AU598751B2 - Pharmaceutical formulations with controlled release of the active substance - Google Patents

Description

COMMONWEALTH OF AUSTRALIA PATENT ACT 1952 COMPLETE SPECIFICATION (Original) FOR OFFICE USE

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Class Int. Class Application Number: 22L\ Lodged: Complete Specification Lodged: Accepted: Published: lTis Jocumen contains th* Priority: lraednoents ra4e undr Related Art: Ii e C I-rt-Cg.- Name of Applicant: Address of Applicant: Actual Inventor(s): Address for Service: SANDOZ LTD.

CH-4002 Basle,

SWITZERLAND

Othmar ZUGER DAVIES COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Complete Specification for the invention entitled: q<'eoe, T .r cMV Ne. >e The following statement is a full description of this invention, including the best method of performing it known to us -1-

I.

Vl 1 -la- Pharmaceutical formulations with controlled release of the active substance This invention relates to pharmaceutical formulations with controlled release of active substances having an influence on blood circulation, including the heart and selected from 4-(2,1,3-benzoxadialzol-4-yl)-1, 4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester, especially Darodipine and Isradipine.

Darodipine is the generic name of diethyl-4-(2,1,3benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5pyridinedicarboxylate. It is disclosed in the British Patent GB 2.037766 B. For pharmaceutical use Darodipine °00 is used as the free base.

S4 The pharmacological and clinical properties have 20 been extensively reviewed. Darodipine is a potent 4 A calcium antagonist on isolated coronary arteries and other peripheral blood vessels. Haemodynamic studies in healthy subjects show a reduction in total peripheral resistance and arterial blood pressure.

Darodipine is indicated for the treatment of angina pectoris, of hypertension, of stroke and of cerebral vasospasms.

Usual oral daily dosages are e.g. for the treatment of angina pectoris 75 to 300 mg, preferably given in 3 divided doses and for the treatment of hypertension 37.5 to 150 mg, given in 2 to 3 divided doses.

900303.db015.let,db63226.resl1 a~a~p i" 2 Isradipine is the generic name of isopropyl methyl- 4-(2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-2,6-dimethyldicarboxylate. It is generally administered as the free base. It is disclosed in the British Patent GB 2.037.766 B.

The pharmacological and clinical properties of Isradipine have been extensively investigated. It is a potent calcium antagonist and influences in particular the coronary and the peripheral arteries. The drug is especially indicated for the treatment of e.g.

hypertension, angina pectoris and cerebral insufficiency.

Usual oral daily dosages are 10 to 20 mg, preferably 0 0 o 15 divided into smaller dosages of 5 to 10 mg two times a day.

The administration of the active substances 0 mentioned above can occasionally be associated with 20 adverse side effects, e.g. headaches in case of Darodipine and headache, flush, palpitation and tachycardia, when Isradipine is administered.

We have now found it is preferred to keep the 25 concentration of the active substance at a therapeutically active level between narrow limits and to 41 avoid the usual drug burst just after administration of non-controlled release preparations, which leads to temporary high blood levels and to proportionately strong S 30 adverse effects.

Therapy can be improved by administering two or three times a day smaller doses, the sum of which equals the total daily dosage. However, this manner is cumbersome and still does not meet the requirement of 6ST/> providing blood levels of active substance only between narrow limits.

900308,db015. et.db63226.res.2 3i 3 The present invention provides a controlled release formulation of the active substances having a prolonged action of the active substance to reduce the number of times the active substance has to be administered each day and to reduce certain adverse reactions.

Additionally the present formulations provide under the test conditions excellent bioavailability in food interaction studies, e.g. as described in Example 4 hereinafter.

The present invention accordingly provides a controlled release formulation for oral administration comprising 15 a 4-(2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-2,6- 0 dimethyl-3,5-pyridine dicarboxylate ester selected Sfrom Isradipine and Darodipine as an active substance o a pharmaceutically acceptable cellulose hydrocolloid o: 20 and a pharmaceutically acceptable fatty acid ester.

In another aspect the present invention provides a controlled release formulation for oral administration 000 00ooo0 and containing Isradipine, and having a relative o" S 25 bioavailability of more than 65% compared with a non Q 0o controlled release oral Isradipine formulation on administration to a subject in the fasted state.

