AU618599B2 - Controlled release bromocriptine formulations - Google Patents

Description

COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION 6 (Original) 68 FOR OFFICE USE Class In' class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: 0 Priority: SRelated Art: 0 p Q p Name of Applicant: oAddress of Applicant: 0 i SANDOZ LTD.

35 Lichtstrasse, CH-4002 Basle, Switzerland OTHMAR ZUGER and NORMAN MAZER Actual Inventor(s): Address for Service: DAVIES COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Complete specification for the invention entitled: "CONTROLLED RELEASE BROMOCRIPTINE FORMULATIONS" The following statement is a full description of this invention, including the best method of performing it known to us 1 i i 1_ 100-6243 -la- "CONTROLLED RELEASE BROMOCRIPTINE

FORMULATIONS"

This invention relates to pharmaceutical compositions, containing bromocripti n.

00 Bromocriptine is the generic name for the compound 2-bromo-12'hydroxy-2'-(1-methylethyl)-5'a-(2-methylpropyl)ergotamin-3',6'- 0 tri-one and is listed in the Merck Index, 1976, Appendix A 2.

S° Bromocriptine is a well-known dopamine agonist used in the treatment of e.g. hyperprolactinemia, acromegaly and Parkinson's disease.

10 It is usually administered in the form of the mesylate in daily dosages of e.g. 5-7.5 mg, 10-60 mg and 20-80 mg respectively.

Its pharmacological and clinical properties have been recently .t extensively reviewed in M O. Thorner et al.: Bromocriptina A clinical and pharmacological review, Raven Press, New York 198 U However the pharmacokinetic profile was not been established c..o conclusively. From extensive pharmacokinetic studies we have found o" that bromocriptine is rapidly absorbed and rapidly eliminated from plasma after oral administration (t 1/2 3 to 5 hours). Although its duration of action appears to extend well beyond t 1/2 in some applications hypoprolactinaemia effect), we have found that it is generally necessary to administer the daily doses in 2 to 4 small doses to achieve a lasting therapy and to decrease potential unwanted side effects, which are thought to be related to the rapid absorption of the drug. Some of these side effects are due to dopaminergic activity of the compound acting on dopaminergic receptors in the gastro-intestinal tract, e.g. nausea and emesis.

I: i-_I~IL~ _C 2 There exists thus a need for a controlled release formulation of bromocriptine which provides a prolonged action of bromocriptine to reduce the number of times bromocriptine has to be administered each day and to reduce certain adverse reactions.

According to the present invention there is provided a controlled release formulation of bromocriptine, which formulation releases less then 50 percent by S 10 weight of bromocriptine within 2.5 hours as measured S, in 0.1 n HCI in-vitro release experiments.

Preferably, the controlled release formulation releases less than 65 percent by weight of o"fo bromocriptine within 8 hours, and at least 80 percent 0, 15 by weight within 24 hours.

Controlled release formulations for oral o administration preferably comprise: 0 o bromocriptine; a pharmaceutically acceptable cellulose hydrocolloid; and a pharma-eutically inert fatty material.

The preferred amounts of bromocriptine in the unit S 25 dosage form are from 2 to 20 mg, especially 5 to mg. The bromocriptine may be in free base form or in the form of a pharmaceutically acceptable acid addition salt. Preferably the bromocriptine is in mesylate salt form. Reference herein to bromocriptine is intended both the free base form and such salt forms.

Hydrophilic swelling substances that can be used include one or more natural, partially or totally C ~yl synthetic anionic or, preferably, nonionic hydrophilic gums, modified cellulosic substances or proteinaceous substances such as, for example, acacia, gum tragacanth, locust bean gum, guar gum, karaya gu1i, agar, pectin, carrageen, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxypolymethylene, gelatin.

o o Preferred are cellulose hydrocolloids which include methyl cellulose, hydroxypropylcellulose and especially hydroxypropylmethylcellulose and sodium o carboxymethylcellulose. Preferably the weigh ratio 15 of bromocriptine to the hydrophilic swelling 0 V substance is from 1;10 to 1:50, more preferably 1:10 to 1:35, and especially from 1:16 to 1:25.

The weight ratios refer to the amount of active substance bromocriptine, not the total weight of any salt.

ao t i 3 100-6243 Usable pharmaceutically acceptable inert fatty materials include beeswax; fatty acids; long chain fatty alcohols such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such as, for example, glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like.

o Fatty materials are preferably such with meltinq ooints between 30 and 90 0

C.

0 0 S 10 Most preferred fatty materials have a melting point from 45 0

°C

j °0 to 65 0 C and include glycerides such as glyceryl palmitates Oe I'd and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate. Preferably the weight ratio of bromocriptine to the fatty material is from °o 15 1:1 to 1:10, espeically from 1:6 to 1:10.

