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1. INTRODUCTION
1.1 BACKGROUND OF STUDY 7, 10

Misoprostol is a prostaglandin E1 analogue. Misoprostol 200 µg tablets are currently registered

for use in Bangladesh for the treatment of acute duodenal and gastric ulcers and for the
prevention of stress induced upper gastrointestinal mucosal bleeding and lesions in post surgical
patients in intensive care units.

Misoprostol has been approved by European Heath Authorities and by the United States Food
and Drug Administration (FDA) for the prevention and treatment of gastric ulcers only.
However, clinicians routinely used this misoprostol off-label for obstetric and gynaecological
purposes, including cervical ripening, labour induction, and mid-trimester terminations of
pregnancy. Multiple clinical studies of misoprostol in this non-approved field have been
published.

Misoprostol has been widely used off-label internationally and in Bangladesh for many years for
these gynecological indications.

The innovator of Misoprostol is Piramal Health Care Ltd.UK. They formulated this drug as tablet
named “Cytotec”and marketed by“Pfizer”. The storage condition of pure Misoprostol is -20C
and 1% HPMC dispersion which is commercially available stable with in 2C to 8 C. It is very
much unstable at normal temperature.

As per ICH Climate zone of Northern Europe are in Zone I (Temperate zone) and USA are in
Zone II (Mediterranean/subtropical zone). Whereas Bangladesh is in Zone IVa (Hot
humid/tropical zone). The stability study conditions of Zone Iva are much different from Zone I
&II. Again for a thermo liable drug like as Misoprostol the risk factor will go up. On the other
hand most of our drug stores are not able to maintain controlled temperature storage area which
is usually common at developed countries.

Although the formula is widely used in many markets around the world, it is not described
officially in any pharmacopeia. There is no published study on development of Misoprostol
tablet in our region.

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The objective of these studies is developing a new stable formulation of Misoprostol tablet which
are bioequivalent to innovator Reference Listed Drug. These studies mainly focused on the
determination of relative bioavailability of the drug after single oral administration, the
determination of the compound using an optical compensation method or by using derivative
spectrophotometric procedures. As there is no method reported in the literature for the
simultaneous determination of Misoprostol in tablet, it was considered useful to develop and
validate a sensitive spectrophotometric method associated with high performance liquid
chromatography HPLC. Accordingly, the aim of this work is to formulation of stable immediate
release tablet & adapt the developed method for the quantitation of compounds in tablet
preparations in the presence of their degradation products for application in long-term both
stability studies of three commercially available batches (Validation batch).

1.2 TABLETS 9, 23

Tablet is defined as a compressed solid dosage form containing medicaments with or without
excipients. According to the Indian Pharmacopoeia Pharmaceutical tablets are solid, flat or
biconvex dishes, unit dosage form, prepared by compressing a drugs or a mixture of drugs, with
or without diluents. They vary in shape and differ greatly in size and weight, depending on
amount of medicinal substances and the intended mode of administration. It is the most popular
dosage form and 70% of the total medicines are dispensed in the form of Tablet. All
medicaments are available in the Tablet form except where it is difficult to formulate or
administer.

1.2.1 THE ADVANTAGES OF THE TABLET DOSAGE FORM:

1. They are unit dosage form and offer the greatest capabilities of all oral dosage form for the
greatest dose precision and the least content variability.
2. Cost is lowest of all oral dosage form.
3. Lighter and compact.
4. Easiest and cheapest to package and strip.
5. Easy to swallowing with least tendency for hang-up.
6. Sustained release product is possible by enteric coating.
7. Objectionable odour and bitter taste can be masked by coating technique.

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8. Suitable for large scale production.

9. Greatest chemical and microbial stability over all oral dosage form.
10. Product identification is easy and rapid requiring no additional steps when employing an
embossed and/or monogrammed punch face.

1.2.2 DISADVANTAGES OF TABLET DOSAGE FORM:

1. Difficult to swallow in case of children and unconscious patients.

2. Some drugs resist compression into dense compacts, owing to amorphous nature, low density
character.
3. Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT may be
difficult to formulate or manufacture as a tablet that will still provide adequate or full drug
bioavailability.
4. Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to oxygen
may require encapsulation or coating. In such cases, capsule may offer the best and lowest cost.

