Microsphere for sustained release comprising ropivacaine

Abstract

A microsphere comprising ropivacaine, a release enhancer, and a biodegradable polymer, according to the present invention, has a high content of ropivacaine as an active ingredient, and controls drug release at a low level for up to 1 hour after administration of the microsphere, prior to the surgical patient's emergence from anesthesia, while releasing a sufficient amount of the drug from 2 hours (or 4 hours) to 1 day, during which severe pain occurs due to the emergence from anesthesia, and thus can be effectively used as an injectable composition for reducing pain after surgery.

Description

Sustained-release microspheres containing ropivacaine

[0001] The present invention relates to sustained-release microspheres comprising ropivacaine, and more specifically, to microspheres comprising an active ingredient selected from the group consisting of ropivacaine and pharmaceutically acceptable salts thereof, a release enhancer, and a biodegradable polymer, which can preferably be used for pain reduction or elimination, and an injectable formulation comprising the same.

[0002] As a treatment for postoperative pain, amide-based local anesthetics such as bupivacaine, lidocaine, and ropivacaine are prescribed, and among them, a sustained-release bupivacaine formulation (Exparel) was developed overseas and is being prescribed.

[0003] Ropivacaine is a relatively long-acting local anesthetic among amide-based local anesthetics. It is also known by its chemical name (S)-(-)-1-propylpipecolic acid 2,6-xylidide, and its hydrochloride salt is widely marketed under the trade name Naropin by AstraZeneca. This compound is a local anesthetic described in European Patent No. 0 239 710. The mechanism of action of ropivacaine is the same as that of other local anesthetics; specifically, it inhibits nerve impulses and conduction by inhibiting sodium channels in nerve cells.

[0004] Ropivacaine differs significantly in physicochemical properties from other local anesthetics, such as bupivacaine. For example, the lipophilicity of bupivacaine and ropivacaine is 30 and 2.8, respectively, and their partition coefficients are 28 and 9, respectively, showing a large difference. Compared to other local anesthetics such as bupivacaine, ropivacaine has the advantage of a shorter onset time, stronger dissociation and blockade, and, being relatively hydrophilic, acts selectively on Aδ or C nerve fibers rather than Aβ nerve fibers, thereby reducing the risk of serious side effects such as cardiotoxicity and central nervous system toxicity. Ropivacaine is known to be relatively safe when its blood concentration is maintained at approximately 2000 ng / mL or lower.

[0005] Currently, ropivacaine hydrochloride injection is primarily used for clinical anesthesia and the treatment of postoperative pain. Postoperative pain associated with all forms of surgery, such as major surgery (e.g., thoracotomy, aortic treatment, and bowel resection), intermediate surgery (e.g., cesarean section, hysterectomy, and appendectomy), and minor surgery (e.g., hernia repair, laparoscopy, arthroscopy, breast biopsy), can persist for 2 to 5 days after surgery.

[0006] It has been reported that such postoperative pain is most severe from 2 to 4 hours after the anesthetic effect wears off until 24 hours, and continues with gradual recovery for 2 to 5 days or even 7 days or more. Although opioid analgesics can be used to control this postoperative pain, their analgesic effect is quite short, requiring frequent administration. In particular, frequent administration may be required within 24 hours of surgery, which can lead to many side effects and, in severe cases, can result in the patient's death.

[0007] In addition, local anesthetics such as ropivacaine can be used to control postoperative pain, similar to narcotic analgesics, but they provide a local anesthetic effect that lasts only a few hours and does not exceed one day. Consequently, there are problems such as the need for frequent administration, relatively high medical costs, and potential discomfort for patients after surgery, which has led to attempts to develop a local drug delivery system capable of providing sustained release.

[0008] However, while it is desirable for the pain-relieving effect after surgery to last only during the treatment period, there is a disadvantage that the pharmacological effect may be maintained unnecessarily if sustained release is not controlled for an appropriate period. Furthermore, in the case of microsphere formulations containing a high concentration of the drug, there is generally a concern that side effects may occur due to the problem of excessive initial burst. Accordingly, there is a need to develop a drug delivery system for ropivacaine that can provide sustained release over a short period to maintain an appropriate body concentration for a desired period after administration, specifically releasing enough drug to produce a sufficient analgesic effect within 2 to 4 hours after the anesthetic effect wears off and within 24 hours when the most severe pain occurs, and continuously releasing the drug to control pain within 2 to 7 days or 2 to 11 days.

[0009] The present invention is proposed to solve the above-mentioned problems and aims to provide microspheres with an optimized drug release pattern so that local anesthetic or analgesic effects can be maximized at the time when pain is most severe after the anesthesia wears off during surgery, while containing a high amount of ropivacaine free base or a pharmaceutically acceptable salt thereof as an active ingredient within the microspheres.

[0010] In addition, the present invention aims to provide a local anesthetic or analgesic injectable composition comprising the microspheres used to reduce postoperative pain.

[0011] Furthermore, the present invention aims to provide a method for manufacturing the above-mentioned microspheres.

[0012] The present disclosure is summarized as follows:

[0013] 1. As an active ingredient, ropivacaine free base or a pharmaceutically acceptable salt thereof;

[0014] As a biodegradable polymer, 1 to 2 types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA); and

[0015] As a release enhancer, the microsphere comprises one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers; and

[0016] Microspheres comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres.

[0017]

[0018] 2. Microspheres according to claim 1, wherein the ropivacaine free base or a pharmaceutically acceptable salt thereof is in crystalline or amorphous form.

[0019]

[0020] 3. Microspheres, wherein, in any one of the preceding claims, the ropivacaine free base is in a crystalline form having major diffraction peaks of 10.45°, 13.00°, 14.26°, 16.40°, 19.03°, 19.39°, 19.93°, 20.26°, 21.65°, 23.63°, 24.35°, 26.21°, and 31.79° at Bragg angles (2θ±0.2°) in X-ray diffraction analysis (CuKα).

[0021]

[0022] 4. Microspheres in which, in any one of the preceding claims, the release increasing agent is included in an amount of 0.1 to 10 weight percent relative to the total weight of the microspheres.

[0023] 5. In any one of the preceding paragraphs above, as the release enhancer,

[0024] The above amphiphilic polymer is poloxamer, and

[0025] The above hydrophilic polymer is PEG (Polyethyleneglycol), and

[0026] Microspheres in which the above hydrophobic monomer is one or more of lactide and glycolide.

[0027]

[0028] 6. In any one of the preceding paragraphs above,

[0029] As the above-mentioned release enhancer,

[0030] The above amphiphilic polymer is a poloxamer with a weight-average molecular weight of 4,000 g / mol or more, and

[0031] The above hydrophilic polymer is PEG (Polyethyleneglycol) with a weight-average molecular weight of 2,000 g / mol or more, and

[0032] Microspheres in which the above hydrophobic monomer is one or more of lactide and glycolide.

[0033]

[0034] 7. As the above-mentioned release enhancer,

[0035] The above amphiphilic polymer is a poloxamer with a weight-average molecular weight of 4,000 to 20,000 g / mol, and

[0036] The above hydrophilic polymer is PEG (Polyethyleneglycol) with a weight-average molecular weight of 2,000 to 20,000 g / mol, and

[0037] Microspheres in which the hydrophobic monomer is lactide or glycolide.

[0038]

[0039] 8. Microspheres, wherein, in any one of the preceding claims, the biodegradable polymer satisfies one or more selected from the group consisting of (i) to (iii) below:

[0040] (i) Intrinsic viscosity 0.1 to 0.7 dL / g;

[0041] (ii) weight-average molecular weight 4,000 to 60,000 g / mol;

[0042] (iii) One or both ends are a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group.

[0043]

[0044] 9. Microspheres, wherein, in any one of the preceding claims, the biodegradable polymer is a poly(lactide-co-glycolide) (PLGA) satisfying one or more selected from the group consisting of (i) to (iv) below:

[0045] (i) Intrinsic viscosity 0.1 to 0.7 dL / g;

[0046] (ii) weight-average molecular weight 4,000 to 60,000 g / mol;

[0047] (iii) one or both ends are a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group;

[0048] (iv) Lactide:glycolide repeating unit molar ratio 40:60 to 99:1.

