Pharmaceutical composition and granules and injection thereof

Abstract

The invention relates to a pharmaceutical composition and granules and an injection thereof. The pharmaceutical composition comprises an active component, fatty acid ester, phospholipid and saturated fatty acid in a specific weight ratio, wherein the saturated fatty acid has a specific content. The injection comprises granules composed of the pharmaceutical composition, and the granules have specific particle size distribution. The obtained injection shows a specific dissolution curve, so that the pain relieving effect and the injectability during drug administration are improved.

Description

Pharmaceutical composition and granules and ampoules thereof TECHNICAL FIELD

[0001] The present invention relates to a pharmaceutical composition and granules and ampoules thereof, and in particular, to a pharmaceutical composition comprising specific components, granules having a specific particle size distribution, and ampoules exhibiting a specific dissolution profile. BACKGROUND

[0002] Pharmaceutical compositions containing bupivacaine are used for postoperative local anesthetics. Local anesthetics can be administered to the site of postoperative injury or its surroundings by the dosage form of ampoules. The ampoules can comprise a known suspension and a known lyophilized powder.

[0003] In the case of the preparation process of the known suspension, organic solvents such as dichloromethane, chloroform, diethyl ether, dimethyl sulfoxide, and N-methyl pyrrolidone are used to dissolve cholesterol, which is used to coat bupivacaine. Subsequently, the organic solvents are removed to meet the regulations on the residual amount of organic solvents in drugs. Therefore, the preparation process of the known suspension is complicated, and the storage conditions thereof are also severe.

[0004] In addition, a polymer containing a lactic acid monomer is used to coat bupivacaine to manufacture ampoules. Since such a polymer is slowly degraded in the body of a subject, it causes local accumulation. For example, the degradation products of poly(lactic-co-glycolic acid) (PLGA) include glycolic acid and lactic acid, and the site to which the drug is administered causes an inflammatory reaction.

[0005] In addition to the above-mentioned disadvantages, the particle size of the granules coated with bupivacaine is not controlled for the known ampoules, thereby reducing the analgesic effect and / or the injectability at the time of drug administration.

[0006] In view of the above-mentioned disadvantages, there is an urgent need to develop a new pharmaceutical composition containing bupivacaine, granules and ampoules thereof, to improve the above-mentioned problems.

[0007] SUMMARY

[0008] To improve the above-mentioned disadvantages, one aspect of the present invention provides a pharmaceutical composition. The pharmaceutical composition comprises an active ingredient, a fatty acid ester, a phospholipid, and a first saturated fatty acid in a specific weight ratio, and the granules composed thereof have a specific particle size distribution. The ampoules containing the granules exhibit a specific dissolution profile, thereby improving the analgesic effect and the injectability at the time of drug administration.

[0009] Another aspect of the present invention provides a granule composed of the aforementioned pharmaceutical composition, the granule having a specific particle size distribution, and the ampoules containing the granule exhibiting a specific dissolution profile, thereby improving the analgesic effect and the injectability at the time of drug administration.

[0010] Yet another aspect of the present application provides a syringe comprising the granules described above, such that the syringe exhibits a specific dissolution profile.

[0011] According to an aspect of the present application, a pharmaceutical composition is provided. The pharmaceutical composition comprises an active ingredient, a fatty acid ester, a phospholipid, and a first saturated fatty acid having a carbon number of 12 to 16, wherein the weight ratio of the active ingredient, the fatty acid ester, and the phospholipid can be, for example, 1 : 2.5 to 3.5 : 0.5 to 2.0. The active ingredient is bupivacaine or a pharmaceutically acceptable salt thereof. The content of the first saturated fatty acid is greater than 1.0% by weight to less than 15% by weight, based on 100% by weight of the phospholipid. The phospholipid has a structure represented by the following Formula (I):

[0012] In the above Formula (I), each R1independently represents a saturated or unsaturated, straight-chain or branched alkyl group having a carbon number of 9 to 17, and each R2independently represents a methyl group or an ethyl group. In some embodiments, each R2represents a methyl group.

[0013] In one embodiment, the fatty acid ester is selected from at least one of the group consisting of monoacylglycerols, diacylglycerols, and triacylglycerols.

[0014] In another embodiment, the fatty acid residue of the monoacylglycerols, the fatty acid residue of the diacylglycerols, and the fatty acid residue of the triacylglycerols each have a carbon number of 14 to 22.

[0015] In yet another embodiment, the pharmaceutical composition further comprises a second saturated fatty acid having a carbon number of 17 to 20.

[0016] In yet another embodiment, the content of the second saturated fatty acid is greater than 0.06% by weight, based on 100% by weight of the fatty acid ester. In some embodiments, the content of the second saturated fatty acid is greater than 0.06% by weight to 5% by weight.

[0017] In yet another embodiment, the pharmaceutical composition further comprises a lysophosphatidylcholine, and the fatty acid residue of the lysophosphatidylcholine has a carbon number of 10 to 18.

