Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-06-22
2003-01-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S434000, C424S486000, C424S488000, C424S490000
Reexamination Certificate
active
06509040
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition for oral administration in the form of a fast dispersing dosage form. The novel dosage form is essentially free of mammalian gelatin and comprises at least one matrix forming agent and a lactose modified starch.
BACKGROUND OF THE INVENTION
The most common pharmaceutical dosage form is the tablet. The main limitations of tablets include poor patient compliance due to difficulty in swallowing tablets and lack of bioavailability of the active through the ineffective dissolution of the tablet. Thus, there is a need in the medical community for rapidly soluble dosage forms. A number of approaches have been utilized to overcome the shortcomings of tablets, including effervescent tablets, chewable tablets, disintegrants, and wicking agents.
Most recently, fast dispersing dosage forms, which are designed to release the active ingredient in the oral cavity, have been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form.
Gelatin B. P., which is normally utilized in such formulations, is defined as a protein obtained by partial hydrolysis of animal collagenous tissues, such as skins, tendons, ligaments and bones. However, such mammalian-derived gelatin has a bland taste and thus necessitates the use of sweeteners and flavors in such fast dispersing dosage forms to mask the taste of the active ingredient. When conventional mammalian derived gelatin is used in the production of such fast dispersing dosage forms, it is necessary to heat the gelatin solution in order to effect solution. This heating step increases processing times and incurs heating costs thereby increasing the overall costs of the process.
Conventional processing can require holding times of up to 48 hours. It has been observed that over this time the viscosity of the gelatin-based mixture can increase, leading to processing difficulties. Furthermore, the use of mammalian gelatin produces dosage forms that readily absorb water and this can lead to shrinkage of the dosage form during normal storage periods.
Another known problem associated with gelatin-based fast dissolving dosage forms is the lack of homogeneity and sedimentation of the liquid mix during holding periods, as some mixtures incorporate the active substance as suspended particles. The use of mammalian-derived gelatin results in sedimentation of the active due to mammalian gelatin's low viscosity. One benefit of the present invention is that the modified starches disclosed herein substantially overcome the homogeneity and sedimentation problems associated with mammalian gelatin.
Another benefit associated with the use of modified starches in the preparation of fast dissolving dosage forms resides in the discovery that the modified starch dosage form is capable of higher drug loadings. This is beneficial in that for a given dose of active, the modified starch dosage form may be substantially smaller than the conventional gelatin dosage form.
Other materials have been tried in place of gelatin in fast dispersing dosage forms but while they may form robust products (reduced propensity to cracking and breaking) they generally disperse slowly or form a gummy mass in the mouth. It has now been found that modified starches may be used instead of mammalian-derived gelatin to prepare fast dispersing dosage forms.
According to the present invention there is therefore provided a pharmaceutical composition for oral administration in the form of a fast dispersing dosage form designed to release an active ingredient rapidly in the oral cavity characterized in that the essentially gelatin free composition comprises a modified starch and at least one matrix forming agent.
The invention provides the possibility of reducing or preferably eliminating gelatin from fast dispersing dosage forms (FDDF). Modified starches may be used as the primary structure forming agent in FDDF's to form physically robust products while maintaining the desired rapid dispersion characteristics of the products. By suitable selection of the modified starch it is possible to obtain particularly desirable properties of cold water solubility, no change in solution viscosity with time and improved stability and physical strength of the dosage form. The use of modified starch allows the level of sweeteners/flavorants, which have previously been used to improve the taste of the dosage form, to be reduced or eliminated. The use of a botanical source material as opposed to the use of an animal source material also has the benefit of eliminating exposure to agents such as BSE.
Starch can be considered a condensation polymer of glucose. These glucose constituents are present as anhydroglucose units (AGU). If starch is treated with either acids or certain enzymes it can be totally degraded, by hydrolysis of glycosidic bonds, into its constituent glucose units. Most starches consist of two types of glucose polymers, each having a wide range of molecular sizes:
(i) a linear chain molecule termed amylose, which can contain up to 6,000 glucose units linked by 1 to 4 linkages and,
(ii) a highly branched polymer termed amylopectin, consisting of short chains (10 to 60 glucose units) connected by &mgr;-1,6-linkages.
The glucose units of starch molecules contain a primary hydroxyl group on carbon-6 and a secondary hydroxyl group on carbon-2 and carbon-3. Starch molecules have a multitude of hydroxyl groups, which impart hydrophilic properties to the starch and lead to the dispersibility of starch on heating with water. However, these hydroxyl groups also tend to attract to each other, forming hydrogen bonds between adjacent starch molecules and preventing dissolution in cold water.
Native starch can be altered by physical, chemical or enzymatic treatment to alter their properties or impart new ones. Properties of these modified starches include solid-viscosity relationships, gelatinization and cooking characteristics, resistance of breakdown in viscosity by acids, heat and/or mechanical shear, ionic character and hydrophilic character.
A range of modified starches are commercially available and useful in the present invention and include:
Pregelatinized starches, produced by drum drying or extrusion;
Low-viscosity starches, produced by controlled hydrolysis of glycosidic bonds;
Dextrins, produced by roasting dry starch in the presence of a small amount of acid;
Acid modified starches, produced by suspension in dilute acid until the required viscosity is reached;
Oxidized starches, oxidizing agents cause the introduction of carbonyl or carboxyl groups, wherein depolymerization occurs, leading to decreased retrogradation and gelling capacities;
Enzymatically modified starch, produced by controlled enzyme degradation to attain required physicochemical properties;
Crosslinked starches, bi- or polyfunctional reagents react with hydroxyl groups to form crosslinks, examples of specific reagents include phosphorus oxychloride, sodium trimetaphosphate and epichlorohydrin; and
Stabilized starches, starches are reacted with etherifying or esterifying reagents in the presence of an alkaline catalyst to give a wide range of products.
BACKGROUND ART
U.S. Pat. No. 5,120,549 discloses a fast dispersing dosage form which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix-forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fas
Green Richard
Grother Leon Paul
Kearney Patrick
Murray Owen James
Nickey Donald O.
R.P. Scherer Corporation
Yang Micah-Paul
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