CN103948571A - Water-soluble ibuprofen prodrug with high skin penetration rate and positive charge - Google Patents

Water-soluble ibuprofen prodrug with high skin penetration rate and positive charge Download PDF

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CN103948571A
CN103948571A CN201310738823.XA CN201310738823A CN103948571A CN 103948571 A CN103948571 A CN 103948571A CN 201310738823 A CN201310738823 A CN 201310738823A CN 103948571 A CN103948571 A CN 103948571A
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carbon atom
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structural formula
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ibuprofen
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于崇曦
徐丽娜
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TIANJIN XINCHEN TAIFEIER PHARMACEUTICAL TECHNOLOGY Co Ltd
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TIANJIN XINCHEN TAIFEIER PHARMACEUTICAL TECHNOLOGY Co Ltd
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Abstract

The invention relates to a water-soluble ibuprofen prodrug with high skin penetration rate and positive charges. The invention discloses the application of a compound shown in a structural formula 1 to preparation of a medicament suitable for transdermal delivery and for treating the conditions that can be treated by ibuprofen, and the application of the compound shown in the structural formula 1 to preparation of an aerosol medicament for treating asthma. The invention also discloses the application of a pharmaceutical composition for transdermal delivery and containing the compound shown in the structural formula 1, the application thereof to preparation of a medicament suitable for transdermal delivery and for treating the conditions that can be treated by ibuprofen, and the application of the pharmaceutical composition to preparation of an aerosol medicament for treating asthma. The invention also discloses a transdermal therapeutic system, which comprises the compound shown in the structural formula 1 or its composition, and a usage method of the transdermal therapeutic system.

Description

There is the positively charged water-soluble prodrugs of ibuprofen of fast skin penetration rate
Division statement
The application is that the application number of submitting on July 18th, 2006 is the divisional application that 200680055379.X, denomination of invention are the Chinese patent application of " with the water-soluble prodrugs of ibuprofen of positive charge ".
Technical field
The present invention relates to the medicable state of any ibuprofen that the water-soluble prodrug with positive charge of 2-(to isobutyl phenenyl) propanoic acid (ibuprofen) and they are applied to treatment human or animal in medical treatment.Specifically, the present invention is the side effect that uses ibuprofen to bring in order to overcome.These prodrugs can pass through oral or transdermal administration.
Technical background
Ibuprofen is a kind of propionic non-steroid AID.Ibuprofen in 1964 by synthetic (J.S.Nicholson and S.S.Adams, Br.Patent No.971,700) first and first in Europe as drug use.In antiinflammatory and the biosynthetic experiment of inhibition prostaglandin, ibuprofen is more effective than aspirin." PDR Generics " (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 243) enumerated the multiple medical application of ibuprofen.Ibuprofen can be used for alleviating the symptom of rheumatic arthritis and osteoarthritis, brings down a fever, and treatment dysmenorrhea.Ibuprofen can be treated Bartter syndrome and chronic anterior uveitis and posterior uveitis separately or as adjuvant.It also can be used for the metrorrhagia that intrauterine device causes, prevents and prevents that patient from causing nausea, vomitting in the time accepting pelvis radiotherapy.Ibuprofen also can be used for diabetic neuropathic disease, acute migraine, and for hemophilic arthosis.Ibuprofen also can be used for treating bone loss (Jee; Webster S.S.U.S.Pat.No.5,604,259), prevention or treatment sunburn (Sunshine:Abraham.U.S.Pat.No.5,100,918).
But, use ibuprofen can cause many side effect, topmost have gastrointestinal upset as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer, and gastritis.Fishman (Fishman; Robert, U.S.Pat.No.7,052,715) point out that another problem of following oral medication to produce is pain or the inflammation producing in order effectively to treat remote location, the concentration of medicine in blood circulation must be very high.These concentration are often required far above the reality of the direct targeting pain of hypothesis medicine energy or injury.The people such as Fishman (Van Engelen et al.U.S.Pat.No.6,416,772; Macrides et al.U.S.Pat.No.6,346,278; Kirby et al.U.S.Pat.No.6,444,234, Pearson et al.U.S.Pat.No.6,528,040, and Botknecht et al.U.S.Pat.No.5,885,597) attempted being used for transdermal administration by the mode developing drugs transmission system of preparation.But, be difficult to make the plasma concentration of ibuprofen to reach effective treatment level by the mode of preparation.Susan Milosovich etc. has designed and synthesized 4-dimethylaminobutyricacid acid testosterone ester hydrochloride (TSBH), and it has a lipophilic portion and a tertiary amine structure existing with protonated form under physiological pH.They find that the transdermal speed of this prodrug (TSBH) is nearly 60 times of female medicine (TS) itself.[Susan?Milosovich，et?al.，J.Pharm.Sci.，82，227(1993)]。
Summary of the invention
Technical problem
Ibuprofen was as medicinal more than 30 year, and it is better than aspirin in effect aspect antiinflammatory and the inhibition of prostaglandin biosynthesis.Ibuprofen can be used for alleviation and treats the symptom of rheumatoid arthritis and osteoarthritis, alleviates light moderate pain, bring down a fever and treat dysmenorrhea.Ibuprofen can be treated bartter syndrome and chronic anterior uveitis and posterior uveitis separately or as adjuvant.Ibuprofen also can be used for diabetic neuropathic disease, acute migraine, and for hemophilic arthosis.It also can be used for the metrorrhagia that intrauterine device causes, prevents and prevents that patient from causing nausea, vomitting in the time accepting pelvis radiotherapy.
