Use of a Pure Narcotic Antagonist, E.G. Nalmefene, Naltrexone, Naloxone Or Diprenorphine, in the Treatment of Mast Cell Disease

Office europeen des brevets (fi) Publication number : 0 471 525 A1

@ EUROPEAN PATENT APPLICATION

@ Application number : 91307365.6 @ Int. CI.5 : A61K 31/485

(22) Date of filing : 09.08.91

(§) Priority : 10.08.90 US 565428 @ Inventor : Frost, Phillip 125 East San Marino Drive Miami Beach, FL 33139 (US) @ Date of publication of application : 19.02.92 Bulletin 92/08 (74) Representative : Ritter, Stephen David et al Mathys & Squire 10 Fleet Street @) Designated Contracting States : London EC4Y 1AY (GB) AT BE CH DE DK ES FR GB GR IT LI LU NL SE

(54) Use of a pure narcotic antagonist, e.g. nalmefene, naltrexone, naloxone or diprenorphine, in the treatment of mast cell disease.

(57) A method of treating a patient suffering from mast cell disease comprising daily administration to such patient of from about 1 to about 150 mg of a pure narcotic antagonist, e.g., nalmefene, naltrexone, naloxane or diprenorphine. The antagonist may be administered in divided doses from one to four times daily, preferably by the oral route. Parenteral, transmucosal and transdermal administration may be utilized where suitable.

