EP1001753A1

EP1001753A1 - Low dosed 15-desoxyspergualine preparations

Info

Publication number: EP1001753A1
Application number: EP98939540A
Authority: EP
Inventors: Niels Franke
Original assignee: Individual
Current assignee: Individual
Priority date: 1997-07-03
Filing date: 1998-06-26
Publication date: 2000-05-24
Also published as: PL337802A1; CA2294785A1; DE19728436A1; JP2002507221A; DE19880842D2; WO1999001123A1; HUP0003038A2; AU8801498A; HUP0003038A3; TR199903322T2; US6166087A

Abstract

15-desoxyspergualine or a pharmaceutically acceptable salt thereof is suitable for producing an immunosuppressive anti-inflammatory or tumor-inhibiting medicament, which is effective in low daily doses of 20 to 600 νg/kg body weight when it is applied to the mucosa. For this purpose, it is specially prepared in the form of a controlled dosage aerosol.

Description

Low-dose 1 5-deoxyspergualin preparations

description

The present invention relates to the use of 15-deoxysperguaIin for the production of an immunosuppressive, anti-inflammatory and anti-tumor drug for administration to the mucous membrane in a dosage in the range from 20 to 600 μg / kg body weight daily, in particular for the treatment of autoimmune diseases, inflammatory skin diseases, cancer diseases and to prevent graft rejection. The active ingredient (±) -1 5-deoxyspergualin of the formula

H ₂ NC (= NH) NH (CH ₂ ) ₈ CONHCH (OH) CONH (CH ₂ ) ₄ NH (CH ₂ ) ₃ NH ₂ (-3HCI)

is a synthetic derivative of the anti-tumor antibiotic Spergualin.

The compound can be prepared either as a racemic mixture (see e.g. US-A-4 51 8 532) or in optically pure form (see e.g. EP-A-0 094 632).

Although numerous publications describe the immunosuppressive properties of this compound and its potential suitability for the treatment of autoimmune diseases such as multiple sclerosis, lupus erythematosus and for the prevention of graft rejection, the clinical benefit is due to the very high doses required and the associated considerable Side effects very limited.

The main side effect of long-term therapy was a temporary drop in the number of leukocytes with all the consequences of strong immunosuppression (see Amemiya, H., et al.: Japanese of Trans- plantation, 26, 61 5). The high doses were considered necessary because of these demonstrable immunosuppressive effects both in the treatment of acute and chronic rejection and in the treatment of autoimmune diseases (cf. Amemiya, H., et al.: Transplantation Proceedings, XXIII, (1), 1087 -1089, Feb. 1,991).

Usually 1 5-deoxyspergualin is administered intravenously in a dose of approx. 4 to 6 / g / kg body weight in order to achieve an immunosuppressive effect. The effect is characterized by an unspecific general suppression of the immune system.

There are currently no long-term, low-side effects that are satisfactory for the treatment of autoimmune diseases and cancer and for the prevention of graft rejection. The object of the invention is therefore to provide a preparation with few side effects for the treatment of the diseases mentioned, which is easy to use, does not develop any significant side effects even with long-term use and is therapeutically effective. Furthermore, the preparation should also be easy for the patient to use himself.

It has now surprisingly been found that the smallest dosages (20 to 600 micrograms / kg KM) are sufficient to achieve the desired immunosuppressive pharmacological effects when the active ingredient is administered via the respiratory mucous membranes. This significantly reduces the risk of undesirable effects. The burden of a daily injection is eliminated. However, low-dose therapy requires that precise dosing systems be used to ensure the dose consistency required for highly effective immunosuppressants. In the dosage according to the invention, the active ingredient DSG can be applied to the mucous membrane of the nose, the respiratory tract or other mucous membranes in the microgram range using the preferred metered dose aerosol, the single dose being determined by the amount of active ingredient per stroke (200 to 800 micrograms per stroke) is determined. The low and precise dosage in the microgram range makes it possible for the first time to practically achieve the pharmacological effects that can be achieved with this dosage. Local as well as systemic effects are created, since a sufficient amount of the active ingredient is absorbed and gets into the bloodstream. In the low dose range, transdermal systems are also suitable for long-term therapy.

