U.S. patent application number 09/803455 was filed with the patent office on 2001-11-29 for inhibiting oxidative degradation of pharmaceutical formulations.
Invention is credited to Wang, Hai.
Application Number | 20010047034 09/803455 |
Document ID | / |
Family ID | 22693191 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010047034 |
Kind Code |
A1 |
Wang, Hai |
November 29, 2001 |
Inhibiting oxidative degradation of pharmaceutical formulations
Abstract
The invention provides methods for inhibiting oxidative
degradation of pharmaceutical formulations comprising at least one
oxidation-susceptible active drug ingredient which methods comprise
adding an oxidation-inhibiting amount of a ferrous ion source,
preferably in the form of a pharmaceuticalexcipient, to the
formulation. The invention further provides pharmaceutical
formulations comprising at least one oxidation-susceptible active
drug ingredient and an oxidation-inhibiting amount of a ferrous
iron source, preferably in the form of a pharmaceuticalexcipient.
The invention still further provides for the use of a ferrous ion
source as an anti-oxidant in pharmaceutical formulations.
Inventors: |
Wang, Hai; (East Lyme,
CT) |
Correspondence
Address: |
Gregg C. Benson
Pfizer Inc.
Patent Department, MS 4159
Eastern Point Road
Groton
CT
06340
US
|
Family ID: |
22693191 |
Appl. No.: |
09/803455 |
Filed: |
March 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60188447 |
Mar 10, 2000 |
|
|
|
Current U.S.
Class: |
514/502 ;
424/648 |
Current CPC
Class: |
Y10S 514/97 20130101;
Y10S 424/06 20130101; A61K 47/02 20130101; Y10S 514/973
20130101 |
Class at
Publication: |
514/502 ;
424/648 |
International
Class: |
A61K 031/295; A61K
033/26 |
Claims
1. A method of inhibiting oxidative degradation of a pharmaceutical
formulation comprising at least one oxidation-susceptible active
drug ingredient which method comprises adding to said formulation
an oxidation-inhibiting amount of a ferrous ion source.
2. A method according to claim 1 wherein said oxidation-susceptible
active drug ingredient comprises at least one amine or benzyl
functional group.
3. A method according to claim 1 wherein said ferrous ion source
comprises ferrous sulfate, ammonium ferrous sulfate, ferrous
gluconate, ferrous citrate, ferrous fumarate, ferrous lactate,
ferrous carbonate, and ferrous chloride, chelated and hydrated
forms thereof, and mixtures thereof.
4. A method according to claim 3 wherein said ferrous ion source is
selected from the group consisting of ferrous sulfate, ammonium
ferrous sulfate hexahydrate, and ferrous chloride.
5. A method according to claim 1 wherein said ferrous ion source
comprises at least a portion of a pharmaceutical excipient.
6. A method according to claim 1 wherein said ferrous ion source
comprises from about 0.001% to about 5.0% by weight of said
formulation.
7. A method according to claim 6 wherein said ferrous ion source
comprises from about 0.002% to about 0.02% by weight of said
formulation.
8. A method according to claim 7 wherein said ferrous ion source
comprises about 0.01% by weight of said formulation.
9. A formulation comprising at least one oxidation-susceptible
active drug ingredient and an oxidation-inhibiting amount of a
ferrous iron source.
10. A formulation according to claim 9 wherein said ferrous ion
source comprises at least a portion of a pharmaceutical
excipient.
11. A formulation according to claim 9 wherein said
oxidation-susceptible active drug ingredient comprises at least one
amine or benzyl functional group.
12. A formulation according to claim 9 wherein said ferrous ion
source comprises ammonium ferrous sulfate, ferrous sulfate, ferrous
gluconate, ferrous citrate, ferrous fumarate, ferrous lactate,
ferrous carbonate, ferrous chloride, chelated and hydrated forms
thereof, and mixtures thereof.
13. A formulation according to claim 12 wherein said ferrous ion
source is selected from the group consisting of ferrous sulfate,
ammonium ferrous sulfatehexahydrate, and ferrous chloride.
14. A formulation according to claim 9 wherein said ferrous ion
source comprises from about 0.001% to about 5.0% by weight of said
formulation.
15. A formulation according to claim 14 wherein said ferrous ion
source comprises from about 0.002% to about 0.02% by weight of said
formulation.
