U.S. patent application number 12/917514 was filed with the patent office on 2011-02-24 for steroid hormone products and methods for preparing them.
Invention is credited to Bradley A. Clark, Angela Falzone, Thomas Schultz.
Application Number | 20110046095 12/917514 |
Document ID | / |
Family ID | 22969374 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046095 |
Kind Code |
A1 |
Schultz; Thomas ; et
al. |
February 24, 2011 |
STEROID HORMONE PRODUCTS AND METHODS FOR PREPARING THEM
Abstract
The present invention relates to steroid hormone products, such
as oral contraceptive products, including at least one steroid
active ingredient mixed with an excipient and having improved
dissolution and release rate properties. The invention further
relates to methods for making such steroid hormone products,
wherein a mixture of the hormone and the excipient is subjected to
sufficient mechanical energy to form a powder blend wherein the
hormone is stabilized by the excipient in substantially
non-crystalline form.
Inventors: |
Schultz; Thomas; (Richboro,
PA) ; Clark; Bradley A.; (Gurnee, IL) ;
Falzone; Angela; (Rantan, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
22969374 |
Appl. No.: |
12/917514 |
Filed: |
November 2, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10022138 |
Dec 13, 2001 |
7867990 |
|
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12917514 |
|
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60255669 |
Dec 14, 2000 |
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Current U.S.
Class: |
514/170 ;
514/182 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 31/565 20130101; A61K 31/567 20130101; A61K 9/145 20130101;
A61K 31/57 20130101; A61P 15/00 20180101; A61P 5/30 20180101; A61K
31/575 20130101; A61K 31/565 20130101; A61K 9/1694 20130101; A61K
2300/00 20130101; A61P 15/18 20180101; A61K 31/569 20130101 |
Class at
Publication: |
514/170 ;
514/182 |
International
Class: |
A61K 31/567 20060101
A61K031/567; A61P 15/18 20060101 A61P015/18 |
Claims
1. A method of preparing a steroid hormone product having improved
dissolution and release rate properties, said product comprising
norgestimate in admixture with an excipient, wherein substantially
all of said norgestimate is in non-crystalline form and wherein
said excipient stabilizes said norgestimate in its non-crystalline
form, said method comprising the steps of: preparing a mixture
comprising at least norgestimate and at least one excipient;
imparting to said mixture sufficient mechanical energy to yield an
excipient/norgestimate powder blend wherein the norgestimate is
stabilized by said excipient in substantially non-crystalline form;
and forming said product from the powder blend.
2. The method of claim 1, wherein the step of preparing the mixture
includes the steps of: preparing a solution of the norgestimate in
a suitable solvent; uniformly mixing the solution with the
excipient; and removing the solvent.
3. The method of claim 1, wherein at least about 0.1 hp-min/kg of
mechanical energy is imparted to the mixture to form the powder
blend.
4. The method of claim 1, wherein the step of imparting mechanical
energy to the mixture is further characterized in that the mixture
is subjected to high energy blending.
5. The method of claim 1, wherein the mixture comprises a
norgestimate/excipient ratio of from about 1/1 to about 1/10.
6. The method of claim 1, wherein the excipient is selected from
the group consisting of dextrose, fructose, sorbitol, xylitol,
sucrose, lactose, mannitol, dextrate, cellulose, starch and
mixtures thereof.
7. The method of claim 6, wherein the excipient is lactose.
8. The method of claim 1, wherein the steroid hormone product
comprises norgestimate and an estrogen.
9. The method of claim 8, wherein the estrogen is ethinyl
estradiol.
10. The method of claim 8 wherein the product is an oral
contraceptive product comprising from about 10 .mu.g to about 50
.mu.g of an estrogen and/or from about 50 .mu.g to about 300 .mu.g
of norgestimate.
11. The method of claim 10, wherein the estrogen is ethinyl
estradiol.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 10/022,138, filed on Dec. 13, 2001, which claims the benefit of
U.S. Provisional Application No. 60/255,669, filed on Dec. 14,
2000, which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to steroid hormone products
comprising at least one steroid active ingredient mixed with an
excipient and having improved dissolution and release rate
properties. More particularly, the invention provides an oral
contraception product having an improved dissolution profile. The
invention further relates to methods for making such steroid
hormone products, either with or without the use of solvents.
[0003] As used herein, the term "steroid hormone product" is a
physically discrete unit suitable as a unitary dosage for a human
host. The product contains a predetermined quantity of at least one
steroid active ingredient effective to produce a desired effect.
Examples, of such products are tablets, capsules, caplets, pills or
discrete quantities of powder.
BACKGROUND OF THE INVENTION
[0004] Oral contraceptives first became available in the early
1960's. Since then, a number of regimens for controlling ovulation
and contraception by the administration of hormones have become
known and are readily available. Oral contraceptive formulations
typically contain an estrogen and a progestin. In addition to these
steroid active ingredients, the formulation may contain an
excipient including various grades of lactose, additives and
fillers such as pregelatinized starch and magnesium stearate, and a
colorant such as an aluminum oxide lake.