[0049]

[0050] 10. Microspheres according to any one of the preceding claims, wherein, when administered by subcutaneous injection to SD rats (Sprague-Dawley Rat), the cumulative drug release rate up to 4 hours after administration is 40 to 80, compared to the cumulative drug release rate up to 1 day after administration.

[0051]

[0052] 11. Microspheres having a cumulative drug release rate of 15% or less up to 1 hour after administration and a cumulative drug release rate of 65% or more up to 1 day after administration, in any one of the preceding paragraphs.

[0053]

[0054] 12. Microspheres according to any one of the preceding paragraphs, wherein the cumulative drug release rate up to 4 hours after administration is 20 to 50% and the cumulative drug release rate up to 1 day after administration is 70% or more.

[0055]

[0056] 13. Microspheres in which, in any one of the preceding paragraphs, the cumulative drug release rate up to 1 day after administration is 75% or more, and the release of residual drug is completed within 2 to 7 days or 2 to 11 days after administration.

[0057]

[0058] 14. Microspheres having a cumulative drug release rate of 80 to 100% up to 3 days after administration, in any one of the preceding paragraphs.

[0059]

[0060] 15. Microspheres having an average particle size of 10 to 150 μm and a porous shape, in any one of the preceding claims.

[0061]

[0062] 16. In any one of the preceding paragraphs above,

[0063] (i) microspheres according to paragraph 1; or

[0064] (ii) a microsphere blend comprising a combination of 2-3 types of microspheres of (i) having different compositions from each other; and

[0065] The 2-3 types of microspheres in the microsphere blend of (ii) above comprise different biodegradable polymers and / or release enhancers, or the 2-3 types of microspheres in the microsphere blend of (ii) above comprise different amounts of biodegradable polymers, release enhancers, and / or active ingredients.

[0066] Injectable composition for local anesthesia or analgesia.

[0067]

[0068] 17. An injectable composition used for reducing postoperative pain in any one of the preceding paragraphs.

[0069]

[0070] 18. (a) a step of forming an emulsion by mixing a dispersed phase comprising an active ingredient, a biodegradable polymer, a release enhancer, and an organic solvent with a continuous phase comprising a surfactant and water; and

[0071] (b) a step of preparing microspheres by extracting the organic solvent in the dispersed phase from the emulsion of step (a) toward the continuous phase; comprising,

[0072] The above active ingredient is a free base of ropivacaine or a pharmaceutically acceptable salt thereof, and

[0073] The above biodegradable polymer is one to two types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA), and

[0074] The above-mentioned release enhancer is one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers, and

[0075] Comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres,

[0076] A method for manufacturing microspheres according to any one of the preceding claims.

[0077]

[0078]

[0079] In order to achieve the above objective,

[0080] The present invention is,

[0081] As an active ingredient, ropivacaine free base or a pharmaceutically acceptable salt thereof;

[0082] As a biodegradable polymer, 1 to 2 types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA); and

[0083] As a release enhancer, the microsphere comprises one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers; and

[0084] Microspheres comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres are provided.

[0085]

[0086] In addition, the present invention,

[0087] (i) the microspheres according to the present invention; or

[0088] (ii) a microsphere blend comprising a combination of 2-3 types of microspheres of (i) having different compositions from each other; and

[0089] The 2-3 types of microspheres in the microsphere blend of (ii) above comprise different biodegradable polymers and / or release enhancers, or the 2-3 types of microspheres in the microsphere blend of (ii) above comprise different amounts of biodegradable polymers, release enhancers, and / or active ingredients.

[0090] Provides a composition for local anesthesia or analgesia injection.

[0091]

[0092] Furthermore, the present invention,

[0093] (a) a step of forming an emulsion by mixing a dispersed phase comprising an active ingredient, a biodegradable polymer, a release enhancer, and an organic solvent with a continuous phase comprising a surfactant and water; and

[0094] (b) a step of preparing microspheres by extracting the organic solvent in the dispersed phase from the emulsion of step (a) toward the continuous phase; comprising,

[0095] The above active ingredient is a free base of ropivacaine or a pharmaceutically acceptable salt thereof, and

[0096] The above biodegradable polymer is one to two types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA), and

[0097] The above-mentioned release enhancer is one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers, and

[0098] Comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres,

[0099] The present invention provides a method for manufacturing the above microspheres according to the present invention.

[0100]

[0101] Microspheres comprising ropivacaine, a release enhancer, and a biodegradable polymer according to the present invention contain a high amount of ropivacaine, which is an active ingredient, while controlling the drug release amount to a low level for up to 1 hour after administration of the microspheres before the surgical patient wakes up from anesthesia, and sufficiently releasing the drug release amount within 2 hours (or 4 hours) to 1 day when the surgical patient wakes up from anesthesia and severe pain occurs, so they can be useful as an injectable composition for reducing postoperative pain.

[0102]

[0103] Figure 1 is a graph showing the blood concentrations confirmed according to a single-dose pharmacokinetic test using rats of Experimental Example 4.

[0104] Figure 2 is a graph showing the cumulative release rate of the drug confirmed according to a single-dose pharmacokinetic test using rats in Experimental Example 4.

[0105] Figure 3 shows a scanning electron microscope image of microspheres prepared according to Example 8.

[0106]

[0107] Definition of Terms

[0108] The term "one or more types" in the present invention means a "number" corresponding to one or more. In the present invention, if a certain composition is one or more types, it may preferably be one type, two or more types, three or more types, one to three types, or one to two types, but is not limited thereto. The term "one or more types" may be used interchangeably with the term "one or more" in the present invention.

[0109] The term “microsphere” in the present invention refers to a spherical particle having an average particle size of several to several hundred μm. Although not limited thereto, for example, the microsphere may be a microsphere having an average particle size of 1 to 500 μm, 1 to 250 μm, 1 to 150 μm, and particularly 10 to 150 μm.

[0110] The term "microsphere blending (blend)" of the present invention refers to a blend of two or more types of microspheres having different compositions. The term "different compositions" means that one or more of the compositions constituting the microspheres are different from each other, and such compositions include drugs, polymer types, etc., but are not limited thereto.

[0111]

[0112] The present invention will be described in detail below.

[0113]

[0114] The present invention is,

[0115] As an active ingredient, ropivacaine free base or a pharmaceutically acceptable salt thereof;

[0116] As a biodegradable polymer, 1 to 2 types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA); and

[0117] As a release enhancer, the microsphere comprises one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers; and

[0118] Microspheres comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres are provided.

[0119]

[0120] In one aspect of the present invention, the content of the active ingredient may be 40 to 80 weight%, 40 to 75 weight%, 40 to 70 weight%, 40 to 65 weight%, 40 to 60 weight%, or 42 to 58 weight% relative to the total weight of the microspheres.

[0121]

[0122] In the present invention, the term "ropivacaine" is a generic name having the chemical formula name 1-propylpipecolic acid 2,6-xylidide and is represented by the structure of Chemical Formula 1 below.

[0123] [Chemical Formula 1]

[0124]

[0125]

[0126] The ropivacaine used in the present invention may be an (S)-type enantiomer, namely (S)-ropivacaine ((S)-(-)-1-propylpipecolic acid 2,6-xylidide).

[0127] Such ropivacaine may be manufactured according to the method disclosed in known technology, such as European Patent No. 0 239 710, for example, or a commercially available product may be used.

[0128] The active ingredient of the present invention, ropivacaine, may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Any salt commonly used in the art may be used without limitation. The term “pharmaceutically acceptable salt” in the present invention refers to any organic or inorganic additive salt of the said compound at a concentration that has a relatively non-toxic and harmless active effect on the patient, such that side effects caused by the salt do not impair the beneficial efficacy of ropivacaine. Specific examples include, but are not limited to, hydrochloride and mesylate salts of ropivacaine.

