U.S. patent application number 11/980345 was filed with the patent office on 2008-05-08 for preparation of formulations of angiotensin ii at1 receptors antagonists for the treatment of arterial hypertension, other cardiovascular illnesses and its complications.
Invention is credited to Washington Xavier De Paula, Robson Augusto Souza Dos Santos, Frederic Jean Georges Frezard, Ruben Dario Sinisterra Millan.
Application Number | 20080108575 11/980345 |
Document ID | / |
Family ID | 3947403 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108575 |
Kind Code |
A1 |
Millan; Ruben Dario Sinisterra ;
et al. |
May 8, 2008 |
Preparation of formulations of angiotensin II AT1 receptors
antagonists for the treatment of arterial hypertension, other
cardiovascular illnesses and its complications
Abstract
Preparation of AT1 receptors antagonists formulations using the
cyclodextrins, their derivatives and/or biodegradable polymers for
the treatment of arterial hypertension, other cardiovascular
disease and their complications. Until now, no applications using
the AT1.sub.1 receptor antagonists and cyclodextrins or derivatives
and/or biodegradable polymers for the treatment of arterial
hypertension, other cardiovascular diseases and their
complications, was found in the technical state of art. The present
invention is characterized by the combination of two different
technologies: one is the molecular encapsulation of AT1.sub.1
receptor antagonists in cyclodextrins and the other is the
microencapsulation in biodegradable polymers. It also comprises the
increase of the effectiveness of the AT1.sub.1 receptor antagonists
as well as an increase in their bio-availability. The present
invention comprises a new more effective alternative for the
treatment of arterial hypertension, other cardiovascular diseases
and their complications.
Inventors: |
Millan; Ruben Dario Sinisterra;
(Bairro Ouro Preto, BR) ; Dos Santos; Robson Augusto
Souza; (Santa Amelia, BR) ; Frezard; Frederic Jean
Georges; (Cidade Jardim, BR) ; De Paula; Washington
Xavier; (Barro Preto, BR) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Family ID: |
3947403 |
Appl. No.: |
11/980345 |
Filed: |
October 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10474640 |
Mar 30, 2004 |
|
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PCT/BR02/00051 |
Apr 9, 2002 |
|
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11980345 |
Oct 31, 2007 |
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Current U.S.
Class: |
514/1.9 ;
514/15.7; 514/381; 514/394; 514/397; 514/777 |
Current CPC
Class: |
A61K 9/19 20130101; A61K
31/4184 20130101; A61P 9/10 20180101; A61P 9/12 20180101; A61K
38/085 20130101; A61P 9/00 20180101; A61K 9/1652 20130101; A61K
31/41 20130101; A61K 31/4178 20130101; A61K 9/5036 20130101; A61K
9/0002 20130101; A61K 31/4155 20130101 |
Class at
Publication: |
514/016 ;
514/381; 514/777; 514/394; 514/397 |
International
Class: |
A61K 47/40 20060101
A61K047/40; A61K 31/41 20060101 A61K031/41; A61K 31/4184 20060101
A61K031/4184; A61K 31/4178 20060101 A61K031/4178; A61K 38/08
20060101 A61K038/08; A61P 9/10 20060101 A61P009/10; A61P 9/12
20060101 A61P009/12 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 10, 2001 |
BR |
PI 0102252-0 |
Claims
1-13. (canceled)
14. A composition comprising an inclusion compound consisting
essentially of: (a) an Angiotensin II AT1 receptor antagonist or
salt thereof and (b) a cyclodextrin.
15. The composition according to claim 14, wherein the composition
is a controlled-release system.
16. The composition according to claim 14, wherein the Angiotensin
II AT1 receptor antagonist or salt thereof is chosen from
valsartan, telmisartan, irbersartan, candesartan, or
eprosartan.
17. The composition according to claim 14 wherein the Angiotensin
II AT1 receptor antagonist is angiotensin (1-7).
18. The composition according to claim 14, wherein the cyclodextrin
has six, seven, or eight units of glucopyranose.
19. The composition according to claim 14, wherein the cyclodextrin
is .beta.-cyclodextrin.
20. The composition according to claim 14, wherein the cyclodextrin
is hydroxyalkylated cyclodextrin.
21. The composition according to claim 20, wherein the
hydroxyalkylated cyclodextrin is
hydroxypropyl-.beta.-cyclodextrin.
22. A pharmaceutical composition comprising the composition as
claimed in claim 14 and a pharmaceutical acceptable carrier,
diluent, excipient, or combination thereof.
23. The pharmaceutical composition according to claim 23, wherein
the composition is for oral, intramuscular, intravenous,
subcutaneous or inhalation administration.
24. The composition according to claim 14, wherein the composition
further comprises a biodegradable or biocompatible polymer.
25. The composition according to claim 24, wherein the polymer has
a degradable surface.
26. The composition according to claim 25, wherein the polymer is
chosen from poly(2-hydroxyethyl methacrylate), polyacrilamide,
poly(lactic acid) (PLA), poly(glycolic acid) (PGA),
poly(lactic-glycolic acid) (PLGA) and poly(anhydrides).
27. The composition according to claim 24, wherein the composition
is a controlled-release system.
28. A pharmaceutical composition comprising the composition as
claimed in claim 24 and a pharmaceutical acceptable carrier,
diluent, excipient, or combination thereof.
29. The pharmaceutical composition according to claim 28, wherein
the composition is for oral, intramuscular, intravenous,
subcutaneous or inhalation administration.
30. A process for the preparation of a composition comprising an
inclusion compound consisting essentially of: (a) an Angiotensin II
AT1 receptor antagonist or salt thereof and (b) a cyclodextrin,
comprising forming an inclusion compound between an Angiotensin II
AT1 receptor antagonist and a cyclodextrin.
