Self-emulsifying drug delivery systems (SEDDS) effective in the treatment of hypertension

Abstract

The invention relates to a medicine formed by means of SEDDS from lipid-based nano drug carrier systems containing nadolol as the active substance and intended for use in the treatment of hypertension, and to the production method of this product. By means of the nano formulation in question, a medicine is obtained that has high bioavailability and medicine compliance values and is also more accessible.

Description

[0001] SELF-EMULSIFYING DRUG DELIVERY SYSTEMS (SEDDS) EFFECTIVE IN THE TREATMENT OF HYPERTENSION

[0002] Technical Field of the Invention

[0003] The invention relates to a nano formulation produced by loading the active substance nadolol onto lipid-based nano drug carrier systems by means of self-emulsifying drug delivery systems (SEDDS), and to the production method thereof. The formulation in question is used in the treatment of hypertension.

[0004] State of the Art

[0005] Hypertension, commonly known as high blood pressure, is a medical condition characterised by a high level of force exerted by the blood against the arterial walls. Blood pressure is measured in millimetres of mercury (mmHg) and expressed by two values: systolic pressure (the force during heartbeats) and diastolic pressure (the force between heartbeats). Normal blood pressure is typically around 120 / 80 mmHg. Hypertension arises when these values consistently exceed the normal range and may lead to potentially serious health complications. Long-term high blood pressure burdens the arteries, the heart and other organs, increasing the risk of cardiovascular diseases such as heart attack, stroke and heart failure. Lifestyle factors, genetics and underlying health conditions may contribute to the development of hypertension. Regular blood pressure monitoring and preventive measures play an important role in maintaining cardiovascular health and reducing the impact of hypertension. Hypertension treatment typically involves a multifaceted approach aimed at lowering blood pressure and reducing the risk of associated complications. Lifestyle changes constitute a fundamental component of hypertension management. These may include adopting a healthy diet, engaging in regular physical activity, maintaining a healthy weight and reducing alcohol consumption. Medicines may also be prescribed to effectively control blood pressure. These medicines generally target various mechanisms in the body, such as diuretics to reduce fluid accumulation, beta blockers to reduce heart rate, angiotensin-converting enzyme (ACE) inhibitors to relax blood vessels, and calcium channel blockers to dilate arteries.

[0006] Nadolol, which is frequently used for the treatment of hypertension, is a medicine classified as a beta blocker, a type of drug that affects the heart and the circulation. Nadolol works by blocking the effects of certain natural substances in the body, such as adrenaline, which can increase heart rate and blood pressure. As a non-selective beta blocker, nadolol affects both the beta-1 receptors in the heart and the beta-2 receptors in the blood vessels. Thus, it helps reduce the workload on the heart and contributes to the dilation of blood vessels, thereby lowering blood pressure. Various drug delivery systems have been developed to bring medicines such as nadolol into contact with the patient’s body.

[0007] Drug delivery systems encompass various techniques and formulations designed for the effective administration of therapeutic agents within the body. Numerous examples of drug delivery systems may be given. Oral drug delivery through tablets or capsules is a common method for systemic drug absorption. Injectable routes such as intravenous or intramuscular injections enable rapid and precise drug delivery, which is vital in critical situations. Transdermal systems use patches or topical formulations to release medicines slowly through the skin. Inhalation methods facilitated by inhalers or nebulisers target the respiratory system and are particularly useful in treating respiratory conditions. Implantable devices, including medicine-releasing implants or microchips, provide controlled, continuous drug release over an extended period. Nanoparticle drug delivery increases stability and targeted distribution by using small carriers to encapsulate the medicine. The selection of a specific delivery system depends on factors such as the characteristics of the drug, the target tissue and the desired release kinetics.