[0129]

[0130] In one embodiment, the ropivacaine free base of the present invention or a pharmaceutically acceptable salt thereof may be amorphous or crystalline.

[0131] For example, the above ropivacaine free base may be in a crystalline form having major diffraction peaks at Bragg angles (2θ±0.20°) of 10.45°, 13.00°, 14.26°, 16.40°, 19.03°, 19.39°, 19.93°, 20.26°, 21.65°, 23.63°, 24.35°, 26.21°, and 31.79° in X-ray diffraction analysis (CuKa).

[0132]

[0133] The above-mentioned release enhancer can be seen as a component for implementing an optimal release pattern for reducing postoperative pain, which includes a high concentration of the active ingredient ropivacaine, while controlling the drug release amount to a low level up to 1 hour after microball administration before the anesthesia wears off during surgery, and releasing a sufficient amount of drug within 2 hours (or 4 hours) to 1 day after the anesthesia wears off and severe pain occurs.

[0134] In one aspect of the present invention, the content of the release-increasing agent in the microspheres may be selected as a lower limit of 0.1 wt% or more, 0.2 wt% or more, 0.3 wt% or more, 0.4 wt% or more, 0.5 wt% or more, 0.6 wt% or more, 0.7 wt% or more, or 0.8 wt% or more with respect to the total weight of the microspheres, and as an upper limit of 10 wt% or less, 9 wt% or less, 8 wt%, 7 wt% or less, 6 wt% or less, or 5 wt% or less. In one example, the content of the release-increasing agent in the microspheres may correspond to a range consisting of a combination of the lower and upper limits with respect to the total weight of the microspheres. Specifically, the content of the release enhancer in the microspheres may be 0.1 to 10 wt%, 0.1 to 9 wt%, 0.1 to 8 wt%, 0.1 to 7 wt%, 0.1 to 6 wt%, 0.1 to 5 wt%, 0.3 to 10 wt%, 0.3 to 9 wt%, 0.3 to 8 wt%, 0.3 to 7 wt%, 0.3 to 6 wt%, or 0.3 to 5 wt% based on the total weight of the microspheres, but is not limited thereto.

[0135] If the content of the above-mentioned release enhancer is less than 0.1% by weight, there may be a problem that the amount of drug released within 2 hours (or 4 hours) to 1 day, when the anesthesia wears off and severe pain occurs, is insufficient, and if it exceeds 10% by weight, there may be a problem that the amount of drug released within 1 hour after administration of microspheres, before the anesthesia wears off during surgery, is excessive.

[0136]

[0137] In one aspect of the present invention, the release enhancer may be one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers.

[0138] Specifically, the amphiphilic polymer is poloxamer, the hydrophilic polymer is PEG (Polyethyleneglycol), and the hydrophobic monomer may be one or more of lactide and glycolide.

[0139] More specifically, the amphiphilic polymer is a poloxamer with a weight-average molecular weight of 4,000 g / mol or more, the hydrophilic polymer is a PEG (Polyethyleneglycol) with a weight-average molecular weight of 2,000 g / mol or more, and the hydrophobic monomer may be lactide and / or glycolide.

[0140] More specifically, the amphiphilic polymer is a poloxamer with a weight-average molecular weight of 4,000 to 20,000 g / mol, the hydrophilic polymer is a PEG (Polyethyleneglycol) with a weight-average molecular weight of 2,000 to 20,000 g / mol, and the hydrophobic monomer may be lactide or glycolide.

[0141] The weight-average molecular weight of the above poloxamer is 4,000 to 20,000 g / mol, 5,000 to 20,000 g / mol, 6,000 to 20,000 g / mol, 7,000 to 20,000 g / mol, 8,000 to 20,000 g / mol, 4,000 to 15,000 g / mol, 5,000 to 15,000 g / mol, 6,000 to 15,000 g / mol, 7,000 to 15,000 g / mol, 8,000 to 15,000 g / mol, 4,000 to 13,000 g / mol, 5,000 to 13,000 g / mol, 6,000 to 13,000 g / mol, It may be 7,000 to 13,000 g / mol, or 8,000 to 13,000 g / mol.

[0142] The weight-average molecular weight of the above PEG may be 2,000 to 20,000 g / mol, 2,500 to 20,000 g / mol, 3,000 to 20,000 g / mol, 2,000 to 15,000 g / mol, 2,500 to 15,000 g / mol, 3,000 to 15,000 g / mol, 2,000 to 10,000 g / mol, 2,500 to 10,000 g / mol, or 3,000 to 10,000 g / mol.

[0143] If the weight-average molecular weight range of the poloxamer and PEG described above is exceeded, there may be a problem in that the desired drug release pattern is not achieved in the microspheres according to the present invention. The desired drug release pattern is to control the drug release amount to a low level up to 1 hour after administration of the microspheres, before the anesthesia wears off during surgery, while ensuring sufficient drug release amount within 2 hours (or 4 hours) to 1 day, when the anesthesia wears off and severe pain occurs.

[0144]

[0145] The above-mentioned biodegradable polymer acts as a matrix of the active ingredient within the microspheres.

[0146] In one aspect of the present invention, as the biodegradable polymer, one or two types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA) may be used. For example, PLA or PLGA may be used alone, PLA and PLGA may be used in combination, or two different types of PLGA may be used in combination. Specifically, PLGA may be used alone as the biodegradable polymer.

[0147] In one embodiment, the biodegradable polymer may satisfy one or more selected from the group consisting of (i) to (iii) below.

[0148] (i) Intrinsic viscosity 0.1 to 0.7 dL / g;

[0149] (ii) weight-average molecular weight 4,000 to 60,000 g / mol;

[0150] (iii) One or both ends are a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group.

[0151] In a specific embodiment, the biodegradable polymer may be a poly(lactide-co-glycolide) (PLGA) satisfying one or more selected from the group consisting of (i) to (iv) below.

[0152] (i) Intrinsic viscosity 0.1 to 0.7 dL / g;

[0153] (ii) weight-average molecular weight 4,000 to 60,000 g / mol;

[0154] (iii) one or both ends are a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group;

[0155] (iv) Lactide:glycolide repeating unit molar ratio 40:60 to 99:1.

[0156]

[0157] In a more specific embodiment, the biodegradable polymer may be a poly(lactide-co-glycolide) (PLGA) satisfying one or more selected from the group consisting of (i) to (iii) below.

[0158] (i) Intrinsic viscosity 0.14 to 0.46 dL / g (specifically 0.16 to 0.44 dL / g);

[0159] (ii) one or both ends are a hydroxyl group or a carboxyl group (specifically, a carboxyl group);

[0160] (iii) Lactide:glycolide repeating unit molar ratio 50:50 to 65:35 (specifically 50:50).

[0161]

[0162] In one example, the intrinsic viscosity of the biodegradable polymer is 0.1 to 0.7 dL / g, 0.1 to 0.6 dL / g, 0.1 to 0.5 dL / g, 0.12 to 0.7 dL / g, 0.12 to 0.6 dL / g, 0.12 to 0.5 dL / g, 0.14 to 0.7 dL / g, 0.14 to 0.6 dL / g, 0.14 to 0.5 dL / g, 0.14 to 0.7 dL / g, 0.14 to 0.6 dL / g, 0.14 to 0.5 dL / g, 0.14 to 0.48 dL / g, 0.14 to 0.46 dL / g, or 0.16 to It can be 0.44 dL / g.

[0163] In one example, the intrinsic viscosity may be measured at a concentration of 0.1% (w / v) in chloroform at 25°C using a Ubbelohde viscometer.

[0164] If the intrinsic viscosity of the above biodegradable polymer exceeds the upper limit, there may be a problem such as the release of the drug being delayed too much (occurrence of a lag phase), and if the intrinsic viscosity of the above biodegradable polymer is below the lower limit, the molecular weight of the polymer is insufficient, so there may be a problem such as excessive drug release occurring in the initial period (within 1 hour) or difficulty in exhibiting a sustained-release pattern for 2 to 7 days or 2 to 11 days.