31. The process of claim 30 further comprising the encapsulation of
the inclusion compound with a biodegradable or biocompatible
polymer.
32. The process of claim 31, wherein the polymer has a degradable
surface.
33. The process according to claim 32, wherein the polymer is
chosen from poly(2-hydroxyethyl methacrylate), polyacrilamide,
poly(lactic acid) (PLA), poly(glycolic acid) (PGA),
poly(lactic-glycolic acid) (PLGA) and poly(anhydrides).
34. A method of treating arterial hypertension comprising
administering to a patient in need thereof a therapeutically
effective amount of at least one pharmaceutical composition of
claim 22.
35. A method of treating arteriosclerosis associated with arterial
hypertension comprising administering to a patient in need thereof
a therapeutically effective amount of at least one pharmaceutical
composition of claim 22.
36. A method of treating stroke associated with arterial
hypertension comprising administering to a patient in need thereof
a therapeutically effective amount of at least one pharmaceutical
composition of claim 22.
37. A method of treating arterial hypertension comprising
administering to a patient in need thereof a therapeutically
effective amount of at least one pharmaceutical composition of
claim 28.
38. A method of treating arteriosclerosis associated with arterial
hypertension comprising administering to a patient in need thereof
a therapeutically effective amount of at least one pharmaceutical
composition of claim 28.
39. A method of treating stroke associated with arterial
hypertension comprising administering to a patient in need thereof
a therapeutically effective amount of at least one pharmaceutical
composition of claim 28.
Description
FIELD OF THE INVENTION
[0001] The present invention comprises the process of preparation
of new formulations of ANGIOTENSIN II AT1 receptors antagonists,
using the cyclodextrins or their derivatives, lipossomes and the
biodegradable polymers for the treatment of arterial hypertension,
other cardiovascular illnesses and its complications.
BACKGROUND OF THE INVENTION
[0002] In the majority of the countries in the world, from 15% to
25% of the adult population presents high arterial pressure
(MacMahon, S. et al., Blood pressure, stroke, and coronary heart
disease, Lancet 335:765-774, 1990). The cardiovascular risk
increases with the level of arterial pressure: the higher the
arterial pressure, the higher the risk of coronary occurrences.
Hypertension, considered to be the main factor responsible for
coronary, cerebral and vascular renal diseases, is the number one
cause of death and incapacity among adults.
[0003] Heart failure is worldwide the main cause of hospitalization
in the age group of 60 to 80 years of age. The ageing of the
population alone is already a factor for the increase of its
incidence: while 1% of the individuals present heart failure
between the age of 25 to 54 years, among the elderly the incidence
is much higher, reaching the level of 10% to those over 75 years of
age (Kannel, W. B. et al., Changing epidemiological features of
cardiac failure, Br. Hear J 1994; 72 (suppl 3):S3-S9).
[0004] Heart failure, owing to its clinical features, is a limiting
disease which, with its aggravation, reduces the quality of life of
the patients and, in the most serious cases, presents the
characteristics of a malignant disease with a mortality rate of
over 60% in the first year, even nowadays (Oliveira, M. T. Clinical
features and prognosis of patients with high congested heart
failure, College of Medicine USP, 1999). It is estimated that
today, in the industrialized world alone, over 15 million people
are affected by it and that only in the US, for example, the number
of cases has increased 450% between 1973-1990 (Kannel, W. B. et
al., Changing epidemiological features of cardiac failure, Br. Hear
J 1994; 72 (suppl 3): S3-S9).
[0005] Hypertension is complex, multifactorial, of high prevalence,
responsible for various deleterious effects and with high morbidity
and mortality (Kaplan, N. M. Blood pressure as a cardiovascular
risk factor: prevention and treatment. JAMA. 275:1571-1576, 1996).
With the aim of improving the understanding of the disease,
countless studies for the evaluation of the efficiency of its
control in the general population and in special groups have been
carried out. The control of blood pressure, without a wide
non-medicament and/or pharmaceutical intervention in the associated
risks factors (diabetes, obesity, tobacco), may reduce
substantially the benefits of the long term treatment of arterial
hypertension in the decrease of mortality (Wilson, P. W. et al.,
Hypertension. Raven Press. 94-114).
[0006] Hypertension is the pathology that most contributes to
cardiovascular arteriosclerosis (The Fifth Report of the Joint
National Committee on detection, evaluation, and treatment of High
Blood Pressure. National Institute of Health (VJNC). Arch, Intem,
Med. 153:154-181, 1994). According to statistics, one in every four
americans is or will be hypertensive, and it is estimated that 4.78
millions of people have heart failure. Each year, 400 thousand new
cases are diagnosed, giving rise to 800 thousand hospitalizations,
with a cost of US$ 17.8 billions of dollars with the treatment.
[0007] In Brazil, data from SUS (Sistema Unificado de Saude) have
shown that in 1997, heart failure was the main cause of
hospitalizations among the cardiovascular diseases, leading the
government to spend R$ 150 million reais with its treatment, a
number equivalent to 4.6% of all the expenses with health (Filho,
Albanesi F. Heart failure in Brazil. Arq. Bras. Cardiol.
71:561-562, 1998).
[0008] The angiotensin II (Ang II), a potent vasoconstrictor, is
the most important active hormone of the renin-angiotensin system
(RAS) and it makes up an important determinant of the
pathophysiology of hypertension. Ang II increases directly and
indirectly the peripheral resistance. Directly, it produces
vasoconstriction of small arteries and, to a lesser extent, at the
level of the post-capillary venules, where a high number of
ANGIOTENSIN II AT1 receptors is found. The constriction of the
arteries mediated by Ang II increases the vascular resistance,
which is a basic hemodynamic mechanism involved in the arterial
pressure rise. The constricting intensity is higher in the kidneys
and lower in the brain, lungs and in the skeletal muscle. Ang II
also leads to the release of aldosterone by the supra-renal gland.
