WO2002024205A1 - TREATMENT OF INFLAMMATORY BOWEL DISEASE BY THE ADMINISTRATION OF Δ5-ANDROSTENE-3β-OL-7,17 DIONE AND METABOLIZABLE PRECURSORS THEREOF - Google Patents

TREATMENT OF INFLAMMATORY BOWEL DISEASE BY THE ADMINISTRATION OF Δ5-ANDROSTENE-3β-OL-7,17 DIONE AND METABOLIZABLE PRECURSORS THEREOF Download PDF

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Publication number
WO2002024205A1
WO2002024205A1 PCT/US2001/028895 US0128895W WO0224205A1 WO 2002024205 A1 WO2002024205 A1 WO 2002024205A1 US 0128895 W US0128895 W US 0128895W WO 0224205 A1 WO0224205 A1 WO 0224205A1
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WIPO (PCT)
Prior art keywords
androstene
inflammatory bowel
dione
bowel disease
compound
Prior art date
Application number
PCT/US2001/028895
Other languages
French (fr)
Inventor
Ronald J. Zenk
John L. Zenk
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Humanetics Corporation
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 Humanetics Corporation filed Critical Humanetics Corporation
Priority to AU2001290989A priority Critical patent/AU2001290989A1/en
Publication of WO2002024205A1 publication Critical patent/WO2002024205A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • This invention broadly relates to the treatment of inflammatory bowel disease (IBD). More specifically, the invention relates to prophylactic, modulatory, ameliorative and curative drug therapies for IBD, including colitis ulcerosa and Crohn's disease.
  • IBD inflammatory bowel disease
  • IBD inflammatory bowel disease
  • ulcerative colitis characterized by an inflammatory reaction involving primarily the colonic mucosa
  • Crohn's disease characterized by inflammation throughout the gastrointestinal tract.
  • Characteristic symptoms include abdominal pain, straining, diarrhea with or without blood, fatigue, fever, and weight loss. Even the mildest of these conditions can carry obvious emotional and psychological burdens. The quality of life of an affected individual can be significantly reduced.
  • Methods of treating IBD generally involve drug therapy directed towards the suppression of gastrointestinal inflammation.
  • adrenal corticosteroids such as prednisone and prednisolone have been found to be the most efficacious treatment of Crohn's disease and ulcerative colitis.
  • corticosteroid side effects including hair loss, increased water and food intake, weight gain and immunosuppression.
  • a variety of treatments for IBD have been patented over the past several years, including the oral administration of 5-aminosahcylic acid in a controlled release form (United States Patent No. 5,041,431 issued to Halskov), the intravenous administration of azathioprine (United States Patent No. 5,733,915 issued to Sandborn), the oral administration of budesonide suspended in an edible oil (United States Patent No. 5,863,910 issued to Bolonick et al.), and the administration of a histamine H 3 -receptor agonist (United States Patent No. 6,028,095 issued to Guglietta).
  • the search continues for a cost-effective treatment which can be safely used in the prophylactic, modulatory, ameliorative and/or curative therapy for IBD.
  • the invention is directed to the administration of ⁇ 5-androstene-3 ⁇ -ol-7,17 dione and metabolizable precursors thereof for the prophylactic, modulatory, ameliorative and curative treatment of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease.
  • IBD inflammatory bowel disease
  • Inflammatory bowel disease can be treated by administering therapeutic amounts of the steroid ⁇ 5-androstene-3 ⁇ -ol-7,17 dione and metabolizable precursors thereof, such as ⁇ 5- androstene-3 ⁇ -acetyl-7,17 dione.
