DESCRIPTION
FIELD OF THE INVENTION
The present invention relates to the pharmaceutical formulation comprising at
least an estrogen, at least a progestogen and L-methyl folate calcium.
5 Further, the estrogen is preferably estradiol and the preferable progestogen is
Nomegestrol Acetate. The invention is also related to a combipack comprising
28 tablets in which 24 tablets are of Nomegestrol, Estradiol and L-methyl
folate calcium and the 4 tablets are of L-Methyl folate calcium. The invention
also provides for the method of contraception in which one tablet of
10 Nomegestrol, Estradiol and L-methyl folate calcium combination to be taken
for 24 days and 4 tablets of L-methyl folate calcium the next 4 days making
the combipack for 28-days use.
BACKGROUND OF THE INVENTION
Folic acid insufficiency is associated with an increased risk of neural tube
15 defects, a debilitating congenital anomaly in which the neural tube does not
close properly. This occurs in 0.5-6.5 out of every 1,000 pregnancies. The
neural tube forms in the first month after conception, with closure by about 28
days; thus, in order to prevent neural tube defects maternal intake of folic acid
should begin before conception and continue through early pregnancy.
20 Some Authors suggested that the absorption of naturally occurring food folate
may be impaired in women using OC. It was further reported that absorption
of the polyglutamyl folate form is reduced by about 50% in OC users versus
non-users with no differences detected in the absorption of monoglutamyl
folate. It was hypothesized that OC may impair the enzymatic cleavage by the
25 intestinal folate conjugated enzyme required for polyglutamyl folate
absorption. An additional proposed mechanism for impaired folate status is
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that OC may .increase the clearance of folate from blood, possibly as a result
of changes in liver enzymes or renal folate binding proteins involved in
reabsorption in the kidney. Other investigators proposed that OC use may
impair folate metabolism via increased activity of microsomal enzymes
5 requiring folate. In addition, there have been several early reports of
increased serum, and leukocyte folate binders in OC users. It should be
considered that the hormonal content of OCs was much higher in the 1960s
and 1970s when these studies were carried out-raising the question of
whether conclusions regarding the effect of OC use on folate status can still
10 be extrapolated (International Journal of Reproduction, Contraception,
Obstetrics and Gynecology Volume 3 • Issue 1). Thus, a decrease of the
folate serum level among oral contraceptive users pose an additional risk for
such users who become pregnant within three to six months following
discontinuation of use. Thus folic acid is required to be used along with oral
15 contraceptives as it will help protect against a number of disease to the fetus
in case the women becomes pregnant within 3-6 months after discontinuation
of OC. Further, the Neural tube closure is completed 28 days (four weeks)
from conception, and the preventive effect of folic acid is not effective after
that period. Moreover, highest serum folate levels require at least three weeks
20 of treatment with folic acid. Therefore, Folic acid supplementation should start
at least one month and preferably two to three months prior to conception.
There is concern that high intakes of folic acid from fortified food and dietary
supplements might mask the macrocytic anemia of vitamin B12 deficiency,
thereby eliminating an important diagnostic sign. One recent study indicates
25 that high serum folate levels during vitamin B12 deficiency exacerbate (rather
than mask) anemia and worsen cognitive symptoms. Also, folic acid
supplementation will not correct the nerve damages occurred due to Vitamin
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B12 deficiency. Thus, as long as there is Vitamin B12 deficiency exists, the
risk of permanent nerve damage also exists.
US 20080160004 relates to a pharmaceutical composition which comprises
progestogens, preferably drospirenone, estrogens, preferably ethinylestradiol
5 and 5-methyl-(6S)-tetrahydrofolate, can be employed as oral contraceptive
and moreover prevents disorders caused by folate deficiency in the
consumers, in particular cardiovascular disorders and, after conception of the
embryo, congenital malformations caused by folate deficiency such as, for
example, neural tube defects, ventricular valve defects, urogenital defects,
10 and cleft lip, jaw and palate, without masking the symptoms of vitamin B12
deficiency, and at the same time even in the case of homozygous or
heterozygous polymorphism of methylenetetrahydrofolate reductase
facilitates unimpaired utilizability of the folate component 5-methyl-(6S)-
tetrahydrofolate by the body and thus its biological activity for preventing the
15 abovementioned congenital malformations caused by folate deficiency.
US 20060057186 disclose a pharmaceutical preparation comprising
progestin, estrogen and a multivitamin agent. The progestin may be between
0 and 0.50 mg Desogesterel and the estrogen may be between 0 and 0.2 mg
Ethinyl Estradiol.
20 . US 20130178452 elates to solid pharmaceutical compositions, in particular to
oral contraceptives, comprising a progestogen, such as drospirenone; an
estrogen, such as ethinylestradiol; a tetrahydrofolic acid or a pharmaceutically
acceptable salt thereof, such as calcium 5-methyl-(6S)-tetrahydrofolate; and
at least one pharmaceutical acceptable excipient or carrier. The compositions
25 of the invention provide good stability of the tetrahydrofolic acid upon storage
while still ensuring a fast and reliable release of the estrogen and the
progestogen present in the composition.
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Thus, due to the above reason, the present inventor has incorporated Lmethyl
folate calcium in the composition, which does not have the
disadvantage of masking the anemia due to Vitamin B12 deficiency and also
provides all the benefits of folic acid.
5 OBJECT OF THE INVENTION
The Object of the present invention is related to formulate an effective
Contraceptive formulation.
Another aspect of the present invention is to provide the formulation
containing L-methyl tetrahydro folate calcium used to reduce the risk of neural
10 tube defects in fetus.
