U.S. patent application number 10/425154 was filed with the patent office on 2003-11-13 for dihydroxy open-acid and salts of hmg-co-a reductase inhibitors.
This patent application is currently assigned to Merck & Co., Inc.. Invention is credited to Asgharnejad, Mandana, Grabowski, Edward J. J., Reider, Paul J., Tillyer, Richard D., Vega, Jose M., Xu, Feng.
Application Number | 20030211151 10/425154 |
Document ID | / |
Family ID | 29407669 |
Filed Date | 2003-11-13 |
United States Patent
Application |
20030211151 |
Kind Code |
A1 |
Tillyer, Richard D. ; et
al. |
November 13, 2003 |
Dihydroxy open-acid and salts of HMG-Co-A reductase inhibitors
Abstract
The instant invention provides methods and pharmaceutical
compositions for inhibiting HMG-CoA reductase, as well as for
treating and/or reducing the risk for diseases and conditions
affected by inhibition of HMG-CoA reductase, comprising orally
administering a therapeutically effective amount of a compound
selected from a dihydroxy open acid statin and a pharmaceutically
acceptable salt or ester thereof in a delayed-release
pharmaceutical dosage form to a patient in need of such treatment
wherein substantial release of the compound from the dosage form is
delayed until after passage of the dosage form through the
stomach.
Inventors: |
Tillyer, Richard D.;
(Cranford, NJ) ; Reider, Paul J.; (Westfield,
NJ) ; Grabowski, Edward J. J.; (Westfield, NJ)
; Xu, Feng; (Staten Island, NY) ; Vega, Jose
M.; (Trappe, PA) ; Asgharnejad, Mandana;
(Ambler, PA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Assignee: |
Merck & Co., Inc.
|
Family ID: |
29407669 |
Appl. No.: |
10/425154 |
Filed: |
April 29, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10425154 |
Apr 29, 2003 |
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09558800 |
Apr 26, 2000 |
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6569461 |
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09558800 |
Apr 26, 2000 |
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09516259 |
Feb 29, 2000 |
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60123227 |
Mar 8, 1999 |
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Current U.S.
Class: |
424/468 ;
514/548 |
Current CPC
Class: |
A61K 9/2833
20130101 |
Class at
Publication: |
424/468 ;
514/548 |
International
Class: |
A61K 031/225; A61K
009/22; A61K 009/16; A61K 009/50 |
Claims
What is claimed is:
1. An oral pharmaceutical composition comprising a therapeutically
effective amount of a compound selected from a dihydroxy open acid
statin and a pharmaceutically acceptable salt or ester thereof and
a pharmaceutically acceptable carrier, formulated as a
delayed-release dosage form wherein substantial release of the
compound from the dosage form after oral administration to a
patient is delayed until after passage of the dosage form through
the stomach.
2. The pharmaceutical composition of claim 1 wherein at most 10% by
weight of the statin is released into the stomach of a patient
after administration.
3. The pharmaceutical composition of claim 2 wherein at most 5% by
weight of the statin is released into the stomach of a patient
after administration.
4. The pharmaceutical composition of claim 3 wherein at most 1% by
weight of the statin is released into the stomach of a patient
after administration.
5. The pharmaceutical composition of claim 1 wherein the
composition is enterically coated.
6. The pharmaceutical composition of claim 5 wherein the dosage
form is surrounded by an enteric coating.
7. The pharmaceutical composition of claim 5 wherein the dosage
form comprises enterically coated granules of the dihydroxy open
acid statin or a pharmaceutically acceptable salt or ester
thereof.
8. The pharmaceutical composition of claim 5 wherein the dosage
form comprises enterically coated granules of dihydroxy open acid
simvastatin or a pharmaceutically acceptable salt or ester
thereof.
9. The pharmaceutical composition of claim 5 wherein the dosage
form comprises enterically coated granules of the dihydroxy open
acid statin or a pharmaceutically acceptable salt or ester thereof,
provided that the dosage form does not contain granules of
aspirin.
10. The pharmaceutical composition of claim 5 wherein the
composition is formulated in an enterically coated rapid-release
pharmaceutical dosage form.
11. The pharmaceutical composition of claim 5 wherein the
composition is formulated in an enterically coated time
controlled-release pharmaceutical dosage form.
12. The pharmaceutical composition of claim 1 wherein the
composition is formulated in a drug delivery device comprised of:
(A) a compressed core prepared from an admixture comprising: (i) a
therapeutically effective amount of the compound; and (ii) a
polymer which upon hydration forms gelatinous microscopic
particles; and (B) a water insoluble, water impermeable polymeric
coating comprising a polymer and a plasticizer, which surrounds and
adheres to the core, the coating having a plurality of formed
apertures exposing between about 1 and about 75% of the core
surface; and wherein the release rate of the compound from the
device is a function of the number and size of the apertures.
13. The pharmaceutical composition of claim 12 wherein the drug
delivery device is additionally comprised of an enteric overcoat
exterior to the water insoluble, water impermeable polymeric
coating.
14. The composition of claim 1 wherein the statin is selected from
the dihydroxy open acid forms of lovastatin, simvastatin,
atorvastatin, cerivastatin, nisvastatin and ZD-4522 and the
pharmaceutically acceptable salts and esters thereof.
15. The composition of claim 1 wherein the statin is selected from
the dihydroxy open acid form of lovastatin, simvastatin and the
pharmaceutically acceptable salts and esters thereof.
16. The composition of claim 1 wherein the statin is selected from
the dihydroxy open acid form of simvastatin and the
pharmaceutically acceptable salts and esters thereof.
17. The composition of claim 1 wherein the statin is a
pharmaceutically acceptable salt of dihydroxy open acid
simvastatin.
18. The composition of claim 1 wherein the statin is a calcium salt
of dihydroxy open acid simvastatin.
19. The composition of claim 1 wherein the statin is an ammonium
salt of dihydroxy open acid simvastatin.
20. The composition of claim 1 wherein the statin is a crystalline
hydrated calcium salt of dihydroxy open acid simvastatin having an
x-ray powder diffraction pattern obtained using CuK.alpha.
radiation characterized by reflections at d-spacings of 30.7, 24.6,
15.9, 11.2, 8.58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.93,
3.84, 3.67, 3.51 and 3.28 .ANG..
21. The composition of claim 5 wherein the statin is selected from
the dihydroxy open acid form of lovastatin, simvastatin,
atorvastatin, cerivastatin, nisvastatin and ZD-4522 and the
pharmaceutically acceptable salts and esters thereof.
22. The composition of claim 5 wherein the statin is selected from
the dihydroxy open acid form of lovastatin, simvastatin and the
pharmaceutically acceptable salts and esters thereof.
23. The composition of claim 5 wherein the statin is selected from
the dihydroxy open acid form of simvastatin and the
pharmaceutically acceptable salts and esters thereof.
24. The composition of claim 5 wherein the statin is a
pharmaceutically acceptable salt of simvastatin.
25. The composition of claim 5 wherein the statin is a calcium salt
of dihydroxy open acid simvastatin.
26. The composition of claim 5 wherein the statin is an ammonium
salt of dihydroxy open acid simvastatin.
27. The composition of claim 5 wherein the statin is a crystalline
hydrated calcium salt of dihydroxy open acid simvastatin having an
x-ray powder diffraction pattern obtained using CuK.alpha.
radiation characterized by refelections at d-spacings of 30.7,
24.6, 15.9, 11.2, 8.58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60,
3.93, 3.84, 3.67, 3.51 and 3.28 .ANG..
28. The composition of claim 27 further comprising BHA.
29. The composition of claim 27 further comprising propyl
gallate.
30. The composition of claim 27 further comprising BHA and propyl
gallate.
31. An oral pharmaceutical composition made by combining a
therapeutically effective amount of a compound selected from a
dihydroxy open acid statin and a pharmaceutically acceptable salt
or ester thereof with a pharmaceutically acceptable carrier in a
delayed-release dosage form.
32. A process for preparing an oral pharmaceutical composition
comprising combining a compound selected from a dihydroxy open acid
statin and a pharmaceutically acceptable salt or ester thereof with
a pharmaceutically acceptable carrier in a delayed-release dosage
form.
33. The composition of claim 18 wherein the composition is coated
with SURETERIC WHITE.RTM..
34. The composition of claim 33 wherein the coating of SURETERIC
WHITE.RTM. surrounds the dosage form.
35. The composition of claim 20 wherein the composition is coated
with SURETERIC WHITE.RTM..
36. The composition of claim 35 wherein the coating of SURETERIC
WHITE.RTM. surrounds the dosage form.
37. The composition of claim 28 wherein the composition is coated
with SURETERIC WHITE.RTM..
38. The composition of claim 29 wherein the composition is coated
with SURETERIC WHITE.RTM..
39. The composition of claim 30 wherein the composition is coated
with SURETERIC WHITE.RTM..
40. The composition of claim 1 wherein the dosage form is comprised
of a core tablet, a sub-coat applied over the core tablet and an
enteric coat applied over the sub-coat, wherein the core tablet is
comprised of a crystalline hydrated calcium salt of dihydroxy open
acid simvastatin having an x-ray powder diffraction pattern
obtained using CuK.alpha. radiation characterized by reflections at
d-spacings of 30.7, 24.6, 15.9, 11.2, 8.58, 7.31, 6.74, 6.06, 5.35,
5.09, 4.93, 4.60, 3.93, 3.84, 3.67, 3.51 and 3.28 .ANG., the
sub-coat is comprised of a 1:1 ratio hydroxypropyl
cellulose:hydroxypropyl methyl cellulose mixture, and the enteric
coat is comprised of SURETERIC WHITE.RTM..
41. The composition of claim 40 wherein the core tablet is further
comprised of an anti-oxidant agent selected from the group
consisting of BHA, propyl gallate and combinations thereof.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
09/516,259, filed Feb. 29, 2000, which claims priority to
provisional application U.S. Serial No. 60/123,227, filed Mar. 8,
1999.
FIELD OF THE INVENTION
[0002] The instant invention relates to the use of dihydroxy open
acid statins and salts and esters thereof, which are inhibitors of
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in such
a way so as to minimize their in vivo lactonization, and to a
particular crystalline hydrated form of the calcium salt of
dihydroxy open acid simvastatin referred to herein as compound
I.
BACKGROUND OF THE INVENTION
[0003] It has been clear for several decades that elevated blood
cholesterol is a major risk factor for coronary heart disease
(CHD), and many studies have shown that the risk of CHD events can
be reduced by lipid-lowering therapy. Prior to 1987, the
lipid-lowering armamentarium was limited essentially to a low
saturated fat and cholesterol diet, the bile acid sequestrants
(cholestyramine and colestipol), nicotinic acid (niacin), the
fibrates and probucol. Unfortunately, all of these treatments have
limited efficacy or tolerability, or both. With the introduction of
lovastatin (MEVACOR.RTM.; see U.S. Pat. No. 4,231,938), the first
inhibitor of HMG-CoA reductase to become available for prescription
in 1987, for the first time physicians were able to obtain
comparatively large reductions in plasma cholesterol with very few
adverse effects.
[0004] In addition to the natural fermentation products, mevastatin
and lovastatin, there are now a variety of semi-synthetic and
totally synthetic HMG-CoA reductase inhibitors, including
simvastatin (ZOCOR.RTM.; see U.S. Pat. No. 4,444,784), pravastatin
sodium salt (PRAVACHOL.RTM.; see U.S. Pat. No. 4,346,227),
fluvastatin sodium salt (LESCOL.RTM.; see U.S. Pat. No. 5,354,772),
atorvastatin calcium salt (LIPITOR.RTM.; see U.S. Pat. No.
5,273,995) and cerivastatin sodium salt (also known as rivastatin;
see U.S. Pat. No. 5,177,080). The structural formulas of these and
additional HMG-CoA reductase inhibitors, are described at page 87
of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry &
Industry, pp. 85-89 (Feb. 5, 1996). The HMG-CoA reductase
inhibitors described above belong to a structural class of
compounds which contain a moiety which can exist as either a
3-hydroxy lactone ring or as the corresponding ring opened
dihydroxy open-acid, and are often referred to as "statins." An
illustration of the lactone portion of a statin and its
corresponding open-acid form is shown below. 1
[0005] Salts of the dihydroxy open-acid can be prepared, and in
fact, as noted above, several of the marketed statins are
administered as the dihydroxy open acid salt forms. Lovastatin and
simvastatin are marketed worldwide in their lactonized form.
