WO2007087700A1

WO2007087700A1 - Process for the preparation of formulations of angiotensin converting enzyme inhibitors and product

Info

Publication number: WO2007087700A1
Application number: PCT/BR2007/000025
Authority: WO
Inventors: Mariangela De Burgos Martins De Azevedo
Original assignee: Universidade Federal De Minas Gerais; Stq Comércio E Servicios De Tecnologia Químical Ltda.
Priority date: 2006-02-03
Filing date: 2007-02-05
Publication date: 2007-08-09
Also published as: BRPI0600636A

Abstract

The process for the preparation of formulations of angiotensin converting enzyme inhibitors and product is directed to obtaining a modified release system of an angiotensin converting enzyme (ACE) inhibitor, preferably captopril, from its molecular inclusion in natural cyclodextrins, preferably β-cyclodextrins, and/or alkyl and acyl derivatives thereof, using an aqueous and/or organic solvent medium. The product thus obtained has reduced solubility and chemical instability of the active principle, enhancing the therapeutic action results.

Description

"PROCESS FOR THE PREPARATION OF FORMULATIONS OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND PRODUCT"

The present invention belonging to the pharmaceutical area relates to the process of preparing novel formulations of Angiotensin Converting Enzyme (ACE) Inhibitors, especially captopril, with cyclodextrins, for the treatment of arterial hypertension, other cardiovascular diseases and their complications. Background of the invention In most countries of the world, 15 to 25% of the adult population has high arterial blood pressure. The cardiovascular risk increases with the arterial blood pressure level. The higher the arterial blood pressure, the greater the risk of a stroke and coronary events. Hypertension is considered to be the major cause of coronary, brain and renal vascular diseases, being the number one cause of death and disability among adults.

Hypertension is a complex, multifactorial, high prevalence medical condition, responsible for several harmful effects and high morbidity and mortality.

Heart failure throughout the world is the main cause of hospitalizations in the age group of 60 to 80 years of age. The aging of the population alone is already a factor for the increase in its incidence: while 1% of the individuals present heart failure between the age of 25 and 54 years old, among the elderly, this incidences is much higher, reaching the level of 10% of those above 75 years of age. Heart failure, given 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. 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.

In Brazil, data from SUS ("Sistema Unificado de Saύde" - Brazilian Public Health System) have shown that in 1997, heart failure was the main cause of hospitalizations among the cardiac diseases, leading the government to spend R$ 199 million reais with its treatment, a number equivalent to 19.6% of the expenses with cardiovascular diseases. The primary objective of the hypertension treatment aims not only to reduce health care expenses, but also to prevent lesions to the target organs and reduce the cardiovascular and renal morbidity and mortality rates through changes in the quality of life and use of medication, when necessary.

The pharmacological treatment is indicated for mild hypertensive patients (systolic blood pressure between 140 mmHg and 159 mmHg and diastolic blood pressure between 90 mmHg and 99 mmHg) when there is no response to the suggested lifestyle changes for a period of three to six months and in case of target-organ lesions (left ventricular hypertrophy, angina or myocardium ischemia, cerebral vascular accident, hypertensive retinopathy, peripheral arterial disease); patients with chronic renal failure, congestive heart failure and diabetics with BP > 130 x 80. All patients with systolic blood pressure above 160 mmHg or diastolic blood pressure above 100 mmHg should be submitted to a pharmacological treatment, regardless of whether or not the other factors are present. Antihypertensive agents may be classified according to their mechanisms or sites of action as: i) diuretics; ii) sympatholytic agents; iii) vasodilators; iv) calcium channel blockers; v) angiotensin converting enzyme (ACE) inhibitors and vi) angiotensin Il receptor antagonists.

Captopril is classified as an ACE inhibitor. In the beginning of the 1970s, is was found that polypeptides inhibited the formation of, or blocked, receptors of angiotensin Il - an octapeptide responsible for the constriction of arterioles, producing an immediate elevation in blood pressure. Experimental studies carried out with these inhibitors have revealed important physiological and physiopathological roles for the renin-angiotensin system. With these results, it was possible to develop a new and very effective class of antihypertensive agents, the Angiotensin Converting Enzyme (ACE) inhibitors. Later, experimental and clinical studies were performed with these inhibitors, revealing additional functions for the renin-angiotensin system in the physiology of hypertension, heart failure, vasculopathy and renal failure, favoring the development of additional classes of agents inhibiting the system. The renin-angiotensin system is an important element for the short- and long-term regulation of the arterial blood pressure. Factors that reduce blood pressure, such as a low-sodium diet, diuretics, blood loss or reductions in the total peripheral resistance caused by vasodilators, activate the release or renin by the kidneys. Renin is an enzyme that acts on its substrate, angiotensinogen, catalyzing the formation of the decapeptide angiotensin I. In turn, it is cleaved by the Angiotensin Converting Enzyme (ACE) producing the octapeptide angiotensin II, a powerful endogenous vasoconstrictor which also stimulates the secretion of aldosterone by the cortex of the adrenal gland, contributing to the retention of sodium and fluids, causing the increase in the blood pressure by different mechanisms.

