IL43947A - Method of treating immunological or inflammatory disorders with dexamethasone 21-adamantane-1' carboxylate and compositions containing adamantane carboxylates of 21-hydroxy pregnanes - Google Patents

Description

43947/3 DEXAMETHASONE 21 -ADAMANTANE- 1 ' -CARBOXYLATE AND COMPOSITIONS CONTAINING ADAMANTANE CARBOXYLATES OF 21 -HYDROXY PREGNANES οΌΌαη o^-neom Ί τνηαΝϋρι *7iu Ό^ΌΡ ΛΊ - f-iNtDDiw-21 The present invention is concerned with improvetnents- pharriiaceutical or veterinary compositions containing -in-^-rela i^- o-4^e-med c-ina-l-u6e--9£ betamethasone 21- adamantane-1' -carboxylate , its 16a-methyl analogue, and the corresponding 11-ketones, as more particularly described hereinafter.

Israeli Patent- Specification No. 39821"' describes- and claims betamethasone 2l-adamantane-l ' -carboxylate and its corresponding 9a-chloro analogue, these compounds being as . described in our said;¾e.eif cation ' having prolonged antiinflammatory activity upon internal administration. As . , . , . Specificatio , . indicated m our. said / -> ^ e above-mentioned compounds may advantageously be administered at intervals of several days in view of their prolonged duration of activity, an interval of 14 days being mentioned for intramuscular and intraarticular administration of the compounds to humans and an interval of 7-21 days for administration to animals. Our said Specification further describes dosages at which the compounds may be administered over such intervals to achieve a satisfactory anti¬ inflammatory effect. Thus, for intramuscular administration to adult humans a dosage rate of 5-40 mg, preferably 10-20 mg of steroid is recommended, while for intra-articular administration the recommended dosage is 1-20 mg, preferably 3-6 mg of steroid. For animals, a recommended dose rate i 0 1 t 0 m t 43947/3Γ ^ I- 50 mg of steroid.

Ue have now discovered that 1n treating Inflammatory disorders associated with a signifi cant Immunologi cal component, very valuable long-lasting therapeutic effects can be achieved by the administrati on of betamethasone 21 -adamantane-l ' -carboxylase, Its 16a- meth l analogue and the corresponding 11-ketones .In Ini ti al doses l arger than those hi therto proposed 1n our said Speci fication.

The 21-adamantane-l '-carboxyl ates of betamethasone and dexamethasone are particularly preferred, the betamethasone compound being especial ly advantageous .

The present Invention 1s thus concerned with pharmaceuti cal and veterinary compositions containing high dose levels of 21-adamantane-l 1 -carboxylates of betamethasone, dexamethasone, I I- dehydrobetamethasone and Π -den drodexamethas one.

The present Invention 1s also concerned with a method for the treatment of non-human animals employing high dose levels of the above-metnloned 21-adamantane-l ' -carboxyl ates .

According to one feature of the present Invention , we provide a method of systemlcally treating Immunological disorders or Infl ammatory disorders having a signifi cant Immunologi cal component which comprises administering wi thin a period of up to 7 days to a non-human animal suffering from such a disorder an niti al dosage of 50 to y 500 mg of betamethasone 21-adamantane-V-carboxylate, dexamethasone 21-adamantane-l '-carboxyl ate, dexamethasone 21-adamantane-l ' -carboxylate or a corresponding 11-ketone.

In order to take advantage of the present fi nding that high initiil doses of the adamantoates are exceptionally beneficial, it is more convenient to formulate them. in dosage units containing more than 50 mg of active steroid and it will be appreciated that dosage units containing such large quantities of corticoids represent a radical departure from previous practice. Thus, betamethasone and dexamethasone are usually administered systemically for treating inflammatory conditions in man in rather low doses, for example about 2 mg. Our" above-mentioned Specification describes dosage units containing up to 50( mg of betamethasone 21-adama tane-l'-carboxylate.