Lovastatin is shown as structural formula II, and simvastatin is
shown as structural formula III, below. 2
[0006] The lactonized forms of the statins are not active
inhibitors of HMG-CoA reductase, but the dihydroxy open acid forms
are. It is known that condensation of the dihydroxy open acid form
of statins to the corresponding lactonized form occurs under acidic
conditions, that is at about pH 4 or under. Therefore, due to the
low gastric pH of the stomach, a statin conventionally administered
by oral dosing in its lactone form will remain largely in its
lactone form in the stomach. The vast majority of the drug will
still be in the lactone form at the time of absorption from the
intestine following oral dosing with the lactone. After absorption,
the lactone enters the liver and it is in the hepatocytes that the
lactone can be metabolized to the active open acid form, a reaction
catalyzed by two hepatic esterases or "lactonases," one which is in
the cytosolic and the other in the microsomal fraction. Once in the
blood there is an additional plasma esterase which can also
hydrolyze the lactone to the open acid. There may be some minimal
chemical, i.e., non-enzymatic, hydrolysis that occurs in blood or
in the liver; however, at the pH in blood and liver, there should
not be any lactonization, i.e., conversion of open acid back to the
lactone.
[0007] A statin conventionally administered by oral dosing in its
dihydroxy open acid form or a pharmaceutically acceptable salt or
ester thereof will tend to convert to its lactone form in the
acidic environment of the stomach, so that a mixture of the open
ring and the corresponding closed ring forms will co-exist there.
For example, see M. J. Kaufman, International Journal of
Pharmaceutics, 1990, 66(December 1), p. 97-106, which provides
hydrolysis data that are used to simulate the extent of drug
degradation that occurs in acidic gastric fluids following oral
administration of several structurally related hypocholesterolemic
agents, including simvastatin and lovastatin, and also see A. S.
Kearney, et al., Pharmaceutical Research, 1993, 10(10), p.
1461-1465, which describes the interconversion kinetics and
equilibrium of CI-981 (atorvastatin in its free acid form).
Therefore, even after conventional oral dosing with a dihydroxy
open acid statin or a salt or ester thereof, a mixture of the open
acid and the corresponding lactone form of the drug could exist by
the time of absorption from the intestine.
[0008] The preparation of the naturally occurring compound
lovastatin and the semi-synthetic analog simvastatin leads to a
mixture of the lactone and the open-ring dihydroxy acid forms.
Several procedures have been published describing ways to make
simvastatin from lovastatin, and most proceed through a lactone
ring opening step at some point in the process and sometimes
formation of a salt at the resulting carboxy acid, and end with a
ring-closing step in order to make the final simvastatin product.
For example, U.S. Pat. No. 4,820,850 describes a process for making
simvastatin which involves opening the lactone ring of lovastatin
and forming an alkyl-amide at the resulting carboxy acid, followed
by protection of the two hydroxy groups and methylation of the 8'
acyl sidechain. After the methylation step, the hydroxy protecting
groups are removed, the amide is hydrolyzed to the free acid and an
ammonium salt of the free acid is formed, followed by a step to
re-lactonize the ring. In U.S. Pat. No. 4,444,784, the 8'-acyl
sidechain of lovastatin is removed and the lactone ring opened in
the first step, followed by re-lactonization of the ring and
protection of its hydroxy group. Next, the 8' position is acylated
to introduce the simvastatin sidechain and a deprotection step is
performed to obtain the simvastatin final product. In another
process disclosed in U.S. Pat. No. 4,582,915, the potassium salt of
the ring opened form of lovastatin is methylated at the 8' acyl
sidechain, the free acid is then re-generated, and the dihydroxy
open acid moiety is re-lactonized.
[0009] Since becoming available, millions of doses of simvastatin
have been administered and these drugs have developed an excellent
safety record. However, as noted in the Physician's Desk Reference
(PDR), in rare instances myopathy has been associated with the use
of all statins, including simvastatin. The mechanism for
statin-related myopathy is currently poorly understood. It is also
known that many drugs, including certain statins such as
simvastatin, are metabolized in the liver and intestine by the
cytochrome P450 3A4 (CYP 3A4) enzyme system. As also noted in the
PDR, there are adverse drug interaction concerns if a potent
inhibitor of CYP3A4, such as itraconazole, and a CYP3A4-metabolized
statin are used together, and some cases of myopathy were found to
have occurred in patients taking such a drug combination.
Simvastatin has been administered to over 20 million patients
worldwide in the past 11 years and has been demonstrated to be
remarkably safe. However, the very low risk of myopathy is
substantially increased when simvastatin is given together with
potent inhibitors of CYP3A4While the overall safety record for
simvastatin is exceptional, it would be desirable to further
optimize its safety profile by reducing the potential for drug
interactions with inhibitors of CYP3A4. It would also be desirable
to further reduce the already low rate of occurrence of myopathy
associated with the use of all statins. Statins are among the most
widely used drugs in the world, and therefor the benefit of any
further optimization of their safety profile would be
significant.
SUMMARY OF THE INVENTION
[0010] One object of this invention is to minimize or eliminate the
in vivo lactonization of a dihydroxy open-acid statin. For oral
administration, the dihydroxy open-acid statin or a
pharmaceutically acceptable salt or ester thereof is to be
administered so as to minimize formation of lactonized statin and
thereby minimize the amount of lactonized statin that is absorbed
from the intestine while maximizing the amount of dihydroxy
open-acid statin that is absorbed from the intestine.
[0011] Accordingly, this invention involves a method of inhibiting
HMG-CoA reductase with an effective inhibitory amount of an orally
dosed statin comprising delivering at least 90% of the dosed statin
in its dihydroxy open acid form to the intestinal mucosa of a
patient in need of such treatment.
[0012] The instant invention further provides a method for
inhibiting HMG-CoA reductase, as well as for treating and/or
reducing the risk for diseases and conditions affected by
inhibition of HMG-CoA reductase, comprising orally administering a
therapeutically effective amount of a compound selected from a
dihydroxy open acid statin and a pharmaceutically acceptable salt
or ester thereof in a delayed-release pharmaceutical dosage form to
a patient in need of such treatment wherein substantial release of
the compound from the dosage form is delayed until after passage of
the dosage form through the stomach.
[0013] One embodiment of the first object is to provide the
above-described method wherein the delayed-release pharmaceutical
dosage form is a gel extrusion module (GEM) drug delivery
device.
[0014] Another embodiment of the first object is to provide the
above-described method wherein the delayed-release pharmaceutical
dosage form is an enterically coated pharmaceutical dosage form. An
additional aspect of this embodiment is to provide the
above-described method wherein the delayed-release pharmaceutical
dosage form is selected from an enterically coated rapid-release
pharmaceutical dosage form and an enterically coated time
controlled-release pharmaceutical dosage form. Yet another aspect
of this embodiment is to provide the above-described method wherein
the delayed-release pharmaceutical dosage form is an enterically
coated gel extrusion module (GEM) drug delivery device.
[0015] The compound used for the above-described object and
embodiments may particularly be dihydroxy open acid simvastatin and
the pharmaceutically acceptable salts thereof, and more
particularly a pharmaceutically acceptable salt thereof.
[0016] A second object of the instant invention is to provide novel
HMG-CoA reductase inhibitors which are crystalline hydrated forms
of the calcium salt of dihydroxy open acid simvastatin, and
particularly the compound referred to herein as compound I.
[0017] Additional objects are to provide the use of the crystalline
hydrated forms of the calcium salt of dihydroxy open acid
simvastatin, particularly compound I, for inhibiting HMG-CoA
reductase, as well as for treating and/or reducing the risk for
diseases and conditions affected by inhibition of HMG-CoA
reductase, and also to provide pharmaceutical formulations,
including conventional rapid-release, delayed-release and time
controlled-release formulations, including the GEM drug delivery
device and enterically coated dosage forms, that can be used with
the compounds. A further embodiment is to provide a composition and
method for improving the long-term stability of a formulated drug
product containing compound I by enterically coating a core tablet
comprised of compound I with an enteric coating, particularly
SURETERIC WHITE.RTM.. A further object is to provide a process for
making compound I. Additional objects will be evident from the
following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a thermogravimetry (TG) weight loss curve for
compound I obtained under a nitrogen flow at a heating rate of
10.degree. C./minute.
[0019] FIG. 2 is a differential scanning calorimetry (DSC) curve
for compound I obtained under a nitrogen flow bubbled through
16.0.degree. C. water at a heating rate of 10.degree. C./minute in
an open cup.
[0020] FIG. 3 is an x-ray powder diffraction (XRPD) pattern for
compound I. The XRPD pattern was obtained using CuK.alpha.
radiation. The ordinate or Y-axis is x-ray intensity (cpm) and the
abscissa or X-axis is the angle two-theta (2.theta.) in
degrees.
[0021] FIG. 4 is a solid-state .sup.13C nuclear magnetic resonance
spectrum for Compound I.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Applicants have now discovered that dihydroxy open acid
statins may be less reliant on CYP3A4 metabolism than their closed
ring lactonized counterparts. The instant invention involves
methods and pharmaceutical compositions for orally administering
open-ring dihydroxy open acid statins and salts and esters thereof,
which are HMG-CoA reductase inhibitors, in such a way so as to
minimize conversion to their lactonized counterparts. This allows
for delivery of a dihydroxy open acid statin without its lactone
counterpart directly to the absorptive mucosa of the small
intestine thus allowing for absorption of the open acid statin into
the portal circulation, penetration by active open acid statin into
hepatocytes to achieve enhanced efficacy, and systemic exposure
consisting of open acid moieties. More particularly,
delayed-release of an orally administered dihydroxy open acid
statin or a pharmaceutically acceptable salt or ester thereof, for
example dihydroxy open acid simvastatin or a salt thereof, until
after passage through the stomach reduces the amount of lactone
formed and absorbed in the body. Maintaining the statin in its open
acid form in the body thereby reduces the potential for drug
interactions between statins whose metabolism is CYP3A4-mediated
and other active agents which inhibit the CYP3A4 enzymatic pathway,
and also can provide enhanced efficacy. Moreover, maintaining the
statin in its open acid form in the body may have additional
clinical benefits for all statins, even for those statins that are
not significantly metabolized by the CYP3A4 enzymatic pathway.
[0023] In addition, a novel crystalline hydrated form of the
calcium salt of dihydroxy open acid simvastatin has now been
discovered to be a pharmaceutically suitable salt form having
desirable physical properties for formulation into an
anti-hypercholesterolemic drug composition.
[0024] The term "statin(s)" as used herein is intended to be
defined as inhibitors of HMG-CoA reductase which belong to a
structural class of compounds that contain a moiety which can exist
as either a 3-hydroxy lactone ring or as the corresponding ring
opened dihydroxy open acid, wherein the lactone portion of the
statin and its corresponding dihydroxy open-acid form is shown
below. 3
[0025] All hydrates, solvates and polymorphic crystalline forms of
HMG-CoA reductase inhibitors having the above-described
lactone/dihydroxy open acid moiety are included within the scope of
the term "statin(s)". Pharmaceutically acceptable salts and esters
of the dihydroxy open-acid statins are included within the scope of
the term "statin(s)".
[0026] Statins inhibit HMG-CoA reductase in their dihydroxy open
acid form. Compounds which have inhibitory activity for HMG-CoA
reductase can be readily identified by using assays well-known in
the art. For example, see the assays described or cited in U.S.
Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
[0027] The term "dihydroxy open acid statin(s)" is intended to be
defined as statins which contain the dihydroxy open acid moiety,
including pharmaceutically acceptable salts and esters thereof. The
phrases "dihydroxy open acid statin(s)" and "dihydroxy open acid
statin(s) and the pharmaceutically acceptable salts and esters
thereof" are used interchangeably herein and are both intended to
encompass the open acid and salt and ester forms of the open acid
of the statin, unless otherwise indicated. All hydrates, solvates
and polymorphic crystalline forms are encompassed within the the
scope of the term "dihydroxy open acid statin(s)."
[0028] In the broadest embodiment, any dihydroxy open acid statin
or a pharmaceutically acceptable salt or ester thereof may be used
with the present invention. Examples of dihydroxy open acid statins
that may be used with the present invention include but are not
limited to the dihydroxy open acid forms and pharmaceutically
acceptable salts and esters thereof of: lovastatin (see U.S. Pat.
No. 4,342,767); simvastatin (see U.S. Pat. No. 4,444,784),
pravastatin, particularly the sodium salt thereof; fluvastatin
particularly the sodium salt thereof; atorvastatin, particularly
the calcium salt thereof; cerivastatin, particularly the sodium
salt thereof, nisvastatin also referred to as NK-104 (see PCT
international publication number WO 97/23200) and ZD-4522 (see U.S.
Pat. No. 5,260,440, and Drugs of the Future, 1999, 24(5), pp.
511-513).