16. A formulation according to claim 15 wherein said ferrous ion
source comprises about 0.01 % by weight of said formulation.
17. The use of a ferrous ion source as an anti-oxidant in a
pharmaceutical formulation.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/188,447 filed Mar. 10, 2000.
BACKGROUND OF THE INVENTION
[0002] The invention relates to methods of inhibiting oxidative
degradation of pharmaceutical formulations comprising at least one
oxidation-susceptible active drug ingredient and to pharmaceutical
formulations comprising oxidation-inhibiting excipients.
[0003] The desirability of providing pharmaceutical formulations in
which an oxidation-susceptible active drug ingredient or
ingredients are protected against oxidative degradation inherent to
prolonged storage is a concept well known to, and appreciated by,
one of ordinary skill in the art. Anti-oxidants commonly employed
in various pharmaceutical formulations may include, inter alia,
vitamin E, ascorbic acid, BHT (butylated hydroxytoluene), BHA
(butylated hydroxyanisole), and the like.
[0004] Pharmaceutical formulations comprising ferrous ion sources
as nutritional supplements are generally well known in the art. The
presence of ferrous ion sources in pharmaceutical formulations has
additional utility in other capacities. For example, it has been
reported that preservation of oral liquid preparations from
bacterial contamination can be achieved by treatment with, inter
alia, certain ferrous sulfate/methylparaben mixtures. See H. van
Doorne, et al., Pharmacy World & Science, 16 (1), 18-21 (1994).
It has also been reported that the addition of ferrous salts to
compositions comprising acetylsalicylic acid, or salts thereof,
reduces the propensity of the compositions to induce gastric
irritation. See A. Goudie, et al., U.S. Pat. No. 4,083,951.
[0005] The present invention discloses methods for protecting an
oxidation-susceptible active drug ingredient or ingredients in a
pharmaceutical formulation from oxidative degradation which methods
comprise adding a ferrous ion source to the formulation, preferably
in the form of a pharmaceutical excipient comprising the
formulation components. In this manner, pharmaceutical formulations
are produced in which the active drug ingredient or ingredients are
protected from oxidative degradation, thus facilitating storage of
the formulation over extended periods of time.
SUMMARY OF THE INVENTION
[0006] The instant invention provides methods for inhibiting
oxidative degradation of pharmaceutical formulations comprising at
least one oxidation-susceptible active drug ingredient which
comprises protecting the formulation by the addition of an
oxidation-inhibiting amount of a ferrous ion source thereto,
preferably in the form of a pharmaceutical excipient.
[0007] The invention further provides pharmaceutical formulations
comprising at least one oxidation-susceptible active drug
ingredient and an oxidation-inhibiting amount of a ferrous iron
source, preferably in the form of a pharmaceuticalexcipient.
[0008] The invention still further provides for the use of a
ferrous ion source as an anti-oxidant in pharmaceutical
formulations.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The instant invention provides methods of inhibiting
oxidative degradation of pharmaceutical formulations comprising at
least one oxidation-susceptible active drug ingredient which
methods comprise adding to the formulation an oxidation-inhibiting
amount of a ferrous ion source, preferably in the form of a
pharmaceuticalexcipient.
[0010] The invention further provides pharmaceutical formulations
comprising at least one oxidation-susceptible active drug
ingredient and an oxidation-inhibiting amount of a ferrous iron
source, preferably in the form of a pharmaceuticalexcipient.
[0011] The invention still further provides for the use of a
ferrous ion source as an anti-oxidant in pharmaceutical
formulations.
[0012] As employed throughout the instant description and appendant
claims, the term "ferrous" denotes a salt comprising the element
iron in its lowest valence state, i.e. Fe.sup.+2.
