WO2004045613A2

WO2004045613A2 - Use of domperidone for reducing fertility in mammalian females

Info

Publication number: WO2004045613A2
Application number: PCT/NL2003/000817
Authority: WO
Inventors: Herman Jan Tijmen Coelingh-Bennink; Rene Frank Van Der Linden
Original assignee: Pantarhei Bioscience B.V.
Priority date: 2002-11-20
Filing date: 2003-11-20
Publication date: 2004-06-03
Also published as: AU2003282629A8; AU2003282629A1; WO2004045613A3

Abstract

The present invention relates to a method of reducing fertility in mammalian females. More specifically the present invention relates to a method of reducing fertility in mammalian females, wherein the method comprises administering to a mammalian female, during a period of at least 1 month, domperidone in an amount which is equivalent to a daily oral dosage of between 0.1 and 10 mg per kg of bodyweight. The present method is particularly effective in lactating females and can advantageously be employed as a family planning method, especially in third world countries, or in cases where alternative contraceptive methods are contraindicated, less effective or simply discarded.

Description

A METHOD OF REDUCING FERTILITY IN MAMMALIAN FEMALES

TECHNICAL FIELD OF THE INVENTION

The present invention is concerned with a method of reducing fertility in mammalian females. More specifically the present invention relates to a contraceptive method, which method comprises the administration of the dopamine antagonist domperidone. The present method can advantageously be employed as a family planning method, especially in third world countries, or in cases where alternative contraceptive methods are contraindicated, less effective or simply discarded.

BACKGROUND OF THE INVENTION

The three aspects that are considered to be most important in pharmaceutical methods of contraception are contraceptive reliability, cycle control and minimum side-effects. Todate the pharmaceutical methods of female contraception that have gained wide acceptance, are based on the administration of hormones, notably progestogen and estrogen. These hormonal contraceptive methods derive their popularity from the high contraceptive reliability and relatively good cycle control they provide. In many females also side-effects of such hormonal methods are minimal.

However, for various groups of females hormonal contraceptive: methods are less suitable or even contraindicated. Examples are: lactating females, females with an increased risk of breast, uterine or cervical cancer; females suffering from diabetes, hypertension, gallstones, impaired liver function or cholestasis, the Dubin- Johnson or Rotor syndromes, hepatic adenoma, porphyria, cardiovascular disease including previous or current thromboembolic disorders, or high risk of them, and arterial disease or multiple risk factors for it, disorders of lipid metabolism, undiagnosed vaginal bleeding, a history during pregnancy of pruritus or cholestatic jaundice, chorea, herpes, pemphigoid gestationis, or deteriorating otosclerosis, suffering from severe migraine, with a history of clinical depression, gallbladder disease, sickle-cell disease, or conditions influenced by fluid retention. Hence there is a need for an alternative contraceptive method for these groups of women which performs as well as hormonal contraceptive methods in terms of reliability, but without these undesirable side-effects.

Hara et al., "Studies on the safety of KW-5338. Effects on fertility", XP 002238938, (1980), 119-134, report on the effects of 0.3-10 mg/kg domperidone on mating rate and fertility rate in rats. The results show that there is a dose dependent lowering effect on mating rate, but that the fertility rate is not affected.

In a review article by Davies, "Drug-related hyperprolactinaemia", Adverse Drug Reactions and Toxicological Reviews (1997) , 16(2), 83-94, it is observed that drug therapy is a common cause of hyperprolactinaemia in clinical practice. According to the author hyperprolactinaemia may be asymptomatic or associated with oligoamenorrhoea, galactorrhoea and infertility in women and impotence and infertility in man. The article briefly discusses the anti-emetics metoclopramxde and domperidone and states that these drugs are potent dopamine receptor antagonists and as such are potent causes of hyperpolactinaemia.

Buvat et al, "Mille mois de contraception par sulphide", Rv. Fr. Gynecol. Obstet (1976), 71(1), pp. 53-61 report on the results of a contraceptive study in which they administered between 50 mg and 800 mg sulpiride (a dopamine antagonist) to a group of 116 females. The authors conclude that they have found sulpiride to possess strong anti-ovulatory properties which has allowed them to successfully use it in a new contraceptive method.

