IL43764A - Orally administrable corticosteroid preparations - Google Patents

Abstract

1458676 Corticosteroid compositions HOECHST AG 10 Dec 1973 [9 Dec 1972] 57090/73 Heading A5B A controlled release unit dosage pharmaceutical composition for oral administration comprises at least two layers, the word "layer" including a core in its meaning (e.g. drageÚ cores), each comprising a corticosteroid in the form of the free alcohol or an ester or salt thereof and each having different release properties. The corticosteroid may be hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, or esters or salts thereof. Each layer may contain the same or different corti- 'costeroids, e.g. prednisolone in one layer and its acetate in another, or cortisone acetate in one layer and prednisolone in another. The preferred form is a dregÚe core such as a pressed tablet as the one corticosteroid-containing layer, having an enteric coat (e.g. cellulose acetate phthalate) resistant to gastric juice but soluble in the dudodenum, and an outer dragÚe coating containing corticosteroid, this coating being freely soluble in gastric juice to liberate its active ingredient for absorption in the stomach. The compositions are intended to enable the corticosteroid to be administered in such a way that its absorption rate and action is synchronised with the circadian rhythm of physiological ACTH secretion, and accordingly, the preferred form provides a small steroid dose immediately (i.e. from the outer, soluble layer), and a larger dose some hours later (i.e. from the inner, enterically coated layer), the dosage form being intended to be taken early in the morning. The invention includes a pack comprising a card carrying at least one pair of inventive unit dosage forms together with instruction that one unit is to be taken at about breakfast time and the other unit is to be taken between midafternoon and bed-time. [GB1458676A]

Description

Orally adminlstrable Corticosteroid preparations ϊΤ5π in o'sn'sn vimoDipnnip *vran \ HOE 72/F 377 ORALLY ADMI ISTRABLE CORTICOSTEROID PREPARATIONS Abstract of the disclosure: Orally administre le corticosteroid preparations with optimal adaptation to the circadian secretion rhythm of ACTH, which contain corticosteroids and/or corticosteroid derivatives with suitable pharmaco-kinetic resorption properties in a medicinal form with controlled and/or delayed release of the active substances, and process for preparing them.

The present Invention relates to orally adminlstrable corticosteroid preparations with release of the active sub- ^ stance adapted to the circadian course of the ACTH secretion.

The latest investigations on the action mechanism and the timely course of action of adrenocortlcosteroids in the human organism have shown that there exist two different circadian activity phases of these hormones which are dependent on the diurnal round of the organism.

For example, Ceresa et al. report in the Journal of Clinical Endocrinology and Metabolism XXIX, No. 8, pages 1074 to 1082 (1969), under the heading "Once-a-day Neurally Stimulated and Basal ACTH Secretion Phases in Man and their Response to Corti-coid Inhibition" on clinical experiments made with corticosteroid solutionsapplied in the form of infusions at different times of a day. They have stated that the ACTH secretion system shows two phases of activity with different control mechanism in the course of a day.

One of these activity phases, the impulsive phase, rises in the early morning hours. It is due to a neural action on the hypothamalus which is overlapping the basal activity and is therefore responsible for the circadian action mechanism.

The ACTH secretion is influenced in this phase by the administration of corticosteroids, i.e. there occurs an inhibition.

The second action phase is characterized by a constant basal secretion of ACTH, which is lasting for 24 hours. This phase is independent on the impulse exerted in the early morning hours and also resistant to any doses, even to massive doses, of corticosteroids.

Corticosteroid compounds and/or galenic preparations of corticosteroids which have an influence, as far as possible, with regard to administration and their resorption, on the Λ above-mentioned receptive and the not receptive phase of the course of the ACTH secretion would considerably reduce , if not completely prevent, one of the most aggravating un- desired side reactions in the therapy with corticosteroids, i.e. the reduction of the pituitary and adrenocortical function and therewith the loss of a hormonal synchronization which is controlling the biological processes.

The conventional corticosteroid preparations do not prevent these side reactions, and if they are administered in low doses during the therapy period, they prevent them to a low degree only.

In consideration of the above-described circadian activity phases, attempts have been made to prepare cortico steroid preparations which contain, in combination, the corticosteroids with different half-life times and or -preparation forms with controlled resorption rate, in order to ensure that a high corticosteroid protection is obtained during the non-sensitive phase and minimum blood levels are obtained during the two to three hours in the early morning. Thereby, the ACTH secretion normally occurring in the early morning hours would not be inhibited. Accordingly, it would remain unaffected with regard to its physiological function.

