Butorinol sustained-release pharmaceutical composition

Abstract

The invention discloses a sustained-release pharmaceutical composition containing a biocompatible organic solvent and a grease mixture of tocopherol and fatty acid ester, the composition comprises amphiphilic neutral lipid with a polar'head 'group and a non-polar'tail' group, and the active ingredient is butorphanol or an acceptable pharmaceutical salt thereof. Compared with other technologies, the composition prescription has the advantage of longer slow release period. The production process of the preparation is greatly simplified, the production process and quality control requirements of the polymer are lower, and large-scale commercial production is more facilitated.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising a biocompatible organic solvent, a fatty acid ester, a phospholipid, tocopherol, and an active ingredient, bortoflavone or a pharmaceutically acceptable salt thereof. The composition can be administered by injection, such as intramuscular injection or subcutaneous injection, and is slowly released in the body for relieving pain caused by cancer, surgery, trauma, etc. Background Art

[0002] Butorphanol is a typical synthetic agonist-antagonist opioid analgesic. The current commercially available preparation is mainly butorphanol tartrate injection, and its indications include acute and chronic pain treatment in adults and children. The elimination half-life of butorphanol in the human body is 2.5~3.5h. The existing preparation has a short administration cycle. When patients are in long-term chronic pain, they need to be injected repeatedly in a short period of time, which can easily lead to poor patient compliance. Therefore, if a new dosage form of butorphanol that can be released for a long time after administration can be developed for pain treatment, it can avoid repeated injections in a short period of time, and provide more stable blood drug concentrations and analgesic effects compared with ordinary injections, which will have important clinical value.

[0003] As excellent biocompatible excipients, amphiphilic materials have good phase transition ability. Since amphiphilic lipids have a "hydrophilic" head and a "lipophilic" tail, after being injected into the subcutaneous tissue, water molecules diffuse into the composition and self-assemble under the influence of hydrophilic-hydrophobic interactions to form various lyotropic liquid crystal ordered structures. With the gradual construction of the ordered structure, the composition gradually changes from a solution state to a semisolid gel state, encapsulating the drug, thereby achieving the purpose of slow drug release. However, the critical stacking parameter CPP of a single phospholipid material is generally 1, so vesicles or lamellar structures are usually generated in the phospholipid-water binary system, which is not conducive to the formation of liquid crystal gels. The addition of tocopherol or fatty acid esters can change the CPP value of amphiphilic lipids. This is because after adding a third substance, during the formation of lyotropic liquid crystals, the hydrophilic and lipophilic properties of the third substance will accumulate on the head group or tail of the amphiphilic lipid or the oil-water interface, which leads to a change in the ratio of the head group and tail of the amphiphilic lipid, thereby affecting the type of lyotropic liquid crystal generated.

[0004] Camurus' Chinese patent CN101014319B uses a phospholipid plus diacyl lipid and / or tocopherol oil system to construct a liquid crystal system. However, the material composition and proportion protected by the patent are not completely suitable for the compound butorphanol. Within the scope of the patent protection part, it is difficult to obtain a butorphanol long-acting injection composition suitable for clinical use. CN111904928 discloses a butorphanol injectable long-acting composition, which is composed of amphiphilic lipids, triglycerides and biocompatible solvents, but the injection has a short sustained release period and fast clearance in the body. It is also difficult to meet the requirements of sustained release of butorphanol. The inventors optimized the mixed mass percentage of tocopherol and fatty acid esters on the basis of the addition of tocopherol and dioleylglycerol disclosed in CN101014319, limited the ratio of the two, and optimized the appropriate ratio of mixed oils and phospholipids and solvents. The in vitro drug release curve of the gel prescription of the composition shows a longer sustained release period, and animal experiments also show good in vivo release control ability, thereby completing the present invention. Summary of the invention

[0005] The purpose of the present invention is to invent a butorphanol sustained-release composition which can release the drug in vivo for a long time, has a simple production process and safe materials.

