Pharmaceutical companies and consumers alike depend upon the government getting it right in both granting and eliminating market exclusivity. The story of Wellbutrin XL illustrates this point. Originally, Wellbutrin was formulated as an immediate release drug requiring thrice daily administration.
A sustained release version introduced in permitted twice daily dosing. In , an extended release formulation, Wellbutrin XL bupropion HCl extended-release tablets , reduced the dosing to once per day. Wellbutrin XL is dispensed in both mg. FDA News Release. Fax: Toggle navigation. For Free Case Evaluation Close Search. Dynamic Chiropractic — May 15, , Vol. Serious Side Effects confusion hallucinations irrational fears fever swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles or lower legs hoarseness difficulty breathing or swallowing chest pain muscle or joint pain rapid, pounding or irregular heartbeat.
References Hensley S. Information about bupropion [Wellbutrin]. National Institutes of Health Medline Plus. Bupropion: medical uses, contraindictions, side effects and mechanism of action. Boxed Warning. Petersen DM. Whalen J. SHARE :. The term "effective amount" as used herein means a "pharmaceutically effective amount".
A "pharmaceutically effective amount" is the amount or quantity of the pharmaceutically acceptable salt of bupropion, which is sufficient to elicit an appreciable biological response when administered to a patient.
It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient and the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician. It is known that bupropion hydrochloride is highly hygroscopic and, as such, is relatively unstable and susceptible to decomposition over time especially under high huanidity conditions. The proportion of the components of the moisture barrier and the amount of the moisture barrier applied onto the control-releasing coat is such that the moisture barrier does not fall within the USP definition and requirement for and enteric coat.
The permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating. The moisture barrier may additionally contain other conventional inert excipients, which may improve processing of the modified-release formulation described herein. The "degradation products" include those listed on page of the 26th edition of the USP and any other degradation products that may appear as peaks on a chromatogram during the assay.
The term "bioequivalent" means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.
Preferably, the modified-release tablet of the present invention contains from about 50 mg to about mg of bupropion hydrochloride. Most preferably, the tablets of the invention contain about mg or mg bupropion hydrochloride. The binder is preferably polyvinyl alcohol. The lubricants useful for the tablets of the present invention may be selected from the group consisting of glyceryl behenate, stearic acid, hydrogenated vegetable oils and any combination thereof.
The preferred lubricant is glyceryl behenate. The water-insoluble water-permeable film forming polymers may be selected from the group consisting of cellulose ethers, cellulose esters, polyvinyl alcohol and any combination thereof.
The preferred water-insoluble water-permeable film- forming polymer is ethyl cellulose grade PR The preferred plasticizes is polyethylene glycol The water-soluble polymer may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and any combination thereof. The preferred water- soluble polymer is polyvinylpyrrolidone. The preferred plasticizes for use in the moisture barrier is a combination of a polyol and organic ester.
The preferred polyol in the combination is polyethylene glycol with triethyl citrate being the preferred organic ester. The ratio of the organic ester to the polyol is preferably SA with the mean steady state plasma bupropion concentrations after multiple dosing of the prior art WellbutrinOO tablet in the fasted state. ZybanO tablets under fasted conditions.
The modified-release tablet of the invention is bioequivalent. The Core [] The core of the modified-release tablet comprises an effective amount of a pharmaceutically acceptable slat of bupropion, a binder, and a lubricant and may contain other conventional inert excipients.
The pharmaceutically acceptable salt of bupropion is preferably bupropion hydrochloride. The tablet comprises an amount of bupropion hydrochloride that can vary from about SOmg to about mg.
Preferably, the tablet comprises mg or mg of bupropion hydrochloride. Binders can be added to the formulation in different ways: 1 as a dry powder, which is mixed with other ingredients before wet agglomeration, 2 as a solution, which is used as agglomeration liquid during wet agglomeration, and is referred to as a solution binder, and 3 as a dry powder, which is mixed with the other ingredients before compaction.
In this form the binder is referred to as a dry binder. Solution binders are generally considered the most effective, and this is therefore the most common way of incorporating a binder into granules. The binder used herein is in the form of a solution binder. Non-limiting examples of binders useful for the core include water- soluble polymers such as modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives such as for example hydroxypropyl methylcellulose HPMC and hydroxypropyl cellulose HPC and polyvinyl alcohol.