The high infantile mortality in developing countries is often associated with the very short time intervals between subsequent pregnancies. Also the early discontinuation of breast feeding is deemed to pose a risk factor as breastfeeding benefits the mother by reducing her risk of postpartum hemorrhage and lowering the risk of breast and ovarian cancers. The benefits to the fully breastfed infant include protection from hypothermia, neonatal hypoclycaemia, and infections, besides various nutritional advantages.

It has been well recognised that contraception can be a very effective tool against infantile mortality in third world countries. However, the contraceptives that are widely used in industrialised countries are not necessarily suitable for developing countries. For instance, the most widely used female contraceptive, the "pill", which comprises a combination of a progestogen and an estrogen, suffers from the severe drawback that it reduces milk secretion in lactating females. Also it has been shown that early postpartum introduction of oral contraceptive pills can actually lead to shorter birth intervals (Bhatia et al., "Oral contraception in Bangladesh", Studies in Family Planning (1984), 15(5), 233-241) The lactational amenorrhoea method (LAM) is the name given to a specific method of contraception in the postpartum period that utilises the temporary infertility caused by breastfeeding. A consensus on the conditions under which lactation would be considered a safe method of contraception was reached at two conferences, held at Bellagio in 1988 and 1995 and at Georgetown University in 1989. If the following three conditions are met, the risk of pregnancy in the first 6 months postpartum would be less than 2 percent (Kennedy et al., "Consensus statement on the use of breastfeeding as a family planning method", Contraception (1989), 39(5), 477-496):

• Amenorrhoeic • Full or nearly full breastfeeding

• Less than 6 months postpartum.

The effectiveness of the LAM method declines if any one of the aforementioned conditions is not met. The guidelines for LAM include the advice that "women who no longer meet these three criteria, or no longer wish to use LAM, should immediately initiate the use of another family planning method if they wish to avoid pregnancy" , and that a fourth parameter, the timely introduction of another contraceptive method, begins when any one of the criteria changes (Labbok et al., "Guidelines: Breastfeeding, Family Planning and Lactational Amenorrhoea Method (LAM), IRH, Washington, pp. 5.).

It is known that the fertility inhibiting effect of lactation is linked with the milk let- down reflex which is a direct result of the suckling stimulus. Therefore, the duration and frequency of breast feeding to a large extent determine the reliability of the LAM method. The need to practise full or nearly full breastfeeding is very important when promoting LAM, as cultural definitions of breastfeeding vary from putting the baby to the breast whenever it cries to feeding only once at night. From the above it can be concluded that the reliability of the LAM method heavily depends on breast feeding behaviour and that it can only be relied upon for a period of less than 6 months postpartum.

A LAM method comprising the administration of sulpiride and a progestogen is known from US 4,639,439 (Societe d'Etudes Scientifiques et Industrielles de lϊle de France). This US patent describes a process for suppressing fertility without inhibiting lactation by administering to a subject a therapeutically effective dosage of a contraceptive composition comprising a prolactin elevating benzamide, a progestogen and a pharmaceutically acceptable carrier. The preferred benzamide is said to be sulpiride, which is a well-known dopamine antagonist. The reported synergistic effect of the combination of a benzamide and a progestogen enables the reduction of progestogen dosages to a range whose maximum is said to typically equal only half the usual dose applied in contraceptive regimens.

It has been shown that exogenous steroids, such as the progestogen, will appear in the milk of lactating females. Although there is no hard evidence as to the detrimental effects of early exposure of a newborns to such exogenous steroids, it will be evident that such exposure should be avoided as much as possible.

Ideally a female contraceptive for use in lactating females in third world countries should be reliable, safe and not adversely affect milk secretion. Furthermore it should be effective for at least 6 months and be user-friendly, i.e. preferably be orally administerable.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a reliable contraceptive method for use in mammalian females, which method offers excellent contraceptive reliability and which may suitably be used by females who do not wish to use an hormonal contraceptive, or for whom such a contraceptive is less suitable or even contraindicated. In particular the present invention aims to provide a contraceptive method which is highly suitable for lactating females, especially lactating females in third world countries.

The present invention is based on the discovery that contraception may effectively be achieved in mammalian females through the continued administration of domperidone in adequate doses. Domperidone is a dopamine antagonist which is currently marketed as an anti-emetic agent. It has also been reported to increase gastrointestinal motility by an unknown mechanism.