[0006] With this purpose in mind, the inventors, after extensive research, unexpectedly discovered that mixing common injection excipients such as biocompatible organic solvents, tocopherol, fatty acid esters, and amphiphilic neutral lipids in a certain proportion can slowly release the active ingredient, botorphanol, after administration, thereby completing the present invention.

[0007] The pharmaceutical composition of the present invention, the active ingredient is butorphanol or its acceptable pharmaceutical salt, such as butorphanol tartrate. Compared with butorphanol tartrate, butorphanol has a more balanced oil-water amphiphilicity, and butorphanol is preferably used in the present invention. Wherein, the mass percentage of the active ingredient butorphanol is 0.5% to 45%.

[0008] In the pharmaceutical composition provided by the present invention, the biocompatible organic solvent has a good dissolving effect on both ester components and water-soluble components. A homogeneous solution is formed during the preparation of this product, which greatly facilitates industrial production and ensures good production reproducibility. As the biocompatible organic solvent of the composition of the present invention, it is necessary to ensure that the active ingredient and the release regulating matrix fatty acid ester and phospholipid can be effectively dissolved into a homogeneous solution, but it cannot be excessive to cause the liquid viscosity to decrease and the release of the active ingredient cannot be controlled.

[0009] The pharmaceutical composition provided by the present invention, wherein the biocompatible organic solvent is selected from anhydrous ethanol, N-methylpyrrolidone, 2-pyrrolidone, ethyl lactate, dimethyl sulfoxide, propylene carbonate, ethyl acetate, triacetin, polyethyleneimine, benzyl benzoate or a mixture thereof, preferably anhydrous ethanol, N-methylpyrrolidone or a mixture thereof.

[0010] In the pharmaceutical composition provided by the present invention, the mass percentage of the biocompatible organic solvent is 10% to 40%, and more preferably 10% to 20%.

[0011] Fatty acid esters, tocopherol and amphiphilic lipids are active ingredient release control substances in the composition of the present invention. After being injected into the body, they slowly release butorphanol in the composition and maintain blood drug concentration for a long time, thereby playing a long-term analgesic effect.

[0012] The pharmaceutical composition provided by the present invention, wherein the fatty acid ester is selected from monoolein, diolein, triolein, oleyl glyceride, sorbitan monooleate, phytyl glyceride or a mixture thereof, preferably monoolein, diolein or a mixture thereof; the mass percentage of the fatty acid ester is 35% to 55%.

[0013] The pharmaceutical composition provided by the present invention, wherein the amphiphilic lipid is selected from soybean lecithin, lecithin or a mixture thereof, and the mass percentage of the amphiphilic lipid is 35% to 55%.

[0014] In the pharmaceutical composition provided by the present invention, the tocopherol is selected from natural or artificially synthesized α-, β-, γ-, δ-tocopherol or its acetate.

[0015] The pharmaceutical composition provided by the present invention has a ratio of fatty acid ester to tocopherol of 50:10 to 50:50. A preparation method of the composition is as follows: the active ingredient is completely dissolved in a suitable biocompatible organic solvent, and amphiphilic lipids and oils are added thereto in sequence, and a volatile solvent is added last if there is one, and the mixture is stirred in a sealed container at room temperature until the mixture is completely dissolved to form a clear and transparent solution.

[0016] The present invention provides a pharmaceutical composition comprising a biocompatible organic solvent, a mixture of tocopherol and fatty acid esters, an amphiphilic lipid, and an active ingredient, bortoflavone or a pharmaceutically acceptable salt thereof, which can be used to relieve pain in cancer, surgery, trauma, etc., and the administration method is subcutaneous injection.

[0017] Effect of active ingredient dosage on drug release rate The pharmaceutical form of the active ingredient butorphanol includes butorphanol or its pharmaceutical salt, and the most commonly used is butorphanol tartrate. The present invention mixes butorphanol and butorphanol tartrate with a biocompatible organic solvent, a fatty acid ester, and a phospholipid in a certain proportion to prepare the pharmaceutical composition of the present invention. The prepared sample is subjected to a release test, and the release test method is as follows: Weigh 1g of the drug composition and put it into the dialysis tube. Put the dialysis tube with the sample into a beaker filled with phosphate buffer (pH=7.2~7.4) that meets the sink conditions, and place it in a constant temperature air bath oscillator (37℃ 65 rpm) for in vitro release. Take samples after 1, 6, 12, 24, 36, 48, 72, and 96 hours and replace with an equal amount of fresh release medium at the same temperature. Use HPLC to detect the concentration of butorphanol in each sample and calculate the cumulative release rate.

