Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

• 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.
• ACE Angiotensin Converting Enzyme
• 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.
• 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.
• 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.
• ACE angiotensin converting enzyme
• Captopril is classified as an ACE inhibitor.
• 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.
• ACE Angiotensin Converting Enzyme
• Renin is an enzyme that acts on its substrate, angiotensinogen, catalyzing the formation of the decapeptide angiotensin I.
• ACE Angiotensin Converting Enzyme
• 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 V growth of smooth muscle cells due to vascular hypertrophy.
• 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.
• ACE inhibitors 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.
• 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.
• captopril and lisinopril are active drugs.
• the other 20 compounds are prodrugs that need to be metabolized to a diacid compound.
• 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.
• 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.
• ACE Angiotensin Converting Enzyme
• 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.
• 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 C 9 H 15 NO 3 S, respectively, and its chemical structure is represented by the formula below [The Merck Index. 12 ed., Merck & Co., Inc., 1996]:
• 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
• WO 9810753 discloses the preparation of captopril tablets comprising a few adjuvants.
• the tablets comprise additives such as diluting agents, binding agents, disintegrating agents, lubricants, etc.
• 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.
• 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.
• ACE inhibitors including captopril, the external coating being composed by a material resistant to gastric juices, such as methacrylic acid polymer - eudragit.
• 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.
• 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.
• 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.
• 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- ⁇ -cyclodextrin (SBE- ⁇ -CD) and hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD), in order to obtain formulations for oral administration in a single unit dose.
• SBE- ⁇ -CD sulfobutylether- ⁇ -cyclodextrin
• HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
• 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.
• Ikeda et al. have also prepared binary systems using captopril, and HP- ⁇ -CD and TB- ⁇ -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 ⁇ -CD, HP- ⁇ - CD and TB- ⁇ -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.
• ⁇ -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.
• 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.
• the pharmacotechnical method implies the inclusion of the active ingredient in an acceptable carrier system.
• 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 ⁇ , ⁇ , ⁇ -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 ⁇ -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 ⁇ -cyclodextrin being preferably recommended.
• 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.
• 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].
• 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- ⁇ -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.
• the relative safety, efficacy in terms of complexation, cost and acceptance in pharmacopeias are some important factors to be considered in selecting a CD.
• 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 (LD 50 ).
• 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 ⁇ -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.
• an ACE inhibitor preferably captopril
• 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.
• 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.
• the formulation of the present invention may also include other components such as pharmaceutically acceptable excipients.
• 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 ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrins, or alkyl and acyl derivatives thereof, or mixture thereof, preferably recommended is ⁇ -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.
• 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.
• the amount of ACE to be used should correspond to the desired medicinal dosage.
• 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 4O 0 C being recommended.
• 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.
• 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.
• the formulation of the present invention may also include other components such as pharmaceutically acceptable excipients.
• 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.
• 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.
• a solution of ⁇ -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 (40 0 C). After this, the solvent was removed at reduced pressure in a rotating evaporator.
• the solid was dried in an oven (40 0 C) 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).
• IR Infrared
• DSC Differential Scanning Calorimetry
• TGA Thermogravimetric Analysis
• XRD X-Ray Diffracftometry
• SEM Scanning Electron Microscopy
• 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 ⁇ - 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 ⁇ -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).
• captopril 2.5 mg/kg
• the inclusion compound of ⁇ -cyclodextrin 15 mg/kg was administered diluted in 0.1 ml_ of saline solution (0.9% NaCI).
• no significant changes were observed in arterial pressure.
• 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.
• the complex diethyl- ⁇ -cyclodextrin:captopril was prepared using an equimolar ratio between the compounds.
• a solution of diethyl- ⁇ - cyclodextrin in ethanol/water medium was prepared under agitation and slight heating (30-45 0 C).
• 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 (40 0 C). After this, the solvent was removed at reduced pressure in a rotating evaporator.
• the solid was dried in an oven (40 0 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.
• Example 3 The complex triacetyl- ⁇ -cyclodextrin:captopril was prepared using an equimolar ratio between the compounds.
• a solution of triacetyl- ⁇ - cyclodextrin in ethanol/water medium was prepared under agitation and slight heating (30-45 0 C).
• 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 (40 0 C). 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.

Applications Claiming Priority (2)

Publications (1)

Family

ID=37944773

Family Applications (1)

Country Status (2)

Cited By (1)

Citations (4)

• 2006
  • 2006-02-03 BR BRPI0600636-1A patent/BRPI0600636A/pt not_active Application Discontinuation
• 2007
  • 2007-02-05 WO PCT/BR2007/000025 patent/WO2007087700A1/en active Application Filing

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events