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(ll)PatentNumber:  KE 379

(45)    Dote ofgnnt' 23/03/2010

A 61K 31/00,31/135,31/4415,311519, 311525,31/565,31/57,31/585,3117028, A 61P 15/12, 15118

(ll) Application Number:KElP/ 2007/ 000666

(22) Filing Date: 1510512006

(30) Priority data: 023 301.5  1310512005  DE and 016 285.4  0310412006  DE

(86) PCT data PCTIEP061004858 15/05/2006 wo 2006/120035 A2    1611112006
 
(73)0wner:BAYER SCHERING PHARMA AKTIENGESELLSCHAFT of Mtillerstrasse 178, 13353 Berlin, Germany and MERCK EPROVA AG of Am Latemenacker 5, CH-8200 Schaffhausen, Switzerland

(72) Inventor: MERCK EPROVA AG; STROTHMANN, Kai [; SMITH, Gavin, Welch; MERCK EPROVA AG ; MOSER, Rudolf and PIETRZIK, Klaus

(74) Agent/address for correspondence:  Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi
 
(54) Title: PHARMACEUTICAL COMPOSITION COMPRISING PROGESTOGENS AND/OR ESTROGENS AND 5-METHYL-(6S)-TETRAHYDROFOLATE

(57) Abstract: The invention relates to a pharmaceutical composition which contains gestagens, preferably drospirenone, estrogens, preferably ethinylestradiol, and 5-methyl-(68)-tetrahydrofolate, can be used as an oral contraceptive, and prevents diseases of the consumer caused by folate deficiency, especially cardiovascular diseases, as well as congenital defects caused by folate deficiency after conceiving the embryo, such as neural tube defects, defects of the ventricular valve, urogenital defects, and cheilognathopalatoschisis, without masking the symptoms of vitamin B 12 deficiency while facilitating

unrestricted usability of the folate component 5-methyl-(68)-tetrahydrofolate by the organism and thus the biological activity thereof in order to prevent said congenital defects caused by folate deficiency in case of a homozygous or heterozygous methylenetetrahydrofolate reductase polymorphism. In addition, an extended protective effect is maintained after discontinuing the contraceptive

Pharmaceutical    composition    comprising    progeatogena

and/or  estrogens  and  5-metbyl-(6S)-tetrahydrofolate

The present invention relates to a pharmaceutical composition which comprises progestogens, estrogens and 5-methyl- (6S) -tetrahydrofolate, can be employed as oral contraceptive and moreover prevents disorders and malformations caused by folate deficiency, without at the same time masking the symptoms of vitamin B12

10    deficiency.

Drugs  companies  active  in  the  area  of  fertility  control

are   always   making   efforts   to   improve   the   available contraceptives.  Included  therein  is  not  only  increasing 15    the    contraceptive    reliability    by    developing    novel substances  and  an  improved  convenience  of  use.   On  the contrary,       innovative      approaches      to      combining contraception   and   disease   prevention   are   also   being

pursued.

20

A  number   of   diseases   is   regarded   as   being   connected with   a    folate    deficiency.    Thus,    administration    of folates   for   example   in   the   form   of   folic   acid   may minimize    the    risk    of    cardiovascular   disorders    and 25    certain   malignant   disorders    (such   as,    for   example,

carcinoma  of  the  breast  or  colon).

Defects in the development of unborn children are particularly serious consequences of folate deficiency

30    in women of childbearing age. Thus, women with low folate levels have an increased risk, compared with those having sufficiently high folate levels, of giving birth to children suffering from congenital malformations such as neural tube, ventricular valve

35    and  urogenital  defects.

Neural tube defects are the cormnonest congenital malformations of the central nervous system. They arise

through  incomplete  closure  of  the  neural  tube  in  about

the    third   to   fourth   week   of   embryonic   development.

Neural  tube  defects  include  spina  bifida  (in  some  cases

with    meningocele   or   meningomyelocele),    encephalocele

and  anencephalies  which  are  characterized  by  partial  or

complete    absence  of  areas  of   the  brain.   Children  with

anencephaly  are  virtually  incapable  of  survival.

Spina  bifida  is  distinguished  by  incomplete  closure  of

10    vertebral arches. Its result, depending on the nature of the lesion, is life-long disability in the form of various sensory but also motor deficits - thus, for example, two thirds of children and adults are dependent on wheelchairs owing to muscular paralyses.

15    Therapy entails covering the defect, fitting a shunt to drain the CSF and lengthy orthopedic and neurological rehabilitation. The costs of the medical treatment average 500 000 € per child.

20    It is assumed that there are about 250 000 neonates with neural tube defects around the world. The rate of neonatal impairments in Germany and the USA is about 1-2 per 1000 births. In Germany each year about 500

babies  are  born  alive  with  neural  tube  defects,  while  a

25    further 500 pregnancies have been terminated on the basis of prenatal ultrasonic diagnosis.

Sufficiently high folate levels at the time of

conception  and  in  the  initial   phase   of  pregnancy   are 30    crucial     for     avoiding     neural     tube    defects.     An erythrocyte   folate   level   of   at   least   906  nmol/1   is generally    regarded    as    desirable    for    reducing    the

frequency  of  neural  tube  defects.

35    It is known that intake of folic acid at the right time around conception can reduce neural tube defects by 50-70%. The folic acid fortification of food products which is practiced in the USA has already markedly reduced the incidence of neural tube defects; in Canada


and  Chile  in  fact  by  more  than  50%.

Both    voluntary  fortification  of   food  products   as,   for

example,    in  Germany,   and  intake  of  folic  acid  products

does  not,  however,   reach  all  women  of  childbearing  age

to  a  sufficient  extent.  Firstly,  many  women  are  unaware

of  the  risk  of  neural  tube  defects  and  the  possibility

of    minimizing  a   corresponding  risk  by  intake  of   folic

acid.   Thus,   in  many  countries,   far   fewer   than   10%  of

10    them take folic acid products around the time of conception. Secondly, despite modern methods of

contraception,    which   are   increasingly   easy   to   use,   a

large  number  of  pregnancies  -   estimated  at  up  to  50%  in

the    USA    (Inst.    of   Medicine   1998,    NEJM   2004)    -    are

15    unplarmed, so that deliberate intake of folic acid products before conception is likewise precluded from the outset. In addition, for example in the USA, about 5-8%: of users do not take oral contraceptives reliably.

20    The object on which the patent US 6, 190,693 (Kafrissen et al.) was based was therefore to prevent certain disorders which can be treated by folic acid in consumers of oral contraceptives. Kafrissen achieved this object by adding folic acid to an oral

25    contraceptive. He disclosed a method for administering folic acid by use of a pharmaceutical composition which comprised both conventional substances with contraceptive activity and folic acid.

30 However, introduction of folic acid into oral contraceptives itself involves a serious health risk, because it may mask the early symptoms, which are still treatable, of a vitamin B12 deficiency such as, for example, a megaloblastic anemia. This is because the

35    hematological  symptoms  caused  by  vitamin  B12   deficiency

can be treated so well by additional folate administration that a vitamin B12 deficiency can be detected only with great difficulty, or not at all, and

consequently    therefore    not    diagnosed.    The
 

neuropsychiatric    symptoms    such    as,    for    example,

paresthesia    and  ataxia  then  remain  untreated,   however,

and  might  deteriorate  irreversibly.

The  object  on  which  the  patent  application  WO  03/070255

(Coelingh    Bennink)   was  based  was   therefore  to  avoid  a

health  risk  arising  from  the  masking  of  the  symptoms  of

a    vitamin   B12    deficiency   in   consumers   of   folic   acid-

containing    oral    contraceptives.    Coelingh    Bennink

10    achieves this object by adding vitamin B12 to an oral contraceptive. He discloses a kit for oral hormonal contraception which comprises estrogens and/or progestogens, tetrahydrofolates and, obligatorily,

vitamin  B12.

