JPS6328047B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel uses of the compounds cyclosporin A and dihydrocyclosporin C. The compounds have now been found to be useful in the treatment of human lymphoproliferative diseases, particularly lymphogranulomatosis, non-Hodgkin's lymphoma, lymphocytic leukemia, and mycosis fungoides, as shown in standard tests. By oral administration of the compound at a daily dose of 10-25 mg/Kg for 2-14 days using a 150 mg capsule, or intramuscularly at the same dose for the same period using a 150 mg/ml injection solution. Upon administration, the compounds are clinically useful in the treatment of lymphoblastic leukemia, as shown by decreased concentrations of leukemic blast cells in plasma and bone marrow. Oral administration of the compound at a daily dose of 10-25 mg/Kg has also shown that the compound is effective in the treatment of mycosis fungoides, as shown by a reduction in the number of lymphoid cells in skin biopsies. Clinically useful. A preferred such compound is cyclosporin A. Of course, in the above applications, the dosage will vary depending on the compound used, the mode of administration and the treatment desired. However, in general, it is about 1 to 1 kg per kg of animal weight.
Satisfactory results were obtained when administered at a daily dose of 100 mg, given in divided doses 2 to 4 times a day,
Or it may be advantageous to give it in a sustained release form. For large mammals, the total daily dosage ranges from about 100 to 2500 mg, e.g. about 100 to 1000 mg.
or 800-1500 mg. Dosage forms suitable for oral or intramuscular administration include the composition in admixture with a solid or liquid pharmaceutical carrier or diluent.
It may consist of 25-500 mg. The composition may be mixed with conventional pharmaceutical diluents and carriers, optionally with other excipients, especially solubilizers for the compound. Such compositions advantageously contain 1 wt% or more of the compound, may be prepared by conventional techniques, and may be formulated, for example, in capsules, tablets, suppositories, for enteral or parenteral administration. It may be in the form of a dispersible powder, syrup, elixir, suspension or solution. Preferably, the compound is administered as a solid composition, preferably as a solid filled gelatin capsule or tablet. The composition may contain pharmaceutically inert organic or inorganic auxiliaries, optionally granulating agents, lubricants, adhesives and the like. Adjuvants for tablet manufacturing include microcrystalline cellulose, mannitol, lactose, and the like. Granulating agents and disintegrants include microcrystalline cellulose and the like. Binders include polyvinylpyrrolidone, methylcellulose. The lubricant may be stearic acid or the like. The tablets may or may not be coated with a coating which is applied in a manner known per se and which delays disintegration and absorption in the gastrointestinal tract; give. Capsules may contain the active substance on its own or together with inert solid diluents such as lactose, mannitol and microcrystalline cellulose. Examples of compositions for use in the invention are known, for example in UK Patent Application No. 2015339A. Such compositions include the components shown below. Labrafil is located in Boulogne, France.
It is a non-ionic ester of triglycerides and polyalkylene polyols available from Etablissement Gattefosse' in Seine. Miglyol is a German
It is a saturated fatty acid glyceride available from Dyamit Nobel Witten. Details of these products
In Fiedler's Lexicon der Hilfsstoffe (1971). Example 1 Drink solution Cyclosporin A 200mg was added to Labrafil M1944 CS
and 1 ml of a mixture of ethanol (40:15 parts by weight)
Dissolve at 25℃ under stirring. Add 0.4ml of olive oil or corn oil. Strain the resulting mixture;
Fill small bottles. The final solution contains 10 parts by weight of Labrafil, 3 parts by weight of Cyclosporin A, 3 parts by weight of ethanol and 5 parts by weight of olive oil or corn oil. Example 2 Parenteral Forms for Intramuscular and Subcutaneous Administration 100 mg of cyclosporine A with 40 mg of ethanol
Dissolve in a mixture of 0.5 ml of Miglyol 812 at 25 °C under stirring. Finally, the mixture is made up to 1 ml with Miglyol 812 and filled into ampoules under aseptic conditions. The final solution contains 10 parts by weight of Miglyol 812, 1 part by weight of cyclosporin A. Example 3 Parenteral Form for Intramuscular and Subcutaneous Administration 100 mg of cyclosporin A was mixed with 40 mg of ethanol,
Labrafil M1944 CS 100mg and Miglyol 812
Dissolve 200 mg of the mixture at 25 °C under stirring. The resulting mixture is made up to 1 ml with olive oil and filled into ampoules under aseptic conditions. The final solution contains 10 parts by weight of Miglyol 812, 5 parts each of Cyclosporin A and Labrafil, and 25 parts by weight of olive oil. Example 4 Parenteral Forms for Intramuscular and Subcutaneous Administration 200 mg of cyclosporin A are dissolved in a mixture of 400 mg of benzyl ester of benzoic acid and 0.3 ml of Miglyol 812 at 25°C. Miglyol the resulting mixture
812 to 1 ml and fill into ampoules under aseptic conditions. The final solution contains 10 parts by weight of Miglyol 812, 6 parts by weight of Cyclosporin A. Example 5 Parenteral Forms for Intramuscular and Subcutaneous Administration 200 mg of cyclosporine A was mixed with 50 mg of ethanol,
Labrafil M1944 CS 300mg and Miglyol 812
Dissolve in 0.5 ml of the mixture at 25 °C under stirring. The resulting solution is made up to 1 ml with Miglyol 812 and filled into ampoules under aseptic conditions. The final solution consisted of 10 parts by weight of Miglyol 812,
Contains 7 parts by weight of Labrafil and 5 parts by weight of Cyclosporin A. Example 6 Capsules for oral administration Cyclosporin A 200mg was added to Labrafil M1944 CS
under stirring into a mixture of 600 mg of ethanol and 30 mg of ethanol.
