U.S. patent application number 11/184341 was filed with the patent office on 2005-11-10 for stabilization of solid drug formulations.
This patent application is currently assigned to Mutual Pharmaceutical Co., Inc.. Invention is credited to Spireas, Spiridon.
Application Number | 20050249801 11/184341 |
Document ID | / |
Family ID | 26930678 |
Filed Date | 2005-11-10 |
United States Patent
Application |
20050249801 |
Kind Code |
A1 |
Spireas, Spiridon |
November 10, 2005 |
Stabilization of solid drug formulations
Abstract
Pharmaceutical formulations and dosage forms are provided having
improved stability to moisture-induced degradation when compared
with conventional dosage forms, especially tablets. The invention
features low compression forms of drugs known to be susceptible to
moisture-induced degradation together with excipients, preferably
in encapsulated forms. In other embodiments, relatively
non-volatile oils can be admixed with the drug and/or the
excipients to stabilize the formulation toward moisture-induced
degradation. Hydrophobic powders are also optionally added to the
formulations.
Inventors: |
Spireas, Spiridon; (Newtown,
PA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Mutual Pharmaceutical Co.,
Inc.
Philadelphia
PA
|
Family ID: |
26930678 |
Appl. No.: |
11/184341 |
Filed: |
July 19, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11184341 |
Jul 19, 2005 |
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09690974 |
Oct 18, 2000 |
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60237442 |
Oct 3, 2000 |
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Current U.S.
Class: |
424/451 |
Current CPC
Class: |
A61K 9/4816 20130101;
A61K 9/4866 20130101; A61K 9/4858 20130101; A61K 9/2054 20130101;
A61K 9/485 20130101 |
Class at
Publication: |
424/451 |
International
Class: |
A61K 009/48 |
Claims
What is claimed is:
1. A drug dosage form comprising a compound susceptible to
moisture-induced degradation and at least one pharmaceutically
acceptable excipient prepared under conditions of low
compression.
2. The drug dosage form of claim 1 comprising a capsule.
3. The drug dosage form of claim 1 comprising a capsule formed of
hydroxypropyl methylcellulose.
4. The drug dosage form of claim 1 wherein the compound is
contained in solid form within a capsule.
5. The drug dosage form of claim 1 wherein the form is subjected to
no compression in excess of about 10,000 psi/g.
6. The drug dosage form of claim 1 wherein the form is subjected to
no compression in excess of about 5,000 psi/g.
7. The drug dosage form of claim 1 wherein the form is subjected to
no compression in excess of about 2,000 psi/g.
8. The drug dosage form of claim 1 wherein the excipient is
hydroxypropyl methylcellulose, carboxymethyl cellulose,
microcrystalline cellulose, amorphous silicon dioxide, magnesium
stearate, starch, sodium starch glycolate, or a combination
thereof.
9. The drug dosage form of claim 1 wherein the excipient has a
residual moisture content of less than about 10% by weight.
10. The drug dosage form of claim 1 exhibiting improved stability
to moisture-induced degradation of the compound as compared with a
tabletted form of the compound.
11. The drug dosage form of claim 1 comprising a unit dosage
form.
12. A drug dosage form for a compound susceptible to
moisture-induced degradation comprising the compound admixed with a
substantially non-volatile, pharmaceutically acceptable oil.
13. The drug dosage form of claim 12 wherein the oil is an animal
or vegetable oil.
14. The drug dosage form of claim 12 wherein said oil is olive,
corn, peanut, nut, soy, rapeseed, cottonseed, vitamin E, fish, or
tallow-derived oil.
15. The drug dosage form of claim 12 wherein the oil is a mineral
oil or silicone oil.
16. The drug dosage form of claim 12 wherein the compound--oil
admixture is present within a capsule.
17. The drug dosage form of claim 12 wherein the compound--oil
admixture is present within a soft shell capsule.
18. The drug dosage form of claim 12 wherein the compound--oil
admixture is present within a specially sealed hard-shell
capsule.
19. The drug dosage form of claim 12 wherein at least some of the
compound--oil admixture is adsorbed on a pharmaceutically
acceptable excipient.
20. The drug dosage form of claim 12 wherein the excipient having
the compound--oil admixture adsorbed thereupon is within a
capsule.
21. The drug dosage form of claim 12 wherein the excipient having
the compound--oil admixture adsorbed thereupon is within a
tablet.
22. A drug dosage form for a compound susceptible to
moisture-induced degradation comprising the drug and a
pharmaceutically acceptable excipient admixed with a substantially
non-volatile, pharmaceutically acceptable oil.
23. The drug dosage form of claim 22 wherein the oil is an animal
or vegetable oil.
24. The drug dosage form of claim 22 wherein said oil is olive,
corn, peanut, nut, soy, rapeseed, cottonseed, vitamin E, fish, or
tallow-derived oil.
25. The drug dosage form of claim 22 wherein the oil is a mineral
oil or silicone oil.
26. The drug dosage form of claim 22 wherein the drug and the
excipient--oil admixture are present within a capsule.
27. The drug dosage form of claim 22 wherein the drug and the
excipient--oil admixture are present within a tablet.
28. A drug dosage form comprising a compound susceptible to
moisture-induced degradation admixed with a first pharmaceutically
acceptable oil together with a pharmaceutically acceptable
excipient admixed with a second pharmaceutically acceptable
oil.
