FR2627985A1 - COADMINISTRATION OF A NON-STEROIDAL ANTI-INFLAMMATORY DRUG AND SUFOTIDINE OR ONE OF ITS PHYSIOLOGICALLY ACCEPTABLE SALTS - Google Patents

Abstract

The invention relates to the co-administration in human or veterinary medicine of a general non-sterodic anti-inflammatory drug and sufotidine or one of its physiologically acceptable salts. The two active ingredients, which can be administered separately or can be combined into a single preparation, are useful in the treatment of inflammatory conditions.

Description

(6 FRENCH REPUBLIC Publication No. 2,627,985 (to be used only

  for the NATIONAL INSTITUTE. Reproduction Orders) OF INDUSTRIAL PROPERTY AND INDUSTRIAL PROPERTY National Registration No .: 89 02778 PARIS () Int Cl ": A61 K 31/445, 31/54 // C07 D 401 / 12; A61 K

  31/445, 31:19, 31/54, 31: 445 (A61 K 31/445, 31: 405).

@ APPLICATION FOR PATENT OF INVENTION 'A1

  Filing Date: March 3, 1989. Q Applicant (s): GLAXO GROUP LIMITED. - GB.

  Q Priority: GB. March 4, 1988, No. 88 05268.

  (Inventor (s): Roger Stables and Keith Thomas Bunce, Glaxo Group Research Limited t Date of public availability of the

  application: BOPI "Patents" No. 36 of 8 September 1989.

  (O) References to other national documents appearing

  : () Holder (s): Agent (s): Cabinet Regimbeau, Martin, Schrimpf,

Warcoin and Ahner.

    Coadministration of a nonsteroidal anti-inflammatory drug and sufotidine or a salt thereof

physiologically acceptable.

  The invention relates to coadministration in human medicine.

  or a veterinarian of a general nonsteroidal anti-inflammatory drug and sufotidine or a salt thereof

physiologically acceptable.

  Both active ingredients, which can be administered

  separately or can be combined into one

  tion, are useful in the treatment of infiammatory states.

  I LE IVE DIES ISSUERS FOR NATIONAL PRINTING, 27, rue de la Convention - 75732 PARIS CEDEX 15 l

  The present invention relates to improvements

  in the treatment of inflammatory conditions. More

  In particular, it concerns the use of a

  non-steroidal anti-inflammatory drug

  sufotidine in the treatment of such conditions, and the pharmaceutical treatment containing both

active ingredients.

  It is known that non-steroidal anti-inflammatory drugs administered by the general route, such as

  aspirin, indomethacin, ibuprofen and

  xicames, give birth to side effects

  undesirable. In particular, we know that they are ul-

  and, for example, may give rise to gastric ulceration when administered orally. This side effect can be further increased by

  combination with other factors such as stress.

  Since in some treatments these compounds

  may have to be used for a prolonged period of time

  However, these side effects may be

it is serious.

  Sufotldine is the approved name of the

  l-methyl-3-methylsulphonylmethyl-N- [3 - [- (1-piperidinyl

  methyl) -phénoxylpropyll-lH-l, 2,4-triazole-5-amine

  which is described and claimed in the British patent

  N 2075007B. The compound is the inhibitor of

  powerful and long-lived histamine H2 receptors that can be used in the treatment of conditions where there is a benefit in lowering gastric acidity. These

  states include peptic ulceration and gastric

  cough, reflux esophagitis and Zollinger-Ellison syndrome. Sufotidine can also be used prophylactically in operations

  surgical procedures and in the treatment of allergic conditions

  inflammatory conditions in which histamine is

a known mediator.

  It has now been discovered that mucosal lesions of the gastrointestinal tract caused by nonsteroidal anti-inflammatory drugs

  can be significantly reduced by co-administering

  treatment of sufotidine with the anti-inflammatory

  matory. This combination therapy can be used to treat inflammatory conditions, particularly acute musculoskeletal inflammatory conditions and

  such as rheumatoid states and osteoarthritis

  thrite as well as ankylosing spondylitis and for analgesia in conditions such as dysmenorrhea,

  particular when the use of the anti-

  inflammatory is limited by gastrointestinal side effects.