[0018] From the results of release test, when the mass percentage of active ingredients exceeds 45%, the release of active ingredients is difficult to control and it is difficult to achieve the technical effect of slow release of drugs. Therefore, the mass percentage of active ingredients should be controlled between 0.5% and 45%.

[0019] Effect of solvent dosage on drug release rate As the biocompatible organic solvent of the composition of the present invention, it is necessary to ensure that the active ingredient and the release regulating matrix oleic acid ester and amphiphilic lipid can be effectively dissolved into a homogeneous solution, but it should not be excessive, resulting in a decrease in liquid viscosity and an inability to control the release of the active ingredient. The present invention mixes different types and amounts of biocompatible organic solvents with butorphanol, fatty acid esters, and amphiphilic lipids in a certain proportion to prepare the pharmaceutical composition of the present invention. The prepared samples are subjected to a release test, and the release test method is as follows: Weigh 1g of the drug composition and put it into the dialysis tube. Put the dialysis tube with the sample into a beaker filled with phosphate buffer (pH=7.2~7.4) that meets the sink conditions, and place it in a constant temperature air bath oscillator (37℃ 65 rpm) for in vitro release. Take samples after 1, 6, 12, 24, 36, 48, 72, and 96 hours and replace with an equal amount of fresh release medium at the same temperature. Use HPLC to detect the concentration of butorphanol in each sample and calculate the cumulative release rate.

[0020] From the results of release determination, when the mass percentage of the biocompatible organic solvent exceeds 40%, the release of the active ingredient is difficult to control and it is difficult to achieve the technical effect of slow release of the drug; when the mass percentage of the biocompatible organic solvent is less than 10%, it is difficult for the composition to form a homogeneous solution. Therefore, the mass percentage of the biocompatible organic solvent should be controlled between 10% and 40%, preferably 10% to 20%.

[0021] Effects of dosage and ratio of tocopherol and fatty acid esters on drug release rate Tocopherol and fatty acid ester are used as release control materials of the composition of the present invention, and their types, amounts and proportions will affect the release rate of the active ingredient. The present invention mixes different types and amounts of tocopherol, fatty acid ester oil mixture with biocompatible organic solvent, butorphanol, and phospholipids in a certain proportion to prepare the pharmaceutical composition of the present invention. The prepared samples are subjected to release degree inspection, and the release degree inspection method is as follows: Weigh 1g of the drug composition and put it into the dialysis tube. Put the dialysis tube with the sample into a beaker filled with phosphate buffer (pH=7.2~7.4) that meets the sink conditions, and place it in a constant temperature air bath oscillator (37℃ 65 rpm) for in vitro release. Take samples after 1, 6, 12, 24, 36, 48, 72, and 96 hours and replace with an equal amount of fresh release medium at the same temperature. Use HPLC to detect the concentration of butorphanol in each sample and calculate the cumulative release rate.

[0022] From the results of the release test, the ratio and dosage of different types of fatty acid esters and tocopherols have a certain effect on the release of this product, but they can all control the release of the active ingredient at a certain rate. Therefore, the fatty acid ester can be selected from monoolein, diolein, triolein, medium-chain triglyceride oil, alcohol glyceride, sorbitan monooleate, phytyl glyceride or a mixture thereof, and monoolein, diolein or a mixture thereof can be further preferred. Tocopherol is selected from natural or synthetic α-, β-, γ-, δ-tocopherol or its acetate. Alpha-tocopherol from natural or synthetic sources is further preferred. In addition, when the proportion of the mixed oil of fatty acid ester and tocopherol is less than 20%, the release of the active ingredient cannot be effectively controlled; when it exceeds 60%, the sample is difficult to effectively dissolve into a homogeneous solution. Therefore, the amount of the mixed oil of fatty acid ester and tocopherol is preferably 35% to 55%.