1.2.3 GENERAL PROPERTIES OF TABLET DOSAGE FORMS:

1. A tablet should have elegant product identity while free of defects like chips, cracks,
discoloration, and contamination.
2. Should have sufficient strength to withstand mechanical shock during its production
packaging, shipping and dispensing.
3. Should have the chemical and physical stability to maintain its physical attributes over time
4. The tablet must be able to release the medicinal agents in a predictable and reproducible
manner.
5. Must have a chemical stability over time so as not to follow alteration of the medicinal agents.

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1.2.4 DIFFERENT TYPES OF TABLETS

(A) Tablets ingested orally:

1. Compressed tablet, e.g. Paracetamol tablet
2. Multiple compressed tablet
3. Repeat action tablet
4. Delayed release tablet, e.g. Enteric coated Bisacodyl tablet
5. Sugar coated tablet, e.g. Multivitamin tablet
6. Film coated tablet, e.g. Metronidazole tablet
7. Chewable tablet, e.g. Antacid tablet

(B) Tablets used in oral cavity:

1. Buccal tablet, e.g. Vitamin-c tablet
2. Sublingual tablet, e.g. Vicks Menthol tablet
3. Troches or lozenges
4. Dental cone

(c) Tablets administered by other route:

1. Implantation tablet
2. Vaginal tablet, e.g. Clotrimazole tablet

(D) Tablets used to prepare solution:

1. Effervescent tablet, e.g. Dispirin tablet (Aspirin)
2. Dispensing tablet, e.g. Enzyme tablet (Digiplex)
3. Hypodermic tablet
4. Tablet triturates e.g. Enzyme tablet (Digiplex)

1.2.4.1 COMPRESSED TABLETS:

Standard uncoated tablets are manufactured by compression. The general methods are by wet
granulation, dry granulation or direct compression, used for rapid disintegration and drug release.
Both type of action – systemic effect and local effect.

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1.2.5 TABLET INGREDIENTS

In addition to active ingredients, tablet contains a number of inert materials known as additives
or excipients. Different excipients are:

1. Diluent
2. Binder and adhesive
3. Disintegrents
4. Lubricants and glidants
5. Colouring agents
6. Flavoring agents
7. Sweetening agents

1.2.5.1 DILUENT:

Diluents are fillers used to make required bulk of the tablet when the drug dosage itself is
inadequate to produce the bulk. Secondary reason is to provide better tablet properties such as
improve cohesion, to permit use of direct compression manufacturing or to promote flow. A
diluent should have following properties:
1. They must be non toxic
2. They must be commercially available in acceptable grade
3. There cost must be low
4. They must be physiologically inert
5. They must be physically & chemically stable by themselves & in combination with the drugs.
6. They must be free from all microbial contamination.
7. They do not alter the bioavailability of drug.
8. They must be color compatible.
Commonly used tablet diluents
1. Lactose-anhydrous and spray dried lactose
2. Directly compressed starch-Sta Rx 1500
3. Microcrystalline cellulose-Avicel (PH 101, PH 102, PH103 and PH112)
4. Mannitol
5. Sorbitol

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Avicel PH102

Microcrystalline Cellulose (MCC) compacts more effectively than any other excipient, and that
makes Avicel PH102 the ideal choice for direct compression formulations. Its versatility in direct
compression extends even to very high dose actives, where compactability is at a premium.
Avicel PH103

Microcrystalline Cellulose (MCC) compacts more effectively than any other excipient, and that
makes Avicel PH103 the ideal choice for direct compression formulations. Its versatility in direct
compression extends even to very high dose actives, where compactability is at a premium. It has
similar physical, chemical, compaction and flow properties to Avicel PH102 only the moisture
content is less than Avicel PH102.

Avicel PH 112

Avicel PH 112 extend its product portfolio for direct compression, beyond a full range of
anhydrous Lactose grades for formulations with moisture sensitive drugs.

