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WO1995001177A1 - Medicaments contenant du chlorhydrate de vapiprost servant au traitement d'affections inflammatoires - Google Patents

Medicaments contenant du chlorhydrate de vapiprost servant au traitement d'affections inflammatoires Download PDF

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Publication number
WO1995001177A1
WO1995001177A1 PCT/EP1994/002105 EP9402105W WO9501177A1 WO 1995001177 A1 WO1995001177 A1 WO 1995001177A1 EP 9402105 W EP9402105 W EP 9402105W WO 9501177 A1 WO9501177 A1 WO 9501177A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
vapiprost
diseases
inflammatory diseases
inflammatory bowel
Prior art date
Application number
PCT/EP1994/002105
Other languages
English (en)
Inventor
Sreekantaswamy S. N. Murthy
Original Assignee
Glaxo Group Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU73839/94A priority Critical patent/AU7383994A/en
Publication of WO1995001177A1 publication Critical patent/WO1995001177A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • Medicaments containi ng vapiprost hydrochloride for the treatment of inflammatory di seases.
  • This invention relates to a new medical use for the hydrochloride salt of [IB-[1 ⁇ (Z), 2 ⁇ , 3 ⁇ , 5 ⁇ ]]-(+)-7-[5-[[(1 ,1 '-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1- piperidinyl)cyclopentyl]-4-heptenoic acid (hereinafter referred to as Vapiprost).
  • Vapiprost the hydrochloride salt of [IB-[1 ⁇ (Z), 2 ⁇ , 3 ⁇ , 5 ⁇ ]]-(+)-7-[5-[[(1 ,1 '-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1- piperidinyl)cyclopentyl]-4-heptenoic acid
  • Vapiprost relates to the use of Vapiprost in the treatment of certain inflammatory diseases, including inflammatory bowel diseases.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are poorly treated, chronic progressive inflammatory conditions.
  • Current management is based on the use of corticosteroids to reduce acute inflammation and sulfasalazine to maintain remission, or resection when chemotherapy fails.
  • corticosteroids to reduce acute inflammation and sulfasalazine to maintain remission, or resection when chemotherapy fails.
  • There is undoubtedly a need for improved therapy to replace or supplement existing management of these diseases which carry a high risk of progressing to serious conditions such as ileal stenosis, peritoneal adhesions, fistula formation, perforation and colon cancer.
  • Vapiprost is a potent thromboxane receptor blocker which inhibits thromboxane A 2 and endoperoxide mediated aggregation of blood platelets and contraction of vascular smooth muscle and is of particular interest as an anti-thrombotic agent.
  • Vapiprost is of use in the treatment of inflammatory bowel diseases such as Crohn's disease or ulcerative colitis and may be used to treat other chronic progressive intestinal inflammatory diseases of unknown aetiology.
  • Vapiprost in the manufacture of a medicament for the treatment of chronic progressive intestinal inflammatory diseases of unknown aetiology (e.g. inflammatory bowel diseases) in a human or non-human animal subject.
  • chronic progressive intestinal inflammatory diseases of unknown aetiology e.g. inflammatory bowel diseases
  • Vapiprost in the manufacture of a medicament for the treatment of Crohn's disease or ulcerative colitis in a human or non-human animal subject.
  • a method of treatment of a human or non-human animal subject suffering from or susceptible to chronic progressive intestinal inflammatory diseases of unknown aetiology e.g. inflammatory bowel diseases
  • which method comprises administering to the said subject an effective amount of Vapiprost.
  • a method of treatment of a human or non-human animal subject suffering from or susceptible to Crohn's disease or ulcerative colitis comprises administering to the said subject an effective amount of Vapiprost.
  • references herein to treatment extend to prophylaxis as well as the treatment of established conditions.
  • Vapiprost in the treatment of inflammatory bowel and related diseases may be demonstrated, for example, by its ability to inhibit dextran sulphate-induced colitis in mice using experiments analogous to those described by Shim et al. in Gastroenterology, 1991 ,100, A841.
  • Figure 1 hereinafter provides the results of such an experiment.
  • Figure 1 demonstrates that GR32191 B (i.e. Vapiprost) suppresses the DSS (i.e. dextran sulphate) effect on mouse colon when measured as a ratio of colon weight per unit length.
  • GR32191 B i.e. Vapiprost
  • DSS i.e. dextran sulphate
  • Vapiprost in the form of a pharmaceutical composition.
  • the present invention therefore also provides a pharmaceutical composition for use in the treatment of chronic progressive intestinal inflammatory diseases of unknown aetiology (e.g. inflammatory bowel disease) comprising Vapiprost, where desirable, together with one or more carriers or excipients.
  • chronic progressive intestinal inflammatory diseases of unknown aetiology e.g. inflammatory bowel disease
  • Vapiprost in combination therapy with another agent useful in the treatment of the same disease.
  • Vapiprost may be co- administered with an immunosuppressive agent such as cyclosporin or FK-506.
  • an immunosuppressive agent such as cyclosporin or FK-506.
  • the present invention encompasses the co- administration of Vapiprost with another suitable agent, such as is described hereinabove, to treat chronic progressive intestinal inflammatory diseases of unknown aetiology, (e.g. inflammatory bowel diseases).
  • the term 'co-administration' means either separate or simultaneous (e.g. as a single pharmaceutical composition) administration of the two active entities.