29. The drug dosage form of claim 28 wherein the first and the
second pharmaceutically acceptable oils are, independently, an
animal or vegetable oil.
30. The drug dosage form of claim 28 wherein the first and the
second pharmaceutically acceptable oils are, independently, olive,
corn, peanut, nut, soy, rapeseed, cottonseed, vitamin E, fish, or
tallow-derived oil.
31. The drug dosage form of claim 28 wherein the first and the
second pharmaceutically acceptable oils are independently, a
mineral oil or silicone oil.
32. The drug dosage form of claim 28 wherein the compound--oil
admixture and the excipient--oil admixture are present within a
capsule.
33. The drug dosage form of claim 28 wherein the compound--oil
admixture and the excipient--oil admixture are present within a
tablet.
34. A drug dosage form comprising a compound susceptible to
moisture-induced degradation and at least one pharmaceutically
acceptable hydrophobic powder.
35. The drug dosage form of claim 34 wherein the hydrophobic powder
is triturated directly with the compound.
36. The drug dosage form of claim 34 wherein the hydrophobic powder
is magnesium stearate.
37. A method for administering a compound susceptible to
moisture-induced degradation to a patient comprising providing a
unit dose of the compound which has not been processed employing
high compression.
38. A method for administering a compound susceptible to
moisture-induced degradation to a patient comprising providing a
unit dose of the compound admixed with a substantially
non-volatile, pharmaceutically acceptable oil.
39. The method of claim 38 wherein the compound--oil admixture is
present within a capsule.
40. The method of claim 38 wherein the compound--oil admixture is
adsorbed on a pharmaceutically acceptable excipient.
41. A method for administering a compound susceptible to
moisture-induced degradation to a patient comprising providing a
unit dose of the compound and a pharmaceutically acceptable
excipient admixed with a substantially non-volatile,
pharmaceutically acceptable oil.
42. A method for administering a compound susceptible to
moisture-induced degradation to a patient comprising providing a
unit dose of the compound and at least one pharmaceutically
acceptable hydrophobic powder.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to stable formulations of
drugs and methods for producing the same. In particular, the
present invention relates to stable formulations of drugs that are
susceptible to moisture-induced degradation and methods for
producing the same.
BACKGROUND OF THE INVENTION
[0002] It is known in the pharmaceutical field that many drugs and
classes of drugs exhibit poor or modest shelf stability. For
example, a number of solid drug formulations experience such
instability that after relatively short periods of time,
significant portions of the active materials in the drug have been
chemically transformed into other compounds. While such compounds
are often relatively benign, occasionally the degradation product
or products can either actually comprise an antagonist for the drug
or give rise to adverse side effects. In any event, the diminution
of desired, active ingredient in such drug formulations is of
obvious, deleterious effect, making therapy with such drugs less
certain. Accordingly, there is a long-felt need for drug
formulations and for unit dosage forms of drugs which experience
diminished degradation when compared to typical formulations.
[0003] Among the drug classes which are known to be liable to
moisture-induced (e.g., hydrolytic) degradation and diminished
shelf stability are the thyroid hormones. Thyroid hormones are
suitable for therapeutic application in the treatment of hormone
disorders. Particularly useful are thyroid hormones of natural or
synthetic origin which bear about two to four iodine atoms.
Examples of such thyroid hormones are levothyroxine, liothyronin,
dextrothyroxine, triiodoacetic acid, thyroglobulin, diiodotyrosine,
and analogs and salts thereof.
[0004] Levothyroxine is the levo isomer of thyroxine, an active
physiological thyroid hormone obtained from the thyroid gland of
animals or prepared synthetically. Clinically, levothyroxine is
prescribed in thyroid replacement therapy for reduced or absent
thyroid function of any etiology, including conditions such as
myxedema, cretinism and obesity. Levothyroxine sodium, the sodium
salt of levothyroxine, is the preferred form of administration of
levothyroxine and is expressed by the chemical formula
C.sub.15H.sub.10I.sub.4NaO.sub.4.xH.sub.2O. It is well known that
the stability of levothyroxine is poor as it hygroscopic and
degrades rapidly under conditions of high humidity or in the
presence of other moisture sources. Levothyroxine also rapidly
degrades in the presence of light, under conditions of high
temperature, or in the presence of other pharmaceutical excipients,
including carbohydrates such as, for example, lactose, sucrose,
dextrose and starch, and certain dyes. Accordingly commercially
available levothyroxine sodium tablet formulations exhibit a short
shelf life.
[0005] Thyroid hormones are used therapeutically for thyroid
diseases of various origins, including hypothyroidism,
hypothyrosis, iodine deficiency and other related secondary
diseases. Thyroid hormones are also used prophylactically. Thyroid
hormones are used as medicaments and are extremely susceptible to
temperature, humidity and oxidation. They are also prone to
decomposition by various reaction mechanisms. Additionally, they
react with many pharmaceutical excipients which makes it difficult
to prepare pharmaceutical formulations containing thyroid hormones
which remain effective for a sufficient period of time under
regular storage conditions.
[0006] Significant efforts have been directed to the development of
stable pharmaceutical formulations containing thyroid hormones for
use as therapeutic agents. U.S. Pat. No. 5,225,204 (Jul. 6, 1993)
is directed to a dosage form containing levothyroxine sodium which
includes a stable complex of levothyroxine sodium and a cellulose
compound, polyvinylpyrrolidone or a Poloxamer wherein the complex
is adsorbed on the surface of a cellulose compound carrier.