V direct vasoconstricting action;

V interaction with the sympathetic system through several mechanisms and sites;

V exacerbation of the response to the alpha adrenergic stimulus; V stimulus to the production of aldosterone, leading to the retention of sodium and water;

V growth of smooth muscle cells due to vascular hypertrophy.

It is currently known that ACE is an enzyme with multiple action, that is, it acts in several substrates. Apart from acting as a dipeptidase in angiotensin I and in bradykinin, it is also capable of cleaving other peptides, indicating that the enzyme may act in several tissues and systems.

An important advantage of ACE inhibitors is to prevent the harmful effects of angiotensin Il in cardiac and vascular remodeling, being the antihypertensive class of highest efficacy in reducing left ventricular hypertrophy and vascular stiffness, also improving endothelial dysfunction. They are useful to heart failure patients with or without associated hypertension, also improving heart failure survival. So they reduce cardiac remodeling in systolic heart failure and in post-acute myocardial infarction. Therefore, the treatment with ACE inhibitors during one year reduces in 31 % the mortality of patients with heart failure (NYHA Class IV).

The ACE inhibitors are excellent when administered in monotherapy because they cause a relatively fast pressure drop in 60 to 70% of the patients with arterial hypertension. In general, they are well tolerated but their use may cause side effects and adverse reactions, some of which relatively severe, among them angioneurotic edema, skin eruptions and dry cough (8 to 10%). The ACE inhibitors prevent the formation of angiotensin II, blocking the renin-angiotensin system, and may be classified in three large groups according to their chemical structure: i) ACE inhibitors containing sulphydryl structurally related to captopril; ii) ACE inhibitors containing dicarboxyl with a structure related to enalapril and iii) ACE inhibitors containing phosphorous with a structure related to fosinopril. There is no reason favoring the use of one ACE inhibitor over the other, because all of them effectively block the conversion of angiotensin I into angiotensin II, and all of them have the same therapeutic indication, the same profile of adverse effects and similar contraindications. Only captopril and lisinopril are active drugs. The other 20 compounds are prodrugs that need to be metabolized to a diacid compound. Although the prodrug has the disadvantage of having an action of less than 1/100 of the active metabolite, its absorption is much better, increasing bioavailability in relation to the absorption of the active molecule. All these drugs are orally absorbed. Commercially there is only one form for parenteral (endovenous) use, which is composed of enalaprilate. The elimination is typically through the kidneys, except for fosinopril, which is eliminated by the liver.

Captopril is one of the best selling drugs in Brazil for the treatment of hypertension. It was the first drug inhibiting the Angiotensin Converting Enzyme (ACE), which is the carboxypeptidase enzyme, responsible for converting angiotensin I (virtually inactive) into angiotensin Il by the removal of two amino acids. Captopril has a sulphydryl grouping that is bond to the zinc atom of the Angiotensin Converting Enzyme, therefore, leaving it inactive. Captopril, such as other ACE inhibitors, affects vessel resistance and capacitance and, thus, reduces both the blood pressure and the cardiac burden. Contrary to other vasodilators, it does not affect the cardiac contractility and, hence, cardiac output normally increases. Captopril preferably acts on the vascular beds sensitive to angiotensin, which include those of the kidneys, heart and brain. This selectivity can be important to keep the proper perfusion of these vital organs in case of a reduction in perfusion. Captopril has a lower cost and a more favorable effect on the quality of life.

Captopril was the first ACE inhibitor drug to be developed for the treatment of hypertension. Its name and chemical formula is 1-[(2S)-3- mercapto-2-methyl-1-oxopropyl-L-proline] and C₉H₁₅NO₃S, respectively, and its chemical structure is represented by the formula below [The Merck Index. 12 ed., Merck & Co., Inc., 1996]:

In commercial formulations using captopril, the patient is submitted to the administration of several doses during the day. This happens as a consequence of the immediate release of the active principle with its rapid absorption in oral administration. Furthermore, captopril presents chemical instability at a pH above 4, suffering oxidative degradation of the sulphydryl group [Timmins, P.I. et al., International Journal of Pharmaceutics, 11 , 328-336, 1982; Pereira, CM. et al., American Journal of

Hospital Pharmacy, 49, 612-615, 1992], being converted into metabolites such as disulphides and mixtures thereof [Hu, M., et al., Journal of

Pharmaceutical Sciences, 77, 1007-1011 ,1988].