According to a further feature of the invention, therefore we provide pharmaceutical and veterinary compositions in dosage unit form, eacli dosage unit containing more than 50mg but not more than 500rng, preferably more than 50mg but not more than 200mg, of betamethasone 21-adamantane-l'- ! carboxylate, dexamethasone 21-adamantane- 1 ' -carboxylate or a corresponding 11-ketone together with at least one pharmaceutical or veterinary carrier or excipient.

By the use of large doses of the active steroid in treating the a.bove-mentioned disorders, it is possible to obtain a. systemic effect having a far longer duration of action than would have been expected solely from the increase in the amount of the compound employed. Indeed, the duration of the effect has been found to be significantly - disorders having a high immunological component for periods of up to 4-8 weeks or even longer using a suitable initial dose of the steroid, as more particularly described hereinafter, whereas steroids such as betamethasone are not observed to g5.ve relief for prolonged periods after administration and in some cases symptoms recur rapidly and may be at an increased level.

We have further discovered that the use of large doses of the active steroids provides an unusually valuable immunosuppressive effect. Experiments have shown that ther appears to be arrest of the pathological immune response whilst normal immunological competence recovers.

Thus, the steroids can generally be employed for the treatment of disorders having an immunological basis, e.g. for the suppression of harmful immunological reactions.

It is further observed from experiments on rats that blood 11-hydroxy corticosteroid levels are lowered for only a relatively short period of time whereas the antiinflammatory and/or immunosuppressive effects appear to persist for longer periods of time.

In the above-described method, an initial dose of the steroid, e.g. betamethasone 21-adamantane-*l,-carboxylate, is preferably 100-200mg.

The initial dosage of steroid given both to human desired adults and children and to animals can if y be expressed on a mg/kg basis. Thus, the dosage range 50 to 500 mg given above " is equivalent tp- 0.7 to. 7.1 mg/kg for a 70 kg human adult. \~ Although those dosages will also be affected by 'the surface area when considering and animals, the dosages will still fall within the above range. A preferred dosage range is '. ' • -.. · " ^ - _ 3 to 7 mg/kg in animals.

In order to achieve the desired therapeutic effect, the above-defined initial dosage may be given on a single day or may be divided into separate doses given over a period ' up to" · "" 7 days, for example at 1-3 day intervals. The dosage regime may thus, for example, comprise three administrations of the steroid over three days or two administrations over two or three days, the total dosage over this initial period being within the limits set out above.

It will be appreciated that the precise initial dosage and the number and frequency of separate divided dosages will generally depend inter alia upon the nature of the disorder being treated, its severity, the precise route of administration of the steroid and the condition, age and weight of the , animal.- The initial dosage of the steroid provides suppression of the disorder for an initial long period, e.g. for a period of 2-8 weeks or even longer. In some cases, particularly in the treatment of rheumatoid' „· · arthritis, the initial dosage of the steroid may, ,result in arrest of the disorder under treatment.

Such arrest .;, has 'not previously been, thought .. feasibleV ' - Further administration of the · steroid at a lower dosage level, may maintain suppression of . the disorder . ,·.'._ The steroid compounds are advantageously administered by injection, preferably by the intramuscular route, although the subcutaneous, intravenous or intraarticular routes may be used if desired. The steroid compounds . , are thus conveniently presented in the form of injectable . preparations adapted for administration of the steroid by such routes . Compositions . adapted for parenteral administration, preferably by- the intramuscular route, may for example be formulated in a sterile aqueous vehicle. The injectable ..' compositions may be conveniently presented in sealed ampoules or vials containing an aqueous suspension of the active steroid formulated for example with the aid of conventional excipients such as dispersing .... or . ·' :' ''.. agents, suspending agents ^stabilising agents Alternatively, the steroids- may be administered via the gastrointestinal tract e.g. in the form of orally acceptable preparations or in the form of suppositories.

For oral administration, the pharma nautical and veterinary compositions according to, the invention.: are formulated with aid of one or more appropriate pliarmaceutical or veterinary carriers or excipients which may be solid or liquid. Such orally administrable compositions may be 1 or formulated for example as tablets, capsules /granules etc. For oral administration, the dosages of the steroid may be greater (for example up to 4 times greater) than those indicated above for administration of the compound by injection. large doaes of The use of/the steroid compounds as described above enables one to treat a wide variety of disorders which in general may be roughly classified as disorders associated with inflammatory conditions/ having a significartimmunological component and disorders arising from harmful immunological reactions .