Although applicant does not wish to be bound by theory it is believed that at least part of the advantageous effect of domperidone in the present method is related to the hyperprolactinaemic impact of this substance. The administration of domperidone, a dopamine D₂ antagonist, in accordance with the present method enhances secretion of prolactin from the pituitary. The increased level of prolactine appears to suppress the pituitary release of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) which in turn prevents menstruation (leading to amenorrhoea) as well as ovulation (causing infertility).

The effect of dopamine antagonists on prolactin secretion may be explained as follows. Prolactin secretion from the pituitary is controlled by dopamine, which is released in the median eminence by neurons of the tuberohypophyseal pathway. The receptors involved are dopamine D₂ receptors at the cell surface of the pituitary cells which secrete prolactin. The blocking of these dopamine D₂ receptors by a dopamine antagonist will increase plasma prolactin concentrations and may even induce hyperprolactinaemia. Dopamine D₂ receptors are present in various parts of the brain. They are abundantly present in the basal ganglia which are involved in movement control. The administration of dopamine antagonists can result in so-called extrapyramidal movement disorders (akathisia, acute dystonia, etc.). However, domperidone is a dopamine antagonist which is largely incapable of crossing the blood-brain barrier, and consequently domperidon has a peripheral rather than a central nervous impact. Thus the use of domperidone offers a major advantage over the use of other known dopamine antagonists which have an undesired central nervous impact.

The present invention provides a contraceptive method that can be regarded as a suitable alternative for hormonal contraceptive methods, especially for females who should not or do not wish to use hormonal contraceptives.

The present method is particularly suitable for use in lactating females since (a) it is more reliable than the standard LAM method and (b) it stimulates milk secretion in the lactating female. It was found that domperidone may advantageously be employed in a LAM method to prolong the period of efficacious lactational amennorhoea whilst at the same time stimulating lactation. The importance of this combined effect should not be underestimated since breast feeding is one of the safest ways of feeding infants in third world countries, and because alternative infant food sources are often scarce in such countries. An additional advantage of the use of domperidone in lactating females is associated with its stimulating effect on gastrointestinal motility, which effectively counteracts obstipation which is often observed in females shortly after childbirth.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly the present invention is concerned with a method of reducing fertility in mammalian females, wherein the method comprises administering to a mammalian female, during a period of at least 1 month, preferably of at least 3 months, domperidone (5-chloro-l- [ 1 -[3-(2,3-dihydro-2-oxo- 1 H-benzimidazo- 1 -yl)-propy]-4-piperidinyl]-l ,3-dihydro-2H- benzimidazol-2-one) in an amount which is equivalent to a daily oral dosage of between 0.1 and 10 mg per kg of bodyweight.

Throughout this document the term domperidone encompasses the substance domperidone perse as well as metabolic products thereof that display similar contraceptive functionality. The term "domperidone" also includes precursors that are capable of liberating domperidone (e.g. esters of domperidone) or contraceptive metabolic products thereof when administered in accordance with the present invention. An example of a precursor of domperidone that may suitably be employed in accordance with the present invention is domperidone maleate. Other esters of domperidone, especially esters of domperidone and C_\- C₆ carboxylic acids, may also suitably be employed in accordance with the present invention. The term "mammalian females", encompasses female humans as well as other female mammals. Examples of mammals, other than humans, which may suitably be subjected to the present method include livestock (e.g. horse, cow, sheep, goat, pig) and pets (e.g. dog, cat and rodents like mouse, guinea pig and hamster). Preferably the mammalian female is a human female.

The requirement that in the present method domperidone is administered in an amount equivalent to a daily oral dosage of between 0.1 and 10 mg per kg of bodyweight means that the biological impact of the administration regimen must be equivalent to the biological impact of a daily oral dosage of between 0.1 and 10 mg domperidone per kg of bodyweight. This is suitably achieved by ensuring that the serum concentration of domperidone achieved by the regimen employed is within the same range as that which is observed for a regimen that employs a daily oral dosage of between 0.1 and 10 mg domperidone per kg of bodyweight.

The present method encompasses various modes of administration known in the pharmaceutical art. It is preferred, however, to employ a method of administration that is very user-friendly. Accordingly domperidone is preferably administered enterally (e.g. orally or rectally), subcutaneously, buccally, nasally or topically (e.g. transdermally). Most preferably domperidone is administered orally.

