the same effective with the calmness of anesthesia expert enforcement.
Compare with tranquilizer midazolam or other similar agents of widespread use; Measure its sedative quality and/or patient and be in time of enough level of sedation; Propofol provides similar or better sedation effect [referring to Fulton B and Sorkin EM, Drugs 50 (1995) 636].Make it become the tranquilizer that the replacement of attraction other medicines are arranged with the recovery faster that Propofol interrelates with similar or less amnesia, especially for only requiring short period of time sedative patient.Yet,, also confirm well so Propofol is used for the long-time sedative patient's of needs method because present propofol formulations has the possibility that causes hyperlipidaemia to develop the tolerance to its sedation effect with being prone to.
Because the oral administration biaavailability that it is very low it has been generally acknowledged that Propofol is not suitable for other administering mode except administered parenterally at the commercial preparation that gets, and generally must intravenous injection or input.When Propofol when vein gives under clinical setting; Suggestion can be used for certain indication through other non-oral route, for example through using the sprays inhalation, through the epithelial mucosa delivery of upper digestive tract; Perhaps with the suppository form rectal administration [referring to; Cozanitis for example, D.A. etc., Acta Anaesthesiol.Scand.35 (1991) 575-7; And referring to U.S. patent 5,496,537 and 5,288,597].Yet the low bioavailability of Propofol through except the alternate manner administration of intravenous route the time limited the development of said treatment.
The water-soluble prodrug of some Propofols has been described among U.S. Pat 6254853, the US6204257.Their proposition possibly be directed against still unsatisfied needs so far, and explores the advantage that water-soluble propofol prodrugs uses as active drug.
Summary of the invention:
The object of the present invention is to provide first phosphorus propofol disodium hydrate and preparation method thereof and purposes, this hydrate not only is prone to absorb, purity is high, good stability, and can realize suitability for industrialized production.
Another object of the present invention provides a kind of medical composition and its use of first phosphorus propofol disodium hydrate.
The structural formula of first phosphorus propofol disodium hydrate is as follows:
The preparation method of first phosphorus propofol disodium hydrate is: in the container that first phosphorus propofol disodium is housed, add 1 to 10 times of water gaging, methyl alcohol or ethanol, stirring and dissolving.Add the one-component that contains Virahol, acetone of 2 to 50 times of amounts or the solution of a plurality of components again, heated and stirred, cooling crystallization 2 hours～24 hours; Filter; The gained solid is with cold isopropanol or cold acetone washing, and 30 ℃～65 ℃ dry down, promptly gets first phosphorus propofol disodium hydrate.
Recrystallization solvent described in the above-mentioned preparation method is Virahol-acetone-water system, Virahol-acetone-pure system or Virahol-aqueous systems, and different recrystallisation solvent systems can obtain containing the compound of different crystal water.
In the first phosphorus propofol disodium hydrate pharmaceutical composition of the present invention; First phosphorus propofol disodium hydrate weight content is 0.01-99%; Wherein preferred per unit preparation (as every, every bottle, every bag) contains first phosphorus propofol disodium hydrate 50mg-3000mg; Preferred 100mg-1500mg, more preferably 250mg-1000mg.
The pharmaceutical composition of first phosphorus propofol disodium hydrate of the present invention can be with the unit dosage form administration, and route of administration can be enteron aisle or non-enteron aisle, like oral, muscle or nasal cavity etc.
The pharmaceutical composition route of administration of first phosphorus propofol disodium hydrate of the present invention can be the vein form administration.Injection comprises intravenous injection, subcutaneous injection, intramuscular injection or acupoint injection therapy etc.
Form of administration can be pharmaceutically acceptable preparations such as tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder.
The preparation method of first phosphorus propofol disodium hydrate infusion preparation of the present invention and injection mixes first phosphorus propofol disodium hydrate and water for injection; Perhaps with the vein acceptable auxiliary; After osmotic pressure regulator, pH regulator agent mixing; Mix with water for injection again, realize obtaining through following step:
A. first phosphorus propofol disodium hydrate is added the dissolving of injection water, add or do not add the medicine acceptable carrier and mix.
B. adjust pH;
C. filter;
D. embedding;
E. sterilization.
Described osmotic pressure regulator is selected from glucose, sodium-chlor, Repone K, borax or their compsn.