But, use ibuprofen can cause many side effect, topmost have gastrointestinal upset as dyspepsia, heartburn, vomiting, stomach and duodenal hemorrhage, gastric ulcer and gastritis.The stomach that ibuprofen causes and duodenal hemorrhage are normally painless, but can cause that stool is hemorrhage and cause lasting iron deficiency anemia.
Solution
The present invention relates to the novel prodrugs of ibuprofen of positive charge and their medical application.These prodrugs have the structure of general formula (1) " structural formula 1 ", and structural formula 1 is as follows:
In structural formula 1, R 1represent H, the thiazolinyl of the alkyl that contains 1-12 carbon atom, the alkoxyl of a 1-12 carbon atom, a 1-12 carbon atom, the alkynyl of a 1-12 carbon atom, or aryl; R 2represent H, the alkyl that contains 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; R 3represent H, the alkyl that contains 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; X represents O, S or NH; A -represent Cl -, Br -, F -, l -, AcO -, citrate or other anion; N=0, all R bases of 1,2,3,4,5,6,7,8,9,10...... can comprise C, H, O, S, N atom, and can contain singly-bound, two key and triple bond.Any CH 2group all can be by O, S, or NH replaces.
No matter medicine is to absorb through gastrointestinal tract or by other position, all need to stride across barrier film with molecular forms.First medicine need dissolve, and if medicine there is desirable biopharmacy characteristic, the region that its can be from the regional diffusion of high concentration to low concentration, strides across biomembrane and enters blood or systemic circulation system.All biomembranes all contain lipid as Main Ingredients and Appearance.In biofilm structure active molecule all have the head construction that contains phosphatic high polarity and, in most of the cases, two highly hydrophobic hydrocarbon tail chains.Biomembrane has double-decker, and hydrophilic head structure is towards the water region of both sides.Very hydrophilic medicine cannot be by through biomembranous lipid layer, very hydrophobic medicine stops wherein as a biomembranous part because of the reason of similar compatibility, thereby can not effectively enter inner Cytoplasm.
The object of the invention is, by improving dissolubility and the raising ibuprofen penetrance to biomembrane and skin barrier of ibuprofen in gastric juice, to make it can pass through transdermal administration (external), thereby avoid the side effect of ibuprofen.The novel prodrugs of these ibuprofen has two identical construction featuress: they have a lipophilic part (oil-soluble part) and an one-level that protonated form exists under physiological pH condition, secondary, or tertiary amine group (water-soluble portion).Water-soluble-oily molten balance is like this that medicine is effectively through barrier film necessary [Susan Milosovich, et al., J.Pharm.Sci., 82,227 (1993)].Greatly increased the dissolubility of medicine with the amino of positive charge.2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate and the dissolubility of 2-(to isobutyl phenenyl) propanoic acid (ibuprofen) in water are respectively >300mg/ml and 0.05mg/ml.In most cases, the dissolving of medicine is the step of the slowest in absorption process and maximum speed limit.The dissolubility of ibuprofen in gastric juice is very low.It rests on intestines and stomach for a long time, therefore may cause gastric mucosal cell damage.When these novel prodrugs are with such as tablet, capsule, can be dissolved in rapidly in gastric juice when the dosage form of solution or suspension is oral.Positive charge on these prodrugs amino can be combined by the negative charge on biomembranous phosphoric acid end group.Therefore, thus medicine in the very high region that contributes to these prodrugs to arrive low concentration by area with high mercury of local concentration in biomembrane outside.After these prodrugs enter into biomembrane, hydrophilic parts can promote prodrug and enter Cytoplasm, a kind of concentrated aqueous solution of semi liquid state or suspension.Because the time of staying in gastrointestinal tract is short, prodrug can not cause damage to gastric mucosal cell.
2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate and the penetrance of 2-(to isobutyl phenenyl) propanoic acid in human body skin are measured by improved Franz pond in vitro, and wherein human body skin separates human skin tissue (360-400 μ m is thick) before huckle position or below.Accepting solution contains 2% bovine serum albumin normal saline by 10ml forms and stirs with the speed of 600 revs/min.2-(to isobutyl phenenyl) propanoic acid (ibuprofen) and the transdermal accumulation total amount of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate are to measure by specific high performance liquid chromatography to the relation of time.To contain the suspension of 30%2-(to isobutyl phenenyl) propanoic acid (ibuprofen) and 2-(to isobutyl phenenyl) ethyl propionate, or 30% the solution of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate that is dissolved in the phosphate buffered saline(PBS) (0.2M) of 2ml pH7.4 as donor solution, result as shown in Figure 1, to ibuprofen, 2-(to isobutyl phenenyl) ethyl propionate (common not positively charged 2-(to isobutyl phenenyl) propionic ester), and 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate to calculate apparent penetrating value be 0.5mg, 1mg, 125mg/cm 2/ h.Presentation of results prodrug, 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate, in human body skin, diffusion velocity is than fast nearly 250 times of 2-(to isobutyl phenenyl) propanoic acid itself, than fast nearly 125 times of 2-(to isobutyl phenenyl) ethyl propionate.Normal ester, the penetration speed of 2-(to isobutyl phenenyl) ethyl propionate and 2-(to isobutyl phenenyl) propanoic acid itself be more or less the same (only 2 times of differences).Positive charge on presentation of results dialkyl amido ethyl is extremely important through biomembrane and skin barrier to medicine.Other prodrug penetrance in general formula " structural formula 1 " is very high, very approaching with 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate penetrance.