[0029] In a narrower embodiment, any dihydroxy open acid statin or
a pharmaceutically acceptable salt or ester thereof may be used
with the present invention, such as those listed above, provided
the statin is not pravastatin or fluvastatin. In a class of this
embodiment, the open acid statin includes dihydroxy open acid
lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin
(also known as NK-104) and pharmaceutically acceptable salts
thereof. Pharmaceutically acceptable salts of dihydroxy open acid
simvastatin, particularly the ammonium and calcium salt forms
thereof, are preferred for use in the methods and compositions of
this invention. More particularly, the calcium salt of dihydroxy
open acid simvastatin includes the crystalline hydrated forms of
the calcium salt of dihydroxy open acid simvastatin, and more
particularly the hydrated calcium salt of dihydroxy open acid
simvastatin referred to herein as compound I.
[0030] Herein, the term "pharmaceutically acceptable salts" shall
mean non-toxic salts of the compounds employed in this invention
which are generally prepared by reacting the free acid with a
suitable organic or inorganic base, particularly those formed from
cations such as sodium, potassium, aluminum, calcium, lithium,
magnesium, zinc and tetramethylammonium, as well as those salts
formed from amines such as ammonia, ethylenediamine,
N-methylglucamine, lysine, arginine, ornithine, choline,
N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine,
procaine, N-benzylphenethylamine,
1-p-chlorobenzyl-2-pyrrolidine-1'-yl-me- thylbenzimidazole,
diethylamine, piperazine, morpholine, 2,4,4-trimethyl-2-pentamine
and tris(hydroxymethyl)aminomethane. Pharmaceutically acceptable
esters at the carboxylic acid group can be made by treating a
dihydroxy open acid statin with an alcohol. Examples of
pharmaceutically acceptable esters of dihydroxy open acid statins
include, but are not limited to, --C.sub.1-4 alkyl and --C.sub.1-4
alkyl substituted with phenyl-, dimethylamino-, and acetylamino.
"C.sub.1-4 alkyl" herein includes straight or branched aliphatic
chains containing from 1 to 4 carbon atoms, for example methyl,
ethyl, n-propyl, n-butyl, iso-propyl, sec-butyl and tert-butyl.
[0031] The instant invention involves methods and pharmaceutical
compositions for orally administering open-ring dihydroxy open acid
statins and salts and esters thereof, which are HMG-CoA reductase
inhibitors, in such a way so as to minimize conversion to their
lactonized counterparts. This allows for delivery of a dihydroxy
open acid statin without its lactone counterpart directly to the
absorptive mucosa of the small intestine thus allowing for
absorption of the open acid statin into the portal circulation,
penetration by active open acid statin into hepatocytes to achieve
enhanced efficacy, and systemic exposure consisting of open acid
moieties. More particularly, delayed-release of an orally
administered dihydroxy open acid statin or a pharmaceutically
acceptable salt or ester thereof, for example dihydroxy open acid
simvastatin or a salt thereof, until after passage through the
stomach reduces the amount of lactone formed and absorbed in the
body. Maintaining the statin in its open acid form in the body
thereby reduces the potential for drug interactions between statins
whose metabolism is CYP3A4-mediated and other active agents which
inhibit the CYP3A4 enzymatic pathway, and also can provide enhanced
efficacy. Administering a statin in its open acid form in such a
way so as to minimize conversion to its lactonized counterpart, for
example by using an oral delayed release dosage form, should reduce
the potential for drug interaction compared to the conventional
administration of an open acid statin or its lactonized
counterpart, for example by using an oral rapid release dosage
form.
[0032] An object of this invention is to provide methods for
reducing the amount of lactonized statin formed and absorbed in the
body after oral administration of a dihydroxy open acid statin in
order to achieve enhanced clinical benefits. A way to achieve this
is to administer the dihydroxy open acid statin in a
delayed-release pharmaceutical dosage form. A delayed-release
pharmaceutical dosage form as defined herein is an orally
administerable pharmaceutical dosage form or device that does not
release a substantial amount of the active compound, i.e., the
dihydroxy open-acid statin, until after the dosage form has passed
through the stomach. Therefore, substantial release of the active
compound would initially occur after entry into the duodenum. By
"substantial release," it is intended that 90% or more by weight of
the active compound in the delayed-release dosage form is released
after entry into the duodenum, and that 10% or less by weight of
the active compound in the delayed-release dosage form is released
in the stomach, i.e., the geometric mean ratio of the plasma AUC
(area under the curve) of active vs. total HMG-CoA reductase
inhibitory activity will be greater than or equal to 90%.
Particularly, the amount of active compound released in the stomach
before entry into the duodenum is 5% or less by weight, i.e., the
geometric mean ratio of the plasma AUC of active vs. total HMG-CoA
reductase inhibitory activity will be greater than or equal to 95%,
and more particularly the amount of active compound released in the
stomach before entry into the duodenum is 1% or less by weight,
i.e., the geometric mean ratio of the plasma AUC of active vs.
total HMG-CoA reductase inhibitory activity will be greater than or
equal to 99%.
[0033] It is to be understood that metabolism of the dihydroxy open
acid statins will occur, primarily in the liver, after orally
dosing in a delayed-release dosage form. However, since
lactonization of the dihydroxy open acid statin would have been
substantially avoided by use of a delayed release dosage form, the
active and inactive metabolites that are formed will also be in the
dihydroxy open acid form. In essence, if the dihydroxy open acid
statin is administered in a delayed release dosage form, the
internal exposure to lactonized parent compound and also to
lactonized active and inactive metabolites will be minimized.
[0034] One example of a suitable delayed-release dosage form is a
pH-dependent enterically coated dosage form. The enteric coating
will not dissolve in the acidic gastric environment, but will
dissolve in the higher pH environment of the duodenum. An
enterically coated dosage form will therefore not permit release of
any significant amount of the active compound from the dosage form
in the stomach, but once the enteric coating dissolves in the
duodenum, the active compound will be released. Suitable
compositions for enteric coatings that can be used with the present
invention are known to those of ordinary skill in the
pharmaceutical arts; for example, see L. Lachman, The Theory and
Practice of Industrial Pharmacy, 3rd Ed., H. Liebermann and J.
Kanig contributors (Lea & Febiger, 1986). An example of a
suitable enteric coating includes but is not limited to SURETERIC
WHITE.RTM. sold by Colorcon which is composed of polyvinyl acetate
phthalate, titanium dioxide, talc, colloidal silicon dioxide,
triethyl citrate, Macrogol/PEG 4000 (a type of polyethylene
glycol), sodium bicarbonate, purified stearic acid, and sodium
alginate. Many other suitable enteric coating materials are
commercially available and are known in the art and include but are
not limited to coatings comprised of any of the following polymers:
polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose
phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate
(HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate
phthalate (CAP), polymethacrylates and shellac. The
polymethacrylates are a class of polymers used in pharmaceutical
coatings for sustained or controlled release. The EUDRAGITs.RTM.
are a particular brand of products based upon this polymer class
and are available from Rohm Pharma GmbH. EUDRAGIT L.RTM.
(methacrylic acid/ethyl acrylate) is one type of marketed enteric
polymer, and is available as a powder for organic or aqueous
dispersion, or as a pseudolatex aqueous dispersion. EUDRAGIT S.RTM.
is another example in this class which is soluble at slightly more
basic conditions than EUDRAGIT L.RTM..
[0035] Most of the materials used for enteric coatings are prepared
as solutions or suspensions prior to coating. In addition to the
polymer, other materials are often added to these formulations to
improve coating integrity or processability. For example, other
materials commonly used in filmcoating formulations include:
plasticizers, which aid in film formation and improve the
flexibility of the final film, making it less susceptible to
cracking; antitacking agents, which prevent the product from
agglomerating during the coating process, and/or opacifiers, which
may improve the elegance of the dosage form, or provide additional
protection from the environment.
[0036] The vehicles used to deliver these formulations are
typically aqueous or organic, or may be mixtures of solvents.
Equipment used to process formulations containing organic solvents
often require a solvent recovery system in order to prevent release
of solvent vapors to the atmosphere, as well as additional safety
and monitoring equipment to minimize the potential for explosivity.
Because of these environmental concerns associated with organic
solvents, aqueous solvent methods are preferred.
[0037] The coating process of pharmaceutical dosage forms, such as
powders, granules, pellets, or tablets, typically takes place in
one of several types of coating equipment, including pan coaters,
fluidized bed coaters, or continuous coaters. The coating of
tablets usually takes place in pan coaters although tablets are
often coated in a fluidized bed if a solvent-based coating is used.
The coating of powders, granules, or pellets is often performed in
fluidized bed apparatus. However, the various types of coating
equipment can be used to coat most pharmaceutical dosage forms,
either directly or with limited modification.
[0038] Coating conditions vary widely, and depend primarily on the
process, substrate, and coating formulation. Spray rate and coating
temperature are targeted as two key parameters to control in order
to obtain an acceptable product and process. There is often a
strong interdependence between spray rate and coating temperature,
and both must be considered during process development and
optimization. The processing conditions are often dictated by the
type of polymer used in the coating formulation, but may also
depend upon the characteristics of the substrate. For example, the
temperature at which the active material (or other components) in
the core begins to degrade may limit the maximum coating
temperature. However, a certain minimum temperature may be
necessary to form a continuous film.
[0039] The level of coating applied to a dosage form is an
important consideration. In the case of certain coatings, for
example, a minimum amount of coating is needed to provide
sufficient resistance to acid or environmental degradation, while
beyond a desired coating level dissolution of the drug may be
delayed or prevented altogether. The key in these formulations is
to provide enough coating to protect the dosage form, but not so
much that the performance of the dosage form is affected.
[0040] Additional coatings employed in the preparation of the
dosage form, such as those used to provide an elegant,
aesthetically pleasing final product or for other purposes, may be
applied before or after, or before and after, application of the
enteric coating.
[0041] Suitable enterically coated pharmaceutical dosage forms for
use with this invention include enterically coated conventional
rapid-release (also referred to as immediate-release)
pharmaceutical dosage forms wherein the drug is relatively rapidly
released once the enteric coating is breached, and enterically
coated time-controlled release dosage forms such as but not limited
to an enterically coated GEM delivery device, described below. Time
controlled-release dosage forms are also well known in the
pharmaceutical art, and are designed so as to slowly release the
active compound in the body over a period of time, for example over
a period of from about 6 to 24 hours. Use of an enteric coated time
controlled-release dosage form is preferred with more potent dosage
amounts of a dihydroxy open acid statin so as to lower the systemic
exposure to the active statin. Whether the dosage form is an
enterically coated rapid-release or time-controlled release dosage
form, the enteric coating will prevent release of any substantial
amount of the active compound from the dosage form in the
stomach.
[0042] Enterically coated pharmaceutical dosage forms also include
but are not limited to those wherein the dosage form or unit is
comprised of the dihydroxy open acid statin in a tablet, capsule or
the like that is surrounded by an enteric overcoating, and those
wherein the dosage form or unit is a tablet, capsule or the like
comprised of enterically coated granules of the dihydroxy open acid
statin. Where the dosage form is surrounded by an enteric overcoat,
the enteric coating may be the outer-most external coating on the
dosage form, or there may be one or more additional finish coatings
applied over the enteric coat. In a more limited embodiment, when
the delayed-release dosage unit contains enterically coated
granules of the drug, the drug is selected from the dihydroxy
open-acid form of lovastatin and simvastatin and the
pharmaceutically acceptable salt and ester forms thereof, and is
more preferably a salt of dihydroxy open acid simvastatin, and most
preferably the calcium or ammonium salt thereof. In an alternative
embodiment, any dihydroxy open acid statin or pharmaceutically
acceptable salt or ester thereof may be used with the present
invention, such as those described herein, provided that the statin
is not dosed in a single pharmaceutical dosage form or unit
comprised of enteric coated granules of the statin and enteric
coated or non-enteric coated granules of aspirin.
[0043] Furthermore, compound I is challenging to stabilize in a
formulated drug product. Surprisingly, stability of the core tablet
comprised of compound I as the active agent is greatly improved by
addition of a polymeric coating, particularly a polymeric coating
comprised of polyvinyl acetate phthalate (PVAP), and more
particularly the enteric polymeric coating SURETERIC WHITE. The use
of the PVAP-based coating has unexpectedly been found to inhibit
the degradation of the active agent in the formulated drug product,
thereby providing enhanced long term stability of the formulated
drug product. A sub-coat may optionally be applied to the core
tablet prior to application of the polymeric coating to aid in
adhesion of the polymeric coating. A sub-coat example includes, but
is not limited to, one comprised of a mixture of 50% hydroxypropyl
cellulose/50% hydroxypropyl methyl cellulose (i.e., a 1:1 ratio
hydroxypropyl cellulose:hydroxypropyl methyl cellulose mixture).