  • Such treatment can be prophylactic, modulatory, ameliorative or curative in nature.
  • the steroid ⁇ 5-androstene-3 ⁇ -ol-7,17 dione is a derivative of dehydroepiandrosterone (DHEA) which does not appreciably stimulate, increase or otherwise enhance the production of sex hormones.
  • DHEA dehydroepiandrosterone
  • the steroid is commercially available from a number of sources including Steraloids, Inc. of Wilton, New Hampshire.
  • a number of procedures are available for synthesizing ⁇ 5-androstene-3 ⁇ -ol-7,17 dione from DHEA, with one such procedure described in United States Patent No. 5,296,481.
  • Precursors of ⁇ 5-androstene-3 ⁇ -ol-7,17 dione may also be usefully employed in the treatment of hypothyroidism. Such precursors are readily metabolized in vivo to the active ⁇ 5-androstene-3 ⁇ -ol-7,17 dione.
  • a metabolizable precursor is the commercially available ⁇ 5-androstene-3 ⁇ -acetyl-7,17 dione.
  • the 3 ⁇ -acetyl group is hydrolyzed in vivo by esterases located in the blood and various tissue to produce the active ⁇ 5-androstene-3 ⁇ -ol-7,17 dione, and is believed to be less susceptible to oxidation during the manufacturing process than the hydroxy group found on the active ⁇ 5-androstene-3 ⁇ -ol-7,17 dione.
  • Other metabolizable precursors include ⁇ 5-androstene-3 ⁇ , 17 ⁇ -diol-7-one, ⁇ 5- androstene-3 ⁇ , 7 ⁇ -diol-17-one, ⁇ 5-androstene-3 ⁇ , 7 ⁇ -diol-17-one and the corresponding acetyl esters of these steroids.
  • the ⁇ 5 Androstene-3-acetyl-7,17-dione can be administered by virtually any of the commonly accepted practices for the administration of pharmaceutical preparations including specifically, but not exclusively, mucosal administration, oral consumption, ocular administration, subcutaneous injection, transdermal administration, etc. Oral administration is generally preferred.
  • Mucosal administration of the steroid includes such routes as buccal, endotracheal, nasal, pharyngeal, rectal, sublingual, vaginal, etc.
  • the steroid may be formulated as an emulsion, gum, lozenge, spray, tablet or an inclusion complex such as cyclodextrin inclusion complexes.
  • Nasal administration is conveniently conducted through the use of a sniffing powder or nasal spray.
  • the steroid may be formulated as a cream, douche, enema or suppository.
  • Oral consumption of the steroid may be effected by incorporating the steroid into a food or drink, or formulating the steroid into a chewable or swallowable tablet or capsule.
  • Ocular administration may be effected by incorporating the steroid into a solution or suspension adapted for ocular application such as drops or sprays.
  • Subcutaneous administration involves incorporating the steroid into a pharmaceutically acceptable and injectable carrier.
  • the steroid may be conveniently incorporated into a lipophilic carrier and formulated as a topical creme or adhesive patch.
  • the range of dosages and dose rates effective for achieving the desired biological response may be determined in accordance with standard industry practices. These ranges can be expected to differ depending upon numerous well known factors such as the severity and/or chronicity of the disease, the species of the patient, the histopathalogic type of the patient, the weight of the patient, the length and course of the treatment, the region of the gastrointestinal tract to be treated, the responsiveness of the patient, and whether the desired response is prophylactic, modulatory, ameliorative or curative in nature.
  • the subject can be a human or a pet such as a cat, dog or horse.
  • the treatment is also suitable for use with commercially valuable livestock such as cattle, pigs and sheep; as well as exotic mammals such as those found in zoos and circuses.

