Oral solution containing opicapone clathrate compound and preparation method of oral solution

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an oral solution containing an opinapone clathrate compound and a preparation method of the oral solution, and the composition comprises water, opinapone, propylene glycol, hydroxypropyl-beta-cyclodextrin, sodium hydroxide and a preservative. Researches show that propylene glycol has an obvious solubilizing effect on olpiapone, so that the solubility of the medicine in a phosphate buffer solution and a hydroxypropyl-beta-cyclodextrin solution is increased, and meanwhile, sodium hydroxide has a synergistic solubilizing effect on propylene glycol. According to the composition disclosed by the invention, the solubility of the olpiapone can be remarkably improved, the consistency of the medicine content is ensured, and the solubility and the bioavailability are improved; the administration dosage can be flexibly adjusted, and different medication requirements can be met without purchasing products of various specifications; the medicine experience feeling is good, and the patient adaptability is improved; used production equipment is simple, and industrial production is easy.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to an oral solution containing an opicapone inclusion compound and a preparation method thereof. Background Art

[0002] Opicapone (OPC) is a new molecular entity (NME) in the class of potent and long-acting catechol-O-methyltransferase (COMT) inhibitor drugs that is biologically active, bioavailable and exhibits low toxicity. 15 H 10 Cl 2 N 4 O 6 , molecular weight: 414.17, chemical name: 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, its structural formula is:

[0003]

[0004] Parkinson's disease (PD) is a common chronic neurodegenerative disease, and its incidence rate increases with age. As the disease progresses, the motor and non-motor symptoms of Parkinson's disease will gradually worsen, which will not only hinder the patient's daily activities, but also bring huge social and medical burdens.

[0005] Drug treatment is usually the first choice for Parkinson's disease. Generally, compound levodopa treatment is the first choice. As symptoms worsen and the efficacy decreases, dopamine receptor agonists (DAs), monoamine oxidase type B inhibitors (MAO-BI) or catechol-O-methyltransferase inhibitors can be added. When levodopa is taken together with dopa decarboxylase inhibitors, COMT will become the main peripheral metabolic enzyme of levodopa, catalyzing its conversion to 3-O-methyldopa. In clinical treatment, OPC can increase the overall exposure of levodopa and reduce the exposure of 3-OMD by inhibiting COMT in peripheral tissues.

[0006] Opicapone was approved for marketing in the United States in April 2020 and in Japan in June 2020, respectively, for the adjuvant treatment of patients with Parkinson's disease and end-of-dose motor fluctuations with levodopa / dopa decarboxylase inhibitors, which can significantly shorten the "OFF" time and increase the "ON" time without bothersome dyskinesias. According to the Japanese IF file of opicapone tablets, opicapone is insoluble in water, soluble in dimethyl sulfone and N-methylpyrrolidone, and is pH-dependent and sensitive to light. Patent CN116133648A discloses a specific method for preparing opicapone solid dispersions, which significantly improves the solubility and oral bioavailability of the active drug. However, the solid dispersion itself has poor physical stability and is prone to aging.

[0007] Mental disorders are special and patients generally have poor compliance. In order to achieve the purpose of treatment, different formulations are often used. The existing formulations of opicapone in the market are solid formulations - tablets and capsules. They usually need to be granulated before other operations during the preparation process. The process is complicated and the particle size of the raw materials is strictly controlled. At the same time, considering that most patients are middle-aged and elderly, and PD is a brain degenerative disease associated with motor symptoms (movements and other complications), a liquid preparation - oral solution is developed, which is not only convenient for patients to take, but also convenient for adjusting the dosage. Summary of the invention

[0008] In order to overcome the above-mentioned deficiencies of the prior art, the present invention aims to provide a stable oral solution containing opicapone inclusion complex and a preparation method thereof.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is:

[0010] The invention provides an oral pharmaceutical composition containing an opicapone inclusion compound. The composition comprises water, opicapone, a co-solvent, a complexing agent, a pH regulator for maintaining the pH at 6-8, and a preservative.