The sub-coat may also contain additional components such as a
coloring agent, for example titanium dioxide. The polymeric coating
is applied to the tablet over the sub-coat, for example by a spray
coating process. An optional additional top-coat can be applied
over the polymeric coating for aesthetic or other purposes; for
example, the top-coat can be the same or similar composition as the
sub-coat and can be used to add color or to aid in the application
of other markings on the finished tablet. The polymeric coating,
particularly SURETERIC WHITE.RTM., can be applied to the tablet in
an amount and thickness to achieve the desired stability
enhancement while also taking into account the desired in vivo
release performance associated with the pH sensitive
characteristics of the enteric coating. For example, SURETERIC
WHITE.RTM. can be applied in a range from, but not limited to, 5%
to 15% tablet weight gain, which corresponds to about 50 to 150
micron coating thickness, and particularly about 10% tablet weight
gain.
[0044] An example of a delayed-release dosage form that also
functions as a time controlled-release dosage form is described in
U.S. Pat. No. 5,366,738, herein incorporated by reference in its
entirety. The controlled-release drug delivery device described in
U.S. Pat. No. 5,366,738 is known as a gel extrusion module (GEM)
delivery device. The GEM device is a drug delivery device for the
controlled in situ production and release of a dispersion
containing a beneficial agent such as a pharmaceutical drug
comprising:
[0045] (A) a compressed core prepared from an admixture
comprising:
[0046] (i) a therapeutically effective amount of the beneficial
agent; and
[0047] (ii) a polymer which upon hydration forms gelatinous
microscopic particles; and
[0048] (B) a water insoluble, water impermeable polymeric coating
comprising a polymer and a plasticizer, which surrounds and adheres
to the core, the coating having a plurality of formed apertures
exposing between about 1 and about 75% of the core surface;
[0049] and wherein the release rate of the beneficial agent from
the device is a function of the number and size of the
apertures.
[0050] In the GEM device, the polymer inside the compressed core is
preferably selected from sodium polyacrylate, carboxypolymethylenes
and the pharmaceutically acceptable salts thereof such as a sodium
salt, wherein the carboxypolymethylenes are prepared from acrylic
acid crosslinked with allylethers of sucrose or pentaerythritol,
and more preferably it is selected from carboxypolymethylenes
prepared from acrylic acid crosslinked with allylethers of sucrose
or pentaerythritol, and the pharmaceutically acceptable salts
thereof. Most preferably, CARBOPOL.RTM. 974P and pharmaceutically
acceptable salts thereof, particularly the sodium salt, is used as
the polymer inside the compressed core. In addition, the compressed
core may also contain one or more polymer hydration modulating
agents, anti-oxidants, lubricants, fillers and excipients. An
optional subcoating may be applied to the compressed core prior to
application of the water insoluble coating as an aid in the
manufacturing process. The subcoating may be comprised of, for
example, hydroxypropyl cellulose and hydroxypropylmethylcellulose.
Additional coatings may be applied for aesthetic or functional
purposes.
[0051] The water insoluble, water impermeable polymeric coating is
preferably comprised of (1) a polymer selected from polyvinyl
chloride, cellulose acetate, cellulose acetate butyrate,
ethylcellulose and combinations of these polymers; and (2) a
plasticizer selected from diethylphthalate, dibutylsebacate and
triethylcitrate. More preferably, the polymeric coating is
comprised of cellulose acetate butyrate and triethyl citrate. The
GEM device does not function as an osmotic drug delivery device,
hence the release function of the device depends on passage of
fluids from the external environment of the body to the internal
environment of the compressed core through the formed apertures. It
is intended that the terms "water insoluble, water impermeable"
used to describe the polymeric coating define a coating which is
essentially water insoluble and water impermeable, meaning that the
polymeric coating allows minimal to no passage of water through the
coating from the external environment of the body to the internal
environment of the compressed core, except for the fluid passage
that occurs through the drilled apertures, during the period of
time the drug is being released from the GEM device in the body.
Any minimal amount of water that does pass through the water
insoluble, water impermeable polymeric coating is insubstantial and
does not significantly contribute to the function of the GEM
device, i.e. the release rate of the drug through the apertures.
Rather the release rate of the drug from the GEM device is
primarily a function of the number and size of the apertures on the
device.
[0052] For an elegant, aesthetically pleasing final product, an
outter finish coat may finally be applied to the GEM delivery
device containing colorants, waxes, and the like. The GEM device
can also be enterically coated, either before or after the
application of additional finish coatings. Even without enteric
coating, extrusion of the polymer which carries the drug out from
inside the compressed core of the GEM device does not occur to a
substantial extent in the acidic pH of the stomach, therefore
substantial release of the drug should not occur in the stomach.
Further details and examples of the GEM delivery device are
described in U.S. Pat. No. 5,366,738. The compound employed with
the GEM device may particularly be a pharmaceutically acceptable
salt of dihydroxy open acid simvastatin, and more particularly the
ammonium salt of dihydroxy open acid simvastatin.
[0053] The term "patient" includes mammals, especially humans, who
use the instant active agents for the prevention or treatment of a
medical condition. Administering of the drug to the patient
includes both self-administration and administration to the patient
by another person. The patient may be in need of treatment for an
existing disease or medical condition, or may desire prophylactic
treatment to prevent or reduce the risk for diseases and medical
conditions affected by inhibition of HMG-CoA reductase.
[0054] The term "therapeutically effective amount" is intended to
mean that amount of a drug or pharmaceutical agent that will elicit
the biological or medical response of a tissue, a system, animal or
human that is being sought by a researcher, veterinarian, medical
doctor or other clinician. The term "prophylactically effective
amount" is intended to mean that amount of a pharmaceutical drug
that will prevent or reduce the risk of occurrence of the
biological or medical event that is sought to be prevented in a
tissue, a system, animal or human by a researcher, veterinarian,
medical doctor or other clinician. Particularly, the dosage a
patient receives can be selected so as to achieve the amount of LDL
(low density lipoprotein) cholesterol lowering desired; the dosage
a patient receives may also be titrated over time in order to reach
a target LDL level. The dosage regimen utilizing a dihydroxy open
acid statin is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of
the patient; the severity of the condition to be treated; the
potency of the compound chosen to be administered; the route of
administration; and the renal and hepatic function of the patient.
A consideration of these factors is well within the purview of the
ordinarily skilled clinician for the purpose of determining the
therapeutically effective or prophylactically effective dosage
amount needed to prevent, counter, or arrest the progress of the
condition.
[0055] The novel compounds of this invention are the crystalline
hydrated forms of the calcium salt of dihydroxy open acid
simvastatin. A particular crystalline hydrated calcium salt of
dihydroxy open acid simvastatin is the one having an x-ray powder
diffraction (XRPD) pattern obtained using CuK.alpha. radiation
characterized by refelections at d-spacings of 30.7, 24.6, 15.9,
11.2, 8.58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.93, 3.84,
3.67, 3.51 and 3.28 .ANG.. For convenience, the crystalline
hydrated form of the calcium salt of dihydroxy open acid
simvastatin having the above-defined XRPD pattern will also be
referred to herein as compound I. Compound I can be represented
two-dimensionally as a hydrated form of the following structural
formula Ia: 4
[0056] In addition to the XRPD pattern described above, compound I
of the instant invention is further characterized by the
thermogravimetry (TG) curve shown in FIG. 1. The TG curve for
compound I was obtained under a nitrogen flow at a heating rate of
10.degree. C./minute and is characterized by a 6.3% weight loss
from ambient room temperature to a stable weight loss plateau at
about 175.degree. C. Additional weight losses due to the onset of
decomposition of the compound are observed above about 190.degree.
C.
[0057] Compound I is still further characterized by the
differential scanning calorimetry (DSC) curve shown in FIG. 2. The
DSC curve for compound I was obtained under a nitrogen flow bubbled
through 16.0.degree. C. water at a heating rate of 10.degree.
C./minute in an open cup, and is characterized by three lower
temperature endotherms with peak temperatures of 52, 77 and
100.degree. C. and associated heats of 48, 90 and 21 J/g,
respectively, and two higher temperature endotherms due to
decomposition with peak temperatures of 222 and 241.degree. C. and
associated heats of 163 and 92 J/g.
[0058] Compound I of the instant invention is still further
characterized by the .sup.1H nuclear magnetic resonance (NMR)
spectral data, .sup.13C NMR and mass spectral (MS) data as given in
Example 1 herein.
[0059] Compound I is also characterized by the solid-state .sup.13C
nuclear magnetic resonance spectrum shown in FIG. 4, which was
completed using a Bruker DSX 400WB NMR system operating at 100.6
MHz for .sup.13C and 400.1 MHz for .sup.1H using a Bruker MAS 400WB
BL7 double-resonance probe with a spinning module housing a 7 mm
zirconia rotor with Kel-f end caps. The solid-state .sup.13C
nuclear magnetic resonance (NMR) spectrum was acquired using cross
polarization (CP), magic-angle spinning (MAS), and high-power
(.about.59 kHz) decoupling with variable-amplitude
cross-polarization and total sideband suppression. Proton and
carbon 90.degree. pulse widths were 4.25 .mu.sec with a contact
time of 2.0 msec. The sample was spun at 7.0 kHz and a total of
1024 scans were collected for the spectrum with a recycle delay of
3.0 seconds. A line broadening of 10 Hz was applied to the spectrum
before FT was performed. Chemical shifts are reported on the TMS
scale using the carbonyl carbon of glycine (176.03 ppm) as a
secondary reference.
[0060] In the methods of treatment and prophylaxis described
herein, as well as the pharmaceutical compositions and medicaments,
a dihydroxy open acid statin or a pharmaceutically acceptable salt
or ester thereof is employed. Preferably the compound employed is a
pharmaceutically acceptable salt of a dihydroxy open acid statin,
more preferably it is a pharmaceutically acceptable salt of
dihydroxy open acid simvastatin such as an ammonium salt or calcium
salt, and particularly a crystalline hydrated form of the calcium
salt of dihydroxy open acid simvastatin such as compound I. All
hydrates, solvates and polymorphic crystalline forms of the
above-described compounds and their use are encompassed within
scope of the instant invention.
[0061] The instant invention provides methods for inhibiting
HMG-CoA reductase, and for treating lipid disorders including
hypercholesterolemia, hypertriglyceridemia and combined
hyperlipidemia, comprising administering a therapeutically
effective amount of a dihydroxy open acid statin to a person in
need of such treatment. Further provided are methods for preventing
or reducing the risk of developing atherosclerosis, as well as for
halting or slowing the progression of atherosclerotic disease once
it has become clinically evident, comprising the administration of
a prophylactically or therapeutically effective amount, as
appropriate, of a dihydroxy open acid statin to a mammal who is at
risk of developing atherosclerosis or who already has
atherosclerotic disease.
[0062] Atherosclerosis encompasses vascular diseases and conditions
that are recognized and understood by physicians practicing in the
relevant fields of medicine. Atherosclerotic cardiovascular disease
including restenosis following revascularization procedures,
coronary heart disease (also known as coronary artery disease or
ischemic heart disease), cerebrovascular disease including
multi-infarct dementia, and peripheral vessel disease including
erectile dysfunction are all clinical manifestations of
atherosclerosis and are therefore encompassed by the terms
"atherosclerosis" and "atherosclerotic disease."
[0063] A dihydroxy open acid statin may be administered to prevent
or reduce the risk of occurrence, or recurrence where the potential
exists, of a coronary heart disease event, a cerebrovascular event,
and/or intermittent claudication. Coronary heart disease events are
intended to include CHD death, myocardial infarction (i.e., a heart
attack), and coronary revascularization procedures. Cerebrovascular
events are intended to include ischemic or hemorrhagic stroke (also
known as cerebrovascular accidents) and transient ischemic attacks.
Intermittent claudication is a clinical manifestation of peripheral
vessel disease. The term "atherosclerotic disease event" as used
herein is intended to encompass coronary heart disease events,
cerebrovascular events, and intermittent claudication. It is
intended that persons who have previously experienced one or more
non-fatal atherosclerotic disease events are those for whom the
potential for recurrence of such an event exists.
[0064] Accordingly, the instant invention also provides a method
for preventing or reducing the risk of a first or subsequent
occurrence of an atherosclerotic disease event comprising the
administration of a prophylactically effective amount of a
dihydroxy open acid statin to a patient at risk for such an event.
The patient may or may not have atherosclerotic disease at the time
of administration, or may be at risk for developing it.
[0065] The instant invention also provides a method for preventing
and/or treating inflammatory diseases or disorders alone or in
conjunction with the treatment of conditions described above,
comprising the administration of a dihydroxy open-acid statin to a
patient in need of such treatment. This includes, for example, the
treatment of inflammatory conditions susceptible to treatment with
a non-steroidal anti-inflammatory agent, arthritis including
rheumatoid arthritis, and degenerative joint diseases
(osteoarthritis), dementia, Alzheimer's disease, multiple
sclerosis, inflammatory bowel disease, asthma, psoriasis, systemic
lupus erythematosis, vasculitis, gout, adrenoleukodystrophy,
diabetic retinopathy, nephropathy and diabetes mellitus type
II.