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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)
  • Steroid Compounds (AREA)

Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, can be treated by the administration of Δ5-androstene-3β-ol-7,17 dione and metabolizable precursors thereof.

Description

TREATMENT OF INFLAMMATORY BOWEL DISEASE
BY THE ADMINISTRATION OF Δ5-ANDROSTENE-3β-OL-7,17 DIONE
AND METABOLIZABLE PRECURSORS THEREOF
FIELD OF THE INVENTION
This invention broadly relates to the treatment of inflammatory bowel disease (IBD). More specifically, the invention relates to prophylactic, modulatory, ameliorative and curative drug therapies for IBD, including colitis ulcerosa and Crohn's disease.
BACKGROUND
Chronic inflammatory disorders of the gastrointestinal tract are generally grouped under the heading of inflammatory bowel disease (IBD), although the disease can affect any part of the gastrointestinal tract from the esophagus to the large intestine. Inflammatory bowel disease is of unknown etiology, although psychological, immunologic, and genetic sources have been discusses as possible etio logic factors. The gastrointestinal inflammation associated with IBD causes a range of symptoms of increasing severity and with a variety of intestinal and extraintestinal manifestations.
The manifestations of chronic IBD range from mild to extreme. Extreme cases including colitis, characterized by an inflammatory reaction involving primarily the colonic mucosa, and Crohn's disease, characterized by inflammation throughout the gastrointestinal tract. The clinical features of ulcerative colitis and Crohn's disease can be similar. Characteristic symptoms include abdominal pain, straining, diarrhea with or without blood, fatigue, fever, and weight loss. Even the mildest of these conditions can carry obvious emotional and psychological burdens. The quality of life of an affected individual can be significantly reduced.
Methods of treating IBD generally involve drug therapy directed towards the suppression of gastrointestinal inflammation. Of the anti-inflammatory drugs, adrenal corticosteroids such as prednisone and prednisolone have been found to be the most efficacious treatment of Crohn's disease and ulcerative colitis. However, the effectiveness of corticosteroid in relieving the symptoms of gastrointestinal inflammation is often accompanied by unfortunate steroid side effects, including hair loss, increased water and food intake, weight gain and immunosuppression. These systemic side effects can develop after even short-term treatment. Thus, a treatment that is effective in controlling the symptoms of gastrointestinal inflammation but with minimal systemic effects has been sought.
A variety of treatments for IBD have been patented over the past several years, including the oral administration of 5-aminosahcylic acid in a controlled release form (United States Patent No. 5,041,431 issued to Halskov), the intravenous administration of azathioprine (United States Patent No. 5,733,915 issued to Sandborn), the oral administration of budesonide suspended in an edible oil (United States Patent No. 5,863,910 issued to Bolonick et al.), and the administration of a histamine H3-receptor agonist (United States Patent No. 6,028,095 issued to Guglietta). However, the search continues for a cost-effective treatment which can be safely used in the prophylactic, modulatory, ameliorative and/or curative therapy for IBD.
SUMMARY OF THE INVENTION
The invention is directed to the administration of Δ5-androstene-3β-ol-7,17 dione and metabolizable precursors thereof for the prophylactic, modulatory, ameliorative and curative treatment of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease.
DETAILED DESCRIPTION OF THE INVENTION INCLUDING A BEST MODE
Inflammatory bowel disease can be treated by administering therapeutic amounts of the steroid Δ5-androstene-3β-ol-7,17 dione and metabolizable precursors thereof, such as Δ5- androstene-3β-acetyl-7,17 dione. Such treatment can be prophylactic, modulatory, ameliorative or curative in nature.
The Compound