  The invention thus provides a method of treating

  inflammatory conditions in which

  to a human subject or an animal a drug ant: i-

  non-steroidal inflammatory drug and the

  sufotidine or a physiologically acceptable salt thereof

tables.

  According to another aspect, the invention ensures the use

  of a non-steroidal anti-inflammatory drug

  in general for the preparation of a medi-

  with a view to joint administration with the

  sufotidine or a physiologically acceptable salt thereof

  tables, for the treatment of inflammatory conditions.

  The non-steroidal anti-inflammatory drug

  than by the general route, and one of its physiological salts

  acceptable, may be administered under the

  form of a single pharmaceutical composition comprising

  effective quantities of the two ingredients

  tive. The two active ingredients can also be co-administered as two compositions

  separate pharmaceutical products for the purpose of

multanate or sequential.

  Non-steroidal anti-inflammatory drugs

  general diques that can be used in the ln-

  traditionally also an activity

  analgesic treatment and include, for example, the

  pirine, indomethacin, ibuprofen, piroxicam,

  fenoprofen, ketoprofen, naxoprofen,

  mefenamic, diflunisal, benorylate,

  propazone, diclofenac, fenbufen, féprozone,

  fenclofenac, flufenamic acid, flurbiprofen

  do oxyphenbutazone, phenylbutazone, sulindac

  and tolmetin. They can be used according to the invention

  in their usual dosage amounts, eg

  ex. 50 mg - lg of aspirin, 10 - 100 mg of indomethacin

  ne, 5 - 50 mg of piroxicam and 100 - 500 mg of ibupro-

  belly per dosage unit taken once or several times daily according to the normal dosage regimen for the drug in question. Particular non-steroidal anti-inflammatory agents for use according to

  the invention include indomethacin and, preferably,

the piroxicam.

  Sufotidine may be administered according to the

  in the form of its free base or one of its

  physiologically acceptable salts. These salts include

  salts of inorganic or organic acids

  me hydrochloride, hydrobromide, sulphate, methanesul-

  fonate, acetate maleate, succinate, citrate, tartrate,

  benzoate and fumatate. In particular, the

  fotidine in the form of its free base. The quantity of

  sufotidine employed in the invention will be a quantitative

  sufficient to reduce gastrointestinal distress

  The antiinflammatory drug-induced tidal fluid will preferably be in a range of 50 to 600 mg per dosage unit, expressed as the weight of the free base. Sufotidine is preferably administered

once or twice a day.

  The exact dose of both ingredients actis depends

  the mode of administration and the condition being treated, and

  that it may be necessary to make changes

  routine doses at the dose according to age and weight of

  as well as the severity of the condition to be treated. A form

  Particularly useful me administration is the oral route. In another aspect, the invention provides a

  pharmaceutical composition, for use in medical

2U27985

  a human and veterinary

  general non-steroidal inflammatory disease and sufotidi-

  ne or one of its physiologically acceptable salts.

  Pharmaceutical compositions according to the invention

  can be presented in a conventional way to help

  of at least one pharmaceutical carrier or excipient.

  The composition can take the form, for example, of

  tablets, capsules, powders, granules,

  solutions, syrups, suspensions or suppositories prepared by conventional means with

  acceptable. The compositions can thus contain

  excipients, for example, binding agents,

  agents facilitating compression, loads,

  curing agents, disintegrating agents and wetting agents.

  lants. If desired, other active ingredients may be

  may also be present in these compositions. The tablets may be coated in conventional manner, for example with a suitable film-forming material,

  such as methylcellulose, ethylcellulose and / or hy-

  droxypropyl methylcellulose or sugar. Liquid preparations may also contain, for example,

  edible oils like peanut oil. The suppositions

  sites may contain, for example,

  in fat or miscible with water.