The release of the aldosterone increases the blood volume through
the increase of sodium and water reabsorption and of the excretion
of potassium by the kidneys (Frohlich, E. D., Angiotensin
converting enzyme inhibitors. Hypertension 13 (suppl I): 125-130,
1989). It is believed that this increases the arterial pressure in
response to the increase of the cardiac output, the second basic
hemodynamic mechanism in the rising of arterial pressure. It has
been suggested that the release of catecholamines from the
supra-renal medulla by Ang II and the stimulation of the release of
the norepinefrine by the nerves terminals and the activation of the
central nervous system leads to an increase of the sympathetic
discharge. (Goodman and Gilman's, The Pharmacological Basis of
Therapeutics 8.sup.th ed. Pergamon Press, New York, p755,
1990).
[0009] The RAS is an endocrine system in which the renin acts over
the angiotensinogen of hepatic origin, to produce angiotensin I in
plasma. This peptide is then converted to Ang II, through the
action of the angiotensin-converting enzyme (ACE). Thereafter, Ang
II is taken to its target organs by the blood flow, binding in a
selective way to the ANGIOTENSIN II AT1 receptors (Sasaki, k. et
al., Cloning and expression of a complementary DNA enconding a
bovine adrenal angiotensin II receptor type-1. Nature, 351:230-233,
1991).
[0010] The treatment of hypertension aims not only the reduction of
health care expenses, but also the prevention of target organs
lesions, through changes in the quality of life and use of
medication, when necessary (The Fifth Report of the Joint National
Committee on detection, evaluation, and treatment of High Blood
Pressure. National Institute of Health (VINC). Arch. Intem. Med.
153:154-181, 1994).
[0011] All the patients with systolic arterial pressure over 180
mmHg or diastolic arterial pressure over 110 mmHg must be submitted
to pharmacological treatment, regardless of other present factors
or not (Report the Canadian Hypertension Society. Consensus
Conference.3. Pharmacologic treatment of essential hypertension.
Xan. Med. Assoc. J. 149 (3):575-584, 1993).
[0012] Since the 60s, however, the anti-hypertensive drugs became
an important tool in the treatment of high arterial pressure
(Menard, J. Anthology of the renin-angiotensin system: A one
hundred reference approach to angiotensin II antagonists. J.
Hypertension 11 (suppl 3): S3-S11, 1993). During the last four
decades, the pharmacological research produced new types of drugs
to treat hypertension: the diuretics in the 60s, the betablockers
in the 70s, the calcium channel blockers and the
angiotensin-converting enzyme inhibitors in the 80s and the
ANGIOTENSIN II AT1 receptor antagonists in the 90s.
[0013] The ACE inhibitors (ACEI) are capable of inhibiting the
conversion of the angiotensin I to Ang II. Thus, the
vasoconstricting actions of Ang II are minimized. Preliminary
studies showed that teprotide, the first inhibitor used clinically,
has an anti-hypertensive action when administered by the
intravenous route, however, is inactive by oral route. This fact
strongly limited its use.
[0014] It is known today that ACE is a multi-action enzyme, which
means that it acts on various substrates. Besides acting as a
dipeptidase in angiotensin I and in bradykinin, it is capable of
hydrolising several peptides, indicating that the enzyme can act in
various tissues.
[0015] ACEI are excellent when administered in monotherapy. ACEI
provokes a relatively fast drop of the arterial pressure in 60 to
70% of the patients with arterial hypertension (Ganong, W.
Neuropeptides in cardiovascular control. J. Hypertens 2(suppl
3):15-22, 1984). They are generally well tolerated, but their use
can bring about adverse side effects and reactions, some of which
relatively serious, among them, angioneurotic edema and dry cough
(8 to 10%).
[0016] The first attempt to develop antagonists of Ang II date from
the beginning of the 70s and efforts were concentrated on the
development of peptides analogous to Ang II, saralasine
(1-sarcosina, 8-isoleucine angiotensin II) being the first one.
However, these derivatives were not clinically acceptable as they
also presented partial agonist activity. In 1982, the two first
non-peptide antagonists of ANGIOTENSIN II AT1 receptor were
developed (S-8307 and S-8308). However, in spite of being highly
specific and without agonist activity, they presented weak binding
to the Ang II receptors. With a series of changes in the molecular
structure of these two precursors, a new potent product for oral
use, and of high specificity was developed, losartan. Since then,
many other non-peptide antagonists were developed, such as
candesartan, irbersatan, valsartan, telmisartan, eprosartan,
tasosartan and zolosartan.
[0017] Losartan is a molecule chemically described as a
monopotassium salt of
2-butyl-4-cloro-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]me-
thyl]-1H-imidazole-5-ethanol. Its empirical formula is
C.sub.22H.sub.22CIKN.sub.6O, a crystal clear powder, white and
pale, of free flow and molar mass of 461.01 g/mol. It is rapidly
absorbed and it presents a bioavailability of 33% and the peak of
maximum concentration is reached within one hour, with an half-life
of about two hours. It is soluble in water, soluble in alcohol and
slightly soluble in common organic solvents, such as acetonitrile
and methyl-ethyl-cetone. Losartan reduces arterial pressure solely
by a new, specific and selective mechanism of action: blockade of
the Ang II receptor, regardless of the origin or way of production
of the Ang II. Losartan does not block other hormone receptors,
enzymes or important ionic channels in the cardiovascular
regulation.
