U.S. patent application number 16/849693 was filed with the patent office on 2020-10-08 for stabilized statin formulations.
This patent application is currently assigned to Cumberland Pharmaceuticals Inc.. The applicant listed for this patent is Cumberland Pharmaceuticals Inc.. Invention is credited to Leo PAVLIV, Andrew Vila.
Application Number | 20200316022 16/849693 |
Document ID | / |
Family ID | 1000004905744 |
Filed Date | 2020-10-08 |
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United States Patent
Application |
20200316022 |
Kind Code |
A1 |
PAVLIV; Leo ; et
al. |
October 8, 2020 |
STABILIZED STATIN FORMULATIONS
Abstract
The present invention is directed to statin formulations having
improved solubility and/or stability and methods for the same.
Inventors: |
PAVLIV; Leo; (Cary, NC)
; Vila; Andrew; (Nashville, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cumberland Pharmaceuticals Inc. |
Nashville |
TN |
US |
|
|
Assignee: |
Cumberland Pharmaceuticals
Inc.
Nashville
TN
|
Family ID: |
1000004905744 |
Appl. No.: |
16/849693 |
Filed: |
June 29, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16231132 |
Dec 21, 2018 |
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16849693 |
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16102381 |
Aug 13, 2018 |
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16231132 |
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15789506 |
Oct 20, 2017 |
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16102381 |
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14538464 |
Nov 11, 2014 |
9820966 |
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15789506 |
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13746999 |
Jan 22, 2013 |
8933115 |
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14538464 |
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12762025 |
Apr 16, 2010 |
8372877 |
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13746999 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/6951 20170801;
A61K 9/19 20130101; A61K 47/40 20130101; A61K 9/0019 20130101; A61K
31/40 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 47/69 20060101 A61K047/69; A61K 9/00 20060101
A61K009/00; A61K 9/19 20060101 A61K009/19; A61K 47/40 20060101
A61K047/40 |
Claims
1-27. (canceled)
28. A stable liquid pharmaceutical formulation comprising sodium
bisulfate, polyvinylpyrrolidone, and an effective amount of
mevastatin complexed with a sufficient amount of
sulfobutyl-ether-.beta.-cyclodextrin in an aqueous solution having
a pH of from about 7 to about 9 to provide a solubilized mevastatin
concentration of at least about 3.32 mg/ml to about 25 mg/ml.
29. The stable liquid pharmaceutical formulation of claim 28,
wherein the sulfobutyl-ether-.beta.-cyclodextrin comprises at least
13.5% of the formulation.
30. The stable liquid pharmaceutical formulation of claim 28,
wherein the solubilized mevastatin concentration is from about 5 to
about 15 mg/ml.
31. The stable liquid pharmaceutical formulation of claim 28,
wherein the solubilized mevastatin concentration is about 10
mg/ml.
32. The stable liquid pharmaceutical formulation of claim 28, which
includes a dose of mevastatin from about 10 mg to about 80 mg.
33. The stable liquid pharmaceutical formulation of claim 28,
wherein the aqueous solution contains a pharmaceutically acceptable
buffer or alkalizing agent selected from the group consisting of
trimethylamine and meglumine L-Arginine.
34. Lyophilized particles consisting essentially of sodium
bisulfate, polyvinylpyrrolidone, and an effective amount of
mevastatin complexed with a sufficient amount of
sulfobutyl-ether-.beta.-cyclodextrin to render the mevastatin
water-soluble when the lyophilized particles are reconstituted in a
pharmaceutically acceptable solution for injection.
35. The lyophilized particles of claim 34, which are reconstituted
to a mevastatin concentration from about 1 mg/ml to about 25
mg/ml.
36. The lyophilized particles of claim 34, which when reconstituted
in solution provide a pH from about 7 to about 9.
37. The lyophilized particles of claim 36, which do not
substantially degrade after storage for 1 month at 40.degree.
C.
38. The lyophilized particles of claim 36, which degrade less than
about 0.1% after storage for 1 month at 40.degree. C.
39. A method of treating a human patient at risk of MI or stroke,
comprising intravenously administering to the human patient the
stable liquid pharmaceutical formulation of claim 1.
40. The method of claim 39, wherein the mevastatin is administered
in an effective amount to lower the human patient's lipid
level.
41. The method of claim 39, further comprising reconstituting the
mevastatin complexed with the sulfobutyl-ether-.beta.-cyclodextrin
from lyophilized particles prior to said administration.
42. The method of claim 39, wherein the solubilized mevastatin
concentration is from about 1 mg/ml to about 25 mg/ml.
43. A method of preparing lyophilized particles according to claim
34 comprising: (a) adding mevastatin to a mixture of the
sulfobutyl-ether-.beta.-cyclodextrin and a suitable solvent; (b)
mixing; (c) adjusting the pH using a pharmaceutically acceptable
buffer to a pH range of between about 7 and about 9. (c)
lyophilizing the mixture to obtain lyophilized particles.
44. The method of claim 43, wherein the lyophilized particles are
reconstituted in an effective amount of a pharmaceutically
acceptable solution for injection into a human patient.
45. The method of claim 43, wherein the
sulfobutyl-ether-.beta.-cyclodextrin comprises at least 13.5% of
the formulation.
46. The method of claim 43, wherein a solubilized mevastatin
concentration of at least about 3.32 mg/ml is obtained.
Description
BACKGROUND OF THE INVENTION
[0001] 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 diet
modification 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--physicians for the first time
were able to obtain comparatively large reductions in plasma
cholesterol with very few adverse effects.
[0002] The HMG CoA reductase inhibitors, commonly known are
statins, are divided into two groups: fermentation-derived and
synthetic. In addition to the natural product lovastatin, there
have been several semi-synthetic and totally synthetic HMG-CoA
reductase inhibitors approved for prescription use, 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 (BAYCOL.RTM.; see U.S. Pat.
No. 5,177,080). Still other HMG-CoA reductase inhibitors are known
to be in development, for example pitavastatin also referred to as
NK-104 (see PCT international publication number WO 97/23200); and
rosuvastatin also known as ZD-4522 (CRESTOR.RTM.; see U.S. Pat. No.
5,260,440, and Drugs of the Future, 1999, 24(5), pp. 511-513). 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 (5 Feb. 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."
[0003] U.S. Patent No. 5,356,896 describes a pharmaceutical dosage
form comprising an HMG-CoA reductase inhibitor compound, e.g.,
fluvastatin sodium, which is stabilized against pH-related
degradation by an alkaline stabilizing medium capable of imparting
a pH of at least 8 to an aqueous solution or dispersion of the
composition. The '896 patent states that the drug substance and the
alkaline medium must be brought into intimate contacting
association, preferably with an aqueous or other solvent-based
preparative process, whereby "the drug substance and alkaline
medium are blended together in the presence of minor amounts of,
e.g., water, to provide particles containing the drug and alkaline
substance in intimate admixture." The resulting particles are dried
and then are blended with filler and remaining excipients, which
were set aside to comprise an "external phase" of said particles,
to result in a composition suitable for encapsulation, tableting or
the like.