In body experiment compared 2-(to isobutyl phenenyl) propanoic acid (IBPP) and 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-lBPP) penetrate alive without hair without the penetrance of skin of hindering mice.Donor by be dissolved in 1ml isopropyl alcohol 30%2-(to isobutyl phenenyl) propanoic acid (IBPP) or 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-lBPP) solution composition.Be applied to hairless mouse back 1cm 2position.In blood plasma, the concentration of the concentration of ibuprofen and 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester is to measure with specific efficient liquid-phase chromatography method.Result (Fig. 2) is presented at the concentration using for system 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester after approximately 30 minutes and reaches peak value.Oral ibuprofen needs just can reach for 1-2 hour ibuprofen concentration peak value.The peak value of 2-(to isobutyl phenenyl) propanoic acid (ibuprofen) is about 0.2mg/ml, and the peak value of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate is about 12mg/ml (differences of approximately 60 times).In blood plasma, the 2-of about 12mg/ml (to isobutyl phenenyl) propanoic acid has exceeded 30 times more than than 2-(to isobutyl phenenyl) the propanoic acid plasma concentration that can effectively ease pain with effective antiinflammatory.This is stem-winding result.Can be easy to by these prodrugs, rapidly the 2-of effective plasma level concentration (to isobutyl phenenyl) propanoic acid be fed in host.These results show that prodrug not only can be oral, and can be used for various treatments by transdermal administration.Other prodrug in general formula " structural formula 1 " penetrance and 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate in vivo approaches.
For the stomach and the duodenal hemorrhage that check that these guiding drugs rise, we are to (two groups of rats every day, every group of 10 rats) oral 100mg/kg ibuprofen or 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate, continuous oral 21 days.We find, on average have 4mg blood, and do not find to have blood in stool in 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate group in every gram of Oletum Ratti norvegici of ibuprofen group.
Ibuprofen has been proved to be antiinflammatory, has eased pain, brings down a fever and antiheumatic effect.A good prodrug should be able to be got back to female medicine in blood plasma.The lignocaine ethyl ester group of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate can be sheared rapidly by the enzyme in human plasma in vitro, exceedes 90% prodrug and gets back to female medicine ibuprofen.Because the absorbance of prodrug is higher, the prodrug curative effect of same dose is better than ibuprofen itself.Our analgesia to 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate, brings down a fever and antiinflammatory action is tested, and compares with ibuprofen.Also other compound in mutual-through type " structural formula 1 " is tested by identical method, and the result of result and 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate is very close.
Analgesic activity: according to the method for D ' Amour-Smith (J.Pharmacol.Exp.Ther., 72,74 (1941)). measure the time expand of the mouse tail threshold of pain.The oral 200mg/kg ibuprofen of mice, after oral and transdermal administration 200mg/kg2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate, is exposed to the tail of mice in thermostimulation, measures threshold of pain time expand.Result as shown in Figure 3.The group of oral (C) and transdermal administration (D) 200mg/kg2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate demonstrates stronger analgesic activities than the group of administration 200mg/kg ibuprofen.
The writhing number of times occurring after mouse peritoneal administration acetum is counted, and calculated the suppression ratio of writhing based on matched group.42 mices are divided into 7 groups (6 every group).The mice administration ibuprofen (IBPP, 50mg/kg and 100mg/kg) of B1 and B2 group, and C1 and C2 organize oral 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-IBPP, 50mg/kg and 100mg/kg).D1 and D2 group transdermal administration 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-IBPP, 50mg/kg and 100mg/kg).A is matched group.Before 30 minutes, test compound was delivered medicine to mice at administration acetum.The results are shown in Table 1.
Table 1. ibuprofen and prodrug thereof the suppression ratio to mouse writhing
Result shows that the analgesic effect of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate is better than ibuprofen.Other compound in general formula " structural formula 1 " has shown similar analgesic activities.
Antipyretic effect: rat is accepted colibacillus deactivating suspension as pyrogen.56 rats are divided into 7 groups.A group is matched group.After 2 hours, oral administration ibuprofen (IBPP, B1 group is that 100mg/kg and B2 group are 150mg/kg), oral administration 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-IBPP, it is that 100mg/kg and C2 group are 150mg/kg that C1 organizes) and transdermal administration 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-IBPP, D1 group is that 100mg/kg and D2 organize as 150mg/kg).Before and after test compounds administration, surveyed body temperature every 90 minutes to rat.The results are shown in following table 2.
The antipyretic effect of table 2. ibuprofen and prodrug thereof
The antipyretic activity of 2-(to isobutyl phenenyl) the propanoic acid lignocaine ethyl ester acetate of result demonstration 100mg/kg dosage is better than ibuprofen.Result shows that 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate transdermal administration is better than oral administration.In general formula " structural formula 1 ", other compound has shown similar antipyretic activity.
Antiinflammatory action: to Oral Administration in Rats or transdermal administration 50mg/kg2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate, oral administration 50mg/kg ibuprofen.After 60 minutes, angle dish sol solution subcutaneous administration is arrived under the meat pad of rat claw.Within after the dish glue of administration angle every 1 hour, measure the volume of a rat hind paw, calculate rear solid end volume rate of increase and as swelling rate (%).The result obtaining as shown in Figure 4.Result shows oral and antiphlogistic effects transdermal administration 50mg/kg2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate is better than the ibuprofen of oral administration same dose.Shown in general formula " structural formula 1 ", the antiphlogistic effects of other compound is similar.