[0018] In yet another embodiment, the content of the lysophosphatidylcholine is 0.25% by weight to 15% by weight, based on 100% by weight of the phospholipid. In some embodiments, the content of the lysophosphatidylcholine can be, for example, 1% by weight to 10% by weight.

[0019] In yet another embodiment, the phospholipid is present in an amount of 100 weight percent, and the first saturated fatty acid is present in an amount of 1.5 to 10 weight percent, based on the weight of the phospholipid. In some embodiments, the first saturated fatty acid can be present in an amount of 1.5 to 5 weight percent, for example.

[0020] According to another aspect of the present application, a granule is provided. The granule is composed of the aforementioned pharmaceutical composition. The D10 particle size of the granule is equal to 2 μm to less than 13 μm, the D50 particle size of the granule is 5.5 μm to 24 μm, and the D90 particle size of the granule is 16 μm to 50 μm.

[0021] According to yet another aspect of the present application, a syringe is provided, which comprises the aforementioned granule. The syringe is subjected to a dissolution test in a USP Type II dissolution apparatus at 36.5°C to 37.5°C using a phosphate buffer having a pH of 7 and a volume of 990 mL at a rotation speed of 50 rpm. The first dissolution rate of the active ingredient is 40% to 80% at 1 hour. The second dissolution rate of the active ingredient is equal to 55% to less than 86% at 3 hours. The third dissolution rate of the active ingredient is 70% to less than 88.8% at 6 hours.

[0022] The pharmaceutical composition, the granule, and the syringe of the present application are used, in which the pharmaceutical composition having a specific composition is used so that the granule composed of the pharmaceutical composition has a specific particle size distribution, and the syringe comprising the granule exhibits a specific dissolution profile, thereby improving the analgesic effect and the injectability upon drug administration.

[0023] BRIEF DESCRIPTION OF DRAWINGS

[0024] For a more complete understanding of the embodiments of the application and the advantages thereof, reference is now made to the following written description taken in connection with the accompanying drawings. In the drawings, various features are not drawn to scale for purposes of clarity and simplicity.

[0025] FIG. 1 is a graph showing the concentration of bupivacaine in the blood of rats over time after subcutaneous injection of the syringe of Example 1 or a syringe of uncoated bupivacaine.

[0026] FIG. 2 is a histogram showing the percentage of pain threshold recorded over time after administration of the syringe of Example 1, the syringe of Example 12, or the syringe of Comparative Example 3 to rats after sciatic nerve injury surgery. DETAILED DESCRIPTION

[0027] The pharmaceutical composition of the present application comprises an active ingredient, a fatty acid ester, a phospholipid, and a saturated fatty acid having a carbon number of 12 to 16 (hereinafter referred to as a first saturated fatty acid), and the pharmaceutical composition is composed of granules. A specific weight ratio of the active ingredient, the fatty acid ester, and the phospholipid, and a specific content of the first saturated fatty acid allow the granules to have a specific particle size distribution. An injectable preparation comprising the granules exhibits a specific dissolution profile, thereby improving analgesic effect and injectability at the time of drug administration (hereinafter referred to as efficacy).

[0028] The term "specific particle size distribution" as used herein means that the particle size distribution of the granules is measured according to the particle size distribution test method described below, in which the D10 particle size is 2 μm to less than 13 μm, the D50 particle size is 5.5 μm to 24 μm, and the D90 particle size is 16 μm to 50 μm.

[0029] Further, the term "specific dissolution profile" as used herein means that the dissolution profile of the injectable preparation is measured according to the dissolution profile test method described below, in which the first dissolution rate of the active ingredient is 40% to 80% at 1 hour, the second dissolution rate of the active ingredient is equal to 55% to less than 86% at 3 hours, and the third dissolution rate of the active ingredient is 70% to less than 88.8% at 6 hours.

[0030] It is noted that the granules having the "specific particle size distribution" allow the injectable preparation to have the "specific dissolution profile" to achieve the aforementioned efficacy. Further, the better the particle size distribution and the better the dissolution profile, the more the aforementioned efficacy is improved.

[0031] The aforementioned active ingredient is bupivacaine or a pharmaceutically acceptable salt thereof. The aforementioned pharmaceutically acceptable salt can be bupivacaine hydrochloride, bupivacaine phosphate, bupivacaine sulfate, bupivacaine pamoate, and any combination of the aforementioned salts. Preferably, the active ingredient is bupivacaine.

[0032] As used herein, the term "about" means within a statistically meaningful range of a numerical value, typically within 2%. The range can also be within a measurement error and measurement uncertainty understood by those skilled in the art, which includes but is not limited to measurement error and measurement uncertainty caused by a detection reagent, a detection instrument, and a detection method.

[0033] In some embodiments, the fatty acid ester is selected from at least one of the group consisting of a monoacylglycerol, a diacylglycerol, and a triacylglycerol. In a specific embodiment, the carbon number of the fatty acid residue of the monoacylglycerol can be 14 to 22. In another specific embodiment, the carbon number of the two fatty acid residues of the diacylglycerol can independently be 14 to 22. In yet another specific embodiment, the carbon number of the three fatty acid residues of the triacylglycerol can independently be 14 to 22. When the carbon number of the fatty acid residue is 14 to 22, the granules have a good particle size distribution, so that the syringe shows a good dissolution profile. Preferably, the fatty acid ester is a triacylglycerol. When the fatty acid ester is a triacylglycerol, the granules have a better particle size distribution, so that the syringe shows a better dissolution profile.