[0066] Persons to be treated with the instant therapy include those
at risk of developing atherosclerotic disease and of having an
atherosclerotic disease event. Standard atherosclerotic disease
risk factors are known to the average physician practicing in the
relevant fields of medicine. Such known risk factors include but
are not limited to hypertension, smoking, diabetes, low levels of
high density lipoprotein (HDL) cholesterol, and a family history of
atherosclerotic cardiovascular disease. Published guidelines for
determining those who are at risk of developing atherosclerotic
disease can be found in: National Cholesterol Education Program,
Second report of the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel II), National Institute of Health, National Heart Lung and
Blood Institute, NIH Publication No. 93-3095, September 1993;
abbreviated version: Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults, Summary of the
second report of the national cholesterol education program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel II), JAMA, 1993, 269,
pp. 3015-23. People who are identified as having one or more of the
above-noted risk factors are intended to be included in the group
of people considered at risk for developing atherosclerotic
disease. People identified as having one or more of the above-noted
risk factors, as well as people who already have atherosclerosis,
are intended to be included within the group of people considered
to be at risk for having an atherosclerotic disease event.
[0067] The oral dosage amount of the dihydroxy open acid statin,
particularly a salt of a dihydroxy open acid statin such as
simvastatin, and more particularly the ammonium salt or a
crystalline form of the calcium salt of dihydroxy open acid
simvastatin such as compound I, is from about 1 to 200 mg/day, and
more preferably from about 5 to 160 mg/day. However, dosage amounts
will vary depending on factors as noted above, including the
potency of the particular compound. Although the active drug of the
present invention may be administered in divided doses, for example
from one to four times daily, a single daily dose of the active
drug is preferred. As examples, the daily dosage amount may be
selected from, but not limited to, 5 mg, 10 mg, 15 mg, 20 mg, 25
mg, 40 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg and 160 mg.
[0068] The active drug employed in the instant therapy can be
administered in such oral forms as tablets, capsules, pills,
powders, granules, elixirs, tinctures, suspensions, syrups, and
emulsions. Oral formulations are preferred.
[0069] For the crystalline hydrated forms of the calcium salt of
dihydroxy open acid simvastatin, for example compound I,
administration of the active drug can be via any pharmaceutically
acceptable route and in any pharmaceutically acceptable dosage
form. This includes the use of oral conventional rapid-release,
time controlled-release and delayed-release (such as described
above) pharmaceutical dosage forms. An oral delayed-release dosage
formulation of the instant drug is preferred, and particularly an
enteric overcoat surrounding a rapid-release dosage unit, or the
GEM controlled-release drug delivery device with an enteric
overcoat surrounding the dosage unit, and most particularly an
enteric overcoat surrounding a rapid-release dosage unit.
Additional suitable pharmaceutical compositions for use with the
present invention are known to those of ordinary skill in the
pharmaceutical arts; for example, see Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa.
[0070] In the methods of the present invention, the active drug is
typically administered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein
as "carrier" materials) suitably selected with respect to the
intended form of administration, that is, oral tablets, capsules,
elixirs, syrups and the like, and consistent with conventional
pharmaceutical practices.
[0071] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with a
non-toxic, pharmaceutically acceptable, inert carrier such as
lactose, starch, sucrose, glucose, modified sugars, modified
starches, methyl cellulose and its derivatives, dicalcium
phosphate, calcium sulfate, mannitol, sorbitol and other reducing
and non-reducing sugars, magnesium stearate, steric acid, sodium
stearyl fumarate, glyceryl behenate, calcium stearate and the like.
For oral administration in liquid form, the drug components can be
combined with non-toxic, pharmaceutically acceptable inert carrier
such as ethanol, glycerol, water and the like. Moreover, when
desired or necessary, suitable binders, lubricants, disintegrating
agents and coloring and flavoring agents can also be incorporated
into the mixture. Stabilizing agents such as antioxidants, for
example butylated hydroxyanisole (BHA),
2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, sodium
ascorbate, citric acid, calcium metabisulphite, hydroquinone, and
7-hydroxycoumarin, particularly BHA, propyl gallate and
combinations thereof, can also be added to stabilize the dosage
forms; the use of at least one stabilizing agent is preferred with
the-instant composition. Preferably an antioxidant is employed with
dihydroxy open acid simvastatin or a salt thereof, and particularly
compound I. Other suitable components include gelatin, sweeteners,
natural and synthetic gums such as acacia, tragacanth or alginates,
carboxymethylcellulose, polyethylene glycol, waxes and the
like.
[0072] The active drug can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes
can be formed from a variety of phospholipids, such as cholesterol,
stearylamine or phosphatidylcholines.
[0073] Active drug may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules
are coupled. Active drug may also be coupled with soluble polymers
as targetable drug carriers. Such polymers can include
polyvinyl-pyrrolidone, pyran copolymer,
polyhydroxy-propyl-methacrylamide- -phenol,
polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polyly-
sine substituted with palmitoyl residues. Furthermore, active drug
may be coupled to a class of biodegradable polymers useful in
achieving controlled release of a drug, for example, polylactic
acid, polyglycolic acid, copolymers of polylactic and polyglycolic
acid, polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates
and cross linked or amphipathic block copolymers of hydrogels.
[0074] The instant invention also encompasses a process for
preparing a pharmaceutical composition comprising combining a
dihydroxy open acid statin with a pharmaceutically acceptable
carrier. Also encompassed is the pharmaceutical composition which
is made by combining a dihydroxy open acid statin with a
pharmaceutically acceptable carrier.
[0075] In a broad embodiment, any suitable additional active agent
or agents may be used in combination with the dihydroxy open acid
statin in a single dosage formulation, or may be administered to
the patient in a separate dosage formulation, which allows for
concurrent or sequential administration of the active agents. One
or more additional active agents may be administered with a
dihydroxy open acid statin. The additional active agent or agents
can be lipid lowering compounds or agents having other
pharmaceutical activities, or agents that have both lipid-lowering
effects and other pharmaceutical activities. Examples of additional
active agents which may be employed include but are not limited to
HMG-CoA synthase inhibitors; squalene epoxidase inhibitors;
squalene synthetase inhibitors (also known as squalene synthase
inhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT)
inhibitors, for example the compound known as F-1394 (described in
J. Kusunoki et al., Jpn. J. Pharmacol. 67, 195-203 (1995) and in
U.S. Pat. No. 5,120,738), and including selective inhibitors of
ACAT-1 or ACAT-2 as well as dual inhibitors of ACAT-1 and -2;
microsomal triglyceride transfer protein (MTP) inhibitors;
probucol; niacin; cholesterol absorption inhibitors such as
SCH-58235, which is described in U.S. Pat. Nos. 5,767,115 and
5,846,966; bile acid sequestrants; LDL (low density lipoprotein)
receptor inducers; platelet aggregation inhibitors, for example
glycoprotein IIb/IIIa fibrinogen receptor antagonists and aspirin;
human peroxisome proliferator activated receptor gamma
(PPAR.gamma.) agonists including the compounds commonly referred to
as glitazones for example troglitazone, pioglitazone and
rosiglitazone and, including those compounds included within the
structural class known as thiazolidinediones as well as those
PPAR.gamma. agonists outside the thiazolidinedione structural
class; PPAR.alpha. agonists such as clofibrate, fenofibrate
including micronized fenofibrate, and gemfibrozil; PPAR dual
.alpha./.gamma. agonists; vitamin B.sub.6 (also known as
pyridoxine) and the pharmaceutically acceptable salts thereof such
as the HCl salt; vitamin B.sub.12 (also known as cyanocobalamin);
folic acid or a pharmaceutically acceptable salt or ester thereof
such as the sodium salt and the methylglucamine salt; anti-oxidant
vitamins such as vitamin C and E and beta carotene; beta-blockers;
angiotensin II antagonists such as losartan; angiotensin converting
enzyme inhibitors such as enalapril and captopril; calcium channel
blockers such as nifedipine and diltiazam; endothelian antagonists;
agents that enhance ABC1 gene expression; FXR and LXR ligands
including both inhibitors and agonists; bisphosphonate compounds
such as alendronate sodium; and cyclooxygenase-2 inhibitors such as
rofecoxib and celecoxib. Additionally, the dihydroxy open acid
statins of this invention, for example compound I, may be used in
combination with anti-retroviral therapy in AIDS infected patients
to treat lipid abnormalities associated with such treatment, for
example but not limited to their use in combination with HIV
protease inhibitors such as indinavir, nelfinavir, ritonavir and
saquinavir.
[0076] A therapeutically or prophylactically effective amount, as
appropriate, of a crystalline hydrated form of the calcium salt of
dihydroxy open acid simvastatin, for example compound I, can be
used for the preparation of a medicament useful for inhibiting
HMG-CoA reductase, as well as for treating and/or reducing the risk
for diseases and conditions affected by inhibition of HMG-CoA
reductase, such as treating lipid disorders, preventing or reducing
the risk of developing atherosclerotic disease, halting or slowing
the progression of atherosclerotic disease once it has become
clinically manifest, and preventing or reducing the risk of a first
or subsequent occurrence of an atherosclerotic disease event. For
example, the medicament may be comprised of about 1 mg to 200 mg of
a crystalline hydrated form of the calcium salt of dihydroxy open
acid simvastatin, or more particularly about 5 mg to 160 mg.
[0077] A therapeutically or prophylactically effective amount, as
appropriate, of a dihydroxy open acid statin can be used for the
preparation of an oral medicament adapted for delayed-release,
wherein substantial release of the statin after oral administration
does not occur until after passage of the medicament through the
stomach, or alternately wherein at least 90% of the statin is
delivered in its dihydroxy open acid form to the intestinal mucosa
of a patient after oral administration. Said oral medicaments are
also useful for inhibiting HMG-CoA reductase, as well as for
treating and/or reducing the risk for diseases and conditions
affected by inhibition of HMG-CoA reductase, as described
above.
[0078] The medicament comprised of a dihydroxy open acid statin,
for example compound I, may also be prepared with one or more
additional active agents, such as those described supra.
[0079] Simvastatin is a semi-synthetic product which can be made
from the natural product lovastatin. Processes for preparing
lovastatin and simvastatin are well documented in the published
literature. For example, U.S. Pat. No. 4,231,938, herein
incorporated by reference, describes a fermentation and isolation
process for obtaining lovastatin using the microorganism
Aspergillus terreus. U.S. Pat. Nos. 4,444,784, 4,820,850, 4,916,239
and 4,582,915, herein all incorporated by reference, describe
methods for making dihydroxy open-acid and lactonized forms of
simvastatin.
[0080] Compound I of the instant invention can generally be
prepared as follows. Simvastatin and its dihydroxy open acid
counterpart, including compound I, tend to form oxidative
by-products; therefore, to minimize the formation of such
by-products, it is preferred that the procedures used to make
compound I are performed under an inert atmosphere such as
nitrogen. Although compound I can be obtained without using an
inert atmosphere, the purity of the desired product will not be
optimized.
[0081] Hydrolysis of the lactone ring of simvastatin can be
accomplished by treating simvastatin with at least one equivalent,
and preferably a slight excess of one equivalent, of an aqueous
base. If more than a slight excess of base is used, the excess base
is preferably neutralized before proceeding to the salt formation
step in order to prevent formation of insoluble calcium hydroxide
or calcium carbonate by-product. The base employed for the
hydrolysis can be an aqueous solution of a metal hydroxide or metal
carbonate, for example but not limited to sodium hydroxide,
potassium hydroxide, lithium hydroxide, sodium carbonate and
potassium carbonate. Sodium hydroxide is preferred. The hydrolysis
can be performed in water, an aqueous-protic organic solvent
mixture, or an aqueous-aprotic organic solvent mixture. Suitable
protic organic solvents include but are not limited to methanol
(MeOH), ethanol (EtOH), isopropyl alcohol, n-propyl alcohol
(propanol). Examples of suitable aprotic organic solvents include
but are not limited to acetonitrile, dimethyl sulfoxide (DMF),
N,N-dimethylformamide (DMSO), tetrahydrofuran (THF), tert-butyl
methyl ether (MTBE) and toluene. Particularly, an aqueous ethanol
or n-propyl alcohol solvent mixture may be used, and more
particularly an aqueous n-propyl alcohol solvent mixture.
[0082] After the hydrolysis reaction is complete, the pH of the
reaction mixture is adjusted to about 6 to 11, particularly 6 to 9,
and more particularly 7 to 8.5, by addition of an acid. In this pH
range, the dihydroxy open acid simvastatin will exist as a metal
salt, for example as the sodium salt if the base used in the
hydrolysis step is sodium hydroxide or sodium carbonate. Any acid
that is capable of forming a soluble calcium salt such as calcium
chloride or calcium citrate, is suitable. A soluble calcium salt is
intended to be a salt that is soluble in the solvent sytem employed
in the instant process. Preferably an acid such as acetic acid
(HOAc) or a mineral acid is employed, particularly HCl.