[0007] U.S. Pat. No. 5,635,209 (June 3, 1997) discloses a
medication consisting of the combination of levothyroxine sodium
with potassium iodide. This patent further discloses methods for
making medication containing levothyroxine sodium comprising
combining together levothyroxine mixed with a carrier, potassium
iodide mixed with a carrier, a disintegrant, and a lubricant.
[0008] U.S. Pat. No. 5,955,105 (Sep. 21, 1999) describes a stable,
solid dosage form pharmaceutical preparation, suitable for the
treatment of thyroid disorders, comprising a thyroxine drug, a
water soluble glucose polymer, and a partially soluble or insoluble
cellulose polymer. This patent also discloses a stable
pharmaceutical preparation comprising a thyroxine drug, a water
soluble polysaccharide and a partially soluble or insoluble
cellulose polymer. This patent further describes a stable
pharmaceutical preparation comprising sodium levothyroxine,
maltodextrin and microcrystalline cellulose.
[0009] U.S. Pat. No. 5,958,979 (Sep. 28, 1999) is directed to
stable medicaments containing thyroid hormones wherein the
medicament contains sodium thiosulfate as the stabilizing
component. This patent also discloses methods for the preparation
of stable medicaments comprising adding sodium thiosulfate in a
dissolved state to a matrix mixture containing thyroid
hormones.
[0010] In view of the extreme instability of thyroid hormones, such
as levothyroxine, in the presence of moisture, light and heat,
there is a long-standing need for stable formulations of thyroid
hormones and methods of making such formulations. It is desirable
to develop stable thyroid hormone-containing formulations which
demonstrate a long enough shelf life for use as therapeutic agents.
Also needed are methods for preparing such formulations wherein
degradation of the thyroid hormones in the formulations is greatly
reduced, thereby providing stable pharmaceutical formulations
containing thyroid hormones for use as therapeutic agents in the
treatment of disorders associated with reduction or absence of
thyroid hormone production
[0011] Accordingly, it is a principal object of the present
invention to provide unit dosage forms of solid drug formulations
having a reduced tendency to degrade over time when compared with
traditional formulations of such drugs. A further object of the
invention is to provide methods of therapy comprising administering
to a patient in need of a drug dosage form in accordance with the
invention having such diminished tendency to degrade. Another
object of the invention is to permit the U.S. and international
registration and permission to market certain drug formulations
which, absent the stabilization of the present invention, would not
be registerable due to an unacceptably high rate of degradation.
Other objects will become apparent from a review of the present
specification and appended claims.
SUMMARY OF THE INVENTION
[0012] The present invention relates to a drug dosage form
comprising a compound susceptible to moisture-induced degradation
and at least one pharmaceutically acceptable excipient prepared
under conditions of low compression. In one embodiment, the
compound is subjected to no compression in excess of about 10,000
psi/g, preferably to no compression in excess of about 5,000 psi/g,
and more preferably to no compression in excess of about 2,000
psi/g. The formulation of the compound into dosage forms under low
compression conditions preferably gives rise to encapsulated forms,
such as hydroxypropyl methylcellulose (HPMC) capsules.
[0013] In another of its aspects, the present invention relates to
a drug dosage form for a compound susceptible to moisture-induced
degradation comprising the compound admixed with a substantially
non-volatile, pharmaceutically acceptable oil. Suitable oils
include animal or vegetable oils such as olive, corn, peanut, nut,
soy, rapeseed, cottonseed, vitamin E, fish, or tallow-derived oils,
mineral oils and silicone oils. The compound--oil admixture is
optionally present within a capsule, a soft shell capsule, or a
specially sealed hard-shell capsule. The compound--oil admixture is
also optionally adsorbed on a pharmaceutically acceptable
excipient.
[0014] In yet another of its aspects, the present invention relates
to a drug dosage form for a compound susceptible to
moisture-induced degradation comprising the drug and a
pharmaceutically acceptable excipient admixed with a substantially
non-volatile, pharmaceutically acceptable oil. Suitable oils
include animal or vegetable oils such as olive, corn, peanut, nut,
soy, rapeseed, cottonseed, vitamin E, fish, or tallow-derived oils,
mineral oils and silicone oils. The excipient--oil admixture is
optionally present within a capsule or a tablet.
[0015] In still another of its aspects, the present invention
relates to a drug dosage form comprising a compound susceptible to
moisture-induced degradation admixed with a first pharmaceutically
acceptable oil together with a pharmaceutically acceptable
excipient admixed with a second pharmaceutically acceptable oil.
Suitable first and second pharmaceutically acceptable oils are,
independently, an animal or vegetable oil such as olive, corn,
peanut, nut, soy, rapeseed, cottonseed, vitamin E, fish, or
tallow-derived oil, a mineral oil or a silicone oil.
[0016] In a further of its aspects, the present invention relates
to a drug dosage form comprising a compound susceptible to
moisture-induced degradation and at least one pharmaceutically
acceptable hydrophobic powder. In one particular embodiment, the
hydrophobic powder is magnesium stearate. Preferably, the
hydrophobic powder is triturated directly with the compound.