[0005] Solvent-based processes, referred to herein as "wet
processing" have been commonly employed for many years to make
commercial quantities of steroid hormone products, such as oral
contraceptives containing steroid active ingredients, According to
one well-known process, an active ingredient, such as a steroid
hormone, is dissolved in an appropriate volatile solvent and
sprayed onto a bed of a pharmaceutically acceptable excipient
powder until a desired concentration of the active ingredient per
unit weight of powder is achieved. In general, the solvent employed
is compatible with the active ingredient and the chosen excipient
and can be removed under conditions that will not result in the
degradation of the active ingredient. Particularly suitable
solvents for use with steroid hormone active ingredients include
alcohols such as methanol, ethanol and propanol, ketones such as
acetone, hydrocarbons such as ethylene chloride and chloroform, and
mixtures of one or more of these solvents with water. The solution
is typically sprayed onto the bed of excipient powder in a suitable
processor, such as a V-blender with an intensifier bar or a fluid
bed processor. The solution and powder are then thoroughly mixed in
the processor to ensure uniform dispersion of the active ingredient
in the excipient. After mixing, the solvent is removed by the
application of heat and/or vacuum to provide a dry mixture.
[0006] In an alternative wet processing technique, referred to by
those skilled in the art as high sheer wet granulation, the solvent
is not sprayed onto the excipient but is, instead, mixed directly
with the excipient powder in a high shear blender. Subsequent to
mixing, the solvent is removed as described above to provide a dry
mixture.
[0007] Wet processing provides a number of advantages, including
powder blends that have a uniform distribution of active ingredient
and that suffer only minimal segregation under usual conditions of
storage and handling. Steroid hormone products prepared from these
blends typically exhibit excellent content uniformity.
[0008] A major disadvantage of these solvent-based processes is
that environmentally objectionable organic solvents are generally
required in those cases where the steroid active ingredient has
poor water solubility. Such solvents often pose safety hazards
during handling, in addition to the hazards they present when they
are released into the environment. Increasingly, health regulatory
authorities are objecting to the use of such solvents due to their
toxicity and mutagenicity.
[0009] Accordingly, a dry granulation or direct compression process
would be preferable for active ingredients that would generally
otherwise require the use of an organic solvent. Such dry
granulation or direct compression processes will be referred to
herein as "dry processing". Dry processing generally involves fewer
steps than solvent-based wet processing and does not require
elevated temperatures that can reduce the potency of
temperature-sensitive active ingredients. Dry processing is also
especially suitable for products that include steroid hormones
sensitive to the moisture associated with wet processing via
aqueous granulation. The absence of expensive organic solvents and
the required evaporation steps also makes dry processing
economically more attractive.
[0010] U.S. Pat. No. 5,382,434 has proposed pharmaceutical
preparations containing steroids (e.g., progestin and/or estrogen)
and an excipient (e.g., lactose) made without the use of solvents.
According to the '434 patent, at least 80% of the steroid must be
bound to the excipient and the excipient must have a low "demixing
potential," which is a measure of content uniformity. The excipient
is mixed with the steroid until a uniform mixture is obtained.
However, the '434 patent is silent as to release characteristics of
these compositions and teaches only a mechanical interaction during
the mixing operation.
[0011] As those skilled in the art recognize, known steroid hormone
products present a number of disadvantages that are not addressed
by either wet or dry processing techniques. Steroids exist in
various polymorphic forms, defined here to include crystalline,
amorphous and solvate forms. In the case of wet processing, the
inability to identify the polymorphic form(s) of the potent
steroid(s) that exists in a steroid hormone product following
removal of the deposited organic solvent is a potential concern
both from a physical/chemical stability prospective and from a
biopharmaceutical prospective. Unfortunately, known methods of dry
processing do not completely eliminate the potential existence of
polymorphic forms.
[0012] In addition, steroid hormone products prepared by either wet
or dry processing methods may present bioavailability problems.
Before a drug that is orally administered as a solid can be
absorbed, it must first dissolve in the gastrointestinal medium,
and then it must be transported in the dissolved state across the
gastrointestinal mucosa into the blood stream. As a surrogate test
to predict bioavailability prior to commercial release of a drug
product, regulatory authorities routinely require that at least 80%
of the active ingredient in the product dissolve within 60 minutes
in a "physiologically relevant" medium, i.e., a dissolution medium
for in-vitro testing. Low dose steroid formulations prepared by
known methods of either wet or dry processing have exhibited an
undesirable variability in release rate, as measured by dissolution
rate techniques in an aqueous medium containing a surfactant.
Notably, upon scale up, formulations containing low dose steroids
manufactured by dry processing and intended for use as oral
contraceptives routinely had slower dissolution rates or at least
suffered from a poorly reproducible dissolution profile.
[0013] Steroid hormones such as estrogen and progestin are also
employed for hormone replacement therapy (HRT). Steroid hormone
products used for HRT may contain up to a ten fold higher amount of
estrogen and, typically, a lesser amount of progestin than oral
contraceptives. Consequently, it is anticipated that such products
may experience similar problems related to dissolution.
Accordingly, it would also be desirable to reduce or eliminate such
problems in the case of HRT steroid hormone products.
SUMMARY OF THE INVENTION
[0014] In accordance with the invention, a steroid hormone product
having an improved dissolution profile and release rate profile is
provided. The product comprises at least one steroid hormone in
substantially non-crystalline form in admixture with primary
excipient, wherein the excipient stabilizes the steroid in its
substantially non-crystalline form. The hormone products taught by
the invention are characterized by highly favorable dissolution
properties. The preferred excipient is lactose, although it should
be understood that the invention is in no way limited in this
regard and other excipients well-know in the art may be utilized,
including dextrose, fructose, sorbitol, xylitol, sucrose, mannitol,
dextrate, cellulose, starch and combinations of two or more of the
foregoing.
