Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1997-10-27
2002-01-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S486000, C424S488000
Reexamination Certificate
active
06337091
ABSTRACT:
BACKGROUND OF THE INVENTION
Controlled release pharmaceutical dosage forms have received much attention in recent years and are highly desirable for providing a constant level of pharmaceutical agent to a patient. The use of single or multiple unit dosage forms as controlled drug delivery devices encompasses a wide range of technologies and includes polymeric as well as nonpolymeric excipients. These dosage forms optimize the drug input rate into the systemic circulation, improve patient compliance, minimize side effects, and maximize drug product efficacy.
The use of controlled release products is frequently necessary for chronic drug administration, such as the use of the calcium-channel blockers nifedipine, diltiazem and verapamil in the management of angina and hypertension. Worldwide sales of these drugs exceeds eight billion dollars. For delivery system design, physiochemical properties and intrinsic characteristics of the drug, such as high or low solubility, limited adsorption, or presystemic metabolism, may impose specific constraints during product development.
Advancements of extended release drug products have come about by the simultaneous convergence of many factors, including the discovery of novel polymers, formulation optimization, better understanding of physiological and pathological constraints, prohibitive cost of developing new drug entities, and the introduction of biopharmaceutics in drug product design.
One aspect of research about controlled-release delivery systems involves designing a system which produces steady-state plasma drug levels, which is also referred to as zero-order drug release kinetics. To meet this objective, numerous design variations have been attempted, and their major controlling mechanisms include diffusion/dissolution, chemical reactions, osmosis, erosion, and swelling.
One attractive design for potential zero-order drug release is hydrophilic swellable matrices with various geometrical modifications. Drug diffusion from the matrix is accomplished by swelling, dissolution and/or erosion. The major component of these systems is a hydrophilic polymer. In general, diffusivity is high in polymers containing flexible chains and low in crystalline polymers. With changes in morphological characteristics, the mobility of the polymer segments will change and diffusivity can be controlled. Addition of other components, such as a drug, another polymer, soluble or insoluble fillers, or solvent, can alter the intermolecular forces, free volume, glass transition temperature, and consequently, can alter the transport mechanisms.
For controlled-drug delivery from hydrophilic matrices, noncross-linked polymers (i.e., in dry form, glassy state), such as hydroxpropyl methylcellulose (HPMC), carboxymethylcellulose, polyvinyl alcohol, or polyethylene oxide, with dispersed drugs in them are often tabletted to achieve simple matrix systems. Depending on the system modifications, various drug release rates and patterns can be accomplished. The swelling mechanisms and kinetics of drug release from these systems are highly complex. In general, when such systems are exposed to dissolution media, drug delivery is governed by two distinctive processes; namely, matrix swelling and dissolution/erosion at the matrix periphery. The initial swelling (i.e., the transition of glassy structure to rubbery state) occurs at a rate that is mainly a function of matrix composition and dissolution medium penetration into the matrix. At some point, front synchronization between the dissolution medium/swollen front and the rubbery/glassy front may occur, after which the drug release could be linear. However, it is reported that linear drug release is also achievable in the absence of front synchronization. The final changes in release rates are associated with the degree of polymer disentanglements and/or dissolution/erosion. The release mechanism operates via polymer relaxation (swelling) and drug diffusion/system erosion, and has been described by the following equation:
Mt
M
∞
=
at
1
/
2
+
γ
t
(
1
)
where amount of drug released, Mt/M∞, is the sum of a diffusional contribution (with t
½
dependence) and a relaxational contribution (with t dependence), and both &agr; and &ggr; are constants describing the diffusion-controlled release mechanism and constant rate process, respectively. However, when gel layer thickness is constant (i.e. at front synchronization), the amount of drug released can been expressed as follows:
Mt
M
∞
=
ξ
+
ε
t
(
2
)
where the contribution of the t
½
term coefficient of equation 1 becomes negligible. More detailed mathematical treatment of drug/polymer matrix swelling and dissolution can be found in the literature. Under conditions where drug release and swelling is not limited to planar geometry, as usually is the case with simple hydrophilic matrix tablets, the exact analysis will be complicated, especially when more than one polymer is incorporated into the matrix. Even so, release profiles and mechanisms can be interpreted and explained according to the principles upon which equations 1 and 2 are based.
To date, many studies have investigated drug release from hydrophilic matrix tablets containing a single polymer, a mixture of synthetic polymers, synthetic and natural gelling agents with an optional cationic cross-linking agent, and polysaccharides and gums capable of cross-linking.
Diltiazem is a benzothiazepine derivative with active metabolites. Its oral adsorption is greater than 90%, its bioavailability ranges from 30 to 60% due to extensive variable first-pass metabolism, and its elimination half-life is 3-6 hours. The protein binding is greater than 90% and it has a high clearance from plasma. The water solubility of diltiazem exceeds 50%. Daily doses of 120 to 360 mg are usually used for angina and hypertension. The drug was approved by the FDA in 1988, and is currently available as once-a-day dosage forms.
Current methods of production of Diltiazem are both complicated and cumbersome. A once-a-day, extended-release diltiazem tablet which consists of a simple matrix and which can be manufactured with high-speed tableting machines will represent a significant advance. Such a matrix could also be used to deliver other highly soluble drugs.
In the past, many controlled-release systems for low or sparingly soluble drugs have been developed, but considerable difficulties have been experienced in the formulation of highly ionized and soluble drugs, such as diltiazem or propranolol especially at relatively high doses (e.g., >100 mg).
SUMMARY OF THE INVENTION
The present invention is directed to a new monolithic tablet that delivers highly soluble drugs at a relatively constant release rate over extended periods of time, typically 16 to 20 hours, and that is easy to manufacture. The monolithic tablet which approaches zero order delivery of highly soluble drugs is comprised of a drug incorporated first in relatively less swellable polymer granules and secondly in a more swellable, erodible polymer matrix surrounding the granules. The relatively less swellable polymer granules have a first diffusion rate coefficient, and the more swellable, erodible polymer matrix has a second diffusion rate coefficient which is greater than the diffusion rate than that of the granules. The incorporation of the drug in the first polymer can consist either of granulating the drug with or encapsulating the drug in the first polymer. The first polymer may be a gum, such as gelatin, gum tragacanth, or pectin. The second polymer is composed of HPMC or polyethyleneoxide, and optionally includes pectin. The highly soluble drug may be diltiazem or propranolol. In a preferred embodiment, the second polymer is composed of HPMC and pectin, and the range of pectin:HPMC ratios is from 2:7 to 4:5 by weight in the matrix.
GLOSSARY
The following illustrative explanations are provided to facilitate understanding of certain terms used frequently herein. The explanations are provided as a conve
Fassihi Reza
Kim Hyun-jo
Page Thurman K.
Ratner & Prestia
Temple University - of the Commonwealth System of Higher Educati
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