Novel vitamin D analogues

This invention relates to vitamin D analogues represented by the general formula I ##STR1## in which formula X stands for hydrogen, lower alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy; R.sup.1 and R.sup.2, which may be the same or different, stand for lower alkyl, optionally substituted with halogen or hydroxy with the proviso that R.sup.1 and R.sup.2 cannot both be methyl when X is other than lower alkyl, or, taken together with the carbon atom numbered 25, R.sup.1 and R.sup.2 can form a saturated or unsaturated C.sub.3 -C.sub.9 carbocyclic ring which may optionally be substituted at any possible position(s) with lower alkyl, halogen or hydroxy; R.sup.3 stands for hydrogen or lower alkyl; R.sup.4 and R.sup.5 represent either each hydrogen, or when taken together constitute a bond, with the result that a double bond connects carbon atoms numbered 22 and 23; and bioreversible derivatives thereof. The compounds of the invention have a favorable therapeutic index and are particularly useful in the treatment of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation.

This invention relates to a hitherto unknown class of compounds which shows 
strong activity in inducing differentiation and inhibiting undesirable 
proliferation of certain cells, including cancer cells and skin cells, to 
pharmaceutical preparations containing these compounds, to dosage units of 
such preparations, and to their use in the treatment of diseases 
characterized by abnormal cell differentiation and/or cell proliferation. 
The compounds of the invention constitute a novel class of vitamin D 
analogues and are represented by the general formula I 
##STR2## 
in which formula (and also throughout the remainder of this disclosure) X 
stands for hydrogen, lower alkyl, halogen or hydroxy; Y stands for 
hydrogen or hydroxy; R.sup.1 and R.sup.2, which may be the same or 
different, stand for lower alkyl, optionally substituted with halogen or 
hydroxy (but with the proviso that R.sup.1 and R.sup.2 cannot both be 
methyl when X is other than lower alkyl), or, taken together with the 
carbon atom numbered 25, R.sup.1 and R.sup.2 can form a saturated or 
unsaturated C.sub.3-C.sub.9 carbocyclic ring (including an aromatic ring) 
which may optionally by substituted at any possible positions(s) with 
lower alkyl, halogen or hydroxy; R.sup.3 stands for hydrogen or lower 
alkyl; R.sup.4 and R.sup.5 represent either each hydrogen, or when taken 
together constitute a bond, with the result that a double bond connects 
carbon atoms numbered 22 and 23; and the two undulated bonds to carbon 24 
indicate that both R and S forms at this centre are within the scope of 
the invention. In the context of this invention the expression "lower 
alkyl" indicates a straight or branched saturated or unsaturated carbon 
chain with a content of from 1 to 6 atoms. 
As it can be seen, the compounds of formula I, depending on the meanings of 
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, and/or X, contain one or 
more additional asymmetric carbon atoms and/or double bonds, and may thus 
form stereoisomeric forms. The invention covers all these compounds in 
pure form and also mixtures of them. It should be noted, however, that our 
investigations indicate a notable difference in activity between the 
stereoisomeric forms. In addition, derivatives of I in which one or more 
of the hydroxy groups are masked as groups which can be reconverted to 
hydroxy groups in vivo are also within the scope of the invention 
("bioreversible derivatives or pro-drugs of I") 
Especially preferred are compounds of formula I in which Y is hydroxy and 
R.sup.3 stands for hydrogen or methyl, and in particular compounds in 
which R.sup.4 and R.sup.5 taken together represent a bond, especially in 
such a way that the resulting 22,23-double bond has the trans 
configuration. 
The term "bioreversible derivatives or prodrugs of I" includes, but is not 
limited to, derivatives of the compounds of formula I in which one or more 
hydroxy groups have been transformed into --O--acyl or --O--glycosyl 
groups, such masked groups being hydrolyzable in vivo. 
It has recently been shown that certain vitamin D derivatives, in 
particular 1,25(OH).sub.2 D.sub.3 (1.alpha.,25-dihydroxy-vitamin D.sub.3) 
are able to stimulate the differentiation of cells and inhibit excessive 
cell proliferation, and it has been suggested that these compounds might 
be useful in the treatment of diseases characterized by abnormal cell 
proliferation and/or cell differentiation such as leukemia, myelofibrosis 
and psoriasis. However, the well known potent effects of these compounds 
on calcium metabolism prohibit the use of higher doses, which will give 
rise to hypercalcemia. Thus, these compounds are not completely 
satisfactory for use as drugs in the treatment of e.g. psoriasis or 
leukemia, which may require continuous administration of the drug in 
relatively high doses. 