According to the prior art, there are many proposals for new formulations involving ACE inhibitors, especially captopril. The most wide range of pharmacotechnical strategies are used in their conception and their aim is to enhance the pharmacological performance of the active principles.

WO 9810753, "Captopril Tablets" (1998), discloses the preparation of captopril tablets comprising a few adjuvants. The tablets comprise additives such as diluting agents, binding agents, disintegrating agents, lubricants, etc. Among the adjuvants is a 1.5:1 - 1 :1 weight ratio mixture of lactose and microcrystalline cellulose, and the total amount of said mixture is 60-80 % by weight of the total weight of the tablet. The standard deviation of the active ingredient content in the individual tablets or in parts thereof is very low.

US 6267990, "Controlled-release pharmaceutical preparation comprising an ACE inhibitor as active ingredient" (2001 ), relates to a pharmaceutical preparation containing ACE inhibitor as active ingredient, especially comprising captopril, allowing the slow release of the active ingredient as a function of time and of the pH value of the medium. The invention relates to a pharmaceutical formulation consisting of the following components: (i) an initial dose of active ingredient combined with excipients; (ii) a first delayed-release type of pellet, in which the active ingredient and excipients are covered with a coating, and (iii) a second delayed-release type of pellet, in which the active ingredient and excipients are again covered with a coating, wherein the active ingredient is an ACE inhibitor, and wherein the amounts of the coatings according to (ii) and (iii) are present in a quantitative ratio, based on weight, within the range of from 1 :2 to 1 :7. Several ACE inhibitors are mentioned, including captopril, the external coating being composed by a material resistant to gastric juices, such as methacrylic acid polymer - eudragit.

US 4666705, "Controlled release formulation" (1987), relates to obtaining tablets containing an ACE inhibitor and other classes of antihypertensives to obtain controlled-release formulations. These formulations are prepared by the dry granulation technique and lubricants such as magnesium stearate were used on a polymeric matrix containing polyvinyl pyrrolidone (PVP) and copolymers. Among the active ingredients of the ACE inhibitors family studied are enalapril and captopril, although antihypertensives from other families have also been investigated, such as propanolol. There are no reports about animal testing, although the patent refers to a release time in an in vitro study varying from 4 to 16 hours. Nothing was said about the pharmacological action at the concentrations found in time.

US 5519012, "Inclusion complexes of optically active 1 ,4- dihydropyridines with methyl-beta-cyclodextrin" (1996), discloses an invention for obtaining novel inclusion complexes involving modified β- cyclodextrins, such as methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin to obtain supramolecular species containing optically-active guests and the racemic mixture of 1 ,4-dihydropyridine, which is poorly soluble in water, involving several derivatives thereof. These materials were used for preparing pharmaceutical formulations as calcium antagonists for the treatment of hypertension, angina pectoris and cerebrovascular disorders. It uses common excipients in the pharmaceutical industry. There are no reports about the performance of the formulations in the pharmacological point of view. US 5728402, "Controlled release formulation of captopril or a prodrug of captopril" (1998), relates to an invention based on a controlled- release formulation for oral administration of an antihypertensive agent comprising: (a) an internal phase which comprises captopril or a prodrug of captopril in admixture with a hydrogel forming agent based on a hydrophilic polymeric material; and (b) an external phase which comprises a coating which resists dissolution in the stomach, shellac. This strategy has provided a prolonged release device for the administration of a single unit dose. Tests in healthy human male volunteers have shown that the drug levels in the blood extended for 24 hours, although no information has been provided associating these concentrations in the blood with the pharmacological activity of the formulation.

US 6087386, "Composition of enalapril and losartan" (2000), discloses a pharmaceutical formulation consisting of an enalapril salt and another layer of a losartan salt, forming a tablet with two layers and an acceptable pharmaceutical carrier, according to the administration route, not including the use of cyclodextrins. The enalapril salt layer contains a dose of about 2.5 mg to 20 mg and that of losartan contains a dose of about 25 mg to 50 mg. The tablet is externally coated by a film. The strategy of this invention has suggested that a beneficial effect could be achieved by the combined oral administration of these two therapeutic classes.