[0023] According to the results of the release test, the ratio of tocopherol and fatty acid ester has a certain influence on the release of this product. When the ratio of fatty acid ester: tocopherol = 50:10~50:50, better sustained-release performance can be obtained.

[0024] Effects of amphiphilic lipid type and dosage on drug release rate The type and amount of amphiphilic lipids used as release control materials in the composition of the present invention will affect the release rate of the active ingredient. The present invention mixes different types and amounts of amphiphilic lipids, tocopherol, anhydrous ethanol, N-methylpyrrolidone, butorphanol, and fatty acid esters in a certain proportion to prepare the pharmaceutical composition of the present invention. The prepared samples are subjected to release test, and the release test method is as follows: Weigh 1g of the drug composition and put it into the dialysis tube. Put the dialysis tube with the sample into a beaker filled with phosphate buffer (pH=7.2~7.4) that meets the sink conditions, and place it in a constant temperature air bath oscillator (37℃ 65 rpm) for in vitro release. Take samples after 1, 6, 12, 24, 36, 48, 72, and 96 hours and replace with an equal amount of fresh release medium at the same temperature. Use HPLC to detect the concentration of butorphanol in each sample and calculate the cumulative release rate.

[0025] From the results of release rate determination, different types of phospholipids have certain effects on the release of this product, but they can all control the release of the active ingredient at a certain rate. Therefore, the phospholipid can be selected from soybean lecithin, egg phosphatidylcholine or a mixture thereof.

[0026] In addition, when the mass percentage of amphiphilic lipids is less than 20%, the release of active ingredients cannot be effectively controlled; when the mass percentage of amphiphilic lipids exceeds 60%, the sample is difficult to effectively dissolve into a homogeneous solution. Therefore, the mass percentage of phospholipids is preferably 20% to 60%, and more preferably 35% to 55%.

[0027] Investigation of the release rate of the composition of the present invention in animals Different formulation compositions within the scope of the present invention were used, and rats were used as experimental animals to investigate the release and absorption of the different formulation compositions in vivo.

[0028] Female SD rats were randomly divided into 5 groups, each with 10 rats in parallel. The four test preparation groups were subcutaneously injected with the butorphanol long-acting injections of Example 8, Example 10, Example 15, and Example 17 in the back of the rat neck, and the dosage of the preparation was 0.5 g / kg. The in vivo release and absorption behavior of the butorphanol long-acting injection was investigated. The control preparation group was injected with 6 mg / kg of common butorphanol tartrate injection by intramuscular injection in the right hind leg of the rat, and the dosage of butorphanol was about 4.1 mg / kg, which was the maximum dose that a normal adult could accept within 1 day. The control preparation group was used to investigate the in vivo release and absorption behavior of common butorphanol tartrate injection.

[0029] Blood was collected from the orbital venous plexus of SD rats at 0.5h, 1h, 3h, 6h, 12h, 24h, 2d, 3d, 4d, 5d, 7d, 10d, 14d, and 21d after administration. 400μL of whole blood was collected in an EP tube and centrifuged at 3000 rpm for 10 min to obtain the supernatant plasma sample. 100ul of plasma was added with 200 μL of methanol, vortexed for 10 min, centrifuged at 3000 rpm for 20 min to obtain the supernatant, and the supernatant was centrifuged at 10000 rpm for 20 min, and then tested by HPLC injection. The content of butorphanol in plasma at different time points was calculated according to the standard curve.

[0030] It can be seen from the drug-time curves of the four groups of rats that after the common butorphanol tartrate injection was given, the control group quickly absorbed and peaked and was quickly eliminated, and no component could be detected in the plasma after 3 hours; the test preparation group of Example 8, the test preparation group of Example 10, the test preparation group of Example 15, and the test preparation group of Example 17 began to detect a certain blood drug concentration in the rats 0.5 hours after the butorphanol long-acting injection was given, and the time when butorphanol was finally detected was 7d, 14d, 21d, and 30d, respectively. It is fully demonstrated that the butorphanol long-acting injection of the present invention has an obvious sustained-release effect compared with the common butorphanol tartrate injection, and the sustained-release time is related to the mass percentage of different components in the composition.