Avicel PH 112 is a directly compressible microcrystalline cellulose with a low moisture content,
especially designed for formulating drugs containing active pharmaceutical ingredients (APIs)
with a high sensitivity for moisture. Avicel PH 112 can be applied in a wide range of oral solid
dosage forms (OSDFs) as binder, compressing agent, diluent and/or disintegrating aid. Its low
moisture content may lead to improved drug stability without compromising on the performance
of the final drug product.
With the exception of the moisture content, Avicel PH 112 has similar physical, chemical,
compaction and flow properties to Avicel PH 112; making these grades excellent fillers and
binders for direct compression and dry granulation processes. Avicel PH 112 can be
characterized by its narrow bulk density specification and its consistent flow properties.

1.2.5.2 BINDERS AND ADHESIVES:

These materials are added either dry or in wet- form to form granules or to form cohesive
compacts for directly compressed tablet.

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Example: Acacia, tragacanth- Solution for 10-25% Conc. Cellulose derivatives- Methyl
cellulose, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose Gelatin- 10-20% solution
Glucose- 50% solution Polyvinylpyrrolidone (PVP)- 2% conc. Starch paste-10-20% solution
Sodium alginate Sorbitol.

1.2.5.3 DISINTEGRANTS:

Added to a tablet formulation to facilitate its breaking or disintegration when it contact in water
in the GIT.
Example: Starch- 5-20% of tablet weight. Starch derivative – Primogel and Explotab (1-8%)
Clays- Veegum HV, bentonite 10% level in colored tablet only Cellulose Cellulose derivatives-
Ac- Di-Sol (sodium carboxy methyl cellulose) Alginate PVP (Polyvinylpyrrolidone).

Superdisintegrants: Swells up to ten fold within 30 seconds when contact water.

Example: Crosscarmellose- cross-linked cellulose, Crosspovidone- cross-linked povidone
(polymer), Sodium starch glycolate- cross-linked starch. These cross-linked products swell upto
10n fold with in 30 seconds when in contact with water.

1.2.5.4 LUBRICANT AND GLIDANTS:

Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and
punches, reduce inter particle friction and may improve the rate of flow of the tablet granulation.
Glidants are intended to promote flow of granules or powder material by reducing the friction
between the particles.
Example: Lubricants- Stearic acid, Stearic acid salt - Stearic acid, Magnesium stearate, Talc,
PEG (Polyethylene glycols), Surfactants
Glidants- Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal silicas such as
Cab-O-Sil, Syloid, Aerosil in 0.25-3% conc.

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1.2.5.5 COLORING AGENT:

The use of colors and dyes in a tablet has three purposes:

(1) Masking of off color drugs.
(2) Product Identification.
(3) Production of more elegant product All coloring agents must be approved and certified by
FDA.
Two forms of colors are used in tablet preparation – FD &C and D & C dyes. These dyes are
applied as solution in the granulating agent or Lake form of these dyes. Lakes are dyes absorbed
on hydrous oxide and employed as dry powder coloring. Example: FD & C yellow 6-sunset
yellow FD & C yellow 5- Tartrazine FD & C green 3- Fast Green FD & C blue 1- Brilliant Blue
FD & C blue 2 - Indigo carmine D & C red 3- Erythrosine. D & C red 22 – Eosin Y

1.2.5.6 FLAVORING AGENTS: For chewable tablet- flavor oil are used.

1.2.5.7 SWEETENING AGENTS: For chewable tablets: Sugar, mannitol. Saccharine

(artificial): 500 time’s sweeter than sucrose Disadvantage: Bitter aftertaste and carcinogenic
Aspartame (artificial) Disadvantage: Lack of stability in presence of moisture.

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1.2.6 DIRECT COMPRESSION: 9

Processing steps are:

RAW MATERIAL → WEIGHING → SCREENING → MIXING → COMPRESSION.

Direct compression consists of compressing tablets directly from powdered materials without
modifying physical nature of materials. This method is applicable for crystalline chemicals
having good compressible characteristic and flow properties such as: Potassium salt (chlorate,
chloride, bromide), Sodium chloride, Ammonium chloride, Methenamine etc. If necessary, direct
compression vehicles can be used which are having good flow and compressible characteristics.
Commonly used directly compression diluents are: MCC (Microcrystalline cellulose (Avicel),
Spray dried lactose, Starch - (Sta Rx 1500, Embdex, Celutab), Sugar ( Sugartab, Nutab),
Dicalcium phosphate dihydrate (DiTab), Mannitol for chewable tablet.