[0083] The resulting pH-adjusted reaction mixture containing the
metal salt of dihydroxy open acid simvastatin is next combined with
a solution of about 0.50 to 0.55 equivalents of calcium acetate
hydrate [Ca(OAc).sub.2.xH.sub.2O] in water or an aqueous-organic
solvent mixture, such as aqueous EtOH, MeOH, i-PrOH, n-PrOH,
acetonitrile, DMF, DMSO, THF, and particularly aqueous EtOH or
aqueous n-propyl alcohol. The pH-adjusted reaction mixture can be
added to the calcium acetate hydrate solution, or the calcium
acetate hydrate solution can be added to the pH-adjusted reaction
mixture. The addition can occur all at once, or optionally it can
be performed in portions over time with periods of aging. For
example, a small portion, e.g., about one-quarter, of the calcium
acetate hydrate solution can be added to the pH-adjusted reaction
mixture over a short period of time, for example over about 30
minutes, and then the resulting mixture can be allowed to age for
an additional short period of time at room temperature, optionally
followed by a further period of aging at a temperature up to about
50.degree. C., for example from about 10.degree. C. up to about
50.degree. C., particularly from room temperature up to about
50.degree. C., more particularly from about 30 to 40.degree. C.,
and most particularly from about 30 to 35.degree. C., after which
the remaining calcium acetate hydrate solution can be added in
portions over several hours at a temperature up to about 50.degree.
C., for example from about 10.degree. C. up to about 50.degree. C.,
particularly from room temperature up to about 50.degree. C., and
more particularly from about 30 to 40.degree. C., and most
particularly from about 30 to 35.degree. C. Optionally, the
reaction mixture can be seeded with crystalline Compound I.
[0084] Whether the pH-adjusted reaction mixture and the calcium
acetate hydrate solution are combined at once or in portions, the
resulting slurry must be aged until turnover of the resulting
amorphous calcium salt of dihydroxy open acid simvastatin to the
crystalline product is complete, usually for at least several
hours. Complete turnover to the crystalline product can be assessed
by standard techniques in the art, for example, by examining a
sample of the product under a microscope. This aging step can be
performed at a temperature up to about 50.degree. C., for example
from about 10.degree. C. up to about 50.degree. C., particularly
from room temperature up to about 50.degree. C., and more
particularly from about 30 to 40.degree. C., and most particularly
from about 30 to 35.degree. C. During the aging period or periods,
the use of lower temperatures will lead to crystallized product;
however, it has been found that as the temperature drops, the rate
of crystal turnover becomes slower, making the procedure less
time-efficient.
[0085] If necessary, the slurry is then allowed to cool to room
temperature and is collected by suction filtration. The recovered
solid is suction dried under a moist atmosphere (about 30 to 70%
relative humidity, particularly 40 to 70%), preferably a moist
inert atmosphere such as nitrogen, and particularly at a
temperature from about 10 to 40.degree. C., and more particularly
25 to 35.degree. C. The final step of suction filtration in the
recovery of compound I should be done under a moist atmosphere, and
preferably a moist inert atmosphere in order to minimize oxidative
by-products. If an additional step of adding an antioxidant to
compound I is performed, as described below, then the final suction
filtration is the one performed after combining the antioxidant
with compound I.
[0086] As noted above, compound I has a tendency to oxidize upon
contact with air, and one way to minimize oxidation is to perform
the reaction sequence under an inert atmosphere. Additionally, one
or more anti-oxidants such as BHA, BHT, propyl gallate, ascorbic
acid, calcium metabisulphite, hydroquinone, nordihydroguaiaracetic
acid (NDGA) or 7-hydroxycoumarin can be combined with compound I.
This is done by agitating a slurry of compound I with one or more
of the antioxidants and recovering the resulting solid by suction
filtration.
[0087] Alternatively, the ammonium salt of dihydroxy open acid
simvastatin can be used as the starting material to be combined
with the calcium acetate hydrate, thus avoiding the hydrolysis and
pH adjustment steps needed when starting with lactonized
simvastatin. The other reaction conditions described above, such as
solvents, temperatures, etc., can otherwise be employed.
[0088] Abbreviations which may appear herein are as follows: MeOH
is methanol; EtOH is ethanol; PrOH is propanol; HOAc is acetic
acid; MeCN is acetonitrile; DMF is dimethyl sulfoxide; DMSO is
N,N-dimethylformamide; Ca(OAc).sub.2 is calcium acetate; HPLC is
high performance liquid chromatography; min. is minutes; h is
hour(s); D.I. is de-ionized; NMR is nuclear magnetic resonance; EI
MS is electron impact mass spectrum; HR-EI MS is high resolution
electron impact mass spectrum; RH is relative humidity. The "seed"
used in the examples is Compound I.
EXAMPLE 1
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I)
[0089] A 22 L four-necked round bottom flask was equipped with a
temperature probe, a N.sub.2 inlet, an addition funnel, and an
overhead stirrer. 8.0 L of 15% EtOH-H.sub.2O was added and the
solution was purged with N.sub.2 for 10 min. Simvastatin (396 g,
0.946 mol) was added, and the slurry was purged with N.sub.2 for 5
min. Then 5N NaOH (198 mL) was added at room temperature. After
about 1 hour, the hydrolysis reaction was complete as analyzed by
HPLC (>99.9% conversion). The pH of the reaction solution was
adjusted to 7 to 8.5 by addition of 1 N HCl (approx. 65 mL). A
solution of Ca(OAc).sub.2.H.sub.2O(116.6 g, 0.662 mol) in 4.0 L of
60% EtOH-H.sub.2O was purged with nitrogen for 5 min. A 1.0 L
portion of this solution was added to solution of the sodium salt
over 30 min. The resulting slurry was aged at room temperature for
30 min, and then at 30 to 35.degree. C. for 1-2 h.
[0090] The rest of Ca(OAc).sub.2 in EtOH-water was added over
approx. 30 min at 30 to 35.degree. C. The slurry was aged at 30 to
35.degree. C. for 5 hours under atmosphere of N.sub.2. The slurry
was cooled to room temperature and was collected by
suction-filtration. The wet cake was washed with 4 L 30%
EtOH-H.sub.2O, 4 L 20% EtOH-H.sub.2O, followed by 6 L.times.3 of
D.I. water. The solid was suction dried under an atmosphere of
moist N.sub.2 (40 to 70% relative humidity) at room temperature for
4 days. Crystalline hydrated calcium salt of dihydroxy open acid
simvastatin was obtained as a white powder.
[0091] The calcium salt was delumped with a single pass through a
cleaned QUADRO.TM. COMIL.RTM. (Model 197S).
[0092] HPLC Conditions
1 Column: YMC Basic 4.6 mm .times. 25 cm Detector: ABS 757 1AU/volt
output Sample solvent: EtOH/CH.sub.3CN/H.sub.2O (1:1:1) Column
temp: 25.degree. C. (Anal. Dept. runs samples at 5.degree. C. to
prevent formation of simvastatin on column). Flow rate: 1.5 mL/min.
Wavelength: 238 and 210 nm Gradient: % H.sub.2O (10 mM
.sub.2HPO.sub.4- Time (min.) % CH.sub.3CN KH.sub.2PO.sub.4, pH =
6.5) 0.00 30 70 20.00 45 55 34.00 70 30 39.00 70 30 39.50 30 70
43.00 30 70 Retention time of simvastatin open acid: 17.07 min.
Retention time of simvastatin: 32.90 min.
[0093] Special Data
[0094] .sup.1H NMR (400 MHz, CD.sub.3OD), .delta.5.97 (d, J=9.6 Hz,
1 H), 5.77 (dd, J=9.6, 5.2 Hz, 1 H), 5.49 (m,1 H), 5.33 (m, 1 H),
4.17 (m, 1 H), 3.70 (m, 1 H), 2.44-2.35 (m, 2 H), 2.42 (dd, J=15.7,
3.6 Hz, 1 H), 2.31 -2.27 (m, 1 H), 2.29 (dd, J=15.7, 8.4 Hz, 1 H),
2.00 (ddd, J=15.7, 7.6, 2.4 Hz, 1 H), 1.93 (m, 1 H), 1.68 (m, 1 H),
1.61 -1.55 (m, 2 H), 1.55 (m, 2 H), 1.42 (m, 1 H), 1.32 (m, 1 H),
1.19(m, 1 H), 1.12 (s, 6 H), 1.08 (d, J=7.2 Hz, 3 H), 0.89 (d,
J=7.2 Hz, 3 H), 0.84 (t, J=7.6 hz, 3 H) ppm.
[0095] .sup.13C NMR (100.55 MHz, CD.sub.3OD), .delta.182.3, 179.3,
134.1, 133.2, 130.3, 129.6, 72.5, 69.8, 45.1, 44.4, 44.1, 38.8,
38.3, 36.4, 34.3, 33.9, 32.0, 28.6, 25.9, 25.37, 25.36, 23.7, 14.3,
9.9 ppm
[0096] EI MS: m/e: 437 (M+H), 419(M+H-H.sub.2O), 303.
[0097] HR-EI MS: Calcd. for C.sub.25H.sub.38O.sub.5 418.2719;
Found: 418.2712.
EXAMPLE 2
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) with BHA
[0098] A 22 L three-necked round bottom flask was equipped with a
temperature probe, a N.sub.2 inlet, an additional funnel, and an
overhead stirrer. 8.0 L of 15% EtOH-H.sub.2O was added and purged
with N.sub.2 for 10 min. Simvastatin (396 g, 0.946 mol) was added,
and the slurry purged with N.sub.2 for 5 min. 198 mL of 5N NaOH
(0.993 mol, 1.05 equiv.) was then added at room temperature. The
hydrolysis reaction is usually complete in 1 h. as analyzed by HPLC
(>99.9% conversion). The pH of the reaction solution was
adjusted to 7 to 8.5 by addition of 1 N HCl (about 65 mL).
[0099] A solution of Ca(OAc)2.H.sub.2O(91.7 g, 0.520 mol, 0.55
equiv.) in 4.0 L of 60% EtOH-H.sub.2O was purged with nitrogen for
5 min. 1.0 L of this solution was added to reaction solution over
30 min. The slurry was aged at room temperature for 30 min, and
then at 30 to 35.degree. C. for 1-2 h. The rest of the
Ca(OAc).sub.2 in EtOH-water was added in portions over 3 h hours at
30-35.degree. C. The slurry was allowed to age at 30 to 35.degree.
C. for 5 h under an atmosphere of N.sub.2. The slurry was allowed
to cool to room temperature and was collected by
suction-filtration. The wet cake was washed with 4 L 30%
EtOH-H.sub.2O, 4 L 20% EtOH-H.sub.2O, followed by 6 L.times.3 of
D.I. water. The solid was suction dried under atmosphere of moist
N.sub.2 (40 to 70% RH) at room temperature to give 1.7 Kg of wet
cake.
[0100] The above wet cake was placed in a clean 20 L three necked
flask under atmosphere of nitrogen. A solution of BHA (2.603 g, 0.2
wt % equiv) in degassed 15% EtOH H.sub.2O (8.5 L) was added,
followed by addition of degassed water (2.55 L), and the slurry was
agitated at room temperature for 1 to 2 h. The solid was collected
by suction filtration under atmosphere of moist N.sub.2 with no
washing to give 1.49 Kg wet cake. The solid was suction dried under
atmosphere of moist N.sub.2 (40 to 70% RH) at room temperature for
4 days. The calcium salt title product was obtained as a white
powder (94% yield. 99.4% A at 238 nm, 0.2 wt % BHA, KF=7.3%
wt).
EXAMPLE 3
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous nPrOH: Conventional
Addition Mode
[0101] Step 1: Hydrolysis
[0102] A 72 L three-necked round bottom flask was equipped with a
temperature probe, a N.sub.2 inlet, an additional funnel, and an
overhead stirrer. 28.5 L of D.I. H.sub.2O was added and purged with
N.sub.2 for 10 min. 1.5 Kg simvastatin was added, followed by 788
mL of 5N NaOH in one portion at room temperature. The hydrolysis
reaction is usually complete in 2 h. as analyzed by HPLC (>99.9%
conversion). 1.5 L of nPrOH was added and the pH of the reaction
solution was adjusted to 9.5 to 11.0 by adding 2 N HOAc (about 170
mL).
[0103] Step 2: Salt Formation
[0104] 150 g of seed (Compound I) was added to the above solution
and the resulting slurry was allowed to warm up to 35 to 40.degree.
