Pharmaceutical composition comprising enalapril maleate, use and preparation method

Abstract

The present invention provides a solid, immediate- and rapid-release pharmaceutical composition with improved stability, comprising enalapril maleate and pharmaceutically acceptable excipients. Also described are the use thereof and a method for preparing the solid, immediate- and rapid-release pharmaceutical composition with improved stability, comprising enalapril maleate and pharmaceutically acceptable excipients.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING ENALAPRIL MALEATE, USE AND PREPARATION PROCESS

[0002] SCOPE

[0003] The present invention relates to the pharmaceutical industry. In particular, it relates to a solid, immediate-release pharmaceutical composition with improved stability comprising enalapril maleate and pharmaceutically acceptable excipients. The process for preparing the pharmaceutical composition is also described.

[0004] BACKGROUND

[0005] The formulation and preparation of a pharmaceutical composition, such as tablets, can lead to destabilization of the active ingredient. Both excipients and the manufacturing process can cause instability problems, resulting in unexpected interactions that can lead to changes in the physicochemical stability of the active ingredient. Enalapril maleate is a good example of this.

[0006] To manufacture pharmaceutical tablets, the active ingredient must be mixed with excipients, which can serve as binders, fillers, disintegrants, lubricants, colorants, or other functionalities, depending on the desired outcome, using various mixing techniques. At the end of the process, the mixture is formed into tablets using different pharmaceutical tablet presses. The processes of preparing the mixture and manufacturing tablets are well understood by experts in the art of pharmaceutical formulation.

[0007] One of the requirements for a suitable pharmaceutical composition is that it must be stable over a long period of time. This means that it should not undergo substantial decomposition of the active ingredient during the time between the composition's manufacture and its use by the patient. The greater the stability of the pharmaceutical composition, the longer its period of effectiveness.

[0008] Enalapril maleate has been reported to be incompatible with several commonly used excipients. Its decomposition is accelerated by many of these excipients due to active ingredient / excipient interactions, making it very difficult to formulate a stable tablet containing enalapril maleate. Enalapril maleate, with the IUPAC name (2S)-1-[(2S)-2-{[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino}propanoyl]pyrrolidine-2-carboxylic acid (2Z)-but-2-enedioate, and chemical structure as shown in Formula (1), is the maleate salt of enalapril, an orally active, long-acting prodrug that suppresses the renin-angiotensin-aldosterone system, responsible for regulating blood pressure and fluid and electrolyte homeostasis. It is used in the treatment of cardiovascular diseases, including hypertension, left ventricular systolic dysfunction, and heart failure, among other pathologies.Specifically, it is indicated for the treatment of essential hypertension when non-pharmacological methods have failed or been insufficient, and, in combination with other drugs, for congestive heart failure. It is also known for significantly delaying the loss of renal function associated with diabetic nephropathy, which is caused by a combination of diabetes mellitus and hypertension. As a prodrug, enalapril is rapidly biotransformed into its active metabolite, enalaprilat, which is responsible for the pharmacological actions of enalapril.

[0009] Formula (1 )

[0010] Numerous previous studies have shown that enalapril maleate is quite stable in its solid state under dry conditions or at varying humidity levels. However, it becomes unstable, even under the same conditions, when mixed with the tablet matrix as part of formulations or compositions. Furthermore, the literature describes the degradation pathway of enalapril maleate as pH-dependent, and it has been observed that in enalapril maleate tablet formulations using both basic and acidic excipient matrices, the formation of any of the degradation products will depend on the type of matrix used. Therefore, the use of an acidic or basic stabilizing agent, depending on the specific case, is of paramount importance.

[0011] Specifically, the stability of formulations containing enalapril maleate can be compromised when the product is exposed to high temperatures and humidity, leading to the formation of two major degradation products: enalaprilat and a diketopiperazine derivative. The type of packaging for enalapril maleate tablets is of paramount importance and must be considered during production. In particular, the primary packaging material, which is in direct contact with the pharmaceutical product, plays a crucial role in providing adequate protection to the tablet throughout the storage period until it is administered to the patient.

[0012] Many pharmaceutical products containing enalapril maleate are packaged in a material called alu-alu or aluminum-aluminum. This material consists of high-quality, cold-forged aluminum with a laminated structure made of polyamide, aluminum, and polyvinyl chloride (PA / AL / PVC). Alu-alu provides excellent insulation of the product from external conditions, but its high cost is a major drawback. Another option is alu-amber packaging, which involves coating one side of the tablet with a layer of PA / AL / PVC (referred to as alu or aluminum) and the other side with amber polyvinylidene chloride (PVDC). This material is perhaps the most widely used primary packaging for products containing enalapril maleate. It is less expensive than alu-alu and provides good light insulation.Finally, the most economical packaging is transparent; however, the product is susceptible to deterioration due to greater exposure to light, temperature, and humidity. These conditions are particularly detrimental to an unstable active ingredient like enalapril maleate.

[0013] Regarding oral administration, especially solid dosage forms such as tablets, it remains the preferred route for administering various rapid-release drugs. Oral administration is the most popular route for achieving systemic effects due to its ease of ingestion, versatility, generally harmless nature for the patient, and, most importantly, its ability to improve patient compliance. Therefore, the combination of these qualities makes tablets the solid dosage form of choice. Furthermore, they are less expensive to manufacture. However, a constant challenge with immediate-release formulations is ensuring that the release of the active ingredient in the gastrointestinal tract is as rapid as possible after ingestion, thus guaranteeing prompt availability for its therapeutic effect.Therefore, it is important to investigate the complex interrelationship between the functionality of excipients commonly used in these types of formulations and the effects of factors such as the manufacturing process, wettability, water absorption, and the release rate of the active ingredient, in order to ensure its rapid release—in this case, of enalapril maleate. Likewise, the release rate of the active ingredient is one of the most important parameters in solid oral drug delivery systems, since the therapeutic response depends on the concentration of the drug available for absorption and entry into the bloodstream. Changes in the drug release profile will affect the absorption rate and, consequently, the therapeutic efficacy.

[0014] This aspect is especially relevant for enalapril maleate, given that it is a highly soluble, low-permeability active ingredient, corresponding to Class III according to the Biopharmaceutical Classification System (BCS). Establishing the class to which an active ingredient belongs in relation to its solubility, according to the BCS, considers solubility tests in an aqueous medium with pH values ​​between 1 and 6.8. Furthermore, as indicated in the FDA Industry Guide, the BCS suggests that in some cases for Class III active ingredients, an 85% dissolution in 0.1 N HCl within 15 minutes can ensure that the drug's bioavailability is not dissolution-limited and that, in these cases, the rate-limiting step for absorption of the active ingredient is gastric emptying.The average gastric residence / emptying time is 15 to 20 minutes under fasting conditions, so a pharmaceutical product that has an 85% dissolution in 15 minutes under mild dissolution test conditions in 0.1 N HCl, behaves as a solution and generally should not have any bioavailability problems.

[0015] In light of the above, continuous improvements are being made to solid dosage forms, particularly tablets, containing enalapril maleate. The aim is to deliver the therapeutic properties of this pharmacological agent to the patient in the best possible way and throughout their treatment.

[0016] PREVIOUS ART

[0017] Currently, there are solid pharmaceutical compositions with the active ingredient enalapril maleate along with various types of pharmaceutically acceptable excipients.

[0018] Thus, in patent application W00066116, a stable solid pharmaceutical composition in tablet or capsule form is disclosed, comprising enalapril maleate as the active ingredient and pharmaceutically acceptable excipients, at least one of which is maleic acid. The pharmaceutical composition also contains conventional pharmaceutical excipients, such as diluents. Among the diluents mentioned are substances such as microcrystalline cellulose, lubricants such as magnesium stearate, and disintegrants such as crosslinked sodium carboxymethylcellulose. It is noted that these substances are considered incompatible with enalapril maleate according to the literature. The solution proposed in this document is that the pharmaceutical composition includes an edible desiccant or a mixture of maleic acid with an edible desiccant, which would provide stability to the composition.