[0018] The oxidation of the 5-hydroxymethyl group in the imidazol
ring results in the active metabolite of losartan, designated by
EXP-3174. The mechanism of the singular action of losartan can be
distinguished from the inhibition of the ACE, by measuring, in the
plasma, the induced increase of the renin activity and of Ang II
levels (Tavares, Agostinho et al, Antagonists of the Receptors of
the Angiotensin II, Pharmacology and Cardiovascular Therapeutics,
305-315, 1998). During the administration of losartan, the renin
activity is increased, leading to the increase of the Ang II in the
plasma. After the discontinuity of the administration of losartan,
the renin activity and the levels Ang II return to the levels of
pre-treatment. About 92% of an oral dose of losartan can be
detected in the urine and in the feces; 5% are excreted with the
losartan, 8% as EXP-3174 and the rest as inactive metabolites
(Melntyre, M. et. al. Losartan, an orally active angiotensin
ANGIOTENSIN II AT1 receptor antagonist: a review of its efficacy
and safety in essential hypertension. Pharmacol. Ther.
74(2):181-194, 1997).
[0019] Valsartan
(1-oxopentyl-N'[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-van-
iline) is a competitive antagonist of the receptor AT1, presenting
bioavailability of 25%, with an half-life of 9 hours, reaching the
maximum peak in about 2 hours. It is minimally metabolized and
excreted especially through the feces and only 15 to 20% appears in
the urine (Criscione, L. de Gasparo et. al. Pharmacological profile
of valsartan. Br. J. Pharmacol 110:761-771, 1993). If administered
with Atenolol, Cimetidine, Digoxin, Furosemide, it presents
pharmacokinetics interactions that enhanced its effect.
[0020] Irbersartan
(2-butyl-3-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl1,3-diazaspiro[[4,-
4]-non-1en-4-olone) is a competitive antagonist of the ANGIOTENSIN
II AT1 receptor. It is metabolized essentially by oxidation, it
presents a peak of concentration between 1.5 and 2 hours and an
half-life around 11 to 15 hours (Nisato, D. A review of the new
angiotensin II antagonist irbesartan. Cardiovasc Drug Rev). Its
availability is of 60 to 80% and it is also excreted mostly by the
bile (80%).
[0021] Candesartan
(2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-1H-benzimidazole-
-7-carboxylic acid), presents high affinity for the ANGIOTENSIN II
AT1 receptor and it dissociates slowly, presenting half-life of 9
hours, bioavailability of about 40% and it is eliminated mostly by
the urine and the bile (Shibouta, Y. et. al. Pharmacological
profile of a highly potent and long-acting angiotensin II receptor
antagonist, J. Pharmacol. Exp. Ther. 266:114-120, 1993). When
administered together with (nifedipine, digoxina or glibenclamide),
it has presented better results.
[0022] Eprosartan
((E)-a-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]--
2-thiofenepropanoic acid), has also high affinity for the
ANGIOTENSIN II AT1 receptor, with a bioavailability of 13 to 15%,
with maximum concentration at about 2 hours. Approximately 90% is
eliminated through the feces and the rest in the urine (Ruddy,
Michael C. et. al. Angiotensin II Receptor Antagonists. 71:621-633,
1999).
[0023] Telmisartan
(4'-[(1,4'-dimethyl]-2'propyl[2,6'-bi-1H-benzimidazole]-1'-yl)methyl]1,1'-
biphenyl]-2-carboxilic acid) is a competitive inhibitor of the
ANGIOTENSIN II AT1 receptor and presents a bioavailability of 45%.
It is excreted mostly by the bile (97%) (Ruddy, Michael C. et. al.
Angiotensin II Receptor Antagonists. 71:621-633, 1999).
[0024] The angiotensin-(1-7), (Asp-Arg-Val-Tyr-Ile-His-Pro), and
its derivative Sar.sup.1-Ang-(1-7) also antagonize the pressure
effect of the Ang II in human beings (Ueda et al., Mol. Biol. Cell
11:259A-260A suppl. S December 2000) and rats. The contraction
produced by Ang II in isolated arteries of rabbits and humans is
also reduced by the angiotensin-(1-7) (Roks et al. Eur. Heart J
22:53-53 Suppl. S Sep, 2001).
[0025] U.S. Pat. No. 4,340,598 (CA1152515, JP56071073, EP0028833,
DE3066313D), Yoshiyasu, Toyonara et al. (1982) have developed a
method to obtain new anti-hypertensive compounds through the
substitution of the imidazol ring by phenyl, halogen, nitro or
amino groups, in order to obtain imidazol derivatives. These
compounds presented an excellent antagonist activity for the
ANGIOTENSIN II AT1 receptor, being utilized as hypotensive
agents.
[0026] U.S. Pat. No. 4,576,958 (U.S. Pat. No. 4,372,964), Wexler,
Ruth R. (1986), has also developed some derivatives of the
4,5-diaryl-1H-imidazol-2-methanol, which presented
anti-hypertensive effect, because of their vasodilating properties.
This finding was based on a series of chemical reactions, among
them, Friedel-Crafts acylation, reflux in formamide and
oxidation.
[0027] U.S. Pat. No. 4,598,070 (CA1215359, DK 356684, EP135044,
ES8506757, GR82322, JP60025967), Mashiro, Rawahara et al. (1986),
have developed an invention based on the preparation of inclusion
compounds between the anti-hypertensive agent, Tripamide, and
cyclodextrins (.quadrature.-cyclodextrin and
.quadrature.-cyclodextrin). The use of cyclodextrin resulted in the
improvement of the solubility of tripamide.
