An effective microemulsion formulation for the treatment of hypertension.

Abstract

The invention relates to a drug formed by microemulsion from lipid-based nano drug delivery systems containing nadolol as the active ingredient, for use in the treatment of hypertension, and the method of producing this product. This nano formulation results in a more accessible drug with high bioavailability and drug compliance values.

Description

1 TARIFF EFFECTIVE MICROEMULSION FORMULATION IN THE TREATMENT OF HYPERTENSION. Technical Field to Which the Invention Relates 5 The invention relates to the delivery of the active ingredient nadolol from lipid-based nano-drug delivery systems. Nano formulations produced by loading them onto a microemulsion system and their production It is related to the method. This formulation is used in the treatment of hypertension. It is used. 10 State of the Art High blood pressure, also known as hypertension, is when blood pressure puts pressure on the walls of the arteries. It is a medical condition characterized by a high level of force. Millimeter of mercury (mmHg) Blood pressure, measured in milligrams, is expressed in two values: systolic pressure (heartbeats per minute) and systolic pressure (in milligrams per minute). blood pressure (force between heartbeats) and diastolic pressure (force between heartbeats). Normal blood pressure is 15 While blood pressure is typically around 120 / 80 mmHg, hypertension is when these values ​​are consistently elevated. It occurs when blood pressure exceeds the normal range. Long-term high blood pressure, by straining the arteries, heart and other organs, it can cause conditions such as heart attack, stroke and heart failure. It can increase the risk of cardiovascular disease. Lifestyle factors, genetics, and others Health conditions can lead to the development of hypertension. Cardiovascular health is crucial. preventive treatments for the protection and reduction of hypertension symptoms and Routine blood pressure tests are of great importance. Hypertension treatment typically aims to lower blood pressure and reduce associated complications. It includes a multifaceted approach aimed at reducing the risk. Lifestyle changes These form a fundamental component of hypertension management. These include a healthy diet (25%). adopting a healthy weight, engaging in regular physical activity, and maintaining a healthy weight. This may include protection and reduction of alcohol consumption. Effectively regulating blood pressure. Medications may also be prescribed to control it. These medications generally reduce fluid retention. diuretics, beta-blockers to reduce heart rate, to relax blood vessels for angiotensin-converting enzyme (ACE) inhibitors and to dilate arteries 30 Like calcium channel blockers, they target various mechanisms in the body. Nadolol, commonly used to treat hypertension, is a medication that affects the heart and circulatory system. Nadolol is a type of medication classified as a beta-blocker. Like adrenaline, nadolol blocks bacteria in the body. 2 by blocking the effects of some natural substances that can increase heart rate and blood pressure It works. As a non-selective beta-blocker, nadolol targets both beta-1 receptors in the heart. It also affects beta-2 receptors in blood vessels. Thus, it reduces the workload on the heart. by helping to lower blood pressure and widening blood vessels It causes it to fall. Various drugs are used to deliver medications like nadolol to the patient's body. Support systems have been improved. Drug delivery systems enable the effective delivery of therapeutic agents within the body. It encompasses various techniques and formulations designed for drug delivery systems. Examples include oral drug delivery via tablets or capsules, and systemic drug absorption. It is a common method for this. Injections such as intravenous or intramuscular injections are used. Accessible routes enable rapid and precise drug delivery, which is vital in critical situations. It allows for the use of patches to slowly release drugs through the skin. or uses topical formulations. by inhalers or nebulizers Facilitated inhalation methods target the respiratory system, and specifically the respiratory system. It is useful in treating these conditions. Including drug-delivering implants or microchips. 