Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-07-06
2001-01-09
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S486000, C424S452000
Reexamination Certificate
active
06171615
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to sustained release pharmaceutical compositions. More particularly, the invention has to do with a method employing certain GELUCIRE® excipients, particularly GELUCIRE 50/13 and GELUCIRE 53/10, in combination with nucleation enhancers to stabilize an excipient system and to prepare a new sustained release theophylline formulation in capsule unit dosage form.
2. Description of Related Art
GELUCIRE, a product of Gattefoss{acute over (e)} s.a., Saint-Priest Cedex, France and Westwood, N.J., USA, is a well known excipient which is available with a range of properties and it is used in various applications including preparing sustained release pharmaceutical compositions, as described in the technical and patent literature. For example, U.S. Pat. No. 4,797,286 describes sustained release, orally administrable pharmaceutical formulations employing GELUCIRE to make a carrier matrix. The compositions were prepared by admixing a pharmaceutically active agent with molten GELUCIRE and then filling capsules with the admixture.
A sustained release formulation containing captopril is described in U.S. Pat. No. 5,433,951. Various GELUCIRE compositions were employed according to the experimental descriptions to make captopril formulations which were then used to fill hard gelatin capsules.
Sustained release compositions of theophylline are described in U.S. Pat. No. 4,988,679. In this case, triglycerides of a medium chain length alkanoic acid or distilled acetylated monoglycerides, a liquid, high HLB polyglyceryl ester and colloidal silicon dioxide were employed to make a liquid sustained release composition.
In a 1991 article, Brossard, C., et al.,
Modelling of Theophylline Compound Release from Hard Gelatin Capsules Containing Gelucire Matrix Granules,
Drug Development and Industrial Pharmacy, 17(10), 1267-1277, the authors describe hard shell gelatin capsules containing four theophylline compounds of different solubilities (theophylline and the theophylline derivatives etofylline, diprophylline and proxyphylline) prepared with various GELUCIRE compositions. The theophylline and its derivatives were incorporated into the GELUCIRE compositions by a process of melting at 80° C., then congealing at 4° C. followed by granulation. Compritol® 888 glyceryl behenate, another product of Gattefoss{acute over (e)}, was used in combination with GELUCIRE to make the sustained release compositions. The authors found that the GELUCIRE compositions were effective in making timed release compositions of the theophylline derivatives, but in the case of theophylline itself the length of its needle-like crystals prevented effective inclusion of the drug in the fatty matrix of the GELUCIRE compositions and release of the theophylline was always faster than expected.
A more recent article, Sutananta, W.,
The Physical Characterization of Complex Glyceride Mixtures,
School of Pharmacy, University of London, March 1993, describes the use of GELUCIRE compositions, including GELUCIRE 50/13, with theophylline. The author concluded that GELUCIRE 50/13 matrices were not effective to resolve problems associated with dissolution upon ageing.
We have now discovered a means of making effective sustained release pharmaceutical compositions of theophylline for delivery in a gelatin capsule by employing certain GELUCIRE excipients in combination with certain nucleation enhancers. The pharmaceutical compositions described in this study are particularly stable with respect to dissolution upon ageing.
All percentages and ratios set forth herein are expressed as weight/weight, unless otherwise specified.
SUMMARY OF THE INVENTION
The invention has to do with a sustained release system for pharmaceutically active agents, a process for stabilizing such systems and the sustained release pharmaceutical compositions thereby prepared. More specifically, the system employs GELUCIRE 50/13 in combination with certain nucleation enhancers which we have found to be particularly effective for preventing dissolution upon ageing in theophylline compositions.
GELUCIRE is a semi-solid excipient composed of fatty acid (C
12
-C
18
) esters of glycerol and polyethylene glycol esters (“PEG esters”). Theophylline is a well-known therapeutic agent for human and veterinary use and is described in the
Merck Index
as 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione. For example, theophylline is a bronchodilator which can be used to treat symptomas from asthma in chronic bronchitis and emphysema.
In the process of making the stabilized pharmaceutical compositions, the GELUCIRE is melted with stirring followed by adding the active ingredient or drug while maintaining heating and stirring until the mixture is homogeneous. The nucleation enhancers are then added, maintaining the stirring and heating and the homogeneous mixture is filled into hard gelatin capsules.
REFERENCES:
patent: 2538127 (1951-01-01), Saunders et al.
patent: 3374146 (1968-03-01), Blicharz et al.
patent: 4454113 (1984-06-01), Hemker
patent: 4755389 (1988-07-01), Jones et al.
patent: 4777048 (1988-10-01), Hersh et al.
patent: 4797286 (1989-01-01), Thakkar et al.
patent: 4880634 (1989-11-01), Speiser
patent: 4988679 (1991-01-01), Chavkin et al.
patent: 5188838 (1993-02-01), Deleuil et al.
patent: 5288505 (1994-02-01), Deboeck et al.
patent: 5368861 (1994-11-01), Ushimaru et al.
patent: 5371109 (1994-12-01), Engstrom et al.
patent: 5433951 (1995-07-01), Serajuddin et al.
patent: 5436230 (1995-07-01), Soudant et al.
patent: 5567439 (1996-10-01), Myers et al.
patent: 5863545 (1999-01-01), Griat
Modelling of Theophylline Compound Released from Hard Gelatin Capsules Containing Gelucire Matrix Granules, Drug Development and Industrial Pharmacy, 17(10), 1267-1277 (1991).
“The Physical Characterisation of Complex Glyceride Mixtures”, Sutananta, Chapter 5, The School of Pharmacy, University of London, Mar., 1993.
Duddu Sarma
Roussin Pascale
Gattefoss{acute over (e)}
Norris & McLaughlin & Marcus
Webman Edward J.
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