In the time of the ibuprofen of oral high dose, it can show anti-reactivity-antasthmatic effect by the activity that suppresses Cycloxygenase.Because these prodrugs have higher biomembrane permeability, thereby can treat asthma by the mode that sprays into mouth or nasal cavity.Because of their antiinflammatory action, these prodrugs can Acne treatment.
The represented compound of above-mentioned general formula (1) " structural formula 1 " can be by ibuprofen or by the functional derivative of ibuprofen, for example, the acid halide of general formula (2) " structural formula 2 " or mixed acid anhydride react to prepare with the compound of general formula (3) " structural formula 3 ".Structural formula 2 is as follows:
In structural formula 2, Y represents halogen, the aryloxy group carboxylic acid ester groups of alkoxy carbonyl group or replacement; Structural formula 3 is as follows:
In structural formula 3, R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; X represents O, S or NH; N=0,1,2,3,4,5,6,7,8,9,10......
Above-mentioned general formula 1 " structural formula 1 " represented compound can pass through coupling agent by ibuprofen and the represented compound of general formula (3) " structural formula 3 ", for example: N, N '-dicyclohexyl carbimide (DCC), N, N '-diisopropyl carbimide (DIC), O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester (HBTU), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (BOP), prepared by the coupling reaction of BTA-1-base-oxygen base-tri-(dimethylamino) phosphorus-hexafluorophosphate etc.
In the time that the X in general formula (1) " structural formula 1 " represents O, the represented compound of general formula (1) " structural formula 1 " can be reacted and be obtained by the slaine of ibuprofen or organic alkali salt compound represented with general formula (4) " structural formula 4 ".Structural formula 4 is as follows:
In structural formula 4, R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; R 3represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; Z represents halogen, or p-toluenesulfonyl; A -represent Cl -, Br -, F -, l -, AcO -, citrate or other anion; N=0,1,2,3,4,5,6,7,8,9,10......
In the time that the represented X of general formula (1) " structural formula 1 " represents O, the represented compound of general formula (1) " structural formula 1 " can be reacted and obtain with the compound shown in general formula (4) " structural formula 4 " by the salt of the fixing choline of the represented ibuprofen of general formula (5) " structural formula 5 ".Structural formula 5 is as follows:
In " structural formula 5 ", R represents crosslinked resin; B represents any basic group, as pyridine radicals, and piperidyl, triethyamino, or other basic group.
The pharmaceutical preparation of the prodrug that the present invention relates to contain the represented ibuprofen of general formula " structural formula 1 " and its typical additives, adjuvant, for example, for oral tablet, capsule or solution etc., or for solution, emulsion, ointment, latex or the gel etc. of transdermal administration.The novel active compound of general formula " structural formula 1 " can be with vitamin as vitamin A, B, C, E, beta-carotene etc., or other medicines, as folic acid, combines the treatable state of any ibuprofen that is used for the treatment of human body or animal.
Ibuprofen can show anti-reactivity-antasthmatic effect by the activity that suppresses Cycloxygenase.Owing to having very high membranes penetration rate, thereby these prodrugs can be treated asthma by the mode that sprays into mouth or nasal cavity.
Because of their antiinflammatory action, these prodrugs also can be used for the treatment of acne and other dermatosiss.They also can be used for treatment and prevention endothelial function disturbance.
These prodrugs are water miscible neutral salt, and eye better tolerance.They can be used for treating eye inflammation, the ocular pain after treatment operation on cornea, treatment glaucoma or treatment ear's inflammation and/or pain status (otitis).
Skin-penetrating therapeutic application system, the compound that contains the compound of general formula (1) " structural formula 1 " expression or contain at least one general formula (1) " structural formula 1 " expression, as the compositions of active component, can be used for treating the medicable state of any ibuprofen in human or animal.These systems can be binder or paster, the protective layer that it contains a hypothallus that comprises active substance and a non-infiltration.Most preferred system is an active substance reservoir, contains a permeable bottom towards skin.By controlling rate of release, thereby this system can make ibuprofen be stabilized in the side effect that optimal treatment blood drug level improves curative effect and reduces ibuprofen.These systems can be worn over any position of wrist, ankle joint, arm, lower limb or health.
Advantage
In these prodrugs of ibuprofen, some is hydrophobicity, and another part is hydrophilic (amido existing with protonated form under physiology pH value).The amino of these prodrug positively chargeds has two large advantages.First, it has greatly improved the dissolubility of medicine; When these new prodrugs with such as tablet, capsule, solution or suspension when oral, it can be dissolved in rapidly in gastric juice.The second, the amino of these prodrug positively chargeds can with biomembranous electronegative phosphate head construction bonding.Therefore, the local concentration outside film can be very high, thereby promote medicine to see through low concentration region from area with high mercury.When these prodrugs enter into after biomembrane, hydrophilic parts enters derivation medicine in Cytoplasm, and Cytoplasm is concentrated semi liquid state aqueous solution or suspension.Because the time that these prodrugs stop in gastrointestinal tract is very short, therefore can not damage gastric mucosa.Experimental result shows that 90% prodrug can become female medicine again.These prodrugs have better absorbance, so under same dose, the curative effect of prodrug is better than ibuprofen.Experimental results show that prodrug, 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate sees through nearly 250 times soon of the speed ratio ibuprofen of human body skin itself, faster nearly 125 times than 2-(to isobutyl phenenyl) ethyl propionate.The interior penetrance of body that 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate sees through the hairless mouse skin of living is very high.Oral ibuprofen tablet after 1-2 hour ibuprofen blood drug level reach peak value, but 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate only needs just can reach for 30 minutes ibuprofen blood drug level peak value.The most exciting result is that prodrug not only can be oral, and can be by the mode of transdermal administration for any Drug therapy and can avoid most of side effect of ibuprofen, wherein most importantly can avoid gastrointestinal upset as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer, gastritis etc.Another large benefit of these prodrug transdermal administrations is that administration is more prone to, particularly to child's administration.