15 Implantable devices, including those that provide controlled, continuous medication over a long period of time. It enables release. Nanoscale drug delivery, tiny carriers for drug encapsulation. By using it, it increases the targeted stability and distribution. The selection of a particular carrier system, The drug's properties depend on factors such as the targeted tissue and the desired release kinetics. Nadolol is an active ingredient with low solubility (between 20% and 40%). Nadolol 20 Its low solubility means that treatment needs to be tailored to achieve the optimum therapeutic effect. This leads to continued high doses. Frequent swallowing, such as in the elderly and children. In patient groups where difficulties are encountered, administering the drug in solid form is different. This leads to problems. The high doses result in a high profile of side effects in clinical practice. While reducing patient adherence to treatment at the first stage, it also reduces adherence to treatment at the production stage. This also leads to high costs. The limitations and inadequacies of current technological solutions, particularly in tablet form, The low solubility of nadolol in medications therefore hinders the optimum therapeutic effect. The necessity of continuing treatment with higher doses to achieve the desired result, swallowing Reasons such as patients having difficulty using the medication due to complications 30 Therefore, a development in the field of effective nano-formulations for the treatment of hypertension. It has been deemed necessary to do so. 3 Brief Description and Objectives of the Invention The invention describes a lipid compound containing the active ingredient nadolol, to be used in the treatment of hypertension. The invention relates to a nano-drug delivery system based on nadolol, microemulsion. The microemulsion, which is the subject of this invention, is loaded onto a nano-drug delivery system in the form of an oil 5. the first phase contains cinnamon oil, the water phase contains distilled water, Tween 20 as surfactant, and the co-surfactant. It contains propylene glycol:ethanol. The developed drug delivery system is for oral use. It is directed towards. Microemulsions have a high surface area, therefore they are suitable for active ingredients. It has a solubility capacity. The surfactants and cosurfactants used have a solubility capacity of 10 in the intestines. By temporarily opening tight intercellular junctions, it contributes to improved bioavailability. This is because surfactants and cosurfactants are non-ionic, providing protection against mucosal irritation. The irritating effect is minimized. In addition, cosurfactants are added to the formulations. By adding it, the amount of surfactant used is reduced. Low Because of its viscosity, it is used in filling, transferring and transporting applications in the pharmaceutical industry. They facilitate the process in different phases. In addition, microemulsions increase the solubility of the active ingredient. By increasing it, it enhances bioavailability. One aim of the invention is to obtain a drug with high bioavailability. This For the purpose of drug delivery systems, solid dosage forms of active substances and It is absorbed faster than emulsions and has a high bioavailability of 20. A microemulsion system was chosen. Another aim of the invention is to improve compliance with nadolol-containing medications. This is particularly relevant for the elderly and children. In patient groups who frequently experience swallowing difficulties, instead of solid drug forms The use of easily swallowed microemulsions improves patient adherence to treatment. This allows it to increase. In addition, by improving nadolol bioavailability, the treatment lasts 25 days. By providing it in low doses, side effects from oral use are minimized. Additionally, the invention aims to create a more accessible drug. Microemulsions exhibit good thermodynamic stability. Their thermodynamic stability... Thanks to this, their production and sterilization are relatively simpler and cheaper. Also, production... It allows for easy scaling up in this phase. For these reasons, nadolol carrier 30 The use of microemulsions as a system increases the accessibility of the drug to be obtained. It increases. 4 Explanation of the Figures Figure 1. Pseudo-triangular phase graph of microemulsion formulation. Figure 2. Percentage release graph in in vitro gastric environment. Figure 3. Percentage release graph in in vitro intestinal environment 5 Figure 4. Percentage survival graph. Figure 5. Estimated human %Fa value determined from in situ perfusion study. Human Peff and rat Peff value graphs Detailed Description of the Invention 10 The invention describes a lipid compound containing the active ingredient nadolol, to be used in the treatment of hypertension. This invention relates to a nano-drug delivery system based on nadolol. In this invention, nadolol is used as a nano-drug carrier. It is loaded into a microemulsion system. Microemulsions are two immiscible phases, such as water and oil, mixed with a surfactant and generally isotropically transparent, formed by stabilization using co-surfactant, 15 They are thermodynamically stable and spontaneously formed dispersion systems. Microemulsions consist of cinnamon oil in the oil phase, distilled water in the water phase, and a surfactant. Tween 20 contains propylene glycol:ethanol as a cosurfactant. Lipid-based nano-formulation for use in the treatment of hypertension; a. oil phase: 10-18% by weight cinnamon oil, water phase: 20% by weight 4-40% distilled water, 1-30% surfactant by weight, by weight A drug in microemulsion form containing 20-65% co-surfactant. carrier system, b. As active ingredient, 0.02-10% by weight (w / w) of the drug delivery system nadolol and / or its salts, which are antihypertensive agents, at a concentration of 25 Microemulsions contain appropriate amounts of the phases used structurally. Because of this, they can be formed with very little energy or spontaneously. The ideal application of the formulation; a. oil phase: 17.22% cinnamon oil by weight, water phase: 5.4% by weight Distilled water, 15.47% by weight of Tween 20 as surfactant, 30% as co-surfactant. 