Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-05-22
2002-12-31
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S488000, C424S484000
Reexamination Certificate
active
06500456
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a nitroglycerin containing pharmaceutical composition, preferably a direct compressed tablet, stabilized by the presence of glyceryl monostearate. The formulation closely replicates the properties of nitroglycerin molded sublingual tablets (e.g., adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g., friability and weight variations). The stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored. The preferred combination of components are: nitroglycerin/lactose dilution, hydrous lactose, glyceryl monostearate, fumed silica, pregelatinized starch and calcium stearate. The preferred process employs direct compression technology to yield a stabilized composition showing adequate disintegration and bioavailability.
BACKGROUND OF THE INVENTION
The stabilization of nitroglycerin in solid dosage forms has been a subject of scientific interest for more than twenty years. This interest can be attributed to the finding that nitroglycerin, which is a liquid at normal temperatures, easily migrates from tablets to other tablets and/or to the container and container components. Nitroglycerin will migrate to the cap-liner and to other tablets such as aspirin if the two products are stored together in the same container. Plastics have various affinities for nitroglycerin depending on their polarity; hence tablets have not been successfully marketed in unit dose containers. In fact, the USP states that nitroglycerin tablets must be stored in glass containers.
Various attempts have been made to improve the molded tablet formulation to assure better stability. However, as of now, significant improvements have not been made in marketed products. In 1973, Parke-Davis & Co. added polyethylene glycol 3350 to molded tablet formulations. While this additive reduced the migration and loss of nitroglycerin to some degree, the content uniformity range increased upon storage. Hence, after one or two years' shelf life, there was a risk of not meeting USP limits.
About this time, a number of stabilizing agents were screened and some were found to decrease the volatility of nitroglycerin in tablets. Among these were microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), and &bgr;-cyclodextrin (BCD). For instance, a compressed tablet was prepared using the combination of MCC and PVP and marketed by Warner Chilcott Laboratories as NitroPRN®. The tablet was far superior to the current molded tablets with respect to nitroglycerin migration and volatility. However, the high amount of water insoluble excipient (MCC) was not desirable since the tablet gave a less acceptable feel and slower disintegration under the tongue.
Several patents on the stabilization of nitroglycerin in tablets have been granted. U.S. Pat. No. 4,091,091 assigned to Eli Lilly and Co., described the use of water soluble PVP to improve the stability of molded nitroglycerin tablets. In this application, PVP is added from a solution and molded tablets are made by the traditional method. Another patent, U.S. Pat. No. 4,059,686 assigned to Nippon Kayaku, indicates that &bgr; cyclodextrin is an effective stabilizing agent.
The manufacturing process for nitroglycerin sublingual tablets is typically the traditional molded tablet method. In this process, a wet mixture of nitroglycerin concentrate and other ingredients is made and, while moist, is pressed into cylindrical cavities. The wet tablets are pushed out using pins, which are accurately aligned to the cavities, and dried. The method produces a porous, fragile, rapidly dissolving tablet. However, a high degree of weight variation occurs and this attribute, coupled with inter-tablet migration of nitroglycerin, does not adequately preserve satisfactory content uniformity upon storage. The higher content variation which occurs after aging of the tablets, even when stored in tightly closed glass containers, is attributed to inter-tablet migration.
Moreover, this method has certain disadvantages; among them are the need to incorporate stabilizing agents like PVP, or the nitroglycerin itself, in alcohol and the subsequent removal of this solvent. It is preferable to employ nitroglycerin in a non-alcoholic solution for safety purposes. Also, wet granulations may require a binder which would retard and reduce the release (dissolution) of nitroglycerin from the tablet matrix. In addition, the extra handling and safety concerns with the processing of a wet granulation make the use of this technique less desirable.
The preferable method to prepare an improved stabilized nitroglycerin tablet appears to be the use of a direct compression technology. By this means the complexity and safety concerns with the wet granulation process is obviated. Although much is known about the problem of nitroglycerin instability, an improved dry compression formulation which closely matches the original sublingual tablet has not been produced. Such a tablet would preferably meet the USP requirements for nitroglycerin molded tablets, be comparable to the molded tablets in texture, size and weight, and effectively reduce the potency loss and inter-tablet migration of the drug.
The literature reports a number of stabilized compositions, but none have been prepared by direct compression technology to mimic the properties of a molded tablet. The technology and formulation techniques used to prepare an improved nitroglycerin tablet, particularly one made by compression, have not been developed. The lack of technical improvement relates to the complexity of the formulation with respect to selection of excipients and stabilizing agents which can be used to closely mimic the physical and chemical attributes of molded tablets and afford a significantly improved stability, and similar disintegration and bioavailability.
SUMMARY OF THE INVENTION
It is an object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that are not susceptible to intertablet migration of nitroglycerin.
It is also an object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that offer improved weight control (i.e., low weight variation).
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that achieve the same pharmacological activity as molded sublingual tablets.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that provide a comparable mouthfeel to molded sublingual tablets.
It is yet another object of the invention to use a non-explosive nitroglycerin triturate to manufacture nitroglycerin sublingual tablets.
It is yet another object of the invention to provide a pharmaceutical composition with no overcharge of nitroglycerin to prolong the shelf life.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets whose manufacture removes the complexity of wet granulation procedures and the safety concerns associated to solvent use.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that are characterized by decreased nitroglycerin volatility and superior stability profiles.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that exceeds current USP requirements for assay and content uniformity.
The invention achieves these objects by employing a nitroglycerin compressed tablet dosage form which is more stable, exhibits less tablet to tablet weight and content uniformity variation and is less prone to powdering (low friability) than compositions prepared by molding techniques. It has now been discovered that pharmaceutical compositions, such as tablets, containing nitroglycerin comprised of: nitroglycerin, glyceryl monostearate, calcium stearate, silica, starch and lactose are sta
Ashbrook Charles
Fubara Blessing
Page Thurman K.
Warner-Lambert & Company
LandOfFree
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