WO 02080910,. "Preparation of formulations of angiotensin Il ATI receptors antagonists for the treatment of arterial hypertension, other cardiovascular illnesses and its complications" (2002), discloses the preparation of AT1 receptor antagonist formulations using cyclodextrins, their derivatives and/or biodegradable polymers for the treatment of arterial hypertension, other cardiovascular diseases and their complications. The invention is characterized by the combination of two different technologies: (a) the molecular encapsulation of AT1 receptor antagonists in cyclodextrins and (b) the microencapsulation in biodegradable polymers, using the solvent emulsion/evaporation method. It also comprises an increase in the effectiveness of the AT1 receptor antagonist blockers, and an increase in their bioavailability. The invention may be included as an alternative for the treatment of arterial hypertension, other cardiovascular diseases and their complications. In this case, as in the others, another class of antihypertensive agents is used, although cyclodextrins are used in the pharmacotechnical strategy. WO 2005081613, "Pharmaceutical compositions of peptides secreted by the venom glands of snakes" (2005), refers to the employment of pharmaceutical compositions of snake venom glands secreted peptides, evasins (endogenous inhibitors of vasopeptidases), and derivatives thereof. The pharmaceutical compositions of the evasins included in cyclodextrins present an increase in the bioavailability, duration and/or efficiency of these compositions in modulating the acetylcholine receptors when administered by different routes of application, such as oral, intravenous, intramuscular and others.

US 5073641 , "Prodrug derivates of carboxilio acid drugs" (1991), discloses novel ester derivatives of carboxylic acid as ACE inhibitors, and among them the ethyl ester pentopril was shown to be highly stable in human plasma.

WO 03028718, "Novel formulations of carvedilol" (2003), discloses the use of cyclodextrin complexes with carvedilol for preparing formulations for use in the treatment of hypertension, congestive heart failure and angina. Inclusion compounds were prepared using hydrophilic cyclodextrins, such as sulfobutylether-β-cyclodextrin (SBE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD), in order to obtain formulations for oral administration in a single unit dose.

Differently from the "Process for formulations of angiotensin converting enzyme inhibitors and product," which is the object of the present invention, WO 03028718 uses a poorly water-soluble active ingredient and hydrophilic cyclodextrin, aiming at increasing the solubility of carvedilol to improve bioavailability, while the present process uses a highly water-soluble ACE inhibitor and a hydrophobic cyclodextrin. lkeda [Ikeda et al., Journal of Controlled Release, 66, 271-280, 2000] discloses ternary systems involving a composition of two β- cyclodextrins (β-CD), one with a hydrophilic nature, a 2-hydroxypropyl-β- cyclodextrin (HP-β-CD), and another of hydrophobic nature, a perbutanoyl-β- cyclodextrin (TB-β-CD), and captopril to obtain controlled-release systems. The results were comparable to those obtained by Seta [Seta, Y. et al., International Journal of Pharmaceutics: a) 41 , 263-269, 1988; b) 41 , 255-262, 1988 and c) 41 , 245-254, 1988], which used the oily semisolid matrix technology for a controlled-release preparation of captopril.

In this same paper, Ikeda et al. have also prepared binary systems using captopril, and HP-β-CD and TB-β-CD. For the purposes of obtaining controlled-release systems, these results are not different from free captopril when the release profile of the active ingredient is compared as a function of time. Inclusion compounds have been prepared involving β-CD, HP-β- CD and TB-β-CD to obtain the effect of controlled-release of captopril, initially in binary systems and later by combining the hydrophilic and the hydrophobic cyclodextrins. The binary systems prepared by Ikeda et al. have presented different results from those obtained in the "Process for formulations of angiotensin converting enzyme inhibitors and product," which is the object of the present patent application, particularly in relation to the supposed inclusion compound with β-CD. In this invention, β-CD forms with captopril a sustained-release system of the active ingredient, evidenced by the prolonged therapeutic action resulting from of the interaction of the ACE inhibitor in the hydrophobic nanocavity of the host. The marked difference in solubility between the guest and host species in the experiments carried out by Ikeda et al. should modulate the sustained availability of the active ingredient. However, the in vitro results have shown that the speed of solubilization is virtually the same when compared to the active ingredient in its free form. This fact suggests that Ikeda et al. probably have obtained an association compound between the species, which occurs when the interaction happens outside the cyclodextrin cavity [Wenz G., Angewandt Chemie International Edition English, 33, 803-822, 1994]. Probably, the process used by Ikeda et al., the kneading method, is responsible for the results as previously commented. In the supramolecular chemistry of cyclodextrins, there are reports of several examples of active ingredients having different biological activity as a result of the form of preparation. When Ikeda et al. used the hydrophobic cyclodextrin, they concluded that they had not arrived at the inclusion compound, but rather at a dispersion or a solid solution among the parts. In all the preparations, Ikeda et al. have used the kneading method.