5 A medication in microemulsion form containing 61.91% Capryol 90 by weight. carrier system, b. As active ingredient, 0.02-10% by weight (w / w) of the drug delivery system nadolol and / or its salts, which are antihypertensive agents in proportion to the percentage. It includes. 5 Another ideal application of the formulation is; a. oil phase: 10.65% cinnamon oil by weight, water phase: 33.25% by weight Distilled water, 28.05% by weight of Tween 20 as surfactant, co-surfactant. Containing 28.05% polyethylene glycol (PEG) by weight:ethanol (3:1) a drug delivery system in microemulsion form, 10 b. As active ingredient, 0.02-10% by weight (w / w) of the drug delivery system nadolol and / or its salts, which are antihypertensive agents in proportion to the percentage, It includes a pseudo-triangular phase to find the ideal component ratio of the formulation. Phase diagrams were created. When creating the phase diagram, oil, surfactant and The chlorinated surfactant mixture is titrated with distilled water until it reaches the point of turbidity, and the amount of water it absorbs is 15. The quantities were recorded. The results obtained were recorded and triangular phase diagrams were drawn. It was drawn using the center of gravity of the region that gives the highest emulsion area. Optimal emulsion formulations were calculated and developed. The resulting ideal content, pseudo-triangle phase graph, is given in Figure 1. (The given image shows...) Program 20 for obtaining optimum component ratios in microemulsion experiments. It is a pseudo-triangular phase system drawn with the help of. The components are located on the sides of the triangle. The oil, surfactant-cosurfactant, and water phases are represented. The numbers on the sides of the triangle indicate the phase. The image shows the water ratios. The dark area in the image represents the amount of water the formulation has absorbed. It represents the ratio of the quantity. The white circle in the area indicates the optimum component ratio. It provides. 25 Microemulsions, due to their oil and water phase composition, can be used in both oil and water. It has the ability to carry the dissolved active ingredient simultaneously. Formulations It contains an active ingredient that is resistant to enzymatic hydrolysis, oxidation, and first-pass effects. It protects against various physiological conditions such as food, bile secretion, and pH. They ensure that it is affected less. 30 6 The invention describes a lipid-based nanotechnology product for use in the treatment of hypertension. The formulation's production method includes the following process steps: i. 10-15% fat phase by weight and 56.1% Surfactant + co-surfactant are mixed with a magnetic stirrer and then 30% is added. Addition of 35% water phase. 5 The invention describes a lipid-based nanotechnology product for use in the treatment of hypertension. An application of the formulation's production method involves the following process steps: i. 10.65% fat phase and 50-55% by weight. surfactant + co-surfactant are mixed with a magnetic stirrer, and then... Addition of 33.25% water phase. 10 The microemulsion formulation is below 200 nm, consistent with the literature, and It has shown droplet size with homogeneous distribution. Emulsion formulations Three heating (4±2˚C)-cooling cycles to evaluate their thermodynamic stability. (40±2˚C) and subjected to freezing (-20±2˚C)-thawing (40±2˚C) cycles, then centrifuged. Physical changes in the ideally selected microemulsion formulation are 15. not observed. In the in vitro release study of the formulation, the microemulsion formulation at pH 1.2 yielded 4 results. It showed emissions of over 95% per hour. The graph given in Figure 2 shows the selected microemulsion formulation (encoded as M2-NDL) at pH 1.2 (gastric environment) This is a release graph. The horizontal column represents time, and the vertical column represents the amount of the factor released into the environment over time. It gives the percentage of the substance. At pH 6.8, the bowel emptying time is 8 hours. It showed emissions exceeding 96%. The graph given in Figure 3 shows the selected microemulsion. This is a release graph of the formulation (encoded as M2-NDL) at pH 6.8 (intestinal environment). The horizontal column represents time, and the vertical column represents the percentage of active ingredient released into the environment over time. It gives the ratio. 