0 Oa Soo 0o It is also convenient to incorporate in the formulation other soluble or insoluble pharmaceutical excipients such as calcium sulfate, calcium phosphate, lactose ,o o 9 20 and colloidal silica, The weight ratio of bromocriptine to'these ooo**oo o other excipients is conveniently from 1:5 to 1:40, e.g. 1:15 to 1:40.

The formulation may be produced in conventional manner by mixing the ingredients together if desired melting the fatty material.

The resultant mixture is in powder form The powder can be pressed to form a tablet, but is preferably filled into a capsule.

I I- II ~lli~Cli~ -X We have surprisingly found that the formulations possess an excellent stability, despite the fact that bromocriptine is sensitive to many chemical reagents, and have a satisfactory pharmacodynamic and pharmacokinetic profile. The controlled release profile of the formulations of the present invention also avoids serious pharmacological side effects associated with bromocriptine administration.

10 The resultant retarded formulations in general have comparable bioavailability in standard clinical trials to conventional non-retarded formulations containing Lhe same amount of bromocriptine. The 0 t .n O' formulations of the invention, even if administered S"o 15 once a day, can still produce a therapeutic effect for at least 24 hours and even as much as 35 hours.

The formulation may thus be administered only once a Sday in the known indications of bromocriptine at Q 00 approximately the same daily doses as employed in the conventional non-retarded forms.

4 0 0 Preferred formulations are such, which show in in 4 vitro release experiments a release rate of (o o bromocriptine of less than 50% in 2.5 hours, 25 preferably a release rate of less than 65% in 8 hours, as measured in 0.1 n HC1 solution. Most preferably, the formulation will release at least of the active ingredient within 24 hours.

i 100-6243 In the following examples all temperatures are in degrees Centigrade and are uncorrected.

Further information on the properties etc. of the 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 angreinzende Gebiete, 2nd Edition 1981, Edito Cantor Aulendorf, W. Germany.

Silica is e.g. brand Aerosil 200 available from Deutsche-Gold und Silberscheidanstalt, Frankfurt, W. Germany, Glycerol ditripalmitostearate is e,g, brand Precirol Ato 5 available from ETS Gattefosse 929100 Boulogne-Brillancourt, France.

Hydroxypropylmethylcellulose 15000 cpp and 4000 cps are e.g.

brands Methocel K15M and Methocel E4M available from Dow Chemical Company, Michigan 48640 USA.

Cetyl palmitate is e.g. brand Cutina CP ailable from Henkel 4000, DUsseldorf, W.Germany.

ii I I- 6 100-6243 EXAMPLE 1: Comqosition__of each_casuyle Ingredient mg 1) Bromocriptine mesylate 5,735 2) Lactose (200 mesh) 124.265 3) Silica 4) Glycerol ditripalmitostearate .oo* 5) Hydroxypropylmethylcellulose ,gJ 4000 cps 110 So. 290 0 0 4 S Capsule (Hard gelatine) 78 10 )equivalent to 5 mg bromocriptine base 0 0 o Preparation (Charge of 6000 capsules) Ingredientsi 2) and 3) are sieved and mixed. Ingredient 4) is melted by leating to 56 0 C 54°C) and is added to the mixture which is heated to 550C. The mass is stirred for 2 minutes 15 or until it is a homogenous mixture and cooled overnight. The crushed mass is broken up and sieved (through 250 micron openings).

Ingredient 5) is sieved (through 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.

-7 100-6243 In vitro release Gastric jutce 0.1 n HC1 (pH- 1,2) Ti me (hours) 4 6 24 Release of bromocriptine 7 13 28 42 100 4 o 4 0 EXAMPLE 2: Comeositioi of each caesuie, 1) 2) 3) 4) ingredient Bromocriptine mesylate Calcium sulfate 2H-20 Cetylpalmi tate HydroXypropyl methyl cellulose (15000 cps) Capsule (hard gelatine) mg 5.735 124.265 20.0 120.0 270.0 78.0 'equivalent to 5 mg bromocriptine base i 100-6243 Preparation Analogous to Example 1, with the difference, that now ingredients 1) and 2) are mixed, followed by addition of ingredient 3) in molten form, after which the mixture is cooled and ingredient 4) is added.

EXAMPLE 3: Composition of each_capsule Ingredient 4 4c o 0 4" 09 0 0 t 00 o D 0 0s ro *4 0U 4 1) Bromocriptine mesylate 2) Maleic acid 11.47 4.00 78,53 10 3) Lactose 4) Silica 5) Cetyl palmitate 6) Hydroxypropylmethylcellulose 15.000 cps 10.00 40.00 130.00 274.00 81.00 355.00 Capsule (hard gelatine) 3*)corresponding to 10 mg bromocriptine base Preparation Analogous to Example 1, with the difference that now ingredients 3) and 4) are mixed, followed by addition of ingredient in molten form, after which the mixture is cooled and ingredient 6) is added.