The adaptation of corticosteroid blood levels to the circadian action range of the ACTH succeeds best by timely adjusted administrations of corticosteroid infusions, as described in the above-mentioned publication. Upon intravenous administration of infusion solution, the active substance reaches without delay and/or without any other influence, for example by resorption . processes in the gastro-intestinal tract, the blood circulati %, which in this way ensures the best timely control of the corticosteroid level in the blood.

Since the administration of infusion solutions in a normal . treatment with corticosteroids is too expensive and can merely be used if the patients are treated stationarily in hospitals, preparation forms of corticosteroids have been sought which could be administered by the patient himself and through which a corticosteroid action synchronized with the ACTH secretion in the above sense would be obtained.

For solving this problem, there can be considered, according to the state of the pharmaceutical art, only medicinal preparations such as tablets, dragees or capsules with different dosages of corticosteroids ^taking into consideration the various resorption rates of the used corticosteroids and which have to be taken by the patients perorally simply in intervals of 1 to 2 hours.

On the other side, the patients consider it particularly desirable not to take the preparations in too short intervals; therefore, the best solution would be to bring the medicament in a form permitting or adjusting its intake twice a day.

The present invention has the task to provide an optimum solution to the above-described problem^.

Up to now, experts had no idea how to solve such a complicated problem, involving the selection of suitable corticosteroids or of their derivatives according to their physical, physical-chemical and pharmaco-kinetic properties, the formation of a dosage unit of the medicament producing an optimal release of the active substance under consideration of the conditions 43764/2 during gastrointestinal resorption and the 1ntra-act1on mechanism of the mentioned factors.

In British patent No. 948,088, In British Patent No. 1,182,124 and In German DOS 1,925,919 there are described various compositions of matter which make possible a gradual release of various pharmaceutical preparations. These result In a substantially uniform rate of release of the active Ingredients, dur ng a comparatively long period of time. None of the above preparations results 1n a reitease of a corticosteroid at a rate which Is adapted to the clrcadlan secretion rhythm of ACTH.

Now, we have found that an orally applicable corticosteroid preparation having an optimal adaptation to the clrcadlan secretion system of ACTH can be prepared, by a) selecting corticosteroids and/or corticosteroid compounds having suitable pharmacokinetic resorption properties and b) bringing them, 1n a suitable dose. Into an orally administrate galenic medicinal preparation form with controlled or delayed release of the active substance.

Suitable corticosteroids or corticosteroid derivatives are for example, the free alcohols, esters and s jlts of the following compounds: 1. hydrocortisone 2. cortisone 3. prednisone 4. prednisolone 5. methylpredn solone The quantity of the corticosteroids 1n the preparation 1s, corresponding to their different potency, in general In the range of from 0.5 to 50.0 mg. The preferred range Is between 2.0 mg and 25.0 mg.

Suitable galenic forms having controlled release of the active substance are the forms of retard-medicaments known n the 1 pharmaceutical technology and whose control principle 1s based on the It is preferred to use dragee preparations which are built up from several layers, wherefrom the active substance is e<^ φ leased after different periods of time after intake.

For example, such dragees may contain in the layer which is soluble in the gastric Juice one part of the dose of corticosteroid, which is thus released for resorption immediately after intake. The kernel of the dragee which is provided with a layer that is resistant to the gastric juice releases then another part of the corticosteroid dose, when the lacquer^ that is soluble in the duodenum^dissolves within the area of the duodenum.

According to a preferred variant of the invention, the individual coatings of the preparation contain different 'Corticosteroids and/or different derivatives of corticosteroids.

It is also possible to overcoat the active substances with coatings of different solubility and then to fill them into capsules. Clinical experiments made with the preparations of the present invention have brought the following results: The composition mentioned P/P in the following examples was administered to the patients at 8 o'clock in the morning and the composition P/C was administered in the afternoon at 15 o'clock. This therapy and dosing scheme gave, when applied to humans, an optimum adaptation of a corticosteroid treatment to the circadian rhythm of the ACTH and largely prevented one of the most important side effects of the corticosteroid therapy which is proved by the following' compilation of the clinical reports obtained: Preparations P/P and P/C showed, when administered at the right time, a rapid increase of corticosteroid blood levels directly after intake, a constant blood level during the day and a rapid and total fall of the corticosteroid level in the^ blood at midnight.