[0034] For example, the monoacylglycerol can include, but is not limited to, monomyristin, monopalmitin, monostearin, monarachidin, and monobehenint. Next, the diacylglycerol can include, but is not limited to, 1,2-diacylglycerol and 1,3-diacylglycerol, such as 1,2-dimyristin, 1,3-dimyristin, 1,2-dipalmitin, 1,3-dipalmitin, 1,2-distearin, 1,3-distearin, 1,2-diarachidin, 1,3-diarachidin, 1,2-dibehenin, and 1,3-dibehenin. Further, the triacylglycerol can include, but is not limited to, tristearin, triarachidin, and 1,3-distearin-2-behenin. Preferably, the triacylglycerol is tristearin. When the triacylglycerol is tristearin, the granules have a better particle size distribution, so that the syringe shows a better dissolution profile.

[0035] Next, the pharmaceutical composition of the present application can further include a fatty acid different from the first saturated fatty acid (hereinafter referred to as a second saturated fatty acid), and the carbon number of the second saturated fatty acid can be 17 to 20, preferably 18 to 20. When the carbon number of the second saturated fatty acid is within the aforementioned range, the granules have a good particle size distribution, so that the syringe shows a good dissolution profile. For example, a preferred example of the second saturated fatty acid can be stearic acid.

[0036] In some embodiments, the content of the second saturated fatty acid is greater than 0.06% by weight, based on the content of the fatty acid ester being 100% by weight. Preferably, the content of the second saturated fatty acid is greater than 0.06% to equal to 5% by weight, and more preferably 0.08% to 1% by weight. When the content of the second saturated fatty acid is within the aforementioned range, the granules have a better particle size distribution, and the syringe shows a better dissolution profile.

[0037] The phospholipid of the present application has a structure represented by the following formula (I):

[0038] In the above formula (I), two R1independently represent a saturated or unsaturated, straight-chain or branched alkyl group having a carbon number of 9 to 17, and three R2independently represent a methyl group or an ethyl group. For example, specific examples of the phospholipid can include, but are not limited to, dimyristoyl phosphatidylcholine.

[0039] Preferably, the three R2all represent a methyl group. More preferably, the two R1are alkyl groups having the same carbon number, and the three R2all represent a methyl group. When R1and R2meet the aforementioned conditions, the granules have a better particle size distribution, so that the injection presents a better dissolution profile.

[0040] In some embodiments, the pharmaceutical composition of the present application can further include lysophosphatidylcholine. When the pharmaceutical composition includes the aforementioned compound, the granules have a better particle size distribution, and the injection presents a better dissolution profile.

[0041] In detail, the phospholipid, the fatty acid ester, and the first saturated fatty acid of the present application coat bupivacaine to form granules. The coating affects the particle size distribution of the granules. Since bupivacaine is a lipophilic compound, the lipophilic portions of the three compounds are close to bupivacaine, and the hydrophilic portions of the three compounds are far from bupivacaine. This makes the surface of the granules hydrophilic, which can be suspended in an aqueous solvent.

[0042] Further, compared with the phospholipid of the present application, lysophosphatidylcholine has a smaller chemical structure and has a lipophilic portion and a hydrophilic portion. Similarly, compared with the fatty acid ester of the present application, the second saturated fatty acid has a smaller chemical structure and has a lipophilic portion. Therefore, when the phospholipid, the fatty acid ester, and the first saturated fatty acid coat bupivacaine, lysophosphatidylcholine and / or the second saturated fatty acid can coat bupivacaine with the lipophilic portion of its chemical structure together with the aforementioned three compounds, so that the granules have a good particle size distribution, and the injection presents a good dissolution profile.

[0043] The carbon number of the fatty acid residue of lysophosphatidylcholine can determine whether the fatty acid residue of lysophosphatidylcholine is hydrophilic or lipophilic. When the carbon number is 10 to 18, lysophosphatidylcholine can more easily coat bupivacaine. Preferably, the carbon number of the aforementioned fatty acid residue can be 12 to 16. Specifically, a preferred specific example of lysophosphatidylcholine can be lysophosphatidylcholine.

[0044] In addition, the chemical structure of the first saturated fatty acid has an aliphatic chain and a carboxylic acid group. The number of carbons in the aliphatic chain can determine whether the first saturated fatty acid exhibits hydrophilic or lipophilic properties. When the number of carbons in the aliphatic chain of the first saturated fatty acid is within a preferred range (e.g., 13 to 15), the first saturated fatty acid can more readily coat the bupivacaine. In particular, a preferred embodiment of the first saturated fatty acid can be myristic acid. Similar conditions also apply to the second saturated fatty acid. For example, the number of carbons of the second saturated fatty acid can preferably be 18 to 20.

