JPS60202812A - Bromocriptine composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] This invention relates to a pharmaceutical composition containing bromocriptine.

[Background technology and composition of the invention]

Bromocriptine is the common name for 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'α-(2-methylpropyl)ergocumine-3;6'-trione, and is listed in the Merck Index. ,
1976) as described in Supplement A2.

Bromocriptine is a well-known dopamine agonist, such as hyperprolactinemia (hyper-prolactinemia).
cL inemia), acromegaly (acromegaly)
aly) and Parkinson's disease (Parkinson'
S disease). Quartz is usually in the form of mesylate, each for example 5-7.5
A daily dose of 9.1 O-6Q mg and 20-80 μ is administered.

Its pharmacological and clinical properties were recently reviewed by Toner et al.
Bromocriptine, a clinical and pharmacological review
e A clinical and pharmaco
logical review)” (Raven Press,
New York, 1980). However, pharmacokinetic aspects have not been conclusively elucidated.

As a result of further studies, the inventors found that bromocriptine is rapidly absorbed and rapidly excreted from plasma after oral administration (tl/2=3 to 5 hours). Its duration of action appears to be well longer than t1/2 for certain indications (e.g. hypoprolactinemia), but according to the inventors, t2 is generally 1/2 for duration of treatment and reduction of undesirable side effects. It has been found that the daily dose needs to be administered as two to four small doses, which is believed to be related to the rapid absorption of the drug. Some of the above side effects are due to the dopaminergic activity of the compound on dopaminergic receptors in the gastrointestinal tract, examples of which are nausea and vomiting.

Therefore, there is a need for a controlled release bromocriptine formulation that prolongs the action of bromocriptine, reduces the number of required daily bromocriptine doses, and reduces side effects.

This invention provides a controlled release formulation for oral administration consisting of bromocriptine, a pharmaceutically acceptable hydrophilic swellable material, and a pharmaceutically acceptable inert fatty material.

A suitable amount of bromocriptine in unit dosage form is 2
-20"i, especially 5 and 10〃l.

Bromocriptine can be in free base form or in pharmaceutically acceptable acid addition salt form. Preferably, bromocriptine is in the mesylate form. In this specification, bromocriptine is intended to include both the free base form and the above-mentioned salt forms.

Hydrophilic swellable materials that can be used include one or more natural, partially or fully synthetic, anionic, or preferably non-ionic, hydrophilic gums, modified cellulosic or proteinaceous materials. Examples include gum arabic, gum tragacanth, locust bean gum, gum guaya, gum karaya, agar, pectin, carrageen, soluble oyster insoluble alginate, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene, gelatin. is included.

Preferred are cellulose hydrocolloids, including nimethylcellulose, hydroxypropylcellulose, and especially hydroxypropylmethylcellulose, as well as sodium carboxymethylcellulose. The weight ratio of bromocriptine to hydrophilic swellable substance is:
1:10 to 1:35, particularly 1:16 to 25 are preferred.

The weight ratio indicates the amount of the active ingredient bromocriptine and does not indicate the total weight of the salt.

Pharmaceutically acceptable inert fatty materials that can be used include honey, fatty acids such as long chain fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, such as glyceryl monostearate;
Included are glycerides such as glyceryl distearate, glyceryl esters of fatty acids or hydrogenated aliphatic acids, such as glyceryl esters of hydrogenated castor oil, and oils such as mineral oils.

Preferably, the fatty material has a melting point of 30 to 90°C.

The most preferred fatty materials are those with a melting point of 45-65°C, including glycerides such as glyceryl palmitates and stearates, and fatty acids such as hydrogenated castor oil, and cetyl palmitate. Contains fatty acid esters.

The weight ratio of bromocriptine to fatty material was 1:
1-1:10. Particularly preferred is 1:6 to 1:10.

The formulations also conveniently include soluble or insoluble pharmaceutical excipients such as calcium sulfate, calcium phosphate, lactose and colloidal silica. The weight ratio of bromocriptine to these other excipients is between 1:5 and 1:4.
0, for example 1:15 to 1:40.

The formulations are prepared in conventional manner by mixing the ingredients and, if desired, melting the fatty material. Although the powder can be compressed into tablets, it is preferably filled into capsules.

Surprisingly, the inventors have discovered that although bromocriptine is unstable to a number of chemical agents,
181 尤1　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　`` Furthermore, the formulation has satisfactory pharmacodynamic and pharmacokinetic aspects.

The resulting retarded formulations generally have bioavailability equivalent to conventional non-retarded formulations containing the same amount of bromocriptine in standard clinical trials. The formulation of this invention is administered once per day.
Even in the case of multiple administrations, a therapeutic effect of up to 35 hours can be produced in at least 24 hours. Therefore, this formulation may be administered only once a day in known bromocriptine indications at approximately the same daily dose used for conventional non-delayed formulations.

Preferred formulations have been tested in in vitro release experiments at 0,1
N-1-(C7: has a release rate of less than 50% of bromocriptine in 2.5 hours, preferably less than 65% of bromocriptine in 8 hours, when measured in solution. Most preferred are formulations that release at least 80% of the active ingredient within 24 hours.

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

For information on the properties of the pharmaceutical excipients mentioned below, please refer to the manufacturers mentioned below, their pamphlets, etc. Ende Gebbete (Lexikon der Hil)
[5stofIe fur PharmazieKos
Meiik und Angrenzende Geb
iete) J 2nd edition.

Obtained from Nybuit Kandl Aulendorf (West Germany) in 1981.

The silica can be obtained, for example, with Aerosil 200 sold by Teutsche Gold Land Zilbergaidanstalt (Frankfurt, West Germany).

Glycerine dittripalmitostearate is, for example, ET
S (Gattefuose, 299100, Boulogne Bottle Brillantcourt, France) Sold by Pregilot/L/ ・7
Precirol Ato5.

Hydroxypropyl methylcellulose 1500Q cP
s and 4000 cps, for example Dow Chemical
Methocel K 15 M and Methocel E4M, sold by Methocel Co., Ltd. (Michigan 48640, USA).

Cetyl palmitate is available from Henkel (-4000,
Cuti (Düsseldorf, West Germany)
na) There is CP.

Example 1 Composition of each capsule m9
Lactose (200 mesh) 124.2653) Silica
1゜4) Glycerin dittripalmitostearate 40 5) Hydroxypropyl methylcellulose 4000CpS 110 90 (hard gelatin) capsule 78
Capsule preparation) Sift and mix ingredients 1), 2) and 3). Heat component 4 to 56℃ to melt it.Melting point 5
4°C), add to the mixture and heat to 55°C.

Stir the mass for 2 minutes or until a homogeneous mixture and cool overnight. This mass is ground into pieces and sieved (through 250 micron holes). Component 5) is sieved (through 360 micron holes) and mixed for 10 minutes. The mixture is then encapsulated.

In vitro release experiment 0.0 as gastric fluid. lN-HC4' (P81.2) time
Release of bromocriptine 1 7% 2 13% 4 28% 6 42% 24 100% Example 2 Composition of each capsule ttrg X) ■ Calcium sulfate 21-120 124.2653
) Cetyl palmitate 20.0 4) Hydroxypropyl methylcellulose (15000cps), 120,02
70.0 (Hard gelatin) capsule 78. .

X) Equivalent amount of bromocriptine base 5η Same as in Preparation Example 1, but here components 1) and 2)
After mixing and adding component 3) in molten form, the mixture is cooled and component 4) is added.

Example 3 Composition of each capsule 1) Bromocriptine mesylate 11.47X) 2
) Maleic acid 4.00 3) Lactose 78.53 4) Silica 10.00 5) Cetyl palmitate 40.00 rR-r+4XI-? ff1LPIl-JflI Cell a, -s (15000cps) 130.00274
．． 00 (Hard gelatin) capsule 81.00 355.00
After mixing 3) and 4) and adding component 5) in molten form, the mixture is cooled and component 6) is added.

(Comparative clinical trial) Purpose: In healthy volunteers, 2
To study the tolerability, bioavailability and prolactin inhibitory effect of controlled release capsules A and B for oral administration of seeds compared with conventional capsules C and placebo capsules D.

A. Ingredients of the composition according to the invention m,! 1. Mesylate form of bromocributy 7 5.735X) 2
, Lactose 184.265 3, Glycerin ditripalmitostearate 20.000 4, Hydroxypropyl methylcellulose (4000 cps) 60.000 After cooling to room temperature, component A4 was mixed with the mixture of AI, A2 and A3.

B. Ingredients of the composition according to the invention mda 1, bromocriptine mesylate 5.7352, lactose 124.265 3, silica io, oo.

4. Glycerine ditripalmitostearate 1 40.000 5. Hydroxypropyl methyl cell ox (4000 cps) 110.000 This mixture is prepared in the same manner as the mixture according to A, but
However, without mixing A1 and A2, B l,, B2. and B3. were mixed.

C1 Conventional Composition Ingredients mg l, Bromocriptine Mesylate 2.87'')2
, Maleic acid grinding 2.00 3, Lactose 170.63 4, Cornstarch 120.00 5, Silica 1.50 6, Magnesium stearate 3.00 Lg Bromocriptine 2.5rrLg equivalent.

Ingredients 1-6 were mixed together.

D. Conventional Flasebo composition components In addition to Di, the mixture was mixed.

For capsules A and B, Bromocriptine 5rrL
However, in order to avoid having an excessively strong effect on healthy volunteers due to expected side effects,
Non-delayed capsule C contains 2.5 m of bromocriptine.
, g was included.

In a randomized, double-blind study, eight healthy male volunteers were administered four different capsule types in divided doses over four dosing days, one week apart. :00 capsule A, B, C or 1)
were administered.

(Prolactin suppression) At fixed time intervals from 8:00 when the capsule was administered to 10:00 on the third day (50 hours in total, with a long interruption from 18:00 to 8:00 on the second day), Blood samples were obtained from eight volunteers using an internal cannula. Prolactin levels were measured by specific radioimmunoassay.

When the brolactin concentrations measured after ear injection of capsules A-B and C are represented in a graph, the corresponding average curve A
(Fig. 1 9, B (Fig. 2 9 and C (Fig. 3)).

The prolactin concentration measured after administration of Kabdel 1] was shown as a curve and compared with curves A, B, and C by drawing it in Figures 1, 2, and 3 (nanocrum/ml!, t
The unit is time].

The prolactin curve represents the standard prolactin concentration in healthy volunteers during one day and night.

Concentrations rise in the afternoon, reaching a maximum during sleep, but upon first awakening, concentrations fall to daytime 'basal levels', where they remain until around 20:00. As curves A and B show, inhibition of prolactin secretion was observed 1 hour after taking the corresponding capsules A and B;
Spanning hours.

In the case of Capsule C, prolactin suppression in healthy volunteers was observed 1 hour after taking Capsule C;
Lasts only 24 hours.

(Pharmacokinetics) In parallel with prolactin concentration, blood samples were collected up to 24 hours after capsule administration to measure bromocriptine concentration.

Bromocriptine concentration in blood is illustrated as average curves A, B and C in Figure 4 (picograms/lne
, (unit is time).

The concentration shown by curve C in Figure 4 is when bromocriptine in Capsule C is 2.5 mg, but this is doubled and shown in Figure 5 as Curve C, which corresponds to twice the amount of Capsule C. This allowed comparison of curves A and B at bromocriptine levels with equal bromocriptine dose t (5 mg).

As can be seen from Figure 5, the initial rate of increase in drug concentration (i.e. absorption rate) is
In the case of curve A, it has decreased slightly, and in the case of curve B, it has decreased significantly.

Also, as can be seen from these average curves, capsule A
The bioavailability (AUG'') of and B is somewhat lower than that of two capsules C.

Based on the individual target materials, the reduction in bioavailability is 5.
For curve A it was 12% on average and for curve B it was 25%.

×Area under the curve (tolerability) The duration and intensity of the side effects experienced by each volunteer were recorded by type (strong, moderate, and weak).

Overall, the following side effects were recorded:

1) Orthostatic hypotension 8) Head compression 2) Dizziness 9) Sleepiness 3] Vomiting 10) Fatigue 4) Nausea 11) Weakness 5] Nosebleed 12) Sweating 6) Headache 13) Feeling of heat 7) Dry mouth 14) Abdomen - Spasticity - Pallor side effects υ~6) are well known for dopamine agonists such as bromocriptine, and the relative tolerability of the formulations in the table below was evaluated with respect to these.

Number of drug-relative side effects A B CI) Strong 10 5 1 1 Fair 16 9 1 0 Weak 12 5 11 3 Capsule A caused significantly more drug-relative side effects than all other dosage forms.

Capsule B had fewer relative drug side effects than Capsule A, and the total number of capsules was not statistically superior to conventional capsule C, which was 2.5 mg.

Capsule C was significantly more il! than Placebo D. Caused relative side effects.

Based on tolerability, Capsule B is preferred over Abcel A.