9 100-6243 Comparative clinical tests Objectives: To study in healthy volunteers the tolerability, bioavailability and the prolactine suppression effects of two oral controlled release capsules A and B according to the S invention in comparison to a conventional capsule C and a placebo capsule D.

A. Composition according to the invention a 0 Ingredient mg o 1. Bromocriptine in mesylate form 5.735 0. 10 2. Lactose 184.265 3. Glycerol-ditripalmito stearate 20.000 4. Hydroxypropylmethylcellulose (4000 cps) 60.000 corresponding to 5 mg bromocriptine I 15 The fatty component A3. was added in molten form to a mixture of components Al. and A2. and mixed therewith after which the mixture was cooled to room temperature and component A4, was mixed with the mixture of Al., A2. and A3.

B. Composition according to the invention Ingredient mg 1. Bromocriptine in mesylate form 5.735 2. Lactose 124.265 3, Silica 10.000

I

100-6243 Glycerol -di tri pal mi to stearate Hydroxypropyirnethylcel lulose (4000 cps) 40.000 110.000 0 04 00 0490 040 0 o o 04 0 0 o 0 0000 0 00 090 0 09 no 00 0 o 0 0 000 0 00 90 0 0 0.0 0 0 9t 0 oo 00 0 090 0 0*09 0 00 94 0 900000 0 4 The mixture was prepared analogous to the mixture under A, with the exception that instead of mixing Al. and A2., Bi. B2. and B3. were mixed.

C, Conventional composition I1.

2.

3.

4.

6.

Ingredient Bromocriptine in mesylate form Maleic acid, milled Lactose Cornstarch Silica MAagnesiurns tearate mg 2,87 2.00 170 .63 120.00 1 3.00 15 *)corresponding to 2,5 mg bromocriptine The ingredients I to 6 were mixed together 0) Conventi onal placebo composition I1.

2.

3.

Ingredi ent Lactose Glycerol ditripalmito stearate Hydroxypropylmethyl cellulose (4000 cps) mg 190.00 20.00 60,00 -11- 100-6243 The fatty component 02 was added in molten form to component 01 and mixed therewith, after which the mixture was cooled to room temperature and mixed with component 03.

Instead of 5 mg bromocriptine, as present in capsule A and B, the non-retarded capsule C contained only 2.5 mg bromocriptine to avoid a too strong influence on the healthy volunteers by expected side effects.

In a randomized double-blind design 8 healthy male volunteers received at 8.00 h in the morning either one capsule A,B,C or D in such o, a manner that each volunteer received the 4 different capsule types, divided over 4 administration days, separated by an interval of a week.

9o 9 o o Prolactin inhibition Blood samples were obtained from the 8 volunteers by an indwelling cannula, in certain time intervals from 8.00 h, the time the a. capsule was received, till 10.00 h on the third day (totally hours), with a longer interruption from 18.00 till 8,00 h in the o 0 o second night. The prolactin levels were determined by a soecific radioimmunoassay, The prolactin concentrations, measured after the administration of capsules A, B and C were plotted graphically as corresponding mean curves A (fig.l), B (fig.2) and C (fig.3).

The prolactin concentrations, determined after the administration of capsule D, were depicted as curve 0 in fig. 1,2 and 3, which was compared with curves A, B and C (in nanogramis/ml,time t in hours).

g~ -12- 100-6243 '4 44 4. 4 V '4 '4 '4 )-a '4 '4 '4l~ ou u 04r 4 '4 4 The prolactin curve D represents the normal prolactin concentration of healthy volunteers during night and day.

In the evening, the concentration rises, during sleeo the maximum is reached and in the first wakening hours the concentration falls to a day-time "basal level" which is mantained to about 20.00 h. From curves A and B a prolactin secretion inhibition is observed 1 hour after taking the corresponding capsules A and B and lasting 35 hours.

Capsule C produces a prolactin inhibition in healthy volunteers, 1 hour after taking a capsule C and lasting only 24 hours.

Pharmacokinetics Parallel to the prolactin concentrations, bromocriptine concentrations were measured in the blood samples obtained up till 24 hours after administration of the capsules.

The bromocriptine concentrations in the blood were plotted as mean curves A, B and C in fig. 4 (in picograms/ml, time t in hours).

The concentrations of curve C in fig. 4, caused by the 2.5 mg bromocriptine containing capsule C were doubled and plotted in fig.5 as a curve C adapted to a double portion of capsule C, together with curves A and B, so that bromocriptine levels of equal dosages of bromocriptine (5 mg) can be compared.

From fig. 5 it is seen that the rate at which drug initially rise absorption phase) is slightly form A and markedly reduced for form B as compared concentrations reduced for with twice form C.