Preferred amounts of Darodipine in unit dosage form S 30 are from 10 to 200 mg, especially 20 to 150, e.g. 100 mg.

Preferred amounts of Isradipine in unit dosage form are from 5 to 40mg, especially 10 to Preferred cellulose hydrocolloids include me.thylcellulose, hydroxypropylcellulose and especially Yhydroxypropylmethylcellulose and sodium S900308.db0i5.1et.db63226.res,3 -4- 4 carboxymethylcellulose.

Preferably the weight ratio of Darodipine to swellable substance is from 1:0.1 to 1:2, especially from 1:0.5 to 1 and of Isradipine to swellable substance from 1:2 to 1:20, especially from 1:4 to 1:10.

A preferred pharmaceutically acceptable fatty acid ester is cetyl palmitate. Such f:.tty acid esters preferably have melting points between 30*C and more preferably 45°C to Preferably the weight ratio of Darodipine to the fatty acid ester is from 10:10.2 to 10:5, especially 15 10:0.5 to 10:1 and of Isradipine to fatty acid ester from 1:0.3 to 1:2, especially 1:0.5 to 1:1.5, in particular e 1:0.5 to 1:1.

00 i The formulations contain preferably both S 20 hydroxypropyl-methyl-cellulose as the cellulose hydrocolloid and cetyl palmitate as the fatty acid ester.

It is also convenient to incorporate in the formulation at least one of other soluble or insoluble pharmaceutical excipients such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica, and magnesium stearate. Preferably a soluble excipient, especially lactose is present. If these other excipients are present, then the weight ratio of Darodipine to the other excipients is conveniently 4, 4 from 10:1 to 1:2, especially 5:1 to 1:1 and of Isradipine to the other excipients from 1:4 to 1:15, especially to 1:10.

The formulation may be produced in conventional manner by mixing the ingredients together, preferably I I melting the fatty acid ester. The resultant mixture is SL0308db015.etdb63226.res.4 0 :0308. db015.1et, db63226.res.4 ~---YWLSlii~-~ii~YL I ii i- li_ cr-rx C 0 00 00 04 0004 0 4 O 0 0 1 00 1 *4 5 in powder form. The powder can be pressed to form a tablet, but is preferably filled into a capsulu.

If the fatty acid ester is melted, the drug and additional excipients such as lactose, silica, calcium sulphate or calcium phosphate may be taken up in the molten fatty acid ester. The mixture is then allowed to solidify and is then divided into small particles (granules).

The resultant granulate may be mixed with a, preferably porous, cellulose hydrochloride and further excipients, e.g. magnesium stearate, and the mixture may be pressed to form a tablet or may be preferably filled 15 into a capsule.

In a preferred aspect the present invention accordingly provides a formulation containing the active substance in a fatty acid ester matrix granulate, the granulate particles being in contact with a cellulose hydrocolloid.

Preferably the cellulose hydrochloride is present in a porous form.

We have surprisingly found that the formulations possess an excellent stability, despite the fact that the active substances are sensitive to many chemical reagents. Moreover, the formulations have a satisfactory 30 pharmacodynamic and pharmacokinetic profile.

The resultant formulations in general have comparable bioavailability in standard clinical trials to conventional non-retarded formulations containing the same amounts of active substances. The formulations of the invention, even if administered once a day, may produce a therapeutic effect for at least 24 hours and 4 A a 0 4440 #0040 0 0 t 900308,dbO15. let, db63226. -6even as much as 35 hours. The formulation for Darodipine and Isradipine may be administered only once a day in the known indications of the active substances at approximately the same daily doses as employed in the conventional non-retarded forms. Steady state studies show a narrow range between maximum and minimum active substance levels in the blood.

The formulations of the present invention are well tolerated.

Moreover, the present formulations provide similar profiles of activity in food interaction studies, e.g.

before and after administration of breakfast, with fasted S 15 subjects.

o 0 The once-a-day formulations may be formulated in 0 02 conventional manner, e.g. to be a capsule or tablet and may contain from 10 to 200 mg of active substance.

o 0 20 Preferably they have the release profile as determined by 00 O in vivo or in vitro dissolution test, e.g. a release of about 34 percent of Darodipin and 50 to 65 percent of Isradipin over 6 hours in 0.1 NHC1, e.g. as in the °o:n experimental conditions in Examples 1 to 3.