Brief description of the drawings
Fig. 1: by 2-(to the isobutyl phenenyl) propanoic acid (IBPP) of the human skin tissue of separation in Franz pond (n=5), the total amount of 2-(to isobutyl phenenyl) ethyl propionate (E-IBPP) and 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-IBPP).IBPP and E-IBPP are 30% suspension.DEAE-IBPP is 30% solution.In various situations, its medium is pH7.4 phosphate buffer solution (0.2M).
Fig. 2: to the local total blood drug level that uses 1ml30%2-(to isobutyl phenenyl) propanoic acid (IBPP) or rear 2-(to the isobutyl phenenyl) propanoic acid (IBPP) of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate (DEAE-lBPP) in hairless mouse (n=5) back.
Fig. 3: at oral 200mg/kg ibuprofen (B), after oral (C) and transdermal administration (D) 200mg/kg2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate, mouse tail threshold of pain time expand.A is matched group.
Fig. 4: the swelling rate (%) after the dish glue of injection angle.Angle dish glue is injected first 1 hour oral 50mg/kg ibuprofen (B), oral (C) and transdermal administration (D) 50mg/kg2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate.A is matched group.
Fig. 5: structural formula 1: wherein, R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; R 3represent H, the alkyl of any 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl; X represents O, S or NH; A -represent Cl -, Br -, F -, l -, AcO -, acetylsalicylate, citrate, or other anion; N=0, all R bases of 1,2,3,4,5,6,7,8,9,10...... can comprise C, H, O, S, N atom, and can contain singly-bound, two key and triple bond.Any CH 2group all can be by O, S, or NH replaces.
Optimum enforcement
Synthesizing of 2-(to isobutyl phenenyl) propanoic acid lignocaine ethyl ester acetate
22.5g (0.1mol) 2-(to isobutyl phenenyl) propionyl chloride is dissolved in the chloroform of 100ml.Mixture is cooled to 0 DEG C.Add 15ml triethylamine and 11.7g N, N-diethylaminoethanol.Mixture at room temperature stirs 3 hours.Solids removed by filtration by-product, and wash three times with 30ml chloroform.In chloroformic solution, stir and add 6g acetic acid.Boil off organic solvent.After dry, obtain 35g moisture absorption target product, productive rate is 92%.Dissolubility in water: 400mg/ml; Elementary analysis: C 21h 35n0 4; Molecular weight: 365.51.Theoretical value (%) C:69.01; H:9.65; N:3.83; O:17.51; Measured value (%) C:68.98; H:9.68; N:3.82; O:17.52. 1h-NMR (400MHz, deuterochloroform solvent): δ: 1.10 (d, 6H), 1.52 (d, 3H), 1.56 (t, 6H), 2.21 (s, 3H), 2.22 (m, 1H), 2.51 (d, 2H), 3.28 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), (7.07 d, 2H).
Embodiment
Synthesizing of 2-(to isobutyl phenenyl) propanoic acid dimethylaminoethyl acetate
22.5g (0.1mol) 2-(to isobutyl phenenyl) propionyl chloride is dissolved in 100ml chloroform.Mixture is cooled to 0 DEG C.Add 15ml triethylamine and 8.9g dimethylaminoethanol.Mixture at room temperature stirs 3 hours.In reactant mixture, stir and add 6g acetic acid.Solids removed by filtration by-product, and wash each 30ml three times with chloroform.Boil off organic facies.After dry, obtain 31g moisture absorption target product, productive rate is 92%.Dissolubility in water: 400mg/ml; Elementary analysis: C 19h 31nO 4; Molecular weight: 337.45.Theoretical value %C:67.63; H:9.26; N:4.15; O:18.96; Measured value %C:67.60; H:7.28; N:4.14; O:18.98. 1h-NMR (400MHz, deuterochloroform solvent): δ: 1.01 (d, 6H), 1.52 (d, 3H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 2.90 (s, 6H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).
Synthesizing of 2-(to isobutyl phenenyl) propanoic acid dimethylamino second thioesters acetate
22.5g (0.1mol) 2-(to isobutyl phenenyl) propionyl chloride is dissolved in the chloroform of 100ml.Mixture is cooled to 0 DEG C.In reactant mixture, stir and add 15ml triethylamine and 9.3g dimethylamino ethyl mercaptan.Mixture stirring at room temperature 3 hours.In reactant mixture, stir and add 6g acetic acid.Solids removed by filtration by-product, and wash three times with 30ml chloroform.Boil off organic facies.After dry, obtain 32g moisture absorption target product, productive rate is 90.5%.Dissolubility in water: 300mg/ml; Elementary analysis: C 19h 31n0 3s; Molecular weight: 353.52.Theoretical value (%) C:64.55; H:8.84; N:3.96; O:13.58, S:9.07; Measured value (%) C:64.52; H:8.86; N:3.95; O:13.62; S:9.05. 1h-NMR (400MHz, deuterochloroform solvent); δ: 1.01 (d, 6H), 1.52 (d, 3H), 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 2.90 (s, 6H), 3.31 (t, 2H), 3.81 (t, 1H), 3.91 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).