15

A  further  problem  associated  with  the  administration  of

folic    acid    and    tetrahydrofolate    products         which comprise   no   5-methyl- (6S) -tetrahydrofolate   -    is   the polymorphism    of    methylenetetrahydrofolate    reductase 20     (MTHFR  C677T),   which   is   heterozygous   in  about   55%   of the    Caucasian    population    and    homozygous    in    about 10-15%.   This  polymorphism  leads   to  a   reduced  activity of   methylenetetrahydrofolate   reductase,    so   that    the women   affected   are   unable   to   metabolize   sufficiently

25    the supplied folate and tetrahydrofolate into 5-methyl-( 6S) -tetrahydrofolate, which is active in the body.

This polymorphism is an acknowledged risk factor for disorders caused by folate deficiency, in particular for neural tube defects.

30

A further problem causing difficulties is that folic acid is a substance which does not naturally occur in foodstuffs. In order to be biologically active, it must first be converted metabolically by the enzyme

35    dihydrofolate reductase into 7, 8-dihydrofolate and ( 6S) -tetrahydrofolate. The metabolic capacity, in

particular the first activation step, for conversion of the provitamin folic acid into its active reduced form is limited and moreover varies greatly from individual

to  individual.  Since  the  enzyme  dihydrofolate  reductase

does    not  play  a   role   in   the  metabolism  of   metafolin,

interactions    between    medicaments    which    inhibit

dihydrofolate reductase, such as, for example, methotrexate and dihydrofolate reductase are not to be

expected.

In order to provide an adequate supply of folate also to women suffering from rnethylenetetrahydrofolate

10    reductase deficiency, EP 0898965 (Muller et al.) proposes the use of 5-rnethyl- (6S) -tetrahydrofolic acid or appropriate pharmaceutically acceptable salts as dietary supplement or as ingredient of medicaments.

EP  1044975  Al   discloses   inter   alia   stable   crystalline

15    salts of 5-methy1- (68) -tetrahydrofolic acid and processes for their preparation.

It    is   known   that   a   large   proportion   of   pregnancies

occurs    shortly   after   discontinuing   the   contraceptive

20    (Farrow et al. , Human Reproduction Vol. 17, No., 10, pp. 2754-2761, 2002). If administration is irregular and unreliable, pregnancy may even occur during intake. It is likewise known that even after termination of additional folate administration a person can profit

25    therefrom for a further 90 days or so (FDA Advisory Committee for Reproductive Health Drugs (ACRHD): The

public    health    issues,     including     the    safety    and potential   clinical   benefit,   associated  with   combining folic   acid   and   an   oral   contraceptive   into   a   single 30    combination    product.     December    15,     2003;     Summary Minutes,  Question  4).  However,   it  is  a  precondition  for this   that   folic   acid   has   been   taken   in   sufficiently large   amount   in   addition   to   the   normal   diet    in   a sufficiently    long    preceding   period.    This    so-called

3 5 tissue depot effect can be seen through elevated folate levels in the erythrocytes.

It is further known that low folate/high homocysteine levels are associated with multiple spontaneous


abortions    (Merlen  et  al.,  Obstet.  et  Gynecol.  2000,  95:

pp.  519-524).

The    present   invention   is   based   on   the   object   of

producing  an  oral  contraceptive  which,  although  able  to

prevent    diseases   caused  by   folate   deficiency,   at   the

same  time  is  unable  to  mask  the  symptoms  of  vitamin  B12

deficiency.    The   invention   is    further   based   on   the

object    of   disclosing   an   administration   regime   which

10    ensures    that    the    consumer    of    the    pharmaceutical

composition  of  the  invention  is  reliably  protected  also

for  a  certain  time  after  discontinuation  from  disorders

or    malformations    caused   by    folate    deficiency,    in

particular    from   neural   tube   defects.   Both   these   also

15    apply in the case of a homozygous or heterozygous polymorphism of methylenetetrahydrofolate reductase in the user, which adversely affects the utilizability of folic acid by the body and thus its biological activity to prevent neural tube defects.

20

The object is achieved according to the invention by a pharmaceutical composition comprising one or more progestogens and/or estrogens and 5-methyl-(65)-tetrahydrofolate, and pharmaceutically acceptable

25    excipients  and  carriers.

The invention is based on the realization, which is surprising in relation to WO 03/070255, that treatment and prevention of disorders caused by folate deficiency

30 is possible even without masking symptoms of vitamin B12 deficiency by administering solely 5-methyl- (6S)-tetrahydrofolate. Administration of vitamin B12 is therefore no longer necessary in order to avoid the health risk described in WO 03/070255. Despite the

35    administration of 5-methyl- (6S) -tetrahydrofolate, a

physician is able to diagnose and, where appropriate, treat vitamin B12 deficiency.

In  the  case  of  existing  vitamin  B12   deficiency  it  is,  of

course, possible to administer vitamin B12 in addition. The addition of further vitamins such as, for example,
vitamin B6 or vitamin B2 is likewise optionally possible. The invention is further based on the

realization,    which    is    surprising    in    relation    to

WO  03/070255,    that,    nnlike    the    administration    of

folates    or   other   tetrahydrofolates,    use   solely   of

5-rnethyl-(6S)-tetrahydrofolate    in    a    contraceptive

enables,    even  in  a   case  of  homozygous  or  heterozygous

10    polymorphism    of    methylenetetrahydrofolate    reductase,

unlimited    and   adequate   utilizability   of   the   folate

component by the body and thus its biological activity to prevent congenital malfonnations caused by folate

deficiency.

15

5-Methy1-(6S)-tetrahydrofo1ate is synthesized metabolically (see Figure 1) from 5, 10-methylene- (6R)-

tetrahydrofolate.      This      biochemical      reaction      is catalyzed    by    the    enzyme    methylenetetrahydrofolate 20    reductase   (MTHFR),   of   which  various   genetic  mutations are  known,   some  of  which  are  manifested  by  restricted biological      activity       (MTHFR  C677T      polymorphism) .

5-Methyl- (6S) -tetrahydrofolate is converted in a further step which is catalyzed by the enzyme

25    methionine synthase (MS) into tetrahydrofolate. This entails transfer of the 5-methyl group of 5-methyl-

(6S) -tetrahydrofolate   to   the   amino   acid   homocysteine (Hey)    which   is   thus   converted   into   the   amino   acid methionine  (Met).  This  vitamin  B12 -dependent  reaction  is 30    also    referred    to    as    homocysteine    methylation    in homocysteine  metabolism.   5-Methyl-(6S)-tetrahydrofolate occupies   a    special   place   in   the   group   of   reduced folates   because   5-methyl- (6S) -tetrahydrofolate   can   be converted      into      tetrahydrofolate      only      by      the

35    homocysteine methylation reaction. Tetrahydrofolate is the actual carrier molecule for one-carbon units of various oxidation states. In metabolism, 5-methyl-(6S)-

tetrahydrofolate    can   be   synthesized   only   from   5,10-

methylene- ( 6R) -tetrahydrofolate    and    can    be    further
 

metabolized only by conversion into tetrahydrofolate. The first enzymatic reaction (MTHFR) is irreversible
under    physiological    conditions ,    and    the    second

enzymatic reaction (MS) is vitamin B12-dependent, meaning that if there is a vitamin B12 deficiency then 5-rnethyl- (6S) -tetrahydrofolate accumulates and cannot be metabolized further. This phenomenon is also known

nnder    the    name    methyl    trap.    Only    5-methyl- (68)-

tetrahydrofolate,    but    not    any    other    oxidized    and

10    reduced  folates   such  as   folic   acid,   7, 8-dihydrofolate,

( 68) -tetrahydrofolate,    5-fomyl- (68) -tetrahydrofolate,

10-fomyl- (6R) -tetrahydrofolate,    5, 10-methenyl- (6R)-

tetrahydrofolate,    5, 10-methylene- (6R) -tetrahydrofolate,

5-formimino-(6S)-tetrahydrofolate,    displays    this

15    particular property. 5-Methyl- ( 6S) -tetrahydrofolate is the only naturally occurring folate which does not mask

vitamin B12 deficiency. This is of particular importance on use of 5-rnethyl-(65)-tetrahydrofolate in combination with oral contraceptives and is an aspect of the

20    present  invention.