In the following examples all temperatures are in o degrees Centigrade and are uncorrected.

Further information on the properties etc. of the S 30 pharmaceutical excipients named hereinafter may be obtained from the manufacturer, listed hereinafter, manufacturer's brochures or other sources, especially H.P. Fiedler Lexikon der Hilfsstoffe fUr Pharmazie, Kosmetik und angrenzende Gebiete, 2nd Edition 1981, Edito Cantor, Aulendorf, West Germany.

900308.db015.1et.db63226.res,6 k 7 Silicon dioxide (silica) is e.g. brand Aerosil 200 available from Deutsche-Gold und Silberscheideanstalt, Frankfurt, West Germany.

Glycerol ditripalmitostearat is e.g. brand Precirol Ato 5 available from ETS Gattefosse 929100 Boulogne- Brillancourt, France.

Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g. brands Methocel K15M and Methocel 4EM available from Dow Chemical Company, Michigan 48640 USA.

Cetyl palmitate is e.g. brand Cutina CPA available from Henkel 4000, Dusseldorf, West Germany, or is 15 available from Gattefosse or from A/S Johan C. Martens and Company, Bergen, Norway.

0 0 0 0t 1 04 O 0 0) 900308,dbOl5.let.db63226.res.7 is1J iiiT--lrnra 8 Example 1: Ingredient mg a) Darodipine 100 b) Lactose (200 mesh) c) Cetyl palmitate 8 d) Hydroxypropylmethylcellulose (100.000 cps) e) Mg stearate 2 200 a Preparation Ingredients a) and b) are sieved and mixed.

Ingredients c) is melted by heating to 60 0 C and is added to the mixture which is heated to 55°C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The rushed mass is broken up and sieved (though 250 micron openings). Ingredients d) and e) are sieved (though 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.

In vitro release Time (hours) Release of Darodipine 1 7 2 14 4 6 34 24 97 900308,dbO15. let,db63226 res,8 9 Example 2: Capsule Ingredient mg a) Isradipine b) Lactose 97 c) Glycerol ditripalmitostearate d) Hydroxypropylmethylcellulose 4000 cps e) Silica 1 f) Magnesium Stearate 2 180 Preparation (Charge of 6000 capsules) Ingredients a) and b) are sieved and mixed.

Ingredients c) is melted by heating to 56°C 54 0

C)

and is added to the mixture which is heated to 55°C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The rushed.mass is broken up and sieved (though 250 micron openings). Ingredients e) and f) are sieved (though 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.

In vitro release Time (hours) Release 1 11 2 19 4 43 6 64 24 102 030,db .etd63226rs 9C0308,dbO15.1etdb63226.res,9 10 Example 3: Capsule Ingredient mg a) Isradipine b) Microcrystalline cellulose 97 c) Cetyl palmitate d) Hydroxypropylmethylcellulose 4000 cps e) Silica 1 f) Magnesium Stearate 2 160 20 Preparation S; In analogous manner to that disclosed in Example 2 SIn vitro release Time (hours) Release 1 11 2 4 36 6 52 24 96 L53 900308.dbO15.1et.db63226.res,10 7 11 Example 4: Capsule Ingredients mg a) Isradipine b) Microcrystalline cellulose 47 c) Cetyl palmitate d) Hydroxypropylmethylcellulose 15000 cps e) Silica 1 f) Magnesium Stearate 2 160 In a clinical test a very good retard profile and o relative bioavailability of the composition of Example 4 0 20 in fasted and in non-fasted subjects could be Sestablished, compared with non-retarded capsules containing the same amount of Isradipine.

Preparation In analogous manner to that disclosed in Example 2.

In vivo release In a study to evaluate the bioavailability of the capsule of Example 4, this capsule and a reference capsule containing Isradipine in a non-prolonged release form were administered to fasting subjects. The prolonged release capsule was additionally administered to nonfasted subjects.

900208,db015.1et.db63226.res, 11 112 12 The composition of the conventional reference capsule containing Isradipine in a non-prolonged release form was as follows: Ingredients mg a) Isradipine b) Lactose 167 c) Corn starch 128 d) Sodium laurylsulphate e) Silica f) Polyethylenglycol 6000 0 00 o° The study employed an ope. -label three-way randomized crossover design in 9 healthy male volunteers. Subjects S were given a single dose of either a non-prolonged 20 release reference capsule (10 mg) in the fasted state or a prolonged release cpasule according to Example 4 mg) in the fasted and in the non-fasted state. The i intervals between the three different administration Speriods were at least 7 days.