Several processes have been developed aimed at obtaining more efficient and/or less toxic drugs for the treatment of arterial hypertension. This is evidenced by the marked number of patents and scientific papers found in the prior art. However, the results of these processes still have serious side effects and the resulting drugs frequently exhibit short half-life and low bioavailability.

The attempt to improve the already existing drugs in some of their properties is relevant and may follow two widely used paths: the chemical or the pharmacotechnical one. Between the two options, the pharmacotechnical strategy is interesting, because it does not comprise the molecular modification of the drug, enabling the reformulation of old medicaments by technologically upgrading them.

The pharmacotechnical method implies the inclusion of the active ingredient in an acceptable carrier system. Among these systems are the macromolecular system and, more specifically, the natural and synthetic cyclodextrins. Because of its interaction in the cyclodextrin cavity, the active ingredient may have some of its properties modified, such as: biodistribution, pharmacokinetics, chemical stability and solubility. Cyclodextrins are chemically stable compounds that may be regioselectively modified. The natural or chemically modified cyclodextrins, because of their bioadaptability and multifunctional characteristics, are capable of attenuating the undesired properties of drug molecules in several routes of administration through the obtainment of inclusion compounds. The cyclodextrins are part of the family of cyclic oligosaccharides, consisting of six, seven or eight units of glucose, respectively called α, β, γ-cyclodextrins. Due to ester interactions, the cyclodextrins (CD) form a cone trunk-shaped structure containing an internal apolar cavity, capable of interacting with guest molecules. However, the size of the α-CD cavity (six units of glucose) is insufficient for many drugs and y- CD (eight units of glucose) is expensive, but technically feasible, the use of β-cyclodextrin being preferably recommended.

It is presented below the spatial structural formula of cyclodextrins with its major dimensions.

In drug carrier systems, the hydrophilic and ionizable CDs may act as carriers of active ingredients in immediate and delayed release formulations, respectively, while the release speed of a water-soluble active ingredient may be delayed by the use of hydrophobic CDs. As they are suitable for use as pharmaceutical additives, the combination of molecular encapsulation with other carrier materials is possible constituting a new important tool in the pharmaceutical formulation [Hirama F. & Uekama K., Advanced Drug Delivery Reviews, 36, 125-141 , 1999; Szejtli J., Journal of Inclusion Phenomena and Macrocyclic Chemistry, 52, 1-11 , 2005].

The CDs are also used in other areas of interest, as in the food and perfume and fragrances industries [Szejtli J. Chemical Reviews, 98, 1743-1753, 1998; Szejtli J., Journal of Materials Chemistry, 7, 575-587, 1997].

Beta-CD (seven units of glucose) has been widely used in the initial stages of pharmaceutical applications as a function of their immediate availability and size of the cavity, which is suitable for encapsulating a wide variety of drugs. Its low solubility in aqueous medium makes it not suitable for use in parenteral application carrier systems. The natural CDs may form complexes with cholesterol and should not be used in parenteral administration. However, studies of nephrotoxicity with HP-β-CD have shown its good tolerance in this application. No unusual metabolite production has been observed in normal physiological conditions [Pitha, J., Journal of Controlled Release, 6, 309-313, 1987]. Chemically modified cyclodextrins, derived from natural CDs, have been prepared aiming at extending physical- chemical properties, such as aqueous solubility increase, physical and microbiological stability, reduced parenteral toxicity, as well as a higher inclusion capacity.

Toxicity, mutagenicity, teratogenicity and carcinogenicity studies of cyclodextrins have been described in Rajewski R. A. & Stella V. J. [Journal of Pharmaceutical Sciences,. 85,. 1142-1169 (1996)] and in www.ispcorp.com/products/pharma/content/forwhatsnew/cvclodex/cvclodex.p df [accessed in January, 2006]. Szejtli [Szejtli J., Journal of Inclusion Phenomena and Macrocyclic Chemistry, 52, 1-1-1 , 2005] discloses in a recent publication the current regulatory status of the CDs.