[0011] The conventional recommended dose of opicapone in existing dosage forms is 50 mg / day / time, and the recommended dose for patients with moderate hepatic insufficiency is 25 mg / day / time. Generally speaking, 25 mg / day is the minimum dose required to reach plasma levels. According to an embodiment of the present invention, the amount of opicapone, an active ingredient of the oral preparation, is selected from 1% to 10% (w / v) by weight based on the total volume of the solution, preferably 5.0% (w / v).

[0012] According to an embodiment of the present invention, in order to increase the dissolution rate of poorly soluble opicapone during the preparation process, a co-solvent is used in the oral preparation of the present invention. The inventors studied and screened co-solvents with good solubility for opicapone, preferably ethanol, propylene glycol or glycerol, and more preferably propylene glycol. Studies have shown that when the amount of the co-solvent is selected from 1% (v / v) to 20% (v / v), the dissolution rate of the active drug can be increased, preferably 10% (v / v).

[0013] According to an embodiment of the present invention, the complexing agent is selected from carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin and (2-carboxymethoxy)propyl-β-cyclodextrin, preferably hydroxypropyl-β-cyclodextrin. The molar ratio of active drug opicapone to hydroxypropyl-β-cyclodextrin is preferably 1:4 to 2:1, preferably 1:2.

[0014] According to an embodiment of the present invention, the preservative is selected from at least one of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium benzoate and sorbic acid, preferably sodium benzoate.

[0015] According to an embodiment of the present invention, the above-mentioned ingredients will produce a strong-tasting medicine after being mixed with each other. In addition to the sour taste caused by the low pH value, there is also a bitter taste derived from the active ingredient, which may also come from the co-solvent (such as propylene glycol). Therefore, the composition also includes a sweetener and a flavor. The sweetener is selected from saccharin sodium, aspartame, acetylglucoside potassium, alose, sorbitol, mannitol, fructose, xylitol, caramel, preferably saccharin sodium. The flavor is selected from at least one of orange flavor, pineapple flavor, cherry flavor, and grape flavor, that is, a mixture of one or more, preferably cherry flavor.

[0016] According to an embodiment of the present invention, the pH adjusting agent is selected from at least one of hydrochloric acid, citric acid, and sodium hydroxide, i.e., a mixture of one or more thereof, preferably sodium hydroxide and hydrochloric acid, and the pH value of the pharmaceutical composition system is adjusted to 6-8, preferably 7.

[0017] According to an embodiment of the present invention, the composition disclosed in the present invention is preferably selected from: (a) 5.0% (w / v) opicapone; (b) 0.02% (w / v) sodium benzoate; (c) a molar ratio of opicapone to hydroxypropyl-β-cyclodextrin of 1:2; (d) 10% (v / v) propylene glycol; (e) 0.2% (w / v) 0.1M sodium hydroxide to adjust the pH to 7.0; (f) 0.06% (w / v) saccharin sodium, 0.02% (w / v) cherry flavor and (g) water to 100%.

[0018] The present invention also provides a method for preparing a pharmaceutical composition of an opicapone inclusion compound, comprising: (a) weighing a prescribed amount of opicapone, adding it to a co-solvent, stirring and dispersing it uniformly, to obtain a drug solution; (b) adding the drug solution to a complexing agent solution, stirring and dispersing it uniformly, to obtain a mixed solution; (c) mixing a sweetener, a preservative and an appropriate amount of purified water, stirring and dispersing them uniformly, to obtain a mixed solution; (d) mixing the mixed solution in (b) and the mixed solution in (c) and stirring them uniformly, adjusting the pH to 7-8 with a pH regulator, and then boiling and keeping them warm; (e) adding essence to the kept warm drug solution, stirring and dispersing it uniformly, adding purified water to the scale, and filtering to obtain the drug solution.

[0019] The oral administration solution of opicapone containing hydroxypropyl-β-cyclodextrin disclosed in the present invention has the following beneficial effects compared with the prior art:

[0020] 1) The composition disclosed in the present invention significantly increases the solubility of opicapone, can ensure the consistency of drug content, and improves solubility and bioavailability;

[0021] 2) The dosage of the composition disclosed in the present invention can be flexibly adjusted, and different medication needs can be met without the need to purchase products of multiple specifications;

[0022] 3) The oral solution composition disclosed in the present invention has a good user experience and improves patient adaptability;

[0023] 4) The composition disclosed in the present invention has simple production equipment and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The blood drug concentration curves of Opicapone oral solution and Opicapone capsule of prescription 6 of the present invention. DETAILED DESCRIPTION

[0025] Experimental materials: opicapone raw material (Bial - Portela&Ca, SA), opicapone reference substance (SincoPharmachem, 98%), opicapone capsules (25 mg, ONGENTYSBial-Portela&Ca, SA), propylene glycol, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin, glycerol, ethanol, hydrochloric acid, and sodium hydroxide.