[0045] In some embodiments, the content of the phospholipid is 100 weight percent, and the content of lysophosphatidylcholine is 0.25 weight percent to 15 weight percent. Preferably, the content of lysophosphatidylcholine is 1 weight percent to 10 weight percent, and more preferably 2 weight percent to 5 weight percent. When the content of lysophosphatidylcholine is within the aforementioned range, the lysophosphatidylcholine can more readily coat the bupivacaine, thereby providing the granules with a better particle size distribution, and further providing the injectable with a better dissolution profile.

[0046] The content of the phospholipid is 100 weight percent, and the content of the first saturated fatty acid is greater than 1.0 weight percent to less than 15 weight percent. If the content of the first saturated fatty acid is not within the aforementioned range, the first saturated fatty acid can not readily coat the bupivacaine, such that the granules do not have a good particle size distribution, and the injectable does not exhibit a good dissolution profile. Preferably, the content of the first saturated fatty acid is 1.5 weight percent to 10 weight percent, and more preferably 1.5 weight percent to 5 weight percent.

[0047] In yet other embodiments, the content of lysophosphatidylcholine and the content of the first saturated fatty acid are both 1.5 weight percent to 5 weight percent. When the content of lysophosphatidylcholine and the content of the first saturated fatty acid are both within the aforementioned range, bupivacaine can be more readily coated, thereby providing the granules with a better particle size distribution, and further providing the injectable with a better dissolution profile.

[0048] In other embodiments, the content of lysophosphatidylcholine and the content of the first saturated fatty acid are both greater than the content of the second saturated fatty acid. When the contents of the three are in accordance with the aforementioned conditions, the three can more readily coat the bupivacaine, thereby providing the granules with a better particle size distribution, and further providing the injectable with a better dissolution profile.

[0049] The weight ratio of the active ingredient, the fatty acid ester, and the phospholipid can be, for example, 1 : 2.5-3.5 : 0.5-2.0. If the weight ratio of the active ingredient, the fatty acid ester, and the phospholipid is not within the aforementioned range, the granules do not have a good particle size distribution, so that the injection does not exhibit a good dissolution profile. If the D10, D50, and / or D90 of the granules is too small, the administration site is prone to granule aggregation after administration of the injection, and the active ingredient fails to spread to the administration target, so that the injectability upon drug administration is reduced and / or the analgesic effect is reduced. If the D10, D50, and / or D90 of the granules is too large, the injectability upon drug administration is reduced.

[0050] It should be noted that the active ingredient is present in an effective amount in the pharmaceutical composition and the injection described below. The term "effective amount" as used herein refers to a dosage sufficient but not toxic to the body to produce an anesthetic or analgesic effect in the individual. As understood by those skilled in the art, the specific effective amount depends on various factors, such as the physiological condition of the individual, the administration route, the excipient, and the use of other active ingredients.

[0051] In some embodiments, the pharmaceutical composition does not include cholesterol. When the pharmaceutical composition excludes cholesterol, the organic solvent can be omitted to simplify the preparation process. In detail, since cholesterol is an oil-soluble compound and has a melting point of 148°C to 150°C, it must be dissolved in an organic solvent in order to coat bupivacaine and prepare an injection.

[0052] In other embodiments, the pharmaceutical composition does not include a polymer containing a lactic acid monomer. When the pharmaceutical composition excludes such a polymer, lactic acid generated when the polymer is degraded in the body can be avoided, thereby avoiding inflammation at the administration site of the drug.

[0053] Another aspect of the present application provides a granule composed of the aforementioned pharmaceutical composition. In some embodiments, the pharmaceutical composition is mixed with an aqueous solvent, heated to form a mixed solution. The solvent is then removed by spray drying to coat the bupivacaine with the fatty acid ester, the phospholipid, and the first saturated fatty acid, and to form a granule, such as a spray-dried powder. When the second saturated fatty acid and the lysophosphatidylcholine are present, they also participate in the coating.

[0054] In other embodiments, the pharmaceutical composition is mixed with an aqueous solvent, heated, and homogenized to form an emulsion. The emulsion is cooled to stabilize the coating of the bupivacaine with the fatty acid ester and the phospholipid, and to form a granule. This granule is suspended in the aqueous solvent to obtain a suspension described below. In the aforementioned embodiments, the suspension can be optionally freeze-dried to remove the solvent to obtain a lyophilized powder described below. For example, specific examples of the aqueous solvent can be a phosphate buffer and / or physiological saline.

[0055] As previously described, in some embodiments, the pharmaceutical composition further comprises lysophosphatidylcholine and / or a second saturated fatty acid, which can coat the bupivacaine together with the phospholipid, the fatty acid ester and the first saturated fatty acid, and thus the components of the granule comprise the lysophosphatidylcholine and the second saturated fatty acid. In addition, the aforementioned spray drying, homogenizing emulsification and freeze drying can use methods well known to those skilled in the art.