CM IO

LU Jouve, 18, rue Saint-Denis, 75001 PARIS 1 EP 0 471 525 A1 2

The invention relates to methods of treating mast sive reticuloendothelial involvement results in death cell disease. in a few months to several years. Patients die from Mast cell disease is manifested in two, somewhat pancytopenia, infection, hemorrhage, cachexia, gas- related conditions: urticaria pigmentosa and systemic troenteritis, perforated peptic ulcer, and leukemia. mastocytosis. 5 Conventional therapy is palliative and symptoma- Urticaria pigmentosa usually begins in early chil- tic and includes transfusions, antimicrobials, antihis- dhood and disappears partially or completely by tamines, adrenal steroids, corticotrophin, roentgen adolescence. Characteristic skin lesions are single or irradiation, and nitrogen mustard. multiple pigmented macules or nodules that urticate Nalmefene (6-methylene-6-desoxy-N-cyclop- on rubbing and contain large numbers of mast cells. 10 ropylmethyl-14-hydroxydihydronormorphine) is a Although uncommon, the disorder is seen in most long-acting, orally available, potent narcotic antagon- dermatolegic and pediatric practices. Light-skinned ist with pure antagonist activity. Apart from its utility in persons are affected most often, and it is slightly more antagonizing the sedation, respiratory depression common in males. The disorder has been reported in and other actions of opioid agents, nalmefene has a parent and child in several families and in both mem- 15 also been found useful in treating diverse conditions bers of monozygotic twins. More than 10 percent of such as hyperkinesia in children (U.S. Pat. No. cases are present at birth; over half develop by six 4,454,142), senile dementia (U.S. Pat. No. months; and the majority appear before puberty. 4,511,570), sudden infant death syndrome (U.S. Pat. Onset after puberty raises the question of systemic No. 4,639,455), autoimmune diseases (U.S. Pat. No. mastocytosis. 20 4,857,533), arthritic and inflammatory diseases (U.S. Conventional treatments for urticaria pigmentosa Pat. No. 4,863,928), interstitial cystitis (U.S. Pat. No. have been relatively ineffective. Antihistamines may 4,877,791), allergic rhinitis (U.S. Pat. No. 4,880,813). attenuate some of the symptoms, but aspirin and In commonly owned U.S. Pat. No. 4,923,875, the pre- codeine degranulate mast cells and may aggravate sent inventor disclosed the utility of topical nalmefene symptoms. Although the disease is generally benign, 25 in treating urticaria, various eczemas, and other mast in rare instances patients have developed serious cell-mediated dermatological disorders, but not the complications such as infected bullae, peptic ulcers use of oral nalmefene in systemic mast cell disease. and bleeding tendencies. In commonly owned, published PCT Application No. Systemic mastocytosis, a rare, recently recog- US86/02268, it was disclosed that nalmefene is use- nized disease, is being reported with increasing fre- 30 ful for the treatment of antigen-induced allergic res- quency. It affects both males and females and usually ponses, including those where degranulation of mast begins in adult life. The cause is unknown. The clinical cells may be a causative factor. manifestations and course may resemble those of Naltrexone (N-cyclopropylmethyl-14-hydroxydi- lymphoma or leukemia, and it seems likely that the hydromor- phinone) is another orally available narco- disorder should be classified with the reti- 35 tic antagonist with pure antagonist activity. culoendothelioses. Naltrexone has additionally been disclosed as useful Skin or mucous membrane lesions may resemble for inducing anorexia (U.S. Pat. Nos. 4,477,457; childhood urticaria pigmentosa, but significant differ- 4,478,840) and for treating shock (U.S. Pat. Nos. ences that indicate systemic mastocytoses are (1) 4,267,182; 4,434,168), as well as for certain of the onset after puberty, (2) multiple, small, confluent 40 conditions cited above where nalmefene has been macules with persistent telangiectasia, (3) papules found useful. and nodules resembling leukemia cutis, (4) chronic In U.S. Pat. Nos. 4,877,791 and 4,923,875 it is lichenified dermatitis, (5) generalized infiltration of disclosed that pure narcotic antagonists such as nal- skin with a "scotch-grain" appearance, (6) less pig- mefene and naltrexone may suppress histamine mentation, (7) less tendency to redden and urticate on 45 release from mast cells found in the bladder walls and stroking, (8) extensive involvement of oral, nasal, or the skin. rectal mucosa, and (9) progressive cutaneous There does not currently exist any modality of change. drug treatment for mast cell disease, particularly sys- Histamine release into the general circulation is temic mastocytosis, which is known to be safe and less likely than in childhood urticaria pigmentosa, yet so effective in a significant number of cases. patients may have flushing, shocklike episodes, and increased histamine in the urine. Diarrhea is often a SUMMARY OF THE INVENTION prominent feature, and peptic ulcer occasionally develops. It is the object of the present invention to provide The prognosis varies with the form of the disor- 55 a method of treatment for mast cell disease which may der. Disease confined to skin and bone is compatible achieve symptomatic relief, prevent recurrence of the with long life and little morbidity, but there is always symptomatic phase and induce remission. In keeping the threat of extension of the morbid process. Exten- with this object and others which will become appa- 2 3 EP 0 471 525 A1 4 rent hereinafter, the present invention resides in the dermal absorption of the active antagonist ingred- daily administration to patients suffering from mast ients. Examples of such transmucosal and transder- cell disease of from about 1 to about 150 milligrams mal vehicles may be found throughout the of a pure narcotic antagonist, e.g., nalmefene or nal- pharmaceutical literature, including in Remington's trexone. The oral route of administration is preferred 5 Pharmaceutical Sciences, 1 7th edition (1 985). for patient convenience, comfort and safety, but By one preferred method, the pure narcotic parenteral and other methods of administration may antagonist may be initially administered to patients be utilized. suffering from mast cell disease in total daily doses of The method of treatment of the present invention about 1.0-10.0 mg, for example for a one-week consists of the daily administration to patients suffer- 10 period, with gradual increments in daily dose of about ing from mast cell disease of from about 1 to about 1-40 mg up to a maximum of 150 mg (50 mg. t.i.d. or 1 50 mg of a pure narcotic antagonist. As used herein, 75 mg b.i.d.). the term "pure narcotic antagonist" refers to subst- In general, the method of the present invention is ances which block or reverse the effects of exogen- not dependent on any particular vehicle for the active ous or endogenous opioids or opiates while having no 15 narcotic antagonist agents or any particular route of intrinsic narcotic agonist activity themselves. administration. Any known method for getting effec- The oral route of administration is preferred so tive treatment amounts of a pure narcotic antagonist that the patient can self-medicate safely and conve- into the-bloodstream of the patient may be utilized. niently. A number of the pure narcotic antagonists, for Although there may be no need to administer the example nalmefene and naltrexone, are highly effec- 20 pure narcotic antagonists more than once or twice tive and substantially bioavailable when administered daily to achieve the results envisioned by the present orally. For purposes of the present invention, how- invention, equally divided doses administered up to ever, any of the pure narcotic antagonists may be four times daily may be utilized. There have been few administered parenterally or via other routes of reports of any significant adverse effects with administration as well (e.g., transmucosally), as long 25 antagonists such as nalmefene or naltrexone at the as adequate blood levels are achieved. dosage levels proposed by the present invention. Any pure narcotic antagonist may be used in the The following example provides an illustration of method of the present invention, but not mixed ago- the method of the present invention. This example is nist-antagonists. Such pure narcotic antagonists not intended to limit or restrict the scope of the inven- include, by way of example but not limitation, 30 tion in any way, and should not be construed as pro- naloxone, nalmefene, naltrexone and diprenorphine. viding dosage forms, regimens or methods of Preferred agents are those which are orally active and administration which must be utilized exclusively to which have a long duration of action, in particular nal- practice the invention. mefene and naltrexone. In accordance with the present invention, the 35 EXAMPLE pure narcotic antagonist may be administered to patients suffering from mast cell disease in any con- A patient diagnosed as suffering from systemic ventional oral, parenteral, transmucosal, transdermal mastocytosis is administered a 0.5 mg. tablet of nal- or other known dosage form. Oral dosage forms may mefene twice daily for 7 days, after which the dosage include conventional tablets, capsules, caplets, pills, 40 is increased on a weekly basis to 1.0 mg, 5.0 mg, 10.0 liquids (solutions, suspensions or elixirs) and the like, mg, 15.0 mg and 30.0 mg b.i.d., respectively. The including generally from about 0.5 to about 75.0 mg patient may be maintained at a total daily dose of 60 of the antagonist per dosage unit together with suit- mg until his symptoms are stabilized and remission of able, pharmaceutically-acceptable excipients, bin- the disease process is observed. ders, sweeteners, coloring agents and other 45 It has thus been shown that there are provided conventional additives. methods which achieve the various objects of the Parenteral dosage forms may include conven- invention and which are well adapted to meet the con- tional injectable solutions of the pure narcotic ditions of practical use. antagonists, for example, isotonic saline solutions, As various possible embodiments might be made together with pharmaceutical-ly acceptable buffers so of the above invention, and as various changes might and preservatives. The parenteral dosage forms gen- be made in the embodiments set forth above, it is to erally contain from about 0.5 to about 75.0 mg of be understood that all matters herein described are to antagonist per dosage unit and may be injected by the be interpreted as illustrative and not in a limiting subcutaneous, intramuscular or intravenous routes. sense. Suitable transmucosal and transdermal dosage 55 forms may include known sublingual, buccal and intranasal vehicles, as well as patches and topical vehicles containing penetrants which enhance trans- 3 5 EP 0 471 525 A1 6

