Title of Invention


Abstract A steroid hormone product having improved dissolution and release rate properties, said product comprising a steroid hormone in substantially non crystalline form in admixture with an excipients, said excipients stabilizing said hormone in its substantially non-crystalline form, wherein the steroid hormone is norgestimate and the excipients is lactose.
Field of the Invention
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.
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
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.
Solvent-based processes, referred to herein as "wet processiing" 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.
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
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.
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.
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.
U.S. Patent 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.
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.
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.
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
Summary of the Invention
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.
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
30 about 10 µg to about 50 µg of an estrogen and/or from about 50 µg to about 300 µg
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.
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 excipent/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.
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
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
As used herein, the following terms shall have the meaning ascribed to them
below, except when the context clearly indicates differently:
"Poor" or "low" solubility refers to substances that are very slightly soluble to
insoluble according to the following USP definitions.
"Content uniformity" means a relative standard deviation in active ingredient
content of ± 1.5%, preferably ± 1.0% and most preferably ± 0.5%.
As stated abbve, 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.
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 p lactose and spray-dried lactose. Spray-dried lactose
(e.g., FAST-FLO lactose available from Foremost Farms, Baraboo, Wl) 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 metastabie 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
Crystaline 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).
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. Hüttenraunch, 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.
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-cystalline 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.
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
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.
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.
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°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.
Employing the current dissolution standard (USP Apparatus 2,75 rpm, 600ml
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.
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 °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.
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 i
norgestimate tablets.
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.
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 °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.
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)
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.
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.
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 microcrystailine
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, filters, 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.
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 ß-estradiol, ethinyl estradiol, 17-a 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
The following examples describe the invention in greater detail and are
intended to illustrate it without limiting its scope.
Example 1
Amorphous Lactose/Noraestimate Dry Ground Mixture
Amorphous norgestimate was prepared by dissolving norgestimate (200. mg)
in 5 ml of (DCM) dichloromethane and 0.26ml ethanol (EtOH). The solution was
filtered through a 0.2µm filter, and solvent was evaporated under reduced pressure
to afford amorphous solid.
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.
A mixture of crystalline norgestimate:cystalline 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.
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 5: Preparation of Amorphous Norgestimate:Lactose by Milling
Example 2
Stability Studies of Amorphous Materials
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 :
latose mixtures.
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:H2O, or 2-BuOH:H20, 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.
The materials for each sample were prepared as follows:
Amorphous Norgestimate
Norgestimate (200 mg) was dissolved in 5 mL of DCM and 0.26 mL of
ethanol. The solution was filtered through a 0.2 µm filter and solvent was evaporated
under reduced pressure to afford the amorphous solid.
Amorphous Lactose
FAST-FLO lactose (516 mg) was dissolved in 17 mL of H2O and filtered
through a 0.2µm filter, then lyophilized to afford dry material. However, the solid was
partially crystalline.
Co-precipitation of Norgestimate/Lactose
Norgestimate (10 mg) and FAST-FLO lactose (91 mg) were dissolved in 143
mL of EtOH:H20 (3.56:1) and filtered through a 0.45 µm filter. The solvent was