Progestogens which can be used in the pharmaceutical composition of the invention are the following substances: levonorgestrel, norgestirnate,

25    norethisterone, dyrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (= etonogestrel),

    17-deacetylnorgestirnate,            19-norprogesterone,
    acetoxypregnenolone,    allyles trenol,    amges tone,
    chlormadinone,    cyproterone,    derneges tone,desoges trel,
30    dienogest,        dihydrogesterone,        dirnethisterone,
    ethisterone,        ethynodiol        diacetate,    fluorogestone
    acetate,    gastrinone,        gestodene,    gestrinone,
    hydroxymethylprogesterone,            hydroxyprogesterone,
    lynestrenol        (=  lynoestrenol),        rnecirogestone,
3 5    rnedroxyproges terone,    rnegestrol,    rnelengestrol,
    nornegestrol,        norethindrone    (=    norethisterone),
    norethynodrel,   norgestrel    (including   d-norgestrel   and
    dl-norgestrel),    norgestrienone,        nonnethis terone,
    progesterone,        quingestanol,    (17alpha) -17-hydroxy-11-

methylene-19-noq::~regna-4,15-dien-20-yn-3-one,  tibolone,

trirneges tone,    algestone    acetophenide,    nestorone,

prornegestone,    17-hyd.roxyprogesterone   esters,    19-nor-

1 7hydroxyprogesterone, 17 alpha-ethynyl testosterone, l?alpha-ethynyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethynylgon-4-en-3-one oxime or the
compounds    disclosed    in    WO  00/66570,    especially

tanaproget.    Levonorges trel,    norgestima te,

norethisterone,    drospirenone,    dydrogesterone    are

10    preferred.  Drospirenone  is  particularly  preferred.

Suitable estrogens are ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol,
estetrol    and   conjugated   equine   estrogens.    In   this

15    connection ethinylestradiol, estradiol and mestranol are preferred, and ethinylestradiol is particularly preferred.

The   amounts   used   according   to   the   invention   of   the

20    respective progestogens and/or estrogens correspond to the amounts normally known in contraceptives.

These amounts are normally for example for the progestogens mentioned below:

25                           
    Drospirenone    0. 5    -    5  mg   
    Levonorgestrel    30    -    250    J.1.9"
    Norgestimate    180    -    250    J.1.9"
    Norethisterone  acetate    0. 5    -    1    mg   
30    Cyproterone  acetate    1    -    2    mg       
    Desogestrel    20    -        150    J.l9"
    Dienogest    2    -    3    mg       
    Gestodene    60    -    75    J.l9"   
    Tibolone    2.5    mg       
35                           
    The  preferred  amount  administered  each  day  according  to
    the   present   invention   is   for    example    0. 5    to   5  mg,
    particularly  preferably  3  mg,  of  drospirenone.


The  amount  of  estrogen  used  according  to  the  invention

is  for  instance  for  the  estrogens  mentioned  below:

Ethinylestradiol    10    -    50  J,lg
Estradiol    1  -    4    mg
Mestranol    50    J.Lg   

The  preferred  amount  administered  each  day  according  to

the  invention  is  for  example  10  to  50  ~.  particularly

10    preferably 10 to 30 J,lg, very particularly preferably 20 to 30 Jl.Q', of ethinylestradiol.

Reference    to    5-methyl- (6S) -tetrahydrofolates    in    the

form    according   to   the   invention   means   the   free   acid

15    form    and    pharmaceutically    acceptable    salts    and

modifications    of    5-methyl- (6S) -tetrahydrofolic    acid

(N- [4- [ [ (2-amino-1, 4, 5, 6, 7, 8-hexahydro-4-oxo-5-methyl-(68) -pteridinyl)methyl] amino]benzoyl]-L-glutamic acid).

20    Pharmaceutically acceptable salts are intended to be both pharmacologically and pharmaceutically acceptable.

Such pharmacologically and pharmaceutically acceptable salts may be alkali metal or alkaline earth metal

salts, preferably sodium, potassium, magnes i urn or 25 calcium salts. The calcium salt is particularly
preferred.

The amount used for example of the calcium salt, which is particularly preferred according to the invention,

30    of 5-methyl-(6S)-tetrahydrofolic acid (metafolin) is between 0 .1 and 10 mg, preferably 0 . 4 to 1 mg, particularly preferably 451 J,lg (equivalent to 400 J,lg of folic acid or 416 J.Lg of 5-methyl- (68) -tetrahydrofolic acid).

35

Crystalline    modifications   disclosed   in   EP  1044975   are

preferably    employed  as   modification   of   5-rnethyl- (6S)-

tetrahydrofolates.


It    is  optionally  possible  for  vitamin  B6    or  vitamin  B2

to    be   present.   However,    a   corresponding   addition   is

UIUlecessary  to  carry  out   the  invention.   Vitamin  B6  may

be used in a dose between 1 mg and 5 mg, preferably between 1 mg and 3 mg per day on normally dosed use. Vitamin B2 can be employed in a dose between 1 mg and

5  mg,    preferably   between   1  mg   and   2  rng   per   day   on

normally  dosed  use,   and  between  2  and  5  mg  per  day  on

high-dosed  use.

10

The proges togens and/ or estrogens are the substances with contraceptive efficacy in this case. 5-Methyl-(6S) -tetrahydrofolate is added as vitamin in order to prevent disorders and malformations caused by folate

15 deficiency without, however, at the same time masking the symptoms of vitamin B12 deficiency which may be present. In addition, those women who, because of their reduced MTHFR enzymic activity (MTHFR C677T polymorphism), are capable of only restricted

20 metabolism of folic acid, but also of reduced folates, also profit from 5-methyl-(68)-tetrahydrofolate.

In    the  preferred  variant  of  the  present  invention,   the

amount    of  drospirenone  administered  each  day  is  0. 5  to

25    5 mg, preferably 3 mg, that of ethinylestradiol is 10 to 50 IJ.g, preferably 10 to 3 0 IJ.g, particularly preferably 20 to 30 IJ.g. The calcium salt of 5-methyl-

(65)    -tetrahydrofolic acid is present in an amount of from 0 .1 to 10 mg, preferably 0. 4 to 1 mg, particularly

30    preferably 451 IJ.g (equivalent to 400 IJ.g of folic acid) in this preferred variant of the present invention.

The  formulation  of  pharmaceutical  products  based  on  the novel    pharmaceutical    composition    takes    place    in   a 35    manner    known    per    se    by    processing    the    active ingredients    with    the    carrier    substances,     fillers, substances       influencing      disintegration,       binders, humectants,    lubricants,    absorbents,    diluents,   masking flavors,    colorants    and    so    on    which    are    used    in
 

pharmaceutical    technology,    and   converting   into    the

desired  administration  forms,   which  also  include  slow-

release  forms.

In  medicaments  of  the  invention  it  is  possible  for  the

estrogen    and   the   progestogen,   and   the   5-rnethyl- (6S)-

tetrahydrofolate,    to  be  present  in  joint  dosage  units.

The  estrogen  with  the  progestogen  on  the  one  hand,   and the   5-methyl- (6S) -tetrahydrofolate   on   the   other   hand, 10    may,    however,    also   be   fonnulated    in   separate   dose

units.