[0004] In another embodiment described in the '896 Patent, a
solvent-based process is utilized to assist subsequent drying in a
fluidized bed, whereby the drug substance and alkaline medium are
wet granulated by known techniques, i.e. blended in the moistened
state, together with an amount of the filler material and the
resulting granules, after drying, are combined with any remaining
filler and other set-asides, e.g., binder, lubricant, and can
therefore be tableted, encapsulated, or otherwise shaped into a
dosage form.
[0005] The '896 Patent states that to achieve extended shelf life
of the compositions, it is important "that the particles prepared
by trituration or wet granulation or other aqueous-based process be
substantially completely dried, i.e. to a weight loss on drying
(L.O.D.) of not greater than 3%, and preferably not greater than
2%." The '896 patent also describes conventionally performed drying
by tray drying or in a fluidized bed, preferably the latter with
drying typically performed at about 50.degree C. inlet temperature,
and below 50% RH. The '896 Patent additionally describes an
alternative preparative procedure to the above-described
trituration or wet granulation techniques, wherein the drug
substance and the alkaline stabilizing medium can be
co-lyophilized, i.e. freeze-dried, from aqueous solution as a step
in situ of the drug manufacturing process.
[0006] Most statins are relatively insoluble, and are considered by
those skilled in the art to be unstable in solution, and therefore
this class of drugs is manufactured in solid form. However, there
are those patients who can not ingest, digest, or otherwise take
medications orally and there is a need for the administration of
medications intravenously. There are clinical indications that
statins through anti-inflammatory and possibly other mechanisms can
reduce the incidence of heart attacks, strokes, as well as other
inflammatory mediated conditions.
SUMMARY OF THE INVENTION
[0007] It is an object of the invention to provide a stable product
containing a statin that can be administered intravenously.
[0008] It is further object of the invention to provide a solid
statin formulation which may be reconstituted in an aqueous
solution suitable for injection into mammals.
[0009] It is another object of the invention to provide lyophilized
particles of a statin and a solubilizing or complexing agent.
[0010] It is a further object to provide a method of preparing
lyophilized particles of a statin and a solubilizing or complexing
agent.
[0011] It is a further object to provide a method of treating human
patients with a statin using the formulations and methods described
herein.
[0012] These objects and others are achieved by the present
invention, which is related in part to a water-insoluble statin
complexed with a sufficient amount of a pharmaceutically acceptable
complexing agent in a solution having a pH of from about 7 to about
9 to provide a solubilized statin concentration of at least about
3.32 mg/ml. The invention is further related to a pharmaceutical
formulation comprising an effective amount of the complexed statin
as described above.
[0013] In certain embodiments, the solubilized statin concentration
is from about 1 mg/ml to about 25 mg/ml. In certain preferred
embodiments, the solubilized statin concentration is from about 5
mg/ml to about 15 mg/ml. In certain preferred embodiments, the
solubilized statin concentration is about 10 mg/ml.
[0014] In some embodiments, the statin may be selected from
lovastatin, simvastatin, mevastatin, atorvastatin, cerivastatin and
rivastatin.
[0015] In some embodiments, the complexing agent is a cyclodextrin.
In certain preferred embodiments, the complexing agent is
hydroxy-propyl-.beta.-cyclodextrin.
[0016] In some embodiments, the complexed statin is
lyophilized.
[0017] The invention is also directed in part to solid particles
comprising a water-insoluble statin which may be readily
solubilized in an aqueous solution suitable for injection into
mammals, which are lyophilized particles comprising a
pharmaceutically acceptable statin and a sufficient amount of a
pharmaceutically acceptable complexing agent.
[0018] The invention is further directed in part to lyophilized
particles comprising a water-insoluble statin and an effective
amount of a complexing agent to provide aqueous solubility to said
statin and to provide stability to the formulation when
reconstituted in an aqueous environment.
[0019] In certain embodiments, the lyophilized particles are
prepared by first adding the water-insoluble statin to a complexing
agent, after which the combination is mixed. In some embodiments,
the formulation is then lyophilized to obtain lyophilized
particles.
[0020] In certain preferred embodiments of the invention, the
lyophilized particles comprising the water-insoluble statin and
complexing agent are stable. By "stable", it is meant that
substantially no degradation of the lyophilized particles (the
product) is observed after storage for 1 month at 40.degree. C. In
preferred embodiments, the term "stable" with respect to the
lyophilized particles comprising the water-insoluble statin and
complexing agent means that there is less than about 0.1%
degradation observed) after storage for 1 month at 40.degree.
C.
[0021] In some embodiments of the present invention, the pH is
adjusted to from about 7 to about 9 using a pharmaceutically
acceptable buffer or alkalizing agent, with suitable alkalizing
agents and buffers including but not limited to NaOH, KOH,
triethylamine, meglumine, L-Arginine, sodium phosphate buffer
(either sodium phosphate tribasic, sodium phosphate dibasic, sodium
phosphate monobasic, or o-phosphoric acid), sodium bicarbonate, and
mixtures of any of the foregoing. In an embodiment of the
invention, the lyophilized particles contain one of the following
statins: lovastatin, simvastatin, pravastatin, mevastatin,
fluvastatin, atorvastatin, rosuvastatin, cerivastatin and
rivastatin. The lyophilized particles in certain embodiments may
contain a cyclodextrin as the complexing agent and in certain
preferred embodiments, the cyclodextrin is
hydroxy-propyl-.beta.-cyclodextrin.
[0022] The invention is also directed in part to a method of
preparing lyophilized particles comprising a pharmaceutically
acceptable statin and a pharmaceutically acceptable complexing
agent wherein the statin is added to a mixture of the complexing
agent and a suitable solvent after which the combination is mixed.
In certain embodiments, the pH is then adjusted using a
pharmaceutically acceptable buffer to a pH range of from about 7 to
about 9. The mixture may then be lyophilized to obtain lyophilized
particles. The pharmaceutically acceptable statin is preferably
water-insoluble, and may be selected, e.g., from the group
consisting of lovastatin, simvastatin, mevastatin, atorvastatin,
cerivastatin and rivastatin. In certain embodiments, the complexing
agent is a cyclodextrin.
[0023] Although in certain preferred embodiments the invention
contemplates the use of a statin that is water-insoluble, in
further embodiments of the invention the statin may be water
insoluble or water soluble. Examples of suitable water soluble
statins include, but are not limited to, risuvastatin, fluvastatin
and pravastatin.