The administration of the compounds in the above described manner will be particularly valuable for the treatment of rheumatoid arthritis since the large dosage will rapidly bring the disorder under control, as indicated by a reduction in fever (if the disorder is severe) relief of pain and reduction in the swelling at the joints. Medical opinion considers that rheumatoid arthritis is a disease. in which both immunological and inflammatory reactions play a part.

The immuno- suppressive component of the activity of the corticosteroids discussed herein can be demonstrated 43947 -3 by their effects in treating experimental allergic encephalomyelitis in rats. This experimental condition which is known to have a considerable immunological component can be regarded as a model for multiple sclerosis in the human. Results have shown that the disorders can be treated successfully using large doses of. steroid as described above.

The large doses of steroid may be used to treat · ... , disorders where there is an inflammatory and/or immunological process causing damage to the tissues. Disorders where such a mechanism is believed to play a part in the pathogenesis are listed i below . ■ In the literature some of these disorders have been referred to as "autoimmune" which in the strict sense of the word means an immune response by the patient to his own tissues. The initiating aetiological event may not itself have been autoimmune but may have been brought about by infectious or toxic agents. However, these agents directly or indirectly set up immunological processes which damage the tissues . For the present purposes such disorders are included. ' . ' in humans ' The disorders ^which may be treated with the compoeition of the present invention include exfoliative dermatitis and severe pemphigus , severe systemic lupus erythematosis , status asthmaticus and severe asthma, complications arising from acute lymphatic leukaemia and other leukaemias, (such as haemolytic anaemia and thrombocytopenic purpura), acquired haemolytic anaemia, severe hypersensitivity reactions (e.g. serum sickness, angioneurotic oedema and trichiniasis) , collagen diseases, rheumatic fever especially if there is cardiac involvement , chronic discoid lupus erythematosus, polyarteritis nodosa, scleroderma, polymyositis, dermatomyositis , giant-cell arteritis (especially if vision is affected) , ankylosing spondylitis, ulcerative colitis, regional ileitis, sarcoidosis (especially if there is hypercalcaemia, pulmonary fibrosis or CNS involvement), blood diseases due to circulating antibodies, (e.g. haemolytic anaemias, thrombocytopenic purpura, agranulocytosis), eye diseases (such as Sjogrens syndrome), nephrotic syndromes, post-hepatic cirrhosis with fever and other autoimmune disorders such as Hashimoto's disease. The steroid compounds can also be employed in accordance with the invention to control or prevent transplant rejection. 4 The method of the present invention can, as · indicated above, be used to treat veterinary disorders associated with inflammatory conditions having a ■ significant immunological component and/or disorders caused by harmful immunological reactions. Such dis¬ orders include, for' example:- . 1. . Chronic eczema in cats and dogs . 2. Inflammatory conditions of the lung (pneumonia) (especially in the bovine). 3. Inflammatory conditions of the bovine udder (mastitis). 4. Inflammatory conditions of the gastrointestinal tract (e.g. calf or piglet scours). 5. Muscle and joint conditions (rheumatic and arthritic)..

The 21 -adamantane-i-carboxyla es of dexamethasone and ; ;. ,v 11-dehydrodexamethasone are new compounds and constitute further features of the present invention.

The adamantoate steroids here concerned may be prepared; for example, as described in the following Preparations .

Preparation 1 Betamethasone 21-adamantane-i 1 -ca boxylate 9a-Fluoro-il ,17-dihydroxy-21-iodo-16 -methylpregna- 1 ,4-diene-3,20-dione 1 (76.65g) was dissolved in warm acetone (400 ml) and then adamantane carboxylic acid (54 g) and . triethylamine (52.5 ml)were added and washed in with more acetone (100 ml). The solution was refluxed for one hour and then poured with good stirring into . cold water (2.5 1). Filtration of the precipitated material and recrystallisation from aqueous methanol with charcoaling afforded betamethasone 21-adamantane- 1' -carboxylate showing extensive melting 245-250° (Kofler) with subsequent crystal formation in the melt followed by slow decomposition and melting at 297-300°, [a] + 114° (c 1.4 dioxan), λ (in EtOH) 238nm D — ' max (ε 16,800).

