EP2038251A1 - Promédicaments hydrosolubles à charge positive de l'aspirine - Google Patents
Promédicaments hydrosolubles à charge positive de l'aspirineInfo
- Publication number
- EP2038251A1 EP2038251A1 EP06780025A EP06780025A EP2038251A1 EP 2038251 A1 EP2038251 A1 EP 2038251A1 EP 06780025 A EP06780025 A EP 06780025A EP 06780025 A EP06780025 A EP 06780025A EP 2038251 A1 EP2038251 A1 EP 2038251A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aspirin
- general formula
- pro
- compounds
- drugs
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- WMLQRTQFMFULOA-UHFFFAOYSA-N prop-2-enyl 2-acetyloxybenzoate Chemical group CC(=O)OC1=CC=CC=C1C(=O)OCC=C WMLQRTQFMFULOA-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- JZLOKWGVGHYBKD-UHFFFAOYSA-M sodium;2-acetyloxybenzoate Chemical compound [Na+].CC(=O)OC1=CC=CC=C1C([O-])=O JZLOKWGVGHYBKD-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
Definitions
- the present invention relates to the preparations of positively charged and water- soluble pro-drugs of aspirin or its analogues and their medicinal use in treating any aspirin-treatable conditions in humans or animals. Particularly, the present invention is to overcome the side effects that are associated with the use of salicylates. These prodrugs can be administered orally or transdermally.
- Acetylsalicylic acid (aspirin) was synthesized in 1853 and first used medicinally in
- Aspirin possesses antipyretic, analgesic, and anti-inflammatory properties. Because salicylates promote the excretion of uric acid, they are useful in the treatment of gouty arthritis. Aspirin also inhibits the platelet aggregation that potentially contributes to heart attacks and stroke [C. H. Hennekens, et al., N. Engl. J. Med., 321, 129(1989); T.A.Gossel, U.S. Pharmacist, February, 1988, p. 34.] and it may be protective against colon cancer as also [MJ.Thun, et al., N.
- the salts may be acidified to acetylsalicylic acid.
- Esters of alkyl- or aralkyl-substituted acetylsalicylic acid such as methyl-, ethyl, allyl-, or benzyl acetyl- salicylate were synthesized and studied (Boghosian, et al., U.S. Pat. No. 4,244,948). Higher fatty acid derivatives of salicylic acid and salts thereof were synthesized for use in treating aspirin-treatable conditions (Guttag, U.S. Pat. No. 5,760,261). Esters of sal sal ate with guaiacol were synthesized and evaluated pharmacologically (Nicolini, U.S. Pat. No. 4,743,704).
- Aspirin is a very old salicylate drug (more than 100 years old) and has demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activities, it is also used to inhibit platelet aggregation, thus reducing cardiac mortality, and the therapeutic utility of aspirin continues to increase.
- PDR Generics PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 243 has listed many medical uses of aspirin.
- GI disturbances such as dyspepsia, heartburn, vomiting, gastroduodenal bleeding, gastric ulcerations, and gastritis .
- Gastroduodenal bleeding induced by salicylates is generally painless but can lead to fecal blood loss and may cause a persistent iron deficiency anemia.
- uncoated aspirin at a dosage of 325 mg tablets given three times a day caused an average fecal blood loss of 4.33 ml per day (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 242).
- Coated aspirin at the same dosage caused an average fecal blood loss of 1.5 ml per day.
- Aspirin and its esters have a very low solubility in water and may stay in the GI tract for a long time and can cause gastric mucosal cell damage.
- Aspirin and its esters are also very hydrophobic, and when they enter the cell membrane (hydrophobic layer), they will stay there as part of the membrane due to their similarity. Due to these reasons, the absorption rate of aspirin is very slow. It takes 2 hours for uncoated aspirin tablets to reach the peak salicylate level and much longer for coated aspirin tablets.
- This invention relates to the preparation of novel positively charged pro-drugs of acetylsalicylic acid or its analogues and their use medicinally. These pro-drugs have the general formula(l) "Structure 1".
- the goal of this invention is to avoid the side effects of aspirin by increasing the solubility of acetylsalicylic acid in gastric juice and the penetration rate of aspirin through the membrane and skin barrier which will make it administrable transdermally (topical application).
- These novel pro-drugs of acetylsalicylic acid have two structural features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the protonated form (hydrophilic part) at physiologic pH. Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993)].
- the positively charged amino groups largely increase the solubility of the drugs.
- the solubilities of diethylaminoethyl acetylsalicylate.AcOH and acetylsalicylic acid in pH 7 phosphate buffer were >300 mg and 0.01 mg/ml.