Both vitamin B12 and 5-rnethyl- ( 68) -tetrahydrofolate are unstable in the presence of atmospheric oxygen and

15    humidity. On attempting to formulate ethinylestradiol and vitamin B12 together it was found that these two substances are incompatible with one another.

Measurements    of    the    incompatibilities    between    the intended  formulation   ingredients  were  carried  out  by  a 20     therrnoanalytical    method    (DSC,    differential    scanning calorimetry) .    This    allows    incornpatibili ties    to    be recognized  through  low  enthalpies  of  fusion  and  melting temperatures.   These  are  caused  for  example  by  a   reduced proportion  of  crystalline  substance  and  the  increase  in

25    imp uri ties.    In   the   dete:rn~ination,  binary   mixtures   of

excipients or active ingredients in each case with vitamin B12 were investigated, and the compatibility was

examined under the influence of various gases and temperatures. Vitamin B12 showed a strong interaction

30    with ethinylestradiol in the described investigations. The results of the incompatibility measurements may be found in Table 1.


Table  1:  Summary  of  the  compatibility  investigation

Substance        Campat-        Type  of        Comments   
                           
        ibility        compatibility               
Drospirenone                mainly  good        0 2 -sensitive       
Ethinylestradiol                strong        very  02-   
                interaction        sensitive       
Ethinylestradiol                mainly  good        0 2 -sensitive,   
P-cyclodextrin                below  60°C        moisture-   
complex                            sensitive       
Lactose                mainly  good        0 2 -sensitive,   
                below  60°C        moisture-   
                            sensitive       
Corn  starch                good  below        0 2 -sensitive,   
                60°C        moisture-   
                            sensitive       
Modified  corn  starch                good  below        0 2 -sensitive,   
                60°C        moisture-   
                            sensitive       
Polyvinylpyrrolidone                mainly  good        0 2 -sensitive,   
                below  60°C        moisture-   
                            sensitive       
Magnesium  stearate        ++I-        indifferent,        02-sensitive,   
                good  below        moisture-   
                60°C        sensitive       
Hydroxypropy!methyl-                good  below        0 2 -sensi ti ve,   
cellulose                60°C        moisture-   
                            sensitive       
Hydroxypropyl-                good  below        02 -sensitive,   
cellulose                60°C        moisture-   
                            sensitive       
Mal todextrin        +I--        indifferent,        02 -sensi tive,   
                good  below        moisture-   
                60°C        sensitive       
Polyethylene  glycol                interaction        02 -sensitive,   
6000                with  moisture        moisture-   
                            sensitive       
Coating  mix                mainly  good            0 2 -sensitive,   
                below  60°C        moisture-   
                            sensitive   
Key:                                   

good    compatibility   expected   below   the   stated

temperature

compatibility  below  the  stated  temperature

++I-    indifferent    compatibility,    possibly    good

compatibility  below  the  stated  temperature
 

+/--    indifferent    compatibility,    appears    to    be

compatible  below  the  stated  temperature

-(---)    (strong)  interaction,  incompatible

Polyvinylpyrrolidone    (PVP)    is    particularly    suitable

because    of    its    wetting    properties    for    hormone

formulations    (Moneghini  et  al. ,   Int  J   Pharm  175,   1998,

177-183).    However,    formulation    of    5-methyl-(68)-

tetrahydrofolate    with    PVP    increases    the    rate    of

10    degradation   of   5-methy1- (68) -tetrahydrofolate   (compare

Table  2  and  3;  process  3).

A    further   object   on  which   this   application  was   based

and    which   is   achieved   by   the   present   invention   is

15    therefore    to    make    stable    formulation    of

ethinylestradiol    in   the   presence    of    5-methy1-(68)-

tetrahydrofolate  and  optionally  of  vitamin  B12   possible.

It    has    been    found    that    incompatibility    between

2 0 ethinylestradiol and vitamin B12 can surprisingly be prevented by employing the ethinylestradiol in the fonnulation as ethinylestradiol-beta-cyclodextrin complex (ethinylestradiol as ~-cyclodextrin clathrate; for preparation, compare WO 02/49675).

25

Corresponding formulations of the invention are described in Example 1 (compare composition A, B and

D).

30    They  comprise  inter  alia  a  mixture  of  corn  starch  and

modified corn starch. Starch consists of amylose and amylopectin. Both are polysaccharides based on a-

glucose units. However, it is also possible to use instead of corn starch in pharmaceutical formulations

35    for example rice starch, potato starch or wheat starch. The starch is employed swollen, suspended or dissolved as binding liquid or as solid. It may be unmodified or partly modified. The corn starch which is preferably used according to the invention has the empirical


formula    (C6Hlo0s)n    with    n  =  300-1000.    Its    molecular

weight  is  50  000-160  000.

The    starch  used   in  pharmaceutical   formulations   serves

only    in  part   as  pure  filler.   It  is   used  otherwise  as

binder.   1-5%,   preferably  -1.8-3%   of   the   tablet   weight

are  to  be  added  according  to  the  invention  as  binder  in

the  form  of  corn  starch.  Besides  the  corn  starch,   it  is

also  possible  to  employ  starch,   a  starch  compound  such

10    as maltodextrin, or cellulose derivatives such as, for example, carboxymethylcellulose, ethylcellulose,

hydroxypropylcellulose,    hydroxypropylrnethylcellulose  or

methylcellulose as binder. It is preferred according to the invention to use low-substituted cellulose

15    derivatives. These have a viscosity of 1-20 mPas in a 2 percent aqueous solution. Derivatives with a viscosity of 2-20 mPas are preferred according to the invention, and those with a viscosity of 3-6 mPas are particularly preferred.

20

Part of the corn starch used in the formulation preferred according to the invention may be replaced by low-substituted hydroxypropylcellulose (HPC) in a

concentration    of   0. 5-5%   (w/w),   preferably  1-3%   (w/w),

25    particularly preferably 2% (w/w) . In the present case, the hydroxypropylcellulose has low substitution when no

fewer than 5% and no more than 16% of its hydroxyl groups are esterified or etherified.

30    Table 2 shows the 5-methyl-(68)-tetrahydrofolate content per tablet in % based on the specified content of 100% as a function of the binder used immediately after preparation. The 5-methyl- (6S) -tetrahydrofolate

content    sho\\IIl  was   measured   in   the   content   uniformity

35    test (CUT). The investigated formulation was prepared (process 2) by mixing the ingredients, granulating with the part of the corn starch used as binder, absorbing the 5-methyl- (6S} -tetrahydrofolate after completion of the granulation process, renewed mixing and tableting.


By  comparison  therewith,   polyvinylpyrrolidone  was  added

as  binder  instead  of  corn  starch  to  the  formulation  by

process    3.   The   5-methyl- (68) -tetrahydrofolate   content

in  the  formulation  prepared  by  process  3  is  lower.

Table  2:  Metafolin  content  as  a  function  of  the  binder

immediately  after  preparation

    Metafolin  content    Metafolin  content
    absorption,    PVP    absorption,  corn  starch
    (process    3)    (process  2)
Average    90.5%        96.1%

10    Table 3 shows the 5-methyl- (68) -tetrahydrofolate content as a function of the binder used after storage at defined temperatures and humidity for one month. The tendency, evident from Table 2, for 5-methyl- ( 68)-

tetrahydrofolate    formulated  with  PVP  to  be  less  stable

15    is confirmed in particular on storage under conditions at 40°C and 75% relative humidity (rH).