[0017] In still a further of its aspects, the present invention
relates to a method for administering a compound susceptible to
moisture-induced degradation to a patient comprising providing a
unit dose of the compound which has not been processed employing
high compression. Alternatively or additionally, the compound
and/or the excipient are pretreated with a non-volatile,
pharmaceutically acceptable oil.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0018] The present invention employs, unless otherwise indicated,
conventional methods of chemistry, drug synthesis and formulation,
all within the knowledge of those skilled in the art. Such
techniques are explained fully in the literature. See, e.g.,
Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.:
Mack Publishing Company, 1990), incorporated herein by
reference.
[0019] In accordance with the present invention, it is
alternatively possible either to pretreat a drug, powder
excipients, or both with one or more non-volatile, water-immiscible
liquids such as oils, and each method of formulation has been found
to be beneficial in improving the stability of drugs such as
levothyroxine sodium and to form new and useful, solid dosage
forms. Without wishing to be bound by theory, the highly desirable
stability performance of these new formulations is believed to be
based on the fact that the oils are acting as a protective device
against extensive contact of the drug with environmental moisture
or the equilibrium moisture inherent in mixed powder excipients. In
this way, hydrolysis and degradation of the drug in such
formulations is significantly reduced.
[0020] The present invention may be applied to any of the solid
drugs which are known to be subject to moisture-induced degradation
in tablet form. Thus, the thyroid hormones such as levothyroxine,
ACE-inhibitors such as quinapril, cyclic amino acids such as
gabapentin, cholesterol lowering agents such as statins (e.g.,
lovastatin), non-steroidal anti-inflammatory agents such as
aspirin, peptides and proteins such as insulin, anticancer and
oncology drugs such as methotrexate, steroids and steroidal esters
such as methylprednisone sodium succinate, antibiotics such as
mitomycin C, nystatin, Rifampin, and others, other cardiac drugs
such as nitroglycerin and dioxin, and other drug classes may
benefit from the present invention, and its application to all such
classes is contemplated hereby. Additionally, in one particular
embodiment, the drug is optionally purified prior to use.
[0021] The phrase "moisture-induced degradation" as used herein
includes, but is not limited to, drug degradation due to hydrolysis
only. Instead, the phrase "moisture-induced degradation" also
includes any other type of degradation pathway such as oxidation,
photodegradation, cyclization, and even dehydration due to ionic
attractions, which may be induced or catalyzed by moisture. Thermal
degradation initiated by compression and facilitated by moisture is
also included in the above phrase.
[0022] The term "excipient" as used herein includes, but is not
limited to, the family of modified celluloses (e.g., carboxymethyl
and ethyl cellulose, hydroxymethyl and ethyl cellulose,
microcrystalline cellulose and others), amorphous silicon dioxide,
magnesium stearate, starch, sodium starch glycolate, or a
combination thereof. In one embodiment, the excipient is at least
one of microcrystalline cellulose, starch, and sodium starch
glycolate.
[0023] Microcrystalline cellulose is known per se and a variety of
such are commercially available. Exemplary among these is the
family of products sold by the FMC Corporation under the trademark
Avicel.RTM.. Any of the members of this family may be used in
connection with the practice of one or more embodiments of the
present invention and all are contemplated hereby. Other cellulose
products which are similar in nature to microcrystalline cellulose
may find utility herein, such a parenchymal cell cellulose.
[0024] In addition to the preferred microcrystalline celluloses and
similar materials, other cellulosic materials may also be employed
in connection with one or more embodiments of the present
invention. Thus, modified celluloses such as methyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl
cellulose, methylhydroxypropyl cellulose, carboxymethyl cellulose
salts and esters, (e.g. sodium, potassium etc. salts), and other
cellulose derivatives may be so employed. It will be appreciated by
persons of ordinary skill in the art that such cellulosic materials
should be consistent with the overall spirit of the invention.
Thus, such materials may be employed which do not adversely effect
the processing set forth herein and which do not interfere with the
stability of the resulting products.
[0025] Particularly useful non-volatile, water-immiscible liquids
include oils such as olive, corn, peanut, nut, soy, rapeseed,
cottonseed, vitamin E, fish, tallow-derived or other oils. The oil
may also be a mineral oil, silicone oil or the like and may be
present as a mixture of oils. By "non-volatile" it is meant that
the oils have a relatively low vapor pressure at conventional
temperatures and other conditions. Oils such as the essential oils
which have relatively high vapor pressures (e.g., aromatic
constitutives) are not preferred for this application, although
some of such species may find some utility herein.
[0026] In accordance with these aspects of the invention, drug and
oil are combined in any ratio which gives rise to the beneficial
properties desired. Conveniently, drug and oil can be combined in
ratios of about 1:1 to about 1:5000 or more, weight to weight.
Ratios of from about 1:40 to about 1:400 are more preferred. When
the oil is admixed with excipient, ratios of excipient to oil of
from about 1:1 to about 1:5000 or more are also conveniently used
with ratios of from about 1:40 to about 1:400 being preferred.
Other ratios may also be used, especially when both drug and
excipient are admixed with oils.
[0027] The drug and/or excipients are mixed with the non-volatile,
water-immiscible liquids using any of a variety of conventional
techniques. For example, when the excipients are to be pretreated,
the liquids can be dissolved in a solvent (e.g., acetone) and the
resulting solution used to granulate the excipients. When the drug
is to be pretreated, the drug can be suspended directly in the
liquids and homogenized to form a drug/liquid suspension.