Advantages:

1. Low labour input.

2. A dry process.
3. Fewest processing steps.
4. Direct compression is a simple process being more economical and less stressful.
to ingredients in terms of heat and moisture.

Disadvantages:

1. Stratification may occur due to differences in particle size and bulk density which results poor
content uniformity.
2. A large dose drug may cause problem in direct compression. It requires diluents. The tablet
becomes large in size which is difficult to swallow and also costly.
3. During handling of dry materials static charge may form which may present uniform
distribution of drug.
4. Direct compression diluent may interact with the drug. For example, amine drug with Lactose
produce discoloration of tablet.

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1.3 DRUG DESCRIPTION 7, 10, 24

Misoprostol contains approximately equal amounts of the two diastereomers presented below
with their enantiomers indicated by (±):

It has four chiral centres and is presented as a mixture of four stereoisomers in approximately
equal proportions. The drug substance is a clear, colourless or yellowish oil liquid, that is soluble
in water. For ease of manufacture (and increased stability) misoprostol is formulated (after full
testing) as a misoprostol-hypromellose (HPMC) 1% dispersion by the drug substance
manufacturer.

1.3.1 MECHANISM OF ACTION

Misoprostol preferentially binds prostaglandin E2 prostanoid (EP) receptor subtype 3,

over other subtypes and preferentially binds the mouse EP3 receptor over the rat EP3
receptor.
Misoprostol seems to inhibit gastric acid secretion by a direct action on the parietal cells through
binding to the prostaglandin receptor. The activity of this receptor is mediated by G proteins
which normally activate adenylate cyclase. The indirect inhibition of adenylate cyclase by
Misoprostol may be dependent on guanosine-5’-triphosphate (GTP). The significant
cytoprotective actions of misoprostol are related to several mechanisms. These include:

1. Increased secretion of bicarbonate,

2. Considerable decrease in the volume and pepsin content of the gastric secretions,
3. It prevents harmful agents from disrupting the tight junctions between the epithelial cells
which stops the subsequent back diffusion of H+ ions into the gastric mucosa,
4. Increased thickness of mucus layer,
5. Enhanced mucosal blood flow as a result of direct vasodilatation,
6. Stabilization of tissue lysozymes/vascular endothelium,
7. Improvement of mucosal regeneration capacity, and

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8. Replacement of prostaglandins that have been depleted as a result of various insults to the
area. Misoprostol has also been shown to increase the amplitude and frequency of uterine
contractions during pregnancy via selective binding to the EP-2/EP-3 prostanoid receptors.
9. Misoprostol is a synthetic prostaglandin E1 methyl analogue. Due to the fact that
prostaglandins increase uterine contractile activity, misoprostol is potentially suitable to be used
as an abortifacient.
10. Misoprostol induced contractile activity in isolated uterine tissue from Hartley guinea pigs.
The 50% effective concentration (EC50) varied depending on the stage of gestation with the
tissue becoming more sensitive later in gestation.

1.3.2 INDICATIONS

Misoprostol is indicated for coadministration with non-steroidal anti-inflammatory drugs

(NSAIDs) for the prevention of ulcers and erosions induced by NSAIDs in adults. Misoprostol is
indicated for the treatment of duodenal and gastric ulcers in adults. Misoprostol is also effective
in healing a significant number of duodenal ulcers refractory to H2-blocker therapy.
Misoprostol is indicated for the treatment of erosive gastroduodenitis associated with peptic ulcer
disease in adults. Misoprostol is indicated in prevention of stress-induced upper GI mucosal
bleeding and lesions in post-surgical adult ICU patients.

1.3.3 PHARMACOKINETICS

The metabolism of misoprostol is well known. Misoprostol is rapidly converted by de-

esterification to its free acid (SC-30695, which possesses significant pharmacological activity).
Further metabolic conversion occurs over time via β-oxidation of the α-side chain, ω-oxidation
of the β-side chain and reduction to the prostaglandin F analogues. The enzymes involved in the
metabolism of misoprostol have not been identified, but they are likely to be the same enzymes
involved in prostaglandin and fatty acid catabolism. The serum protein binding of the free acid
metabolite of misoprostol is ~81–89%.
The main route of elimination of misoprostol’s metabolites is via the urine and it is expected that
most of misoprostol’s metabolites will be eliminated in about 24 h.
Misoprostol did not inhibit or induce cytochrome P450 (CYP450) enzyme levels/activity in rats.
Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with
food and total availability of misoprostol acid is reduced by use of concomitant antacid.