Table  3:  Metafolin  content  as  a   function  of  the  binder

after  storage

20

250C/60%  rH    25°C/60%  rH    40°C/75%  rH    4QOC/75%  rH

absorption    absorption    absorption    absorption

PVP    corn  starch    PVP    corn  starch

(process  3)    (process  2)    (process  3)    (process  2)

Vials  open    89.5%    92.1%    37.7%    67.7%

An oral formulation is normally prepared by granulation, tableting and film-coating. However, 5-methyl- (68) -tetrahydrofolate is, because of its

25 sensitivity to oxygen and moisture, degraded even during the granulation. The further degradation of 5-methyl-(68)-tetrahydrofolate during storage is, however, particularly noteworthy. In a formulation in which as usual all the components of the

30    medicament,    including    5-methyl-(68)-tetrahydrofolate,

are    mixed  first   and  only  then  granulated,   the   residue

remaining  after  a  storage  time  of  one  month  at  40°C  and

75%  relative  humidity  in  closed  vials  was  only  just  60%

(compare    Table  5)   of  the  originally  employed  5-rnethyl-

(68) -tetrahydrofolate.    The    losses    during    the

granulation    process   can   be   reduced   by   absorbing   the

5-rnethyl-(68)-tetrahydrofolate  only  after  completion  of

the    granulation   process.    Dry   admixture    during    the

preparation    thus    leads    to    stabilization    of    the

10    5-rnethyl-(68)-tetrahydrofolate. However, in addition, this also surprisingly has the effect of further stabilization during storage. The 5-rnethyl-(68)-tetrahydrofolate content in a formulation prepared by

later    absorption   is   above   90%   with   identical   storage

15    times  Wlder  identical  conditions   (compare  Table  5) .

Table shows the 5-methyl-(68)-tetrahydrofolate content per tablet in % as a fWlction of the preparation process used immediately after preparation.

20 The difference between process 1 and process 2 derives from the time at which the 5-methyl- (6S)-

tetrahydrofolate was added during the preparation of the investigated tablet. In process 1, the 5-methyl-( 6S) -tetrahydrofolate was present in the mixture even

25    during the granulation, whereas in process 2 it was absorbed only after the granulation. The 5-methyl-(6S)-tetrahydrofolate content in the formulation prepared by process 1 is distinctly lower.

30

Table 4: Metafolin content as a function of the preparation process immediately after preparation

    Metafolin  content    Metafolin  content
    granulation    absorption
    (process  1)    (process  2)
Average    88.5%    96.1%
Distribution  coefficient    6.1    2.5


Table  5    shows    the    5-methyl-(68)-tetrahydrofolate

content    as  a   function  of   the  preparation  process  used

after  storage  for  one  month  at  defined  temperatures  and

humidity.    The    tendency,    evident    from    Table  4,    for

5-methyl-(68)-tetrahydrofolate    added    before    the

granulation    to    be    less    stable    is    confirmed    in

particular  on  storage  under  conditions  of  40°C  and  75%

relative  humidity  (rH).

10    Table  5:    Metafolin   content    as    a    function    of    the

preparation  process  after  storage

    25°C/60%    rH    25°C/60%    rH    40°C/75%    rH    40°C/75%    rH
    granulation    absorption    granulation    absorption
    (process    1)    (process    2)    (process    1)    (process    2)
Vials  open        63.2%        92.1%        43.4%        67.7%   
Vials    74.5%        92.5%        58.9%        90.1%   
closed                                   

It    is  kno\'m.   that   release  takes  place  more  slowly  with

15    dry admixture than in the case of granulation. However, it was surprisingly found that dry admixture of the 5-

m.ethyl- (6S) -tetrahydrofolate does not delay release, but in fact accelerates it . For this purpose, the tablets were investigated in an in vitro dissolution

20    test using a USP paddle apparatus at 50 rpm and 37°C in a 0. 03 percent aqueous ascorbic acid solution. Table shows the results of the in vitro dissolution tests.
 



                                -    19    -                                   
Table  6:  Dissolution  in  %                                           
                                                                           
Time  [min}                5-Methyl- ( 6S)-                5-Methyl- ( 6S)-   
                            tetrahydrofolate                tetrahydrofolate   
                                        process    1                    process    2   
                            dissolution    (%]                dissolution    [%]   
0                        0                    0       
10                        59.2                    81.4       
15                        66.8                    89.3       
30                        73.1                    91.3       
                                                   
45                        76.7                    91.1       
60                        75.8                    91.2       
                                                                                           
                                                                                           
            120                                                                               
        r:                                                       
                                            ...... ••••••••••......                   
        i..    60                                                                               
                                                                                           
    :1    .00                                                                               
                ~                                                       
    11                                                                   
    ~    20                    ~lly/a'IIJI!dn*lal11,pfOCIII2           
                                                                       
                                •Q+S'Ii(80111>M.. 3tlmln                           
            0            ---    I           
                0    10            '"'ti..""(noln)    ""'  50    00               
                                                       
                                                                                           

Regular  intake  of  the  pharmaceutical  composition  of  the

invention    with    the   particularly   preferred   dose    of

451  ~    of    the    calcium    salt    of    5-methy1-(6S)-

tetrahydrofolic    acid  per   day   leads   to   an   increase   in

10    the folate concentrations in the serum and erythrocytes until a steady state is reached. The corresponding erythrocyte folate invasion kinetics are described by

half-life  of  from  6  to  10  weeks.  On  the  basis  of  this

half-life,   about   97%   of   the   steady-state   erythrocyte
 

folate    level  can  be  expected  to  be  reached  after  about

5    half-lives   (corresponding  to  about  30   to   50  weeks).

If    daily   intake   of   the   pharmaceutical   cornposi tion   of

the    invention   is   continued,    the   erythrocyte   folate

levels    remain    in    the    region    of    the    steady-state

concentrations.    After    discontinuation    of    the

pharmaceutical    composition    of    the    invention,    the

erythrocyte folate levels slowly fall with a half-life likewise of about 6 to 10 weeks. The erythrocyte folate

10    levels thus remain even without further continuation of intake of the pharmaceutical cornposi tion of the invention for several weeks in a range above the lirni t of 906 nmol/1 which is generally regarded as sufficient to prevent neural tube defects. The product of the

15    invention thus ensures a reduction in the risk of disorders caused by folate deficiency and congenital malformations caused by folate deficiency, even after

termination of long-term intake of the medicament of the invention ("pill") .

20

The use of 5-methyl- (6S) -tetrahydrofolate, one or more estrogens and/or progestogens, and optionally vitamin B6 and/or vitamin B2 , and pharmaceutically acceptable excipients and carriers for producing a medicament for

25 reducing the risk of disorders caused by folate deficiency and congenital malformations caused by folate deficiency for at least weeks after termination of previous long-term and continual intake of this medicament is also according to the invention.

30

Likewise according to the invention is a kit comprising at least 20 daily dose units comprising the medicament of the invention and at least one daily dose unit comprising 5-rnethyl- (6S) -tetrahydrofolate, and

35    optionally vitamin B12 , vitamin B6 and/or vitamin B2 , where the number of all the dose units present in the kit is at least 28, and the dose units are disposed so that first the dose units comprising the medicament of the invention, and then the dose units comprising

neither    estrogen  nor  progestogen,   are  to  be  taken.   It

is also possible in the case of the first-mentioned at least 20 daily dose units comprising the medicament of the invention for the 5-methyl-(68)-tetrahydrofolate to

be    formulated   separately  and   to  be   disposed  spatially

as  additional  dose  units  such  that  joint  intake  of  both

dose  units  is  evident  from  this  disposition.

Further    developments   of   the   invention   for   different

10    kits  are  reflected  in  claims  18  to  22,  38,   39  and  40.

It  is  also  possible  in  particular,   according  to  claims

43 to 50, for the medicament of the invention to be administered in a so-called extended regime. By this is

15 meant continuous administration of the medicament for more than 28 days, the extended cycle of use being completed by administration for 1 to 7 days of dose units exclusively compr~s~ng 5-methyl-(68)-tetrahydrofolate or by intake of 1 to 7 placebos (dose

20    units active agent) or 1 to 7 blank pill days (no administration of any dose unit).