[0015] The steroid hormone products of the invention are
particularly useful as either oral contraceptives or HRT products.
In a preferred embodiment of this aspect of the invention, the
steroid hormone product is an oral contraceptive comprising from
about 10 .mu.g to about 50 .mu.g of an estrogen and/or from about
50 .mu.g to about 300 .mu.g of a progestin. The progestin is
preferably either norgestimate, norgestrel, levonorgestrel,
norethindrone or desogestrel, and the estrogen is preferably either
ethinyl estradiol, estradiol, estopipate or mestranol.
[0016] In a second aspect, the invention provides a method of
preparing such a steroid hormone product, which method comprises
preparing a mixture of at least one steroid hormone and an
excipient, preferably lactose, and imparting to said mixture
mechanical energy sufficient to yield an excipient/steroid powder
blend in which the steroid is stabilized by the excipient in a
substantially non-crystalline form. Preferably, at least about 0.1
hp-min/kg of mechanical energy is imparted to the mixture. Any
method of high energy processing may be employed to impart
sufficient mechanical energy to carry out the process of the
invention. One preferred method of imparting sufficient mechanical
energy involves high energy blending of the lactose and steroid,
but other high energy mixing processes known in the art may be
employed such as co-grinding or milling the mixture.
[0017] Preferably, the mixture is prepared with a steroid hormone
to excipient ratio in the range of from about 1/1 to about 1/10.
However, it should be understood that the invention is in no way
limited in this regard and other hormone/excipient ratios may be
employed depending on the desired concentration of hormone in the
final product. Typically, the ratio of steroid to excipient in the
mixture is the same as that required for the final product.
However, it should be understood that an initial mixture of steroid
hormone and excipient may be prepared, with additional excipient
added subsequently to produce a final mixture. The final mixture is
then subjected to high energy processing to impart sufficient
mechanical energy to carry out the invention.
[0018] In one preferred embodiment of the invention, the
steroid/excipient mixture is formed by standard wet processing. For
example, a solution of at least one steroid hormone dissolved in an
appropriate solvent is prepared and then sprayed onto the excipient
powder. The solution and excipient are mixed in a suitable
processor to ensure uniform distribution of the solvent in the
excipient. The resulting mixture is then dried by removing the
solvent via the application of heat and/or vacuum. Mechanical
energy is then imparted to the mixture as described above to
provide the steroid/excipient powder blend. In another preferred
embodiment of the invention, the steroid and excipient are mixed by
standard dry processing and mechanical energy is then imparted to
the mixture as described above to provide the steroid/excipient
powder blend.
DETAILED DESCRIPTION OF THE INVENTION
[0019] As used herein, the following terms shall have the meaning
ascribed to them below, except when the context clearly indicates
differently:
[0020] "Poor" or "low" solubility refers to substances that are
very slightly soluble to insoluble according to the following USP
definitions.
TABLE-US-00001 Part of Solvent USP Descriptive Required for 1
Equivalent Term Part of Solute mg/mL Sparingly Soluble From 30 to
100 33.3 mg/mL-10 mg/mL Slightly Soluble From 100 to 1000 10
mg/mL-1 mg/mL Very Slightly Soluble From 1000 to 10000 1 mg/mL-0.1
mg/mL Practically Insoluble, 10000 and over .ltoreq.0.1 mg/mL or
Insoluble
[0021] "Content uniformity" means a relative standard deviation in
active ingredient content of .+-.1.5%, preferably .+-.1.0% and most
preferably .+-.0.5%.
[0022] As stated above, it is known that steroid hormones such as
estrogens and progestins can exist in various solid state forms and
that the particular form of the steroid may significantly effect
properties such as dissolution rate and physical/chemical
stability. An increase in dissolution rate and the extent of
dissolution, as well as a decrease in physical/chemical stability
are two potential consequences of modifying the stable crystalline
form of these steroid hormones. In general, the higher energy,
non-crystalline solid state form will exhibit an increase in
dissolution rate over the more stable, lower energy crystalline
form.
[0023] This is also the case with certain excipients such as
lactose. Lactose is commonly selected as an excipient in tablets
and capsules. It is commercially available in an assortment of
grades including anhydrous a lactose, a lactose monohydrate,
anhydrous .beta. lactose and spray-dried lactose. Spray-dried
lactose (e.g., FAST-FLO lactose available from Foremost Farms,
Baraboo, Wis.) is commonly selected as an excipient in direct
compression formulations due to its superior flow and compression
characteristics. This grade of lactose predominately contains pure
a lactose monohydrate in combination with non-crystalline lactose.
The non-crystalline component enhances the compressibility of
lactose. Morita et al., "Physiochemical Properties of Crystalline
Lactose, II. Effect of Crystallinity on Mechanical and Structural
Properties", Chem. Pharm. Bull., Vol. 32, p. 4076 (1984). The
non-crystalline state is metastable in nature and recrystallization
to a more thermodynamically stable form is inevitable. The tendency
for non-crystalline lactose to rapidly recrystallize upon exposure
to relative humidity greater than approximately 60% is well
documented. Sebhatu et al., "Assessment of the Degree of Disorder
in Crystalline Solids by Isothermal Microcalorimetry",
International Journal of Pharmaceuticals, Vol. 104, p. 135 (1994).
