Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
• adenylate cyclase is activated, which converts Mg + 2-ATP to cAMP at an accelerated rate.
• Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma.
• an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
• compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
• the principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
• PDE IV cyclic nucleotide phosphodiesterase
• PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
• PDE IV inhibitors would be effective in the lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
• Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
• this invention relates to a method for treating an inflammatory disease in a mammal by administering to a patient in need thereof an effective amount of a PDE 4-specific inhibitor and an effective amount of a non-steriodal anti-inflammatory agent wherein the drugs are administered concomitantly, or separately and sequentially where the sequential administration is close in time or remote in time.
• the combination therapy contemplated by this invention comprises administering a PDE4 inhibitor with a non-steroidal anti-inflammatory agent to treat an inflammatory disease.
• the compounds may be administered together in a single dosage form. Or they may be administered as two different formulations.
• both drugs may be provided separately as oral formulations, or one may be an oral preparation or as a suppository or by injection or as an intravenous drip. They may be administered at the same time. Or they may be administered close in time or remotely, such as where one drug is administered in the morning and the second drug is administered in the evening.
• the PDE4-specific inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4.
• a PDE4 antagonists which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE IV catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
• PDE inhibitors like theophylline and pentoxyfyllin inhibit all or most all PDE isozymes indiscriminately in all tissues. These compounds exhibit side effects, apparently because they non-selectively inhibit all PDE isozyme classes in all tissues.
• the target disease may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain diseases.
• clinical studies with the selective PDE 4 inhibitor rolipram which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis.
• the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity” binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity” binding site (HPDE 4).
• LPDE 4 low affinity binding site
• HPDE 4 high affinity binding site
• yeast were transformed by known methods and the expression of recombinant PDE 4 was followed over a 6 hour fermentation period.
• Western blot analysis using an antibody directed against PDE 4 indicated that the amount of PDE 4 expressed increased with time, reaching a maximum after 3 hour of growth.
• greater than 90% of the immunoreactive product was in the high speed (100,000 x g) supernatant of yeast lysates.
• H]R-Rolipram binding and PDE activity were monitored along with protein expression.
• PDE 4 activity was co-expressed with rolipram- binding activity, indicating that both functions exist on the same gene product. Similar to results with the Western plot analysis, greater than 85% of the rolipram-inhibitable PDE activity and H]-rolipram binding activity was found to be present in the yeast supernatant fraction.
• the preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
• the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE 4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
• a further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of InM of H]R-rolipram to a form of PDE 4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE IV catalytic activity of a form which binds rolipram with a low affinity using 1 microM[ ⁇ H]-cAMP as the substrate.
• PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
• a preferred compound is cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylic acid (Ariflo®).
• the following PDE4 inhibitors may be useful in the practice of this invention: AWD-12-281 from Astra (Hofgen, N. et al.
• NSAIDs non-steroidal anti-inflammatory drugs
• COX-1 cyclo-oxygenase-1
• COX-2 cyclo- oxygenase-2
• NSAIDs can be use herein: aspirin, carprofen, choline salicylate, ketoprofen, Mg salicylate, salicylaminde, salsalate, , sodium salicylate, sodium thiosalicylate, meclofenamate sodium, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin and tolmetin sodium, mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone. All are available from commercial sources or are well described in the medical and other scientific literature.
• the combined analgesic and anti-inflammatory effects of NSAIDs and PDE4-specific inhibitors make this combination particularly useful for the symptomatic relief of painful and/or inflammatory conditions including rheumatic disorders such as rheumatoid arthritis, osteoarthritis, and the spondyloarthropathies, and also in peri-articular disorders, and soft-tissue rheumatism.
• the combination may also be useful in treating pulmonary diseases involving an inflammatory condition.
• both active agents would be administered at the same time, or very close in time.
• one drug could be taken in the morning and one later in the day.
• one drug could be taken twice daily and the other once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
• both drugs would be taken together at the same time.
• the present compounds and pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules, controlled- release preparation or lozenges.
• a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerin or water with a flavoring or coloring agent.
• a liquid carrier for example, ethanol, peanut oil. olive oil, glycerin or water with a flavoring or coloring agent.
• any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
• compositions are in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
• composition is in the form of a soft gelatin shell capsule
• any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
• Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
• compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as fluroinated hydrocarbons such as trichlorofluoromethane.
• the composition for the PDE4 inhibitors is a unit dosage form such as a tablet or capsule, or a controlled release preparation.
• NSAIDs are normally taken by mouth, some of them such as diclofenac, ketoprofen, ketorolac, piroxicam, and tenoxicam can be given by intramuscular injection. Ketorolac and tenoxicam can also be given by intravenous injection.
• the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. Preferably, the active ingredient is administered about once or twice a day, more preferably twice a day. As for the amount of drug administered, it is believed that for the PDE4 inhibitors will be administered in an amount of between 1 and 200 micrograms per day per adult human. NSIADs be administered in conformity with approved labeling.
• Example 1A Isolated human monocyte PDE 4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE 4 can be assessed using standard assays for
• Rat brain high speed supematants were used as a source of protein and both enantionmers of H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol.
• PDE activity was assayed using a [ 3 H]cAMP SPA or [ 3 H]cGMP scintillation proximity analysis (SPA) enzyme assay as described by the supplier (Amersham Life Sciences).
• the reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 M Tris-HCl, pH 7.5, 8.3 itiM MgC12, 1.7 mM EGTA, [ 3 H]cAMP or [ 3 H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors.
• the assay was allowed to proceed for 1 hr and was terminated by adding 50 ⁇ l of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry. Activities of PDE3 and PDE7 were assessed using 0.05 ⁇ M [ 3 H]cAMP, whereas PDE4 was assessed using 1 uM [ 3 H]cAMP as a substrate. Activity of PDE1B, PDE1C, PDE2 and PDE5 activities were assessed using l ⁇ M [ 3 H]cGMP as a substrate. PHlR-rolipram binding assay
• the assay was performed at 30°C for 1 hr in 0.5 ⁇ l buffer containing (final concentrations): 50 mM Tris- HCl, pH 7.5, 5 mM MgC12, 0.05% bovine serum albumin, 2 nM [ 3 H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors.
• the reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [ 3 H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5-ml of cold buffer, dried, and counted via liquid scintillation spectrometry.
• Example 2 Preparation of a Controlled Release Tablet A controlled-release formulation was prepared using the ingredients set out in Table
• Blending and compression techniques Blending
• Excipients and drug were placed in a blender and mixed. The magnesium stearate was then added and mixed for an additional 3 minutes. During the blending process, excipients and drug were mixed, passed through a screen and then mixed again. Compression
• Opadry White was suspended in the purified water and that suspension was used to coat the tablets; water was removed during the coating process an ddid not form part of the final product.
• Immediate release tablets were prepared by standard means and contained the ingredients set out in Table 2.
• Example 4 Treatment of Arthritis A patient diagnosed with arthritis and experiencing pain due to an inflammation of a joint is given a controlled-release tablet containing 30mg of Ariflo® prepared as per Example 2 and a 500mg tablet of Relafen (nabumetone) twice daily. Treatment is continued until such time as the inflammation goes into remission.

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• 2001
  • 2001-02-08 AU AU72057/01A patent/AU7205701A/en not_active Abandoned
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  • 2001-02-08 CN CN01804708A patent/CN1398181A/zh active Pending
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