  • the active ingredients must of course be stable and mutually compatible in the particular formulation employed.
  • Vapiprost may be used according to the present invention in various formulations for oral, parenteral or rectal administration. Suitable formulations for oral or parenteral use according to the present invention are described in GB-B-2097397, GB-B-2127406 and GB-B-2211737. Specific examples of oral and parenteral formulations for use according to the present invention are given hereinafter. Suitable formulations for rectal use according to the present invention include, for example, enemas in suitable buffered aqueous vehicles and suppositories prepared, for example, with commercial suppository bases. Vapiprost is preferably administered by the oral route for use according to the present invention.
  • Vapiprost to be administered will, of course, depend on a number of factors including, for example, the age, weight and condition of the patient, the route of administration and the specific disease to be treated.
  • An effective oral dose is likely to be in the range from 0.05 to 20mg/kg body weight, preferably 0.05 to 5mg/kg body weight, per day, and administered in suitable dosage units.
  • Vapiprost was dissolved in 35ml water suitable for injection and the ⁇ - cyclodextrin was added. This solution was titrated to pH7 with 0.02M sodium hydroxide solution and then adjusted to volume with water suitable for injection.
  • the solution may then be sterilised by filtration and filled into vials or ampoules.
  • Vapiprost was dissolved in approximately 25ml water suitable for injection.
  • the ⁇ -cyclodextrin was dissolved therein and the resulting solution was titrated to pH6 with 0.02M sodium hydroxide solution and the phosphate buffer added.
  • the sodium chloride was added to the solution and the pH adjusted to pH7 with sodium hydroxide.
  • the solution was made up to volume with water suitable for injection. A sample of this solution was filled into a glass vial which was sealed with a rubber plug and metal overseal. This was then autoclaved.
  • Vapiprost was dissolved in approximately 25ml water suitable for injection and the hydroxypropyl- ⁇ -cyclodextrin was added. The mannitol was then added and the solution titrated to pH 6 with 0.02M sodium hydroxide solution. The phosphate buffer solution was added and the solution adjusted to volume with water suitable for injection. The solution was then filtered and filled into glass vials which were sealed with rubber plugs and metal overseals. These were then autoclaved.
  • Vapiprost was dissolved in approximately 25ml water suitable for injection.
  • the ⁇ -cyclodextrin and mannitol were dissolved therein and the solution titrated to pH 6 with 0.02M sodium hydroxide solution.
  • the sodium acid phosphate and anhydrous disodium phosphate were dissolved in water suitable for injection. This solution was added to the bulk solution which was made up to volume with water suitable for injection. The solution was filtered and filled into glass ampoules which were sealed and then autoclaved.
  • Vapiprost was dissolved in approximately 25ml water suitable for injection and the cyclodextrin(s) was (were) added. The mannitol was then added and the solution titrated to pH 6 with 0.02M sodium hydroxide solution. The phosphate buffer solution was added and the solution was adjusted to volume with water suitable for injection. The solution was then filtered and filled into glass vials which were sealed with rubber plugs and metal overseals.
  • Vapiprost (equivalent to 2.5mg base)
  • These may be prepared by direct compression or wet granulation.
  • the direct compression method is preferred but may not be suitable in all cases as it is dependent upon the dose level of the active ingredient.
  • Vapiprost is sieved through a 250 n ⁇ 6 sieve, blended with the excipients and compressed using 10.0mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.
  • Vapiprost is sieved through a 250 m "6 sieve and blended with the lactose, starch and pre-gelatinised starch.
  • the mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stearate.
  • the lubricated granules are compressed into tablets as described for the direct compression formula.
  • the tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxypropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.
  • suitable film forming materials e.g. methyl cellulose or hydroxypropyl methyl cellulose using standard techniques.
  • the tablets may be sugar coated.
  • Vapiprost is sieved through a 250 r ⁇ r 6 sieve and blended with the other materials.
  • the mix is filled into No.2 hard gelatin capsules using a suitable filling machine.
  • Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à l'utilisation du sel chlorhydrate de l'acide [IR^_-[1α(Z^_),2β,3β,5α]]-(+)-7-[5-[[(1,1'-biphényl)-4-yl]méthoxy]-3-hydroxy-2-(1-pipéridinyl)cyclopentyl]-4-hepténoïque (c'est-à-dire Vapiprost) dans le traitement de certaines affections inflammatoires comprenant les affections intestinales inflammatoires non spécifiques.
PCT/EP1994/002105 1993-07-01 1994-06-29 Medicaments contenant du chlorhydrate de vapiprost servant au traitement d'affections inflammatoires WO1995001177A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73839/94A AU7383994A (en) 1993-07-01 1994-06-29 Medicaments containing vapiprost hydrochloride for the treatment of inflammatory diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939313649A GB9313649D0 (en) 1993-07-01 1993-07-01 Medicaments
GB9313649.7 1993-07-01