[0028] A further way has also been found to greatly reduce unwanted
moisture-induced degradation in drugs. For example, with respect to
levothyroxine, it has now been surprisingly discovered that an
important factor which can be used to achieve stable powder
formulations of levothyroxine and other solid drugs which can
experience undesired rates of moisture-induced degradation, is the
avoidance of high degrees of compression. Without being bound by
theory, it has now been found that when a powder formulation
comprising levothyroxine mixed with pharmaceutically acceptable
powder excipients is compressed into tablets, some of the
equilibrium moisture inherently possessed by such inert powder
excipients is squeezed out of the interior bulk of the powder
particles to the exterior surfaces of the powder particles; those
surfaces being in contact with the drug particles. Such
drug-moisture contact is believed to result in initializing at a
relatively high rate, the hydrolysis of levothyroxine to its
degradation products.
[0029] It has actually been reported that the degradation of
levothyroxine from highly compressed systems, i.e., tablets, is
biphasic wherein, at a first stage immediately after compression
into tablets, the drug degrades at a much higher rate as compared
to a second, slower degradation stage. It has now been found that
the drug degradation stage occurring immediately after compression
is associated with the aforementioned contact of the drug particles
with the equilibrium inherent moisture squeezed onto the particle
surfaces of the inert powder excipients included in the tableting
mixture. Several commonly used and pharmaceutically acceptable
powder excipients may possess inherent moisture levels equivalent
of up to 10% of their weight. It is desired to continue to use such
excipients, however, especially those with moisture contents of 5%
and even 10% by weight. Thus, the compression of such materials can
force very significant amounts of moisture onto the surfaces of
such particles with the attendant, rapid moisture-induced
degradation of drugs in contact with such compressed particles.
[0030] Accordingly, it has now been found that provision of
levothyroxine in dosage forms which are highly compressed, such as
tablets, should be avoided when neither the drug nor the excipients
are pretreated as described above. Rather, in accordance with the
invention, the drug is preferably provided in unit dosage forms in
which the drug has not been compressed in the presence of
moisture-containing excipients to a degree such that moisture is
exuded onto the surfaces of the excipient particles. For example, a
hard-shell capsule of levothyroxine, in which the powder mixture is
not strongly compressed exhibits very greatly improved stability to
moisture-induced degradation as compared to previously available,
highly-compressed tablets of the drug.
[0031] It is also known that cyclic amino acids of the general
formula: 1
[0032] wherein R.sub.1 is H or a lower alkyl radical and n is 4, 5,
or 6, are subject to degradation during storage. The degradation is
believed to be due, at least in part, to conversion of the cyclic
amino acid to its lactam form: 2
[0033] Cyclization of the amino acid to form the lactam impurity
results in the loss of water. The cyclization is believed to be
catalyzed by highly ionized, electronegative anion impurities
(e.g., Cl.sup.-). Pretreatment of the amino acid and/or the
excipients with which it is compounded in accordance with the
present invention is expected to serve to isolate the amino acid
from the anion impurities, thereby stabilizing the amino acid
relative to its lactam form.
[0034] In addition, ACE inhibitors, or inhibitors of Angiotensin
Converting Enzymes, are drugs useful in the treatment of
cardiovascular disorders, especially hypertension. ACE inhibitors
include, but are not limited to, enalapril maleate and similar
salts; quinapril hydrochloride and similar salts; benazepril
hydrochloride and similar salts; moexipril hydrochloride and
similar salts; lisonopril hydrochloride and similar salts; ramipril
hydrochloride and simnilar salts; and indopril hydrochloride and
similar salts. Typical breakdown products of ACE inhibitors
include, but are not limited to, enalaprilat and/or
enalapril-diketopiperazine (DKP) for enalapril species, quinaprilat
and/or quinapril-DKP for quinapril drugs, and other breakdown
products well-known to those of skill in the art.
[0035] However, it has been widely observed that ACE inhibitors are
susceptible to breakdown, especially due to degradation and/or
cyclization between the time of manufacture and the time of desired
usage. Breakdown of ACE inhibitors has been found to occur both in
solid and in liquid states. Such breakdown is due, at least in
part, to hydrolysis of the drug by water. As breakdown of ACE
inhibitor increases, the concentration of available, functional ACE
inhibitor decreases. Also, at least some of the degradation
products of such breakdown are believed to be deleterious.
Accordingly, such breakdown is to be avoided. It is expected that
the moisture-induced hydrolysis of ACE inhibitors can be reduced by
pretreating the drug and/or the excipients with which it is
compounded in accordance with the present invention.
[0036] Persons of ordinary skill in the pharmaceutical formulation
art will recognize that the present invention distinguishes between
highly compressed drug forms and unit dosages and such forms and
dosages which have not been highly compressed. It is believed that
the relationship between the compression of solid forms of drugs
susceptible to moisture-induced degradation and the rate of or
tendency toward such degradation for such drugs has not been
appreciated heretofore. For purposes of this invention, the degree
of compression can be defined functionally. Thus, a drug form or
unit dosage has been "highly compressed" if the amount of pressure
applied to the form or dosage is such as to exacerbate the
moisture-induced degradation of the drug comprising the form or
dosage. This amount of compression can vary with the identity of
drug, excipient and other factors. However, it is believed that no
more than ordinary skill and routine evaluation is needed to
determine whether the foregoing conditions have been met with
respect to any particular drug composition, form, formulation or
unit dose. Without departing from the generality of the foregoing,
it is believed that compression in excess of about 10,000 pounds
per square inch per gram of compacted mass (psi/g), preferably
about 5,000 psi/g and still more preferred about 2,000 psi/g should
be avoided in such processing. For the purposes of the present
invention, formulation of drug forms, dosage forms and the like
with the avoidance of compression in excess of about 10,000 psi/g
or which otherwise avoids the above-described exacerbation of
moisture-induced degradation of drugs which are susceptible to such
degradation is referred to as "conditions of low compression."
