Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-12-17
2004-06-22
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
56, C514S534000
Reexamination Certificate
active
06753442
ABSTRACT:
The present invention relates to nitroxy derivatives of the hydroxybenzoic acid in a modified physical form, and the pharmaceutical formulations thereof, said derivatives having general formula
A—X
1
—NO
2
(I)
wherein A is an hydroxybenzoic acid derivative as defined hereunder; X
1
is a linking bivalent radical as defined hereunder, said formulations capable to induce in very short times, of the order of 2-2.5 hours, the plasmatic concentration peak of the hydroxybenzoic acid derivative, defined as A.
The compositions of the invention can be used to prepare oral dosage forms suitable to induce a fast beginning of the pharmacological effect.
As well known the pharmacologically active substances when administered per os produce a systemic effect only after having undergone an absorption process through the gastroenteric duct walls. The drug absorption process is a complex phenomenon which depends on various factors, among which drug liposolubility and hydrosolubility. It is difficult to theoretically foresee, in practice it is impossible to know which is the optimal combination of these factors to obtain the maximum absorption peak of the active principle in short times, of about 2-2.5 hours at most.
Generally the therapeutic effect of a drug which shows its activity by systemic route when administered per os depends, in particular, on the following factors:
drug absorption through the gastrointestinal wall,
concentration in the hematic fluid,
possible interaction whith the target tissue.
In particular for the drugs having an antiinflammatory and analgesic activity, an essential feature is the action quickness, i.e. the effect onset has to show in relatively short times after consumption.
The nitroderivative compounds of formula (I), in the unmodified physical form according to the present invention, are known from the patent applications WO 95/30641 and WO 97/16405 in the name of the Applicant. These compounds with respect to the antiinflammatory precursor drugs have a global comparable or higher efficacy, but they have the advantage to show lower side effects. The drawback of these products is that they do not show chemical physical properties such as to allow an haematic peak of maximum absorption in the period of time of 2.5 hours at most. Pharmacokinetic studies carried out by the Applicant using a conventional pharmaceutical formulation for oral use of the nitroderivative compounds of formula (I), not treated as reported in the present invention, have shown that there is no haematic concentration peak in the above mentioned short times, therefore the product does not timely show its therapeutic properties. See the Examples showing that the haematic peak takes place after too long times from the consumption, of about 6 hours.
The need was felt to have available pharmaceutical compositions for oral use, comprising the nitroderivative compounds of formula (I), such as to produce a maximum plasmatic concentration peak (C
max
) in short times, such that t
max
(t
max
being the time at which C
max
occurs) is of about 2.5 hours at most, preferably lower than or equal to 2 hours.
It has been found by the Applicant that it is possible to solve this technical problem with the compounds and formulations thereof for oral use as indicated hereinafter.
An object of the present invention are compounds of formula (I) and pharmaceutical compositions for oral use comprising as active principle said compounds
A—X
1
—NO
2
(I)
wherein
A=R(COX),
X=O, NH, NR
1C
, wherein R
1C
is a linear or branched C
1
-C
10
alkyl, R is selected from the following radicals:
wherein
R
1
is a OCOR
3
group; wherein R
3
is methyl, ethyl or linear or branched C
3
-C
5
alkyl, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, which can be aromatic or completely or partially saturated, said heterocyclic ring containing one or more heteroatoms independently selected between O and N;
R
2
is hydrogen, hydroxy, halogen, linear or branched when possible C
1
-C
4
alkyl, linear or branched when possible C
1
-C
4
alkoxyl; linear or branched when possible C
1
-C
4
perfluoroalkyl, for example trifluoromethyl; mono—or di—(C
1
-C
4
) alkylamino;
R
1
and R
2
together are the dioxymethylene group, with the proviso that when X=NH, then Y is ethylene and R
2
=H as defined hereinder;
R
1
cannot be OCOR
3
in position
2
when R
3
is methyl;
nI is an integer and is
)
or 1.
Preferably in (Ia X=
0
, R
1
is acetoxy and is in ortho position with respect to the -CO- group, R
2
hydrogen; preferably in Ib) R
3=CH
3
, nI=
0
; X is equal to O, and the bond of the aromatic ring with the COX group is in the 1 or 2 positions;
X
1
is a bivalent linking bridge selected from the following:
YO:
Y=linear or branched when possible C
1
-C
20
, preferably
C
2
-C
5
, alkylene; or
C
5
-C
7
cycloalkylene optionally substituted;
or X
1
is selected from the following:
wherein n3 is an integer from 0 to 3, n3′ is an integer from 1 to 3;
wherein n3 and n3′ have the above mentioned meaning;
wherein nf′ is an integer from 1 to 6, preferably from 1 to 4;
wherein R
1f
=H, CH
3
and nf′ is as above defined; said compounds of formula (I) being completely or partially in amorphous form.
The amorphization degree can be measured by well known methods such as for example DSC, RX, IR, etc. For partially amorphous it is meant that in the pharmaceutical compositions of the invention the compounds of formula (I) are generally amorphous for at least 5%, preferably 10%, more preferably for at least 80%, as measured by DSC.
The amorphization degree is determined by DSC as variation reduction) of the subtended area of the endothermic melting peak of the active principle. When the amorphization is complete, the melting peak characteristic of the active principle of formula (I) substantially disappears. This means that there is a variation of the enthalpy associated to the melting peak.
A test for measuring the amorphization degree according to the present invention is the following: an amount of nitroderivative of formula (I) is added with hydroxypropyl-&bgr;-cyclodextrin in the molar ratio 1:2; 43 g of the compound of formula (I) are dissolved in 5 l of ethyl alcohol; the so obtained organic solution is mixed at room temperature with 5 l of deionized water containing 7% w/v (350 g) of hydroxypropyl-&bgr;-cyclodextrin. The hydroalcoholic solution is treated in the spray-drying LabPlant SD-05 Spray-Drying equipment, with an hot air flow at the inlet at the temperature of 60° C., maintaining an air flow such as to allow outlet temperatures of about 45° C.; the crystallinity loss is evaluated on the powder (5-10 mg) by the DSC method and the variation of the peak area is determined by comparing the area with that of the precursor treated under the same conditions without the addition of cyclodextrin.
An indicative test of the crystallinity decrease of the compounds of formula (I) is based on the determination of their dissolution rate in water.
The dissolution rate test is carried out in a dissolving equipment according to United States Pharmacopeia 23 by using a volume of deionized water of 1000 ml. The blade stirrer speed is of 100 rpm and the temperature is 37±0.5° C.
In a little glass vessel an exact amount of each sample is weighed so that it contains an amount of the active principle equal to 30 mg, which is directly introduced in the vessel containing the deionized water. At predetermined times, respectively of 5, 10, 15, 30, 45, 50, 60, 90 and 120 minutes from the beginning of the test, the amount of the nitroderivative compound passed in solution is determined, by measuring the concentration w/v (weigh/volume) thereof by UV spectrophotometry at the wave length of 235 nm, using a calibration line. The data are expressed as percentage of nitroderivative compound passed in solution in connection with the time. The amount of the compound of formula (I) passed in solution at the time of 10 minutes is at least about
Antognazza Patrizia
Benedini Francesca
Arent & Fox PLLC
Killos Paul J.
Nicox S.A.
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