In particular in case domperidone is administered orally, it is preferred to administer said composition at least once daily. Since the in vivo halflife of domperidone is rather low, it is advantageous to administer domperidone in the form of a slow release formulation. Thus, once daily administration without the occurrence of dramatic fluctuations in serum concentration may be feasible. Oral drug delivery systems that may be used to achieve slow or sustained release are well known in the pharmaceutical art and may suitably be employed in accordance with the present invention. Particularly preferred sustained release formulations are oral dosage units that comprise an external coating that envelops an interior core that contains domperidone. The coating is gradually degraded during the passage of the dosage unit through the gastrointestinal tract, following which domperidone is released and absorbed. The release of domperidone from the core material may result from disintegration or dissolving of the core material and/or domperidone may simply diffuse out of the core material.

The external coating advantageously based on waxes; cellulose derivatives (e.g. hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethyl- cellulose phtalate and hydroxy propyl cellulose); poly-hydroxymethylmethacrylate; ethylene vinylacetate copolymer, poly-(ethylene oxide); poly-(propylene oxide); acrilic resins (Eudragits ®); poly vinylalcohol or combinations of these materials. In a particularly preferred embodiment the sustained release formulation comprises an enteric coating, i.e. a coating that does not degrade under the acidic conditions prevailing in the stomach, but which does degrade in the colon. The enteric coating is suitably based on cellulose acetate phtalate and/or polymethyl acrylate. The core of the sustained release formulation may contain additional active ingredients, such as a bone resorption inhibitor, and a pharmaceutically acceptable excipient.

Specific examples of sustained release formulations that can suitably be employed in accordance with the present invention may be found in US 5,885,616; US 6,156,343; US 6,228,398; US 6,342,250 and US 6,372,255. The full contents of each of these patent documents is incorporated herein by reference.

In order to obtain reliable contraception domperidone is to be administered in an amount which is equivalent to a daily oral dosage of at least 0.1 mg per kg of bodyweight. Even more preferably domperidone is administered in an amount which is equivalent to a daily oral dosage of at least 0.2 mg per kg of bodyweight, most preferably in an amount which is equivalent to a daily oral dosage of at least 0.4 mg per kg of bodyweight. Preferably the administered amount does not exceed the equivalent of a daily oral dosage of 6 mg per kg of bodyweight. More preferably said amount does not exceed the equivalent of a daily oral dosage of 4 mg per kg of bodyweight and most preferably it does not exceed 3 mg per kg of bodyweight.

In particular in human females reliable contraception is usually achieved by administering domperidone in an amount which is equivalent to a daily oral dosage of at least 4 mg, preferably at least 10 mg and most preferably at least 15 mg. Preferably, the administered dosage does not exceed the equivalent of a daily oral dosage of 400 mg. More preferably said dosage does not exceed the equivelent of a daily oral dosage of 200 mg, most preferably it does not exceed 150 mg.

Typically, as a result of the present method, the endogenous prolactin concentration is increased by at least 100%, preferably by at least 200%). Generally this increase in prolactin concentration is observed within 10 days after the first administration of domperidone. In a preferred embodiment of the present method, the serum concentration of prolactin is increased with at least 10 μg 1, more preferably with at least 20 μg/1, within 10 days after the first administration of domperidone. As mentioned herein before, the present invention offers the important advantage that it not only provides reliable contraception, but that it also stimulates milk secretion in the lactating female. Hence in a particularly preferred embodiment of the present method the domperidone is administered to a lactating female. Preferably domperidone is administered in a therapeutically effective amount to significantly increase the female's milk secretion. Typically the average amount of milk secreted on a daily basis will increase by at least 20%. Generally this increase is observed within 10 days after the first administration of domperidone.

Throughout this document the term lactating female is used to describe a female that is nursing a new-born infant. More particularly said term encompasses females who nurse their new-born infant(s) at least twice, preferably at least thrice a day.