Said pH regulator agent is selected from organic acid or mineral acid example hydrochloric acid, sulfuric acid, lactic acid, phosphoric acid, Citric Acid, amino acid etc.
The preparation method of first phosphorus propofol disodium hydrate freeze-dried powder contains following a few step:
A. first phosphorus propofol disodium hydrate is added the dissolving of injection water, add or do not add caffolding agent or stablizer;
B. adjust pH;
C. depyrogenation;
D. degerming;
E. embedding;
F. freeze-drying.
Said caffolding agent is selected pharmaceutically acceptable caffolding agent, preferred glucose, sodium-chlor, lactose, gelatin hydrolysate, N.F,USP MANNITOL, amino acid etc. or their compsn.
Described pH value regulator organic acid, mineral acid or acidic buffer salt system, example hydrochloric acid, sulfuric acid, lactic acid, Hydrocerol A, amino acid, acetic acid, oxysuccinic acid, toxilic acid, citric acid-sodium citrate damping fluid, acetic acid-sodium acetate buffer system.
First phosphorus propofol disodium hydrate of the present invention has kept it water-soluble than its no hydrate, and because agent of low hygroscopicity has the handlability of unexpected improvement, this makes it can be used for oral and parenteral admin.
First phosphorus propofol disodium hydrate shows the thick handlability of improving than no hydrate in preparation and compacting (compression behavior) in addition, thereby is applicable to solid preparation,
First phosphorus propofol disodium hydrate also shows better solid-state stability.The solid-state stability here refers at environment and/or quickens the API stability under the condition of storage.For example, first phosphorus propofol disodium hydrate has lower water absorbability than anhydride.
The compsn of first phosphorus propofol disodium hydrate of the present invention can be used for preparing the medicine of anesthesia, with the narcotic in operating.
Below in conjunction with embodiment the present invention is done further detailed description, but should understand the scope of the non-embodiment of only limiting to of scope of the present invention.
Embodiment:
Embodiment 1: the preparation of first phosphorus propofol two sodium trihydrates
First phosphorus propofol disodium 300g puts in the container, adds the water dissolution of 600ml, stirs to add 6000ml Virahol/acetone (8: 1) down; Stirring is warming up to 60 ℃, insulated and stirred 20 minutes, and solution is placed crystallization 8 hours in 5 ℃ after being cooled to room temperature; Filter; The gained solid washs with cold isopropanol, 50 ℃ of dryings 6 hours, first phosphorus propofol two sodium trihydrate 212g.
The crystal water number is measured:
Method 1: thermogravimetric is measured, and the content of crystal water is 14.1%, and is very identical with the theoretical water cut of 3 molecular crystal water, and promptly these article contain 3 molecular crystal water.
Method 2: moisture determination: karl Fischer method, moisture determination amount are 13.9%, and be very identical with the theoretical water cut of 3 molecular crystal water, and promptly these article contain 3 molecular crystal water.
The mensuration of related substance: adopt high-efficient liquid phase technique, recording related substance is 0.12%;
Determination on content: adopt the perchloric acid titration method, measuring content is 99.7%.
Embodiment 2: the preparation of first phosphorus propofol disodium duohydrate
First phosphorus propofol disodium 300g puts in the container, adds 90% dissolve with methanol of 600ml, stirs to add 6000ml Virahol/acetone (1: 1) down; Stirring is warming up to 60 ℃, insulated and stirred 20 minutes, and solution is placed crystallization 8 hours in 5 ℃ after being cooled to room temperature; Filter; The gained solid washs with cold isopropanol, 50 ℃ of dryings 8 hours, first phosphorus propofol disodium duohydrate 228g.
The crystal water number is measured:
Method 1: thermogravimetric is measured, and the content of crystal water is 9.7%, and is very identical with the theoretical water cut of 2 molecular crystal water, and promptly these article contain 2 molecular crystal water.
Method 2: moisture determination: karl Fischer method, moisture determination amount are 10.1%, and be very identical with the theoretical water cut of 2 molecular crystal water, and promptly these article contain 2 molecular crystal water.
The mensuration of related substance: adopt high-efficient liquid phase technique, recording related substance is 0.21%;
Determination on content: adopt the perchloric acid titration method, measuring content is 99.6%.