[0019] The document does not specify the type of release mechanism of the active ingredient in the tablet. Furthermore, it omits another important aspect: it fails to explain the implications of the packaging material on the stability of enalapril maleate. Instead, it only mentions that the tablets were packaged in high-density polyethylene bottles.

[0020] The document published under number CN107951835 specifically discloses an enalapril maleate preparation and its application. The pH of the enalapril maleate preparation is 6.4–7.4. The described formulation may contain magnesium stearate as an excipient. The document states that the stability of the enalapril maleate preparation can be effectively improved by controlling the pH. It also notes that impurities in enalapril maleate preparations in different dosage forms, such as powder, granules, and tablets, can be effectively controlled by pH control, thus improving bioavailability. The document does not address the release mechanism of enalapril maleate, nor does it discuss the implications of the packaging material on the stability of this active ingredient.

[0021] The document published under number IN2021121035760A refers to an immediate-release tablet comprising enalapril maleate, a diluent, a superdisintegrant, a sweetener, and other pharmaceutical additives, including a glidant, a lubricant, and anti-adherents selected from talc, magnesium stearate, colloidal silicon dioxide, and stearic acid, among others. It also describes a process for preparing an immediate-release enalapril maleate tablet. This document describes tablets comprising enalapril maleate, which also contain magnesium stearate.

[0022] Regarding the release of the active ingredient, document IN2021121035760A highlights that it is a faster release than described in the prior art. The document does not address the implications of the packaging material on the stability of enalapril maleate, only mentioning that the tablets were packaged in suitable containers. This document presents stability studies, including results for hardness, disintegration time, active ingredient content, and its release from the tablets under the following conditions: 40±2°C and 75%±2% relative humidity, conducted for a maximum of 90 days for evaluation. The results showed that at 90 days, the tablets maintained an active ingredient content of 96.94±1.52% and achieved a release of 96.57±0.32% at pH 7.4. Based on these results, a trend was observed where the enalapril maleate content in the tablets decreased over time.Results are not shown beyond 3 months.

[0023] As can be seen, the problem of stability in enalapril maleate formulations with pharmaceutically acceptable excipients has proven difficult to address due to interactions between enalapril maleate and various types of excipients. Low stability also impacts the amount of active ingredient released after oral administration, which is directly related to the concentration of the drug available in the patient's bloodstream to achieve an adequate therapeutic response.

[0024] The state of the art describes various alternatives to improve the stability of enalapril maleate, such as modifying the pH of the formulation or incorporating stabilizing agents. However, the published results appear to be inadequate if storage conditions and times are much longer than those studied, such as those required by health authorities.

[0025] Based on these challenges, it is proposed that the appropriate selection of excipients, particularly the lubricating agent, in an enalapril maleate formulation is a determining factor in achieving remarkable stability results in the final product. It also ensures rapid release of the active ingredient for availability in the patient's bloodstream, facilitating an appropriate therapeutic response.

[0026] One of the most commonly used lubricating agents in immediate-release pharmaceutical compositions is magnesium stearate. Magnesium stearate is a mixture of magnesium salts of various fatty acids, primarily composed of stearic and palmitic acids, and, in smaller proportions, other fatty acids. It is a widely used excipient in cosmetics, food, and pharmaceutical formulations. Its main function is as a lubricant in the production of capsules and tablets at concentrations between 0.25% and 5.0%. However, for an enalapril maleate composition, it appears to be unsuitable as it negatively impacts its stability.However, the decision to discontinue this lubricant presents a significant challenge, given its excellent properties. It guarantees a release effect in the production of both tablets and capsules, ensuring that the active ingredient is easily released from the molds of the manufacturing equipment. It also improves the flowability of the powdered ingredients, facilitating their handling during the manufacturing process, and helps prevent both adhesion and agglomeration throughout production. Furthermore, it facilitates the release of the active ingredient from the tablets in the digestive tract for optimal absorption.

[0027] Most, if not all, commercially available and disclosed pharmaceutical compositions containing enalapril maleate include magnesium stearate as a lubricating agent. However, as reported, although magnesium stearate is an effective lubricating agent, it can adversely affect the long-term stability of the enalapril maleate compound.

[0028] The foregoing highlights the crucial importance of conducting compatibility and stability tests of the active ingredient against any excipients that may be included in the formulation when preparing a pharmaceutical product containing enalapril maleate. As is known from the prior art, other pharmaceutically acceptable excipients commonly present in enalapril maleate tablets could also influence its stability. Such compatibility tests may include thermal analyses and other methods that reveal which excipients are most compatible with the active ingredient under various temperature and humidity ranges.

[0029] This is of great importance due to the need to minimize incompatibility between the active ingredient and the chosen pharmaceutically acceptable excipients. However, it is important to highlight that magnesium stearate is a key excipient to consider, especially for tablet formulations, as it acts as a lubricating agent, although it does not provide superior stability compared to a pharmaceutical composition containing enalapril maleate.

[0030] In light of the foregoing, the objective of the present invention is to provide an orally administered pharmaceutical composition in the form of an immediate and rapid-release tablet with high stability, containing the active ingredient enalapril maleate along with appropriate excipients, thus avoiding the stability problems that this active ingredient presents with commonly used excipients. Furthermore, the active ingredient is rapidly released and dissolves from the tablet once ingested by the patient, facilitating a rapid therapeutic effect. A process for manufacturing the pharmaceutical composition is also provided. DESCRIPTION OF THE INVENTION

[0031] Achieving a stable pharmaceutical composition of enalapril maleate presents a significant challenge. The pharmaceutical compound enalapril maleate exhibits stability issues when mixed with pharmaceutically acceptable excipients to create a pharmaceutical composition containing it. The stability of the pharmaceutical composition impacts the amount and rate of release of the active ingredient, and consequently, the onset of therapeutic effect. Therefore, these aspects are intertwined and difficult to address comprehensively for a composition comprising enalapril maleate.

[0032] The present invention reveals that the use and / or selection of excipients, particularly the lubricating agent, can be a determining factor in achieving remarkable results in terms of the stability of the final product, as well as the rapid release and dissolution of this active ingredient. The various alternatives described in the prior art for improving the stability of enalapril maleate, such as modifying the pH of the formulation or incorporating stabilizing agents, do not provide solutions that cover all these aspects, which are essential for obtaining a quality product that ensures the best therapeutic effect in the shortest possible time.

[0033] Pharmaceutical compositions of enalapril maleate, primarily those commercially available, include magnesium stearate as a lubricating agent, even though it affects the stability of this active ingredient, as it is a very good lubricating agent according to the literature. Indeed, magnesium stearate remains key because it performs very well as a lubricating agent, despite not providing superior stability compared to a pharmaceutical composition of enalapril maleate alone.

[0034] In this regard, the invention proposed herein consists of a stable pharmaceutical composition comprising pharmaceutically acceptable excipients compatible with enalapril maleate, selected from at least one lubricating agent, one superdisintegrating agent, and diluting agents, in which the stability is significantly greater and the release / dissolution of enalapril maleate is significantly faster compared to that observed in immediate-release tablets described in the prior art containing magnesium stearate as a lubricant. Because the release of enalapril maleate is much faster than previously observed, there is improved efficacy of the active ingredient in the patient and, consequently, better adherence to treatment.Furthermore, the proposed pharmaceutical composition makes it possible to control the effects of temperature and humidity on the active ingredient enalapril maleate, preventing its degradation without the need to use a high-cost primary packaging material, which significantly reduces production costs.

[0035] Given the high stability of the pharmaceutical composition, it is proposed to use a more economical packaging material than those currently used, such as a PA / AL / PVC sheet (called alu or aluminum) on one side and a transparent PVDC sheet on the opposite side of the solid pharmaceutical form to be packaged, in this case a tablet.

[0036] A stable pharmaceutical composition in the form of tablets is also proposed, which is small in size, weighing no more than 100 mg, to facilitate swallowing, especially in elderly patients who are the ones who most need this type of composition comprising enalapril maleate.

