Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-04-20
2004-02-24
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S458000, C424S464000, C424S469000, C424S470000, C424S489000, C424S490000, C252S363500
Reexamination Certificate
active
06696084
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel spray drying process for the preparation of pharmaceutical compositions containing small particles of phospholipid-stabilized fenofibrate. This invention also relates to spray dried powdered compositions prepared according to this process, and to dosage forms of fenofibrate (capsules, tablets, powders, granules, and dispersions) prepared from these powdered compositions. The powdered compositions and dosage forms are useful in the treatment of dislipidemia and dislipoproteinemia and have the advantage that they provide reduced in vivo variability in the bioavailability of fenofibrate active species among fed and fasted patients when administered orally.
In a preferred aspect, the present invention relates to a process for the preparation of an orally administered pharmaceutical composition containing microparticles of solid fenofibrate comprising the formation of a homogenized molten microdroplet aqueous suspension of fenofibrate in the presence of and stabilized by a phospholipid surface active substance and then spray drying the molten microdroplets in the presence of a bulking agent to produce solid microparticles in dried bulking agent as a powder. The powder can be further processed into an orally administerable dosage form such as a capsule, tablet, powder, or granule which provides a therapeutically effective amount of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 80% of the quantity of fenofibrate active species provided by the same amount to the same patient when the patient is fed at least 1000 calories 50% of which are from fat.
The present invention also relates to a method of treatment of dislipidemia and dislipoproteinemia in a mammal which comprises administering to the mammal a therapeutically effective oral dosage form comprising microparticles of a solid poorly water soluble fibrate that are stabilized by a phospholipid surface active substance and prepared according to the process of this invention, wherein the dosage form provides into the blood of the mammal in a fasted state a therapeutically effective amount of the fibrate active species that is at least 90% of the AUC amount of the fibrate active species provided by the dosage form into the blood of the patient in a fed state.
The present invention also relates to novel pharmaceutical compositions containing small particles of phospholipid-stabilized fenofibrate prepared according to the process of this invention that provide reduced in vivo variability in the bioavailability of the fenofibrate active species among fed and fasted patients when administered orally. In particular, the present invention relates to an orally administered pharmaceutical composition comprising microparticles of solid fenofibrate that are prepared in the presence of and stabilized by a phospholipid surface active substance according to the process of this invention, wherein a therapeutically effective amount of the composition provides a quantity of fibrate active species to a human patient in need of treatment by the fibrate that is independent of the amount of food taken by the patient.
This invention also relates to an oral dosage form of a pharmaceutical composition comprising a combination of a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin and spray dried microparticles of fenofibrate that are stabilized by a phospholipid surface active substance and a carbohydrate bulking agent prepared according to the process of this invention wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% and especially at least 85% of the quantity of fenofibrate active species, particularly the AUC quantity of fenofibrate active species, provided by said amount to said patient when fed a meal containing fat, especially when fed at least 1000 calories 50% of which are from fat.
It has long been known that the bioavailability of many hydrophobic drugs can be improved if the drugs are administered with food, i.e., the drugs' uptake into the blood or other part of the body exhibit a food effect. A patient is often instructed to take the drug at meal times or with food. Various explanations of the food effect have been advanced including: delayed gastric emptying to allow more drug to dissolve before reaching the small intestine thereby producing longer residence times at specific absorption sites in the small intestine; direct interaction and solubilization of drug by food, especially by hydrophobic food components such as fats and lipids; food-related increases in hepatic blood flow to cause a decrease in first-pass metabolism; and increased gastrointestinal secretions that can improve drug solubility.
Dosage forms or quantities of compositions containing a fibrate such as fenofibrate have been marketed and prescribed for the treatment of dyslipidemia and dyslipoproteinemia. dyslipidemia and dyslipoproteinemia are herein defined to include the group selected from hypercholesterolemia, abnormal and elevated levels of cholesterol, abnormal and elevated levels of LDL cholesterol, abnormal and elevated levels of total cholesterol, abnormal and elevated levels of plasma cholesterol, abnormal and elevated levels of triglycerides, hypertrigylceridaemia, abnormal levels of lipoproteins, abnormal and elevated levels of low density lipoproteins (LDLs), abnormal and elevated levels of very low density lipoproteins, abnormal and elevated levels of very low intermediate density lipoproteins, abnormal levels of high density lipoproteins, hyperlipidemia, hyperchylomicronemia, abnormal levels of chylomicrons, related disorders, and combinations thereof such as those described in The ILIB Lipid Handbook for Clinical Practice, Blood Lipids and Coronary Heart Disease, Second Edition, A. M. Gotto et al, International Lipid Information Bureau, New York, N.Y., 2000, which is hereby incorporated by reference.
Elevation of serum cholesterol, triglyercides, or both is characteristic of hyperlipidemias. Differentiation of specific abnormalities usually requires identification of specific lipoprotein fractions in the serum of a patient. Lipoproteins transport serum lipids and can be identified by their density and electrophoretic mobility. Chylomicrons are among the largest and least dense of the lipoproteins. Others, in order of increasing density and decreasing size include very low density lipoproteins (VLDL or pre-beta), intermediate low density lipoproteins (ILDL or broad-beta), low density lipoproteins (LDL or beta), and high density lipoproteins (HDL or alpha). Triglycerides are transported primarily by chylomicrons and very low density lipoproteins. Cholesterol is transported primarily by low density lipoproteins. Hyperlipidemia types include type I, type IIa, type IIb, type III, type IV, and type V. These types can be characterized according to the levels relative to normal of lipids (cholesterol and triglycerides) and lipoproteins described above. Hyperlipidemia types are listed in Table 1 below, wherein “N” refers to normal levels of the substance in the left column, “+” refers to slightly elevated levels, “++” refers to elevated levels, “−” refers to slightly decreased levels, and “−−” refers to decreased levels, all relative to normal. The data in the table are derived from Drug Facts and Comparisons, 52nd Edition (1998) page 1066. Treatment of a patient presenting one of more of the symptoms listed in Table 1 by the method of treatment and composition of the dosage forms of this invention will lead to a lowering in elevated levels of lipids and lipoproteins in the patient.
TABLE 1
Hyperlipidemia types as a function of relative Lipid
and Lipoprotein levels.
Hyperlipidemia type
I
II a
II b
III
IV
V
Lipids
Cholesterol
N+
++
++
N+&p
Guivarc'h Pol-Henri W.
Mishra Awadesh K.
Pace Gary W.
Parikh Indu
Snow Robert A.
Edwards & Angell LLP
Kishore Gollamudi S.
RTP Pharma Inc.
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