Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-02-20
2001-11-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S465000, C424S490000, C424S494000, C424S497000, C424S499000
Reexamination Certificate
active
06319519
ABSTRACT:
This invention relates to pharmaceutical formulations of anti-inflammatory drugs, particularly non-steroid and anti-inflammatory drugs (NSAIDs).
These NSAIDs are used for the treatment of inflammatory conditions such as osteoarthritis or rheumatoid arthritis. A side effect of the oral administration of NSAIDs particularly with long term usage, is a liability to ulcerogenic effects. NSAID induced ulcers in the stomach are potentially dangerous because few or no symptoms may be detected until significant damage has been caused. Certain prostoglandins, for example misoprostol have been shown to reduce and even prevent such ulcers.
It has been found experimentally that it is necessary for the prostaglandin to be released before the NSAID so as to protect the stomach from the effects of the NSAID. It is therefore preferable that the NSAID is coated to delay release. The coating may be a standard hydroxypropyl methyl cellulose coat of a thickness sufficient to delay release in the stomach for a short period, an enteric coat to delay NSAID release until it reaches the intestine, or a delay release coating to allow drug release over a period of time to permit less frequent dosing.
In addition the coating may act as a barrier between the NSAID and the prostaglandin to prevent decomposition of the prostaglandin caused by instability in the pressure of the NSAID.
EP-527887B discloses a pharmaceutical composition comprising a core of an NSAID surrounded by a coating containing the prostaglandin. The core is preferably coated with a barrier of enteric coat before a mantle coat is added. No experimental details are given. It appears that this dosage form is made by press-coating, ie a tablet core containing the drug is made, and coated before being put in a second tableting operation to cover the coated core. Such a procedure requires use of specialised equipment which is not a normal pharmaceutical production tool and hence would need significant investment.
According to the present invention an oral pharmaceutical dosage form comprises a tablet containing a non-steroidal anti inflammatory drug and misoprostol, wherein the non-steroidal anti inflammatory drug is in the form of coated pellets.
The NSAID is preferably but not exclusively one of reasonably low weight per standard dose. That is an NSAID where the usual dose is 200 mg or below. Examples of such NSAIDs include indomethacin, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam or similar molecules. Most preferably the drug is diclofenac sodium.
Enteric coated or delay release coated pellets have not been widely used because many workers have found damage or cracking to the enteric or delay release coating during the tablet compression stage. The present invention will work most effectively if the coating remains intact during compression.
It is possible to produce such pellets by conventional means although care is needed to ensure coat cracking does not occur. Techniques which can be used include coating the drug on a non-pariel core preferably composed of inert sugar or similar substance and then overcoating with the required coating before compression.
A preferred method is to form pellets by co-acervation or alternatively by precipitation of the pellets from solution as described by Zaruboru, Fell and Collett, (Int.J.Pharm, 1995, 125, 151-5).
In another preferred technique the pellets may be formed by spheronisation, rotogranulation or a similar technique. Preferably the pellets should be soft enough to deform slightly under compression to avoid cracking but not too soft so as to deform significantly which will also cause cracking or rupture of the coat. A suitable mixture of drug with a suitable amount of an excipient or several excipients can be found by simple, routine experiments. Suitable excipients include polyvinyl pyrolidone, sugars and cellulose derivatives particularly microcrystalline cellulose. A coating for the pellets may employ cellulose derivatives eg hydroxypropyl methyl cellulose, methacrylic acid and derivatives eg methyl methacrylates for example, Eudragrit® (Rhom Pharma), especially Eudragrit L or S. Other standard enteric coating materials for example phthalates, eg cellulose acetate phthalate or preferably hydroxypropylacetate phthalate or polyvinylacetate phthalate. Mixtures of these and other materials may be used to produce delay release coated beads. Normally coating will include plasticisers eg polyethylene glycol, triacilin or phthalate esters.
It has been found in practice that smaller pellets are better for use in accordance with this invention, preferably between 0.25 mm to 1.5 mm in diameter. Most preferably pellets between 0.8 mm to 1.2 mm diameter are employed. Pellets of this diameter show less tendency to crack under the compression forces.
The external compression material will include a prostaglandin, preferably misoprostol together with inert excipients. The prostaglandin may be used neat or it may be preferably diluted on an inert material. A preferred material is misoprostol diluted on hydroxypropyl methyl cellulose or polyvinyl pyrolidone. Other diluents may be used. The other materials which may be employed include inert fillers, binders, lubricants and colorants as used in normal pharmaceutical tablet making. An especially useful material for this invention is microcrystalline cellulose. The dosage of prostaglandin will be chosen to be suitable to prevent or reduce stomach ulceration caused by the NSAID. A suitable dose of misoprostol is between 100-200 micrograms per tablet but this may be increased or decreased depending on the NSAID used.
The coated pellets and prostaglandin mixture are then compressed on conventional tableting equipment. Tablets may have a break line or break lines to facilitate smaller doses. The tablet may be film or sugar coated if required.
Bilayer tablets may be employed. The non-steroidal anti inflammatory drug and excipients may be compressed into the lower half of the tablet and the misoprostol together with excipients superimposed and pressed onto it. A barrier layer may be provided between the two active ingredient-containing layers. The misoprostol containing layer may incorporate excipients to facilitate rapid dissolution of this active ingredient.
REFERENCES:
patent: 5232704 (1993-08-01), Franz et al.
patent: 1020182A2 (2000-07-01), None
patent: 1068867A2 (2001-01-01), None
patent: WO91/16895 (1991-11-01), None
patent: WO91/16886 (1991-11-01), None
patent: WO00/01368 (2000-01-01), None
patent: WO00/15200 (2000-03-01), None
patent: WO0056339 (2000-09-01), None
patent: WO/91/16895 (1991-11-01), None
McIntyre Gordon
Sheth Nitin Vadilal
Woolfe Austen John
Beyer Weaver & Thomas LLP
Evans Chareese L.
Norton Healthcare Ltd.
Page Thurman K.
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