Another aspect of the present invention is to provide adequate quantity of Lmethyl
folate so as to reduce the risk of fetal defects.
Yet another object of the present invention is to negate the side effect of daily
oral contraceptives.
15 DETAILED DESCRIPTION OF THE INVENTION
In the invention's context, the term "estrogen" is meant to encompass all
compounds exhibiting estrogenic activity. Suitable forms of estrogen include,
without limitation, 17p-estradiol, mestranol, conjugated estrogens, estrone,
ethinyl estradiol, and combinations thereof, as well as salts, esters or
20 prodrugs of any thereof. Further, the term also encompasses the complexes
of estrogen such as complex with cyclodextrin and derivatives thereof. The
preferable estrogen is selected from the group consisting of ethinylestradiol,
estradiol and mestranol. The most preferred estrogen is ethinyl estradiol. The
progestogen used in the present invention is nomegesterol and
25 pharmaceutically accepted salts, esters or prodrugs thereof. Further, the
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complexes of nomegesterol are also under the purview of this invention. The
complexion material is preferably cyclodextrin and its derivatives. In addition
to the estrogen and the progestogen, the composition of the invention further
comprises a tetrahydrofolic acid or a salt thereof. Specific examples of such
5 tetrahydro folic acids include 5-methyl-(6S)-tetrahydrofolic acid, (68)
tetrahydrofolic acid, 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-
tetrahydrofolic acid, 5,10-methylene-(6R) tetrahydrofolic acid, 5,10-methenyl-
(6R)-tetrahydrofolic acid, 5-formimino-(6S) tetrahydrofolic acid, including
pharmaceutical^ acceptable salts of these tetrahydrofolic acids and glutamyl
10 derivatives of these tetrahydrofolic acids. In a preferred embodiment of the
invention, the tetrahydrofolic acid is 5-methyl-(6S) tetrahydrofolic acids or a
pharmaceutically acceptable salt thereof. In a more preferred embodiment of
the invention the salt of 5-methyl-(6S) tetrahydrofolic acids is an alkaline earth
metal salt, in particular the calcium salt.
15 For formulation of the oral dosage forms according to the invention, various
pharmaceutically acceptable excipients are used.
Suitable fillers may be microcrystalline cellulose, powdered cellulose, lactose,
starch, pregelatinized starch, or sucrose preferably microcrystalline cellulose
and lactose. Suitable binders are starch, polyvinylpyrrolidone, alginic acid,
20 methylceilulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylceilulose, polymethacrylates, and others preferably
hydroxypropyl cellulose, hydroxypropyl methylceilulose and
polyvinylpyrrolidone. Suitable disintegrants are starch, pregelatinized starch,
sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium
25 carboxymethylcellulose, cross-linked polyvinylpyrrolidone, algihic acid,
* sodium alginate, and others preferably sodium starch glycolate, cross-linked
sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
Suitable glidants are magnesium stearate, calcium stearate, aluminium
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stearate, stearic acid, palmitic acid, cetanol, stearol, colloidal silicon dioxide,
talc, powdered cellulose, starch and others, preferably, colloidal silicon
dioxide. Suitable lubricants are stearic acid, calcium, magnesium, zinc or
aluminium stearate, siliconized talc, glycerol monostearate, and others.
5 Preferred lubricants are calcium or magnesium stearate and stearic acid. The
release of all the ingredients from the pharmaceutical formulations of the
present invention can be immediate or modified, controlled, delayed,
sustained, and extended. The release rate for all active drugs can be the
same or different. The dosage formulation of the combination may be orally
10 administered.
The cyclodextrin is typically selected from a- cyclodextrin, p-cyclodextrin and
*
y-cyclodextrin and the derivatives thereof. The preferred cyclodextrin is (3-
cyclodextrin.
According to one preferred embodiment of the invention, the formulation
15 comprises Nomegetsrol acetate is 2.5 mg, 17-Beta estradiol 1.5 mg and Lmethylfolate
calcium 451 meg.
Another preferred formulation is in the form of combipack comprising 24 tablet
of Nomegetsrol acetate is 2.5 mg, 17-Beta estradiol 1.5 mg and Lmethylfolate
calcium 451 meg and 4 tablets of L-methylfolate Calcium 451
20 meg.
SIGNATURE of Sanjeev Jain (Inventor and Authorized representative of
Applicant)

CLAIMS
We claim:
1) A pharmaceutical formulation comprising progestogen, estrogen and L-methyl folate
along with at least a pharmaceutical excipient.
2) Progestogen as claimed in claim 1 is preferably be nomegesterol and
pharmaceutically accepted salts, esters or prodrugs thereof.
3) Nomegesterol as claimed in claim 2 is in amount 2.5 mg.
4) The estrogen as claim in claim 1 can be selected from the group comprising ethinyl
estradiol, 17- beta estradiol and mestranol or combinations thereof.
5) The estrogen as claimed in claim 4 will preferably be 17-beta estradiol.
6) Ethinyl estradiol as claimed in claim 5 is in amount 1.5 mg.
7) The amount of L-methyl folate as claimed in claim 1 will be 451 meg.
8) A kit comprising
At least 24 units of the formulation claimed in claim 1 and
4 tablets of L-methyl folate and
the dosage are disposed in such a way that initially 24 tablets are used for the first
24 days and then 4 tablets are consumed for the next four days making the whole kit
for a 28 days therapy.
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9) The excipients claimed in claim 1 can be selected from fillers, binders, disintegrants,
glidants, lubricants, binders or the combinations thereof.
10) The formulation claimed in claim 1 may be coated or uncoated and immediate or
modified release.