Preparation 2 Dexamethasone 21-adamantane- 1 ' rcarboxylate.

A solution of dexamethasone (3 g) in dry tetrahydro furan (100 ml) was treated with adamantane carbonyl chloride (7.6 g) in tetrahydrofuran (35 ml) and pyridine (7 ml) and the mixture refluxed for 5.5 hours. The cooled solution was filtered from solid material and evaporated in vacuo to small bulk. Dilution with dilut sodium bicarbonate solution afforded an oil which was extracted with ethyl acetate . The washed and dried extracts were evaporated in vacuo to yield the crude ester contaminated with adamantane carbonyl chloride.

This solid was heated on a steam-bath in pyridine (36 ml) and water (6 ml) for 2.5 hours. Dilution with water gave the adamantane carboxylate which was crystallised twice from ethyl acetate to give dexamethasone 21-adamantane-l ' -carboxylate m.p. 285-289° decomp., [a]Q + 85° (c, 1.0, dioxan) , λ^χ 239 nm (ε 15,540).

Preparation 3 11-Dehydrobetamethasone 21-adamantane-l 1 -carboxylate A solution of betamethasone 21-adamantane-l ' -carboxylate (0.3 g) in acetone (180 ml) was cooled and stirred in an ice-bath whilst Jones reagent (1.5 ml; prepared by dissolving 66.7 g chromium trioxide in 53.3 ml concentrated sulphuric acid and making up to 250 ml with water) was added dropwise over a period of 10. minutes. Further portions of reagent (0.8 m] and 0.4 ml) were added after 20 minutes and 80 minutes. When the reaction was judged complete, the green chromium salts were removed by filtration and the mother liquors partially evaporated in vacuo. The resulting solution was diluted with water and extracted with ethyl acetate. The washed and dried (MgSO^) extracts were evaporated and the residue recrystallised twice from methanol to afford 11-dehydrobetamethasone - 1 - 21-adamantane-l' -carboxylate , m.p. 241-244° decomp., [a] + 149° (c 1.0 dioxan), λ 236 nm (ε 15,800). D — ' max The active steroids employed in accordance with the present invention may be administered in the form of the following injectable preparations.

Example 1 Composition Active steroid (particle size; 2.00% < 100 μ; 10-75% > 5μ) Benzalkonium chloride (anhydrous equivalent) 0.015 Tween 80 (polyoxyethylene-(20) sorbitan mono-oleate) . 0.010 Tween 81 0.005 Hydroxyethylcellulose 0.100 Sodium dihydrogen phosphate (dihydrate) 0.017 Disodium hydrogen phosphate (anhydrous) 0.043 Sodium chloride 0.710 Benzyl alcohol 1.00% v Water for injection to 100.00 pH 6.0 - 7.0 Preparation of Injectable Suspension The sodium chloride and phosphates are mixed with the hydroxyethyl cellulose, dissolved in water, benzyl alcohol added and the solution then sieved or filtered and then sterilized by autoclaving to provide the vehicle for the suspension. The Tweens and ben-zalkonium chloride are together dissolved or dispersed in a small portion of the available water, mixed with the active steroid and the suspension is sterilized by autoclaving at 10 psi for 1 hour.

The sterile vehicle and the steroid suspension are then mixed aseptically and subjected to high shear stirring. The suspension is made up to volume with water, sieved, and filled into 3, 4, or 5 ml ampoules each containing 20 mg/ml of active steroid.

Similar preparations may be made in 1, 2, 3, 4 or 5 ml ampoules each containing 50 mg/ml of active steroid or 2, 3, 4 or 5 ml ampoules each containing 30 mg/ml active steroid.