[0013] According to the methods of the invention, a formulation
comprising at least one oxidation-susceptible active drug
ingredient is protected against oxidative degradation by the
addition of an oxidation-inhibiting amount of a ferrous ion source
thereto. Although a broad spectrum of pharmaceutical formulations
comprising at least one oxidation-susceptible active drug
ingredient will benefit from the augmented protection to oxidative
degradation provided by the methods of the instant invention,
formulations comprising an active ingredient or ingredients
incorporating at least one amine or benzyl functional group are
particularly benefited. Preferably, the ferrous ion source should
be, for purposes of penultimate formulation, substantially soluble
in water or a lower molecular weight alcohol, for example,
methanol, ethanol, or isopropanol, and should also be chemically
compatible with the active drug ingredient or ingredients and any
additional components comprising the formulation. The ferrous ion
source comprising the formulation should also be toxicologically
compatible with the subject being treated. Accordingly, ferrous ion
sources that are unstable, chemically incompatible with the active
ingredient or ingredients comprising the formulation, or
toxicologically incompatible with the subject being treated, are
not preferred. Generally preferred ferrous ion sources may
comprise, for example, ferrous sulfate, ammonium ferrous sulfate,
ferrous chloride, ferrousgluconate, ferrous citrate, ferrous
fumarate, ferrous lactate, ferrous carbonate, chelated and hydrated
forms thereof, and mixtures thereof. Particularly preferred ferrous
ion sources comprise those compounds selected from the group
consisting of ferrous sulfate, ammonium ferrous sulfate
hexahydrate, and ferrous chloride. Ammonium ferrous sulfate
hexahydrate is especially preferred.
[0014] Although the ferrous ion source and the active drug
ingredient or ingredients comprising the formulation may be
compounded by simple intimate admixture, it is generally preferred
that the ferrous ion source comprise at least a portion of a
pharmaceutical excipient. Such excipients are well known to one of
ordinary skill in the art and may comprise, for example, dicalcium
phosphate, sodium citrate, calcium carbonate, microcrystalline
cellulose, silicified microcrystalline cellulose, lactose, kaolin,
mannitol, starch, sucrose, dextrose, and the like. The excipient
comprising the ferrous ion source may be prepared by conventional
methods well known to one of ordinary skill in the art. For
example, the excipient may be prepared by spraying or intimately
admixing a solution of the ferrous ion source at an appropriate or
desired concentration with the other components comprising the
excipient. Once the excipient comprising the ferrous ion source has
been uniformly admixed, for example, by mixing in a high shear
mixer, it is dried thoroughly, for example, in a fluid bed dryer or
an oven dryer. Preferably, the dried excipient is then passed
through a mill or screen to ensure that a uniform particle size has
been achieved. Although the concentration of the ferrous ion source
may vary, it typically comprises from about 0.001% to about 5.0% by
weight of the formulation. Preferably, the concentration of the
ferrous ion source comprises from about 0.002% to about 0.02% by
weight, based upon the amount of the excipient present in the
formulation. For example, if a fomulation contained 100 g of
excipients, it would preferably contain about 1 mg to about 5 g of
ferrous ion source. An amount comprising about 0.01% by weight of
the formulation is especially preferred. These amount ranges may,
of course, be varied somewhat according to the active drug
ingredient or ingredients to be stabilized as will be recognized
and appreciated by one of ordinary skill in the art having benefit
of the teachings of the instant disclosure. The ability to select
an appropriate ferrous ion source as well as an effective amount
thereof to protect a particular pharmaceutical formulation
comprising at least one oxidation-susceptible active drug
ingredient against oxidative degradation according to the methods
of this invention is within the purview of one of ordinary skill in
the art having the benefit of the instant disclosure.
[0015] Generally, methods of preparing solid dosage formulations
comprising an active ingredient or ingredients and a pharmaceutical
excipient are well known, or will be readily apparent in light of
the instant disclosure, to of one of ordinary skill in the art.
See, for example, Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa., 18th Edition (1990). The
pharmaceutical formulations of this invention may comprise any
conventional solid dosage form including, for example, tablets,
pills, capsules, and the like. The formulations may further
comprise a binder such as hydroxypropylmethyl cellulose, gum
tragacanth, acacia gum, corn starch or gelatin; a disintegrating
agent such as corn starch, potato starch,alginic acid, sodium
starch gylcolate, croscamellose sodium, or crospovidone; a
lubricant such as magnesium stearate; and a sweetening agent such
as sucrose, lactose, or saccharin. Various other materials may be
present in the form of coatings or to modify the physical form of
the dosage unit. For instance, tablets may be coated with mixtures
comprising, for example, titanium dioxide, dextrose, polyethylene
glycol, sodium carboxymethyl cellulose, dextrin, and the like. The
coatings may also comprise the form of an enteric polymer including
phthalate derivatives, such as cellulose acetate phthalate,
polyvinylacetate phthalate and hydroxypropylmethyl cellulose
phthalate, polyacrylic acid derivatives, such as methacrylic acid
copolymer, vinyl acetate, and crotonic acid copolymers.