A

r I -13- 100-6243 It also appears from these mean curves, that the bioavailabilities (AUC*) of capsules A and B are somewhat lower than of two capsules C.

Based on the individual subjects data, the reduction in bioavailability was an average of 12% for form A and 25% for form B.

Tolerability The side effects experienced by to type, duration and intensity the following side effects were cta 9 0 a 0 aor a a a a 0 o a a aQ 0190 a a orthostatic hypotonia dizziness vomiting nausea nasalcongestion headache dry mouth each volunteer were recorded as (strong, moderate and weak). Overall, noted:head pressure drowsiness tiredness weakness sweating heat senation abdominal cramps palor Side effects 1) to 6) are well krown for dopamine agonist drugs like Bromocriptine and were used to assess the relative tolerability of the formulations in the table below: *Area under the curve -14- 100-6243 number of drug related side effects Intensity A B C D mg drug 5 mq drug 2.5 mg drug placebo strong 10 5 1 1 moderate 16 9 1 0 weak 12 5 11 3 total 38 19 13 4 I, 44 00 I 0004I 0404 o 0494 0 4p 00 0 A "A 04 00 0B 0 04.04 9 4 00 0 40 04 0) 0 Capsule A produced significantly more drug than all other forms.

Capsule B produced fewer drug related side and the total number was not statistically mg conventional form C.

Capsule C produced significantly more drug than placebo D.

On the basis of tolerability, Capsule B is capsule A.

related side effects effects than A, different from the related side effects to be preferred over I, i 100-6243 In in vitro experiments (USP XXI, page 1243-1244, Apparatus 1, 1000 ml 0.1 n HCi,100 rotations per min.) the following release results were obtained with capsules A, B and C:- Release time in hours Release of of weight) bromocriptine (in percents Capsule A Capsule B Capsule C 13 4 99 1 23 8 100 2 42 4 66 28 6 81 39 8 89 48 94 57 14 98 68 24 100 86 From the viewpoint of pharmacokinetics capsules A and B are preferred and capsule B is especially preferred.

Summary: A daily dosage of two capsules of C, if administered simultaneouslywould not be tolerated in clinical practice as reported before.

Both capsules A and B, if administered once a day surprisingly cause a satisfactory therapeutically effective bromocriptine concentration for 24 hours and a prolactin suppression for 35 hours in the blood, notwithstanding a slightly decreased bioavailability in comparison with two capsules C. Capsule B is preferably used, since it causes less side effects and its controlled absorption is better.

I u 16- EXAMPLE 4 A composition is prepared in the form of microparticles having a bromocriptine mesylate drug loading content of percent in a matrix of polylactic acid (Mw 47,000).

6 microparticle portions of 100 mg each were tested according to the Rotating Paddle Method described in the US Pharmacopoeia XXI, p. 1243-1244 in a medium of 500 ml 0.1 N HC1, stirred at 50 rotations per minute at a temperature of 37°C. 2.5 ml portions of liquid medium were analysed after 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 and 6 hours stirring.

It was found that 40.53% of bromocriptine was released after 2.5 hours from the microparticles.

*f Time Measured Value Average Deviation (hrs) 15.6 16.2 17.7 18.9 17.7 18,8 17.54 1,3 24.5 25.3 26.8 29.3 26.8 29.2 27.03 1,9 31.4 31.1 33.5 37.1 33.4 36,8 33,93 35.5 35.5 37.7 42.0 37.5 41,3 38.30 2.8 38.0 37.9 39.8 44.4 49.0 43.9 40.53 2,9 45.2 44.9 47.1 52.4 46,5 52.7 48.19 48.8 47.9 50.7 57.2 49.7 56,6 51.86 53.3 53.6 56.2 63.5 55.5 63.1 57.57 57.1 61.8 59.0 67.0 58.8 66.3 61.70 4.1 911009,immdaL 13,N\3506sarcs,16 I _i

Claims (4)

1. A controlled release formulation for oral use comprising bromocriptine and formulation excipients enabling release of less than 50 percent by weight of bromocriptine within 2.5 hours as measured in 0.1 n HC1 in-vitro release experiments.

2. A controlled release formulation according to claim 1 releasing less than 65 percent by weight within 8 hours.

3. A controlled release formulation according to claims 1 or 2 releasing at least 80 percent by weight within 24 hours. I,, I, I

4. A controlled release formulation as one of the preceding claims containing 2 bromocriptine per unit dosage form. A controlled release formulation of substantially as hereinbefore described. claimed in any to 20 mg of bromocriptine DATED this 9th day of October, 1991. SANDOZ LTD. By Its Patent Attorneys DAVIES COLLISON 91009, 4 immndat123,aA\35006sanrcs,17