[0024] Thus, in certain embodiments, the invention is directed to
stable formulations of a soluble statin and methods for preparing
the same. In such embodiments, the soluble statin(s) is stabilized
via a lyophilization step as described herein.
[0025] The invention is also directed to a method of preparing a
stable pharmaceutical formulation comprising lyophilized particles
of statin, wherein the statin is complexed with an effective amount
of a pharmaceutically acceptable complexing agent in an aqueous
solution and the pH is adjusted to from about 7 to about 9 prior to
lyophilization.
[0026] In certain embodiments, the lyophilized particles are
reconstituted in an effective amount of a pharmaceutically
acceptable solution for injection into a human patient. In certain
further embodiments, the reconstituted lyophilized particles are
injected into a human patient
[0027] The present invention is also directed in part to a method
of treatment comprising (a) preparing lyophilized particles by
adding a statin to a mixture of a complexing agent and a suitable
solvent and lyophilizing the mixture to obtain lyophilized
particles; (b) reconstituting the lyophilized particles in a
pharmaceutically acceptable solution for injection; and (c)
administering a suitable quantity of the solution to provide an
effective amount of statin to a human patient in need of treatment.
In certain embodiments, the statin is administered in an effective
amount to lower the patient's lipid level and/or to produce a
desired (therapeutically effective) anti-inflammatory effect or
other therapeutic effect.
[0028] In some embodiments, after the statin is added to the
mixture of the complexing agent and the solvent, the mixture is
vortexed and sonicated and the pH of the mixture is adjusted to
from about 7 to about 9 using a pharmaceutically acceptable
buffer.
[0029] In certain embodiments, the statin is selected from the
group consisting of lovastatin, simvastatin, pravastatin,
mevastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin
and rivastatin and the complexing agent is a cyclodextrin.
[0030] In certain embodiments of the present invention, the
complexing agent comprises at least about 13.5% of the
formulation.
[0031] It certain embodiments of the present invention, a
solubilized statin concentration of at least about 3.3 mg/ml is
provided.
[0032] As mentioned above, objects of the present invention also
comprise pharmaceutical compositions containing at least a compound
of the present invention of formula (I) together with non toxic
adjuvants and/or carriers usually employed in the pharmaceutical
field.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 is shows a linear regression analysis of the minimum
amount of HP.beta.-CD needed to solubilize AS-Ca.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention is directed in part to pharmaceutical
formulations comprising an effective amount of a pharmaceutically
acceptable statin complexed with a sufficient amount of a
pharmaceutically acceptable complexing agent and method for
preparing the same.
[0035] The present invention is further directed in part to
formulations which include a water-insoluble statin which is
complexed with a sufficient amount of a pharmaceutically acceptable
complexing agent to render the water-insoluble statin soluble in an
aqueous environment, which formulation is also lyophilized in order
to provide a stable formulation of a water-insoluble statin that
can be solubilized in an aqueous environment.
[0036] Suitable water insoluble statins for use in the present
invention include, but are not limited to, lovastatin, simvastatin,
mevastatin, atorvastatin, cerivastatin and rivastatin,
pharmaceutically acceptable salts thereof, and pharmaceutically
acceptable complexes thereof. The term "water-insoluble" as it is
used herein, means the USP definition range of very slightly
soluble to insoluble (solubility not more than (NMT) 1:1000). In
addition, the present invention is intended to cover compositions
comprising other HMG-CoA reductase inhibitor compounds of formula I
herein, including both the erythro racemate and its constituent
isomers (i.e. the 3R,5S and 3S,5R isomers, preferably the 3R,5S
isomer).
##STR00001##
[0037] These compounds are disclosed, e.g., in the following
commonly assigned patents, published patent applications and
publications which are all hereby incorporated herein by reference:
U.S. Pat. No. 4,739,073, and EP-A-114,027 (R=indolyl and
derivatives thereof); EP-A-367,895 (R=pyrimidinyl and derivatives
thereof); U.S. Pat. No. 5,001,255 (R=indenyl and derivatives
thereof); U.S. Pat. No. 4,613,610 (R=pyrazolyl and derivatives
thereof); U.S. Pat. No. 4,851,427 (R=pyrrolyl and derivatives
thereof); U.S. Pat. Nos. 4,755,606 and 4,808,607 (R=imidazolyl and
derivatives thereof); U.S. Pat. No. 4,751,235 (R=indolizinyl and
derivatives thereof); U.S. Pat. No. 4,939,159 (R=azaindolyl and
derivatives thereof); U.S. Pat. No. 4,822,799 (R=pyrazolopyridinyl
and derivatives thereof); U.S. Pat. No. 4,804,679 (R=naphthyl and
derivatives thereof); U.S. Pat. No. 4,876,280 (R=cyclohexyl and
derivatives thereof); U.S. Pat. No. 4,829,081 (R=thienyl and
derivatives thereof); U.S. Pat. No. 4,927,851 (R=furyl and
derivatives thereof); U.S. Pat. No. 4,588,715 (R=phenylsilyl and
derivatives thereof); and F. G. Kathawala, Medicinal Research
Reviews, Vol. 11 (2), p.121-146 (1991), and F. G. Kathawala,
Atherosclerosis Research--Review, June 1992, p. B73-B85.
[0038] Further compounds of formula I are disclosed e.g. in
EP-A-304,063 (R=quinolinyl and derivatives thereof); EP-A-330,057
and U.S. Pat. Nos. 5,026,708 and 4,868,185 (R=pyrimidinyl and
derivatives thereof); EP-A-324,347 (R=pyridazinyl and derivatives
thereof); EP-A-300,278 (R=pyrrolyl or derivatives thereof); and
U.S. Pat. No. 5,013,749 (R=imidazolyl and derivatives thereof),
hereby incorporated by reference.
[0039] "Complexing agents" are small molecular weight molecules
which can form an inclusion complex and after suitable curing time,
can solubilize the drug and may impart additional stability to the
drug. Accordingly, for purposes of the present invention, the term
"complexing agent" is meant to encompass agents that complex and/or
solubilize a water-insoluble statin. In certain embodiments of the
present invention, the pharmaceutically acceptable complexing agent
is a dextrin. Other suitable dextrins include cyclodextrins such as
hydroxy-propyl-.beta.-cyclodextrin and
sulfobutyl-ether-.beta.-cyclodextrin. Additional cyclodextrins
could include alpha-cyclodextrins, beta-cyclodextrins,
gamma-cyclodextrins, beta-cyclodextrin ether comprising one or more
hydroxybutyl sulfonate moieties and cyclodextrins as described in
U.S. Pat. No. 6,610,671 or U.S. Pat. No. 6,566,347 (both of which
are incorporated by reference).
