NL194822C - Preparation for oral administration with controlled release and method for its preparation. - Google Patents

Description

1 194822

Preparation for oral administration with controlled release and method for its preparation

The present invention relates to a preparation for oral administration with a controlled release of an active compound, which contains - a pharmaceutically active substance, - a cellulose hydrocolloid and - a hydrophobic material of esters of fatty acids with a melting point between 30 and 90 ° C.

Such a preparation is known from U.S. Pat. No. 3,147,187. In this document, the compositions are prepared by mixing the above ingredients together, whether or not at elevated temperature.

A drawback of such known preparations is that they cannot achieve a sufficiently flat release profile. In particular with active substances that can cause adverse side effects, it is preferable to keep the concentration of the active material within narrow limits, as described in GB-A 2,154,874 for the dopamine agonist bromocriptine mesylate as a pharmaceutical active substance and in EP-A 0.040,439, for example, for an antihypertensive agent such as pindolol, wherein fatty acids and metal salts thereof were recommended to obtain the intended flat release profile.

It has been found that the administration of a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate dialkyl ester such as Darodipine and Isradipine is sometimes accompanied by adverse side effects. for example headaches in the case of Darodipine and headache, blood flow to the brain, palpitations and tachycardia when Isradipine is administered.

The present invention now provides a preparation according to the preamble, characterized in that the pharmaceutically active substance comprises a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5 pyridine dicarboxylate dialkyl ester, and the pharmaceutically active substance is embedded in a granulate of the hydrophobic material and the granulate is mixed with particles of hydroxypropyl methyl cellulose hydrocolloid and then encapsulated.

In particular, the active substance is Darodipine or Isradipine, preferably Isradipine.

Darodipine is the general name of diethyl 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-oyridine dicarboxylate. This compound is described in British Patent Specification GB-A 2,037,766. Darodipine is used as the free base for pharmaceutical use.

The pharmacological and clinical properties have been thoroughly investigated. Darodipine is a powerful calcium antagonist on isolated coronary arteries and other periphereal blood vessels. Haemodynamic studies on healthy adults show a reduction in total periphereal resistance and arterial blood pressure.

Darodipine is indicated for the treatment of angina pectoris, hypertension, hemorrhage, and cerebral vasospasm.

For example, usual oral daily doses are for the treatment of angina pectoris 75-300 mg, preferably administered in three separate doses and for the treatment of hypertension 37.5-150 mg administered in 2 or 3 separate doses. In GB-A 2,037,766 it is stated that also a pharmaceutical preparation with a delayed release can be used.

40 Israpidine is the general name of isopropylmethyl-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. This prevention is generally administered as a free base and, like Darodipine, is described in British Patent No. 2,037,766.

The pharmacological and clinical properties of israpidine have been extensively investigated. The compound is a powerful calcium antagonist and particularly affects the coronary arteries and peripheral veins. The drug is particularly indicated for the treatment of, for example, hypertension, angina pectoris and cerebral insufficiency. Conventional oral, daily doses are between 10 and 20 mg, preferably in smaller doses of 5 to 10 mg, administered 2 times daily.

With the preparation according to the invention, a controlled release and prolonged action of the active material is obtained in order to reduce the number of times that the active material must be administered every day and to reduce certain adverse reactions. In addition, the present compositions provide excellent bioavailability in food interaction studies under the test conditions, as described, for example, in the examples below.

Recommended amounts of Darodipine in unit dosage form are between 10 and 200 mg, in particular between 20 and 150 mg, for example 100 mg.

Recommended amounts of Isradipine in unit dosage form are between 5 and 40 mg, in particular between 10 and 20 mg.

194822 2

The preparation according to the invention contains a cellulose hydrocolloid, which includes methyl cellulose, hydroxypropyl cellulose and in particular hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose.

Preferably, the weight ratio of Darodipine to the cellulose hydrocolloid is from 1: 0.2 to 1: 2, in particular from 1: 0.5 to 1, and from Isradipine to cellulose hydrocolloid from 1: 2 to 1:20, in particular from 1: 4 to 1:10.

The hydrophobic material preferably has a melting point of 45 to 65 ° C and includes glycerides such as glyceryl palmitates and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.