- the slowest or rate-limiting step in the sequence is the dissolution of the drug.
- Aspirin has a very low solubility in gastric juice. It stays in the GI tract for a long time and may cause gastric mucosal cell damage. When these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately.
- the positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane.
- the local concentration of the outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration.
- the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in GI tract , the pro-drugs will not cause gastric mucosal cell damage.
- Plasma levels of salicylic acid (acetylsalicyclic acid has a very short half-live, -15 minutes in plasma, so the amount of it is difficult to be determined) were determined by a specific high-performance liquid chromatography method.
- the results ( Figure 2) show that the peak levels of salicylic acid were reached -20 minutes after application of the donor systems. It takes 2 hours for uncoated aspirin tablets to reach the peak salicylate level and much longer for coated aspirin tablets when they are taken orally. The peaks were ⁇ 0.01mg/ml for salicylic acid and -10 mg/ml for diethylaminoethyl acetylsalicylate.AcOH (approximately 100 times difference).
- ⁇ 10mg/ml of salicylic acid in plasma is more than 33-67 times higher than the salicylate plasma level (0.15-0.3 mg/ml) for effective analgesia and 33-50 times higher than the salicylate plasma level (0.2-0.3 mg/ml) for effective anti-inflammatory activity.
- This is a very exciting result. It will be very easy and fast to deliver therapeutically effective plasma levels of aspirin into the host by these pro-drugs.
- the pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments.
- the in vivo rates of penetration of other prodrugs of the general "Structure 1" are close to that of diethylaminoethyl acetylsalicylate.AcOH .
- the acute toxicity of the pro-drugs were investigated.
- the LD 50 orally in rats are:
- Acetylsalicylic acid has demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activity, inhibits platelet aggregation, reduces cardiac mortality , but salicylic acid has only analgesic and antipyretic activity.
- Diethylaminoethyl acetylsalicylate.AcOH has two ester function groups. One (acetyl) is from acetylsalicylic acid itself, and the one is the diethylaminoethyl ester (the added one). Both ester groups can be rapidly cleaved by the enzymes in human plasma in vitro. If the acetate group losses faster than diethylaminoethyl, the pro-durg will be changed to diethylaminoethyl salicylate, then to salicylic acid instead of acetylsalicylic acid.
- Diethylaminoethyl acetylsalicylate.AcOH and Acetylsalicylic acid have very short half-lives ( ⁇ 4 min. and 15 min.) in whole human blood.
- To determine how much the pro-drugs of acetylsalicylic acid were changed back to the drug itself or diethylaminoethyl salicylate we diluted whole human blood 20 times with a pH 7.4 phosphate buffer (0.2M). The cumulative amounts of diethylaminoethyl salicylate, acetylsalicylic acid, and salicylic acid were determined by a specific high-performance liquid chromatography method.
- the rate of diethylaminoethyl salicylate vs acetylsalicylic acid is 1 vs 4. This means that 80% of the pro-drug was changed back to the drug itself. Due to the pro-drug having a much better absorption rate, the pro-drug will have more strength than the acetylsalicylic acid itself at the same dosage.
- Analgetic activity The prolongation time of pain the threshold of a mouse tail was determined in accordance with the D'Amour-Smith Method (J. Pharmacol. Exp. Ther., 72, 74(1941)). After 200mg/kg of aspirin was administered orally and 200mg/kg of diethylaminoethyl salicylate.AcOH was administered orally and transdermally, the tails of mice were exposed to heat and the prolongation time of pain threshold was determined. The results obtained are shown in Figure 3.
- mice were divided into 7 groups (6 mice each).
- Aspirin ASA, 50 mg/kg and 100 g
- AcOH Diethylaminoethyl acetylsalicylate.
- AcOH (DEAE-ASA, 50 mg and 100 mg/kg) was administered transdermally to groups D land D2.
- the A group is the control group.
- the test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in following Table 1.
- Antipyretic activity Rats received a sterilized E. coli suspension as a pyrogen. 56 rats were divided into 7 groups. The control group is group A. 2 hours later, Aspirin (ASA, Bl for lOOmg/kg and B2 for 150mg/kg) and diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA, Cl for 100mg/kg and C2 for 150 mg) were administered orally and diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA, Dl for 100 mg and D2 for 150 mg/kg) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in the following Table 2.
- Anti-inflammatory activity 50 mg/kg of diethylaminoethyl acetylsalicylate.AcOH was administered orally or transdermally to rats and 50 mg/kg of aspirin was administered orally. 60 minutes later, a carrageenin solution was administered subcu- taneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling(%). The results obtained are shown in Figure 4.