[0028] U.S. Pat. No. 4,666,705, de Crosta, Mark. T. et al. (1987)
have proposed a new drug-controlled release system for the
treatment of hypertension. An inhibitor of ACE, the Captopril, was
used because its fast absorption, with half-life of two hours. In
order to prolong its presence in the organism, Captopril was
associated to polymer or co-polymer in the form of tablets. The
polymer utilized was the (polyvinyl pirrolidone) (PVP) and the
technique used was the dry granulation. As a result, the drug
permanence was increased from 4 to 16 hours.
[0029] U.S. Pat. No. 5,064,825, Chakravarty, Prasun, K. et al.
(1991), have obtained new derivatives of the imidazol ring,
presenting seven member-rings and showing antagonist activity for
the ANGIOTENSIN II AT1 receptor.
[0030] U.S. Pat. No. 5,073,641, Bundgaard, Hans et al. (1991), have
obtained new ester derivatives of the carboxylic acid as inhibitors
to the ACE. Among them, the ethyl-ester, Pentopril, was found to be
highly stable in the human plasma.
[0031] U.S. Pat. No. 5,171,748 (JP3005464, CA2017065, EP0399732),
Roberts, David et al. (1992), have also obtained new heterocyclics
derivatives of the imidazol ring, which antagonize the action of
angiotensin II.
[0032] U.S. Pat. No. 5,256,687, Becker, Reinhard et. al. (1993),
have claimed a pharmaceutical composition, consisting of an
inhibitor of the ACE (Tandolpril or Pamipril) associated to a
diuretic (Furosemide or Piretanide), and its use in the treatment
of hypertension, this way increasing the efficiency of the ACE
inhibitors.
[0033] U.S. Pat. No. 5,266,583, Otawa, Masakatsu (1993), have
isolated a metabolite of the Losartan, which presented an
antagonist activity for the ANGIOTENSIN II AT1 receptor.
[0034] U.S. Pat. No. 5,519,012, Fercej-Temeljoov, Darja et. al.
(1996), have claimed a new inclusion compound for the
anti-hipertensive agent, 1,4-dihydropiridine, with
methyl-.beta.-cyclodextrin and other derivatives such as
cyclodextrin hydroxilate.
[0035] U.S. Pat. No. 5,728,402, Chen, Chih-Ming et al. (1998), have
claimed the preparation and use of a pharmaceutical composition
containing an internal phase, composed by Captopril (ACE inhibitor)
and an hydrogel, and an external phase insoluble in the stomach.
This formulation resulted in the increase of the duration of drug
absorption.
[0036] U.S. Pat. No. 5,834,432, (AU5990796, CA2221730, EP0828505,
WO09639164, JP115073625), Rodgers, Kathlen Elizabeth et al. (1998),
utilized agonists of the AT2 receptors to improve wound
healing.
[0037] U.S. Pat. No. 5,859,258 (HR970565, CN124186, SK57099,
EP0937068, AU5089898), Breen, Patrick et al. (1999), have developed
a process for crystallizing the ANGIOTENSIN II AT1 receptor
antagonist, Losartan through the addition of solvents (among them,
isopropanol, water, cyclohexane) and followed by the
distillation.
[0038] AU200012728-A, Anker, S D and Cats, Aj. S. (1999), have
developed a new derivative of the imidazol ring, more efficient
than Losartan when administered orally.
[0039] WO9916437, Remuzzi, Giuseppe (1999), have developed a new
imidazol derivative. The resulting drug was capable of increasing
the survival of patients with renal and cardiac transplants.
[0040] WO0110851, Galbiat Barbara Via Goldomi (1999) et. al have
developed a process for the preparation of lysine-carboxyanidride,
an intermediate product in the synthesis of the Lisonopril.
[0041] WO0037075, Synthelabo, Elizabeth Sanofi et. al. (1999)
claimed the use of a combination of an ANGIOTENSIN II AT1-receptor
antagonist (Irbesartan) and an immunosupressor (cyclosporin). This
combination was found to be efficient in the treatment of
cardiovascular problems.
[0042] U.S. Pat. No. 6,087,386 (WO9749392A1) Chen, Tzyy-Show H. et
al. (2000) claimed the preparation an use of a pharmaceutical
containing one layer of Losartan (ANGIOTENSIN II AT1 receptor
antagonist) and the other layer of maleate de enalapril (ACE
inhibitor). This formulation resulted in the improvement of the
pharmacological action, decreasing the side effects and prolonging
the absorption.
[0043] U.S. Pat. No. 6,096,772 (AU1184097, AU706660, CA2225175,
HU9901448, CN1192681, JP11507921T, ZA9604690), Fandriks, Lars et al
utilized ANGIOTENSIN II AT1 receptor antagonists for the treatment
or prophylaxis of dispeptidic symptoms.
[0044] U.S. Pat. No. 6,178,349, Kieval, Roberts S. et al. (2001)
have developed a device based on the release of the drug via neural
stimulation for the treatment of cardiovascular diseases. This
device consists of an electrode connected to the nerve, an
implantable pulse generator and a reservoir which contains the drug
to be applied. During the use, the electrode and the release of the
medicine stimulate the nerve, which affects the control over the
cardiovascular system.
DETAILED DESCRIPTION
[0045] Various processes have been developed in order to obtain
more efficient and/or less toxic drugs for the treatment of
arterial hypertension. This is evident from the large number of
patents identified in the technical state of art. However, these
processes still present serious side effects, and the resulting
drugs often exhibit short half-life and low bioavailability. The
present finding, heron, comprises the preparation and use of
controlled-release systems for the ANGIOTENSIN II AT1-receptor
antagonists, using cyclodextrins and their derivatives which
increase the drug half-life from 9 to 60 hours, resulting in an
increase of the bioavailability of the antagonists in the
biological system. This means that the resulting formulations
presents a great potential as alternative drugs to be used in the
treatment of hypertension in warm blood animals.