Preferably, the weight ratio of Darodipine to the hydrophobic material is from 10: 10.2 to 10.5, in particular from 10: 0.5 to 10: 1 and from Isradipine to the hydrophobic material from 1: 0.3 to 1: 2, in particular from 1: 0.5 to 1: 1.5, even more particularly from 1: 0.5 to 1: 1.

The compositions preferably contain hydroxypropyl methylcellulose as a cellulose hydrocolloid and cetyl palmitate as a hydrophobic material.

It is also suitable to include in the composition at least one soluble or insoluble pharmaceutical excipient, such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica and magnesium stearate. A soluble excipient, in particular lactose, is preferably present.

If these other excipients are present, a weight ratio of Darodipine to the other excipients is suitably between 10: 1 and 1: 2, in particular between 5: 1 and 1: 1 and of Isradipine to the other excipients suitably between 1: 4 and 1:15, in particular between 1: 5 and 1:10.

The resulting mixture is a powder. This powder can be compressed into a tablet, but preferably a capsule is filled with this.

If the hydrophobic material of fatty acids or esters thereof is melted, the drug and additional excipients, such as lactose, silica, calcium sulfate or calcium phosphate, can be incorporated into the melted, hydrophobic material. The mixture is then allowed to solidify and then divided into small particles (granulate; granules).

The compositions according to the invention, even if administered once a day, can provide a therapeutic effect for at least 24 hours or even 35 hours.

The compositions of the present invention are well supported.

In addition, the present compositions may provide similar activity profiles in food interaction investigations, for example, before and after eating a breakfast, with persons who have fasted.

The compositions to be administered once daily may be formulated in a conventional manner, for example into a capsule or tablet, and may contain 10-200 mg of active material. They preferably have the release profile as determined by the in vivo or in vitro solution test, for example a release of 34% Darodipine and 50 to 65% Isradipine, in 6 N hydrochloric acid for 6 hours, for example under the experimental conditions of the examples 1,2-5,16 and 17.

In the following examples, all temperatures specified in degrees Celsius are uncorrected.

40 Further information regarding the properties etc. of the pharmaceutical excipients listed below can be obtained from the manufacturers listed below, manufacturers' brochures and from other sources, in particular H.P. Fiedler Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und analogue Gebiete, 2nd edition 1981, Edito Cantor, Aulendorf, West Germany.

Silicon dioxide (silica) is, for example, Aerosil 200 available from Deutsche-Gold und Silberscheidenantstalt, Frankfurt, West Germany.

For example, Glycerol ditripalmitostearate (mixture of di- and triglycerides with C16 and C18 fatty acid residues) is available at Precirol Ato 5 from ETS Gattefosse 929100 Boulogne-Brillancourt, France.

Hydroxypropyl methylcellulose 15000 cps. and 4000 cps. for example, Methocel K15M and Methocel 4EM from the Dow Chemical Company, Michigan 48640 United States of America.

Cetyl palmitate is, for example, Cutina CPA available from Henkel 4000, Düsseldorf, West Germany or may be purchased from Gattefosse or from A / S Johan C. Marlens and Company, Bergen, Norway.

The method used for determining the in v / fro delivery according to the method as found in EP-A 040,439. The original description of this method is described in US Pharmacopeia, 20th edition.

3 194822 * Example /:

Components m9 5 a) Darodipine 100 b) lactose (74 µm) 30 c) cetyl palmitate 8 d) hydroxypropyl methylcellulose (100,000 cps) 60 e) Mgstearate 2 10 200

Manufacture 15 Components a) and b) are sieved and mixed.

Component c) is melted by heating to 60 ° C and added to the mixture, which is heated to 55 ° C. The mass is stirred for two minutes or until it is homogeneous and cooled overnight. The solidified mass is crushed and sieved (through a sieve with openings of 250 microns). Components d) and e) are sieved (through a sieve with 360 micron openings) and mixed for 10 minutes. The mixture is then encapsulated in the usual manner with hard gelatin.

In vitro release time (hours) Release of Darodipine 25 -—-—- 1 7 2 14 4 25 6 34 30 24 97

Example II: Capsule

Components m9 35_____ a) Isradipine 10 b) lactose 97 c) glycerol ditripalmitostearate 10 d) hydroxypropyl methylcellulose 4000 cps 60 e) Silica 1 f) magnesium stearate 2 180 45

Manufacture (charge of 6000 capsules)

Components a) and b) are sieved and mixed.

