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WO2008012605A1 - Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide - Google Patents

Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide Download PDF

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WO2008012605A1
WO2008012605A1 PCT/IB2006/052575 IB2006052575W WO2008012605A1 WO 2008012605 A1 WO2008012605 A1 WO 2008012605A1 IB 2006052575 W IB2006052575 W IB 2006052575W WO 2008012605 A1 WO2008012605 A1 WO 2008012605A1
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Prior art keywords
ketoprofen
fenoprofen
general formula
propionate
acoh
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PCT/IB2006/052575
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Chongxi Yu
Lina Xu
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Techfields Biochem Co Ltd
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Techfields Biochem Co Ltd
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Priority to CN201810082471.XA priority Critical patent/CN108250090B/zh
Priority to CNA2006800554684A priority patent/CN101500984A/zh
Priority to PCT/IB2006/052575 priority patent/WO2008012605A1/fr
Application filed by Techfields Biochem Co Ltd filed Critical Techfields Biochem Co Ltd
Publication of WO2008012605A1 publication Critical patent/WO2008012605A1/fr
Priority to US12/351,804 priority patent/US20090238763A1/en
Anticipated expiration legal-status Critical
Priority to US12/397,308 priority patent/US20090221703A1/en
Priority to US15/379,866 priority patent/US11135153B2/en
Priority to US15/402,618 priority patent/US9872846B2/en
Priority to US15/402,575 priority patent/US20170209585A1/en
Priority to US16/421,735 priority patent/US20210353579A1/en
Priority to US17/493,321 priority patent/US20220096370A1/en
Ceased legal-status Critical Current