[0008] Nadolol is an active substance with low solubility (between 20% and 40%). The low solubility of nadolol causes treatment to continue with higher doses in order to achieve optimum therapeutic effect. In patient groups such as the elderly and children, where swallowing difficulty is frequently encountered, administration in solid dosage form leads to further problems. The high side-effect profile brought about by high doses reduces the patient’s compliance with treatment at the clinical stage and also results in high cost at the production stage. The limitations and inadequacies of the solutions in the current technique, such as the low solubility of nadolol in tablets used, the necessity of continuing treatment with higher doses in order to achieve optimum therapeutic effect, and the difficulty for patients with swallowing problems to use the medicine, have made it necessary to develop an effective nano formulation for the treatment of hypertension.

[0009] Brief Description and the Aims of the Invention

[0010] The invention relates to lipid-based nano drug carrier systems containing the active substance nadolol and intended for use in the treatment of hypertension. In the invention, nadolol is loaded onto self-emulsifying drug delivery systems (SEDDS). The SEDDS forming the subject of the invention contain cinnamon oil as the oil phase, Tween 20 as the surfactant and Transcutol HP:propylene glycol as the co-surfactant. The developed drug carrier system is designed for oral use.

[0011] SEDDS have a high dissolution capacity for active substances due to their high surface area. The surfactants and co-surfactants used contribute to improving bioavailability by temporarily opening the tight junctions between the cells in the intestines. Since the surfactants and co-surfactants are non-ionic, the irritating effect on the mucosa is minimised. In addition, the inclusion of co-surfactants in the formulations enables a reduction in the amount of surfactant used. Due to their low viscosity, they provide convenience in stages such as filling, transfer and transport in the pharmaceutical industry. Furthermore, SEDDS increase the solubility of the active substance and thereby increase bioavailability.

[0012] One aim of the invention is to obtain a medicine with a high bioavailability value. For this purpose, SEDDS systems, which provide faster absorption and higher bioavailability compared to solid dosage forms and emulsions of active substances, have been preferred as the drug carrier system.

[0013] Another aim of the invention is to increase the compliance of medicines containing nadolol. For this purpose, by improving the bioavailability of nadolol, treatment is provided with a lower dose and the side effects in oral use are minimised, thereby increasing medicine compliance. Additionally, the invention aims to obtain a more accessible medicine. SEDDS exhibit physical durability because the formulation does not contain water. They are systems that remain stable for a long period, which provides a long shelf-life. For these reasons, the use of SEDDS as a nadolol carrier system increases the accessibility of the medicine to be obtained.

[0014] Description of the Drawings

[0015] Figure 1. Pseudo ternary phase diagram of the self-emulsifying systems (SEDDS) formulation

[0016] Figure 2. Percentage release graph in in vitro gastric medium

[0017] Figure 3. Percentage release graph in in vitro intestinal medium

[0018] Figure 4. Percentage viability graph

[0019] Figure 5. Graphs showing the estimated human A) %Fa value, estimated human B) Peff, and rat C) Peff values determined from the in situ perfusion study

[0020] Detailed Description of the Invention

[0021] The invention relates to a medicine obtained by adding the active substance nadolol to self-emulsifying systems (SEDDS) from lipid-based nano drug carrier systems, and used for the treatment of hypertension, and to the production method thereof.

[0022] A lipid-based nano formulation to be used for the treatment of hypertension comprises; a. a drug carrier system in the form of a self-emulsifying drug delivery system (SEDDS), containing cinnamon oil at 10-20% by weight as the oil phase, surfactant at 30-80% by weight, and co-surfactant at 4-29% by weight, and b. as the active substance, nadolol and / or its salts, an antihypertensive agent at 0.02-10% (w / w) of the weight of the drug carrier system.

[0023] An ideal application of the formulation comprises; a. a drug carrier system in the form of a self-emulsifying drug delivery system (SEDDS), containing 17.83% by weight cinnamon oil as the oil phase, 73.96% by weight Tween 20 as the surfactant, and 8.22% by weight Transcutol HP:Capryol 90 (1 :1 ) as the co-surfactant, and b. as the active substance, nadolol and / or its salts, an antihypertensive agent at 0.02-10% (w / w) of the weight of the drug carrier system.