[0046] A particular drug could be chemically modified in order to
alter its properties such as biodistribution, pharmacokinetics and
solubility. Various methods have been used to increase the
solubility and stability of drugs, among them the use of organic
solvents, their incorporation within emulsions or liposomes, the
adjustment of pH, their chemical modifications and their
complexation with the cyclodextrins.
[0047] The cyclodextrins are oligosacharides cyclic family, which
include six, seven or eight units of glucopyranose. Due to sterics
interactions, the cyclodextrins, CD's, form a cycle structure in
the shape of a (cone truncado) with an internal cavity apolar.
Those are compounds chemically stable that can be modified in a
regioselective way. The cyclodextrins hosts form complexes with
various hydrophobic guests in their cavity. The CD's have been used
for the solubilization and encapsulation of the drugs, perfumes and
fragrances as described by Szejtli, J., Chemical Reviews, (1998),
98, 1743-1753. Szejtli, J., J. Mater. Chem., (1997), 7,
575-587.
[0048] According to detailed studies of toxicity, mutagenecity,
teratogenecity and carcinogenecity about the cyclodextrins,
described in [Rajewski, R. A., Stella, V., J. Pharmaceutical
Sciences, (1996), 85, 1142-1169], these are presented with low
toxicity specially of the (hydroxypropyl-.beta.-cyclodextrin, as
reported in Szejtli, J. Cyclodextrins: properties and applications.
Drug investing., 2(suppl. 4):11-21, 1990. Except for some high
concentrations of some derivates which cause harm to the
eritrocites, these products in general are not harmful to the
health. The use of cyclodextrins as additives in foods has already
been authorized in countries such as Japan and Hungary, and for
more specific applications, in France and Denmark. Besides this,
they are obtained from a renewable source of degradation of the
amide. All these characteristics are a high motivation for the
research findings of new applications. The structure of the
molecule of CD is similar to a cone truncate one, of Cn
approximately simmetry. The primary hydroxilas are located in the
narrowest side of the cone by the connections of hydrogen
intramoleculars, this element is flexible enough to allow a
considerable deviance in the regular shape.
[0049] The known cyclodextrin derivatives can be classified
according to their polarity, size, biological activity, etc. As for
their practical uses are classified as follows: 1. Carriers
(solubilizers, stabilizers) for biologically active substances; 2.
Enzyme models; 3. Separating agents (for chromatography or
batch-processes); 4. Catalysts and additives (as detergents,
viscosity modifiers, etc), L. Szente and J. Szejtli, Adv. Drug
Deliv. Rev. 36 (1999), 17. The CD's are moderately soluble in
water, methanol and ethanol and readily soluble in polar solvents,
such as the dimethyl sulfoxide, dimethylformamide,
N,N-dimethylacetamide e piridine.
[0050] Numerous research works exist in the literature about the
effects of the increase of solubility in water of the guests little
soluble in water, using the cyclodextrins through the using
compounds of inclusion were describe in Szejtli, J., Chemical
Reviews, (1998), 98, 1743-1753. Szejtli, J., J. Mater. Chem.,
(1997), 7, 575-587.
[0051] In order to design a drug delivery system (DDS) various
kinds of high performance carrier materials are being developed to
deliver the necessary amount of drug to the targeted site for a
necessary period of time, both efficiently and precisely.
[0052] Cyclodextrins, biodegradable or non biodegradable polymers,
liposomes, emulsions, multiple emulsions are potential candidates
for such a role, because of their ability to alter physical,
chemical, and biological properties of guest molecules Besides the
cyclodextrins, a number of drug delivery systems have been
investigated, including polymer microcapsules, microparticles,
liposomes and emulsion. Many of these are prepared from synthetic
biodegradable polymers such as polyanhydrides and poly(hydroxy
acids). In these systems the drugs incorporate in a polymeric
microspheres, which release the drug inside the organism, in small
and controlled daily doses, during days, months or until years.
[0053] Several polymers already were tested in controlled release
systems. Such as: polyuretans for its elasticity, polysiloxans or
silicons for being a good one insulating, polymethyl-metacrilate
for its physical force, polyvinilalcohol for its hydrofobicity and
resistance, polyethilene for its hardness and impermeability
(Gilding, D. K. Biodegradable polymers. Biocompat. Clin. Impl.
Mater. 2:209-232, 1981). Biodegradable polymers and biocompatible
polymers, have been extensively investigated as vehicle for
controlled release systems due to their ability to undergo surface
degradation. These kind of polymers can be chose from:
poly(2-hydroxi-ethylmetacrilate), polyacrilamide, polymer from
lactic acid (PLA), from glicolic acid (PGA), and the respective
ones co-polymers, (PLGA) and the poly(anidrides), as described by
Tamada and Langer, J. Biomater. Sci. Polym. Edn, 3(4):315-353.
[0054] A formulation of the present invention can also include
other components such as a pharmaceutical acceptable excipient. For
example, formulation of the present invention can be formulated in
an excipient that the animal to be protected can tolerate.
Excipients can also contain minor amounts of additives, such as
substances that enhance isotonicity and chemical stability of
buffers. Standard formulation can either be liquid injectables or
solids which can be taken up in a suitable liquid as a suspension
or solution for injection or oral formulation. Suitable controlled
release vehicles include, but are not limited to, biocompatible
polymers, other polymeric matrices, capsules, microcapsules,
nanocapsules, microparticles, nanoparticles, bolus preparations,
osmotic pumps, diffusion devices, liposomes, lipospheres and
transdermal delivery systems, implantable or not.