[0037] BRIEF DESCRIPTION OF THE FIGURES

[0038] Figure 1: Dissolution profile of the pharmaceutical composition of the present invention under pH conditions of 1.2 (black square symbols); pH 4.5 (gray cross symbols) and pH 6.8 (dark gray diamond symbols). The same results are shown in the insert, but on narrower scales of the OX and OY axes to visualize the values ​​in greater detail at each pH condition.

[0039] Figure 2: Dissolution over time of tablets according to formulations #1 and #2 in phosphate buffer pH 6.8, measured at 5, 10, 15 and 30 minutes.

[0040] Figure 3: Graph of results of the evaluation of the composition of the present invention measured under stability conditions: A) accelerated (40°C / 75%RH), B) intermediate, Zone IVa (30°C / 65%RH), C) long term, Zone II (25°C / 60%RH).

[0041] Figure 4: Graph of the results of impurities and related substances of the composition of the present invention measured under stability conditions: A) accelerated (40°C / 75%RH), B) intermediate, Zone IVa (30°C / 65%RH), C) long term, Zone II (25°C / 60%RH).

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] A pharmaceutical formulation or composition in tablet form, comprising enalapril maleate and pharmaceutically acceptable excipients, having prolonged stability and an immediate and rapid release dissolution profile achieving an average dissolution at 5 minutes of 102.1% ± 2.4% at pH 1.2, 102.2% ± 2.2% at pH 4.5 and 100.2% ± 2.6% at pH 6.8, resulting in complete dissolution at 5 minutes regardless of the pH conditions in which the pharmaceutical composition of the present invention is found.

[0044] The present invention, in one of its main aspects, relates to a pharmaceutical composition comprising enalapril maleate and suitable, pharmaceutically acceptable excipients in determined amounts.

[0045] In one embodiment of the invention, the composition contains between 5% and 20% w / w of enalapril maleate and between 80% and 95% w / w of pharmaceutically acceptable excipients.

[0046] In a preferred embodiment, the pharmaceutical composition contains pharmaceutically acceptable excipients commonly used in the pharmaceutical field, such as, for example, diluents, superdisintegrants, lubricants, colorants, sweeteners, among other excipients.

[0047] Preferably, the present invention relates to a pharmaceutical composition in the form of tablets comprising:

[0048] 5.0% to 20.0% enalapril maleate

[0049] 74.0 to 87.0% w / w of two or more diluents

[0050] 4.0% to 5.0% w / w of a superdisintegrant

[0051] 2.0% to 3.0% w / w of a lubricant where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0052] Diluents are substances added to the formulation to increase volume, so that the tablet is of a practical size for compression. The diluent may be selected from one or a mixture of starches, microcrystalline cellulose, lactose monohydrate, pregelatinized starch, among others.

[0053] Superdisintegrants, or disintegrants, are substances or mixtures thereof that facilitate the disintegration of a tablet in an aqueous medium, increasing its surface area and allowing the rapid release of the active substance. The superdisintegrant may be selected from one or more of the following: sodium starch glycolate, crospovidone, crospovidone sodium, copovidone, starch, among others. In a preferred embodiment, the superdisintegrant is selected from crospovidone sodium.

[0054] Lubricating agents are substances that perform several functions, the main one being to prevent tablets from sticking to the punch surface and to reduce friction between particles. The lubricating agent is selected from talc, glyceryl dibehenate, polyethylene glycol, colloidal silicon dioxide, among others. In a preferred embodiment, the lubricating agent is glyceryl dibehenate.

[0055] In a preferred embodiment of the invention, the total weight of the tablet is 100 mg.

[0056] Preferably, the tablets are packaged in a transparent aluminum (PA / AL / PVC)-PVDC packaging material.

[0057] The composition of the present invention is useful for the treatment of hypertension and essential hypertension when non-pharmacological methods have failed or have been insufficient.

[0058] Finally, a process for preparing enalapril maleate tablets is described in accordance with the technological characteristics developed by the researchers of the present invention.

[0059] The present invention discloses a pharmaceutical composition comprising: 5.0% to 20.0% w / w of enalapril maleate, 74.0% to 87.0% w / w of one or more diluents, and 4.0% to 5.0% w / w of a superdisintegrant.

[0060] 2.0% to 3.0% w / w of glyceryl dibehenate as a lubricating agent where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0061] Specifically, this pharmaceutical composition may comprise:

[0062] 5.0% to 20.0% w / w enalapril maleate

[0063] 20.0% to 27% w / w of microcrystalline cellulose

[0064] 54.0% to 60.0% w / w lactose monohydrate

[0065] 4.0% to 5.0% w / w crospovidone sodium

[0066] 2.0% to 3.0% w / w of glyceryl dibehenate, where the “% w / w” of each ingredient refers to the total weight of the pharmaceutical composition. More specifically, said pharmaceutical composition may comprise:

[0067] 5.0% to 20.0% w / w enalapril maleate

[0068] 34.0% to 44.0% w / w of microcrystalline cellulose

[0069] 40.0% to 43.0% w / w lactose monohydrate

[0070] 4.0% to 5.0% w / w crospovidone sodium

[0071] 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0072] Specifically, this pharmaceutical composition may comprise:

[0073] 5.0% to 20.0% w / w enalapril maleate

[0074] 20.0% to 27.0% w / w of microcrystalline cellulose grade 102

[0075] 14.0 to 17.0% w / w of microcrystalline cellulose grade 101

[0076] 40.0% to 43.0% w / w lactose monohydrate

[0077] 4.0% to 5.0% w / w crospovidone sodium

[0078] 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0079] Alternatively, this pharmaceutical composition may comprise:

[0080] 5.0% to 20.0% w / w enalapril maleate

[0081] 26.0% to 32.0% w / w of grade 200 microcrystalline cellulose

[0082] 8.0 to 12.0% w / w of microcrystalline cellulose grade 101

[0083] 40.0% to 43.0% w / w lactose monohydrate

[0084] 4.0% to 5.0% w / w crospovidone sodium

[0085] 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0086] Specifically, the pharmaceutical composition comprises:

[0087] 5.0% to 20.0% w / w enalapril maleate

[0088] 22.0% to 25.0% w / w of microcrystalline cellulose grade 102

[0089] 17.0 to 22.0% w / w of pregelatinized starch

[0090] 35.0% to 40.0% w / w lactose monohydrate

[0091] 4.0% to 5.0% w / w crospovidone sodium

[0092] 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0093] Alternatively, a pharmaceutical composition is available that comprises:

[0094] 5.0% to 20.0% w / w enalapril maleate

[0095] 22.0% to 25.0% w / w of grade 200 microcrystalline cellulose

[0096] 17.0 to 22.0% w / w of pregelatinized starch

[0097] 35.0% to 40.0% w / w lactose monohydrate

[0098] 4.0% to 5.0% w / w crospovidone sodium

[0099] 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0100] Next, the pharmaceutical composition selects the diluting agents from microcrystalline cellulose, lactose monohydrate, pregelatinized starch, or a mixture thereof. Similarly, the pharmaceutical composition selects the superdisintegrating agent from crospovidone and crospovidone sodium.

[0101] The pharmaceutical composition is then found in the form of tablets, particularly the pharmaceutical composition is found in the form of 100 mg tablets.

[0102] The pharmaceutical composition comprises between 5 and 20 mg of enalapril maleate, particularly the pharmaceutical composition comprises 10 mg of enalapril maleate.

[0103] The pharmaceutical composition comprises 74 to 87 mg of at least one diluent, wherein the diluent is selected from microcrystalline cellulose and lactose monohydrate or starch or a mixture thereof. The diluent microcrystalline cellulose is selected from microcrystalline cellulose grade 101, microcrystalline cellulose grade 102, microcrystalline cellulose grade 200, or a mixture thereof.

[0104] The pharmaceutical composition comprises 4.0 to 5.0 mg of the superdisintegrant selected from crospovidone or crospovidone sodium, and 2.0 to 3.0 mg of the lubricating agent glyceryl dibehenate. The diluent lactose monohydrate is selected from lactose monohydrate and spray-dried lactose monohydrate.