[0056] The D10 particle size of these granules is equal to 2 μm to less than 13 μm, the D50 particle size of these granules is 5.5 μm to 24 μm, and the D90 particle size of these granules is 16 μm to 50 μm. If the particle size distribution of the granules does not meet the aforementioned conditions, the injection comprising the same does not have a good dissolution curve, thus increasing the maximum blood concentration of the active ingredient in the individual, reducing the analgesic effect and / or reducing the injectability at the time of drug administration.

[0057] Preferably, the D10 particle size is 2 μm to 12 μm, the D50 particle size is 10 μm to 20 μm, and the D90 particle size is 18 μm to 45 μm. More preferably, the D10 is 5 μm to 11 μm, the D50 is greater than 12 μm to less than 20 μm, and the D90 is 20 μm to 41 μm. When the particle size distribution of the granules meets the aforementioned conditions, the injection exhibits a good dissolution curve, thereby reducing the maximum blood concentration of the active ingredient in the individual, improving the analgesic effect and / or improving the injectability at the time of drug administration.

[0058] Another aspect of the present application provides an injection. The injection comprises the aforementioned granule. The injection can be a lyophilized powder or a suspension. In some embodiments, the injection can further comprise a suspending agent. The suspending agent is used to help the granule stably suspend and disperse in an aqueous phase, such as suspension in a phosphate buffer or physiological saline.

[0059] The suspending agent is selected from the group consisting of cellulose derivatives, salts thereof, and mixtures of the aforementioned two. The cellulose derivatives can include, but are not limited to, alkyl cellulose, hydroxyalkyl cellulose, and acylated cellulose. Specific examples of alkyl cellulose can be methyl cellulose, ethyl cellulose, and propyl cellulose. Specific examples of hydroxyalkyl cellulose can be hydroxypropyl cellulose and hydoxypropyl methylcellulose. Specific examples of acylated cellulose can be cellulose acetate (CA), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinyl acetate phthalate (PVAP). In addition, the salts of cellulose derivatives can include, but are not limited to, sodium carboxymethyl cellulose.

[0060] In addition to the suspensions, the injectable can optionally contain other excipients such as a buffer, a solvent, an isotonic agent, an acid agent, a basic agent, or any combination of the foregoing excipients. In particular, a specific example of the solvent can be sterile water or water for injection. A specific example of the isotonic agent can be sodium chloride, D-mannitol, propylene glycol, D-sorbitol, xylitol, lactose, sucrose, D-fructose, and dextran. A specific example of the buffer can be disodium hydrogen phosphate, sodium monohydrogen phosphate, dipotassium hydrogen phosphate, potassium monohydrogen phosphate, and a mixture thereof. The foregoing buffer, acid agent, and basic agent can be used to adjust the pH of the pharmaceutical composition to be within the range of 7.0 to 8.0.

[0061] In some embodiments, the injectable is subjected to a dissolution test at 36.5°C to 37.5°C in a type II dissolution apparatus according to the United States Pharmacopoeia using a phosphate buffer solution having a pH of 7 and a volume of 990 mL at a rotation speed of 50 rpm.

[0062] In the dissolution test, the dissolution rate of the active ingredient at 1 hour (hereinafter referred to as the first dissolution rate) is 40% to 80%. The dissolution rate of the active ingredient at 3 hours (hereinafter referred to as the second dissolution rate) is equal to 55% to less than 86%. The dissolution rate of the active ingredient at 6 hours (hereinafter referred to as the third dissolution rate) is 70% to less than 88.8%. If the dissolution curve of the injectable does not meet the foregoing conditions, the injectable containing the same does not have a good dissolution curve, thereby increasing the maximum blood concentration of the active ingredient in the subject, reducing the analgesic effect, and / or reducing the injectability at the time of drug administration.

[0063] Preferably, the first dissolution rate is equal to 50% to less than 80%, the second dissolution rate is equal to 65% to less than 86%, and the third dissolution rate is equal to 75% to less than 88.5%. More preferably, the first dissolution rate is 53% to 78%, the second dissolution rate is 67% to 85%, and the third dissolution rate is equal to 77% to less than 88.5%. When the dissolution curve of the active ingredient of the injectable meets the foregoing conditions, the maximum blood concentration of the active ingredient in the subject is reduced, the analgesic effect is improved, and / or the injectability at the time of drug administration is improved.

[0064] In some embodiments, the administration of the injectable can be in a manner known to one skilled in the art, such as subcutaneous injection, perineural injection, intramuscular injection, wound infiltration injection, wound instillation administration, and direct administration to a damaged nerve caused by surgery.

[0065] In some embodiments, the subject to which the injectable is administered can be a subject known to one skilled in the art, such as a mammal. Specific examples of the mammal can include, but are not limited to, a rat, a pig, an ape, a monkey, a rabbit, and a human.

[0066] For example, in a vial of lyophilized powder, the effective amount of active ingredient can be 300 mg / mg to 350 mg / mg, for example 337 mg / mg. In a vial of suspension, the effective amount of active ingredient can be 5 mg / mL to 40 mg / mL, for example 10 mg / mL. In addition, as will be understood by those in the art, the vial can be diluted with normal saline to achieve the desired concentration. The desired concentration can depend on the route of administration and the individual to whom the administration is being made.