C. A solution of Ca(OAc).sub.2.H.sub.2O (347 g) in 15 L of 20%
nPrOH was purged with nitrogen for 5 min. and added to slurry over
3 h. The resulting slurry was aged at 35 to 40.degree. C. for 5 h.
under an atmosphere of N.sub.2 and then cooled to room temperature.
The solid was collected by filtration and was washed with 10%
nPrOH-H.sub.2O (15 L.times.3).
[0105] Step 3: BHA Loading
[0106] The above wet cake (9.1 kg) was transferred into a clean 72
L three necked flask under an atmosphere of nitrogen. A solution of
BHA (7.6 g) in degassed 10% nPrOH (45 L) was added and the slurry
was agitated at room temperature for 1 h. and filtered under
atmosphere of N.sub.2, and then suction dried under atmosphere of
moist N.sub.2 (30 to 70% RH) at room temperature for 7 days. 1.78
Kg of Ca salt title product was obtained as a white powder (94%
yield. 99.4% A at 238 nm, 0.2 wt % BHA, KF=6.6% wt).
EXAMPLE 4
Preparation of Hydrated Crystalline Calcium Salt of Dihydroxy Open
Acid Simvastatin in Aqueous PrOH: Simultaneous Addition Mode
[0107] The process described in this example allows for keeping
half of the batch in the vessel at all times as seed in a
semi-continuous process.
[0108] 100 g of simvastatin was hydrolyzed in 1.9 L water as
described in Example 3. Then, 100 ml nPrOH was added and the
solution pH was adjusted to 9 to 11 with 1 N HOAc. The resulting
solution and a solution of Ca(OAc).sub.2.H.sub.2O (23.2 g) in 1.0 L
of 20% nPrOH were added separately but simultaneously to a
suspension of 10-50 wt % Ca salt in 10% nPrOH (30 volume 10% PrOH
relative to the amount of the seed) at 30 to 40.degree. C. over 3
h. After 5 h age at 30 to 40.degree. C., the slurry was cooled to
room temperature, filtered, and loaded with anti-oxidant and dried
as described in conventional addition mode process. 95% yield.
EXAMPLE 5
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous PrOH: Loading BHA Through
Co-Crystallization
[0109] Method A: 100 g of simvastatin was hydrolyzed in 1.9 L water
as described in Example 3. Then, 100 ml nPrOH was added and the
solution pH was adjusted to 9 to 11 with 1 N HOAc. 10 wt % seed was
added and the slurry was allowed to warm up to 35 to 40.degree. C.
A solution of Ca(OAc).sub.2.H.sub.2O (23.2 g) and BHA (540 mg) in
1.0 L of 20% nPrOH were added to the slurry at 35 to 40.degree. C.
over 3 h. After 5 h age at 30 to 40.degree. C., the slurry was
cooled to room temperature, filtered and washed with a solution of
BHA (0.1 g/L) in 10% nPrOH (1L.times.3). The wet cake was dried
under moist N.sub.2 as described in conventional addition mode
process. The final dried Ca salt title product contained 0.2 wt %
BHA. 95% yield.
[0110] Method B: The procedure of Method A was employed with the
following change. Instead of adding BHA to a Ca(OAc).sub.2
solution, the same amount of BHA was added into the pH adjusted
solution of hydrolyzed simvastatin at room temperature. The
solution was warmed to 35 to 40.degree. C. to dissolve BHA. Then,
10 wt % seed was introduced. The rest of the steps were as
described in Method A. The final dried Ca salt title product
contained 0.2 wt % BHA. 95% yield.
EXAMPLE 6
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous PrOH: Loading BHA/Propyl
Gallate
[0111] Starting with 2.0 Kg of simvastatin, the calcium salt of
dihydroxy open acid simvastatin was crystallized, isolated, and
washed as described in Example 3. The first wet cake was
transferred to a clean 100 L vessel under atmosphere of N.sub.2. A
solution of BHA (9.2 g) and propyl gallate (11.2 g) in 50 L 10%
nPrOH was added to above vessel. The slurry was aged at room
temperature for 1 h. The slurry was filtered with no wash. The wet
cake was dried under moist N.sub.2. 95% yield. The dried salt was
loaded with 0.07 wt % propyl gallate and 0.2 wt % BHA.
EXAMPLE 7
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous PrOH: Loading Propyl
Gallate
[0112] Starting with 2.0 Kg of simvastatin, the calcium salt of
dihydroxy open acid simvastatin was crystallized, isolated, and
washed as described in Example 3. Then, the wet cake was washed
with 10 L of a solution of propyl gallate in 10% nPrOH (propyl
gallate concentration=0.224 g/L). Then, 20 L of propyl gallate
solution in 10% nPrOH (propyl gallate concentration=0.224 g/L) was
added and the wet cake was mixed in the filtration pot before
filtration. The wet cake was dried under moist N.sub.2. 95% yield.
The dried salt was loaded with 0.07 wt % propyl gallate.
EXAMPLE 8
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) Loading BHA, BHA/Vitamin E, and
Vitamin E in Heptane
[0113] 100 g of simvastatin was hydrolyzed in 1.9 L water as
described in Example 3. Then, 100 ml nPrOH was added and the
solution pH was adjusted to 9 to 11 with 1 N HOAc. 10 wt % seed was
added and the slurry was allowed to warm up to 35 to 40.degree. C.
A solution of Ca(OAc).sub.2.H.sub.2O (23.2 g) in 1.0 L of 20% nPrOH
was added to a slurry at 35 to 40.degree. C. over 3 h. After 5 h
age at 30 to 40.degree. C., the slurry was cooled to room
temperature. The calcium salt slurry was filtered and washed with
10% nPrOH (500 mL.times.1), followed by water (1 L.times.3). The
wet cake (KF=75 to 80 wt % water) was then washed with 1 L of
heptane, to displace most of the water. This wet cake was washed
with a solution of BHA or Vitamin E or BHA/Vitamin E (conc.=1.38
g/L, 800 mL) and dried under moist N.sub.2.
EXAMPLE 9
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous MeCN
[0114] A 7.2 L three-necked round bottom flask was equipped with a
temperature probe, a N.sub.2 inlet, an additional funnel, and an
overhead stirrer. 2.1 L of D.I. H.sub.2O was added and purged with
N.sub.2 for 10 min. 150 g simvastatin was added, followed by 78.8
mL of 5N NaOH in one portion at room temperature. The hydrolysis
reaction is usually complete in 2 h. as analyzed by HPLC (>99.9%
conversion). 900 mL of MeCN was added and the pH of the reaction
solution was adjusted to 9.5 to 11.0 by adding 2 N HOAc (about 17
mL).
[0115] 30.0 g crystalline seed was added to above solution and the
resulting slurry was allowed to warm up to 30 to 35.degree. C. A
solution of Ca(OAc).sub.2.H.sub.2O (34.7 g) in 1.5 L of 30% MeCN
was purged with nitrogen for 5 min. and added to reaction slurry
over 3 h. The slurry was at 35 to 40.degree. C. for 5 h. under
atmosphere of N.sub.2. The slurry was allowed to cool to room
temperature and the solid was collected by filtration. The wet cake
was washed with 30% MeCN (1.5 L) and 10% MeCN (1.0 L), and
rinsed/washed with a solution of BHA (0.9 g/L) in degassed 10% MeCN
(1.0 L.times.2). The solid was suction dried under atmosphere of
moist N.sub.2 (30 to 70% RH) at room temperature for 5 days. 1.67
Kg of the title compound was obtained as a white powder (88% yield.
99.4% A at 238 nm, 0.2 wt % BHA, KF=6.6% wt).
EXAMPLE 10
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous MeOH
[0116] 50 g simvastatin was hydrolyzed in 850 mL water as described
in Example 3. Then, 150 ml MeOH was added and the solution pH was
adjusted to 7 to 11 with 1N HOAc. 10 wt % seed was added and the
slurry was allowed to warm up to 30-35.degree. C. A solution of
Ca(OAc).sub.2.H.sub.2O (11.6 g) in 500 mL of 30% MeOH was added to
the slurry at 30-35.degree. C. over 3 h. After 5 h age at
30-35.degree. C., the slurry was cooled to room temperature. The
dihydroxy open acid simvastatin calcium salt slurry was filtered
and washed with 20% MeOH (200 ml) and water (500 ml.times.3). The
wet cake was dried under moist N.sub.2. The final dried Ca salt
title product was isolated in 96% yield.
EXAMPLE 11
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Aqueous i-PrOH, DMF, DMSO
[0117] 50 g simvastatin was hydrolyzed in 850 mL water as described
in Example 3. Then, 150 ml i-PrOH was added and the solution pH was
adjusted to 7 to 11 with 1 N HOAc. 10 wt % seed was added and the
slurry was allowed to warm up to 30-35.degree. C. A solution of
Ca(OAc).sub.2.H.sub.2O (11.6 g) in 500 mL of 30% i-PrOH was added
to the slurry at 30-35.degree. C. over 3 h. After 5 h age at
30-35.degree. C., the slurry was cooled to room temperature. Ca
salt slurry was filtered and washed with 20% ml i-PrOH (200 ml) and
with water (500 ml.times.3). The wet cake was dried under moist
N.sub.2. The final dried Ca salt title product was isolated in 96%
yield.
[0118] The same procedure could be applied to prepare Compound I in
DMF, DMSO, and similar solvents.
EXAMPLE 12
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) in Water
[0119] 50 g of simvastatin was hydrolyzed in 1.0 L water as
described in Example 3. Then, the solution pH was adjusted to 11
with 1 N HOAc. 10 wt % seed was added and the slurry was allowed to
warm up to 35-40.degree. C. A solution of Ca(OAc).sub.2.H.sub.2O
(11.6 g) in 500 mL of water was added to the slurry at
35-40.degree. C. over 5 h. After 10 h age at 35-40.degree. C., the
slurry was cooled to room temperature. Ca salt slurry was filtered
and washed with water (500 ml.times.3). The wet cake was dried
under moist N.sub.2. The final dried Ca salt title product was
isolated in 96% yield.
EXAMPLE 13
Preparation of Crystalline Hydrated Calcium Salt of Dihydroxy Open
Acid Simvastatin (Compound I) from Dihydroxy Open Acid Simvastatin
Ammonium Salt
[0120] Method A: 50 g of dihydroxy open acid simvastatin ammonium
salt was dissolved into 800 ml of 25% nPrOH which was then added
dropwise to a solution of Ca(OAc).sub.2.H.sub.2O (10.7 g) in 75 ml
of water at room temperature over 2 h. The resulting slurry was
aged at 30 to 35.degree. C. 5 h. After cooling to room temperature,
the slurry was isolated by filtration. The wet cake was washed with
10% nPrOH (500 ml.times.3). The wet cake was loaded with
antioxidants and dried under moist N.sub.2 as described above to
give the title product.
[0121] Method B: 50 g of dihydroxy open acid simvastatin ammonium
salt was added into a solution of Ca(OAc).sub.2.H.sub.2O (10.7 g)
in 1.5 L of 10% nPrOH in one portion at room temperature. The
resulting slurry was aged at 30 to 35.degree. C. 5 h. After cooling
to room temperature, the slurry was isolated by filtration. The wet
cake was washed with 10% nPrOH (500 ml.times.3). The wet cake was
loaded with antioxidants and dried under moist N.sub.2 as described
above to give the title product.
[0122] By using both Methods A and B described as above, the title
product could also prepared from ammonium salt in the following
aqueous solvents: acetone, MeOH, EtOH, iPrOH,, MeCN, neat water,
DMF, DMSO, and similar solvents.
EXAMPLE 14
Recrystallization Procedure Using nPrOH-H.sub.2O
[0123] Dried Compound I (21 g) was dissolved in 150 ml of 40% nPrOH
at 35.degree. C. and line filtered. This solution was added
dropwise to a slurry of 10 wt % seed in 480 ml of 4% PrOH at 35 to
40.degree. C. over 3 to 5 h. After aging overnight at 35 to
40.degree. C., the slurry was allowed to cool to room temperature.
The solid was filtered and washed with 10% nPrOH (200 ml.times.2).
The wet cake was dried under moist N.sub.2. 95% yield.
EXAMPLE 15
Recrystallization Process Using EtOH-H.sub.2O
[0124] Method A: 25 g of Compound I was dissolved into 425 ml of
95% EtOH at 40.degree. C. and line filtered. The filtered solution
was added dropwise to 825 ml of water in the presence of 10% wt
seed at 30 to 35.degree. C. over 3 to 5 h. The slurry was aged
overnight and cooled to 0 to 5.degree. C. before filtration. The
wet cake was washed with 250 ml of 30% EtOH and dried under moist
N.sub.2 at room temperature. 92% yield.