Melt at 50℃. The final solution is encapsulated in soft or hard gelatin capsules. Example 7 Capsule for oral administration 400 mg of cyclosporin A is dissolved in 600 mg of glycerol monooleate at 40° C. with stirring, and the solution is encapsulated in a soft gelatin capsule. The toxicity of such compounds is known. For example, cyclosporine A was used in 45 patients without any side effects.
Oral doses of 25-1000 mg were tolerated. In rats, 15 mg/Kg/day for 3 weeks is tolerated. Dihydrocyclosporine C is tolerated orally in mice at a dose of 11 mg/Kg/day. In guinea pigs, intraperitoneal administration of 2 x 70 mg/Kg of dihydrociclosporin C does not cause any side effects. The effects of the medicament of the present invention are demonstrated by the following pharmacological tests. (Method) Patients with advanced lymphogranulomatosis (Hodgkin's disease)
Ten people were used in the test. The patients had relapsed after first and second-line chemotherapy, and all had B symptoms, measurable lesions, normal renal function, and extranodal disease. Recurrence was confirmed by biopsy to distinguish it from similar diseases. Cyclosporin A was diluted with milk or fruit juice and administered orally twice a day. Initial daily dose is patient 2
12.5mg/Kg for one person, 7.5 for the remaining eight people
mg/Kg. Total blood cyclosporine trough concentrations were measured by radioimmunoassay, and the daily dose was adjusted as necessary to maintain blood cyclosporine concentrations in the range of 400-800 ng/ml. The treatment is
Treatment was continued until complete remission, progression, or unacceptable side effects were observed. The reactions were classified into the following five categories. Complete response, Partial response with >50% reduction in tumor size (lasting at least 2 months), Minimal response of 25-50% (lasting at least 2 months), Stability with no progression for 2 months with resolution of B symptoms disease, disease progression. Be careful of toxicity and have the patient drink fluids to prevent dehydration. Nephrotoxicity, which frequently occurs with cyclosporine treatment, was monitored by controlling serum creatinine and endogenous creatinine clearance (ECC). Nephrotoxicity was classified into five levels. Degree 0: Creatinine and ECC are normal Degree 1: Creatinine is normal, ECC decreases Degree 2: Increases to 150 μmol/creatinine, Reversible grade 3: Increases creatinine 150 μmol/or more, Reversible grade 4: Creatinine 150 μmol/or more Progressive Continues even with escalation, dose reduction, and treatment cessation. (Results) Symptom B rapidly remitted in most patients several days after the start of treatment. The effect was closely related to blood cyclosporine concentration. For example, in two patients, recurrence of B symptoms occurred when the blood cyclosporine trough concentration reached 400 ng/ml, and improvement was seen with increasing cyclosporine dose and concentration. Improvement in tumor lesions was slow, usually taking 1-2 months before objective reactions were seen. Treatment was well tolerated, with occasional gastrointestinal discomfort being the only complaint during the first 3 months. Nephrotoxicity was seen in patients treated for more than 2 months. Five patients showed third-degree toxicity, four of whom also showed increased serum uric acid. In all cases, serum creatinine, ECC, and uric acid returned to normal values after hydration and dose reduction. Records for all patients are shown in the table below.

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Claims (1)

[Scope of Claims] 1. A composition for treating lymphoproliferative diseases characterized by containing cyclosporin A or dihydrocyclosporin C. 2. The composition of item 1 above, wherein the compound is cyclosporin A. 3. 25-150 mg of the compound in a unit dosage
The composition of item 1 above, comprising: