Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-01-20
2004-05-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S464000, C424S451000
Reexamination Certificate
active
06733789
ABSTRACT:
This invention relates to a bisoprolol multiparticulate formulation for oral administration and, in particular, to a bisoprolol formulation for chronotherapeutic delivery which can be used for night-time dosing so as to minimise the likelihood of acute cardiovascular occurrences in the well-documented high risk period in the morning.
Bisoprolol (1-[4-[[2-(1-methylethoxy)ethoxy]-methyl]phenoxy]-3-[1-methylethyl)amino]-2-propanol) is a &bgr;-adrenoreceptor blocking drug which was first synthesised and developed by E. Merck (U.S. Pat. No. 4,258,062) and was first introduced into the German market in 1986. It is highly &bgr;-adrenoreceptor selective and is cleared in equal parts unchanged by the kidneys, and by biotransformation in the liver. Bisoprolol is indicated for therapeutic use in the following areas; the control of arterial hypertension, the management of ischaemic heart disease, the control of some forms of cardiac arrhythmias and in the adjunctive management of hyperthyroidism.
Following oral administration, 90% of bisoprolol is absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved after three hours, (40 ng/ml after a 10 mg dose), and appear not to be affected by concomitant food intake or fasting. The systemic bioavailability of bisoprolol is 90% and hence pre-systemic metabolism is below 10%. The mean plasma half life of 10-12 hours is long compared to other &bgr;-blockers. About 50% is excreted unchanged in the urine, the other 50% is biotransformed in the liver with subsequent elimination of pharmacologically inactive metabolites via the kidneys. The pharmacokinetic properties of bisoprolol are not dependent on age or dose in the range 2.5-100 mg.
Generally &bgr;-blockers are well tolerated drugs. As far as symptomatic adverse effects are concerned, bisoprolol shows a similar pattern to other &bgr;-blockers. Dizziness, headache and tiredness are the most frequent adverse effects spontaneously mentioned by patients treated with bisoprolol. Occasionally cold extremities, sleep disturbances, gastrointestinal upset, weakness of the legs, impotence and sweating have been reported. These effects disappeared in the course of the treatment or when dosage was reduced.
It has been well documented that there is a high risk period in the morning in which there is an increase in acute cardiovascular occurences such as sudden death, myocardial infarction and acute cerebrovascular events. Bisoprolol formulations which are currently dosed in the morning, (with an elimination half life of 10-12 hours), provide therapeutic plasma concentrations over the entire day. However, in order to ensure therapeutic plasma concentrations of bisoprolol on wakening, an evening dosed formulation might be more appropriate.
The aim of the present invention was to achieve such a bisoprolol formulation suitable for night-time dosing with the attendant advantages.
The invention provides a multiparticulate bisoprolol formulation for once-daily oral administration, each particle comprising a core of bisoprolol or a pharmaceutically acceptable salt thereof surrounded by a polymeric coating, said polymeric coating being effective to achieve an initial lag of bisoprolol release in vivo of at least 4-6 hours following administration and thereafter maintaining therapeutic concentrations of bisoprolol for the remainder of the twenty-four hour period.
By lag in bisoprolol release herein is meant zero or minimal release.
The formulation according to the invention enables one to achieve a sufficient delay in release while the patient is asleep, immediate drug release just prior to or following wakening and additionally maintenance of therapeutic concentrations over the dosing interval.
Preferably, the polymeric coating is effective to prevent quantifiable bisoprolol plasma concentrations, such as concentrations of bisoprolol greater than 1 ng/ml, in vivo for a period of at least 3-6 hours.
The initial lag period can be followed by a rapid rise in bisoprolol concentration.
Preferably, the formulation according to the invention contains a pharmaceutically acceptable salt of bisoprolol such as acid addition salts produced by reacting bisoprolol with a suitable acid to produce a pharmaceutically acceptable salt. Suitable salts include those of inorganic acids such as sulphuric acid, nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, and phosphoric acid, such as orthophosphoric acid, and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenyl-propionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, p-tolunesulphonic acid and naphthalene-mono- and di-sulphonic acids.
A preferred salt is bisoprolol fumarate. A particularly preferred salt is bisoprolol hemifumarate, also referred to as bisoprolol fumarate 2:1.
While bisoprolol is typically available in racemic form, formulations according to the invention can contain racemic bisoprolol or enantiomers of bisoprolol either as enantiomeric mixtures or as a substantially purified enantiomer. Thus, as used herein, bisoprolol refers to both racemic and enantiomeric forms of bisoprolol.
Preferably, the bisoprolol active ingredient will comprise 0.5-20%, more especially to 0.5-8%, and most especially 0.5-4% of the total weight of the multiparticulates.
A provisional in vitro dissolution profile for a bisoprolol multiparticulate formulation suitable for night-time dosing was considered to be:
Time (hours)
% Released
0-6
<10%
6-7
40-60%
10
65-80%
12
>80%
14
>90%
In practice little correlation was found between in vitro release and in vivo plasma concentration required to achieve the desired therapeutic effects. Although not wishing to be bound by any theoretical explanation of the invention, the delayed release obtained in vivo following night-time dosing is considered to be affected by decreased gastric and possibly intestinal motility during sleep.
A representative in vitro dissolution profile for pH independent multiparticulates is an in vitro dissolution which when measured in a U.S. Pharmacopoeia 2 Apparatus (Paddles) in phosphate buffer at pH 6.8 at 37° C. and 50 rpm substantially corresponds to the following:
(a) from 0% to 10% of the total bisoprolol is released after 2 hours of measurement in said apparatus;
(b) from 0% to 50% of the total bisoprolol is released after 4 hours of measurement in said apparatus; and
(c) greater than 50% of the total bisoprolol is released after 10 hours of measurement in said apparatus.
A representative in vitro dissolution profile for pH dependent multiparticulates is an in vitro dissolution which when measured in a U.S. Pharmacopoeia 1 Apparatus (Baskets) at 37° C. and 50 rpm in 0.01 N HCl for the first 2 hours followed by transfer to phosphate buffer at pH 6.8 for the remainder of the measuring period substantially corresponds to the following:
(a) from 0% to 10% of the total bisoprolol is released after 2 hours of measurement in said apparatus;
(b) less than 50% of the total bisoprolol is released after 4 hours of measurement in said apparatus; and
(c) greater than 20% of the total bisoprolol is released after 10 hours of measurement in said apparatus.
A sealant or barrier layer can be applied to the core prior to the application of the polymeric coating.
The sealant or barrier layer does not modify the release of bisoprolol significantly. Suitable sealants or barriers are permeable or soluble agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose and xanthan gum. Hydroxypropyl methylcellulose is preferred.
Other agents can b
Fanning Niall M.
Kelly Catherine Mary
Stark Paul
Biovail Laboratories, Inc.
Crowell & Moring
Jones Robert M.
Page Thurman K.
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