[0055] In the last years, several systems of drugs delivery systems
have been studied to improve the drug absorption, to increase the
drug stability and target it to a certain cell population. These
studies led to the development of several products based on
cyclodextrins, emulsions, liposomes and polymers for drug carrying
and deliverying. These formulations can be administered through
intramuscular, intravenous, subcutaneous injection, oral
application, inhalation or devices that can be implanted.
[0056] Until now, no application using the ANGIOTENSIN II AT1
receptor antagonists, the cyclodextrins or their derivatives,
lipossomes and the biodegradable polymers and combinations thereof
has been found in the technical state of the art for the treatment
of arterial hypertension or other cardiovascular diseases, such as
the heart failure in warm blood animals. This characterizes the
present invention as a novel more effective alternative for the
treatment of these pathologies and their complications.
[0057] The present invention is characterized by the combination of
two different technologies: one is the molecular encapsulation of
ANGIOTENSIN II AT1 receptor antagonists in cyclodextrins and/or
lipossomes and the other is the microencapsulation in biodegradable
polymers. It is also characterized by the increase of the
effectiveness of the ANGIOTENSIN II AT1 receptor antagonists as
well as by an increase in their bioavailibility.
[0058] In addition, the present invention represent the increase
hypotensor effect of the ANGIOTENSIN II AT1 receptors antagonists
associated with cyclodextrins and the ones biodegradable
polymers.
[0059] The present invention can be better understood by some of
the following examples, but are not limited.
EXAMPLE 1
Preparation of the Inclusion Compounds between .beta.-cyclodextrin
and ANGIOTENSIN II AT1 Receptors Antagonists: Losartan as
Example
[0060] The preparation is made in equimolar proportions of
cyclodextrin and AT1 receptors antagonists. In briefly,
.beta.-cyclodextrin and/or its derivatives is dissolved in water
using stirring and heating. Then the respective amount of losartan
is added to the aqueous solution. Following the dissolution, the
mixture is frozen in liquid nitrogen and submitted to the
lyophilization process, obtaining a dry solid. The solid obtained
is then submitted to the physical-chemistry characterization using
the spectroscopy absorption in Infrared range, thermal analysis
(TG/DTG and DSC) and X-ray diffraction. In the infrared spectra of
the .beta.-cyclodextrin bands were observed around 3500 cm.sup.-1,
.nu..sub.OH, in 2910 cm.sup.-1, .nu..sub.CH3 asymmetric, and in
1440 cm.sup.-1, .nu..sub.C.dbd.O. For the losartan bands were
verified around 3400 cm.sup.-1 corresponding to the .nu..sub.NH, in
2980 cm.sup.-1, .nu..sub.CH3 asymmetric, in 2770 cm.sup.-1,
.nu..sub.CH3 symmetric, around 1600 cm.sup.-1, .nu..sub.C.dbd.C of
aromatic, around 1350 cm.sup.-1, .nu..sub.CH, in 1500-1600
cm.sup.-1 associated to the combination of the manners vibrational
.nu..sub.C.dbd.C+C.dbd.N, and in 760 cm.sup.-1 a strong band
corresponding to the movement CH3 `rock`. In the IR spectra of the
inclusion compound the absence of the bands of CH3 `rock`,
.nu..sub.C--H symmetrical in 2770 cm.sup.-1 and .nu..sub.N--H in
3400 cm.sup.-1, and decrease of the bands in 1500-1600 cm.sup.-1
associated to the modes of the imidazolic and aromatic rings. These
observations evidence the formation of the inclusion compound.
[0061] The curves TG/DTG of .beta.-cyclodextrin presented two
decompositions stages, one around 85.degree. C., due to the loss of
seven molecules of water included in the cavity, and other around
320.degree. C., corresponding to the decomposition of the
substance, this resulted is reinforced through the respectively DSC
curves. The curves TG/DTG for the Losartan presented three
decompositions, being first around 110.degree. C. corresponding a
loss of water, another one around 190.degree. C. indicating the
melting of the material and a third around 400.degree. C., where it
happens total decomposition of the losartan. Curve TG of the
inclusion compound shows an increase of the thermal stability when
compared to the pure losartan. On the other hand in the same TG
curve two thermal decompositions events are observed, being the
first around 60.degree. C., corresponding to the loss of three
molecules of water and another one in about 300.degree. C., due to
the total decomposition of the supramolecular compound.
[0062] X-ray pattern diffraction of inclusion compound presented
new crystalline phases, when observed the XRD pattern of the
.beta.-cyclodextrin presented main peaks in 4, 12 e 25.degree.
2.theta., the XRD pattern of the Losartan in 11, 15.2, 19, 23 and
29.2.degree. 2.theta., while the XRD pattern of the inclusion
compound presented a more amorphous profile with the disappearance
of peaks in 4, 23 and 25.degree. 2.theta. and appearance of new
peaks in 6 and 15.degree. 2.theta..
EXAMPLE 2
Preparation of the Inclusion Compound between
Hydroxypropil-.beta.-cyclodextrin and the ANGIOTENSIN II AT1
Receptors Antagonists: Losartan as Example
[0063] The preparation was prepared in a molar ratio 1:1,
Hydroxypropil-.beta.-cyclodextrin and the ANGIOTENSIN II AT1
receptors. In briefly, Hydroxypropil-.beta.-cyclodextrin and/or its
derivatives is dissolved in water using stirring and heating. Then
the respective amount of losartan is added to the aqueous solution.
Following the dissolution, the mixture is frozen in liquid nitrogen
and submitted to the lyophilization process, obtaining a dry solid.