Synthesizing of N-dimethylaminoethyl 2-(to isobutyl phenenyl) propionyl ammonia acetate
22.5g (0.1mol) 2-(to isobutyl phenenyl) propionyl chloride is dissolved in 100ml chloroform.Mixture is cooled to 0 DEG C.In reactant mixture, add 15ml triethylamine and 8.9g dimethylamino ethamine.Mixture at room temperature stirs 3 hours.In reactant mixture, stir and add 6g acetic acid.Solids removed by filtration by-product, and wash three times with 30ml chloroform.Boil off organic facies.After dry, obtain 30g moisture absorption target product, productive rate is 89.1%.Dissolubility in water: 300mg/ml; Elementary analysis: C 19h 32n 20 3; Molecular weight: 336.47.Theoretical value (%) C:67.82; H:9.59; N:8.33; O:14.27; Measured value %C:67.80; H:9.61; N:8.31; O:14.26. 1h-NMR (400MHz, deuterochloroform solvent): δ: 1.01 (d, 6H), 1.52 (d, 3H), 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 2.90 (s, 6H), 3.50 (t, 2H), 3.64 (t, 2H), 3.89 (m, 1H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H), 7.8 (b, 1H).
Synthesizing of 2-(to isobutyl phenenyl) propanoic acid lignocaine second thioesters acetate
20.6g (0.1mol) 2-(to isobutyl phenenyl) propanoic acid is dissolved in 100ml dichloromethane (DCM).Mixture is cooled to 0 DEG C.In reactant mixture, add 20.6g1,3-Dcci (DCC).Mixture stirs 30 minutes at 0 DEG C.In reactant mixture, add 13.4g (0.1mol) N, N-diethylamino ethanethiol.Mixture at room temperature stirs 3 hours.In reactant mixture, stir and add 6g acetic acid.Solids removed by filtration by-product, and wash three times with 50ml chloroform.Boil off organic facies.After dry, obtain 34 grams of moisture absorption target products, productive rate is 89.1%.Dissolubility in water: 300mg/ml; Elementary analysis: C 21h 35nO 3s; Molecular weight: 381.57; Theoretical value (%) C:66.10; H:9.25; N:3.67; O:12.58, S:8.40; Measured value (%) C:66.10; H:9.29; N:3.66; O:12.60, S:8.38. 1h-NMR (400MHz, deuterochloroform solvent): δ: 1.01 (d, 6H), 1.52 (d, 3H), 1.56 (t, 6H) 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 3.26 (m, 4H), 3.31 (t, 2H), 3.81 (t, 1H), 3.91 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).
Synthesizing of N-dimethylamino-propyl 2-(to isobutyl phenenyl) propionyl ammonia acetate
20.6g (0.1mol) 2-(to isobutyl phenenyl) propanoic acid is dissolved in 100ml acetonitrile.In reactant mixture, add 32.1g BTA-N, N, N ', N '-tetramethylurea tetrafluoro phosphate ester (BOP) and 30ml triethylamine.In reactant mixture, add 13.1g dimethylaminopropylamine.Mixture stirring at room temperature 3 hours.Boil off solvent.In reactant mixture, add 250ml ethyl acetate, 100ml washing three times for mixture.Organic facies anhydrous sodium sulfate drying.Remove by filter sodium sulfate.In reactant mixture, stir and add 6g acetic acid.Add 200ml hexane.Solid collected by filtration product.After dry, obtain 32g moisture absorption target product, productive rate is 91.2%.Dissolubility in water: 320mg/ml; Elementary analysis: C 20h 34n 2o 3; Molecular weight: 350.5.Theoretical value %C:68.54; H:9.78; N:7.99; O:13.69; Measured value %C:68.51; H:9.80; N:7.98; O:13.71. 1h-NMR (400MHz, deuterochloroform solvent): δ: 1.01 (d, 6H), 1.52 (d, 3H), 1.98 (m, 2H), 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 2.90 (s, 6H), 3.20 (m, 2H), 3.24 (m, 2H), 3.89 (m, 1H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H), 7.8 (b, 1H).
Synthesizing of 2-(to isobutyl phenenyl) propanoic acid dipropyl amino ethyl ester acetate
22.3g (0.1mol) 2-(to isobutyl phenenyl) sodium propionate is suspended from 180ml chloroform.In mixture, add 28.8g (0.1mol) dipropyl amino-ethyl bromine hydrogen bromide salt, reactant liquor at room temperature stirs 5 hours.In reactant mixture, stir and add 8.2g (0.1mol) sodium acetate.Mixture stirs 2 hours.Solids removed by filtration, and wash three times with 50ml chloroform.Solution for vacuum concentration is to 100ml.Then in solution, add 300ml hexane.Solid collected by filtration product, and wash three times with 100ml hexane.After dry, obtain 35g moisture absorption target product, productive rate is 88.9%.Dissolubility in water: 300mg/ml; Elementary analysis: C 23h 39n0 4; Molecular weight: 393.56.Theoretical value %C:70.19; H:9.99; N:3.56; O:16.26; Measured value %C:70.14; H:10.03; N:3.55; O:16.28. 1h-NMR (400MHz, deuterochloroform solvent): δ: 0.96 (d, 6H), data: 1.10 (d, 6H), 1.52 (d, 3H), 1.77 (m, 4H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 3.24 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).