  The pharmaceutical compositions can be prepared

  of the invention according to well-known conventional techniques

  in the pharmaceutical industry. For example, for example

  the anti-inflammatory drug and sufotidine or its salt may be administered together if it is

  desires, with suitable excipients. We can prepare

  tablets, for example, by direct compression

  of such a mixture. Capsules can be prepared in

  mixture with appropriate excipients in

  gelatin capsules, using a filling machine

pleating fit.

  Alternatively, the pharmaceutical compositions

  of the invention may be presented in a form

  me to appropriate controlled release so that the

  sufotidine or its salt are rapidly made available

  for absorption and that the anti-

  1C non-steroidal inflammatory is released more slowly.

  Thus, for example, the pharmaceutical compositions can

  may be presented for oral administration of

  traditional way, associated with

  trolled. In order to better understand the invention,

  gives the following examples for illustration only

  LEMENT. Example 1 - tablets (a) mg / tablet sufotidine 300.00 ibuprofen 400.00 lactose.245.00 hydroxypropyl methylcellulose 5.00 sodium starch glycolate 40.00 magnesium stearate 10.00 compressional weight 1000.00

  Sufotidine and ibuprofen are sifted through a

  250 micron and mixed with lactose. We granulate

  this mixture with a hydroxypropyl methylcellulose solution

  lulose. The granules are dried, sieved and

  mixture with sodium starch glycolate and stearyl

  te of magnesium. Lubricated granules are compressed

  to give tablets using punches

  properties (b) mg / tablet sufotidine 300.00 indomethacin 50.00 microcrystalline cellulose 46.00 magnesium stearate 4.00 lu Compression weight 400.00

  Sufotidine and indomethacin are sieved through

  to a 250 μm sieve and mixed with the cellulose

  microcrystalline and magnesium stearate then compressed using punches of 10.0 mm (c) mg / tablet sufotidine 300.00 piroxicam, 20.00 microcrystalline cellulose 76.00 2u magnesium stearate 4.00 Compression weight 400.00 Sufotidine and piroxicam are sieved through

  a 250 μm sieve and mixed with the medium cellulose

  crystalline and magnesium stearate and

  premium using 10.0 mm punches.

  Example 2 - capsules (a) mg / capsule sufotidine 300.00 ibuprofen 400.00 q starch 1500 ** 96.0 magnesium stearate 4.00 Weight of a filled capsule 800.00

  1C ** directly compressible starch form,

  Denied by Colorcon Ltd., Orpington, Kent.

  Sufotidine and ibuprofen are sieved through

  to a sieve of 250 μm and mixed with starch 1500

  and magnesium stearate. The resulting mixture is poured

  both in hard gelatin capsules of size 0 in

  using an appropriate filling machine.

  (b) mq / capsule sufotidine 300.00 indomethacin 50.00 starch 1500 147.50 magnesium stearate 2.5 Weight of one capsule filled 500.00 Sufotidine and indomethacin are sieved at

  through a 250 μm sieve and mixed with the

  don 1500 and magnesium stearate. Pour the mixture

  resulting in hard gelatin capsules of

  the 1 using an appropriate filling machine.

  (C) mg / capsule sufotidine 300.00 piroxicam 20.00 starch 1500 177.50 magnesium stearate 2.50 Weight of a filled capsule 500.00

  Sufotidine and piroxicam are sieved through

  to a sieve of 250 m and mixed with starch 1500

  lU and magnesium stearate. The resulting mixture is poured

  both in hard gelatin capsules size I in use

  reading an appropriate filling machine.

  Example 3 - suppositories (a) mg / suppository sufotidine 300.0 piroxicam 10.0 Adeps solidus 670.0 colloidal silica 20.0 or Weight of a filled suppository 1000.0

  Sufotidine and piroxicam are sieved through

  to a 100 μm sieve and mixed with the molten Adeps solidus containing the colloidal silica. The resulting mixture is poured into suppository cavities

  using an appropriate filling machine.