[0016] It is to be understood that the examples of the invention
set forth hereinbelow are not to be construed as limitations
thereof, as additional embodiments within the scope of the
appendant claims will be known, or apparent in light of the instant
disclosure, to one of ordinary skill in the art.
EXPERIMENTAL
[0017] The compound
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphen-
ylmethyl-1-azabicyclo[2.2.2]octan-3-amine, to be referred to
hereinafter as Compound 1, prepared as described in U.S. Pat. No.
5,807,867; and the tartrate salt of the compound
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy-
)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (lasofoxifene
tartrate), to be referred to hereinafter as Compound 2, prepared as
described in U.S. Pat. No. 5,552,412. were formulated into solid
dosage formulations as described hereinbelow.
[0018] Compound 1 was formulated with, inter alia, excipients
comprising about 0.01% by weight of ammonium ferrous sulfate
hexahydrate into solid binary pharmaceutical formulations as
follows. A solution of 350 mg of ferrous ammonium sulfate
hexahydrate, dissolved in 100 ml of pure water, was added to 500 g
of microcrystalline cellulose (Avicel.RTM.; FMC; Philadelphia, Pa.)
and the mixture was mixed thoroughly for about ten minutes. The
mixture was then dried in an Aeromatic fluid-bed dryer (Niro Inc.;
Columbia, Md.) at an inlet temperature of 65.degree. C. The dried
Avicel.RTM. excipient so prepared comprising the ferrous ion source
was milled through a Mini-Comil 193 (Quadro Engineering; Waterloo,
Ontario, Canada) with a stainless steel screen. This identical
procedure was employed to prepare excipients comprising lactose and
the ferrous ion source. A pre-determined amount of Compound 1, the
dried Avicel.RTM. or lactose excipient comprising the ferrous ion
source, and crospovidone (BASF Corp.; Mount Olive, N.J.) were added
to a stainless steel V-blender and blended for about 20 minutes.
Magnesium stearate was then added and the resulting mixture was
blended for an additional five minutes. The lubricated granulate so
prepared was roll-compacted on a TF-min Roller Compactor (Vector
Corporation; Marion, Iowa) utilizing a roller speed of six rpm, a
screw-feeder speed of 16 rpm, and a roller pressure of 20
kg/cm.sup.2. The compacted ribbons so produced were milled with a
rotary granulator with a 20 mesh stainless steel screen. The
granulate so produced was transferred into a four quarter V-blender
and blended for five minutes. The second half portion of magnesium
stearate was then added and blended for an additional five minutes.
The lubricated granulate so produced was compressed on a
rotary-type Kilian T-100 tablet press (Kilian & Co.; Horsham,
Pa.). Tablets were compressed at a weight of about 300 mg for 100
mg potency formulations using a standard round concave 3/8"
punch.
[0019] The tablets so prepared were stored under accelerated
stability conditions, i.e. at 40.degree. C. at 75% relative
humidity and 50.degree. C. at 20% relative humidity for six weeks.
Reversed-phase ion pair liquid chromatography (RPLC) was then
employed to separate Compound I from its isopropyloxide (M+16) and
isopropylperoxide (M+32) oxidative degradation products. RPLC was
performed utilizing a Waters Symmetry C.sub.8 column (Waters
Instrument Co.; Milford, Mass.) 15 cm length.times.3.9 mm I.D. at a
temperature of 40.degree. C. using a mobile phase of 0.1 M
C.sub.8H.sub.17O.sub.3SNa in 0.05 M KH.sub.2PO.sub.4 (pH 3.0):
acetonitrile (55:45 v/v), a flow rate of 1.0 mL/min., and an
injection volume of 20 .mu.L at a run time of 60 minutes. 1
[0020] As summarized hereinbelow in Tables 1 and 2, the formation
of the isopropyloxide (M+16) and isopropylperoxide (M+32) oxidative
degradation by-products of Compound 1 was inhibited significantly
by the addition of the ferrous ion source to the formulation.