However for many drug substances, this process can be delayed by
the addition of such materials as microcrystalline cellulose,
polyvinylpyrrolidone or citric acid. Buckton et al., "The Influence
of Additives on the Recrystallization of Amorphous Spray-Dried
Lactose", International Journal of Pharmaceuticals, Vol. 121, p. 81
(1995).
[0024] Various unit operations are routinely employed during the
manufacture of conventional steroid hormone products, including
milling, blending, wet granulation, drying and compression. Each
process is associated with the incorporation of mechanical and/or
thermal energy into the system. Consequently, the potential for
modification of various solid state properties of steroid active
ingredients and excipients exists. Huttenraunch, et al.,
"Mechanical Activation of Pharmaceutical Systems", Pharmaceutical
Research, Vol. 2, p. 302 (1985). As noted above, such changes may
significantly alter properties such as dissolution rate and
dissolution extent, as well as physical/chemical stability (e.g.,
conversion to a different solid state form, hydrolysis, etc).
Increases in dissolution rate and extent and a decrease in
physical/chemical stability are two potential consequences of
modifying the stable crystalline form of a material. However it
would be highly desirable to increase the dissolution rate while
either improving or at least not reducing the physical/chemical
stability. The probability of encountering such crystalline form
modifications during dosage form processing is directly related to
the propensity of each ingredient to exist in a variety of
polymorphic forms.
[0025] Norgestimate is a potent progestational agent. A thorough
investigation of the polymorphic potential of this substance
demonstrated the existence of at least two solid state forms, a
stable crystalline form and a relatively higher energy
non-crystalline form. It is also known that a relatively higher
energy non-crystalline form of lactose exists in addition to the
stable crystalline form routinely employed in tablet manufacture.
Similar to lactose, the higher energy non-crystalline form of
norgestimate can be generated via physical or mechanical processes.
The present inventors have found that non-crystalline norgestimate
can be physically generated from solution subsequent to the rapid
evaporation of various organic solvents. Laboratory experiments
clearly demonstrate that non-crystalline norgestimate can also be
generated by ball milling. An obvious reduction in norgestimate
crystallinity can be observed within 5 minutes of milling.
Considering the relative ease of crystalline structure modification
via mechanical energy, as well as the inherent non-crystalline
lactose content in conventional lactose preparations, it was
hypothesized that co-processing of lactose and norgestimate could
result in the generation of a solid solution. In theory this solid
solution would consist of non-crystalline norgestimate solubilized
within the non-crystalline domains of lactose resulting in a
composition exhibiting a more rapid dissolution rate and possibly
enhanced physical/chemical stability.
[0026] Research efforts were thus made to generate the
non-crystalline form of norgestimate in the presence and absence of
lactose via physical and mechanical processes. Various mixtures of
norgestimate and lactose were prepared. To permit qualitative or
semi-quantitative analysis, the ingredients were thoroughly mixed
in ratios of 1:1 and 1:9 by either dissolving them in a co-solvent
mixture or by co-grinding. Qualitative assessment of the degree of
crystallinity was performed employing Powder X-Ray Diffractometry
(PXRD). The minimum detectable level of crystalline norgestimate in
this solid mixture was demonstrated to be approximately 3%.
[0027] The physical stability of non-crystalline norgestimate and
non-crystalline lactose were assessed prior to investigation of the
drug/excipient interaction. Room temperature storage conditions
employed at various relative humidities (% RH) of 0%, 31% and 76%
RH were employed. Complete recrystallization of amorphous
norgestimate was observed within 3 days at all conditions tested.
Based on these data, the ability of lactose to inhibit
recrystallization and enhance the physical stability of
non-crystalline norgestimate was investigated.
[0028] Co-precipitation of norgestimate and FAST-FLO lactose from a
solvent mixture of ethanol and water was achieved by solvent
evaporation under reduced pressure. In the presence of lactose,
norgestimate remained totally amorphous for at least 32 days at
room temperature in a 0% RH chamber. Norgestimate recrystallized
within 3 days in the absence of lactose under the same conditions.
As anticipated, PXRD analysis of both the 1:1 and 1:9
norgestimate:FAST-FLO lactose mixtures made in this manner
demonstrated recrystallization of lactose within 1 hour at 75% RH.
This was anticipated since non-crystalline lactose undergoes rapid
recrystallization at approximately 60% RH. Sebhatu et al., supra.
However, the norgestimate remained partially non-crystalline for at
least 6 days at this high relative humidity. The fact that
norgestimate remains in a non-crystalline form subsequent to the
recrystallization of lactose implies that the two compounds are
miscible in the solid state. These findings further support the
hypothesis that a metastable solid solution is formed between
lactose and norgestimate when dissolved in a hydro-alcoholic system
and co-precipitated.
[0029] In an attempt to more closely mimic the process employed in
the manufacture of steroid hormone tablets by dry processing, 1:9
crystalline norgestimate/FAST-FLO lactose mixtures were ball milled
together for 20 minutes. PXRD analysis indicated an absence of
crystalline norgestimate. However no visually obvious reduction in
the crystallinity of lactose was observed. The milled mixture was
stored at room temperature at 0% RH and at 31% and 40.degree. C. at
75% RH. Based on visual observation, norgestimate remained in a
non-crystalline form at room temperature for at least 103 days in
this mixture. Recrystallization of norgestimate at the accelerated
temperature/humidity condition was initiated between 54 and 82
days. These data further support the hypothesis that a
non-crystalline form of norgestimate is physically stabilized by
lactose even in the absence of detectable modification in the
crystallinity of lactose. One would also anticipate a more rapid
dissolution of norgestimate from a solid solution than from the
crystalline form.