[0037] As used herein, the terms "dosage form," "pharmaceutical
dosage form," "pharmaceutical formulation," and "pharmaceutical
preparation" refer to the final solid pharmaceutical product. These
terms include, but are not limited to, tablets included molded
tablets, caplets, beads, wafers, and capsules (including both hard
shell capsules and soft gelatin capsules). These terms also refer
to liquisolid systems which are flowing and compressible powdered
forms of liquid medications. The processes of preparing
pharmaceutical preparations and dosage forms are well known to
those of skill in the art. See, e.g., Theory & Practice of
Industrial Pharmacy, 3.sup.rd Edition, Liberman, Lachman, and
Kanig, eds. (Philadelphia, Pa.: Lea & Febiger), incorporated
herein by reference.
[0038] The formulation of solid drugs into dosage forms under low
compression conditions may conveniently and preferably give rise to
encapsulated forms. Hard shell capsules filled with low compression
powdered drug composition are most convenient; their manufacture
and processing is well-known and routine. A particularly preferred
capsule shell type is one comprising hydroxypropyl methylcellulose
(HPMC), although all capsule forms may beneficially be used in
conjunction with this invention. Other capsule shells, such as
those consisting of polyethylene glycols or other cellulosic
derivatives may also be advantageously used herein.
[0039] Other examples of solid dosage forms which do not require
high-compression conditions during their preparation are pellets,
beads, liquisolid systems, soft gelatin capsules containing liquid,
specially-sealed hard-shell capsules containing liquid, molded
tablets, wafers, etc.
[0040] A "liquisolid system" refers to formulations formed by
conversion of liquid drugs, drug suspensions or drug solutions in
non-volatile solvents into dry, nonadherent, free-flowing and
compressible powder admixtures by blending the suspension or
solution with selected carriers and coating materials. Based upon
the type of liquid medication contained, liquisolid systems are
classified into three categories: (I) powdered drug solution
(containing a drug solution); (ii) powdered drug suspension
(containing a drug suspension); and (iii) powdered liquid drug
(containing a liquid drug). Liquisolid systems are described in
U.S. Pat. Nos. 5,968,550 and 5,800,834, each of which is
incorporated herein by reference in its entirety. It will be
appreciated that such liquisolid systems may be prepared in
accordance with the present invention and that the same is within
the spirit hereof. Although not generally preferred, when the drug
and/or excipients are pretreated with a water-immiscible liquid in
accordance with the present invention, liquisolid powder systems
can be also compressed into tablets. Such tablets possess stability
properties superior to those of commercial products.
[0041] Significant stability enhancement benefits of premixing the
drug with some traditionally hydrophobic powders have also been
discovered as a way to reduce unwanted moisture-induced degradation
in drugs. The hydrophobic powders are preferably triturated
directly with the drug. In one particular embodiment, the
hydrophobic powders are triturated directly with the drug prior to
blending the drug with other powder excipients, including powder
excipients previously admixed with a non-volatile oil. Suitable
hydrophobic powders include, but are not limited to, lubricants
such as magnesium stearate, antioxidants, other solid waterproofing
agents, and combinations thereof. It would be appreciated by those
skilled in the art that this method can be used in various
intensities and in combination with one or more of the other
methods described herein. However, it is well known that extensive
use of such hydrophobic powders (i.e., magnesium stearate) may
deleteriously affect the dissolution of drugs in aqueous media by
waterproofing the drugs to irreversible levels. Accordingly, the
use of hydrophobic powders should be optimized to also maintain
acceptable drug dissolution properties.
[0042] As used herein, "substantially free" refers to compositions
that have significantly reduced levels of detectable breakdown
products or degradation products. The terms "breakdown products"
and "degradation products" refer to undesired contaminants formed
by the decomposition or degradation of the thyroid hormone.
Decomposition or degradation of thyroid hormones may be caused by
exposure of the thyroid hormone to moisture, heat or light.
[0043] By "pharmaceutically acceptable" or "pharmacologically
acceptable" is meant a material which is not biologically or
otherwise undesirable, i.e., the material can be administered to an
individual along with the stabilized drug formulation without
causing any undesirable biological effects or interacting in a
deleterious manner with any of the components of the formulation in
which it is contained.
EXAMPLES
[0044] Drug formulations in accordance with the present invention
were prepared and tested as follows. Powder formulations having the
composition of Example No. 1 listed in Table 1a was prepared by
pretreating the drug with oil (the "drug-oil-pretreatment" method).
Accordingly, the drug was suspended in oil and homogenized to form
a drug/oil suspension. The drug/oil suspension was then
incorporated onto a powder carrier comprising microcrystalline
cellulose and hydoxypropyl methylcellulose. The resulting wet
liquid/powder admixture was then mixed with fine silicon dioxide
particles to produce a free-flowing and readily compressible
liquisolid system. A disintegrant, sodium starch glycolate, and a
lubricant, magnesium stearate, were then mixed with the liquisolid
powders to produce the final powders.
[0045] Powder formulations having the compositions of Example No.