- the compounds of the general formula(l) "Structure 1" indicated above can be prepared from ASA or its analogues, or from functional derivatives of ASA or its analogues.
- R represents CH , C H , C H , or other lower alkyl groups
- Y represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy, by reaction with compounds of the general formula (3) "Structure 3".
- R represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues
- R represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues
- X represents O, S or NH
- n 0,l,2,3,4,5
- ASA or its analogues by reaction with compounds of the general formula (3) "Structure 3" by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide , N,N'-Diisopropylcarbodiimide, O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluoro phosphate, Benzotriazol- 1 -yl-oxy-tris(dimethylamino)phosphonium hexafluo- rophosphate, et al.
- coupling reagents such as N,N'-Dicyclohexylcarbodiimide , N,N'-Diisopropylcarbodiimide, O
- R represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues
- R represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues
- R 4 represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues
- Z represents halogen, or p-toluenesulphonyl
- a " represents Cl “ , Br “ , F, I " , AcO , acetyl- salicylate, citrate, salicylate, or any negative ions
- n 0,l,2,3,4,5
- R represents cross-linked resin
- R represents CH , C H , C H , or other lower alkyl group
- B represents any base groups, such as pyridine, piperidine, tri- ethylamine, or other base groups, by reaction with compounds of the general formula(4) "Structure 4" .
- the present invention relates to pharmaceutical preparations comprising pro-drugs of acetylsalicylic acid and its analogues of the general formula(l) "Structure 1" in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for administration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration transdermally.
- the new active compounds of the general "Structure 1" can be combined with vitamins such as A,B,C or E or beta-carotene, or other pharmaceuticals, such as folic acid, et. al for treating any aspirin-treatable conditions in humans or animals .
- Structure 1 or a composition comprising at least one compound of the general formula( 1) "Structure 1", as an active ingredient, for treating any aspirin-treatable conditions in humans or animals, especially for preventing thrombosis and other cardiovascular diseases, and cancer prophylaxis can be developed.
- These systems can be a bandage or a patch comprising one active substance-containing matrix layer and an impermeable backing layer.
- the most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables aspirin to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of aspirin.
- These systems can be worn on wrist, ankle, arm, leg, or any part of body.
- pro-drugs of aspirin have a lipophilic portion and a hydrophilic portion (the amine groups that exist in the protonated form at physiologic pH).
- the positively charged amino groups of these pro-drugs have two major advantages. The first, it largely increases the solubility of the drugs; when these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. The second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration.
- pro-drugs When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drugs into the cytosol, a semiliquid concentrated aqueous solution or suspension. Due to the short stay in the GI tract, the pro-drugs will not cause gastric mucosal cell damage. Experiment results show that 80% of the prodrug was changed back to the drug itself. The pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than the acetylsalicylic acid itself at the same dosage.
- pro-drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of aspirin, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis.
- SA salicylic acid
- ASA acetylsalicylic acid
- DEAE-ASA diethylaminoethyl acetylsalicylate.AcOH
- FIG. 4 The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 100 mg/kg of spirin was administered orally (B), 100 mg/kg of diethylaminoethyl salicylate.AcOH (C) was administered orally and transdermally (D). A is the control line.
- R represents CH , C H , C H , or other lower alkyl groups
- R represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues;
- R represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues;
- R 4 represents H, one of any alkyl, alkyloxy, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues;
- X represents
- the pro-drugs of of the general "Structure 1" are superior to aspirin. They may be used medicinally in treating any aspirin-treatable conditions in humans or animals. They may be used in the long-term palliative treatment of mild to moderate pain and inflammation of arthritis and other inflammatory conditions. They may be used alone or as an adjunct in the treatment of Kawasaki syndrome, thromboembolism after surgery, and unstable angina. They can be used to decrease stool volume and increase weight in acute childhood gastroenteritis, as an adjunct to prevent aortocoronary-artery -bypass graft occlusion, and to prevent thromboembolic complications in chronic artrial fibrillation.
- They can be used as an adjunct in carotid endarterectomy to reduce platelet aggregation and thromboxane suppression, and they may be prescribed to reduce the development of cataracts, to prevent recurrence of stenosis after coronary angioplasty, and to improve cognitive performance and cerebral blood flow in patients with multi-infract dementia. They may be used as an adjunct to lower plasma glucose in diabetes mellitus and diabeties-induced complications, including diabetic retinopathy, necrobiotic ulcers, and diabetic proteinuria, and to decrease total and cardiovascular mortality.