[0026] Experimental equipment: electronic balance (Mettler-Toledo International Trading (Shanghai) Co., Ltd.), heat collecting magnetic stirrer (DF-101S, Gongyi Yuhua Instrument Co., Ltd.), pH meter (S210, METTLER TOLEDO), water bath constant temperature oscillator (SHA-B, Jinan Hepu Instrument Equipment Co., Ltd.), high-speed refrigerated centrifuge (Multifuge X1R, Thermo Fisher Scientific, USA), nitrogen blowdown concentrator (MTN-2800D, Tianjin Aotesense Instrument Co., Ltd.).

[0027] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0028] Example 1 Saturated solubility of opicapone in different media

[0029] Phosphate buffer: Take 38.0g of sodium dihydrogen phosphate and 5.04g of disodium hydrogen phosphate, add 1000mL of water, and adjust the pH to 1.0, 3.0, 5.0, 7.0 and 8.0 with 1.0mol / L sodium hydroxide or dilute hydrochloric acid.

[0030] Hydroxypropyl-β-cyclodextrin solution: Weigh 70 g of hydroxypropyl-β-cyclodextrin (MS 0.45), slowly add it into 930 mL of pH 7.0 phosphate buffer in a stirring state, and stir for 60 minutes to obtain the solution.

[0031] A sufficient amount of opicapone raw material (5 g) and 25 mL of buffer solution were placed in a 50 mL conical flask, shaken at 25 °C for 24 h, centrifuged (4000 rpm, 15 min), and the supernatant was taken to determine the drug content by spectrophotometry (detection wavelength 273 nm).

[0032] The experimental results are as follows:

[0033] Table 1 Saturated solubility of opicapone in different media

[0034]

[0035] From the above experimental data, it can be seen that opicapone is a pH-dependent drug, and its solubility is positively correlated with the pH value of the solution. When the pH is 1-5, opicapone is slightly soluble in water; when the pH is 7-8, the solubility of opicapone increases significantly. And the solubility of opicapone in hydroxypropyl-β-cyclodextrin solution is significantly higher than that in phosphate buffer at pH 7.0.

[0036] Example 2 Solubility and stability of opicapone in pH 7.0 solution

[0037] Opicapone solution 1: Add 5.0 g of Opicapone into 200 mL of propylene glycol and stir until homogeneous.

[0038] Opicapone solution 2: Add 5.0 g of Opicapone to 200 mL of propylene glycol alkalized with sodium hydroxide and stir until homogeneous.

[0039] Solution A: Add 100 mL of opicapone solution to 900 mL of pH 7.0 phosphate buffer, stir at 25°C for 60 min, centrifuge (4000 rpm, 15 min), take the supernatant, and determine the drug content by spectrophotometry.

[0040] Solution B: Add 100 mL of opicapone solution II to 900 mL of pH 7.0 phosphate buffer, stir at 25°C for 60 min, centrifuge (4000 rpm, 15 min), take the supernatant, and determine the drug content by spectrophotometry.

[0041] Solution C: Add 100 mL of opicapone solution to 900 mL of hydroxypropyl-β-cyclodextrin solution, stir at 25°C for 60 min, centrifuge (4000 rpm, 15 min), take the supernatant, and determine the drug content by spectrophotometry.

[0042] Solution D: Add 100 mL of opicapone solution II to 900 mL of hydroxypropyl-β-cyclodextrin solution, stir at 25°C for 60 min, centrifuge (4000 rpm, 15 min), take the supernatant, and determine the drug content by spectrophotometry.

[0043] The filtered solution was poured into a polypropylene bottle and stored at 25°C. Samples were taken at the end of 0, 2, 4, 6 and 8 weeks to determine the drug content using a high performance liquid chromatograph.

