Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-02-07
2003-09-30
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S469000, C424S458000, C424S457000, C424S490000, C424S492000, C424S460000, C424S478000
Reexamination Certificate
active
06627223
ABSTRACT:
BACKGROUND OF THE INVENTION
Oral dosage forms are known which provide a zero order or first order release in which the drug is released at a substantially steady rate of release per unit of time. These dosage forms are satisfactory for the administration of pharmaceutical dosage forms of many drugs. However, there are instances where maintaining a constant blood level of a drug is not desirable. In such cases (e.g., optimization of chemotherapy, reducing nocturnal or early morning systems of chronic diseases such as ischemic heart disease, asthma, arthritis, avoiding developing a tolerance to nitrates, antibiotics and steroidal contraceptives, or where absorption windows exist), a ‘time-controlled’ pulsatile drug delivery system may be more advantageous. There are also instances in which a ‘position-controlled’ drug delivery system (e.g. treatment of colon disease or use of colon as an absorption site for peptide and protein based products) may prove to be more efficacious.
A pulsatile delivery system is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms. Ishino et al. disclose a dry-coated tablet form in Chemical Pharm. Bull. Vol. 40 (11), p3036-3041 (1992). U.S. Pat. No. 4,851,229 issued Jul. 25, 1989 to P. R. Magruder et al., U.S. Pat. No. 5,011,692 issued Apr. 30, 1991 to K. Fujioka et al., U.S. Pat. No. 5,017,381 issued May 21, 1991 to Maruyama and R. Cortese, U.S. Pat. No. 5,229,135 issued Jul. 20, 1993 to F. Philippon et al., and U.S. Pat. No. 5,840,329 issued Nov. 24, 1998 to J. P. -F. Bai disclose preparation of pulsatile release systems. Some other devices are disclosed in U.S. Pat. No. 4,871,549 issued Oct. 3, 1989 to Y. Ueda et al., U.S. Pat. Nos. 5,260,068 and 5,260,069 both issued Nov. 9, 1993 to C. M. Chen and U.S. Pat. No. 5,508,040 issued Apr. 16, 1996 to C. M. Chen. U.S. Pat. No 5,229,135 issued Jul. 20, 1993 and U.S. Pat. No. 5,567,441 issued Oct. 22, 1996 both to C. M. Chen disclose a pulsatile release system consisting of pellets coated with delayed release or water insoluble polymeric membranes incorporating hydrophobic water insoluble agents or enteric polymers to alter membrane permeability. U.S. Pat. No. 5,837,284 issued Nov. 17, 1998 to A. M. Mehta et al. discloses a dosage form which provides an immediate release dose of methylphenidate upon oral administration, followed by one or more additional doses spread over several hours. Thus there is a need for a pulsatile drug delivery system which is intended to provide for the simultaneous delivery of a single or a combination of drug substances as well as time-controlled series of pulses for efficacious treatment of diseases with maximum patient compliance and minimum side effects. Provision of a single targeted pulse several hours after oral administration, with or without an immediate release pulse upon oral administration, is a desired manifestation of the timed pulsatile release drug delivery systems of the present invention.
SUMMARY OF THE INVENTION
The present invention provides a method for manufacturing a pharmaceutically elegant multi-particulate dosage form having timed pulsatile release characteristics, i.e., a well time-controlled series of pulses occurring several hours after oral administration, with or without an immediate release pulse upon oral administration. The present invention also provides a novel multicoated particulate dosage form having an active core and a first membrane of an enteric polymer and a second membrane of a mixture of water insoluble and enteric polymers. An organic acid containing membrane may be provided between the first and second membrane layers referred to above to provide for time-separated pulses. While the membranes can be applied in any order, the enteric polymer membrane is usually applied as the innermost membrane.
DETAILED DESCRIPTION OF THE INVENTION
The active core of the novel dosage form of the present invention may be comprised of an inert particle such as a commercially available non-pareil sugar sphere. The amount of drug in the core will depend on the drug and the dose that is desired. Generally, the core will contain about 5 to 60% by weight of the drug based on the total weight of the core. Those skilled in the art will be able to select an appropriate amount of drug for coating or incorporation into the core to achieve the desired dosage form.
An aqueous or a pharmaceutically acceptable solvent medium may be used for preparing core particles. The type of inert binder that is used to bind the water soluble drug to the inert particle is not critical but usually water soluble or alcohol soluble binders are used. Binders such as polyvinylpyrrolidone (PVP), carboxyalkylcelluloses, polyethylene oxide, polysaccharides such as dextran, corn starch, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, may be used by dispersing them in water at a concentration of from about 0.5 to 5 weight %. The drug substance may be present in this coating formulation in the solution form or may be suspended. The drug concentration may vary from about 10 to 30 weight % depending on the viscosity of the coating formulation.
In one embodiment, the active core may be prepared by granulation or by extrusion and spheronization. The drug substance, a binder such as PVP, an optional dissolution rate controlling polymer such as high viscosity HPMC, and optionally other pharmaceutically acceptable excipients are blended together in a high shear granulator, such as Fielder granulator, or a fluid bed granulator, such as Glatt GPCG granulator, and granulated to form agglomerates by adding/spraying a granulating fluid such as water or alcohol and dried. The wet mass can be extruded and spheronized to produce spherical particles (beads) using an extruder/marumerizer. In these embodiments, the drug load could be as high as 90% by weight based on the total weight of the extruded or granulated core.
One of the layers of membrane coating on the water soluble/dispersible drug containing particle may comprise a plasticized enteric polymer while the other layer may comprise a mixture of a water insoluble polymer and a plasticized water dispersible/enteric polymer wherein said water insoluble polymer and said water dispersible polymer may be present at a weight ratio of 10:1 to 1:1 and typically about 4:1 to 1:1 and the total weight of the coatings is about 15 to 80 weight % and more typically about 20 to 60 weight % based on the total weight of the multiparticulate dosage form.
The intermediate acid containing membrane, if present, may be comprised of an organic acid such as fumaric acid, citric acid, succinic acid, tartaric acid, malic acid, and maleic acid; and a binder such as PVP. The nature of the binder is not critical, but water or alcohol soluble polymers are usually used. The weight of this acid coating is about 5 to 20% based on the total weight of the coated beads. The acid in this membrane delays dissolution of the enteric polymer in the inner layer thereby increasing the lag time as well as decreasing the rate of release of the active ingredient from the coated bead. The composition of the outer layer of the polymeric membrane, as well as the individual weights of the inner, intermediate and outer membrane layers are optimized to achieve pulsatile release profiles for a given therapeutic agent or agents, which are predicted based on in vitro/in vivo correlations.
Representative examples of enteric polymers useful in the invention include esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac. These polymers may be used as a dry powder or an aqueous dispersion. Some commercially available materials that may be used are metha
Percel Phillip
Venkatesh Gopi M.
Vishnupad Krishna S.
Bennett Rachel M.
Eurand Pharmaceuticals Ltd.
Page Thurman K.
Thompson Hine LLP
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