In lactating females, typically the period during which amennorhoea is maintained exceeds at least 4 months postpartum. Preferably said period exceeds at least 6 months and more preferably it exceeds 8 months. Usually the maximum period during which amennorhoea can be maintained is around 24 months. In order to minimise the risk of unwanted pregnancies in lactating females, the present method should start shortly after the female gave birth. Preferably, domperidone is first administered before 2 months, preferably before 1 month has passed since the female has given birth to her last offspring. As mentioned herein before, it is an important advantage of the present invention that it does not require the use of hormones such as estrogen and progestogen. Thus, in a preferred embodiment the present method does not comprise the administration of a progestogen. More preferably, the method does not make use of a progestogen or an estrogen. Most preferably the present method does not employ any steroids at all. The prolonged administration of domperidone in accordance with the present invention may, in some women, lead to reduced estrogen blood serum levels. Low estrogen blood serum levels have been associated with bone loss (osteoporosis). In order to prevent such bone loss it was found to be very advantageous to co-administer a bone resorption inhibitor. Consequently, in particularly preferred embodiment of the invention, the present method comprises the co-administration of a bone resorption inhibitor selected from the group consisting of estrogens, selective estrogen receptor modulators (SERM's), phosphonates and mixtures thereof in an amount sufficient to prevent or suppress symptoms of osteoporosis. Since the present method is particularly beneficial to females for whom hormonal contraceptives are less suitable or even contraindicted, it is preferred to employ a bone resorption inhibitor selected from the group consisting of SERM's, phosphonates and mixtures thereof. Since SERM's, like estrogens are also capable of modulating estrogen receptors, it is particulary preferred to employ phosphonates as a bone resorption inhibitor.

In case the bone resorption inhibitor is an estrogen , said estrogen is suitably administered in an amount which is equivalent to a daily oral dosage of between 0.1 and 10 mg 17β-estradiol. Preferably the estrogen is selected from the group of estrogens consisting of ethinyl estradiol, estradiol, estetrol, precursors capable of liberating such an estrogen in vivo when used in the present method and mixtures thereof.

If the bone resorption inhibitor is a SERM, the SERM is preferably administered in an amount which is equivalent to a daily oral dosage of between 0.5 and 100 mg raloxifene. The SERM used in accordance with the present invention may suitably be selected from the group consisting of raloxifene, tamoxifen, precursors capable of liberating such a SERM in vivo when used in the present method and mixtures thereof.

Phosphonates are advantageously administered in an amount that is equivalent to a daily oral dosage of between 0.0005 and 1.0 mg phosphonates per kg of bodyweight per day. Examples of phosphonates that can advantageously be employed in the present method include those belonging to the group consisting of bisphosphonic acids, phosponoalklylphosphinates, pharmaceutically acceptable salts or esters of these phosphonates and mixtures thereof. Most preferably the present phosphonates are selected from the group consisting of bisphosphonic acids, pharmaceutically acceptable salts or esters of these acids and mixtures of these phosphonates.

Another aspect of the invention relates to a pharmaceutical composition containing at least 0.5 mg of a dopamine antagonist; at least 10 μg of a bone resorption inhibitor selected from the group consisting of estrogens, selective estrogen receptor modulators (SERM's),bone active phosphonates and mixtures thereof; and a pharmaceutically acceptable excipient.

The estrogens are preferably selected from the group consisting of ethinyl estradiol, estradiol, precursors capable of liberating such an estrogen in vivo when used in the present method and mixtures thereof. The SERM's may be selected from the group consisting of raloxifene, tamoxifen, precursors capable of liberating such a SERM in vivo when used in the present method and mixtures thereof. Suitable phosponates can be selected from the group consisting of bisphosphonic acids, phosponoalklylphosphinates, pharmaceutically acceptable salts or esters of these phosphonates and mixtures thereof. Yet another aspect of the invention is concerned with an oral dosage unit comprising the aforementioned pharmaceutical composition, wherein the dosage unit comprises the dopamine antagonist in an amount equivalent to between 4 and 300 mg domperidone and the bone resorption inhibitor, in case it is an estrogen, in an amount equivalent to between 0.1 and 10 mg 17β-estradiol, in case it is a SERM, in an amount equivalent to between 0.5 and 100 mg raloxifen and in case it is a bone active phosponate in an amount of 0.05-50 mg phosphonate.