[0044] The experimental results are as follows:

[0045] Table 2 Solubility of opicapone in pH 7.0 solution

[0046]

[0047] Table 3 Stability of opicapone in solution

[0048]

[0049] As shown in Table 2, propylene glycol has a significant solubilizing effect on opicapone, increasing the solubility of the drug in phosphate buffer and hydroxypropyl-β-cyclodextrin solution, and sodium hydroxide has a synergistic effect on the solubilization of propylene glycol. As shown in Table 3, the content of opicapone in solutions A and B gradually decreases with the increase of staking time. After 8 weeks of staking, the content decreased by 26.9% and 10.3%, respectively; while the opicapone in solutions C and D is relatively stable. After 8 weeks of placement, the content of opicapone in solution C decreased by 3.5%, and the content in solution D did not change significantly. This is mainly because in solutions C and D, opicapone forms a stable inclusion complex with hydroxypropyl-β-cyclodextrin in the solution, and at the same time, the sodium hydroxide in the solution inhibits the degradation of opicapone, thereby improving the stability of the drug.

[0050] Example 3 Prescription Study

[0051] Prescription 1-4

[0052] Prescriptions 1-4 respectively provide an opicapone oral solution, the formula of which is as follows:

[0053]

[0054] The steps for preparing the opicapone oral solution in prescription 1-4 are as follows:

[0055] Adding opicapone to propylene glycol alkalized with sodium hydroxide, stirring until homogeneous, to obtain drug solution 1;

[0056] Dissolve the prescribed amount of hydroxypropyl-β-cyclodextrin (hydroxypropyl cellulose or α-cyclodextrin or β-cyclodextrin) in 600 mL of purified water at 40° C., and stir at 500 rpm for 60 min to obtain a mixed solution 1;

[0057] Mix saccharin sodium, sodium benzoate and 200 mL of purified water and stir evenly to obtain a mixed solution 2;

[0058] Slowly add the drug solution into the mixed solution 1, stir at 300 rpm for 30 min, and obtain the mixed solution 3;

[0059] Mix the mixture 2 and the mixture 3, stir evenly, adjust the pH to 7.0 with 0.1M sodium hydroxide, and boil and keep warm for 30 minutes;

[0060] Add cherry essence to the warm liquid and stir evenly, then add purified water to the full amount, stir evenly, and filter;

[0061] The filtrate is taken for testing, and the test indicators include properties, pH, and content. After passing the test, it is filled to obtain the opicapone oral solution.

[0062] Prescription 5-8

[0063] Prescriptions 5-8 each provide an opicapone oral solution, the formula of which is as follows:

[0064]

[0065] The preparation method of opicapone oral solution in prescription 5-8 is the same as that of prescription 1-4, and finally opicapone oral solution is prepared.

[0066] Prescription 9-11

[0067] Prescriptions 9-11 each provide an opicapone oral solution, the formula of which is as follows:

[0068]

[0069] The preparation method of opicapone oral solution in prescription 9-11 is the same as that in prescription 1-4, and finally opicapone oral solution is prepared.

[0070] Prescription 12-15

[0071] Prescriptions 12-15 each provide an opicapone oral solution, the formula of which is as follows:

[0072]

[0073] The preparation method of opicapone oral solution in prescription 12-15 is the same as that of prescription 1-4, and finally opicapone oral solution is prepared.

[0074] Prescription 16

[0075] Prescription 16 provides an opicapone oral solution, the formulation of which is consistent with Prescription 6, and is prepared according to the following steps:

[0076] Adding opicapone to propylene glycol alkalized with sodium hydroxide, stirring until homogeneous, to obtain drug solution 1;

[0077] Dissolve the prescribed amount of hydroxypropyl-β-cyclodextrin in 600 mL of purified water at 40°C, and stir at 500 rpm for 60 min to obtain a mixed solution 1;

[0078] Mix and dissolve saccharin sodium and sodium benzoate with 200 mL of purified water, stir evenly, and obtain a mixed solution 2;

[0079] The drug solution was slowly added into the mixed solution 1, and ultrasonic treatment was performed for 30 min to obtain the mixed solution 3;

[0080] Mix the mixture 2 and the mixture 3, stir evenly, adjust the pH to 7.0 with 0.1M sodium hydroxide, and boil and keep warm for 30 minutes;

[0081] Add cherry essence to the warm liquid and stir evenly, then add purified water to the full amount, stir evenly, and filter;

[0082] The filtrate is taken for testing, and the test indicators include properties, pH, and content. After passing the test, it is filled to obtain the opicapone oral solution.