The relative safety, efficacy in terms of complexation, cost and acceptance in pharmacopeias are some important factors to be considered in selecting a CD. For oral administration, all CDs can be considered virtually nontoxic due to lack of CD absorption through GIT and, hence, the relative safety profile of CDs is related to the dose of active ingredient used in drug/CD complexes and the lethal dose of CD (LD₅₀). The present invention, "Process for formulations of angiotensin converting enzyme inhibitors and product," discloses the process of preparation and use of modified release systems using an ACE inhibitor and employing cyclodextrins and derivatives thereof, which increase the half-life of the active principle from 2.5 hours to 24 hours, resulting in an increase of bioavailability in the biological system.

The novelty of the "Process for formulations of angiotensin converting enzyme inhibitors and product" lies in the process for obtaining a modified release system of an ACE inhibitor, preferably captopril, from its molecular inclusion in natural cyclodextrins, preferably β-cyclodextrins, and/or alkyl and acyl derivatives thereof, using an aqueous and/or organic solvent medium, and the product thus obtained, with the novel technical effect of reducing the solubility and the chemical instability of the active principle, enhancing the therapeutic action results.

This means that the resulting formulation presents a large potential as an alternative for the utilization of an ACE inhibitor in the treatment of arterial hypertension, heart failure and their complications, wherein the decrease in the frequency of administration may lead to a better patient compliance with the treatment and, consequently, an improvement in clinical efficacy, particularly in prolonged therapies.

With a view to design a drug carrier system, several species of carrier materials are studied and developed in order to take an amount of needed active ingredient to a biological target for a period of time in an efficient and precise manner. Thus, the present invention was directed to develop ACE formulations, specially captopril, which provide, via oral administration, greater comfort to the patient with better drug efficacy in the treatment of hypertension, other cardiovascular diseases and their complications.

To achieve this objective, process and products have been developed based on the pharmacotechnical strategy of including the active ingredient in suitable cyclodextrins in order to obtain a carrier system for preparing the drug. The molecular inclusion of an active ingredient in the nanocavity of a cyclodextrin may significantly modify its characteristics, specially in the pharmacotechnical plan: modification of the solubility and bioavailability, reduction of certain side effects, improvement of chemical stability in solid state, increase of shelf life in storage and stability in liquid medium. The formulation of the present invention may also include other components such as pharmaceutically acceptable excipients. For example, the formulation may contain substances suitable for human applications, such as additives for increasing isotonicity and chemical stability with the use of buffers. The standard formulation may contain a solid that may be transformed into a proper liquid, such as a suspension, or oral formulation.

The modified release device includes binary drug:CD systems, but it is not limited to them, being also possible to have a combination of binary and/or ternary system devices, CD:drug:CD, in vehicles such as capsules, tablets, diffusion devices and transdermal carrier systems, either implantable or not.

The process for preparing the formulations consists of a solubilization step of the natural or synthetic cyclodextrins, or mixture thereof, in an organo-aqueous solution, in which the ratio of solvents varies from 0- 100:100-0 and in sufficient amounts for the solubilization, wherein the organic solvent may be chosen among those water-miscible solvents normally used in preparations of inclusion complexes, such as: methanol, ethanol, acetone, ethyl ether or dimethyl sulfoxide, among others; ethanol being preferably recommended. The cyclodextrins used may be α-cyclodextrin, β-cyclodextrin or γ-cyclodextrins, or alkyl and acyl derivatives thereof, or mixture thereof, preferably recommended is β-cyclodextrin, the solubilization temperature and time being dependent upon the cyclodextrin and solvents used. This cyclodextrin solution should be enough to obtain the final product desired.

Then, the solubilization step of the active principle is effected in water or suitable solvent compatible with the solution containing cyclodextrin, or in the mixture thereof, in a sufficient amount to complete the total volume to be prepared. The ACE inhibitor may be: i) ACE inhibitors containing the sulphydryl group in their molecule, captopril being preferably recommended; ii) ACE inhibitors containing the dicarboxyl group in their molecule, enalapril being preferably recommended, and iii) ACE inhibitors containing phosphorous in their molecule, fosinopril being preferably recommended. Obviously the amount of ACE to be used should correspond to the desired medicinal dosage.

Then, the mixture of the solutions is effected under constant agitation, preferably lower than 100 RPM, during enough time for hostguest interaction, with heating compatible with the cyclodextrin and solvents used, because the reaction is exothermal, generally about 4O⁰C being recommended.

Optionally, the simultaneous solubilization of the host and guest in a same container may be effected, consequently obtaining the mixture that generates the host:guest interaction, provided the compatibilities of the process variables are duly assessed.