Embodiment 3: the preparation of first phosphorus propofol two sodium-hydrates
First phosphorus propofol disodium 300g puts in the container, adds 95% dissolve with ethanol of 800ml, stirs to add 5500ml Virahol/acetone (1: 5) down; Stirring is warming up to 60 ℃, insulated and stirred 20 minutes, and solution is placed crystallization 8 hours in 5 ℃ after being cooled to room temperature; Filter; The gained solid washs with cold isopropanol, 55 ℃ of dryings 24 hours, first phosphorus propofol two sodium-hydrate 198g.
The crystal water number is measured:
Method 1: thermogravimetric is measured, and the content of crystal water is 5.2%, and is very identical with the theoretical water cut of 1 molecular crystal water, and promptly these article contain 1 molecular crystal water.
Method 2: moisture determination: karl Fischer method, moisture determination amount are 5.3%, and be very identical with the theoretical water cut of 1 molecular crystal water, and promptly these article contain 1 molecular crystal water.
The mensuration of related substance: adopt high-efficient liquid phase technique, recording related substance is 0.13%;
Determination on content: adopt the perchloric acid titration method, measuring content is 99.7%.
Embodiment 4: the preparation of first phosphorus propofol disodium tetrahydrate
First phosphorus propofol disodium 300g puts in the container, adds the water dissolution of 600ml, stirs to add the 6000ml Virahol down; Stirring is warming up to 60 ℃, insulated and stirred 20 minutes, and solution is placed crystallization 8 hours in 5 ℃ after being cooled to room temperature; Filter; The gained solid washs with cold isopropanol, 40 ℃ of dryings 6 hours, first phosphorus propofol disodium tetrahydrate 186g.
The crystal water number is measured:
Method 1: thermogravimetric is measured, and the content of crystal water is 17.8%, and is very identical with the theoretical water cut of 4 molecular crystal water, and promptly these article contain 4 molecular crystal water.
Method 2: moisture determination: karl Fischer method, moisture determination amount are 17.6%, and be very identical with the theoretical water cut of 4 molecular crystal water, and promptly these article contain 4 molecular crystal water.
The mensuration of related substance: adopt high-efficient liquid phase technique, recording related substance is 0.21%;
Determination on content: adopt the perchloric acid titration method, measuring content is 99.48%.
Embodiment 5: the preparation of injection first phosphorus propofol disodium
Prescription:
The water for injection that in liquid dispensing container, adds 2000ml adds first phosphorus propofol two sodium trihydrates of accurate recipe quantity, stirs and makes dissolving; Slowly add Citric Acid, transferring pH is 8.5, mends and adds water to full dose; The Medicinal Charcoal that adds 0.05% (W/V) then; Stirred 60 minutes, sand filtration rod coarse filtration is taken off charcoal, and filter to clarity with the millipore filtration essence of 0.22 μ m qualified; Measure midbody content qualified after, decide loading amount and be sub-packed in the cillin bottle, add half plug, sample vacuumizes-45 ℃ of pre-freezes 4 hours, maintenance vacuum tightness 10-30Pa slowly is warming up to-20 ℃, keeps 12 hours; Slowly be warming up to 20 ℃ again, kept 4 hours, control moisture 1%, lid is rolled in tamponade.
Embodiment 6: the preparation of first phosphorus propofol disodium hydrate injection liquid
Prescription:
The water for injection that in liquid dispensing container, adds 4500ml adds first phosphorus propofol two sodium trihydrates of accurate recipe quantity, stirs and makes dissolving; Slowly add Citric Acid, transferring pH is 8.5, mends and adds water to full dose; The Medicinal Charcoal that adds 0.05% (W/V) then; Stirred 60 minutes, sand filtration rod coarse filtration is taken off charcoal, and filter to clarity with the millipore filtration essence of 0.22 μ m qualified; After mensuration midbody content is qualified, decide the loading amount embedding.
Embodiment 7: the preparation of first phosphorus propofol disodium hydrate sodium-chlor transfusion
Prescription:
Take by weighing the first phosphorus propofol disodium tetrahydrate and the sodium-chlor of recipe quantity, add injection water 9.5L, stir; Using Citric Acid to transfer pH is 7.0, mends and adds water to full dose, in above-mentioned solution, adds 0.1% gac, stirs, and places 15 minutes, and 5 microns titanium rods take off charcoal, filters through 0.45 micron of filter cartridge and 0.22 micron millipore filtration essence again; Embedding is in the 100ml glass infusion bottle, and 115 ℃ of flowing steams were sterilized 30 minutes, promptly gets the transfusion of first phosphorus propofol disodium tetrahydrate sodium-chlor.