[0083] Prescription 17

[0084] Prescription 17 provides an opicapone oral solution, the formulation of which is consistent with Prescription 6, and is prepared according to the following steps:

[0085] Adding opicapone to propylene glycol alkalized with sodium hydroxide, stirring until homogeneous, to obtain drug solution 1;

[0086] Dissolve the prescribed amount of hydroxypropyl-β-cyclodextrin in 600 mL of purified water at 40°C, and stir at 500 rpm for 60 min to obtain a mixed solution 1;

[0087] The drug solution was slowly added to the mixed solution 1, and stirred at 300 rpm for 30 min to obtain a mixed solution 3, and the pH was adjusted to 7.0 with 0.1 M sodium hydroxide to obtain a mixed solution 2;

[0088] Add sodium saccharin, sodium benzoate and cherry essence to the second mixture, stir evenly, boil and keep warm for 30 minutes, add purified water to the full amount, stir evenly and filter;

[0089] The filtrate is taken for testing, and the test indicators include properties, pH, and content. After passing the test, it is filled to obtain the opicapone oral solution.

[0090] Prescription 18

[0091] Prescription 18 provides an opicapone oral solution, the formulation of which is consistent with Prescription 6, and is prepared according to the following steps:

[0092] Add opicapone to warm propylene glycol and stir evenly to obtain a drug solution;

[0093] Dissolve the prescribed amount of hydroxypropyl-β-cyclodextrin in 600 mL of purified water at 40°C, and stir at 500 rpm for 60 min to obtain a mixed solution 1;

[0094] Mix saccharin sodium, sodium benzoate and 200 mL of purified water and stir evenly to obtain a mixed solution 2;

[0095] Slowly add the drug solution into the mixed solution 1, stir at 300 rpm for 30 min, and obtain the mixed solution 3;

[0096] Mix the mixture 2 and the mixture 3, stir evenly, adjust the pH to 7.0 with 0.1M sodium hydroxide, and boil and keep warm for 30 minutes;

[0097] Add cherry essence to the warm liquid and stir evenly, then add purified water to the full amount, stir evenly, and filter;

[0098] The filtrate is taken for testing, and the test indicators include properties, pH, and content. After passing the test, it is filled to obtain the opicapone oral solution.

[0099] Example 4 Product property detection

[0100] Table 4 Product property test

[0101]

[0102] The results showed that the samples of prescriptions 1, 4 and 8 were viscous, mainly due to excessive dosage of chelating agents (hydroxypropyl-β-cyclodextrin, hydroxypropyl cellulose); the samples of prescriptions 2, 3, 5 and 7 were turbid, mainly due to incomplete packaging of the chelating agents; the samples of prescriptions 10, 12, 15 and 16 were turbid and the content was less than 90%, mainly due to incomplete dissolution or precipitation of the drugs in the solution; a distinct ethanol smell could be smelled in prescription 9; the samples of prescriptions 6, 11, 13, 14, 17 and 18 were slightly yellow clear liquids and the content was qualified, indicating that the sample quality preliminarily met the requirements.

[0103] Example 5 Oral Evaluation of Opicapone Oral Solution

[0104] 80 people were invited to evaluate the taste of prescriptions 6, 11, 13, 14, 17 and 18, and the rating levels were as follows: A: good taste, no bitterness; B: average taste, slight bitterness; C: poor taste, obvious bitterness.

[0105] Table 5 Oral evaluation of opicapone oral solution

[0106]

[0107] The results showed that the oral liquids of prescriptions 6, 11 and 18 had a good taste and were well received by the public; the oral liquid of prescription 13 had a noticeable bitter taste in some people, and the taste of prescriptions 14 and 17 was average, indicating that the pH of the prescription and the order of adding excipients had a great influence on the taste of the preparation. In a comprehensive comparison, the taste of the samples of prescriptions 6, 11 and 18 met the requirements.