[0031] The composition disclosed in the present invention establishes a ternary system and defines the preferred ratio of tocopherol. The composition prescription has the advantage of a longer sustained release period compared to other technologies. The preparation production process of this method is greatly simplified, the production process and quality control requirements of the polymer are lower, and it is more conducive to large-scale commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 : In vitro release curves of the butorphanol long-acting injections prepared in Examples 1 to 6 Figure 2 : In vitro release curves of the butorphanol long-acting injections prepared in Examples 7 to 12 Figure 3 : In vitro release curves of butorphanol long-acting injections prepared in Examples 13 to 17 Figure 4 : Blood drug concentration-time curves of rats prepared from control preparation, butorphanol long-acting injections of Examples 8, 10, 15, and 17 (24 h) Figure 5 : Blood drug concentration-time curve of rats prepared from control preparation, butorphanol long-acting injection of Examples 8, 10, 15 and 17 (720 h) Specific implementation method: The following examples are used to further explain the present invention, but the scope of the present invention is not limited to the following examples.

[0033] Embodiment 1~6 The unit preparation prescriptions of Examples 1 to 6 are shown in Table 1: Table 1 Unit preparation prescription table of Examples 1 to 6

[0034] Preparation process: Weigh the raw materials accurately and place them in a dry and clean vial. After filling with nitrogen and sealing, wrap it with tin foil to avoid light. Place it on a magnetic stirrer at a stirring temperature of 25°C, a stirring speed of 300 rpm, and a stirring time of 6 h. After sterilization by filtering through a 0.22 μm filter membrane, fill it with nitrogen and seal it, and store it at room temperature away from light.

[0035] The butorphanol long-acting injection prepared in Examples 1 to 6 was subjected to release determination using the aforementioned release determination method. The release curves are shown in the attached Figure 1 .

[0036] Embodiments 7 to 12 The unit preparation prescriptions of Examples 7 to 12 are shown in Table 2: Table 2 Unit preparation prescription table of Examples 7 to 12

[0037] Preparation process: Weigh the raw materials accurately and place them in a dry and clean vial. After filling with nitrogen and sealing, wrap it with tin foil to avoid light. Place it on a magnetic stirrer at a stirring temperature of 25°C, a stirring speed of 300 rpm, and a stirring time of 6 h. After sterilization by filtering through a 0.22 μm filter membrane, fill it with nitrogen and seal it, and store it at room temperature away from light.

[0038] The butorphanol long-acting injection prepared in Examples 7 to 12 was subjected to release determination using the aforementioned release determination method. The release curves are shown in the attached Figure 2 .

[0039] Embodiments 13 to 18 The unit preparation prescriptions of Examples 13 to 18 are shown in Table 3: Table 3 Unit preparation prescription table of Examples 13 to 18

[0040] Preparation process: Weigh the raw materials accurately and place them in a dry and clean vial. After filling with nitrogen and sealing, wrap it with tin foil to avoid light. Place it on a magnetic stirrer at a stirring temperature of 25°C, a stirring speed of 300 rpm, and a stirring time of 6 h. After sterilization by filtering through a 0.22 μm filter membrane, fill it with nitrogen and seal it, and store it at room temperature away from light.

[0041] Example 18 could not be dissolved into a homogeneous solution, did not meet the predetermined requirements, and no release test was performed. The butorphanol long-acting injection prepared in Examples 13 to 17 was tested for release using the aforementioned release test method. The release curves are shown in the attached Figure 3 .