The invention relates to the use of 15-deoxysperguaiine or a pharmaceutically acceptable salt thereof as an active ingredient, optionally together with customary auxiliaries and carriers and / or other active ingredients for producing an immunosuppressive anti-inflammatory or anti-tumor drug in the form of a drug for application to the mucous membrane in a dosage of 20 to 600 // g / kg body mass daily preparation, preferably in the form of a metered dose.

Since the immunosuppressive anti-inflammatory and anti-tumor effects produced at this low dose are very selective, even with long-term therapy there are no or only minor side effects, e.g. Dysesthesia to be expected.

This allows autoimmune diseases, certain cancers and graft rejection reactions to be treated with few side effects. According to the invention, autoimmune diseases of every genesis and of every organ can be treated, for example myasthenia gravis, myositis, multiple sclerosis, Hashimoto's thyroiditis, athrophic gastritis, ulcerative colitis, nephrotoxic nephritis, lupus diseases, arthritis, scleroderma, granulomatosis, autoimmune myocarditis Autoimmune cytopenia, psoriasis, neurodermatitis, dermatitis herpetiformis, eczema, Graves' disease, pancreatitis, uveitis, iritis, glomerulonephritis, rheumatoid arthritis, Alzheimer's, AIDS and the like. Treatment is preferred of multiple sclerosis, lupus erythematosus, virus-induced autoimmune diseases, AIDS, glomerulonephritis, psoriasis and neurodermatitis. Cancers that can be treated include leukemia and solid tumors, such as the lungs, breast, sarcomas, ovaries, lymphomas. Graft rejection reactions can occur in the transmission of any human organ or tissue. The fate of the transplant depends largely on the type and extent of the immune response in the recipient. The survival time of the transplant is considerably improved by the immunosuppression caused by the medicament obtained according to the invention.

Until now, the active ingredient deoxyspergualin could only be administered intravenously or intramuscularly due to the high doses required. In contrast, the invention allows the active ingredient in the low dosage according to the invention to be administered effectively by mucosal application.

The dosage essential in the context of the invention is in the range of 20 to 600 / g / kg of body weight daily. It is preferably reliably observed in that the medicament obtained in accordance with the invention is packaged and used in a metered dose aerosol applicator, which administers a fixed amount of active substance with each actuation. If, for example, the metered dose aerosol device is set up in such a way that aerosol with a content of 500 μg of active ingredient is sprayed off with each stroke, this results in a patient with a body weight of 60 kg and a dose of 100 g / kg body weight daily per nose side overall 6 pump pulses, corresponding to 2 pump pulses per side 3 times a day. The daily dose is suitably administered in one to three single doses.

The dose to be administered in each case is determined by the doctor depending on the severity of the condition to be treated, the age, Gender and weight of the patient and the duration of treatment.

The medicament produced according to the invention is preferably formulated as an aerosol, but can also be present, for example, in the form of an ointment, a cream, drops, or a lotion which are formulated for application to the mucous membrane, in particular the nasal mucosa.

Administration to the nasal mucosa or respiratory mucosa is preferred, e.g. in the form of a nasal spray, aerosol, nasal ointment or nasal drops, as this significantly reduces the burden on the patient and can therefore improve patient compliance. Due to the low dosage of the active ingredient, such a nasal administration is possible for the first time since the low concentrations do not cause irritation to the mucous membrane. There is also no influence on the ciliary function. The buccal form of administration, in which the active ingredient is absorbed through the oral mucosa, is also suitable. Dosed administration of the medicament produced according to the invention is also possible via the vaginal mucosa and the intestinal mucosa, the formulation then being the usual form of preparation for these applications, e.g. as a suppository.