[0108] Example 6 The following test was performed to test the opicapone oral solution in prescriptions 6, 11 and 18.

[0109] 1. Accelerated test

[0110] Take the opicapone oral solution in prescriptions 6, 11 and 18, place it in a constant temperature and humidity chamber at a temperature of 40℃±2℃ and a humidity of RH75%±5%, and take samples at the end of 1 month, 3 months and 6 months respectively to test its properties, pH, content and related substances.

[0111] Content determination: The content of opicapone was detected by HPLC coupled with a UV / Vis detector (Waters series, USA). A C18 column was used, the mobile phase was 0.1% phosphoric acid: acetonitrile = 68:32 (v / v), the injection volume was 20u1, and the flow rate was 1.0mL / min. The sample was accurately measured and diluted to 100μg / mL with the mobile phase as the test solution; an appropriate amount of opicapone reference substance was accurately weighed, dissolved in a small amount of acetonitrile, and then diluted to 0.1mg / mL with the mobile phase as the reference solution.

[0112] Determination of related substances: According to the high performance liquid chromatography method, octadecylsilane bonded silica gel is used as the filler and potassium dihydrogen phosphate aqueous solution-acetonitrile is used as the mobile phase for determination. Accurately measure the sample in an appropriate amount and dilute it with the mobile phase to 5 mg / mL as the test solution; accurately measure the test solution into a 50mL volumetric flask and dilute it with the mobile phase to make up the volume as the self-control. The injection volume is 20uL, the flow rate is 1.0mL / min, and the total amount of related impurities shall not exceed 3.0%.

[0113] Table 6 Accelerated test data of Opicapone oral solution

[0114]

[0115] The results showed that the relevant impurities of prescription 11 opicapone oral solution increased significantly with the increase of the sampling time under the conditions of temperature 40℃±2℃ and humidity RH75%±5%. When accelerated for 6 months, the relevant impurities (total impurities) were 3.51%, exceeding the limit. For prescription 18 opicapone oral solution, the pH, properties, content and relevant impurities of the sample changed significantly with the increase of the sampling time. When accelerated for 6 months, the sample was slightly yellow and turbid as a whole, with a content of 90.60%, a pH of 7.6, and relevant impurities (total impurities) of 6.48%. The properties, pH value, content and related substances (total impurities) of prescription 6 opicapone oral solution were not significantly changed after being placed under accelerated conditions for 6 months, indicating that its properties are stable and its quality is reliable.

[0116] 2. Pharmacokinetics of Opicapone Oral Solution

[0117] The pharmacokinetics of opicapone oral solution were evaluated in 12 male Sprague-Dawley rats at a dose of 3 mg / kg opicapone administered orally with Formulation 6 oral solution or opicapone capsules (25 mg, ONGENTYS, Bial-Portela&Ca, SA);

[0118] Opicapone capsules were dosed appropriately according to the rats' body weight, the granules were poured out, and a 10 mg / g suspension was prepared with purified water for later use;

[0119] During the experiment, blood was collected from the orbit at different time points, added to a centrifuge tube containing heparin, and centrifuged at 1500 rpm for 10 min using a low-temperature centrifuge. The serum was collected for processing and then tested for content;

[0120] Serum sample pretreatment: 200 μl of plasma was vortexed with 800 μl of acetonitrile for 2 min, and then centrifuged in a low-temperature high-speed centrifuge at 16,000 rpm for 10 min. The supernatant was concentrated by nitrogen blowing, and the residue was redissolved with 200 μl of mobile phase (0.1% phosphoric acid: acetonitrile = 68:32), and the supernatant was taken for content detection.

[0121] 3. Calculation of Pharmacokinetic Parameters

[0122] Calculate the blood drug concentration at each time point and draw the blood drug concentration-time curve. The DAS pharmacokinetic software automatically fits the data and calculates the relevant pharmacokinetic parameters, see Table 7, and the blood drug concentration-time curve is shown in the attached Figure 1 .

