Controlled release formulation

Details Controlled release formulation Controlled release formulation

2002-01-22

2004-01-06

Azpuru, Carlos (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S480000, C424S481000, C424S488000

Reexamination Certificate

active

06673369

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a controlled release pharmaceutical composition comprising amounts ranging from about 0.1 to about 4.5% w/w, of one or more of rate controlling cellulosic ether polymers.
BACKGROUND OF THE INVENTION
It is well known to those skilled in the art that controlled release formulations which are effective in maintaining therapeutic blood levels over extended periods to time result in optimal therapy. They not only reduce the frequency of dosing for enhanced patient convenience and compliance, but they also reduce the severity and frequency of side effects, as they maintain substantially constant blood levels and avoid fluctuations associated with conventional immediate release formulations administered three to four times a day. It is however very difficult to develop controlled release formulations of high dose drugs due to the unacceptably large sizes of the finished dosage form.
In an effort to overcome the problem of size and patient compliance, Abbott has marketed its clarithromycin extended release tablets “Biaxin XL™” as two 500 mg strength tablets to be administered together once a day. Each 500 mg strength tablet weighs around 1000 mg. In their U.S. Pat. No. 6,010,718 Abbott have claimed formulations containing 5%-50% by weight of total polymer. The specification and examples of this patent discloses preferred formulations containing 10%-20% by weight of rate controlling polymer in the formulation in addition to other excipients. The formulation disclosed in this patent has a total tablet weight of about 1000 mg for a tablet containing 500 mg clarithromycin. A tablet containing 1000 mg drug when made in accordance with this invention would therefore be unacceptably large at 2000 mg.
U.S. Pat. No. 5,705,190 describes controlled release compositions for poorly soluble basic drugs comprising a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid to facilitate dissolution of the basic drug at a high pH. The examples disclosed in this patent describe formulations containing 10-20% w/w of rate controlling polymer. The total tablet weight of each tablet containing 500 mg drug as described in the examples of this invention is more than 900 mg, as substantial amounts of polymers are required for controlling the rate of drug release. A single tablet containing 1000 mg drug, when made according to this invention would weigh at least 1800 mg. This would be unacceptably large for human consumption.
U.S. Pat. No. 4,389,393 describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form, of hydroxypropyl methyl cellulose or a mixture of hydroxypropyl methylcellulose with certain other rate controlling polymers. In the specification of this patent, the inventors disclose that they have been able to achieve sustained release from solid dosage forms containing as little as 5 to about 30 weight percent of these hydroxypropyl methylcelluloses. All the examples disclose compositions containing 9% or more of the rate controlling polymer.
Accordingly, none of the oral controlled drug delivery systems heretofore described is completely satisfactory for the delivery of high dose drugs with low water solubility.
It has now surprisingly been found that high dose drugs with low water solubility when formulated with amounts ranging from about 0.1% to about 4.5% w/w of one or more high viscosity cellulosic ether polymers resulted in extended release formulations which release the drug over an extended period of time.
Clarithromycin when formulated with amounts ranging from 0.1% to about 4.5% w/w of one or more high viscosity hydroxypropyl methylcellulose polymers resulted in extended release formulations wherein the area under the concentration time curve and the maximum plasma concentration are within the interval 0.80-1.25 when compared with two tablets of Biaxin XL® administered together as approved by the United States Food and Drug Administration (US FDA).
The use of the claimed amounts of rate controlling polymers not only ensures a more economical formulation compared to one made using larger amounts of polymers, it also ensures better patient compliance as patients have to take only one tablet instead of two tablets together.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a controlled release formulation suitable for once daily administration, comprising a pharmaceutically effective amount of at least one drug having a water solubility of less than one part per 30 parts water, and from about 0.1% to about 4.5% w/w of one or more rate controlling high viscosity cellulosic ether polymers.
The present invention may apply also to even less soluble drugs for example up to a solubility of one part in 10,000 parts water.
Although, the invention is particularly suitable for high dose drugs but it can advantageously be used for low dose drugs as well, wherein use of small amounts of polymers will result in a more economical formulation.
It is further object of the present invention to provide a controlled release formulation for once daily administration of high dose drugs with low water solubility, wherein the formulation is of an acceptable size and is convenient for oral administration. The use of small amounts of polymers ensures that total weight of the dosage form is low and a single dosage unit is sufficient to provide therapeutic dosage of the drug even when the dosage form has to carry a high payload of the drug. The present formulation provides obvious benefits with respect to small tablets which are more economical and easier to administer therefore ensuring better patient convenience and thereby patient compliance.
The drugs used in accordance with the present invention may be present at a dosage range of about 100-1500 mg. They include, but are not limited to those belonging to the class of:
Analgesics such as Etodolac, Fenoprofen, Tramadol, Paracetamol, Ibuprofen,
Mefenamic acid, Naproxen etc.
Anthelmintics such as Albendazole, Thiabendazole etc.
Cardiovascular drugs such as Chlorothiazide, Dipyridamole etc.
Antibacterials such as Ciprofloxacin, Erythromycin and its derivatives, Norfloxacin
Cefaclor, Cefpodoxime, Cefuroxime, Cefalexin and the like.
Bronchodilators/anti-asthmatics such as Doxyfylline, Zileuton, Theophylline etc.
Gastrointestinal drugs such as Cimetidine and Mesalamine,
Oral Antidiabetics such as Tolbutamide and Tolazamide,
Antiprotozoals such as Tinidazol, Nifuratel, Ornidazole, Secnidazole etc.
Antivirals such as Aciclovir
Antiepileptics such as Carbamazepine, Felbamate, Methoin etc.
The cellulosic ether polymers which are effective in the present invention include, but are not limited to hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and carboxy methylcellulose polymers. They are all commercially available in a wide variety of viscosity grades which can be used either alone or in combination with other cellulosic ether polymers.
Hydroxypropylmethyl cellulose polymers are commercially available in different viscosity grades. These include 4000 and 15000 cps viscosity grades of Methocel K i.e. Methocel K4M and Methocel K15M available from the Dow Chemical Co, USA and 4000, 15,000 and 39000 cps viscosity grades of Metalose 90 SH available from Shin Etsu Ltd, Japan, the 5,000, 12,000 and 75,000 cps viscosity grades of Methocel J i.e. Metocel JSM, J12M, J20M and J75M, available from Dow Chemical Co and high viscosity grades of Methocel E available from Dow Chemical Co., USA.
One or more hydroxypropyl methylcelluloses having a viscosity of 4000 cps or more can be used as the sole carrier base material or in admixture with other cellulosic ether polymers of the same or higher viscosity.
Hydroxypropyl celluloses are commercially available in a wide range of viscosity grades under the trade name of Klucel® from Nippon Soda, Japan.
In addition to the drug and rate controlling cellulosic ether polymers, the composition may contain about 6 to 50% w/w of other pharmace

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