[0165] The weight-average molecular weight of the above-mentioned biodegradable polymer is a value correlated with intrinsic viscosity, and if the intrinsic viscosity is limited, a separate limitation of the weight-average molecular weight may not be necessary. In one example, the lower limit of the weight-average molecular weight of the biodegradable polymer may be 4,000 or more, 5,000 or more, 6,000 or more, 7,000 or more, 8,000 or more, 9,000 or more, 10,000 or more, 15,000 or more, 20,000 or more, 21,000 or more, 22,000 or more, 23,000 or more, or 24,000 or more, and the upper limit may be 60,000 or less, 50,000 or less, 40,000 or less, 38,000 or less, 35,000 or less, 30,000 or less, or 28,000 or less, and may be a range consisting of a combination of the upper and lower limits.

[0166] In one example, one or both ends of the biodegradable polymer may be a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group. Specifically, it may be a hydroxyl group or a carboxyl group, and more specifically, it may be a carboxyl group.

[0167] When using the above poly(lactide-co-glycolide), the molar ratio of lactide:glycolide repeating units in the copolymer may be 40:60 to 99:1, 45:55 to 95:5, 50:50 to 85:15, 50:50 to 75:25, or 50:50 to 65:35, specifically 50:50, 65:35, 75:25, or 85:15, and more specifically 50:50 or 65:35.

[0168]

[0169] Commercially available examples of the above polymers include Evonik’s Resomer series RG502H, RG503H, RG504H, RG502, RG503, RG504, RG653H, RG752H, RG753H, RG752S, RG755S, RG756S, RG858S, R202H, R203H, R205H, R202S, R203S, R205S, and Covion’s PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG 7502, PDLG 7507, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG 5004, PDLG Examples include 5010, PDL 20, PDL 45, etc. Specific examples include Resomer RG502H, RG503H, RG652H, RG653H, RG752H, RG753H, RG852H, RG853H, and combinations thereof.

[0170] The above biodegradable polymer may be included in an amount of 20 to 59.9 wt%, 25 to 59.9 wt%, 30 to 59.9 wt%, 35 to 59.9 wt%, 40 to 59.9 wt%, 41 to 59.9 wt%, 42 to 59.9 wt%, 43 to 59.9 wt%, 44 to 59.9 wt%, or 45 to 59.9 wt% relative to the total weight of the microspheres.

[0171] In an in-vitro experiment of microspheres according to the present invention, the drug release pattern may be such that the cumulative drug release rate up to 3 hours is 20 to 55 weight%, the cumulative drug release rate up to 1 day is 40 to 80 weight%, and the cumulative drug release rate up to 2 days is 50 to 95 weight% or 55 to 90 weight%.

[0172]

[0173] In an in-vivo experiment in which microspheres according to the present invention are administered subcutaneously to SD rats (Sprague-Dawley Rats), the drug release pattern may be such that the amount of drug released from the cumulative drug release rate up to 4 hours after administration, i.e., the amount released from 4 hours after administration to 24 hours after administration, is 40 to 80 (%p) relative to the total weight of the drug administered.

[0174] In addition, the cumulative drug release rate from 4 hours after administration up to 24 hours may be 40 to 80 (%p).

[0175] In addition, the cumulative drug release rate up to 1 hour after administration may be 15% or less, and the cumulative drug release rate up to 1 day after administration may be 65% or more.

[0176] Furthermore, the cumulative drug release rate up to 4 hours after administration may be 20 to 50%, and the cumulative drug release rate up to 1 day after administration may be 70% or more.

[0177] In addition, the cumulative drug release rate up to 1 day after administration may be 75% or more, and the release of residual drug may be completed within 2 to 7 days or 2 to 11 days after administration.

[0178] Furthermore, the cumulative drug release rate up to 3 days after administration may be 80 to 100%.

[0179] For example, the value obtained by subtracting the cumulative drug release rate up to 4 hours after administration from the cumulative drug release rate up to 1 day after administration may be 40 to 80 (%p), the cumulative drug release rate up to 1 hour after administration may be 15% or less, and the cumulative drug release rate up to 1 day after administration may be 65% or more.

[0180] As another example, the value obtained by subtracting the cumulative drug release rate up to 4 hours after administration from the cumulative drug release rate up to 1 day after administration may be 40 to 80 (%p), the cumulative drug release rate up to 1 hour after administration may be 15% or less, the cumulative drug release rate up to 4 hours after administration may be 20 to 50%, and the cumulative drug release rate up to 1 day after administration may be 70% or more.

[0181] As another example, the value obtained by subtracting the cumulative drug release rate up to 4 hours after administration from the cumulative drug release rate up to 1 day after administration is 40 to 80 (%p), the cumulative drug release rate up to 1 hour after administration is 15% or less, the cumulative drug release rate up to 4 hours after administration is 20 to 50%, the cumulative drug release rate up to 1 day after administration is 75% or more, and the release of residual drug may be completed within 2 to 7 days or 2 to 11 days after administration.

[0182] As another example, the value obtained by subtracting the cumulative drug release rate up to 4 hours after administration from the cumulative drug release rate up to 1 day after administration may be 40 to 80 (%p), the cumulative drug release rate up to 1 hour after administration may be 15% or less, the cumulative drug release rate up to 4 hours after administration may be 20 to 50%, the cumulative drug release rate up to 1 day after administration may be 75% or more, and the cumulative drug release rate up to 3 days after administration may be 80 to 100%.

[0183]

[0184] In the above description, the in vivo behavior (PK profile) of the drug released from the microspheres according to the present invention was explained based on the SD Rat, which is a small animal. That is, rather than directly limiting the PK profile in the human body, a standardized test method called 'SD Rat subcutaneous injection' was used as a standard to confirm the unique release characteristics of the microspheres according to the present invention (see Experimental Example 4).

[0185] According to the conventional allometric scaling theory in the field of pharmacokinetics, the point at which blood concentration reaches its peak in small animals (T max ) tends to appear faster than in large animals. This is because, as one moves from small animals to large animals (such as humans), for example, as the body weight of the subject being administered becomes heavier, the metabolic rate, heart rate, and blood circulation rate slow down, thus delaying the absolute time required for the absorption, distribution, and excretion of the drug.

[0186] Therefore, the drug release pattern confirmed in SD Rat Experimental Example 4 of the present invention is such that, even when administered to the human body, the point at which the blood concentration reaches its peak (T max Although the release may be delayed somewhat, it may exhibit a tendency similar to the drug release pattern observed in SD rats. That is, for humans as well, the amount of drug released up to 1 hour after administration of microspheres, before the anesthesia wears off during surgery, can be controlled to a low level, while the amount of drug released within 2 hours (or 4 hours) to 1 day, when the anesthesia wears off and severe pain occurs, can be sufficiently released.

[0187]

[0188] Upon completion of surgery, microspheres containing ropivacaine according to the present invention are injected in various locations around the surgical site, and approximately 2 to 4 hours after surgery, the anesthesia of the surgical patient begins to wear off. That is, the period between 2 (or 4) and 24 hours after surgery is the time when the surgical anesthesia wears off and pain is most severe, and it may be desirable for the amount of drug released during this time to be as high as possible. After 24 hours after surgery, it is a period when pain gradually decreases, and it may be desirable for the amount of drug released during this time to gradually decrease and be maintained for about 2 to 7 days or 2 to 11 days.

[0189] The microspheres according to the present invention contain a high amount of the active ingredient ropivacaine, and while the amount of drug released up to 1 hour after administration of the microspheres before the anesthesia wears off during surgery is controlled to a low level, the amount of drug released within 2 hours (or 4 hours) to 1 day after the anesthesia wears off and severe pain occurs is sufficiently released.