The following examples serve to explain the subject matter of the invention in more detail without wishing

25    to  restrict  it  thereto.


Bxample  11

The composition of tablets (80 mg) of the invention can be found in Table 7.

Table  7:  Composition  of  tablets  of  the  invention

Ingredient                    Amount               
Composition    A        B        c        D           
Drospirenone    3  mg        3  mg                3  mg       
Ethinylestradiol *    0. 03    mg    0.02    mg            0. 03    mg   
Metafolin    0.451    rng    0.451    mg    0.451    mg    0.451    mg   
Vitamin  B12                            0.1    mg   
Lactose  monohydrate    to  80    mg    to  80  mg    to  80    mg    to    80  mg   
Corn  starch    16.40  mg    16.40  mg    16.40    mg    16.40  mg   
Corn  starch**    2  mg***    2  mg***    2  mg***    2  mg***   
Modified  corn    9. 60    mg    9. 60    mg    9. 60    mg    9. 60    mg   
starch                                       
Magnesium  stearate    0. 80    rng    0. 80    rng    0. 80    rng    0.80    rng   

*•    optionally    as    ethinylestradiol-beta-cyclodextrin

10    complex; the stated amount refers in this case to uncomplexed ethinylestradiol. If the ethinylestradiol-beta-cyclodextrin complex is used, about ten times the

amount    is    to    be    employed.    This    is    because    the

ethinylestradiol    content   in  the   ~-cyclodextrin complex

15    is  about  9.5  to  12.5%   (compare  WO  02/49675).

**    • the part of the corn starch identified by ** can be replaced by an alternative binder such as, for example, 1.6 mg of low-substituted hydroxypropyl-

cellulose.

2 0 * * *: the amount of corn starch * * employed as binder may also be for example 1.8 mg.

The oral formulation is produced by mixing the abovementioned ingredients, granulating with the part

25    of the corn starch used as binder, absorbing the calcium salt of 5-methyl- ( 68) -tetrahyd.rofolic acid after completion of the granulation process, renewed
 
mixing,    tableting  and  film-coating.

Example  21

Blood    is   taken   at   8-week   intervals   from   80   healthy

young    women   of   childbearing   age,   and   the   erythrocyte

folate    level    is    determined    using    a    validated

microbiological,    irrununological   or   instrumental    (e.g.

HPLC,    LC-MS/MS)   method   or   a   suitable   combination   of

10    these  methods.

8 Weeks after the first blood sampling (screening phase),

451  ~  of the    calcium    salt of 5-methyl-(68)-

15    tetrahydrofolic  acid  each  day

is    administered    over    a    period    of    40    weeks    or,

alternatively:

3  rng   of   drospirenone,    3 0  J.Lg   of   ethinylestradiol

and    451  ~ of   the   calcium  salt   of   5-methyl- (6S)-

20    tetrahydrofolic    acid    is    administered
    simultaneously  on  each  of  the  first  21  days  of  the
    respective    cycle(tablet    ofcomposition    A   in
    Example  1) .Administrationof451  llQ'   ofthe
    calcium  salt  of  5-methyl-(68)-tetrahydrofolic  acid
25    is   continued   for   7   days   in   a   phase   immediately
    subsequentthereto(compositionC).3  mgof
    drospirenone 1     30  ~g    of  ethinylestradiol  and  451  ~g
    of    the    calcium    salt    of    5-methyl- ( 6S)-

tetrahydrofolic    acid    (composition   A)    are   again

30    administered for a further 21 days (second cycle) 1 and only 451 ~g of the calcium salt of 5-methyl-(6S) -tetrahydrofolic acid (composition C) are administered for a further 7 days 1 and so on (medication phase) .

35

5-Methyl-(6S)-tetrahydrofolate is no longer administered after 48 weeks. Alternatively 1 drospirenone and ethinylestradiol can be administered further for a further 40 weeks or likewise be

discontinued.

The    last   blood   sample   is   taken   after   88   weeks.   The

drop-out  rate  may  be  up  to  50%  because  of  the  long-term

nature  of  the  study.

~le3•

Blood    is   taken   at   8-week   intervals   from   80   healthy

10    young women of childbearing age, and the erythrocyte folate level is determined using a validated

microbiological,    immunological   or   instrumental    (e.g.

HPLC,    LC-MS/MS)   method   or   a   suitable   combination   of

these  methods.

15

Weeks    after   the   first   blood   sampling,    3  mg   of

drospirenone,    20  J.Lg  of   ethinylestradiol   and   451  ~  of

the    calcium  salt   of   5-methyl- (68) -tetrahydrofolic  acid

(composition  B)   is  administered  simultaneously  in  each

20    case in the first 24 days of the respective cycle for a period of 40 weeks. In a phase immediately subsequent thereto, administration of 451 ~ of the calcium salt of 5-methyl- (68) -tetrahydrofolic acid is continued for

7  days   (composition  C).   For  a   further  21  days   (second 25    cycle),      3  mg      of      drospirenone      and      20  IJ.g      of ethinylestradiol   and   451  ~  of   the   calcium   salt   of 5-methyl- (68) -tetrahydrofolic   acid   (composition   B)   are again  administered,  and  only  451  IJ.g  of  the  calcium  salt

of    5-methyl- (6S) -tetrahydrofolic   acid   (composition   C)

30    are  administered  for  a  further  7  days,  and  so  on.

5-Methyl- (6S) -tetrahydrofolate is no longer

administered after 48 weeks, while drospirenone and ethinylestradiol is administered further for a further

35    40  weeks  or  likewise  discontinued.

The last blood sample is taken after 88 weeks. The drop-out rate may be up to 50% because of the long-term nature of the study.
 

The  initial  erythrocyte  folate  level  in  the  subjects  is

about    500    to   700  nmol/1,    depending   on   the   eating

habits, but is in every case below 906 nmol/1. This value rises on administration of the pharmaceutical cornposi tion of the invention in subsequent days, while

the  eating  habits  remain  the  same,   and  reaches  a  value

of    about   906  nmol/1   after   only   6   to   8   weeks   -    i . e .

after  the  second  cycle.  After  continuous  administration

for  at  least  30  weeks   (corresponding  to  five  times  the

10    lower limit of the half-life), while the eating habits remain the same, the erythrocyte folate level reaches about 1200 to 1600 nmol/1 (steady state) . After termination of the administration of 5-rnethyl- (68)-

tetrahydrofolate,    the   erythrocyte   folate   level   falls

15    continuously. Starting from an average steady state concentration of 1400 nmol/1 and with the eating habits remaining the same, the erythrocyte folate level is

expected  to  fall  below  906  nmol/1,   and  thus  the  minimum concentration   in   erythrocytes   generally   sufficient   to 2 0    prevent    neural    tube    defects,    in    the    eleventh    to thirteenth     week     after     discontinuation     of      the

pharmaceutical  composition  of  the  invention.

Bxample  4:    Long-ter.m  folate  stud¥

25

180 healthy young women of child-bearing age (half of whom receive a diet fortified with folic acid) have
bloodtaken    atintervalsof    weeks,and    the
erythrocytefolatelevelisdeterminedusinga
30validated    microbiological,    immunological    or
instrumental   (e.g.   HPLC,   LC-MS/MS)   method  or  a  suitable
combination  of    these  methods.       