Claims daily.

1 . The use of a pure narcotic antagonist in the man- 13. The use according to any preceding claim whe- ufacture of a pharmaceutical composition for rein said disease is urticaria pigmentosa or sys- treating a patient suffering from a mast cell dis- temic mastocytosis. ease, the treatment comprising the daily administration to the patient of from about 1 to about 1 50 mg of said pure narcotic antagonist.

The use according to Claim 1 wherein said 10 antagonist is selected from the group consisting of naloxone, nalmefene, naltrexone and diprenorphine.

3. The use according to claim 1 wherein the 15 antagonist is nalmefene or naltrexone.

4. The use according to any of claims 1 to 3 wherein the antagonist is administered to the patient orally. 20

5. The use according to claim 4 wherein the antagonist is administered to the patient in an oral dosage form comprising a tablet, capsule, caplet, pill or liquid containing from about 0.5 to about 25 75.0 mg of antagonist per unit.

6. The use according to any of claims 1 to 3 wherein the antagonist is administered to the patient parenterally. 30

7. The use according to claim 6 wherein the antagonist is administered to the patient by the subcutaneous, intramuscular or intravenous routes. 35

8. The use according to claims 1 to 3 wherein the antagonist is administered to the patient transmucosally or transdermally. 40 9. The use according to any preceding claim wherein the antagonist is administered to the patient from one to four, preferably 1 to 3 times daily.

10. The use according to any preceding claim whe- 45 rein about 1 to about 10 mg of antagonist is administered to the patient daily for an initial period, after which the dosage amount is gradually increased to a maximum of 150 mg daily. 50 11. The use according to Claim 10 wherein said antagonist is nalmefene.

12. The use according to Claim 11 wherein about 1 mg of nalmefene is orally administered to the 55 patient daily for an initial period of about seven days, after which the dosage is gradually increased on a weekly basis up to about 60 mg 4 EP 0 471 525 A1

European Patent PARTIAL EUROPEAN SEARCH REPORT Application Number Office which under Rule 45 of the European Patent Convention shall be considered, for the purposes of subsequent proceedings, as the European search report EP 91 30 7317365

DOCUMENTS CONSIDERED TO BE RELEVAN Category Citation of document frith indication, where appropriate, Relevant CLASSIFICATION OF THE of relevant passages to claim APPLICATION a»t. CI. 5) D,X US-A-4 923 875 (PHILLIP FROST) 1-3,8,9 A 61 K 31/485 & EP-A-0 409 392 (BAKER CUMMINS ,13 DERMATOLOGICALS, INC. ) * Abstract, columns 1,2; claims 1,3,9,10 * (Cat. P,X)

D,X US-A-4 877 791 (FRED P. SHERMAN) 1-7,9 * Abstract; column 1; claims 1-7 *

ANNALS OF INTERNAL MEDICINE, vol. 97, 1,2,6,7 no. 5, November 1982, pages 788-789, ,13 American College of Physicians; S. SMITZ et al . : "Naloxone, Itch, Asthma, Urticaria, and Angi oedema" * The whole article *

TECHNICAL FIELDS SEARCHED ant. C1.5)

A 61 K

INCOMPLETE SEARCH The Search Division considers that the present European patent application does not comply with the provisions of the European Patent Convention to such an extent that it is not possible to carry out a meaningful search into the state of the art on the basis of some of the claims Claims searched completely : Claims searched incompletely : Claims not searched : Reason for the limitation of the search: Remark : Although claims 1-13 are partially directed to a method of treatment of the human or animal body (Article 52(4) EPC) the search has been carried out and based on the alleged effects of the compound or composition.