It has not surprisingly turned out that the compounds of the invention have 
a favourable therapeutic index and are particularly useful in the 
treatment of human and veterinary disorders which are characterized by 
abnormal cell proliferation and/or cell differentiation, such as certain 
dermatological disorders including psoriasis and certain cancer forms, 
e.g. leukemia and myelofibrosis. 
A number of cells, including skin cells and cancer cells, contain receptors 
for 1,25(OH).sub.2 D.sub.3. The compounds of the invention have thus been 
tested in vitro for their ability to interact with the receptor in such 
cells, and for their effect on the proliferation and differentiation of 
such cells (e.g. the human monocytic tumour cell line U 937). In vivo, the 
compounds were tested after p.o. and i.p. administration to rats for 
effects on calcium metabolism. The compounds were compared with 
1,25(OH).sub.2 D.sub.3 in the in vitro experiments and with 
1.alpha.(OH)D.sub.3 and 1,25(OH).sub.2 D.sub.3 in the in vivo experiments. 
From the above tests, it was shown that e.g. compound 59* binds strongly to 
the receptor and is a potent inhibitor of cell proliferation and inducer 
of cell differentiation in vitro. In vivo, compared to 1,25(OH).sub.2 
D.sub.3 and 1.alpha.(OH)D.sub.3, it showed only weak vitamin D activity 
and could be administered at much higher doses without having any toxic 
effects. 
FNT * See Table 2 
Thus, a favourable separation of the biological effects on cell 
differentiation/proliferation and on calcium metabolism has been clearly 
demonstrated. 
Compound I can be prepared by total synthesis, or, more conveniently, by 
partial synthesis from readily available precursors, either steroidal, for 
example dinorcholenic acid, ergosterol, stigmasterol, or seco-steroidal 
e.g. vitamin D.sub.2. The route described below by way of example utilises 
vitamin D.sub.2 as starting material, and is considered to be the most 
flexible of the routes explored to date, being very suitable for the 
synthesis of a large number of compounds represented by formula I. 
However, it should be noted that the synthesis of a particular compound on 
a production scale may well be more conveniently carried out from an 
alternative starting material and/or by an alternative route. Two such 
routes are outlined later on. The compound I can readily be obtained in 
crystalline form by crystallization from common organic solvents or 
mixtures thereof, as well known in the art. 
The synthetic strategy involves the modification of the ring D side chain 
present in the (seco-)steroidal precursor to a 1S-formylethyl group 
followed by elaboration of the new side chain present in the particular 
target compound I. At some stage in the synthesis the rest of the full 
vitamin D skeleton must be elaborated. The way this is done in practice 
depends on the starting material and the new side chain in question, and 
in addition the order of some of the reaction steps can be altered with 
the result that not all the possible intermediates can be exemplified 
here. Furthermore, the nature of the various activating groups, protecting 
groups, and methods for masking the triene moiety can be different to 
those exemplified. However, any such changes still fall within the scope 
of this invention. 
One synthetic route will now be described in detail. In the reaction 
scheme, the triene moiety of the vitamin D nucleus is masked as the adduct 
with SO.sub.2 (other dienophiles which can be used include for example 
4-phenyl-1,2,4-triazoline-3,5-dione and phthalazine-1,4-dione, as known in 
the art), and the ring A hydroxyl groups are protected as 
tert-butyl-dimethylsilyl (t-BuMe.sub.2 Si) ethers (other suitable 
protecting groups are well known in the art and include the etherifying 
and esterifying groups e.g. as described in "Protective Groups in Organic 
Synthesis", T. W. Greene, Wiley, New York, 1981). The coupling of the 
aldehyde function with a side chain fragment is done at the 5,6-trans 
vitamin stage (other possibilities include the cis-vitamin stage or masked 
triene stage, the requisite aldehyde being obtained by altering the order 
of reactions). The incorporation of the side chain fragment involves a 
Wittig reaction (other types of coupling, e.g. aldol reaction, or reaction 
with a sulphone anion, followed by elimination or reductive elimination, 
are well known in the art), the ylide being a triphenylphosphorane (other 
types of ylide being well known in the art). Finally, [X] represents 
either X of formula I, or a protected or masked derivative which can be 
converted to X at some stage in the synthesis (and not necessarily the 
last stage as indicated on the Scheme). 
