Field of the Invention
The present invention relates to a method of reducing the incidence of nausea and
vomiting associated with the administration of oral contraceptive formulation comprising
progestin and /or estrogen and an antiemetic.
More particularly the present invention relates to oral contraceptive formulation
comprising levonorgestrel and ondensatron
The present invention relates to the method of preparation of oral contraceptive
formulation comprising progestin and /or estrogen and an antiemetic.
Background of the Invention
The ovarian/menstrual cycle is a complex event characterized by an estrogen rich
follicular phase and, after ovulation, a progesterone rich luteal phase. Each has a
duration of approximately 14 days resulting in an intermenstrual interval of about 28
days. The endometrial tissue responds to the changes in hormonal milieu.
The onset of menstruation is the beginning of a new menstrual cycle and is counted as
day 1. During a span of about 5 to 7 days, the superficial layers of the endometrium,
which grew and developed during the antecedent ovarian/menstrual cycle, are sloughed
because demise of the corpus luteum in the non-fertile menstrual cycle is associated
with a loss of progesterone secretion. Ovarian follicular maturation occurs progressively
resulting in a rise in the circulating levels of estrogen, which in turn leads to new
endometrial proliferation.
The dominant ovarian follicle undergoes ovulation at mid-cycle, generally between
menstrual cycle days 12 to 16 and is converted from a predominantly estrogen source to
a predominantly progesterone source (the corpus luteum). The increasing level of
progesterone in the blood converts the proliferative endometrium to a secretory phase in
which the tissue proliferation has promptly abated, leading to the formation of
endometrial glands or organs. When the ovulated oocyte is viably fertilized and
continues its progressive embryonic cleavage, the secretory endometrium and the
conceptus can interact to bring about implantation (nidation), beginning about 6 to 8
days after fertilization.
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If an ongoing pregnancy is to be established via implantation, the embryo will attach and
burrow into the secretory endometrium and begin to produce human chorionic
gonadotropin (HCG). The HCG in turn stimulates extended corpus luteum function, i.e.
the progesterone production remains elevated, and menses does not occur in the fertile
menstrual cycle. Pregnancy is then established. In the non-fertile menstrual cycle, the
waning level of progesterone in the blood causes the endometrial tissue to be sloughed.
This starts a subsequent menstrual cycle.
Because endometrial proliferation serves to prepare the uterus for an impending
pregnancy, manipulation of hormones and of the uterine environment can provide
contraception. For example, estrogens are known to decrease follicle stimulating
hormone secretion by feedback inhibition.
Progestins can also provide contraception. Endogenous progesterone after estrogen is
responsible for the progestational changes of the endometrium and the cyclic changes of
cells and tissue in the cervix and the vagina. Administration of progestin makes the
cervical mucus thick, tenacious and cellular which is believed to impede spermatozoal
transport. Administration of progestin also inhibits luteinizing hormone secretion and
blocks ovulation in humans.
Several devices and pharmaceutical compositions are available for the prevention of
undesirable conception in the case of regular and planned coitus. For example, condom,
pessary, intrauterine devices as well as the different mono-or multi-phasic oral
contraceptives. The most prevalent form of oral contraception is a pill that combines an
estrogen and/or a progestin, a so-called combined oral contraceptive preparation.
Further sometimes unintentional pregnancies occur for any number of reasons.
Certainly, they can occur following sexual intercourse when neither party uses a
contraceptive device or drug. However, this is by no means, the only reason for
unintended pregnancies. Condoms are known to break; diaphragms to slip; and
traditional contraceptive pills are, by their own admission, not 100 percent effective, even
when taken properly. Moreover, when pills are missed, particularly with the newer, low-
dose products, the risk of pregnancy increases substantially. In fact, each year in the
U.S. alone, approximately 750,000 pregnancies occur to women using traditional oral
contraceptive regimens. Of course, some of these pregnancies occur because the
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patient has failed to completely and dogmatically follow the prescribed pharmaceutical
regimen.
Emergency contraceptive ("EC") pills are an available treatment for women who are
concerned they may have become pregnant by their most recent unprotected sexual
encounter. These pills are intended for administration within days, and preferably within
hours after unprotected sex and often contain relatively high doses of for example, a
progestin and/or an estrogen. Reports in the scientific literature describe other drugs
which may be effective for emergency contraception as well. Dosages and protocols will
vary with the drug(s) used. However, in each case, the "pills" help to prevent pregnancy,
i.e. either preventing a fertilized ovum from implanting in the lining of the uterus and/or
depending on the timing of intercourse, preventing the sperm from fertilizing an egg.