[0040] Additional complexing agents include, but are not limited
to, the group consisting of phenol, phenolic salts, aromatic acids
and esters, carboxylic acids and salts and esters thereof,
inorganic acids and bases and amino acids and esters and salts
thereof: methylparaben, propylparaben, potassium methylparaben,
parabens, ascorbic acid and its derivatives, methyl anthranilate,
salicylic acid, acetosalicyclic acid, tocopherol, organic acids,
carboxylic acids, aromatic acids, aromatic esters, acid salts of
amino acids, benzaldehyde, cnnimaldehyde, imidazole, menthol,
thiophenol, m-aminobenzoic acid, anthranilic acid, picolinic acids
and alkyl esters thereof, toluidides, sodium benzoate, sodium
metabisulphite, malic acid, isoascorbic acid, citric acid, tartaric
acid, sodium sulphite, sodium bisulphate, water- and fat-soluble
derivatives of tocopherol, sulphites, bisulphites and hydrogen
sulphites, propyl/gallate, nordihydroguaiaretic acid, phosphoric
acids, sorbic and benzoic acids, methylparaben, sodium
methylparaben, para-aminobenzoic acid and esters, sorbic and
benzoic acids, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol,
t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone,
butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), pyrocatechol,
pyrogallol, esters, isomeric compounds thereof, pharmaceutically
acceptable salts thereof, and mixtures of any of the foregoing.
[0041] In certain embodiments of the present invention, the
complexing agent comprises at least 13.5% of the formulation.
[0042] In certain embodiments, the statin and complexing agent are
combined by adding the statin to a mixture of the complexing agent
in an aqueous solution. The aqueous solution may be a suitable
pharmaceutically acceptable solvent, such as water for injection or
Na2HPO4 in water for injection. After complexation of the statin,
the pH may be adjusted to a pH of over 6.5. In certain embodiments
the pH is modified to from about 7 to about 9. Suitable agents for
modifying the pH include sodium phosphate buffer (either sodium
phosphate tribasic (Na.sub.3PO.sub.4) or sodium phosphate dibasic
(Na.sub.2HPO.sub.4)), o-phosphoric acid, NaOH and L-Arginine
(L-dArg).
[0043] In certain embodiments of the present invention, the mixture
is mixed by a variety of means including vortexing and sonication.
The mixing may be repeated more than 1 time. It may be desirable to
adjust the volume of solution and/or its pH between each mixing
step.
[0044] In an embodiment of the invention, the mixture of statin and
complexing agent is lyophilized.
[0045] The stability of the formulations of the present invention
is determined by any suitable method known to those of skill in the
art. An example of a suitable method of testing stability is using
high performance liquid chromatography or other common analytical
technology.
[0046] The daily dose of active ingredient can administered as a
single dose. The dosage regimen and administration frequency for
treating the mentioned diseases with the compound of the invention
and/or with the pharmaceutical compositions of the present
invention will be selected in accordance with a variety of factors,
including for example age, body weight, sex and medical condition
of the patient as well as severity of the disease, pharmacological
considerations, half-life of the drug, and eventual concomitant
therapy with other drugs. In some instances, dosage levels below or
above the aforesaid range and/or more frequent may be adequate, and
this logically will be within the judgment of the physician and
will depend on the disease state.
[0047] Where the active ingredient is atorvastatin, the total daily
dose may be in amounts preferably from 10 to 80 mg but may be lower
or higher as required. The preferable starting dose of atorvastatin
is 10 or 20 mg once daily, though if needed large LDL-C reduction
may start at 40 mg once daily. The pediatric starting dose of
atorvastatin is 10 mg once daily with a maximum does of 20 mg once
daily. For HMG CoA reductase inhibitors other than atorvastatin, it
is within the understanding of one of skill in the art to calculate
conversion dosing based on the preferable dosing for atorvastatin.
In addition, conversion tables for such calculation are readily
available for many of the known statins.
[0048] The compounds of the invention may be administered orally,
parenterally, rectally or topically, by inhalation or aerosol, in
formulations eventually containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles as
desired. Topical administration may also involve the use of
transdermal administration such as transdermal patches or
iontophoresis devices. The term "parenteral" as used herein,
includes subcutaneous injections, intravenous, intramuscular,
intrasternal injection or infusion techniques.
[0049] Injectable preparations, for example sterile injectable
aqueous or oleaginous suspensions may be formulated according to
known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents are water, Ringer's solution and isotonic
sodium chloride. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono or diglycerides, in addition fatty acids such as oleic acid
find use in the preparation of injectables.
[0050] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and the like.
[0051] Newer statin nitroderivatives in addition to lowering lipid,
possess enhanced anti-inflammatory, antiplatelet and antithrombotic
effects as compared to native statins. Moreover, they can be
effective also in the other pathologies such as acute coronary
syndromes, stroke, peripheral vascular diseases such as peripheral
ischemia, all disorders associated with endothelial dysfunctions
such as vascular complications in diabetic patients and
atherosclerosis, neurodegenerative diseases such as Alzheimer's
disease (AD) and Parkinson's disease (PD), autoimmune diseases such
as multiple sclerosis.
[0052] In alternative embodiments of the treatment methods
described herein, a pharmaceutical formulation comprising a statin
is administered to a patient via an injection method. In such
embodiments the pharmaceutical formulation of the statin is a
formulation suitable for administration to a patient via the
injection method. Suitable injection methods include, in addition
to intravenous injection, intraarterial infusion, intramuscular
injection, transdermal injection, and subcutaneous injection.
[0053] Suitable carriers for intravenous administration include
physiological saline or phosphate buffered saline (PBS), and
solutions containing solubilizing agents, such as glucose,
polyethylene glycol, and polypropylene glycol and mixtures
thereof.
[0054] The formulation may include an aqueous vehicle. Aqueous
vehicles include, by way of example and without limitation, Sodium
Chloride Injection, Ringers Injection, Isotonic Dextrose Injection,
Sterile Water Injection, Dextrose, and Lactated Ringers Injection.
Nonaqueous parenteral vehicles include, by way of example and
without limitation, fixed oils of vegetable origin, cottonseed oil,
corn oil, sesame oil and peanut oil. Antimicrobial agents in
bacteriostatic or fungistatic concentrations must be added to
parenteral preparations packaged in multiple dose containers which
include phenols or cresols, mercurials, benzyl alcohol,
chlorobutanol, methyl and propyl p hydroxybenzoic acid esters,
thimerosal, benzalkonium chloride and benzethonium chloride.