The present oral dosage units can be prepared according to well known pharmaceutical procedures. The active ingredient(s) are combined with a pharmaceutically acceptable excipient and converted into a pharmaceutically acceptable form for oral administration, e.g. a tablet, capsule, cachet, pellet, pill, powder or granules. The excipient may include appropriate pharmaceutical carriers such as diluents, binders and lubricants. For example gums, starches and sugars are commonly used as pharmaceutical carriers. Tablets and other oral dosage units can suitably contain materials such as binders (e.g. hydroxypropylmethyl cellulose, polyvinyl pyrrolidine, other cellulosic materials and starch), diluents (e.g. lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g. starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).

The active ingredient(s) may comprise from about 0.01% by weight to about 50% by weight of the formulation in the dosage unit, the remainder consisting of excipient. The active ingredient(s) are compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet moulding apparatus to form the tablets. Alternatively the compounded material may be incorporated as a powder or granules in a capsule. Various other options that may suitably be used in accordance with the present invention are well known to the person skilled in the pharmaceutical art. The dosage units according to the present invention usually have a weight of between 0.05 and 1 grams. More preferably these units have a weight of between 0.08 and 0.5 grams.

Another aspect of the invention relates to a pharmaceutical kit comprising a plurality of oral dosage units containing at least 0.5 mg domperidone and a plurality of oral dosage units containing at least 10 μg of a bone resorption inhibitor selected from the group consisting of estrogens, selective estrogen receptor modulators (SERM's), bone active phosphonates and mixtures thereof. The domperidone and bone resorption inhibitor may be present in the kit in the form of separate dosage units or, alternatively, they may be incorporated in the same oral dosage units. Preferably these active principles are both present in the oral dosage units contained in the pharmaceutical kit. The preferred embodiments described above in connection with the pharmaceutical composition and oral dosage units of the present invention are equally applicable to the pharmaceutical kit.

The invention is further illustrated by means of the following examples:

EXAMPLES

Example 1

A clinical study is conducted in 30 women, who are selected according to the following main criteria:

- fully breastfeeding with the intention to do so for up to 1 year; - 1-2 months postpartum at the beginning of the study;

- did not menstruate yet after parturition.

Volunteers are randomly assigned to receive either domperidone (4 times 20 mg a day) or placebo (4 times a day) per os, for up to 12 months post partum. The following parameters are studied:

- serum prolactine levels;

- the success rate of breastfeeding;

- the endocrine ovarian function activity; - occurrence of first spontaneous menses.

The results obtained are as follows:

Serum prolactine levels measured before the start of the study and regularly thereafter (3, 6, 9 and 12 months post partum) show that the serum prolactine levels are similar in the 2 groups at baseline, but that they are significant higher in the domperidone group than in the placebo group at all other measurement points.

The success rate of breastfeeding, based on the need to provide supplementary artificial milk and/or failure according to the mother, is found to be significantly higher in the domperidone group than in the placebo group.

The endocrine ovarian function is studied, measuring pregnadiol in urine, and estradiol, FSH and LH in serum at 3, 6, 9 and 12 months post partum. All hormones are found to be significantly lower in the domperidone group than in the placebo group.

The first spontaneous menstruation postpartum occurs significantly later in the domperidone group than in the placebo group.

Example 2

Another study is conducted with 20 healthy women who are selected on the basis of the same criteria as mentioned in example 1. Volunteers are randomly assigned to receive either domperidone (3 times 10 mg) or placebo (3 times a day) er os, for up to 12 months post partum. The same parameters as described in example 1 are studied. Results show that: the serum prolactine levels are significantly higher in the domperidone group than in the placebo group; - the success rate of breastfeeding, is significant higher in the domperidone group than in the placebo group; the endocrine ovarian function is significantly lower in the domperidone group than in the placebo group; the first spontaneous menstruation postpartum occurs significantly later in the domperidone group.

Example 3

Another study is conducted with 25 healthy women who are selected on the basis of the same criteria as mentioned in example 1. Volunteers are randomly assigned to orally receive either domperidone (4 x 2.5 mg) or placebo (4 times a day), for up to 12 months post partum. The same parameters as described in example 1 are studied.

Results show that: the serum prolactine levels are significantly higher in the domperidone group than in the placebo group; the success rate of breastfeeding, is significant higher in the domperidone group than in the placebo group; the endocrine ovarian function is significantly lower in the domperidone group than in the placebo group; - the first spontaneous menstruation postpartum occurs significantly later in the domperidone group.