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1.3.4 PHARMACODYNAMIC DRUG INTERACTIONS

Administration on gestational days (GDs) 13–15 of 0.1 mg/kg/day PO Misoprostol (around twice
the proposed clinical dose in mg/m2) in conjunction with mifepristone (≥0.025 mg/kg/day)
increased the incidence of complete abortions in Hartley Guinea pigs relative to treatment with
mifepristone alone. However, the incidence of complete abortions was around 50% at the highest
tested dose of mifepristone (0.1 mg/kg/day; around 100 times lower than the proposed clinical
dose on a mg/m2 basis) plus misoprostol.
In rats, administration on GD8 of 0.3 mg/kg/day PO misoprostol (3.4 times the proposed clinical
dose in mg/m2) 2h after 1 mg/kg mifepristone (0.05 times the proposed clinical dose in mg/m2)
caused 100% termination of pregnancy. These studies generally support the proposed indication.

1.3.5 PHARMACOKINETIC DRUG INTERACTIONS

The potential for pharmacokinetic interactions between misoprostol and other drugs, particularly
with mifepristone, was not examined in vivo in animals. Mifepristone is mainly metabolized by
CYP450 isozyme CYP3A4. Mifepristone irreversibly inhibits CYP3A4, with likely clinically
significant inhibition in vivo. Mifepristone also inhibits CYP1A, 2B1 and 2D6, albeit to a lesser
degree and reversibly. None of these enzymes are likely to be involved in misoprostol
metabolism. Misoprostol was not an inducer/inhibitor/substrate of CYP3A4. Therefore, it is not
expected that concomitant administration of misoprostol and mifepristone will alter the
pharmacokinetics of, or alter the exposureto either drug. Maximum plasma concentrations of
misoprostol acid are diminished when the dose is taken with food and total availability of
misoprostol acid is reduced by use of concomitant antacid.

1.3.6 TOXICOLOGY

1.3.6.1 ACUTE TOXICITY

Data were obtained in mice, rats and dogs. The most prominent adverse effects after single oral
misoprostol administration were diarrhoea, emesis and decreased motor activity. Hypertrophy of
mucous cells and deepening of the gastric pits were observed microscopically. These gastric
effects have been observed and described previously under the nonclinical evaluation of the use
of misoprostol for GI tract (GIT) ulcers. The lowest acute oral 50% lethal dose (LD50) dose was

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observed in mice, at 27 mg/kg (81 mg/m2), which is 153 times the recommended human single
dose of 800 µg (0.016 mg/kg or 0.53 mg/m2) for a 50 kg woman, on a mg/m2 basis. ) to
ascertain the adequacy of the studies.

1.3.6.2 REPEAT-DOSE TOXICITY

Published studies of up to 90 days duration in rats and 11 weeks in dogs were submitted. Only
GIT tissues were examined microscopically. The studies were not GLP compliant and drug
batches and strains of animals were not identified. It would have been advantageous to have used
the mouse as the rodent species instead of the rat, as pharmacodynamic studies showed that
mouse EP3 receptors are ~16 times more sensitive to misoprostol than their rat counterparts and
closer in sensitivity to human EP3. The highest doses tested in the longest studies were >100
times (rats) and ~11 times (dogs) the human dose on a body surface area basis. Body weight gain
was not affected in rats receiving misoprostol at 300 µg/kg/day for 21 days but was decreased
after treatment with ≥90 µg/kg/day for 90 days. The known effect of mucosal thickening of the
stomach and duodenum was observed, with doses of ≥15 µg/kg/day for 21 days in rats. In dogs,
stomach weight and gland length were increased with treatment at 300 μg/kg/day for 11 weeks,
while body weight was unaffected. Regarding the well known hyperplasia associated with the
administration of exogenous prostaglandins, in a study in rats it was concluded that misoprostol
increases cell survival and decreases cell shedding. However, in a study in dogs the authors
concluded that the hyperplasia is caused by increased cell production and not decreased cell loss.