Component c) is melted by heating to 56 ° C (melting point: 54 ° C) and added to the mixture heated to 55 ° C. The mass is stirred for 2 minutes or until a homogeneous mixture is obtained and cooled overnight. The solidified mass is crushed and sieved (through a sieve with openings of 250 microns). Components d), e) and f) are sieved (through a sieve with 360 micron openings) and mixed for 10 minutes. The mixture is then encapsulated in the usual manner with hard gelatin.

194822 4

In vitro release

Time (hours) Release% 5 1 2 19 4 43 6 64 24 102 10 ---—-

Example III: Capsule

Components m9 a) Isradipine 1 15 b) microcrystalline cellulose 97 c) cetyl palmitate 5 d) hydroxypropyl methyl cellulose 4000 cps 45 e) Silica 1 f) magnesium stearate 2 20 160

Manufacture 25 In an analogous manner as described in Example II.

In vitro release

Time (hours) Release% 30 1 11 2 20 4 36 6 52 24 96 35 -----

Example IV: Capsule

Components m9 a) Isradipine 1 40 b) microcrystalline cellulose 47 c) cetyl palmitate 10 d) hydroxypropyl methyl cellulose 15000 cps 90 e) Silica 1 f) magnesium stearate 2 45 160

In a clinical trial, a very good delayed release profile and relative bioavailability of the preparation of Example IV were found in both those who had fasted and who had not had fasted, compared to capsules containing the same amount of Isradipine but with a non-delayed release.

Manufacture 55 In the same way as described in Example II.

Delivery in vivo

Claims (3)

194822 In a study to determine the bioavailability of the capsule of Example IV, this capsule was administered to persons who had fasted and to persons who had not fasted. The composition of a conventional reference capsule containing Isradipine in the non-delayed (non-sustained) release form was: Components m9 a) Isradipine 10 b) Lactose 167 10 c) corn starch 128 d) sodium lauryl sulfate 5.5 e) Silica 1> 5 f) polyethylene glycol 6000 8.0 15 The study used an "open-label three-way randomized crossover" scheme in 9 healthy male volunteers. A single oral dose of an extended-release capsule according to Example IV was applied to the subjects (10) mg) in both fasting and non-fasting conditions The time periods between the three different administration periods were at least 7 days Blood samples from each volunteer were taken 0-48 hours after each dose and the plasma was analyzed for Isradipine by applying an RIA technique (detection limit 0.1 nanogram / ml) The average temporary plasma concentration values are plotted in the figures, where n • = 10 mg prolonged-release capsule in a fasting condition 25 O = 10 mg sustained-release capsule in a non-fasting condition Δ = 10 mg conventional capsule in which the active material was not released for a long time Plasma concentration in nanograms / ml vs time. The following values were calculated from the curves: 30 capsule (10 mg) with a prolonged capsule (10 mg) with a prolonged release in a non-release condition with fasted AUCq8 in ng h / ml 34.73 34, 67 Cmax in ng / ml 3.70 1.77 (in hours) 8.55 9 40 Geometric average for n = 9 people AUCJS ^ area under the curve from 0 to 48 hours 45 Composition for oral administration with a controlled release of an active compound, comprising - a pharmaceutically active substance, - a cellulose hydrocolloid and - a hydrophobic material of esters of fatty acids with a melting point between 30 and 90 ° C, characterized in that that the pharmaceutically active substance is a 4- (2,1,3-benzoxadiazol-4-yi) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate dialkyl ester, and that the pharmaceutically active substance is in a granulate of the hydrophobic material is embedded and the granulate is mixed with particles of hydroxypropylmethyl cellulose hydrocolloid and then encapsulated. Preparation according to claim 1, characterized in that the pharmaceutically active substance is Isradipine and the 194822 weight ratio of Isradipine to the cellulose hydrocolloid is between 1: 2 and 1:20 and the weight ratio of Isradipine to the hydrophobic material is between 1: 0 , 3 and 1: 2. Preparation according to claim 1 or 2, characterized in that the hydrophobic material is cetyl palmitate. Hereby 1 sheet drawing