As shown on the Reaction Scheme which follows, the synthesis involves the 
preparation of the important key intermediate 12 which is used to prepare 
compounds of formula I in which Y stands for OH. The corresponding 
compound I in which Y=H is prepared analogously from 13. An alternative 
key intermediate is the corresponding 5,6-cis aldehyde 14, which can be 
used analogously to 13 or 12 in the subsequent step on the Scheme to give 
the corresponding 5,6-cis isomer of II and hence III. Reaction h then 
converts these isomers directly to the corresponding V. The continuation 
of the synthesis after 12 or 13 (or 14) requires the reaction with a side 
chain fragment (D), the synthesis of which can be achieved for example by 
the following route:- 
##STR3## 
The side chain fragments shown in Table I are selected for the purposes of 
illustration and are described in the Preparations. 
TABLE I 
______________________________________ 
Side Chain Fragment (D) 
R.sup.1 R.sup.2 X or [X] 
______________________________________ 
D(i) --(CH.sub.2).sub.2 -- 
H 
D(ii) --(CH.sub.2).sub.4 -- 
H 
D(iii) --(CH.sub.2).sub.5 -- 
H 
D(iv) CH.sub.3 CH.sub.3 
CH.sub.3 
D(v) .dbd.CH--(CH.dbd.CH).sub.2 -- 
______________________________________ 
The ketone A, if not commercially available, may be prepared by literature 
methods and is converted to the bromomethyl ketone B by literature 
methods. In some cases B are commercially available starting materials. 
In the Preparations, the starting materials/intermediates A, B and C (if 
desired) are also given corresponding suffixes (i)-(v) to indicate the 
nature of R.sup.1, R.sup.2 and [X] (e.g. for the sequence 
A(i).fwdarw.B(i).fwdarw.C(i).fwdarw.D(i)). In order to describe further 
the invention, but not in any way to limit it, the details for the 
synthesis of some particular examples of compounds of formula I are given. 
For the purpose, the Reaction Scheme and Notes should be read with 
reference to Tables 1 and 2 and to the Preparations and Examples. 
NOTES TO REACTION SCHEME 
On the Scheme, Z' represents an optionally protected hydroxy group, and Z 
also represents an optionally protected hydroxy group (which may be the 
same or different to Z') unless it is stated that Z=H, in which case Z 
represents hydrogen. For the specific numbered compounds described in 
Table 2 and in the Preparations and Examples, Z'=t-BuMe.sub.2 SiO, and 
Z=Z' unless stated otherwise, which requires step "b" to be a 
tert-butyldimethylsilylation reaction e.g. with t-BuMe.sub.2 
CiCl-imidazzole) and step "j" to be a de-tert-butyldimethylsilylation 
reaction (e.g. with n-Bu.sub.4 NF). a. SO.sub.2 ; b. Optional hydroxyl 
protection reaction; c. NaHCO.sub.3 (boiling EtOH); d. SeO.sub.2 
-N-methylmorpholine N-oxide (MeOH--CH.sub.2 Cl.sub.2); e. (i) O.sub.3 (ii) 
PPh.sub.3 ; f. Side chain fragment D (see Table 1); g. 1,4-Reduction under 
suitable conditions with a selective reducing agent, e.g. Na.sub.2 S.sub.2 
O.sub.4 under phase transfer conditions; h. Formal source of 
"R.sup.3.crclbar. "-when R.sup.3 =H; e.g. NaBH.sub.4 or other reducing 
agent; when R.sup.3 =alkyl, e.g. Grignard or other organometallic reagent. 
A radiolabel can be conveniently introduced at this stage by using a 
suitable source of radioactive R.sup.3 (e.g. for R.sup.3 =.sup.3 H or 
.sup.14 CH.sub.3); i. h.gamma.-triplet sensitizer; j. Optional hydroxyl 
deprotection reaction(s); k. Any necessary reaction (sequence) for 
converting [X] to X. 