Synthesizing of 2-(to isobutyl phenenyl) propanoic acid dipropyl amino ethyl ester acetate
The triethylamine (3mmol/g, 100-200 order) of 60g polymer cure is suspended from 180ml chloroform.In mixture, stir and add 20.6g (0.1mol) 2-(to isobutyl phenenyl) propanoic acid.In mixture, add 43g (0.15mol) dipropyl amino-ethyl bromine hydrogen bromide salt, mixture at room temperature stirs 5 hours.Remove by filter polymer, and wash three times with 50ml oxolane.In reactant mixture, stir and add 8.2g (0.1mol) sodium acetate.Mixture stirs 2 hours.Solids removed by filtration, and wash three times with 50ml chloroform.Filtrate vacuum concentration is to 100ml.In solution, add 300ml hexane.Solid collected by filtration product, and wash three times with 100ml hexane.After dry, obtain 36g moisture absorption target product, productive rate is 91.5%.Dissolubility in water: 350mg/ml; Elementary analysis: C 23h 39nO 4; Molecular weight: 393.56.Theoretical value %C:70.19; H:9.99; N:3.56; O:16.26; Measured value %C:70.14; H:10.03; N:3.55; O:16.28. 1h-NMR (400MHz, deuterochloroform solvent): δ: 0.96 (d, 6H), 1.10 (d, 6H), 1.52 (d, 3H), 1.77 (m, 4H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 3.24 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07(d, 2H).
Commercial Application
Prodrug shown in general formula (1) " structural formula 1 " is better than ibuprofen.They can be for the medicable state of any ibuprofen of human or animal's treatment.They can be used for sign and the symptom of rheumatoid arthritis and osteoarthritis, bring down a fever, and treatment dysmenorrhea.They can treat bartter syndrome and chronic anterior uveitis and posterior uveitis separately or as adjuvant.They also can treat intrauterine device metrorrhagia, and what prevention and treatment patient caused in the time of pelvis radiotherapy feels sick, vomits.These prodrugs also can be used for treating diabetic neuropathy, acute migraine and hemophilic arthritis.They can be treated bone and run off, prevention or treatment sunburn.They perhaps can also be used for prophylaxis of cancer.Owing to there being very high biomembrane transmitance, these prodrugs also can be treated asthma by the mode that sucks host.Because these prodrugs have antiinflammation, they also can Acne treatment.These prodrugs are water miscible neutral salt, to eye better tolerance.They also can be used for treating eye inflammation, the ocular pain after treatment operation on cornea, treatment glaucoma or treatment ear's inflammation and/or otalgia state (otitis).

Claims (23)

1. the purposes of the compound as shown in structural formula 1 in the medicine that is suitable for transdermal administration for the preparation of the medicable state for the treatment of ibuprofen, structural formula 1 is as follows:
Wherein, in structural formula 1,
R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 3represent H;
X represents O, S or NH;
A -represent Cl -, Br -, F -, l -, AcO -, acetylsalicylate, citrate or other anion;
N=0,1,2,3,4,5,6,7,8,9, or 10; With
R 1and R 2in CH 2group can be by O, S, or NH replaces.
2. purposes claimed in claim 1, wherein said A -represent Cl -, Br -, F -, l -, AcO -, acetylsalicylate, or citrate.
3. purposes claimed in claim 1, wherein said R 1and R 2represent independently of one another H, or the alkyl of 1-12 carbon atom.
4. purposes claimed in claim 1, wherein said medicine is solution, suspensoid, spray, emulsion, ointment, latex or gel dosage form.
5. purposes claimed in claim 1, the medicable state of wherein said ibuprofen is selected from: the metrorrhagia that pain, fever, cancer, bartter syndrome and chronic anterior uveitis and posterior uveitis, intrauterine device cause, vomiting, diabetic neuropathy, hemophilic arthosis, eye inflammation, glaucoma, ear's inflammation, the bone that nauseating, radiotherapy causes run off and dermatosis.
6. purposes claimed in claim 5, wherein said pain comprises the pain that ocular pain, arthritis and other inflammation after toothache, headache, myalgia, operation on cornea causes, and dysmenorrhea.
7. purposes claimed in claim 6, wherein said headache is acute migraine.
8. purposes claimed in claim 5, wherein said dermatosis comprises acne, sunburn or other dermatosiss.
9. the compound shown in structural formula 1 is in the purposes for the preparation for the treatment of by spray delivery in the medicine of asthma, and structural formula 1 is as follows:
Wherein, in structural formula 1,
R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 3represent H;
X represents O, S or NH;
A -represent Cl -, Br -, F -, l -, AcO -, acetylsalicylate, citrate or other anion;
N=0,1,2,3,4,5,6,7,8,9, or 10; With
R 1and R 2in CH 2group can be by O, S, or NH replaces.
10. purposes claimed in claim 9, wherein said medicine is spray.
11. 1 kinds of pharmaceutical compositions for transdermal administration, it comprises the compound shown in structural formula 1, and structural formula 1 is as follows:
Wherein, in structural formula 1,
R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 3represent H;
X represents O, S or NH;
A -represent Cl -, Br -, F -, l -, AcO -, acetylsalicylate, citrate or other anion;
N=0,1,2,3,4,5,6,7,8,9, or 10; With
R 1and R 2in CH 2group can be by O, S, or NH replaces.
Pharmaceutical composition described in 12. claim 11, it is solution, suspensoid, spray, emulsion, ointment, latex or gel dosage form.
The purposes of pharmaceutical composition described in 13. claim 11 in the medicine that is suitable for transdermal administration for the preparation of the medicable state for the treatment of ibuprofen.