[0067] Hereinafter, the present disclosure will be specifically described with examples. However, the present disclosure is not limited to these examples.

[0068] Manufacture of pharmaceutical composition

[0069] Examples 1 to 12 and Comparative Examples 1 to 3

[0070] In Examples 1 to 10 and Example 12, according to Table 1 below, sodium carboxymethylcellulose, sodium dihydrogen phosphate, disodium hydrogen phosphate, bupivacaine, glycerol triestearate, dimyristoyl phosphatidylcholine, and water for injection were mixed at about 90°C to prepare a bupivacaine-containing mixture containing 1 mg / mL (milligram / milliliter) or 6 mg / mL of sodium carboxymethylcellulose and 50 mM of phosphate, and having a pH of 7.4. The bupivacaine-containing mixture was homogenized at a speed of 5,000 rpm to 15,000 rpm to obtain an emulsion. When the emulsion is at room temperature, the bupivacaine is coated with glycerol triestearate and dimyristoyl phosphatidylcholine, and forms granules. When stearic acid, lyso- lecithin, and myristic acid are present, they also participate in the coating. The sodium carboxymethylcellulose surrounds the aforementioned granules to help them suspend in the phosphate buffer, which is a suspension. In the suspension, the concentration of bupivacaine is 30 mg / mL to 35 mg / mL. Then, the suspension was optionally subjected to a lyophilization step according to Table 1 below to obtain a lyophilized powder.

[0071] According to Table 1 below, in Example 11, sodium carboxymethylcellulose was not used compared to Example 1. In Comparative Example 1, too little glycerol triestearate and too little dimyristoyl phosphatidylcholine were used. In Comparative Example 2, dimyristoyl phosphatidylcholine was replaced with cholesterol. In Comparative Example 3, too much myristic acid was used. In addition to the compositions listed in Table 1, Examples 2 to 12 and Comparative Examples 1 to 3 were manufactured using the same components and preparation method as Example 1, so a detailed description thereof will not be provided.

[0072] Table 1

[0073] NA: represents that the cholesterol is not soluble in glyceryl tristearate, the comparative example cannot make the injection, so it cannot be evaluated.

[0074] V: represents that the example / comparative example is the dosage form.

[0075] -: represents that the example / comparative example does not use the ingredient or is not the dosage form.

[0076] : represents that the injectability is good; : represents that the injectability is fair; : represents that the injectability is poor; : represents that the injectability is very poor.

[0077] According to the results of Examples 1 to 12 of Table 1, each example uses an appropriate amount of ingredients, so the granules have a good particle size distribution, and the injection containing the above granules can provide a good dissolution curve. However, according to the results of Comparative Examples 1 to 3 of Table 1, Comparative Example 1 uses too little glyceryl tristearate and too little dimyristoyl phosphatidylcholine, and Comparative Example 3 uses too much myristic acid, so the particle size distribution of the granules is not ideal, and the injection containing the above granules fails to provide a good dissolution curve. Secondly, in Comparative Example 2, cholesterol is used to replace dimyristoyl phosphatidylcholine, and cholesterol is not soluble in glyceryl tristearate, so the injection cannot be made, and it cannot be evaluated.

[0078] Method for testing pharmaceutical composition

[0079] 1. Particle size distribution

[0080] The injection (suspension dosage form) or the reconstituted injection (lyophilized powder dosage form) is diluted with a dispersant to prepare a test solution of bupivacaine with a laser obscuration rate of 5%, wherein the dispersant is an aqueous solution containing 0.03 wt.% (weight percent) of Tween 80. After the test solution is stirred at a speed of 2400 revolutions per minute and ultrasonically vibrated, the particle size of the test solution is measured using a Malvern Mastersizer 3000 to obtain the particle size distribution (D10 particle size, D50 particle size and D90 particle size) of the granules, wherein the absorption index is set to 0.01, and during the measurement, the test solution is maintained at 16°C to 20°C using a water circulator.

[0081] 2. Dissolution curve

[0082] A test solution of bupivacaine at a concentration of 30 mg / mL was prepared by dissolving the injection in 0.45 wt.% sodium chloride aqueous solution. Then, 10 to 11 mL of the test solution was added to 990 mL of 0.05 M phosphate buffer at pH 7.0. The phosphate buffer was stirred at 50 rpm in a USP Type II dissolution apparatus (with paddles) at 36.5 to 37.5°C. At various time points after the test solution was added to the phosphate buffer, samples were taken from the phosphate buffer, and the concentration of bupivacaine in the samples was determined by high performance liquid chromatography to obtain the dissolution profile of the injection. The phosphate buffer contained potassium dihydrogen phosphate, di-potassium hydrogen phosphate, and sodium azide. In the high performance liquid chromatography, the detection wavelength was 263 nm, and a column of X-Bridge C18 (4.6 mm in inner diameter and 250 mm in length, packed with 5 μm in particle size) was used for isocratic elution with a mixture of acetonitrile and phosphate buffer as the mobile phase.

