DESCRIPTION 0 4 SEP 3Mh
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical formulation comprising
progesterone in a lyophilized form, which on mixing with suitable liquid solvent
is ready to inject. The constituted formulation remains stable up to a suitable
period.
BACKGROUND OF THE INVENTION
US 20110104289 A1 relates to the development of a method and
pharmaceutical compositions for obtaining plasmatic progesterone levels in
humans and for maintaining a plasmatic progesterone concentration between
42 and 3.5 ng/mL for eight days as well as maximum plasmatic concentrations
(Cmax) between 12 and 42 ngImL, sufficient for use in different therapeutic
options that require said progesterone concentrations.
US 201 100821 27 relate to injectable progesterone formulations and processes
for their preparation.
This prior art has the following problemsa)
The stirring time was less (app. 40 minutes) which does not allow the
whole of progesterone to complex with the hydroxypropyl betacyclodextrin.
b) In this prior art, the hydroxypropyl betacyclodextrin used should not
contains unsubstituted beta cyclodextrin more than 0.3%, which requires an
extra step to reduce the percentage of unsubstituted betacyclodextrin.
CN 101 1521 86 provides a progesterone injection and the preparation method,
which solves the problems of strong pungency, inconvenient use with prior
progesterone injection, the problems of low stability and poor quality with prior
progesterone micro-emulsion, and the problems of high cost with asepsis
preparation process. The weight percentage of the progesterone injection is:
0.5 to 2 percent of progesterone, 15 to 35 percent of oil for injection, 1 to 12
percent of emulsifier, 0.1 to 1 percent of assistant emulsifier, 0.2 to 2 percent of
stabilizer, 0.01 to 2.5 percent of antioxidant and allowance of water.
US 4727064 comprise pharmaceutical preparations consisting generally of a
drug with substantially low water solubility and amorphous, water-soluble
cyclodextrin-based mixtures. In these preparations a stable amorphous state
can be achieved. This improves the dissolution properties of the drug and
hence its absorption by the body. The required cyclodextrin-based mixtures
were prepared from a-, P-, or y-cyclodextrin which were rendered amorphous
through non-selective alkylation. The alkylation agents suitable for that
purposes are exemplified by propylene oxide, glycidol, iodoacetamide,
chloroacetate, or 2-diethylaminoethylchloride; their reactions with cyclodextrins
were performed in a manner to yield mixtures containing many components, a
circumstance which effectively prevents crystallization processes within the
above pharmaceutical preparation.
Although there are patents of progesterone aqueous injection and there are
also the application of patents, but there is at present no commercially available
aqueous formulation of progesterone. This clearly indicates a practical
impossibility of implementing the process discussed in the above patents.
Thus there is strong need of a formulation that provides a stable aqueous
formulation of progesterone and also has industrial applicability and commercial
viability.
OBJECTIVES OF THE INVENTION
The object.of the present invention is to provide stable progesterone injection.
5
Another object of the present invention is to provide a stable progesterone
injection that does not contain oil,
Yet another object of the present invention is to provide a progesterone injection
which does not &use pain at the site of injection.
Another object of the present invention is to provide a formulation that will
provide an appropriate amount of progesterone which is required to raise the
drug concentration at therapeutic level.
DESCRIPTION OF THE INVENTION
Progesterone is a C-21 steroid hormone involved in the female menstrual cycle,
pregnancy and embryogenesis of humans and other species. Progesterone
belongs to a class of hormones called progestogens, and is the major naturally
occurring human progestogen.
Progesterone is lipophilic in nature and diffuse freely into cells, where they bind
to the progesterone receptors and exert their progestational activity. The
steroid-receptor complex binds to DNA in the nucleus, thereby inducing the
synthesis of specific proteins. Progesterone receptor concentrations are low in
absence of estrogens, and increase following estrogen administration.
In threatened miscarriage therapy, high plasma levels of progesterone, at least
200nmol/ml, must be attained and maintained in order to achieve a therapeutic
effect.
However, because of the slow gastrointestinal absorption and high hepatic
metabolism of this hormone, such plasma levels of progesterone are not
achieved by oral administration. Therefore, in the treatment of those
pathologies where high concentration of progesterone is required, it is generally
administered in injectable form.
Since progesterone is lipophiilic in nature, thus the prior art has the oil based
injection which upon administration causes irritation at the site of injection.
Further, the oil has its own action on the body. The oil based injection cannot be
given subcutaneously.
Thus there is a need to formulate an aqueous injection of progesterone.
The present invention relates to a stable pharmaceutical injection of
progesterone which is formulated as an aqueous injection with the help of
cyclodextrin derivatives, preferably Wydroxypropyl betacyclodextrin (HP
Betacyclodextrin). The ratio of Progesterone with Cyclodextrin derivative ranges
from 1:10 to 1:13, preferably 1:12.
There are prior art in which progesterone is complexed with cyclodextrin but the
prior art have the following practical difficulties:
a) The stirring time was less (app. 40 minutes) which does not allow the
whole of progesterone to complex with the hydroxypropyl betacyclodextrin, thus
reducing the overall yield of the complex.
b) In this prior art, the hydroxypropyl betacyclodextrin used should not
contains unsubstituted beta cyclodextrin more than 0.3%, which requires an
extra step to reduce the percentage of unsubstituted betacyclodextrin.
It was surprisingly found by the inventor that if the stirring time of the process is
considerably increased (approximately 3-4 times of the prior art), then whole of
the HP betacyclodextrin is complexed with progesterone resulting in greater
yield of the complex.
Following are the steps of the present invention:
a) HP-Betacyclodextrin was weighed and mixed with water through slow
mechanical stirring.
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b) Progesterone was weighed and added to the solution obtained in step a)
and make up the required volume.
c) The solution was kept under stirring for 120 minutes.
d) The solution so obtained after stirring was lyophilized.
e) The powder obtained after lyophilization was filled in the vials.
SIGNATURE of Mr. Sanjeev Jain (Inventor and Authorized representative of
Applicant)
Delhi
(Sh. Sanjeev Jain)
ORIGINAL
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CLAIMS
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We Claim:
1) An Injectable formulation comprising progesterone, with a complexing
agent
2) The complexing agent as claimed in claim 1 is Hydroxy propyl
betacyclodextrin.
3) The formulation as claimed in claim 1 is prepared with the following
process:
a) HP Betacyclodextrin was weighed and mixed with water through slow
mechanical stirring.
b) Progesterone was weighed and added to the solution obtained in step a)
and make up the required volume.
c) The solution was kept under stirring for 120 minutes.
d) The solution so obtained after stirring was lyophilized.
e ) The powder obtained after lyophilization was filled in the vials.