[0105] Furthermore, the pharmaceutical composition includes the following pharmaceutically acceptable excipients: binding agents, colorants, and / or sweeteners. The aforementioned pharmaceutical composition is used to prepare a medication for treating hypertension. This is further explained by the fact that the aforementioned pharmaceutical composition is used to prepare a medication for treating essential hypertension.

[0106] The present invention also relates to a process for preparing the pharmaceutical composition, wherein the process comprises the following steps:

[0107] (a) weigh separately, each of the ingredients to be used and which correspond to: enalapril maleate, three diluting agents, a superdisintegrant and glyceryl dibehenate as a lubricating agent;

[0108] (b) sieve the enalapril maleate through a #30 mesh, together with the superdisintegrant and a first diluent, and then mix these three ingredients for 10 to 15 minutes in a “V” mixer;

[0109] (c) sieve a second diluent through a #30 mesh and mix together with the previous mixture using a “V” mixer for 10-15 minutes;

[0110] (d) Sieve a third diluent through a #30 mesh and mix together with mixture (c) for 25-30 minutes in a “V” mixer.

[0111] (e) sieve the lubricant through a #30 mesh and then mix together with the powder mixture from step (d) in a V-mixer for a time of 5-10 minutes; and

[0112] (f) Place the mixture from step (e) in a compression machine and compress the mixture to obtain the tablets.

[0113] Specifically, there is a process for preparing the pharmaceutical composition described above, which comprises the following steps:

[0114] (a) weigh separately each of the ingredients to be used, which correspond to: enalapril maleate, two diluting agents, superdisintegrant and glyceryl dibehenate as a lubricating agent;

[0115] (b) Sieve the enalapril maleate through a #30 mesh, together with the superdisintegrant and a first diluent, and then mix these three ingredients for 10 to 15 minutes in a V-mixer; (c) Sieve a second diluent through a #30 mesh and mix with the previous mixture using a V-mixer for 25-30 minutes;

[0116] (d) sieve the lubricant through a #30 mesh and then mix with the powder mixture from step (c) in a V-mixer for a time of 5-10 minutes; and

[0117] (e) place the mixture from step (d) in a compression machine and compress the mixture to obtain the tablets.

[0118] Both processes for preparing the pharmaceutical composition, described above, require that in step (a) each of the ingredients is weighed according to the concentration indicated below:

[0119] 5.0% to 20.0% w / w enalapril maleate;

[0120] 74.0 to 87.0% w / w of one or more diluents;

[0121] 4.0% to 5.0% w / w of a superdisintegrant; and

[0122] 2.0% to 3.0% w / w of glyceryl dibehenate as a lubricating agent; where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

[0123] Finally, both processes of preparing the pharmaceutical composition also include packaging the tablets obtained in transparent polyamide, aluminum and polyvinyl chloride (PA / AL / PVC) - polyvinylidene chloride (PVDC) packaging material.

[0124] DEFINITIONS

[0125] The following definitions are provided to clarify the terms used in describing the present invention:

[0126] - Ingredient or active principle or API: any substance or mixture of substances intended for the manufacture of a medicinal product and which, when used in its production, become an active component of said medicinal product intended to exert a pharmacological, immunological or metabolic action in order to restore, correct or modify physiological functions, or to establish a diagnosis.

[0127] - Immediate or conventional release: Preparations in which the release of the active ingredient is not deliberately modified by a particular formulation design or a special manufacturing method. In the case of a solid dosage form, such as tablets, the dissolution profile of the active ingredient depends essentially on its intrinsic properties. - Rapid release: According to the present invention, in rapid-release tablets, the dissolution of the active ingredient must be at least 100% ± 3% within 5 minutes.

[0128] - Acceptable pharmaceutical excipient: An inactive or inert substance that is mixed with active ingredient(s) to give consistency, shape, flavor, or other qualities to medicines that facilitate their dosage and use. They may also be used to aid in the manufacturing process of a product.

[0129] - Matrix: The tablet matrix refers to when the active ingredient is homogeneously dispersed in the inert material or excipients.

[0130] - Stability of a pharmaceutical composition: corresponds to the maintenance of the chemical and structural characteristics of the active ingredient without substantial decomposition during the time between the manufacture of the pharmaceutical composition and its use by the patient.

[0131] EXAMPLES

[0132] Example 1. API-excipient compatibility study

[0133] To determine the excipients to be tested in the API-excipient compatibility studies from the widely available range, a qualitative formulation of the enalapril maleate 10 mg tablet product, declared as the reference product (hereinafter, “RP”) and with a 24-month shelf life, was used as a starting point. The excipients included in this RP are listed in Table 1:

[0134] Table 1

[0135] Other excipients besides those already included in the PR formulation were also considered. These are commonly used in this type of product and are functionally related to the PR excipients. These include pregelatinized starch, colloidal silicon dioxide, talc, and copovidone VA 64. Copovidone was used as a stereotype for polyvinylpyrrolidones in general, as they have a very similar chemical structure, and the results obtained could be extrapolated to various types of polyvinylpyrrolidones. Therefore, the excipients used in the compatibility tests are as follows:

[0136] Excipients:

[0137] • Lactose monohydrate Spray Dried

[0138] • Microcrystalline cellulose (Grade 200)

[0139] • Croscarmellose sodium

[0140] • Glyceryl dibehenate

[0141] • Magnesium stearate

[0142] • Pregelatinized starch

[0143] • Colloidal silicon dioxide

[0144] • Talc

[0145] • Copovidone VA 64

[0146] 1.1 Procedure a.- The following API-excipient mixtures were prepared: i) Mixture of ratio 1 : 1 = 100 mg of the active ingredient and 100 mg of the excipient iii) Mixture of ratio 1 :5 = 100 mg of the active ingredient and 500 mg of the excipient iii) Mixture of ratio 1 : 10 = 100 mg of the active ingredient and 1000 mg of the excipient b.- Each mixture was weighed individually, carrying both components API and excipient, to a 3 mL vial.

[0147] The homogeneity of the components was achieved using a vortex mixer; the mixture was vortexed for 30 seconds, followed by three manual turnings. This was performed in triplicate for each prepared mixture.

[0148] Two experimental conditions were established, condition A, at 60°C and with a relative humidity (RH) of 75 ± 5% and condition B, at 80 °C and without relative humidity (RH).

[0149] The sample set for condition B is placed in the oven as prepared, in vials, after homogenization, and with caps. Meanwhile, the sample set for condition A is quantitatively poured into open dishes and placed in a desiccator containing a saturated NaCl solution (48 g / 100 mL). Both conditions are maintained for 21 days, with sampling and analysis at 0, 7, 14, and 21 days. The analytical method used is based on USP 43 practices, which is capable of quantifying enalapril maleate and its main organic impurities: enalaphlate and enalapril diketopiperazine.

[0150] Subsequently, each sample is quantitatively transferred to a 500 mL volumetric flask, with rinses, using the solvent described in the method, of the vials, for condition B, and the plates, for condition A. The final concentration of each sample is 0.2 mg / mL of enalapril maleate.

[0151] It should be mentioned that the mixtures were not made at the actual concentration used in the formula, but at a much higher concentration to exacerbate possible incompatibility reactions (1:1, 1:5 and 1:10 ratios).

[0152] 7.2 Results

[0153] The results are shown as the percentage assay of enalapril maleate and the organic impurities, enalaphlate and enalapril diketopiperazine, in Tables 2 to 7, as indicated below, where EM corresponds to enalapril maleate.

[0154] Table 2: Results of the binary mixtures studied under condition A expressed as a percentage of enalapril maleate. Table 3: Results of the binary mixtures studied under condition B expressed as a percentage of enalapril maleate.

[0155] Table 4: Results of the binary mixtures studied under condition A expressed as a percentage of enalaprilat. Table 5: Results of the binary mixtures studied under condition B expressed as a percentage of enalaprilat.