8 weeks after the first taking of blood, a first group 35 of 90 women receives over a period of 24 weeks

administration of simultaneously mg of drospirenone, 30 11g of ethinylestradiol and 451 11g

of    the   calcium   salt   of   5-methyl- (6S) -tetrahydro-


folic    acid   in   each   of   the   first   21   days   of   the

respective    cycle.   In  a   phase   directly   subsequent

thereto,    administration  of   451  119  of   the   calcium

salt    of    5-methyl- (6S)-tetrahydrofolic    acid    is

continued    for   7   days.    For   a    further    21    days

(second  cycle),   again  3  mg  of  drospirenone,   30  119

of  ethinylestradiol  and  451  119  of  the  calcium  salt

of    5-methyl- ( 6S)-tetrahydrofolic   acid,   and   for   a

further    7  days  only  451  119  of  the  calcium  salt  of

10    5-methyl- (6S) -tetrahydrofolic acid, are administered, and so on (medication phase) .

A group of 90 women receive administration of 3 mg of drospirenone, 30 119 of ethinylestradiol and 400 119 of

15    folic acid according to the same administration scheme as control group.

The    last  blood  is   taken  in  both  cases  after  24  weeks.

This   is   followed  by  an  observation  period  of  20  weeks 20    in     which     the     contraceptive    product     Yasmin®      is administered   for   20  weeks,   i.e.   in   each   of   the   first 21  days   of   the  respective  cycle,   3  mg  of   drospirenone and     30  11g     of     ethinylestradiol     are     administered simultaneously;   directly  subsequent   thereto,   no  active

25 substance is administered (placebos or no administration) for 7 days. The dropout rate may be up

to  30%.

The  initial  erythrocyte  folate  level  in  the  subjects  is

30    below 906 nmol/1. This value increases in subsequent days, if the eating habits remain the same, with administration of the pharmaceutical composition of the

invention  and,   in  most  of  the  women,   reaches  a  value  of

about    906  nmol/1   after   6  to   8  weeks.   After  continuous

35    administration for 24 weeks and with the eating habits remaining the same, an erythrocyte folate level is reached in both groups which shows equivalence between the two treatment groups (bioequivalence criterion 80-125%) . After termination of administration of 5-methyl-


(6S)-tetrahydrofolate,    the    erythrocyte    folate    level

falls    continuously.    It    is    ascertained    when    the

erythrocyte    folate   level   falls   below   the   acknowledged

threshold  of  906  nmol/1,  which  is  generally  regarded  as

sufficient  to  avoid  neural  tube  defects.

such    an   adequate   erythrocyte   folate   level   is   still

shown  by  most  of  the  women  in  the  first  group  3  months

after  termination  of  intake.
   
Claims       
1 .    A  medi camen t    cornpr ising :   
    5-methyl- ( 6S) -tetrahydrofo1ate   
    one  or  more  estrogens  and/or  progestogens,
    optionally  vitamin  B6   and/or  vitamin  B2,
    and    pharmaceutically    acceptable

excipients I carriers .

10    2.    The  medicament  as   claimed  in  claim  1,   comprising

at    least  one  estrogen  selected  from  the  group  of

ethinylestradiol,    mestranol,    quines tranol,

estradiol,    estrone,   estrane,   estriol,  estetrol  and

conjugated  equine  estrogens.

15

3.    The  medicament  as   claimed  in  claim  1,   comprising

at    least  one  progestogen  selected  from  the  group

    of   levonorgestrel,    norgestirnate,    norethisterone,
    dyd.rogesterone,    d.rospirenone,    3-beta-
20    hydroxydesogestrel,    3-ketodesogestrel
    (= etonogestrel) ,    17-deacetylnorgestimate,    19-
    norproges terone,    acetoxypregnenolone,
    allylestrenol,    amgestone,    chlormadinone,

cyproterone,    dernegestone,   desogestrel,   dienogest,

25    dihydrogesterone, dirnethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinone, gestodene, gestrinone,

hydroxymethylprogesterone,    hydroxyproges terone,

lynestrenol    (=  lynoestrenol),    rnecirogestone,

30    rned.roxyproges terone, rnegestrol, melengestrol, nomeges trol, norethindrone ( = norethis terone) ,
norethynodrel,    norgestrel   (including   d-norgestrel

and    dl-norgestrel),    norgestrienone,

normethisterone,    progesterone,    quinges tanol,

35    (17a1pha) -17-hydroxy-ll-methy1ene-19-norpregna-

4,15-dien-20-yn-3-one,    tibolone,    trimegestone,

algestone-acetophenide,    nestorone,    promegestone,

17-hyd.roxyprogesterone    esters,    19-nor-
1 7hyd.roxyproges terone,        17a1pha-
 
ethynyltestosterone,    17a1pha-ethyny1-19-

nortes tos terone,    d-17beta -acetoxy-13beta -ethyl-

l?alpha-ethynylgon-4-en-3-one    oxime    or    the

compounds    disclosed    in   WO  00/66570,    especially

tanaproget.

4.    The medicament as claimed in claim comprising a crystalline calcium salt of 5-methyl- (68)-tetrahydrofolic acid.

10

5.    The  medicament   as   claimed  in  claim  1,   comprising

5-rnethyl-(65)-tetrahydrofolate,    drospirenone    and

ethinylestradiol.

15    6.    The  medicament  as  claimed  in  claim  5  comprising  a

daily  dose  of   from  0.1  to  10  mg  of  5-methyl-(68)-

tetrahydrofolate.

7.    The  medicament  as  claimed  in  claim    comprising  a

20    daily dose of from 0.4 to 1 mg of 5-methyl-(68)-tetrahydrofolate.

8.    The  medicament  as  claimed  in  claim  5  comprising  a

daily    dose   of   451  ~  of   the   calcium   salt   of   5-

25    methyl- (68) -tetrahydrofolic  acid.

9. The medicament as claimed in claim comprising a daily dose of from 0. 5 to 5 mg of drospirenone.

30 10. The medicament as claimed in claim 5 comprising a daily dose of 3 mg of drospirenone.

11.    The  medicament  as  claimed  in  claim comprising  a

    daily    dose    of    from    10    to    50    1'9"    of
35    ethinylestradiol.                       
    12.The  medicament  as  claimed  in  claim  5  comprising  a
    daily    dose    of    from    10    to    30    1'9"    of

ethinylestradiol.


13.    The medicament as claimed in claim 5 comprising a daily dose of 20 ~of ethinylestradiol.

14.    The medicament as claimed in claim 5 comprising a daily dose of 30 11g of ethinylestradiol.

15.    The  medicament  as  claimed  in  claim  5  comprising

a    daily  dose  of   451  Jl9'  of   the  calcium  salt  of

5-methyl-(68)-tetrahydrofolic  acid,

10    a  daily  dose  of  3  mg  of  drospirenone  and

a  daily  dose  of  20  ~of ethinylestradiol.

16.    The  medicament  as  claimed  in  claim  5  comprising

a    daily  dose  of   451  Jl9'  of   the  calcium  salt  of

15    5-methyl- ( 68) -tetrahydrofolic  acid,

a  daily  dose  of  3  mg  of  drospirenone  and

a  daily  dose  of  30  ~of ethinylestradiol.

17.    A kit  comprising

20    at least 20 daily dose units comprising a medicament as claimed in any of the preceding

30
 
claims  and

at    least   one   daily   dose   unit   comprising   5-

methyl- (6S) -tetrahydrofolate, and optionally vitamin B6 and/ or vitamin B2 1

where the number of all the dose units present in the kit is at least 28 and

the dose units are disposed so that first the dose units comprising the medicament as claimed in any of the preceding claims 1 and subsequently the dose units comprising only 5-methyl-(65)-tetrahydrofolate, are to be taken.
 

18.    The  kit  as  claimed  in  claim  17  comprising

35    20-30 daily dose units comprising a medicament as claimed in any of claims 1 to 16 and

1-10 daily dose units comprising 5-methyl- (6S)-tetrahydrofolate.


19.    The  kit  as  claimed  in  claim  17  comprising

21-26  daily  dose  units  comprising  a  medicament

as  claimed  in  any  of  claims  1  to  16  and

2-7   daily  dose  units   comprising  5-rnethyl- (6S)-

tetrahydrofolate

where  the  number  of  all  the  dose  units  present

in  the  kit  is  28.