  (b) mg / suppository sufotidine 300.0 indomethacin 100.0 polyethylene glycol 400 80.0 3U polyethylene glycol 4000 520.0 Weight of a filled suppository 1000.0

  Sufotidine and indomethacin are sieved through

  to a 100 μm sieve and mixed with the molten polyethylene mixture. The resulting mixture is poured into suppository cavities using a suitable filling machine. l1

Claims (19)

  1. Pharmaceutical composition for application   in human or veterinary medicine including a medical   general non-steroidal anti-inflammatory drug and   sufotidine or a physiologically acceptable salt thereof ceptable.   2. Pharmaceutical composition according to claim   cation 1, in which sufotidine is used in the form of the free base or in the form of its hydrochloride salt, hydrobromide salt, sulfate, methanesulfonate,   acetate, maleate, succinate, tartrate, benzoate or Marate.   3. Pharmaceutical composition according to claim   cation 2, in which sufotidine is used under the shape of the free base.   4. Pharmaceutical composition according to one of the   1 to 3 in unit dosage form and containing 50 to 600 mg of sufotidine per unit dose   expressed as the weight of the free base.   5. Pharmaceutical composition according to one of the   Claims 1 to 4 in which the anti-inflammatory   non-steroidal flammatory is chosen between aspirin,   indomethacin, ibuprofen, piroxicam, fenopro-   fene, ketoprofen, naproxen, mefenamic acid,   diflunisal, benorylate, azapropazone, diclo-   fenac, fenbufen, frazrazone, fenclofenac,   flufenamic acid, flurbiprofen, oxyphenbutazone,   phenylbutazone, sulindac and tolmetin.   6. Pharmaceutical composition according to claim   cation 5, wherein the anti-inflammatory drug Non-steroidal is piroxicam.   7. Pharmaceutical composition according to the claim   6, in unit dosage form and containing - 50 mg of piroxicam per unit dose.   8. Pharmaceutical composition according to any one   conque of claims 1 to 7 in a suitable form oral administration.   9. Pharmaceutical composition according to one of   conque of claims 1 to 8 containing at least one   pharmaceutical carrier or excipient.   10. A process for preparing a pharmaceutical composition   maceutical plant according to any one of claims 1   9, in which the components are treated by means of a   classic way to form a pharmaceutical composition   ceutical. 11. Application of sufotidine or a salt thereof   physiologically acceptable for the preparation of a   for the purpose of administration together with a   general non-steroidal anti-inflammatory drug in   treatment of an inflammatory condition.   12. Application according to claim 11, in which sufotidine is used in the form of the free base or in the form of its hydrochloride salt, hydrobromide salt, methanesulfonate, acetate, maleate,   succinate, tartrate, benzoate or fumarate.   The use according to claim 12 wherein sufotidine is used in the form of the free base.   14. Application according to any one of the   11 to 13, wherein the medicament is in unit dosage form containing from 50 to 600 mg of sufotidine per unit dose expressed as the weight of the free base.   15. Application according to any one of the   11 to 14 according to which the anti-   non-steroidal inflammatory drug is selected.   indomethacin, ibuprofen, piroxicam, fenoprofen, ketoprofen, meproxen, mefenamic acid, diflunisal, benorylate, azapropazone, diclofenac, fenbufen, feprazone, fenclofenac,   flufenamic acid, flurbiprofen, oxyphenbutazo   ne, phenylbutazone, sulindac and tolmetin.   I1C 16. Application according to claim 15, in   which the non-steroidal anti-inflammatory drug what is piroxicam.   17. Application according to claim 16, in   piroxicam is used in a posopro-   unit logic containing 5 - 50 mg of piroxicam per unit dose.   18. Application according to any one of the claims.   11 to 17, in which the medicament is   a form suitable for oral application.   19. Application according to any one of the   claims 11 to 18 in which the medicament is   for administration together with the anti-   inflammatory non-steroidal but separately from him.