[0156] Table 6: Results of the binary mixtures studied under condition A expressed as a percentage of enalapril diketopiperazine Table 7: Results of the binary mixtures studied under condition B expressed as a percentage of enalapril diketopiperazine

[0157] In complementary experiments, the reference product (RP) and the raw material enalapril maleate alone (EM Standard) were subjected to accelerated stability conditions for 21 days under condition A and 21 days under condition B. Under condition A, the RP was exposed as unblistered tablets, i.e., without its primary packaging, so that the tablets were fully exposed to the humidity conditions of the test. Under condition B, the RP tablets, without relative humidity, remained in their respective primary packaging. The results are shown in Table 8.

[0158] Table 8: Results of tests performed on the raw material enalapril maleate (EM Standard) and the reference product (RP) under the indicated conditions, expressed as a percentage of enalapril maleate (EM), enalaphlate (ET) and enalapril diketopiperazine (DKP) According to the results obtained in the API-excipient compatibility tests, the presence of moisture is a determining factor in the stability of the active ingredient enalapril maleate. Moisture has a negative effect on its behavior, not only in prepared mixtures but also at the formulation level (Table 8), where there is closer contact between the multiple components. Mixtures exposed to condition A (humid heat, Table 2) suffered greater degradation than those exposed to condition B (dry heat, Table 3). Therefore, the packaging material is particularly important, as it can provide protection against moisture and temperature changes.

[0159] In these tests, the lability of the product with respect to high temperatures could be observed, showing a significant degradation of the active ingredient in both humid and dry heat conditions, being considerably greater in the presence of moisture (Table 8).

[0160] As a control, the API enalapril maleate alone was subjected to the same conditions A and B, and it was observed that there was no formation of the related impurity enalapril diketopiperazine and minimal generation of enalaphlate under both conditions, moist heat and dry heat (Table 8). This confirms that enalapril maleate is stable with respect to temperature and humidity.

[0161] The API-excipient compatibility results showed that enalapril maleate experienced significant degradation from magnesium stearate, in contrast to the effect observed with the other lubricant, glyceryl dibehenate (Tables 2 and 3), where API degradation was considerably lower, even when the mixture contained a higher proportion of glyceryl dibehenate (1:5). Furthermore, degradation from magnesium stearate was very high even under dry heat (Condition B, Table 3), unlike what was observed for other excipients such as glyceryl dibehenate and copovidone. While degradation from these excipients did occur under dry heat, it was to a much lesser degree than under moist heat (Condition A). This clearly demonstrates the instability of enalapril maleate in the presence of magnesium stearate.

[0162] Regarding the behavior of the API with the polyvinylpyrrolidone derivative copovidone, it was observed that any incompatibility with enalapril maleate is ratio-dependent, with greater API degradation at a 1:5 ratio than at 1:1 (Table 2). Due to this concentration dependence, and considering that the proportion used in a pharmaceutical formulation is considerably lower, polyvinylpyrrolidone proves to be a suitable excipient for use in a formulation with enalapril maleate. This was corroborated by the stability studies performed on the final formulations (below).

[0163] Furthermore, it was observed that enalapril maleate undergoes very high degradation when compared to croscarmellose sodium (Table 2), also demonstrating the incompatibility of this excipient with said API.

[0164] Regarding the effect on enalapril maleate of the other excipients tested: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide and talc; minimal, or no, degradation of the API was observed (tables 2 and 3), which makes it possible to indicate that enalapril maleate maintains its intrinsic stability against these excipients.

[0165] Tables 4 to 7 show the percentage by which two of the main degradation components were generated during the tested process.

[0166] The results of these studies suggested the replacement of the superdisintegrant croscarmellose sodium and the elimination or replacement of magnesium stearate, both contained in the formulation of the reference product, PR, (Table 1).

[0167] Example 2. Pharmaceutical formulation according to the present invention

[0168] Considering the results presented above, formulations in the form of tablets containing enalapril maleate were prepared according to the present invention, using the excipients most compatible with this API and discarding those that showed a clearly detrimental effect on the stability of a formulation containing them. Thus, magnesium stearate was omitted, and only glyceryl dibehenate was used as a lubricating agent. Furthermore, instead of using the superdisintegrant croscarmellose sodium, also included in the PR formulation, and given the improved stability observed of the API mixture with the polyvinylpyrrolidone copovidone, formulations were prepared comprising a crosslinked polyvinylpyrrolidone acting as a superdisintegrant, crospovidone sodium.In addition, microcrystalline celluloses of different grades (PH-101, PH-102, and PH-200) were used as diluents, which determines their particle size and moisture content. Other excipients that proved to be harmless to the API enalapril maleate, such as lactose monohydrate and / or pregelatinized starch, were also used as diluents. The following formulation examples are provided to illustrate the present invention; these should not be interpreted in a limiting manner.

[0169] Example 2.1 Example 2.2

[0170] Example 2.3

[0171] Example 2.4 CROSPOVIDONE SODIUM 4.0 - 5.0

[0172] Example 2.5

[0173] To evaluate quality, stability and kinetic parameters, 100 mg tablets according to the present invention were used, comprising 10% enalapril maleate together with the excipients in the amounts indicated in the following formulation examples:

[0174] Example 2.6 (Formulation #1) Example 2.7 (Formulation #2)

[0175] Example 2.8 (Formulation #3)

[0176] Example 2.9 (Formulation #4)

[0177] Example 2.10 (Formulation #5) Example 3. Preparation procedure

[0178] The manufacture of the pharmaceutical tablet according to the present invention comprises the following steps:

[0179] (a) Each of the ingredients to be used, which correspond to: active ingredient, three diluents, superdisintegrant and lubricant, were rigorously weighed separately.

[0180] (b) The active ingredient, enalapril maleate, was sieved through a #30 mesh screen, along with the superdisintegrant and a first diluent. These three ingredients were then mixed for 10 to 15 minutes in a V-mixer.

[0181] (c) A second diluent was sieved through #30 mesh and mixed with the previous mixture using a “V” mixer for 10-15 minutes.

[0182] (d) A third diluent was then sieved, also through #30 mesh, and mixed with mixture (c) for 25-30 minutes in a “V” mixer.

[0183] (e) Subsequently, the lubrication stage was carried out, for which the lubricant was sieved through a #30 mesh and mixed with the powder mixture from stage (d) in a “V” mixer for a time of 5-10 minutes.

[0184] (f) Then, for the compression stage, the mixture from the previous stage was placed in a compression machine and the mixture was compressed to obtain the tablets according to the present invention.

[0185] The three diluents used were

[0186] Alternatively, manufacturing may comprise the following steps if two diluents are used instead of three:

[0187] (a) Each of the ingredients to be used, which correspond to: active ingredient, two diluents, superdisintegrant and lubricant, were rigorously weighed separately.

[0188] (b) The active ingredient, enalapril maleate, was sieved through a #30 mesh screen, along with the superdisintegrant and a first diluent. These three ingredients were then mixed for 10 to 15 minutes in a V-mixer.

[0189] (c) A second diluent was then sieved through #30 mesh and mixed with the previous mixture using a “V” mixer for 25-30 minutes.

[0190] (d) Subsequently, the lubrication stage was carried out, for which the lubricant was sieved through a #30 mesh and mixed with the powder mixture from stage (c) in a V-mixer for 5-10 minutes. (e) Then, for the compression stage, the mixture from the previous stage was placed in a compression machine and the mixture was compressed to obtain the tablets according to the present invention.

[0191] Finally, the tablets prepared by any of the above procedures were packaged with transparent aluminum (PA / AL / PVC) - PVDC packaging material.