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90010P,41-01 I e A 1'22ei, r-n 12 i-il -I _I 13 Blood samples of each volunteer were collected from 0 to 48 hours after each dose and plasma was analysed for Isradipine by using a RIA technique (detection limit 0.1 nanogram/ml).

The mean temporal plasma concentration data are plotted graphically in figure 2, in which 10 mg prolonged release capsule in the fasted state 10 mg prolonged release capsule in the non-fasted state and 10 mg conventional non-prolonged release capsule.

Plasmaconcentration in nanogram/ml vs. time 15 in hours From the curves the following data are calculated: 0 0.

o n 044 Prolonged release capsule (10 mg) non-fasted state Prolonged release capsule (10 mg) fasted state Reference tablet (10 mg) fasted state 48

AUC

48 34.73 34.67 49.65 0 in ng h/ml max 3.70 1.77 14,22 in ng/ml

T

max 8,55 9 1.89 (in hours) Geometric mean for n 9 subjects, 48

AUC

48 Aerea under the curve from 0 to 48 hours.

Compared with the reference form the relative bioavailability is more than Let.df5;;;5 re;. 1 1

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Claims (9)

1. A controlled release formulation for oral administration comprising S a 1, 3-benzoxadiazol-4-yl)-l,4-dihydro-2,

6-dimethyl-3, 5-pyridine dicarboxylate ester selected from Isradipine and Darodipine as an active substance a pharmaceutically acceptable cellulose hydrocolloid and a pharmaceutically acceptable fatty acid ester. 1" 2. A formulation according to Claim 1, wherein the oo active substance is Isradipine. 0 0 4 o 1 3. A formulation according to any one of the preceding claims wherein the hydrocolloid is hydroxypropylmethylcellulose. 4. A formulation according to any one of the preceding claims wherein the fatty acid ester is a hydrophobic material with a melting point between 30 and A formulation according to any one of the preceding claims wherein the fatty acid ester is cetyl palmitate. 6. A formulation according to any one of the preceding claims containing from 5 to 40 mg of Isradipine.

7. A formulation according to any one of the preceding claims, wherein the weight ratio of Isradipine to the hydrocolloid is from 1:2 to 1:20. L S t 900308 etd63226re 9003odb8LC:5. et.db6322.res. 14 Hn

8. A formulation according to any one of the preceding claims, wherein the weight ratio of Isradipine to the fatty acid ester is from 1:0.3 to 1:2.

9. A formulation according to any one of the preceding claims containing hydroxpropylmethylcellulose as the hydrocolloid and cetyl palmitate as a fatty acid ester. A formulation according to any one of the preceding claims containing the active substance in the fatty acid ester matrix as a granulate, the granulate particles being in contact with the cellulose S 15 hydrocolloid. O 0 0 o 11. A formulation according to any one of the preceding 0 02 claims containing Isradipine, for use in the treatment or prevention of disorders of blood S 20 circulation or hypertension, in unit dosage form, containing 5 to 40 mg of Isradipine.

12. A controlled release formulation for oral administration according to any preceding claims and containing Isradipine, and having a relative bioavailability of more than 65% compared with a non controlled release oral Isradipine formulation on administration to a subject in the fasted state.

13. A formulation according to Claim 1 substantially as hereinbefore described with reference to any one of the Examples.

14. A method for the preparation of the formulation of any one of the preceding claims, which comprises mixing the active substance with the fatty acid (r ester and cellulose hydrocolloid. 900308,db015.1et,db63226.res.15 L l-r*llrr rr~ ri C 16 A method for the preparation of the formulation of any one of the preceding claims, which comprises mixing the active substance with the molten fatty acid ester, solidifying and granulating the mixture and mixing the granulate particles with cellulose hydrocolloid.

16. A formulation produced according to the method of Claim 14 or DATED this 5th day of March 1990 08 0 0 one on a 0~ SANDOZ LTD. By Its Patent Attorneys DAVIES COLLISON 900308,db015 1et,db6322.-es, 16