Isotonic agents include, by way of example and without limitation,
sodium chloride and dextrose. Buffers include phosphate and
citrate. Antioxidants include sodium bisulfate. Local anesthetics
include procaine hydrochloride. Suspending and dispersing agents
include sodium carboxymethylcelluose, hydroxypropyl methylcellulose
and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80
(TWEEN.RTM. 80) A sequestering or chelating agent of metal ions
include EDTA.] Pharmaceutical carriers also include, by way of
example and without limitation, ethyl alcohol, polyethylene glycol
and propylene glycol for water miscible vehicles and sodium
hydroxide, hydrochloric acid, citric acid or lactic acid for pH
adjustment.
[0055] Typically a therapeutically effective dosage is formulated
to contain a concentration of at least about 0.1% w/w up to about
90% w/w or more, such as more than 1% w/w of the statin. In certain
embodiments, the solubilized statin concentration of the
formulation will be at least about 3.3 mg/ml.
[0056] All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification and claims are
to be understood as being modified in all instances by the term
"about." Accordingly, unless indicated to the contrary, the
numerical parameters set forth in the specification and attached
claims are approximations that may vary depending upon the desired
properties sought to be obtained by the present invention. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
parameter should be construed in light of the number of significant
digits and ordinary rounding approaches.
[0057] In certain embodiments, the invention is directed to a
method of reducing the risk of MI, stroke, revascularization
procedures, angina in patients without CHD but with multiple risk
factors, reducing the risk of MI and stroke in patients with type 2
diabetes without CHD, but with multiple risk factors, reducing the
risk of non-fatal MI, fatal and non-fatal stroke, revascularization
procedures, hospitalization for CHF, and angina in patients with
CHD, reducing elevated total-cholesterol, LDL-cholesterol,
apolipoprotein-B, and triglyceride levels in patients with primary
hyperlipidemia (heterozygous familial and nonfamilial and mixed
dyslipidemia), reducing elevated triglyceride levels in patients
with hypertriglyceridemia and primary dysbetalipoproteinemia,
reducing total cholesterol and LDL-cholesterol in patients with
homozygous familial hypercholesterolemia, reducing elevated
total-C, LDL-C, and apo B levels in boys and postmenarchal girls,
10 to 17 years of age, with heterozygous familial
hypercholesterolemia after failing an adequate trial of diet
therapy, mixed dyslipidaemia; and heterozygous familial
hyperlipidemia, homozygous familial hypercholesterolaemia as an
adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or
if such treatments are unavailable.
[0058] Particularly, the non-statin pharmaceutical drugs for use in
the practice of this invention are any of the PPAR receptor
agonists, including those that are selective for one PPAR receptor
sub-type as well as those that are active for two or more receptor
sub-types. More particularly, the non-statin pharmaceutical drugs
are PPAR alpha agonists such as the fibric acid derivatives; PPAR
gamma agonists; and dual PPAR alpha/gamma agonists, i.e., those
having dual activity for both the alpha and the gamma receptor
sub-types.
[0059] When a statin and a non-statin are referred to as
competitively binding to an enzyme or enzyme isoform (i.e.,
isozyme), it means both the statin and the non-statin bind to the
same enzyme or isozyme. An adverse pharmacokinetic drug interaction
is intended to mean an in vivo interaction between a statin and a
co-administered non-statin pharmaceutical drug in a mammal,
particularly a human, which raises the plasma level of active
open-acid statin above the level it would be at if the statin was
administered alone, i.e., absent the co-administered
non-statin.
Detailed Description of the Preferred Embodiments
[0060] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLES 1-3
[0061] Examples 1-3 compare solubilization methods to evaluate the
affect of pH, buffer strength, and different mixing methods. In
Example 1, samples were made in 100 mM sodium phosphate dibasic
(Na.sub.2HPO.sub.4) at pH 5.5, 6.5, 7.5, and 8.5. The samples were
only vortexed. In Example 2, samples were made in 100 mM Na2HPO4 at
pH 5.5, 6.5, 7.5, and 8.5 and then both vortexed and sonicated. In
Example 3, samples were made in either 25 or 50 mM
Na.sub.2HPO.sub.4 at either pH 7.5 or 8.5.
Example 1
[0062] 10 mg of atorvastatin calcium trihydrate ("AS-Ca") was added
to approximately 0.9 mls of a solution containing 0.8 mls of 34.7%
hydroxy-propyl-.beta.-cyclodextrin ("HP.beta.-CD") and 0.1 ml of 1
M Na2HPO4 in ultrapure water and then vortexed at top speed for 5
minutes. The pH of the samples were then adjusted to pH 5.5, 6.5,
7.5, or 8.5 with 0.85% o-phosphoric acid or 0.1 M NaOH. Each sample
was vortexed, and then ultra-pure water was added to q.s. to 1.0
mls, after which the sample was filtered through a 0.45 .mu.m nylon
filter, and analyzed by HPLC (see Table 1).
Example 2
[0063] The formulations of Example 2 were prepared in the same
manner as those of Example 1, except that after vortexing, the
formulations of Example 2 were additionally sonicated. The samples
were analyzed by HPLC (See Table 1).
Example 3
[0064] 10 mg of AS-Ca was added to approximately 0.9 mls of a
solution containing 0.8 mls of 34.7% HP.beta.-CD and either 0.025
or 0.050 ml of 1 M Na.sub.2HPO.sub.4 in ultrapure water and then
vortexed for 5 min. The pH of the samples was adjusted to either
7.5 or 8.5 using 0.1 M NaOH, and then ultrapure water was added
q.s. to 1 mL, after which the samples were vortexed for 5 min,
filtered, and then analyzed by HPLC (See Table 1).
TABLE-US-00001 TABLE 1 Na2HPO4 Solubilized Sample concentration
Mixing Atorvastatin Example pH (mM) Method (mg/ml) 1 5.5 100 Vortex
3.32 6.5 100 Vortex 8.42 7.5 100 Vortex 8.89 8.5 100 Vortex 7.97 2
5.5 100 Sonication 3.27 6.5 100 Sonication 9.21 7.5 100 Sonication
9.06 8.5 100 Sonication 9.26 3 7.5 25 Vortex 8.34 7.5 50 Vortex
8.58 8.5 25 Vortex 9.26 8.5 50 Vortex 9.65
Results: The solubility of AS-Ca was greatly improved by adjusting
the pH to 6.5 and above.
EXAMPLES 4-5
[0065] The solubility of AS-Ca in formulations using different
methods of pH adjustment are compared in Examples 4 and 5 to
evaluate complexation efficiency. In Example 4, the pH was adjusted
to 9 using NaOH and then phosphoric acid was added to reduce the pH
back to pH 7.0-8.5. In Example 5, the pH was adjusted to a pH
between 7.0-8.5 with either 0.85% o-phosphoric acid or 0.1 M
NaOH.