[0190]

[0191] The particle size of the microspheres according to the present invention is preferably 10 μm or more, 20 μm or more as an average particle size, preferably 10 to 150 μm, 15 to 150 μm, 20 to 150 μm, 20 to 140 μm, 20 to 130 μm, 20 to 100 μm, 20 to 80 μm, or 20 to 60 μm, and it is desirable to have a uniform particle size distribution. The term "average particle size" used in the present invention refers to a particle size corresponding to 50% of the volume in the particle size distribution curve, and is indicated as D50 or D(v, 0.5).

[0192] The microspheres according to the present invention may have a porous shape.

[0193]

[0194] In addition, the present invention,

[0195] (i) the microspheres according to the present invention; or

[0196] (ii) a microsphere blend comprising a combination of 2-3 types of microspheres of (i) having different compositions from each other; and

[0197] The 2-3 types of microspheres in the microsphere blend of (ii) above comprise different biodegradable polymers and / or release enhancers, or the 2-3 types of microspheres in the microsphere blend of (ii) above comprise different amounts of biodegradable polymers, release enhancers, and / or active ingredients.

[0198] Provides a composition for local anesthesia or analgesia injection.

[0199] The injectable composition according to the present invention may be used to reduce postoperative pain.

[0200]

[0201] The injectable composition according to the present invention may include, in addition to microspheres containing an active ingredient, a sterile aqueous solution, a non-aqueous solvent, a suspending agent, an emulsion, a lyophilized preparation, etc. As non-aqueous solvents and suspending agents, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, medium-chain triglycerides (MCT), etc. may be used.

[0202] The pharmaceutical composition according to the present invention may be administered to subjects, such as mammals including humans, rats, mice, dogs, cats, and livestock, by injection via various routes. The pharmaceutical composition according to the present invention may be administered via an optimal route in which the drug contained within the microspheres can immediately produce an anesthetic or analgesic effect at the desired site, for example, by local injection. Additionally, as examples of such local injection administration, it may be administered via routes such as intramuscular administration or subcutaneous administration. The preferred dosage of the pharmaceutical composition according to the present invention varies depending on the condition and body weight of the subject (human or animal), the size of the surgical site, the degree of anesthetic or analgesic effect required, the route of administration, and the duration, and may be appropriately adjusted or selected by a person skilled in the art.

[0203]

[0204] Furthermore, the present invention,

[0205] (a) a step of forming an emulsion by mixing a dispersed phase comprising an active ingredient, a biodegradable polymer, a release enhancer, and an organic solvent with a continuous phase comprising a surfactant and water; and

[0206] (b) a step of preparing microspheres by extracting the organic solvent in the dispersed phase from the emulsion of step (a) toward the continuous phase; comprising,

[0207] The above active ingredient is a free base of ropivacaine or a pharmaceutically acceptable salt thereof, and

[0208] The above biodegradable polymer is one to two types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA), and

[0209] The above-mentioned release enhancer is one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers, and

[0210] Comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres,

[0211] The present invention provides a method for manufacturing microspheres.

[0212]

[0213] In the manufacturing method of the present invention, the detailed description regarding the active ingredient, biodegradable polymer, and release enhancer is replaced by the description above for the microspheres according to the present invention.

[0214]

[0215] In the manufacturing method according to the present invention, the organic solvent used in step (a) refers to a substance capable of dissolving a biodegradable polymer, a release enhancer, and / or the active ingredient, and can be easily and appropriately selected by a person with ordinary knowledge in the art depending on the type of biodegradable polymer, and may be dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, dimethylformamide, ethyl acetate, glacial acetic acid, formic acid, or a mixture thereof.

[0216]

[0217] In the manufacturing method according to the present invention, the water used in step (a) may be purified water, distilled water, water for injection, etc. The surfactant is not limited to a specific type and may be used as long as it causes the dispersed phase to be dispersed into stable droplets within the continuous phase when the continuous phase is mixed with the dispersed phase to form an emulsion. In one example, the surfactant may be a single type selected from polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil derivative, or a mixture of two or more types. In one example, the surfactant may be polyvinyl alcohol. For example, the content of the surfactant in the continuous phase may be 0.01 w / v% to 20 w / v%, 0.03 w / v% to 18 w / v%, 0.05 w / v% to 15 w / v%, 0.07 w / v% to 10 w / v%, or 0.1 w / v% to 5 w / v% based on the total volume of the continuous phase containing the surfactant, but is not limited thereto. If the content of the surfactant is less than 0.01 w / v% relative to the total volume of the continuous phase, an emulsion in which the dispersed phase in the form of droplets is dispersed within the continuous phase may not be formed when the dispersed phase and the continuous phase are mixed. Additionally, if the content of the surfactant exceeds 20 w / v% relative to the total volume of the continuous phase, an excess amount of surfactant remains, so it may be difficult to remove the surfactant after microspheres are formed within the continuous phase.

[0218]

[0219] In the manufacturing method according to the present invention, the method of mixing the dispersed phase and the continuous phase in step (a) is not particularly limited, but can be performed using a high-speed stirrer, an inline mixer, a static mixer, a membrane emulsification method, a microfluidic emulsification method, etc. When forming an emulsion using a high-speed stirrer, an inline mixer, or a static mixer, it is difficult to obtain a uniform emulsion, so it is preferable to perform an additional sieving process, etc. after step (b) described later. When using a membrane emulsification method or a microfluidic emulsification method, an emulsion of uniform size can be obtained, so an additional sieving process, etc. is not required after step (b) described later, which is more preferable.

[0220]

[0221] In the manufacturing method according to the present invention, in step (b), if an emulsion comprising a droplet-shaped dispersed phase and a continuous phase containing a surfactant is maintained or stirred at a temperature below the boiling point of the organic solvent for a certain period of time, for example, 2 to 48 hours, the organic solvent can be extracted from the droplet-shaped dispersed phase into the continuous phase. A portion of the organic solvent extracted into the continuous phase can evaporate from the surface of the particulate composition. As the organic solvent is extracted and evaporated from the droplet-shaped dispersed phase, the droplet-shaped dispersed phase may solidify to form microspheres.

[0222] In order to further efficiently remove the organic solvent in step (b) above, heat can be applied to the continuous phase for a certain period of time.

[0223] In addition, the process may further include a substitution process in which a portion of the continuous phase (contaminated continuous phase) containing the organic solvent extracted in step (b) is removed and a fresh continuous phase is supplied. When the continuous phase is substituted in this way, the precipitation of crystals that may occur on the outer surface of the microspheres can be significantly reduced, thereby minimizing the problem of rapid initial drug release caused by this. This continuous phase substitution process can be performed continuously or discontinuously, and the amount of substitution can be 100% to 1000%, 200% to 500%, 100% to 400%, 200% to 1000%, or 100% to 300% of the volume of the initially introduced continuous phase, but can be appropriately adjusted.

[0224]

[0225] The present invention will be explained in more detail below through the following examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited by the following examples.

[0226]

[0227]

[0228] [Example]

[0229] Preparation of sustained-release microspheres containing ropivacaine of Examples 1 to 14 and Comparative Examples 1 to 5

[0230] The dispersion phase was prepared by mixing Resomer RG502H, RG503H, or RG753H (Manufacturer: Evonik, Germany) as a biodegradable polymer, ropivacaine free base (Manufacturer: Dishman, India) as a drug, and Poloxamer 188, Poloxamer 407, lactide, glycolide, PEG 1000, PEG 3350, PEG 8000, or salicylic acid as a release enhancer with dichloromethane (Manufacturer: JT Baker, USA) in the composition listed in Table 1. The dispersion phase was used after being sufficiently dissolved by stirring for at least 30 minutes.

[0231] For the continuous phase, an aqueous solution of 0.5 (w / v)% to 1 (w / v)% polyvinyl alcohol (viscosity: 4.8–5.8 mPa·s) was used, and the continuous phase was connected to an emulsification device equipped with a porous membrane with a diameter of 10 μm. The prepared dispersed phase was connected to the porous membrane and injected together with the continuous phase, and the flow of the continuous phase generated shear stress in a direction perpendicular to the flow of the dispersed phase to prepare an emulsion containing ropivacaine, and the suspension of the emulsion was placed in a preparation container and stirred at a speed of 200 rpm.