Usually one tablet of levonorgestrel 0.75mg should be taken orally as soon as possible
within 72 hours after unprotected intercourse. The second tablet should be taken 12
hours after the first dose. Efficacy is better if levonorgestrel is taken as directed as soon
as possible after unprotected intercourse. Further 1.5mg of levonorgestrel can also be
administered at one time as an emergency contraceptive pill. But all such emergency
contraceptive pills, which contain high doses of contraceptive hormone, are associated
with high incidence of nausea and vomiting. Further if vomiting occurs within three hours
of taking the tablet; another tablet of emergency contraceptive pill should be taken
immediately.
Norgestrel and levonorgestrel, namely/the D isomer of norgestrel [.+-.-17.alpha.-13-
ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-in-3-on] have been used in combined
preparations as contraceptives for a long time. Further the dose range of levonorgestrel,
as emergency contraceptive pill is 1.50 mg in divided doses or 1.5mg in single dose.
Another common problem associated with oral contraceptives as well as an emergency
contraceptive pill is the incidence of nausea, which occurs, in a significant percentage of
patients. Women may experience vomiting and nausea as major side effect due to
contraceptive. It had been observed that about 23.1% of patient experience nausea and
5.6% vomiting when 0.75mg of levonorgestrel is administered. This is not only
uncomfortable, but may also compromise the efficacy of the contraceptive as the
associated vomiting may expel out the contraceptive pill. Certainly, a woman who has
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taken an emergency contraceptive pill and has had an adverse effect, is less likely to
take the steps to assure efficacy, including taking more emergency contraceptive pills.
One prior art CN 1485093 discloses a combination of maxeran preparation and
acyeterion.
Therefore, there remains a need for an oral contraceptive formulation which shows
reduced incidence of nausea and vomiting associated with the administration of oral
contraceptive and in turn increase the patient compliance.
Further it has also been recommended in the current therapy that if vomiting occurs
within three hours of taking the tablet; another tablet of emergency contraceptive pill
should be taken immediately to prevent contraceptive failure. Thus the present invention
also eliminates the need to administer second pill to substitute the expelled emergency
contraceptive pill and alleviates patient anxiety related to contraceptive failure.
Objects of the Invention
The present invention provides a method of reducing the incidence of nausea and
vomiting associated with the administration of oral contraceptive.
The present invention also provides an oral contraceptive formulation comprising an
antiemetic in immediate release formulation and oral contraceptive in delayed release
formulation.
Another object of the invention is to provide an oral contraceptive formulation comprising
antiemetic in immediate release and oral contraceptive in pulsatile release.
Another objective of the present invention relates to an oral contraceptive formulation
comprising ondensatron and levonorgestrel.
Another objective of the present invention relates to the process of preparing an oral
contraceptive formulation.
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Detailed Description of Invention
The present invention provides an oral contraceptive formulation, which shows reduced
incidence of nausea and vomiting, associated with oral contraceptives hormones. The
oral contraceptive formulation of the present invention comprises an antiemetic and oral
contraceptive. The oral contraceptives hormones used according to present invention
are progestin and /or estrogen.
The term "delayed release" is used in its conventional sense to refer to a drug
formulation in which there is a time delay provided between oral administration of a drug
dosage form and the release of the drug therefrom. "Delayed release" may or may not
involve gradual release of drug over an extended period of time, and thus may or may
not be "sustained release."
Estrogens which may be used in the present invention include, for example, ethinyl
estradiol, 17.beta.-estradiol, 17.beta.-estradiol-3-acetate, mestranol, conjugated
estrogens, USP and estrone or salts thereof. Furthermore the natural estrogens can be
used, e.g., estrone, estradiol or estriol, and the esters thereof, inter alis estradiol
valerate. 17.alpha.-Ethinylestradiol and estradiol valerate are preferred. The amount of
estrogen used is described herein as that which is "equivalent" in estrogenic potency to
an amount of ethinyl estradiol. The equivalent estrogenic potency of an estrogen to
ethinyl estradiol may be readily determined by one of ordinary skill in the art.