[0021] As indicated in Table 1, formation of the M+16 and M+32
oxidative degradation by-products of Compound 1 was reduced from
0.22% and 0.41%, in the samples comprising only Compound 1 and
Avicel.RTM., to 0.07% and 0.04%, respectively, in the samples
comprising Compound 1, Avicel.RTM., and 0.01% of ferrous ion.
[0022] Similarly, as indicated in Table 2, formation of the M+16
and M+32 oxidative degradation by-products of Compound 1 was
reduced from 0.16% and 0.27%, in the samples comprising only
Compound 1 and lactose, to 0.06% and 0.00%, respectively, in the
samples comprising Compound 1, lactose, and 0.01% of ferrous
ion.
[0023] Compound 2 was similarly formulated with, inter alia,
excipients comprising about 0.01% of ferrous ammonium sulfate
hexahydrate into solid binary pharmaceutical formulations. The
excipients further included microcrystalline cellulose
(Avicel.RTM.), lactose, or silicified microcrystalline cellulose
(Prosolv.RTM.; Penwest Pharmaceuticals; Patterson, N.Y.).
[0024] The formulations so prepared were then stored under
accelerated stability conditions, i.e. at 40.degree. C. at 75%
relative humidity and 50.degree. C. at 20% relative humidity for
six weeks. Reversed-phase ion pair liquid chromatography (RPLC) was
used to separate Compound 2 from its N-oxide oxidative degradation
product. RPLC was performed utilizing a Waters Symmetry C.sub.18
column (Waters Instrument Co.; Milford, Mass.) 15 cm
length.times.3.9 mm I.D. at a temperature of 40.degree. C. using a
mobile phase of buffer (20 mM KH.sub.2PO.sub.4 (pH adjusted to 3.0
with phosphoric acid, with 0.1% octanesulfonic acid): acetonitrile
(60:40 v/v), a flow rate of 1.0 mL/min., and an injection volume of
10 .mu.L at a run time of 35 minutes. 2
[0025] As summarized hereinbelow in Table 3, the formation of the
N-oxide oxidative degradation by-product of Compound 2 was
inhibited significantly by the addition of the ferrous ion source
to the formulations. For example, formation of the N-oxide
oxidative degradation by-product of Compound 2 was reduced from
5.07%, in the formulation comprising only Compound 2 and lactose,
to 0.07% in the formulation comprising Compound 2, lactose and
0.01% of ferrous ion. Similarly, formation of the N-oxide oxidative
degradation by-product of Compound 2 was reduced from 5.50%, in the
formulation comprising only Compound 2 and Avicel.RTM., to 0.70% in
the formulation comprising Compound 2, Avicel.RTM. and 0.01% of
ferrous ion. Finally, formation of the N-oxide oxidative
degradation by-product of Compound 2 was reduced from 3.30%, in the
formulation comprising only Compound 2 and Prosolv.RTM., to 0.30%
in the formulation comprising Compound 2, Prosolv.RTM. and 0.01% of
ferrous ion.
1TABLE 1 Stability Results of Binary Mixture of Avicel .RTM. and
Compound 1 % M + 16 by-product % M + 32 by-product by RPLC by RPLC
Compound 1 0.22% 0.41% and Avicel .RTM. Compound 1, Avicel .RTM.
0.07% 0.04% and 0.01% Fe.sup.+2
[0026]
2TABLE 2 Stability Results of Binary Mixture of Lactose and
Compound 1 % M + 16 by-product % M + 32 by-product by RPLC by RPLC
Compound 1 0.16% 0.27% and lactose Compound 1, lactose and 0.06%
0.00% 0.01% Fe.sup.+2
[0027]
3TABLE 3 Stability Results of Binary Mixture of Lactose, Avicel
.RTM., or Prosolv .RTM. With Compound 2 % Compound 2 N-Oxide by
RPLC Compound 2 5.07% and lactose Compound 2, lactose and 0.07%
0.01% Fe.sup.+2 Compound 2 5.50% and Avicel .RTM. Compound 2,
Avicel .RTM. and 0.70% 0.01% Fe.sup.+2 Compound 2 3.30% and Prosolv
.RTM. Compound 2, Prosolv .RTM. and 0.30% 0.01% Fe.sup.+2
* * * * *