[0192] Example 4. Physical and physicochemical tests

[0193] Quality tests were performed on formulations #1 through #5, including the evaluation of pre-compression parameters. For this purpose, 200-gram samples of the powder mixture from each formulation were taken before the compression stage. Subsequently, once the manufacturing process was complete, the hardness of the tablets was determined. The results of these manufacturing and theological studies are reflected in Table 9 below:

[0194] Table 9 Assay tests were also performed on enalapril maleate in each of the tablet formulations. The results were expressed as a percentage of the declared value according to the analytical specifications and are shown in Table 10 below:

[0195] Table 10 *AV: Acceptance value obtained

[0196] The results obtained from the quality tests performed on the formulations of the present invention showed that all formulations met the physical and physicochemical properties. However, formulations #1 and #2 were selected for the release-dissolution and stability studies because they best represent the scope of the invention. While the values ​​obtained for the Carr and Hausner indices suggest a flowability ranging from fair to passable, according to USP 37, angles of repose between 25° and 40° indicate excellent to adequate flowability, which all formulations of the present invention meet (Table 9). Furthermore, all tablets met the hardness specifications, falling within the range of 3.0 to 11 Kp.The identity of the API and its concentration in the tablets was validated with the assay tests that showed an AV (acceptance value) of less than 15% (Table 10), which is within the standard established in the pharmacopoeias.

[0197] With these excellent results, in order to determine the release and dissolution of the tablets, the inventors conducted dissolution profile studies at different pH values ​​and also performed short-, medium-, and long-term stability studies under different temperature and humidity conditions, following national and international standards. These tests and their results are described below.

[0198] Example 5. Evaluation of release-dissolution profiles

[0199] In vitro release-dissolution kinetic studies were carried out for the tablets according to Formulation #1 and Formulation #2 of the present invention as indicated below:

[0200] Example 5.1

[0201] Studies were performed on 12 tablets prepared according to Formulation #2, using the paddle method (apparatus USP II) at 50 rpm in 900 mL of a buffer solution pH 1, 2; 4, 5 and 6, 8.

[0202] 5.1.1 Methodology a) Approximately 7 liters of buffer medium were prepared. b) The dissolution equipment was programmed according to the conditions indicated in the previous paragraph. c) 900 mL of buffer medium were placed in six beakers for the dissolution test. d) One tablet of the product to be tested was placed in each of the six beakers. e) 10 mL were taken from each beaker at the following sampling times (min): 5, 10, 15, and 30. f) The samples were analyzed by HPLC (high-performance liquid chromatography). g) Steps b) through f) were then repeated with another six beakers.

[0203] 5.1.2 Results

[0204] The results obtained for the release-dissolution profiles under each pH condition are shown in Tables 11, 12, and 13, where “CV%” corresponds to the coefficient of variation expressed as a percentage. These results are plotted in Figure 1. a) Release-dissolution profile in hydrochloric acid buffer, pH 1.2

[0205] Table 11 b) Dissolution profile in acetate buffer pH 4.5

[0206] Table 12 c) Dissolution profile in phosphate buffer pH 6.8

[0207] Table 13 | 30 | 97.3 | 3J) |

[0208] For the evaluation of dissolution profiles, buffer solutions at pH 1.2, 4.5, and 6.8 were used, following the guidelines that define the experimental conditions for release-dissolution kinetic studies and that immediate-release products must meet. This is established in the G-Biof 02 Technical Guide of the Public Health Institute of Chile (hereinafter, “ISP Technical Guide”), which is based on the conditions stipulated by the World Health Organization (WHO) and official pharmacopoeias such as the United States Pharmacopeia (USP35 / NF30). The FDA's Industry Guide indicates that, whenever possible, dissolution tests should be performed under physiological conditions; that an aqueous medium with a pH range of 1.2 to 6.8 should be used; that a dissolution medium with a pH of 6.8 should be used to simulate intestinal fluid; and that the use of a higher pH should be justified.These guidelines specify the following dissolution media: (1) pH 1.2 HCl or Simulated Gastric Fluid USP with enzymes; (2) pH 4.5 buffer (Acetate); and (3) pH 6.8 buffer (Phosphate) or Simulated Intestinal Fluid USP without enzymes. The FDA Industry Guide suggests at least 85% dissolution within 15 minutes for rapid-release tablets, while the ISP Technical Guide suggests 85% dissolution within 30 minutes.

[0209] The results of the release-dissolution kinetic studies performed on the tablets according to the present invention surprisingly showed a very rapid release profile, reaching at least 100% ± 3% dissolution of the active ingredient in just 5 minutes, under all pH conditions tested, as shown in Figure 1 and the corresponding data tabulated in Tables 11, 12, and 13. This far exceeded the minimum USP requirement of 85% dissolution at 15 minutes for immediate-release tablets. Furthermore, it was achieved in accordance with the ISP Technical Guide, which defines a pharmaceutical form as rapid-release-dissolution when at least 85% of the active ingredient dose dissolves within 30 minutes.

[0210] These results have demonstrated that the dissolution of the formulation of the present invention is not only rapid but also pH-independent, achieving complete dissolution in just 5 minutes under all pH conditions suggested by pharmacopoeias. In other words, this formulation achieves very rapid release under pH conditions that simulate both gastric and intestinal pH, thus ensuring that all of the enalapril maleate is available for rapid absorption in the digestive tract and can be metabolized to exert its therapeutic effect as quickly as possible after ingestion.This is especially relevant for enalapril maleate, a class III active ingredient, since, as the FDA-US points out in its Guide for Industry, having an 85% dissolution in 15 minutes in 0.1 N HCI medium (that is, pH 1.2), it can be ensured that the bioavailability of the drug is not limited by dissolution, behaving as a solution, and that it should generally not have any bioavailability problems.

[0211] These results are absolutely surprising and unexpected, and nothing similar is reported in the literature. In contrast, in the publication of patent application IN2021121035760A (hereinafter IN'5760), it was found that their enalapril maleate formulation, comprising magnesium stearate, achieved a dissolution of only 22.98% at 5 minutes and 68.62% at 15 minutes. A key finding is that this formulation (designated F4 in that publication) is their best formulation, achieving an API release of 98%, but only at 20 minutes. These dissolution results, compared to those obtained in the present invention, are quite low, especially considering that enalapril maleate is a Class III active ingredient according to the BCS and the importance of its dissolution being at least 85% at 15 minutes to ensure that absorption is not limited by its dissolution.

[0212] Now, the literature on the formulation of tablets containing enalapril maleate has extensively described the degradation pathway of enalapril maleate as pH-dependent. However, based on the results obtained from the dissolution profiles performed under pH conditions of 1, 2, 4.5, and 6.8 (Tables 11, 12, and 13, respectively, and Figure 1), it can be concluded that the enalapril maleate contained in this formulation undergoes zero or a very low level of degradation under any pH condition. This is supported by the fact that the average percentage of dissolved enalapril maleate obtained at different times and pH values ​​remains above 97.3% ± 3%. In other words, the degradation of enalapril maleate is minimal, and the formulation according to the present invention is not affected by the pH to which it is exposed.This is clearly an advantage over what has been described in the previous art, since most of those compositions are affected by pH, requiring stabilizers in their formulation.

[0213] Example 5.2 The dissolution over time of tablets according to Formulation #1 of the present invention in a phosphate buffer solution pH 6.8 was evaluated in parallel with the measurement of tablets according to Formulation #2 of the present invention, under the same conditions. The results showed that the tablets of both formulations had similar, if not identical, dissolution rates over time, as shown in Figure 2, reaching complete release at 5 minutes. At longer times, dissolution close to 100% was observed for both cases, demonstrating very low or no degradation of the active ingredient in these formulations.

[0214] Example 6. Stability studies

[0215] To accurately determine the stability of the formulation according to the present invention, long-term, intermediate-term, and accelerated stability studies were conducted on three different batches of tablets prepared according to Formulation #2. These studies followed the requirements of the relevant ICH guidelines, “Stability Testing of New Drug Substances and Products” CPMP / ICH / 2736 / 99-ICH Q1 A (R2), under temperature and relative humidity (RH) conditions corresponding to climatic zones classified by the WHO (World Health Organization), which are detailed below. a.- Long-term stability study under climatic conditions Zone II

[0216] Storage conditions: 25°C ± 2°C / 60% RH ± 5% RH. Storage period of 36 months with testing intervals at 0, 3, 6, 9, 12, 18, 24, and 36 months. b. Intermediate stability study, under climatic conditions of Zone IVa

[0217] Storage conditions: 30°C ± 2°C / 60% RH ± 5% RH. Storage period of 12 months with testing intervals at 0, 3, 6, 9 and 12 months. c.- Accelerated stability study

[0218] Storage conditions: 40°C ± 2°C / 75% RH ± 5% RH. Storage period: 6 months with testing intervals at 0, 3 and 6 months.