[0030] Employing the current dissolution standard (USP Apparatus 2,
75 rpm, 600 ml of 0.05% Tween 20), the dissolution rates and extent
of dissolution for individual samples of both crystalline and
non-crystalline norgestimate were compared. Not surprisingly, this
preliminary investigation demonstrated a difference in dissolution
behavior of the two solid state forms of norgestimate. The results
of the study are set forth below in Table 1.
TABLE-US-00002 TABLE 1 Dissolution Amorphous Crystalline Time
(min.) Norgestimate Norgestimate 5 0.44 ug/mL 0.43 ug/mL 60 1.38
ug/mL 0.81 ug/mL 120 1.88 ug/mL Not Determined 140 Not Determined
1.36 ug/mL
[0031] The dissolution rate and extent of norgestimate dissolution
subsequent to co-milling with lactose at a ratio of 1:9 was also
evaluated. PXRD indicated that norgestimate was rendered
non-crystalline while lactose was rendered partially crystalline
following milling. Employing a 100 ml volume of 0.05% Tween 20 as a
medium, dissolution characteristics of norgestimate were determined
as a function of storage time at approximately 40.degree. C. at 75%
RH. PXRD was employed to follow the recrystallization kinetics of
the solid solution formed. As anticipated, lactose recrystallized
between 0 and 2 days. Initiation of norgestimate recrystallization
was noted between 17 and 22 days. Norgestimate remained partially
crystalline for at least 44 days under the accelerated storage
conditions. The results of the evaluation are set forth in Table
2.
TABLE-US-00003 TABLE 2 Dissolution Norgestimate Concentration
Norgestimate Concentration Time (min.) Time = 0 Days Time = 44 Days
10 5.3 ug/mL 2.4 ug/mL 20 5.1 ug/mL 5.2 ug/mL 30 6.2 ug/mL 6.5
ug/mL 60 8.7 ug/mL 5.9 ug/mL 240 10 ug/mL 6.7 ug/mL 720 10.3 ug/Ml
7.3 ug/mL
[0032] These data demonstrate that the dissolution properties of
norgestimate in combination with lactose (1:9 ratio) change as
norgestimate begins to recrystallize from the metastable solid
solution. These data further demonstrate the potential influence of
mechanical energy on the solid state form of norgestimate and
lactose in norgestimate tablets.
[0033] Differences in the dissolution behavior of norgestimate from
tablets manufactured by dry processing on both a pilot scale and a
production scale were also evaluated. The minimum mechanical energy
of 0.1 hp-min/kg can be imparted in a dry process using a geometric
tumbler blender equipped for additional mixing energy with blades
or choppers. A progestin such as norgestimate can be combined with
lactose and additives. Increasing the length of processing time
with the blades or choppers in use would impart sufficient energy
to produce the forms identified in this invention. The results of a
dissolution rate study at two different equipment scales is
presented in Tables 3a and 3b. With an increase in dissolution rate
being an indirect measure of the presence of the invention, the
data indicate higher levels of the less crystalline progestin as
greater energy is imparted over time. The importance of dissolution
rate as a function of mixing time is also noted. The results of the
evaluation are reported in Tables 3a and 3b, respectively.
TABLE-US-00004 TABLE 3a Pilot Scale Percent Norgestimate Mixing
Time (Minutes) Dissolved in 20 Minutes 2.5 74.9 5 78.4 10 85 20
88.5 30 97.4 33 93.6
TABLE-US-00005 TABLE 3b Production Scale Percent Norgestimate
Mixing Time (Minutes) Dissolved in 20 Minute 4.8 64.7 12 81.2 15
90.3 30 92.8 45 96.2 60 97.4 75 97.2
[0034] As the data set forth below in Table 4 demonstrate, the
relative stability of dissolution properties of tablets
manufactured by wet processing and stored unprotected under
accelerated conditions are also sensitive to changes in mixing
energetics. The data in Table 4 further support the existence of a
high energy form of norgestimate in the presence of lactose. In
addition, changes in dissolution behavior when stored at 40.degree.
C. at 75% RH is demonstrated in Table 4. Like the data reported in
Table 2, dissolution properties are dependent on storage
conditions. However it is apparent that the extent of such changes
is further dependent on the mixing energetics imparted during the
process.
TABLE-US-00006 TABLE 4 Blend Time Percent Norgestimate Dissolved in
30 Minutes (minutes) Initial 1 month 40.degree. C./75% RH 0 75.4 36
2* 91 45 20 90.1 45 40 92.6 46 60 94.5 85
[0035] Based on the studies reported above, it has been determined
that when a mixture of an excipient and a steroid active ingredient
is subjected to sufficient mechanical energy, the excipient and the
steroid active ingredient form a less crystalline, more highly
energetic composition. Furthermore, under appropriate mixing
conditions, the lactose component stabilizes the steroid in a
highly energetic, substantially non-crystalline state, thus
preventing recrystallization of the steroid. This is particularly
important in the case of a progestin such as norgestimate that is
quite unstable in the non-crystalline form and prone to rapid
recrystallization. The highly energetic, non-crystalline steroid
active ingredient dissolves more readily and is better able to
maintain desirable dissolution characteristics under a variety of
conditions of ambient humidity and ambient temperature. In addition
it has been demonstrated that the high-energy steroid:lactose
mixture has a higher recrystallization temperature than the same
steroid lactose mixture has under conditions where it has not been
subjected to high energy mixing and where the mixture components
remain in the amorphous state. (Table 7, Example 3)
[0036] As noted previously, preferably at least about 0.1
(hp-min)/kg of mechanical energy is imparted to the mixture, most
preferably at least about 0.12 (hp-min)/kg of mechanical energy.