Example 4
[0066] Mixtures of 20 mg/ml of AS-Ca were prepared by adding 20 mg
AS-Ca to approximately 0.8 mL mixture of 27.78% HP.beta.-CD, 50 mM
Na.sub.2HPO.sub.4, and ultrapure water and then phosphoric acid
and/or NaOH were added to q.s. to 1 ml. The mixture of 20 mg/ml
AS-Ca was then vortexed for 5 min and sonicated for 15 minutes.
[0067] The pH of the samples were adjusted to pH 9.0 using 0.1 M
NaOH after which the pH was further adjusted to pH 7.0, 7.5, 8.0,
or 8.5 with 0.85% o-phosphoric acid. Each sample was vortexed, q.s.
to 1.0 mls with ultra-pure water, filtered, and then analyzed by
HPLC.
Example 5
[0068] Mixtures of 20 mg/ml of AS-Ca was prepared by adding 20 mg
AS-Ca to approximately 0.8 ml mixture of 27.78% HP.beta.-CD, 50 mM
Na2HPO4, and ultrapure water and then phosphoric acid and/or NaOH
were added to q.s. to 1 ml. The mixture of 20 mg/ml AS-Ca was then
vortexed for 5 min and sonicated for 15 minutes.
[0069] The pH of the samples were adjusted to pH 7.0, 7.5, 8.0, or
8.5 with either 0.85% o-phosphoric acid or 0.1 M NaOH. Each sample
was vortexed, q.s. to 1.0 mls with ultra-pure water, filtered, and
then analyzed by HPLC.
Results: Results are provided below in Table 2.
TABLE-US-00002 TABLE 2 Atorvastatin Sample Concentration Example pH
mg/ml 4 7.0 18.45 7.5 17.90 8.0 19.62 8.5 18.51 5 7.0 16.93 7.5
17.83 8.0 18.97 8.5 19.44
Example 6
[0070] The relationship between AS-Ca and HP.beta.-CD was examined
by evaluating the complexation efficiency of different
concentrations of HP.beta.-CD. A stock solution of HP.beta.-CD was
first prepared at 34.7% and serially diluted to 0.5375%
HP.beta.-CD.
[0071] Samples were prepared by adding 20 mg of AS-Ca to 0.8 mls of
HP.beta.-CD dilutions (final concentration in 1 ml from 27.78% to
0.5375% HP.beta.-CD) and 0.05 ml of 1 M Na.sub.2HPO.sub.4. Each
sample was adjusted to pH 9.0 with 0.1 M NaOH and then the samples
were vortexed for 5 minutes and then sonicated for 15 minutes. The
pH was then adjusted to either 7.5 or 8.5 with 0.85% o-phosphoric
acid. The samples were vortexed and sonicated again, then filtered
and analyzed by HPLC (see Table 3).
Results: The solubility of AS-Ca increased linearly with
HP.beta.-CD concentration. Linear regression analysis showed that
the minimum amount of HP.beta.-CD needed to solubilize AS-Ca at 10
mg/ml was 14.4% at pH 7.5 and 13.5% at pH 8.5. (See FIG. 1).
TABLE-US-00003 TABLE 3 pH 8.5 pH 7.5 Atorvastatin Atorvastatin
Concentration HP.beta.-CD (%) (mg/ml) HP.beta.-CD (%) (mg/ml) 27.78
19.48 27.78 19.72 13.89 10.01 13.89 12.42 6.94 5.13 6.94 5.54 3.47
1.38 3.47 1.58 1.74 0.43 1.74 0.52 0.87 0.34 0.87 0.215
Example 7
[0072] Forced degradation and preliminary stability studies showed
that AS-Ca solubilized with HP.beta.-CD did not exhibit good
stability. Therefore, lyophilization was evaluated using a manifold
freeze dryer to determine whether stability could be improved by
this method.
[0073] 100 mg of AS-Ca was added to approximately 9 mls of a
solution containing 5.333 ml of 37.5% HP.beta.-CD and 0.5 ml of 1 M
Na.sub.2HPO.sub.4. The sample was vortexed for 5 minutes and then
sonicated for 15 minutes. The pH was then adjusted to 9.0 using
0.1M NaOH, after which the sample was again vortexed and
sonicated.
[0074] Next, the pH of the sample was adjusted to pH 8.5 using
0.85% o-phosphoric acid followed by vortexing and sonication. The
sample was q.s. to 10 mls with NaOH and 1% phosphoric acid to a pH
of 8.47, filtered and then analyzed by HPLC. The final formulation
contained 10 mg/ml AS-Ca2+, 20% HP.beta.-CD, 50 mM
Na.sub.2HPO.sub.4, q.s. with 0.1 M NaOH and 1% phosphoric acid at a
pH of 8.47.
Results: AS-Ca solubilized with HP.beta.-CD was lyophilized and
then placed on stability at 40.degree. C. for 1 month alongside a
control solution of the same mixture. Lyophilized AS-Ca degraded
.about.3.5% and AS-Ca in solution degraded .about.15.5%. Therefore,
the sample was not stable in solution or when lyophilized using a
manifold freeze-dryer.
Example 8
[0075] Atorvastatin was prepared as described in example 6, except
it was prepared at 20 mg/mL in 30% HP.beta.-CD in 100 mM sodium
phosphate adjusted to a final pH of 8.5. The sample was then
diluted 1:1 into an 8% sucrose solution and transferred to 5 mL
vials. The vials were capped with lyophilization stoppers.
[0076] The samples were frozen at -40.degree. C. on a shelf freezer
followed by a 60 min hold. After the freezing step, the condenser
was adjusted to -85.degree. C. and held at that temperature
throughout the run. The pressure was approximately 20 mtorr. The
shelf temperature was then adjusted to -20.degree. C., -10.degree.
C., and 0.degree. C. and held for 180 min at each temperature while
maintaining vacuum. Next the temperature was ramped to 10.degree.
C. and then to 20.degree. C. (240 minutes for each step). The
temperature was then adjusted to 40.degree. C. and held until the
vacuum was released and vials removed and visually inspected.
Results: When AS-Ca was solubilized with HP.beta.-CD and then
lyophilized using a shelf freeze dryer, no degradation (less than
0.1%) was observed after storage for 1 month at 40.degree. C.
Although not wishing to be bound by this theory, the enhanced
stability is likely due to rapid removal of water and low residual
moisture levels obtained by conditions of the lyophilization
cycle.