After the hostguest interaction, the concentration of the solution is made by removing the solvent, preferably at reduced pressure, and the solid obtained is preferably dried in an oven for sterilization or vacuum-dried. It is obvious that the drying of solid material should be effected at compatible temperature and time conditions and the use of vacuum ovens facilitates the concentration and drying of solid materials in a single sequential operation. The ACE inhibitor contained in the solution may also be added, as well as other ACE inhibitors, by means of the molecular interaction of ACE inhibitors outside the nanocavity of cyclodextrins, adding the excess of active ingredient to the solution during or after product drying.

Finally, the solid is characterized by the usual physical-chemical analysis techniques contained in the prior art, such as absorption spectroscopy in the Infrared (IR) Region, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-Ray Diffracftometry (XRD), and Scanning Electron Microscopy (SEM) Furthermore, for better commercialization, the formulation of the present invention may also include other components such as pharmaceutically acceptable excipients. For example, the formulation may contain substances suitable for human applications, such as additives to increase isotonicity and chemical stability with the use of buffers or contain solids that may be transformed into a suitable liquid, such as a suspension, or oral formulation.

The product thus obtained can be used in formulations of ACE inhibitors for oral application, intramuscular injection, intravenous injection, subcutaneous injection, inhalation or with controlled release devices, including biocompatible polymers, other polymeric matrices, capsules, microcapsules, nanocapsules, microparticles, nanoparticles, diffusion devices, liposomes, lipospheres, transdermal carrier devices that may be implanted or injected, or other controlled release compositions, including liquids forming a solid or a gel in situ.

Examples are presented below for a better understanding of the present disclosure.

Example 1

Preparation of β-cyclodextrin:captopril complex at an equimolar ratio between the components.

A solution of β-cyclodextrin in ethanol/water medium was prepared under agitation and slight heating (30-450C). The respective amount of captopril dissolved in water was added to the host solution and kept under agitation for one hour using a magnetic agitator with slight heating (40⁰C). After this, the solvent was removed at reduced pressure in a rotating evaporator. The solid was dried in an oven (40⁰C) and characterized by the usual physical-chemical analysis techniques employed in inclusion compounds, such as absorption spectroscopy in the Infrared (IR) Region, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-Ray Diffracftometry (XRD), and Scanning Electron Microscopy (SEM). For the characterization, a physical mixture was prepared between the components respecting the same molar ratio, in order to compare the results.

In vitro sustained release studies have been performed obtaining data about the concentration of the active ingredient released (cumulative) in a percentage as a function of time. Tablets of 5 mg of captopril were prepared using an uniaxial press; they were put into closed vials containing 30 mL of distilled water (pH 7.0 at 25°C). The captopril concentrations were determined by high performance liquid chromatography (HPLC). The curve profile has shown a sustained release without an explosion effect. In vivo studies: Comparison of the effect of captopril included in β-cyclodextrin and the ACE hypotensor effect in spontaneously hypertensive rats (SHR).

To test the antihypertensive effect of the inclusion compound of β-cyclodextrin:captopril, 4 spontaneously hypertensive rats were used and the results are illustrated in Figures 1 , 2 and 3, wherein Figure 1 shows the graph of the Mean Arterial Pressure Variation in Time, after the administration of captopril (2.5 mg/kg); Figure 2 shows the graph of the Mean Arterial Pressure Variation in Time, after the administration of β- cyclodextrin:captopril (15 mg/kg), and Figure 3 shows the graph of the Mean Arterial Pressure Variation in Time, after the administration of captopril and β-cyclodextrin:captopril. The animals were divided into 2 experimental groups and submitted to gavage, one of the groups using captopril (2.5 mg/kg) dissolved in 0.1 ml_ of saline solution (0.9% NaCI). In the other group, the inclusion compound of β-cyclodextrin (15 mg/kg) was administered diluted in 0.1 ml_ of saline solution (0.9% NaCI). In the group submitted to gavage with captopril no significant changes were observed in arterial pressure. In the group submitted to gavage with the inclusion compound of β-cyclodextrin and captopril, a reduction in arterial blood pressure was observed starting about 2 hours after gavage, having a maximum mean arterial pressure drop of about 12 mmHg 15 hours after the administration of the compound.