Progestogens which may be used in the present invention include, for example,
progesterone and its derivatives such as 17-hydroxy progesterone esters and 19-nor-17-
hydroxy progesterone esters, 17-alpha-ethinyl testosterone, 17-alpha-ethinyl-19-
nortestosterone (norethindrone) and derivatives thereof, norethindrone acetate,
norgestrel, nogestimate, desogestrel, levonorgestrel, medroxyprogesterone, dienogest.
Other exemplary progestogens include demegestone, drospirenone, dydrogesterone,
gestodene, medrogestone, medroxy progesterone and esters thereof. The amount of
progestogen used is described herein as that which is "equivalent" in progestogenic
potency to an amount of norethindrone acetate. The equivalent progestogenic potency
of a progestogen to norethindrone acetate may be readily determined by one of ordinary
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skill in the art. The most preferable progestogen for the present invention is
levonorgestrel and the preferable dose is 1.5mg in divided doses.
Suitable antiemetic for the present invention includes dopamine antagonist, 5HT3
receptor antagonist, anticholinergics, antihistaminics, cannabinoids and other drugs,
which have antiemetic effects. The dopamine antagonists include metoclopramide,
droperidol, domperidone, perphenazine, prochlorperazine, promethazine, triflupromazine
na dthe likes. 5HT3 antagonist includes ondansetron, granisetron, dolasetron,
tropisetron, and the likes. Anticholinergic drugs used as antiemetics are hyoscine,
scopolamine and the likes. Anti-histaminics as promethazine, meclizine, buclizine, and
likes are used as antiemetic. The most preferable antiemetic is ondansetron and the
preferable dosage range is 1-50mg. Other antiemetics which are used as OTC
antiemetics can also be combined together with levonorgestrel to prepare a OTC
emergency contraceptive formulation.
According to the methods of the invention, the method of reducing nausea and vomiting
associated with administration of oral contraceptives includes as combination of
progestin and anti emetic or estrogen and antiemetic or estrogen, progestin and
antiemetic. The preferable method of invention is the combination of progestin and
antiemetic. The preferred progestin is levonorgestrel and anti-emetic is ondansetron.
The formulation of the present invention comprises of combination of antiemetic and oral
contraceptive hormone in immediate release. The present invention may also have
antiemetic in immediate release or controlled release and oral contraceptive hormone in
immediate or delayed release or controlled release or pulsatile release. The formulation
may be manufactured by any of the standard manufacturing procedures
Thus the present invention allows the administration of emergency contraceptive pill or
any other dosage form comprising an anti emetic, preferably ondensatron or any other
antiemetic, in immediate release or controlled release and progestin and/ or estrogen,
preferably levonorgestrel preferably used in dose of 0.75mg, in immediate or delayed or
controlled release. The formulation needs to be administered as soon as possible after
unprotected intercourse, the second dose to be taken after 12 hours of taking the first
dose.
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According to one other method of the present invention the formulation may comprise of
an antiemetic preferably ondensatron or any other antiemetic, in immediate or controlled
release and progestin and/ or estrogen, preferably levonorgestrel preferably used in
dose of 1.5mg, in pulsatile release in such a way that the oral contraceptive hormone is
released in pulses.
According to one other method of the present invention the formulation may comprise of
an antiemetic preferably ondensatron or any other antiemetic, in immediate or controlled
release and progestin and/ or estrogen, preferably levonorgestrel preferably used in
dose of 1.5mg, in controlled release.
According to one other method of the present invention the formulation may comprise of
an antiemetic preferably ondensatron or any other antiemetic, in immediate or controlled
release and progestin and/ or estrogen, preferably levonorgestrel preferably used in
dose of 1.5mg, in delayed release. The antiemetic is released prior to release of oral
contraceptive hormone.
According to the one of the method of the invention an oral contraceptive combination
with reduced incidence of nausea and vomiting comprise of an antiemetic in immediate
release formulation and progestin and / or estrogen in delayed release formulation. It is
preferred that antiemetic is released at least about 30 minutes prior to the release of oral
contraceptive hormones. Preferably the release of antiemetic is about one hour prior to
the release of oral contraceptive hormones. This reduces the incidence of nausea and
vomiting associated with the administration of oral contraceptive formulation, which in
turn increases patient compliance, and efficacy of oral contraceptive formulation and
emergency contraceptive pill.