Publications (1)

Publication Number Publication Date
WO1995001177A1 true WO1995001177A1 (fr) 1995-01-12

Family

ID=10738145

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002105 WO1995001177A1 (fr) 1993-07-01 1994-06-29 Medicaments contenant du chlorhydrate de vapiprost servant au traitement d'affections inflammatoires

Country Status (5)

Country Link
AU (1) AU7383994A (fr)
GB (1) GB9313649D0 (fr)
IL (1) IL110169A0 (fr)
WO (1) WO1995001177A1 (fr)
ZA (1) ZA944671B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011057262A3 (fr) * 2009-11-09 2011-08-11 Evolva Inc. Traitement des infections par des antagonistes du récepteur tp
US8486994B2 (en) 2007-01-18 2013-07-16 Evolva Sa Prodrugs of substituted 1,3-dioxanes and their uses
US8536196B2 (en) 2007-01-18 2013-09-17 Evolva Sa Substituted 1,3-dioxanes useful as PPAR modulators

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0448274A2 (fr) * 1990-03-19 1991-09-25 E.R. Squibb & Sons, Inc. Utilisation d'un antagoniste du récepteur de thromboxane a2 pour l'obtention d'un médicament destiné au traitement des conditions ulcératives gastro-intestinales

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0448274A2 (fr) * 1990-03-19 1991-09-25 E.R. Squibb & Sons, Inc. Utilisation d'un antagoniste du récepteur de thromboxane a2 pour l'obtention d'un médicament destiné au traitement des conditions ulcératives gastro-intestinales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Vapiprost Hydrochloride GR-32191", DRUGS FUTURE, vol. 16, no. 11, 1991, pages 1075 - 5 *
BR.J.CLIN.PHARMAC., vol. 29, 1990, pages 431 - 36 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8486994B2 (en) 2007-01-18 2013-07-16 Evolva Sa Prodrugs of substituted 1,3-dioxanes and their uses
US8536196B2 (en) 2007-01-18 2013-09-17 Evolva Sa Substituted 1,3-dioxanes useful as PPAR modulators
US8952053B2 (en) 2007-01-18 2015-02-10 Evolva Sa Prodrugs of substituted 1,3-dioxanes and their uses
US9260406B2 (en) 2007-01-18 2016-02-16 Evolva Sa Substituted 1,3-dioxanes useful as PPAR modulators
WO2011057262A3 (fr) * 2009-11-09 2011-08-11 Evolva Inc. Traitement des infections par des antagonistes du récepteur tp

Also Published As

Publication number Publication date
GB9313649D0 (en) 1993-08-18
ZA944671B (en) 1995-01-16
IL110169A0 (en) 1994-10-07
AU7383994A (en) 1995-01-24

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