Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-06-12
2003-02-25
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S469000, C424S486000, C424S488000, C424S489000, C514S772300, C514S770000, C514S777000, C514S781000, C514S866000, C514S965000, C514S951000
Reexamination Certificate
active
06524618
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a directly compressible extended-release matrix formulaton containing N,N-dethyl-imidodicaboimdic diarnide hydrochloride (hereinafter referred to as “metformin hydrochlorido” or “metformin HCl”). The formulaton is prepared in the form of a tableting powder which is capable of being directly compressed into metformin HCl tablets. The invention also relate to a process for preparing extended-release metformin HCl tablets by blending the drug with specific excipients and therefore directly compressing the blend into tablets.
BACKGROUND OF THE INVENTION
Metformin is an antihyperglycemic agent of the bigande elms used in the treatment of non-insulin dependent diabetes mellitus (“NIDDM”). It is usually marketed in the form of its hydrochloride salt as Glucophage®. Metformin hydrochloride is hygroscopic and somewhat unstable. Moreover, metformin hydrochloride is not inherently compressible and thus presents formulation problems.
Metformin hydrochloride has intinsically poor permeability in the lower portion of the gastrointestinal tract leading to absorption almost exclusively in the upper part of the gastrointestinal tract. Its oral bioavailability is in the range of 40 to 60% decreasing with increasing dosage, which suggests some kind of saturable absorption process, or permeability/transit time limited absorption. It also has a very high water solubility (>300 mg/ml at 250° C.). This can lead to difficulty in providing an extended, i.e., slow, release rate from a formulation and problems in controlling the initial burst of drug from such a formulaton. These two difficulties are further compounded by the high unit dose, about 500 mg to about 750 mg per tablet, usually required for metformin hydrochloride to provide optimal dosing.
Drugs with very high solubility in water (for example, greater than 100 mg/ml) can be difficult to formulate into a controlled release oral dosage form. Solubility is a driving force for a drug substance to dissolve in water; the greater the solubility the greater the rate of dissolution when all other factors are maintained constant.
In a controlled release dosage form, the formulator tries to reduce the rate of dissolution by, for example, embedding the drug in a polymeric matrix or surrounding it with a polymeric barrier membrane through which drug must diffuse to be released for absorption To reduce the rate of release of drug from the dosage form to an appropriate level consistent with the blood level profile desired for a drug possessing very high water solubility, very large amounts of polymer would be required for the matrix or Per membrane. If the total daily dose of drug to be delivered is of the order of only a few milligrams this may be feasible, but many drugs having the solubility properties described require total daily doses of the order of many hundreds of milligrams. Whilst it is possible to create oral controlled release dosage forms for such products by use of large amounts of polymer, however, this leads to an unacceptably large dosage form.
A further problem with highly water soluble drugs formulated into a controlled release dosage form is that a significant and variable burst of the drug can occur from these systems. The burst of a highly water-soluble drug is the initial rapid release of drug that occurs from oral controlled release dosage forms when first contacting fluid, such as gastric fluids, prior to release controlling mechanisms of the dosage form establishing themselves and a stable release rate being provided. Hydration of any polymer matrix used to formulate the dosage form is a prerequirement of establishing a stable release rate. Thus, a readily hydrating polymer is required to establish the desired stable release rate. However, if the polymer used is slow to hydrate, then an undesirable variable burst can occur.
The three processes for making compressed tablets are wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and type of excipients are selected to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets. After compression, the tablets must have a number of additional attributes such as appearance, hardness, disintegrating ability, and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing, and the properties of the final tablets. Preformulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients.
The properties of the drug, its dosage forms, and economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet.
The dry granulation method may be used where one of the constitutes, either the drug or the diluents, has sufficient cohesive properties to be tableted. The method consists of blending; slugg the ingredients, dry screening, lubrication, and compression. The wet granulation method is used to convert powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation The damp mass is then screened through a suitable screen and dried by tray dying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes: weighing dry powder blending, wet granulating, drying, milling, blending lubrication and compression.
In general, powders do not have sufficient adhesive or cohesive properties to form hard, strong granules. A binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders. Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation. The large number of processing steps and processing time are problems due to high labor and manufacturing costs.
Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing was believed to be essential in order to prepare pharmaceutically acceptable dosage forms. For example, Remington's Pharmaceutical Sciences (“RPS”), 17
th
edition(1985), cautions pharmaceutical scientists that the manner in which a lubricant is added to a formulation must be carefully controlled. Accordingly, lubricants are usually added to a granulation by gentle mixing. RPS warns that prolonged blending of a lubricant with a granulation can materially affect hardness and disintegration time for the resulting tablets. Furthermore, Ansel et al., (“Pharmaceutical Dosage Forms and Drug Delivery Systems”, 6
th
edition, pp. 199 and 213-220) indicate that excessive blending of lubricants with the granulate ingredients cause waterproofing of the granule and reduces tablet hardness or strength of the compressed tablet For these reasons, high shear mixing conditions have not been used to prepare direct compression dosage forms. The advantages of direct compression include uniformity of blend, few manufacturing steps involved, (i.e., the overall process involves weighing of powders, blending and compression, hence less cost), elimination of heat and moisture, prime particle dissociation, and physical stability.
A solid dosage form containing a high dose drug (i.e., the drug itself comprises a substantial portion of the total compressed tablet weight) could only be directly compressed if the drug itself had sufficient physical characteristics (e.g., cohesiven
Kumar Vijai
McGuffy Kevin Scott
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