2-7 listed in Table 1a were prepared by pretreating the excipient
with oil (the "excipient-oil-pretreatment" method). Accordingly,
the oil was dissolved in acetone and the resulting solution was
used to granulate the inactive powder excipients (i.e.,
hydroxypropyl methylcellulose, microcrystalline cellulose, and
amorphous silicone dioxide, blended together). After drying, the
oil-treated excipients were mixed with levothyroxine and
encapsulated in HPMC capsules to produce the final product
[0046] A first aliquot (about 1 kg) of each formulation was then
compressed into tablets. A second aliquot of each formulation was
encapsulated in gelatin capsules. A third aliquot of each
formulation was encapsulated in hard-shell HPMC capsules. All unit
doses contained 0.025 mg of levothyroxine. Samples of each of the
tablets and capsules were then stored at 60.degree. C. and a
relative humidity of 75% for 4-6 days. At the end of the desired
storage time, the extent to which the drug had degraded was
determined as the percent decrease in the weight of the drug (%
Degradation={([initial weight of drug in mg]-[final weight of drug
in mg]).times.100}/[0.025 mg]). The % Degradation data is shown in
Table 1b. For comparison purposes, when tablets of a commercial
product (Synthroid 0.025 mg; Lot #000090074, Expiration date: 4/02)
were stored under the same conditions for 5 days, the tablets
showed a degradation of 36.7%.
1TABLE 1a Ingredient Example No. (mg per unit dose)* 1 2 3 4 5 6 7
levothyroxine sodium 0.025 0.025 0.025 0.025 0.025 0.025 0.025
olive oil 10 5 3 -- 5 5 1.4 soybean oil -- -- -- 2 -- -- --
acetone.sup.a -- 40 40 40 40 20 56 hydroxypropyl methylcellulose
20.sup.b 10.sup.b 10.sup.c 10.sup.c -- 10.sup.c 14.1.sup.c
amorphous silicon dioxide.sup.d 11 15 15 15 15 8 21.1
microcrystalline cellulose.sup.e 144 150 150 150 150 80 210.9
sodium starch glycolate.sup.f 23 -- -- -- -- -- -- magnesium
stearate 2 -- -- -- -- -- 2.5 *As weighed prior to manufacturing.
.sup.aNot present in final product. .sup.bMethocel K100LV.
.sup.cMethocel K100M. .sup.dSyloid 244 FP. .sup.eAvicel PH 200.
.sup.fExplotab.
[0047]
2 TABLE 1b Example No. 1 2 3 4 5 6 7 storage time (days) 4 6 5 5 5
5 5 % Degradation.sup.a gelatin capsule 12.1 20.8 22.7 -- -- -- --
HPMC capsule 6.5 11.3 5.9 8.7 7.2 4.2 16.0 tablet 26.1 30.3 -- 14.0
17.6 18.5 25.7 .sup.aResults reported as percent of drug degraded
after storage at 60.degree. C. and 75% relative humidity.
[0048] The data of Table 1b show that the most stable products were
the HPMC capsules followed by the gelatin capsules. The highly
compressed tablet forms presented, in a significant and consistent
manner, the worst stability characteristics. For example, when a
powder formulation of levothyroxine sodium (Example No. 1) was
compressed into tablets, the tablets presented 26.1% degradation
after storage for 4 days at 60.degree. C. and 75% relative
humidity. On the other hand, when the same powder system was
encapsulated under low compression conditions in hard-shell
capsules consisting of gelatin or HPMC, they degraded only 12.1% or
6.5%, respectively, at the same storage conditions.
[0049] The data of Table 1b also show that pretreated liquisolid
powder systems can be compressed into tablets. Such tablets possess
stability properties superior to those of commercial products. For
example, when stored for 5 days at 60.degree. C. and 75% relative
humidity, optimized liquisolid tablets of Levothyroxine Sodium
(Example No. 4) degraded at a level of only 14%, whereas the
market-leading Synthroid 0.025 mg Tablets (Lot: 000090074, Exp.:
04/02) displayed a 36.7% degradation at the same storage
conditions.
[0050] Stability results of levothyroxine liquisolid formulations
encapsulated in hard-shell HPMC capsules and prepared by
pretreating the excipient with oil (the
"excipient-oil-pretreatment" method) are shown in Table 2. The oil
was dissolved in acetone and the resulting solution was used to
granulate the inactive powder excipients (i.e., microcrystalline
cellulose and amorphous silicone dioxide, blended together). After
drying, the oil-treated excipients were mixed with levothyroxine
and encapsulated in HPMC capsules to produce the final product.
Several batches of 2-3 kg were prepared using this methodology and
scalable equipment such as a Collette 10 L granulator.
3 TABLE 2 Example No. 8 9 10 11 12 13 Ingredient levothyroxine
0.025 0.025 0.025 0.025 0.025 0.025 (mg per sodium unit dose)*
olive oil 1.0 0.5 1.5 0.2 0.8 1.0 acetone.sup.a 25 25 25 25 25 25
amorphous 9.0 9.0 9.0 9.0 9.0 9.0 silicon dioxide.sup.b
microcrystalline 90 90 90 90 90 90 cellulose.sup.c %
Degradation.sup.d 7.0 6.8 5.2 8.9 7.7 8.4 *As weighed prior to
manufacturing. .sup.aNot present in final product. .sup.bAvicel PH
200. .sup.cExplotab. .sup.dReported as the percent of drug degraded
after storage at 60.degree. C. and 75% relative humidity for 5
days.