[0083] 3. Syringability

[0084] When the injection is a suspension, 10 mL of the injection can be directly taken out using a plastic syringe with a volume of 10 mL. When the injection is a lyophilized powder, the injection is first reconstituted with 10 mL of 0.45 wt.% sodium chloride aqueous solution, and then 10 mL of the reconstituted injection is taken out using a syringe. Then, a syringe needle is attached to the syringe, and the injection (or the reconstituted injection) is expelled from the syringe with a force of less than 4.5 kgf. The syringability of the injection is evaluated by the gauge (G) of the needle used when the injection (or the reconstituted injection) can be expelled from the syringe. When the injection (or the reconstituted injection) can pass through a needle of G 22 or a finer gauge, the syringability is good (indicated by a symbol of ). When the injection (or the reconstituted injection) can pass through a needle of G 20 but cannot pass through a needle of a gauge finer than G 20, the syringability is fair (indicated by a symbol of ). When the injection (or the reconstituted injection) can pass through a needle of a gauge coarser than G 20, the syringability is poor (indicated by a symbol of ). When the injection (or the reconstituted injection) is too viscous to be filled into a syringe, the syringability is very poor (indicated by a symbol of ).

[0085] Animal Test Method

[0086] 1. Pharmacokinetic study

[0087] Example 1 or uncoated bupivacaine was subcutaneously injected into rats (3 rats per group) at a dose of 120 mg / kg of bupivacaine for the Example 1 injection and at a dose of 20 mg / kg of bupivacaine for the uncoated bupivacaine injection. Blood samples were collected from the rats at various time points after the single injection. After centrifugation, plasma samples were obtained and stored at -80°C. The plasma samples were analyzed by high performance liquid chromatography to obtain the concentration of bupivacaine in the blood, and the results are shown in Figure 1. The foregoing analysis was performed in a manner known to those skilled in the art, and will not be described here.

[0088] In the pharmacokinetic study, please refer to Figure 1, which shows the concentration of bupivacaine in the blood of rats over time after subcutaneous injection of the Example 1 injection or uncoated bupivacaine. The maximum value of the curve is the maximum blood concentration (Cmax), and the total area under the curve (AUC) indicates the bioavailability of the injection. In the single subcutaneous injection test of Figure 1, the dose of the Example 1 injection was 6 times the dose of the uncoated bupivacaine injection. As shown in Figure 1, the Example 1 injection can reduce the maximum concentration (Cmax) of bupivacaine in the blood of rats to 401 ng / mL, but the Cmax of the uncoated bupivacaine injection is as high as 965 ng / mL. Compared with the uncoated bupivacaine injection, the Example 1 injection can maintain a relatively stable concentration of bupivacaine in the blood of rats 48 hours after injection into the rats.

[0089] 2. Efficacy study

[0090] After the rats were anesthetized, an opening was cut on the thigh of the rats with sterilized surgical instruments, and two of the three branch nerves (deep peroneal nerve, superficial peroneal nerve and tibial nerve) at the end of the sciatic nerve of the rats were cut off, and then the opening was sutured. After a recovery period of one week, the Example 1 injection, the Example 12 injection or the Comparative Example 3 injection (6 rats per group) was directly injected into the cavity around the sciatic nerve injury, and the dose was 30 mg / kg of bupivacaine. Before the operation, after the operation and at various time points after the injection (also known as administration), the Von Frey filament was used to prick the middle area of the plantar of the hind paw of the rats to measure the mechanical paw withdrawal threshold (PWT) as the pain threshold (g). The pain threshold before the operation was taken as 100%, and the pain threshold after the operation was taken as 0%. The percentage of the pain threshold was calculated using the following formula (II), and the results are shown in Figure 2.

[0091] When the difference between the average of the percentage of the pain threshold after administration and the average of the percentage of the pain threshold before surgery is within a certain range, the injection can reduce the pain caused by surgery and the phenomenon of hypoalgesia does not occur. For example, the difference is between -31% and 90%, preferably between -30% and 60%. However, when the aforementioned difference exceeds 90%, it indicates that the analgesic effect of the injection affects the sensory nerves of the animal, resulting in a lack of sensitivity to allodynia and the occurrence of hypoalgesia. Or when the aforementioned difference is less than -31%, it indicates that the analgesic effect of the injection cannot inhibit the allodynia caused by surgery, and the occurrence of allodynia.

[0092] Percentage of the pain threshold = {(pain threshold after administration (g) - pain threshold after surgery (g)) / (pain threshold before surgery (g) - pain threshold after surgery (g))} x 100% (II).

[0093] In the pharmacodynamic study, according to Table 1, compared with Comparative Example 3, the injection of Example 1 can provide better injectability. Secondly, within 24 hours after administration, the injection of Example 1 can maintain the concentration of bupivacaine in the blood of rats more stably, wherein the maximum concentration (Cmax) of bupivacaine in the blood of rats is 873 ng / mL, which is lower than the Cmax (916 ng / mL) of Comparative Example 3.