##STR4## 
TABLE 2 
__________________________________________________________________________ 
Compounds Indicated on the Reaction Scheme and/or 
Referred to by Number in the Preparations and Examples 
Compound Formula (Z' = t-BuMe.sub.2 SiO) 
Number Y or Z X or [X] 
R.sup.1 
R.sup.2 
R.sup.3 
R.sup.4 
R.sup.5 
__________________________________________________________________________ 
15 II H H --(CH.sub.2).sub.2 -- 
-- -- 
16 II t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
-- -- 
17 II t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.4 -- 
-- -- 
18 II t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.5 -- 
-- -- 
19 II t-BuMe.sub.2 SiO 
CH.sub.3 
CH.sub.3 
CH.sub.3 
-- -- 
20 II t-BuMe.sub.2 SiO 
--(CH.dbd.CH).sub.2 --CH.dbd. 
-- -- 
21 III t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
-- -- 
22 
IV H H --(CH.sub.2).sub.2 
H bond 
23 
24 
IV t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
H H H 
25 
26 
IV t-BuMe.sub.2 SiO 
H --(CH.sub.2 -- 
H bond 
27 
28 
IV t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.4 -- 
H bond 
29 
30 
IV t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.4 -- 
H bond 
31 
32 
IV t-BuMe.sub.2 SiO 
CH.sub.3 
CH.sub.3 
CH.sub.3 
H bond 
33 
34 
IV t-BuMe-.sub.2 SiO 
--(CH.dbd.CH).sub.2 --CH.dbd. 
H bond 
35 
36 
IV t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
CH.sub.3 
bond 
37 
38 
V t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
H bond 
39 
40 
V H H --(CH.sub.2).sub.2 -- 
H bond 
41 
42 
V t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.4 -- 
H bond 
43 
44 
V t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.5 -- 
H bond 
45 
46 
V t-BuMe.sub.2 SiO 
CH.sub.3 
CH.sub.3 
CH.sub.3 
H bond 
47 
48 
V t-BuMe.sub.2 SiO 
--(CH.dbd.CH).sub.2 --CH.dbd. 
H bond 
49 
50 
V t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
H H H 
51 
52 
V t-BuMe.sub.2 SiO 
H --(CH.sub.2).sub.2 -- 
CH.sub.3 
bond 
53 
54 
VI OH H --(CH.sub.2).sub.2 -- 
H bond 
55 
72 
VIII 
OH H --(CH.sub.2).sub.2 -- 
H bond 
73 
56 
I H H --(CH.sub.2).sub.2 -- 
H bond 
57 
58 
I OH H --(CH.sub.2).sub.2 -- 
H bond 
59 
60 
I OH H --(CH.sub.2).sub.4 -- 
H bond 
61 
62 
I OH H --(CH.sub.2).sub.5 -- 
H bond 
63 
64 
I OH CH.sub.3 
CH.sub.3 
CH.sub.3 
H bond 
65 
66 
I OH --(CH.dbd.CH).sub.2 --CH.dbd. 
H bond 
67 
68 
I OH H --(CH.sub.2).sub.2 -- 
H H H 
69 
70 
I OH H --(CH.sub.2).sub.2 -- 
CH.sub.3 
bond 
71 
__________________________________________________________________________ 
Notes. 
(a) Where "bond" appears in the last column, the trans configuration of 
the 22,23double bond is to be understood; 
(b) Each formula I, IV, V, VI and VIII (and IX and XI, see later), 
represents two deparate numbered compounds. These differ only in their 
absolute configuration at C24. In the Preparations and Examples, no 
attempt has been made to identify these configurations, but it is clearly 
indicated which of the two isomers is concerned in relative terms by 
differentiating unambiguously between their physical and/or spectroscopic 
properties (when possible) and/or by correlation with a particular 
starting material. 
The compounds I may also be synthesized from steroidal precursors. Such an 
approach is illustrated in the conversion of the compound VII(a) or VII(b) 
(both available from dinorcholenic acid acetate) into the "pre-vitamin" 
VIII(a) or VIII(b), respectively, as outlined below:- 
##STR5## 
(i) Side Chain Fragment (D) (see text) (dimethyl sulphoxide, 100.degree. 