[0232] The temperature of the membrane emulsification device and the preparation container was maintained at 25°C, and after the injection of the dispersed phase was finished, the temperature of the emulsion suspension was maintained at 40°C for 3 hours to extract and evaporate the organic solvent from the emulsion toward the continuous phase to produce microspheres. After the removal of the organic solvent was finished, the temperature of the microsphere suspension was lowered to 25°C. The microspheres were washed repeatedly with ultrapure water several times to remove residual polyvinyl alcohol from the surface of the microspheres, and the obtained microspheres were freeze-dried.

[0233] The exchange of the continuous phase was performed after the transfer of the suspension to the preparation container was completed. Specifically, a fresh continuous phase was supplied to the preparation container while the continuous phase contaminated with an organic solvent was discharged, thereby matching the inflow and outflow rates of the dispersed phase to maintain the volume of the suspension within the entire container. At this time, the total amount of the exchanged continuous phase can be controlled by adjusting the ratio of the continuous phase exchanged per hour and the time relative to the volume of the suspension within the preparation container.

[0234] Table 1 shows the method for manufacturing ropivacaine microspheres.

[0235] Dispersed Phase Continuous Phase Theoretical Content Polymer API Release Enhancer Solvent (DCM) Polymer / DC MP VA Aqueous Solution wt% Type gg Type gg w / w% mL Example 1 57.5 RG50 3H4 0.0 57.50 Poloxamer 188 2.50 24 2.4 21 6.5 33900 Example 2 55.0 RG50 3H4 0.50 Lactide 0.50 16.7 223.9 2800 Example 3 57.5 RG50 2H4 0.5.75 PEG 33500 0.25 18.0 42 2.2 3300 Example 4 55.0 RG50 3H4 0.5.50 PEG 33500 0.50 23.38 17.1 3100 Example 5 59.0 RG50 3H4 0.5.90 PEG 33500.1018.0022.22800 Example 645.0RG503H4.54.50PEG 33501.0023.5119.13000 Example 757.5RG503H4.05.75PEG 80000.2523.5717.03100 Example 857.5RG503H4.05.75Poloxamer 1880.2523.4717.03100 Example 957.5RG503H4.05.75Poloxamer 4070.2523.5917.03100 Example 1057.5RG503H40.057.50 Poloxamer 1882.50235.4017.033000 Example 1157.5RG503H40.057.50 Poloxamer 1882.50235.4017.033000 Example 1257.5RG503H44.864.4 Poloxamer 1882.8271.5016.536000 Example 1357.5RG503H4.05.75 Glycolide 0.2524.2416.53400 Example 1457.5RG503H4.05.75 Poloxamer 1880.2524.2416.53400 Comparative Example 160.0RG503H4.06.00-0.0016.7024.02800Comparative Example 255.0RG503H4.05.50Salicylic Acid 0.5016.6924.02800Comparative Example 350.0RG503H4.05.00Salicylic Acid 1.0016.7123.92800Comparative Example 439.6RG753H2.41.60PEG 10000.0414.1417.02950Comparative Example 560.0RG503H4.06.00-0.0016.7223.92800

[0236] Experimental Example 1: Measurement of the content of ropivacaine and release enhancer in microspheres

[0237] (1) Measurement of ropivacaine content in microspheres

[0238] To measure the ropivacaine content in the microspheres prepared in the examples and comparative examples, 10 mg of microspheres were completely dissolved in DMSO and then diluted with the mobile phase. 20 μL of the diluted solution was injected into an HPLC and measured at a detection wavelength of 230 nm. The column used in this measurement was Inertsil ODS-3, 5 μm, 4.6 x 150 mm, and the mobile phase consisted of a mixture of 0.1% trifluoroacetic acid in deionized water and 0.1% trifluoroacetic acid in acetonitrile in a 7:3 ratio (v / v). The ropivacaine content was measured and is shown in Table 2 below. Here, the drug encapsulation rate can be calculated using the formula (actual drug content / theoretical drug content) * 100, and the theoretical drug content can be calculated as [drug usage / (drug usage + polymer usage + release enhancer usage)] * 100.

[0239] Active Ingredient (API) Content (Weight%) Encapsulation Rate (%) Example 1: 51.389.2 Example 2: 51.593.6 Example 3: 54.394.4 Example 4: 55.2100.4 Example 5: 55.293.6 Example 6: 45.9102.0 Example 7: 52.992.0 Example 8: 49.586.1 Example 9: 49.886.6 Example 1: 50.087.0 Example 11: 51.389.2 Example 12: 50.487.7 Example 13: 52.691.5 Example 14: 51.589.6 Comparative Example 155.692.7 Comparative Example 252.294.9 Comparative Example 3: 42.585.0 435.589.6 Comparative Example 559.899.7

[0240] (2) Measurement of the content of the release-increasing agent in the microspheres

[0241] In order to determine the amount of release-increasing agent used in the manufacture of microspheres and the degree of change in the amount of residual release-increasing agent within the manufactured microspheres, the amount of residual release-increasing agent within the microspheres manufactured in Example 14 was measured.

[0242] Specifically, 800 mg of microspheres were accurately weighed and placed in a 25 mL volumetric flask, dissolved in tetrahydrofuran (THF), and then marked with THF to be used as the test solution. The standard solution and the test solution were tested according to the liquid chromatography (HPLC) method under the following analytical conditions.

[0243] - Detector: Refractive Index Detector

[0244] - Detector temperature: 35℃

[0245] - Column: ABC

[0246] A: Waters, Styragel HR 4 THF (7.8mm×300mm)

[0247] B: Waters, Styragel HR 4 THF (7.8mm×300mm)

[0248] C: Waters, Styragel HR 2 THF (7.8mm×300mm)

[0249] - Column temperature: 35℃

[0250] - Flow rate: 0.3 mL / min

[0251] - Injection volume: 50uL

[0252] - Analysis time: 60 minutes

[0253] - Auto sampler temperature: 20℃

[0254] - Mobile phase: Tetrahydrofuran

[0255]

[0256] The theoretical content of the release enhancer can be calculated as [amount of release enhancer / (amount of drug + amount of polymer + amount of release enhancer)] * 100, and the theoretical content of the release enhancer in Example 14 was 2.5 wt%, and the actual content was measured to be 0.9 wt%. The encapsulation rate of the release enhancer can be calculated using the formula (actual content of release enhancer / theoretical content of release enhancer) * 100, and was confirmed to be approximately 36%.

[0257]

[0258] Experimental Example 2: Particle Size Analysis of Microspheres Using a Laser Diffraction Particle Size Analyzer

[0259] The test was conducted to measure the average particle size, distribution, and uniformity of the microspheres of the examples and comparative examples prepared in the present invention, and the test procedure is as follows.

[0260] 50 mg of the composition was mixed with 1 mL of ultrapure water and mixed with a vortex mixer for 20 seconds, then placed in an ultrasonic generator for 1 minute to disperse it. The dispersion of the composition was placed in a particle size analyzer (Microtrac Bluewave, Japan) and measured for 20 seconds.

[0261]

[0262] Table 3 shows D10, D50, and D90 for each microsphere. D10, D50, and D90 correspond to the particle sizes at 10%, 50%, and 90% of the volume percentage, respectively, on the particle size distribution curve. The Span value is a well-known factor indicating how uniform the particle size is, and a smaller Span value means that the particle size distribution is narrower (more uniform). The Span value can be calculated using the mathematical formula (D90-D10) / D50.