Any method of high energy processing may be employed to impart
sufficient mechanical energy to carry out the process of the
invention. One preferred method involves high energy blending
carried out in equipment which is able to impart the energy level
needed to achieve the invention. Examples of such equipment include
a geometric tumble blender with an intensification system, a bowl
type blender with a high shear blade or impeller or a ribbon
blender with appropriate energy capacity. The blending system would
be operated with parameters appropriate to deliver the energy
necessary to achieve the invention. Alternatively, grinding or
milling, may be employed. This is accomplished in a commonly
available mill grinder. Milling conditions can vary within a
substantial range, typically the mixture is milled for a period of
10-30 minutes, preferably about 20 minutes when a small mill with a
ball is employed.
[0037] Although not critical, it is preferable to control humidity
before and during the mixing operation to 55% relative humidity or
lower to further inhibit crystallization of the components, and
mixing is also preferably conducted at an ambient temperature.
[0038] As also noted previously, additional ingredients may be
added to the mixture, preferably such ingredients are added to the
excipient powder prior to the high energy mixing operation.
Typically employed ingredients include: (i) disintegrants such as
clays, alginic acid and alginates, celluloses such as
microcrystalline cellulose, croscarmellose sodium, cross-linked
polymers such as cross-linked polyvinylpyrrolidone (crospovidone)
or cross-linked sodium carboxymethylcellulose, and polacrilin
potassium, starches such as sodium starch glycolate, starch and
pregelatinized starch; (ii) lubricants such as talc, magnesium
stearate, calcium stearate, stearic acid, colloidal silicon
dioxide, magnesium carbonate, magnesium oxide, calcium silicate;
and (iii) colorants such as caramel, D&C and FD&C dyes, for
example. Other additional ingredients include glidants, fillers,
binders and the like. The foregoing additional ingredients, as well
as any other excipients or processing aids, can be added as
required to yield a material suitable to be processed into a
steroid hormone product.
[0039] The process of this invention is most suitable for the
preparation of oral contraceptives containing one or more steroids,
preferably a progestin, most preferably norgestimate, and/or an
estrogen preferably ethinyl estradiol as the active ingredient(s).
Instead of norgestimate, oral contraceptives containing norgestrel,
levonorgestrel, desogestrel, 3-ketodesorgestrel, or norethindrone
as the progestin can be prepared by the present invention. The oral
contraceptives may also contain an estrogen compound such as
.beta.-estradiol, ethinyl estradiol, 17-.alpha. ethinyl estradiol,
3-methyl ether estropipate and mestranol. However, the process has
applicability to the preparation of any pharmaceutical preparation
which contains as the active ingredient, a material having low to
moderate solubility in water and which exists in a variety of
polymorphs some of which may be stabilized via a physical
interaction with an excipient such as lactose to yield a more
rapidly soluble material. Furthermore, the process is particularly
applicable to the preparation of oral contraceptives containing
within a kit solid oral dosage forms of varying potency as to a
particular active ingredient, as described above. Alternatively,
the process of the invention can be used to prepare HRT products
which also contain an estrogen and/or a progestin generally in
different active ingredient amount combinations than the oral
contraceptives.
[0040] The following examples describe the invention in greater
detail and are intended to illustrate it without limiting its
scope.
Example 1
Amorphous Lactose/Norgestimate Dry Ground Mixture
[0041] Amorphous norgestimate was prepared by dissolving
norgestimate (200 mg) in 5 ml of (DCM) dichloromethane and 0.26 ml
ethanol (EtOH). The solution was filtered through a 0.2 .mu.m
filter, and solvent was evaporated under reduced pressure to afford
amorphous solid.
[0042] Mixtures of norgestimate and lactose, in amorphous and
crystalline forms, were milled for 20 minutes. The amorphous state
of each ingredient and of the mixture was confirmed by powder x-ray
pattern diffraction (PXRD). The results are described below and
summarized in Table 5.
[0043] A mixture of crystalline norgestimate:crystalline lactose
(1:9) was milled in a Wig-I-Bug mill. A small mill containing a
ball afforded amorphous norgestimate with mostly crystalline
lactose, whereas a larger mill containing a bar yielded both as
crystalline materials. Milling a 1:1 mixture of crystalline
norgestimate:crystalline lactose afforded partially crystalline
norgestimate with mostly crystalline lactose.
[0044] A mixture of amorphous norgestimate and amorphous lactose
(1:9) was milled also. The resulting solid mixture showed an
amorphous PXRD pattern for both components. Milling 1:1 mixtures of
amorphous norgestimate and amorphous lactose also afforded
non-crystalline mixtures.