C.); 
(ii) N-bromosuccinimide (CCl.sub.4, reflux); 
(iii)(a) Bu.sub.4 NBr, then (b) Bu.sub.4 NF (tetrahydrofuran (THF), 
20.degree. C.); 
(iv) 4-Phenyl-1,2,4-triazoline-3,5-dione (CHCl.sub.3, 20.degree. C.); 
(v)* Na.sub.2 S.sub.2 O.sub.4 /(C.sub.10 H.sub.21).sub.3 NMeCl/NaHCO.sub.3 
PhH-H.sub.2) reflux); either 
(vi).sup.+ NaBH.sub.4 /CeCl.sub.3 (THF-MeOH, 0.degree. C.) (for R.sup.3 
=H); or 
(vii).sup.+ R.sup.3 MgBr or R.sup.3 Li (THF, -10.degree. C.) (for R.sup.3 
=C.sub.n H.sub.2n+1 ; n=1-6); 
(viii) LiAlH.sub.4 (THF, reflux); 
(ix) Irradiation with medium-pressure Hg lamp through a Vycor filter 
(PhH-EtOH, 0.degree. C.) 
FNT * If step (v) is included, the compounds VIII having R.sup.5 =R.sup.4 =H 
are produced; if step (v) is omitted, the compound VIII having R.sup.5, 
R.sup.4 =bond (trans) are produced. 
FNT .sup.+ Chromatographic separation of C-24 epimers may be conveniently 
effected after stage (vi) or (vii). 
The pre-vitamin VIII may be partially converted to the corresponding 
compound I by keeping in an inert solvent (e.g. ether, ethanol or benzene, 
or a mixture) at a temperature from about 0.degree. C. to 100.degree. C., 
preferably from about 20.degree. C. to about 80.degree. C. until 
equilibrium is reached or until an acceptable, less complete, conversion 
has been achieved (e.g. from two weeks at 20.degree. C. to a few minutes 
at 80.degree. C.). This equilibration may also be performed on a 
hydroxy-protected derivative of VIII, such as an acylated or 
trialkylsilylated derivative to give the corresponding derivative of I 
which is converted to I by conventional deprotection reaction(s). 
Implicit in the routes to the compound I illustrated heretobefore is the 
key reaction establishing the 24-hydroxy group from a 24-oxo compound. The 
reactions exemplified all give rise to a mixture of diastereoisomers at 
this centre, which means that a separation step is required unless the 
particular compound I can be administered as a mixture. However, 
biological results have shown that of a pair of C-24 diastereoisomeric 
compounds I, one isomer is normally more active than the other. It is 
therefore advantageous to increase the proportion of the intermediate 
having the C-24 configuration corresponding to the more active compound I. 
This is possible by using a diastereoselective organometallic reagent (for 
R.sup.3 =alkyl) or reducing agent (for R.sup.3 =H). Methodology for the 
latter, reductive, reaction especially is now highly developed, and is 
particularly well applicable to compounds in which the 22,23-double bond 
is present in the 24-oxo intermediate. 
Thus, the proportion of for example either compound IV (see Reaction 
Scheme) in the mixture, obtained by reducing compound II or III, can be 
increased by the use of for example the one or the other antipode of a 
chiral reducing agent. Examples of this type or reaction are reviewed for 
example in "Asymmetric Synthesis", ed. J. D. Morrison, Academic Press, 
London, Volume 2, 1983. 
An alternative practical approach to an efficient reduction process is to 
recycle the undesired C-24 isomer (either in essentially pure form or 
admixed with smaller amounts of the desired isomer) after separation of 
either essentially all or just some of the desired isomer. This recycling 
is achieved by a mild oxidation back to the 24-oxo compound. For example, 
either compound 26 or 27 (or a mixture) is readily reconverted to 16 by 
reaction with active manganese dioxide. 
It should be noted however that a minor amount of the less active C-24 
isomer of I in admixture with the more active isomer does not interfere 
with the efficacy of the formulated drug. 
A second alternative synthesis of compound I is illustrated in the coupling 
of an optionally hydroxy-protected form of the "top-half" fragment IX of 
the molecule with the anion derived from the protected "botton-half" 
fragment X to give XI, followed by conventional deprotection step(s) and 
any necessary modification of [X]. 
##STR6## 
In formulae IX, X and XI, Z' is protected OH, e.g. t-BuSiMe.sub.2 O; Z is 
either H or protected OH, e.g. t-BuSiMe.sub.2 O; W is either OH or 
protected OH, e.g. t-BuSiMe.sub.2 O; and [X] is either X of formula I or a 
group which can be converted to X. 