See sheet -C- Place of search Date of completion of the search Examiner THE HAGUE 16-10-1991 KRAUTBAUER B. CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document

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European Patent PARTIAL EUROPEAN SEARCH REPORT Application Number Office EP 91 30 7365

CLASSIFICATION OF THE DOCUMENTS CONSIDERED TO BE RELEVANT APPLICATION ant. CI. 5) Category Citation of document with indication, where appropriate, Relevant of relevant passages to claim X BRITISH JOURNAL OF DERMATOLOGY, vol. 1,2,6,7 108, no. 6, June 1983, pages 723-724, ,13 Published for the British Association of Dermatologists by Blackwell Scientific Publications, Oxford, GB; A.D. 0RMER0D et al . : "Acute urticaria due to alcohol" * The whole article *

D,X WO-A-8 702 586 (KEY PHARMACEUTICALS, 1-8,13 INC.) * Abstract; pages 1-4; claims 1,2,5-7,12,18,20 * TECHNICAL FIELDS X THE JOURNAL OF ALLERGY AND CLINICAL 1-3,13 SEARCHED a»t. C1.5) IMMUNOLOGY, vol. 81, no. 1, January 1988, page 252, abstract no. 337, The C. V. Mosby Company, US; D. BANERJI et al . : "Controlled antipruritic trial of nalmefene (N) in chronic urticaria (CU) and atopic dermatitis (AD)" * Abstract *

X TOXICOLOGY AND APPLIED PHARMACOLOGY, 1,2 vol. 104, no. 3, July 1990, pages 403-410, Academic Press, Inc.; R.A. MACIA et al . : "Hypotension induced by growth-hormone-rel easing peptide 1s mediated by mast cell serotonin release in the rat" * Summary; pages 408-409 *

^NNALS OF INTERNAL MEDICINE, vol. 98, 1-3,6,7 no. 1, January 1983, pages 30-34, ,13 American College of Physicians; D.J. GOLDSTEIN et al . : "A case of episodic fl using and organic psychosis: Reversal by opiate antagonists" * Abstract; the whole article *

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PARTIAL EUROPEAN J) European Patent SEARCH REPORT Application Number Office EP 91 30 7365

DOCUMENTS CONSIDERED TO BE RELEVANT CLASSIFICATION OF THE -i ~ . — . — _ . — APPLICATION (Int. CI. 5) Citation of document with indication, where appropriate, Relevant of relevant passages to claim THE JOURNAL OF PHARMACOLOGY AND 1,2,6,7 EXPERIMENTAL THERAPEUTICS, vol. 243, ,13 no. 1, October 1987, pages 378-383, The American Society for Pharamacology and Experimental, US; Z. TERASHITA et al . : "A lethal role of platelet activating factor in anaphylactic shock in mice" * Abstract; pages 378,381,383 *

THE JOURNAL OF ALLERGY AND CLINICAL 1,2 IMMUNOLOGY, vol. 74, no. 4, part 1, October 1984, pages 499-504, The C.V. Mosby Company, US; F. SHANAHAN et al.: "The influence of endorphins on TECHNICAL FIELDS peritoneal and mucosal mast cell SEARCHED ant. CI.5) secretion" * Abstract; pages 499,502,503 *

THE JOURNAL OF ALLERGY AND CLINICAL 1,2 IMMUNOLOGY, vol. 73, no. 6, June 1984, pages 775-781, The C. V. Mosby Company, US; T.B. CASALE et al . : "Induction of human cutaneous mast cell degranulatlon by opiates and endogenous opioid peptides: Evidence for opiate and nonopiate receptor participation" * Abstract; pages 775,778,780 *

EP-A-0 171 742 (E.I. DU PONT DE JEMOURS AND COMPANY) " Claims 1,2 *

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EP 91 30 7365 -C-

Claims searched incompletely 1-13 :

The subject matter of claims 1-13 are not supported by pharmacological evidence. In the absence of pharmacological data the evaluation of the technical nature of the subject matter and of the prior art is equivocal and subjective. As a consequence it may well be that relevant prior art has not been retrieved.