[0042] According to the results of Examples 1 to 6, the higher the proportion of organic solvents and the higher the proportion of active pharmaceutical ingredients, the faster the release of the gel. In order to control the slow release of the drug and obtain the most suitable gel precursor with the best viscosity, the proportion of organic solvents is preferably 10% to 20%. According to the results of Examples 7 to 12, the ratio of fatty acid esters to tocopherol acetate is different, and the controlled release rate is significantly different. When the ratio of fatty acid esters to tocopherol acetate is close to 50:50, the controlled release effect is better, and when the ratio of fatty acid esters to tocopherol acetate is in the range of 50:10 to 50:50, different prescriptions for controlling the release rate can be obtained, so it can be adjusted within the preferred ratio to obtain different sustained release cycles of gel prescriptions. A higher proportion of organic solvents affects the encapsulation of the gel matrix to the drug, and the release is obviously faster. According to the comparison of the results of Examples 1 to 17, within the preferred ratio of fatty acid esters to tocopherol acetate, tocopherol has a better sustained release ability than tocopherol acetate.

[0043] The results of this study show that the ternary gel system of phospholipids, fatty acid esters and tocopherol provides a better burst release control and sustained release cycle.

[0044] Study on release and absorption in rats Rats were used as experimental animals, and the release and absorption of the compositions of the present invention prepared by the control preparation, Example 8, Example 10, Example 15, and Example 17 according to the aforementioned prescription ratio and preparation process were investigated in rats. The in vivo drug release curves of the gels of Preferred Examples 8 and 10 at different proportions of tocopherol acetate were selected for investigation. Examples 15 and 17 were selected for investigation of the in vivo drug release behaviors of the gels at different drug loadings under the same administration volume.

[0045] See attached for blood drug concentration-time curve Figure 4 The peak time (tmax) and peak concentration (Cmax) of Examples 15 and 17 are significantly lower than those of Examples 8 and 10, and the sustained release time of the gel is longer. The peak concentration (Cmax) of Example 8 is higher than that of Example 10, and the blood drug concentration is maintained for a short time, indicating that the ratio of tocopherol and fatty acid ester has a greater influence on the release control of the drug, and the sustained release effect is better when the ratio of the two is close to 50:50.

Claims

1. A butorphanol sustained-release pharmaceutical composition, comprising: a biocompatible organic solvent, a fat mixture of tocopherol and fatty acid esters, an amphiphilic neutral lipid comprising a polar "head" group and a non-polar "tail" group, and an active ingredient, butorphanol or an acceptable pharmaceutical salt thereof. It is characterized in that: a The amount of the oil mixture of tocopherol and fatty acid ester is limited to 35%~55% (by mass percentage, excluding active ingredients); b The mass percentage of the neutral amphiphilic lipid is preferably 20% to 60%, more preferably 35% to 55%; c. The amount of biocompatible organic solvent is limited to 10%-40%, preferably 10%-20%; The composition can effectively maintain the sustained release of the active ingredient for 3-7 days.

2. The composition according to claim 1, wherein The mass percentage of active ingredients is 0.5%~45%.

3. The mixture according to claim 1, wherein the ratio of fatty acid ester to tocopherol is preferably 50:10 to 50:

50.

4. The composition according to claim 1, wherein The biocompatible organic solvent is selected from anhydrous ethanol, N-methylpyrrolidone, 2-pyrrolidone, ethyl lactate, dimethyl sulfoxide, propylene carbonate, ethyl acetate, triacetin, polyethyleneimine, benzyl benzoate or a mixture thereof, preferably water ethanol and N-methylpyrrolidone.

5. The composition according to claim 1, wherein The fatty acid ester is selected from monoolein, diolein, triolein, medium chain triglyceride, oleyl glyceride, sorbitan monooleate, phytyl glyceride or a mixture thereof, preferably one or more of monoolein and diolein.

6. The composition according to claim 1, wherein The tocopherol is selected from α-, β-, γ-, δ-tocopherol or its acetate from natural or synthetic sources, wherein the tocopherol is preferably α-tocopherol from natural or synthetic sources.

7. The composition according to claim 1, wherein The amphiphilic lipid is selected from natural or artificially synthesized phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl inositol (PI), phosphatidylserine (PS) or a mixture thereof. Among them, the amphiphilic lipid is preferably phosphatidylcholine. The composition according to claim 1 , wherein the administration route of the composition is subcutaneous injection.

Images