The steroid Δ5-androstene-3β-ol-7,17 dione is a derivative of dehydroepiandrosterone (DHEA) which does not appreciably stimulate, increase or otherwise enhance the production of sex hormones. The steroid is commercially available from a number of sources including Steraloids, Inc. of Wilton, New Hampshire. A number of procedures are available for synthesizing Δ5-androstene-3β-ol-7,17 dione from DHEA, with one such procedure described in United States Patent No. 5,296,481.
Precursors of Δ5-androstene-3β-ol-7,17 dione may also be usefully employed in the treatment of hypothyroidism. Such precursors are readily metabolized in vivo to the active Δ5-androstene-3β-ol-7,17 dione. One example of such a metabolizable precursor is the commercially available Δ5-androstene-3β-acetyl-7,17 dione. The 3β-acetyl group is hydrolyzed in vivo by esterases located in the blood and various tissue to produce the active Δ5-androstene-3β-ol-7,17 dione, and is believed to be less susceptible to oxidation during the manufacturing process than the hydroxy group found on the active Δ5-androstene-3β-ol-7,17 dione. Other metabolizable precursors include Δ5-androstene-3β, 17β-diol-7-one, Δ5- androstene-3β, 7α-diol-17-one, Δ5-androstene-3β, 7β-diol-17-one and the corresponding acetyl esters of these steroids.
Administration
Administration Route
The Δ5 Androstene-3-acetyl-7,17-dione can be administered by virtually any of the commonly accepted practices for the administration of pharmaceutical preparations including specifically, but not exclusively, mucosal administration, oral consumption, ocular administration, subcutaneous injection, transdermal administration, etc. Oral administration is generally preferred. Mucosal administration of the steroid includes such routes as buccal, endotracheal, nasal, pharyngeal, rectal, sublingual, vaginal, etc. For administration through the buccal/sublingual/pharyngeal/endotracheal mucόsal, the steroid may be formulated as an emulsion, gum, lozenge, spray, tablet or an inclusion complex such as cyclodextrin inclusion complexes. Nasal administration is conveniently conducted through the use of a sniffing powder or nasal spray. For rectal and vaginal administration the steroid may be formulated as a cream, douche, enema or suppository.
Oral consumption of the steroid may be effected by incorporating the steroid into a food or drink, or formulating the steroid into a chewable or swallowable tablet or capsule.
Ocular administration may be effected by incorporating the steroid into a solution or suspension adapted for ocular application such as drops or sprays.
Subcutaneous administration involves incorporating the steroid into a pharmaceutically acceptable and injectable carrier.
For transdermal administration, the steroid may be conveniently incorporated into a lipophilic carrier and formulated as a topical creme or adhesive patch.
Dose Rate
The range of dosages and dose rates effective for achieving the desired biological response may be determined in accordance with standard industry practices. These ranges can be expected to differ depending upon numerous well known factors such as the severity and/or chronicity of the disease, the species of the patient, the histopathalogic type of the patient, the weight of the patient, the length and course of the treatment, the region of the gastrointestinal tract to be treated, the responsiveness of the patient, and whether the desired response is prophylactic, modulatory, ameliorative or curative in nature.
The treatment of LBD is often idiosyncratic and adjustment of dosages and dose rate is well within the level of one having skill in the art. Subject
The subject can be a human or a pet such as a cat, dog or horse. The treatment is also suitable for use with commercially valuable livestock such as cattle, pigs and sheep; as well as exotic mammals such as those found in zoos and circuses.
EXPERIMENTAL
Experiment 1
Two female subjects, aged 66 and 70 and suffering from years of chronic Crohn's colitis, orally consumed 100 mg capsules of Δ5-androstene-3β-acetyl-7,17 dione twice daily for two months. Both subjects visited their personal doctor at the end of both the first and second months and reported a lessening in the severity of abdominal cramping, less frequent stools and a significant decrease in fatigue at both visits.