The active ingredient deoxyspergualin can be packaged for use in accordance with the invention in a manner known per se and processed for pharmaceutical use. For this purpose, customary auxiliaries and carriers are used in the field of pharmaceutical formulation for the respective administration form.

The active ingredient can be used either as a free base or as a pharmaceutically acceptable acid addition salt together with conventional carriers and other common pharmaceutical additives. Examples of pharmaceutically acceptable acid addition salts with organic and Inorganic acids are, for example, chlorides, hydroxides, lactates, malates, fumarates, acetates, carbonates, citrates, tartrates, glycolates etc.

The 1 5-deoxyspergualin can be administered either as the only active ingredient or together with other active ingredients as well as vitamins, minerals and known drug additions. Examples of suitable further active ingredients are those with pharmacological activity, provided that they are compatible with 1 5-deoxyspergualin, e.g. Corticosteroids such as cortisone, camphor, echinacea, euphorbium etc., or active substances with a supplementary accompanying effect, e.g. Fumaric acid, active ingredients with absorption and penetration-promoting action on 1 5-deoxyspergualin, e.g. Isopropanol or propylene glycol, active substances with a caring effect, e.g. Chamomile oil, azulene, panthenol, retinol palmitate, glycerin.

For the preparation of a preparation to be administered to the mucous membrane, preferably to the respiratory or nasal mucous membrane, it is possible to use all auxiliaries and carriers which are customarily used in the field of mucosal agents. In addition to the preferred training as a metered dose inhaler, the preparation can also take any other form that is suitable for precisely metered administration via the mucous membrane and can, for example, in the form of a nasal spray, nasal drops, nasal ointment, nasal suspension, nasal gel or the like. available. For this purpose, the usual dosage forms adapted to the administration form, such as medium-chain triglycerides, peanut oil, carbonner, macrogol, wool wax, alcohol ointment base, water for injection, paraffin liquid and excipients, such as preservatives, for example benzalkonium chloride, thiomer sal, butylated hydroxytoluene, PHB esters, isotonic agents, and isotonic agents - Drug phosphate, sodium monohydrogen phosphate or sodium chloride, and flavorings and aromas, such as fennel oil, eucalyptus oil, peppermint oil, mountain pine oil, cedar leaf oil and the like, are used. The nasal spray can be in the form of a pump spray or in a pressure can with a pharmacologically acceptable propellant. Packaging in a metered dose aerosol container is particularly preferred.

The combination of deoxyspergualin with magnesium is particularly preferred. It has been found that this combination is particularly well tolerated. Magnesium reliably prevents the (rarely) occurring subjective complaints (e.g. dysesthesia) during treatment with 1 5-deoxyspergualin.

The following examples illustrate the invention.

EXAMPLES

Example 1 Nasal Spray

By mixing 2, 5 mg or 5 mg of powdered 1 5-deoxyspergualin with 100 g of a carrier, e.g. Glucose in purified water, a nasal spray is produced in a manner known per se. The application is carried out according to the instructions of the doctor.

Example 2 Nose drops

By mixing 2.5 mg, 5 mg or 10 mg of powdered 1 5-deoxyspergualin with 100 ml of a liquid carrier medium, e.g. Glycol, and customary auxiliaries, nose drops are produced in a manner known per se. The dosage is done according to the instructions of the doctor.

Example 3 Ointment 10 mg of 1 5-deoxyspergualin and 50 g of Eucerin are mixed with customary auxiliaries and additives and processed to form an ointment. The ointment is applied to the mucous membrane several times a day. Example 4 Ointment

1 0 mg 1 5-deoxyspergualin are processed with 50 g of purified petroleum jelly, essential oils and azulene in a manner known per se to form an ointment. The ointment is applied to the mucous membrane several times a day.

Example 5 Ointment 10 mg 1 5-deoxyspergualin are processed with 50 g Eucerin and 1.0 g fumaric acid, optionally with the addition of fragrances and preservatives, to form an ointment. The ointment is applied to the mucous membrane several times a day.