The oral pharmaceutical compositions useful in this invention may be in any orally
acceptable dosage form including, but not limited to granules, sachets, capsules, matrix
tablets, layered tablet, coated tablets and the likes.
The immediate-release portion of the dosage form according to present invention may
be either a coating applied or deposited over the entire surface of a unitary delayed-
release core, or a single layer of a tablet constructed in two or more layers, one of the
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other layers being the delayed-released portion or in the form of granules admixed with
delayed release granules. Further the formulation may be in the form plurality of delayed
release and immediate release granules, which may be compressed or filled in capsules
along with other pharmaceutical excipients. Immediate release of the drug from the
immediate-release portion is achieved in any of a variety of ways. One example is by
placing the drug in a layer or coating that is sufficiently thin to allow fast penetration by
gastrointestinal fluid, which then leaches the drug at a rapid rate. Another example is by
incorporating the drug in a mixture that includes a supporting binder or other inert
material that dissolves readily in gastrointestinal fluid, releasing the drug as the material
dissolves. A third is the use of a supporting binder or other inert material that rapidly
disintegrates into fine particles upon contact with gastrointestinal fluid, with both the
binder particles and the drug quickly dispersing into the fluid. Examples of materials that
rapidly disintegrate and disperse are lactose and microcrystalline cellulose.
Hydroxypropylmethylcellulose is a component that can serve both as a suspending
agent and as a binder.
The immediate-release drug can thus be deposited as a suspension or a solution over a
unitary core of the delayed-release drug, which may optionally be coated with the
intermediate layer. Deposition can be achieved by coating techniques commonly used in
the pharmaceutical formulation art, such as spraying, pan coating, and the like.
Alternatively, the immediate-release drug can be combined with particles of a binding
matrix and compressed over a preformed layer of the delayed-release drug to form a
layered tablet. In either case, the immediate-release coating or layer separates relatively
quickly from the remainder of the tablet after ingestion, leaving the remainder intact. The
formulation may have delayed release granules/ pellets and immediate release
granules/pellets compressed in tablet or filled in capsule.
Dosage forms with delayed release portion may be manufactured using standard
manufacturing procedures. The formulation may be prepared into granules or may be
coated with delayed release polymers. An delayed release coating can be applied to a
tablet, tablet segment, bead, granule, caplet or capsule using a coating pan, an airless
spray technique, fluidized bed coating equipment, or the like. The coating thickness, as
noted above, must be sufficient to ensure that the oral contraceptive hormone is
releases after the release of antiemetic. The "coating weight", or relative amount of
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coating material per dosage unit, generally dictates the time interval between ingestion
and drug release. The preferred coating weights for particular coating materials may be
readily determined by those skilled in the art by evaluating individual release profiles for
tablets, beads and granules prepared with different quantities of various coating
materials.
Such procedures are known to those skilled in the art. The formulations of the present
invention may comprise of excipients known in the art. The polymers may include
hydrophlic and / or hydrophobic polymer as cellulose derivative as hydroxypropylmethyl
cellulose, methyl cellulose, ethyl cellulose, polysaccharides, gums, the polymerized
gelatin, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate
phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose
acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose,
hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from
acrylic acid, methacrylic acid, and/or esters thereof preferably formed from acrylic acid,
methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl
methacrylate, and/or other vinyl monomers. Preferred enteric polymers are acrylic acid
and methacrylic acid polymers and copolymers, particularly those that are commercially
available under the tradenames Eudragit.RTM. L and Eudragit.RTM. S, in which the ratio
of free carboxyl to ester groups is about1:1 and 1:2, respectively, and wherein each
copolymer has a (weight average) molecular weight of aboutl 35,000 Da.
The delayed release dosage units in any of the embodiments of the invention can be
prepared, for example, by coating a drug or a drug-containing composition with a
selected coating material. The drug-containing composition may be, e.g., a tablet for
incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage
form, or a plurality of drug-containing beads, particles or granules, for incorporation into
either a tablet or capsule. Preferred coating materials are comprised of bioerodible,
gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable
polymers, and preferred delayed release coatings are comprised of enteric coating
materials.
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The coating may contain a plasticizer to prevent the formation of pores and cracks that
would permit the penetration of the gastric fluids. Suitable plasticizers include, but are
not limited to, triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl
citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl
citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and
dibutyl phthalate. The coating can also contain other coating excipients such as
detackifiers, antifoaming agents, lubricants (e.g., magnesium stearate), and stabilizers
(e.g., hydroxypropylcellulose, acids and bases) to solubilize or disperse the coating
material, and to improve coating performance and the coated product.