Purposes described in 14. claim 13, the medicable state of wherein said ibuprofen is selected from: the metrorrhagia that pain, fever, cancer, bartter syndrome and chronic anterior uveitis and posterior uveitis, intrauterine device cause, vomiting, diabetic neuropathy, hemophilic arthosis, eye inflammation, glaucoma, ear's inflammation, the bone that nauseating, radiotherapy causes run off and dermatosis.
Purposes described in 15. claim 14, wherein said pain comprises the pain that ocular pain, arthritis and other inflammation after toothache, headache, myalgia, operation on cornea causes, and dysmenorrhea.
Purposes described in 16. claim 15, wherein said headache is acute migraine.
Purposes described in 17. claim 14, wherein said dermatosis comprises acne, sunburn or other dermatosiss.
Pharmaceutical composition described in 18. claim 11 is in the purposes for the preparation for the treatment of by spray delivery in the medicine of asthma.
Purposes described in 19. claim 18, wherein said medicine is spray.
20. skin-penetrating therapeutic application systems, it comprises the pharmaceutical composition described in the compound shown in structural formula 1 or claim 11, and structural formula 1 is as follows:
Wherein, in structural formula 1,
R 1represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 2represent H, the alkyl of 1-12 carbon atom, the alkoxyl of 1-12 carbon atom, the thiazolinyl of 1-12 carbon atom, the alkynyl of 1-12 carbon atom, or aryl;
R 3represent H;
X represents O, S or NH;
A -represent Cl -, Br -, F -, l -, AcO -, acetylsalicylate, citrate or other anion;
N=0,1,2,3,4,5,6,7,8,9, or 10; With
R 1and R 2in CH 2group can be by O, S, or NH replaces.
Skin-penetrating therapeutic application system described in 21. claim 20, it is binder or paster, and comprises the protective layer that contains a hypothallus that comprises active substance and a non-infiltration.
Skin-penetrating therapeutic application system described in 22. claim 20, it comprises active substance reservoir, wherein contains permeable bottom towards skin.
The using method of the transdermal application system described in 23. claim 20, it comprises:
Use described transdermal application system; With
Skin by described compound or pharmaceutical composition transdermal delivery to user.
CN201310738823.XA 2006-07-18 2006-07-18 Water-soluble ibuprofen prodrug with high skin penetration rate and positive charge Pending CN103948571A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021244637A1 (en) * 2020-06-05 2021-12-09 Techfields Pharma Co. Ltd. Topical administration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate for treatment of diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1573322A (en) * 1975-12-24 1980-08-20 Hisamitsu Pharmaceutical Co Phenylactic acid ester derivatives
CN1304321A (en) * 1998-06-02 2001-07-18 株式会社Lg化学 Composition for transdermal administration of non-steroidal anti-inflammatory drugs
CN1538951A (en) * 2001-02-27 2004-10-20 ��ķ�ɷ����޹�˾ Omega-aminoalkylamides of R-2-aryl-propionic acids as inhibitors of chemotaxis of polymorphonucleate and mononucleate cells

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1573322A (en) * 1975-12-24 1980-08-20 Hisamitsu Pharmaceutical Co Phenylactic acid ester derivatives
CN1304321A (en) * 1998-06-02 2001-07-18 株式会社Lg化学 Composition for transdermal administration of non-steroidal anti-inflammatory drugs
CN1538951A (en) * 2001-02-27 2004-10-20 ��ķ�ɷ����޹�˾ Omega-aminoalkylamides of R-2-aryl-propionic acids as inhibitors of chemotaxis of polymorphonucleate and mononucleate cells

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
K.温斯顿•凯恩等: "《关注你的身体—个人健康必备（男性卷）》", 31 January 2001, 东方出版社 *
SUSAN MILOSOVICH,ET AL.: "Testosteronyl-4-dimethylaminobutyrate•HCl:A prodrug with improved skin penetration rate", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 *
VRLNDA R. SHANBHAG, ET AL.: "Ester and Amide Prodrugs of Ibuprofen and Naproxen: Synthesis, Anti-inflammatory Activity, and Gastrointestinal Toxicity", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 *
中国实用妇科与产科杂志编辑部: "《中国妇产科专家经验文集》", 31 March 1994, 沈阳出版社 *
乐光熙等: "《皮肤疮病防治120问》", 28 February 1999, 金盾出版社 *
刘栋霞: "布洛芬致哮喘发作1例", 《中国临床药学杂志》 *
卫生专业技术资格考试专家委员会: "《卫生专业技术资格考试指南，药学专业》", 30 September 2001, 知识出版社 *
施桂英等: "《关节炎概要》", 31 October 2004, 中国医药科技出版社 *
王丽天等: "《眼科医师进修必读》", 31 January 1999, 人民军医出版社 *
王金辉: "《国家执业药师资格考试分级考点详解与练习 药物专业知识（一）》", 30 June 2006, 清华大学出版社 *
袁梅卿: "布洛芬药理作用和临床研究", 《陕西新医药》 *
贾民谊等: "《现代内科研究与进展》", 31 August 1995, 天津科学技术出版社 *
龚兰生: "《内科手册》", 30 September 1998, 上海科学技术出版社 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021244637A1 (en) * 2020-06-05 2021-12-09 Techfields Pharma Co. Ltd. Topical administration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate for treatment of diseases
CN115715284A (en) * 2020-06-05 2023-02-24 于崇曦 Treatment of disease with topical administration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate

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