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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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P27/16—Otologicals
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to the preparations of positively charged and water- soluble prodrugs of 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) and their medicinal use in treating any ketoprofen and fenoprofen-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of ketoprofen and fenoprofen. These prodrugs can be administered orally or transdermally.
  • ketoprofen and fenoprofen are members of the propionic acid group of nonsteroidal anti-inflammatory drugs.
  • Ketoprofen was introduced in 1986 and has gained wide acceptance and is used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and for the treatment of dysmenorrhea.
  • Ketoprofen is used alone or as an adjunct in the treatment of acute biliary colic, pain due to renal colic, pain associated with oral surgery, severe postpartum pain and for fever. (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1812) .
  • Ketoprofen may be used for bone regeneration (Alfano, M.C.; Troullos, E.S., US Patent No. 5,902,110). Fenoprofen is used for acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Fenoprofen is used alone or as an adjunct in the treatment of acute gout, episiotomy pain, and migraine headache (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1290) . Fenoprofen may be used for treatment of shock (Toth, P.D., U.S. Pat. No. 4,472,431).
  • ketoprofen and fenoprofen most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis.
  • Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. These levels are often much higher than would be necessary if it were possible to accurately target the particular site of pain or injury. Fishman and many others (Van Engelen et al. U.S. Pat. No. 6,416,772; Macrides et al. U.S.
  • testosteronyl- 4-dimethylaminobutyrate.HCl which has a lipophilic portion and a tertiary amine groups that exists in the protonated form at physiological pH. They found that the prodrug (TSBH) diffuses through human skin -60 times faster than does the drug (TS) itself [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993). Disclosure of Invention
  • Ketoprofen and fenoprofen have been used medicinally for more than 30 years.
  • ketoprofen and fenoprofen most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. They are not soluble in aqueous solution and gastric juice.
  • This invention relates to the preparation of novel positively charged pro-drugs of ketoprofen and fenoprofen and their use medicinally. These pro-drugs have the general formula (1) 'Structure 1'.
  • R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;
  • R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;
  • R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;
  • R 4 represents
  • X represents O, S or NH
  • a " represents Cl “ , Br “ , F “ , I “ , AcO “ , citrate, or any negative ions
  • n 0,l,2,3,4,5,6,7,8,9,10
  • All R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
  • the goal of this invention is to avoid the side effects of ketoprofen and fenoprofen by increasing the their solubility in gastric juice and their penetration rate through the membrane and skin barrier which will make it administrable transdermally (topical application).
  • These novel pro-drugs 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 physiological 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 solubility of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, 2-(3-benzoylphenyl) propionic acid (ketoprofen), and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) in water are >450 mg, >450 mg, 0.1 mg, and 0.1 mg/ml.
  • the slowest or rate-limiting step in the sequence is the dissolution of the drug.
  • Ketoprofen and fenoprofen have a very low solubility in gastric juice.
  • 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.
  • the penetration rates of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen through human skin were measured in vitro by using modified Franz cells, which were isolated from human skin tissue (360-400 ⁇ m thick) of the anterior and posterior thigh areas.
  • the receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm.
  • Apparent flux values of 115 mg, 125 mg, 0.9 mg and 1 mg/cm /h were calculated for diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen diffuses through human skin.
  • the donor consisted of a 10% solution diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen in 1 mL of isopropanol applied to a 1 cm on the backs of the hairless mice.
  • Plasma levels of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen were determined by a specific high-performance liquid chromatography method.
  • the results show that the peak levels of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, were reached -40 minutes after application of the donor systems.
  • ketoprofen and fenoprofen It takes 1-2 hours for ketoprofen and fenoprofen to reach their peak plasma level when they are taken orally.
  • the peaks were -0.02 mg/ml for ketoprofen and fenoprofen and -2 mg/ml for diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (approximately 100 times difference).
  • -2 mg/ml of diflunisal in plasma is more than 50 times higher than kenoprofen and fenoprofen plasma level for effective analgesia and effective anti-inflammatory activity. This is a very exciting result.
  • 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 Pro-drugs of the general 'Structure 1' are close to that of diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH.
  • rats (six groups, each group had 10 rats) were orally administered with 100 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen per day for 21 days.
  • the acute toxicity of the prodrugs was investigated.
  • the LD orally in rats are: 0.2 g/kg and 1.2 g for diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate AcOH.
  • Ketoprofen and fenoprofen have demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activity.
  • a good prodrug should go back to the drug itself in plasma.
  • Diethylaminoethyl ester group of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH can be rapidly cleaved by the enzymes in human plasma in vitro and more than 90% of the pro-drugs are changed back to ketoprofen and fenoprofen.
  • the prodrugs will have more strength than their parent drugs at the same dosage.
  • the analgetic, antipyretic, and anti-inflammatory activities of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH were tested using ketoprofen and fenoprofen as a comparison.