Example 6

Nasal oil

250 mg deoxyspergualin are processed with Paraffinum liquidum, benzalkonium chloride and sodium citrate to 10 ml nasal oil in a manner known per se. The nasal oil is applied to the nose according to the doctor's dose instructions.

Example 7 Nose drops

20 mg deoxyspergualin are processed with 2 mmol magnesium chloride and 100 ml purified water, optionally with the addition of chamomile flower fluid extract, in a manner known per se to give nose drops. The dosage is done according to the instructions of the doctor.

Example 8 MDI

50 mg deoxyspergualin are mixed with ethyl acetate, sorbitan trioleate, dichlorodifluoromethane and trichlorofluoromethane to form a metered dose aerosol 200 single cans processed. Dosing is done according to the doctor's instructions.

Example 9 Treatment of Multiple Sclerosis, Relapsing Form (EDSS <5)

Patient 1: female, 31 years, 60 kg body weight, MS diagnosis 1 989 by clinic, magnetic resonance imaging and detection of oligoclonal bands in the cerebrospinal fluid, since then approx. 2 relapses per year, slowly increasing disability, presentation 8/1 994, walking distance approx. 1 00 m with stick, light paraspastic, dysesthesia, retired for 1 2 months.

Therapy was carried out with 1 50 // g / kg body weight 1 5-deoxyspergualin daily as an aerosol with application to the nasal mucosa for 1 4 days. At the re-presentation after 6 weeks, the walking distance was now about half an hour. There were no more dysesthesias and paraspastics. The gait was normal. A renewed therapy with 1 5-deoxyspergualin for 1 4 days led to the normal condition which has remained unchanged since then. Back in business since 6/1 997, no new relapses. Neither subjective nor objective side effects of the therapy were observed.

Patient 2: male, 25 years, 81 kg body weight, MS diagnosis 1 992 by clinic, magnetic resonance imaging and detection of oligoclonal bands in the cerebrospinal fluid, since then approx. 4 relapses per year, slowly increasing disability, presentation 7/1 995, walking distance approx. 50 m, ataxia, atactic-spastic gait pattern, severe fatigue.

A nasal aerosol therapy with 1 50 // g / kg body weight 1 5-deoxyspergualin for 1 4 days showed a clear improvement at the next presentation after 7 weeks. The tiredness was gone, the walking distance increased to about 5 km and the gait normalized. Another 1 4-day therapy with 1 50 // g / kg body weight 1 5 daily Deoxyspergualin showed a further improvement. There were no new relapses and overall mobility is now normal. Neither subjective nor objective side effects of the therapy were observed.

Example 1 0

Treatment of multiple sclerosis, primarily chronic progressive form

Patient 1: male, 29 years, 65 kg, MS diagnosis 1 991 by clinic, magnetic resonance imaging and oligoclonal bands in the cerebrospinal fluid, presentation 3/1 996, walking distance approx. 100 m, spastic-atactic gait pattern, disturbed fine motor skills, severe fatigue, Inability to work (student).

1 6-day aerosol therapy with 1 00 // g / kg body weight 1 5-deoxyspergualin daily brought about a clear improvement at the next presentation after 6 weeks. The tiredness was gone, the walking distance increased to approx. 500 m, fine motor skills became normal again and the gait improved visibly. The patient felt himself able to cope with his requirements again, a further therapy with 1 5-deoxyspergualin for 1 6 days brought about a further stabilization of the general well-being, and the patient felt himself to be able to cope with his requirements. Neither subjective nor objective side effects of the therapy were observed.

Patient 2: female, 41 years, 57 kg, MS diagnosis 1 987 by clinic, magnetic resonance imaging and oligoclonal bands in the cerebrospinal fluid, presentation 5/1 996, chronic fatigue, walking distance approx. 1 50 m, spastic-atactic gait pattern, strength of the hands significantly reduced, slight ataxia of the hands.