[0219] The results obtained, which are detailed in Figure 3, graphs A, B and C, show that for the three batches under study the assessment of the active ingredient remained within specifications, 90% to 110% of the declared value (DV), in the three storage conditions tested over time, demonstrating that the product is stable under established conditions.

[0220] Additionally, from the results plotted in Figure 4, graphs A, B and C, it was clearly observed that the three lots under study, under the indicated storage conditions, are within specifications for the sum of all impurities, including enalaphlate and enalapril diketopiperazine, for the entire time they were exposed.

[0221] These results show that the enalapril maleate tablets of the present invention maintained a total impurity level well below 5%, the maximum limit value allowed by health regulations, under all conditions studied and for all storage periods tested.

[0222] It is very important to highlight that, at the end of the stability study at 36 months, excellent results were obtained, with total impurities reaching only 2.8% for each of the three batches, as shown in Figure 4C, which is well below the 5% allowed by current local and international regulations for this API.

[0223] Furthermore, the reference product (RP) has a declared shelf life of only 24 months. This indicates that the stability of enalapril maleate in the RP was insufficient to reach 36 months. In contrast, as demonstrated by the stability studies, the formulation of the present invention has a shelf life of at least 36 months. Additionally, it has been observed that the RP, under conditions of high temperature and humidity (humid heat) and high temperature in the absence of humidity (dry heat), undergoes significant degradation of the active ingredient, reaching enalapril maleate levels as low as 0.92% under humid heat and 37.2% under dry heat (Table 8).

[0224] The absolutely amazing results obtained in the present invention allow it to be above the quality of the reference product (RP), by demonstrating a longer period of effectiveness, 36 months vs 24 months, which was possible solely and duly due to the better stability of the tablets according to the pharmaceutical formulation of the present invention.

[0225] For the formulation of the present invention, other stability indicator parameters such as hardness, friability, weight, dimensions and dissolution of the tablet, among others, were also evaluated under the three conditions indicated above, which are: a) 25°C / 60% RH; b) 30°C / 60% RH; c) 40°C / 75% RH. The results obtained are shown in the following tables 16 to 18.

[0226] Table 16: Parameters under long-term stability conditions, 25°C / 60% RH Table 17: Parameters under intermediate-term stability conditions, 30°C / 60% RH

[0227] Table 18: Parameters under accelerated stability conditions, 40°C / 75% RH As previously stated, the samples were stored for 36 months, 12 months, and 6 months under the following conditions: a) 25°C / 60% RH; b) 30°C / 60% RH; and c) 40°C / 75% RH, respectively. All tests performed, as suggested by the ICH standard, yielded results within specifications (Tables 16 to 18). Thus, the tablets according to the present invention exhibited an appearance, hardness, friability, average weight, and dimensions consistent with specifications. This was observed for all three batches studied.

[0228] Regarding the dissolution determined in these stability studies, the FDA's Guide for Industry was followed, which states that, as a quality control test for Class I and III active pharmaceutical ingredients, a single-point dissolution test specification should be performed to ensure 85% dissolution within 60 minutes or less, and that Q should not be less than 80%. As observed in each of the tests (Tables 16 to 18), the dissolution of the tablets stored under the three test conditions at the different time points was complete in all cases, again far exceeding the minimum required by the technical specifications.

[0229] The essential characteristics of the formulation of the present invention and its differences from the prior art that led to the surprising and unexpected results can be summarized as follows: The type of lubricating agent included in the formulations of the present invention. This is because, based on the API-excipient compatibility results obtained here, as well as on what is known from the prior art, magnesium stearate is the excipient that causes significant degradation of enalapril maleate. Therefore, the formulation of the invention contains glyceryl dibehenate as the sole lubricant. Although there are other excipients that also differ from the PR formulation, such as the superdisintegrant and the diluent, these did not significantly impact the stability of the active ingredient (API-excipient compatibility studies). Therefore, the observed effects can be attributed to the lubricating agent.It could be hypothesized that the surprising results of the present invention may also, or alternatively, be due to the combined effect of the excipients. This cannot be completely ruled out, but what is beyond doubt is that by eliminating magnesium stearate from the formulation and opting for the advantages provided by glyceryl dibehenate, along with the other excipients, completely unexpected dissolution and stability results were achieved. This is further supported by the evidence discussed below.Returning to document IN'5760, which discloses formulations comprising enalapril maleate, the substantial difference from the formulations of the present invention also lies in the lubricating agent. In the present invention, glyceryl dibehenate is used, with magnesium stearate explicitly excluded; whereas in document IN'5760, magnesium stearate is used in all the formulations tested. The other excipients are the same as or equivalent to those of the present invention, particularly formulation F4 of IN'5760, which is the 'chosen' formulation in that document, and which also comprises microcrystalline cellulose as a diluent and crospovidone as a superdisintegrant.Also, the other excipients, lactose monohydrate or pregelatinized starch in the invention and talc in IN'5760, proved to be quite harmless to enalapril maleate (Tables 2 to 7 of the present invention), so no significant change in the properties of the formulation can be attributed to them.

[0230] It is worth mentioning here that accelerated stability studies for enalapril maleate tablets containing magnesium stearate as a lubricant were disclosed in document IN'5760, conducted under storage conditions of 40°C / 75% RH. This condition corresponds to that of the accelerated stability test used in the present invention, with the difference that in the present invention the test was carried out for up to 6 months (180 days), whereas in document IN'5760 it was only carried out for up to 90 days. After these storage conditions, the preparations made according to the present invention showed a higher percentage of release-dissolution of the active ingredient than that observed in document IN'5760.Specifically, in the present invention, the percentage of release of the active ingredient at 3 months was complete, with an average of 102.5% ± 1.6%, unlike the magnesium stearate tablets disclosed in the aforementioned document, which at 3 months (90 days) showed an average dissolution of 96.57%. The stability of the formulation of the present invention was evaluated up to 180 days, under conditions of 40°C / 75% RH, finding an average API dissolution of 98.3%, which is still higher than that found at 90 days in the enalapril maleate tablets of document IN'5760, which contain magnesium stearate as a lubricant. That document does not mention the behavior of the formulation beyond 90 days.These results are a further indication of the greater stability of the formulation of the present invention compared to the prior art, which in this case discloses a formulation very similar to that of the present invention, differing substantially in the lubricating agent.

[0231] Now, an expert in the technique might have expected less degradation of enalapril maleate by providing a formulation that includes a lubricating agent with less or minimal impact on the stability of this API, but an expert in the field could not have deduced that a significantly improved stability would be achieved that would even give the formulation an effectiveness period 12 months longer than the reference product containing magnesium stearate, reaching 36 months vs 24 months.

[0232] This improved stability has also made it possible to use a less expensive packaging material for the tablets of the present invention than those generally used for enalapril maleate products, such as the reference product, PR. Thus, for the present invention, the use of blisters or primary packaging called transparent aluminum-PVDC, consisting of a sheet of PA / AL / PVC and another of transparent PVDC, was sufficient to ensure the tablets maintained their stability over time. The use of this packaging material was only possible due to the high stability achieved with the product of the present invention. This material has the significant advantage of being less expensive compared to 'aluminum-aluminum' packaging, and even more economical than 'aluminum-amber' packaging, both of which are used for enalapril maleate products. It is worth noting that for product P...Even using an 'aluminum-amber' packaging material, which provides greater protection to the tablet, did not achieve such a high period of effectiveness as that achieved by the present invention.