[0024] Another ideal application of the formulation comprises; a. a drug carrier system in the form of a self-emulsifying drug delivery system (SEDDS), containing 19.96% by weight cinnamon oil as the oil phase, 72.04% by weight Tween 20 as the surfactant, and 8.00% by weight Transcutol HP:propylene glycol (1 :1 ) as the co-surfactant, and b. as the active substance, nadolol and / or its salts, an antihypertensive agent at 0.02-10% (w / w) of the weight of the drug carrier system.

[0025] To determine the ideal component ratio of the formulation, ternary phase diagrams were created. While preparing the phase diagram, the mixture of oil, surfactant and cosurfactant was titrated with distilled water until the point of turbidity, and the amounts of water taken up were recorded. The results obtained were recorded and ternary phase diagrams were drawn. Suitable regions among the obtained areas were selected. After determining the ideal ratios, the formulation was prepared without containing water.

[0026] The ideal composition obtained is given in the pseudo ternary phase diagram in Figure 1. The visual provided is the pseudo-ternary phase system drawn by means of a software programme for the optimum component ratios obtained in trials of selfemulsifying drug delivery systems. The components located on the edges of the triangle belong to the oil, surfactant-co-surfactant and water phases. The numbers on the edges of the triangle indicate the phase ratios. The dark area in the visual represents the proportion of water taken up by the formulation. The white circle in the area indicates the optimum component ratio.

[0027] SEDDS have the property of carrying both oil-soluble and water-soluble active substances simultaneously due to their oil and water phases. The formulations protect the active substance in their content against enzymatic hydrolysis, oxidation and first- pass effect. Additionally, they ensure that the active substance is less affected by various physiological conditions such as food, bile secretion and pH. A production method of a lipid-based nano formulation intended for use in the treatment of hypertension and forming the subject of the invention comprises the process step of; i. mixing 15-20% by weight oil phase and 80-85% by weight surfactant+co- surfactant using a magnetic stirrer.

[0028] One application of the production method of a lipid-based nano formulation intended for use in the treatment of hypertension and forming the subject of the invention comprises the process step of; i. mixing 19.9% by weight oil phase and 80.1 % by weight surfactant+co-surfactant using a magnetic stirrer.

[0029] The SEDDS formulation has shown a droplet size below 200 nm and a homogeneous distribution, in accordance with the literature. To evaluate the thermodynamic stability of the emulsion formulations, they were subjected to three heating (4±2°C)-cooling (40±2°C) cycles and freezing (-20±2°C)-thawing (40±2°C) cycles and centrifuged. No physical change was observed in the SEDDS formulation selected as ideal.

[0030] In the in vitro release study of the formulation, the SEDDS formulation exhibited over 95% release within 4 hours at pH 1 .2. The graph given in Figure 2 is the release profile at pH 1.2 (gastric medium) of the selected SEDDS formulation (coded as S2-NDL). The horizontal axis gives the time and the vertical axis gives the percentage of active substance released into the medium over time. At pH 6.8, it exhibited over 96% release within 8 hours, which is the intestinal transit time. The graph given in Figure 3 is the release profile at pH 6.8 (intestinal medium) of the selected SEDDS formulation (coded as S2-NDL). The horizontal axis gives the time and the vertical axis gives the percentage of active substance released into the medium over time.

[0031] In cytotoxicity studies, the formulations exhibited over 95% cell viability. Considering the studies in the literature, they were accepted as non-toxic. In Figure 4, the graph shows the effect of the selected SEDDS formulation (coded as S2-NDL) on the cell viability of the human colon epidermal adenocarcinoma cell line (Caco-2). The values measured at the times given on the horizontal axis were presented as percentages on the vertical axis. Cell permeability studies were carried out using the Caco-2 cell line. In the study, three carrier systems were compared with each other. Measurements were made both from the apical direction to the basolateral direction (A^B) and from the basolateral direction to the apical direction (B^A). The A— >B direction was designed to mimic the passage of the studied molecule from the intestinal lumen to the systemic circulation, while the B^A direction was designed to mimic the passage from the blood to the intestinal lumen. It was observed that the passage in the A— >B direction was higher.