[0051] The data of Table 2 show that optimized capsule formulations
of levothyroxine made with powder excipients that have been
previously treated and waterproofed with oils can give increased
stability properties as compared to commercial products.
[0052] Stability results of levothyroxine liquisolid formulations
encapsulated in hard-shell HPMC capsules and prepared by
pretreating the drug with oil (the "drug-oil-pretreatment" method)
are shown in Table 3. The drug was suspended in oil and homogenized
to form a drug/oil suspension. The drug/oil suspension was then
incorporated onto a powder carrier comprising microcrystalline
cellulose and hydoxypropyl methylcellulose. The resulting wet
liquid/powder admixture was then mixed with fine silicon dioxide
particles to produce a free-flowing and readily compressible
liquisolid system. A disintegrant, sodium starch glycolate, and a
lubricant, magnesium stearate, were then mixed with the liquisolid
powders to produce the final powders, which were encapsulated in
hard-shell HPMC capsules. Several batches of 2-3 kg each were
prepared using this methodology and scalable equipment.
4 TABLE 3 Example No. 14 15 16 17 18 19 Ingredient levothyroxine
0.025 0.025 0.03 0.025 0.025 0.025 (mg per sodium unit dose)* olive
oil 10 10 15 15 5 5 hydroxypropyl 10 -- 6 6 6 16
methylcellulose.sup.a amorphous 11 11 16 16 16 16 silicon
dioxide.sup.b microcrystalline 144 144 144 144 144 144
cellulose.sup.c sodium starch 23 23 17 17 17 17 glycolate.sup.d
magnesium stearate 2 2 2 2 2 2 % Degradation.sup.e 17.6 15.5 10.8
15.0 12.6 18.6 *As weighed prior to manufacturing.
.sup.aMethocelK100LV. .sup.bSyloid 244 FP. .sup.cAvicel PH 200.
.sup.dExplotab. .sup.eReported as the percent of drug degraded
after storage at 60.degree. C. and 75% relative humidity for 5
days.
[0053] The data of table 3 show that optimized capsule formulations
of levothyroxine made with levothyroxine that has been previously
treated and waterproofed with oils can give increased stability
properties as compared to commercial products
[0054] Stability results of a levothyroxine liquisolid formulation
encapsulated in hard-shell HPMC capsules and prepared by combining
the excipient-oil-pretreatment and the drug-oil-pretreatment
methods are shown in Table 4. Oil was dissolved in acetone and the
resulting solution was used to granulate and pretreat the inactive
powder excipients (microcrystalline cellulose and silicon-dioxide),
as described above in connection with the formulations of Table 2.
Additionally, the drug was suspended in oil, as described in
connection with the formulations of Table 3. The dried oil-treated
excipients were then mixed with the drug/oil suspension to yield a
free-flowing and readily compressible liquisolid system. Magnesium
stearate, a lubricant, was also added to produce the final powder,
which was encapsulated into hard-shell HPMC capsules.
5 TABLE 4 Example No. 20 Ingredient levothyroxine sodium 0.025 (mg
per unit dose)* olive oil (for drug) 3 olive oil (for excipient) 1
acetone.sup.a 40 amorphous silicon dioxide.sup.b 22
microcrystalline cellulose.sup.c 224 magnesium stearate 2 %
Degradation.sup.d 11.9 *As weighed prior to manufacturing.
.sup.aNot present in final product. .sup.bSyloid 244 FP.
.sup.cAvicel PH 200. .sup.dReported as the percent of drug degraded
after storage at 60.degree. C. and 75% relative humidity for 5
days.
[0055] The data of Table 4 show that a combination of
drug-oil-pretreatment and excipient-oil-pretreatment can give
increased stability properties as compared to commercial
products.
[0056] Significant stability enhancement benefits of premixing the
drug with some traditionally hydrophobic powders such as the
lubricant magnesium stearate have also been discovered. In general,
the use of antioxidants and other solid waterproofing agents in
combination with the above methods may be also beneficial. As shown
in Table 5, improved stability of levothyroxine is also obtained
when the drug is pretreated with a hydrophobic solid powder (the
"hydrophobic-powder-waterproofing" method). Accordingly, the drug
was first mixed with a hydrophobic powder, magnesium stearate, at
various levels. The other powder excipients were then blended in.
Several pilot batches of 2-3 kg each were prepared using this
methodology and scalable equipment.
6 TABLE 5 Example No. 21 22 23 24 Ingredient levothyroxine 0.025
0.025 0.025 0.025 (mg per sodium unit dose)* hydroxypropyl 20 10 10
10 methylcellulose.sup.a amorphous 14 15 15 15 silicon
dioxide.sup.b microcrystalline 150 150 150 150 cellulose.sup.c
magnesium stearate 10 5 2.5 1.0 % Degradation.sup.d 0 5.9 3.9 9.5
*As weighed prior to manufacturing. .sup.aMethocel K100M.
.sup.bSyloid 244 FP. .sup.cAvicel PH 200. .sup.dReported as the
percent of drug degraded after storage at 60.degree. C. and 75%
relative humidity for 5 days.
[0057] The data of Table 5 show that superior stability properties
are obtained for the formulations made according to the
hydrophobic-powder-waterproofing method.
[0058] While the present invention has been described in accordance
with certain of its preferred embodiments, it is not to be
construed as limited thereto.
* * * * *