[0263]

[0264] Example and Comparative Example Number D10 (um) D50 (um) D90 (um) Span Value Example 1 23.87 32.45 46.19 0.69 Example 2 25.90 35.15 48.97 0.66 Example 3 22.23 29.33 40.12 0.61 Example 4 20.69 27.68 38.53 0.64 Example 5 25.00 33.27 47.24 0.67 Example 6 21.35 28.41 39.30 0.63 Example 7 22.08 29.29 40.27 0.62 Example 8 22.23 29.53 40.63 0.62 Example 9 22.02 29.25 40.28 0.62 Example 1024.8132.7746.000.65 Example 1125.0833.0646.470.65 Example 1427.1036.2749.380.61 Comparative Example 140.8555.0975.540.63 Comparative Example 232.5044.5362.270.67 Comparative Example 328.6142.6562.970.81 Comparative Example 421.8428.3933.730.41 Comparative Example 527.8937.9253.060.66

[0265] Experimental Example 3: In-vitro release test

[0266] To evaluate the release pattern of ropivacaine from microspheres according to the present invention, an in-vitro release test was conducted. The experimental procedure is as follows.

[0267] 25 mg of the particulate compositions of Examples 1 to 14 and Comparative Examples 1 to 5 and 50 mL of 10 mM phosphate buffer (pH 7.4) containing 100 mM NaCl, 0.1% Tween 20, and 0.02% sodium azide were placed in a wide-mouthed bottle and stored in a 37°C incubator. At predetermined intervals, 1 mL of the solution was taken from the wide-mouthed bottle and an equal amount of fresh release test solution was added. The taken solution was filtered through a 0.45 μm syringe filter, and 20 μL was injected into an HPLC. As a result, the in-vitro cumulative release rate (%) of ropivacaine is shown in Table 4.

[0268] In-vitro cumulative release rate of ropivacaine (%) 0 Day 1 Hour 3 Hour 6 Hour 1 Day 2 Day 7 Day 14 Day Example 10 15.4 4 29.0 7 40.9 8 62.2 57 6.49 -- Example 20 15.5 23.3 30.2 64 4.9 65 7.22 -- Example 30 32.1 839.6 24 4.7 85 6.7 46 4.27 -- Example 40 33.7 133.7 138.3 54 9.1 60.4 87 8.59 -- Example 50 15.3 523.6 730.4 94 5.2 75 7.43 -- Example 60 35.6 35.6 41.6 85 4.6 46 9.2 29 3.32 -- Example 7044.0951.5657.1467.1276.4186.58 - Example 8036.7448.7255.466.1374.52 - Example 9022.3930.2935.5250.3461.93 - Example 10039.0548.4856.2268.4576.21 - Example 11035.2448.5560.2670.5180.96 - Example 12032.2946.7955.6172.4381.90 - Example 13018.732.444.566.578.3 - Example 14015.1525.737.9360.6374.92--Comparative Example 106.1410.9715.6927.3737.36--Comparative Example 2013.5213.7616.3529.5840.1174.1187.76Comparative Example 304.074.547.1719.2531.2780.9596.81Comparative Example 400.000.000.000.001.102.9223.14Comparative Example 504.9510.0314.7427.8637.47--

[0269] Upon completion of the surgery, microspheres containing ropivacaine are injected into several locations around the surgical site, and the anesthesia begins to wear off approximately 2 to 4 hours after the surgery. That is, the period between 2 (or 4) and 24 hours after the surgery is when the surgical anesthesia wears off and pain is most severe, so it may be desirable to have a higher drug release rate during this time. After 24 hours, the pain gradually decreases, and it may be desirable to have the drug release rate gradually reduced and maintained for about 2 to 7 days or 2 to 11 days.

[0270]

[0271] As can be seen in Table 4 above, the microspheres of Examples 1 to 14 according to the present invention can be seen to release a sufficient amount of drug with a drug release rate of 44.96 to 72.43% within 24 hours in an in vitro drug release test, and the drug is slowly released even after 1 day. On the other hand, the microspheres of Comparative Examples 1 to 6 can be seen to release an insufficient amount of drug with a drug release rate of 0 to 29.58% within 24 hours, and the drug release period is maintained for an unnecessarily long time.

[0272]

[0273] Experimental Example 4: Single-dose pharmacokinetics test using rats

[0274] To evaluate the release pattern of the drug in the body of the microspheres according to the present invention, blood ropivacaine concentrations were measured after administration to rats.

[0275] Microspheres prepared in Example 2, Example 8, and Comparative Example 5 were each weighed to achieve a ropivacaine dosage of 2.66 mg / head and dispersed in a 0.1 mL suspension. The ropivacaine was then administered subcutaneously (SC) to approximately 9-week-old male SD rats (Sprague-Dawley rats) with an average body weight of approximately 310 g. 0.25 to 0.5 mL of blood was collected at predetermined intervals, and the blood ropivacaine concentration was measured using HPLC. For each sample, the ropivacaine was administered to three rats, and the average blood ropivacaine concentration was calculated.

[0276] The measured blood concentration (ng / mL) and cumulative release rate of ropivacaine are shown in Tables 5 and 6, and Figures 1 and 2.

[0277] Blood Concentration (ng / ml) Comparative Example 5 Example 8 Example 20 days 0000 0.5 hours 175.93 75.01 02.5 1 hours 41.11 61.82 41.7 2 hours 150.33 99.82 24.14 hours 84.13 91.33 83.96 hours 71.91 61.51 21.08 hours 69.81 26.41 79.7 12 hours 40.86 2.68 4.81 days 22.01 7.53 7.32 days 18.12 0.00 5.523 days 6.50 0.000 0.455 days 1.86 0.000 247 days 0.000.000.00

[0278] Cumulative Emission Rate (%) Comparison Example 5 Example 8 Example 20 Days 0000 0.5 Hours 1.9 2.9 0.7 1 Hours 4.2 7.1 3.1 2 Hours 8.3 15.9 9.5 4 Hours 18.3 40.5 26.3 6 Hours 24.9 57.7 40.2 8 Hours 31.0 66.7 48.5 12 Hours 40.4 78.5 63.1 1 Days 56.4 93.5 83.3 2 Days 77.0 100 97.4 3 Days 89.6 -99.45 Days 98.1 -99.87 Days 100.0 -100.0

[0279] Upon completion of surgery, microspheres containing ropivacaine are injected into multiple locations around the surgical site, and the anesthesia begins to wear off approximately 2 to 4 hours after surgery. That is, the drug release rate should be controlled to a low level during the first 1 hour after microsphere administration, before the anesthesia wears off. However, between 2 (or 4) and 24 hours after surgery, the anesthesia wears off and pain is most severe, so a higher drug release rate during this period may be desirable. After 24 hours, the pain gradually decreases, and the drug release rate should gradually decrease and may be maintained for about 2 to 7 days or 2 to 11 days.

[0280]

[0281] First, in the PK profile of Fig. 1, the first peak of blood concentration is C max1 It is referred to as, and the second peak is C max2 It is referred to as, and the point at which maximum blood concentration occurs is T maxIt is explained by referring to it as such. As can be seen in Fig. 1 and Table 5,

[0282] C of Comparative Example 5 max1 It was found to be 175.9 ng / mL at 0.5 hours, and C max2 It was found to be 150.3 ng / mL at 2 hours. That is, the maximum blood concentration was 0.5 hours after administration (C max1 , T max As shown in ), it was confirmed that there was excessive release very early after administration, and insufficient drug release during the period of most severe pain. Therefore, it can be confirmed that Comparative Example 5 exhibits an inappropriate release pattern.

[0283] On the other hand, C of Example 8 max1 It was found to be 375.0 ng / mL at 0.5 hours, and C max2 It was found to be 399.8 ng / mL at 2 hours. That is, the maximum blood concentration was 2 hours after administration (C max2 , T max As shown in ), it was confirmed that very early initial release after administration was controlled, and the drug release amount during the period of most severe pain was sufficient. Therefore, it can be confirmed that Example 8 exhibits an appropriate release pattern.

[0284] Also, C of Example 2 max1 It was found to be 241.7 ng / mL at 1 hour, and C max2 It was found to be 383.9 ng / mL at 4 hours. That is, the maximum blood concentration was 4 hours after administration (C max2 , T max As shown in ), it was confirmed that very early initial release after administration was controlled, and the drug release amount during the period of most severe pain was sufficient. Therefore, it can be confirmed that Example 2 exhibits an appropriate release pattern.