In vitro experiments (USP) XXI, 124
pp. 3-1244, Apparatus 1.0. lN-HCl! 18n
n-n 1n ^rFi'IfG /IA )lr-h
z+) The following release results were obtained for capsules A-B and C.

Release time Bromocriptine release (hours) (% by weight) Capsule A Capsule B Capsule C O,513499 1238100 24215 46628 68139 88948 109457 149868 2410086 Pharmacokinetically, capsules A and B are preferred, and capsule B is particularly preferred.

SUMMARY As mentioned above, in clinical practice it is not acceptable to administer two daily doses of Capsule C at the same time.

For both capsules A and B, once daily administration:
Although slightly inferior in terms of bioavailability compared to 2 capsules C, surprisingly satisfactory treatment for 24 hours in the blood - effective bromocriptine concentrations and 35 hours of prolactin inhibition bring about. Capsule TS is preferred because it has fewer side effects and better controlled absorption.

[Brief explanation of drawings]

FIG. 11, FIG. 2, and FIG. 3 are graphs showing blood prolactin concentrations after administration of Capsules A, B, and C in comparison with that after administration of Capsule 1 in comparative clinical trials, respectively. Figure 4 is a graph showing the blood bromocriptine concentration after administration of capsules A, B, and C, and Figure 5 is a graph showing curve C in Figure 4, which is doubled in height and compared with curves A and B. It is a graph. Patent applicant Sand Akchengesellschaft Patent attorney Haka Aoyama 1 personFIG, 4

Claims (1)

[Scope of Claims] (1) A controlled release formulation for oral administration, comprising: bromocriptine, a pharmaceutically acceptable hydrophilic swellable substance, and a pharmaceutically acceptable inert fatty material. (2) 2 to 2 bromocriptine per unit dosage form
The formulation according to claim 1, containing 0 mg. (3) The preparation according to claim 2, characterized by 5 to bromocriptine. (4) The formulation according to claim 2, which contains bromocriptine 10INi. (5) The preparation according to any one of claims 1 to 4, wherein the swelling substance is a cellulose hydrocolloid. (6) The preparation according to any one of claims 1 to 5, wherein the swelling substance is hydroxypropylmethylcellulose. (7) Weight ratio of bromocriptine and swelling substance is 1:1
7. A formulation according to any one of claims 1 to 6, wherein the ratio is 0 to 1:35. (8) Weight ratio of bromocriptine and swelling substance is 1=1
6 to 1:25. (9) The preparation according to any one of claims 1 to 8, wherein the fatty material is a hydrophobic material with a melting point of 30 to 90°C. (10) The preparation according to any one of claims 1 to 9, wherein the fatty material has a melting point of 45 to 65°C. (11) The preparation according to any one of claims 1 to 10, wherein the fatty material is a glyceride. (121 The preparation according to claim 11, wherein the glyceride is glycerine ditripalmitostearate. (13) The weight ratio of bromocriptine and fatty material is 1:1.
13. A formulation according to any one of claims 1 to 12, wherein the ratio is from 1:10 to 1:10. (14) The weight ratio is 1=6 to 1:10. The formulation according to claim 13. (15) Claims 1-14, which include hydroxypropyl methyl cellulose as a swelling substance and glycerin ditripalmitostearate as a fatty substance.
The preparation according to any one of paragraphs. (16) The formulation according to claim 15, comprising bromocriptine, hydroxypropyl methylcellulose and glycerin ditripalmitostearate in a weight ratio of about 1:22:8 to 1:12:4. 17) Controlled release formulations and processes for oral administration comprising admixing bromocriptine, a hydrophilic swellable substance, and a fatty material. (18) A method for treating or preventing hyperprolactinemia, acromegaly, or Parkinson's disease, which comprises administering a therapeutically effective amount of the controlled-release formulation according to claim 1 to a subject in need of treatment. (19) A preparation in unit dosage form for use in the treatment or prevention of hyperprolactinemia, acromegaly or Parkinson's disease by the method according to claim 18, comprising bromocriptine 2 to 20. (Support)) The formulation according to claim 1, as described in one of the Examples. (21) In an in vitro release experiment, 0. IN
A controlled release formulation of bromocriptine that releases less than 50 parts by weight of bromocriptine in 2.5 hours when measured in -H (, /). Claims characterized by less than 65 parts by weight in 8 hours. 22. The controlled release formulation according to item 21. 23. A controlled release formulation according to any one of claims 21 or 22, characterized in that at least 80 ft% by weight within 24 hours.