Embodiment 8:: the preparation method of first phosphorus propofol disodium hydrate sheet
Prescription:
Method for making: prepare 4% Vltra tears (E-30) solution, subsequent use.Taking by weighing 30g starch, to put 105 ℃ of dryings 5 hours subsequent use.Take by weighing first phosphorus propofol two sodium trihydrates, the Microcrystalline Cellulose of 90g starch and recipe quantity, mixing was pulverized 80 mesh sieves., granulate with 20 mesh sieves, material system softwood with 4% Vltra tears (E-30) solution in 50-60 ℃ of moisture content about 3% that is dried in the particle.Cross the whole grain of 20 mesh sieves, add dry starch (105 ℃ drying 5 hours), the magnesium stearate of recipe quantity, mix eventually, survey midbody content, stator is heavy; Compressing tablet.
Embodiment 9: the effect experiment of first phosphorus propofol two sodium trihydrates in test dog surgical operation:
Method: 13 experimental dogs are all done out laparoscopic surgery.Art preceding 24 little fasting water.Skin clean is handled, the belly preserved skin.The amount of intravenous drip first phosphorus propofol two sodium trihydrate 30mg/kg is breathed after the anesthesia onset and is slowed down, and limb activity reduces gradually and even disappears, and eyeball is fixing blunt in fading away with corneal reflex.Carry out trachea cannula rapidly.
Anaesthetic effect evaluation index: limb action, nociceptive reflex and eye situation etc. that animal is observed in the injection back; Understand depth of anesthesia, record anesthesia onset time, single dose anesthesia are held time, repeated doses is held time, the evaluation index of multiplicity and animal anaesthetic effects such as death condition in test.
Statistical analysis: adopt SPSS13.0 software that data are analyzed.
The result: (body weight 18.7 ± 2.3kg) all adopts Compound C anesthesia to 13 experimental dogs, carries out carrying out the part operation around laparotomy and the biliary tract.Onset time (30 ± 5) s, initial dose hold time (16.4 ± 3.9) minute, operating time (61.1 ± 15.9) minute, repeat administration 3.7 times, repeated doses hold time (13.1 ± 3.5) minute.Experimental dog does not have the tractive reaction in the operation, and degree of flaccid muscles is satisfied, and anaesthetic effect is steady, and no heartbeat stops to wait the anesthesia emergency situation to occur.Postoperative recovery time 5-15 minute, the back test dog that revives has no adverse reaction, and the mental status is good, recovers autonomous respiration and autonomic activities, survival rate 100% at once.The survival time all reaches requirement of experiment behind the experimental dog.
Embodiment 10: first phosphorus propofol two sodium trihydrates and first phosphorus propofol disodium anhydride Journal of Sex Research steady in a long-term
Test-results for a long time keeps sample
Claims (10)
1. first phosphorus propofol disodium hydrate, the chemical structural formula of said first phosphorus propofol disodium hydrate is as follows:
2. a pharmaceutical composition is characterized in that, the active ingredient that said compsn contains is the described first phosphorus propofol of claim 1 disodium hydrate, and weight content is 0.01～99%.
3. compsn according to claim 2 is characterized in that, said compsn is a non-intestinal drug delivery agent.
4. compsn according to claim 2 is characterized in that, said compsn is an oral Preparation.
5. compsn according to claim 3 is characterized in that, described non-intestinal drug delivery agent is infusion preparation, injection, injection powder pin.
6. compsn according to claim 4 is characterized in that, described oral Preparation is tablet, dispersible tablet, capsule, granule or oral liquid.
7. according to the described compsn of claim 2-6, it is characterized in that, contain first phosphorus propofol disodium hydrate 50～3000mg in each unit package of said composite preparation.
8. according to of the application of the said pharmaceutical composition of claim 2 at the preparation anaesthetic.
9. a preparation method who prepares first phosphorus propofol disodium hydrate is: in the container that first phosphorus propofol disodium is housed, add 1 to 10 times of water gaging, methyl alcohol or ethanol, stirring and dissolving.Add the one-component that contains Virahol, acetone of 2 to 50 times of amounts or the solution of a plurality of components again, heated and stirred, cooling crystallization 2 hours～24 hours; Filter; The gained solid is with cold isopropanol or cold acetone washing, and 30 ℃～65 ℃ dry down, promptly gets first phosphorus propofol disodium hydrate.