TABLE-US-00007 TABLE 5 Preparation of Amorphous
Norgestimate:Lactose by Milling PXRD PXRD Norgestimate: Sample
Pattern.sup.b Pattern.sup.b Method.sup.a Lactose No. Norgestimate
Lactose WLB(30 m) 1:9.sup.c 161-55-01.sup.d C C WLB(20 m) 1:1.sup.c
256-33-1.sup.e PC C WLB(20 m) 1:9.sup.c 256-33-03.sup.e A C WLB(20
m) 1:1.sup.f 268-25-01.sup.d A A WLB(20 m) 1:1.sup.f
314-10-01.sup.d A A WLB(20 m) 1:9.sup.f 268-24-01.sup.d A A
.sup.aSolid was milled using a Wig-L-Bug .RTM. (WLB) mill for the
specified time in minutes. .sup.bC = crystalline; A = amorphous; PC
= partially crystalline. .sup.cBoth crystalline samples were used.
.sup.dSmall Wig-L-Bug .RTM. mill containing a ball was used.
.sup.eLarge Wig-L-Bug .RTM. mill containing a bar was used.
.sup.fBoth amorphous samples were used.
Example 2
Stability Studies of Amorphous Materials
[0045] This study shows that amorphous norgestimate is stabilized
by lactose in a number of norgestimate:lactose preparations. Stress
studies as well as thermal analyses (Example 3) showed the
stabilization of norgestimate in norgestimate:lactose mixtures.
[0046] Amorphous norgestimate was prepared from DCM:EtOH solution,
and its stability was studied under various humidity conditions to
establish a baseline of norgestimate stability. In order to
simulate drug products, non-crystalline norgestimate:lactose
mixtures were obtained from one of the following four methods:
co-precipitation from EtOH:H.sub.2O, or 2-BuOH:H.sub.20, spray
drying onto amorphous lactose, milling of crystalline mixtures, or
milling of amorphous mixtures. The physical stability of
non-crystalline norgestimate to resist recrystallization was also
studied in the absence of and with an equal amount of lactose.
[0047] The materials for each sample were prepared as follows:
Amorphous Norgestimate
[0048] Norgestimate (200 mg) was dissolved in 5 mL of DCM and 0.26
mL of ethanol. The solution was filtered through a 0.2 .mu.m filter
and solvent was evaporated under reduced pressure to afford the
amorphous solid.
Amorphous Lactose
[0049] FAST-FLO lactose (516 mg) was dissolved in 17 mL of H.sub.20
and filtered through a 0.2 .mu.m filter, then lyophilized to afford
dry material. However, the solid was partially crystalline.
Co-Precipitation of Norgestimate/Lactose
[0050] Norgestimate (10 mg) and FAST-FLO lactose (91 mg) were
dissolved in 143 mL of EtOH:H.sub.20 (3.56:1) and filtered through
a 0.45 .mu.m filter. The solvent was evaporated under reduced
pressure to afford amorphous solid.
[0051] Norgestimate (20 mg) and FAST-FLO lactose (180 mg) were
dissolved in 65 mL of 2-Butanol:Water (68:32) and filtered through
a 0.2 .mu.m filter. The solvent was evaporated under reduced
pressure at 30.degree. C. to afford a non-crystalline solid.
[0052] Norgestimate (10 mg) and FAST-FLO lactose (90 mg) were
dissolved in 29 mL of ACN:H.sub.20 (2.6:1) at 60.degree. C. and
filtered through a 0.2 .mu.m filter. The solvent was evaporated
under reduced pressure at 35.degree. C. to afford a non-crystalline
solid.
Spray Drying of Norgestimate/Lactose
[0053] Amorphous lactose was placed in a round bottom flask and
attached to a vacuum pump. A solution of norgestimate in 95:5
EtOH:H.sub.20 (0.5 mg/mL) was filtered through a 0.2 .mu.m filter
and sprayed into the round-bottom flask containing lactose while
the vacuum was applied. The solution of norgestimate dried on the
surface of the lactose solid to afford non-crystalline
norgestimate.
[0054] A solution of amorphous lactose in methanol was applied on
silica gel TLC and observed under a short-wave UV lamp. An UV
active spot was observed. Lactose alone showed no UV active
spots.
Milling of Norgestimate/Lactose
[0055] Norgestimate (50 mg) and FAST-FLO lactose (450 mg) were
placed in a Wig-L-Bug mill, and milled with a bar for 20 minutes to
afford non-crystalline norgestimate.
Physical Mixing of Norgestimate/Lactose
[0056] Norgestimate (2.2 mg) and lactose (2.6 mg) were mixed with a
spatula in a vial for 1 minute. Additional amounts of lactose (4.6
mg) were added and then mixed with a spatula for another minute.
This was repeated until all of the lactose was added (9.0 mg, 2.6
mg, total of 18.8 mg).
Stability Studies of Amorphous Material
[0057] A vial containing a small amount of amorphous material was
placed in a humidity chamber containing an aqueous salt solution
and the chamber was sealed. The sample was analyzed at specified
time points by PXRD.
PXRD
[0058] PXRD analyses were carried out on a Shimadzu XRD-6000 X-ray
powder diffractometer using Cu K.alpha. radiation (1.5406.A). The
instrument is equipped with a fine-focus X-ray tube. The tube
voltage and amperage was set at 40 kV and 40 mA, respectively. The
divergence and scattering slits were set at 1.degree. and the
receiving slit was set at 0.15 mm. Diffracted radiation was
detected by a NaI scintillation detector. A theta-two theta
continuous scan at 3/min (0.4 sec/0.02 step) from 2.5 to 40.degree.