After therapy with 1 00 / g / kg body weight 1 5-deoxyspergualin over 1 8 days by infusion, the next time after 6 weeks the walking distance had increased to approx. 200 m, the gait pattern was more regular, the strength in the hands increased who have favourited Fine Motor Skills Better. Another therapy with 7.5 mg 1 5-deoxyspergualin over 1 8 days as Nasal spray further stabilized the condition so that the patient feels able to cope with her housework again.

Example 1 1 Treatment of Lupus Erythematosus a. Lupus erythematosus (LE), cutaneous form

Patient: male, 1 2 years, 40 kg, diagnosis 1 995 by skin biopsy and clinic, presentation 7/96, numerous skin spots and lesions all over the body, previous therapy 40 mg decortin / day, chronic fatigue.

Therapy with 50 // g / kg 1 5-deoxyspergualin for 20 days by aerosol resulted in a significant improvement when reintroduced 6 weeks later. The skin lesions and tiredness had disappeared and Decortin could be stopped. Another 20-day therapy with 2 mg 1 5-deoxyspergualin daily via a nasal spray brought about a stabilization of the condition. No side effects of the therapy were observed.

b. Lupus erythematosus (LE), systemic LE (SLE)

Patient: male, 1 6 years, 42 kg, diagnosis 1 989 by clinic and laboratory tests, presentation 7/1 994, nephrotic syndrome with high protein loss (7.5 g / l) from the kidney, butterfly erythema on the face, chronic fatigue, school attendance not possible for 2 years.

Therapy with 250 // g / kg 1 5-deoxyspergualin per day for 14 days by aerosol brought about a clear improvement in the clinical picture at the next presentation 5 weeks later. The patient was able to go to school again, the tiredness had disappeared, the protein excretion by the kidney (2.9 g / l) was significantly reduced, the butterfly erythema subsided. Another therapy with 0.25 mg / kg body weight 1 5- Deoxyspergualin over 1 6 days by infusion showed further improvement. There was no longer any protein excretion from the kidney, the patient's condition was stable, regular school attendance was possible.

Example 1 2 Treatment of Glomerulonephritis

Patient: male, 29 years, 74 kg, diagnosis 1 995 by kidney biopsy, chronic fatigue, presentation 1 1/1 995, fatigue, increased creatinine (1, 9 mg), fluid retention.

Therapy with 1 50 // g / kg body weight 1 5-deoxyspergualin over 1 8 days by aerosol resulted in a clearly improved clinical picture after a re-presentation after 6 weeks. The serum creatinine level was reduced (1.3 mg). A renewed therapy with 1 50 // g / kg body weight 1 5-deoxyspergualin over 1 8 days by infusion resulted in a further normalization of the creatinine level (0.7 mg). The kidney biopsy showed a significant decrease in the signs of glomerulonephritis. Neither subjective nor objective side effects of the therapy were observed.

Example 1 3 Treatment of Rheumatoid Arthritis (RA)

Patient: male, 36 years, 79 kg, diagnosis 1 987 by clinic and positive rheumatoid factor, presentation 6/1 996, chronic fatigue, painful, restricted movement in the finger, knee and shoulder joints.

Therapy with 200 // g / kg body weight 1 5-deoxyspergualin for 1 8 days by aerosol resulted in a new presentation after 6 Weeks a significant improvement in the clinical picture. The tiredness was gone. The mobility of the joints was improved, as was the pain. A renewed therapy with 7.5 mg 1 5-deoxyspergualin daily through a nasal spray for 20 days brought about further stabilization of the clinical picture. There were no further episodes of disease, the rheumatoid factor was negative. Neither subjective nor objective side effects were observed.

Example 14 Treatment of HIV Infection

Patient: male, 29 years old, 72 kg, with confirmed HIV infection and low values for suppressor cells (<750), no symptoms of AIDS, presentation 4/1 995, chronic fatigue.