[0285]

[0286] Referring to Table 6 regarding the cumulative release rate, it can be confirmed that there is a significant difference in the drug release amount between 4 hours and 1 day after administration for Examples 2 and 8 compared to Comparative Example 5. The period between 4 hours and 1 day after administration is when the anesthesia from surgery wears off and pain is most severe, requiring a sufficient drug release amount. Specifically, for Comparative Example 5, the value obtained by subtracting the cumulative release rate up to 4 hours from the cumulative release rate up to 1 day was 38.2 (%p), whereas for Example 8 it was 52.9 (%p) and for Example 2 it was 57 (%p). This result indicates that Examples 2 and 8 provide a sufficient drug release amount during the period of most severe postoperative pain, whereas Comparative Example 5 is insufficient.

[0287]

[0288] Experimental Example 5: Morphological analysis of microspheres using an electron microscope

[0289] In this experiment, scanning electron microscopy observations were conducted to analyze the morphological characteristics of the manufactured microspheres.

[0290] 5 mg of microspheres prepared according to Example 8 were placed on an aluminum stub attached with carbon tape and platinum coated using an ION-COATER (COXEM, Korea). The aluminum stub was mounted on a field emission scanning electron microscope (Hitachi S-4800, Japan), and the morphological characteristics of the composition were observed at an acceleration voltage of 3 kV. Among the results, an image of the microspheres prepared in Example 8 analyzed through an electron microscope is shown in Figure 3.

[0291] As shown in Figure 3, the microspheres produced through the present invention were confirmed to be spherical particles having a diameter in the micro range and a porous shape.

[0292]

[0293] Experimental Example 6. Crystal analysis of a composition containing microspheres using an X-ray diffraction analyzer

[0294] X-ray diffraction analysis was performed to analyze whether the composition containing microspheres according to the present invention is crystalline. X-ray diffraction analysis was measured by irradiating with Cu Ka radiation (λ=1.5418Å, 40kV, 40mA) using a Rigaku Ultima IV X-ray Diffractometer (Rigaku, Japan).

[0295]

[0296] The average Bragg angle of the X-ray diffraction peaks of ropivacaine free base was based on the average of the Bragg angles of the X-ray diffraction peaks of ropivacaine free base and the Bragg angles of the X-ray diffraction peaks of ropivacaine microspheres. The average Bragg angles of the X-ray diffraction peaks of ropivacaine free base were found to be 10.45°, 13.00°, 14.26°, 16.40°, 19.03°, 19.39°, 19.93°, 20.26°, 21.65°, 23.63°, 24.35°, 26.21°, and 31.79°.

[0297] As a result of the above experiment, it was confirmed that the free base of ropivacaine forms a crystalline structure within the microspheres, while the polymer is amorphous. In other words, it was confirmed that microsphere manufacturing can proceed without changing the physical properties of the crystalline drug.

Claims

1. As an active ingredient, ropivacaine free base or a pharmaceutically acceptable salt thereof; As a biodegradable polymer, 1 to 2 types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA); and As a release enhancer, the microsphere comprises one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers; and Microspheres comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres.

2. In claim 1, the ropivacaine free base or a pharmaceutically acceptable salt thereof is a microsphere that is crystalline or amorphous.

3. In paragraph 2, the ropivacaine free base is a crystalline sphere having major diffraction peaks of 10.45°, 13.00°, 14.26°, 16.40°, 19.03°, 19.39°, 19.93°, 20.26°, 21.65°, 23.63°, 24.35°, 26.21°, and 31.79° at Bragg angles (2θ±0.2°) in X-ray diffraction analysis (CuKα).

4. Microspheres according to claim 1, wherein the release increasing agent is included in an amount of 0.1 to 10 weight percent relative to the total weight of the microspheres.

5. In Paragraph 1, As the above-mentioned release enhancer, The above amphiphilic polymer is poloxamer, and The above hydrophilic polymer is PEG (Polyethyleneglycol), and Microspheres in which the above hydrophobic monomer is one or more of lactide and glycolide.

6. In Paragraph 5, As the above-mentioned release enhancer, The above amphiphilic polymer is a poloxamer with a weight-average molecular weight of 4,000 g / mol or more, and The above hydrophilic polymer is PEG (Polyethyleneglycol) with a weight-average molecular weight of 2,000 g / mol or more, and Microspheres in which the above hydrophobic monomer is one or more of lactide and glycolide.

7. In Paragraph 6, As the above-mentioned release enhancer, The above amphiphilic polymer is a poloxamer with a weight-average molecular weight of 4,000 to 20,000 g / mol, and The above hydrophilic polymer is PEG (Polyethyleneglycol) with a weight-average molecular weight of 2,000 to 20,000 g / mol, and Microspheres in which the hydrophobic monomer is lactide or glycolide.

8. Microspheres according to claim 1, wherein the biodegradable polymer satisfies one or more selected from the group consisting of (i) to (iii) below: (i) Intrinsic viscosity 0.1 to 0.7 dL / g; (ii) weight-average molecular weight 4,000 to 60,000 g / mol; (iii) One or both ends are a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group.

9. In Paragraph 8, Microspheres in which the above-mentioned biodegradable polymer is a poly(lactide-co-glycolide) (PLGA) satisfying one or more selected from the group consisting of (i) to (iv) below: (i) Intrinsic viscosity 0.1 to 0.7 dL / g; (ii) weight-average molecular weight 4,000 to 60,000 g / mol; (iii) one or both ends are a hydroxyl group, a carboxyl group, a methoxy group, a methyl group, an amine group, or an ester group; (iv) Lactide:glycolide repeating unit molar ratio 40:60 to 99:

1.

10. The microsphere according to claim 1, wherein when the microsphere is administered by subcutaneous injection to an SD rat (Sprague-Dawley Rat), the value obtained by subtracting the cumulative drug release rate up to 4 hours after administration from the cumulative drug release rate up to 1 day after administration is 40 to 80.

11. Microspheres according to claim 10, wherein the cumulative drug release rate up to 1 hour after administration is 15% or less, and the cumulative drug release rate up to 1 day after administration is 65% or more.

12. Microspheres according to claim 11, wherein the cumulative drug release rate up to 4 hours after administration is 20 to 50% and the cumulative drug release rate up to 1 day after administration is 70% or more.

13. Microspheres according to claim 12, wherein the cumulative drug release rate up to 1 day after administration is 75% or more, and the release of residual drug is completed within 2 to 7 days or 2 to 11 days after administration.

14. Microspheres according to claim 13, wherein the cumulative drug release rate up to 3 days after administration is 80 to 100%.

15. Microspheres according to claim 1, having an average particle size of 10 to 150 μm and a porous shape. 16.(i) Microspheres according to paragraph 1; or (ii) a microsphere blend comprising a combination of 2-3 types of microspheres of (i) having different compositions from each other; and The 2-3 types of microspheres in the microsphere blend of (ii) above comprise different biodegradable polymers and / or release enhancers, or the 2-3 types of microspheres in the microsphere blend of (ii) above comprise different amounts of biodegradable polymers, release enhancers, and / or active ingredients. Injectable composition for local anesthesia or analgesia.

17. An injectable composition used for reducing postoperative pain in accordance with Clause 16.

18. (a) a step of forming an emulsion by mixing a dispersed phase comprising an active ingredient, a biodegradable polymer, a release enhancer, and an organic solvent with a continuous phase comprising a surfactant and water; and (b) a step of preparing microspheres by extracting the organic solvent in the dispersed phase from the emulsion of step (a) toward the continuous phase; comprising, The above active ingredient is a free base of ropivacaine or a pharmaceutically acceptable salt thereof, and The above biodegradable polymer is one to two types selected from the group consisting of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA), and The above-mentioned release enhancer is one or more selected from the group consisting of amphiphilic polymers, hydrophilic polymers, and hydrophobic monomers, and Comprising 40 to 80 weight percent of an active ingredient relative to the total weight of the microspheres, Method for manufacturing microspheres of claim 1.

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