25 In cytotoxicity studies, the formulations showed over 95% cell viability. This has been shown. When studies in the literature are evaluated, it is accepted that it is not toxic. Figure 4 shows the graph of the selected microemulsion formulation (M2-NDL). (encoded) human colon epidermal adenocarcinoma cell (Caco-2) cell line The effect on cell viability was measured and obtained at the times given in the horizontal column. 30 The obtained values ​​are given as percentages in the vertical column. 7 Cell permeability studies were conducted with the Caco-2 cell line. In the study, both from the apical direction to the basolateral direction (A→B) and from the basolateral direction to the apical direction (B→A) The measurement was accurate. The molecule studied moved in the A→B direction from the intestinal lumen into the system. A→A refers to the passage from blood to the intestinal lumen, mimicking the passage of blood into the circulation. It was designed that the transition in the A→B direction was higher. 5 In situ single-pass intestinal perfusion (SPIP) study of NDL passage in the intestine. The effects of different support systems on it have been evaluated. The study was conducted in Anatolia. Supplied by the University's Experimental Animal Research and Application Unit (Eskişehir). This study was conducted at Anadolu University using Sprague-Dawley rats (File). (Registration no. 21-43, Decision no. 2021-43). The SPIP study was approved by the FDA for in vivo testing in humans on 10... It is a proposed method for estimating oral bioavailability. In the SPIP study, surgical procedures were performed under anesthesia. Anesthesia The combination of ketamine (90 mg / kg) and xylazine (10 mg / kg) is administered intraperitoneally. This was achieved by making an incision in the abdominal wall under anesthesia and exposing the intestines. The ileum was removed and identified. The length of the segment to be perfused is 8.0-15 cm for the ileum. It is set to 10.0 cm. The flow rate will be 0.2 ml / min via the peristaltic pump. It was set up in this way. Samples were taken every 10 minutes for 60 minutes. It was analyzed using HPLC. Golytely solution was used as the perfusion medium in the in situ intestinal perfusion study. The golytely solution used was 25 mmol / L NaCl, 10 mmol / L KCl, and 40 mmol / L 20 oxide. It was formulated with Na2SO4, 20 mmol / L NaHCO3 and 80 mmol / L mannitol. The pH value was... It is adjusted to 7.4. It is used as a model drug to investigate intestinal absorption. Nadolol, a biopharmaceutical, was used to compare intestinal permeability. Metoprolol, belonging to the Classification System (BCS) class I, has high permeability. Tartrate (MTT) and phenol red (PR) were used for water balance determination. 25 samples were examined. The concentration of the active ingredient NDL was selected as 40 mg / ml. Perfused... Studies conducted after the intestinal segments reached equilibrium are described below. This was done in this way. GROUP – 1: NDL was added to the ileum perfusion solution and perfused for 60 minutes. Samples were collected every 10 minutes, and the MTT, PR, and NDL levels in the samples were measured at 30%. The quantity was determined using an enhanced HPLC method. 8 GROUP – 2: NDL-loaded formulation (NDL-loaded M2), added to the perfusion solution. The ileum was perfused for 60 minutes. Samples were collected every 10 minutes and The amounts of PR and NDL in the samples were determined using an enhanced HPLC method. It has been done. GROUP – 3: NDL and empty formulation (Empty M2) are added to the perfusion solution and injected into the ileum, 5 The mixture was perfused for 60 minutes. Samples were collected every 10 minutes and the samples were analyzed. The amounts of PR and NDL within it were determined using an enhanced HPLC method. The graphs representing the data obtained from the study are given in Figure 5. Figure 5 / A Estimated absorption in humans using effective permeability (Peff) determined from rats. This is a graph showing the percentage of active ingredient fraction (Fa). Figure 5 / B shows the results of the experiments: 10 The graph showing the estimated Peff value in humans is given. Experiments are shown in Figure 5 / C. The graph shows the Peff value determined from the rats as a result. The first group was formed to evaluate the permeability of MTT and NDL, and NDL... Its permeability in golytely solution is quite low compared to MTT. It has been observed that in experiments conducted with the second and third groups, 15 loaded with the active substance... The transfer of active ingredients from empty formulations and microemulsions was evaluated. It has been determined that the formulation increases the transfer of the active ingredient. In the formulation Penetration-enhancing excipients such as surfactants target the apical area of ​​enterocytes. by providing structural arrangements in the tight junction connections found on the surface It is thought to improve paracellular transport from the intestines. 20 25