Alternatively, a delayed release dosage unit may be formulated by dispersing an active
agent within a matrix of a suitable material such as an delayed coating material or other
delayed release polymeric materials.
Other additives may be incorporated in the formulation, such as diluents, binders,
lubricants, antioxidants, colorings, sweeteners, flavorings and acidulants, wetting agents,
hydrophilizing agents such as sorbitol and cyclodextrins, osmotic agents or pore forming
agents such as mannitol, pH correctors, stabilizing agents such as trehalose and
mannitol, adsorbants, chelating and sequestering agents and gastroresistant film-coating
excipients of the type including cellulose acetylphthalate and polymethacrylates.
By way of example, there may be chosen any one of the following diluents or
alternatively a combination thereof: calcium carbonate, calcium sulfate, sucrose, dextrin,
dextrose, dicalciumphosphatedihydrate, kaolin, magnesium carbonate, magnesium
oxide, maltodextrin, cellulose, microcrystalline cellulose, sorbitol, starches,
pregelatinized starch, talc, tricalciumphosphate and lactose.
Among the binders, there may be mentioned: gum arabic, gum tragacanth, guar gum,
alginic acid, sodium alginate, sodiumcarboxymethylcellulose, dextrin, gelatin,
hydroxyethylcellulose, hydroxypropylcellulose, liquid glucose, magnesium and
aluminium silicate, maltodextrin, povidone, pregelatinized starch, starch and zein.
The lubricants are glidants (such as anhydrous colloidal silica, magnesium trisilicate,
magnesium silicate, cellulose, starch, talc or tricalcium phosphate) or alternatively
antifriction adhering agents (such as calcium stearate, glyceryl monostearate, glyceryl
11

palmitostearate, hydrogenated vegetable oils, paraffin, magnesium stearate,
polyethylene glycol, sodium benzoate, sodium lauryl sulfate, fumaric acid, stearic acid or
zinc stearate and talc).
As examples of antioxidants, persons skilled in the art may select any of the following
compounds: ascorbic acid, ascorbyl palmitate, fumaric acid, propyl gallate, sodium
ascorbate and sodium metabisulfite, alpha-tocopherol, malic acid, BHA and BTH.
Preferred wetting agents are: sodium docusate and sodium lauryl sulfate which are
anionic surfactants; benzalkonium chloride, benzethonium chloride and cetrimide which
are cationic surfactants; glyceryl monooleate, fatty acid esters of polyoxyethylene
sorbitan, polyvinyl alcohol) and sorbitans, which are nonionic surfactants.
Among the pH regulators, there are acidifying agents of the type including citric acid,
hydrochloric acid, lactic acid, tartaric acid, as well as alkalinizing agents of the type
including monoethanolamine, diethanolamine and triethanolamine, potassium citrate,
sodium bicarbonate, sodium citrate dihydrate.
Examples of adsorbents are bentonite, anhydrous colloidal silica, kaolin, magnesium
and aluminium silicate, microcrystalline cellulose and cellulose.
As chelating and sequestering agents, there may be used citric acid monohydrate,
edetic acid, disodium phosphate, monosodium phosphate, potassium citrate, tartaric
acid and sodium citrate dihydrate.
The quantities of these additives are those normally used in the art.
The formulation of the present invention may be prepared by conventional techniques
well known to those skilled in the art such as wet granulation, melt granulation, direct
compression or dry compaction and/or slugging and the like. The invention is illustrated
by the following not limiting examples:
Example 1

Coated Granules of
Levonorgestrel 1.5mg
Uncoated granules of
Ondansetron 16mg
Hydrophilic colloidal silica 0.5mg
Maize starch 23.5mg
Potato starch 0.5mg
Lactose monohydrtae 70.25mg
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Example 2

Core / First Layer
Levonorgestrel 0.75mg
Excipients
Delayed release coating 12%
Second Immediate
release layer
Ondensatron 16mg
Film Coating 2%
Other technologies known to those skilled in the art can be used in order to achieve
immediate release of antiemetic and delayed release of oral contraceptive hormones for
the present invention.
Dated this 25th day of October 2007

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