  • Other compounds of the general 'Structure 1 ' were tested by the same methods and have very similar results as that of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH.
  • 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 50mg/kg of ketoprofen and fenoprofen were administered orally and 50mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH were administered 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 4.
  • mice were divided into 5 groups (6 mice each). Ketoprofen (50 mg/kg) was administered to groups B of mice, fenoprofen (50 mg/kg) was administered to groups C of mice, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH (50 mg/kg) was administered transdermally to groups D of mice, and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (50 mg/kg) was administered transdermally to groups E of mice. 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 Table 1.
  • Antipyretic activity Rats received a sterilized E. coli suspension as a pyrogen. 30 rats were divided into 6 groups. The control group is group A. 2 hours later, ketoprofen (50 mg/kg, B) and fenoprofen (50 mg/kg, C) were administered orally and diethy- laminoethyl 2-(3-benzoyphenyl) propionate.AcOH (50mg/kg, D) and diethy- laminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (50 mg/kg, E) 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 Table 2. Table 2. Antipyretic Activity of ketoprofen and related compounds
  • Anti-inflammatory activity 50 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH was administered orally or transdermally to rats and 50 mg/kg of ketoprofen was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously 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 5.
  • pro-drugs are water-soluble neutral salt and can be tolerated very well by the eye. They can be used for treating eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/ or painful conditions (otitis).
  • the present invention relates to pharmaceutical preparations comprising of prodrugs of the general '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, etc., for treating any ketoprofen and fenoprofen-treatable conditions in humans or animals.
  • 'Structure 1' or a composition comprising of at least one compound of the general 'Structure 1', as an active ingredient can be used for treating any ketoprofen and fenoprofen-treatable conditions in humans or animals.
  • These systems can be a bandage or a patch comprising of 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 ketoprofen and fenoprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ketoprofen and fenoprofen.
  • These systems can be worn on the wrist, ankle, arm, leg, or any part of body.
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from functional derivatives of 2-(3-benzoyphenyl) propionic acid and 2-(3-phenoxyphenyl) propionic acid, for example, acid halides or mixed anhydrides of the general formula (2) 'Structure 2'.
  • R 4 represents
  • 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, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen), 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 hexafluorophosphate, Benzotriazol- 1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from metal salts or organic base salts of 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen), by reaction with compounds of the general formula (4) 'Structure 4'.
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from immobilized base salts of 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) of the general formula (5) 'Structure 5',
  • R represents cross-linked resin
  • R 4 represents
  • B represents any base groups, such as pyridine, piperidine, triethylamine, or other base groups, by reaction with compounds of the general formula (4) 'Structure 4' .
  • pro-drugs of ketoprofen and fenoprofen have a lipophilic portion and a hy- drophilic portion (the amine groups that exist in the protonated form at physiological pH).
  • the positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new prodrugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. 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.
  • 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.
  • the hydrophilic part will push the pro-drugs into the cytosol, a semi-liquid 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 more than 90% of the pro-drugs were changed back to the drugs itself.
  • the pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than ketoprofen or fenoprofen at the same dosage.
  • ketoprofen or fenoprofen It takes 1-2 hours for ketoprofen or fenoprofen to reach the peak ketoprofen or fenoprofen plasma level when they are taken orally, but diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH or diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH only took about 40 minutes to reach the ketoprofen or fenoprofen peak plasma level.
  • the 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 ketoprofen or fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis.
  • Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
  • Figure 2 Total plasma levels of ketoprofen after topical application of 1 ml of a
  • Figure 3 Total plasma levels of fenoprofen after topical application of 1 ml of a
  • Figure 4 The prolongation time of the pain threshold of mice tails after 50mg/kg of ketoprofen (B) was administered orally, 50mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH (C) and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (D) were administered transdermally.
  • a group is the control group.
  • FIG. 5 The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 50 mg of 2-(3-benzoyphenyl) propionic acid (ketoprofen, B) was administered orally, 50 mg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH was administered orally (C), and transdermally (D). A group is the control group.
  • R represents H, one of any alkyl, alkyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents
  • R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
  • the pro-drugs of the general formula (1) 'Structure 1' are superior to ketoprofen and fenoprofen. They may be used medicinally in treating any ketoprofen and fenoprof en-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. They may be also prescribed for diabetic neuropathy and acute migraine headache. Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by inhalation to a host. They can be used to treat acne due to their anti-inflammatory properties.
  • pro-drugs are water-soluble neutral salt and can be tolerated very well by the eye. They can be used for treating eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/or painful conditions (otitis).