Claims

9 REQUESTS 1. It is a lipid-based nano-formulation for use in the treatment of hypertension. feature; a. oil phase: 10-18% by weight cinnamon oil, water phase: 5% by weight 4-40% distilled water, 1-30% surfactant by weight, by weight A drug in microemulsion form containing 20-65% co-surfactant. carrier system b. As active ingredient, 0.02-10% by weight (w / w) of the drug delivery system nadolol and / or its salts, which are antihypertensive agents, in a certain percentage (10) It includes.

2. A lipid-based nano-derivative for use in the treatment of hypertension, according to Claim 1. Its formulation has the following characteristics: a. oil phase: 17.22% by weight cinnamon oil, water phase: 5.4% by weight 15 Distilled water, 15.47% by weight of Tween 20 as surfactant, co-surfactant. A medication in microemulsion form containing 61.91% Capryol 90 by weight. carrier system, b. As active ingredient, 0.02-10% by weight (w / w) of the drug delivery system nadolol and / or its salts, which are antihypertensive agents, at a rate of 20 It includes.

3. A lipid-based nano-derivative for use in the treatment of hypertension, according to Claim 1. Its formulation has the following characteristics: a. oil phase: 10.65% cinnamon oil by weight, water phase: 33.25% by weight. Distilled water, 28.05% by weight of Tween 20 as surfactant, co-surfactant. Containing 28.05% polyethylene glycol (PEG) by weight:ethanol (3:1) a drug delivery system in microemulsion form, b. As active ingredient, 0.02-10% by weight (w / w) of the drug delivery system nadolol and / or its salts, which are antihypertensive agents, at a concentration of 30 It includes.

4. A lipid-based nano-derivative for use in the treatment of hypertension, according to Claim 1. The formulation is characterized by the surfactant being a polysorbate or one of its derivatives. 10 or PEG sorbitan monolaurate or one of the PEG sorbitan monolaurate derivatives or poloxyethylenesorbitan monolaurate or poloxyethylenesorbitan monolaurate It is one of the derivatives.

5. A lipid-based nano 5 for use in the treatment of hypertension according to Claim 1. The formulation is characterized by the fact that the co-surgent is derived from capyrol 90 or capyrol 90 derivatives. One of them is either propylene glycol or glycerin or ethanol.

6. A medicine containing a formulation according to any of claims 1-5. 10 7. According to claim 6, it is a medicine and its characteristic is that it is in the form of a gel, capsule or syrup.

8. A drug to be used in the treatment of hypertension according to any of claims 1-5. It is a production method for lipid-based nanoformulations, and its characteristic feature is; a. 4% (w / w) nadolol in cinnamon oil at room temperature for 5 minutes to 2 hours 15 minutes. The oil phase is obtained by dissolving the mixture while stirring at a speed of 50-1000 rpm throughout. being done, b. Add Tween 20 to the prepared oil phase and let it sit at room temperature for 5 minutes. Dissolving by stirring at a speed of 50-1000 rpm for 2 minutes to 2 hours, It includes the steps of the process. 20 9. According to Claim 8, a lipid-based nano-derivative is proposed for use in the treatment of hypertension. The formulation's production method and its characteristic feature is that Capryol 90 is used as a co-surgery agent. If used, the cinnamon oil mentioned in step (a) will contain 17.22% by weight. in proportion to 15.47% by weight of Tween 20 mentioned in step (b) 25 It is the fact that.

10. According to Claim 8, a lipid-based nano-derivative is proposed for use in the treatment of hypertension. The formulation's production method and its characteristic feature is that polypropylene is used as a co-surfactant. If glycol:ethanol (3:1) is used, 30 of the cinnamon oil mentioned in step (a) 10.65% by weight of Tween 20 mentioned in step (b) The rate is 28.05%. 11 11. According to Claim 8, a lipid-based nano-derivative is proposed for use in the treatment of hypertension. The formulation's production method and its characteristic feature is that Capryol 90 is used as a co-surgery agent. if used in continuation of step (b) c. Addition of 62.90% by weight of Capryol 90 to the oil phase and room phase, respectively. Mixed at a temperature of 5 minutes to 2 hours at a speed of 50-1000 rpm. dissolution, d. by titration method, adding 5.4% by weight of distilled water drop by drop Add to the mixture obtained above and 50-1000 for 5 minutes to 2 hours. Mixing and homogenization at rpm speed It includes the steps. 10 12. According to Claim 8, a lipid-based nano-derivative is proposed for use in the treatment of hypertension. The formulation's production method and its characteristic feature is that polypropylene is used as a co-surfactant. If a glycol:ethanol (3:1) mixture is used, proceed with step (b) c. Addition of 28.05% by weight of Capryol 90 to the oil phase and room 15 mixed at a speed of 50-1000 rpm for 5 minutes to 2 hours at [temperature not specified] dissolution, d. by titration method, 33.25% by weight of distilled water added drop by drop Add to the mixture obtained above and 50-1000 for 5 minutes to 2 hours. Mixing and homogenization at rpm speed 20 It includes the steps. 25 30

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