Therapy with 7.5 mg 1 5-deoxyspergualin daily via a nasal spray for five times 1 8 days improved tiredness and led to an increase in CD8 cells to a value above 900. Neither subjective nor objective side effects were observed.

Example 1 5 Treatment of Neurodermatitis

Patient: male, 1 0 years, 22 kg with neurodermatitis, diagnosis 1 990, presentation 8/95, painful, itchy areas of the skin on the trunk and on the extremities, improvement with cortisone ointment.

Therapy with fat-free 1 5-DSG emulsion (1 0 mg / 1 0 g emulsion), applied to the nasal mucosa for 20 days. After two repetitions at intervals of 6 weeks, the skin areas healed without complications, no new itchy areas appeared. Neither subjective nor objective side effects were observed. Example 1 6 Treatment of myasthenia gravis

Patient: female, 39 years, 62 kg, diagnosis 1 983 by clinic and serology, therapy with 1 50 // g / kg body weight 1 5-deoxyspergualin aerosol for two 1 4 days. There was continued neurological improvement with no relapses. Neither subjective nor objective side effects were observed.

Example 1 7

Treatment of leukemia

Patient: male, 1 9 years, ALL, diagnosis 1 995 secured by clinic, blood count, immunohistochemistry and BM puncture, presentation 5/1 996.

A therapy with 50 / g / kg body weight 1 5-deoxyspergualin for 25 days and a renewed therapy with 5 mg 1 5-deoxyspergualin by nasal spray after 8 weeks has so far resulted in complete remission. Neither subjective nor objective side effects were observed.

Claims

Expectations

1. Use of 15-deoxyspergualin or a pharmaceutically acceptable salt thereof as an active ingredient, optionally together with customary auxiliaries and carriers and / or other active ingredients for producing an immunosuppressive, anti-inflammatory or anti-tumor drug in the form of a dosage for application to the mucous membrane from 20 to 600 // g / kg body mass daily preparation.

2. Use according to claim 1, d a d u rc h g e k e n n z e i c h n et that the drug is prepared as a metered dose.

The method of claim 1, d a d u r c h g e k e n n z e i c h n et that the application to the mucous membrane of the nose or the respiratory tract takes place.

Use according to claim 1 or 2 for the treatment of autoimmune diseases, cancer diseases or graft rejection reactions.

5. Use according to claim 4 for the treatment of multiple sclerosis, myasthenia gravis, lupus erythematosus, virus-induced autoimmune diseases, AIDS, glomerulonephritis or psoriasis, neurodermatitis, eczema.

6. Use according to one of the preceding claims, dadu rc hgekennzeichn et, that the medicament additionally contains magnesium and / or a corticosteroid.

7. Use according to one of claims 1 to 6 for the manufacture of the medicament as a metered dose aerosol.

8. A method for achieving immunosuppression by applying a deoxyspergualin or a pharmaceutically acceptable salt thereof as an active substance-containing aerosol in a dosage of 20 to 600 // g / kg body mass daily on the mucous membrane.

9. The method of claim 8, d a d u rc h g e k e n n z e i c h n et that one treats an autoimmune disease, inflammatory disease, cancer or graft rejection reaction.

10. The method according to claim 9, d a d u rc h g e k e n n z e i c h n et that multiple sclerosis, lupus erythematosus, a virus-induced autoimmune disease, AIDS, glomerulonephritis or psoriasis,

Treated neurodermatitis, eczema, myasthenia gravis.

11. Dosiererosolvorrichtung, dadu rc hgekennzeichn et that it contains a drug with 15-deoxyspergualin or a pharmaceutically acceptable salt thereof as an active ingredient, optionally together with conventional auxiliaries and carriers and / or other active ingredients for the manufacture of an immunosuppressive anti-inflammatory or anti-tumor drug, which is formulated for application to the mucous membrane and contains the active ingredient in such a concentration that this in an amount of 20 to 600 // g / kg body mass is released daily in the aerosol with normal use of the device.