Example 2

The complex diethyl-β-cyclodextrin:captopril was prepared using an equimolar ratio between the compounds. A solution of diethyl-β- cyclodextrin in ethanol/water medium was prepared under agitation and slight heating (30-45⁰C). The respective amount of captopril dissolved in water was added to the host solution and kept under agitation for one hour using a magnetic agitator with slight heating (40⁰C). After this, the solvent was removed at reduced pressure in a rotating evaporator. The solid was dried in an oven (40⁰C) and characterized using physical-chemical techniques, as cited in example 1. In vitro sustained release studies and in vivo hypotensor effect studies were performed following the same methodology described in example 1.

Example 3 The complex triacetyl-^β-cyclodextrin:captopril was prepared using an equimolar ratio between the compounds. A solution of triacetyl-β- cyclodextrin in ethanol/water medium was prepared under agitation and slight heating (30-45⁰C). The respective amount of captopril dissolved in water was added to the host solution and kept under agitation for one hour using a magnetic agitator with slight heating (40⁰C). After this, the solvent was removed at reduced pressure in a rotating evaporator. The solid was dried in an oven (40°C) and characterized using physical-chemical techniques, as cited in example 1. In vitro sustained release studies and in vivo hypotensor effect studies were performed following the same methodology described in example 1.

Claims

1 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, characterized in that the process comprises a solubilization step of cyclodextrin in an organo-aqueous solution, a solubilization step of the active ingredient in water or suitable solvent, or a mixture thereof, the solvent being pharmaceutically acceptable and compatible with the solution containing cyclodextrin, and in a sufficient amount to complete the total volume to be prepared, a host:guest interaction step, and a solution concentration step by removing the solvent, the solid obtained is dried at temperature and time conditions compatible with the products used.

2 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the cyclodextrins are α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrins, or alkyl or acyl derivatives thereof, or a mixture thereof.

3 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the organic solvents of the organo-aqueous solutions are selected from methanol, ethanol, acetone, ethyl ether, dimethyl sufoxide or a mixture thereof, at the ratio of 0-100:100-0 with water.

4 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the organo-aqueous solutions are in a sufficient amount for the solubilization of cyclodextrin to the desired product.

5 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the solubilization of cyclodextrins occurs under agitation and at solubilization temperature and time conditions dependent upon the cyclodextrin and solvents used.

6 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the active ingredient is an ACE inhibitor containing the sulphydryl group in its molecule, or an ACE inhibitor containing the dicarboxyl group in its molecule or an ACE inhibitor containing phosphorous in its molecule, or a mixture thereof, and in an amount corresponding to the medicinal dosage desired. 7 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that, in the process, the mixture of the solutions occurs under agitation during sufficient time for the hostguest interation, with a heating compatible with cyclodextrin, the active principle and the solvents used. 8 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 or 7, characterized in that, in the process, the solubilization of the host and guest is effected simultaneously in a same container, consequently obtaining the mixture that generates the host:guest interaction. 9 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the organic solvents or mixtures thereof, the cyclodextrin solubilization temperature and time conditions, the active principle and the solvents used are compatible. 10 - A process for the preparation of formulations of angiotensin converting enzyme inhibitors, according to claim 1 , characterized in that the concentration and drying of the product obtained are carried out in a continuous manner, in a sequential operation.

11 - A product for formulations of angiotensin converting enzyme inhibitors, characterized in that the product obtained has molecular inclusion of ACE inhibitors in the cyclodextrin nanocavities, modifying the physical- chemical characteristics of the active principles.

12 - A product for formulations of angiotensin converting enzyme inhibitors, according to claim 11 , characterized in that the product obtained has molecular inclusion of ACE inhibitors outside the cyclodextrin nanocavities, maintaining the physical-chemical characteristics of the active principles. 13 - A product for formulations of angiotensin converting enzyme inhibitors, according to claims 11 or 12, characterized in that the modified release devices include combinations of binary or ternary complexes, or both.

14 - A product for formulations of angiotensin converting enzyme inhibitors, according to claims 11 or 12, characterized in that the formulations include or not other substances suitable for human applications as additives to increase isotonicity, buffers for chemical stability or solids for suspensions or oral administration.

15 - A product for formulations of angiotensin converting enzyme inhibitors, according to claims 11 or 12, characterized in that the product obtained may be used in ACE inhibitors for oral application, intramuscular injection, intravenous injection, subcutaneous injection, inhalation or with controlled release devices, including biocompatible polymers, other polymeric matrices, capsules, microcapsules, nanocapsules, microparticles, nanoparticles, diffusion devices, liposomes, lipospheres, transdermal carrier devices that may be implanted or injected, or other controlled release compositions, including liquids forming a solid or a gel in situ.