[0032] By means of the in situ single-pass intestinal perfusion (SPIP) study (Figure 5), the effects of different carrier systems on the passage of NDL in the intestine were evaluated. The study was conducted at Anadolu University using Sprague-Dawley rats obtained from the Experimental Animals Research and Application Unit of Anadolu University (Eski§ehir) (File registration no. 21 -43, Decision no. 2021 -43). The SPIP study is a method recommended by the FDA for estimating in vivo oral bioavailability in humans.

[0033] In the SPIP study, surgical procedures were performed under anaesthesia. Anaesthesia was provided by intraperitoneal administration of a ketamine (90 mg / kg)- xylazine (10 mg / kg) combination. Under anaesthesia, the abdominal wall was incised, the intestines were exposed and the ileum was identified. The length of the segment to be perfused was adjusted to 8.0-10.0 cm for the ileum. The flow rate was adjusted to 0.2 ml / min using a peristaltic pump. Samples were taken every 10 minutes for 60 minutes and analysed by HPLC.

[0034] In the in situ intestinal perfusion study, golytely solution was used as the perfusion medium. The golytely solution used was prepared with 25 mmol / L NaCI, 10 mmol / L KCI, 40 mmol / L Na2SO4, 20 mmol / L NaHCO3 and 80 mmol / L mannitol. The pH value was adjusted to 7.4. Nadolol was used as the model drug to investigate intestinal absorption, metoprolol tartrate (MTT), a high-permeability substance belonging to class I of the biopharmaceutics classification system (BCS), was used for comparison of intestinal permeability, and phenol red (PR) was used for water balance determination. The concentration of the active substance NDL examined was selected as 40 mg / ml. After the perfused intestinal segments reached equilibrium, the studies were carried out as described below. GROUP - 1 : The ileum perfused with NDL added to the perfusion solution for 60 minutes. Samples were collected every 10 minutes and the amounts of MTT, PR and NDL in the samples were determined by a developed HPLC method.

[0035] GROUP - 2: The ileum perfused for 60 minutes with NDL-loaded formulation (NDL- loaded S2) added to the perfusion solution. Samples were collected every 10 minutes and the amounts of PR and NDL in the samples were determined by a developed HPLC method.

[0036] GROUP - 3: The ileum perfused for 60 minutes with NDL and empty formulation (Empty S2) added to the perfusion solution. Samples were collected every 10 minutes and the amounts of PR and NDL in the samples were determined by a developed HPLC method.

[0037] The graphs of the data obtained from the study are given in Figure 5. Figure 5 / A is the graph showing the estimated percentage fraction absorbed (Fa) in humans using the effective permeability (Peff) determined from rats. Figure 5 / B shows the graph of the estimated Peff value in humans obtained from the experiments. Figure 5 / C shows the graph of the Peff value determined from rats obtained from the experiments.

[0038] With the first group conducted to evaluate the permeability of MTT and NDL, it was observed that the permeability of NDL in the golytely solution was considerably lower compared to MTT. In the experiments conducted with the second and third groups, the passage of active substance from the active-substance-loaded and empty formulations was evaluated. It was determined that the SEDDS formulation increased the passage of the active substance. It was considered that penetration-enhancing excipients in the formulation, such as surface-active agents, provide structural rearrangements at the tight junctions on the apical surface of enterocytes, thereby improving paracellular transport from the intestines.

Claims

CLAIMS1. A lipid-based nano formulation for use in the treatment of hypertension, comprising; a. a drug carrier system in the form of a self-emulsifying drug delivery system (SEDDS) containing, as the oil phase, 10-20% by weight cinnamon oil, 30- 80% by weight surfactant, and 4-29% by weight co-surfactant, and b. as the active substance, nadolol and / or salts thereof, an antihypertensive agent at 0.02-10% (w / w) of the weight of the drug carrier system.