Claims

I claim:
1. A method of treating inflammatory bowel disease comprising administering a therapeutically effective amount of a compound to a mammal in need of such treatment wherein the compound is selected from Δ5-androstene-3β-ol-7,17 dione and metabolizable precursors thereof.
2. The method of claim 1 wherein the subject is a mammal.
3. The method of claim 2 wherein the subject is a dog or a cat.
4. The method of claim 2 wherein the subject is a human.
5. The method of claim 1 wherein the compound is administered orally.
6. The method of claim 1 wherein the compound is Δ5-androstene-3β-acetyl-7,17 dione.
7. The method of claim 1 wherein the compound is administered daily.
8. The method of claim 1 wherein the inflammatory bowel disease is ulcerative colitis.
9. The method of claim 1 wherein the inflammatory bowel disease is Crohn's disease.
10. A method of prophylactically protecting against the onset of inflammatory bowel disease comprising administering a prophylactically effective amount of a compound to a mammal desiring prophylactic protection against the onset of inflammatory bowel disease wherein the compound is selected from Δ5-androstene-3β-ol-7,17 dione and metabolizable precursors thereof.
11. The method of claim 10 wherein the subj ect is a mammal.
12. The method of claim 11 wherein the subject is a dog or a cat.
13. The method of claim 11 wherein the subj ect is a human.
14. The method of claim 10 wherein the compound is administered orally.
15. The method of claim 10 wherein the compound is Δ5-androstene-3 β-acetyl-7, 17 dione.
16. The method of claim 10 wherein the compound is administered daily.
17. The method of claim 10 wherein the inflammatory bowel disease is ulcerative colitis.
18. The method of claim 10 wherein the inflammatory bowel disease is Crohn' s disease.
PCT/US2001/028895 2000-09-19 2001-09-18 TREATMENT OF INFLAMMATORY BOWEL DISEASE BY THE ADMINISTRATION OF Δ5-ANDROSTENE-3β-OL-7,17 DIONE AND METABOLIZABLE PRECURSORS THEREOF WO2002024205A1 (en)

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US66564000A 2000-09-19 2000-09-19
US09/665,640 2000-09-19

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024460A1 (en) * 2001-09-14 2003-03-27 Laboratoires Mayoly Spindler Use of 7-alpha hydroxy dhea and 7-oxo dhea for treating inflammatory or functional intestinal diseases
US8324192B2 (en) 2005-11-12 2012-12-04 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US8497258B2 (en) 2005-11-12 2013-07-30 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US8679545B2 (en) 2005-11-12 2014-03-25 The Regents Of The University Of California Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract
US8865692B2 (en) 2007-11-13 2014-10-21 Meritage Pharma, Inc Compositions for the treatment of gastrointestinal inflammation
US10293052B2 (en) 2007-11-13 2019-05-21 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5411988A (en) * 1993-10-27 1995-05-02 Bockow; Barry I. Compositions and methods for inhibiting inflammation and adhesion formation
WO1999025333A1 (en) * 1997-11-19 1999-05-27 Humanetics Corporation USE OF Δ5-ANDROSTENE-3β-OL-7,17-DIONE IN THE TREATMENT OF LUPUS ERYTHEMATOSUS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5411988A (en) * 1993-10-27 1995-05-02 Bockow; Barry I. Compositions and methods for inhibiting inflammation and adhesion formation
WO1999025333A1 (en) * 1997-11-19 1999-05-27 Humanetics Corporation USE OF Δ5-ANDROSTENE-3β-OL-7,17-DIONE IN THE TREATMENT OF LUPUS ERYTHEMATOSUS

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024460A1 (en) * 2001-09-14 2003-03-27 Laboratoires Mayoly Spindler Use of 7-alpha hydroxy dhea and 7-oxo dhea for treating inflammatory or functional intestinal diseases
US10272037B2 (en) 2005-11-12 2019-04-30 The Regents Of The University Of California Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract
US8497258B2 (en) 2005-11-12 2013-07-30 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US8679545B2 (en) 2005-11-12 2014-03-25 The Regents Of The University Of California Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract
US8975243B2 (en) 2005-11-12 2015-03-10 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US9119863B2 (en) 2005-11-12 2015-09-01 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US9782347B2 (en) 2005-11-12 2017-10-10 The Regents Of The University Of California Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract
US8324192B2 (en) 2005-11-12 2012-12-04 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US11197822B2 (en) 2005-11-12 2021-12-14 The Regents Of The University Of California Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US8865692B2 (en) 2007-11-13 2014-10-21 Meritage Pharma, Inc Compositions for the treatment of gastrointestinal inflammation
US9050368B2 (en) 2007-11-13 2015-06-09 Meritage Pharma, Inc. Corticosteroid compositions
US10293052B2 (en) 2007-11-13 2019-05-21 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
US11357859B2 (en) 2007-11-13 2022-06-14 Viropharma Biologics Llc Compositions for the treatment of gastrointestinal inflammation

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