EXAMPLES 9 AND 10
[0077] In Examples 9 and 10, Sulfobutyl-ether-.beta.-cyclodextrin
("SBE-.beta.-CD") was evaluated as a possible alternative to
HP.beta.-CD by means of AS-Ca complexation with SBE-.beta.-CD. The
effect of sodium phosphate salt versus ultrapure water on the
solubilization of AS-Ca with SBE-.beta.-CD at different pH was also
evaluated.
Example 9
[0078] In Example 9, AS-Ca complexation with SBE-.beta.-CD was in
sodium phosphate buffers with different pH values. 20 mg/ml of
AS-Ca was added into 27.78% SBE-.beta.-CD in 50-100 mM of either
NaH.sub.2PO.sub.4 (pH 2.13 samples) or Na.sub.2HPO.sub.4 (pH 7.07,
8.75, and 11.75 samples). Each sample was then vortexed and
sonicated, after which the pH was adjusted to 2.13 and 7.07 using
0.85% 0-phosphoric acid or 8.75 and 11.50 with 0.1 M NaOH. The
samples were then vortexed, sonicated, q.s. to 1.0 ml with
ultrapure water, and then filtered and analyzed by HPLC (see Table
4 below).
Results: The solubility of AS-Ca was roughly 10-fold lower when
complexed with SBE-.beta.-CD than when complexed with
HP.beta.-CD.
TABLE-US-00004 TABLE 4 Sample Atorvastatin pH (mg/ml) 2.13 0.228
7.07 1.993 8.75 1.267 11.75 1.927
Example 10
[0079] In Example 10, the AS-Ca complexation with SBE-.beta.-CD was
in ultrapure water to investigate the impact of phosphate buffer
salt on the ability of SBE-.beta.-CD to complex AS-Ca. Based on the
solubility findings of Example 8, the formulation was tried at
neutral and basic pH.
[0080] Neutral pH: 20 mg/ml AS-Ca was added to 27.78% SBE-.beta.-CD
in ultrapure water. The sample was vortexed and sonicated, after
which the pH determined to be 7.09. The sample was then q.s. to 1.0
ml with ultrapure water, filtered, and analyzed by HPLC. (See Table
5)
[0081] Basic pH: 20 mg/ml AS-Ca was added to 27.78% SBE-.beta.-CD
in approximately 0.8 mL ultrapure water. The sample was processed
as described above, except the pH was adjusted to 11.0 using 0.1 M
NaOH and q.s. to 1.0 mL.
Results: Phosphate buffer does not appear to have a significant
effect on the solubility of atorvastatin combined with
SBE-.beta.-CD.
TABLE-US-00005 TABLE 5 Sample Atorvastatin pH (mg/ml) 7.09 1.392
11.0 1.927
Example 11
[0082] Additional AS-Ca formulations were prepared using other
cyclodextrins, including .gamma.-cyclodextrin and
hydroxyl-propyl-.gamma.-cyclodextrin. The solubility was found to
be less than that achieved with SBE-.beta.-CD or HP.beta.-CD.
Example 12
[0083] In Example 12, the AS-Ca was solubilized with a co-solvent
to evaluate co-solvent/aqueous solubility as a function of pH. The
pH dependence on propylene glycol and ethanol co-solvent
formulations was, in particular, examined.
[0084] 10 mg of AS-Ca was added to approximately 0.9 mls of
solution containing 4.0 mls of propylene glycol and 1.0 ml of
ethanol in ultrapure water. The sample was vortexed and sonicated
as described above, then adjusted to pH 9.0 with 0.1 M NaOH. The
samples were vortexed and sonicated again and then the pH was
adjusted to pH 7.0, 7.5, 8.0, or 8.5 with 0.85% o-phosphoric acid
or left at pH 9.0. The samples were vortexed, sonicated, the sample
was q.s. to 1.0 ml with ultrapure water, filtered, and then
analyzed by HPLC. (See Table 6)
Results: There was no difference in solubility when pH was varied
from 7.0 to 9.0. However, when the samples were diluted 1:1 into
water, the samples adjusted to pH 7.5 and 8.0 precipitated.
Therefore, a pH>8.0 is preferable when the product is to be
diluted in aqueous vehicles.
TABLE-US-00006 TABLE 6 Sample Atorvastatin pH (mg/ml) 9.00 9.280
8.50 9.506 8.00 8.641 7.50 9.361 7.00 8.876
Example 13
[0085] Example 13 examines the amount of solvent needed to
solubilize AS-Ca by evaluating co-solvent/aqueous solubility as a
function of co-solvent proportions.
[0086] 10 mg of atorvastatin calcium was added to approximately 0.9
mls of solution containing the following solvent ratios in
ultrapure water: [0087] a. 40/10, 4.0 mls of propylene glycol and
1.0 ml of ethanol [0088] b. 30/10, 3.0 mls of propylene glycol and
1.0 ml of ethanol [0089] c. 20/10, 2.0 mls of propylene glycol and
1.0 ml of ethanol [0090] d. 40/5, 4.0 mls of propylene glycol and
0.5 ml of ethanol [0091] e. 40/0, 4.0 mls of propylene glycol and
0.0 ml of ethanol
[0092] The samples were each vortexed for 5 min and then sonicated
for 15 minutes. The samples were first adjusted to pH 9.00 with 0.1
M NaOH, vortexed, and then sonicated. The pH of the samples was
adjusted to pH 8.50 with 0.85% o-phosphoric acid and the samples
were again vortexed and sonicated. The samples were q.s. to 1.0 ml
with ultrapure water, filtered, and then analyzed by HPLC (see
Table 7).
Results: The best solubility was achieved with 40% propylene glycol
(v/v) and 10% ethanol (v/v). Forced degradation studies showed that
anything less than 40% propylene glycol and 10% ethanol resulted in
atorvastatin precipitation when diluted with normal saline.
TABLE-US-00007 TABLE 7 PG/ Concentration Sample EtOH mg/ml A 40/10
21.27 B 30/10 17.87 C 20/10 16.80 D 40/5 18.11 E 40/0 16.06
Example 14
[0093] Forced degradation studies also showed significant
degradation with co-solvent/aqueous vehicles. Therefore,
non-aqueous co-solvents were examined.
[0094] 10 mg of AS-Ca was added to a 1.0 ml of propylene glycol and
ethanol (4/1). The samples were vortexed and then the pH of the
sample was adjusted to pH 11.0 with 0.1 M NaOH. The samples were
then filtered, and analyzed by HPLC.
Results: The sample was completely soluble (9.34 mg/ml). When the
solution was diluted 1:3 in saline, it precipitated.
Example 15
[0095] Forced degradation analysis showed that AS-Ca was relatively
stable at high pH. Therefore, the pH was adjusted with L-Arginine
(L-Arg), NaOH, or sodium phosphate buffer (either sodium phosphate
tribasic (Na.sub.3PO.sub.4) or Na.sub.2HPO.sub.4).