The solid obtained is then submitted to the physical-chemistry
characterization using the spectroscopy absorption in Infrared
range, thermal analysis (TG/DTG and DSC) and X-ray diffraction. The
Infrared spectra of the hydroxypropil-.beta.-cyclodextrin presented
absorption bands in 3400 cm.sup.-1, .nu..sub.O--H, around 2900
cm.sup.-1, .nu..sub.C--H in 1140 cm.sup.-1, .nu..sub.C--O--C and in
1630 cm.sup.-1, .nu..sub.OH. In the IR spectra of the inclusion
compound is verified the absence of the bands of CH3 `rock`,
.nu..sub.C--H symmetrical in 2770 cm.sup.-1 and .nu..sub.N--H in
3400 cm.sup.-1, which evidence the formation of the inclusion
compound.
[0064] The curves TG/DTG for the hydroxypropil-.beta.-cyclodextrin
shown a loss of mass around 60.degree. C. associated to the loss of
two water molecules. Soon after, it happens a thermal stability to
approximately 300.degree. C., when the sample suffers complete
decomposition. The same phenomena was verified in the DSC curve,
where it was observed a exothermic peak at 367.degree. C.,
indicating decomposition of the material. The TG/DTG curve of the
inclusion compound shown two decomposition process. Being the first
around 100.degree. C. corresponding to the loss of three molecules
of water and another in about 300.degree. C. due to the total
decomposition. It is still verified an increase of the thermal
stability of guest after inclusion.
[0065] The X-ray pattern diffraction of the inclusion compound
presented new crystalline phases, when compared to the X-ray
pattern of the hydroxypropil-.beta.-cyclodextrin, which it shown as
amorphous substance. The X-ray pattern of the Losartan presented
peaks in 11, 15.2, 19, 23 and 29.2.degree. 2.theta..
EXAMPLE 3
Preparation of the Microspheres in the Basis of Biodegradable
Polymer (PLGA) and the Inclusion Compound Obtained from Example 1
and 2
[0066] Firstly a emulsion constituted of an organic phase
constituted of poli(acid lactic-glycolic) (PLGA) dissolved in
dichlorometane and an aqueous phase constituted of the antagonist
of ANGIOTENSIN II AT1 receptors, as the losartan for example is
prepared. That emulsion is then submitted to the sonication for
half minute and is added to 1% (PVA) solution, forming a second
emulsion, which suffers stirring for 1 minute to complete
homogenization of the microemulsion. The system is maintained under
stirring without heating for 2 hours until the evaporation of the
solvent. The mixture is centrifuged by 2 to 3 times, and washed
three times with water to remove the surface-adsorbed PVA and
finally resuspended in 2 mL of water and freeze-dried. Then the
solid microspheres were characterized through the thermal analysis
and scanning electron microscopy SEM. The microspheres DSC curve
shown a vitreous transition similar to which it was observed to the
PLGA polymer. The respectively SEM micrographs shown 50 microns of
particles size. It is still verified the porous surface of the
microspheres. To determine the capacity of encapsulation of the
different used systems calibration curves they were built through
the UV-VIS spectroscopy obtaining a relationship between
concentration and absorbance, and thus was determined the amount of
losartan incorporated (see Table 1). TABLE-US-00001 TABLE 1
Percentage of encapsulation of the different used systems System
Percentage of encapsulation losartan + PLGA 36.7% losartan +
HP-.beta.Cd + PLGA 72.0% losartan + .beta.Cd + PLGA 85.0%
HP-.beta.Cd (hydroxypropil-.beta.-cyclodextrin) PLGA (poly(acid
lactic-glicolic) .beta.Cd (.beta.-cyclodextrin)
[0067] From data of Table 1 was verified the great differences
among the values of encapsulation percentage. This fact is due to
the different solubilities of losartan, .beta.-cyclodextrin and of
the hydroxypropil-.alpha.-cyclodextrin, and the .beta.-cyclodextrin
presents smaller solubility, presenting larger encapsulation
percentage.
EXAMPLE 4
Comparison of the Effect of Losartan Included in
.beta.-cyclodextrin and HP-.beta.-cyclodextrin in the Pressor
Effect of in Ang II in Rats
[0068] Rats with cateters implanted in the femoral artery and
femoral vein were submitted to the injection of graded doses of
Angiotensina II (5, 10 and 20 ng/100 .mu.L) before and 2, 6, 24 and
48 hours after the losartan administration (0.2 mg/Kg) and losartan
included in cyclodextrin (gavage). The losartan included in
cyclodextrins blocked in approximately 75% the pressor effect of
Ang II for up to 48 hours. Losartan alone blocked the effect of Ang
II for about 8 hours
EXAMPLE 5
Comparison of the Effect of Losartan with Losartan Incorporated in
Biodegradable Polymer in the Pressor Effect of Ang II in Rats
[0069] Male rats weighing (330-350 g) instrumented for telemetric
recording of arterial pressure (Data Science System) were
anesthetized and submitted to the implantation of cateters in the
femoral vein. Injections of Ang II (5, 10 and 20 ng/100 .mu.L) they
were done before and after the subcutaneous injections of losartan
(0.7 mg), losartan incorporated in biodegradable polymers
containing 0.7 mg of the drug or polymer only. Injections of Ang II
were made after 2, 8 and 24 hours and then at intervals of 24
hours, for 15 days. Significant blockade of the pressor effect of
Ang II with the combination biodegradable
polymer-losartan-.beta.-cyclodextrin could be demonstrated for up
to 15 days. No significant changes were observed with the vehicle
administration. Losartan alone blocked the Ang II effect for about
8 hours.
* * * * *