[0123] Table 7 Pharmacokinetic parameters (N=6)

[0124]

[0125] The blood concentration of Opicapone capsule ONGENTYS and oral solution was determined by a single-cycle single-dose administration regimen, and its pharmacokinetic characteristics in rats were investigated. The results showed that the peak time of the oral solution was advanced, and the area under the peak concentration-drug-time curve increased. On the one hand, because the solubility of the inclusion complex increased, Opicapone was promoted to pass through the mucus layer and the immobile water layer, increasing its contact surface with the cell membrane; on the other hand, the oil-water partition coefficient of the inclusion complex increased. It is speculated that in order to maintain the coexistence balance of the inclusion complex and the non-inclusion complex, hydroxypropyl-β-cyclodextrin plays a transfer role at the interface of the water-biological phase, which will increase the amount of Opicapone passing through the biological membrane, thereby increasing the blood concentration.

[0126] This indicates that when taking opicapone oral solution, the dosage can be reduced while also achieving rapid onset of action. This will ensure that the bioavailability of opicapone is maximized and the dosage can be minimized, which can not only reduce side effects but also has significant advantages in terms of cost.

[0127] In summary, the Opicapone oral solution of the present invention has a good taste, a quick onset of action compared to other dosage forms, and meets the patient's dosage requirements. The preparation method of Opicapone oral solution uses simple equipment, has good product stability, and is easy to mass-produce.

Claims

1. A pharmaceutical composition containing an opicapone inclusion compound, characterized in that: The composition comprises water, opicapone, a co-solvent, a complexing agent, a pH regulator for maintaining the pH at 6-8, and a preservative.

2. A pharmaceutical composition containing an opicapone inclusion compound according to claim 1, characterized in that: The amount of opicapone is 5% (w / v) by weight based on the total volume of the solution.

3. A pharmaceutical composition containing an opicapone inclusion compound according to claim 1, characterized in that: The co-solvent is selected from ethanol, propylene glycol or glycerol.

4. A pharmaceutical composition containing an opicapone inclusion compound according to claim 3, characterized in that: The co-solvent is selected from propylene glycol, and the amount used is 10% by volume.

5. The pharmaceutical composition containing opicapone inclusion compound according to claim 1, characterized in that: The complexing agent is selected from hydroxypropyl-β-cyclodextrin.

6. A pharmaceutical composition containing an opicapone inclusion compound according to claim 5, characterized in that: The molar ratio of opicapone to hydroxypropyl-β-cyclodextrin is selected from 1:4 to 2:1, preferably 1:

2.

7. A pharmaceutical composition containing an opicapone inclusion compound according to claim 1, characterized in that: The preservative is selected from sodium benzoate.

8. The pharmaceutical composition containing opicapone inclusion compound according to claim 1, characterized in that: The pharmaceutical composition further comprises a sweetener and an essence, wherein the sweetener is selected from saccharin sodium and the essence is selected from cherry essence.

9. The pharmaceutical composition containing opicapone inclusion compound according to claim 1, characterized in that: The pH regulator is selected from hydrochloric acid and sodium hydroxide.

10. The pharmaceutical composition containing opicapone inclusion compound according to claim 1, characterized in that: The composition comprises: (a) 5.0% (w / v) opicapone; (b) 0.02% (w / v) sodium benzoate; (c) a molar ratio of opicapone to hydroxypropyl-β-cyclodextrin of 1:2; (d) 10% (v / v) propylene glycol; (e) 0.2% (w / v) 0.1M sodium hydroxide to adjust the pH to 7.0; (f) 0.06% (w / v) saccharin sodium, 0.02% (w / v) cherry flavor and (g) water to 100%.

11. A method for preparing the pharmaceutical composition containing the opicapone inclusion compound according to any one of claims 1 to 9, comprising: (a) weighing a prescribed amount of opicapone, adding it to a co-solvent, stirring and dispersing it uniformly to obtain a drug solution; (b) adding the drug solution to the complexing agent solution and stirring evenly to obtain a mixed solution; (c) mixing the sweetener, preservative and an appropriate amount of purified water and stirring evenly to obtain a mixed solution; (d) mixing the mixed solution in (b) and the mixed solution in (c) and stirring evenly, adjusting the pH to 7-8 with a pH adjuster, and then boiling and keeping warm; (e) adding flavor to the drug solution after keeping warm, stirring evenly, adding purified water to make up to the scale, and filtering to obtain the product.

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