The present compounds are intended for use in pharmaceutical compositions 
which are useful in the treatment of human and veterinary disorders which, 
as mentioned above, are characterized by abnormal cell-proliferation 
and/or differentiation. 
The amount required of a compound of formula I (hereinafter referred to as 
the active ingredient) for therapeutic effect will, of course, vary both 
with the particular compound, the route of administration and the mammal 
under treatment. The compounds of the invention can be administered by the 
parenteral, enteral or topical routes. They are well absorbed when given 
enterally and this is the preferred form of administration in the 
treatment of systemic disorders. In the treatment of dermatological 
disorders like psoriasis, topical forms like ointments, creams or lotions 
are preferred. In the treatment of systemic disorders daily doses of from 
1-1000 .mu.g, preferably from 2-250 .mu.g, of a compound of formula I are 
administered. In the topical treatment of dermatological disorders, 
ointments, creams or lotions containing from 1-1000 .mu.g/g, and 
preferably from 10-500 .mu.g/g, of a compound of formula I are 
administered. The oral compositions are formulated, preferably as tablets, 
capsules, or drops, containing from 0.5-500 .mu.g, preferably from 1-250 
.mu.g, of a compound of formula I, per dosage unit. 
While it is possible for an active ingredient to be administered alone as 
the raw chemical, it is preferable to present it as a pharmaceutical 
formulation. Conveniently, the active ingredient comprises from 1 ppm to 
0.1% by weight of the formulation. 
By the term "dosage unit" is meant a unitary, i.e. a single dose which is 
capable of being administered to a patient, and which may be readily 
handled and packed, remaining as a physically and chemically stable unit 
dose comprising either the active material as such or a mixture of it with 
solid or liquid pharmaceutical diluents or carriers. 
The formulations, both for veterinary and for human medical use, of the 
present invention comprise an active ingredient in association with a 
pharmaceutically acceptable carrier therefor and optionally other 
therapeutic ingredient(s). The carrier(s) must be "acceptable" in the 
sense of being compatible with the other ingredients of the formulations 
and not deleterious to the recipient thereof. 
The formulations include e.g. those in a form suitable for oral, rectal, 
parenteral (including subcutaneous, intramuscular and intravenous), and 
topical administration. 
The formulations may conveniently be presented in dosage unit form and may 
be prepared by any of the methods well known in the art of pharmacy. All 
methods include the step of bringing the active ingredient into 
association with the carrier which constitutes one or more accessory 
ingredients. In general, the formulations are prepared by uniformly and 
intimately bringing the active ingredient into association with a liquid 
carrier or a finely divided solid carrier or both, and then, if necessary, 
shaping the product into the desired formulation. 
Formulations of the present invention suitable for oral administration may 
be in the form of discrete units as capsules, sachets, tablets or 
lozenges, each containing a predetermined amount of the active ingredient; 
in the form of a powder or granules; in the form of a solution or a 
suspension in an aqueous liquid or non-aqueous liquid; or in the form of 
an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient 
may also be administered in the form of a bolus, electuary or paste. 
A tablet may be made by compressing or moulding the active ingredient 
optionally with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing, in a suitable machine, the active ingredient 
in a free-flowing form such as a powder or granules, optionally mixed with 
a binder, lubricant, inert diluent, surface active or dispersing agent. 
Moulded tablets may be made by moulding, in a suitable machine,a mixture 
of the powdered active ingredient and a suitable carrier moistened with an 
inert liquid diluent. 
Formulations for rectal administration may be in the form of a suppository 
incorporating the active ingredient and a carrier such as cocoa butter, or 
in the form of an enema. 
Formulations suitable for parenteral administration conveniently comprise a 
sterile oily or aqueous preparation of the active ingredient which is 
preferably isotonic with the blood of the recipient. 
Formulations suitable for topical administration include liquid or 
semi-liquid preparations such as liniments, lotions, applications; 
oil-in-water or water-in-oil emulsions such as creams, ointments or 
pastes; or solutions or suspensions such as drops. 
In addition to the aforementioned ingredients, the formulations of this 
invention may include one or more additional ingredients such as diluents, 
buffers, flavouring agents, binders, surface active agents, thickeners, 
lubricants, preservatives, e.g. methyl hydroxybenzoate (including 
anti-oxidants), emulsifying agents and the like. 
The compositions may further contain other therapeutically active compounds 
usually applied in the treatment of the above mentioned pathological 
conditions.