2. The lipid-based nano formulation for use in the treatment of hypertension according to Claim 1 , comprising; a. a drug carrier system in the form of a self-emulsifying drug delivery system (SEDDS) containing, as the oil phase, 17.83% by weight cinnamon oil, 73.96% by weight Tween 20 as the surfactant, and 8.22% by weight Transcutol HP:Capryol 90 (1 :1 ) as the co-surfactant, and b. as the active substance, nadolol and / or salts thereof, an antihypertensive agent at 0.02-10% (w / w) of the weight of the drug carrier system.

3. The lipid-based nano formulation for use in the treatment of hypertension according to Claim 1 , comprising; a. a drug carrier system in the form of a self-emulsifying drug delivery system (SEDDS) containing, as the oil phase, 19.96% by weight cinnamon oil, 72.04% by weight Tween 20 as the surfactant, and 8.00% by weight Transcutol HP:propylene glycol (1 :1 ) as the co-surfactant, and b. as the active substance, nadolol and / or salts thereof, an antihypertensive agent at 0.02-10% (w / w) of the weight of the drug carrier system.

4. The lipid-based nano formulation for use in the treatment of hypertension according to Claim 1 , wherein the surfactant is one of polysorbate or a polysorbate derivative, PEG sorbitan monolaurate or a PEG sorbitan monolaurate derivative, or polyoxyethylene sorbitan monolaurate or a polyoxyethylene sorbitan monolaurate derivative.

5. The lipid-based nano formulation for use in the treatment of hypertension according to Claim 1 , wherein the co-surfactant is one of Capryol 90 or a Capryol 90derivative, Transcutol or a Transcutol derivative, propylene glycol, glycerine or ethanol.

6. A medicine comprising a formulation according to any one of Claims 1 -5.

7. The medicine according to Claim 6, wherein it is in the form of a gel, capsule or syrup.

8. A production method of a lipid-based nano formulation for use in the treatment of hypertension according to any one of Claims 1-5, comprising the process steps of; a. obtaining the oil phase by dissolving 4% (w / w) nadolol in cinnamon oil by mixing at 50-1000 rpm for 5 minutes to 2 hours at room temperature, and b. adding Tween 20 to the prepared oil phase and dissolving it by mixing at 50- 1000 rpm for 5 minutes to 2 hours at room temperature.

9. The production method of a lipid-based nano formulation for use in the treatment of hypertension according to Claim 8, wherein in case Transcutol HP:Capryol 90 (1 :1 ) is used as the co-surfactant, the cinnamon oil referred to in step (a) is 17.83% by weight and the Tween 20 referred to in step (b) is 73.96% by weight.

10. The production method of a lipid-based nano formulation for use in the treatment of hypertension according to Claim 8, wherein in case Transcutol HP:propylene glycol (1 :1 ) is used as the co-surfactant, the cinnamon oil referred to in step (a) is 19.96% by weight and the Tween 20 referred to in step (b) is 72.04% by weight.

11. The production method of a lipid-based nano formulation for use in the treatment of hypertension according to Claim 8, wherein in case Transcutol HP:Capryol 90 (1 :1 ) is used as the co-surfactant, step (b) is followed by; c. adding Transcutol HP:Capryol 90 at 8.22% by weight to the oil phase, respectively, and dissolving it by mixing at 50-1000 rpm for 5 minutes to 2 hours at room temperature.

12. The production method of a lipid-based nano formulation for use in the treatment of hypertension according to Claim 8, wherein in case Transcutol HP:polypropylene glycol (1 :1 ) is used as the co-surfactant, step (b) is followed by;d. adding Transcutol HP:Capryol 90 at 8.00% by weight to the oil phase, respectively, and dissolving it by mixing at 50-1000 rpm for 5 minutes to 2 hours at room temperature.

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