Example 2 Injectable Preparations containing betamethasone 21-adamantane-l' -carboxylate Composition Betamethasone 21-adamantane-l' -carboxylate (sterile reprecipitated; particle size < 100μ; 10-75% > 5μ) 2.00% Benzalkonium chloride (anhydrous equivalent) 0.015 Tween 80 (polyoxyethylene-(20) sorbitan mono- oleate) 0.010 Tween 81 0.005 w/v Hydroxyethylcellulose 0.100. II Sodium dihydrogen phosphate (dihydrate) 0.017 I I Disodium hydrogen phosphate (anhydrous) 0.043 II Sodium chloride 0.710 It Benzyl alcohol 1.00% v/v Water for Injection to 100.00 pH 6.0 - 7.0 Preparation of the reprecipitated betamethasone 21-adamantane-1 ' -carboxylate 100 g of betamethasone 21-adamantane-l'-carboxylate are dissolved in a mixture of 1100 mis of dimethyl aeetamide with 21.6 grams of Tween 80. This solution is added with stirring to 7.5 litres of 1% v/v aqueous solution of benzyl alcohol. The resulting suspension is centrifuged, the supernatant liquid removed and the suspended material washed with water and recentrifuged.

The supernatant liquid is again removed and the suspension made up to 2.0 litres with water. The suspension is then sieved (200 mesh).

Preparation of Injectable Suspension The sodium chloride and phosphates are mixed with the hydroxyethyl cellulose, dissolved in water, benzyl - - alcohol added and the solution then sieved or filtered and then sterilized by autoclaving to provide the vehicle for the suspension. The Tweens and benzalkonium chloride are together dissolved or dispersed in a small portion of the available water, mixed with the reprecipitated betamethasone 21-adamantane-l' -carboxylate and the suspension is sterilized by autoclaving at 10 psi for 1 hour.

The sterile vehicle and the betamethasone 21-adamantane-1 ' -carboxylate suspension are then mixed aseptically and subjected to high shear stirring. The suspension is made up to volume with water, sieved, and filled into 3, 4, or 5 ml ampoules each containing 20 mg/ml of betamethasone 21-adamantane-l ' -carboxylate .

Similar preparation may be made in 1,2,3,4 or 5ml ampoules each containing 50 mg/ml of active steroid, or 2, 3, 4 or 5 ml ampoules each containing 30 mg/ml of active steroid.

Claims (1)

1. What claim Λ of systemically immunological disorders or disorders having a significant immunological component which comprises administering a period of to 7 days to a animal sufferin from such a disorder an initial of 50 to 500 of betamethasone or a corresponding A method as claimed in claim 1 wherein the initial dosage is 100 to 200 rng of the said carbox A method as in claim 1 wherein the initial dosage is to mg of said carboxylate of body weight of the A method defined in claim 3 wherein the dosage is 5 7 m of the body of the A method as defined in claim 1 wherein the said initial dosage is divided and is administered to the on two or days over a period of up to 7 days A hod as de in cl 5 wherein said dosage is administered to the animal on two or more days w a period of up to 7 days and at A defined in claim 5 wherein s initial dosage is divided and is administered to the animal on three successive Λ method as defined in claim 5 wherein said initial dosage is divided and is administered to the two days over a period of 2 or 3 A method as defined in claim 1 wherein administration of said to the animal s by A as defined in claim 9 wherein administration is effected by intramuscular A method as in claim 1 wherein said is betamethasone and veterinary compositions in dosage each dosage unit containing more than but not more tlian mg of betamethasone 1 or a corresponding together with at least one pharmaceu or veterinary carrier or as defined in claim 12 wherein each dosage unit ii is than 50mg but not more titan 200mg of the as defined in claim 12 adapted for Compositions as in claim 12 adapted for intramuscular admini as defined in claim 14 containing a sterile aqueous Compositions defined in claim 16 in the form of ampoules Compositions as claim 12 each dosage unit more than 50rng but not more than 500mg of amethasone as in claim each dosage unit contains more than but not more than 500rng of dexamethasone Dexamethasone 21 A process for preparing the compound as claimed 1n claim substantially as herein described reference ttorneys for App cant insufficientOCRQuality