Accordingly, this preparation did not have an influence on the circadian biorhythm of cortlcotropine (ACTH) and, in parti- . cular, on the impulsive phase rising in the morning and ensures thus the full function of the adrenal cortex during and after a treatment with corticosteroids.

The following Example show how the ideas of the invention set forth can be realized: The following Examples illustrate the invention; EXAMPLE it r* Dragees were prepared which had the following composition: Composition: P/P P/C 1. Dragee kernel resistant to'gastric Juice and soluble in small intestine a) prednisolone (free alcohol) 4.00 mg ... . . . b) cortisone acetate - 15.00 mg c) maize starch 38.00 mg 39.00 mg d) lactose, pulverized 55.00 mg 53.00 mg e) talcum 2.50 mg 2.50 mg f) magnesium stearate 0.50 mg 0.50 mg 100.00 m 110.00 mg cellulose acetate phthalate 15.00 mg 15.00 mg 115.00 mg 125.00 mg 2. Dragee coating soluble in the gastric juice prednisolone acetate 7.00 mg prednisolone (free alcohol) - 3.00 mg dragee coating ad about 250.00 mg 250.00 mg Preparation: 1. Dragee kernels Mi- Log A homogeneous mixture was prepared from substances a) , c) and d) and b) to d), respectively, indicated above.

Granulating This mixture was pasted up with maize starch glue, passed through a sieve having a mesh size of 0,75 mm and dried.

Powdering The granulate was powdered with a lubricant mixture prepared from e) to f) .

Tabletting The powdered granulate was pressed to tablets. 2. Lacquering of the kernels with a lacquer which is resistant to the gastric juice and soluble in the small intestine The kernels were coated with a solution of cellulose ace-tate«*phthalate . 3· Dragee formation The lacquered kernels were made up to dragees having a final weight of about 250 mg, while strewing in P/P P/C prednisolone acetate 7.00 mg prednisolone (free alcohol) 3.00 mg EXAMPLE 2t Dragees were prepared which had the following composition Composit on { P/P P/C 1. Dragee kernel resistant to gastric juice and soluble in small intestine a) prednisolone (free alcohol) 2.00 mg b) cortisone-acetate - 7..50 mg c) maize starch 39.00 mg 42.50 mg d) lactose, pulverized 56.00 mg 57.00 mg e) talcum 2.50 mg 2.50 mg f) magnesium stearate 0.50 mg 0.50 mg 100.00 mg 110.00 mg Cellulose-acetate-phthalate 15.00 mg 15.00 mg 115.00 mg 125.00 mg 2. Dragee coating resistant to gastric juice prednisolone acetate 3.50 mg prednisolone (free alcohol) - 1.50 mg dragee coating ad about 250.00 mg 250.00 mg Preparation; 1. Dragee kernels Mixing A homogeneous mixture was prepared from substances a), c) and d) and b) to d), respectively.

Granulating; This mixture was pasted up with maize starch, passed through & sieve having a mesh size of 0.75 mm and dried.

Powdering The granulate was powdered with a lubricant mixture pre-pared from e) to f).

Tabletting The powdered granulate was pressed to tablets. 2. Lacquering of the kernels with a lacquer which is resistant to the gastric juice and soluble in the small intestine The kernels were coated with a cellulose-acetate phthalate lacquer solution. 3. Dragee formation The lacquered kernels were made up to dragees having a final weight of about 250 mg,by strewing in P/P P/C prednisolone acetate 3.50 mg prednisolone (free alcool) - 1.50 mg Release of active substance When introduced into artificial gastric juice, at least 95 % of the corticosteroid were released from the dragee coating which was soluble in the gastric . juice and after transfer into artificial intestinal juice at least 95 % of the corticosteroid were released from the dragee kernel which was soluble in the small intestine.

An almost 100 % release of active substances was obtained from the dragees P/P and P/C.

Claims (2)

1. 43764/2 WHAT IS CLAIMED IS: 1 ) Orally adminlstrable corticosteroid preparations with optimal adaptation to the circadlan secretion rhythm^ of ACTH containing In di fferent layers at least two corticosteroids and/or derivatives of corticosteroids with suitable pharmacokinetic resorption properties 1n the form of pharmaceutical compositions with controlled and/or delayed release of the active Ingredients .

2. ) Orally adminlstrable corticosteroid preparations 1n unit dosage form with optimal adaptation to the circadlan secretion rhythm, substantially as hereinbefore described and with reference to the examples.