2O was used. A silicon standard was analyzed each day to check the
instrument alignment. Each sample was analyzed on a quartz sample
holder.
[0059] Table 6 summarizes the results of the stability studies. The
data demonstrate that the simulated drug products of this invention
show superior physical stability compared to amorphous norgestimate
alone. In the absence of lactose, amorphous norgestimate
recrystallizes in less 3 days at 0% relative humidity and less than
1 day at 31% and 76% relative humidities. Co-precipitates from
EtOH:H.sub.2O or 2-BuOH:H.sub.2O show stability (ie. onset of
norgestimate recrystallization) to 90 days or 25 days,
respectively, at 0% RH. In spray-dried or milled mixtures,
norgestimate remained essentially non-crystalline during the entire
study period (97 days) at 0% or 31% RH. A milled mixture showed the
best stability at 76% RH, stabilizing non-crystalline norgestimate
up to about 82 days. A 1:1 milled amorphous mixture showed
partially crystalline norgestimate and after 93 days it remained
partially crystalline. From these studies, it can be concluded that
lactose stabilized norgestimate in an essentially non-crystalline
form.
TABLE-US-00008 TABLE 6 Stability of Amorphous Norgestimate
Stability of Amorphous Norgestimate Amorphous Sample Method 0% RH
31% RH 76% RH Norgestimate Evaporated <3 days <1 day <1
day 1:9 Norgestimate:Lactose Co-precipitated from <90 days --
<1 day EtOH:H.sub.2O 1:1 Norgestimate:Lactose Co-precipitated
from -- -- .sup. <7 days EtOH:H.sub.2O 1:9 Norgestimate:Lactose
Co-precipitated from 2- <25 days <6 days <1 day
BuOH:H.sub.2O 1:9 Norgestimate:Lactose Spray-dried from
EtOH:H.sub.2O >97 days >97 days -- 1:9 Norgestimate:Lactose
Milled crystalline mixture >103 days >103 days <82 days
1:9 Norgestimate:Lactose Milled amorphous mixture >93 days
>93 days <1 day 1:1 Norgestimate:Lactose Milled amorphous
mixture.sup.h <1 day.sup.i <1 day.sup.i <1 day
Example 3
[0060] The lactose/norgestimate mixtures made as in Example 2 were
subjected to thermal analysis, according to conventional
Differential Scanning Calorimetry (DSC).
Glass-Transition Temperature and Crystallization Exotherm
Measurements
[0061] Amorphous materials exhibit glass-transition temperatures
(T.sub.g) that reflect the physical stability of the amorphous
form. The stabilized mixtures, norgestimate:lactose (1:9) mixtures,
were examined along with individual amorphous materials to obtain
T.sub.g values that might give insight to the stability of each
mixture compared to a single-component system. Glass-transition
temperature measurements generally entail trial runs on a DSC to
obtain an optimal method for observing glass-transition events.
Amorphous lactose exhibits a very strong T.sub.g event at
114-115.degree. C. However, amorphous norgestimate does not produce
consistent T.sub.g events. Some amorphous norgestimate samples
produce a weak T.sub.g event at 122-123.degree. C., while other
samples shown an exothermic event, probably because of norgestimate
crystallization. All of the norgestimate samples show a similar
endothermic event at 226-228.degree. C. The thermal gravimetric
analysis (TGA) of samples show rapid weight loss at that
temperature, therefore, the endotherm over 220.degree. C. primarily
corresponds to decomposition. The Merck Index lists the melting
temperature of the crystalline norgestimate at 214-218.degree.
C.
[0062] Another DSC method used revealed a consistent thermal event
corresponding to the crystallization of norgestimate (Tc). This
thermal event (Tc) was used to measure the stability of different
simulated drug products. The temperature of Tc- should be higher if
norgestimate is stabilized by lactose.
[0063] The simulated drug products show the absence or a higher
crystallization event (T.sub.c) compared to pure amorphous
norgestimate (Table 7). The T.sub.c data are consistent with the
physical stability data, proving that amorphous norgestimate
stabilization is achieved by lactose.
TABLE-US-00009 TABLE 7 T.sub.c Measurements of Amorphous Mixtures
Sample T.sub.c Amorphous norgestimate 105.degree. C. 1:9
Norgestimate:lactose co-precipitate from 2-BuOH:H.sub.2O
164.degree. C. 1:1 Norgestimate:lactose co-precipitate from
2-BuOH:H.sub.2O 1:9 Norgestimate:lactose spray-dried 1:9
Crystalline norgestimate:lactose milled 132.degree. C. 1:9
Amorphous norgestimate:lactose milled 1:1 Amorphous
norgestimate:lactose milled 126.degree. C.
Example 4
Wet/Dry Processing
[0064] A progestin such as norgestimate is dissolved in an
appropriate solvent such as methanol or ethanol. The solution is
then deposited onto a powder bed containing lactose and several
other additives. The deposition involves creating droplets of the
solution which are sprayed onto the powder bed with mixing to
prevent lumps. After sufficient time for all the solution to be
deposited the solvent is removed using vacuum and heat. When a
predetermined minimum quantity of solvent has been removed, the
mixture is then subjected to further blending. The blending is
performed, for example, in a geometric tumble blender equipped with
an impeller or chopper blades for a length of time sufficient to
impart mechanical energy as described above to produce a
lactose/progestin powder blend with the progestin stabilized in
substantially non-crystalline form.
* * * * *