evaporated under reduced pressure to afford amorphous solid.
Norgestimate (20 mg) and FAST-FLO lactose (180 mg) were dissolved in 65
mL of 2-Butanol: Water (68:32) and filtered through a 0.2µm filter. The solvent was
evaporated under reduced pressure at 30°C to afford a non-crystalline solid.
Norgestimate (10 mg) and FAST-FLO lactose (90 mg) were dissolved in 29
mL of ACN: H2O (2.6:1) at 60°C and filtered through a 0.2µm filter. The solvent was
evaporated under reduced pressure at 35°C to afford a non-crystalline solid.
Spray Drying of Norgestimate/Lactose
Amorphous lactose was placed in a round bottom flask and attached to a
vacuum pump. A solution of norgestimate in 95:5 EtOH:H2O (0.5 mg/mL) was filtered
through a 0.2µm 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.
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
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
Physical Mixing of Norgestimate/Lactose
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
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 analyses were carried out on a Shimadzu XRD-6000 X-ray powder
diffractormeter using Cu Ka 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 ° and the receiving
slit was set at 0.15 mm. Diffracted radiation was detected by a Nal scintillation
detector. A theta-two theta continuous scan at 3 /min (0.4 sec/0.02 step) from 2.5 to
40° 20 was used. A silicon standard was analyzed each day to check the
instrument alignment. Each sample was analyzed on a quartz sample holder.
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:H2O or 2-BuOH:H2O
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 6: Stability of Amorphous Norgestimate
Example 3
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
Amorphous materials exhibit glass-transition temperatures (Tg) 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 Tg 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 Tg
event at 114-115 °C. However, amorphous norgestimate does not produce
consistent Tg events. Some amorphous norgestimate samples produce a weak Tg
event at 122-123 °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 °C. The thermal gravimetric analysis (TGA) of
samples show rapid weight loss at that temperature, therefore, the endotherm over
220°C primarily corresponds to decomposition. The Merck Index lists the melting
temperature of the crystalline norgestimate at 214-218°C.
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.
The simulated drug products show the absence or a higher crystallization
event (Tc) compared to pure amorphous norgestimate (Table 7). The Tc data are
consistent with the physical stability data, proving that amorphous norgestimate
stabilization is achieved by lactose.
Table 7: Tc Measurements of Amorphous Mixtures
Wet/Dry Processing
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.
We Claim:
1. A steroid hormone product having improved dissolution and
release rate properties, said product comprising a steroid hormone
in substantially non crystalline form in admixture with an
excipients, said excipients stabilizing said hormone in its
substantially non-crystalline form, wherein the steroid hormone is
norgestimate and the excipients is lactose.
2. A method of preparing a steroid hormone product having improved
dissolution and release rate properties, said method comprising the
steps of:
preparing a mixture comprising at least one steroid hormone and at
least one excipients;
imparting to said mixture sufficient mechanical energy to yield an
excipients/hormone powder blend wherein the hormone is
stabilized in its substantially non-crystalline form by said
excipients and forming said product from the powder blend,
wherein the steroid hormone is norgestimate and the excipients is
3. The method as claimed in claim 2, wherein 0.1 hp-min/kg of
mechanical energy is imparted to the mixture to form the powder
4. The method as claimed in claim 2 or claim 3, 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 as claimed in any one of claims 2 to 4, wherein the
mixture comprises a hormone/excipients ratio of from 1/1 to 1/10.
6. The method as claimed in any one of claims 2 to 5, wherein the
step of preparing the mixture includes the steps of:
preparing a solution of the hormone in a suitable solvent;
uniformly mixing the solution with the excipients; and
removing the solvent.
A steroid hormone product having improved dissolution and release rate
properties, said product comprising a steroid hormone in substantially non
crystalline form in admixture with an excipients, said excipients stabilizing
said hormone in its substantially non-crystalline form, wherein the steroid
hormone is norgestimate and the excipients is lactose.






779-kolnp-2003-granted-description (complete).pdf

779-kolnp-2003-granted-examination report.pdf

779-kolnp-2003-granted-form 1.pdf

779-kolnp-2003-granted-form 18.pdf

779-kolnp-2003-granted-form 2.pdf

779-kolnp-2003-granted-form 26.pdf

779-kolnp-2003-granted-form 3.pdf

779-kolnp-2003-granted-form 5.pdf

779-kolnp-2003-granted-letter patent.pdf

779-kolnp-2003-granted-reply to examination report.pdf


779-kolnp-2003-granted-translated copy of priority document.pdf

Patent Number 216078
Indian Patent Application Number 779/KOLNP/2003
PG Journal Number 10/2008
Publication Date 07-Mar-2008
Grant Date 06-Mar-2008
Date of Filing 13-Jun-2003
Applicant Address US ROUTE 202, RARITAN, NJ 08869-0602
# Inventor's Name Inventor's Address
PCT International Classification Number A 61 K 31/567
PCT International Application Number PCT/US01/48862
PCT International Filing date 2001-12-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/255,669 2000-12-14 U.S.A.