1.3.6.3 GENOTOXICITY

The potential genotoxicity of misoprostol was examined in the following tests described in the
literature submitted by the sponsor: assays for mutagenicity in bacterial, yeast and mammalian
(mouse lymphoma tk) cells; and for clastogenicity in vitro (Chinese hamster ovary cells) and in
vivo (mouse bone marrow micronucleus test). All tests returned negative results for Misoprostol.

1.3.6.4 CARCINOGENICITY
The carcinogenic potential of misoprostol by the oral route was investigated in a published 2
year study in rats and a 21 month study in mice. Group size (>50/group) was appropriate and
dual control groups were used. Three suitable dose levels were selected, with the highest dose
levels causing survival to be reduced but not excessively so. There was no evidence of an effect

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of misoprostol on tumour occurrence or incidence in rats or mice receiving oral doses of up to

2.4 mg/kg/day for 2 years or 16 mg/kg/day for 21 months, respectively, which are 27–91 times
the recommended human single dose of 800 µg (0.016 mg/kg for a 50 kg woman) on a mg/m2
basis.

1.3.6.5 REPRODUCTIVE TOXICITY

In two fertility studies performed in rats, male rats were treated from 70–71 days premating until
mating and female rats were treated from 14–15 days before mating to gestationonal day (GD) 7
or until parturition; treated males were paired with treated females. The number of implantations
was decreased at ≥1600 μg/kg/day. An increase in resorptions occurred at 1000 μg/kg/day in one
study, but not at 1600 μg/kg/day in the other, and at 10000 μg/kg/day. Fetal and pup survival and
development were not affected. In two teratology studies performed in rats, there was no
evidence of embryotoxicity, fetotoxicity or teratogenicity with dosing at ≤10 mg/kg/day on GDs
6–15 or ≤1600 μg/kg/day on GDs 7–17. In rabbits, administration at 100, 300 or 1000 μg/kg/day
GDs 6 to 18 showed no evidence of fetotoxicity or teratogenicity, although there was an
increased number of resorptions at 1000 μg/kg/day.
In a teratogenicity study, pregnant Han:NMRI mice were treated with single oral doses of 20 or
30 mg/kg of misoprostol on Day 10 of pregnancy. Maternal toxicity was evidenced by slight and
reversible decrease in pregnancy weight gain at both doses. No embryofetal toxicity was
observed at 20 mg/kg. However, the proportion of resorptions per implantation site was
increased at 30 mg/kg. An increased incidence of cleft palate and skeletal abnormalities was also
observed in surviving fetuses at this dose. Therefore, misoprostol was embryotoxic and
teratogenic to mice at 30 mg/kg PO (170 times the proposed clinical dose on a mg/m2 basis).
The dose at which teratogenicity was observed in mice (30 mg/kg PO, or 90 mg/m2) was not
evaluated in rats or rabbits. The lack of effects in rats could also be explained by the fact that
misoprostol is 16 times more potent at binding to EP3 receptors from mice than for rats.
Based on pharmacology parameters, mice are probably a better animal model for misoprostol-
induced uterine contractile activity than rats. In a rat pre/postnatal study using doses of 0.1, 1 and
10 mg/kg/day from GD 15 to day 20 postpartum, pup survival was unaffected, although a
decrease in pup weight gain during lactation was observed at 10 mg/kg/day.

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1.3.7 PREGNANCY CLASSIFICATION

Misoprostol is contraindicated in women who are pregnant because it induces uterine

contractions and is associated with abortion, premature birth, and fetal death. Miscarriages
caused by misoprostol may be incomplete, which could lead to potentially dangerous bleeding,
hospitalisation, surgery, infertility or death. Use of misoprostol has been associated with birth
defects.

1.3.8 USE IN LACTATION

Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active
and is excreted in breast milk. Misoprostol should not be administered to breastfeeding mothers
because the excretion of misoprostol acid could cause undesirable effects such as diarrhoea in
breastfeeding infants.
A decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the expected benefit of the drug to the mother.

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