Example 4

Example 1 is repeated with the exception that the women receive a single daily oral dose of 100 mg domperidone (or a placebo once daily). The results obtained show that the parameters mentioned in example 1 are affected in much the same way as described in example 1.

Example 5 Example 1 is repeated with the exception that the women receive a single daily oral dose of 50 mg domperidone in the form of a sustained release capsule that releases less than 50% of the domperidone within 6 hours after ingestion. The results obtained show that the parameters mentioned in example 1 are affected in essentially the same way as described in that example.

Example 6

A clinical study is conducted in 30 healthy cycling women, aged 25-50, who do not want to conceive. The participants are divided at random in 2 groups of 15 women each, i.e group A and group B. Group A receives 20 mg domperidone 4 times a day and 10 mg Fosamax® once daily.

Group B receives 20 mg domperidone 4 times a day and a placebo tablet once daily. Both groups take the medication through oral administration for a period of 3 months.

Immediately before the start of the study and just before completion of the study, the following bone turn-over is measured by a bone resorption marker (cross-links) and by a bone formation marker (osteocalcin) .

Results of the measurements show that in group A, the markers of bone resorption and bone formation are decreased significantly during the study. In contrast, no significant change in any of these parameters is observed in group B.

Claims

1. Use of domperidone in the manufacture of a pharmaceutical composition for use in a method of reducing fertility in mammalian females, wherein the method comprises administering to a mammalian female, during a period of at least 1 month, preferably of at least 3 months, domperidone in an amount which is equivalent to a daily oral dosage of between 0.1 and 10 mg per kg of bodyweight.

2. Use according to claim 1, wherein domperidone is administered in a therapeutically effective amount to prevent ovulation.

3. Use according to claim 1 or 2, wherein domperidone is administered orally.

4. Use according to any one of claims 1-3, wherein domperidone is administered at least once daily.

5. Use according to any one of claims 1-4, wherein domperidone is administered in an amount which is equivalent to a daily oral dosage of between 4 and 300 mg.

6. Use according to any one of claims 1-5, wherein domperidone is administered as a slow release formulation, preferably once daily.

7. Use according to any one of claims 1-6, wherein the female is a lactating female.

8. Use according to claim 7, wherein domperidone is first administered before 2 months, preferably before 1 month has passed since the female gave birth to her last offspring.

9. Use according to any one of claims 1-8, wherein domperidone is administered in a therapeutically effective amount to increase the female's serum prolactin concentration with at least 10 μg/1.

10. Use according to any one of claims 1-9, wherein the method does not comprise the co- administration of a progestogen.

11. Use according to any one of claims 1-10, wherein the method comprises the co- administration of a bone resorption inhibitor selected from the group consisting of estrogens, selective estrogen receptor modulators (SERM's), phosphonates and mixtures thereof in an amount sufficient to prevent or suppress symptoms of osteoporosis.

12. A pharmaceutical composition containing at least 0.5 mg domperidone; at least 10 μg of a bone resorption inhibitor selected from the group consisting of estrogens, selective estrogen receptor modulators (SERM's), bone active phosphonates and mixtures thereof; and a pharmaceutically acceptable excipient

13. Pharmaceutical composition according claim 12, wherein the bone resorption inhibitor is selected from the group of phosponates consisting of bisphosphonic acids, phosponoalklylphosphinates, pharmaceutically acceptable salts or esters of these phosphonates and mixtures thereof.

14. An oral dosage unit comprising the pharmaceutical composition according to claim 12 or 13, wherein the dosage unit comprises the dopamine antagonist in amount equivalent to between 4 and 300 mg domperidone and the bone resorption inhibitor, in case it is an estrogen, in an amount equivalent to between 0.1 and 10 mg 17β-estradiol, in case it is a SERM, in an amount equivalent to between 0.5 and 100 mg raloxifen and in case it is a bone active phosponate in an amount of 0.05-50 mg phosphonate.

15. A pharmaceutical kit comprising a plurality of oral dosage units containing at least 0.5 mg domperidone and a plurality of oral dosage units containing at least 10 μg of a bone resorption inhibitor selected from the group consisting of estrogens, selective estrogen receptor modulators (SERM's), bone active phosphonates and mixtures thereof.