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Abstract

L'invention concerne la conception et la synthèse de nouveaux promédicaments à charge positive de kétoprofène et de fénoprofène, de formule générale (1) 'structure 1' et de formule générale (2) 'structure 2'. Les composés de formule générale (1) 'structure 1' précités peuvent être préparés à partir de dérivés fonctionnels du kétoprofène et du fénoprofène (par exemple, des halogénures d'acide ou des anhydrides mixtes), par réaction avec des alcools, des thiols ou des amines appropriés. Les groupes amino à charge positive de ces promédicaments peuvent non seulement augmenter largement la solubilité de ces médicaments, mais également se lier à la charge négative sur le groupe de tête phosphatique de membranes et pousser le promédicament vers le cytosol. Les résultats suggèrent que ces promédicaments diéthylaminoéthyl 2-(3-benzoylphényl) propionate.AcOH et diéthylaminoéthyl 2-(3-phénoxyphényl) propionate.AcOH diffusent à travers la peau humaine ∼ 150 fois plus rapidement que le kétoprofène et le fénoprofène. On compte 1 à 2 heures pour le kétoprofène ou le fénoprofène pour atteindre le pic de niveau de plasma pour le kétoprofène ou le fénoprofène, lorsqu'ils sont administrés par voie orale, alors que le diéthylaminoéthyl 2-(3-benzoylphényl) propionate-AcOH ou le diéthylaminoéthyl 2-(3-phénoxyphényl) propionate.AcOH ne prend qu'environ 40 minutes pour atteindre le pic de niveau de plasma pour le kétoprofène ou le fénoprofène. Dans le plasma, plus de 90% de ces promédicaments peuvent redonner le médicament en quelques minutes. Les promédicaments peuvent être utilisés médicalement dans le traitement de n'importe quel état pouvant être traité par le kétoprofrène et le fénoprofène chez l'homme ou chez l'animal. Les promédicaments peuvent être administrés non seulement par voie orale, mais également par voie transdermique pour tout type de traitements médicaux, tout en évitant la plupart des effets secondaires du kétoprofène et du fénoprofène, plus particulièrement les troubles gastro-intestinaux tels que la dyspésie, le saignement gastroduodénal, les ulcérations gastriques et la gastrite. Des systèmes d'administration par voie transdermique contrôlée des promédicaments permettent au kétoprofène et au fénoprofène d'atteindre en permanence des concentrations sanguines thérapeutiques optimales pour une plus grande efficacité et pour une réduction des effets secondaires du kétoprofène et du fénoprofène. Comme autre avantage important de l'administration transdermique de ces promédicaments, on mentionne la plus grande facilité d'administration médicamenteuse, notamment chez l'enfant.
PCT/IB2006/052575 2006-07-09 2006-07-27 Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide Ceased WO2008012605A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CN201810082471.XA CN108250090B (zh) 2006-07-27 2006-07-27 具有快速皮肤穿透速度的带正电荷的水溶性酮洛芬及相关化合物的前药
CNA2006800554684A CN101500984A (zh) 2006-07-27 2006-07-27 具有快速皮肤穿透速度的带正电荷的水溶性酮洛芬及相关化合物的前药
PCT/IB2006/052575 WO2008012605A1 (fr) 2006-07-27 2006-07-27 Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide
US12/351,804 US20090238763A1 (en) 2006-07-09 2009-01-09 High penetration compositions and uses thereof
US12/397,308 US20090221703A1 (en) 2006-07-09 2009-03-03 High penetration composition and uses thereof
US15/379,866 US11135153B2 (en) 2006-07-09 2016-12-15 High penetration composition and uses thereof
US15/402,575 US20170209585A1 (en) 2006-07-09 2017-01-10 High penetration compositions and uses thereof
US15/402,618 US9872846B2 (en) 2006-07-09 2017-01-10 High penetration compositions and uses thereof
US16/421,735 US20210353579A1 (en) 2006-07-09 2019-05-24 High penetration compositions and uses thereof
US17/493,321 US20220096370A1 (en) 2006-07-09 2021-10-04 High penetration composition and uses thereof

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PCT/IB2006/052575 WO2008012605A1 (fr) 2006-07-27 2006-07-27 Promédicaments hydrosolubles à charge positive de kétoprofène et composés associés à vitesse de pénétration cutanée très rapide

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PCT/IB2006/052563 Continuation-In-Part WO2008012603A1 (fr) 2006-07-09 2006-07-26 Promédicaments hydrosolubles à charge positive du diflunisal et composés associés présentant une vitesse de pénétration cutanée très rapide
PCT/IB2006/052732 Continuation-In-Part WO2008017903A1 (fr) 2006-07-09 2006-08-08 Promédicaments hydrosolubles chargés positivement d'acides aryl- et heteroarylacetiques avec une vitesse de pénétration de la peau très rapide

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PCT/IB2006/052732 Continuation-In-Part WO2008017903A1 (fr) 2006-07-09 2006-08-08 Promédicaments hydrosolubles chargés positivement d'acides aryl- et heteroarylacetiques avec une vitesse de pénétration de la peau très rapide

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