The amount of binder present may vary from about 0. The preferred binder is polyvinyl alcohol. High friction during tabletting can cause a series of problems, including inadequate tablet quality capping or even fragmentation of tablets during ejection, and vertical scratches on tablet edges and may even stop production. Accordingly, lubricants are added to almost all tablet formulations including the bupropion hydrochloride tablet formulation described herein.
The lubricant is preferably glyceryl behenate. For the mg and mg dose modified-release tablets of the invention the lubricant is present at about 2.
Ideally the core comprises only an effective pharmaceutical amount of pharmaceutically acceptable salt of bupropion, a binder, preferably polyvinyl alcohol, and a lubricant, preferably glyceryl behenate. However, if necessary, additional inert excipients consistent with the objects of the invention may be added to the core formulation. The additional inert excipients may be added to facilitate the preparation andlor improve patient acceptability of the final modified-release bupropion hydrochloride dosage form as described herein.
The additional inert excipients are well known to the skilled artisan and can be found in the relevant literature, for example in the Handbook of Pharmaceutical Excipients. Non-limiting examples of such excipients include spray dried lactose, sorbitol, mannitol, and any cellulose derivative. Essentially, wet granulation involves agitation of a powder the active drug by convention in the presence of a liquid the solution binder followed by drying.
For forming the granules, which are to be eventually compressed into the tablet cores, the bupropion hydrochloride is first granulated, preferably with a solution binder, in a granulator, preferably but not necessarily a fluidized bed granulator such as for example a fluidized bed granulator manufactured by Glatt Germany or Aeromatic Switzerland. The binder, preferably polyvinyl alcohol, is first dissolved or dispersed in a suitable solvent, preferably water.
Alternatively, granulation can also be performed in a conventional or high shear mixer. If necessary, the additional inert excipients such as for example a filler can be mixed with the bupropion hydrochloride prior to the granulation step. Preferably, the dried granules are sieved through a 1. The sieved granules are then blended with the lubricant, and if necessary, any other additional inert excipients, which may improve processing of the modified-release tablets of the invention.
Blending of the granules with the lubricant, and if necessary, any additional inert excipients, such as for example a glidant, may be performed in a V-blender or any other suitable blending apparatus. Glidants improve the flowability of the powder. This is especially important during tablet production at high production speeds and during direct compaction.
However, because the requirement for adequate flow is high, a glidant is often also added to a granulation before tabletting. The blended granules are subsequently pressed into tablets and are hereinafter referred to as tablet cores.
Tablet cores can be obtained by the use of standard techniques and equipment well known to the skilled artisan. Ideally, but not necessarily, the tablet cores are obtained by a rotary press also referred to as a multi-station press fitted with suitable punches. Tablet Coatings [] The tablet cores are coated in two stages. The control-releasing coating is applied directly onto the surface of the tablet cores and functions to control the release of the pharmaceutically acceptable salt of bupropion.
The moisture barrier is applied directly onto the surface of the control-releasing coat to impede or retard the absorption of moisture [] 2. The preferred water-insoluble, water-permeable film forming polymers are the ethyl celluloses, and can be selected from the group consisting of ethyl cellulose grade PR, ethyl cellulose grade PRO and any combination thereof. Ethyl cellulose grade PR is the preferred water-insoluble, water-permeable film forming polymer.
Preferably, the amount of the water-insoluble water- permeable film-forming polymer is present at about 6. Preferably, the amount of water-insoluble water-permeable film forming polymer is present at about 3. The amount and choice of the plasticizer contributes to the hardness of a tablet and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability. One important property of plasticizers is their ability to make a coat elastic and pliable, thereby decreasing the coat's brittleness.
The preferred plasticizer is polyethylene glycol Meanwhile, experts say both Chantix and Zyban are safe — far safer than smoking, which kills about , Americans each year. But Chantix, approved in , has patent protection until in the U. Lifting the black box warning — and similar warnings in countries around the world — likely would boost Chantix sales until those patents expire and cheaper generic copycats arrive.
Months ago, the companies sent the FDA detailed study results showing the risk of suicidal thoughts or behavior for patients taking either drug is the same as for dummy pills. The results, being published online Friday evening by the British medical journal The Lancet, echo findings of about 40 earlier studies. Freda C.
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