[0125] Method B: 25 g of Compound I was dissolved into 625 ml of
95% EtOH at 30 to 40.degree. C. and line filtered. 525 ml of water
was added at 30 to 40.degree. C. After adding 10 wt % seed, 825 ml
of water was added dropwise at 30 to 40.degree. C. over 3 h. The
slurry was aged overnight and cooled to 0 to 5.degree. C. before
filtration. The wet cake was washed with 250 ml of 30% EtOH and
dried under moist N.sub.2 at room temperature. 92% yield.
EXAMPLE 16
An Open, Randomized, Four-Period, Crossover Study to Compare the
Effect of Itraconazole on the Single-Dose Pharmacokinetics of
Intraduodenally Administered Dihydroxy Open Acid Simvastatin Versus
Orally Administered Simvastatin in Healthy Male Subjects
[0126] Objectives: (1) To determine the effect of itraconazole, a
potent CYP3A inhibitor, on the plasma AUC of active and of total
HMG-CoA reductase inhibitory activity following a single
intraduodenal dose of a solution containing 5 mg dihydroxy open
acid simvastatin; (2) to determine and compare the dose-adjusted
plasma AUC of active HMG-CoA reductase inhibitory activity
following a single intraduodenal dose of a solution containing 5 mg
dihydroxy open acid simvastatin versus a single oral administration
of simvastatin 20-mg film coated tablet (FCT); (3) to determine the
effect of itraconazole on the plasma AUC's of dihydroxy open acid
simvastatin and of simvastatin lactone concentration following a
single intraduodenal dose of a solution containing 5 mg dihydroxy
open acid simvastatin.
[0127] Study Design: This study was designed in an open,
four-period crossover randomized fashion. Twelve healthy male
subjects received four treatments (A, B, C and D). In Treatment A,
subjects received itraconazole 200 mg (2.times.100-mg capsule) for
4 days followed by a single dose of 5-mg dihydroxy open acid
simvastatin solution administered intraduodenally on day 4, 1 hour
after the fourth daily dose of itraconazole. In Treatment B,
subjects were given a single dose of 5-mg dihydroxy open acid
simvastatin solution administered intraduodenally on day 1.
Intraduodenal administration was accomplished via a nasoduodenal
tube placed under fluoroscopic guidance by an experienced
gastroenterologist just prior to dosing and removed following the
1-hr postdose measurements. Treatments C and D were similar to
those of Treatments A and B, except that orally dosed simvastatin
20-mg conventional film coated tablet was used. The wash out
between treatment periods was at least 7-days following a treatment
containing itraconazole or at least 3 days following a treatment
without itraconazole. Plasma samples were collected at appropriate
time intervals for up to 24 hours following simvastatin or
dihydroxy open acid simvastatin administration, for analysis of
total and active HMG-CoA reductase inhibitory activities as well as
for simvastatin and dihydroxy open acid simvastatin
concentrations.
[0128] Analytical Methodology: Plasma concentrations of simvastatin
and dihydroxy open acid simvastatin acid were determined
simultaneously by an improved liquid chromatography/tandem mass
spectrometry (LC/MS/MS) method using lovastatin and dihydroxy open
acid lovastatin acid as internal standards. An enzymatic assay
method was used to determine plasma concentrations of active and
total (active plus potentially active) HMG-CoA reductase inhibitory
activity.
[0129] Pharmacokinetics: The area under the plasma
concentration-time profile from time zero to the last sampling time
(AUCO-last) was calculated using linear trapezoidal rule. The
apparent elimination rate constant (k) of simvastatin and dihydroxy
open acid simvastatin was estimated by least-squares regression
analysis of the log-linear portion of the simvastatin and dihydroxy
open acid simvastatin concentration-time data, and the apparent
elimination half-life (t.sub.1/2) was calculated as
t.sub.1/2=0.693/k. All calculations were based on designated
sampling times or actual sampling times when they differed from the
designated times by more than 10 minutes.
[0130] Discussion of Results: This was an open, randomized,
four-period crossover study in twelve healthy male subjects. The
results showed that intraduodenal administration of dihydroxy open
acid simvastatin 5-mg solution yielded higher (.about.4-fold)
dose-adjusted plasma AUC of the active HMG-CoA reductase inhibitory
activity than oral administration of simvastatin 20-mg tablet
(Table 1). Following dihydroxy open acid simvastatin
administration, the unchanged dihydroxy open acid simvastatin was
the major component (.about.60%), while simvastatin was a minor
component (<10%) contributing to plasma HMG-CoA reductase
inhibitory activity. As evident by comparable AUC values for both
the total and active inhibitors (see Table 1) as well as low plasma
levels of simvastatin in plasma (AUC<10% of dihydroxy open acid
simvastatin AUC) (see Table 3), lactonization of either dihydroxy
open acid simvastatin or its active metabolites occurred minimally
following intraduodenal administration of dihydroxy open acid
simvastatin. Pretreatment with itraconazole caused minimal changes
(1.3-1.5-fold) in the systemic exposure as measured by AUC and
C.sub.max of HMG-CoA reductase inhibitory activity (total or
active) following administration of dihydroxy open acid simvastatin
5-mg intraduodenally, as compared to that observed following oral
administration of simvastatin 20-mg tablet (1.3-3.8-fold) (see
Table 2) When measured as the unchanged drug, the effect of
itraconazole observed following dihydroxy open acid simvastatin
administration was also minimal (1.5-fold) and was much less than
the corresponding measure obtained following simvastatin
administration (19-fold) (see Table 3). A moderate effect (3-4-fold
increase) was noted for the AUC and Cmax of simvastatin following
treatment with itraconazole prior to dihydroxy open acid
simvastatin administration (see Table 3). However, apparent t1/2
values for dihydroxy open acid simvastatin or simvastatin were
essentially unchanged by itraconazole(see Table 3). Overall, these
results indicate that the pharmacokinetics of dihydroxy open acid
simvastatin is less prone to alteration by itraconazole, a potent
CYP3A inhibitor, than that of simvastatin in humans. From these
results it appears that dihydroxy open acid simvastatin, although a
substrate for CYP3A, is metabolized with a much lower intrinsic
clearance than that of simvastatin in human liver microsomes.
2TABLE 1 Pharmacokinetic parameters for total and active HMG-CoA
reductase inhibitors following administration of 5 mg dihydroxy
open acid simvastatin (SVA) intraduodenally or 20 mg simvastatin
(SV) tablet orally to 12 healthy male volunteers. Results are means
from 12 subjects. Values in parentheses are SD. Drug Administered 5
mg SVA (ID) 20 mg SV (FCT) N 12 12 AUC Total 56.0 (28.6) 180.7
(57.2) (ng eq. hr/ml) Active 54.1 (28.5) 59.7 (18.1) SV 1.02 (0.5)
16.9 (10.5) SVA 33.9 (16.7) 7.7 (4.9) Cmax Total 6.2 (3.6) 67.1
(27.2) (ng eq./ml) Active 5.7 (3.0) 16.1 (4.4) SV 0.13 (0.05) 6.84
(4.6) SVA 3.78 (1.93) 0.92 (0.58) Tmax (hr) Total 3.3 (2.3) 1.2
(0.5) Active 3.6 (2.5) 1.4 (0.5) SV 4.9 (2.0) 1.1 (0.5) SVA 4.1
(2.1) 3.7 (2.1) t1/2 (hr) SV 6.7 (1.7) 4.2 (1.9) n = 8 SVA 2.3
(0.5) 3.5 (1.0)
EXAMPLE 17
Coating Formulation and Process: SURETERIC WHITE.RTM.
[0131] SURETERIC WHITE.RTM. is a powdered enteric coating
formulation available from Colorcon, a division of Berwind
Pharmaceutical Services, Inc, West Point, Pa. This formulation is
first reconstituted with water, then coated as an aqueous
dispersion. In addition to PVAP, the polymer which imparts the
enteric properties, the formulation contains a number of components
to improve the processability of the material and the performance
of the final coated product. The dispersion is stirred during
preparation and during the coating run, in order to prevent
settling of the formulation components.
[0132] The tablet substrate was coated in a 19-inch coating pan,
with a batch size of approximately 4-8 kg. The coating formulation
was applied via a spray nozzle at a rate of approximately 20-40
g/min, and pressurized air was used to atomize the coating
solution. During the coating operation heated air was introduced
into the coater to maintain the tablet bed temperature at
approximately 35-45 degrees C. Outside this temperature range, the
tablet bed is more likely to agglomerate due to either inadequate
drying (low temperature) or to the tackiness of the enteric
polymer, which increases at elevated temperatures.
[0133] During the coating operation, the weight and/or thickness
gain of the dosage form can be used to monitor the coating
endpoint. A weight gain of approximately 10% (based on the starting
weight of the dosage form) was targeted for this product,
corresponding to an approximate coating thickness of 100
microns.
EXAMPLE 18
Coating Formulation and Process: EUDRAGIT.RTM.
[0134] EUDRAGIT L.RTM. aqueous dispersion with additional water, a
plasticizer, and an antitacking agent are combined to obtain the
final formulation. The formulation is mixed constantly during
preparation and during the coating operation, in order to prevent
sedimentation of the formulation components.
[0135] A batch of approximately 1 kg of tablets was placed into a
12-inch coating pan; and heated air was introduced to the coater to
maintain a temperature of approximately 25-35 degrees C. for the
duration of the coating operation. The coating formulation was
applied via a spray nozzle at a rate of approximately 3-6 g/min,
and pressurized air was used to atomize the coating solution. The
coating temperature and spray rate are controlled in order to
prevent agglomeration of the product due to overwetting or polymer
tackiness.
[0136] During the coating operation, the weight and/or thickness
gain of the dosage form can be used to monitor the coating
endpoint. A weight gain of approximately 4-6 mg enteric polymer per
cm.sup.2 tablet surface area (approximately 40-80 micron coating
thickness, and approximately 6-10% weight gain based on the
starting weight of the dosage form) was targeted as the coating
endpoint. (However, a range of coating levels outside this target
has been shown to provide adequate product performance as
well).
EXAMPLE 19
[0137] Core tablets comprised of compound I with a 50%
hydroxypropyl cellulose/50% hydroxypropyl methyl cellulose with
titanium dioxide sub-coat and SURETERIC WHITE.RTM. enteric coat
("Enteric Coated Tablets"), core tablets comprised of compound I
without sub-coat or enteric coat ("Core Tablets"), and core tablets
comprised of compound I with a sub-coat but no enteric coat
("Sub-Coated Tablets") were tested at the temperature, humidity
levels and time points noted in Table 4 below. The amount of API
(active pharmaceutical ingredient, which is compound I) in the
tablet was measured at the beginning of the study. At the specified
timepoint, the API was remeasured and reported as a percentage of
the value measured at the beginning of the study (% initial). The
amount of deg(s) (degradent(s))was also measured at the end of the
indicated study period and expressed as % label claim based on the
total theoretical drug content (label claim) of the tablet. The
label claim for all tested tablets was 25 mg of compound I per
tablet. RH is relative humidity; AMB is ambient; and "Lactone"
refers to simvastatin.
[0138] In all cases, core tablets and sub-coated tablets did not
exhibit enhanced stability as indicated by a decrease in API
content in the tablets. However, tablets coated with SURETERIC
WHITE.RTM. showed remarkably improved stability at all temperature
and humidity stations. These results are summarized below.
3 TABLE 4 Enteric Coated Tablets Core or Sub-Coated* Tablets Total
Other Total Other Lactone Degs. Lactone Degs. Station API (Deg.)
(>0.1%) API (Deg.) (>0.1%) Timepoint % Initial % label claim
% label claim % Initial % label claim % label claim 40.degree.
C./75% RH 100 0.37 0 87.3* 5.21* 0.73* 4 weeks 40.degree. C./75% RH
100.5 0.47 0 93.7 6.37 0.70 4 weeks 60.degree. C./AMB RH 97.0 0.39
0.10 69.3 0.21 4.6 1 week 60.degree. C./AMB RH 100.6 0.17 0.21 34.8
0.12 7.6 1 week 60.degree. C./AMB RH 99.4 0.31 0 62.8 0.22 4.7 1
week 60.degree. C./AMB RH 98.7 0.24 0.13 72.6 0.20 3.16 1 week
[0139] While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled
in the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the particular dosages as set forth herein above may be
applicable as a consequence of variations in the responsiveness of
the mammal being treated for any of the indications for the active
agents used in the instant invention as indicated above. Likewise,
the specific pharmacological responses observed may vary according
to and depending upon the particular active compound selected or
whether there are present pharmaceutical carriers, as well as the
type of formulation employed, and such expected variations or
differences in the results are contemplated in accordance with the
objects and practices of the present invention. It is intended,
therefore, that the invention be defined by the scope of the claims
which follow and that such claims be interpreted as broadly as is
reasonable.
* * * * *