10. according to the preparation method of the said first phosphorus propofol of claim 9 disodium hydrate, its recrystallization solvent is Virahol-acetone-water system, Virahol-acetone-pure system or Virahol-aqueous systems.
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| CN2011102263794A CN102351895A (en) | 2011-08-08 | 2011-08-08 | Fospropofol disodium hydrate, preparation method and purpose thereof |
| CN2012100785188A CN102633831A (en) | 2011-08-08 | 2012-03-13 | Methyl phosphorus propofol disodium dihydrate and preparation method and application thereof |
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| CN2012100785188A Pending CN102633831A (en) | 2011-08-08 | 2012-03-13 | Methyl phosphorus propofol disodium dihydrate and preparation method and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102579328A (en) * | 2012-02-27 | 2012-07-18 | 黄剑锋 | Pharmaceutical composition for injection |
| CN102633831A (en) * | 2011-08-08 | 2012-08-15 | 陕西合成药业有限公司 | Methyl phosphorus propofol disodium dihydrate and preparation method and application thereof |
| CN103172658A (en) * | 2011-12-26 | 2013-06-26 | 宜昌人福药业有限责任公司 | Prodrug crystal form suitable for medicine, preparation method and pharmaceutical composition |
| WO2017205632A1 (en) * | 2016-05-27 | 2017-11-30 | The Johns Hopkins University | Buccal, sublingual and intranasal delivery of fospropofol |
| US11439653B1 (en) | 2021-03-30 | 2022-09-13 | Epalex Corporation | Fospropofol formulations |
| US11478490B1 (en) | 2021-03-30 | 2022-10-25 | Epalex Corporation | Fospropofol formulations |
| US11547714B2 (en) | 2020-02-05 | 2023-01-10 | Epalex Corporation | Fospropofol salts, methods and compositions |
| US11628178B2 (en) | 2019-03-26 | 2023-04-18 | Epalex Corporation | Fospropofol methods and compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2058320B1 (en) * | 2001-12-21 | 2012-11-21 | Guilford Pharmaceuticals Inc. | Process for preparing water-soluble phosphonooxymethyl derivatives of alcohol and phenol |
| CN101845057B (en) * | 2009-03-27 | 2013-10-23 | 四川大学 | Substituted phenol for methylal phosphate anesthetic and sedative drugs and preparation method thereof |
| CN102351895A (en) * | 2011-08-08 | 2012-02-15 | 陕西合成药业有限公司 | Fospropofol disodium hydrate, preparation method and purpose thereof |
-
2011
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102633831A (en) * | 2011-08-08 | 2012-08-15 | 陕西合成药业有限公司 | Methyl phosphorus propofol disodium dihydrate and preparation method and application thereof |
| CN103172658A (en) * | 2011-12-26 | 2013-06-26 | 宜昌人福药业有限责任公司 | Prodrug crystal form suitable for medicine, preparation method and pharmaceutical composition |
| CN103172658B (en) * | 2011-12-26 | 2016-01-20 | 宜昌人福药业有限责任公司 | A kind of applicable medicinal prodrug crystal formation, preparation method and medicinal compositions |
| CN102579328A (en) * | 2012-02-27 | 2012-07-18 | 黄剑锋 | Pharmaceutical composition for injection |
| CN102579328B (en) * | 2012-02-27 | 2013-07-10 | 黄剑锋 | Pharmaceutical composition for injection |
| WO2017205632A1 (en) * | 2016-05-27 | 2017-11-30 | The Johns Hopkins University | Buccal, sublingual and intranasal delivery of fospropofol |
| US11331271B2 (en) | 2016-05-27 | 2022-05-17 | The Johns Hopkins University | Buccal, sublingual and intranasal delivery of fospropofol |
| US11628178B2 (en) | 2019-03-26 | 2023-04-18 | Epalex Corporation | Fospropofol methods and compositions |
| US11547714B2 (en) | 2020-02-05 | 2023-01-10 | Epalex Corporation | Fospropofol salts, methods and compositions |
| US11439653B1 (en) | 2021-03-30 | 2022-09-13 | Epalex Corporation | Fospropofol formulations |
| US11478490B1 (en) | 2021-03-30 | 2022-10-25 | Epalex Corporation | Fospropofol formulations |
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Open date: 20120215 |