[0233] Additionally, based on prior art, an expert in the field could not have deduced that the formulation comprising glyceryl dibehenate as the sole lubricating agent would exhibit such a high dissolution rate, that enalapril maleate being a class III active ingredient (high solubility / low permeability) would achieve a dissolution like that of a liquid formulation, thus avoiding, as indicated in the FDA Industry Guide, bioavailability problems.

[0234] The tests carried out regarding the incompatibility of excipients could have been designed by an expert in the field considering the usual practice, however, the effect that the suppression of magnesium stearate has had on the developed formulation, both in its stability and in the dissolution, was not expected by any expert in the field.

[0235] Finally, the total tablet weight obtained with this formulation is noteworthy, being only 100 mg. This characteristic is significant because it makes the tablet a more patient-friendly size while containing the same concentration of active ingredient as the formulation in IN'5760, which is 10 mg, but with a total weight of 200 mg. This will clearly allow for greater adherence to treatment with enalapril maleate using the formulation of the present invention, especially in patients with dysphagia and elderly adults. In conclusion, it is demonstrated that the elimination of magnesium stearate improves the pharmaceutical properties of the enalapril maleate tablet formulation, something not considered in the prior art.

[0236] Based on the results detailed here, it is possible to conclude that the pharmaceutical composition presents better and unexpected stability properties, as well as a surprisingly faster release-dissolution of the active ingredient compared to what is described in the state of the art.

Claims

CLAIMS 1. A pharmaceutical composition, CHARACTERIZED in that it comprises 5.0% to 20.0% w / w enalapril maleate 74.0 to 87.0% w / w of one or more diluents 4.0% to 5.0% w / w of a superdisintegrant 2.0% to 3.0% w / w of glyceryl dibehenate as a lubricating agent where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

2. A pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises: 5.0% to 20.0% w / w enalapril maleate 20.0% to 27% w / w microchstaline cellulose 54.0% to 60.0% w / w lactose monohydrate 4.0% to 5.0% w / w crospovidone sodium 2.0% to 3.0% w / w glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

3. A pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises: 5.0% to 20.0% w / w enalapril maleate 34.0% to 44.0% w / w microchstaline cellulose 40.0% to 43.0% w / w lactose monohydrate 4.0% to 5.0% w / w crospovidone sodium 2.0% to 3.0% w / w glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

4. A pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises: 5.0% to 20.0% w / w enalapril maleate 20.0% to 27.0% w / w of microcrystalline cellulose grade 102 14.0 to 17.0% w / w of microcrystalline cellulose grade 101 40.0% to 43.0% w / w lactose monohydrate 4.0% to 5.0% w / w crospovidone sodium 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

5. A pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises: 5.0% to 20.0% w / w enalapril maleate 26.0% to 32.0% w / w of grade 200 microcrystalline cellulose 8.0 to 12.0% w / w of microcrystalline cellulose grade 101 40.0% to 43.0% w / w lactose monohydrate 4.0% to 5.0% w / w crospovidone sodium 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

6. A pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises: 5.0% to 20.0% w / w enalapril maleate 22.0% to 25.0% w / w of microcrystalline cellulose grade 102 17.0 to 22.0% w / w of pregelatinized starch 35.0% to 40.0% w / w lactose monohydrate 4.0% to 5.0% w / w crospovidone sodium 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

7. A pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises: 5.0% to 20.0% w / w enalapril maleate 22.0% to 25.0% w / w of grade 200 microcrystalline cellulose 17.0 to 22.0% w / w of pregelatinized starch 35.0% to 40.0% w / w lactose monohydrate 4.0% to 5.0% w / w crospovidone sodium 2.0% to 3.0% w / w of glyceryl dibehenate where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the diluting agents are selected from microcrystalline cellulose, lactose monohydrate, pregelatinized starch, or a mixture thereof.

9. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the superdisintegrant agent is selected from crospovidone and crospovidone sodium.

10. The pharmaceutical composition according to claim 1, CHARACTERIZED in that it is in the form of tablets.

11. The pharmaceutical composition according to claim 1, CHARACTERIZED in that it is in the form of 100 mg tablets.

12. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the composition comprises between 5 and 20 mg of enalapril maleate.

13. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the composition comprises 10 mg of enalapril maleate.

14. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the composition comprises between 74 and 87 mg of at least one diluent.

15. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the composition comprises between 4.0 and 5.0 mg of the superdisintegrant agent selected from crospovidone or crospovidone sodium.

16. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the composition comprises between 2.0 and 3.0 mg of the lubricating agent glyceryl dibehenate.

17. The pharmaceutical composition according to claim 1, CHARACTERIZED in that the diluting agent is selected from microcrystalline cellulose and lactose monohydrate or starch or a mixture thereof.

18. The pharmaceutical composition according to claim 17, CHARACTERIZED in that the diluting agent microcrystalline cellulose is selected from microcrystalline cellulose grade 101, microcrystalline cellulose grade 102, microcrystalline cellulose grade 200, or a mixture thereof.

19. The pharmaceutical composition according to claim 17, CHARACTERIZED in that the diluent lactose monohydrate is selected from lactose monohydrate and spray dried lactose monohydrate.

20. The pharmaceutical composition according to claim 1, CHARACTERIZED in that it further comprises as pharmaceutically acceptable excipients: binding agents, colorants, and / or sweeteners.

21. Use of the pharmaceutical composition according to claim 1 CHARACTERIZED in that it is used to prepare a medicament useful for treating hypertension.

22. Use of the pharmaceutical composition according to claim 1 CHARACTERIZED in that it is used to prepare a medicament useful for treating essential hypertension.

23. A process for preparing the pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises the following steps: (a) weigh separately, each of the ingredients to be used and which correspond to: enalapril maleate, three diluting agents, a superdisintegrant and glyceryl dibehenate as a lubricating agent; (b) sieve the enalapril maleate through a #30 mesh, together with the superdisintegrant and a first diluent, and then mix these three ingredients for 10 to 15 minutes in a “V” mixer; (c) sieve a second diluent through a #30 mesh and mix together with the previous mixture using a “V” mixer for 10-15 minutes; (d) Sieve a third diluent through a #30 mesh and mix together with mixture (c) for 25-30 minutes in a “V” mixer. (e) sieve the lubricant through a #30 mesh and then mix together with the powder mixture from step (d) in a V-mixer for a time of 5-10 minutes; and (f) Place the mixture from step (e) in a compression machine and compress the mixture to obtain the tablets.

24. A process for preparing the pharmaceutical composition according to claim 1, CHARACTERIZED in that it comprises the following steps: (a) weigh separately each of the ingredients to be used, which correspond to: enalapril maleate, two diluting agents, superdisintegrant and glyceryl dibehenate as a lubricating agent; (b) sieve the enalapril maleate through a #30 mesh, together with the superdisintegrant and a first diluent, and then mix these three ingredients for 10 to 15 minutes in a “V” mixer; (c) sieve a second diluent through a #30 mesh and mix with the previous mixture using a “V” mixer for 25-30 minutes; (d) sieve the lubricant through a #30 mesh and then mix with the powder mixture from step (c) in a V-mixer for a time of 5-10 minutes; and (e) place the mixture from step (d) in a compression machine and compress the mixture to obtain the tablets.

25. The preparation process according to claim 23 or 24, CHARACTERIZED in that in step (a) each of the ingredients is weighed according to the concentration indicated below: 5.0% to 20.0% w / w enalapril maleate; 74.0 to 87.0% w / w of one or more diluents; 4.0% to 5.0% w / w of a superdisintegrant; and 2.0% to 3.0% w / w of glyceryl dibehenate as a lubricating agent; where the “% w / w” of each of the ingredients refers to the total weight of the pharmaceutical composition.

26. The preparation process according to claim 23 or 24, CHARACTERIZED in that it further comprises packaging the tablets obtained in transparent polyamide, aluminum and polyvinyl chloride (PA / AL / PVC) - polyvinylidene chloride (PVDC) packaging material.

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