- They can be prescribed to reduce the incidence of hemodialysis shunt thrombosis, to decrease the deterioration of renal function and occurrence of end-stage renal disease in patients with type-1 membranoproliferative glomerulonephritis, and to slow the progression of peripheral occlussive arterial disease. They may be used in the prevention of colon cancer and rectal cancer, and arterial embolic complications in patients' prosthetic heart valves. They can also be prescribed to lower the incidence of pregnancy-induced hypertension and preeclamptic toxemia in high- risk women. It is also known that high dose of oral acetylsalicylic acid shows an an- tireactive activity by the inhibition of the cyclooxygenase activity (Bianco, Sebastiano, U.S.
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Vascular Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13155198.8A EP2610242A1 (fr) | 2006-07-09 | 2006-07-09 | Promédicaments hydrosolubles positivement chargés d'aspirine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB2006/052318 WO2008007171A1 (fr) | 2006-07-09 | 2006-07-09 | Promédicaments hydrosolubles à charge positive de l'aspirine |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2038251A1 true EP2038251A1 (fr) | 2009-03-25 |
EP2038251A4 EP2038251A4 (fr) | 2010-04-21 |
Family
ID=38922980
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP13155198.8A Withdrawn EP2610242A1 (fr) | 2006-07-09 | 2006-07-09 | Promédicaments hydrosolubles positivement chargés d'aspirine |
EP06780025A Pending EP2038251A4 (fr) | 2006-07-09 | 2006-07-09 | Promédicaments hydrosolubles à charge positive de l'aspirine |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
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EP13155198.8A Withdrawn EP2610242A1 (fr) | 2006-07-09 | 2006-07-09 | Promédicaments hydrosolubles positivement chargés d'aspirine |
Country Status (6)
Country | Link |
---|---|
EP (2) | EP2610242A1 (fr) |
JP (1) | JP5759672B2 (fr) |
CN (1) | CN101484415B (fr) |
AU (1) | AU2006346195B2 (fr) |
CA (1) | CA2656858C (fr) |
WO (1) | WO2008007171A1 (fr) |
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US20090221703A1 (en) | 2006-07-09 | 2009-09-03 | Chongxi Yu | High penetration composition and uses thereof |
US20090238763A1 (en) | 2006-07-09 | 2009-09-24 | Chongxi Yu | High penetration compositions and uses thereof |
ES2616315T3 (es) * | 2006-07-18 | 2017-06-12 | Techfields Biochem Co. Ltd | Profármacos de ibuprofeno solubles en agua cargados positivamente con una velocidad de penetración en la piel muy rápida |
EP2084124B9 (fr) | 2006-10-02 | 2015-07-01 | Techfields Biochem Co. Ltd | Promédicaments hydrosolubles de prostaglandines et composés analogues, positivement chargés, à taux de pénétration cutanée très élevé |
CN101541743A (zh) | 2006-11-08 | 2009-09-23 | 于崇曦 | 多肽及相关化合物的透皮给药系统 |
JP5324463B2 (ja) | 2006-12-10 | 2013-10-23 | チョンシー ユー | β−ラクタム抗生物質の経皮送達システム |
EP2125697B1 (fr) | 2007-01-15 | 2016-09-28 | Chongxi Yu | Promédicaments positivement chargés solubles dans l'eau de rétinoïdes et de composés semblables à des rétinoïdes ayant des vitesses de pénétration dans la peau très élevées |
JP5389668B2 (ja) | 2007-01-31 | 2014-01-15 | チョンシー ユー | 皮膚浸透率の非常に高い1H−イミダゾ[4,5−c]キノリン−4−アミン及び関連化合物の正に荷電した水溶性プロドラッグ |
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CA2755069A1 (fr) * | 2009-03-16 | 2010-09-23 | Genmedica Therapeutics Sl | Conjugues anti-inflammatoires et anti-oxydants utiles pour traiter des troubles metaboliques |
CN108084246A (zh) | 2009-05-08 | 2018-05-29 | 上海泰飞尔生化技术有限公司 | 多肽和多肽相关化合物的高穿透力前药组合物 |
US9969751B2 (en) | 2009-06-10 | 2018-05-15 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds |
US9359376B2 (en) * | 2011-04-08 | 2016-06-07 | Sphaera Pharma Pte. Ltd | Substituted methylformyl reagents and method of using same to modify physicochemical and/or pharmacokinetic properties of compounds |
IN2014KN02583A (fr) | 2012-05-16 | 2015-05-08 | Techfields Pharma Co Ltd | |
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JP5905411B2 (ja) * | 2013-06-12 | 2016-04-20 | テックフィールズ バイオケム カンパニー リミテッド | アスピリンの正荷電水溶性プロドラッグ |
CN104276962B (zh) * | 2013-07-08 | 2019-04-12 | 浙江越甲药业有限公司 | 一种阿司匹林衍生物及其组合物与应用 |
US20150072005A1 (en) * | 2013-09-10 | 2015-03-12 | Vitalis Llc | Aspirin formulation for increased efficacy |
US20160168108A1 (en) | 2014-12-16 | 2016-06-16 | Adt Pharmaceuticals, Inc. | Method of treating or preventing ras-mediated diseases |
US9862698B2 (en) | 2014-12-16 | 2018-01-09 | Adt Pharmaceuticals, Inc. | Indenyl compounds, pharmaceutical compositions, and medical uses thereof |
JP6153264B2 (ja) * | 2015-01-05 | 2017-06-28 | テックフィールズ インコーポレイテッド | 非常に速い皮膚及び膜浸透速度を有するnsaiaプロドラッグ及びその新規医薬使用 |
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JP6289438B2 (ja) * | 2015-12-03 | 2018-03-07 | テックフィールズ バイオケム カンパニー リミテッド | アスピリンの正荷電水溶性プロドラッグ |
JP6588485B2 (ja) * | 2017-02-21 | 2019-10-09 | テックフィールズ バイオケム カンパニー リミテッド | アスピリンの正荷電水溶性プロドラッグ |
EP3701937A4 (fr) | 2017-10-26 | 2021-07-28 | Zhejiang Yuejia Pharmaceuticals Co., Ltd | Composition pharmaceutique stable contenant un dérivé de médicament anti-inflammatoire non stéroïdien |
WO2019095879A1 (fr) | 2017-11-17 | 2019-05-23 | 浙江越甲药业有限公司 | Anesthésique local |
US11186596B2 (en) | 2018-04-26 | 2021-11-30 | Adt Pharmaceuticals, Llc | Anticancer indenes, indanes, azaindenes, azaindanes, pharmaceutical compositions and uses |
WO2020135560A1 (fr) | 2018-12-29 | 2020-07-02 | 侯再华 | Dérivé d'acide acétylsalicylique et son utilisation |
CN111925362B (zh) * | 2020-08-20 | 2023-06-23 | 陕西中医药大学 | 一种抗癌化合物及其合成方法和应用 |
CN113599375B (zh) * | 2021-06-21 | 2023-08-18 | 李萍 | 一种治疗口腔疾病的经口给药药物及用途 |
WO2023134732A1 (fr) * | 2022-01-17 | 2023-07-20 | Techfields Pharma Co., Ltd. | Prévention ou traitement de maladies cardiovasculaires à l'aide de promédicaments d'aspirine et d'autres ains à forte pénétration |
WO2023134733A1 (fr) * | 2022-01-17 | 2023-07-20 | Techfields Pharma Co., Ltd. | Traitement de signes, de symptômes et/ou de complications d'infections virales, bactériennes, protozoaires et/ou fongiques par des promédicaments à pénétration élevée |
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2006
- 2006-07-09 WO PCT/IB2006/052318 patent/WO2008007171A1/fr active Application Filing
- 2006-07-09 AU AU2006346195A patent/AU2006346195B2/en not_active Ceased
- 2006-07-09 CN CN2006800553018A patent/CN101484415B/zh not_active Ceased
- 2006-07-09 EP EP13155198.8A patent/EP2610242A1/fr not_active Withdrawn
- 2006-07-09 JP JP2009518987A patent/JP5759672B2/ja active Active
- 2006-07-09 CA CA2656858A patent/CA2656858C/fr active Active
- 2006-07-09 EP EP06780025A patent/EP2038251A4/fr active Pending
Patent Citations (2)
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GB958186A (en) * | 1962-10-02 | 1964-05-21 | Biosedra Lab | Salicylamide derivatives |
EP0152379A2 (fr) * | 1984-02-15 | 1985-08-21 | Ciba-Geigy Ag | Procédé pour la préparation de compositions pharmaceutiques contenant des liposomes unilamellaires |
Non-Patent Citations (4)
Also Published As
Publication number | Publication date |
---|---|
JP5759672B2 (ja) | 2015-08-05 |
EP2038251A4 (fr) | 2010-04-21 |
AU2006346195B2 (en) | 2013-03-07 |
EP2610242A1 (fr) | 2013-07-03 |
WO2008007171A1 (fr) | 2008-01-17 |
AU2006346195A1 (en) | 2008-01-17 |
CN101484415B (zh) | 2013-08-14 |
CN101484415A (zh) | 2009-07-15 |
JP2009542797A (ja) | 2009-12-03 |
CA2656858A1 (fr) | 2008-01-17 |
CA2656858C (fr) | 2016-01-19 |
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