20.    The  kit  as  claimed  in  claim  17  comprising

10    21 daily dose units comprising a medicament as claimed in any of claims 1 to 16 and

7 daily dose units comprising 5-rnethyl- (6S)-tetrahydrofolate.

15    21.    The  kit  as  claimed  in  claim  17  comprising

24 daily dose units comprising a medicament as claimed in any of claims 1 to 16 and

4    daily   dose   units   comprising   5-rnethyl- (6S)-

tetrahydrofolate.

20

22.    The  kit  as   claimed  in  claim  17   comprising  451  J.1.Q'
 


25    23.



30
 

of    the    calcium    salt    of    5-methyl-(68)-

tetrahydrofolic  acid  in  each  daily  dose  unit.

The  use  of

5-methyl- (6S) -tetrahydrofolate

one or more estrogens and/or progestogens, optionally vitamin BG and/or vitamin B2,

and pharmaceutically acceptable excipients/carriers,

for producing a medicament for reducing the risk of disorders caused by folate deficiency and congenital malformations caused by folate deficiency for at least 6-10 weeks after
 

35    termination of previous long-term and continual intake of this medicament.

24.    The  use  as   claimed   in  claim  23,   characterized  in

that    the    preceding    long-term    regular    intake
 
amounts  to  at  least  30  weeks.

25. The use as claimed in either of claims 23 or 24, where the estrogen is selected from the group of

ethinylestradiol,    mestranol,    quinestranol,

estradiol,    estrone,   estrane,   estriol,   estetrol  or

conjugated  equine  estrogen.

26.    The  use  as   claimed  in  either  of  claims  23   or  24,

10    where the progestogen is selected from the group of levonorges trel, norges tirna te, norethisterone,
dydroges terone,    drospirenone,    3-beta-
hydroxydesoges trel,    3-ketodesogestrel
( =  etonoges trel) ,    17-deacetylnorgestimate,

15    19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, dernegestone, desogestrel, dienogest, dihydrogesterone, dirnethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate,

20 gastrinone, gestodene, gestrinone, hydroxyrnethy lproges terone, hydroxyprogesterone, lynestrenol (= lynoestrenol), rnecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone (= norethisterone),

25    norethynodrel, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol,

(17alpha)-17-hydroxy-11-rnethylene-19-norpregna-

4, 15-dien-20-yn-3-one,    tibolone,    trirnegestone,

30    algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19-nor-

17hydroxyproges terone,    17alpha-
ethynyl testosterone,        17alpha-ethynyl-19-
nortestosterone,    d-17beta-acetoxy-13beta-ethyl-

35    17alpha-ethynylgon-4-en-3-one oxime or the compounds disclosed in WO 00/66570, especially tanaproget.

27.    The  use  as  claimed  in  claim  25  or  26  for  reducing
 



-    33  -

the  risk  of  neural  tube  defects.

28.    The use as claimed in claim 25 or 26 for reducing the risk of cardiac defects, in particular ventricular valve defects.

29.    The use as claimed in claim 25 or 26 for reducing the risk of malformations of the urinary tract

(urogenital  defects).

10

30.    The use as claimed in claim 25 or 26 for reducing the risk of cleft lip, jaw and palate.

31.    The  use  as  claimed  in  claim  25  or  26  for  reducing

15    the  risk  of  spontaneous  abortions.

32.    The use as claimed in claim 25 or 26 for reducing the risk of malignant disorders, in particular carcinoma of the breast or colon.

20

33.    The use as claimed in claim 25 or 26 for reducing the risk of cardiovascular disorders.

34.    The use of 5-methyl-(68)-tetrahydrofolate,

25    drospirenone and ethinylestradiol as claimed in claim 27 to 33.

35.    The  use  of  451  ~g of  the  calcium  salt  of  5-methyl-

(68) -tetrahydrofolic   acid,    mg   of   drospirenone

30    and  20  ~ of  ethinylestradiol  as  claimed  in  claim

27  to  33.

36.    The  use  of  451  ~g of  the  calcium  salt  of  5-methyl-

(6S) -tetrahydrofolic   acid,    3  mg   of   drospirenone

35    and  30  ~ of  ethinylestradiol  as  claimed  in  claim

27  to  33.

37.    The use as claimed in claim 23 or 24, characterized in that the preceding intake of at
 



-    34  -

least    5-methyl-(68)-tetrahydrofolate   takes   place

in  a  slow-release  form.

38.    The  kit  as  claimed  in  claim  17,  comprising

21    daily  dose  units  comprising  a   medicament  as

claimed  in  claim  15  and

7    daily   dose   units   comprising   5-methyl- (6S)-

tetrahydrofolate.

10    39.    The  kit  as  claimed  in  claim  17,  comprising

24    daily  dose  units  comprising  a  medicament  as

claimed  in  claim  15  and

4    daily   dose   units   comprising   5-methyl- (6S)-

tetrahydrofolate.

15

40.    The  kit  as  claimed  in  claim  17,  comprising

21    daily  dose  units  comprising  a  medicament  as

claimed  in  claim  16  and

7    daily   dose   units   comprising   5-methyl- (6S)-

20    tetrahydrofolate.

41.    A method for formulating the medicament as claimed in any of claims 1 to 16, characterized in that the 5-methyl- (6S) -tetrahydrofolate is absorbed

25    only  after  the  granulation.

42. The method as claimed in claim 41, characterized in that low-substituted hydroxypropylcellulose is used as binder.

30

43. The kit as claimed in claim 17, comprising more than 28 daily dose Wlits, where at least 28 daily dose W'l.its comprise a medicament as claimed in any of claims 1 to 16, and where at least one daily

35    dose unit comprises 5-methyl- (6S)-tetrahydrofolate, and where the dose Wli ts are disposed so that firstly the dose units comprising the medicament as claimed in any of claims 1 to 16, and subsequently the dose units comprising


only    5-rnethyl-(68)-tetrahydrofolate,    are    to    be

taken.

44.    The   kit   as   claimed   in   claim   43,    in   which   the

number    of   dose   units   comprising   a   medicament   as

claimed in any claims 1 to 16 is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integral multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of daily dose units which comprise only 5-

10    rnethyl-(6S)-tetrahydrofolate is 7, 6, 5, 4, 3, 2 or 1.

45.    The   kit   as   claimed   in   claim   44,    in   which   the

multiple  is  2,  3,  4,  5,  6,  7,  8,  9,  10,  11  or  12.

15

46.    A  kit   comprising  more   than   28   daily  dose   units,

where at least 28 daily dose units comprise a medicament as claimed in any of claims 1 to 16, where at least one daily dose unit is a placebo or

20    a blank pill day, and where the dose units are disposed so that first the dose units comprising the medicament as claimed in any of claims 1 to 16 are to be taken.

25 4 7. The kit as claimed in claim 46, in which the number of dose units comprising as claimed in any of claims 1 to 16 is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integral multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of

30    placebos  or  blank  pill  days  is  7,   6,   5,   4,   3,   2  or

1.

48.    The kit as claimed in claim 4 7, in which the multiple is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

35

49.    The kit as claimed in any of claims 43 to 48, in which the dose units comprising medicament comprise a medicament as claimed in claim 15.
 



-    36  -

50.    The kit as claimed in any of claims 43 to 48, in which the dose units comprising medicament comprise a medicament as claimed in claim 16.
 



1/1

Figure 1

10-FormyHHF
.......    t
ATP
Folic acid (PGA)

15
Incorporation of C1 units in purine ring

Folate metabolism

THF: tetrahydrofolate
MTHFR: methylenetetrahydrofolate reductase
MS: methionine synthase
20    SAM: S-adenosylmethionine SAH: 5-adenosylhomocyste

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