[0094] Further, please refer to FIG. 2, which is a histogram showing the percentage of the pain threshold recorded over time after the rats were subjected to surgery of sciatic nerve injury and then administered with the injection of Example 1, the injection of Example 12, or the injection of Comparative Example 3 (in the same group, each time point is compared with before surgery, *: P < 0.05, #: P < 0.01). According to the results of FIG. 2, the injection of Example 1 can provide a stronger and longer analgesic effect compared with Comparative Example 3, wherein the average of the percentage of the pain threshold 2 hours after administration of Example 1 is 70%, and the average of the percentage of the pain threshold 4 hours after administration of Comparative Example 3 is 67%. In addition, after the rats administered with the injection of Comparative Example 3 were sacrificed, the site where the drug was administered was dissected, and it was observed that the granules contained in the injection were aggregated and accumulated at the administration site (not shown in the figure), which hindered the release of bupivacaine.

[0095] Accordingly, Example 1 uses appropriate amounts of components, the granules composed thereof have a better particle size distribution, and the injection containing the granules exhibits a better dissolution curve, which is conducive to the stable release of bupivacaine to maintain the stability of the concentration of bupivacaine in the blood of rats and reduce the Cmax of bupivacaine. In addition, the injection can improve the analgesic effect and injectability.

[0096] It is incidentally noted that the dose administered of the injection of Example 1 in the pharmacokinetic study can be 120 mg / kg, which is higher than the known rat median lethal dose of bupivacaine injection, for example, F.P. Luduena et al., in the article entitled "Optical isomers of mepivacaine and bupivacaine", published in the journal Arch. In. Pharmacodyn. Ther., vol. 200, No. 2, pages 359 to 369, December 1972, discloses a rat median lethal dose of bupivacaine injection of 63 mg / kg, so that the biological toxicity of the injection of Example 1 is lower.

[0097] In addition, according to Figure 2, the injection of Example 12 also makes it possible to provide an analgesic effect superior to that of the injection of Comparative Example 3.

[0098] Although the application has been described with the aid of the preceding examples, it is not intended to be limited to the details of those examples. Various modifications and variations on the described embodiments are possible and are within the scope of the application, as those skilled in the art will appreciate. Therefore, the scope of the application should be determined not with reference to the description of the examples but with reference to the claims appended hereto.

Claims

1. A pharmaceutical composition, characterized in that, Comprising: an active ingredient which is bupivacaine or a pharmaceutically acceptable salt thereof; a fatty acid ester; phospholipids having the structure shown in the following formula (I): in the formula (I), each R1 independently represents a saturated or unsaturated linear or branched alkyl group having a carbon number of 9 to 17, and each R2 independently represents a methyl group or an ethyl group; and a first saturated fatty acid having a carbon number of 12 to 16, and wherein the weight ratio of the active ingredient, the fatty acid ester, and the phospholipid is 1:2.5 to 3.5:0.5 to 2.0, and based on the content of the phospholipid being 100 weight percent, the content of the first saturated fatty acid is greater than 1.0 weight percent to less than 15 weight percent.

2. The pharmaceutical composition of claim 1, wherein wherein the fatty acid ester is selected from at least one of the group consisting of a monoglyceride, a diglyceride, and a triglyceride.

3. The pharmaceutical composition of claim 2, wherein wherein the carbon number of the fatty acid residue of the monoglyceride, the fatty acid residue of the diglyceride, and the fatty acid residue of the triglyceride is 14 to 22.

4. The pharmaceutical composition of claim 1, wherein wherein the pharmaceutical composition further comprises a second saturated fatty acid having a carbon number of 17 to 20, and based on the content of the fatty acid ester being 100 weight percent, the content of the second saturated fatty acid is greater than 0.06 weight percent.

5. The pharmaceutical composition of claim 1, wherein wherein the pharmaceutical composition further comprises lysophosphatidylcholine, the carbon number of the fatty acid residue of the lysophosphatidylcholine is 10 to 18, and based on the content of the phospholipid being 100 weight percent, the content of the lysophosphatidylcholine is 0.25 weight percent to 15 weight percent.

6. The pharmaceutical composition of claim 1, wherein wherein the content of the first saturated fatty acid is 1.5 weight percent to 10 weight percent.

7. A granule characterised in that, consisting of the pharmaceutical composition of any one of claims 1 to 6; wherein the D10 particle size of the granules is 2 μm to less than 13 μm, the D50 particle size of the granules is 5.5 μm to 24 μm, and the D90 particle size of the granules is 16 μm to 50 μm.

8. A needle characterized in that, comprising the granules of claim 7.

9. The needle of claim 8, wherein wherein the injection is subjected to a dissolution test at 36.5°C to 37.5°C in a USP Type II dissolution apparatus using a phosphate buffer having a pH of 7 and a volume of 990 mL at a rotation speed of 50 rpm, at 1 hour, the first dissolution rate of the active ingredient is 40% to 80%; at 3 hours, the second dissolution rate of the active ingredient is 55% to less than 86%; and at 6 hours, the third dissolution rate of the active ingredient is 70% to less than 88.8%.

10. The needle of claim 8 or 9, wherein wherein the injection is a lyophilized powder or a suspension.

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