[0096] 20 mg of AS-Ca was added to approximately 0.8 mL ml of the
solutions 1-5 below, followed by vortexing and sonication. The pH
of the samples was adjusted to a basic pH followed by q.s. to a
volume of 1 mL with ultrapure water, vortexing, sonication,
filtering, and HPLC analysis.
[0097] Solution 1: 20 mg of AS-Ca was added to water containing
16.54 mM L-Arg (1:1 Atorvastatin:L-Arg molar ratio). The pH was
adjusted to 10.98 with 10% L-Arg. The resulting AS-Ca concentration
was 0.46 mg/ml.
[0098] Solution 2: 20 mg of AS-Ca was added to water and the pH was
adjusted to 11.68 with 0.1 M NaOH. The resulting AS-Ca
concentration was 0.222 mg/ml.
[0099] Solution 3: 20 mg AS-Ca was added to water containing 0.1 M
Na.sub.3PO.sub.4. The measured pH was 11.75. The resulting AS-Ca
concentration was 0.46 mg/ml.
[0100] Solution 4: 20 mg AS-Ca was added to water containing 0.1 M
Na.sub.3PO.sub.4 and 16.54 mM L-Arg. The measured pH was pH 10.79.
The resulting AS-Ca concentration was 3.17 mg/ml.
[0101] Solution 5: 20 mg AS-Ca was added to water containing 0.1 M
Na.sub.2HPO.sub.4 and 16.54 mM L-Arg. The measured pH was 10.79.
The resulting AS-Ca concentration was 3.43 mg/ml.
Results: The solubility of AS-Ca in basic solutions with no
HP.beta.-CD varied from .about.0.2 to 3.5 mg/mL. Using 16.54 mM
L-Arg with either 0.1 M Na.sub.3PO.sub.4 or Na.sub.2HPO.sub.4
resulted in AS-Ca concentrations of >3mg/mL. Therefore using a
combination of L-Arg with either Na.sub.3PO.sub.4 or
Na.sub.2HPO.sub.4 also provides adequate solubility for preparation
of AS-Ca in solutions.
EXAMPLES 16 -19
[0102] Atorvastatin free acid solubility ("AS") was examined as an
alternative to the calcium trihydrate version.
Example 16
[0103] The solubility of AS with complexation was evaluated by
examining the solubility of AS-Ca in 27.78% of either HP.beta.-CD
or SBE-.beta.-CD in 50 mM Na.sub.2HPO.sub.4 adjusted to pH 10.35
and 10.65 using 0.1 M NaOH respectively. The same methods of
solubilization were used as example 4.
Results: AS solubility was 13.3 mg/ml with HP.beta.-CD and 1.96
mg/ml with SBE-.beta.-CD complexation.
Example 17
[0104] In Example 17, solubilization of AS with a co-solvent was
evaluated by testing whether AS could be dissolved in a non-aqueous
co-solvent at high pH and then diluted into saline, without
precipitation. Previous data (example 13) showed that the AS-Ca
would precipitate when prepared in non-aqueous co-solvents and then
diluted into saline.
[0105] 20 mg AS (20 mg) was added to approximately 0.9 mls of
propylene glycol and ethanol (4/1 ratio) co-solvent. The measured
pH was 6.64. The pH was adjusted to pH 11.0 with 0.1 M NaOH, q.s.
to a volume of 1 mL with ultrapure water. The sample was then
vortexed, filtered, after which it was analyzed by HPLC.
Results: The sample degraded rapidly (approximately 50% in 2
hours). The peak area was conserved between atorvastatin and its
degradation peaks. The AS concentration was estimated to be about
20 mg/ml.
Example 18
[0106] In Example 18, AS solubility in either 100% propylene glycol
or 100% ethanol similar to the propylene glycol/ethanol (4/1)
solvent using the same methods of solubilization described above.
Atorvastatin free acid was completely soluble in either 100%
propylene glycol or 100% ethanol similar to the propylene
glycol/ethanol (4/1) solvent. Both solutions precipitated when
diluted 1:1 with saline and were found to be unstable.
Example 19
[0107] In Example 19, the solubility of AS was examined by
adjusting to a high pH with L-Arginine (L-Arg), NaOH, or sodium
phosphate buffer (either (Na.sub.3PO.sub.4) or
Na.sub.2HPO.sub.4)..
[0108] 20 mg of AS was added to approximately 0.8 ml of the
solutions below followed by vortexing and sonication. The pH of the
samples was adjusted to a basic pH, followed by q.s. to a volume of
1 mL with ultrapure water. The sample was then vortexed, sonicated,
filtered, and HPLC analysis was conducted.
[0109] Sample 1: 20 mg AS was added to a solution of 16.54 mM
L-Arg. The measured pH was 10.35, which was then adjusted to 10.71
with L-Arg. The resulting AS-Ca concentration was 1.91 mg/ml.
[0110] Sample 2: 20 mg AS was added to ultrapure water and the pH
was adjusted to 11.15 with 0.1 M NaOH. The resulting AS
concentration was 0.06 mg/ml.
[0111] Sample 3: 20 mg AS was added to 16.54 mM L-Arg and 0.1M
Na3PO4. The measured pH was 11.42. The resulting AS concentration
was 0.44 mg/ml
[0112] Sample 4: 20 mg AS was added to 0.05 M Na.sub.3PO.sub.4. The
measured pH was 11.55. The resulting AS concentration was <LOQ
(Limit of Quantitation).
Results: The solubility of AS in basic solutions using
Na.sub.3PO.sub.4, NaOH, or Na.sub.3PO.sub.4 and L-Arg was <1.0
mg/mL. ASs solubility was 1.91 mg/mL when using L-Arg alone.
Therefore using L-Arg at an elevated pH provides an adequate
solubility.
Conclusion
[0113] Non-aqueous formulations composed of propylene
glycol/ethanol (4/1) at pH 11.0 were examined to decrease the
observed degradation. However, that formulation precipitated when
diluted 1:1 into normal saline. To improve stability, preliminary
lyophilized formulations of AS-Ca with HP.beta.-CD were examined.
Initial stability of this formulation showed improved stability
over leaving the sample in solution.
[0114] It will be readily apparent to one of ordinary skill in the
relevant arts that other suitable modifications and adaptations to
the methods and applications described herein are suitable and may
be made without departing from the scope of the invention or any
embodiment thereof. While the invention has been described in
connection with certain embodiments, it is not intended to limit
the invention to the particular forms set forth, but on the
contrary, it is intended to cover such alternatives, modifications
and equivalents as may be included within the spirit and scope of
the invention as defined by the following claims.
* * * * *